Within 6 hours after death, acidic compounds accumulate  within the muscles because of the breakdown of carbohydrate  and the depletion of ATP. This interferes with ATP-dependent  detachment of myosin from actin (contractile proteins), and  muscle stiffening, or rigor mortis, develops. The smaller mus-  cles are usually affected first, particularly the muscles of the jaw.  Within 12 to 14 hours, rigor mortis usually affects the entire  body. Rigor mortis gradually diminishes and the body becomes  flaccid in 12 to 14 hours.   Signs of putrefaction—state of decay with foul-smelling  odor—are generally obvious about 24 to 48 hours after death.  Putrefactive changes vary depending on the temperature of the  environment. The most visible is greenish discoloration of the  skin, particularly on the abdomen. The discoloration is thought  to be related to the diffusion of hemolyzed blood into the tis-  sues and the production of sulfhemoglobin. Slippage or loosen-  ing of the skin from underlying tissues occurs at the same time.  After this, swelling or bloating of the body and liquefactive  changes occur, sometimes causing opening of the body cavities.  At a microscopic level, putrefactive changes are associated with  the release of enzymes and lytic dissolution called postmortem  autolysis.   1. Injury to cells and their surrounding environment, called the  extracellular matrix, leads to tissue and organ injury. Cellular  adaptation is an alteration that enables the cell to maintain a  steady state despite adverse conditions.   2. Atrophy is a decrease in cellular size. The mechanisms prob-  ably include decreased protein synthesis, increased protein  catabolism, or both.   3. Physiologic atrophy occurs with early development; for  example, the thymus gland involutes and atrophies. Patho-  logic atrophy occurs as a result of decreases in workload, use,  pressure, blood supply, nutrition, hormonal stimulation, and  nervous stimulation.   4. Aging causes brain cells and endocrine-dependent organs,  such as the gonads, to become atrophic.   5. Hypertrophy is an increase in the size of cells caused by  increased work demands or hormonal stimulation. Hyper-  trophy can be physiologic or pathologic. Amounts of protein  in the plasma membrane, endoplasmic reticulum, microfila-  ments, and mitochondria are increased.   6. Hyperplasia is an increase in the number of cells caused by  an increased rate of cellular division. Compensatory hyper-  plasia enables certain organs to regenerate. Hormonal hyper-  plasia is stimulated by hormones to replace lost tissue or  support new growth, such as during pregnancy.   7. Pathologic hyperplasia is the abnormal proliferation of nor-  mal cells in response to excessive hormonal stimulation of  growth factors on target cells.    8. Dysplasia, or atypical hyperplasia, is an abnormal change in  the size, shape, and organization of mature tissue cells.   9. Metaplasia is the reversible replacement of one mature cell  type by another less mature cell type. Metaplasia is thought  to develop from a reprogramming of stem cells existing in  most epithelia or of undifferentiated mesenchymal cells in  connective tissue.   1. Injury to cells and to the extracellular matrix (ECM) leads  to injury of tissues and organs, ultimately determining the  structural patterns of disease. Injured cells may recover  (reversible injury) or die (irreversible injury).   2. Cellular injury is caused by a lack of oxygen (hypoxia),  free radicals, caustic or toxic chemicals, infectious agents,  unintentional and intentional injury, inflammatory and  immune responses, genetic factors, insufficient nutrients,  or physical trauma from many causes. Injurious stimuli  cause cell stress.   3. Cell injury can be acute or chronic, and it can be reversible  or irreversible. It can involve necrosis, apoptosis, autoph-  agy, accumulation, or pathologic calcification.   4. Four biochemical themes are important to cell injury:  (a) depletion of ATP, (b) decreased levels of oxygen  and increased levels of oxygen-derived free radicals, (c)  increased concentration of intracellular calcium and loss  of calcium steady state, and (d) defects in membrane  permeability.    The sequence of events leading to cell death is commonly  decreased ATP production, failure of active transport  mechanisms (the Na*-K* pump), cellular swelling, detach-  ment of ribosomes from the endoplasmic reticulum, cessa-  tion of protein synthesis, mitochondrial swelling as a result  of calcium accumulation, vacuolation, leakage of digestive  enzymes from lysosomes, autodigestion of intracellular  structures, lysis of the plasma membrane, and death.    cessation of blood flow into vessels that supply the cell with  oxygen and nutrients.    caused by free radicals, including oxidative stress. Free radi-  cals are difficult to control and initiate chain reactions.    . Free radicals can cause (a) lipid peroxidation or the destruc-    tion of unsaturated fatty acids, (b) alterations of proteins,  and (c) alterations in DNA.    . The initial insult in chemical injury is damage or destruc-    tion of the plasma membrane. Examples of chemical agents  that cause cellular injury include lead, carbon monoxide,  ethanol, mercury, and social or street drugs. The leading  cause of child poisoning is medications.   Unintentional and intentional injuries are an important  health problem in the United States. Death caused by inju-  ries is more common in men than women and more preva-  lent among blacks vs. whites and other racial groups.  Injuries by blunt force are the result of the application of  mechanical energy to the body resulting in tearing, shear-  ing, or crushing of tissues. The most common types of  blunt-force injuries include motor vehicle accidents and  falls.    . Asphyxial injuries are caused by a failure of cells to receive or    use oxygen. These injuries can be grouped into four general  categories: suffocation, strangulation, chemical asphyxiants,  and drowning.   Injury from microorganisms lies in their ability to survive  and proliferate in the human body. Injury depends on the  microorganisms’ ability to invade and destroy cells, produce  toxins, and produce damaging hypersensitivity reactions.   A leading cause of errors in health care is medication errors.  Activation of inflammation and immunity, which occurs  after cellular injury or infection, involves powerful bio-  chemicals and proteins capable of damaging normal (unin-  jured and uninfected) cells.   Genetic disorders injure cells by altering the nucleus and  the plasma membrane’s structure, shape, receptors, or  transport mechanisms.   Deprivation of essential nutrients (proteins, carbohydrates,  lipids, vitamins) can cause cellular injury by altering cellu-  lar structure and function, particularly of transport mecha-  nisms, chromosomes, the nucleus, and DNA.   Injurious physical agents include temperature extremes and  climate change, changes in atmospheric pressure, ionizing  radiation, illumination, mechanical stresses (e.g., repetitive  body movements), and noise.    Manifestations of cellular injury include accumulations of  water, lipids, carbohydrates, glycogen, proteins, pigments,  hemosiderin, bilirubin, calcium, and urate.    by causing excessive (and sometimes harmful) metabolites  to be produced during their catabolism. The metabolites are  released into the cytoplasm or expelled into the extracellular  matrix.    cell, is caused by the failure of transport mechanisms and is a  sign of many types of cellular injury.    glycogen, proteins, and pigments—are caused by disorders  in which (a) cellular uptake of the substance exceeds the cell’s  capacity to catabolize (digest) or use it or (b) cellular anabo-  lism (synthesis) of the substance exceeds the cell’s capacity to  use or secrete it.    always a sign of pathologic change because it occurs only in  injured or dead cells. Free calcium in the cytosol can cause  activation of protein kinases, activation of phospholipases  and membrane damage, and damage or disassembly of the  cytoskeleton. Metastatic calcification, however, can occur in  uninjured cells in individuals with hypercalcemia.    mia and deposition of sodium urate crystals in tissue, lead-  ing to a painful disorder called gout.    kocytosis, increased heart rate, pain, and serum elevations of  enzymes in the plasma.    Two main types of cell death are necrosis and apoptosis. Type  I cell death (e.g., caspases) is often referred to as apoptosis,  whereas type II is called autophagic cell death.    . Necrosis is the sum of the changes after local cell death and    caseous, and fat. Different types of necrosis occur in different  tissues.    sion to necrosis are the dense clumping and disruption of  genetic material and the disruption of the plasma and organ-  elle membranes.    . Apoptosis, a different type of cellular death, is a process of    selective cellular self-destruction called programmed cell  death. Other forms of programmed cell death (type II)  include autophagic (“eat oneself”) cell death.    It is difficult to determine the physiologic (normal) from the  pathologic changes of aging. One of the hallmarks of aging is    the accumulation of damaged macromolecules. Life span can  be experimentally changed.   . Humans have an inherent maximal life span (80 to 100 years)  that is dictated by currently unknown intrinsic mechanisms.  . Although the maximal life span has not changed signifi-  cantly over time, the average life span, or life expectancy, has  increased. However, this increase in life expectancy in the  United States is not experienced by all Americans.   . The emerging focus in the biology of aging includes epigen-  etic and genetic changes, inflammatory response, oxidative  stress, metabolic and endocrine regulation, intrauterine and  lifelong patterns of health, decline in cell renewal by adult  stem cells, and accumulated cell damage related to cancer  and aging.   . Frailty is a common clinical syndrome in older adults,  leaving a person vulnerable to falls, functional decline,    disability, disease, and death. The syndrome is complex,  involving oxidative stress, dysregulation of inflammatory  cytokines and hormones, malnutrition, physical inactivity,  and muscle apoptosis. Women have a higher risk of frailty  than men.   Manifestations of somatic death include cessation of respira-  tion and circulation, gradual lowering of body temperature,  dilation of pupils, loss of elasticity and transparency in the  skin, stiffening of muscles (rigor mortis), and discoloration  of the skin (livor mortis). Signs of putrefaction are obvious  about 24 to 48 hours after death.   Choking asphyxiation, 74  Coagulative necrosis, 90  Compensatory hyperplasia, 52  Compression, 82   Dysplasia (atypical hyperplasia), 97, 98  Dystrophic calcification, 87  Endoplasmic reticulum stress (ER stress), 91  Fat necrosis, 91   Hepatocyte growth factor (HGF), 53  High altitude cerebral edema (HACE), 78  High altitude pulmonary edema (HAPE), 78  Hormonal hyperplasia, 53  Hydrogen sulfide (sewer gas), 74  Hyperglycemia, 75  Hyperlipidemia, 75   Hyperthermia, 76  Hyperthermic injury, 76  Hypertrophy, 51  Hypolipidemia, 75  Hypothermic injury, 76  Hypoxia, 56   Ligature strangulation, 74  Lipid-acceptor protein (apoprotein), 63  Lipid peroxidation, 60  Lipofuscin, 51   Lysosomal storage disease, 84  Malignant hyperthermia, 77  Manual strangulation, 74  Maximal life span, 94  Mechanotransduction, 82  Melanin, 85    Metastatic calcification, 87  Mitochondrial DNA (mtDNA), 61  Mucolipidosis (ML), 84  Mucopolysaccharidosis (MPS), 84  Necrosis, 88   Pathologic hyperplasia, 53  Physiologic atrophy, 50  Postmortem autolysis, 97  Postmortem change, 97   Primary accidental hypothermia, 76  Programmed necrosis (necroptosis), 88  Psammoma body, 87   Type I programmed cell death, 92  Type II programmed cell death, 92  Ubiquitin-proteasome pathway, 50  Up-regulation of proteasome, 50  Urate, 88    Dahlmann B: Role of proteasomes in disease, BMC Biochem 8(Suppl):  $3, 2007.   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As part of your Pageburst Digital Book, you can access the following Integrated Resources:  Animations    Distribution of Body Fluids, 103  AGING and Distribution of Body Fluids, 104  Water Movement Between ICF and ECF, 105  Water Movement Between Plasma and Interstitial Fluid, 105  Alterations in Water Movement, 105  Edema, 105  Sodium, Chloride, and Water Balance, 108  Sodium and Chloride Balance, 108  Water Balance, 109  Alterations in Sodium, Chloride, and Water Balance, 109  Isotonic Alterations, 109  Hypertonic Alterations, 110  Hypotonic Alterations, 112    The cells of the body live in a fluid environment that requires  electrolyte and acid-base concentrations maintained within  a very narrow range. A balance is maintained by an integra-  tion of renal, hormonal, and neural functions. Changes in the  composition of electrolytes affect electrical potentials of excit-  atory cells and cause shifts of fluid from one compartment to  another that can affect cell function. Fluid fluctuations also  affect blood volume and therefore blood pressure. Alterations  in pH (measure of the acidity or alkalinity of a solution) dis-  rupt the cellular function of enzyme systems and can cause cell  injury. Disturbances in fluid and electrolyte or acid-base bal-  ance are common and can be life threatening. Understanding    Alterations in Potassium, Calcium, Phosphate,  and Magnesium Balance, 114  Potassium, 114  Calcium and Phosphate, 119  Magnesium, 122  Acid-Base Balance, 122  Hydrogen Ion and pH, 122  Buffer Systems, 123  Acid-Base Imbalances, 126    how alterations occur and the body’s ability to compensate or  correct the disturbance is important for comprehending many  pathophysiologic conditions.    The fluids of the body are distributed among functional com-  partments, or spaces, and provide a transport medium for  cellular and tissue function. Water moves freely among body  compartments and is distributed by osmotic and hydrostatic  forces. Two thirds of the body’s water is intracellular fluid (ICF)  and one third is in the extracellular fluid (ECF) compartments.    The two main ECF compartments are the interstitial fluid and  the intravascular fluid, the latter being the blood plasma. Other  ECF compartments include the lymph and the transcellular flu-  ids, such as the saliva, intestinal, biliary, hepatic, pancreatic, and  cerebrospinal fluids; sweat; urine; and pleural, synovial, perito-  neal, pericardial, and intraocular fluids (Table 3-1).   The sum of fluids within all compartments constitutes the  total body water (TBW) (Table 3-2). The volume of TBW is  usually expressed as a percentage of body weight in kilograms.  The standard value for TBW is 60% of the weight of a 70-kg  adult male, which is equivalent to 42 L of fluid (Table 3-3). The  rest of the body weight is composed of fat and fat-free solids,  particularly bone.   Although daily fluid intake may fluctuate widely, the body  regulates water volume within a relatively narrow range. The  primary sources of body water are drinking of fluids, ingestion  of water in food, and derivation of water from oxidative metab-  olism. Normally, the largest amounts of water are lost through  renal excretion. Lesser amounts are eliminated through the  stool and through vaporization from the skin and lungs (insen-  sible water loss) (Table 3-4).   Although the amount of fluid within the various compart-  ments is relatively constant, exchange of solutes (e.g., salts) and  water occurs between compartments to maintain their unique   FLUID (mEq/L) (mEq/L) (mEq/L)  Saliva 20 34  Gastric juice* 84  Bile 101  Pancreatic 71    *The Cl- concentration exceeds the Nat, K+ concentration by 15  mEq/L in gastric juice. This largely represents the secretions of hydro-  chloric acid by parietal cells.    Intracellular fluid (ICF) 40  Extracellular fluid (ECF) 20  Interstitial (15)  Intravascular (5)  Total body water (TBW) 60    compositions. The percentage of TBW varies with the amount  of body fat and age. Because fat is water repelling (hydropho-  bic), very little water is contained in adipose cells. Individuals  with more body fat have proportionately less TBW and tend to  be more susceptible to fluid imbalances that cause dehydration.    The distribution and amount of TBW change with age (see  Table 3-3). In newborn infants, TBW is about 75% to 80%  of body weight because infants store less fat. In the immedi-  ate postnatal period, a physiologic loss of body water occurs,  equivalent to about 5% of body weight as the infant adjusts to a  new environment. Infants are particularly susceptible to signifi-  cant changes in TBW because of their high metabolic rate and  potential for evaporative fluid loss attributable to their greater  body surface area in proportion to total body size. Loss of fluids  from diarrhea can represent a significant proportion of body  weight in infants. Renal mechanisms that regulate fluid and  electrolyte conservation may not be mature enough to counter  the losses, so dehydration can develop rapidly.   During childhood, TBW slowly decreases to 60% to 65% of  body weight. At adolescence the percentage of TBW approaches  adult proportions, and gender differences begin to appear.  Males eventually have a greater percentage of body water as a  function of increasing muscle mass. Females have more body  fat and less muscle as a function of estrogens and therefore have  less body water.   With increasing age the percentage of TBW declines further  still. The decrease is caused in part by an increased amount of fat    TBW  TBW  TBW   BUILD ADULT MALE ADULT FEMALE _ INFANT  Normal 60 50 70    *NOTE: TBW (total body water) is a percentage of body weight.    CHAPTER 3 The Cellular Environment: Fluids and Electrolytes, Acids and Bases    and a decreased amount of muscle and by a reduced ability to  regulate sodium and water balance. With older age the kidneys  becomes less efficient at conserving sodium and therefore have  difficulty concentrating the urine. Insensible water loss through  the skin may increase and thirst perception may be impaired.  The normal reduction of TBW in older adults becomes clini-  cally important when the body is under stress, such as develop-  ment of fever or dehydration; loss of body fluids at such times  can be severe and life threatening.'    The movement of water between ICF and ECF compartments  is primarily a function of osmotic forces. (Osmosis and other  mechanisms of passive transport are discussed in Chapter 1.)  Water moves freely by diffusion through the lipid bilayer cell  membrane and through aquaporins, a family of water chan-  nel proteins that provide permeability to water.” The osmolal-  ity (number of osmoles of solute per kilogram of fluid [Osm/  kg]) of TBW is normally at equilibrium. Sodium is responsible  for the osmotic balance of the ECF space. Potassium main-  tains the osmotic balance of the ICF space. The osmotic force  of ICF proteins and other nondiffusible substances is balanced  by the active transport of ions out of the cell. Water crosses  cell membranes freely so the osmolality of TBW is normally at  equilibrium. Normally the ICF is not subject to rapid changes  in osmolality but when ECF osmolality changes, water moves  from one compartment to another until osmotic equilibrium is  reestablished (see Figure 3-6, p. 110).   The distribution of water and the movement of nutrients and  waste products between the plasma in the tissue capillaries and  interstitial spaces occur as a result of changes in hydrostatic  pressure and osmotic forces at the arterial and venous ends of  the capillary. Water, sodium, and glucose move readily across  the capillary membrane. The plasma proteins maintain the  effective osmolality (concentration of solutes per kilogram of  solution), do not cross the capillary membrane, and generate  plasma oncotic pressure. Albumin is the plasma protein that is  primarily responsible for the plasma oncotic pressure because it  has the highest concentration. Osmotic forces within the capil-  lary are balanced by the hydrostatic pressure, which is primarily  determined by blood pressure and blood volume.   As plasma flows from the arterial to the venous end of the  capillary, four forces determine if fluid moves out of the capil-  lary and into the interstitial space (filtration) or if fluid moves  back into the capillary from the interstitial space (reabsorption):   tates the outward movement of water from the capillary  to the interstitial space.    The movement of fluid back and forth across the capillary  wall is called net filtration and is best described by the Starling  hypothesis:    Forces favoring filtration = Capillary hydrostatic  pressure and interstitial oncotic pressure    Forces opposing filtration = Capillary oncotic pressure  and interstitial hydrostatic pressure    Normally the interstitial forces are negligible because only a  very small percentage of plasma proteins crosses the capillary  membrane and interstitial fluid moves into cells or is drawn  back into the plasma. Thus the major forces for filtration are  within the capillary.   As the plasma flows from the arterial to the venous end of the  capillary, the force of hydrostatic pressure facilitates the move-  ment of water across the capillary membrane. Oncotic pressure  remains fairly constant because plasma proteins normally do not  cross the capillary membrane. At the arterial end of the capillary,  hydrostatic pressure is greater than capillary oncotic pressure and  water filters into the interstitial space. Because of oncotic forces,  some water moves back into the capillary, but the net effect is loss  of water from the capillary. This loss of water from the plasma  decreases the hydrostatic pressure within the capillary; thus at  the venous end of the capillary, oncotic pressure exceeds hydro-  static pressure. Fluids then are attracted back into the circula-  tion, balancing the movement of fluids between the plasma and  the interstitial space. The overall effect is filtration at the arterial  end and reabsorption at the venous end (Figure 3-1). Interstitial  hydrostatic pressure promotes the movement of about 10% of  the interstitial fluid along with small amounts of protein into the  lymphatics, which eventually returns to the circulation.   An important factor in capillary filtration of fluid is the  integrity of the capillary membrane. Changes in membrane  permeability may permit the escape of plasma proteins into the  interstitial space. The normal relationship defined by the Star-  ling hypothesis is altered with the osmotic movement of water  into the interstitial space, causing tissue edema.    Edema is the excessive accumulation of fluid within the inter-  stitial spaces. It is often a problem of fluid distribution and  does not necessarily indicate a fluid excess. In some conditions,  sequestered fluids can cause both edema and intravascular  dehydration. The pathophysiologic process of edema is related  to an increase in the forces favoring fluid filtration from the  capillaries or lymphatic channels into the tissues. The four most  common mechanisms are:   Capillary hydrostatic pressure 35 mmHg Capillary hydrostatic pressure 18 mmHg  Interstitial fluid hydrostatic 2 mmHg Interstitial fluid hydrostatic 1 mmHg  pressure pressure  Net hydrostatic pressure 33 mmHg Net hydrostatic pressure 17 mmHg  Capillary oncotic pressure 24 mmHg Capillary oncotic pressure 25 mmHg  Interstitial fluid oncotic pressure 0 mmHg Interstitial fluid oncotic pressure 0 mmHg  Net oncotic pressure 24 mmHg Net oncotic pressure 25 mmHg  Net filtration pressure 19 mmHg Net filtration pressure 28 mmHg   FIGURE 3-1 Capillary Filtration Forces. Water, electrolytes, and small molecules exchange freely between the vascular   compartment and the interstitial space at the site of capillaries and small venules. The rate and amount of exchange are driven   by the physical forces of hydrostatic and oncotic pressures and the permeability and surface area of the capillary membranes.   The two opposing hydrostatic pressures are capillary hydrostatic pressure and interstitial hydrostatic pressure. The two oppos-    ing oncotic pressures are capillary oncotic pressure and interstitial oncotic pressure. The forces that favor filtration from the    c pressure and interstitial oncotic pressure, and the forces that oppose filtration are capillary    of their effects is known as net filtration pressure (NFP). In the  of fluid moves to the lymph vessels, which accounts for the net    filtration difference between the arterial and venous ends of the capillary.    PATHOPHYSIOLOGY. Increased capillary hydrostatic pressure can  result from venous obstruction or sodium and water retention.  Venous obstruction causes hydrostatic pressure to increase behind  the obstruction, pushing fluid from the capillaries into the intersti-  tial spaces. Venous blood clots, hepatic obstruction, right heart fail-  ure, tight clothing around the extremities, and prolonged standing    are common causes of venous obstruction. Right congestive heart  failure, renal failure, and cirrhosis of the liver are conditions asso-  ciated with excessive sodium and water retention, which in turn  cause volume overload, increased venous pressure, and edema.  Decreased plasma oncotic pressure results from losses or  diminished production of plasma albumin. Decreased oncotic    CHAPTER 3 The Cellular Environment: Fluids and Electrolytes, Acids and Bases    plasma proteins  (cirrhosis, malnutrition)  Increased loss of plasma proteins  (nephrotic syndrome)  Increased plasma Nat  and H,O retention  (dilution of plasma proteins)    attraction of fluid within the capillary causes fluid to move into  the interstitial space, resulting in edema. Decreased synthesis of  plasma protein and decreased oncotic pressure may occur with  liver disease or protein malnutrition. Losses of plasma proteins  occur with glomerular diseases of the kidney (nephrotic syn-  drome), hemorrhage, and serous drainage from open wounds  or burns.   Increased capillary permeability is usually associated with  inflammation and the immune response. (Immunity is discussed  in Chapters 7, 8, and 9; inflammation is discussed in Chapters  7 and 9.) These responses are often the result of trauma such as  burns or crushing injuries, neoplastic disease, allergic reactions,  and infection. Excess amounts of fluid escape from the plasma  to the interstitial space and produce edema. This type of edema  is often very severe because of loss of proteins from the vascular  space, which decreases capillary oncotic pressure and increases  interstitial oncotic pressure.   Lymphatic obstruction occurs when the lymphatic channels  are blocked because of infection or tumor. Proteins and fluids  are not reabsorbed and accumulate in the interstitial space,  causing lymphedema. Lymphedema of the arm or leg also can  occur after surgical removal of axillary or femoral lymph nodes,  respectively, for treatment of cancer.’   CLINICAL MANIFESTATIONS. Edema may be localized or general-  ized. Some localized edema is usually limited to the site of tissue  injury, as in a sprained joint. Local edema can also occur within  particular organs, causing, for example, cerebral edema in the  brain and pulmonary edema in the lungs. Edema of specific  organs, such as the brain, lung, or larynx, can be life threatening.   Generalized edema is manifested by a more uniform distribu-  tion of fluid in interstitial spaces throughout the body. Depen-  dent edema, in which fluid accumulates in gravity-dependent  areas of the body, might appear in the feet and legs when stand-  ing and in the sacral area and buttocks when supine. Depen-  dent edema can be identified by using the fingers to press away    FIGURE 3-3 Pitting Edema. (From Bloom A, Ireland J: Color atlas of diabetes,  ed 2, St Louis, 1992, Mosby.)    edematous fluid in tissues overlying bony prominences. A pit  will be left in the skin; hence the term pitting edema (Figure 3-3).   Edema is usually associated with swelling and puffiness,  tight-fitting clothes and shoes, and limited movement of the  affected area. Weight gain can be significant. The accumulation  of fluid increases the distance required for nutrients, oxygen,  and wastes to move between capillaries and cells in the tissues.  Increased tissue pressure also may diminish capillary blood  flow, leading to ischemia. Therefore, wounds heal more slowly  and formation of pressure sores increases (see Chapter 46).   As edematous fluid accumulates, it is trapped in a “third  space” (i.e., the interstitial space) and dehydration can develop  as a result of this sequestering of fluid. Such sequestration    occurs with severe burns, in which large amounts of vascular  fluid are lost to the interstitial spaces, reducing plasma volume  and causing shock (see Chapter 48).   EVALUATION AND TREATMENT. Specific conditions causing  edema require diagnosis. Edema may be treated symptom-  atically until the underlying disorder is corrected. Supportive  measures include elevating edematous limbs, using compres-  sion stockings or devices, avoiding prolonged standing, restrict-  ing salt intake, and taking diuretics.    The kidneys and hormones have a central role in maintaining  sodium and water balance. Because water follows the osmotic    gradients established by changes in salt concentration, sodium  balance and water balance are intimately related. Sodium is  regulated by the renal effects of aldosterone from the adrenal  cortex and natriuretic peptides from the heart. Water balance is  primarily regulated by antidiuretic hormone (ADH; also known  as arginine-vasopressin) from the posterior pituitary.    Sodium accounts for 90% of the ECF cations (positively charged  ions). The distribution of electrolytes in body compartments is  summarized in Table 3-5 and the concentration of electrolytes is  summarized in Table 3-1. As the most abundant ECF cation, along  with its constituent anions (negatively charged ions) chloride  and bicarbonate, sodium regulates extracellular osmotic forces  and therefore regulates water balance. Sodium is important in  other body functions, including maintenance of neuromuscular  irritability for conduction of nerve impulses (in conjunction with  potassium and calcium), regulation of acid-base balance (through  sodium bicarbonate and sodium phosphate), participation in cel-  lular chemical reactions, and transport of substances across the  cellular membrane (see Chapter 1).   The kidney, in conjunction with neural and hormonal medi-  ators, maintains normal serum sodium concentration within  a narrow range (135 to 145 mEq/L) primarily through renal  tubular reabsorption. The average dietary intake of sodium  ranges from 5 to 6 g/day; the minimal daily requirement of  sodium is 500 mg. Sweating depletes sodium and water volume  and increases the body’s sodium requirement.   Hormonal regulation of sodium balance is mediated by  aldosterone, a mineralocorticoid (steroid) synthesized and  secreted from the adrenal cortex as the end product of the renin-  angiotensin-aldosterone system (Figure 3-4) (also see Chapters  21 and 37). When circulating blood pressure and renal blood  flow, or serum sodium concentrations, are reduced, renin, an  enzyme secreted by the juxtaglomerular cells of the kidney, is  released. Renin stimulates the formation of angiotensin I, an    FIGURE 3-4 The Renin-Angiotensin-Aldosterone System. BP Blood pressure; ECF extracellular fluid; Na, sodium.  (From Lewis et al: Medical-surgical nursing: assessment and management of clinical problems, ed 8, St. Louis, 2011, Mosby.)    CHAPTER 3 The Cellular Environment: Fluids and Electrolytes, Acids and Bases    inactive polypeptide. Angiotensin-converting enzyme (ACE)  in pulmonary vessels converts angiotensin I to angiotensin IL.  Angiotensin II has two major functions: it causes vasoconstric-  tion, which elevates systemic blood pressure, and it stimulates  the secretion of aldosterone. Aldosterone promotes sodium and  water reabsorption by the proximal tubules of the kidneys, thus  conserving sodium, blood volume, and blood pressure. Aldo-  sterone also stimulates secretion (and therefore excretion) of  potassium by the distal tubule of the kidney, reducing potas-  sium concentrations in the ECF. The restoration of sodium  levels, blood volume, and renal perfusion then inhibits further  release of renin.   Natriuretic peptides are hormones that include atrial natri-  uretic peptide (ANP) produced by myoendocrine atrial cells,  brain natriuretic peptide (BNP—named brain since it was  first discovered in porcine brain) produced by myoendocrine  ventricular cells, and urodilatin (an ANP analog) synthesized  within the kidney. ANP and BNP are released when there is an  increase in transmural atrial pressure caused by increased intra-  atrial volume as may occur with heart failure.‘ ANP and BNP  increase sodium and water excretion by the kidneys, which low-  ers blood volume and pressure. Urodilatin is released from dis-  tal tubular kidney cells when there is increased arterial pressure  and increased renal blood flow. These hormones are natural  antagonists to the renin-angiotensin-aldosterone system. The  restoration of lower atrial pressure then inhibits further release  of ANP and BNP.   Chloride is the major anion in the ECF and provides elec-  troneutrality, particularly in relation to sodium. Chloride  transport is generally passive and follows the active transport  of sodium so that increases or decreases in chloride are propor-  tional to changes in sodium. Chloride concentration tends to  vary inversely with changes in the concentration of bicarbonate  (HCO; ), the other major ECF anion.    One manner by which water balance is regulated is through the  perception of thirst. Thirst is a sensation that stimulates water-  drinking behavior. Thirst is experienced when water loss equals  2% of an individual’s body weight or when there is an increase  in osmolality. Dry mouth, hyperosmolality, and plasma volume  depletion activate hypothalamic osmoreceptors. The action of  the osmoreceptors then causes thirst. Drinking water restores  plasma volume and dilutes the ECF osmolality.   Water balance also is directly regulated by antidiuretic hor-  mone (arginine-vasopressin), which is secreted when plasma  osmolality increases or circulating blood volume decreases and  blood pressure drops (Figure 3-5). Increased plasma osmolality  occurs with a water deficit or sodium excess in relation to water.  The increased osmolality stimulates hypothalamic osmorecep-  tors. In addition to causing thirst, the stimulated osmorecep-  tors signal the posterior pituitary to release ADH. The action  of ADH is to increase the permeability of renal tubular cells to  water, increasing water reabsorption and promoting the res-  toration of plasma volume and blood pressure. Urine concen-  tration increases, and the reabsorbed water decreases plasma  osmolality, returning it toward normal. Like most hormones,    ADH is regulated by a feedback mechanism. The restoration  of plasma osmolality, blood volume, and blood pressure then  inhibits ADH secretion.   With fluid loss (dehydration) (e.g., from vomiting, diarrhea,  or excessive sweating), a decrease in blood volume and blood  pressure often occurs. Baroreceptors (volume/pressure sensi-  tive receptors) (stretch receptors that are sensitive to changes  in arterial volume and pressure) also stimulate the release of  ADH. Baroreceptors are located in the right and left atria and  large veins, and in the aorta, pulmonary arteries, and carotid  sinus. When arterial and atrial pressure drops baroreceptors  signal the hypothalamus to release ADH. The reabsorption  of water mediated by ADH then promotes the restoration of  plasma volume and blood pressure (see Figure 3-5). ADH also  stimulates arterial vasoconstriction.    Alterations in sodium and water balance are closely related.  Water imbalances may develop because of changes in osmotic  gradients caused by gain or loss of salt. Likewise, sodium imbal-  ances occur with alterations in body water volume. Generally  the alterations can be classified as changes in tonicity, or the  change in concentration of electrolytes in relation to water (see  Chapter 1). Alterations can therefore be classified as isotonic,  hypertonic, or hypotonic (Table 3-6 and Figure 3-6).   The term isotonic refers to a solution that has the same concen-  tration of solutes as the plasma. Isotonic alterations occur when  changes in TBW are accompanied by proportional changes    in the amounts of electrolytes and water. For example, if an  individual loses pure plasma or ECF, fluid volume is depleted  but the number and type of electrolytes (e.g., sodium) and the  osmolality remain within a normal range. Excessive amounts  of isotonic body fluids can result from excessive administra-  tion of intravenous normal saline (0.9% NaCl) or oversecre-  tion of aldosterone with renal retention of both sodium and  water. Isotonic fluid loss results in hypovolemia. Causes include    Gain or loss of extracellular fluid (ECF)  resulting in a concentration equivalent to a  0.9% sodium chloride (salt) solution (normal   Imbalance that results in an ECF  concentration >0.9% salt solution; that is,  water loss or solute gain; cells shrink ina  hypertonic fluid   Imbalance that results in an ECF <0.9% salt  solution; that is, water gain or solute loss;  cells swell in a hypotonic fluid    hemorrhage, severe wound drainage, and excessive diaphore-  sis (sweating). Loss of extracellular volume results in weight  loss, dryness of skin and mucous membranes, decreased urine  output, increased hematocrit value, and symptoms of hypo-  volemia. Indicators of hypovolemia include a rapid heart rate  and flattened neck veins, and can present with a normal or  decreased blood pressure. In severe states, hypovolemic shock  (severe hypotension) can occur (see Chapter 48).   Isotonic fluid excesses result in hypervolemia. Causes include  excessive administration of intravenous fluids, hypersecretion  of aldosterone, the effects of drugs such as cortisone, or renal  failure. Weight gain and a decrease in hematocrit level and  plasma protein concentration caused by the diluting effect of  excess plasma volume will occur. The neck veins may distend,  and the blood pressure increases. Increased capillary hydro-  static pressure leads to edema formation. If the plasma volume  is great enough, pulmonary edema and heart failure develop.    Hypertonic fluid alterations develop when the osmolality of the  ECF is elevated above normal (greater than 294 mOsm). The  most common causes are an increased concentration of ECF  sodium (hypernatremia) or a deficit of ECF free water. In both  instances the hypertonicity of the ECF attracts water from the  intracellular space, causing ICF dehydration. A primary increase    FIGURE 3-6 Effects of Alterations in Extracellular Sodium Concentration in RBC, Body Cell, and Neuron. A, Hypo-  tonic Alteration: Decrease in ECF sodium (Na) concentration (hyponatremia) results in ICF osmotic attraction of water with  swelling and potential busting of cells. B, /sotonic Alteration: Normal concentration of sodium in the ECF and no change in  shifts of fluid in or out of cells. €, Hypertonic Alteration: An increase in ECF sodium concentration (hypernatremia) results in  osmotic attraction of water out of cells with cell shrinkage. ABC, Red blood cell.    CHAPTER 3 The Cellular Environment: Fluids and Electrolytes, Acids and Bases    in the amount of ECF sodium causes an osmotic attraction of  water and symptoms of hypervolemia. In contrast, a hypertonic  state caused primarily by free water loss leads to hypovolemia  (Table 3-7).    PATHOPHYSIOLOGY. Hypernatremia occurs when serum  sodium levels exceed 147 mEq/L. Increased serum sodium con-  centration may be caused by loss of water (most common) or an  acute gain in sodium. With water loss, both ICF dehydration and  ECF dehydration occur. Hyperosmolality is a common result of  hypernatremia. Because sodium is largely in the ECF, increases  in the concentration of sodium cause intracellular dehydration  and hypervolemia (see Table 3-7 and Figure 3-6, C).   Increased sodium concentration caused by water deprivation  or water loss is associated with fever or respiratory tract infec-  tions, which increase the respiratory rate and enhance water loss  from the lungs. Diabetes insipidus (deficiency of ADH), polyuria  (frequent urination), profuse sweating, and diarrhea cause water  loss in relation to sodium concentration. Infants with severe  diarrhea are particularly vulnerable. Insufficient water intake  also can cause hypernatremia (e.g., individuals who are immo-  bilized or receiving gastric feedings, those who are comatose or  confused, or infants because they cannot communicate thirst).   Increased sodium retention occurs because of (1) inap-  propriate administration of hypertonic saline solution  (e.g., as sodium bicarbonate for treatment of acidosis during  cardiac arrest); (2) oversecretion of aldosterone (as in primary    hyperaldosteronism), where sodium reabsorption exceeds  water reabsorption; or (3) Cushing syndrome (caused by excess  secretion of adrenocorticotropic hormone [ACTH], which also  causes increased secretion of aldosterone). High amounts of  dietary sodium rarely cause hypernatremia in a healthy individ-  ual because the sodium is eliminated by the kidneys. However,  increased amounts of dietary sodium (greater than 5 grams per  day) is associated with cardiovascular disease (see Chapter 32).   CLINICAL MANIFESTATIONS. Water is redistributed to the extra-  cellular space, and intracellular dehydration ensues. Thirst,  fever, dry mucous membranes, hypotension, tachycardia, low  jugular venous pressure, and restlessness are associated with  hypernatremia as a result of water loss. Pulmonary edema  occurs when water shifts from the ICF to the interstitial space.  Central nervous system symptoms are the most serious and are  related to alterations in membrane potentials and shrinking of  brain cells. Symptoms include muscle twitching and hyperre-  flexia (hyperactive reflexes), confusion, coma, convulsions, and  cerebral hemorrhage from stretching of veins.   EVALUATION AND TREATMENT. The serum sodium level is usually  more than 147 mEq/L. If there is water loss, urine specific gravity  will be greater than 1.030 and the levels of hematocrit and plasma  proteins will be elevated. The treatment of hypernatremia is to  give an isotonic salt-free fluid (5% dextrose in water) until the  serum sodium level returns to normal.° Fluid replacement must  be given slowly to prevent cerebral edema and serum sodium  levels need to be closely monitored. Hypervolemia and hypovo-  lemia require treatment of the underlying clinical condition.    Hypervolemia Intracellular dehydration  Weight gain Thirst  Bounding pulse Fever  Increased blood pressure Decreased urine output  Edema Shrinkage of brain cells    Water deprivation  Confusion or coma  Inability to communicate  Loss of thirst   Isotonic dehydration treated with  intravenous D;W; glucose in D-W  solution is metabolized to water,  contributing to hyponatremia    D;W, Dextrose 5% in water; ECF, extracellular fluid; /CF, intracellular fluid.    Because chloride follows sodium, hyperchloremia (elevation of  serum chloride concentration greater than 105 mEq/L) often  accompanies hypernatremia, as well as plasma bicarbonate defi-  cits, as in hyperchloremic metabolic acidosis (see p. 126). There  are no specific symptoms or treatment for chloride excess and  treatment is related to management of the underlying disorder.    PATHOPHYSIOLOGY. Dehydration refers to water deficit, but  also is commonly used to indicate both sodium and water  loss (isotonic or isoosmolar dehydration). Pure water deficits  (hyperosmolar or hypertonic dehydration) are rare because  most people have access to water. Individuals who are coma-  tose or paralyzed continue insensible water losses through the  skin and lungs with a minimal obligatory formation of urine.  Hyperventilation caused by fever also may precipitate water  deficit. The most common cause of water loss is increased  renal clearance of free water as a result of impaired tubular  function or inability to concentrate the urine, as with diabe-  tes insipidus (decreased or absent ADH) (see Table 3-7 and  Chapter 22).   CLINICAL MANIFESTATIONS. Marked water deficit is manifested  by symptoms of dehydration: headache, thirst, dry skin and  mucous membranes, weight loss, decreased urine output, and  concentrated urine (with the exception of diabetes insipidus).  Skin turgor may be normal or decreased. Symptoms of hypovo-  lemia, including tachycardia, weak pulses, and postural hypo-  tension, may be present.    Extracellular volume contraction  and hypovolemia (but may not if  there is water excess)    Extracellular volume expands with  hypervolemia (but may not if fluid  is trapped in intracellular space)    EVALUATION AND TREATMENT. Elevated levels of hematocrit,  serum sodium concentration, urine and serum osmolality, and  urine specific gravity are associated with moderate water loss.   Treatment is to give water and stop fluid loss. Fluid replace-  ment must be given slowly enough to prevent rapid movement  of water into brain cells, which causes cerebral edema, seizures,  brain injury, and death. When intravenous replacement is  required, hypotonic saline solutions or 5% dextrose in water is  used because pure water lyses red blood cells.   Hypotonic fluid imbalances occur when the osmolality of the  ECF is less than normal (less than 280 mOsm). The most com-  mon causes are sodium deficit (hyponatremia) or free water  excess (water intoxication). Both causes lead to an intracel-  lular overhydration (cellular edema) and cell swelling when  water moves into the cell, where the osmotic pressure is greater  (see Figure 3-6, A). Cerebral and pulmonary edema occur in  conjunction with these fluid shifts.° With hyponatremia, the  plasma volume then decreases, leading to symptoms of hypo-  volemia. With free water excess, the ECF volume is elevated,  causing symptoms of hypervolemia (Table 3-8).    PATHOPHYSIOLOGY. Hyponatremia develops when the serum  sodium concentration decreases to less than 135 mEq/L. It is the  most common electrolyte disorder in hospitalized individuals.’  Hyponatremia may be caused by sodium loss, inadequate sodium  intake, or dilution of the body’s sodium level. Clinical syndromes    CHAPTER 3 The Cellular Environment: Fluids and Electrolytes, Acids and Bases    Hyponatremia (serum sodium concentration <135 mmol/L) and severe hypo-  natremia (serum sodium concentration <120 mmol/L) are the most common  electrolyte abnormalities among hospitalized individuals with risk for severe  morbidity and mortality. Hyponatremia can be difficult to diagnose because  it can develop with euvolemia, hypervolemia, or hypovolemia. In addition to  older adults, children and premenopausal women are at particular risk as well  as those receiving treatment in intensive care units and persons with cirrhosis  with ascites, heart failure syndromes, brain injury, sepsis, or multiple organ  failure. Death or brain damage may range from 50% to 83% and is related  to cerebral edema, increased intracranial pressure, and cerebral hypoxemia,  with symptoms of seizure, respiratory arrest, coma, and death. Use of thiazide  diuretics is a common cause of hyponatremia and can occur within 2 weeks  of initiation of treatment. Postoperative hyponatremia is caused by adminis-  tration of hypotonic fluids and dysregulation of the secretion of antidiuretic  hormone (arginine-vasopressin). Treatment with fluid restriction, diuretic  treatment, sodium replacement, and urea administration is effective in less  severe cases. Hypertonic sodium chloride is usually safe with acute hypona-  tremia. Brain myelinolysis is a risk if treatment is given too rapidly. Arginine-  vasopressin receptor antagonists (vaptans) can provide effective treatment  and they work by increasing blood flow to the kidney with increased urine  formation without loss of electrolytes. Vaptans are contraindicated in hypovo-  lemic hyponatremia. Frequent monitoring with attention to subtle symptoms  and early treatment lead to improved outcomes.    Data from Aperis G, Alivanis P: Rev Recent Clin Trials 6(2):177-188,  2011; Chawla A et al: Clin J Am Soc Nephrol 6(5):960-965, 2011;  Elhassan EA, Schrier RW: Exp Opin Investig Drugs 20(3):373-380,  2011; Human T: Pharmacother 31(5 Suppl):18S—24S, 2011; Robertson  GL: Nat Rev Endocrinol 7(3):151-161, 2011; Pfennig CL, Slovis CM:  Emerg Med Pract 14(10):1-26, 2012; Vaishya R et al: J Indian Med  Assoc 110(2):94-97, 2012; Konishi M et al: J Card Fail 18(8):620-625,  2012; Lindner G, Schwarz C: Minerva Med 103(4):279-291, 2012.    that may cause hyponatremia include syndrome of inappropriate  secretion of antidiuretic hormone (SIADH, excess ADH) or fail-  ure of the distal tubules to reabsorb sodium. Sodium deficits usu-  ally cause hypoosmolality and water moves into cells, resulting in  cell swelling (see Figure 3-6, A, and What’s New? Hyponatremia  and Hospitalization).   Pure sodium deficits are usually caused by diuretics® and  extrarenal losses such as vomiting, diarrhea, gastrointestinal  suctioning, or burns. Inadequate intake of dietary sodium is  rare but can occur in individuals consuming low-sodium diets,  particularly among those taking diuretics. Dilutional hypo-  natremias occur when there is an excess of TBW in relation  to total body sodium or a shift of water from the ICF to the  ECF space (e.g., administration of mannitol). Replacement of  fluid loss with intravenous 5% dextrose in water also can cause  a dilutional hyponatremia because once the glucose is metabo-  lized, a hypotonic solution remains with a diluting effect. Use  of excess hypotonic saline (e.g., 0.45% NaCl) may also result  in dilution. In addition, excessive sweating may stimulate thirst  and intake of large amounts of water, which dilute sodium; this  condition may be associated with endurance exercise in which  there is only pure water replacement.   Hyponatremia may cause hypotonic or hypertonic altera-  tions. During acute oliguric renal failure, severe congestive heart    failure, or cirrhosis, renal excretion of water is impaired. Both  TBW and sodium levels are increased, but TBW level exceeds  the increase in sodium level, producing a hypotonic hypona-  tremia. Hypertonic hyponatremia develops with the shift of  water from the ICF to the ECF as occurs with hyperglycemia,  hyperlipidemia, and hyperproteinemia. The osmotic fluid shift  to the ECF in turn dilutes the concentration of sodium and  other electrolytes.   CLINICAL MANIFESTATIONS. Cellular swelling and deficits of  intracellular sodium alter the ability of cells to depolarize and  repolarize normally (see Chapter 1). Neurologic changes char-  acteristic of hyponatremia include lethargy, headache, confu-  sion, apprehension, seizures, and coma. Pure sodium losses  may be accompanied by loss of ECF, causing hypovolemia with  symptoms of hypotension, tachycardia, and decreased urine  output. Dilutional hyponatremia is accompanied by weight  gain, edema, ascites, and jugular vein distention. Cerebral  edema can be a life-threatening complication of hypervolemic  hyponatremia caused by increases in intracranial pressure.   EVALUATION AND TREATMENT. In hyponatremic states, serum  sodium concentration falls to less than 135 mEq/L. With pure  sodium deficits, the hematocrit and plasma protein levels may  be elevated. Urine specific gravity is less than 1.010 when renal  function is normal because sodium is maximally conserved.   Treatment of hyponatremia is related to the contributing  disorder. Losses of sodium and water volume are calculated  from the clinical evaluation, and appropriate solutions then are  selected for replacement. Restriction of water intake is required  in most cases of dilutional hyponatremia because body sodium  levels may be normal or increased even though serum concen-  trations are low. Hypertonic saline solutions are used cautiously  with severe hyponatremia or the presence of symptoms such as  seizures.”    Hypochloremia, a low level of serum chloride (less than 97  mEq/L), usually occurs with hyponatremia or an elevated  bicarbonate concentration, as in metabolic alkalosis (see  p. 128). Sodium deficit related to restricted intake, use of diuret-  ics, and vomiting are accompanied by chloride deficiency. Cys-  tic fibrosis is a genetic disease characterized by hypochloremia  (see Chapters 36 and 42). In all cases, treatment of the underly-  ing cause is required.    PATHOPHYSIOLOGY. When the body is functioning normally, it  is almost impossible to produce an excess of TBW since water  balance is regulated by the kidneys. However, some individuals  with psychogenic disorders develop water intoxication from  compulsive water drinking. Intensive exercise with replacement  of large volumes of electrolyte-free water also causes overhydra-  tion. Acute renal failure, severe congestive heart failure, and cir-  rhosis are clinical conditions that can precipitate water excess.  Decreased urine formation from renal disease or decreased  renal blood flow contributes to water excess. The overall effect  is dilution of the ECF with the movement of water to the intra-  cellular space by osmosis. The syndrome of inappropriate    secretion of ADH (SIADH), also known as vasopressin dys-  regulation, enhances water retention because ADH levels are  elevated (see Chapter 22, p. 718). Water excess is usually accom-  panied by hyponatremia.   CLINICAL MANIFESTATIONS. The symptoms of water excess are  related to the rate at which water loading has occurred. Acute  excesses cause cerebral edema with confusion and convulsions.  Weakness, nausea, muscle twitching, headache, and weight gain  are common symptoms of chronic water accumulation.   EVALUATION AND TREATMENT. Serum sodium concentration can  be decreased, but this also can occur with a pure sodium defi-  cit. Serum and urine osmolalities are decreased because water  concentration will be in excess of sodium concentration. Urine  sodium concentration will be reduced. The hematocrit value is  reduced from the dilutional effect of water excess.   Fluid restriction for 24 hours is an effective treatment if there  are no severe neurologic symptoms or convulsions. Small amounts  of intravenous hypertonic sodium chloride (i.e., 3% sodium chlo-  ride) can be given when neurologic symptoms are severe.    Potassium (K*) is the major intracellular electrolyte and is  found in most body fluids (see Table 3-5, p. 108). The ICF con-  centration of K* is 150 to 160 mEq/L; the ECF concentration is  3.5 to 5.0 mEq/L. Total body potassium content is about 4000  mEq, with most of it located in the cells. Daily dietary intake of  potassium is 40 to 150 mEq/day, with an average of 1.5 mEq/kg  body weight.   Potassium balance is maintained by renal excretion of Kt  absorbed from the gastrointestinal tract. Absorbed dietary  Kt moves rapidly into cells. However, the distribution of Kt  between intracellular and extracellular fluids can fluctuate and  is influenced by several factors. Aldosterone, insulin, epineph-  rine (B-adrenergic stimulation), and alkalosis facilitate the shift  of K* into cells. Insulin deficiency, aldosterone deficiency, aci-  dosis, and strenuous exercise facilitate the shift of K* out of  cells. a-Adrenergics impair K* entry into cells. Glucagon blocks  entry of K* into cells, and glucocorticoids promote K* excre-  tion. Potassium also will move out of cells along with water  when there is increased ECF osmolarity (number of osmoles of  solute per liter of fluid). If cells lyse, they release their intracel-  lular K* into the ECF, which can cause an acute rise in plasma  K* levels.   Besides acting to conserve sodium, aldosterone is a major fac-  tor in potassium regulation. Elevated plasma K* concentration  causes adrenal secretion of aldosterone. Aldosterone then stim-  ulates the release of K* into the urine by the distal renal tubules.   Insulin contributes to the regulation of plasma potassium levels  by stimulating the Nat-K*t-ATPase pump, thereby promoting  the movement of K* into liver and muscle cells simultaneously  with glucose transport. The intracellular movement of K* pre-  vents an acute hyperkalemia related to food intake. Insulin  also can be used to treat hyperkalemia. However, dangerously  low levels of plasma K* can result from the administration    of insulin when K* levels are depressed. Potassium balance is  especially significant in the treatment of conditions requiring  insulin administration, such as insulin-dependent diabetes  mellitus (type 1).   The difference in the K* intracellular to extracellular con-  centration is maintained by a sodium-potassium active trans-  port system (Na*t-K*-ATPase pump). The ratio of ICF K*  concentration to ECF K* concentration is the major determi-  nant of the resting membrane potential, which is necessary for  the transmission and conduction of nervous impulses, main-  tenance of normal cardiac rhythms, and contraction of skel-  etal and smooth muscles (see Figure 1-35, p. 35). The constant  diffusion of positively charged K* out of the cell (i.e., down its  concentration gradient) makes the interior of cells electronega-  tive in relation to the ECF. Changes in the ratio of ICF to ECF  potassium are responsible for many of the symptoms associated  with K* imbalance.   As the predominant ICF ion, K* exerts a major influence on  the regulation of ICF osmolality and fluid balance, as well as on  intracellular electrical neutrality in relation to hydrogen (H*)  and Na* levels. Potassium is also necessary for a variety of meta-  bolic functions and is required for glycogen deposition in liver  and skeletal muscle cells.   The kidney provides the most efficient regulation of K* level  balance over time. The amount of K* excreted varies in propor-  tion to the dietary intake (40 to 120 mEq/day). Potassium is  freely filtered by the renal glomerulus, and 90% is reabsorbed  by the proximal tubule and loop of Henle. Principal cells in the  collecting duct secrete K* and intercalated cells in the collect-  ing duct reabsorb K*. Dietary K* intake, aldosterone level, and  distal tubule urine flow determine the amount of K* excreted  from the body. Unlike sodium, the renal mechanism for con-  serving K* is weak, even when total body K* stores are depleted.  The gut also may sense the amount of K* ingested and stimulate  renal K* excretion.!° However, a low K* intake also suppresses  renal K* excretion.   1. The concentration gradient for K* at the distal tubule and   The concentration of K* in the distal tubular cells is deter-  mined primarily by the plasma concentration in the peritubular  capillaries. When plasma K* concentration increases because  of increased dietary intake or shifts from the ICF to the ECF  occur, K* is secreted into the urine by principal cells in the col-  lecting ducts. Decreased levels of plasma K* result in decreased  collecting duct secretion and reabsorption by intercalated cells,  although Kt losses of approximately 5 to 15 mEq/day will  continue.   Changes in distal tubule flow rate and distal tubule sodium  delivery also influence the concentration gradient for K* secre-  tion. When the flow rate and sodium delivery are high, as  occurs with the administration of diuretics, the concentration  of K* in the distal tubular urine is lower, favoring the secretion    CHAPTER 3 The Cellular Environment: Fluids and Electrolytes, Acids and Bases    of K* into the tubule. Potassium secretion decreases when distal  tubule flow rate and sodium delivery are low. However, aldoste-  rone stimulates K* secretion by the distal tubule and serves to  preserve K* secretion and K* balance during dehydration and  extracellular volume depletion, when tubular delivery of Nat  and flow rate are reduced.   Changes in pH and thus in hydrogen ion concentration also  affect K* balance.'' Hydrogen ions move from the ECF to the  ICF during states of acidosis. When hydrogen is moving into  the cell, K* shifts out of the cell to the ECF to maintain a balance  of cations across the cell membrane. This occurs in part because  of a decrease in Na*-K*-ATPase pump activity. The decreased  ICF K* level in the distal tubular cells results in decreased secre-  tion of K* into the urine, contributing to hyperkalemia (hyper-  kalemic acidosis), although total body K* level may not change.  In contrast, intracellular fluid levels of hydrogen are diminished  during states of alkalosis. Alkalosis causes K* to shift into the  cell, so the distal tubular cells increase their secretion of K* into  the urine, contributing to hypokalemia (hypokalemic alkalo-  sis). The management of alterations associated with acid-base  imbalances requires that the acid-base imbalances must be  treated before or concurrently with treatment of changes in Kt  concentration.   Potassium adaptation is the ability of the body to adapt to  increased levels of K* intake over time. A sudden increase in  K* level may be fatal, but if the intake is slowly increased by  amounts of more than 120 mEq/day, the kidney can increase  the urinary excretion of K* and maintain K* concentration  balance.    PATHOPHYSIOLOGY. Potassium deficiency, or hypokalemia,  develops when the serum K* concentration decreases to less  than 3.5 mEq/L. Because intracellular and total body stores of  K* are difficult to measure, changes in K* balance are described  by the plasma concentration, although changes in total body  K* level are not always reflected in the plasma K* concentra-  tion. Generally, lowered serum K* level indicates a loss of total  body K*. Because K* is lost from the ECF, the change in the  concentration gradient favors movement of K* from the cell to  the ECF. The ICF/ECF concentration ratio is maintained, but  the amount of total body K* is depleted.!”   Factors contributing to the development of hypokalemia  include reduced intake of potassium, increased entry of K* into  cells, and increased losses of body K*. Dietary deficiency of Kt  is a rare cause but may occur in elderly individuals with both  low protein intake (meat) and inadequate intake of fruits and  vegetables, and in individuals with alcoholism or anorexia ner-  vosa. Reduced K* intake generally becomes a problem when  combined with other causes of K* depletion.   ECF hypokalemia can develop without losses of total body  K* when K* is redistributed between the ECF and ICF. Alka-  losis, particularly respiratory alkalosis, is the most common  clinical cause of these shifts. In alkalosis, ECF hydrogen moves  out of the cell to correct the alkalosis, which causes K* to move  into the cell to maintain an ionic balance. Insulin also promotes  cellular uptake of K* and can cause an ECF potassium deficit,    particularly with the intake of high carbohydrate loads. Severe,  even fatal, hypokalemia may occur if insulin is administered  without also providing K* supplements.   Treatment of pernicious anemia with vitamin Bj, or folate  also may precipitate hypokalemia if the formation of new red  blood cells causes enough K* uptake to effect an extracellular  decrease in K* concentration. Familial hypokalemic periodic  paralysis is a rare genetically transmitted disease that also  causes K* to shift into the intracellular space.   Hypokalemia also can occur when K* shifts from the ICF to  the ECF, as occurs in conjunction with renal losses. For exam-  ple, in diabetic ketoacidosis, the increased hydrogen ion con-  centration in the ECF causes H* to shift into the cell in exchange  for K* at the same time diuresis is occurring. A normal level of  K* is maintained in the plasma, but K* continues to be lost in  the urine, causing a deficit in the amount of total body potas-  sium. Total body K* depletion becomes evident when insulin  treatment and rehydration therapy are initiated.   Potassium loss also occurs through normal body functions,  but without causing hypokalemia. Average daily losses of K* are  as follows:    Losses of Kt from body stores are most commonly caused by  gastrointestinal and renal disorders. Diarrhea (from any cause),  intestinal drainage tubes or fistulae, and laxative abuse also may  result in hypokalemia. Normally, only 5 to 10 mEq of potas-  sium and 100 to 150 ml of water are excreted in the stool each  day. With diarrhea, fluid and electrolyte losses can be volumi-  nous, with several liters of fluid and 100 to 200 mEq of K* lost  per day. Vomiting or applying continuous nasogastric suction  frequently is associated with K* depletion, partly because of the  K* lost from the gastric fluid but principally because of renal  compensation for volume depletion and the metabolic alka-  losis (elevated bicarbonate levels) that occurs from sodium,  chloride, and hydrogen ion losses. The loss of fluid and sodium  stimulates the secretion of aldosterone and ADH, which in turn  causes renal loss of K*. The elevated flow of bicarbonate at the  distal tubule contributes to renal excretion of K* because of  increased tubular lumen electronegativity.   Renal losses of K* are related to increased secretion of K* by  the distal tubule. Use of diuretics, excessive aldosterone secre-  tion, increased distal tubular flow rate, and low plasma mag-  nesium concentration all may contribute to urinary losses of  K*. Many diuretics, including thiazides, furosemide, ethacrynic  acid, and osmotic diuretics, inhibit the reabsorption of sodium  chloride, causing the diuretic effect. The distal tubular flow rate  then increases, promoting K* excretion. If sodium loss is severe,  the compensating aldosterone secretion (which causes second-  ary hyperaldosteronism) may further deplete K* stores. Primary  hyperaldosteronism with excessive secretion of aldosterone from  an adrenal adenoma also causes K* wasting. Many kidney diseases  result in a reduced ability to conserve sodium. The disordered    FIGURE 3-7 Effects of Potassium (K+) and Calcium (Ca*+) on Membrane Excitability. A, Normal membrane excitability:  Potassium affects resting membrane potential (E,,), and calcium affects threshold potential (E,). B, Effects of potassium (K*)  changes on membrane potential. C, Effect of calcium (Ca**) on threshold potential. Note: Hyperpolarization can be caused by  either hypokalemia (E,, more negative) or hypercalcemia (E; less negative}-distance between E,, and E, is increased (decreased  excitability); and hypopolarizationcan be caused by either hyperkalemia (E,, less negative) or hypocalcemia (E, more negative) —  distance between E,, and E; is decreased (increased excitabillity).    sodium reabsorption produces a diuretic effect, and the increased  distal tubule flow rate favors the secretion of Kt. Magnesium  deficits stimulate renin release and hyperaldosteronism, causing  hypokalemia. Several antibiotics, including amphotericin B, gen-  tamicin, and carbenicillin, are known to cause hypokalemia.  CLINICAL MANIFESTATIONS. Mild losses of K* are usually asymp-  tomatic. A wide range of dysfunctions may result from severe  hypokalemia (<2.5 mEq/L). Neuromuscular and cardiac effects of  hypokalemia produce the most common symptoms.'’ Neuro-  muscular excitability is decreased, causing skeletal muscle weak-  ness, smooth muscle atony, and cardiac dysrhythmias. As Chapter  1 describes, the resting membrane potential (E,,) is determined  by the ratio of extracellular to intracellular K* ion concentration.  Because the concentration of K* in the ECF is small, only small  changes in ECF potassium level are required to influence the rest-  ing membrane potential and affect neuromuscular excitability (the  difference between resting membrane and threshold potentials)!  (Figure 3-7, A). When extracellular K* levels decrease rapidly,  intracellular K* diffuses more readily out of the cell and the rest-  ing membrane potential becomes more negative (ie., from —90  to —100 millivolts). If the threshold potential (E,) remains stable,  the difference between resting membrane potential and threshold  potential increases and the cell membrane becomes hyperpolar-  ized, requiring a stronger stimulus (decreased excitability) to initi-  ate depolarization and an action potential (Figure 3-7, B [low K*]).  The cardiac effects of hypokalemia are related to decreased mem-  brane excitability (see Figure 3-7, B). Because K* contributes to the  repolarization phase of the action potential, hypokalemia delays  ventricular repolarization and the frequency of action poten-  tials. The membrane potential remains partially depolarized with    slowed conduction and abnormal pacemaker activity. A variety of  dysrhythmias may occur, including sinus bradycardia, atrioven-  tricular block, and paroxysmal atrial tachycardia. The characteris-  tic changes in the electrocardiogram reflect delayed repolarization.  For instance, the amplitude of the T wave is decreased, the ampli-  tude of the U wave is increased, and the ST segment is depressed  (Figure 3-8). In severe states of hypokalemia, P waves peak and  the QRS complex is prolonged. Hypokalemia also increases the  risk of digitalis toxicity by slowing the sodium-potassium pump,  which augments the action of digitalis in cardiac muscle by exces-  sively increasing intracellular calcium and sodium concentrations.   Plasma calcium concentration also contributes to changes  in neuromuscular excitability associated with hypokalemia.  Increases in ECF calcium concentration tend to make the thresh-  old potential (E,) less negative and decrease membrane excitabil-  ity, potentiating hyperpolarization, decreased excitability, and  the neuromuscular effects of hypokalemia (Figure 3-7, C).   Carbohydrate metabolism is affected because hypokale-  mia depresses insulin secretion and alters hepatic and skeletal  muscle glycogen synthesis. Renal function is impaired, with  a decreased ability to concentrate urine. Polyuria (increased  urine) and polydipsia (increased thirst) are associated with  decreased responsiveness to ADH. Chronic potassium defi-  cits lasting more than 1 month may damage renal tissue, with  resulting interstitial fibrosis and tubular atrophy.   The onset of symptoms is related to the rate of potassium deple-  tion. Because the body can accommodate slow losses of K*, the  decrease in ECF concentration may be slow enough to allow K*  to shift from the intracellular space. The extracellular to intracel-  lular K* concentration gradient then is restored toward normal,    CHAPTER 3 The Cellular Environment: Fluids and Electrolytes, Acids and Bases    with less severe neuromuscular changes. With acute losses of  K*, changes in neuromuscular excitability are more profound.  Skeletal muscle weakness initially occurs in the larger muscles  of the legs and arms and ultimately affects the diaphragm and  depresses ventilation. Paralysis and respiratory arrest then can  occur. Loss of smooth muscle tone is manifested by orthostatic  hypotension, constipation, intestinal distention, anorexia, nau-  sea, vomiting, and paralytic ileus. Table 3-9 contains a summary  of K* alterations.   EVALUATION AND TREATMENT. The diagnosis of hypokalemia is  based on serum K* levels; however, it is important to exam-  ine the medical history and identify disorders associated with  K* loss or shifts of extracellular K* to the intracellular space.  Treatment involves an estimation of total body K* losses and  correction of acid-base imbalances. Further losses of K* should  be prevented, and the individual should be encouraged to eat  foods rich in Kt. Potassium replacement is instituted cautiously  to prevent hyperkalemia. The maximal rate of oral replacement  is 40 to 80 mEq/day if renal function is normal. A maximal  safe rate of intravenous replacement is 20 mEq/hr for adults.  Because K* is irritating to blood vessels, a maximal concentra-  tion of 40 mEq/100 ml should be used. Serum K* values can be  monitored until normokalemia is achieved.    PATHOPHYSIOLOGY. An elevation of ECF potassium concen-  tration above 5.5 mEq/L constitutes hyperkalemia. Because of  efficient renal excretion, excesses of total body potassium are  relatively rare. Acute increases in serum K* concentration are  handled quickly through an increase in cellular uptake and  renal excretion of body K* excesses.   Excesses of serum K* may be caused by excessive intake, a  shift of potassium from the ICF to the ECE, or decreased renal  excretion.'* If renal function is normal, slow, long-term increases  in Kt intake are usually well tolerated through K* adaptation,  although acute K* loading can exceed renal excretion rates. Use  of stored whole blood, administration of intravenous boluses  of penicillin G, or replacement of K* can precipitate hyperkale-  mia, particularly if renal function is impaired. Dietary excesses  of Kt are uncommon, but accidental ingestion of K* salt substi-  tutes can cause toxicity.   Potassium shifts from the ICF to the ECF occur with a change  in cell membrane permeability (e.g., from cell hypoxia, acidosis,  or insulin deficiency). Burns, massive crush injuries, and exten-  sive surgeries can cause cell trauma and loss of ICF potassium  to the ECF. If renal function is sustained, K* will be excreted.  As cell repair begins, hypokalemia develops if the excreted Kt  is not replaced.   Hypoxia can lead to hyperkalemia by diminishing the effi-  ciency of cell membrane active transport, resulting in the escape  of K* to the ECF. In states of acidosis, hydrogen ions shift into  the cells in exchange for ICF potassium; hyperkalemia and aci-  dosis therefore often occur together. Because insulin promotes  cellular entry of K*, insulin deficits, which occur with conditions  such as diabetic ketoacidosis, are accompanied by hyperkale-  mia. Digitalis overdose may cause hyperkalemia by inhibiting  the Na*-Kt-ATPase pump. This pump normally maintains  intracellular K* concentration and moves sodium and calcium  to the ECF (see Chapter 1).   Decreased renal excretion of potassium is commonly associ-  ated with hyperkalemia. Renal failure that results in oliguria  (urine output <30 ml/hr) is accompanied by elevations of serum  K* concentration. The severity of hyperkalemia is related to the  severity of renal dysfunction, the amount of K* intake, and the  degree of acidosis from the renal failure. In acute renal failure  K* levels rise more rapidly with more serious consequences than  the slower rises associated with chronic renal failure. Hypoaldo-  steronism also can cause decreases in the urinary excretion of  K*. For example, Addison disease results in decreased produc-  tion and secretion of aldosterone and thus contributes to hyper-  kalemia. Drugs that decrease renal potassium excretion (i.e.,  ACE inhibitors, angiotensin receptor blockers, and aldosterone  antagonists) also may contribute to hyperkalemia. Frequently,  however, these drugs are used in combination with diuretics  that cause K* wasting in an attempt to balance renal K* gains  and losses.   CLINICAL MANIFESTATIONS. Symptoms of hyperkalemia vary,  but common characteristics are muscle weakness or paralysis  and dysrhythmias with changes in the electrocardiogram. Dur-  ing mild attacks, increased neuromuscular irritability may be  manifested as tingling of lips and fingers, restlessness, intestinal   Loss Increased renal loss: renal tubular failure, K*-losing diuretics,  hyperaldosteronism, vomiting, diarrhea, use of selected antibiotics    ECG changes (flattened T waves, U waves, ST depression, peaked P wave,    prolonged OT interval)  Weak, irregular pulse rate  Ventricular fibrillation  Cardiac arrest  Lethargy  Fatigue  Confusion  Paresthesias  Decreased tendon reflexes  Nausea and vomiting  Decreased motility  Distention  Decreased bowel sounds  lleus  Inability to concentrate urine  Water loss  Thirst  Kidney damage  Weakness  Flaccid paralysis  Respiratory arrest  Constipation  Bladder dysfunction    cramping, and diarrhea. Severe hyperkalemia causes muscle  weakness, loss of muscle tone, and paralysis. In mild states of  hyperkalemia, the more rapid repolarization is reflected in the  electrocardiogram as narrow and taller T waves with a short-  ened QT interval. Severe hyperkalemia (serum levels 26 mEq/L)  depresses the ST segment, prolongs the PR interval, and wid-  ens the QRS complex (loss of atrial activity) (see Figure 3-8).  Delayed conduction and bradydysrhythmias are common in  hyperkalemia, with alterations in cardiac conduction causing  ventricular fibrillation or cardiac arrest.   As with hypokalemia, changes in the ratio of intracellular  to extracellular K* concentration contribute to the symptoms  of hyperkalemia. If extracellular K* concentration increases  without a significant change in intracellular K* concentra-  tion, the resting membrane potential becomes more positive  (i.e., changes from —90 to —80 millivolts) and the cell membrane  is hypopolarized (the inside of the cell becomes less negative or  partially depolarized [increased excitability] ) (see Figure 3-7, B).  (Electrical properties of cells are discussed in Chapter 1.) With  relatively mild elevations in extracellular K* concentration,  the cell more rapidly repolarizes and becomes more irritable  (peaked T waves). An action potential then is initiated more  rapidly because the distance between the resting membrane   ECG changes (peaked T waves, prolonged PR interval,  absent P wave with widened ORS complex)    potential and the threshold potential has been shortened. With  more severe hyperkalemia, the resting membrane potential  approaches or exceeds the threshold potential (wide QRS merg-  ing with T wave). In this case the cell is not able to repolarize  and therefore does not respond to excitation stimuli. The most  serious consequence is cardiac standstill.   Like the effects of hypokalemia, the neuromuscular effects  of hyperkalemia are related to the rate of increase in the ECF  potassium concentration and the presence of other contribut-  ing factors, such as acidosis and calcium balance. Long-term  increases in ECF potassium concentration result in shifts of Kt  into the cell because the tendency is to maintain a normal ratio  of intracellular/extracellular potassium concentrations. Acute  elevations of extracellular K* concentration affect neuromus-  cular irritability because this ratio is disrupted.   Because calcium influences the threshold potential, changes in  extracellular fluid calcium concentration can augment or over-  ride the effects of hyperkalemia. With hypocalcemia the threshold  potential becomes more negative, enhancing the neuromuscu-  lar effects of hyperkalemia. Hypercalcemia causes the threshold  potential to become less negative, counteracting the effects of  hyperkalemia on resting membrane potential (see Figure 3-7, C).  See Table 3-9 for a summary of potassium alteration.    CHAPTER 3 The Cellular Environment: Fluids and Electrolytes, Acids and Bases    J Intestinal absorption of calcium  J Renal reabsorption of calcium  and J excretion of phosphate  J Calcium resorption from bone    T Intestinal absorption of calcium  T Renal reabsorption of calcium  and T excretion of phosphate    EVALUATION AND TREATMENT. Hyperkalemia should be investi-  gated when there is a history of renal disease, massive trauma,  insulin deficiency, Addison disease, use of potassium salt sub-  stitutes, or metabolic acidosis. The acuity of the onset of symp-  toms may be related to the underlying cause.   Management of hyperkalemia is related to treating the con-  tributing causes and correcting the potassium excess. Normal-  izing the extracellular potassium concentration can be achieved  with a variety of methods; the treatment chosen is related to  the cause and severity of the problem. Calcium gluconate can  be administered to restore normal neuromuscular irritability  when serum potassium levels are dangerously high. Adminis-  tration of glucose, which readily stimulates insulin secretion,  or administration of glucose and insulin for those with diabe-  tes, facilitates cellular entry of potassium. Buffered solutions  correct metabolic acidosis and lower serum potassium level.  Oral or rectal administration of cation exchange resins, which  exchange sodium for potassium in the intestine, can be effec-  tive. Dialysis effectively removes potassium when renal failure  has occurred.    The total body content of calcium is about 1200 g. Most cal-  cium (99%) is located in bone as hydroxyapatite (an inorganic  compound that contributes to bone rigidity), and the remain-  der is in the plasma and body cells. The total fraction of calcium  circulating in the blood is small (9.0 to 10.5 mg/dl) and about  50% is bound to plasma proteins, primarily albumin. About  40% is in the free or ionized form (5.5 to 5.6 mg/dl). Ionized  calcium has the most important physiologic functions.  Calcium (Ca**) is a necessary ion for many fundamental  metabolic processes. It is the major cation associated with the  structure of bones and teeth. It serves as an enzymatic cofac-  tor for blood clotting and is required for hormone secretion  and the function of cell receptors. Plasma membrane stability  and permeability are directly related to calcium ions, as is the  transmission of nerve impulses and the contraction of muscles.  Intracellular calcium is located primarily in the mitochondria.  Phosphate (HPO, ) is found primarily in bone (85%), with  smaller amounts found within the intracellular and extracel-  lular spaces. In the plasma, phosphate exists in phospholipids    and phosphate esters and as inorganic phosphate, which is the  ionized form. The normal serum levels of inorganic phosphate  range from 2.5 to 4.5 mg/dl and may be as high as 6.0 to 7.0 mg/  dl in infants and young children. Intracellular phosphate has  many metabolic forms, including the high-energy structures  creatine phosphate and adenosine triphosphate (ATP). Phos-  phate acts as an intracellular and extracellular anion buffer in  the regulation of acid-base balance; in the form of ATP it pro-  vides energy for muscle contraction.   Calcium and phosphate concentrations are rigidly con-  trolled. They are related by the product of calcium (Ca**) and  phosphate (HPO;), which is a constant (K) [Catt x HPO; =  K]. Thus, if the concentration of one ion increases or decreases,  that of the other increases or decreases.   Calcium and phosphate balance is regulated by three hor-  mones: parathyroid hormone (PTH), vitamin D, and calcito-  nin. Acting together, these substances determine the amount  of dietary calcium and phosphate absorbed from the intestine,  the deposition and absorption of calcium and phosphate from  bone, and the renal reabsorption and excretion of calcium and  phosphate by the kidney.   The parathyroid glands secrete PTH in response to low levels  of serum calcium. (The specific actions of PTH in relation to  calcium and phosphate are described in Chapter 21.) Parathy-  roid hormone controls levels of ionized calcium and phosphate  in the blood and other extracellular fluids. The renal regula-  tion of calcium and phosphate balance requires PTH. PTH  stimulates reabsorption of calcium along the distal tubule of the  nephron and inhibits phosphate reabsorption by the proximal  tubule of the nephron. The net result is an increase in serum  calcium concentration and increased urinary excretion of phos-  phate. Figure 3-9 summarizes hormonal regulation of calcium.   Another compound important to calcium and phosphate  regulation is vitamin D. Vitamin D (cholecalciferol) is a fat-  soluble steroid ingested in food or synthesized in the skin in  the presence of ultraviolet light. Several steps of activation are  required before vitamin D can act on target tissues. The first  step occurs in the liver; final activation is in the kidney. The  renal activation of vitamin D begins when the serum calcium  level decreases and stimulates secretion of PTH. PTH then acts  to increase calcium reabsorption and enhance renal excretion of    phosphate, producing decreased phosphate levels. The combi-  nation of low calcium level and increased PTH secretion causes  the renal activation of vitamin D. The activated vitamin D (vita-  min D;—calcitriol) then circulates as a hormone in the plasma  and acts to increase absorption of calcium and phosphate in the  small intestine, enhance bone calcification, and increase renal  tubular reabsorption of calcium and phosphate. When renal  failure occurs, vitamin D is not activated; serum calcium levels  decrease; and phosphate levels increase.   As calcium levels increase, an opposite adaptation occurs,  leading to suppression of PTH secretion, decreased renal vita-  min D activation, decreased intestinal calcium absorption, and  increased renal phosphate reabsorption. Calcitonin (produced  by C cells of the thyroid gland) primarily decreases calcium lev-  els by inhibiting osteoclastic activity in bone.   The fractions of serum calcium that are freely ionized or  bound to plasma proteins are influenced by pH. In states of  acidosis, levels of ionized calcium increase. When alkalosis  develops, with an increase in pH, the amount of protein-bound  calcium increases and the physiologically active, ionized cal-  cium level decreases. The decreased concentration of ionized  calcium may be great enough to cause symptoms of hypocalce-  mia, such as tetany.    PATHOPHYSIOLOGY. Hypocalcemia occurs when serum total  calcium concentrations are less than 8.5 mg/dl and ionized lev-  els are less than 4.0 mg/dl. In general, deficits in calcium are  related to inadequate intestinal absorption, decreases in levels  of PTH and vitamin D, or deposition of ionized calcium into  bone or soft tissue.   Nutritional deficiencies of calcium can occur in the instance  of inadequate sources of dairy products or green, leafy vegeta-  bles. Excessive amounts of dietary phosphorus also bind with  calcium, so neither mineral is absorbed when such an excess  occurs. Removal of the parathyroid glands (e.g., during total  thyroidectomy) with the resulting loss of PTH also causes  hypocalcemia. Vitamin D deficiency, which can result from  inadequate intake or avoidance of sunlight, causes decreased  intestinal absorption of calcium. Malabsorption of fat, includ-  ing fat-soluble vitamin D, also may contribute to calcium  deficiency. Neoplastic bone metastases tend to inhibit bone  resorption and increase calcium deposition into bone, thereby  decreasing serum calcium levels.   Blood transfusions are also a common cause of hypocalcemia  because the citrate solution used in storing whole blood binds  with calcium and makes it unavailable to the tissues. Pancre-  atitis causes release of lipases into soft tissue spaces, so the free  fatty acids that are formed bind calcium, causing a decrease in  the concentration of ionized calcium. Metabolic or respiratory  alkalosis causes symptoms of hypocalcemia because the change  in pH enhances protein binding of ionized calcium. Hypoal-  buminemia lowers total serum calcium levels by decreasing the  amount of bound calcium in the plasma.   CLINICAL MANIFESTATIONS. The clinical manifestations of hypo-  calcemia are caused primarily by an increase in neuromuscu-  lar excitability. Calcium deficits cause partial depolarization    of nerves and muscle as the threshold potential becomes more  negative and approaches the resting membrane potential (hypo-  polarization) (see Figure 3-7, C). Therefore, a smaller stimulus  is required for initiating the action potential. The symptoms are  related to neuromuscular irritability and include paresthesias  around the mouth and in the digits, carpopedal spasm (muscle  spasms in the hands and feet), laryngospasm, hyperreflexia, sei-  zures, and dysrhythmias.   Two clinical signs are Chvostek sign and Trousseau sign.  Chvostek sign is elicited by tapping on the facial nerve just below  the temple. A positive sign is a twitch of the nose or lip. Trous-  seau sign is contraction of the hand and fingers when the arterial  blood flow in the arm is occluded for 5 minutes.   Severe symptoms include convulsions and tetany, a con-  tinuous severe muscle spasm that can interfere with breathing  and cause death. The characteristic electrocardiogram (ECG)  change is a prolonged QT interval, indicating prolonged ven-  tricular depolarization and decreased cardiac contractility.  Intestinal cramping and hyperactive bowel sounds also may be  present because hypocalcemia affects the smooth muscles of  the gastrointestinal tract. Table 3-10 contains a summary of the  manifestations of calcium level alterations.   EVALUATION AND TREATMENT. The health history may signify  underlying pathologic conditions that require further evalua-  tion and treatment. Severe symptoms of hypocalcemia require  emergency treatment with intravenous 10% calcium gluconate.  Oral calcium replacement should be initiated, and serum cal-  cium levels should be monitored. Decreasing phosphate intake  facilitates long-term management of hypocalcemia.'“*    PATHOPHYSIOLOGY. Hypercalcemia with total serum calcium  concentrations exceeding 12 mg/dl can be caused by a number  of diseases. The most common among these are hyperparathy-  roidism; bone metastases with calcium resorption from breast,  prostate, or cervical cancer, or hematologic malignancy; sar-  coidosis; and excess vitamin D. Many tumors produce PTH and  elevate the serum calcium levels. Sarcoidosis appears to increase  vitamin D levels. Prolonged immobilization can also lead to  hypercalcemia from enhanced bone resorption and decreased  calcium deposition into bone. Acidosis decreases serum bind-  ing of calcium to albumin, increasing ionized calcium levels.   CLINICAL MANIFESTATIONS. Many symptoms of hypercalcemia  are nonspecific. Because serum calcium levels are increased, a  greater amount of calcium is also contained inside the cells. The  threshold potential becomes more positive (hyperpolarized)  (e.g., moves from —60 to —50 millivolts) and the cell membrane  becomes refractory to depolarization (decreased excitability)  because there is a greater difference between threshold potential  and resting membrane potential (see Figure 3-7, C). Thus many  of the symptoms are related to loss of cell membrane excit-  ability. (Membrane potentials and membrane excitability are  discussed in Chapter 1.) Fatigue, weakness, lethargy, anorexia,  nausea, and constipation are common.   Mental status changes and confusion may occur. Impaired  renal function frequently develops, and kidney stones form  as precipitates of calcium salts. A shortened QT segment and    CHAPTER 3 The Cellular Environment: Fluids and Electrolytes, Acids and Bases   Inadequate intestinal absorption, deposition of ionized calcium into bone or  soft tissue, blood administration, or decreases in PTH and vitamin D levels;  nutritional deficiencies occur with inadequate sources of dairy products or  green, leafy vegetables; alkalosis, elevated calcitonin level   Hyperparathyroidism; bone metastases with calcium resorption from breast,  prostate, renal, and cervical cancer; sarcoidosis; excess vitamin D; many  tumors that produce PTH; calcium-containing antacids   Intestinal malabsorption related to vitamin D deficiency, use of magnesium-  and aluminum-containing antacids, long-term alcohol abuse, and  malabsorption syndromes; respiratory alkalosis; increased renal excretion  of phosphate associated with hyperparathyroidism   Acute or chronic renal failure with significant loss of glomerular filtration;  treatment of metastatic tumors with chemotherapy that releases large  amounts of phosphate into serum; long-term use of laxatives or enemas  containing phosphates; hypoparathyroidism    Hypomagnesemia (<1.5 mEq/L)  Malnutrition, malabsorption syndromes, alcoholism, urinary losses (renal  tubular dysfunction, loop diuretics)    Hypermagnesemia (>3.0 mEq/L)  Usually renal insufficiency or failure; also excessive intake of magnesium-  containing antacids, adrenal insufficiency    depressed widened T waves also may be observed on the ECG,  with bradycardia and varying degrees of heart block.   EVALUATION AND TREATMENT. With elevated serum calcium  levels, often a reciprocal decrease in serum phosphate values  occurs. Specific diagnostic procedures to identify the contribut-  ing pathologic condition are required.   Treatment is related to the severity of symptoms and the  underlying disease. When renal function is normal, oral phos-  phate administration is effective. When acute illness and high  calcium levels are present, treatment options include intra-  venous administration of large amounts of normal saline to  enhance renal excretion of calcium, administration of bisphos-  phonates in the absence of renal failure, and administration of  calcitonin. Corticosteroids and the cytotoxic drug mithramycin  (blocks osteoclastic function) also are used to treat hypercalce-  mia. Ultimately, the underlying pathologic condition must be  treated. (Table 3-10 contains a summary of the manifestations  of alterations in calcium levels.)   PATHOPHYSIOLOGY. Hypophosphatemia is a serum phosphate  level less than 2.5 mg/dl and is usually an indication of phos-  phate deficiency. In some conditions, total body phosphate is    in hands, feet, and facial muscles), intestinal cramping, hyperactive bowel  sounds; osteoporosis and fractures; severe cases show convulsions and tetany;  prolonged OT interval, cardiac arrest    impaired renal function, kidney stones; dysrhythmias, bradycardia, cardiac  arrest; bone pain, osteoporosis, fractures    Conditions related to reduced capacity for oxygen transport by red blood cells    and disturbed energy metabolism; leukocyte and platelet dysfunction; deranged  nerve and muscle function; in severe cases, irritability, confusion, numbness,  coma, convulsions; possibly respiratory failure (because of muscle weakness),  cardiomyopathies, bone resorption (leading to rickets or osteomalacia)    Symptoms primarily related to low serum calcium levels (caused by high    phosphate levels) similar to symptoms of hypocalcemia; when prolonged,  calcification of soft tissues in lungs, kidneys, joints    Lethargy, drowsiness; loss of deep tendon reflexes; nausea and vomiting; muscle    normal but serum concentrations are low. The most common  causes are intestinal malabsorption and increased renal excretion  of phosphate. Inadequate absorption is associated with vitamin  D deficiency, use of magnesium- and aluminum-containing ant-  acids (which bind with phosphorus), long-term alcohol abuse,  and malabsorption syndromes. Respiratory alkalosis can cause  severe hypophosphatemia because of cellular use of phospho-  rus for accelerated glycolysis (ATP) formation. Increased renal  excretion of phosphorus is associated with hyperparathyroidism.   CLINICAL MANIFESTATIONS. The consequences of phosphate  deficiency are not clinically evident until hypophosphatemia is  severe. There is reduced capacity for oxygen transport by red  blood cells and disturbed energy metabolism. Transport and  release of oxygen are associated with 2,3-diphosphoglycerate  (2,3-DPG) and ATP levels. When phosphate is depleted, 2,3-  DPG and ATP levels become low and diminish release of oxy-  gen to the tissues. The oxyhemoglobin curve shifts to the left  (see Chapter 34), and hypoxia can occur with bradycardia and  varying degrees of heart block.   Leukocyte and platelet dysfunctions also are associated  with hypophosphatemia. There is a greater risk of infection  and blood-clotting impairment, with potential for hemor-  rhage. Nerve and muscle function can be affected because of    derangement in energy metabolism. Muscle weakness may  become serious enough to cause respiratory failure, and cardio-  myopathies also can develop. Irritability, confusion, numbness,  coma, and convulsions develop with severe phosphate losses.  In response to low phosphate levels, bone resorption occurs  and may lead to rickets or osteomalacia. (Table 3-10 contains a  summary of the manifestations of phosphate level alterations.)  EVALUATION AND TREATMENT. To correct the condition, the  underlying cause must be identified and treated. The rate and  amount of replacement are determined by the cause and pre-  senting symptoms.!° (Table 3-10 contains a summary of the  manifestations of alterations in phosphate levels.)    PATHOPHYSIOLOGY. Hyperphosphatemia, or an elevated serum  phosphate level of more than 4.5 mg/dl, develops with exogenous  or endogenous addition of phosphorus to the ECF or with sig-  nificant loss of glomerular filtration.'° Because most phosphate is  located in cells, the cell destruction associated with treatment of  metastatic tumors with chemotherapy can release large amounts  of phosphate into the ECF. Long-term use of phosphate-con-  taining enemas or laxatives also may lead to hyperphosphate-  mia. Hypoparathyroidism can cause elevated phosphate levels  by increasing renal tubular reabsorption of phosphate.   High levels of serum phosphate also lower serum calcium  levels, and increased amounts of phosphate and calcium are  deposited in bone and soft tissues. Serum calcium levels may  become low enough to cause symptoms of hypocalcemia,  including tetany.   CLINICAL MANIFESTATIONS. Symptoms of hyperphosphatemia  are related primarily to low serum calcium levels and thus are  comparable to symptoms of hypocalcemia. With prolonged  hyperphosphatemia, calcification of soft tissues occurs in the  lungs, kidneys, and joints.   EVALUATION AND TREATMENT. To correct hyperphosphatemia,  the underlying pathologic condition must be identified and  treated. Aluminum hydroxide may be administered because it  binds phosphate in the gastrointestinal tract and is then elimi-  nated; however, aluminum can be toxic, causing encephalopathy  and osteomalacia. Non-aluminum and non-calcium phosphate  binders (lanthanum carbonate or sevelamer) are being evalu-  ated but cost and toxicity are concerns.” Dialysis is required for  management of renal failure. (Table 3-10 contains a summary of  the manifestations of alterations in phosphate concentration.)    Magnesium (Mg**) is a major intracellular cation, second to  potassium. About 40% to 60% is stored in muscle and bone  with 30% in the cells. A small amount (1%) is in the serum.  Plasma concentration is 1.8 to 2.4 mg/dl with about one third  bound to plasma proteins and the rest in ionized form. Regula-  tion of magnesium metabolism is balanced by the small intes-  tine and kidney. Low serum levels cause renal conservation of  magnesium. Magnesium is a cofactor in intracellular enzymatic  reactions, protein synthesis, nucleic acid stability, and neuro-  muscular excitability. Calcium and magnesium often interact  in reactions at the cellular level.'®    Hypomagnesemia occurs when serum magnesium concen-  tration is less than 1.5 mEq/L and increases in neuromuscular  excitability and tetany are present. Malnutrition, malabsorption  syndromes, alcoholism, renal tubular dysfunction, metabolic  acidosis, and use of loop and thiazide diuretics can cause mag-  nesium losses. Hypomagnesemia is associated with insulin resis-  tance, diabetes mellitus, left ventricular hypertrophy, systemic  inflammation, hypoalbuminemia, and osteoporosis.'? Because  magnesium inhibits potassium channels, loss of magnesium  results in movement of potassium out of the cell, with renal  excretion resulting in hypokalemia. Signs and symptoms of  hypomagnesemia are similar to those of hypocalcemia. Depres-  sion, confusion, irritability, increased reflexes, muscle weakness,  ataxia, nystagmus, tetany, convulsions, and tachydysrhythmias  may be observed.” Treatment is intramuscular or intravenous  administration of magnesium sulfate.   Magnesium supplements have several benefits including  improved myocardial metabolism and cell function; improved  vascular smooth muscle tone and peripheral vascular resistance,  afterload, and cardiac output; reduced cardiac dysrhythmias; and  improved lipid and glucose metabolism. Magnesium also reduces  vulnerability to oxygen-derived free radicals and systemic inflam-  mation, improves human endothelial function, and inhibits  platelet function, including platelet aggregation and adhesion.!””°   Hypermagnesemia, in which magnesium concentration is  greater than 2.5 mEq/L, is rare and usually is caused by renal  failure.2! Magnesium-containing antacids (e.g., Gaviscon,  Gelusil) can potentiate excess magnesium. Excess magnesium  depresses skeletal muscle contraction and nerve function. Signs  and symptoms include nausea and vomiting, muscle weakness,  hypotension, bradycardia, and respiratory depression. Treat-  ment is avoidance of magnesium-containing substances and  removal of magnesium by dialysis. (Table 3-10 contains a sum-  mary of the manifestations of magnesium level alterations.)    Acid-base balance and hydrogen ion concentration must be  regulated within a narrow range for the body to function nor-  mally. Slight changes in amounts of hydrogen can significantly  alter biologic processes in cells and tissues. Hydrogen ion is nec-  essary to maintain membrane integrity and the speed of enzy-  matic reactions. Most pathologic conditions disturb acid-base  balance, and the degree of severity may be more harmful than  the disease process.    The hydrogen ion concentration, [H*], is commonly expressed  as the pH, the negative logarithm of hydrogen ions in solution.  The symbol pH represents the acidity or alkalinity of a solution.  The logarithmic value means that as the pH changes 1 unit (e.g.,  from 7.0 to 6.0), the [H*] changes tenfold (i.e., from 0.0000001  to 0.000001). The relationship is commonly expressed as follows:    CHAPTER 3 _ The Cellular Environment: Fluids and Electrolytes, Acids and Bases    As the [H*] increases, the pH decreases; likewise, as the [H*]  decreases, the pH increases. The greater the [H*], the more  acidic the solution and the lower the pH. The lower the [H*],  the more basic the solution and the higher the pH. In biologic  fluids, a pH of less than 7.4 is defined as acidic and a pH greater  than 7.4 is defined as basic.    Body Fluid pH  Gastric juices 1.0-3.0  Urine 5.0-6.0  Arterial blood 7.38-7.42  Venous blood 7.32-7.36  Cerebrospinal fluid 7.28-7.32  Pancreatic fluid 7.8-8.0    Body acids are formed as end products of cellular metabo-  lism. The average person generates 50 to 100 mEq/day of acid  from the metabolism of protein, carbohydrates, and fats and  from loss of alkaline fluids in the stools. To maintain a nor-  mal pH, an equal amount of acid therefore must be neutralized  or excreted. The lungs, kidneys, and bone are the major organs  involved in the regulation of acid-base balance. The systems  are interrelated and work together to regulate short- or long-  term changes in acid-base status. Body acids exist in two forms:  volatile (respiratory acids—eliminated as carbon dioxide [CO}]  gas) and nonvolatile (metabolic acids—eliminated by the kid-  ney or metabolized by the liver). The volatile acid is carbonic  acid (H,CO3), which is formed from the hydration of carbon  dioxide:    Carbonic acid is a weak acid, and in the presence of car-  bonic anhydrase, it readily dissociates into carbon dioxide  and water. CO, is produced as an end product of oxidative  metabolism. The more oxygen that is consumed, the more  CO, is produced. The carbon dioxide is then eliminated by  pulmonary ventilation. Sulfuric, phosphoric, and other meta-  bolic acids (lactic acid, pyruvic acid, and keto acids [such as    acetoacetic acid and f-hydroxybutyric acid, associated with  diabetes mellitus]) are nonvolatile strong acids produced  from the incomplete metabolism of proteins, carbohydrates,  and fats. (Strong acids are those that readily give up their  hydrogen; weak acids do not.) Nonvolatile acids are elimi-  nated by the renal tubules in conjunction with the regulation  of the concentration of HCO; . Thus the lungs and kidneys,  with the help of body buffer systems, are the prime regulators  of acid-base balance.   Buffering occurs in response to changes in acid-base status.  Buffers can absorb excessive H* (acid) or OH” (base) to mini-  mize fluctuations in pH. The buffer systems are located in both  the ICF and ECF compartments, and they function at different  rates. Buffer systems exist as buffer pairs, consisting of a weak  acid and its conjugate base (Table 3-11). The most impor-  tant plasma buffer systems are bicarbonate—carbonic acid and  hemoglobin. Phosphate and protein are the most important  intracellular buffers. Ammonia and phosphate are important  renal buffers.   An important factor for effective buffering is a function  known as the pK value, which represents the pH at which a buf-  fer pair is half dissociated. Buffer pairs can associate and dis-  sociate (see Table 3-11).   The pK provides a rate constant for the chemical reaction.  A buffer system is most effective when the pK for the buffer is  close to the pH of the fluid in which the buffer is acting. There  is an equal concentration of acid and its conjugate base when  pK equals pH. For the bicarbonate—carbonic acid buffer system,  the pK is 6.1. This value is not as high as the pK for other buf-  fer systems (see Table 3-11), but this buffer system is still very  effective because carbon dioxide is rapidly removed from the  blood by the lungs.   The pK value is also a term in the equation used to deter-  mine pH. The relationships among pH, pK, and the ratio of  bicarbonate to carbonic acid can be expressed as follows by the  Henderson-Hasselbalch equation:   Ht + HCO; 2 H,0 oF CO,  HHb = H+ + Hb-  HPO-y + Ht = H2POq  HPr = Ht + Pr-    H+, Hydrogen ion; HCO}, bicarbonate; HyCO3, carbonic acid; Hb-, hemoglobin; H2POZ, monobasic phosphate; HPOz, dibasic phosphate; HPr,    The pH then can be determined when specific values are  included in the equation:  S [HCO3 ]  pH= pK + lOSTHECOsl   The bicarbonate—carbonic acid buffer pair operates in both the  lung and the kidney. The greater the carbon dioxide partial pres-  sure (Pco,), the more carbonic acid is formed. The relationship  that exists between carbonic acid concentration ({H,CO3]) and  carbon dioxide partial pressure (Pco,) can be expressed as follows:    The 0.03 represents the solubility coefficient for carbon  dioxide in water. The Pco, of arterial blood (Paco;) is normally  about 40 mmHg. Therefore the amount of H,CO; is equal to  about 1.2 mmol/L (0.03 x 40). As the amount of carbon diox-  ide increases or decreases, the amount of H,CO; changes in the  same direction.   The relationship between the levels of bicarbonate and car-  bonic acid is usually expressed as a ratio. When the pH is 7.40,  this ratio is 20:1 (bicarbonate/carbonic acid) (Figure 3-10). The  ratio is defined by the amount of bicarbonate and carbon diox-  ide (carbonic acid) in the arterial blood. Bicarbonate concen-  tration ({HCO; ]) is normally about 24 mEq/L. Therefore, the  20:1 ratio can be developed as follows:   FIGURE 3-10 Ratio of Carbonic Acid and Bicarbonate Concentration in  Maintaining pH within Normal Limits. An increase in HCO; or decrease in HCO3  concentration causes acidosis. A decrease in HyCO3 or increase in HCO; concentra-    The values for [HCO; |] and Paco, ([H,CO3]) can increase  or decrease proportionately, but the 20:1 ratio is maintained.   The lungs can decrease the amount of carbonic acid by exhal-  ing CO, and leaving water. The kidneys can reabsorb bicarbon-  ate or regenerate new bicarbonate from CO, and water. The  renal mechanism does not act as rapidly as the lungs, but the  two systems are very effective together because acid concentra-  tion can be rapidly adjusted by the lungs and bicarbonate is eas-  ily reabsorbed or regenerated by the kidneys. The pH equation  can be symbolically expressed as follows:    Changes in either the numerator or the denominator will  change the pH. For example, if the amount of bicarbonate is  decreased, the pH also decreases, causing a state of acidosis. The  pH can be returned to a normal range if the value of the denom-  inator or the amount of carbonic acid also decreases. When a  disease process causes an alteration in the bicarbonate/carbonic  acid ratio, the kidneys or lungs (i-e., the organ not responsible for  causing the alteration) respond to restore the ratio and maintain    20:1  cs 13:1  20:1  7.38  HCO;} 24 mEq/L  16 mEq/L  18 mEq/L  40 mmH 40 mmH  Pco, F :    (respiratory  buffering response)  FIGURE 3-11 Compensated Maintenance of [HCO  ]/Pco, (H,CO;) Ratio  in Metabolic Acidosis.    CHAPTER 3 The Cellular Environment: Fluids and Electrolytes, Acids and Bases    a normal pH. Renal and respiratory adjustments to primary  changes in pH are known as compensation. With compensation,  a 20:1 ratio may be achieved, but the actual values for HCO; and  H,CO concentrations are not normal. The respiratory system  compensates for changes in pH by increasing or decreasing ven-  tilation, a rapid response occurring within minutes to hours. The  renal system compensates by producing more acidic or more  alkaline urine, which may take hours to days. Correction occurs  when the values for both components of the buffer pair ratio  (bicarbonate and carbonic acid) return to normal (Figure 3-11).    Both intracellular and extracellular proteins have negative  charges and can serve as buffers for H*, but because most    proteins are inside cells, they are primarily an intracellular buf-  fer system. Hemoglobin (Hb) is an excellent intracellular blood  buffer because of its ability to bind with H* (forming HHb) and  carbon dioxide (forming HHbCO,). Hemoglobin bound to Ht  becomes a weak acid. Less saturated hemoglobin (venous blood)  is a better buffer than hemoglobin saturated with oxygen (arte-  rial blood). The pH control system is illustrated in Figure 3-12.   The respiratory system regulates acid-base balance by control-  ling the rate of ventilation when there is metabolic acidosis or  alkalosis. Central chemoreceptors sense increases or decreases  in pH and Paco, (see Figure 32-11). When acidemia exists,  the respiratory rate increases (eliminating CO, and reducing    FIGURE 3-12 Integration of pH Control Mechanisms. CO, is produced in tissue cells and diffuses to plasma, where  it is transported as dissolved COz, or it combines with water to form carbonic acid (H2CO3), or it combines with protein from  which hydrogen has been released. Most of the CO, diffuses into the red blood cells and combines with water to form HCO3.  The HCO; dissociates to form hydrogen ion (H+) and bicarbonate (HCO; ). Hydrogen ion combines with hemoglobin that has  released its oxygen to form HHb, which buffers the hydrogen ion and makes venous blood slightly more acidic than arterial  blood. The increase in H* concentration coupled with elevated CO, levels results in HHbCO3 and an increase in the respiratory    carbonic acid concentration) (see Figure 3-12). When alkale-  mia occurs, the respiratory rate decreases (retaining CO, and  increasing carbonic acid concentration).   The distal tubule of the kidney regulates acid-base balance by  secreting hydrogen into the urine and regenerating bicarbonate  with a maximum urine acidity of about pH 4.4 to 4.7. Buffers in  the tubular fluid combine with hydrogen ions, allowing more  H* to be secreted before the limiting pH value is reached. Diba-  sic phosphate (HPO) and ammonia (NH3) are two important  renal buffers. Dibasic phosphate is filtered at the glomerulus.  About 75% is reabsorbed, and the remainder is available for  buffering H*. Secreted H* combines with HPO, to form mono-  basic phosphate (H2POj7). The remaining negative charge on  the molecule makes it lipid insoluble, preventing it from dif-  fusing back across the tubular cells and into the blood. Thus  the H,PO; containing the secreted H* is excreted in the urine  (Figure 3-13).   Ammonia (NH3) is an important renal buffer; it is not ion-  ized (does not carry a charge), and therefore it is lipid soluble  and can cross the tubular cell membrane. The presence of NH;  in the tubular cells creates a concentration gradient, and it dif-  fuses into the renal tubular fluid, where it combines with hydro-  gen to form ammonium ion (NHf), which is eliminated in the  urine (see Figure 3-13). NHj is lipid insoluble and does not  readily diffuse back into the tubular cells. The renal buffering of  hydrogen ions requires the use of CO, and H,O to form H;CO3.  The enzyme carbonic anhydrase catalyzes the formation of Ht +  HCO; . The hydrogen is secreted from the tubular cell and buff-  ered in the lumen by phosphate and ammonia. The bicarbonate  is reabsorbed. The end effect is the addition of new bicarbonate,  which contributes to the alkalinity of the plasma, because the  hydrogen ion is excreted from the body (see Figure 3-13).    A cellular ion exchange mechanism is also an important buff-  ering system. The best example is the shift of potassium in  exchange for hydrogen during states of acidosis or alkalosis.  During acidosis, potassium tends to leave the intracellular space  in exchange for hydrogen. The reverse occurs during alkalosis.  Although the ionic shifts facilitate buffering, the changes in  intracellular or extracellular potassium concentrations may  have serious consequences (e.g., hyperkalemia or hypokalemia).    Pathophysiologic changes in the concentration of hydrogen ion  or base in the blood lead to acid-base imbalances. Acidemia is  a state in which the pH of arterial blood is less than 7.35. A sys-  temic increase in hydrogen ion concentration or loss of base is  termed acidosis. Alkalemia is a state in which the pH of arterial  blood is greater than 7.45. A systemic decrease in hydrogen ion  concentration or an excess of base is termed alkalosis. Acid-  base imbalances may have a metabolic or respiratory etiology  or may be of mixed etiology. Acid-base imbalances are assessed  using a measurement of arterial blood gases that includes the  reporting of pH, Paco, and HCO; concentration. The medical  history is important to determining the cause of the disorder.  Figure 3-14 summarizes the relationships among pH, Pacoy,    FIGURE 3-13 Renal excretion of acid. 1, Conservation of Filtered Bicarbon-  ate. Filtered bicarbonate combines with secreted hydrogen ion in the presence of  carbon anhydrase (CA) to form carbonic acid (H,CO3), which then dissociates to  water (H,0) and carbon dioxide (CO,); both diffuse into the epithelial cell. The CO,  and H,0 combine to form H,CO3 in the presence of CA, and the resulting bicarbon-  ate ion (HCO;) is reabsorbed into the capillary. 2, Formation of Titratable Acid.  Hydrogen ion is secreted and combines with dibasic phosphate (HPO;) to form  monobasic phosphate (H,PO;). The secreted hydrogen ion is formed from the  dissociation of H,CO3, and the remaining HCO; is reabsorbed into the capillary.  3, Formation of Ammonium. Ammonia (NH3) is produced from glutamine in the  epithelial cell and diffuses to the tubular lumen, where it combines with H* to form  ammonium ion (NHz). Once NH has been formed, it cannot return to the epithelial  cell (diffusional trapping), and the bicarbonate remaining in the epithelial cell is  reabsorbed into the capillary.   PATHOPHYSIOLOGY. In metabolic acidosis, the concentration  of non-carbonic acids increases or bicarbonate (base) is lost  from the extracellular fluid or cannot be regenerated by the kid-  ney (Table 3-12). This can occur quickly, as in lactic acidosis  from poor perfusion or hypoxemia, or more slowly, as in renal  failure (failure to excrete acid) or diabetic ketoacidosis (excess  production of keto acids from lack of insulin) (see Chapter 23).   The buffer systems compensate for the excess acid and  attempt to maintain the arterial pH within a normal range.    CHAPTER 3 _ The Cellular Environment: Fluids and Electrolytes, Acids and Bases    FIGURE 3-14 Primary and Compensatory Acid-base Changes. A systematic approach can be used to interpret the  cause of an acid-base imbalance. 1, Is the pH low or high? 2, If the pH is low there is acidemia; if the pH is high there is alkale-  mia. 3, If the pH is low (acidemia), is the cause respiratory (high Paco.) or metabolic (low HCO; )? If the pH is high (alkalemia),  is the cause respiratory (low Paco,) or metabolic (high HCO; )? 4, Is there compensation for the primary acid-base disorder?    be =24 mEq/L if there is renal compensation for a primary respiratory acidosis; (b) Paco, wil    there is respiratory compensation of a primary metabolic acidosis; (c) HCO3 will <24 mEq/L if there is renal compensation for  primary respiratory alkalosis; (d) Paco, will be >40 mmHg if there is respiratory compensation for primary metabolic alkalosis.  NOTE: Examine the pH first. Then examine the changes in HCO; and Pacoy. HCO3 will be elevated when there is primary  metabolic alkalosis or renal compensation for primary respiratory acidosis. HCO3 will be decreased when there is primary  metabolic acidosis or renal compensation for primary respiratory alkalosis. Paco, will be elevated when there is primary respi-  ratory acidosis or respiratory compensation for primary metabolic alkalosis. Paco, will be decreased when there is primary    Increased H* load  Ketoacidosis (e.g., diabetes mel-  litus, starvation)  Lactic acidosis (e.g., shock)  Ingestions (e.g., ammonium chlo-    Hydrogen ions will move to the intracellular space, and potas-  sium will move to the extracellular space to maintain an ionic  balance (see p. 115). Buffering by bicarbonate lowers the serum  value of hydrogen ions and increases the pH. The respiratory  system compensates for a metabolic acidosis as the reduced  pH stimulates hyperventilation, lowering the Paco, and the  amount of H,CO; circulating in the blood. The kidneys excrete  the excess acid as NHj and titratable acid (H.PO;). When aci-  dosis is severe, buffers become depleted and cannot compensate  for the increasing H* load and the pH continues to decrease.  The ratio of bicarbonate to carbonic acid decreases to less than  20:1 (Figure 3-15). In states of metabolic acidosis, potassium is  redistributed from the intracellular to the extracellular space,  and is reabsorbed at the apical membrane of the renal collecting  tubule (see p. 114). There is also an increase in the levels of ion-  ized calcium because acidosis decreases the amount of calcium  bound to albumin (see p. 114).   The evaluation of the anion gap can be helpful when used  cautiously to distinguish different types of metabolic acidosis.”    HCO} decreases  because of excess  presence of ketones,  chloride, or organic  acid ions    FIGURE 3-15 Metabolic Acidosis with Compensation and Correction.  See text for abbreviations. (From Patton KT, Thibodeau GA: Anatomy & physiology,  ed 8, St Louis, 2013, Mosby.)    Normally, the concentrations of cations and anions in the plasma  are equivalent. Some anions, such as protein, sulfates, phos-  phates, and organic acids, however, are not measured in the com-  mon laboratory evaluations of the blood. Therefore the normal  anion gap represents these unmeasured negative ions (sulfate,  phosphate, lactate, keto acids, albumin). A convenient measure  of the anion gap is the difference between the sum of Nat and Kt  and the sum of HCO; and CI, or about 10 to 12 mEq/L:    Anion gap = [Na* (140) + K* (4.0)]—  [HCO3 (24) +Cl~ (110)] = 10-12 mEd/L    In metabolic acidosis a normal anion gap is characteristic of  conditions related to bicarbonate loss with retention of chloride    to maintain an ionic balance. This is called hyperchloremic  metabolic acidosis and it occurs with renal failure, diabetic  ketoacidosis, or prolonged diarrhea with bicarbonate loss. An  elevated anion gap is characteristic of acidosis associated with  accumulation of anions other than chloride (see Table 3-12).   CLINICAL MANIFESTATIONS. Metabolic acidosis is manifested  by changes in the neurologic, respiratory, gastrointestinal, and  cardiovascular systems. Headache and lethargy are early symp-  toms, which progress to coma with severe acidosis. Deep, rapid  respirations (Kussmaul respirations) are indicative of respira-  tory compensation. Anorexia, nausea, vomiting, diarrhea, and  abdominal discomfort are common. Severe acidosis can com-  promise ventricular contraction and produce life-threatening  dysrhythmias.   EVALUATION AND TREATMENT. The diagnosis of metabolic acido-  sis is established from the health history, clinical symptoms, and  laboratory findings. Arterial blood pH is below 7.35, and bicar-  bonate concentration is less than 24 mEq/L. The anion gap can  isolate the specific cause. The oxyhemoglobin curve is shifted  to the right (see Figure 34-18), reducing hemoglobin affinity  for oxygen.   The underlying condition must be diagnosed to establish  effective treatment of a buffering solution. During severe aci-  dosis (pH $7.1), administration is required to elevate the pH to  a safe level, particularly if there is renal failure. Accompanying  sodium and water deficits must also be corrected.”    PATHOPHYSIOLOGY. Metabolic alkalosis occurs when bicar-  bonate concentration is increased, usually caused by excessive  loss of metabolic acids. Conditions that can result in metabolic  alkalosis are prolonged vomiting, gastric suctioning, excessive  bicarbonate intake, hyperaldosteronism with hypokalemia, and  diuretic therapy.”   Respiratory compensation for metabolic alkalosis occurs  when the elevated pH inhibits the respiratory center. The rate  and depth of ventilation are decreased, causing retention of  carbon dioxide. The ratio of HCO; concentration to H,CO;  concentration is reduced toward normal. Respiratory compen-  sation is not very efficient, however, and chronic or severe met-  abolic alkalosis requires therapeutic intervention (Figure 3-16).   Hypochloremic metabolic alkalosis occurs when acid loss  is caused by vomiting or gastric suctioning with depletion of  ECF sodium, chloride, and potassium. Renal compensation  is not very effective because the volume depletion and loss of  electrolytes stimulate a paradoxical response by the kidneys.  The kidneys increase bicarbonate reabsorption to maintain  an anionic balance because the ECF chloride concentra-  tion is decreased. The resulting excretion of H* and reab-  sorption of bicarbonate prevent correction of the alkalosis  (Figure 3-17). The kidneys also increase sodium reabsorp-  tion. When potassium concentration is depleted, hydrogen  ion moves to the intracellular space and is excreted to main-  tain an electrochemical balance.   With alkalemia, hydrogen ions are redistributed from the  intracellular to the extracellular space and potassium moves  to the intracellular space to preserve electroneutrality. With    CHAPTER 3 The Cellular Environment: Fluids and Electrolytes, Acids and Bases    hyperaldosteronism, the excess aldosterone causes sodium  retention and loss of hydrogen and potassium ions. Mild vol-  ume expansion ensues, and bicarbonate is retained along with  the sodium, thereby causing alkalosis. Diuretics, such as thia-  zides, ethacrynic acid, and furosemide, produce mild alkalosis  by enhancing sodium, potassium, and chloride excretion more  than bicarbonate excretion.   CLINICAL MANIFESTATIONS. Because of the many causes of meta-  bolic alkalosis, the symptoms vary. Some common symptoms,  such as weakness, muscle cramps, and hyperactive reflexes, are  related to volume depletion and electrolyte losses. Because alka-  losis increases binding of Ca** to plasma proteins (albumin),  ionized calcium concentration decreases, causing excitable cells  to become hypopolarized, which initiates an action potential    Dyrctapotic balance  before onset of H,CO3: Carbonic acid  alkalosis HCO; : Bicarbonate ion  (Nat+- HCO3)  (K*- HCO3)  (Mg**- HCO3)  (Ca**- HCO3)  @   by Cl~ ions  FIGURE 3-16 Metabolic Alkalosis with Compensation and Correction.  See text for abbreviations. (From Patton KT, Thibodeau GA: Anatomy & physiology,  ed 8, St Louis, 2013, Mosby.)    more easily. Paresthesias (especially numbness/tingling of the  fingertips and perioral area), tetany, and seizures may develop  (see Hypocalcemia, p. 120).   Respirations are slow and shallow to increase carbon dioxide  retention. Confusion and convulsions occur with severe alka-  losis. Atrial tachycardia is a potential problem. The oxyhemo-  globin curve is shifted to the left (see Figure 34-18), decreasing  the dissociation of oxyhemoglobin and increasing the risk of  dysrhythmias.   EVALUATION AND TREATMENT. The health history provides sig-  nificant clues to the diagnosis of metabolic alkalosis. The arterial  pH is greater than 7.45, and bicarbonate levels exceed 26 mEq/L.  With respiratory compensation, the Paco, rises above 40 mmHg.  With hypochloremic metabolic alkalosis, serum chloride values  are below normal. Serum potassium levels are usually depleted  because hydrogen is released from the cells in exchange for potas-  sium to help regulate the pH level. The potassium is then secreted  from renal distal tubule cells into the urine.   With hypochloremic alkalosis or contraction alkalosis with  volume depletion, a sodium chloride solution is required for  correction. The renal stimulus to increase ECF volume by retain-  ing Na* is diminished, and HCO; can be excreted as NaHCO,  in the urine. The administration of potassium corrects alkalosis  caused by hyperaldosteronism or hypokalemia. The potassium  causes hydrogen to move back into the ECF and decreases loss  of hydrogen from the distal tubule.    PATHOPHYSIOLOGY. Respiratory disorders of acid-base balance  are caused by increases or decreases of alveolar ventilation in  relation to the metabolic production of carbon dioxide. Respi-  ratory acidosis occurs when there is alveolar hypoventila-  tion. Carbon dioxide is retained, increasing [H*] (as H,CO3)  and producing acidosis. Carbon dioxide excess in the blood is  called hypercapnia. The common causes include depression  of the respiratory center (brainstem trauma, oversedation),  paralysis of the respiratory muscles, disorders of the chest wall  (kyphoscoliosis, pickwickian syndrome, flail chest), and disor-  ders of the lung parenchyma (pneumonitis, pulmonary edema,  emphysema, asthma, bronchitis).   Respiratory acidosis may be acute or chronic. Airway  obstruction is the most common cause of acute respiratory aci-  dosis. Acute compensation for respiratory acidosis is not effec-  tive because the renal buffer mechanism takes time to function.  Further, the protein buffers provide marginal compensation,  and HCO; is not a good buffer for CO. Acute uncompensated  respiratory acidosis is characterized by decreased arterial pH,  elevated Paco,, and normal or slightly increased bicarbonate  concentration.   Chronic respiratory acidosis is commonly associated with  chronic obstructive pulmonary disease and deformities of the  chest wall or neuromuscular disorders. Renal compensation  is effective and is established over several days. The acidosis  produced from CO, retention stimulates the kidney to secrete  hydrogen ions and regenerate bicarbonate. Serum bicarbonate  and Paco, levels are elevated, and pH is restored toward normal  (Figure 3-18).    CLINICAL MANIFESTATIONS. The symptoms of respiratory acido-  sis are related to acuity of onset and severity of Paco, reten-  tion. Initial symptoms include headache, restlessness, blurred  vision, and apprehension followed by lethargy, muscle twitch-  ing, tremors, convulsions, and coma. Neurologic symptoms  are caused by a decrease in the pH of cerebrospinal fluid and  vasodilation because CO) readily crosses the blood-brain bar-  rier. The respiratory rate is rapid at first and gradually becomes  depressed because over time, the respiratory center adapts to  increasing levels of CO,. Cyanosis does not occur unless there is  an accompanying hypoxemia, and the skin may instead be pink  from vasodilation caused by the elevated CO, level.   EVALUATION AND TREATMENT. The primary diagnostic indica-  tors are an arterial pH less than 7.35 and hypercapnia. Acute  respiratory acidosis must be distinguished from chronic acido-  sis; the health history and clinical laboratory data are therefore  helpful.   In many cases, restoration of adequate alveolar ventilation  removes excess CQO. If alveolar ventilation cannot be main-  tained spontaneously because of drug overdose or neuromus-  cular disorders, mechanical ventilation is required. When the  hypercapnea is caused by alterations in gas diffusion at the  alveolar-capillary membrane, ventilation may not be effective.  The values of arterial pH, Pco, Po,, and HCO; must be care-  fully monitored. Rapid reduction of Paco, can cause respira-  tory alkalosis with seizures and death.   The underlying diseases are treated to achieve maximal  ventilation. In the presence of hypoxemia and hypercapnia,    oxygen can function as a respiratory depressant when the  respiratory center is no longer stimulated by the lower pH  and elevated Paco, value. Therefore, oxygen should be given  cautiously.   PATHOPHYSIOLOGY. Respiratory alkalosis occurs when there  is alveolar hyperventilation and decreased concentration of  plasma carbon dioxide (termed hypocapnia). Stimulation of  ventilation is precipitated by hypoxemia (i.e., high altitudes);  hypermetabolic states such as fever, anemia, and thyrotoxico-  sis; early salicylate intoxication; or anxiety or panic disorder.  Improper use of mechanical ventilators can cause iatrogenic  respiratory alkalosis. Secondary respiratory alkalosis may  develop from hyperventilation stimulated by metabolic acido-  sis, causing a mixed acid-base disorder.   The onset of acute respiratory alkalosis occurs within  minutes of hyperventilation. Cellular buffers provide imme-  diate compensation (i.e., protein and shifts of H* from ICF  to ECF). The Ht shifts are not very effective, however, if the  Paco, level is significantly decreased. When chronic respi-  ratory alkalosis is present, renal compensation restores pH  toward normal by decreasing H* excretion and bicarbonate  absorption (Figure 3-19).   CLINICAL MANIFESTATIONS. Respiratory alkalosis, like metabolic  alkalosis, is irritating to the central and peripheral nervous  systems. Symptoms include dizziness, confusion, tingling of  extremities (paresthesias), convulsions, and coma. Carpopedal    CHAPTER 3 The Cellular Environment: Fluids and Electrolytes, Acids and Bases    See text for abbreviations. (From Patton KT, Thibodeau GA: Anatomy & physiology,  ed 8, St Louis, 2013, Mosby.)    spasm and other symptoms of hypocalcemia are similar to those  of metabolic alkalosis (see p. 128). Deep and rapid respirations  (tachypnea) are primary symptoms of the disorders that cause  respiratory alkalosis.   EVALUATION AND TREATMENT. The underlying disturbance must  be identified. The arterial pH is greater than 7.45, and the Paco,  is less than 38 mmHg. In acute states, bicarbonate levels are  normal. With chronic respiratory alkalosis, a compensatory    0.5  HCO; ions are replaced  by CI7 ions  FIGURE 3-19 Respiratory Alkalosis with Compensation and Correction.  See text for abbreviations. (From Patton KT, Thibodeau GA: Anatomy & physiology,  ed 8, St Louis, 2013, Mosby.)    decrease in the bicarbonate level occurs and the pH is closer to  normal.   Treating the underlying disturbance is the most effective  treatment. Hypoxemia must be corrected and hypermetabolic  states reversed. Symptoms from hysterical hyperventilation can  be corrected by rebreathing from a paper bag, which increases  the concentration of inspired carbon dioxide and reverses the  respiratory alkalosis.    Body fluids are distributed among functional compartments  and are classified as ICF or ECE.    . The sum of all fluids is the TBW, which varies with age and    . Movement across the capillary wall is called net filtration and    Edema is a problem of fluid distribution that results in accu-  mulation of fluid within the interstitial spaces.    to an increase in forces favoring fluid filtration from the cap-  illaries into the tissues.    . Edema may be localized or generalized and usually is associ-    ated with swelling and puffiness, tighter-fitting clothes and  shoes, limited movement of the affected area, and, in severe  cases, weight gain.    Sodium balance and water balance are intimately related;  chloride levels are generally proportional to changes in  sodium levels.    . Water balance is regulated by the sensation of thirst and by    the level of antidiuretic hormone, which is initiated by an  increase in plasma osmolality or a decrease in circulating  blood volume.    Alterations in water balance may be classified as isotonic,  hypertonic, or hypotonic.    ECF is elevated above normal, usually because of an increased  concentration of ECF sodium or a deficit of ECF water.    by an acute increase in sodium level or a loss of water.    lack of access to water, pure water losses, hyperventilation,  arid climates, or increased renal clearance.    . Hyperchloremia is caused by an excess of sodium or a defi-    . Water excess is rare but can be caused by compulsive water    drinking, decreased urine formation, or the syndrome of  inappropriate secretion of ADH.   Hyponatremia (serum sodium concentration <135 mEq/L)  usually causes movement of water into cells.  Hypochloremia is usually the result of hyponatremia or  elevated bicarbonate concentrations.    Potassium is the predominant ICF ion; it functions to regu-  late ICF osmolality, maintain the resting membrane poten-  tial, and deposit glycogen in liver and skeletal muscle cells.   (serum potassium concentration <3.5  mEq/L) indicates loss of total body potassium, although  ECF hypokalemia can develop without losses of total body  potassium and plasma K* levels may be normal or elevated  when total body potassium is depleted.    increased ICF-to-ECF potassium concentration, loss of  potassium from body stores, increased aldosterone secre-  tion (e.g., caused by hypernatremia), and increased renal  excretion.    caused by increased potassium intake, a shift from ICF to  ECF potassium, or decreased renal excretion.    . Calcium is a necessary ion in the structure of bones and    teeth, in blood clotting, in hormone secretion and the func-  tion of cell receptors, and in membrane stability.    . Phosphate acts as a buffer in acid-base regulation and pro-   Hypocalcemia (serum calcium concentration <8.5 mg/dl)  is related to inadequate intestinal absorption, deposition of  ionized calcium into bone or soft tissue, blood administra-  tion, or decreased PTH and vitamin D levels.  Hypercalcemia (serum calcium concentration >12 mg/dl)  can be caused by a number of diseases, including hyper-  parathyroidism, bone metastases, sarcoidosis, and excess  vitamin D.    CHAPTER 3 The Cellular Environment: Fluids and Electrolytes, Acids and Bases    8. The lungs and kidneys act to compensate for changes in pH    Hypophosphatemia is usually caused by intestinal malab-  sorption and increased renal excretion of phosphate.  Hyperphosphatemia develops with acute or chronic renal  failure with significant loss of glomerular filtration.  Magnesium is a major intracellular cation and is principally  regulated by PTH.   Magnesium functions in enzymatic reactions and often  interacts with calcium at the cellular level.  Hypomagnesemia (serum magnesium concentrations  <1.5 mEq/L) may be caused by malabsorption syndromes.  Hypermagnesemia (serum magnesium concentrations  >2.5 mEq/L) is rare and is usually caused by renal failure.    Hydrogen ions, which maintain membrane integrity and the  speed of enzymatic reactions, must be concentrated within a  narrow range if the body is to function normally.    . Different body fluids have different pH values.  . The renal and respiratory systems, together with the body’s buf-    . Buffers are substances that can absorb excessive acid or base    . Buffer pairs can associate and dissociate; the pK value is the    by increasing or decreasing ventilation and by producing  more acidic or more alkaline urine.   Correction is a process different from compensation; cor-  rection occurs when the values for both components of the  buffer pair are returned to normal.   Acid-base imbalances are caused by changes in the concen-  tration of H* in the blood; an increase causes acidosis, and  a decrease causes alkalosis.   An abnormal increase or decrease in bicarbonate concen-  tration causes metabolic acidosis or metabolic alkalosis;  changes in the rate of alveolar ventilation produce respira-  tory acidosis or respiratory alkalosis.   Metabolic acidosis is caused by an increase in the concen-  trations of non-carbonic acids or by loss of bicarbonate  from the extracellular fluid.   Metabolic alkalosis occurs with an increase in bicarbon-  ate concentration usually caused by loss of metabolic acids  from conditions such as vomiting, gastrointestinal suction-  ing, excessive bicarbonate intake, hyperaldosteronism, and  diuretic therapy.   Respiratory acidosis occurs with a decrease of alveolar  ventilation and an increase in levels of carbon dioxide, or  hypercapnia.   Respiratory alkalosis occurs with alveolar hyperventilation  and excessive reduction of carbon dioxide concentration,  or hypocapnia.   Hypotonic hyponatremia, 113  Inadequate intake of dietary sodium, 113  Increased capillary hydrostatic pressure, 106  Increased capillary permeability, 107  Intercalated cell, 114   Interstitial hydrostatic pressure, 105  Interstitial oncotic pressure, 105  Intracellular fluid (ICF), 103   Lymphatic obstruction, 107  Lymphedema, 107  Magnesium (Mg**), 122  Metabolic acidosis, 126  Metabolic alkalosis, 128  Natriuretic peptide, 109  Net filtration, 105  Nonvolatile, 123   Normal anion gap, 128  Osmoreceptor, 109  Parathyroid hormone (PTH), 119  pH, 122   Starling hypothesis, 105  Total body water (TBW), 104  Vitamin D, 119    Maughan RJ: Hydration, morbidity, and mortality in vulnerable popula-  tions, Nutr Rev 70(Suppl 2):S152-S155, 2012.   Verkman AS: Aquaporins in clinical medicine, Annu Rev Med 63:303—  316, 2012.   Paskett ED et al: Cancer-related lymphedema risk factors, diagnosis,  treatment, and impact: a review, J Clin Oncol 30(30):3726-3733, 2012.  Nishikimi T, Kuwahara K, Nakao K: Current biochemistry, molecu-   lar biology, and clinical relevance of natriuretic peptides, J Cardiol  57(2):131-140, 2011.   Sam R, Feizi I: Understanding hypernatremia, Am J Nephrol 36(1):97—  104, 2012.   Agrawal V et al: Hyponatremia and hypernatremia: disorders of water  balance, J Assoc Physicians India 56:956—964, 2008.   Waikar SS, Mount DB, Curhan GC: Mortality after hospitalization with  mild, moderate, and severe hyponatremia, Am J Med 122(9):857-865,  2009.   Egom EE, Chirico D, Clark AL: A review of thiazide-induced hyponatrae-  mia, Clin Med 11(5):448-451, 2011.   Lindner G, Schwarz C: An update on the current management of hypo-  natremia, Minerva Med 103(4):279-291, 2012.   Youn JH, McDonough AA: Recent advances in understanding integrative  control of potassium homeostasis, Annu Rev Physiol 71:381—401, 2009.  Aronson PS, Giebisch G: Effects of pH on potassium: new explanations  for old observations, J Am Soc Nephrol 22(11):1981-1989, 2011.   Unwin RJ, Luft FC, Shirley DG: Pathophysiology and management of  hypokalemia: a clinical perspective, Nat Rev Nephrol 7(2):75-84, 2011.   Pepin J, Shields C: Advances in the diagnosis and management of hypoka-  lemic and hyperkalemie emergencies, Emerg Med Pract 14(2):1-17, 2012.  Fong J, Khan A: Hypocalcemia: updates in diagnosis and management  for primary care, Can Fam Physician 58(2):158-162, 2012.   Cirillo M, Bilancio G, Marcarelli F: Ageing and changes in phosphate  transport: clinical implications, J Nephrol 23(Suppl 16):S152-S157, 2010.  Hutchison AJ, Smith CP, Brenchley PE: Pharmacology, efficacy and  safety of oral phosphate binders, Nat Rev Nephrol 7(10):578-589, 2011.  Romani AM: Cellular magnesium homeostasis, Arch Biochem Biophys  512(1):1-23, 2011.   Rosanoff A, Weaver CM, Rude RK: Suboptimal magnesium status in the  United States: are the health consequences underestimated? Nutr Rev  70(3):153-164, 2012.    based on the centrality of stimulated collecting duct ion transport, Am J  Kidney Dis 58(4):626-636, 2011.    CHAPTER 3 _ The Cellular Environment: Fluids and Electrolytes, Acids and Bases    As part of your Pageburst Digital Book, you can access the following Integrated Resources:   Chromosome Aberrations and Associated Diseases, 143  Elements of Formal Genetics, 151    In the nineteenth century, microscopic studies of cells led scien-  tists to suspect that the nucleus of the cell contained the impor-  tant mechanisms ofinheritance. Scientists found that chromatin,  the substance that gives the nucleus a granular appear-  ance, is observable in nondividing cells (also see Chapter 6).  Just before the cell divides, the chromatin condenses to form  microscopically observable, threadlike structures called chro-  mosomes. (Cell division and chromosomes are discussed in  Chapter 1.) With the rediscovery of Gregor Mendel’s important  breeding experiments at the turn of the twentieth century, it  soon became apparent that the chromosomes contained genes,  the basic units of inheritance. Genes are composed of sequences  of deoxyribonucleic acid (DNA), a primary constituent of  chromosomes; the other primary constituent consists of pro-  teins, such as histones, that cause the DNA to coil into a highly  compressed structure (Figure 1-2, Chapter 1). By serving as the    Transmission of Genetic Diseases, 151  Autosomal Dominant Inheritance, 152  Autosomal Recessive Inheritance, 154  X-Linked Inheritance, 156  Evaluation of Pedigrees, 159   Linkage Analysis and Gene Identification, 159  Classic Pedigree Analysis, 159  Assigning Loci to Specific Chromosomes, 160    blueprints of proteins in the body, genes ultimately influence all  aspects of body structure and function. Humans have approxi-  mately 20,000 to 25,000 genes. An error in one of these genes  can lead to a recognizable genetic disease. The composition of  genes at a given locus is known as the genotype. The outward  appearance of an individual, which is the result of both geno-  type and environment, is the phenotype (p. 151).   To date, more than 21,000 human genetic traits have been  identified and cataloged.! About one third of pediatric inpa-  tients are children with genetic diseases.” In addition, many  common diseases that affect primarily adults, such as hyper-  tension, coronary heart disease, diabetes, and cancer, are now  known to have important genetic components. (These diseases  are also affected by environmental factors. The interaction  between genetic and environmental components is discussed in  Chapter 5.)    The genetic causes of several thousand different diseases have now been iden-   sible to perform genetic tests to help determine whether an individual carries   More than 2700 diseases can now be diagnosed by testing for specific mutations   developed to help predict susceptibility for a number of common, genetically   complex diseases.  Genetic testing can be applied in a variety of contexts, including:   1. Carrier screening. Genetic tests can identify heterozygous carriers for many  recessive diseases, such as cystic fibrosis, sickle cell disease, and Tay-Sachs  disease. It is becoming increasingly common for couples to undergo carrier  screening to help make reproductive decisions, especially in populations in  which specific diseases are relatively common (e.g., Tay-Sachs disease in the  Ashkenazi Jewish population, 6-thalassemia in Mediterranean populations).  As a result, the prevalence of some of these diseases has declined dramati-  cally in the past two decades.   . Prenatal diagnosis. Several forms of prenatal genetic diagnosis are available,  including:  a. Amniocentesis. This procedure, which is usually carried out at about 16   weeks’ gestation, involves the withdrawal of a small amount of amniotic  fluid from the uterus. This fluid contains fetal cells, which can be cultured  and karyotyped to detect chromosome abnormalities. In addition, genetic  testing for single-gene disorders can be undertaken using DNA from these  cells. Neural tube defects (spina bifida and anencephaly) can be detected  as an elevation of a-fetoprotein level in amniotic fluid. Because there is a  risk of fetal loss as a result of this procedure (estimated to be less than  1/200 above the background loss rate), it is usually recommended for  women whose age is greater than 30 to 35 years or for couples who have  a known increased risk of a specific genetic disease.   . Chorionic villus sampling (CVS). Carried out at 10 to 12 weeks’ gestation,  CVS is performed by extracting a small amount of villous tissue directly  from the chorion. This procedure does not require in vitro culturing of cells  for chromosome analysis because sufficient numbers are directly available  in the extracted tissue. Chorionic villus sampling involves a slightly higher  fetal loss rate (approximately 1%) than that of amniocentesis.   . Preimplantation genetic diagnosis (PGD). This relatively new procedure i  carried out on early embryos (typically 8 to 12 cells) created by in vitro fe  tilization. One or two cells are removed from the embryo (which causes no  damage), and these cells can be tested for chromosome abnormalities or    single-gene disorders. If a genetic disorder is found in the cell, the embryo  is not implanted in the mother’s uterus.   . Analysis of fetal DNA in maternal circulation. By approximately 6 to 8  weeks’ gestation, fetal cells can be found in the mother’s bloodstream  and these cells (or cell-free fetal DNA) can be tested for some disease-  causing mutations. This approach is still largely experimental, but it  is developing rapidly and has the advantages of early diagnosis and  minimal risk to the mother and fetus. In addition to these diagnostic  procedures, prenatal screening is now routinely carried out by measur-  ing various analytes in maternal serum samples to assess the risk of  conditions, such as trisomy 21, 13, and 18, and neural tube defects.  Newborn screening also is commonly performed for a variety of genetic  conditions such as PKU and galactosemia. A positive screening result is  an indication for a subsequent diagnostic test (e.g., amniocentesis for  a positive prenatal screening result or DNA sequencing for a positive  newborn screening result).   3. Presymptomatic diagnosis. Many hereditary diseases, such as familial breast  or colon cancer, can be tested genetically before an individual develops the  disease. For some of these conditions, measures can be taken either to diag-  nose the disease early (e.g., colonoscopy) or to minimize the risk of develop-  ing the disease.   . Testing for drug efficacy or sensitivity. A number of genes are now known to  be associated with sensitivity to specific therapeutic drugs, and people are  sometimes tested for variants in these genes to help guide drug treatment.  For example, abacavir, an antiviral drug used in treating human immunodefi-  ciency virus (HIV) infection, can cause severe adverse reactions in those who  have a specific HLA-B variant (HLA-B*57:01), and the FDA now recommends  testing for this variant before administering abacavir. For other drugs, such as  warfarin, genetic testing for variants in specific genes (CYP2C9 and VKORC1)  may help to guide drug dosage.   Although genetic testing can be very informative, it also has limitations.  Genetic testing usually reveals the presence or absence of a disease-causing  mutation, but many genetic diseases have incomplete penetrance. For example,  a woman who carries a mutation in the BRCA7 or BRCA2 genes has a lifetime  breast cancer risk of approximately 70% to 80% (but not 100%). In addition, the  absence of a disease-causing mutation does not guarantee that the disease in  question will not occur (e.g., a woman who does not have a BRCA7 or BRCAZ  mutation still has nearly the same risk of developing breast cancer as do other  women because these genes account for only a few percent of all cases of  breast cancer). Individuals and families should be advised of these and other  limitations of genetic testing.    Data from Harper JC, Sengupta SB: Hum Genet 131(2):175-186, 2012; South ST et al: Clin Obstet Gynecol 51(1):62-73, 2008.    Great progress is being made in the diagnosis of genetic dis-  eases and the understanding of genetic mechanisms underlying  them. Genetic testing is used increasingly to guide drug choice  and dosage, and gene therapy—the direct alteration of genes in  cells—is now carried out effectively for some diseases. Genet-  ics is now one of the most rapidly advancing fields of medicine  (Boxes 4-1 and 4-2).    Composition and Structure  Genes are composed of DNA and the most important constit-  uent of DNA is four types of nitrogenous bases (Figure 4-1).    The four bases, adenine, cytosine, guanine, and thymine, are  commonly represented by their first letters: A, C, G, and T,  respectively.   In the early 1950s, James Watson and Francis Crick deter-  mined the physical structure of DNA. They proposed the now-  famous double-helix model, in which DNA can be envisioned  as a twisted ladder with chemical bonds as its rungs (see Fig-  ure 4-1). Projecting from each side of the ladder, at regular  intervals, are the nitrogenous bases. The base projecting from  one side is bound to the base projecting from the other by a  weak hydrogen bond. Therefore, the nitrogenous bases form  the rungs of the ladder; adenine pairs with thymine, and gua-  nine pairs with cytosine. Each DNA subunit—consisting of one  deoxyribose molecule, one phosphate group, and one base (see  Figure 4-1)—is called a nucleotide.    Gene therapy, in which the harmful effects of a disease-causing mutation are  corrected by altering the person's DNA, has been a long-sought goal in human  genetics. Hundreds of individuals are currently enrolled in dozens of clinical  trials of gene therapy. Many technical challenges have arisen, but gene ther-  apy is now beginning to yield positive therapeutic results.   In somatic cell gene therapy, the DNA of a specific set of an individual's  somatic cells is altered (it is also possible to perform germline therapy, which  affects all cells, including reproductive cells; however, for technical and ethi-  cal reasons, this is not being pursued in humans). Most commonly, somatic  cell therapy is used for conditions in which a mutation has caused the absence  of a gene product in a cell (e.g., adenosine deaminase in T cells, which leads  to immunodeficiency). A “vector” is used to carry a normal copy of the mutated  gene into the individual's cells. These vectors are usually viruses, such as ret-  roviruses or adenoviruses, which have been genetically modified so that they  contain the normal human gene and cannot make copies of themselves (oth  wise they could cause a viral infection). Once inside the individual's cells,  normal human gene begins to encode the missing gene product.   This approach faces a number of technical hurdles, including immune  responses against the vector and difficulties in producing sufficient quantities  of the desired gene product. In one case, an immune response against an  adenoviral vector proved fatal, and several cases of leukemia have resulted  from the insertion of a modified retrovirus near an oncogene. Nevertheless,  gene therapy has now been successful in treating a number of inherited con-  ditions, including two forms of severe combined immunodeficiency (SCID),  B-thalassemia, and X-linked adrenoleukodystrophy. In some cases, symptoms  have been completely reversed through gene therapy. In addition to the treat-  ment of hereditary diseases, gene therapy is being used to alter tumor cells in  the treatment of various types of cancer. It is hoped that further research will  lead to safe, efficient, and cost-effective treatment of many human diseases  through gene therapy.    To serve as the basis of genetic inheritance DNA must be able  to provide a code for all the body’s proteins. Proteins are com-  posed of one or more polypeptides (intermediate protein com-  pounds), which are in turn composed of sequences of amino  acids (organic acids containing NH,). The body contains 20  different types of amino acids, and the amino acid sequences  that make up polypeptides must in some way be specified by  the DNA molecule.   Because there are 20 possible amino acids and only four  bases, each single nucleotide cannot specify an amino acid. Sim-  ilarly, the amino acids cannot be specified by couplets of bases  (e.g., adenine-guanine, thymine-guanine, guanine-cytosine)  because there are only 4 x 4, or 16, possible couplets. If series  of 3 bases are translated into amino acids, however, there are  4x 4x 4, or 64, possible combinations—more than enough to  specify each different amino acid. By manufacturing synthetic  nucleotide sequences and allowing them to direct the formation  of amino acids in the laboratory, it was proved that amino acids  were specified by these triplets of bases, or codons.   Of the 64 possible codons, three signal the end of a gene and  are known as termination, or nonsense, codons. The remain-  ing 61 all specify amino acids, which means that most amino  acids can be specified by more than one codon. The genetic    code is thus said to be redundant, although each codon can  specify only one amino acid.   Another significant feature of the genetic code is that it is  nearly universal: with the exception of ciliated protozoa and  some plants, all organisms use precisely the same DNA codes  to specify proteins. An important general exception to this rule  occurs in mitochondria—cytoplasmic organelles that are the  sites of cellular respiration (see Chapter 1). The mitochondria  have their own extranuclear DNA. Several codons of mito-  chondrial DNA encode different amino acids than do the same  nuclear DNA codons.   In addition to having the ability to specify amino acid sequences,  DNA must be able to replicate itself accurately during cell divi-  sion if it is to serve as the basic genetic material. DNA replication  consists of the breaking of the weak hydrogen bonds between  the bases, leaving a single strand with each base unpaired. The  consistent pairing of adenine with thymine and of guanine with  cytosine, known as complementary base pairing, is the key to  accurate replication. The principle of complementary base pair-  ing dictates that the unpaired base will attract a free nucleotide  only if the nucleotide has the proper complementary base. Thus  a portion of a single strand with a sequence of bases labeled  ATTGCT will bond with a series of free nucleotides with the  bases TAACGA. When replication is complete, a new double-  stranded molecule identical to the original is formed (Figure  4-2, A). The single strand is said to be a template (guide), or  molecule on which a complementary molecule is built, and is  the basis for synthesizing the new double strand.   Several different proteins are involved in DNA replication.  One protein unwinds the double helix, one holds the strands  apart, and others perform different distinct functions. The most  important of these proteins is the enzyme known as DNA poly-  merase. This enzyme travels along the single DNA strand, add-  ing the correct nucleotides to the free end of the new strand (see  Figure 4-2, B). Besides adding the new nucleotides, the DNA  polymerase performs a proofreading procedure. After the new  nucleotide has been added to the chain, the DNA polymerase  checks to make sure that its base is actually complementary to  the template base. If it is not, the incorrect nucleotide is excised  and replaced with a correct one. This procedure, one of the  mechanisms of DNA repair, substantially enhances the accu-  racy of DNA replication.    A mutation is any inherited alteration of genetic material.  Microscopically observable alterations of chromosome num-  ber or structure are examples of mutations. Some mutations  are much too small to be observed under a microscope. An  example is the base pair substitution, in which one base pair  is replaced by another. This mutation is sometimes called mis-  sense mutation because the “sense” of the codon produced  after transcription of the mutant gene is altered (Figure 4-3).  This substitution sometimes results in a change in amino acid  sequence, but because of the redundancy of the genetic code, it  may have no consequence. Profound consequences can result    FIGURE 4-1 Structure of DNA. A, Double helix. Shown with the phospho-  diester backbone as a ribbon on top and a space-filling model on the bottom.  The bases protrude into the interior of the helix where they hold it together by  base pairing. The backbone forms two grooves, the larger major groove and  the smaller minor groove. B, Base pairing holds strands together. The H-bonds  that form between A and T and between G and C are shown with dashed lines.  These produce AT and GC base pairs that hold the two strands together. This  always pairs a purine with a pyrimidine, keeping the diameter of the double  .34 nm helix constant. A, Adenine; C, cytosine; G, guanine; 7, thymine. (From Raven PH  et al: Biology, ed 8, New York, 2008, McGraw-Hill.)    A  Template Strand New Strand Template Strand New Strand  HO 3 5  Sugar-    FIGURE 4-2 Replication and Action of DNA. A, Replication of DNA. B, Action of DNA polymerase. DNA polymerases  add nucleotides to the 3’ end of a growing chain. The nucleotide added depends on the base that is in the template strand.  Each new base must be complementary to the base in the template strand. With the addition of each new nucleotide, tri-  phosphate, two of its phosphates are cleaved off as pyrophosphate. A, Adenine; 7, thymine; G, guanine; C, cytosine. (A from  Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby; B adapted from Raven PH et al: Biology, ed 8,  New York, 2008, McGraw-Hill.)    FIGURE 4-3 Base Pair Substitution. Missense mutations (A) produce a single amino acid change, whereas nonsense  mutations (B) produce a stop codon in the mRNA. Stop codons terminate translation of the polypeptide. (From Jorde LB et al:    when an amino acid sequence is altered by a base pair substitu-  tion. (Many of the serious genetic diseases discussed later are  the result of base pair substitutions.)   A second major type of mutation is the frameshift muta-  tion. This alteration involves the insertion or deletion of one  or more base pairs to the DNA molecule. As Figure 4-4 shows,  these mutations can change the entire “reading frame” of the  DNA sequence because codons consist of groups of three base  pairs. A frameshift mutation thus can greatly alter the resulting  amino acid sequence.   A large number of agents are known to increase the frequency  of mutations. These agents are known collectively as mutagens.  Radiation, such as that produced by x-rays and nuclear fallout,  is an important mutagen and is known to cause cell damage (see  Chapter 12). Radiation can fragment the DNA molecule and it  can cause chemical reactions that can alter a DNA base. A vari-  ety of chemicals also can induce mutations, often because they  are chemically similar to DNA bases. Other chemicals mimic  the effects of ionizing radiation, and still others interfere with  the process of base pairing. Hundreds of chemicals are now  known to be mutagenic in humans or laboratory animals, such  as nitrogen mustard, vinyl chloride, alkylating agents, form-  aldehyde, and sodium nitrite. Some of these chemicals, how-  ever, are much more potent mutagens than others. Nitrogen  mustard, for example, is extremely mutagenic, whereas sodium  nitrate is a weak mutagen.   Measurement of the mutation rate in humans is difficult, in  part because mutations are very rare events. Current estimates    FIGURE 4-4 Frameshift Mutations. Frameshift mutations result from the  addition or deletion of a number of bases that is not a multiple of 3. This mutation  alters all of the codons downstream from the site of insertion or deletion. (From  Jorde LB et al: Medical genetics, ed 4, St Louis, 2010, Mosby.)    and bind to specific sites on DNA. They read and interpret the genetic blueprint of the DNA thereby controlling transcription  or the flow of genetic information from DNA to mRNA. Transcription factors are essential for gene expression; for example,  proteins that function as receptors, enzymes, or biomarkers. Environmental stimuli: for example, hormones involve signaling  cascades that can involve transcription factors. Transcription factors can alter gene expression to promote pathophysiology.    are that the mutation rate in humans is about 10~ to 1077 per  gene per generation. This rate appears to vary from one gene  to another, with greater mutation rates for larger genes. At the  nucleotide level, the human mutation rate is approximately  10-8 per nucleotide per generation. Certain DNA sequences  have particularly high mutation rates and are known as muta-  tional hot spots. In particular, sequences consisting of a cyto-  sine base followed by a guanine base (CG) are highly susceptible  to mutation and are known to account for a disproportionately  large percentage of disease-causing mutations.”   Whereas DNA is formed and replicated in the cell nucleus, pro-  tein synthesis takes place in the cytoplasm. The transport of the  DNA code from nucleus to cytoplasm and the subsequent pro-  tein formation involve two basic processes: transcription and  translation. Both of these processes are mediated by ribonu-  cleic acid (RNA), a type of nucleic acid that is chemically very  similar to DNA. RNA differs from DNA in that uracil rather  than thymine is one of the four nitrogenous bases. The other  bases of RNA, as in DNA, are adenine, cytosine, and guanine.  Uracil is structurally very similar to thymine, so it also can pair  with adenine. Whereas DNA usually occurs as a double strand,  RNA usually occurs as a single strand.   Transcription is the process by which RNA is synthesized from  a DNA template. The result is the formation of messenger RNA  (mRNA) from the base sequence specified by the DNA mol-  ecule. Transcription of a gene begins when an enzyme called  RNA polymerase binds to a promoter site on the DNA. A pro-  moter site is a sequence of DNA that specifies the beginning of a  gene. In addition to RNA polymerase, proteins called transcrip-  tion factors bind to DNA sequences called transcription factor  binding sites near genes to regulate the timing of transcrip-  tion, as well as the specific tissues in which genes are actively  transcribed (e.g., clotting factor VII primarily in hepatocytes)  (Figure 4-5). Transcription factors can either activate or repress  the expression of genes. In addition, transcription is sometimes  up-regulated by the binding of nearby DNA sequences called  enhancers. The RNA polymerase pulls a portion of the DNA  strands apart from one another, allowing unattached DNA  bases to be exposed. One of the DNA strands then provides the  template for the sequence of mRNA nucleotides.   The sequence of bases in the mRNA is thus complementary  to that of the template strand, and with the exception of the  presence of uracil instead of thymine, the mRNA sequence is  identical to that of the other DNA strand. Transcription con-  tinues until a DNA sequence called a termination sequence is    Cx Cytosine  G&D Adenine  GG Guanine  CUT Uracil  (TX Thymine  FIGURE 4-6 General Scheme of RNA Transcription. See text for explanation.  (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    reached. Then the RNA polymerase detaches from the DNA,  and the transcribed mRNA is freed to move out of the nucleus  and into the cytoplasm. Figure 4-6 summarizes the process of  transcription.   After the mRNA first has been transcribed from the DNA  template, it reflects exactly the base sequence of the DNA. In  eukaryotes an important step takes place before this RNA leaves  the nucleus. Many of the RNA sequences are removed and the  remaining sequences are spliced together to form the func-  tional mRNA that will migrate to the cytoplasm. The excised  sequences are called introns, and the sequences that are left  to code for proteins are called exons. The functions of most  introns remain poorly understood.    Translation is the process by which RNA directs the synthesis  of a polypeptide (Figure 4-7). However, mRNA cannot code    directly for amino acids. Instead, it interacts with transfer RNA  (tRNA), a cloverleaf-shaped strand of about 80 nucleotides.  The tRNA molecule has a site for the attachment of an amino  acid. At the opposite side of the cloverleaf is a sequence of three  nucleotides called the anticodon. The anticodon undergoes  complementary base pairing with an appropriate codon in the  mRNA. The mRNA thus specifies the sequence of amino acids  by acting through the tRNA. As each codon is processed, an  amino acid is translated by the interaction of mRNA and tRNA,  which is aided by cytoplasmic structures called ribosomes.  Bonds are formed between adjacent amino acids to make a  growing polypeptide. When the ribosome arrives at a termina-  tion signal on the mRNA sequence, translation and polypeptide  formation cease. The mRNA, ribosome, and polypeptide sepa-  rate from one another and the polypeptide is released into the  cytoplasm to perform its required function.    Human cells can be categorized into two types: gametes (sperm  and egg cells) and somatic cells, which include all cells other  than gametes. Each somatic cell has 46 chromosomes in its  nucleus. These are diploid cells, meaning that the chromosomes  occur in pairs. Thus each cell actually contains 23 pairs of chro-  mosomes. One member of each pair comes from an individual’s  mother, and one comes from the father. New somatic cells are  formed through mitosis and cytokinesis, through which the cell  nucleus and cytoplasm are replicated. (The division process  that creates new copies of somatic cells is described in Chapter  1.) Gametes are haploid cells: they have only one member of  each chromosome pair, giving them a total of 23 chromosomes.  The process by which these haploid cells are formed from dip-  loid cells is called meiosis (Figure 4-8).   In 22 of the 23 chromosome pairs, the two members of each  pair are virtually identical in microscopic appearance and DNA  sequence and are thus said to be homologous to one another.  These 22 chromosome pairs are homologous in both males  and females and are termed autosomes. The remaining pair of  chromosomes, the sex chromosomes, consists of two homolo-  gous X chromosomes in females and a nonhomologous pair, X  and Y, in males.   Figure 4-9, A, illustrates a metaphase spread, which is a pho-  tograph of the chromosomes as they appear in the nucleus of a  somatic cell during metaphase. (Chromosomes are easiest to  visualize during this stage of mitosis.) A karyotype is an ordered  display of chromosomes. In Figure 4-9, B, the chromosomes  are arranged according to size, with the homologous chromo-  somes paired. The 22 autosomes are numbered according to  length, with chromosome 1 as the longest and chromosome 22  as the shortest. Some natural variation in relative chromosome  length can be expected from person to person, however, so it  is not always possible to distinguish each chromosome by its  length. Therefore, the position of the centromere is also used to  classify the chromosomes (Figure 4-10).   The chromosomes in Figure 4-9, A, were stained with a  substance that binds preferentially to certain areas of chro-  mosomes. The resulting distinctive chromosome bands are    FIGURE 4-7 Protein Synthesis. Protein synthesis begins with transcription, a process in which an mRNA molecule forms  along one gene sequence of a DNA molecule within the cell's nucleus (1-3). As it is formed, the mRNA molecule separates  from the DNA molecule (4), is edited (5), and leaves the nucleus through the large nuclear pores (6). Outside the nucleus, ribo-  some subunits attach to the beginning of the mRNA molecule and begin the process of trans/ation (7). In translation, transfer  RNA (tRNA) molecules bring specific amino acids—encoded by each mRNA codon—into place at the ribosome site (8). As the  amino acids are brought into the proper sequence, they are joined together by peptide bonds (9) to form long strands called  polypeptides (10). Several polypeptide chains may be needed to make a complete protein molecule. A, Adenine; C, cytosine;  G, guanine; U, uracil. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.    evident in various patterns in the different chromosomes so  that each chromosome can be distinguished easily. One of the  most commonly used stains is Giemsa stain. By using banding  techniques, chromosomes can be unambiguously numbered,  and individual variation in chromosome composition can be  studied. Missing or duplicated portions of chromosomes, which  often result in serious diseases, also can be readily identified.    Chromosome abnormalities are the leading known cause of  mental retardation and miscarriage. A major chromosome    aberration occurs in more than half of conceptions. Most of  these fetuses do not survive to term; in fact, about 50% of all  recovered first-trimester spontaneous abortuses have major  chromosomal aberrations.* About 1 in 150 live births has a  major diagnosable chromosome abnormality.”   Cells that have a multiple of the normal number of chromo-  somes are said to be euploid cells (Greek eu = good or true).  Because normal gametes are haploid and most normal somatic  cells are diploid, they are both euploid forms. When a euploid    FIGURE 4-8 Stages of Meiosis. From these stages, haploid gametes are formed from a diploid stem cell. For brevity,  prophase II and telophase II are not shown. Note the relationship between meiosis and spermatogenesis and oogenesis. (From    Jorde LB et al: Medical genetics, ed 4, St Louis, 2010, Mosby.)    cell has more than the diploid number of chromosomes, it is  said to be a polyploid cell. Several types of body tissues, includ-  ing some liver, bronchial, and epithelial tissues, are normally  polyploid. A zygote having three copies of each chromosome,  rather than the usual two, has a form of polyploidy called trip-  loidy. Tetraploidy, a condition in which euploid cells have 92  chromosomes, also has been observed. Nearly all triploid and  tetraploid conceptions are spontaneously aborted or stillborn,  and the small proportion that survive to term die shortly after  birth. Triploidy and tetraploidy are relatively common condi-  tions at conception, accounting for approximately 10% of all  known miscarriages.*   Aneuploid cells are defined as those that do not contain a  multiple of 23 chromosomes. An aneuploid cell contain-  ing three copies of one chromosome is said to be trisomic  (a condition termed trisomy). Monosomy, the presence of  only one copy of a given chromosome in a diploid cell, is the  other common form of aneuploidy. Among the autosomes,  monosomy of any chromosome is lethal, but newborns with  trisomy of chromosomes 13, 18, or 21 can survive. This differ-  ence illustrates an important principle: loss of chromosome  material has more serious consequences than duplication of  chromosome material.    FIGURE 4-9 Karyotype of Chromosomes. A, Human karyotype. B, Homologous chromosomes and sister chromatids.  (A courtesy of the Clinical Cytogenetics Section, Laboratory of Pathology, National Cancer Institute, National Institutes of  Health, Bethesda, MD. B from Raven PH et al: Biology, ed 8, New York, 2008, McGraw-Hill.)    FIGURE 4-10 Structure of Chromosomes. A, Human chromosomes 2, 5, and 13. Each is replicated and consists of two  chromatids. Chromosome 2 is a metacentric chromosome because the centromere is close to middle; chromosome 5 is sub-  metacentric because the centromere is set off from the middle; chromosome 13 is acrocentric because the centromere is at or  very near the end. B, During mitosis, the centromere divides and chromosomes move to opposite poles of the cell. At the time  of centromere division, the chromatids are designated chromosomes.    Aneuploidy of the sex chromosomes is usually less serious  than that of the autosomes. For the Y chromosome, this is true  because very little genetic material is located on this chromo-  some. For the X chromosome, inactivation of extra chromo-  somes largely diminishes their effect. A zygote bearing no X  chromosome, however, will not survive.   Aneuploidy is usually the result of nondisjunction, an error  in which homologous chromosomes or sister chromatids fail  to separate normally during meiosis or mitosis (Figure 4-11).  Nondisjunction during either stage of meiosis produces some  gametes that have two copies of a given chromosome and oth-  ers that have no copies of the chromosome. When such gametes    unite with normal haploid gametes, the resulting zygote is  monosomic or trisomic for that chromosome.   Autosomal Aneuploidy. Trisomy can occur for any  chromosome at conception, but the only forms seen with  an appreciable frequency in live births are trisomies of the  thirteenth, eighteenth, or twenty-first chromosome. Fetuses  with most other chromosomal trisomies do not survive to term.  Trisomy 16, for example, is the most commonly known trisomy  among abortuses, but it is not seen in live births.*   Partial trisomy, in which only an extra portion of a chromo-  some is present in each cell, also can occur. The consequences  of partial trisomies are not as severe as those of complete    FIGURE 4-11 Nondisjunction Causes Aneuploidy When Chromosomes or Sister Chromatids Fail to Divide  Properly. (From Jorde LB et al: Medical genetics, ed 4, St Louis, 2010, Mosby.)    FIGURE 4-12 Down Syndrome. A, The karyotype of Down syndrame consists of 47 chromosomes and shows trisomy 21.  B, A child with Down syndrome. (A from Damjanov |: Pathology for the health professions, ed 4, Philadelphia, 2012, Saunders;  B courtesy Olney A, MacDonald M, University of Nebraska Medical Center, Omaha.)    trisomies. Trisomies also may occur in only some cells of the  body. Individuals thus affected are said to be chromosomal  mosaics, meaning that the body has two or more different cell  lines, each of which has a different karyotype. Mosaics are usu-  ally formed by early mitotic nondisjunction occurring in one  embryonic cell but not in others.   The most well-known example of aneuploidy in an auto-  some is trisomy of the twenty-first chromosome, which causes  Down syndrome (named after J. Langdon Down, who first  described the disease in 1866). Down syndrome was formerly    called mongolism, but this inappropriate term is no longer  used. Down syndrome is seen in 1 in 800 live births.* Indi-  viduals with this disease typically have intelligence quotients  (IQs) between 25 and 70. The facial appearance is distinc-  tive (Figure 4-12), with a low nasal bridge, epicanthal folds,  protruding tongue, and flat, low-set ears. Poor muscle tone  (hypotonia) and short stature are both characteristic. Con-  genital heart defects affect about one third to one half of live-  born children with Down syndrome; a reduced ability to fight  respiratory tract infections and an increased susceptibility    FIGURE 4-13 Down Syndrome Incidence Increases with Maternal Age.  Rate is per 1000 live births related to maternal age.    to leukemia also contribute to reduced survival rate. By 40  years of age, individuals with Down syndrome virtually  always develop symptoms that are nearly identical to those  of Alzheimer disease because one of the genes that can cause  Alzheimer disease is located on chromosome 21. About three  fourths of fetuses known to have Down syndrome are sponta-  neously aborted or stillborn. About 20% of infants born with  Down syndrome die during their first 10 years of life. For  those who survive beyond 10 years, average life expectancy is  now about 60 years.   About 97% of Down syndrome cases are caused by nondis-  junction during the formation of one of the parent’s gametes or  during early embryonic development. The remaining 3% result  from translocations (discussed later). In approximately 90%  to 95% of cases, the nondisjunction occurs in the formation of  the mother’s egg cell. Paternal nondisjunction is responsible for  the remaining cases. Among individuals with Down syndrome,  about 1% are known to be mosaics. Because mosaics have a  large number of normal cells, the effects of the trisomic cells are  attenuated and symptoms are sometimes less severe.   The risk of having a child with Down syndrome increases  greatly with maternal age. As Figure 4-13 demonstrates, women  younger than 30 years have a risk ranging from about 1 in 1000  births to 1 in 2000 births. The risk begins to rise substantially  after 35 years of age, and it reaches 3% to 5% for women older  than 45 years of age. This dramatic increase in risk is a conse-  quence of the age of maternal egg cells, which are held in an  arrested state of prophase I from the time they are formed in the  female embryo until they are shed in ovulation. Thus an egg cell  formed by a 45-year-old woman is itself 45 years old. This long  suspended state may allow for the accumulation of errors lead-  ing to nondisjunction. The risk of Down syndrome, as well as  other trisomies, does not appear to increase with paternal age.°   Sex Chromosome Aneuploidy. Among live births, about 1 in  400 males and 1 in 650 females have a form of sex chromosome    FIGURE 4-14 Turner Syndrome. A sex chromosome is missing, and the  person's chromosomes are 45,X. Characteristic signs are short stature, female  genitalia abnormality, webbed neck, shieldlike chest with underdeveloped breasts  and widely spaced nipples, and imperfectly developed ovaries. (From Patton KT,  Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    aneuploidy.’ Because these conditions are generally less severe  than autosomal aneuploidies, all forms except complete absence  of an X chromosome allow at least some individuals to survive.  One of the most common sex chromosome aneuploidies,  affecting about 1 in 1000 newborn females, is trisomy X. Instead  of two X chromosomes, these females have three X chromo-  somes in each cell. Most of them have no overt physical abnor-  malities, although sterility, menstrual irregularity, or cognitive  deficits are sometimes seen. A very small proportion of females  have four or even five X chromosomes, and their mental func-  tion is more severely compromised. Another sex chromosome  aneuploidy is the presence of a single X chromosome and no  homologous X or Y chromosome, resulting in a total of 45  chromosomes. The karyotype is designated 45,X, and it causes  a set of symptoms known as Turner syndrome (Figure 4-14).  Because they have no Y chromosome, only females are affected  by Turner syndrome. They are usually sterile, however, and have  gonadal streaks rather than ovaries. These streaks of connec-  tive tissue are susceptible to cancer in mosaics who have some  cells containing a Y chromosome. Other features of the disorder  include short stature, webbing of the neck in about half of cases,  widely spaced nipples, coarctation (narrowing) of the aorta (in  15% to 20% of cases), edema of the feet in newborns, and sparse  body hair. Their IQs are typically in the normal range, although  they often have some impairment of spatial and mathematical  reasoning ability. About three fourths of recognized 45,X con-  ceptions inherit their X chromosome from the mother. Thus  most cases are caused by a loss of the paternal X chromosome.    FIGURE 4-15 Klinefelter Syndrome. This young man exhibits many charac-  teristics of Klinefelter syndrome: small testes, some development of the breasts,  sparse body hair, and long limbs. This syndrome results from the presence of two  or more X chromosomes with one Y chromosome (genotypes XXY or XXXY, for  example). (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis,  2013, Mosby.)    The frequency of Turner syndrome is low compared with  that of other sex chromosome aneuploidies: only about 1 in  2500 newborn females is affected.* The 45,X karyotype is more  common among conceptions, however, and about 15% to 20%  of spontaneous abortions with chromosome abnormalities  have this karyotype, making it one of the most common single-  chromosome aberrations. Thus the condition is highly lethal  during gestation: less than 1% of 45,X conceptions survive to  term. Most fetuses that survive to term are mosaics, with com-  binations of 45,X cells and XX, XXX, or XY cells. It is likely that  the presence of some normal cells in mosaic fetuses enhances  fetal survival.   Teenagers with Turner syndrome are typically treated with  estrogen to promote the development of secondary sexual  characteristics. The dose is then continued at a reduced level  to maintain these characteristics and to help avoid osteopo-  rosis. Human growth hormone is sometimes administered to  increase stature.   Individuals with at least two X chromosomes and a Y chro-  mosome in each cell (47,XXY karyotype) have a disorder known  as Klinefelter syndrome (Figure 4-15). Because of the presence  of a Y chromosome, these individuals have a male appearance,  but they are usually sterile, and about half develop female-like  breasts (a condition called gynecomastia). The testes are small,  body hair is sparse, the voice is often somewhat high pitched,  stature is elevated, and a moderate degree of mental impair-  ment may be present. Klinefelter syndrome is found in about    1 in 1000 male births. About two thirds of the cases are caused  by nondisjunction of the X chromosomes in the mother, and  the frequency of the disorder rises with maternal age. Individu-  als with the XXXY and XXXXY karyotypes also are considered  to have Klinefelter syndrome, and the degree of physical and  mental impairment increases with each additional X chromo-  some. Regardless of the number of X chromosomes, however,  these individuals have a male appearance. The presence of a sin-  gle Y chromosome, which causes the undifferentiated gonads to  become testes, always produces a male. Mosaicism is sometimes  seen in Klinefelter syndrome and results in less severe disease;  the most prevalent combination is XXY and XY cells.   About 1 in 1000 males has an extra Y chromosome, pro-  ducing the 47,XYY karyotype. Individuals with this karyotype  tend to be taller than average, and they have a 10- to 15-point  reduction in average IQ. This condition, which causes few seri-  ous physical problems, achieved notoriety when it was found  that its incidence was significantly elevated in prison popula-  tions. This discovery led to the suggestion that this chromo-  some might predispose affected individuals to violent, criminal  behavior. Several dozen studies have addressed this issue, and  they have shown that 47,XYY males are not inclined to commit  violent crimes. However, even after adjusting for the effects of  decreased IQ, some evidence exists for an increased incidence of  behavioral disorders.    In addition to the loss or gain of whole chromosomes, parts of  chromosomes can be lost or duplicated as gametes are formed,  and the arrangement of genes on chromosomes can be altered.  Unlike aneuploidy and polyploidy, these changes sometimes do  not have serious consequences for an individual’s health. Some  of them can even remain entirely unnoticed, especially when  very small pieces of chromosomes are involved. Nevertheless,  abnormalities of chromosome structure also can produce seri-  ous disease in individuals or their offspring.   During meiosis and mitosis, chromosomes usually maintain  their structural integrity very well, but chromosome break-  age occasionally does occur. Mechanisms exist to “heal” these  breaks, and generally the break is repaired perfectly with no  damage resulting to the daughter cell. Sometimes, however, the  breaks remain, or they heal in a fashion that alters the structure  of the chromosome. Chromosome breakage occurs spontane-  ously, but it also can be caused by ionizing radiation, some viral  infections, and certain chemicals.   Deletions. Broken chromosomes and loss of DNA cause  deletions (Figure 4-16, A). Usually a gamete with a deletion  unites with a normal gamete to form a zygote. The zygote thus  has one chromosome with the normal complement of genes and  one with some missing genes. Because a fairly large number of  genes can be lost in a deletion, serious consequences can result  even though one copy of the chromosome is normal. An often  cited example of a disease caused by a chromosomal deletion  is the cri du chat syndrome (Figure 4-17). The term, which  literally means “cry of the cat,” describes the characteristic cry  of the affected child. Other symptoms include low birth weight,  severe mental retardation, microcephaly (smaller than normal    FIGURE 4-16 Chromosomal Mutations. Larger-scale changes in chromo-  somes are also possible. Material can be deleted (A), duplicated (B), and inverted  (C). Translocations occur when one chromosome is broken and becomes part of  another chromosome. This often occurs where both chromosomes are broken and  exchange material, an event called a reciprocal translocation (D). (From Raven PH  et al: Biology, ed 8, New York, 2008, McGraw-Hill.)    head size), heart defects, and the typical facial appearance  shown in Figure 4-17. The disease is caused by a deletion of part  of the short arm of chromosome 5.   Duplications. Duplications of chromosome material are,  like deletions, a form of chromosome aberration (see Figure  4-16, B). Because a deficiency of genetic material is more  harmful than an excess, duplications usually have less serious  consequences than deletions. For example, a deletion of a  region of chromosome 5 causes cri du chat syndrome, but a  duplication of the same region causes less severe disease.   Inversions. An inversion is the occurrence of two breaks  on a chromosome, followed by the reinsertion of the missing  fragment at its original site but in inverted order (see Figure  4-16, C). Thus a chromosome symbolized as ABCDEFG might  become ABEDCFG after an inversion.   Unlike deletions and duplications, inversions result in  no loss or gain of genetic material. They are thus said to be  a “balanced” alteration of chromosome structure, and they  often have no apparent physical effect. Genes are sometimes  influenced by neighboring DNA sequences, however, and this  position effect, a change in a gene’s expression caused by its    FIGURE 4-17 Infant with Cri Du Chat Syndrome. This syndrome is caused by  deletion of part of the short arm of chromosome 5. (From Nussbaum RL, McInnes  RR, Willard HF: Thompson & Thompson genetics in medicine, ed 7, Philadelphia,  2007, Saunders.)   The serious problems caused by inversions usually occur  in the offspring of individuals carrying the inversion. Because  chromosomes must line up in perfect order during prophase I,  a chromosome with an inversion must form a loop to align with  its normal homolog. Crossing over within this loop can result in  duplications or deletions in the chromosomes of daughter cells.  Thus the offspring of individuals who carry inversions often  have chromosome deletions or duplications.   Translocations. The interchanging of genetic material  between nonhomologous chromosomes is called translocation,  and the most clinically significant type of translocation is termeda  Robertsonian translocation. In this translocation the long arms  of two nonhomologous chromosomes fuse at the centromere,  forming a single chromosome (Figure 4-18). Robertsonian  translocations are confined to chromosomes 13, 14, 15, 21, and  22 because the short arms of these chromosomes are very small  and contain no essential genetic material. When a Robertsonian  translocation takes place, the short arms are usually lost during  subsequent cell divisions. Because the carriers of Robertsonian  translocations (about 1 in 500 individuals) lose no important  genetic material, they are normal, although they have only 45  chromosomes in each cell. Their offspring, however, may have  serious deletions or duplications (see Figure 4-18). For example,  a common Robertsonian translocation involves the fusion of  the long arms of chromosomes 21 and 14. An offspring who  inherits a gamete carrying the fused chromosome receives an  extra copy of the long arm of chromosome 21 and thus develops  Down syndrome. Robertsonian translocations are responsible    Possible chromosome combinations in offspring  of normal parent and translocation-carrier parent    b-c a a-b c a-c b  i Q  14 21  Normal Balanced Translocation Monosomy Trisomy Monosomy  translocation Down 21 14 14   FIGURE 4-18 Possible Segregation Patterns for the Gametes Formed by a Carrier of a Robertsonian Transloca-  tion. Alternate segregation (quadrant a alone, or quadrant b with quadrant c) produces either a normal chromosome constitu-  tion or a translocation carrier with a normal phenotype. Adjacent segregation (quadrant a with b, quadrant c alone, quadrant  a with c, or quadrant b alone) produces unbalanced gametes and results in conceptions with translocation Down syndrome,  monosomy 21, trisomy 14, or monosomy 14, respectively. For example, monosomy 14 is produced when the parent who car-  ries the translocation transmits a copy of chromosome 21 but does not transmit a copy of chromosome 14 (as in the lower  right corner). (From Jorde LB et al: Medical genetics, ed 4, St Louis, 2010, Mosby.)    for approximately 3% to 5% of Down syndrome cases. Parents  who carry a Robertsonian translocation involving chromosome  21 have an increased risk for producing multiple offspring with  Down syndrome.   A reciprocal translocation occurs when breaks take place in  two different chromosomes and the material is exchanged (see  Figure 4-16, D). As with Robertsonian translocations, the car-  rier of a reciprocal translocation is usually normal because the  individual has a normal complement of genetic material. How-  ever, the carrier’s gametes can be normal, can carry the translo-  cation, or can have duplications and deletions.   Fragile Sites. For reasons not yet fully understood, a  number of areas on chromosomes develop microscopically  observable breaks and gaps when the cells are cultured in a  folate-deficient medium. Most of these fragile sites have no  apparent relationship to disease. However, one fragile site,  located on the long arm of the X chromosome, is associated  with a disorder of considerable importance, both clinically and  genetically. This disorder is known as fragile X syndrome, and  it is associated with substantial cognitive impairment. With a  relatively high population prevalence (affecting approximately  1 in 4000 males and 1 in 8000 females), fragile X syndrome is  the second most common genetic cause of mental retardation  (after Down syndrome).’   Fragile X syndrome is usually caused by an elevated num-  ber (more than about 200) of repeated DNA sequences in the  first exon of the fragile X gene. These “repeats” consist of CGG  sequences that are duplicated many times. Most individuals  have fewer than 50 of these repeats, but those who have 50 to  200 are more likely to produce affected offspring because DNA  replication becomes unstable.? An increase in the number of  these repeated sequences in successive generations can lead to  expression of fragile X syndrome. More than 20 other genetic  diseases also are caused by this mechanism.'°!!    The mechanisms by which an individual’s set of paired chro-  mosomes produces traits are the principles of genetic inheri-  tance. Mendel's work with garden peas first defined these  principles. Later geneticists have refined Mendel's work to  explain patterns of inheritance for traits and diseases that  appear in families.   Many traits can be attributed primarily to single genes and  are often called mendelian traits (after Gregor Mendel). Each  gene occupies a position along a chromosome known as a  locus. The genes at a particular locus can take different forms  (i.e., they can be composed of different nucleotide sequences)  called alleles. For example, most people have a type of hemo-  globin known as hemoglobin A. A few individuals have an alter-  native form of hemoglobin, termed hemoglobin S, which differs  from hemoglobin A by a single amino acid substitution in the  6-globin component of the molecule. The §-globin locus thus  has two different alleles, one that encodes hemoglobin A and  another that encodes hemoglobin S. A locus containing two or  more alleles that each occur with an appreciable frequency in a  population is said to be polymorphic or a polymorphism.    Because humans are diploid organisms, each chromosome  is represented twice, with one member of the chromosome pair  contributed by the father and one by the mother. At a given  locus an individual has one gene whose origin is paternal and  one whose origin is maternal. When the two genes are identical,  the individual is homozygous at that locus. When the genes are  not identical, the individual is heterozygous at the locus.   The composition of genes at a given locus is known as the geno-  type. The outward appearance of an individual, which is the  result of both genotype and environment, is the phenotype  (see also Chapter 6, epigenetics). For example, an infant who  is born with an inability to metabolize the amino acid phenyl-  alanine has the single-gene disorder known as phenylketonuria  (PKU) and thus has the PKU genotype. If the condition is left  untreated, abnormal metabolites of phenylalanine will begin to  accumulate in the infant’s brain and irreversible mental retar-  dation will occur. Mental retardation is thus one aspect of the  PKU phenotype. By imposing dietary restrictions to limit the  intake of food containing phenylalanine, however, retardation  can be prevented. Although the child still has the PKU geno-  type, a modification of the environment (in this case the child’s  diet) produces an outwardly normal phenotype.   In many loci the effects of one allele mask those of another when  the two are found together in a heterozygote. The allele whose  effects are observable is said to be dominant. The allele whose  effects are hidden is said to be recessive (from the Latin root for  “hiding”). Traditionally, for loci having two alleles, the domi-  nant allele is denoted by an uppercase letter and the recessive  allele is denoted by a lowercase letter. When one allele is domi-  nant over another, the heterozygote genotype Aa has the same  phenotype as the dominant homozygote AA. For the recessive  allele to be expressed, it must exist in the homozygote form, aa.   When the heterozygote is distinguishable from both homo-  zygotes, the locus is said to exhibit codominance. For example,  in the MN blood group, both alleles, M and_N, of the heterozy-  gote are detectable and therefore codominant. Another exam-  ple is the ABO blood group, in which heterozygotes having the  A and B alleles express both of them as A and B antigens on their  red cells (forming blood group AB).   A carrier is an individual who has a disease-causing allele but  is phenotypically normal. Most recessive disease-causing alleles  occur in heterozygotes who carry one copy of the allele but do not  express the disease. Because many recessive alleles are lethal in the  homozygous state, they are eliminated from the population when  they occur in homozygotes. By “hiding” in carriers, however, most  recessive alleles survive to be passed on to the next generation.    An important aspect of a genetic disease is the pattern in which  it is inherited through the generations of a family, or its mode  of inheritance. Once the mode of inheritance is known, much  can be learned about the disease-causing gene itself, and reliable    genetic counseling can be given to members of families in which  the disease is present.   Modes of inheritance were systematically studied by Mendel,  who formulated two basic laws of inheritance. His principle of  segregation states that homologous genes separate from one  another during reproduction and that each reproductive cell  carries only one of the homologous genes. Mendel’s second law,  the principle of independent assortment, states that the hered-  itary transmission of one gene has no effect on the transmission  of another. Mendel discovered these laws in the mid-nineteenth  century by performing breeding experiments with garden peas.  He had no knowledge of chromosomes. Early in the twentieth  century geneticists found that the behavior of chromosomes  does essentially correspond to Mendel’s laws, which now form  the basis for the chromosome theory of inheritance.   The known single-gene diseases can be classified into four  major modes of inheritance: autosomal dominant, autosomal  recessive, X-linked dominant, and X-linked recessive. The first  two types involve genes known to occur on the 22 pairs of auto-  somes. The last two types occur on the X chromosome; only a  few disease-causing genes, primarily affecting male fertility, are  found on the Y chromosome. The number of diseases assigned  to each category is growing rapidly. Current catalogs of single-  gene traits, which include disease-producing and nonclinical  traits (e.g., attached earlobes), list nearly 20,000 known autoso-  mal traits and nearly 1200 X-linked traits."   An important tool in the analysis of modes of inheritance  is the pedigree chart. It summarizes family relationships and  shows which members of a family are affected by a genetic dis-  ease (Figure 4-19). Generally, the pedigree begins with one indi-  vidual in the family, the proband, also termed the propositus  (male) or proposita (female). This individual is usually the first  person in the family diagnosed or seen in a clinic.   Diseases caused by autosomal dominant genes are rare. The most  common occur in fewer than 1 in 500 individuals, so it is uncom-  mon for two individuals both affected by the same autosomal  dominant disease to produce offspring together. Figure 4-20, A,  illustrates this unusual pattern. More often, affected offspring are  produced by the union of a normal parent with an affected het-  erozygous parent. The diagram (Punnett square) in Figure 4-20,  B, illustrates this mating. The affected parent can pass either a dis-  ease gene or a normal gene to his or her children. Each event has  a probability of 0.5; thus on average, half of the children will be  heterozygous and will express the disease, and half will be normal.   sion of an autosomal dominant gene. The gene shown here  causes achondroplasia (Figure 4-21, B). Several important char-  acteristics of this pedigree support the conclusion that the trait  is caused by an autosomal dominant gene:   1. The two sexes exhibit the trait in approximately equal  proportions, and males and females are equally likely to  transmit the trait to their offspring.   2. There is no skipping of generations. If an individual has  achondroplasia, one parent must also have it. If neither    parent has the trait, none of the children has it (with the  exception of new mutations, as discussed later).   3. Affected heterozygous individuals transmit the trait to  approximately half of their children, but because gamete  transmission is subject to chance fluctuations, it is pos-  sible that all or none of the children of an affected parent  may have the trait. When large numbers of matings of  this type are studied, however, the proportion of affected  children will closely approach one half.    Parents at risk for producing children with a genetic disease  nearly always ask the question, “What is the chance that our child  will have this disease?” The probability that a family member    Normal parents and normal offspring,  two girls and a boy, in birth order  indicated by the numbers; | and II  indicate generations    Darkened square or circle means  affected individual; arrow (when present)  indicates the affected individual is    d  DD  D Homozygous affected =  7 Heterozygous affected  paren (usually rare)  parent  d Dd dd  Heterozygous affected | Homozygous normal  A  Normal parent  d d  Dd Dd  7 Heterozygous affected | Heterozygous affected  Affected  parent  dd dd  d Homo | H |  Zygous norma lomozygous norma  B    FIGURE 4-20 Punnett Square and Autosomal Dominant Traits. A, Punnett  square for the mating of two individuals with an autosomal dominant gene. Here  both parents are affected by the trait. B, Punnett square for the mating of a norma  individual with a carrier for an autosomal dominant gene.    will have a genetic disease is termed the recurrence risk. When  one parent is affected by an autosomal dominant disease (and is  a heterozygote) and the other is normal, the recurrence risks for  each child are one half.   An important principle is that each birth is an independent  event, much like a coin toss. Thus, even though parents may  already have had a child with the disease, their recurrence risk  remains one half. If they have had several children, all affected  (or all unaffected) by the disease, the law of independence dic-  tates that the probability that their next child will have the dis-  ease is still one half. Parents’ misunderstanding of this principle  is acommon problem encountered in genetic counseling.   If a child has been born with an autosomal dominant dis-  ease and there is no history of the disease in the family, the  child is probably the product of a new mutation. The gene  transmitted by one of the parents has thus undergone a muta-  tion from a normal to a disease-causing allele. The genes  at this locus in most of the parent’s other germ cells would  still be normal. In this situation the recurrence risk for the  parent’s subsequent offspring is not greater than that of the  general population. The offspring of the affected child, how-  ever, will have a recurrence risk of one half. Because these  diseases often reduce the potential for reproduction, a large  proportion of the observed cases of many autosomal domi-  nant diseases are the result of new mutations. For example,  approximately seven eighths of all cases of achondroplasia are  caused by new mutations.    FIGURE 4-21 Achondroplasia. A, Pedigree showing the transmission of an autosomal dominant disease. B, Achondro-  plasia. This girl has short limbs relative to trunk length. She also has a prominent forehead, low nasal root, and redundant skin  folds in the arms and legs. (B from Jorde LB et al: Medical genetics, ed 4, St Louis, 2010, Mosby.)    Occasionally, two or more offspring will present symptoms  of an autosomal dominant disease when there is no family his-  tory of the disease. Because mutation is a rare event, it is unlikely  that this disease would be a result of multiple mutations in the  same family. The mechanism most likely to be responsible is  termed germline mosaicism. During the embryonic develop-  ment of one of the parents, a mutation occurred that affected all  or part of the germline but few or none of the somatic cells of  the embryo. Thus the parent carries the mutation in his or her  germline but does not actually express the disease. As a result,  the unaffected parent can transmit the mutation to multiple  offspring. This phenomenon, although relatively rare, can have  significant effects on recurrence risks.    An important variation seen in some genetic diseases is incom-  plete penetrance. The penetrance of a trait is the percentage  of individuals with a specific genotype who also exhibit the  expected phenotype. Incomplete penetrance means that indi-  viduals who have a disease-causing allele may not exhibit the  disease phenotype at all, even though the allele and the associ-  ated disease may be transmitted to the next generation. A pedi-  gree illustrating the transmission of an autosomal dominant  allele with incomplete penetrance is given in Figure 4-22. Reti-  noblastoma, the most common malignant eye tumor affect-  ing children, typically exhibits incomplete penetrance. About  10% of the individuals who are obligate carriers of the allele  (i.e., those who have an affected parent and affected children  and therefore must themselves carry the allele) do not have the  disease. The penetrance of the disease-causing genotype is then  said to be 90%.   The gene responsible for retinoblastoma encodes a tumor-  suppressor gene: the normal function of its protein product  is to regulate the cell cycle so that cells do not divide in an  uncontrollable manner. When a mutation alters the protein, its  tumor-suppressing capacity is lost and a tumor can form!*!*  (see Chapters 12 and 20).   Huntington disease is another well-known autosomal domi-  nant condition and its main features are progressive dementia and  increasingly uncontrollable movements of the limbs (discussed  further in Chapter 18). The latter is known as chorea (Greek  khoreia = dance; the disease is sometimes called Huntington chorea).   One of the key features of this disease is that symptoms are  not usually seen until age 40 years or later, a pattern known as  age-dependent penetrance. Thus people who develop the dis-  ease often have had children before they are aware that they  have the disease-causing allele. If the disease were present at  birth, nearly all those affected would die before reaching repro-  ductive age, and the occurrence of the allele in the population  would be much lower. An individual whose parent has the dis-  ease has a 50% chance of developing it during middle age. He  or she is thus confronted with a torturous question: “Should I  have children, knowing that there is a 50-50 chance that I may  have this disease gene and pass it to half my children?” Age-  dependent penetrance characterizes a number of important  genetic diseases, including familial breast cancer, hemochro-  matosis, and polycystic kidney disease.    FIGURE 4-22 Pedigree for Retinoblastoma Showing Incomplete Pen-  etrance. The female with marked arrow in line Il must be heterozygous, but she  does not express the trait.    Most genetic diseases exhibit variable expressivity. Expres-  sivity is the extent of variation in phenotype associated with a  particular genotype. If the expressivity of a disease is variable,  the penetrance may be complete but the severity of the disease  can vary greatly. A well-known example of variable expressiv-  ity in an autosomal dominant disease is type 1 neurofibroma-  tosis, or von Recklinghausen disease. Like the retinoblastoma  gene, the neurofibromatosis gene normally encodes a tumor  suppressor.!° The expression of this gene can vary from a few  harmless café-au-lait spots (“coffee with milk,” describing the  light brown color) on the skin to malignant tumors, scolio-  sis, seizures, gliomas, hypertension, learning disabilities, and  neuromas (Figure 4-23). A parent with mild expression of the  disease—so mild that he or she is not aware of it—can trans-  mit the gene to a child, who can then exhibit severe expression  of the disease. Several factors can cause variation in expressiv-  ity. Genes at other loci can sometimes modify the expression  of a disease-causing gene (these are termed modifier genes).  Environmental factors also can influence the expression of a  disease gene. Finally, different types of mutations at a locus  can cause variation in severity. For example, a base substitu-  tion resulting in a single amino acid change usually produces  a mild form of the clotting disorder hemophilia A. A base sub-  stitution resulting in a “stop” codon (and thus premature ter-  mination of translation) usually produces a more severe form  of hemophilia A.    Autosomal Recessive Inheritance  Characteristics of Pedigrees  Like autosomal dominant diseases, those caused by autosomal  recessive alleles are rare in populations, although the number  of carriers for recessive diseases can be high. The most com-  mon lethal recessive disease in white children, cystic fibrosis,  occurs in about 1 in 2500 births. Approximately 1 in 25 whites  carries one copy of an allele that can cause cystic fibrosis (see  Chapter 36). Because an individual must be homozygous for a  recessive allele to express the disease, the carriers are phenotypi-  cally normal. Because most recessive alleles are maintained in  normal carriers, they are able to survive in the population from  one generation to the next. As with many autosomal dominant  diseases, many autosomal recessive diseases are characterized  by delayed age of onset, incomplete penetrance, and variable  expressivity.   Figure 4-24 shows a pedigree for cystic fibrosis. The cystic  fibrosis gene encodes a protein product that forms chloride    large plexiform neurofibroma hanging from lower right back, causing considerable inconvenience and discomfort (substantially  improved by surgical removal of tumor). (A from Jorde LB et al: Medical genetics, ed 3, St Louis, 2003, Mosby. B courtesy  Dr. D. Viskochil, University of Utah Health Sciences Center, Salt Lake City.)    channels in the membranes of specialized epithelial cells.'°  Defective transport of chloride ions leads to a salt imbalance  that results in secretions of abnormally thick, dehydrated  mucus. Some of the digestive organs, particularly the pan-  creas, become obstructed, causing malnutrition, and the lungs  become clogged with mucus, making them highly suscep-  tible to bacterial infections (especially Pseudomonas). Death  from lung disease or heart failure occurs on average by about  40 years of age. In the pedigree shown, the two affected indi-  viduals are the offspring of the marriage of two first cousins.  Marriage between related individuals, termed consanguinity  (from the Latin root meaning “with blood”), is often a factor  in producing children with recessive diseases because related  individuals are more likely to share the same recessive genes.  Consanguinity is seen most often in rare recessive diseases  because carriers of common recessive diseases (such as cystic  fibrosis) have a fairly high probability of encountering one  another just by chance.    D d  DD Dd  D Homozygous Heterozygous  normal carrier  Dd dd  d Heterozygous Homozygous    FIGURE 4-25 Punnett Square for the Mating of Heterozygous Carriers.  This is typical of most cases of recessive disease.    Important criteria for discerning autosomal recessive inheri-  tance include the following:  1. Males and females are affected in equal proportions.  2. Consanguinity is sometimes present.  3. The disease is seen in siblings but usually not in their parents.  4. On the average, one fourth of the offspring of carrier parents  will be affected.    In most cases of recessive disease, both parents of affected indi-  viduals are heterozygous carriers. On the average, one fourth  of their offspring will be normal homozygotes, one half will be  phenotypically normal carrier heterozygotes, and one fourth  will be homozygotes with the disease (Figure 4-25). Thus the  recurrence risk for the offspring of carrier parents is 25%. In  any given family, chance fluctuations are likely, but a study of  a large number of families would yield figures close to these  proportions.    If two parents have a recessive disease, they each must be  homozygous for the disease. Therefore, when two parents are  affected by a recessive disease, all their children also must be  affected. This observation helps to distinguish recessive from  dominant inheritance, because two parents both affected by a  dominant gene are nearly always both heterozygotes, and thus  one fourth of their children will be unaffected.   Because carrier parents usually are unaware that they both  carry the same recessive gene, they often produce an affected  child before realization of their condition. Carrier detection  tests can identify heterozygotes by measuring the reduced  amount of a critical enzyme available. The critical enzyme is  lacking in a homozygous recessive individual, but an essen-  tially normal phenotype is seen when it is present in a reduced  quantity in the carrier. Often carriers can be detected by direct  examination of the disease locus for a mutation. Such testing  is especially valuable for siblings of known carriers, who may  themselves be carriers. Genetic testing is now available for more  than 2000 diseases.   Consanguinity and inbreeding are related concepts. Consan-  guinity refers to the mating of two related individuals, and the  offspring of such matings are said to be inbred. Consanguinity  is often an important characteristic of pedigrees for recessive  diseases because relatives share a certain proportion of genes  received from a common ancestor. The proportion of shared  genes depends on the closeness of their biologic relationship.  For example, siblings share one half of their DNA, on aver-  age, because of their descent from the same parents. With each  decreasing degree of relationship, this proportion is reduced by  one half. Uncles share one fourth of their DNA with nephews  and nieces; first cousins share one eighth; first cousins once  removed* share one sixteenth; second cousins share one thirty-  second; and so on. With consanguineous matings, recessive dis-  orders are significantly increased. Most empirical studies show  that the proportion of offspring of marriages of first cousins  who are affected by genetic diseases is approximately double  that of the general population.!” Marriages between first cous-  ins are prohibited in most states of the United States. Marriages  between closer relatives (except between double first cousins")  are prohibited throughout the United States.    Not all genetic diseases are caused by genes located on the  22 autosomes. Some conditions are instead caused by genes  located on the sex chromosomes, and that mode of inheritance  is referred to as sex-linked. The Y chromosome contains only  a few dozen genes, so most sex-linked traits are located on the  X chromosome and are said to be X-linked. Only a few diseases  are known to be inherited as X-linked dominant traits. Because  these diseases are so seldom encountered, only the much more  common X-linked recessive diseases are discussed here.    *First cousins once removed are the offspring of one’s own first cousins.  *Double first cousins share both sets of grandparents; ordinarily, first  cousins share just one set of grandparents.    Females receive two X chromosomes, one from the father  and one from the mother, so they can be homozygous for a dis-  ease allele at a given locus, homozygous for the normal allele at  the locus, or heterozygous. Males, having only one X chromo-  some, are said to be hemizygous for genes on this chromosome.  A male who inherits a recessive disease gene on the X chromo-  some will be affected by the disease because the Y chromosome  does not carry a normal allele to counteract the effects of the  disease-causing allele. Males are more frequently affected by  X-linked recessive diseases, with the difference becoming more  pronounced as the disease becomes rarer.    In the late 1950s Mary Lyon proposed that one X chromosome  in the somatic cells of females is permanently inactivated, a proc-  ess termed X inactivation.'* This explains why most gene prod-  ucts coded by the X chromosome are present in equal amounts  in males and females, even though males have only one X  chromosome and females have two X chromosomes. This phe-  nomenon is called dosage compensation. The inactivated X  chromosomes are observable in many interphase cells as highly  condensed chromatin bodies, termed Barr bodies (after Barr  and Bertram, who discovered them in the late 1940s). Normal  females have one Barr body in each somatic cell, whereas nor-  mal males have no Barr bodies.   The actual process of inactivation occurs very early in  embryonic development—approximately 7 to 14 days after fer-  tilization. In each somatic cell one of the two X chromosomes  is inactivated. In some cells the X chromosome contributed  by the father is inactivated; in others the maternal X chromo-  some is inactivated. Because the inactivation process is random,  the maternal X chromosome is inactivated in approximately  half the cells and the paternal X chromosome is inactivated in  approximately half the cells. Once the X chromosome has been  inactivated in a cell, all the descendants of that cell have the  same chromosome inactivated. Thus inactivation is said to be  random but fixed.   Some individuals do not have the normal number of X  chromosomes in their somatic cells. For example, males with  Ninefelter syndrome typically have two X chromosomes and  one Y chromosome and they have one Barr body in each cell.  Females whose cell nuclei have three X chromosomes have two  Barr bodies in each cell, and females whose cell nuclei have four  X chromosomes have three Barr bodies in each cell. Females  with Turner syndrome have only one X chromosome and no  Barr bodies. Thus the number of Barr bodies is always one less  than the number of X chromosomes in the cell. All but one X  chromosome are always inactivated.   People with abnormal numbers of X chromosomes, such as  those with Turner syndrome or Klinefelter syndrome, are not  physically normal. This situation presents a puzzle because they  presumably have only one active X chromosome, the same as  individuals with normal numbers of chromosomes. However,  the distal portions of the short and long arms of the X chro-  mosome, as well as several other regions on the chromosome,  are not inactivated. Thus X inactivation is also known to be  incomplete.    Although the mechanism underlying X inactivation is still  incompletely understood, the gene responsible for initiating X  inactivation, XIST, has been located.'? This gene encodes an  mRNA that coats one of the X chromosomes, which is then  inactivated. Methylation of X chromosome DNA, a process in  which DNA is inactivated when cytosine bases are enzymati-  cally converted to 5-methylcytosine, occurs on the inactivated  X chromosome. Inactive X chromosomes can be at least par-  tially reactivated in vitro by administering 5-azacytidine, a  demethylating agent.    The process of sexual differentiation, in which the embryonic  gonads become either testes or ovaries, begins during the sixth  week of gestation. A key principle of sex determination in mam-  mals is that one copy of the Y chromosome is sufficient to initi-  ate the process of gonadal differentiation that produces a male  fetus (Figure 4-26, A). The number of X chromosomes does  not alter this process. For example, an individual with two X  chromosomes and one Y chromosome in each cell is still phe-  notypically a male. Thus it is logical that the Y chromosome  must contain a gene that begins the process of male gonadal  development.   This gene, termed SRY (for “sex-determining region on  the Y”), has been located on the short arm of the Y chromo-  some.””?! The SRY gene lies immediately proximal to the dis-  tal tip of the Y chromosome, known as the pseudoautosomal  region (Figure 4-26, B). This portion of the Y chromosome is so  named because it pairs with the distal tip of the short arm of the  X chromosome during meiosis and exchanges genetic material  with it (crossover), just as autosomes do. The DNA sequences  of these regions on the X and Y chromosomes are highly simi-  lar. The remainder of the X and Y chromosomes, however, do  not exchange material and are not similar in DNA sequence.  An important piece of evidence that supports SRY as the male-  determining gene is that female mouse embryos injected with  this gene develop as phenotypic males.   Although the SRY gene is located on the Y chromosome, the  other genes that contribute to male differentiation are located  on other chromosomes. Thus SRY appears to act as a trigger  that initiates the action of genes on other chromosomes (e.g.,  those that control Sertoli cell differentiation or secretion of  miillerian-inhibiting substance). This concept is supported by  the fact that the SRY gene is similar in sequence to other genes  that are known to regulate the transcription of DNA (ie., they  turn other genes on and off).   Occasionally the crossover between X and Y occurs closer to  the centromere than it should, placing the SRY gene on the X  chromosome after crossover. This variation can result in off-  spring with an apparently normal XX karyotype but a male phe-  notype. Such XX males are seen in about 1 in 20,000 live births  and closely resemble males with Klinefelter syndrome, although  their stature is normal. Conversely, it is possible to inherit a Y  chromosome that has lost the SRY gene (because of either a cross-  over error or a deletion of the gene). This situation produces an  XY female. Such females have gonadal streaks rather than ovaries  and have poorly developed secondary sex characteristics.    FIGURE 4-26 The Distal Short Arms of the X and Y Chromosomes  Exchange Material During Meiosis in the Male. A, X and Y chromosomes.  B, The region of the Y chromosome in which this crossover occurs is called the  pseudoautosomal region. (Xp and Yp refer to the short arms of each chromosome.)  The SRY gene, which triggers the process leading to male gonadal differentiation,  is located just outside the pseudoautosomal region. Occasionally, the crossover  occurs on the centromeric side of the SRY gene, causing it to lie on an X chromo-  some instead of a Y chromosome. An offspring receiving this X chromosome will  be an XX male, and an offspring receiving the Y chromosome will be an XY female.  (A from Raven PH et al: Biology, ed 8, New York, 2008, McGraw-Hill. B from Jorde  LB et al: Medical genetics, ed 3, St Louis, 2003, Mosby.)   1. The trait is seen much more often in males than in females  because females must inherit two copies of the recessive  allele (one from each parent) to express the disease, while  males need only inherit one copy (from their mother) to  express the disease.   2. Because a father can give a son only a Y chromosome, the  trait is never transmitted from father to son.   3. The gene can be transmitted through a series of carrier  females, causing the appearance ofa “skipped generation.”    4. The gene is passed from an affected father to all his daugh-  ters, who, as phenotypically normal carriers, transmit it  to approximately half their sons, who are affected.   The most common and severe of all X-linked recessive dis-  orders is Duchenne muscular dystrophy (DMD), which affects  approximately 1 in 3500 males. As its name suggests, this dis-  order is characterized by progressive muscle degeneration.  Affected individuals are usually unable to walk by 10 to 12 years  of age. The disease affects the heart and respiratory muscles,  and death caused by respiratory or cardiac failure usually occurs  before 20 years. Until recently, the underlying pathologic ori-  gin of this disorder was a mystery. However, identification of  the disease-causing gene has greatly increased our understand-  ing of the disorder.” The DMD gene is the largest gene ever  found in the human, spanning more than 2 million DNA bases.  It encodes a previously undiscovered muscle protein, termed  dystrophin. Extensive study of dystrophin indicates that it  plays an essential role in maintaining the structural integrity of  muscle cells: one end of the protein binds to actin filaments in  the cytoplasm of the cell, and the other end binds to a group  of membrane-spanning proteins known as the dystrophin-  associated glycoproteins. When dystrophin is absent, as in indi-  viduals with DMD, the muscle cell cannot survive, and muscle  deterioration ensues.   Most cases of Duchenne muscular dystrophy are caused by  deletions of portions of the DMD gene. They generally involve  frameshift deletions in which all the amino acids following the  deletion are altered. It is interesting that an “in frame” deletion  (in which a multiple of three bases is deleted, and the amino  acids following the deletion are not altered) produces a milder  form of muscular dystrophy, the Becker type. These two types  of dystrophy are examples of a disease in which different types  of mutations at the same locus produce variable expression of  the disease.    The most common mating type involving X-linked recessive  genes is the combination of a carrier female and a normal male.  On the average, the carrier mother will transmit the disease-  causing allele to half her sons and half her daughters. As Figure  4-27, A, shows, half the daughters in such a mating will be car-  riers, whereas half will be normal. Half the sons will be normal,  on the average, whereas half will have the disease.   The other common mating type is an affected father and  a normal mother (see Figure 4-27, B). In this situation all the  sons must be normal because the father can transmit only his  Y chromosome to them. Because all the daughters must receive  the father's X chromosome, they will all be heterozygous car-  riers. Because the sons must receive the Y chromosome and  the daughters must receive the X with the disease gene, these  are predictions and not probabilities. None of the children will  express the disease.   The final mating pattern, less common than the other two,  involves an affected father and a carrier mother (see Figure  4-27, C). With this pattern, on average, half the daughters will  be heterozygous carriers and half will be homozygous for the  disease allele and thus affected. Half the sons will be normal,    Mother  Xy X,  XH XuXy XyXy  Father  Y XuY  A  Xy Xy  Xh XuXh, XuXh,  Father  Y XuY XuY  B  Mother  Xy  Xh XuXh,  Father  Y XyY  Cc  Normal  Carrier  DD Affected    FIGURE 4-27 Punnett Square and X-linked Recessive Traits. A, Punnett  square for the mating of a normal male (X,Y) and a female carrier of an X-linked  recessive gene (X4X;,). B, Punnett square for the mating of a normal female (XX)  with a male affected by an X-linked recessive disease (X,Y). €, Punnett square for  the mating of a female who carries an X-linked recessive gene (X4X;,) with a male  who is affected with the disease caused by the gene (X,Y).    and half will be affected. Some X-linked recessive diseases, such  as DMD, are fatal or incapacitating before the affected individ-  ual reaches reproductive age, and therefore affected fathers are  rare or nonexistent.    Confusion sometimes exists regarding the difference between  traits that are sex-linked and those that are sex-limited or sex-  influenced. A sex-limited trait is one that can occur in only one  of the sexes, often because of anatomic differences. Inherited  uterine and testicular defects are two obvious examples.   A sex-influenced trait is one that occurs much more often in  one sex than in the other. A good example of a sex-influenced  trait is male-pattern baldness, which occurs in both males and  females but is much more common in males. Another example  is breast cancer, which is approximately 70 times more com-  mon in females than males.    FIGURE 4-28 The Genetic Results of Crossing Over. A, No crossing over: A; and B, remain together after meiosis. B,  Crossing over between A and B results in a recombination: A, and B, are inherited together on one chromosome, and Ay and By  are inherited together on another chromosome. C, A double crossover between A and B results in no recombination of alleles.    With complications such as incomplete penetrance, variable  expressivity, delayed age of onset, and sex-influenced traits, it  is not always possible simply to look at a disease pedigree and  determine the mode of inheritance. A sophisticated statistical  approach has evolved to deal with such complications. Incor-  porated into computer programs, these statistical techniques  assess the probability of observing a certain pedigree if a par-  ticular mode of inheritance (e.g., autosomal dominant with  incomplete penetrance) is in effect.    Locating the positions of genes on chromosomes has been one  of the most important endeavors in human genetics. It is an  important first step in identifying a disease-causing gene and  can be used to predict the likelihood that certain individuals  will develop a genetic disease.    Mendel’s second law, the principle of independent assortment,  states that an individual’s genes will be transmitted to the next  generation independently of one another. This law is only  partly true, however, because genes located close together on  the same chromosome do tend to be transmitted together to the  offspring. Thus Mendel’s principle of independent assortment  holds true for most pairs of genes but not those that occupy the  same region of a chromosome. Such loci demonstrate linkage  and are said to be linked.    During the first meiotic stage, the arms of homologous chro-  mosome pairs intertwine and sometimes exchange portions  of their DNA (Figure 4-28) in a process known as crossing  over. During crossing over, new combinations of alleles can be  formed. For example, two loci on a chromosome have alleles A  and a and alleles B and b. Alleles A and B are located together  on one chromosome arm, and alleles a and b are located on the  other arm. The genotype of this individual is denoted as AB/ab.   As Figure 4-28, A, shows, the allele pairs AB and ab would be  transmitted together when no crossing over occurs. However,  when crossing over does occur (see Figure 4-28, B), all four pos-  sible pairs of alleles can be transmitted to the offspring: AB, aB,  Ab, and ab. The process of forming such new arrangements of  alleles is called recombination. Crossing over does not neces-  sarily lead to recombination, however, because double crossing  over between two loci can result in no actual recombination of  the alleles at the loci (see Figure 4-28, C).   The rate of crossing over can be used to infer the distance  between two loci on a chromosome because the probability  of crossovers occurring between two loci increases as the loci  become more distant. For example, if an individual with geno-  type AB/ab produces recombinant offspring gametes (composi-  tion of Ab and aB) 2% of the time, it is said that the two loci  are two map units apart. One map unit equals a 1% recom-  bination rate between two loci. When loci on the same chro-  mosome are 50 or more map units apart, they are considered  unlinked because their recombination frequency is just as great  as it would be if they were on different chromosomes (where the  probability of being transmitted together must equal one half).  Recombination frequencies provide a good estimate of actual    marker locus assayed to determine, with 99% or greater cer-  tainty, whether each member carries the disease-causing allele.  For most genetic diseases, it is now possible to test directly  for the disease-causing mutation, often by sequencing the DNA  in family members. In some cases, however, the actual disease-    UNIT Il Genes and Gene-Environment Interaction  =. 2  1,2  2  mn Genotype Genotype  n2/n2 N1/n2    physical distance between loci: on average, each map unit is  equal to approximately 1 million DNA base pairs.   Pedigrees can be used to determine recombination rates  between loci. Figure 4-29 shows a pedigree in which neurofibro-  matosis type 1 (NF1), an autosomal dominant disease discussed  previously, is being transmitted in a family. The NF1 alleles are  labeled N (the dominant disease-causing allele) and n (the nor-  mal allele). The individuals in this pedigree have been typed for  a marker polymorphism, a small DNA sequence whose chro-  mosome location is known and can be typed in the laboratory.  The alleles of the marker polymorphism are labeled 1 and 2.  Examination of generations I and II shows that the NF1 locus  must be on the same chromosome as marker allele 1 because  the mother, whose marker genotype was 2,2, was unaffected  with the disease. The daughter’s genotype would then be N1/n2,  in which N indicates the disease allele and n indicates the nor-  mal allele. The daughter’s husband (individual II-1) must have  the genotype n2/2n2. If the marker locus and NF1 are linked,  the children of this union who are affected with NF12 should  have marker allele 1; those who are unaffected should have the  marker genotype 2,2 (i.e., they inherited a copy of the normal  chromosome from their affected mother). In six of seven cases  we find this to be true. In one case a recombination occurred  (individual II-6), indicating a recombination rate of 1 in 7, or  14%. The two loci are therefore 14 map units apart. In prac-  tice, a much larger sample of families would be used to ensure  against statistical artifacts.   Once a close linkage has been established between a disease  locus and a marker polymorphism and once the alleles of the  two loci that are inherited together within a family have been  determined, reliable predictions of whether a member of a fam-  ily will develop the disease can be made. If, for example, the  recombination rate between a disease locus and a marker poly-  morphism is less than 1%, family members can simply have the    causing mutation cannot be identified, but linked marker loci  can be assayed providing an indirect genetic test. These genetic  tests are now used routinely to confirm diagnosis of a genetic  disease, to identify carriers of recessive diseases, and to presymp-  tomatically identify individuals who are at risk for inheriting a  disease with delayed age of onset, such as autosomal dominant  breast or colon cancer, Huntington disease, and many others.  In some cases, testing can help provide preventive treatment,  such as prophylactic oophorectomy in women who have inher-  ited a dominant allele that can cause breast or ovarian cancer.    With completion of the human DNA sequence (see following),  computer analysis of the published sequence has become an  effective and popular approach for identifying genes. Comput-  erized databases of known DNA sequences play an important  role in gene identification. When studying a specific region  of DNA to find a gene, it is common to search for similarity  between DNA sequences from the region and DNA sequences  in the database. The sequences in the database may derive from  genes with known function or tissue-specific expression pat-  terns. Suppose, for example, that we have used linkage analysis  to identify a region containing a gene that causes a developmen-  tal disorder such as a limb malformation. As we evaluate DNA  sequences in the region, we would look for similarity between a  DNA sequence from this region and a plausible sequence from  the database (e.g., sequence from a gene that encodes a protein  involved in bone development, such as a fibroblast growth fac-  tor). Because genes that encode similar protein products usu-  ally have similar DNA sequences, a match between the sequence  from our region and a sequence in the database could be a vital  clue that this particular DNA sequence is actually part of the  gene that causes the limb malformation.   As the cost of sequencing whole human genomes has  declined, it is now common to search for a disease-causing  mutation in an individual or a family by evaluating their entire  DNA sequence. Their sequences are compared with those  of unaffected individuals, and statistical methods are used to  determine which, if any, of their DNA variants cause disease.  Linkage results, as discussed previously, can help to define a  specific chromosome region that contains a disease-causing  variant in a family. Currently, the genetic causes of about 3000  mendelian conditions have been determined, enabling genetic  testing, more accurate diagnosis, and in some cases more effec-  tive treatment of disease.    Genes, the basic units of inheritance, are composed of DNA  and are located on the chromosomes.    . The most important constituent of DNA is the four types    of nitrogenous bases, labeled A, C, G, and T. The physical  structure of DNA is a double helix.    . The DNA bases code for amino acids, which in turn make    up proteins. The amino acids are specified by triplet codons  of nitrogenous bases.    in which a single strand of DNA serves as the template for  attracting bases that form a new strand of DNA.    . Substances that cause mutations are called mutagens.  . The mutation rate in humans varies from locus to locus and    which proteins are specified by DNA, both involve RNA.  RNA is chemically similar to DNA, but it is single stranded  and has uracil rather than thymine as one of its four nitrog-  enous bases.   Transcription is the process by which DNA specifies a  sequence of mRNA.   Much of the RNA sequence is spliced from the mRNA  before the mRNA leaves the nucleus. The excised sequences  are called introns, and those that remain to code for pro-  teins are called exons.   Transcription factors bind to DNA sequences called tran-  scription factor binding sites near genes to regulate the tim-  ing of transcription, as well as the specific tissues in which  genes are actively transcribed.   Translation is the process by which RNA directs the synthesis  of polypeptides. This process takes place in the ribosomes.  During translation, mRNA interacts with tRNA, a molecule  that has an attachment site for a specific amino acid.    Human cells consist of diploid somatic cells (body cells)  and haploid gametes (sperm and egg cells).    . Humans have 23 pairs of chromosomes: 22 of these pairs    are autosomes. The remaining pair consists of the sex  chromosomes. Females have two homologous X chromo-  somes as their sex chromosomes; males have an X and a Y  chromosome.    . Various types of stains can be used to make chromosome    . About 1 in 150 live births has a major diagnosable chro-    mosome abnormality. Chromosome abnormalities are the  leading known cause of mental retardation and miscarriage.    6. Polyploidy is a condition in which a euploid cell has some  multiple of the normal number of chromosomes. Humans  have been observed to have triploidy (three copies of each  chromosome) and tetraploidy (four copies of each chromo-  some); both conditions are lethal.   7. Somatic cells that do not have a multiple of 23 chromo-  somes are aneuploid. Aneuploidy is usually the result of  nondisjunction.   8. Trisomy is a type of aneuploidy in which one chromosome is  present in three copies in somatic cells. A partial trisomy is one  in which only part of a chromosome is present in three copies.   9. Monosomy is a type of aneuploidy in which one chromo-  some is present in only one copy in somatic cells.   10. In general, monosomies cause more severe physical defects  than do trisomies, illustrating the principle that the loss of  chromosome material has more severe consequences than  the duplication of chromosome material.   11. Down syndrome, a trisomy of chromosome 21, is the most  well-known disease caused by a chromosome aberration. It  affects 1 in 800 live births and is much more likely to occur  in the offspring of women older than 35 years of age.   12. Most aneuploidies of the sex chromosomes have less severe  consequences than those of the autosomes.   13. The most commonly observed sex chromosome aneuploi-  dies are the 47,XXX karyotype, 45,X karyotype (Turner  syndrome); 47,XXY karyotype (Klinefelter syndrome); and  47,XYY karyotype.   14. Abnormalities of chromosome structure include deletions,  duplications, inversions, and translocations.   1. Mendelian traits are caused by single genes, each of which  occupies a position, or locus, on a chromosome.   2. Alleles are different forms of genes located at the same locus  on the chromosome.   3. At any given locus in a somatic cell, an individual has two  genes, one from each parent. An individual may be homo-  zygous or heterozygous for a locus.   4, An individual’s genotype is his or her genetic makeup,  and the phenotype reflects the interaction of genotype and  environment.   5. At a heterozygous locus, a dominant gene’s effects mask  those of a recessive gene. The recessive gene is expressed  only when it is present in two copies.   1. Genetic diseases caused by single genes usually follow auto-  somal dominant, autosomal recessive, or X-linked recessive  modes of inheritance.   2. Pedigree charts are an important tool in the analysis of  modes of inheritance.   3. Recurrence risks specify the probability that future off-  spring will inherit a genetic disease. For single-gene dis-  eases, recurrence risks remain the same for each offspring,  regardless of the number of affected or unaffected offspring.   Germline mosaicism can alter recurrence risks for genetic  diseases because unaffected parents can produce multiple  affected offspring. This situation occurs because the germ-  line of one parent is affected by a mutation but the parent's  somatic cells are unaffected.   Skipped generations are not seen in classic autosomal dom-  inant pedigrees.   Males and females are equally likely to exhibit autosomal  dominant diseases and to pass them on to their offspring.  A gene that is not always expressed phenotypically is said to  have incomplete penetrance.   Penetrance may be age-dependent, as in Huntington dis-  ease and familial breast cancer.   Most commonly, parents of children with autosomal reces-  sive diseases are both heterozygous carriers of the disease  gene. In this case, the recurrence risk for autosomal reces-  sive diseases is 25%.   Males and females are equally likely to be affected by auto-  somal recessive diseases.   Consanguinity is sometimes present in families with auto-  somal recessive diseases, and it becomes more prevalent  with rarer recessive diseases.   Carrier detection tests for an increasing number of autoso-  mal recessive diseases are available.   The frequency of genetic diseases approximately doubles in  the offspring of first-cousin matings.   In each normal female somatic cell, one of the two X chro-  mosomes is inactivated early in embryogenesis.   X inactivation is random, fixed, and incomplete (i.e., only  part of the chromosome is actually inactivated). It may  involve methylation.    Gender is determined embryonically by the presence of  the SRY gene on the Y chromosome. Embryos that have  a Y chromosome (and thus the SRY gene) become males,  whereas those lacking the Y chromosome become females.  When the Y chromosome lacks the SRY gene, an XY female  can be produced. Similarly, an X chromosome that con-  tains the SRY gene can produce an XX male.   X-linked genes are those that are located on the X chro-  mosome. Nearly all known X-linked diseases are caused by  X-linked recessive genes.   Males are hemizygous for genes on the X chromosome.  X-linked recessive diseases are seen much more often in  males than in females because males need only one copy of  the gene to express the disease.   Skipped generations are often seen in X-linked recessive  disease pedigrees because the gene can be transmitted  through carrier females.   Recurrence risks for X-linked recessive diseases depend on  the carrier and affected status of the mother and father.   A sex-limited trait is one that occurs in only one of the  sexes.   A sex-influenced trait is one that occurs more often in one  sex than in the other.    During meiosis I, crossing over occurs and can cause  recombinations of alleles located on the same chromosome.  The frequency of recombinations can be used to infer the  map distance between loci on the same chromosome.   A marker locus, when closely linked to a disease-gene locus,  can be used to predict whether an individual will develop a  genetic disease.   The complete human genome sequence will facilitate gene  identification, diagnosis, and disease treatment.    Haploid cell, 142  Hemizygous, 156  Heterozygote, 151  Heterozygous, 151  Homologous, 142  Homologous chromosome, 142  Homozygote, 151  Homozygous, 151  Inbreeding, 156   Messenger RNA (mRNA), 141  Metaphase spread, 142  Missense mutation, 137  Mode of inheritance, 151   Reciprocal translocation, 151  Recombination, 159  Recurrence risk, 153  Ribonucleic acid (RNA), 141  Ribosome, 142   RNA polymerase, 141  Robertsonian translocation, 149  Sex chromosome, 142  Sex-influenced trait, 158  Sex-limited trait, 158  Sex-linked, 156    REFERENCES Il.  1. Online: Mendelian inheritance in man. Available at www.omim.org. 12.  . Hall JG et al: The frequency and financial burden of genetic disease in a   pediatric hospital, Am J Med Genet 1(1):417—436, 1978. 13.  3. Crow JF: The origins, patterns and implications of human spontaneous   mutation, Nat Rev Genet 1:40—47, 2000. 14.  4. Hall H, Hunt P, Hassold T: Meiosis and sex chromosome aneuploidy: 15.   errors, Curr Opin Genet Dev 16(3):323-329, 2006. 16.  5. Tolie JL, MacFayden U et al: Clinical genetics of common autosomal tri-   somies. In Rimoin DL, editor: Emery and Rimoin's principles and practice 17.   1015-1037. 18.  6. Antonarakis SE, Epstein CJ: The challenge of Down syndrome, Trends   Mol Med 12(10):473-479, 2006. 19.  7. Jorde LB, et al: Medical genetics, ed 4, St Louis, 2010, Mosby.  8. Graham GE, Allanson JE, Gerritsen JA: Sex chromosome abnormalities. 20.   In Rimoin DL, et al: Emery and Rimoin's principles and practice of medical   genetics, ed 5, Philadelphia, 2007, Churchill Livingstone, pp 1038-1057. 21,  9. Garber KB, Visootsak J, Warren ST: Fragile X syndrome, Eur J Hum   152 Termination (nonsense) codon, 137  Termination sequence, 141  Tetraploidy, 144  Thymine, 136  Transcription, 141  Transcription factor, 141  Transcription factor binding site, 141  Transfer RNA (tRNA), 142  Translation, 142  Translocation, 149  Triploidy, 144  Trisomy, 144  Tumor-suppressor gene, 154  Turner syndrome, 147    Orr HT, Zoghbi HY: Trinucleotide repeat disorders, Annu Rev Neurosci  30:575-621, 2007.   McDermott U, Downing JR, Stratton MR: Genomics and the continuum  of cancer care, N Engl J Med 364:340-350, 2011.   Knudson AG: Cancer genetics, Am J Med Genet 111(1):96-102, 2002.  Jett K, Friedman JM: Clinical and genetic aspects of neurofibromatosis 1,  Genet Med 12:1-11, 2010.   Mogayzel PJ Jr, Flume PA: Update in cystic fibrosis 2009, Am J Respir Crit  Care Med 181:539-544, 2010.   Jorde LB: Inbreeding in human populations. In Dulbecco R, editor:  Encyclopedia of human biology, vol. 5, New York, 1997, Academic Press.  Lyon MF: Sex chromatin and gene action in the mammalian X-chromo-  some, Am J Hum Genet 14:135-148, 1962.   Chow J, Heard E: X inactivation and the complexities of silencing a sex  chromosome, Curr Opin Cell Biol 21:359-366, 2009.   Fleming A, Vilain E: The endless quest for sex determination genes, Clin  Genet 67(1):15—25, 2005.   Bushby K et al: Diagnosis and management of Duchenne muscular  dystrophy, part 1: diagnosis, and pharmacological and psychosocial  management, Lancet Neurol 9:77—93, 2010.   Lander ES: Initial impact of the sequencing of the human genome,  Nature 470:187-197, 2011.    As part of your Pageburst Digital Book, you can access the following Integrated Resources:    http://evolve.elsevier.com/McCance/  * Review Questions and Answers  * Online Course: Module 3    Factors Influencing Incidence of Disease in Populations, 164  Concepts of Incidence and Prevalence, 164  Analysis of Risk Factors, 165  Principles of Multifactorial Inheritance, 165  Basic Model, 165  Threshold Model, 166  Recurrence Risks and Transmission Patterns, 167    Chapter 4 focuses on diseases that are caused by single genes  or by abnormalities of single chromosomes. Much progress has  been made in identifying specific mutations that cause these  diseases, leading to better risk estimates and, in some cases,  more effective treatment of the disease. However, these condi-  tions form only a small portion of the total burden of human  genetic disease. Most congenital malformations are not caused  by single genes or chromosome defects. Many common adult  diseases, such as cancer, heart disease, and diabetes, have  genetic components, but again they are usually not caused by  single genes or by chromosomal abnormalities.! These diseases,  whose treatment collectively occupies the attention of most  healthcare practitioners, are the result of a complex interplay of  multiple genetic and environmental” factors.    *In human genetics, it is common practice to use the term “environ-  ment” to designate all nongeneric factors, such as diet and lifestyle.    Nature and Nurture: Disentangling the Effects of Genes  and Environment, 169  Twin Studies, 169  Adoption Studies, 170  Genetics of Common Diseases, 171  Congenital Malformations, 171  Multifactorial Disorders in the Adult Population, 171   How common is a given disease, such as diabetes, in a popula-  tion? Well-established measures are used to answer this ques-  tion.’ The incidence rate is the number of new cases of a disease  reported during a specific period (typically 1 year) divided by  the number of individuals in the population. The denomina-  tor is often expressed as person-years. The incidence rate can  be contrasted with the prevalence rate, which is the propor-  tion of the population affected by a disease at a specific point  in time. Prevalence is thus determined by both the incidence  rate and the length of the survival period in affected individu-  als. For example, the prevalence rate of acquired immunodefi-  ciency syndrome (AIDS) is larger than the yearly incidence rate  because most people with AIDS survive for at least several years  after diagnosis.    Many diseases vary in prevalence from one population to  another. Cystic fibrosis is relatively common among Europeans,  occurring about once in every 2500 births. In contrast, it is quite  rare in Asians, occurring only once in every 90,000 births. Simi-  larly, sickle cell disease affects approximately 1 in 600 American  blacks, but it is seen much less frequently in whites. Both of  these diseases are single-gene disorders, and they vary among  populations because disease-causing mutations are more or less  common in different populations. (This is in turn the result of  differences in the evolutionary history of these populations.)  Nongenetic (environmental) factors have little influence on the  current prevalence of these diseases.   The picture often becomes more complex with the com-  mon diseases of adulthood. For example, colon cancer was  until recently relatively rare in Japan, but it is the second most  common cancer in the United States. Stomach cancer, on  the other hand, is common in Japan but relatively rare in the  United States. These statistics, in themselves, cannot distinguish  environmental from genetic influences in the two populations.  However, because large numbers of Japanese emigrated first  to Hawaii and then to the U.S. mainland, we can observe what  happens to the rates of stomach and colon cancer among the  migrants. It is important that the Japanese émigrés maintained  a genetic identity, marrying largely among themselves. Among  first-generation Japanese in Hawaii, the frequency of colon  cancer rose several-fold—not yet as high as in the U.S. main-  land but higher than that in Japan. Among second-generation  Japanese on the U.S. mainland, colon cancer rates rose to 5%,  equal to the U.S. average. At the same time, stomach cancer has  become relatively rare among Japanese-Americans.   These observations strongly indicate an important role for  environmental factors in the etiology of cancers of the colon  and stomach. In each case, diet is a likely culprit—a high-fat,  low-fiber diet in the United States is thought to increase the risk  of colon cancer, whereas techniques used to preserve and sea-  son the fish commonly eaten in Japan are thought to increase  the risk of stomach cancer. It is interesting that the incidence  of colon cancer in Japan has increased dramatically during the  past several decades as the Japanese population has adopted a  more “Western” diet. These results do not, however, rule out  the potential contribution of genetic factors in common can-  cers. Genes also play a role in the etiology of colon and other  cancers.    The comparison just discussed is one example of the analysis  of risk factors (in this case, diet) and their influence on the  prevalence of disease in populations. A common measure of the  effect of a specific risk factor is the relative risk. This quantity is  expressed as a ratio:    Increased rate of the disease among individuals  exposed to a risk factor    Incidence rate of the disease among individuals  not exposed to a risk factor    A classic example of a relative risk analysis was carried out in  a sample of more than 40,000 British physicians to determine    the relationship between cigarette smoking and lung cancer.  This study compared the incidence of death from lung cancer in  physicians who smoked with those who did not. The incidence  of death from lung cancer was 1.66 (per 1000 person-years) in  heavy smokers (more than 25 cigarettes daily), but it was only  0.07 in the nonsmokers. The ratio of these two incidence rates  is 1.66/0.07, which yields a relative risk of 23.7 deaths. Thus, it  is concluded that the risk of dying from lung cancer increased  by about 24-fold in heavy smokers compared with nonsmokers.  Many other studies have obtained similar risk figures.   Although cigarette smoking clearly increases one’s risk of  developing lung cancer (as well as heart disease, as we will see  later), it is equally clear that most smokers do not develop lung  cancer. Other lifestyle factors are likely to contribute to one’s  risk of developing this disease (e.g., exposure to cancer-causing  substances in the air, such as asbestos fibers). In addition, dif-  ferences in genetic background may be involved. Smokers who  have variants in genes, such as CYPIA1 and GSTM1, that are  involved in the metabolism of components of tobacco smoke  are at significantly increased risk of developing lung cancer.   Many factors can influence the risk of acquiring a common  disease such as cancer, diabetes, or high blood pressure. These  include age, gender, diet, amount of exercise, and family history  of the disease. Usually, complex interactions occur among these  genetic and nongenetic factors. The effects of each factor can be  quantified in terms of relative risks. The following discussion  demonstrates how genetic and environmental factors contrib-  ute to the risk of developing common diseases.    Traits in which variation is thought to be caused by the com-  bined effects of multiple genes are polygenic (“many genes”).  When environmental factors are also believed to cause variation  in the trait, which is usually the case, the term multifactorial  trait is used.’ Many quantitative traits (those, such as blood  pressure, that are measured on a continuous numeric scale) are  multifactorial. Because they are caused by the additive effects  of many genetic and environmental factors, these traits tend to  follow a normal, or bell-shaped, distribution in populations.  An example illustrates this concept. To begin with the sim-  plest case, suppose (unrealistically) that height is determined by  a single gene with two alleles, A and a. Allele A tends to make  people tall, whereas allele a tends to make them short. If there  is no dominance at this locus, then the three possible genotypes  (AA, Aa, aa) will produce three phenotypes: tall, intermediate,  and short, respectively. Assume that the gene frequencies of A  and a are each 0.50. If we look at a population of individuals, we  will observe the height distribution depicted in Figure 5-1, A.  Now suppose, a bit more realistically, that height is deter-  mined by two loci instead of one. The second locus also has two  alleles, B (tall) and b (short), and they affect height in exactly the  same way as alleles A and a. There are now nine possible geno-  types in our population: aabb, aaBb, aaBB, Aabb, AaBb, AaBB,  AAbb, AABb, and AABB. An individual may have zero, one,    From extension of this example, many genes and environ-  mental factors influence height, each having a small effect. Then  many phenotypes are possible, each differing slightly from the  others, and the height distribution of the population approaches  the bell-shaped curve shown in Figure 5-1, C.   It should be emphasized that the individual genes underly-  ing a multifactorial trait such as height follow the mendelian  principles of segregation and independent assortment, just like  any other gene. The only difference is that many of them act  together to influence the trait. More than 100 genes have now  been shown to be associated with variation in human height.   Blood pressure is another example of a multifactorial trait.  A correlation exists between parents’ blood pressures (systolic  and diastolic) and those of their children. The evidence is good  that this correlation is partially caused by genes, but blood pres-  sure is also influenced by environmental factors, such as diet,  exercise, and stress. Two goals of genetic research are the iden-  tification and measurement of the relative roles of genes and  environment in the causation of multifactorial diseases.    A number of diseases do not follow the bell-shaped distribu-  tion. Instead, they appear to be either present or absent in indi-  viduals, yet they do not follow the inheritance patterns expected  of single-gene diseases. A commonly used explanation for such  diseases is that there is an underlying liability distribution for  the disease in a population (Figure 5-2). Those individuals who  ” end of the distribution have little chance of  developing the disease in question (i.e., they have few of the  alleles or environmental factors that would cause the disease).  Individuals who are closer to the “high” end of the distribution  have more of the disease-causing genes and environmental fac-  tors and are more likely to develop the disease. For diseases that  are either present or absent, it is thought that a threshold of  liability must be crossed before the disease is expressed. Below  the threshold, an individual appears normal; above it, he or she  is affected by the disease.    FIGURE 5-1 Distribution of Height. A, Distribution of height in a population,  assuming that height is controlled by a single locus with genotypes AA, Aa, and  aa. B, Distribution of height, assuming that height is controlled by two loci. Five  distinct genotypes are shown instead of three, and the distribution begins to look  more like the normal distribution. €, Height is portrayed, realistically, as a trait with  a continuous statistical distribution. Because many genes contribute to height and  tend to segregate independently of one another, the cumulative contribution of dif-  ferent combinations of alleles to height forms a continuous distribution of possible  heights, in which the extremes are much rarer than the intermediate values. Varia-  tion also can be due to environmental factors such as nutrition. (A and B adapted  from Jorde LB et al: Medical genetics, ed 4, St Louis, 2010, Mosby; € from Raven  PH et al: Biology, ed 8, New York, 2008, McGraw-Hill.)    two, three, or four “tall” alleles, so now five distinct phenotypes  are possible (see Figure 5-1, B). Although the height distribu-  tion in our fictional population is still not normal compared  with an actual population, it approaches a normal distribution  more closely than in the single-gene case just described.    A disease that is thought to correspond to this thresh-  old model is pyloric stenosis, a disorder that presents shortly  after birth and is caused by a narrowing or obstruction of the  pylorus, the area between the stomach and intestine. Chronic  vomiting, constipation, weight loss, and imbalance of electro-  lyte levels result from the condition, but it sometimes resolves  spontaneously or can be corrected by surgery. The prevalence  of pyloric stenosis is about 3 per 1000 live births in whites. It is  much more common in males than females, affecting 1 of 200  males and 1 of 1000 females. It is thought that this difference in  prevalence reflects two thresholds in the liability distribution—  a lower one in males and a higher one in females (see Figure  5-2). A lower male threshold implies that fewer disease-causing  factors are required to generate the disorder in males.   The liability threshold concept may explain the pattern of  recurrence risks for pyloric stenosis seen in Table 5-1. Note that  males, having a lower threshold, always have a higher risk than  females. However, the sibling risk also depends on the gender  of the proband (i.e., the individual from which the pedigree  begins). It is higher when the proband is female than when the    Liability  FIGURE 5-2 A Liability Distribution in a Population for a Multifactorial  Disease. To be affected with the disease, an individual must exceed the threshold  on the liability distribution. This figure shows two thresholds, a lower one for males    and a higher one for females (as in pyloric stenosis; see text). (From Jorde LB et al:  Medical genetics, ed 4, St Louis, 2010, Mosby.)    proband is male. This reflects the concept that females, having  a higher liability threshold, must be exposed to more disease-  causing factors than males to develop the disease. Thus a family  with an affected female must have more genetic and environ-  mental risk factors, producing a higher recurrence risk for  pyloric stenosis in future offspring. It would be expected that  the highest risk category would be male relatives of female pro-  bands; Table 5-1 shows that this is the case.   A similar pattern has been observed in a study of autism, a  behavioral disorder in which the male/female ratio is approxi-  mately 4:1. As expected for a multifactorial disorder, the recur-  rence risks for siblings of male probands (3.5%) is substantially  lower than that of siblings of female probands (7%). When the  sex ratio for a disease is reversed (i.e., more affected females  than males), one would expect a higher recurrence risk when  the proband is male.   A number of other congenital malformations are thought  to correspond to this model. They include isolated cleft lip and/  or cleft palate (CL/P), neural tube defects (anencephaly, spina  bifida), clubfoot (talipes), and some forms of congenital heart    TABLE 5-1 RECURRENCE RISKS   FOR PYLORIC STENOSIS,  SUBDIVIDED BY GENDERS  OF AFFECTED PROBANDS    Data from Carter CO: Br Med Bull 32(1):21-26, 1976.  Note that the risks differ somewhat between the two populations.    disease. In this context, isolated means that this is the only  observed disease feature (i.e., the feature is not part of a larger  constellation of findings, as in CL/P secondary to trisomy 13).  In addition, many common adult diseases, such as hyperten-  sion, coronary heart disease, stroke, diabetes mellitus (types 1  and 2), and some cancers, are caused by complex genetic and  environmental factors and can thus be considered multifacto-  rial diseases.    Whereas recurrence risks can be given with confidence for  single-gene diseases (e.g., 50% for typical autosomal dominant  diseases, 25% for autosomal recessive diseases), the situation is  more complicated for multifactorial diseases. This is because  the number of genes contributing to the disease is usually not  known, the precise allelic constitution of the parents is not  known, and the extent of environmental effects can vary sub-  stantially. For most multifactorial diseases, empirical risks (i.e.,  risks based on direct observation of data) have been derived. To  estimate empirical risks, a large series of families is examined  in which one child has developed the disease (the proband).  Then the siblings of each proband are surveyed to calculate the  percentage of siblings who also have developed the disease. For  example, in the United States about 3% of siblings of individu-  als with neural tube defects also have neural tube defects (Box  5-1). Thus the recurrence risk for parents who have had one  child with a neural tube defect is 3% in the United States. For  conditions such as CL/P that are not lethal or severely debilitat-  ing, recurrence risks also can be estimated for the offspring of  affected parents. Empirical recurrence risks are, of course, spe-  cific for each multifactorial disease.   In contrast to most single-gene diseases, recurrence risks  for multifactorial diseases can change substantially from one  population to another because gene frequencies as well as  environmental factors can differ among populations (note the  differences between the London and Belfast populations in  Table 5-1).   It is sometimes difficult to distinguish polygenic or multi-  factorial diseases from single-gene diseases that have reduced  penetrance or variable expression. Large data sets and good  epidemiologic data are necessary to make the distinction.  Several criteria are commonly used to define multifactorial  inheritance.    Neural tube defects (NTDs), which include anencephaly, spina bifida, and  encephalocele (as well as several other less common forms), are one of the most  important classes of birth defects, and they are seen in 0.5 to 2 of 1000 pregnan-  cies.’ The prevalence of NTDs among different populations varies considerably,  with an especially high rate among some northern Chinese populations (as high  as 6 or more per 1000 births). The prevalence of NTDs has been decreasing in  many parts of the United States and Europe during the past three decades, partly  because of dietary changes.   Normally the neural tube closes at about the fourth week of gestation. A defect  in closure, or a subsequent reopening of the neural tube, results in a neural tube  defect. Spina bifida (Figure 5-3, A) is the most commonly observed NTD and  consists of a protrusion of spinal tissue through the vertebral column (the tissue  usually includes meninges, spinal cord, and nerve roots). About 75% of individu-  als with spina bifida have secondary hydrocephalus, which sometimes in turn  produces mental retardation. Paralysis or muscle weakness, lack of sphincter  control, and clubfeet are often observed. A study conducted in British Columbia  showed that survival rates for people with spina bifida have improved dramati-  cally over the past several decades. Less than 30% of people born between 1952  and 1969 survived to 10 years of age, whereas 65% of those born between 1970  and 1986 survived to this age. Anencephaly (see Figure 5-3, B) is characterized  by partial or complete absence of the cranial vault and calvarium and partial or  complete absence of the cerebral hemispheres. At least two thirds of newborns  with anencephaly are stillborn; term deliveries do not survive more than a few  hours or days.   NTDs are thought to arise from a combination of genetic and environmental  factors. In most populations surveyed thus far, empirical recurrence risks for sib-  lings of affected people range from 2% to 5%. Consistent with a multifactorial  model, the recurrence risk increases with additional affected siblings. Studies  conducted in Great Britain showed that the sibling recurrence risk was approxi-  mately 5% when one sibling was affected and 10% when two were affected.    First, the recurrence risk becomes higher if more than one  family member is affected. For example, the sibling recur-  rence risk for a ventricular septal defect (VSD, a type of con-  genital heart defect) is 3% if one sibling has been affected by  a VSD but increases to approximately 10% if two siblings  have been diagnosed with VSDs.° In contrast, the recurrence  risk for single-gene diseases remains the same regardless of  the number of affected siblings. It should be emphasized  that this increase does not mean that the family’s risk has  actually changed. Rather, it means that there is more infor-  mation about the family’s true risk; because they have had  two affected children, they are probably located higher on  the liability distribution than a family with only one affected  child. In other words, they have more risk factors (genetic or  environmental) and are more likely to produce an affected  child.   Second, if the expression of the disease in the proband is more  severe, the recurrence risk is higher. This is again consistent with  the liability model because a more severe expression indicates  that the affected individual is at the extreme tail end of the  liability distribution (see Figure 5-2). His or her relatives are  thus at a higher risk for inheriting disease genes. For example,  the occurrence of a bilateral (both sides) CL/P confers a higher  recurrence risk on family members than does the occurrence of  a unilateral (one side) cleft.    A Hungarian study showed that the overall prevalence of NTDs was 1 in 300  births and that the sibling recurrence risks were 3%, 12%, and 25% after one,  two, and three affected offspring, respectively. Recurrence risks tend to be  slightly lower in populations with lower NTD prevalence rates, as predicted by  the multifactorial model. Recurrence risk data support the idea that the major  forms of NTDs are caused by similar factors. An anencephalic conception  increases the recurrence risk for subsequent spina bifida conceptions, and vice  versa.   NTDs can usually be diagnosed prenatally, sometimes by ultrasound and usu-  ally by an elevation in a.-fetoprotein (AFP) level in the maternal serum or amniotic  fluid (see Chapter 20). A spina bifida lesion can be either open or closed (i.e.,  covered with a layer of skin). Fetuses with open spina bifida are more likely to  be detected by AFP assays.   A major epidemiologic finding is that mothers who supplement their diet with  folic acid at the time of conception are less likely to produce children with NTDs.  This result has been replicated in several different populations and thus appears  to be well confirmed. It has been estimated that as many as 50% to 70% of  NTDs can be avoided simply by dietary folic acid supplementation.® (Traditional  prenatal vitamin supplements have little effect because administration does not  usually begin until well after the time that the neural tube closes.) It is now  recommended that all women of reproductive age supplement their diet with  0.4 mg of folic acid each day; many foods in the United States are supplemented  with folic acid. Consequently, average folate levels in U.S. females have doubled  and the incidence of neural tube defects has declined by 30% to 50% in the past  decade.   Because mothers would be likely to ingest similar amounts of folic acid  from one pregnancy to the next, folic acid deficiency could well account for at  least part of the elevated sibling recurrence risk for NTDs. This is an impor-  tant example of a nongenetic factor that contributes to familial clustering of  a disease.    Third, the recurrence risk is higher if the proband is of the  less commonly affected gender (see the preceding discussion of  pyloric stenosis). This is because an affected individual of the  less susceptible gender is usually at a more extreme position on  the liability distribution.   Fourth, the recurrence risk for the disease usually decreases  rapidly in more remotely related relatives (Table 5-2). Whereas  the recurrence risk for single-gene diseases decreases by 50%  with each degree of relationship (e.g., an autosomal dominant  disease has a 50% recurrence risk for siblings, 25% for uncle-  nephew relationships, 12.5% for first cousins), it decreases  much more quickly for multifactorial diseases. This reflects the  fact that many genes and environmental factors must combine  to produce a trait. All the necessary risk factors are unlikely to  be present in less closely related family members.   Finally, if the prevalence of the disease in a population is f,  the risk for offspring and siblings of probands is approximately  vf. This does not hold true for single-gene traits because their  recurrence risks are independent of population prevalence. It  is not an absolute rule for multifactorial traits either, but many  such diseases tend to conform to this prediction. Examination  of the risks given in Table 5-2 shows that the first three diseases  follow the prediction fairly well. However, the observed sib-    ling risk for the fourth disease, infantile autism, is substantially  higher than that predicted by yf.    FIGURE 5-3 Spina Bifida and Anencephaly. A, Spina bifida in a newborn.  B, Anencephaly, showing the absence of the cranial vault. (From Jones KL: Smith's  recognizable patterns of human malformation, ed 6, Philadelphia, Saunders, 2006,  p. 705.)    Family members share genes and a common environment.  Family resemblance in traits such as blood pressure reflects  both genes (nature) and environment (nurture). For centu-  ries people have debated the relative importance of these two  types of factors. It is a mistake, of course, to view them as  mutually exclusive. Few traits are influenced only by genes  or only by environmental factors. Most are influenced by  both. It is useful to try to determine the relative influence of  genetic and environmental factors (Figure 5-4). This can lead  to a better understanding of disease etiology. It can also help  in planning public health strategies. A disease in which the  genetic influence is relatively small, such as lung cancer, may  be prevented most effectively through emphasis on lifestyle  changes (avoidance of tobacco). When a disease has a rela-  tively larger genetic component, as in breast cancer, examina-  tion of family history should be emphasized in addition to  lifestyle modification.    FIGURE 5-4 Continuum of Genetic Diseases. Some diseases (e.g., cystic  fibrosis) are strongly determined by genes, whereas others (e.g., infectious dis-  eases) are strongly determined by environmental factors. (Adapted from Jorde LB  et al: Medical genetics, ed 4, St Louis, 2010, Mosby.)    TABLE 5-2 RECURRENCE RISKS  FOR  FIRST-, SECOND-, AND  THIRD-DEGREE RELATIVES    FIRST SECOND THIRD GENERAL  DEGREE DEGREE DEGREE POPULATION  Cleft lip/palate 4 0.7 0.3 0.1  Clubfoot 25) 0.5 0.2 0.1  Congenital hip 8) 0.6 0.4 0.2    Here, two research strategies are reviewed that often are used  to estimate the relative influence of genes and environment:  twin studies and adoption studies.   Twins occur with a frequency of about 1 in 100 births in white  populations. They are a bit more common in blacks and a bit  less common among Asians. Monozygotic (MZ, identical)  twins originate when, for unknown reasons, the developing  embryo divides to form two separate but identical embryos.  Because they are genetically identical, MZ twins are an example  of natural clones. Dizygotic (DZ, fraternal) twins are the result  of a double ovulation followed by the fertilization of each egg  by a different sperm. Thus dizygotic twins are genetically no  more similar than siblings. Because two different sperm cells  are required to fertilize the two eggs, it is possible for each DZ  twin to have a different father. Whereas MZ twinning rates are  constant across populations, DZ twinning rates vary somewhat.  DZ twinning increases with maternal age until about 40 years,  after which it declines.   Because MZ twins are genetically identical, any differences  between them should be caused only by environmental effects.’  MZ twins should thus resemble one another very closely for  traits that are strongly influenced by genes. DZ twins provide  a convenient comparison because their environmental differ-  ences should be similar to those of MZ twins, but their genetic  differences are as great as those between siblings. Twin studies  thus usually consist of comparisons between MZ and DZ twins.®  If both members of a twin pair share a trait (e.g., a cleft lip), it is  said to be a concordant trait. If they do not share the trait, it is  a discordant trait. For a trait determined totally by genes, MZ  twins should always be concordant, whereas DZ twins should    be concordant less often, because they, like siblings, share only  50% of their genes. Concordance rates may differ between  opposite-sex DZ twin pairs and same-sex DZ pairs for some  traits, such as those that have different frequencies in males and  females. For such traits, only same-sex DZ twin pairs should be  used when comparing MZ and DZ concordance rates, because  MZ twins are necessarily of the same sex.   Table 5-3 gives concordance rates for a number of traits.  Note that the concordance rates for contagious diseases such as  measles are quite similar in MZ and DZ twins. This is expected  because a contagious disease is unlikely to be influenced mark-  edly by genes. On the other hand, the concordance rates are  quite dissimilar for schizophrenia and bipolar affective disorder,  suggesting a sizable genetic component for these diseases. The  MZ correlations for dermatoglyphics (fingerprints), which are  determined almost entirely by genes, are close to 1.0.   At one time, twins were thought to provide a perfect “natu-  ral laboratory” in which to determine the relative influences of  genetics and environment, but several difficulties arose. One of  the most important is the assumption that the environments  of MZ and DZ twins are equally similar. As one would expect,  MZ twins are often treated more similarly than DZ twins. A  greater similarity in environment can make MZ twins more  concordant for a trait, inflating the apparent influence of genes.  In addition, MZ twins may be more likely to seek the same type  of environment, further reinforcing environmental similarity.  On the other hand, it has been suggested that MZ twins tend  to develop personality differences in an attempt to assert their  individuality.    Studies of adopted children also are used to estimate the genetic  contribution to a multifactorial trait. Children born to par-  ents who have a disease but are then subsequently adopted by  parents lacking the disease can be studied to find out whether  these children develop the disease. In some cases such children  develop the disease more often than a comparative control  population (i.e., adopted children who were born to parents  who do not have the disease). This provides some evidence that  genes may be involved in the causation of the disease, because  the adopted children do not share an environment with their  affected natural parents. For example, about 8% to 10% of  adopted children of a schizophrenic parent develop schizophre-  nia, whereas only 1% of adopted children of normal parents  develop schizophrenia.   As with twin studies, several precautions must be exercised  in interpreting the results of adoption studies. First, prenatal  environmental influences could have long-lasting effects on an  adopted child. Second, children are sometimes adopted after  they are several years old, ensuring that some environmental  influence would have been imparted by the natural parents.  Finally, adoption agencies sometimes try to match the adoptive  parents with the natural parents in terms of background, socio-  economic status, and so on. All of these factors could exaggerate  the apparent influence of biologic inheritance.   These reservations, as well as those summarized for twin  studies, underscore the need for caution in basing conclusions    TABLE 5-3 CONCORDANCE RATES IN MZ  AND DZ TWINS FOR SELECTED  TRAITS AND DISEASES    Affective disorder 0.79 0.24 site  (bipolar)  Affective disorder 0.54 f 0.7  (unipolar)  Alcoholism ! 0.6  Autism >1  Blood pressure  (diastolic)'  Blood pressure 0155  (systolic)!  Body fat percentage’ 0.73 0.22  Body mass index’ 0.95 0.53  Cleft lip/palate 0.38 0.08  Clubfoot 0.32 0.03  Dermatoglyphics 0.95 0.49  (finger ridge count)"  Diabetes mellitus 0.45-0.96 0.03-0.37  Diabetes mellitus O55 —  (type 1)  Diabetes mellitus  (type 2)  Epilepsy (idiopathic)  Height!  Intelligence quotient  (0)"  Measles  Multiple sclerosis  Myocardial infarction  (males)  Myocardial infarction  (females)  Schizophreni  Spina bifida    *Note: Heritability, which is defined as the proportion of the variation  in a trait that is due to genetic factors, can be measured as 2(Cyz -  Cpz), where Cyz and Cp are the concordance rates for MZ twins and  DZ twins, respectively. These figures were compiled from a large vari-  ety of sources and represent primarily European and U.S. populations.  Several heritability estimates exceed 1. Because it is impossible for  >100% of the variance of a trait to be genetically determined, these  values indicate that other factors, such as shared environmental fac-  ors, must be operating.   Because these are quantitative traits, correlation coefficients are  given rather than concordance rates.    on twin and adoption studies. These approaches do not provide  definitive measures of the role of genes in multifactorial dis-  ease nor can they identify specific genes responsible for disease.  Instead, they serve a useful purpose in providing a preliminary  indication of the extent to which a multifactorial disease may be  caused by genetic factors. Sophisticated molecular techniques  are being used to identify the specific genes that underlie pre-  disposition to multifactorial diseases.    o.,-Antitrypsin (c.,-AT) deficiency is one of the most common autosomal reces-  sive disorders among whites, affecting approximately 1 in 2500 members of  this ethnic group. o-AT, synthesized primarily in the liver, is a serine protease  inhibitor. It does bind trypsin, as its name suggests. However, o-AT binds  much more strongly to neutrophil elastase, a protease that is produced by  neutrophils (a type of leukocyte) in response to infections and irritants. It car-  ries out its binding and inhibitory role primarily in the lower respiratory tract,  where it prevents elastase from digesting the alveolar septi of the lung.   Individuals with less than 10% to 15% of the normal level of a,-AT activ-  ity will experience significant lung damage and typically develop emphysema  during their 30s, 40s, or 50s. In addition, at least 10% develop liver cirrhosis  as a result of the accumulation of variant o.,-AT molecules in the liver; a,-AT  deficiency accounts for nearly 20% of all nonalcoholic liver cirrhosis cases in  the United States. An important feature of this disease is that cigarette smok-  ers with a-AT deficiency develop emphysema much earlier than do nonsmok-  ers. This is because cigarette smoke irritates lung tissue, increasing secretion  of neutrophil elastase. At the same time it inactivates a-AT, so there is also  less inhibition of elastase. One study showed that the median age of survival  of nonsmokers with o,-AT deficiency was 62 years, whereas it was only 40  years for smokers with this disease. Because the combination of cigarette  smoking (an environmental factor) and the a,;-AT mutation (a genetic factor)  produces more severe disease than either factor alone, it is an example of a  gene-environment interaction.    This discussion should make clear that most common dis-  eases are not the result of either genetics or environment.  Instead, genetic and nongenetic factors usually interact to  influence one’s likelihood of developing a common disease. In  some cases a genetic predisposition may interact with an envi-  ronmental factor to increase the risk of disease acquisition to  a much higher level than would either factor acting alone. A  good example of a gene-environment interaction is given by  ,-antitrypsin deficiency, a genetic condition that causes pul-  monary emphysema and is greatly exacerbated by cigarette  smoking (Box 5-2).    Some common multifactorial disorders, the congenital malfor-  mations, are by definition present at birth. Others, including  heart disease, cancer, diabetes, and most psychiatric disorders,  are seen primarily in adolescents and adults. Because these dis-  orders are complex, unraveling their genetics is a daunting task.  Nonetheless, significant progress is being made.    Congenital diseases are present at birth. Approximately 2%  of newborns present with a congenital malformation; most of  these are multifactorial in etiology. Table 5-4 lists some more  common congenital malformations. In general, sibling recur-  rence risks for most of these disorders range from 1% to 5%.  Some congenital malformations, such as CL/P and pyloric  stenosis, are relatively easy to repair and thus are not consid-  ered to be serious problems. Others, such as the neural tube    defects, usually have more severe consequences. Although some  cases of congenital malformations occur in the absence of any  other problems, it is quite common for them to be associated  with other disorders. For example, hydrocephaly and clubfoot  are often seen secondary to spina bifida, CL/P is often seen in  babies with trisomy 13, and congenital heart defects are seen in  children with many other disorders, including Down syndrome.   Environmental factors also cause some congenital malfor-  mations. An example is thalidomide, a sedative used during  pregnancy in the early 1960s. When ingested during early preg-  nancy this drug often caused phocomelia (severely shortened  limbs) in babies. Maternal exposure to retinoic acid, which is  used to treat acne, can cause congenital defects of the heart,  ear, and central nervous system. Maternal rubella infection can  cause congenital heart defects.    Until quite recently, very little was known about specific genes  responsible for common adult diseases. With the more powerful  laboratory and analytic techniques now available, this situation  is changing. This section reviews recent progress in understand-  ing the genetics of the major common adult diseases. Table 5-5  gives approximate prevalence figures for these disorders in the  United States.    It is well-known that coronary heart disease (CHD) is the lead-  ing killer of Americans, accounting for approximately 25% of  all deaths in the United States. It is caused by atherosclerosis  (narrowing as a result of the formation of lipid-laden lesions)  of the coronary arteries. This narrowing impedes blood flow  to the heart and can eventually result in a myocardial infarc-  tion (destruction of heart tissue caused by an inadequate  supply of oxygen). When atherosclerosis occurs in arteries sup-  plying blood to the brain, a stroke can result. Many risk fac-  tors for heart disease have been identified, including obesity,  cigarette smoking, hypertension, elevated cholesterol level, and  positive family history (usually defined as having one affected  first-degree relative). Many studies have examined the role of  family history in CHD, and they show that an individual with a  positive family history is two to seven times more likely to have  heart disease than is an individual with no family history (this  would be the relative risk of heart disease as a result of a positive    TABLE 5-5 PREVALENCE OF COMMON  ADULT DISEASES IN THE  UNITED STATES    Alcoholism 14 million  Alzheimer disease 4 million  Arthritis 43 million  Asthma 17 million  Cancer 8 million  Cardiovascular disease (all forms)   Stroke 5 million  Depression and bipolar disorder 17 million  Diabetes (type 1) 1 million  Diabetes (type 2) 15 million  Epilepsy 2.5 million  Multiple sclerosis 350,000  Obesity* 60 million  Parkinson disease 500,000  Psoriasis 3-5 million  Schizophrenia 2 million    Data from National Center for Chronic Disease Prevention and Health  Promotion; American Heart Association (2002 Heart and Stroke Sta-  tistical Update); National Institute on Alcohol Abuse and Alcoholism;  Office of the U.S. Surgeon General; American Academy of Allergy,  Asthma and Immunology; Cown WM, Kandel ER: JAMA 285:594-600,  2001; Flegal et al: JAMA 288:1723-1727, 2002.    family history). Generally, these studies also show that the risk  increases if (1) there are more affected relatives; (2) the affected  relative or relatives are female (the less commonly affected sex)  rather than male; and (3) the age of onset in the affected rela-  tive is early (before 55 years). For example, one study showed  that men between the ages of 20 and 39 years had a relative risk  of 3 for CHD if they had one affected first-degree relative. The  relative risk increased to 13 if two first-degree relatives were  affected with CHD before 55 years of age.'!   What part do genes play in the familial clustering of heart  disease? Because of the key role of lipids in atherosclerosis,  many studies are focusing on the genetic determination of  various lipoproteins.'* An important advance in this area has  been the isolation and cloning of the gene for the low-density  lipoprotein (LDL)-receptor defects that cause familial hyper-  cholesterolemia (Box 5-3). Many other genes involved in lipid  variation, coagulation, and hypertension have been identified,  including several genes encoding apolipoproteins (the protein  components of lipoproteins) (Table 5-6).!> Functional analy-  sis of these genes is leading to an increased understanding, and  eventually more effective treatment, of CHD.   Environmental factors, many of which are easily modified,  are also important causes of CHD. Abundant epidemiologic  evidence shows that cigarette smoking and obesity increase the  risk of CHD, whereas exercise and a diet low in saturated fats    decrease the risk. Indeed, the approximate 50% decline in CHD  prevalence in the United States during the past 40 years is usu-  ally attributed to a decrease in the proportion of adults who  smoke cigarettes, a decreased consumption of saturated fats,  and an increased emphasis on exercise and a generally healthier  lifestyle.    Systemic hypertension, which has a worldwide prevalence  of approximately 25% to 30%, is a key risk factor for heart  disease, stroke, and kidney disease. Studies of blood pres-  sure correlations within families indicate that about 20%  to 40% of the variation in both systolic and diastolic blood  pressure is caused by genetic factors. The fact that this figure  is substantially less than 100% indicates that environmen-  tal factors also must be important causes of blood pressure  variation. The most important environmental risk factors for  hypertension are increased sodium intake, decreased physi-  cal activity, psychosocial stress, and obesity (but, as discussed  later, the latter factor is itself influenced by both genes and  environment).   Blood pressure regulation is a highly complex process that  is influenced by many physiologic systems, including various  aspects of kidney function, cellular ion transport, and heart  function.'* Because of this complexity, much research is now  focused on specific components that may influence blood pres-  sure variation, such as the renin-angiotensin system (involved  in sodium reabsorption and vasoconstriction), vasodilators  such as nitric oxide and the kallikrein-kinin system, and ion-  transport systems such as adducin and sodium-lithium coun-  tertransport (Figure 5-7). These individual factors are more  likely to be under the control of smaller numbers of genes than  is blood pressure itself, simplifying the task of identifying these  genes and their role in blood pressure regulation. For example,  linkage and association studies have implicated several genes  involved in the renin-angiotensin system (e.g., the genes that  encode angiotensinogen, angiotensin-converting enzyme,  type 1 and angiotensin II type 1 receptor) in the causation of  hypertension.    Cancer is the second leading cause of death in the United States.  It is well established that many major types of cancer (e.g.,  breast, colon, prostate, ovarian) cluster strongly in families.  This is caused by both shared genes and shared environmental  factors. Although numerous cancer genes are being isolated,'°  environmental factors also play an important role in causing  cancer. In particular, tobacco use is estimated to account for  one third of all cancer cases in the United States, making it the  most important known cause of cancer.!°   Breast Cancer. Breast cancer is the most common cancer  among women, affecting approximately 12% of American  women who live to 85 years or more. Formerly the leading cause  of cancer death among women, it has been surpassed by lung  cancer. Breast cancer aggregates strongly in families. If a woman  has one affected first-degree relative, her risk of developing  breast cancer doubles. This risk increases if the age of onset in    Autosomal dominant familial hypercholesterolemia (FH) is an important cause  of heart disease, accounting for approximately 5% of myocardial infarctions in  individuals less than 60 years of age. FH is one of the most common autosomal  dominant disorders: in most populations surveyed to date, about 1 in 500 people  is a heterozygote. Plasma cholesterol levels are approximately twice as high as  normal (i.e., about 300 to 400 mg/dl), resulting in substantially accelerated ath-  erosclerosis and distinctive cholesterol deposits in skin and tendons (xanthomas  see Figure 5-5]). Data compiled from five studies showed that approximately  75% of men with FH developed coronary disease and 50% had a fatal myocardial  infarction by 60 years. The corresponding percentages for women were lower  (45% and 15%) because women generally develop heart disease at a later age  than men.   Consistent with Hardy-Weinberg predictions, about 1 in 1 million births is  homozygous for the FH gene. Homozygotes are much more severely affected,  with cholesterol levels ranging from 600 to 1200 mg/dl. Most experience myo-  cardial infarctions before 20 years of age, and a myocardial infarction at 18  months of age has been reported. If untreated, most FH homozygotes die before  30 years of age.   All cells require cholesterol as a component of their plasma membrane. They   can either synthesize their own cholesterol or, preferably, obtain it from the  extracellular environment, where it is carried primarily by low-density lipopro-  tein (LDL). In a process known as endocytosis, LDL-bound cholesterol is taken  into the cell via LDL receptors on the cell's surface (see Figure 5-6). FH is most  commonly caused by a reduction in the number of functional LDL receptors on  cell surfaces. Lacking the normal number of LDL receptors, cellular cholesterol  uptake is reduced and circulating cholesterol levels increase.  Much of what we know about endocytosis has been learned through the study  of LDL receptors. The process of endocytosis and the processing of LDL in the  cell are described in detail in Figure 5-6 (endocytosis is discussed in Chapter 1).  These processes result in a fine-tuned regulation of cholesterol levels within  cells, and they influence the level of circulating cholesterol as well.   The identification of the LDL receptor gene in 1984 was critical in understand-  ing exactly how LDL receptor defects cause FH. More than 1000 different muta-  tions, including missense and nonsense substitutions as well as insertions and    deletions, have been identified in the LDL receptor gene. These can be grouped  into five broad classes according to their effects on the activity of the receptor. '?  Class 1 mutations result in no detectable protein product. Thus heterozygotes  would produce only half the normal number of LDL receptors. Class 2 mutations  in the LDL receptor gene result in production of the LDL receptor, but it is altered  such that it cannot leave the endoplasmic reticulum. It is eventually degraded.  Class 3 mutations produce an LDL receptor that is capable of migrating to the  cell surface but incapable of normal binding to LDL. Class 4 mutations, which are  comparatively rare, produce receptors that are normal except that they do not  migrate specifically to coated pits and thus cannot carry LDL into the cell. The  final group of mutations, class 5, produces an LDL receptor that cannot dissoci-  ate from the LDL particle after entry into the cell. The receptor cannot return to  the cell surface and is degraded. Each class of mutations reduces the number of  effective LDL receptors, resulting in decreased LDL uptake and hence elevated  levels of circulating cholesterol. The number of effective receptors is reduced  by about half in FH heterozygotes, and homozygotes have virtually no functional  LDL receptors.   Understanding the defects that lead to FH has helped to develop effective  therapies for the disorder. Dietary reduction of cholesterol (primarily through the  reduced intake of saturated fats) has only modest effects on cholesterol levels  in FH heterozygotes. Because cholesterol is reabsorbed into the gut and then  recycled through the liver (where most cholesterol synthesis takes place), serum  cholesterol levels can be reduced by the administration of bile acid—absorbing  resins, such as cholestyramine. The absorbed cholesterol is then excreted. It is  interesting that reduced recirculation from the gut causes the liver cells to form  additional LDL receptors, lowering circulating cholesterol levels. However, the  decrease in the concentration of intracellular cholesterol also stimulates choles-  terol synthesis by liver cells, so the overall reduction in plasma LDL level is only  about 15% to 20%. This treatment is much more effective when combined with  agents that reduce cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutary|  coenzyme A (HMG-CoA) reductase (the “statin” class of drugs). Decreased synthe-  sis leads to further production of LDL receptors. When these therapies are used  in combination, serum cholesterol levels in FH heterozygotes can be reduced to  approximately normal levels.   The picture is less encouraging for FH homozygotes. The therapies just dis-  cussed can enhance cholesterol elimination and reduce its synthesis, but they  are largely ineffective because homozygotes have few or no LDL receptors.  Liver transplants, which provide hepatocytes that have normal LDL receptors,  have been successful in some cases, but this option is often limited by a lack  of donors. Plasma exchange, carried out every 1 to 2 weeks, in combination  with drug therapy, can reduce cholesterol levels by about 50%. However, this  therapy is difficult to continue for long periods. Somatic cell gene therapy, in  which hepatocytes carrying normal LDL receptor genes are introduced into the  portal circulation, is now being tested. It may eventually prove to be an effective  treatment for FH homozygotes.   The FH story illustrates how medical research has made important contribu-  tions both to our understanding of basic cell biology and to advances in clinical  therapy. The process of receptor-mediated endocytosis, elucidated largely by  research on the LDL receptor defects, is of fundamental significance for cellular  processes throughout the body. Equally important is that this research, by clarify-  ing how cholesterol synthesis and uptake can be modified, has led to significant  improvements in therapy for this important cause of heart disease.    Illustration from Damjanov |: Pathology for the health professions, ed 4, Philadelphia, 2012, Saunders.    FIGURE 5-5 Xanthoma. Fatty deposits, referred to as xanthomas as seen here  on the knuckles, are often noted in individuals with familial hypercholesterolemia.  (From Jorde LB et al: Medical genetics, ed 4, St Louis, 2010, Mosby.)    the affected relative is early and if the cancer is bilateral (tumors  in both breasts).   An autosomal dominant form of breast cancer accounts for  approximately 5% of breast cancer cases in the United States.  Genes responsible for this form of breast cancer have been  mapped to chromosomes 17 (BRCA1) and 13 (BRCAZ2). It is  possible to test each of these genes for inherited cancer-caus-  ing mutations.'? Women who inherit a mutation in BRCA1 or  BRCA2 experience a 50% to 80% lifetime risk of developing  breast cancer. BRCAI mutations also increase the risk of ovar-  ian cancer among women (20% to 50% lifetime risk), and they  confer a modestly increased risk of prostate and colon cancers.  BRCA2 mutations also confer an increased risk of ovarian can-  cer (10% to 20% lifetime prevalence). Approximately 6% of  males who inherit a BRCA2 mutation will develop breast can-  cer; this represents a 100-fold increase over the risk in the gen-  eral male population. The evaluation of the BRCA1 and BRCA2  gene products, which are both involved in deoxyribonucleic  acid (DNA) repair, is yielding valuable evidence on the etiology  of breast cancer in general.   Although BRCA1 and BRCA2 mutations are the most com-  mon known causes of inherited breast cancer, this disease also  can be caused by inherited mutations in several other tumor-  suppressor genes (e.g., the CHK2 and TP53 genes). Germline  mutations in a tumor-suppressor gene called PTEN are respon-  sible for Cowden disease, which is characterized by multiple  benign tumors and an increased susceptibility to breast cancer.   Colorectal Cancer. Colorectal cancer is second only to lung  cancer in the number of cases occurring annually in the United  States, with approximately 143,000 new cases (and 52,000  deaths) estimated in 2012.'* Approximately 1 in 20 Americans  will develop colorectal cancer. Like breast cancer, it clusters in  families (in fact, familial clustering of this form of cancer was  reported in the medical literature as early as 1881). The risk  of colorectal cancer in people with one affected first-degree  relative is two to three times higher than that in the general  population.    This familial aggregation is caused in part by subsets of  colorectal cancer cases that are inherited as single-gene traits.  Familial adenomatous polyposis occurs in approximately 1  in 8000 whites. The gene responsible for this disorder, APC,  encodes a tumor suppressor.'? Importantly, somatic muta-  tions of APC are found in at least 85% of all colon tumors. Thus  although inherited APC mutations play a vital role in relatively  rare familial adenomatous polyposis, somatic mutations are  involved in the great majority of all common colon cancers.   Hereditary nonpolyposis colorectal cancer, which may account  for as many as 5% of colorectal cancer cases, is caused by muta-  tions in any of six genes.”° Identification has shown that all of  these genes are involved in the vital process of DNA repair.  When this function is compromised, cancer-causing mutations  can persist in cells, leading eventually to growth of a tumor.   Other colorectal cancer cases are likely to be caused by a  complex interaction of multiple genes. In addition, environ-  mental factors, such as a high-fat, low-fiber diet, are thought to  increase the risk of colorectal cancer.   Other Cancers. The genetic basis of various other cancers,  including retinoblastoma, has been discussed. Although  each of these cancers is relatively rare, study of the causative  genes has provided many important insights into the nature  of carcinogenesis in general. This will lead to more effective  treatment and prevention of all cancers.    Like the other disorders discussed in this chapter, the etiology  of diabetes mellitus is complex and not fully understood. Nev-  ertheless, progress is being made in understanding the genetic  basis of this disorder, which is a leading cause of blindness,  heart disease, and kidney failure.*!? An important advance has  been the recognition that diabetes is actually a heterogeneous  group of disorders, all characterized by elevated blood glucose  level. The focus here is on the two major types of diabetes: type  1 (insulin-dependent diabetes mellitus [IDDM]) and type 2  (non—insulin-dependent diabetes mellitus [NIDDM]).   Type 1 Diabetes. Type 1 diabetes, which is characterized by  T-cell infiltration of the pancreas and destruction of the insulin-  producing beta cells, usually (though not always) presents  before age 40. Individuals with type 1 diabetes must receive  exogenous insulin to survive. In addition to T-cell infiltration of  the pancreas, autoantibodies are formed against pancreatic cells;  the latter can be observed long before clinical symptoms occur.  These findings, along with a strong association between type 1  diabetes and the presence of several human leukocyte antigen  (HLA) class II alleles, indicate that this is an autoimmune  disease.   Siblings of individuals with type 1 diabetes face a substan-  tial elevation in risk: approximately 6%, as opposed to a risk of  about 0.3% to 0.5% in the general population. The recurrence  risk is also elevated when there is a diabetic parent, although  this risk varies with the sex of the affected parent. The risk for  offspring of diabetic mothers is only 1% to 3%, whereas it is  4% to 6% for the offspring of diabetic fathers (because type 1  diabetes affects males and females in roughly equal proportions  in the general population, this risk difference is inconsistent    FIGURE 5-6 Process of Receptor-Mediated Endocytosis. Numbers in parentheses correspond to numbers shown in  the figure. (1) The low-density lipoprotein (LDL) receptors, which are glycoproteins, are synthesized in the endoplasmic reticu-  lum of the cell. (2) From here, they pass through the Golgi apparatus to the cell surface, where part of the receptor protrudes  outside the cell. (3) The circulating LDL particle is bound by the LDL receptor and localized in cell surface depressions called  coated pits (so named because they are coated with a protein called clathrin). (4) The coated pit invaginates, bringing the  LDL particle inside the cell. (5) Once inside the cell, the LDL particle is separated from the receptor, taken into a lysosome,  and broken down into its constituents by lysosomal enzymes. (6) The LDL receptor is recirculated to the cell surface to bind  another LDL particle (each LDL receptor goes through this cycle approximately once every 10 minutes even if it is not occupied  by an LDL particle). (7) Free cholesterol is released from the lysosome for incorporation into cell membranes or metabolism  into bile acids or steroids. Excess cholesterol can be stored in the cell as a cholesterol ester or removed from the cell by asso-  ciating with high-density lipoprotein (HDL). (8) As cholesterol levels in the cell rise, cellular cholesterol synthesis is reduced  by inhibition of the rate-limiting enzyme HMG-CoA (3-hydroxy-3-methylglutary! coenzyme A) reductase. (9) Rising cholesterol  levels also increase the activity of acyl coenzyme A (acyl CoA): cholesterol acyltransferase (ACAT), an enzyme that modifies  cholesterol for storage as cholesterol esters. (10) In addition, the number of LDL receptors is decreased by lowering the tran-  scription rate of the LDL receptor gene itself. This decreases cholesterol uptake. (From Jorde LB et al: Medical genetics, ed 4,  St Louis, 2010, Mosby.)   Ligand for LDL receptor; involved in formation of VLDL, LDL, IDL, and chylomicrons  HDL component    Adapted in part from King RA, Rotter JI, editors: The genetic basis of common diseases, ed 2, New York, 2002, Oxford University Press.  HDL, High-density lipoprotein; IDL, intermediate-density lipoprotein; LCAT, lecithin cholesterol acyltransferase; LDL, low-density lipoprotein; VLDL,  very-low-density lipoprotein.    Feedback to kidneys  J Renin secretion  FIGURE 5-7 Renin-Angiotensin-Aldosterone System. (Modified from King RA, Rotter JI, Motulsky AG (eds): The  genetic basis of common diseases, New York, Oxford University Press, 1992. In Jorde LB et al: Medical genetics, ed 4,  St. Louis, 2010, Mosby.)    with the sex-specific threshold model for multifactorial traits).  Twin studies show that the empirical risks for identical twins of  people with type 1 diabetes range from 30% to 50%. In contrast,  the concordance rates for dizygotic twins are 5% to 10%. The  fact that type 1 diabetes is not 100% concordant among iden-  tical twins indicates that genetic factors are not solely respon-  sible for the disorder. There is good evidence that specific viral  infections contribute to the causation of type 1 diabetes in at  least some individuals, possibly by activating an autoimmune  response.   The association of specific HLA class II alleles (see Chap-  ter 22) and type 1 diabetes has been studied extensively, and  it is estimated that the HLA system accounts for about 40% of  the familial clustering of type 1 diabetes. Approximately 95%  of whites with type 1 diabetes have the HLA DR3 and/or DR4  alleles, whereas only about 50% of the general white population  has either of these alleles. If an affected proband and a sibling  are heterozygous for the DR3 and DR4 alleles, the sibling’s risk  of developing type 1 diabetes is nearly 20% (i.e., about 40 times  higher than the risk in the general population). In addition,  the presence of aspartic acid at position 57 of the DQ chain is  strongly associated with resistance to type 1 diabetes. In fact,  those who do not have this amino acid at position 57 (and  instead are homozygous for a different amino acid) are 100  times more likely to develop type 1 diabetes. The aspartic acid  substitution alters the shape of the HLA class II molecule and  thus its ability to bind and present peptides to T cells. Altered  T-cell recognition may help protect individuals with the aspar-  tic acid substitution from an autoimmune episode.   The insulin gene, which is located on the short arm of chro-  mosome 11, is another logical candidate for type 1 diabetes sus-  ceptibility. Polymorphisms within and near this gene have been  tested for association with type 1 diabetes. It is estimated that  inherited genetic variation in the insulin region accounts for  approximately 10% of the familial clustering of type 1 diabetes.   Within the past several years, additional genes have been  shown to be associated with susceptibility to type 1 diabetes. The  most significant of these are cytotoxic lymphocyte associated-4  (CTLA4), which encodes a protein involved in the regulation of  T-cell proliferation, and PTPN22, which encodes a lymphoid-  specific tyrosine phosphatase that negatively regulates T-cell  activation. It is interesting that variation in the latter gene has  been associated with several other autoimmune diseases, includ-  ing systemic lupus erythematosus (SLE), rheumatoid arthritis,  and autoimmune thyroid disease.   Type 2 Diabetes. Type 2 diabetes accounts for more than  90% of all diabetes cases and affects 10% to 20% of the adult  populations of many developed countries. A number of  features distinguish it from type 1 diabetes. There is nearly  always some endogenous insulin production in people with  type 2 diabetes, and the disease can often be treated successfully  with dietary modification and/or oral drugs. People with type  2 diabetes suffer from insulin resistance (i.e., their cells have  difficulty in using insulin). This disease typically occurs among  people older than age 40 and, in contrast to type 1 diabetes,  is seen more commonly among the obese. The incidence of  type 2 diabetes is rising dramatically among adolescents and    young adults in developed countries, however, and is strongly  correlated with an increased incidence of obesity. Neither HLA  associations nor autoantibodies are seen commonly in this  form of diabetes. Monozygotic twin concordance rates are  substantially higher than those seen in type 1 diabetes, often  exceeding 90% (because of age dependence, the concordance  rate increases if older subjects are studied). The empirical  recurrence risks for first-degree relatives of type 2 diabetes  cases are higher than those for type 1, generally ranging from  15% to 40%. The differences between type 1 and type 2 diabetes  are summarized in Table 5-7.   Hundreds of studies have been undertaken to identify genes  that may contribute to type 2 diabetes susceptibility. The most  significant gene identified thus far is TCF7L2, which encodes a  transcription factor involved in the secretion of insulin. A vari-  ant of TCF7L2 is associated with a 50% increased risk of devel-  oping type 2 diabetes. A significant association has also been  observed between type 2 diabetes and a common allele of the  gene that encodes peroxisome proliferator—activated receptor-  gamma (PPAR-y), a transcription factor that is involved in  adipocyte differentiation and glucose metabolism. Although  this allele confers only a 25% increase in the risk of developing  type 2 diabetes, it is found in more than 75% of individuals of  European descent and thus helps to account for a significant  proportion of type 2 diabetes cases. Variation in KCNJ11, which  encodes a potassium channel necessary for glucose-stimulated  insulin secretion, confers an additional 20% increase in type 2  diabetes susceptibility. The associations between diabetes sus-  ceptibility and each of these genes have been widely replicated  in multiple populations.   The two most important risk factors for type 2 diabetes are  positive family history and obesity; the latter increases insulin  resistance. The disease tends to rise in prevalence when pop-  ulations adopt a diet and exercise pattern typical of U.S. and  European populations. Increases have been seen, for example,  among Japanese immigrants to the United States and among  some native populations of the South Pacific, Australia, and the  Americas. Several studies, conducted on male and female sub-  jects, have shown that regular exercise can substantially lower    one’s risk of developing type 2 diabetes, even among individuals  with a family history of the disease. This is partly because exer-  cise reduces obesity. However, even in the absence of weight  loss, exercise increases insulin sensitivity and improves glucose  tolerance.   Because of the dramatic increase in obesity in the United  States and other developed countries, the prevalence of type 2  diabetes is also rising rapidly, and the average age of onset is  decreasing. A small proportion of type 2 diabetes cases occurs  early in life, typically before 25 years of age, and typically exhib-  its autosomal dominant inheritance (unlike most type 2 diabe-  tes cases). This subset is termed maturity-onset diabetes of the  young (MODY). Studies of MODY pedigrees have shown that  about half of cases of the disease are caused by mutations in  the glucokinase gene. Glucokinase converts glucose to glucose-  6-phosphate in the pancreas. In addition to the glucokinase  gene, five other genes, all of which are involved in pancreatic  development or regulation of insulin levels, have now been  shown to be causes of MODY.    Obesity is most commonly defined as a body mass index (BMI)  greater than 30.* Using this criterion, approximately one third  of American adults are obese, and an additional one third are  overweight (BMI greater than 25 but less than 30). The propor-  tion of obese adults and children continues to increase rapidly.  Although obesity itself is not a “disease,” it is an important risk  factor for several common diseases, including heart disease,  stroke, hypertension, and type 2 diabetes.   As one might expect, there is a strong correlation between  obesity in parents and their children. This could easily be  ascribed to common environmental effects: parents and chil-  dren usually share similar dietary and exercise habits. How-  ever, there is good evidence for genetic components as well.  Four adoption studies each showed that the body weights of  adopted individuals correlated significantly with their natural  parents’ body weights but not with those of their adoptive par-  ents. Twin studies also provide evidence for a genetic effect on  body weight, with most studies yielding heritability estimates  between 0.60 and 0.80.   Research, aided substantially by mouse models, has shown  that several genes each play a role in human obesity. Important  among these are the genes that encode leptin (Greek, “thin”)  and its receptor. The leptin hormone is secreted by adipocytes  (fat storage cells) and binds to receptors in the hypothalamus,  the site of the body’s appetite control center. Cloning of the  human leptin gene and its receptor led to optimistic predic-  tions that leptin could be a key to weight loss in humans (with-  out the perceived unpleasantness of dieting and exercise).  Although mutations in the human leptin gene and its recep-  tor have been identified in a few humans with severe obesity  (BMI >40), they both appear to be extremely rare. Clinical  trials using recombinant leptin have demonstrated moderate  weight loss in a subset of obese individuals. In addition, leptin    *BMI is defined as W/H?, in which W is weight in kilograms and H is  height in meters.    participates in important interactions with other components  of appetite control, such as neuropeptide Y and a-melanocyte-  stimulating hormone and its receptor, the melanocortin-4  receptor (MC4R). Mutations in the gene that encodes MC4R  have been found in 3% to 5% of severely obese individuals.  Recently, homozygosity for a DNA variant in the FTO gene  (which is seen in 16% of whites) has been associated with  40% and 70% increases in the risks of overweight and obesity,  respectively. Identification of these human genes is leading to  a better understanding of natural weight control in the human,  and it could eventually lead to effective treatments for some  cases of obesity.   Alzheimer disease (AD), which is responsible for 60% to 70%  of cases of progressive cognitive impairment among older  adults, affects approximately 5% to 10% of the population  older than 65 years of age and 40% of the population older  than 85 years of age. Because of the aging of the population,  the number of Americans with AD is predicted to increase  substantially during the coming decade. AD is characterized  by progressive dementia and memory loss and by the forma-  tion of amyloid plaques and neurofibrillary tangles in the  brain, particularly in the cerebral cortex and hippocampus.  The plaques and tangles lead to progressive neuronal loss, and  death usually occurs within 7 to 10 years after the first appear-  ance of symptoms.   The risk of developing AD doubles in individuals who have  an affected first-degree relative. Although most cases do not  appear to be caused by single loci, approximately 10% follow  an autosomal dominant mode of transmission. About 3% to  5% of AD cases occur before age 65 and are considered early  onset; these are much more likely to be inherited in autosomal  dominant fashion.”   AD is a genetically heterogeneous disorder. Approximately  half of early-onset cases can be attributed to mutations in any  of three genes, all of which affect amyloid-f deposition.** Two  of the genes, presenilin 1 (PS1) and presenilin 2 (PS2), are very  similar to one another, and their protein products are involved  in cleavage of the amyloid-B precursor protein (APP). When  APP is not cleaved normally, a long form of it accumulates  excessively and is deposited in the brain. This is thought to be a  primary cause of AD. Mutations in PS] typically result in espe-  cially early onset of AD, with the first occurrence of symptoms  in the fifth decade of life.   A small number of cases of early-onset AD are caused by  mutations of the gene that encodes APP itself, which is located  on chromosome 21. These mutations disrupt normal cleavage  sites in APP, again leading to the accumulation of the longer  protein product. It is interesting that this gene is present in  three copies in trisomy 21 individuals, in which the extra gene  copy leads to amyloid deposition and the occurrence of AD in  those with Down syndrome (see Chapter 4).   An important risk factor for the more common late-onset  form of AD is allelic variation in the apolipoprotein E (APOE)  locus, which has three major alleles: ¢2, ¢3, and e4. Studies con-  ducted in diverse populations have shown that persons who    have one copy of the ¢4 allele are at least 2 to 5 times more likely  to develop AD, whereas those with two copies of this allele are  at least 5 to 10 times more likely to develop AD. The risk var-  ies somewhat by population, with higher ¢4-associated risks in  Europeans and Japanese and relatively lower risks in Hispanics  and blacks. Despite the strong association between e4 and AD,  approximately half of individuals who develop late-onset AD  do not have a copy of the e4 allele, and many who are homozy-  gous for ¢4 remain free of AD even at advanced age. The apoli-  poprotein E protein product is not involved in cleavage of APP  but instead appears to be associated with clearance of amyloid  from the brain.   At some point, alcoholism is diagnosed in approximately  10% of adult males and 3% to 5% of adult females in the  United States. The national cost of alcoholism, in terms of  lost productivity and direct medical costs, is approximately  $200 billion per year. More than 100 studies have shown  that this disease clusters in families.*? The risk of develop-  ing alcoholism among individuals with one affected parent  is three to five times higher than for those with unaffected  parents.   Most twin studies have yielded concordance rates for DZ  twins less than 30% and concordance rates for MZ twins in  excess of 60%. Adoption studies have shown that the offspring  of an alcoholic parent, even when raised by nonalcoholic par-  ents, have a fourfold increased risk of developing the disorder.  To control for possible prenatal effects in an alcoholic mother,  some studies have included only the offspring of alcoholic  fathers. The results have remained the same. One study showed  that the offspring of nonalcoholic parents, when reared by alco-  holics, did not have an increased risk of developing alcoholism.  These data argue that there may be genes that predispose some  people to alcoholism.   It has long been known that an individual’s physiologic  response to alcohol can be influenced by variation in the key  enzymes responsible for alcohol metabolism: alcohol dehy-  drogenases (ADHs), which convert ethanol to acetaldehyde;  and aldehyde dehydrogenases (ALDHs), which convert acetal-  dehyde to acetate. In particular, an allele of the ALDH2 gene  (ALDH2*2) results in excessive accumulation of acetaldehyde  and thus in facial flushing, nausea, palpitations, and lighthead-  edness. Because of these unpleasant effects, individuals who  have the ALDH2*2 allele are much less likely to become alco-  holics. This “protective” allele is common in some Asian popu-  lations but is rare in other populations.   A number of other genes are associated with susceptibility  to alcohol addiction, including genes that encode components  of gamma-aminobutyric acid (GABA) receptors. This finding  is biologically plausible, because the GABA neurotransmitter  system inhibits excitatory signals in neurons, exerting a calm-  ing effect. Alcohol has been shown to increase GABA release,  and allelic variation in GABA receptor genes may modulate this  effect.   It should be underscored that genes may increase one’s  susceptibility to alcoholism. Obviously this is a disease that    Dizygotic twin 12.1  Offspring 9.4  Sibling UB  Niece/nephew aT  Grandchild 2.8  First cousin 1.6  Spouse 1    Data from McGue M, Gottesman II, Rao DC: Behav Genet 16(1):75-87,  1986.   Figures are based on multiple studies of Western European popula-  tions.   The major psychiatric diseases, schizophrenia and affective dis-  order, have been the subjects of numerous genetic studies.”°  Twin, adoption, and family studies have shown that both disor-  ders aggregate in families.   Schizophrenia. Schizophrenia is a severe emotional disorder  characterized by delusions, hallucinations, retreat from reality,  and bizarre, withdrawn, or inappropriate behavior. (Contrary  to popular belief, schizophrenia is not a “split personality”  disorder.) The lifetime recurrence risk for schizophrenia  among the offspring of one affected parent is approximately  8% to 10%, which is about 10 times higher than the risk in  the general population.’” As one might expect, the empirical  risks increase when more relatives are affected. For example,  an individual with an affected sibling and an affected parent  has a risk of about 17%, and an individual with two affected  parents has a risk of 46%. The risks decrease when the affected  family member is a second- or third-degree relative. Details  are given in Table 5-8. On inspection of Table 5-8, it may  seem puzzling that the proportion of schizophrenic probands  who have a schizophrenic parent is only about 5%, which is  substantially lower than the risk for other first-degree relatives  (e.g., siblings, affected parents and their offspring). This can be  explained by the fact that people with schizophrenia are less  likely to marry and produce children than are other individuals.  Thus substantial selection against schizophrenia occurs in the  population.   Twin and adoption studies also indicate that genetic factors  are likely to be involved in schizophrenia. Data pooled from  five different twin studies show a 47% concordance rate for MZ  twins, compared with a concordance rate of only 12% for DZ  twins. When the offspring ofa schizophrenic parent are adopted  by normal parents, their risk of developing the disease is about  10%, which is approximately the same as the risk when raised  by a schizophrenic biologic parent. Recent studies have identi-  fied promising associations between schizophrenia and several    brain-expressed genes whose products interact with glutamate  receptors. These include dysbindin (DTNBP1; chromosome  6p), neuregulin 1 (NRG1; chromosome 8p), and p-amino acid  oxidase activator (G30; chromosome 13q). Another suscepti-  bility gene is DISC1 (Disrupted-in-Schizophrenia-1), which  was originally identified by its consistent translocation in  affected members of a large schizophrenia pedigree. Each of  these associations has been replicated in multiple populations.  However, the precise mechanisms through which mutations in  these genes contribute to schizophrenia susceptibility are not  yet known.   Bipolar Disorder. Bipolar disorder, also known as manic-  depressive disorder, is a form of psychosis with extreme mood  swings and emotional instability. The incidence of the disorder  in the general population is approximately 0.5%, but it rises to  5% to 10% among those with an affected first-degree relative.  A study using the Danish twin registry yielded concordance  rates of 79% and 24% for MZ and DZ twins, respectively.** The  corresponding concordance rates for unipolar disorder (major  depression) were 54% and 19%. In general, it appears that  bipolar disorder is more strongly influenced by genetic factors  than is unipolar disorder.   As with schizophrenia, many large-scale studies have been  undertaken to identify genes associated with susceptibility to  bipolar disorder. Some of these loci were identified because  their products are involved in neurotransmitter systems that  are targets of drugs used to treat the disease (e.g., the sero-  tonin, dopamine, and noradrenaline systems). Examples of  these genes include those that encode monoamine oxidase A  (MAOA), the serotonin transporter (SHTT), and catechol-  O-methyltransferase (COMT), a gene that has also been associ-  ated with schizophrenia susceptibility. In addition, the NRGI  and DISC1 genes, which were discussed previously because of  their association with schizophrenia, have been shown in some  studies to be associated with susceptibility to bipolar disorder.   Comments on Psychiatric Disorders. Large-scale linkage  studies involving hundreds of polymorphisms throughout the  genome have been carried out for both schizophrenia and bipolar  affective disorder. Most of these studies have produced negative  results, although a few recent large-scale studies have yielded  promising findings. A number of candidate genes have been  tested for linkage or association with both diseases. Most of these  candidates were chosen on the basis of the known involvement  of certain neurotransmitters, receptors, or neurotransmitter-  related enzymes in each disease (e.g., schizophrenia can be  treated by drugs that block dopamine receptors, and bipolar  affective disorder is sometimes treated with lithium). None  of the candidate genes tested thus far, including those for  sodium-lithium countertransport, various components of the  dopaminergic system, and several neurotransmitter-related  enzymes (e.g., monoamine oxidase, dopamine-f-hydroxylase,  tyrosine hydroxylase), have been shown unequivocally to be  linked or associated with either disease.   These results reflect some of the difficulties encountered  in conducting genetic studies of psychiatric disorders. These  disorders are undoubtedly heterogeneous, reflecting the influ-  ence of numerous genetic and environmental factors. Also,    definition of the phenotype is not always straightforward and  it may change through time, significantly complicating genetic  analysis.    The disorders discussed in this chapter represent some of the  most common multifactorial disorders and those for which sig-  nificant progress has been made in identifying genes. Many other  multifactorial disorders are being studied as well, and in some  cases specific susceptibility genes have been identified. These  include, for example, Parkinson disease, hearing loss, mul-  tiple sclerosis, amyotrophic lateral sclerosis, epilepsy, asthma,  inflammatory bowel disease, and some forms of blindness.    Some general principles can be deduced from the results  obtained thus far on the genetics of complex disorders. First,  the more strongly inherited forms of complex disorders gener-  ally have an earlier age of onset (e.g., breast cancer, AD, heart  disease). Often these represent subsets of cases in which there  is single-gene inheritance. Second, when laterality is a compo-  nent, the bilateral forms are more likely to cluster strongly in  families (e.g., breast cancer, CL/P). Third, although the sex-  specific threshold model fits some of the complex disorders  (e.g., pyloric stenosis, CL/P, autism, heart disease), it fails to fit  others (e.g., type 1 diabetes).   A tendency exists, particularly among the lay public, to  assume that the presence of a genetic component means that  the course of a disease cannot be altered. This is incorrect. Most  of the diseases discussed in this chapter have both genetic and  environmental components. Thus lifestyle modification (e.g.,  diet, exercise, stress reduction) often can reduce risk signifi-  cantly. Such modification may be especially important for indi-  viduals with a family history of a disease because they are likely  to develop the disease earlier in life. Those with a family history  of heart disease, for example, can often add many years of pro-  ductive living with relatively minor lifestyle alterations. By tar-  geting those who can benefit most from intervention, genetics  helps to serve the goal of preventive medicine.   In addition, it should be stressed that the identification of a  specific genetic lesion can lead to more effective prevention and  treatment of the disease. Identification of mutations that cause  autosomal dominant breast cancer may enable early screening  and prevention of metastasis. Pinpointing a gene responsible  for a neurotransmitter defect in a behavioral disorder such as  schizophrenia could lead to the development of more effec-  tive drug treatments. In some cases, such as those with familial  hypercholesterolemia, gene therapy may prove to be useful in  treating the disease. It is important for healthcare practitioners  to help individuals understand these facts.   Although the genetics of common disorders is complex and  often confusing, the community health effect of these diseases,  together with the evidence for hereditary factors in their etiol-  ogy, demands that genetic studies be pursued. Substantial prog-  ress is already being made. The next decade will undoubtedly  witness many further advances in the understanding and treat-  ment of these disorders.    The incidence rate is the number of new cases of a disease  reported during a specific period (typically 1 year) divided  by the number of individuals in the population.    affected by a disease at a specific point in time. This rate,  and the incidence rate, can be used to compare population  variations in disease frequency.    . Relative risk is a common measure of the effect of a specific    risk factor. It is expressed as a ratio of the incidence rate  of the disease among individuals exposed to a risk factor  divided by the incidence of the disease among individuals  not exposed to a risk factor.    . Many factors can influence the risk of acquiring a common    disease, such as cancer, diabetes, or hypertension. The fac-  tors can include age, gender, diet, exercise, and family his-  tory of the disease.    Traits in which variation is thought to be caused by the  combined effects of multiple genes are polygenic.    . Because traits are caused by the additive effects of many    genetic and environmental factors, they tend to follow a  normal or bell-shaped distribution in populations.    distribution appear to be either present or absent in indi-  viduals. They do not follow the inheritance patterns of  single-gene disease. Instead, such diseases may follow  an underlying liability distribution. It is thought that a  threshold of liability must be crossed before the disease is  expressed.    include pyloric stenosis, neural tube defects, CL/P, and  some forms of congenital heart disease.    coronary heart disease, stroke, diabetes mellitus (types 1  and 2), and some cancers, are caused by complex genetic  and environmental factors and are thus multifactorial  diseases.    for multifactorial diseases can change significantly from  one population to another because gene frequencies, as well  as environmental factors, can differ among populations.    Several criteria are used to define multifactorial inheri-  tance: (a) the recurrence risk becomes higher if more than  one family member is affected; (b) if the expression of the  disease in a proband is more severe, the recurrence risk is  higher; (c) the recurrence risk is higher if the proband is  of the less commonly affected sex; (d) the recurrence risk  for the disease usually decreases rapidly in more remotely  related relatives; and (e) if the prevalence of the disease in  a population is f, the risk for offspring and siblings of pro-  bands is approximately yf.    Family members share genes and a common environ-  ment; therefore, resemblance in traits, such as high blood  pressure, reflects both genetic and environmental factors  (nature and nurture, respectively).    . Few traits are influenced only by genes or only by environ-    as in breast cancer, examination of family history should be  emphasized in addition to lifestyle modification.    . Two research strategies often are used to estimate the rela-    tive influence of genes and environment-lifestyle: twin  studies and adoption studies.    . Dizygotic twins are the result of a double ovulation fol-    lowed by the fertilization of each egg by a different sperm.    . Ifboth members of a twin pair share a trait, they are said to    be concordant. If they do not share the same trait, they are  discordant.    . Studies of adopted children also are used to estimate the    tal-lifestyle factor to increase the risk of disease; this is called  a gene-environment interaction.    Congenital diseases are those present at birth. Most of these  diseases are multifactorial in etiology.   Multifactorial diseases in adults include coronary heart  disease, hypertension, breast cancer, colon cancer, diabetes  mellitus, obesity, AD, alcoholism, schizophrenia, and bipo-  lar affective disorder.    . It is incorrect to assume that the presence of a genetic    component means that the course of a disease cannot be  altered—most diseases have both genetic and environmen-  tal aspects.    King RA, Rotter JI, Motulsky AG: The genetic basis of common diseases,  ed 2, Oxford, 2002, Oxford University Press.   Rothman KJ: Modern epidemiology, New York, 1998, Lippincott.  Tiwari HK et al: Multifactorial inheritance and complex diseases. In  Rimoin DL, et al, editor: Emery and Rimoin’s principles and practice   Greene ND et al: Genetics of human neural tube defects, Hum Mol Genet  18(R2):R113-R129, 2009.   Daly LE et al: Folate levels and neural tube defects: implications for pre-  vention, JAMA 274(21):1698-1702, 1995.   Harper PS: Practical genetic counseling, ed 7, London, 2010, Hodder  Arnold.   Boomsma D, Busjahn A, Peltonen L: Classical twin studies and beyond,  Nat Rev Genet 3(11):872—882, 2002.   Kaprio J, Silventoinen K: Advanced methods in twin studies, Methods  Mol Biol 713:143-152, 2011.   Marks D et al: A review on the diagnosis, natural history, and treatment  of familial hypercholesterolaemia, Atherosclerosis 168(1):1—14, 2003.  Varret MM et al: Genetic heterogeneity of autosomal dominant hyper-  cholesterolemia, Clin Genet 73(1):1—13, 2008.   Hunt SC, Williams RR, Barlow GK: A comparison of positive fam-   ily history definitions for defining risk of future disease, J Chronic Dis  39(10):809-821, 1986.   Libby P et al: Progress and challenges in translating the biology of athero-  sclerosis, Nature 473(7347):317—325, 2011.   O’Donnell CJ, Nabel EG: Genomics of cardiovascular disease, N Engl J  Med 365(22):2098-2109, 2011.    Liability distribution, 166  Monozygotic (MZ, identical) twin, 169  Multifactorial trait, 165    Polygenic, 165  Prevalence rate, 164  Quantitative trait, 165  Relative risk, 165  Threshold of liability, 166    Jeunemaitre X et al: Molecular basis of human hypertension. In Rimoin  DL, et al, editor: Emery and Rimoin’s principles and practice of medical  genetics, ed 5, Philadelphia, 2007, Churchill Livingstone, pp 1283-1300.  Vogelstein B, Kinzler KW: The genetic basis of human cancer,   Peto J: Cancer epidemiology in the last century and the next decade,  Nature 411(6835):390—395, 2001.   Robson M, Offit K: Management of an inherited predisposition to breast  cancer, N Engl J Med 357(2):154—162, 2007.   Galiatsatos P, Foulkes WD: Familial adenomatous polyposis, Am J Gas-  troenterol 101(2):385—398, 2006.   Feero WG et al: Genomics, type 2 diabetes, and obesity, N Engl J] Med  363(24):2339-2350, 2010.   Concannon P et al: Genetics of type 1 diabetes, N Engl J Med  360(16):1646—-1654, 2009.   Bertram L et al: The genetics of Alzheimer disease: back to the future,  Neuron 68(2):270—281, 2010.   Blennow K, de Leon MJ, Zetterberg H: Alzheimer’s disease, Lancet  368(9533):387—403, 2006.   Gelernter J, Kranzler HR: Genetics of alcohol dependence, Hum Genet  126(1):91-99, 2009.   Burmeister M et al: Psychiatric genetics: progress amid controversy,  Nat Rev Genet 9(7):527—540, 2008.   Gejman PV et al: Genetics of schizophrenia: new findings and challenges,  Annu Rev Genom Hum Genet 12(1):121-144, 2011.   Bertelsen A, Harvald B, Hauge MA: Danish twin study of manic-  depressive disorders, Br J Psychiatry 130:330-351, 1977.    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:   Twin Studies Provide Insights on Epigenetic Modification, 185  Epigenetics and Cancer, 186    The traditional focus of human genetics has been on the ways   with the same DNA sequences (such as identical twins) to have   1. DNA methylation: The attachment of a methyl group to a  cytosine base is followed by a guanine base (a “CpG dinu-  cleotide”) (Figures 6-1 and 6-2).2 DNA methylation causes  a gene to become transcriptionally inactive or silent.?  When the DNA sequence in the promoter region of a gene  becomes heavily methylated, the DNA is less likely to be  transcribed into mRNA. Methylation along with histone    Prader-Willi and Angelman Syndromes, 187  Beckwith-Wiedemann Syndrome, 188  Russell-Silver Syndrome, 188    hypoacetylation (the acetyl group consists of a methyl  group single-bonded to a carbonyl) and condensation of  chromatin together inhibit the binding of transcription-  binding factors (see Chapter 4) that regulate transcrip-  tion. In other words, the gene becomes transcriptionally  inactive. Aberrant methylation can lead to silencing of  tumor-suppressor genes in the development of cancer (see  Chapter 12 and Figure 6-1). DNA methylation is a key  component of X-inactivation, the transcriptional silencing  of genes on the X chromosome, discussed in Chapter 4.  As with X-inactivation, epigenetic modifications are main-  tained in successive mitotic cell divisions, but most are  erased from the genome when new gametes (sperm or egg  cells) are formed.    lation, alterations in chromatin): Chromatin compaction  and organization help to regulate gene expression, determin-  ing and maintaining cell identity. Chromatin structure must    FIGURE 6-1 Three Major Types of Epigenetic Processes. Investigators are studying the following epigenetic mecha-  nisms: (1) DNA methylation, (2) histone modifications, and (3) RNA based-mechanisms. See text for discussion.    be controlled in self-renewing and differentiated cells in cell  renewal systems. For example, there are differences in chro-  matin structure in stem cells and terminally differentiated  cells.*   . Micro-ribonucleic acids (miRNAs or miRs): These  RNAs are encoded by short DNA sequences (approxi-  mately 22 nucleotides) located in introns of genes or  transcribed from noncoding DNA located between genes.  Gene expression networks can be regulated by changes in  miRNAs and other noncoding RNAs. Noncoding RNAs  (ncRNAs) have been shown to regulate gene expression  by novel mechanisms such as RNA interference, gene co-  suppression, gene silencing, imprinting (see p. 187), and  DNA demethylation. It is becoming clear that these novel  RNAs perform critical functions during development and  cell differentiation. MicroRNAs regulate diverse signal-  ing pathways, and those that stimulate cancer develop-  ment and progression are called oncomirs. For example,  miRNAs have been linked to carcinogenesis because they  can act as either oncogenes or tumor-suppressor genes  (see Chapter 12).    Early in embryonic development, all cells of the embryo have the  potential to become any type of cell in the fetus or adult. These  embryonic stem cells are said to be pluripotent. A key event in  early embryogenesis is the differential epigenetic modification  (including extensive methylation) of specific DNA nucleotide  sequences in these cells. This modification helps to determine  the fate of each cell (ie., the type of cell it becomes, such as a  myocyte, neuron, or fibroblast) by helping to ensure that spe-  cific genes are expressed only in the cells and tissue types in  which their gene products are needed (e.g., factor VIII expres-  sion primarily in hepatocytes, or dopamine receptor expression  in neurons). Thus, even though nearly all cells have the same  DNA sequence, the transcriptional activity of most genes var-  ies substantially and depends on cell and tissue type. A small  percentage of genes, termed housekeeping genes, are necessary  for the function and maintenance of all cells. These genes escape  the methylation process and remain transcriptionally active in  all cells.   Much remains to be learned about factors that cause epi-  genetic modifications. Findings so far indicate that specific    FIGURE 6-2 Epigenetic Modifications. Because DNA is a long molecule, it needs packaging to fit in the tiny nucleus.  Packaging involves coiling of the DNA in a “left-handed” spiral around spools, made of four pairs of proteins individually  known as histones and collectively as the histone octamer. The entire spool is called a nucleosome (also see Figure 1-2).  Nucleosomes are organized into chromatin, the repeating building blocks of a chromosome. Histone modifications are  correlated with methylation, are reversible, and occur at multiple sites. Methylation occurs at the 5 position of cytosine  and provides a “footprint” or signature as a unique epigenetic alteration (red). When genes are expressed, chromatin  is open or active; however, when chromatin is condensed because of methylation and histone modification, genes are    environmental or nongenetic factors, such as diet and exposure  to certain chemicals, can drive such modifications. For example,  alcohol has been shown to affect methylation patterns in animal  models,’ so the harmful effects of fetal alcohol exposure may  be mediated through epigenetic mechanisms. Maternal dietary  deficiency during pregnancy may cause epigenetic modifica-  tions of fetal genes, leading to an increased risk of obesity and  diabetes in the offspring later in life.° In some animal models,  the insulin-like growth factor 2 gene (IGF2) is a target of these  epigenetic modifications. Although the observed changes in  methylation status of CpG sequences in these genes are typically  small, it is possible that they affect phenotypic development.  The hereditary transmission of epigenetic changes to succes-  sive generations has been termed epigenetic transgenerational  inheritance. If demonstrated to occur in humans, transgenera-  tional inheritance could have important implications for dis-  ease and disease prevention.   A powerful means to test for epigenetic effects is to compare  methylation and other signatures of epigenetic modification in  identical (monozygotic) twin pairs, whose DNA sequences are  essentially the same. As twins age, they demonstrate increas-  ing differences in methylation patterns of the DNA sequences  of their somatic cells; these changes are reflected in increasing  numbers of phenotypic differences.’ Twins with significant life-  style differences (e.g., smoking vs. nonsmoking) accumulated  larger numbers of differences in their methylation patterns. The  twins, despite having identical DNA sequences, become more  and more different as a result of epigenetic changes, which in  turn affect the expression of genes. These results, along with  findings generated in animal studies, suggest that changes  in epigenetic patterns may be an important part of the aging  process.®    The best evidence for epigenetic effects on disease risk comes  from studies of human cancer (Figure 6-3).”!° Tumor cells  typically exhibit hypomethylation (decreased methylation),  which can increase the activity of oncogenes (see Chapter 12).  Hypomethylation increases as tumors progress from benign  neoplasms to malignancy. In addition, the promoter regions  of tumor-suppressor genes are often hypermethylated, which  decreases their rate of transcription and their ability to inhibit  tumor formation. Hypermethylation of the promoter region of  the RBI gene is often seen in retinoblastoma,'! and hypermeth-  ylation of the BRCAI gene is seen in some cases of inherited  breast cancer.'? Similarly, von Hippel-Lindau disease, in which  renal cell carcinomas frequently occur, can be caused by hyper-  methylation of the VHL promoter region.   A major cause of one form of inherited colon cancer (heredi-  tary nonpolyposis colorectal cancer [HNPCC]) is the methylation  of the promoter region of a gene, MLH1, whose protein product  repairs damaged DNA. When MLHI1 becomes inactive, dam-  aged DNA accumulates, eventually resulting in colon tumors!*!*  (see Figure 41-28).   Hypermethylation also is seen in miRNA genes, which  encode small (22 base pair) RNA molecules that bind to  the ends of mRNAs, degrading them and preventing their  translation. More than 1000 miRNA sequences have been  identified in humans, and hypermethylation of specific sub-  groups of miRNAs is associated with tumorigenesis. When  miRNA genes are methylated, their mRNA targets are over-  expressed, and this over-expression has been associated with  metastasis.’   Unlike DNA sequence mutations, which cannot be directly  altered, epigenetic modifications can be reversed. For example,  5-azacytidine, a demethylating agent, has been used as a thera-  peutic drug in the treatment of leukemia and myelodysplastic  syndrome. Another class of drugs, histone deacetylase (HDAC)  inhibitors, counteracts the removal of acetyl groups from his-  tone proteins, which can silence the activity of tumor-suppressor  genes. HDAC inhibitors have been used in the treatment of  T-cell lymphomas. A major challenge in developing drugs that  modify epigenetic alterations is to target only the genes respon-  sible for a specific cancer.    FIGURE 6-3 Global Epigenomic Alterations and Cancer. Oncogenesis involves accumulated genetic alterations com-  bined with the epigenetic changes: DNA methylation, histone modifications, and miRNAs. In cancer cells, tumor-suppressor  genes become hypermethylated and with histone modifications cause abnormal gene silencing. The gene silencing of tumor-  suppressor genes results in tumor progression. Global hypomethylation leads to chromosomal instability and fragility. Addi-  tionally, these modifications create abnormal mRNA and miRNA expression, which leads to activation of oncogenes and  silencing of tumor-suppressor genes. (Adapted from Sandoval J, Esteller M: Curr Opin Genet Dev 22:50—55, 2012.)    Gregor Mendel’s nineteenth century experiments with garden  peas indicated that the phenotype is typically the same whether  a given allele is inherited from the mother or the father. It is now  clear that this principle, which has long been part of the cen-  tral dogma of genetics, does not always hold. For some human  genes, the gene is transcriptionally active on only one copy of a  chromosome (e.g., the copy inherited from the father). On the  other copy of the chromosome (in this example, the one inher-  ited from the mother), the gene is transcriptionally inactive.  This process of gene silencing, in which genes are predictably  silenced depending on which parent transmits them, is known  as imprinting, and the transcriptionally silenced genes are then  said to be “imprinted.” Approximately 100 human genes are  thought to be imprinted. Imprinted genes are usually heavily  methylated (in contrast to the nonimprinted copy of the allele,  which is typically not methylated). Next we describe some  important human diseases that can be caused by abnormal  imprinting patterns.   A well-known disease example of imprinting is associated with  a deletion of about 4 million base pairs (Mb) of the long arm  of chromosome 15. When this deletion is inherited from the  father, the child manifests Prader-Willi syndrome, whose fea-  tures include short stature, hypotonia, small hands and feet,    obesity, mild to moderate mental retardation, and hypogonad-  ism (Figure 6-4, A).!° The same 4-Mb deletion, when inherited  from the mother, causes Angelman syndrome, which is char-  acterized by severe mental retardation, seizures, and an ataxic  gait (Figure 6-4, B).'° These diseases are each seen in about 1 of  every 15,000 live births, and chromosome deletions are respon-  sible for about 70% of cases of both diseases. The deletions that  cause Prader-Willi and Angelman syndromes are indistinguish-  able at the DNA sequence level and affect the same group of  genes.   For several decades, it was unclear how the same deletion  could produce such disparate results in different persons. Fur-  ther analysis showed that the 4-Mb deletion (the critical region)  contains several genes that are normally transcribed only on  the copy of chromosome 15 that is inherited from the father.'”  These genes are transcriptionally inactive (imprinted) on the  copy of chromosome 15 inherited from the mother. Similarly,  other genes in the critical region are transcriptionally active  only on the chromosome copy inherited from the mother and  are inactive on the chromosome inherited from the father.  Thus, several genes in this region are normally active on only  one chromosome copy (Figure 6-5). If the single active copy  of one of these genes is lost because of a chromosome deletion,  then no gene product is produced at all, resulting in disease.   Molecular analysis has revealed much about genes in this  critical region of chromosome 15.!”!*° The gene responsible  for Angelman syndrome encodes a ligase involved in protein    FIGURE 6-4 Prader-Willi and Angelman Syndromes. A, A child with Prader-Willi syndrome (truncal obesity, small  hands and feet, inverted V-shaped upper lip). B, A child with Angelman syndrome (characteristic posture, ataxic gait, bouts of  uncontrolled laughter). (From Jorde LB, Carey JC, Bamshad MJ: Medical genetics, ed 4, Philadelphia, 2010, Mosby.)    FIGURE 6-5 Prader-Willi Syndrome and Angelman Syndrome Pedigrees. These pedigrees illustrate the inheritance  patterns of Prader-Willi syndrome, which can be caused by a 4-Mb deletion of chromosome 15q when inherited from the father.  In contrast, Angelman syndrome can be caused by the same deletion but only when it is inherited from the mother. The reason  for this difference is that different genes in this region are normally imprinted (inactivated) in the copies of 15q transmitted by  the mother and the father. (From Jorde LB, Carey JC, Bamshad MJ: Medical genetics, ed 4, Philadelphia, 2010, Mosby.)    degradation during brain development (consistent with the  mental retardation and ataxia observed in this disorder). In  brain tissue, this gene is active only on the chromosome copy  inherited from the mother. Consequently, a maternally trans-  mitted deletion removes the single active copy of this gene. Sev-  eral genes in the critical region are associated with Prader-Willi  syndrome, and they are transcribed only on the chromosome  transmitted by the father. A paternally transmitted deletion  removes the only active copies of these genes, producing the  features of Prader-Willi syndrome.    Another well-known example of imprinting is Beckwith-  Wiedemann syndrome, an overgrowth condition accompanied  by an increased predisposition to cancer. Beckwith-Wiedemann  syndrome is usually identifiable at birth because of large size for  gestational age, neonatal hypoglycemia, a large tongue, creases  on the earlobe, and omphalocele.'? Children with Beckwith-  Wiedemann syndrome have an increased risk of developing  Wilms tumor or hepatoblastoma. Both of these tumors can  be treated effectively if they are detected early, so screening at  regular intervals is an important part of management. Some  children with Beckwith-Wiedemann syndrome also develop  asymmetric overgrowth of a limb or one side of the face or  trunk (hemihyperplasia).   As with Angelman syndrome, a minority of Beckwith-  Wiedemann syndrome cases (about 20% to 30%) are caused  by the inheritance of two copies of a chromosome from the  father and no copy of the chromosome from the mother  (uniparental disomy, in this case affecting chromosome 11).  Several genes on the short arm of chromosome 11 are imprinted  on either the paternally or the maternally transmitted chromo-  some. These genes are found in two separate, differentially  methylated regions (DMRs). In DMRI, the gene that encodes  insulin-like growth factor 2 (IGF2) is inactive on the maternally    transmitted chromosome but active on the paternally transmit-  ted chromosome. Thus, a normal individual has only one active  copy of IGF2. When two copies of the paternal chromosome  are inherited (i.e., paternal uniparental disomy) or there is loss  of imprinting on the maternal copy of IGF2, an active IGF2  gene is present in double dose. This produces increased levels  of insulin-like growth factor 2 during fetal development, con-  tributing to the overgrowth features of Beckwith-Wiedemann  syndrome. (Note that, in contrast to Prader-Willi and Angel-  man syndromes, which are produced by a missing gene product,  Beckwith-Wiedemann syndrome is caused, in part, by over-  expression of a gene product.)   Russell-Silver syndrome is characterized by growth retarda-  tion, proportionate short stature, leg length discrepancy, and  a small, triangular-shaped face. About one third of Russell-  Silver syndrome cases are caused by imprinting abnormali-  ties of chromosome 11p15.5 that lead to down-regulation of  IGF2 and therefore diminished growth. Another 10% of cases  of Russell-Silver syndrome are caused by maternal uniparen-  tal disomy. Thus, while up-regulation, or extra copies, of active  IGF2 causes overgrowth in Beckwith-Wiedemann syndrome,  down-regulation of IGF2 causes the diminished growth seen in  Russell-Silver syndrome.    Robust experimental observations are clarifying the roles of epi-  genetic states in determining cell fates and disease phenotypes.  The well-documented involvement of epigenetic abnormalities  in carcinogenesis and the mounting evidence for these epigenetic  changes in other common diseases (discussed in other chapters)  will likely elucidate possibilities for reversing the epigenetic abnor-  malities and preventing their establishment in utero.    1. Epigenetics bridges DNA information and function by can be reversed through pharmaceutical intervention. For  modifying gene expression without any alteration in DNA example, 5-azacytidine, a demethylating agent, has been  sequence. These often heritable chemical modifications of used as a therapeutic drug in the treatment of leukemia and  DNA sequence are collectively termed epigenetics. myelodysplastic syndrome.   2. Investigators are studying three major types of epigenetic  processes: (a) DNA methylation, which results from attach- | Genomic Imprinting  ment of a methyl group to a cytosine base that is followed 1. Gregor Mendel’s experiments with garden peas demon-  by a guanine base (a “CpG dinucleotide”); (b) histone modi- strated that the phenotype is the same whether a given allele  fication, which includes histone acetylation and alterations is inherited from the mother or the father. This principle,  in chromatin; and (c) micro-ribonucleic acids (miRNAs or which has long been part of the central dogma of genetics,  miRs), short nucleotides derived from introns of protein does not always hold. For some human genes, a given gene  coding genes or transcribed as independent genes from is transcriptionally active on only one copy of a chromosome  regions of the genome whose functions, if any, remain poorly (e.g., the copy inherited from the father). On the other copy  understood. MiRNAs regulate diverse signaling pathways. of the chromosome (the one inherited from the mother), the   3. DNA methylation is, at present, the best-studied epigenetic gene is transcriptionally inactive. This process of gene silenc-  process. When a gene becomes heavily methylated the DNA ing, in which genes are silenced depending on which parent  is less likely to be transcribed into mRNA. transmits them, is known as imprinting, and the transcrip-   4. Methylation, along with histone hypoacetylation and con- tionally silenced genes are said to be “imprinted.”  densation of chromatin, inhibits the binding of proteins that | 2. When an allele is imprinted, it typically has heavy meth-  promote transcription, such that the gene becomes tran- ylation. By contrast, the nonimprinted allele is typically not  scriptionally inactive. methylated.   5. Environmental factors, such as diet and exposure to certain 3. A well-known disease example of imprinting is associated  chemicals, may cause epigenetic modifications. with a deletion of about 4 million base pairs (Mb) of the long   6. The heritable transmission to future generations of epige- arm of chromosome 15. When this deletion is inherited from  netic modifications is called transgenerational inheritance. the father, the child manifests Prader-Willi syndrome.   7. As twins age, they demonstrate increasing differences in 4. The same 4-Mb deletion, when inherited from the mother,  methylation patterns of their DNA sequences, causing causes Angelman syndrome.  increasing numbers of phenotypic differences. 5. Another well-known example of imprinting is Beckwith-   8. In studies of twins with significant lifestyle differences (e.g., Wiedemann syndrome, an overgrowth condition accompa-  smoking vs. nonsmoking) large numbers of differences in nied by an increased predisposition to cancer.  their methylation patterns are observed to accrue over time. 6. Although up-regulation, or extra copies, of active IGF2    causes overgrowth in Beckwith-Wiedemann syndrome,  down-regulation of IGF2 causes the diminished growth seen    1. The best evidence for epigenetic effects on disease risk comes in Russell-Silver syndrome.  from studies of human cancer.  2. Methylation densities decline as tumors progress, which can _ Future Directions  increase the activity of oncogenes, causing tumors to prog- —-1. Robust experimental observations are defining the roles of  ress from benign neoplasms to malignancy. Additionally, epigenetic states in shaping cell fates.  the promoter regions of tumor-suppressor genes are often 2. The well-documented involvement of epigenetic abnor-  hypermethylated. These elevated methylation levels decrease malities in carcinogenesis and the mounting evidence  their rate of transcription at these critical genes, thus reduc- for these epigenetic changes in other common diseases  ing the ability to inhibit tumor formation. (discussed throughout the text) will likely elucidate new  3. Hypermethylation also is seen in miRNA genes and is associ- therapies with the possibilities of reversing the epigenetic    Esteller M: An introduction to epigenetics: epigenetics in biology and medi-  cine, Boca Raton, FL, 2009, CRC Press Taylor & Francis Group.  Robertson KD: DNA methylation and human disease, Nat Rev Genet  6:597-610, 2005.   Cedar H, Bergman Y: Programming of DNA methylation patterns, Annu  Rev Biochem 81:97-117, 2012.   Johnstone SE, Baylin SB: Stress and the epigenetic landscape: a link to the  pathobiology of human diseases? Nat Rev Genet 11:806-812, 2010.  Kaminen-Ahola N et al: Maternal ethanol consumption alters the epi-  genotype and the phenotype of offspring in a mouse model, PLoS Genet  6(1):e1000811, 2010.   Feil R, Fraga MF: Epigenetics and the environment: emerging patterns  and implications, Nat Rev Genet 13:97-109, 2011.   Fraga MF et al: Epigenetic differences arise during the lifetime of mono-  zygotic twins, Proc Natl Acad Sci U S A 102:10604-10609, 2005.  Berdasco M, Esteller M: Hot topics in epigenetic mechanisms of aging:  2011, Aging Cell 11(2):181—186, 2012.   Esteller M: Epigenetics in cancer, N Engl J Med 358:1148-1159, 2008.    Sandoval J, Esteller M: Cancer epigenomics: beyond genomics, Curr Opin  Genet Dev 22:50-55, 2012.   Giacinti C, Giordano A: RB and cell cycle progression, Oncogene  25(38):5220—-5227, 2006.   Hansmann T et al: Constitutive promoter methylation of BRCA1 and  RADS51C in patients with familial ovarian cancer and early-onset sporadic  breast cancer, Hum Mol Genet 21(21):4669-4679, 2012.   Lynch HT, de la Chapelle A: Hereditary colorectal cancer, N Engl J Med  348:919-932, 2003.   Pino MS, Chung DC: Microsatellite instability in the management of  colorectal cancer, Expert Rev Gastroenterol Hepatol 5(3):385-399, 2011.  Cassidy SB et al: Prader-Willi syndrome, Genet Med 14:10-26, 2012.  Williams CA, et al: Angelman syndrome 2005: updated consensus for  diagnostic criteria, Am J Med Genet A 140A:413—418, 2006.   Horsthemke B, Wagstaff J: Mechanisms of imprinting of the Prader-Willi/  Angelman region, Am J Med Genet A 146A:2041-2052, 2008.   Jiang Y-H, Bressler J, Beaudet AL: Epigenetics and human disease, Annu  Rev Genom Hum Genet 5:479-510, 2004.   Weksberg R, Shuman C, Smith AC: Beckwith-Wiedemann syndrome,  Am J Med Genet C Semin Med Genet 137:12—23, 2005.    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Human Defense Mechanisms, 192  First Line of Defense: Physical, Mechanical, and Biochemical  Barriers, 192  Physical and Mechanical Barriers, 192  Biochemical Barriers, 192  Second Line of Defense: The Inflammatory  Response, 195  Vascular Response, 195  Plasma Protein Systems, 197  Cellular Mediators of Inflammation, 201  Local Manifestations of Inflammation, 213    People are exposed daily to an environment containing a  large variety of toxic substances and potentially infectious and  disease-causing microorganisms. Without an efficient system of  protection most individuals would succumb to these hazards  early in life. That system consists of multiple complementary  and interdependent layers. An outer layer of specialized epi-  thelium, including the skin and mucosal surfaces, is relatively  resistant to most environmental hazards and resists infection  with disease-causing microorganisms.’ If the epithelial bar-  rier is damaged, a highly efficient local and systemic response  (inflammation) is mobilized to limit the extent of damage, pro-  tect against infection, and initiate repair of the damaged tissue.  The natural epithelial barrier and inflammation confer innate    Systemic Manifestations of Acute Inflammation, 213  Fever, 213  Leukocytosis, 213  Plasma Protein Synthesis, 214  Chronic Inflammation, 214  Resolution and Repair, 215  Reconstructive Phase, 216  Maturation Phase, 218  Dysfunctional Wound Healing, 218  PEDIATRICS and Mechanisms of Self-Defense, 220  AGING and Mechanisms of Self-Defense, 220    resistance and protection, commonly referred to as innate,  native, or natural immunity. Inflammation associated with  infection usually initiates an adaptive process that results in a  long-term and very effective immunity to the infecting micro-  organism, referred to as adaptive, acquired, or specific immu-  nity. Adaptive immunity is relatively slow to develop but has  memory and more rapidly targets and eradicates a second infec-  tion with a particular disease-causing microorganism.   The information presented in this chapter introduces  the components and processes of innate immunity and sets  the stage for Chapter 8, which discusses adaptive immunity.  Although inflammation and adaptive immunity provide pro-  tection, either genetic or acquired aberrations in these processes    can lead to disease. Diminution of innate or adaptive immunity  may lead to critically decreased resistance to infection. Exces-  sive inflammation or adaptive immunity may lead to damage to  normal tissue or organs. Both may result in severe and poten-  tially fatal disease, examples of which are discussed in Chapter 9.  Many microorganisms that cause disease have developed meth-  ods of bypassing our protective systems. These are discussed in  Chapter 10. Each chapter is designed to render an overview and  is not intended to be all-inclusive. Protective mechanisms con-  sist of a very large number of soluble factors and cells and would  require many more pages to discuss in adequate detail. Differ-  ent classes or groups of molecules and cells will be discussed,  but only a few examples will be described in detail. Some com-  ponents directly participate in the protective response, whereas  others are designed to limit the extent of the response.    Innate immunity includes two lines of defense: natural barri-  ers and inflammation (Table 7-1). Natural barriers are physi-  cal, mechanical, and biochemical barriers at the body’s surfaces  and are in place at birth to prevent damage by substances in  the environment and thwart infection by pathogenic microor-  ganisms. If the surface barriers are breached, the second line of  defense, the inflammatory response, is activated to protect the  body from further injury, prevent infection of the injured tis-  sue, and promote healing. The inflammatory response is a rapid  activation of biochemical and cellular processes that is relatively  nonspecific, with similar responses being initiated against a  wide variety of causes of tissue damage.   Protection includes anatomic  barriers (i.e., skin and  mucous membranes), cells  and secretory molecules or  cytokines (e.g., lysozymes,  low pH of stomach and  urine), and ciliary activity    Second line of defense; occurs as a response to  tissue injury or infection    Mast cells, granulocytes (neutrophils, eosinophils,  basophils), monocytes/macrophages, natural  killer (NK) cells, platelets, endothelial cells    Protection includes vascular responses, cellular  components (e.g., mast cells, neutrophils,  macrophages), secretory molecules or cytokines,  and activation of plasma protein systems   The physical barriers that protect against damage and infec-  tion are composed of tightly associated epithelial cells including  those of the skin and of the membranous sheets lining the gas-  trointestinal, genitourinary, and respiratory tracts (Figure 7-1).  The mucosal epithelial cells are highly interconnected junctions  that prohibit the passage of microorganisms into the underly-  ing tissue.” The normal turnover of the cells in these sites as well  as mechanisms for “washing” the surfaces may mechanically  remove many infectious microorganisms and prevent their  residence on the epithelial surfaces. For instance, the routine  sloughing off and replacement of dead skin cells also removes  adherent bacteria. Mechanical cleansing of the surfaces includes  vomiting and urination. Goblet cells of the upper respiratory  tract produce mucus that coats the epithelial surface and traps  microorganisms that are removed by hairlike cilia that mechan-  ically move the mucus upward to be expelled by coughing or  sneezing. Additionally, the low temperature on the skin gen-  erally inhibits microorganisms, most of which prefer tempera-  tures near 37° C for more efficient growth.    Epithelial surfaces also provide biochemical barriers by synthe-  sizing and secreting substances meant to trap or destroy micro-  organisms. Mucus, perspiration (or sweat), saliva, tears, and  earwax are all examples of biochemical secretions that can trap  and kill potential disease-causing microorganisms. Sebaceous    Third line of defense; initiated when innate  immune system signals the cells of  adaptive immunity   Delay between primary exposure to antigen  and maximum response; immediate  against secondary exposure to antigen    glands in the skin secrete antibacterial and antifungal fatty acids  and lactic acid. Perspiration, tears, and saliva contain an enzyme  (lysozyme) that attacks the cell walls of gram-positive bacteria.  These glandular secretions result in an acidic skin surface (pH 3  to 5), which is an inhospitable environment for most bacteria.    The epithelial surfaces of the body secrete a complex array  of proteins that destroy potential pathogens. Epithelial cells  secrete small-molecular-weight antimicrobial peptides.’ These  are generally positively charged polypeptides of approximately  15 to 95 amino acids and can be divided into two classes—  cathelicidins and defensins—based on their 3-dimensional  structures. Both classes are in very high local concentrations  and are toxic to several bacteria, fungi, and viruses. Catheli-  cidins have a linear a-helical shape, and only one is currently  known to function in humans. In contrast, about 50 different  defensins have been identified thus far. All are triple-stranded  B-sheet structures. Defensin molecules contain 3 intrachain  disulfide bonds and can be further subdivided into a (at least  6 identified in humans) and 6 types (at least 10 identified, but  perhaps up to 40 different molecules), depending on how the    cysteine residues are connected during formation of the disul-  fide linkages.’ The a-defensins often require activation by pro-  teolytic enzymes, whereas the {-defensins are synthesized in  active forms. Bacteria have cholesterol-free cell membranes,  which may allow cathelicidins to insert into and disrupt their  membranes. Given the similarity in their chemical charges,  defensins may kill bacteria in the same way. These same chemi-  cals also may contribute to other means of protection because  they are also produced by monocytes, macrophages, and neu-  trophils, which are components of the inflammatory response.  Cathelicidin is stored in neutrophils, mast cells, and a variety  of epithelial cells. The a-defensins are particularly rich in the  granules of neutrophils and may contribute to the killing of  bacteria by those cells. They are also found in Paneth cells lin-  ing the small intestine, where they protect against a variety of  disease-causing microorganisms. The $-defensins are found in  a variety of epithelial cells lining the respiratory, urinary, and  intestinal tracts, as well as in the skin. In addition to antibac-  terial properties, B-defensins may also help protect epithelial  surfaces from human immunodeficiency virus (HIV) infection.  Both classes of antimicrobial peptides also can activate cells of  innate and adaptive immunity.    FIGURE 7-1 The Closed Barrier. The digestive, respiratory, and genitourinary tracts and the skin form closed barriers  between the internal organs and the environment. (From Grimes DE: /nfectious diseases, St Louis, 1991, Mosby.)    The lung also produces and secretes a family of glycopro-  teins, collectins, which includes surfactant proteins A through  D and mannose-binding lectin. The binding site of each col-  lectin reacts with different affinities to a range of monosaccha-  rides, enabling collectins to recognize a wide array of pathogenic  microorganisms. Collectin binding facilitates recognition of  the microorganism by macrophages, enhancing macrophage  attachment, phagocytosis, and killing. Collectins play a major  role in protection against respiratory tract infections.   Other epithelial antimicrobials include resistin-like molecule  6, bactericidal/permeability-inducing protein, and antimicro-  bial lectins. Resistin-like molecule f is found in the intestinal  goblet cells, where it appears to protect against helminth infec-  tions. Bactericidal/permeability-inducing (BPI) protein is  stored in neutrophils and intestinal epithelium. BPI protein  specifically reacts with lipopolysaccharide on the surface of  gram-negative bacteria, resulting in bacterial lysis. Antimi-  crobial lectins are carbohydrates that are found in intestinal  epithelium and have activity against gram-positive bacteria.    The body’s surfaces are colonized with a spectrum of microor-  ganisms, the normal microbiome. Each surface, including the  skin and the mucous membranes of the eyes, upper and lower  gastrointestinal tracts, urethra, and vagina, is colonized by a  combination of mostly bacteria and occasionally fungi that is  unique to the particular location. The microorganisms in the  microbiome do not normally cause disease, and although their  relationship with humans has been referred to as commensal (to  the benefit of one organism without affecting the other), the  relationship may be more mutualistic (to the benefit of both  organisms). Using the colon for an example, at birth the lower    gut is relatively sterile but colonization with bacteria begins  quickly, with the number, diversity, and concentration increas-  ing progressively during the first year of life. To the benefit of  humans, many of these microorganisms help digest fatty acids,  large polysaccharides, and other dietary substances; produce  biotin and vitamin K; and assist in the absorption of various  ions, such as calcium, iron, and magnesium.°   These bacteria contribute to our innate protection against  pathogenic microorganisms in the colon. They compete with  pathogens for nutrients and block attachment to the epithelium.  Members of the normal microbiome also produce chemicals  (ammonia, phenols, indoles, and other toxic materials) and toxic  proteins (bacteriocins) that inhibit colonization by pathogenic  microorganisms. Prolonged treatment with broad-spectrum  antibiotics can alter the normal intestinal microbiome, decreas-  ing its protective activity, and lead to an overgrowth of pathogenic  microorganisms, such as the yeast Candida albicans or the bacte-  ria Clostridium difficile (overgrowth can cause pseudomembra-  nous colitis, an infection of the colon). Additionally, the normal  microbiome of the gut help train the adaptive immune system  by inducing the growth of gut-associated lymphoid tissue (where  cells of the adaptive immune system reside) and the development  of both local and systemic adaptive immune systems.°   The bacterium Lactobacillus is a major constituent of the normal  vaginal microbiome in healthy women.’ This microorganism pro-  duces a variety of chemicals (e.g., hydrogen peroxide, lactic acid,  bacteriocins) that help prevent infections of the vagina and urinary  tract by other bacteria and yeast. Prolonged antibiotic treatment  can diminish colonization with Lactobacillus and increase the risk  for urologic or vaginal infections, such as vaginosis.   Some members of the normal bacterial microbiome are  opportunistic; opportunistic microorganisms can cause disease    Both omega-3 and omega-6 polyunsaturated fatty acids are essential fatty acids  available only in the diet. They are essential because human physiologic proc-  esses cannot add the necessary double bonds to the carbon chains. Omega-6  fatty acids are contained in vegetable oils, and most are linolenic acid. Omega-3  essential fatty acids, which are mostly alpha-linolenic acid, are found in green  leafy vegetables, walnuts, flaxseed, and canola oil. The metabolic products of  alpha-linolenic acid are eicosapentaenoic acid (EPA) and docosahexaenoic acid  (DHA), and the richest source of these acids is in the oils of deep-sea cold-water  fish. Both the omega-3 and omega-6 fatty acids use the same enzymes to produce  their metabolic products, and they compete for this enzyme, delta-5-desaturase.  Delta-5-desaturase converts EPA into anti-inflammatory prostaglandins (PGs) of  the PGE, series. The omega-6 fatty acid dihomogamme-linolenic acid (DGLA)  can be converted to either anti-inflammatory PG, or arachidonic acid (AA), a pre-  cursor of inflammatory PG, and leukotrienes. Conversion of DGLA into PG, does  not require any enzymes, but conversion of DGLA into AA requires the enzymes  delta-6- and delta-5-desaturase. When the diet is high in omega-3 fatty acids,  most of the delta-5-desaturase will be used in the omega-3 pathway and the    production of anti-inflammatory prostaglandins. Little delta-5-desaturase will  be available to convert DGLA into arachidonic acid, and subsequent inflamma-  tory mediators. DGLA ends up being converted into the anti-inflammatory PG,,  and, overall, inflammation is decreased. The resulting anti-inflammatory effects  of omega-3 essential fatty acids decrease the risk for cardiovascular disease,  cancer, and other conditions associated with inflammation. Omega-3 fatty acids  have been shown to decrease blood triglyceride concentrations; decrease pro-  duction of chemoattractants, growth factors, and adhesion molecules; lower  blood pressure; increase nitric oxide production and endothelial relaxation and  vascular compliance; decrease thrombosis and cardiac dysrhythmias; and sta-  bilize atherosclerotic plaque. The American diet tends to be high in saturated  and omega-6 fatty acids and deficient in omega-3 fatty acids, with a ratio esti-  mated at about 15:1. The Mediterranean-style diet has more whole grains, fish,  olive oil, fresh fruits and vegetables, and a more balanced ratio of omega-6 to  omega-3 fatty acids estimated at about (3-4):1. Increasing omega-3 fatty acids  in the diet may significantly improve health and reduce the risk of cardiovascular  disease and cancer.    Data from Abeywardena MY, Patten GS: Endocr Metab Immune Disord Drug Targets 11(3):232-246, 2011; Berquin IM et al: Cancer Lett  269(2):363-377, 2008; Calder PC: Clin Sci (Lond) 107(1):1-11, 2004; Chrysohoou C et al: J Am Coll Cardiol 44(1):152-158, 2004; Das UN: Lipids  Health Dis 7:37, 2008; Esposito K et al: JAMA 292(12):1440-1446, 2004; Manson JE et al: Contemp Clin Trials 33(1):159-171, 2012; Pottala JV  et al: Circ Cardiovasc Qual Outcomes (4):406-412, 2010; Sijoen JW, Calder PC: Proc Nutr Soc 66(2):237-259, 2007.    if the individual’s defenses are compromised. These microor-  ganisms are normally controlled by the innate and adaptive  immune systems and contribute to our defenses. For example,  Pseudomonas aeruginosa is a member of the normal microbi-  ome of the skin and produces a toxin that protects against infec-  tions with staphylococcal and other bacteria. However, severe  burns compromise the integrity of the skin and may lead to life-  threatening systemic pseudomonal infections.    If cells and tissues are damaged the inflammatory response is  usually activated (Figure 7-2). Injury can have a variety of causes  including infection, mechanical damage, oxygen deprivation  (ischemia), nutrient deprivation, genetic or immune defects, chem-  ical agents, temperature extremes, or ionizing radiation. Inflam-  mation (1) depends on the activity of both cellular and chemical  components, and (2) is nonspecific, meaning that it takes place in  approximately the same way regardless of the type of stimulus or  whether exposure to the same stimulus has occurred in the past.   Inflammation occurs in tissue that has a blood supply (vascu-  larized) and results in a group of easily observable characteris-  tics: redness, heat, swelling, and pain. This tetrad represents the    “cardinal signs of inflammation” and was identified in the first  century by a Roman writer, Celsus. Microscopically, inflam-  matory changes occur at the vascular level (Figure 7-3). The  three characteristic changes in the microcirculation (arterioles,  capillaries, and venules) near the site of an injury include the  following:   3. White blood cell adherence to the inner walls of vessels   and their migration through vessel walls to the site of  injury (diapedesis)   The effects of inflammation are visible within seconds. First,  arterioles near the site of infection or injury constrict briefly.  Vasodilation then causes slower blood velocity and increases  local blood flow to the injured site. The increased flow and cap-  illary permeability result in leakage of plasma from the vessels,  causing swelling (edema) in the surrounding tissue. As plasma  moves outward, blood remaining in the microcirculation flows  more slowly and becomes more viscous. The increased blood  flow and increasing concentration of red cells at the site of  inflammation cause locally increased warmth and redness. Leu-  kocytes adhere to vessel walls. At the same time, biochemical  mediators (e.g., histamine, bradykinins, leukotrienes, prosta-  glandins) stimulate the endothelial cells that line capillaries and  venules to retract, creating spaces at junctions between the cells,    FIGURE 7-2 Acute Inflammatory Response. Inflammation is usually initiated by cellular injury, which results in mast  cell degranulation, the activation of three plasma systems, and the release of subcellular components from the damaged cells.  These systems are interdependent, so that induction of one (e.g., mast cell degranulation) can result in activation of the other  two. The result is the development of microscopic changes in the inflamed site, as well as characteristic clinical manifesta-  tions. The figure numbers refer to those in which more detailed information may be found on that portion of the response.    FIGURE 7-3 Sequence of Events in the Acute Inflammatory Response. See text for details.    allowing leukocytes and plasma to enter the surrounding tissue  (intercellular junctions are described in Chapter 1).   Each of the characteristic changes associated with inflam-  mation is the direct result of the activities and interactions  of a host of chemicals and cellular components found in the  blood and tissues. The vascular changes deliver leukocytes,  plasma proteins, and other biochemical mediators to the site  of injury. Once in the tissues, the cells and chemicals associ-  ated with the inflammatory response act in concert to do the  following:   1. Prevent infection and further damage by contaminating  microorganisms through the influx of fluid to dilute tox-  ins produced by bacteria and released from dying cells,  the influx and activation of plasma protein systems that  help destroy and contain bacteria (e.g., complement sys-  tem, clotting system), and the influx of cells (e.g., neutro-  phils, macrophages) that “eat” and destroy cellular debris  and infectious agents.   2. Limit and control the inflammatory process through the  influx of plasma protein systems (e.g., clotting system),  plasma enzymes, and cells (e.g., eosinophils) that prevent  the inflammatory response from spreading to areas of  healthy tissue.    3. Interact with components of the adaptive immune sys-  tem to elicit a more specific response to contaminating  pathogen(s) through the influx of macrophages and  lymphocytes.®   4. Prepare the area of injury for healing through removal  of bacterial products, dead cells, and other products of  inflammation (e.g., by way of channels through the epi-  thelium or drainage by lymphatic vessels) and initiation  of mechanisms of healing and repair.   Fluid and debris that accumulate at an inflamed site are  drained by lymphatic vessels. This process also facilitates the  development of adaptive immunity because microbial anti-  gens in lymphatic fluid pass through the lymph nodes, where  they activate both B and T lymphocytes. (This process is dis-  cussed in Chapter 8, and the lymphatic system is described in  Chapter 27.)   Inflammation and repair can be divided into several phases  (Figure 7-4). The characteristics of the early (i.e., acute) inflam-  matory response differ from those of the later (i.e., chronic)  response, and each phase involves different biochemical media-  tors and cells that function together. The acute inflammatory  response is of short duration; that is, it continues only until the  immediate threat to the host is eliminated. This usually takes    CHAPTER 7_ Innate Immunity: Inflammation  Complement System  Cellular  injury The complement system consists of several plasma proteins  (sometimes called complement components) that together con-  I | stitute about 10% of the total circulating serum protein. The    FIGURE 7-4 Inflammatory Phases. Cellular injury leads to acute inflamma-  tion and may result in resolution and healing of the injured site or may progress  into chronic inflammation. Chronic inflammation in turn may result in healing  or progress to development of a granuloma. The final step of the inflammatory  process is usually healing and reconstruction of the damaged tissue. The figure  numbers refer to those in which more detailed information on that portion of the  process may be found.    8 to 10 days from onset to healing. The acute inflammatory  response begins immediately after cellular injury or infection  occurs and involves a vascular response, activation of plasma  protein systems, and activation of a variety of cells. (Mecha-  nisms of cellular injury are described in Chapter 2.)   Three key plasma protein systems are essential to an effective  inflammatory response. These are the complement system, the  clotting system, and the kinin system (Figures 7-5, 7-6, and 7-7,  respectively). Although each system has a unique role in inflam-  mation, they also have many similarities. Each system consists  of multiple proteins in the blood. To prevent activation in  unnecessary situations, each protein is normally in an inactive  form. Several of the proteins are enzymes that circulate in inac-  tive forms as proenzymes. Each system contains a few proteins  that can be activated by products of tissue damage or infection.  Activation of the first component of a system results in sequen-  tial activation of other components, leading to a biologic func-  tion that helps protect the individual. This sequential activation  is referred to as a cascade. Thus, we refer to the complement cas-  cade, the clotting cascade, or the kinin cascade. In some cases,  activation of a protein may require that it be enzymatically cut  into two pieces or fragments of different size. Usually the larger  fragment continues the cascade by activating the next compo-  nent, and the smaller fragment frequently has potent biologic  activities to promote inflammation.    complement system is extremely important because activation  of the complement cascade may destroy pathogens directly and  can activate or collaborate with virtually every other compo-  nent of the inflammatory response. Proteins of the complement  system are among the body’s most potent defenders, particu-  larly against bacterial infection.   Activation of the complement system can be accomplished  in three different pathways, all of which converge at the third  component (C3) of the pathway:   1. Classical pathway: activated by proteins of the adaptive  immune system (antibodies) bound to their specific tar-  gets (antigen)   3. Alternative pathway: activated by gram-negative bacte-  rial and fungal cell wall polysaccharides   The principal routes by which the complement cascade may  be activated are shown in Figure 7-5.   Activation of the classical pathway begins with the activa-  tion of complement protein C1 and is preceded by formation  of a complex between an antigen and an antibody to form an  antigen-antibody complex (immune complex) (discussed in  Chapter 8). The antigen may be a unique chemical component  of the surface of a bacterium or other microorganism. Most  pathogens express multiple antigens; therefore, multiple anti-  bodies are usually bound in the complex. The first component  of the classical complement cascade, C1, has six sites that can  bind to antibodies, and efficient activation of the complement  cascade usually requires concurrent binding of C1 to at least two  antibody molecules. The complex formed by antigen-antibody-  complement binding is shown in Figure 7-5. Cl is a macromo-  lecular complex consisting of Clq and two molecules each of  Clr and Cls. A conformational change in Cl results in an enzy-  matically active molecule whose substrates are C4 and C2. The  resultant complex formed by the interaction of C1, C4, and C2  uses C3 as a substrate, resulting in the production of C3a and  C3b. A complex that has C3 as a substrate is generally referred to  as a C3 convertase. The addition of C3b to the complex changes  the substrate specificity to C5, resulting in the conversion of C5  to C5a and C5b. A complex that has C5 as a substrate is gener-  ally called a C5 convertase. Thus activation of Cl initiates the  sequential enzymatic activation of all other components of the  classical pathway, ultimately resulting in the activation of C5.  The classical pathway also can be activated to a lesser degree  by biologic molecules other than antibody, including heparin  (a charged molecule that prevents clotting), deoxyribonucleic  acid (DNA) or ribonucleic acid (RNA), and C-reactive protein,  which is increased in the blood during inflammation.   Even under normal conditions small amounts of circulat-  ing C3 are spontaneously broken down into C3b and C3a by a  number of naturally occurring enzymes in the blood. The rate  of C3 spontaneous activation is generally very low, and C3b is  readily inactivated by complement regulator proteins in the    FIGURE 7-5 Pathways of Complement Cascade Activation. The complement system is activated by three pathways:  the classical pathway, the lectin pathway, and the alternative pathway. During activation, many complement components are  cleaved into fragments (2b, 4a, Ba, C3a, and C5a). The smaller fragments frequently have potent biologic activities and may  serve as chemotactic factors and anaphylatoxins. The larger activated fragments are usually converted into active enzymes  (indicated by the bar above the names) and form complexes with additional components in the cascade. The classical path-  way is usually activated by antigen-antibody complexes through component C1, which consists of C1q and two Ctr and C1s    blood (e.g., factor H and factor I). However, materials produced  by some infectious microorganisms (e.g., lipopolysaccharides  [endotoxins] on the bacterial surface, yeast cell wall carbohy-  drates [zymosans]) can bind the naturally produced C3b and  protect it from inactivation. This will initiate activation of the  alternative complement pathway. The C3b bound to bacterial  products can react with another normally occurring compo-  nent, factor B. The complex of C3b and factor B is recognized  by an enzyme, factor D, which activates factor B, producing fac-  tor Bb. The resultant C3b/Bb complex is very unstable unless  it binds to properdin (P). The C3b/Bb/P complex is a C3 con-  vertase that produces further C3b, resulting in a C3b/Bb/P/C3b  complex that is a C5 convertase, which activates C5.   The lectin pathway is similar to the classical pathway but is  antibody independent. It is activated by a plasma protein called  mannose-binding lectin (MBL). MBL is similar to Clq and  binds to bacterial polysaccharides containing the carbohydrate    molecules. As indicated, the C1q must simultaneously bind to two antibody molecules (indicated by Y-shaped structures). The   ctin pathway is activated by mannose-binding lectin (MBL), which binds to two mannose-rich pathogen-associated molecu-  lar patterns on the surface of a bacterium. MBL contains two associated enzymes, MASP-1 and MASP-2, and functions in a   anner similar to C1. C1 and MBL each activate complement components C4 and C2. The alternative pathway is activated by  any agents, such as bacterial polysaccharides, which bind and stabilize C3b, which is produced by normal breakdown of C3  the blood. The C3b forms the site of binding of factor B (fB), which is activated by factor D (fD) into Bb and the small frag-  ent Ba. Properdin (P) helps stabilize the complex. Each pathway produces C3 and C5 convertases, which are enzymatically  active complexes that activate C3 and C5, respectively. C3b produced by the C3 convertase can function as an opsonin. C5b  tiates assemblage of the membrane attack complex (MAC), which results in multiple C9 molecules forming a pore in the    mannose. MBL-associated serine proteases (MASP-1 and  MASP-2) substitute for Clr and Cls and activate C4 and C2 to  create a C3 convertase.   After activation of C5, the cascade continues through the  terminal components C6, C7, C8, and C9. Components C5b  through C9 assemble to form complexes (membrane attack  complex, or MAC) capable of creating pores in cell membranes  and permitting the influx of water and ions and may ultimately  result in cell lysis.   The most important result of complement activation is the  production of fragments during the activation of C4, C2, C3,  and C5. The fragments C4a, C2b, C3a, and C5a are soluble  and of low-molecular-weight that contribute in other ways to  the inflammatory response. C2b affects smooth muscle, caus-  ing vasodilation and increased vascular permeability. C3a and  C5a, and to a limited extent C4a, are anaphylatoxins; that is,  they induce rapid mast cell degranulation (release of granular    FIGURE 7-6 Coagulation Cascade. Clotting is activated through two pathways: the intrinsic pathway and the extrinsic  pathway. The intrinsic pathway is initiated by the activation of Hageman factor (XII) into Xlla (activated factors are enzymes  and are indicated by a lowercase a). The sequential activation of other intrinsic pathway components results in formation of a  complex of |Xa, Villa, and X. The extrinsic pathway is activated by exposure of tissue factor (TF) during tissue damage. TF com-  plexes with factor VII, which is activated (Vlla) and forms a complex with factor X (TF, Vlla, X). Both the intrinsic and the extrinsic  pathway complexes are dependent on calcium, form on phospholipid membranes that are rich in phosphatidylserine, and have  “tenase” activity (can activate factor X into Xa). Factor X begins a common pathway in which Xa complexes with Va and pro-  thrombin (PT), with calcium and phospholipid membranes, to form an active prothrombinase (activates prothrombin into throm-  bin). Thrombin is an enzyme that cuts high-molecular-weight fibrinogen into fibrin molecules. Fibrin polymerizes to form a clot.    FIGURE 7-7 Plasma Kinin Cascade. The kinin pathway is activated by factor  Xlla from the clotting system, which functions as an enzyme (prekallikrein activa-  tor) to convert prekallikrein into kallikrein. Enzymatically active kallikrein converts  kininogen into bradykinin.    contents) and the release of histamine (see Figure 7-11, p. 206),  causing vasodilation and increased capillary permeability.? C5a  is the major chemotactic factor for neutrophils. C3a is approxi-  mately 100 times less potent in chemotactic and anaphylatoxic  activity. A chemotactic factor is a biochemical substance that  attracts leukocytes to the site of inflammation.   The dual functions of a chemotactic factor and an anaphyl-  atoxin are not needed simultaneously or to the same degree.  Anaphylatoxic activity is necessary early in inflammation and  occurs close to the inflammatory site to induce local mast cell  degranulation and to increase the number of soluble mediators  available to enhance vascular permeability and vasodilation.  Chemotactic activity, on the other hand, is required for a much  longer period and occurs distal to the inflammatory site to    attract leukocytes from the circulation. Thus it is beneficial to an  effective inflammatory response to limit the range of anaphyla-  toxic activity while allowing widespread chemotactic activity. A  plasma enzyme, a carboxypeptidase, removes a terminal argi-  nine on both C3a and C5a peptides, thereby producing “C3a  desArg” and “C5a desArg,” which are inactive as anaphylatox-  ins but retain chemotactic activity. Thus chemotactic activity is  retained, while not inducing distal mast cell degranulation that  would result in considerable enlargement of the inflammatory  response to the detriment of surrounding healthy tissue.   C3b adheres to the surface of a pathogenic microorganism  and serves as an efficient opsonin. Opsonins are molecules that  “tag” microorganisms for destruction by cells of the inflam-  matory system (primarily neutrophils and macrophages [see  pp. 208 and 209]). C3b on the cell surface also can be broken  down by several enzymes in the blood into inactive fragments  (e.g., iC3b), which retain opsonic activity.   In summary, the complement cascade can be activated by  at least three different means, and its products have four func-  tions: (1) anaphylatoxic activity resulting in mast cell degranu-  lation, (2) leukocyte chemotaxis, (3) opsonization, and (4) cell  lysis.   The clotting (coagulation) system is a group of plasma proteins  that form a fibrinous meshwork at an injured or inflamed site.  This (1) prevents the spread of infection to adjacent tissues, (2)  traps microorganisms and foreign bodies at the site of inflamma-  tion for removal by infiltrating cells (e.g., neutrophils and mac-  rophages), (3) forms a clot that stops bleeding, and (4) provides    FIGURE 7-8 Interactions Between the Complement, Clotting, and Kinin Systems. Thick colored arrows denote the activation of factors within a system. Thin arrows  denote where a particular factor activates another system.    a framework for future repair and healing. The main substance  in this fibrinous mesh is an insoluble protein called fibrin that is  the end product of the coagulation cascade.   The clotting system can be activated by many substances that  are released during tissue injury and infection, including col-  lagen, proteinases, kallikrein, and plasmin, as well as by bacte-  rial products such as endotoxins. Like the complement cascade,  the coagulation cascade can be activated through different con-  vergent pathways (see Figure 7-6). The tissue factor (extrinsic)  pathway is activated by tissue factor (TF) (also called tissue  thromboplastin) that is released by damaged endothelial cells  in blood vessels and reacts with activated factor VII (VIa). The  contact activation (intrinsic) pathway is activated when the ves-  sel wall is damaged and Hageman factor (factor XII) in plasma  contacts negatively charged subendothelial substances. The  pathways converge at factor X. Activation of factor X begins a  common pathway leading to activation of fibrin that polymer-  izes to form a fibrin clot. The coagulation system is discussed in  more detail and illustrated again in Chapter 27.   As with the complement system, activation of the clotting  system produces fragments that enhance the inflammatory  response. Two low-molecular-weight fibrinopeptides, A and  B, are released from fibrinogen when fibrin is produced. Both  fibrinopeptides (especially fibrinopeptide B) are chemotactic  for neutrophils and increase vascular permeability by enhanc-  ing the effects of bradykinin (formed from the kinin system).    Kinin System  The third plasma protein system, the kinin system, augments  inflammation in several ways. The primary kinin produced from  the kinin system is bradykinin, which causes dilation of blood  vessels, acts with prostaglandins to stimulate nerve endings and  induce pain, causes smooth muscle cell contraction, increases  vascular permeability, and may increase leukocyte chemotaxis  (see Figure 7-2). Bradykinin induces smooth muscle contraction  more slowly than histamine and, along with prostaglandins of the  E series, is probably responsible for endothelial cell retraction and  increased vascular permeability in the later phases of inflamma-  tion (endothelial cell retraction is shown in Figures 7-3 and 7-15).  The kinin system is activated by stimulation of the plasma  kinin cascade (see Figure 7-7). The conversion of plasma  prekallikrein to kallikrein is induced by prekallikrein activa-  tor, which is identical to factor XIla (the product that results  from activation of Hageman factor—factor XII) of the clot-  ting cascade. Kallikrein then converts kininogen to bradykinin.  Although the plasma kinin cascade is one pathway that leads to  the production of bradykinin, tissue kallikreins in saliva, sweat,  tears, urine, and feces provide other sources for this inflamma-  tory mediator. These tissue kallikreins convert serum kinino-  gens to kallidin, also known as Lys-bradykinin, which may be  converted to bradykinin by plasma aminopeptidase. In order to  limit the extent of inflammation, kinins are rapidly degraded by  kininases, enzymes present in plasma and tissues.    The three plasma protein systems are highly interactive so that  activation of one system results in the production of a large    number of very potent, biologically active substances that fur-  ther activate the other systems (Figure 7-8). Very tight control  of these processes is essential for two reasons:   1. The inflammatory process is critical for an individual’s  survival; thus, efficient activation must be guaranteed  regardless of the cause of tissue injury.   2. The biochemical mediators generated during these proc-  esses are so potent and potentially detrimental to the  host itself that their actions must be strictly confined to  injured or infected tissues only.   Therefore, multiple mechanisms are available to either acti-  vate or inactivate (regulate) these plasma protein systems. As an  example, plasmin regulates clot formation by degrading fibrin  and fibrinogen, and it can activate the complement cascade  through components C1, C3, and C5. Plasmin can activate the  plasma kinin cascade as well by activating Hageman factor (fac-  tor XII) and producing prekallikrein activator. This activation  of Hageman factor has four effects that impact all three of the  plasma protein systems:   2. Control of clotting through conversion of plasminogen  proactivator to plasminogen activator, resulting in the  generation of plasmin   3. Activation of the kinin system by activated Hageman fac-  tor (prekallikrein activator)   The activity of plasmin itself is also regulated because it is  synthesized as a proenzyme, plasminogen. Plasminogen is con-  verted to plasmin by several factors, including plasminogen  activator generated from the kallikrein system, thrombin gen-  erated from the clotting system, bacterial factors such as strep-  tokinase produced by hemolytic streptococci, plasminogen  activators produced by endothelial cells, and several cellular  enzymes released during tissue destruction.   Many enzymes from the plasma regulate the activity of these  pathways, such as carboxypeptidase that inactivates the ana-  phylatoxic activities of C3a and C5a, and kininases that degrade  kinins. Many other natural inhibitors are present, including  enzymes that degrade histamine (histaminase), activated com-  plement components, kallikrein, and plasmin. Another example  of a common regulator is Cl-esterase inhibitor (Cl-inh).!°  C1-inh inhibits complement activation through reactivity with  C1 (classical pathway), MASP-2 (lectin pathway), and C3b  (alternative pathway). It is also a major inhibitor of the clotting  and kinin pathways (e.g., kallikrein, activated Hageman factor  XWa). A genetic defect in Cl-inh (Cl-inh deficiency) results in  hereditary angioedema, which is a self-limiting edema of cuta-  neous and mucosal layers resulting from stress, illness, or rela-  tive minor or unapparent trauma. The disease is characterized  by hyperactivation of all three plasma protein systems, although  excessive production of bradykinin appears to be the principal  cause of increased vascular permeability.   Inflammation is a process in vascular tissue; thus the cellular  components of inflammation are found in the blood and in  the tissue surrounding the blood vessels. The vessels are lined    with endothelial cells, which under normal conditions actively  maintain normal blood flow. During inflammation the vascular  endothelium becomes a principal coordinator of blood clotting  and the passage of cells and fluid into the tissue. The tissue close  to the vessels contains mast cells, which are probably the most  important activators of inflammation. The tissue also contains  dendritic cells, which connect the innate and adaptive immune  responses. The blood contains a complex mixture of cells (see  Figure 7-3). Blood cells are divided into erythrocytes (red blood  cells), platelets, and leukocytes (white blood cells). Erythrocytes  carry oxygen to the tissues, and platelets are small cell frag-  ments involved in blood clotting. Leukocytes are subdivided  into granulocytes (containing many enzyme-filled cytoplasmic  granules), monocytes, and lymphocytes. Granulocytes are the  most common leukocytes and are classified by the type of stains  needed to visualize their granules (basophils, eosinophils, and  neutrophils). Monocytes are precursors of macrophages that  are found in the tissues. Various forms of lymphocytes partici-  pate in the innate (natural killer [NK] cells) and the adaptive  immune response (B and T cells).   The cells of the inflammatory system secrete and respond to  biochemical mediators. Thus most of these cells are recruited  and activated by products of the plasma protein systems and by  biochemicals released during cell destruction, secreted by other  inflammatory cells, or produced by microbes. These inflamma-  tory cells and protein systems, along with the substances they  produce, preferably act at the site of tissue injury to confine the  extent of damage, kill microorganisms, and remove the debris  of “battle” in preparation for healing: tissue regeneration or  repair (processes known as resolution).    Cells of both innate and adaptive immunity must recognize and  respond to their environment, whether to products of damaged  cells or to potential pathogenic microorganisms. Each cell has  receptors on the cell surface that specifically bind soluble sub-  stances (ligands) produced during tissue damage or infection.  The binding of a ligand to its receptor results in activation of  intracellular signaling pathways and activation of the cell. As  will be discussed in Chapter 8, B and T lymphocytes of the  adaptive immune system have evolved surface receptors (Le.,  the T-cell receptor, or TCR, and the B-cell receptor, or BCR)  that bind a large spectrum of antigens. Cells involved in innate  resistance have evolved a different set of receptors that recog-  nize a much more limited array of specific molecules. These  are referred to as pattern recognition receptors (PRRs), and  they recognize molecular “patterns” on infectious agents or  their products (pathogen-associated molecular patterns, or  PAMPs), or products of cellular damage (necrosis or apoptosis;  damage-associated molecular patterns, or DAMPs). PRRs are  generally found on cells at the interface of the host and environ-  ment (i.e., skin, respiratory tract, gastrointestinal tract, geni-  tourinary tract), where they monitor for products of cellular  damage and potentially infectious microorganisms. Although  most PRRs are on the cell surface, some are secreted or intra-  cellular.!' An example of a secreted PRR is mannose-binding  lectin of the lectin pathway of complement activation. Cellular    PRRs include Toll-like receptors, complement receptors (CRs),  scavenger receptors, glucan receptors, and mannose receptors.  A group of intracellular protein complexes, called inflamma-  somes, function as PRRs within cells.!* Inflammasomes pri-  marily bind cellular stress—related molecules, a type of DAMPs,  and control the production of interleukin-1f (IL-18).!°   In humans, at least 11 different Toll-like receptors (TLRs)  have been described, 10 of which are functional.'* They are  expressed on the surface of many cells that have direct and  early contact with potential pathogenic microorganisms. These  include mucosal epithelial cells, mast cells, neutrophils, macro-  phages, dendritic cells, and some subpopulations oflymphocytes.  (Dendritic cells are found in the skin, mucosa, and lymphoid  tissues, where they have developed from Langerhans cells and  function as highly specialized initiators of the adaptive immune  response.) TLRs recognize a large variety of PAMPs located on  the microorganism’s cell wall or surface (e.g., bacterial lipopoly-  saccharide [LPS], peptidoglycans, and lipoproteins, yeast zymo-  san, viral coat proteins), other surface structures (e.g., bacterial  flagellin), or microbial nucleic acid (e.g., bacterial DNA, viral  double-stranded RNA). Some TLRs recognize host factors that  are produced by “stressed” or damaged cells (e.g., breakdown  products of extracellular matrix proteins, chromatin). Interac-  tions between PAMPs and TLRs, with the collaboration of other  cellular receptors (e.g., CD14), can result in activation of the cell  and the release of soluble products (e.g., cytokines) that increase  local resistance to the pathogenic microorganism. TLRs are also  one of the bridges between innate resistance and the adaptive  immune response through the induction of cytokines that  increase the response of lymphocytes to foreign antigens on the  pathogens. Genetic polymorphisms in TLRs may explain some  observed differences among individuals’ resistance and suscep-  tibility to infections. Information on each of the TLRs found in  humans is shown in Table 7-2.   Complement receptors are found on many cells of the innate  and adaptive immune responses (e.g., granulocytes, monocytes/  macrophages, lymphocytes, mast cells, erythrocytes, platelets),  as well as some epithelial cells. They recognize several fragments  produced through activation of the complement system. Under  a variety of normal and disease-related conditions, immune  complexes of antibody, antigen, and complement form in the  blood and are removed by cells expressing surface complement  receptor-1 (CR1), which binds to C4b, C3b, and C3b break-  down products (e.g., iC3b). CR2 is found on B lymphocytes, as  well as dendritic cells and some epithelial cells, and recognizes  C3b breakdown products (particularly iC3b). CR2 appears to  facilitate B-cell function and antibody production. Both CR3  and CRé4 are integrins that primarily recognize C3b break-  down products (particularly iC3b). CR3 (integrin aMB2, also  called CD11b/CD18) facilitates phagocytosis by neutrophils  and monocytes/macrophages. CR4 (aX2, also called CD11c/  CD18) is found primarily on platelets. (Integrins are cell sur-  face receptors that have a role in cell adhesion and attachment  and mediate intracellular signaling within the extracellular  matrix [see Figure 1-14, p. 15].)   Scavenger receptors are primarily expressed on macro-  phages and facilitate recognition and phagocytosis of bacterial    dendritic cells, T cells, B cells, NK cells  LR2 Cell surface: neutrophils, monocytes/macrophages, dendriti  cells   LR3 Intracellular: monocytes/macrophages, dendritic cells, T ce  NK cells, epithelial cells   LR4 Cell surface: granulocytes, monocytes/macrophages, dendriti  cells, T cells, B cells, epithelial cells  LR5 Cell surface: granulocytes, monocytes/macrophages, dendriti  cells, NK cells, epithelial cells   LR6 Cell surface: monocytes/macrophages, dendritic cells, B ce  NK cells  LR7 Intracellular: monocytes/macrophages, dendritic cells, B cells    Intracellular: monocytes/macrophages, dendritic cells, B cells  Cell surface: monocytes/macrophages, dendritic cells, B cells  TLR11 gene does not code a full length protein in humans    Fungal (yeast zymosan), bacterial (gram-positive bacterial peptidoglycan,  lipoproteins), viral (lipoproteins)  Double-stranded RNA produced by many viruses    Bacterial (primarily gram-negative bacterial LPS, lipoteichoic acids), viral  (RSV F protein, hepatitis C)   Natural ligand uncertain; may bind fungal PAMPs or viral single-stranded RNA  Bacterial (unmethylated DNA [CpG dinucleotides})    DNA, Deoxyribonucleic acid; LPS, lipopolysaccharide; NK, natural killer; PAMPs, pathogen-associated molecular patterns; RNA, ribonucleic acid;    pathogens, as well as damaged cells and altered soluble lipo-  proteins associated with vascular damage (e.g., high-density  lipoprotein [HDL], acetylated low-density lipoprotein [LDL],  oxidized LDL). More than eight receptors have been identi-  fied. Some scavenger receptors (e.g., SR-PSOX) recognize the  cell membrane phospholipid phosphatidylserine (PS). PS is  normally sequestered on the cytoplasmic surface of the cell  membrane, but is externalized under a very limited variety of  conditions, including erythrocyte senescence and cellular apop-  tosis. Thus macrophages, through this receptor, can identify  and remove old red blood cells and cells undergoing apoptosis.  Another important scavenger receptor is CD14, which recog-  nizes the complex of LPS and LPS-binding protein. LPS-binding  protein is up-regulated during inflammation by the cytokines  interleukin-6 (IL-6) and IL-1 and helps remove bacterial LPS  (endotoxin) from the circulation.   To elicit an effective inflammatory (or adaptive immune)  response, it is necessary that many different kinds of cells coop-  erate. Many cells secrete soluble factors that contribute to the  regulation of innate or adaptive resistance by affecting other  neighboring cells (Figure 7-9). These factors are referred to as  chemokines or cytokines and are either proinflammatory or anti-  inflammatory in nature, depending on whether they respec-  tively tend to induce or inhibit the inflammatory response.  These molecules usually diffuse over short distances, bind to  the appropriate target cells, and affect the function of the target  cell. Some effects occur over long distances, such as the systemic  induction of fever by some cytokines (i.e., endogenous pyro-  gens) that are produced at an inflammatory site. The binding  of chemokines or cytokines to a target cell often induces syn-  thesis of additional cellular products. For example, binding of  the cytokine tumor necrosis factor-alpha (TNF-a) to a cell may    result in synthesis and release of IL-1. Chemokine and cytokine  binding is mediated through specific cell surface receptors that  are themselves sometimes under the regulation of secreted cel-  lular products.   The actions of chemokines and cytokines are pleiotropic,  indicating that the same molecule may have a large variety of  different biologic activities depending on the particular target  cell to which it binds. In addition, the same molecule may be  produced by a large spectrum of cells, many of which are not  part of inflammation or the immune system. These molecules  may be synergistic, so that their combined activity exceeds the  sum of their individual activities, or have antagonistic proper-  ties that cause them to inhibit each other.!° (A partial list of  relevant cytokines is provided in Chapter 8, Table 8-5.)   Cytokines. The majority of important cytokines are classified  as interleukins or interferons. Other critical cytokines, however,  are not classified as either. Many of these same cytokines are  produced by cells of the acquired immune system in response to  specific antigens and are discussed further in Chapter 8.   The interleukins (ILs) are biochemical messengers produced  predominantly by macrophages and lymphocytes in response  to their recognition of a microorganism or stimulation by other  products of inflammation. One important function of this class  of cytokines is enhancement of the adaptive immune response  against pathogenic microorganisms and other foreign sub-  stances. Interleukins, however, are both produced by and have  effects on a large variety of cells, often independent of infection.   Two major proinflammatory cytokines are IL-1 and IL-6.  IL-1 is produced mainly by macrophages that have been stimu-  lated by substances associated with infection, including many of  the PAMPs discussed earlier in this chapter, as well as by other  cytokines. IL-1 is synthesized in two forms, a and £, that often  elicit the same biologic responses. IL-1 is an endogenous pyro-  gen (ie., fever-causing cytokine) that reacts with receptors on    Leukocytosis  Leukocytes (IL-1, TNF- «)  Mast cells and eosinophils (IL-4, IL-5)    Acute phase reactants  IL-1, IL-6, IL-8, TNF-a, C-reactive  protein and other proteins    Repair and healing  IFN-Y (activates macrophages)  TGF-B (stimulates fibroblast growth)  Angiogenic factors [VEGF, FGF-2] (stimulate  endothelial and fibroblast growth)    FIGURE 7-9 Principal Mediators of Inflammation. C3b, Large fragment produced from complement component C3;  C5a, small fragment produced from complement component C5; ECF-A, eosinophil chemotactic factor of anaphylaxis; ENA,  epithelial-dermoid neutrophil attractant; FGF fibroblast growth factor; G-CSF granulocyte colony-stimulating factor; /FN, inter-  feron; /gG, immunoglobulin G (predominant class of antibody in the blood); /L, interleukin; MCF monocyte chemotactic factor;  M-CSF monocyte colony-stimulating factor; NCF neutrophil chemotactic factor; PAF platelet-activating factor; TGF T-cell  growth factor; TNF tumor necrosis factor; VEGF vascular endothelial growth factor.    cells of the hypothalamus and affects the body’s thermostat. It  also activates phagocytes and lymphocytes, thereby enhancing  both innate and adaptive immunity, and acts as a growth factor  for many cells. It has several effects on neutrophils, including  induction of proliferation (resulting in an increase in the num-  ber of circulating neutrophils), chemotaxis, increased cellular  respiration, and increased lysosomal enzyme activity. IL-6 is  produced by macrophages, lymphocytes, fibroblasts, and other  cells. IL-6 directly induces hepatocytes (liver cells) to produce  many of the proteins needed in inflammation (acute-phase  reactants, discussed later in this chapter). IL-6 also stimulates  growth and differentiation of blood cells in the bone marrow  and the growth of fibroblasts (required for wound healing).  Some cytokines are anti-inflammatory and diminish the  inflammatory response. The most important are IL-10 and  transforming growth factor-beta (TGF-. IL-10 is primarily  produced by lymphocytes and suppresses the growth of lym-  phocytes and the production of proinflammatory cytokines by  macrophages, leading to the down-regulation of both inflam-  mation and the adaptive immune response. TGF-f and other  transforming growth factors are produced by many types of    cells in response to inflammation and induce differentiation of  other cell types, such as immature blood cells.   More than 30 human interleukins have been identified,  although the functions of several have not yet been defined.  Their varied effects include the following:   Interferons (IFNs) are low-molecular-weight proteins that  primarily protect against viral infections and modulate the  inflammatory response. (Mechanisms of viral infection are  described in Chapter 10.) IFNs are produced and released by  virally infected cells in response to viral double-stranded RNA  and other viral PAMPs. Different kinds of IFNs are produced by  different types of cells—macrophages are the primary produc-  ers of type I interferons (IFN-a and IFN-f), whereas T lympho-  cytes release type II interferon (IFN-y). These IFNs do not kill    Interferon binds to  uninfected cell and  induces synthesis  of antiviral protein    viruses directly but instead prevent them from infecting addi-  tional healthy cells.!° Interferons also enhance the efficiency of  developing an adaptive immune response.'”   IFN-a and IFN-B induce production of antiviral proteins,  thereby conferring protection on uninfected cells. IFN-a or IFN-  6 is released from virally infected cells, attaches to a receptor  on a neighboring cell, and, if the neighboring cell is uninfected,  stimulates the production of a variety of antiviral proteins that  will interfere with transcription of viral nucleic acids or with viral  replication'® (Figure 7-10). These interferons have no effect on  cells that have already been virally infected. IFN-y enhances the  inflammatory response by increasing the microbicidal activity of  macrophages. This cytokine also facilitates development of the  adaptive immune response against viral antigens on infected cells.  Interferons are species specific, meaning that human interferon is  effective only in humans; however, these cytokines are not virus  specific, meaning that they are effective against almost all viruses.   Despite the numerous interleukins and interferons, other  essential cytokines are needed to mount an efficient inflam-  matory response. One of the most important of these is tumor  necrosis factor-alpha (TNF-c).!? Macrophages secrete TNF-  a in response to recognition of PAMPs by TLRs. Other cells,  such as mast cells, are additional and crucial sources of this  proinflammatory cytokine. TNF-a is initially synthesized as a  membrane-spanning protein, which is cleaved into a soluble  form by a membrane-associated protease, TNF-converting  enzyme (TACE). Soluble TNF-a induces a multitude of pro-  inflammatory effects, including enhancement of endothelial  cell adhesion molecule expression and induction of chemokine  production by both endothelial cells and macrophages. When  secreted in large amounts, TNF-a has systemic effects as well:   thrombosis as a consequence of prolonged production in  cases of severe infection or cancer    4. Probably responsible for fatalities from shock caused by  gram-negative bacterial infections   Chemokines. Chemokines are members of a family of  low-molecular-weight (8 to 10 kDa) peptides that function  primarily to induce leukocyte chemotaxis. This response can  be elicited either by soluble chemokines or by chemokines that  are bound to extracellular glycosaminoglycan carbohydrates.  Chemokines can be synthesized by multiple cell types, including  macrophages, fibroblasts, and endothelial cells, in response to  proinflammatory cytokines. Macrophages can be stimulated  to produce chemokines by recognition of either infectious  microorganisms or a §-defensin (both through TLR4). To date,  more than 40 different human chemokines have been described,  the vast majority of which are classified as either CC-chemokines  (6-chemokines) orCXC-chemokines (a-chemokines),depending  on the arrangement of cysteine amino acids in the protein. This  amino acid arrangement also determines which target cell(s)  will respond to a given chemokine. CC-chemokines affect  mainly monocytes, lymphocytes, and eosinophils, whereas  CXC-chemokines generally affect neutrophils. Examples of  CC-chemokines include RANTES (regulated on activation,  normal T expressed and secreted), monocyte/macrophage  chemotactic proteins (MCP-1, MCP-2, and MCP-3), and  macrophage inflammatory proteins (MIP-la and MIP-  1B). CXC-chemokines include IL-8 and epithelial-dermoid  neutrophil attractant (ENA-78).    A central cell in inflammation is the mast cell. Mast cells, first  described by Paul Ehrlich”® in 1877, are cellular bags of gran-  ules located in the loose connective tissues close to blood ves-  sels (Figure 7-11). They are found in large numbers in areas  directly exposed to the environment including the skin and the  linings of the gastrointestinal and respiratory tracts. A great  number of stimuli cause mast cells to become activated, result-  ing in initiation of the inflammatory response.’! Typical causes  of mast cell activation include (1) physical injury (e.g., heat,    mechanical trauma, ultraviolet light, and x-rays), (2) chemi-  cal agents (e.g., toxins, snake and bee venoms, proteolytic  enzymes, and antimicrobial peptides), (3) immunologic means  (e.g., anaphylatoxins released during activation of complement  components or particular types of antibody [e.g., immuno-  globulin E (IgE)] produced by cells of the adaptive immune  response [see Chapter 8]), and (4) activation of TLRs by bac-  teria and viruses. Soluble and extremely potent chemicals from  the mast cell are responsible for its effects on inflammation.  These are released in two ways: by release of the contents of  their preformed granules (degranulation) and by new synthe-  sis of lipid-derived inflammatory mediators. Mast cells are also  involved in initiating many allergic responses (discussed in  Chapters 8 and 9).   Mast Cell Degranulation. In response to a stimulus,  biochemical mediators in the mast cell granules, including  histamine, chemotactic factors (e.g., neutrophil chemotactic  factor, eosinophil chemotactic factor of anaphylaxis or    ECF-A), and cytokines (e.g., TNF-a, IL-4), are released  within seconds and exert their effects immediately (see  Figure 7-11).   Histamine is a vasoactive amine that causes temporary, rapid  constriction of the large vessel walls and dilation of the postcapil-  lary venules, both of which result in increased blood flow into  the microcirculation. Histamine also causes increased vascular  permeability resulting from retraction of endothelial cells lining  the capillaries (see Figure 7-3). The pharmacologic effects of his-  tamine are partially determined by histamine receptors on the  person’s target cells. Two main histamine receptors are the H1  and H2 receptors (Figure 7-12), and two other receptors, H3 and  H4, have been described. Binding of histamine to the H1 recep-  tor is essentially proinflammatory; that is, it promotes inflamma-  tion. On the other hand, binding to the H2 receptor is generally  anti-inflammatory because it results in suppression of leukocyte  function. The H1 receptor is present on smooth muscle cells,  especially those of the bronchi, and causes bronchial smooth    Lymphocyte Decreased activity  Eosinophil Decreased activity  Neutrophil Decreased chemotaxis  Mast cell Decreased degranulation    FIGURE 7-12 Effects of Histamine Through H1 and H2 Receptors. Effects depend on (1) density and affinity of H1 or  H2 receptors on the target cell, and (2) the identity of the target cell. ATP Adenosine triphosphate; cAMP cyclic adenosine  monophosphate; cGMP cyclic guanosine monophosphate; G7P guanosine triphosphate.    muscle to contract (bronchoconstriction) when stimulated. Both  types of receptors are distributed among many different cells and  are often present on the same cells and may act in an antagonistic  fashion. For instance, neutrophils express both types of recep-  tors, with stimulation of H1 receptors resulting in the augmenta-  tion of neutrophil chemotaxis, and H2 stimulation resulting in  its inhibition. The H2 receptor is especially abundant on parietal  cells of the stomach mucosa and induces the secretion of gastric  acid as part of the normal physiology of the stomach. The role of  H1 and H2 receptors is discussed further in Chapter 9.   Two chemotactic factors, neutrophil chemotactic factor  and ECF-A, are also released during mast cell degranulation.  Chemotaxis is directional movement of cells along a chemical  gradient formed by a chemotactic factor (see Figure 7-3). Neu-  trophil chemotactic factor attracts neutrophils, and ECF-A  attracts eosinophils to the site of inflammation. Neutrophils are  the predominant leukocytes at work during the early phases of  acute inflammation, and eosinophils have several functions in  the inflammatory process; both of these important inflamma-  tory cells are discussed in more detail later in this chapter.   Mast Cell Synthesis of Mediators. Activated mast cells begin  new synthesis of other mediators of inflammation, including  those derived from plasma membrane lipids, cytokines (TNF-  a, various interleukins), and factors that stimulate cell growth  and angiogenesis. Leukotrienes, prostaglandins, and platelet-  activating factor are lipid-derived products that are synthesized  during mast cell activation (Figure 7-13). Leukotrienes are a  product of another lipid, arachidonic acid, which is released  from mast cell membranes by an intracellular phospholipase  that acts on membrane phospholipids.’? Leukotrienes are  acidic, sulfur-containing lipids that produce effects similar  to those of histamine, namely, smooth muscle contraction,  increased vascular permeability, and perhaps neutrophil and  eosinophil chemotaxis. Leukotrienes appear to be important    in the later stages of the inflammatory response because they  stimulate slower and more prolonged responses than do  histamines.”°   The mast cell also synthesizes prostaglandins, which, like  leukotrienes, are a product of arachidonic acid and cause  increased vascular permeability and neutrophil chemotaxis.  Prostaglandins also induce pain. They are long-chain unsatu-  rated fatty acids produced by the action of the enzyme cyclo-  oxygenase and are classified into groups (E, D, A, F, and B)  according to their structure. Prostaglandins E,; and E, cause  increased vascular permeability and smooth muscle contrac-  tion, apparently acting directly on postcapillary venules.**  They can inhibit some aspects of inflammation by suppressing  both the release of histamine from mast cells and the release  of lysosomal enzymes (enzymes responsible for killing and  digesting microorganisms) from neutrophils. Enhancement or  suppression of the inflammatory response may be related to the  concentration of prostaglandins. Aspirin and some other non-  steroidal anti-inflammatory drugs (NSAIDs) block the synthe-  sis of prostaglandins of the E series and other arachidonic acid  derivatives, thereby inhibiting inflammation.   Platelet-activating factor (PAF), another mast cell-derived  lipid, is produced by removal of a fatty acid from the plasma  membrane phospholipid phosphatidylcholine by phospholipase  A,. Although mast cells are a major source of PAF, this mol-  ecule also can be produced during inflammation by neutrophils,  monocytes, endothelial cells, and platelets. The biologic activity  of PAF is virtually identical to that of leukotrienes, namely, caus-  ing endothelial cell retraction to increase vascular permeability,  leukocyte adhesion to endothelial cells, and platelet activation.    The blood vessel walls consist of a layer of endothelial cells  that adhere to an underlying matrix of connective tissue that    FIGURE 7-13 Production of Lipid Vasoactive Substances by Mast Cells. L7A4 LIC4, LTD4, LTE4, LTB4, Various leu-  kotriene molecules; PAF platelet-activating factor; PGD2, prostaglandin D2.    contains a variety of proteins, including collagen, fibronectin,  and laminins. Circulating cells and platelets and components  of plasma protein systems continually contact endothelial  cells, which contribute to regulation of normal blood flow by  preventing spontaneous activation of platelets and members  of the clotting system. Endothelial cells produce nitric oxide  (NO) from arginine and prostacyclin (PGI,) from arachidonic  acid. Both NO and PGI, maintain blood flow and pressure and  inhibit platelet activation. PGI, and NO are synergistic. NO is  released continually to relax vascular smooth muscle and sup-  press the effects of low levels of cytokines, thus maintaining vas-  cular tone. PGI, production varies a great deal and is increased  when additional regulation is needed.   Damage to the endothelial cell lining of the vessel exposes the  subendothelial connective tissue matrix, which is prothrombo-  genic, and initiates platelet activation and formation of clots  (the contact activation [intrinsic] clotting pathway). Proinflam-  matory cytokines affect the endothelium, resulting in adherence  of leukocytes to the vessel surface, invasion of leukocytes into  the tissue, and efflux of plasma from the vessel.    Platelets (thrombocytes) are cellular fragments formed from  megakaryocytes. They circulate in the bloodstream until vas-  cular injury occurs, after which platelets can be activated by  many products of both the innate and the adaptive immune  responses, including collagen, thrombin, thromboxane, PAF,  and antigen-antibody complexes.” Activation results in (1) the    interaction of platelets with components of the coagulation cas-  cade to stop bleeding, and (2) degranulation. Platelets contain  alpha (a) granules and dense granules. Alpha granules generally  contain polypeptides that affect inflammation, including coag-  ulation proteins (e.g., fibrinogen, factor V), soluble adhesion  molecules (e.g., von Willebrand factor, vitronectin), growth  factors (e.g., platelet-derived growth factor, epidermal growth  factor), protease inhibitors (e.g., plasminogen activator inhibi-  tor-1, @-antiplasmin), and membrane adhesion molecules  (e.g., P-selectin, allb§3). Dense granules contain several small  molecules, including adenosine diphosphate (ADP), serotonin,  calcium, and magnesium. Serotonin is a vasoactive amine with  vascular effects similar to those of histamine. (Platelet function  is described in detail in Chapter 27.)   The primary role of most granulocytes (neutrophils, eosino-  phils, basophils) and monocytes/macrophages is phagocytosis;  the process by which a cell ingests and disposes of damaged cells  and foreign material, including microorganisms.   Neutrophils. The neutrophil, or polymorphonuclear  neutrophil (PMN), is a member of the granulocytic series  named for the characteristic staining pattern of its granules as  well as its multilobed nucleus. Neutrophils are the predominant  phagocytes in the early inflammatory site, arriving within 6 to  12 hours after the initial injury, where they ingest (phagocytose)  bacteria, dead cells, and cellular debris. Several inflammatory  mediators (e.g., some bacterial proteins, complement fragments    C3a and C5a, and mast cell neutrophil chemotactic factor)  specifically attract neutrophils from the circulation and activate  them. Macrophages and lymphocytes, on the other hand, enter  the site later, usually after 24 hours, and gradually replace the  neutrophils.   Because the neutrophil is a mature cell incapable of divi-  sion and sensitive to the acidic environment of inflammatory  lesions, it is short-lived at the inflammatory site and becomes a  component of the purulent exudate, or pus, which is removed  from the body through the epithelium or through the lym-  phatic system. (The lymphatic system is described in Chapter  27.) The primary roles of the neutrophil are removal of debris  in sterile lesions, such as burns, and phagocytosis of bacteria in  nonsterile lesions.   Eosinophils. Another population of granulocytes is the  eosinophil. Eosinophils have two specific functions: (1) they  serve as the body’s primary defense against parasites and (2)  they help regulate vascular mediators released from mast cells.  Their role in resistance to parasites occurs in collaboration with  specific antibodies produced by the adaptive immune system  and will be discussed in Chapter 8.   The second function, regulation of mast cell—derived inflam-  matory mediators, is a critical function of eosinophils. As with  most defense systems of the body, the acute inflammatory  response is usually needed only in a circumscribed area and for  a limited time. Therefore, control mechanisms are necessary to  prevent biochemical mediators from evoking more inflamma-  tion than is needed. Mast cells produce ECF-A, which attracts  eosinophils to the site of inflammation. Eosinophil lysosomes  contain several enzymes that degrade vasoactive molecules,  thereby controlling the vascular effects of inflammation. These  enzymes include histaminase, which mediates the degradation  of histamine, and arylsulfatase B, which mediates the degrada-  tion of some of the lipid-derived mediators produced by mast  cells.   Basophils. The basophil is the least prevalent granulocyte  in the blood. It is very similar to mast cells in the content of  its granules and, in addition, is an important source of the  cytokine IL-4, which is a key regulator of the adaptive immune  response. Although often associated with allergies and asthma,  its primary role is yet unknown.   Monocytes and Macrophages. Monocytes are the largest  normal blood cells (14 to 20 wm in diameter) and have a  nucleus that is often indented, or horseshoe shaped. Monocytes  are produced in the bone marrow, enter the circulation, and  migrate to the inflammatory site where they develop into  macrophages. Monocytes also appear to be the precursors of  macrophages that are found in tissues (tissue macrophages,  discussed in Chapter 8), including Kupffer’s cells in the liver,  alveolar macrophages in the lungs, and microglia in the  brain.”° Macrophages are generally larger (20 to 40 pm) and  are more active as phagocytes than their monocytic precursors.  Macrophages, particularly those residing in the tissues, are  often important cellular initiators of the inflammatory response  (Figure 7-14).   Phagocytosis. Because most phagocytes are circulating  in the blood, they must leave the bloodstream and migrate    FIGURE 7-14 Scanning Electron Micrograph of Lymphocytes and Mac-  rophages. The lymphocytes are small and spherical; the macrophages are larger  and more irregular in shape. (From Raven PH, Johnson GB: Biology, St Louis, 1992,  Mosby.)    to the site of inflammation before initiating phagocytosis  (Figure 7-15). Under normal conditions, the circulation in the  capillaries and venules is rapidly moving with red blood cells in  the main stream and neutrophils and other leukocytes tending  to flow more slowly along the vessel’s periphery. Many of the  biochemical products produced early at inflammatory sites (e.g.,  histamine, TNF-a, bradykinin, leukotrienes, prostaglandins)  diffuse to the vessels and affect both leukocytes and endothelial  cells. Both cell populations respond by producing new  adhesion molecules (selectins and integrins) on their surfaces  (Table 7-3) (see p. 202 for integrins). Selectins are adhesion  molecules that bind carbohydrate ligands. The reciprocal  change in adhesion molecules on leukocytes, as well as platelets,  promotes their interaction with the endothelial cells. The  initial change of surface molecules increases the adhesion, or  stickiness, between leukocytes and endothelial cells, causing the  leukocytes to adhere more avidly to the walls of the capillaries  and venules in a process called margination, or pavementing.  Adhesion molecules that are expressed later lead to diapedesis,  or emigration of the cells through the endothelial junctions  that have retracted in response to the same mediators. The  leukocytes digest the basement membrane and migrate into the  surrounding tissues.   Additionally, endothelial cells release NO, a gas that under  normal conditions maintains vascular tone. Inflammation  induces additional endothelial nitric oxide synthase, increas-  ing the amount of NO production. Effects of NO on inflam-  mation include vasodilation by inducing relaxation of vascular  smooth muscle, a response that is local and short-lived, and  suppression of mast cell function as well as platelet adhesion  and aggregation.   Once inside the connective tissue in the perivascular space,  leukocytes migrate to the inflammatory site by means of che-  motaxis. They detect chemotactic factors in the environment  through chemoreceptors at multiple locations on their plasma  membranes and migrate in the direction of highest concen-  tration (see Figure 7-15). The primary chemotactic factors  include many bacterial products, complement fragments  C3a and C5da, kallikrein, plasminogen activator, products of  fibrin degradation (fibrinopeptides), and chemokines. Eosin-  ophils and neutrophils also respond to chemotactic factors    FIGURE 7-15 Process of Phagocytosis. The process that results in phagocytosis is characterized by three interrelated  steps: adherence and diapedesis, tissue invasion by chemotaxis, and phagocytosis. A, Tissue damage. Adherence, margin-  ation, and diapedesis: The primary phagocyte in the blood is the neutrophil, which usually moves freely within the vessel (1).  At sites of inflammation, the neutrophil progressively develops increased adherence to the endothelium, leading to accumula-  tion along the vessel wall (margination or pavementing) (2). At sites of endothelial cell retraction the neutrophil exits the blood  by means of diapedesis (3). Chemotaxis: In the tissues, the neutrophil detects chemotactic factor gradients through surface  receptors (1) and migrates towards higher concentrations of the factors (2). The high concentration of chemotactic factors  at the site of inflammation immobilizes the neutrophil (3). B, Recognition and attachment. Specific receptors and ligands  for recognition and attachment. C, Phagocytosis. (1) Opsonized microorganisms bind to the surface of a phagocyte through  specific receptors. (2) The microorganism is engulfed (ingested) into a phagocytic vacuole, or phagosome. (3) Lysosomes fuse  with the phagosome, resulting in the formation of a phagolysosome. During this process the microorganism is exposed to  products of the lysosomes, including a variety of enzymes and products of the hexose-monophosphate shunt (e.g., H»0., 07 ).  (4) The microorganism is killed and digested. Ab, Antibody; AbR, antibody receptor; Ag, antigen; C3b, complement component  C3b; C3bR, complement C3b receptor; PAMP pathogen-associated molecular pattern; PAA, pattern recognition receptor.    released from mast cells (ECF-A, neutrophil chemotactic fac-  tor [NCF]). Monocytes are attracted toward a factor (mono-  cyte chemotactic factor) that has been released by neutrophils  already at the site of injury. And although histamine is not  itself chemotactic, it may facilitate the chemotactic effects of  other factors.    Once the phagocytic cell enters the inflammatory site, the  process of phagocytosis involves four steps: (1) opsonization  (recognition of the target and adherence of the phagocyte to  it); (2) engulfment (ingestion or endocytosis) and formation  of phagosome; (3) fusion with lysosomal granules within the  phagocyte (phagolysosome); and (4) destruction of the target    TABLE 7-3 EXAMPLES OF CELLULAR ADHESION MOLECULES (CAMS) INVOLVED IN  LEUKOCYTE INTERACTION WITH ENDOTHELIAL CELLS    Selectins (lectin-like molecules): L-selectin, leukocyte selectin; P-selectin, platelet selectin; E-selectin, endothelial selectin.  Integrins (noncovalent heterodimers of alpha [a] and beta [8] subunits): VLA-4, very late antigen-4; LFA-1, lymphocyte function antigen-1; MAC-7,    Immunoglobulin-like molecules: VCAM-1, vascular cell adhesion molecule-1; /CAM-1, I[CAM-2, immunoglobulin-like molecules-1 and -2; PCAIV-1, platelet-    (see Figure 7-15, C) (lysosomes are described in Chapter 1).  Throughout the process, both the target and the digestive  enzymes are isolated within membrane-bound vesicles. Isola-  tion protects the phagocyte itself from the harmful effects of the  target microorganisms, as well as its own enzymes.   Most phagocytes can trap and engulf bacteria using cellular  PRRs and PAMPs normally expressed on the bacterial surface  (see Figure 7-15, B). However, that process is slow and ineffi-  cient. Opsonization, usually by antibody or complement com-  ponent C3b, greatly enhances both recognition and adherence.  Phagocytosis of an opsonized (antibody and/or complement-  protein coated) red blood cell is illustrated in Figure 7-16.  Opsonins function as “glue” between the phagocyte and the  target cell because receptors on the phagocyte are specific for  sites on the opsonin (Fc receptors for antibody, C3b receptors  for C3b). This enables the phagocyte to bind an opsonized tar-  get very tightly to its surface. Antibody forms a stronger attach-  ment, but C3b facilitates phagocytosis to a greater extent.   Although the inflammatory response is considered to be  nonspecific, opsonins and other recognition molecules add a  degree of specificity to efficient phagocytosis. Antibodies on the  surface of bacteria are directed against antigens that are highly  specific to that particular microorganism. If the complement  fragment C3b serves as an opsonin, those bacteria with certain  polysaccharide coatings are particularly sensitive to activation  of the alternative and lectin pathways of complement activation.   Engulfment (endocytosis) is carried out by small pseudo-  pods that extend from the plasma membrane and surround the  adherent microorganism (see Figures 7-15 and 7-16), form-  ing an intracellular phagocytic vacuole, or phagosome. The  membrane that surrounds the phagosome consists of inverted  plasma membrane. After the formation of the phagosome, lyso-  somes converge, fuse with the phagosome, and discharge their  contents, creating a phagolysosome. The primary lysosomal  granules (azurophilic granules) contain a variety of bactericidal  molecules, including myeloperoxidase, lysozyme, defensins,  acid hydrolases, elastase, and others. Most phagocytes also con-  tain secondary granules (specific granules) with molecules that  are bactericidal and involved in remodeling the surrounding  tissue, including lysozyme, collagenase, lactoferrin, and other    proteases. Destruction of the bacterium takes place within the  phagolysosome and is accomplished by both oxygen-dependent  and oxygen-independent mechanisms.   Phagocytosis is accompanied by a burst of oxygen uptake  by the phagocyte, termed the “respiratory burst,” which results  from a shift in much of the cell’s glucose metabolism to the hex-  ose-monophosphate shunt. The nicotinamide adenine dinucle-  otide phosphate (NADPH) that is produced because of this shift  is used by a membrane-associated enzyme, NADPH oxidase, to  generate superoxide, a reactive oxygen intermediate that is con-  verted to hydrogen peroxide and other reactive oxygen species.  These steps comprise the oxygen-dependent killing mechanism.  Many of the reactive oxygen species are directly toxic to the  microorganism. Hydrogen peroxide also can collaborate with  the lysosomal enzyme myeloperoxidase and halide anions (Cl-  and Br-) to form acids, such as hypochlorous (HCIO) and hypo-  bromous (HBrO) acids.’’ These acids probably kill bacteria and  fungi by adding Cl or Br~ to the surface of these cells. Oxygen-  independent mechanisms of microbial killing are likely the result  of (1) the acidic pH (3.5 to 4.0) of the phagolysosome caused  by lactic acid production; (2) the presence of cationic proteins,  such as defensins and cathelicidins, that bind to and damage tar-  get cell membranes; (3) enzymatic attack of the mucopeptides in  the target cell wall by lysozyme and elastase; and (4) inhibition  of bacterial growth by lactoferrin binding of iron.   When a phagocyte dies at an inflammatory site, it frequently  lyses (breaks open) and releases its cytoplasmic contents, includ-  ing the lysosomal enzymes, into the tissue. Enzymes released  from lysosomes can digest the connective tissue matrix, caus-  ing much of the tissue destruction associated with inflamma-  tion. The destructive effects of many enzymes released by dying  phagocytes are minimized by natural inhibitors found in the  blood, such as a,-antitrypsin, a plasma protein produced by  the liver. An inherited deficiency of a-antitrypsin often results  in chronic lung damage and emphysema as a result of inflam-  mation. (The pulmonary effects of a,-antitrypsin deficiency are  described in Chapter 35.) Released lysosomal products also may  contribute to inflammation by increasing vascular permeabil-  ity, attracting additional monocytes, and activating the comple-  ment and kinin systems.    FIGURE 7-16 Steps in Phagocytosis. This scanning electron micrograph shows the progressive steps in phagocytosis.  A, Red blood cells (A) attach to the surface of a macrophage (I). B, Part of the macrophage (M) membrane starts to enclose  the red cell (A). C, The red blood cells are almost totally engulfed by the macrophage. (From King DW, Fenoglio CM, Lefwitch  JH: General pathology: principles and dynamics, Philadelphia, 1983, Lea & Febiger.)    Monocyte-derived macrophages from the circulation may  appear at the inflammatory site as soon as 24 hours after the  initial neutrophil infiltration, but usually arrive 3 to 7 days  later. They migrate to the site more slowly than neutrophils  because they move more sluggishly and also because many of  the chemotactic factors that attract them, such as macrophage  chemotactic factor, must first be released by neutrophils.7*  Macrophages are better suited than neutrophils to long-term  defense against infectious agents because macrophages can sur-  vive and divide in the acidic inflammatory site or where there is  low oxygen tension.    5. Role in the immune response: Macrophages, but not  neutrophils, are involved in activation of the adaptive  immune system.   6. Role in wound repair: Macrophages are the primary cells  that infiltrate tissue in wounds, remove cells and cellu-  lar debris, and produce cytokines that suppress further  inflammation and initiate healing.  crophag Several bacteria are resistant   to killing by granulocytes and can even survive inside  macrophages. Microorganisms such as Mycobacterium  tuberculosis (tuberculosis), Mycobacterium leprae (leprosy),  Salmonella typhi (typhoid fever), Brucella abortus (brucellosis),  and Listeria monocytogenes (listeriosis) can remain dormant  or even multiply inside the phagolysosomes of macrophages.  However, the bactericidal activity of macrophages can be  markedly increased with the help of inflammatory cytokines  produced by cells of the adaptive immune system (subsets of  T lymphocytes) or cells activated through Toll-like receptors  (TLRs). (Cytokines were discussed in detail earlier in this  chapter [see p. 203]) Macrophages have cell surface receptors    for these cytokines and are further activated to become more  effective killers of infectious microorganisms.   Macrophage activation results in increased (1) phagocytic  activity, (2) size, (3) plasma membrane area, (4) glucose metab-  olism, and (5) number of lysosomes. Activated macrophages  also secrete factors that stimulate the growth, differentiation,  and activation of additional inflammatory cells as well as control  the initiation of healing processes. These include granulocyte  colony-stimulating factor (G-CSF), interferon-gamma (IFN-y),  interleukin-1f (IL-16), angiogenic factor, fibroblast activating  factor, and growth factors that promote regrowth of damaged  tissues. Macrophages are also the primary cells that infiltrate  wounds to remove cellular debris and initiate the regenera-  tive process. In some cases, inadequate macrophage activation  results from defects in the adaptive immune responses and defi-  cits in the production of appropriate cytokines. For example, a  form of leprosy called lepromatous leprosy is characterized by  the survival of phagocytosed M. leprae bacteria in macrophage  phagolysosomes. In individuals with lepromatous leprosy, cells  of the adaptive immune system have failed to secrete the cyto-  kines necessary to transform macrophages into highly efficient  killing cells.   The main function of natural killer (NK) cells is recognition  and elimination of cells infected with viruses, although they are  also somewhat effective at elimination of other abnormal host  cells, specifically cancer cells. NK cells seem to be more efficient  in this role when they encounter an infected cell within the  circulatory system as opposed to within tissues.”? Along with  TLRs, NK cells have additional inhibitory and activating recep-  tors that allow differentiation between infected or tumor cells  and normal cells. If the NK cell binds to a target cell through  activating receptors, it produces several cytokines and toxic  molecules that can kill the target. NK cells and lymphocytes,  which are the principal cells of the adaptive immune response,  will be discussed in much more detail in Chapter 8.    The cells and plasma protein systems described previously inter-  act to produce all the characteristics of inflammation, whether  local or systemic, as well as determine the duration of inflamma-  tion, either acute or chronic. Local inflammation accompanies  all types of cellular and tissue injury, whether infected or sterile,  from fractures or strains of the musculoskeletal system to burn  injuries (see Chapter 2), and is responsible for initiating healing.   All the local manifestations of acute inflammation (i.e.,  swelling, pain, heat, and redness) result from vascular changes  and the subsequent leakage of circulating components into  the tissue. Heat and redness are the result of vasodilation and  increased blood flow through the injured site. Swelling occurs  as exudate (fluid and cells) accumulates. Swelling is usually  accompanied by pain caused by pressure exerted by exudate  accumulation, as well as the presence of soluble biochemical  mediators such as prostaglandins and bradykinin. Loss of func-  tion may be associated with these manifestations.    Exudate varies in composition, depending on the stage of  the inflammatory response and, to some extent, the injurious  stimulus. In early or mild inflammation, the exudate is watery  (serous) with very few plasma proteins or leukocytes. An exam-  ple of serous exudate is the fluid in a blister. In more severe or  advanced inflammation, the exudate may be thick and clotted  (fibrinous exudate), such as in the lungs of individuals with  pneumonia. If a large number of leukocytes accumulate, as in  persistent bacterial infections, the exudate consists of pus and  is called a purulent (suppurative) exudate. Purulent exudate  is characteristic of walled-off lesions (cysts or abscesses). If  bleeding occurs, the exudate is filled with erythrocytes and is  described as a hemorrhagic exudate.   Although the local manifestations of inflammation can affect  all vascularized tissues, lesions vary depending on the organ or  tissue involved. The lesion resulting from widespread cellu-  lar death (necrosis), for example, differs in myocardial (heart  muscle), brain, and hepatic (liver) tissues. Cellular death result-  ing from myocardial infarction (deprivation of oxygen caused  by cessation of blood flow) causes a response that proceeds to  replacement of the dead tissue with a fibrinous scar. The same  injury to brain tissue is more likely to result in the formation  of an abscess filled with necrotic tissue (types of necrosis are  described in Chapter 2). Destruction of liver tissue stimulates  the regrowth, or regeneration, of liver cells.    The three primary systemic changes associated with the acute  inflammatory response are fever, leukocytosis (a transient  increase in the levels of circulating leukocytes), and plasma pro-  tein synthesis (increased levels of circulating plasma proteins).   An early systemic response is fever, which is partially induced by  specific cytokines, for example, IL-1 released from neutrophils and  macrophages. These fever-causing cytokines are known as endog-  enous pyrogens to differentiate them from pathogen-produced  exogenous pyrogens. Pyrogens act directly on the hypothalamus,  the portion of the brain that controls the body’s thermostat. The  release of endogenous pyrogens by inflammatory cells occurs  after phagocytosis, after exposure to bacterial endotoxins, or after  exposure to antigen-antibody complexes. (Mechanisms of tem-  perature regulation are discussed in Chapter 16.)   The generation of a febrile response can be beneficial because  the microorganisms that cause some conditions (e.g., syphilis,  gonococcal urethritis) are highly sensitive to small increases in  body temperature. On the other hand, fever may have some  harmful side effects because it may enhance the person’s sus-  ceptibility to the effects of endotoxins associated with gram-  negative bacterial infections (bacterial toxins are described in  Chapter 2).    Another systemic change associated with acute inflamma-  tion is leukocytosis. During many infections, the numbers of    of an acute inflammatory response. Other symptoms of acute  inflammation include somnolence (drowsiness), malaise (gen-  eralized feeling of discomfort or illness), anorexia (lack of desire    circulating leukocytes, primarily neutrophils, increase. This  increase is usually accompanied by a “left shift” in the ratio of  immature to mature neutrophils, so that the more immature  forms of neutrophils, such as band cells, metamyelocytes, and  occasionally myelocytes, are present in relatively greater than  normal proportions. (Chapter 27 discusses the development  and maturation of blood cells.) Production of immature leu-  kocytes increases primarily because proliferation and release  of granulocyte and monocyte precursors in the bone marrow  are stimulated by several products of inflammation, including  complement product C3a and G-CSF.    The synthesis of many plasma proteins, most of which are  products of the liver, is increased during the primary stages  of inflammation. These proteins, which can be either proin-  flammatory or anti-inflammatory in nature, are referred to as  acute-phase reactants (Table 7-4). Acute-phase reactants reach  maximal circulating levels within 10 to 40 hours of initial infec-  tion. In addition to inducing fever, IL-1 also indirectly induces  the synthesis of acute-phase reactants. IL-1 up-regulates release  of IL-6, which then increases synthesis of acute-phase reactants  directly by stimulating liver cells. Administration of IL-1 into  animals leads to fever and elevation of most acute-phase reac-  tants, including fibrinogen, C-reactive protein, haptoglobin,  amyloid A, a,-antitrypsin, and ceruloplasmin.   Acute inflammation can be verified by a series of hematologic  tests, which are described in detail in Chapter 27. For example,  an increase in blood levels of acute-phase reactants, primarily  fibrinogen, is usually associated with an increased erythrocyte  sedimentation rate. The alteration in plasma proteins probably  leads to an enhanced erythrocyte rouleaux formation (stacking  of erythrocytes, as in a stack of coins) and thereby an increased  rate of sedimentation. Although increased erythrocyte sedimen-  tation is a nonspecific reaction, it is considered a good indicator    Superficially, the difference between acute and chronic inflam-  mation is purely one of duration, in that chronic inflammation  lasts 2 weeks or longer, regardless of cause. Characteristic his-  tologic and mechanistic differences also may be present (Figure  7-17). Chronic inflammation is sometimes preceded by an  unsuccessful acute inflammatory response. For example, if bac-  terial contamination or foreign objects (e.g., dirt, wood splin-  ters, glass) persist in a traumatic wound, an acute response may  be prolonged beyond 2 weeks. Pus formation, suppuration  (purulent discharge), and incomplete wound healing may char-  acterize this type of chronic inflammation.   Chronic inflammation can occur also as a distinct process with-  out much previous acute inflammation. Some microorganisms  (e.g., mycobacteria that cause tuberculosis) have cell walls with a  very high lipid and wax content, making them relatively insensitive  to degradation by phagocytes and therefore relatively resistant to  clearance in an acute inflammatory response. Other microorgan-  isms, such as those that cause leprosy, syphilis, and brucellosis, can  survive within the macrophage and thereby also avoid clearance  by the acute inflammatory response. In addition, some microor-  ganisms produce toxins that stimulate tissue-damaging reactions  even after they themselves are killed. Persistent inflammation can  result from prolonged irritation by these toxins. Finally, chemi-  cals, particulate matter, or physical irritants (e.g., inhaled dusts,  wood splinters, and suture material) also can cause an inflamma-  tory response that lasts longer than 2 weeks.   Chronic inflammation is characterized by a dense infiltration  of lymphocytes and macrophages. If macrophages are unable  to limit the tissue damage or infection, the body attempts to  wall off and isolate the infected area, thus forming a granu-  loma (Figure 7-18).°° Granulomas may form if neutrophils  and macrophages are unable to destroy microorganisms dur-  ing the acute inflammatory response. For example, infections  caused by some bacteria (Listeria sp., Brucella sp.), fungi (his-  toplasmosis, coccidioidomycosis), and parasites (leishmaniasis,  schistosomiasis, toxoplasmosis) can result in granuloma forma-  tion. Large antigen-antibody complexes such as those present  in rheumatoid arthritis also can result in the formation of these  structures. The process of granuloma formation begins when  some of the macrophages differentiate into large epithelioid  cells, cells that are incapable of phagocytosing large bacteria  but are capable of taking up debris and other small particles.  Other macrophages fuse into multinucleated giant cells, which  are active phagocytes that can engulf very large particles—larger  than those that can be engulfed by a single macrophage. These  two types of differentiated macrophages form the center of the  granuloma, which is surrounded by a wall of lymphocytes. The  granuloma itself is also often encapsulated by fibrous deposits  of collagen and may become cartilaginous or possibly calcified  by deposits of calcium carbonate and calcium phosphate.    (Figure 7-19)  FIGURE 7-17 The Chronic Inflammatory Response. Inflammation usually becomes chronic because of the persistence  of an infection, an antibody, or a foreign body in the wound. Chronic inflammation is characterized by the persistence of many  of the processes of acute inflammation. In addition, the presence of large amounts of neutrophil degranulation and death, the  activation of lymphocytes, and the concurrent activation of fibroblasts result in the release of mediators that induce the infiltra-  tion of more lymphocytes and monocytes/macrophages and the beginning of wound healing and tissue repair.    FIGURE 7-18 Tuberculous Granuloma. A central area of amorphous case-  ous necrosis (C) is surrounded by a zone of lymphocytes (L) and enlarged epitheli-  oid cells (E). Activated macrophages frequently fuse to form multinucleated cells  (Langhans giant cells). In tuberculoid granulomas the nuclei of the giant cells move  to the cellular margins in a horseshoe-like formation.    The classic granuloma associated with tuberculosis is char-  acterized by a wall of epithelioid cells surrounding a center of  dead and decaying tissue (caseous necrosis, see Chapter 2) and  mycobacteria. Decay of cells within the granuloma results in the  release of acids and the enzymatic contents of lysosomes from  dead phagocytes. In this inhospitable environment, the cellular  debris is broken down and a clear fluid remains (liquefaction  necrosis, see Chapter 2). Eventually this fluid diffuses out and  leaves a hollow, thick-walled structure in the tissue that may  remain for the life of the individual.    Destruction of tissue is followed by a period of healing that  begins during acute inflammation and may not be complete for  as long as 2 years. The most favorable outcome of healing is  tissue regeneration with complete return to normal structure  and function. This is an ideal that is often not possible, par-  ticularly in adults. If damage is minor, no complications occur,  and destroyed tissues are capable of regeneration, it is possible  to return injured tissues to an approximation of their original  structure and physiologic function. This restoration is called  resolution. If extensive damage is present, injury occurs in tis-  sues not capable of regeneration, infection results in abscess or  granuloma formation, or fibrin persists in the lesion, resolu-  tion is not possible and repair takes place instead. Repair is the  replacement of destroyed tissue with scar tissue. Scar tissue is    composed primarily of collagen that seals the lesion and restores  tensile strength but cannot execute the physiologic functions of  destroyed tissue.   Both regeneration and repair actually begin with phagocy-  tosis of the particulate matter found at the site of injury (fibrin  from dissolved clots, microorganisms, erythrocytes, and dead  tissue cells). This cleanup of the lesion, which also involves dis-  solution of fibrin clots (or scabs) by fibrinolytic enzymes, is  called débridement. After débridement, the remaining debris  is drained away by blood vessels and lymphatics, and the vas-  cular dilation and permeability associated with inflammation  are reversed, thus preparing the lesion for either regeneration  or repair.   Healing always involves processes that (1) fill in, (2) seal,  and (3) shrink the wound.*! These common denominators of  healing vary in importance and duration among different types  of wounds. A clean incision, such as a paper cut or a sutured  surgical wound, heals primarily through the process of colla-  gen synthesis. Because sealing of this type of wound has already  been facilitated by minimal tissue loss and close apposition  of the wound edges, very little sealing (epithelialization) and  shrinkage (contraction) are required for healing. Wounds that  heal under conditions of minimal tissue loss are said to heal by  primary intention (Figure 7-19).   Other wounds do not heal so neatly and easily. Healing of an  open wound, such as a stage IV pressure sore (decubitus ulcer),  requires a great deal more tissue replacement than healing of a  sutured surgical incision. With an open wound, epithelializa-  tion, scar formation, and contraction take longer and healing  occurs through secondary intention (see Figure 7-19). Healing  by either primary or secondary intention may occur at different  rates for different types of tissue injury.   Both resolution and repair occur in two overlapping phases.  The first phase, called the reconstructive phase, begins 3 to 4  days after the initial injury and continues for as long as 2 weeks.  During this phase the lesion is characterized by fibroblast (con-  nective tissue cell) proliferation, followed by collagen synthesis  by the fibroblasts, epithelialization, contraction of the wound,  and cellular differentiation. The second phase, the maturation  phase, begins several weeks after injury and is normally com-  plete within 2 years. During this phase cellular differentiation,  scar formation, and scar remodeling continue.    Because surgical wounds exhibit both the reconstructive and  the maturation phases, they are useful models of both normal  and abnormal (dysfunctional) healing. Such wounds are ini-  tially sealed off by a blood clot containing fibrin and trapped  cells. The cross-linked mesh of fibrin is created by activation  of the coagulation cascade and initially traps platelets to form  a platelet plug that further seals damaged vessels (see Chapter  27). Most surgical wounds are completely sealed with platelet  plugs within hours after closure. This sealing helps unite the  wound edges and acts to create a physical barrier to bacterial  invasion, although pathogenic invasion is not always prevented.  The fibrin mesh ultimately acts as a scaffold for the collagen or  regenerated tissue cells that ultimately fill the wound.    For healing to proceed, the fibrin clot must be dissolved and  then replaced by normal tissue (for resolution) or scar tissue  (for repair). Enzymatic digestion of the clot usually occurs after  activation of the plasma fibrinolytic system (plasmin genera-  tion, see Chapter 27) or release of lysosomal enzymes from dead  neutrophils. Macrophages invade the dissolving clot and, by  phagocytosis, clear away debris and dead cells. Débridement by  macrophages and remaining neutrophils is followed by regen-  eration of destroyed cells (resolution) or, if regeneration is not  possible, by repair (see Figure 7-19).   The process of healing begins as granulation tissue grows  inward from surrounding healthy connective tissue. Granu-  lation tissue is filled with new capillaries (angiogenesis) that  give it a red, granular appearance and is surrounded by fibro-  blasts and macrophages. First, capillary buds sprout from vas-  cular endothelial cells around the wound and extend into the  débrided areas. Loops form when the young capillaries join  (anastomose). The loops are more fragile and permeable than  mature vessels, resulting in leakage of erythrocytes and neutro-  phils. The erythrocytes are phagocytosed by macrophages and  the neutrophils assist in further débridement of the inflamma-  tory lesion. Many of the new capillaries differentiate into larger  vessels as repair continues promoting influx of nutrients and  removal of metabolic wastes. New lymphatic vessels also grow  into the granulation tissue by a similar process.   In addition to their role in débriding, macrophages at the site  of injury secrete several biochemical mediators and cytokines  that orchestrate and promote healing. The following are some  examples of these mediators:   1. Transforming growth factor-beta (TGF-f) stimulates  fibroblasts entering the lesion to synthesize and secrete  the collagen precursor procollagen.   2. Angiogenesis factors, such as vascular endothelial growth  factor (VEGF) and fibroblast growth factor-2 (FGF-2),  stimulate vascular endothelial cells to form capillary buds  that grow into the wound.   3. Matrix metalloproteinases (MMPs) may function in the  degradation and remodeling of extracellular matrix pro-  teins (e.g., collagen and fibrin) at the site of injury.   As the clot or scab is being dissolved and granulation tis-  sue is being formed, the healing wound must be protected.  This is accomplished by epithelialization, the process by which  epithelial cells grow into the wound from surrounding healthy  tissue. Epithelial cells migrate through the collagenous matrix  under the clot or scab using MMPs to unravel collagen as they  travel. Unraveling the collagen enables the epithelial cells to  move rather than remain immobile (see Figure 7-19); the intact  collagen ahead of them provides a pathway on which they can  maneuver forward. Eventually the migrating epithelial cells  contact similar cells from all sides of the wound and seal it,  thereby halting migration and proliferation. The epithelial cells  undergo differentiation to give rise to the various epidermal  layers (see Chapter 46). Epithelialization of a skin wound can  be hastened if the wound is kept moist, preventing the fibrin  clot from becoming a scab.   Fibroblasts are the most important cells during the recon-  structive phase of wound healing because they synthesize and    Present in inflammatory exudate: neutrophils,  Reconstructing phase macrophages, bacteria, dead cells, and   erythrocytes. Macrophages release (1) angio-  genesis factor to attract epithelial cells ad  vascular endothelial cells (capillary and  lymphatic buds) and (2) fibroblast-activating  actor to attract fibroblasts.    Reconstructing phase  Epithelialization includes formation of  granulation tissue, inward migration of fibroblasts,  and the beginning of collagen synthesis and  secretion. Granulation tissue becomes scar tissue,  contraction begins, and differentiation begins.    Maturation phase  This phase includes completion of contraction,  Scar tissue differentiation and remodeling of scar tissue, and  disappearance of capillaries a scar tissue.    FIGURE 7-19 Wound Repair by Primary or Secondary Intention. A-D, Healing by primary intention. E-I, Healing by  secondary intention.    secrete collagen and other connective tissue proteins. Fibro-  blasts are stimulated by macrophage-derived TGF-f to prolif-  erate, enter the lesion, and produce these proteins. The collagen  and connective tissue proteins produced by fibroblasts are  deposited in débrided areas about 6 days after the fibroblasts  have entered the lesion. Collagen is the most abundant protein  in the body. It contains high concentrations of the amino acids  glycine, proline, and lysine, although many of the proline and  lysine amino acids are enzymatically modified as the protein is  being synthesized. Modification of these amino acids requires  several cofactors and is absolutely necessary for proper collagen  polymerization and function. The required cofactors include  iron, ascorbic acid (vitamin C), and molecular oxygen (O,);  the absence of any of these results in incomplete or impaired  wound healing.   Immature collagen (i-e., procollagen) is secreted by fibro-  blasts as a complex of three polypeptide chains cross-linked by  intermolecular bonds. Procollagen is converted to mature col-  lagen by the proteolytic removal of small polypeptide sequences  at both ends of the trimer. As healing progresses, collagen mole-  cules are cross-linked by intramolecular covalent bonds to form  collagen fibrils that are further cross-linked to form collagen  fibers. The process of complete collagen matrix assembly takes  several months because collagen is initially deposited randomly  but then is remodeled by repeated dissolution (by MMPs) and  reassembly. During this remodeling period, collagen fibers ori-  ent along the lines of mechanical stress; further cross-linking  adds strength to the final collagen matrix.   Wound contraction is the final process of the reconstructive  phase of healing. It is necessary for closure of all wounds, but  especially those that heal by secondary intention. Contraction is  noticeable 6 to 12 days after injury and may amount to inward  movement of the wound edge by approximately 0.5 mm/day  in normal healing. The granulation tissue of a healing wound  contains myofibroblasts—specialized cells that are likely  responsible for wound contraction. As their name implies,  myofibroblasts have features of both smooth muscle cells and  fibroblasts. They appear microscopically similar to fibroblasts,  but differ in that their cytoplasm contains bundles of parallel  fibers similar to those found in smooth muscle cells. Wound  contraction occurs as extensions from the plasma membrane  of myofibroblasts establish connections between neighboring  cells, contract their fibers, and exert tension on the neighboring  cells while anchoring themselves to the wound bed.    Collagen matrix assembly, tissue regeneration, and wound  contraction all begin during the reconstructive phase but are  not yet completed when the reconstructive phase ends, about  2 weeks after injury. Therefore, these processes continue into  the maturation phase—a phase that can persist for years. Dur-  ing the maturation phase scar tissue is remodeled and capillar-  ies disappear, leaving the scar avascular. Within 2 to 3 weeks  after maturation has begun, the scar tissue has gained about two  thirds of its eventual maximal strength.   Neither epidermal wounds that heal by secondary inten-  tion nor unsutured internal lesions are completely restored by    healing. At best, repaired tissue regains 80% of its original ten-  sile strength. Only epithelial, hepatic (liver), and bone marrow  cells are capable of the complete mitotic regeneration known  as compensatory hyperplasia (hyperplasia is described in Chap-  ter 2). In fibrous connective tissue such as joints and ligaments,  normal healing results in replacement of the original tissue  with new tissue that does not have exactly the same structure or  function as that of the original tissue. Some tissues heal without  replacement of cells. For example, damage resulting from myo-  cardial infarction heals with a scar composed of fibrous tissue  rather than with cardiac muscle cell replacement.** Although  the composition of various healed tissues may differ, the heal-  ing process—reconstruction followed by wound maturation—  is essentially the same for all wounds.    Dysfunctional wound healing may occur if any of the involved  processes occurs abnormally. This can include abnormalities  in the inflammatory response itself, insufficient or excessive  repair, or reinfection of the wound. Abnormalities may result  from a predisposing disease, such as diabetes mellitus, or from  an adaptive condition, such as hypoxemia (insufficient oxygen  concentration in arterial blood). Numerous drugs and nutri-  tional deficiencies can affect wound healing as well.°°    Healing may be prolonged if bleeding is not stopped during  acute inflammation. Hemorrhage in a damaged area delays  healing for several reasons. Initially the excess blood cells that  accumulate at the site of injury must be cleared—a process that  requires additional time. In addition to the cellular accumula-  tion caused by excessive bleeding, formation of a clot increases  the amount of space that granulation tissue has to fill and  serves as a mechanical barrier to oxygen diffusion. The great  amount of fibrin that is released during hemorrhage also must  eventually be reabsorbed in order to prevent its organization  into fibrous adhesions. Once formed, these adhesions can bind  organs together by fibrous bands; with time, shrinkage of these  bands can distort or strangulate nearby organs. This is clinically  significant, particularly if they form within the pleural, pericar-  dial, or abdominal cavities.   Accumulated blood as a result of hemorrhage also serves as  an excellent culture medium for bacteria, promoting continued  infection and prolonging inflammation by increasing purulent  exudate formation. Prolonged infection can promote excess scar  formation or even prevent healing completely. Continued infec-  tion of a wound, termed wound sepsis, can be clinically treated  in several ways. Most important is the débridement of necrotic  tissue and foreign bodies. This removal is accomplished either  through surgery or through the use of absorbent dressings.  Wound irrigation and antibiotic therapy also may assist in  combating continued infection.   Although local hemorrhage during the inflammatory process  can pose a huge impediment to healing, many additional factors,  both physiologic and pharmacologic, also may adversely affect  the healing ofan inflamed tissue. Hypovolemia—decreased blood  volume—hinders inflammation. The physiologic response    to hypovolemia is vessel constriction rather than the dilation  required to deliver inflammatory cells to the site of injury. Opti-  mal nutrition is important during all phases of healing because  metabolic needs are increased. The most essential nutrients  for healing are glucose, oxygen, and amino acids. Because leu-  kocytes need glucose to produce the energy needed for che-  motaxis, phagocytosis, and intercellular killing, the wounds  of persons with diabetes who receive insufficient insulin heal  poorly, mainly attributable to a prolonging of the infection.  Persons with diabetes are also at risk for ischemic wounds  because they are likely to have both small-vessel diseases that  impair the microcirculation and altered (glycosylated) hemo-  globin, which has an increased affinity for oxygen and thus does  not readily release oxygen in tissues. (Hemoglobin’s function  as the oxygen-carrying component of blood is described in  Chapter 27.) Oxygen delivery is also compromised by hypox-  emic states because ischemic tissue is susceptible to infection.  Hypoproteinemia prolongs inflammation because the associated  decrease in available amino acids is an impediment to fibroblast  proliferation. Finally, anti-inflammatory steroids can have an  impact upon wound healing. These drugs prevent macrophages  from migrating to the site of injury and inhibit their release of  collagenase and plasminogen activator. Anti-inflammatory ste-  roids also inhibit fibroblast migration into the wound during  the reconstructive phase of healing and impair angiogenesis,  wound contraction, and reepithelialization.    Three of the essential processes that occur during the recon-  structive phase are assembly and remodeling of the collagen  matrix, epithelialization of the wound bed, and contraction of  the wound. Dysfunctional wound healing can result from the  impairment of any of these processes.   Impaired Collagen Matrix Assembly. A number of factors  may interfere with the production of collagen in healing tissues,  most being nutritional. Scurvy, for example, is a condition  caused by a deficiency in ascorbic acid, one of the cofactors  required for the amino acid modification that is necessary for  proper collagen matrix assembly. The complication of scurvy  is a poorly formed collagen matrix and, therefore, greatly  impaired wound healing. Other nutrients, including iron,  copper, and calcium, play additional roles in the enzymatic  reactions required for collagen modification and assembly.  Usually, however, such minute amounts of these substances  are required that deficiencies are not clinically significant.  Nutritionally, appropriate protein intake is also essential for  collagen synthesis. The amino acid methionine that is found in  proteins is converted to cysteine, the role of which in collagen  synthesis is twofold: (1) it functions as an important cofactor in  the enzymatic reactions required for collagen synthesis; and (2)  it contains sulfur, which contributes to formation of the strong  covalent bonds in cross-linked collagen fibrils.   Dysfunctional healing also may result from excessive pro-  duction of collagen. Overproduction of collagen causes surface  overhealing, which is manifested in the skin by formation of a  keloid or a hypertrophic scar (Figure 7-20). A keloid is a raised  scar that extends beyond the original boundaries of the wound.    FIGURE 7-20 Keloids. (From Damjanov I, Linder J: Anderson’s pathology, ed  10, St Louis, 1996, Mosby.)    It invades surrounding tissue and is likely to recur after surgical  removal. A familial tendency toward keloid formation has been  observed, with a greater incidence in blacks relative to whites.  Similar to a keloid, a hypertrophic scar is also raised but dif-  fers in that it remains within the original boundaries of the  wound. Hypertrophic scars tend to regress over time, whereas  keloids do not. Both keloids and hypertrophic scars are caused  by an imbalance between collagen synthesis and collagen deg-  radation in which synthesis is increased relative to degradation.  Although the precise mechanism of this imbalance is unknown,  recent evidence suggests that keloid fibroblasts have lower rates  of apoptosis and an inability to respond to normal suppressive  feedback.   Impaired Epithelialization. The process of epithelialization  is suppressed by anti-inflammatory steroids, hypoxemia, and  nutritional deficiencies. Anti-inflammatory steroids inhibit  phagocyte production of the biochemical mediators required  for epithelialization, hypoxemia deprives cells of the energy  required for the process, and dietary zinc is necessary for the  MMP activity that is crucial to cellular migration.   Wound care techniques also may greatly influence epithelial  cell migration. External wounds that are draining or healing by  secondary intention often are clinically débrided and protected  with dressings.°** The ideal dressing is one that absorbs some  drainage without being incorporated into the clot or granu-  lation tissue. Because epithelial cells must migrate across the  wound during healing, dressings that débride healthy epithe-  lial cells along with necrotic tissue prolong epithelialization.  Many solutions that traditionally have been used to clean or  irrigate wounds are now known to be deleterious to the fragile  new cells in the wound bed. Normal saline is the most innocu-  ous solution that can be used to cleanse or irrigate a wound  that is healing primarily by epithelialization. Solutions such as  povidone-iodine and hydrogen peroxide are desiccating (dry-  ing) and, as such, inhibit rather than promote epithelial cell  migration.    Excessive wound contraction may result in a deformity or  contracture. Burn wounds are especially susceptible to the  development of contractures. Internal contractures may occur  as well, and are common in cirrhosis of the liver. Internally,  scar tissue that becomes contracted constricts blood flow that  may contribute to the development of portal hypertension  and esophageal varices. Other types of internal contraction  deformity include duodenal strictures caused by dysfunc-  tional healing of an ulcer and esophageal strictures caused by  chemical burns.   Proper positioning and range-of-motion exercises, as well  as surgery, are among the physical means used to overcome  the excessive myofibroblast-derived tension that results in  contractures. Clinical use of pharmacologic methods for con-  trol of wound contracture is still largely experimental, but  includes control of myofibroblast contraction by the admin-  istration of smooth muscle cell inhibitors such as colchicine  and inhibition of proper collagen matrix assembly with drugs  that prevent either collagen cross-linking or MMP activity.  These latter treatments are based on the knowledge that myo-  fibroblast binding to collagen can “lock” contracted cells into  position.   Finally, a potential complication in the healing of wounds that  are sutured closed is dehiscence, in which the wound pulls  apart at the suture line. The greatest incidence of dehiscence  occurs 5 to 12 days after suturing, paradoxically at the time  when collagen synthesis is at its peak. Approximately 50%  of dehiscence occurrences are associated with wound sepsis,  although dehiscence also may occur when sutures break as a  result of excessive strain. Obesity increases the risk of suture  breakage because adipose tissue is difficult to suture. Wound  dehiscence usually is heralded by an increase in serous drain-  age from the wound. In addition, patients may report a feel-  ing that “something gave way.” Prompt surgical attention is  required.    Neonates commonly have transiently depressed inflammatory  and immune function. For example, neutrophils and perhaps  monocytes may not be capable of efficient chemotaxis. Insuf-  ficient response to chemotactic factors appears to be caused  by lack of fluidity in the phagocyte’s plasma membrane so that  pseudopod formation and migration are impaired. Neonates  are prone to infections associated with chemotactic defects,  including cutaneous abscesses caused by staphylococci and  cutaneous candidiasis. Further, neutrophils in neonates who    were stressed by in utero infection or respiratory insufficiency  have diminished oxidative and bacterial responses. (Acquired  phagocytic defects, which may be induced by a variety of infec-  tions, metabolic disorders, nutrition deficiencies, or drugs, are  described in Chapter 9.)   Neonates also are partially deficient in complement, espe-  cially components of the alternative pathway. They tend to have  a relative deficiency of factor B and to develop severe, over-  whelming sepsis and meningitis when infected with bacteria  against which there is no transferred maternal antibody. Low  levels of mannose-binding lectin increase the risk for neona-  tal hospital-acquired sepsis.°°? Neonates also may be deficient  in some of the collectins and collectin-like proteins. This is  especially true of preterm neonates. Some preterm infants with  respiratory distress syndrome are deficient in at least one col-  lectin, which provides innate defense against respiratory tract  infections.    The older adult population is also at risk for impaired inflam-  mation and wound healing. In some cases, impaired healing is  not directly associated with aging in general but can instead be  linked to a chronic illness such as cardiovascular disease or dia-  betes mellitus. In addition, many older adults require medica-  tions such as anti-inflammatory steroids that can interfere with  the healing process.   Older adults have increased susceptibility to bacterial  infections of the lungs, urinary tract, and skin. Because of  impaired sensation or mobility and physiologic changes in the  skin, older adults are at increased risk for sustaining various  wounds. With aging, subcutaneous fat is lost, diminishing a  layer of protection. Collagen fibers become thicker and a cer-  tain percentage of elastin is lost, further contributing to loss  of protection. The regenerative capability of the skin is main-  tained with aging, but the epidermis undergoes age-associated  changes that include atrophy of the underlying capillaries.  The consequent decrease of perfusion makes older adults  more susceptible than younger people to the adverse effects of  hypoxia in the wound bed. In addition, aging fibroblasts may  have a slower rate of proliferation, and therefore wound heal-  ing is attenuated.   Infections of other organ systems in older adults may be due  to a diminished natural ability to ward off infection. Several cel-  lular components of innate resistance are deficient in number  (e.g., alveolar macrophages) or have diminished activity (e.g.,  neutrophil chemotaxis, degranulation, and phagocytosis). One  explanation for this diminished inflammatory cellular activity  is an age-related decrease in expression and function of several,  if not all, TLRs.    There are two types of human defense mechanisms: innate  resistance or immunity conferred by natural barriers and the  inflammatory response; and the adaptive (acquired) immune  system.    Physical and mechanical barriers are the first lines of defense  encountered by invading pathogens; these include the skin  and mucous membranes.    saliva, tears, and other secretions provide a biochemical bar-  rier against invading pathogens in the extracellular space.    The inflammatory response, our body’s second line of  defense against invading microorganisms, is nonspecific, is  rapidly initiated, and has no memory cells.    dilation, increased capillary permeability, and white blood  cell adherence to inner vessel walls and their migration  through vessel walls.    rier against invading pathogens in the circulation. These  include the complement system, the clotting system, and  the kinin system.    . The plasma protein systems work with each other as well as    with antimicrobial peptides and the cellular component of  the innate immune system to prevent microbial infection.    ways: the classical pathway, the alternative pathway, and the  lectin pathway.    microorganisms, contains microorganisms and foreign  bodies at the site of greatest inflammatory cell activity, and  provides a framework for repair and healing.    vate the clotting cascade, the complement system, and the  kinin proteins.   The plasma proteins are finely regulated to prevent injury to  host tissue and to guarantee activation when needed. Some  of the inhibitors in the plasma protein systems include  carboxypeptidase, histaminases, kinases, and Cl esterase  inhibitor.    Many different types of cells are involved in the inflamma-  tory process including mast cells, granulocytes (neutrophils,  eosinophils, basophils), monocytes/macrophages, NK cells  and lymphocytes, and cellular fragments (platelets).   The cells of the innate immune system secrete many bio-  chemical mediators that are responsible for the vascular  changes associated with inflammation and for modulating  the localization and activities of other inflammatory cells.  The mediators include histamine, chemotactic factors, leu-  kotrienes, prostaglandins, and platelet-activating factor.  The inflammatory response is initiated upon tissue injury  or when PAMPs are recognized by PRRs on cells of the  innate immune system.   TLRs recognize PAMPs, complement receptors recognize  complement fragments, and scavenger receptors promote  phagocytosis.   Cytokines are soluble factors that regulate the inflamma-  tory response and include interleukins, interferons, and  tumor necrosis factor.   ILs are biochemical messengers primarily produced by  macrophages and lymphocytes and significantly help regu-  late the inflammatory response.   Tumor necrosis factor is primarily produced by macro-  phages and promotes inflammation with both local and  systemic effects.   Chemokines are synthesized by a number of different cells  and induce leukocyte chemotaxis, and are classified as  either CC or CXC, depending on their amino acid arrange-  ment. CC chemokines affect monocytes, lymphocytes, and  eosinophils. CXC chemokines generally affect neutrophils.  Mast cells are central cells of inflammation and release his-  tamine, chemotactic factors, cytokines, leukotrienes, pros-  taglandins, growth factors, and other mediators.  H1-histamine receptors promote inflammation, and  H2-histamine receptors inhibit the inflammatory response.  Endothelial cells line the circulatory system (vascular endo-  thelium) and maintain normal blood flow by preventing  spontaneous activation of platelets and clotting.   During inflammation the endothelium expresses recep-  tors that help leukocytes leave the circulation and retract to  allow fluid to pass into the tissues.   Platelets interact with the coagulation cascade to stop  bleeding and release a number of mediators that promote  and control inflammation.   Neutrophils are the predominant phagocyte of early inflam-  mation. They are attracted to the inflammatory site by che-  motactic factors.   Eosinophils help control mast cell vascular mediators and  defend against parasite infection.    29. The monocyte/macrophage is the predominant phagocyte  in the late inflammatory response, is highly phagocytic, is  responsive to cytokines, and promotes wound healing.   30. Phagocytosis is the destruction of microorganisms and cel-  lular debris.   31. The stages of phagocytosis include recognition and adher-  ence, engulfment, lysosomal fusion, and destruction.   32. Opsonins, such as antibody and complement component  C3b, coat microorganisms and make them more suscep-  tible to phagocytosis.   33. Phagocytic killing can be oxygen-dependent with the  production of reactive oxygen intermediates or oxygen-  independent with lysosomal enzymes.   34, Monocytes and macrophages arrive at the inflammatory  site later than neutrophils and remain longer to clean up  debris and promote wound healing.   35. NK cells recognize and eliminate viruses, cancer cells, and  other abnormal cells.   1. Local manifestations of inflammation are the result of the  vascular changes associated with the inflammatory process,  including vasodilation and increased capillary permeability.  The symptoms include redness, heat, swelling, and pain.   2. The functions of the vascular changes are to dilute toxins,  carry plasma proteins and leukocytes to the injury site, and  carry bacterial toxins and debris away from the site.   1. The three primary systemic effects of inflammation are  fever, leukocytosis, and increase in levels of circulating  plasma proteins.   2. Acute-phase reactants are proteins produced by the  liver during acute inflammation and include fibrinogen,  C-reactive protein, haptoglobin, amyloid A, a,-antitrypsin,  and ceruloplasmin.    Chronic Inflammation  1. Chronic inflammation can be a continuation of acute inflam-  mation that lasts 2 weeks or longer. It also can occur as a dis-  tinct process without much preceding acute inflammation.    2. Chronic inflammation is characterized by a dense infiltra-  tion of lymphocytes and macrophages. The body may wall  off and isolate the infection to protect against tissue damage  by formation of a granuloma.   1. Resolution (regeneration) is the return of tissue to nearly  normal structure and function. Repair is healing by scar tis-  sue formation.   2. Inflammatory lesions proceed to resolution, meaning that  original tissue structure and function have been restored if  little tissue has been lost or injured tissue is capable of regen-  eration. This is called healing by primary intention.   3. Inflammatory lesions that involve extensive damage or tis-  sues incapable of regeneration heal by the process of repair  that results in the formation of a scar. This is called healing by  secondary intention.   4. Resolution and repair occur in two separate phases: the  reconstructive phase, in which the wound begins to heal,  and the maturation phase, in which the healed wound is  remodeled.   5. Dysfunctional wound healing can occur as a result of abnor-  malities in either the inflammatory response or the recon-  structive phase of resolution and repair.   2. Infants often have deficiencies in complement and in a num-  ber of collectins, making them more susceptible to bacterial  infection.   1. Older adults are at risk for impaired wound healing, often  because of underlying illnesses.   2. 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Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    General Characteristics of Adaptive Immunity, 225  Humoral and Cell-Mediated Immunity, 226  Active vs. Passive Immunity, 227   Recognition and Response, 227  Antigens and Immunogens, 228  Molecules That Recognize Antigen, 229  Molecules That Present Antigen, 233  Molecules That Hold Cells Together, 235  Cytokines and Their Receptors, 235   Generation of Clonal Diversity, 236  T-Cell Maturation, 237  B-Cell Maturation, 240    The third line of defense in the human body is adaptive  (acquired) immunity, often called the immune response or  immunity.! Once external barriers have been compromised  and inflammation (see Chapter 7) has been activated, the  adaptive immune response is called into action. The molecules  and cells of the immune response are closely integrated with  those of the innate response. Both systems are essential for  complete protection against infectious disease: inflammation  is relatively rapid, nonspecific, and short-lived, whereas adap-  tive immunity is slower acting, specific, and very long-lived.  Thus, inflammation is the “first responder” that contains the    Induction of an Immune Response: Clonal Selection, 241  Secondary Lymphoid Organs, 242  Antigen Processing and Presentation, 242  T-Helper Lymphocytes, 245  B-Cell Activation: The Humoral Immune Response, 247  T-Cell Activation: The Cellular Immune Response, 249  Effector Mechanisms, 251  Antibody Function, 251  T-Lymphocyte Function, 255  FETAL and NEONATAL Immune Function, 257  AGING and Immune Function, 257    initial injury and slows spread of infection, whereas adaptive  immunity slowly augments the initial defenses against infec-  tion and provides long-term security against reinfection.  The collaborative and beneficial nature of inflammation and  adaptive immunity can, on occasion, fail. Chapter 9 discusses  these medically relevant aberrations in both inflammation and  immunity, including allergies, diseases that involve unwanted  immunologic destruction of healthy tissue, and diseases that  are caused by a deficiency in the normal immune or inflamma-  tory responses. Chapter 10 presents an overview of infection  and Chapter 11 discusses the connection between stress and    Neutralize or destroy  pathogenic microorganisms  (e.g., antibody response  against viral infections)   Cancers Prevent tumor growth or  spread (e.g., immune  surveillance to prevent early  cancers)   Prevent entrance into body  (e.g., secretory IgA limits  systemic exposure to  potential allergens)    Immune system tolerance to  self-antigens, which may  be altered by an infectious  agent leading to autoimmune    Some cases of vaccination  alter tolerance to  self-antigens leading to  autoimmune disease    disease and the interrelatedness of the immune, nervous, and  endocrine systems.    The immune system of the normal adult is continually chal-  lenged by a spectrum of substances that it may recognize as for-  eign, or “non-self.” These substances, called foreign antigens,  are often associated with pathogens such as viruses, bacteria,  fungi, or parasites, although they are also found on noninfec-  tious environmental agents such as pollens, foods, and bee  venom, and still others are associated with clinically derived  drugs, vaccines, transfusions, and transplanted tissues (Table  8-1). Unlike inflammation, which is nonspecifically activated  by damage to cells as well as by the action of pathogenic micro-  organisms, the immune response is primarily designed to afford  long-term specific protection (i.e., immunity) against particular  invading microorganisms; that is, it has a “memory” function.  The products of the adaptive immune response include a type  of serum protein—immunoglobulins, or antibodies—and a  type of blood cell—lymphocytes (Figure 8-1).   Specificity and memory are the primary characteristics that  differentiate the immune response from other protective mech-  anisms. This chapter first discusses the nature of that specific-  ity by defining the various types of antigens that may be seen  by the immune system, the ways in which they are recognized  by antibodies and lymphocytes, and the specific intercellular  recognition molecules that are necessary for effective immune  responses. After the recognition molecules are defined, the  development of the immune response is discussed. An immune  response can be divided into two phases (Figure 8-2). Before  birth, humans produce a large population of T lymphocytes    Measure circulating antigen from  infectious agent or antibody (e.g.,  diagnosis of hepatitis B infection)    Passive treatment with  antibody to treat or  prevent infection (e.g.,  administration of antibody  against hepatitis A)   Immunotherapy (e.g.,  administration of antigen  for desensitization of  individuals with severe  allergies)    Measure circulating antigen (e.g.,  circulating PSA for diagnosis of  prostate cancer)    Measure circulating antigen or  antibody (e.g., diagnosis of allergy by  measuring circulating IgE)    Measure circulating antibody against  self-antigen for diagnosis of  autoimmune disease (see Chapter 9)    FIGURE 8-1 Scanning Electron Micrograph Showing Lymphocytes (Yel-  low), Red Blood Cells, and Platelets. (Copyright Dennis Kunkel Microscopy, Inc.)    (T cells) and B lymphocytes (B cells) that have the capacity to  recognize almost any foreign antigen found in the environment.  Each individual T or B cell, however, specifically recognizes only  one particular antigen, but the sum of the population of lym-  phocyte specificities may represent millions of foreign antigens.  This process is called the generation of clonal diversity and occurs  in specialized (primary) lymphoid organs—the thymus for T  cells and the bone marrow for B cells. While passing through  these tissues, the lymphocytes mature and undergo changes that  commit them to becoming either B or T cells. Lymphocytes are  released from these organs into the circulation as immature cells  that have the capacity to react with antigen (immunocompe-  tent). These cells migrate to other (secondary) lymphoid organs  in the body in preparation for exposure to antigen (Figure 8-3).    Production of T and B cells  with all possible receptors for antigen    Selection, proliferation, and differentiation of individual  T and B cells with receptors for a specific antigen    Antibody  FIGURE 8-2 Overview of Immune Response. The immune response can be separated into two phases: the generation  of clonal diversity and clonal selection. During the generation of clonal diversity, lymphoid stem cells from the bone marrow  migrate to the central lymphoid organs (the thymus or regions of the bone marrow), where they undergo a series of cellular  division and differentiation stages resulting in either immunocompetent T cells from the thymus or immunocompetent B cells  rom the bone marrow. (This process is outlined in more detail in Figures 8-10 and 8-12.) These cells are still naive in that  hey have never encountered foreign antigen. The immunocompetent cells enter the circulation and migrate to the secondary  ymphoid organs (e.g., spleen and lymph nodes), where they take up residence in B- and T-cell—rich areas. The clonal selec-  ion phase is initiated by exposure to foreign antigen. The antigen is usually processed by antigen-presenting cells (APCs)  or presentation to helper T cells (Th cells) (more detail in Figure 8-16). The intercellular cooperation among APCs, Th cells,  and immunocompetent T and B cells results in a second stage of cellular proliferation and differentiation (more details in    Figures 8-19 and 8-22). Because antigen has “selected” those T and B cells with compatible antigen receptors, only a small  population of T and B cells undergo this process at one time. The result is an active cellular immunity or humoral immunity, or  both. Cellular immunity is mediated by a population of “effector” T cells that can kill targets (cytotoxic T cells) or regulate the  immune response (T-regulatory cells), as well as a population of memory cells (memory T cells) that can respond more quickly  0 a second challenge with the same antigen. Humoral immunity is mediated by a population of soluble proteins (antibodies)    produced by plasma cells and by a population of memory B cells that can produce more antibody rapidly to a second challenge    The lymphocytes remain dormant until antigen initiates the  second phase of the immune response, clonal selection. This pro-  cess involves a complex interaction among cells. To initiate an  effective immune response, most antigens must be “processed”  because they cannot react directly with cells of the immune  system but must be shown or “presented” to the immune cells  in a very specific manner. This is the job of antigen-processing  (antigen-presenting) cells, generally referred to as APCs. In gen-  eral, three groups of cells must cooperate to make an immune  response. The APCs interact with subpopulations of T cells that  facilitate immune responses (T-helper cells), and immunocom-  petent B or T cells, resulting in differentiation of B cells into  active antibody-producing cells (plasma cells) and T cells into  effector cells, such as T-cytotoxic cells. The last portion of this  chapter discusses how these products (antibody and T cells)    protect against infection, including how they interact with com-  ponents of the inflammatory process.    The immune response has two arms: antibody and T cells, both  of which protect against infection.* Antibody circulates in the  blood and binds to antigens on infectious agents. This interac-  tion can result in direct inactivation of the microorganism or  activation of a variety of inflammatory mediators (e.g., comple-  ment, phagocytes) that will destroy the pathogen. Antibody is  primarily responsible for protection against many bacteria and  viruses. This arm of the immune response is termed humoral  immunity.   T cells also undergo differentiation during an immune  response and develop into several subpopulations of cells that    FIGURE 8-3 Lymphoid Tissues: Sites of B-Cell and T-Cell Differentiation. Immature lymphocytes migrate through  central (primary) lymphoid tissues: the bone marrow (central lymphoid tissue for B lymphocytes) and the thymus (central  lymphoid tissue for T lymphocytes). Mature lymphocytes later reside in the T and B lymphocyte-rich areas of the peripheral    react directly with antigen on the surface of infectious agents.  Some develop into T cells that can stimulate the activities of  other leukocytes via cell-to-cell contact or through the secretion  of cytokines. Others develop into T-cytotoxic cells (Tc cells) that  attack and kill targets directly. Targets for Tc cells include cells  infected by a variety of viruses, as well as cells that have become  cancerous. This arm of the immune response is termed cellular  immunity. As discussed in this chapter, the humoral and cel-  lular immune responses are interdependent at many levels. In  the end, the success of an acquired immune response depends  on the functions of both the humoral and the cellular responses,  as well as the appropriate interactions between them. Addition-  ally, both arms produce specialized subpopulations of memory  cells that are long-lived and capable of “remembering” the anti-  gen and responding more rapidly and efficiently on subsequent  exposure to the same antigen. On reexposure, memory cells do  not require much further differentiation and will therefore rap-  idly become new plasma cells or effector T cells.    Adaptive immunity can be either active or passive, depend-  ing on whether the antibodies or T cells are produced by the    individual in response to antigen or are administered directly.  Active acquired immunity (active immunity) is produced by  an individual either after natural exposure to an antigen or after  immunization, whereas passive acquired immunity (passive  immunity) does not involve the host’s immune response at all.  Rather, passive immunity occurs when preformed antibodies or  T lymphocytes are transferred from a donor to the recipient.  This can occur naturally, as in the passage of maternal antibod-  ies across the placenta to the fetus, or artificially, as in a clinic  using immunotherapy for a specific disease. Unvaccinated  individuals who are exposed to particular infectious agents  (e.g., hepatitis A virus, rabies virus) often will be given immu-  noglobulins that are prepared from individuals who already  have antibodies against that particular pathogen. Whereas  active acquired immunity is long-lived, passive immunity is  only temporary because the donor’s antibodies or T cells are  eventually destroyed.    The foundation of any successful immune response is the spe-  cific recognition of antigen by antibody or receptors on the    TABLE 8-2 SELECT CD MOLECULES AND THEIR FUNCTIONS  CD MOLECULES PRIMARY LOCATION FUNCTIONS   T-cell marker; adhesion molecule that binds to CD58 (LFA-3) and provides a co-stimulatory signal  Associated with TCR and provides intracellular signaling   Receptor for complement that complexes with CD19 to form a co-receptor for B cells   a-Chain of IL-2 receptor  Adhesion molecule that binds to CD80 to provide co-stimulatory signal for Tc cells  Adhesion molecule that binds to CD154 to provide co-stimulatory signal for B cells  Has multiple types; augments antigen signal   Adhesion molecule that binds to CD2 to provide a co-stimulatory signal    surface of B or T cells, followed by a set of complex intercellular  communications among a variety of antigen-presenting cells  and lymphocytes. To fully understand the immune response,  it is necessary to initially understand the basis for that recogni-  tion. Many of the molecules discussed in this chapter are part of  a nomenclature that uses the prefix “CD” followed by a num-  ber (e.g., CD1 or CD2) (Table 8-2). The definition of the CD  (cluster of differentiation) format has changed over time. It  was originally used to describe proteins found on the surface of  lymphocytes. Currently, CD is the accepted format for labeling  a very large family of proteins found on the surface of many  cells. Many have alternative names, which may be used in this  chapter. The list of identified molecules is constantly increasing  (the number of molecules with a CD designation is probably in  excess of 250). Ina similar fashion, the list of known cytokines is  continually growing, with more than 100 having been identified  so far. A large number of CD molecules and cytokines contrib-  ute to the acquired immune response. We have attempted to  focus on a small number of highly important examples to illus-  trate the immensely complicated, but highly effective, interac-  tions that take place to produce a protective immune response.    An antigen is a molecule that can react with antibodies or anti-  gen receptors on B and T cells. Most, but not all, antigens are  also immunogens. An antigen that is immunogenic will induce  an immune response resulting in the production of antibodies  or functional T cells. Although the terms antigen and immuno-  gen commonly are used as synonyms, there are some differences  between the two, so a substance may be antigenic yet not be  immunogenic.   To function as an antigen, at least a portion of a molecule’s  chemical structure must be recognized by and bound to an anti-  body and/or to specific receptors on a lymphocyte. The precise  portion of the antigen that is configured for recognition and  binding is called its antigenic determinant, or epitope. The  matching portion on the antibody or the lymphocyte receptor    Adhesion molecule that binds to CD28 to provide a co-stimulatory signal  Adhesion molecule that binds to CD40 to provide a co-stimulatory signal    ity complex; NK, natural killer; 7c, cytotoxic cell; TCR, T-cell receptor;    FIGURE 8-4 Antigenic Determinants (Epitopes). Shown are generic exam-  ples of epitopes on protein (A) and polysaccharide (B) molecules. In A, an anti-  genic protein may have multiple different epitopes (epitopes 1 and 2) that react  with different antibodies. Each sphere represents an amino acid with the yellow  spheres representing epitope 1 and the red spheres representing epitope 2. Indi-  vidual epitopes may consist of eight or nine amino acids. In B, a polysaccharide is  constructed of a backbone with branched side chains. Each sphere represents an  individual carbohydrate with the yellow spheres representing the carbohydrates  that form the epitope. In this example, two identical epitopes are shown that would  bind two identical antibodies.    is sometimes referred to as the antigen-binding site, or para-  tope. The size of an antigenic determinant is relatively small,  perhaps just a few amino acids or carbohydrate residues on the  surface of a large molecule (Figure 8-4). Therefore, macromol-  ecules (e.g., proteins, polysaccharides, nucleic acids) usually  contain multiple and diverse antigenic determinants, and the  immune response against the macromolecule will usually con-  sist of a mixture of specific antibodies against several of these  determinants.    Certain criteria influence the degree to which an antigen  is immunogenic. These include: (1) being foreign to the host,  (2) being appropriate in size, (3) having an adequate chemical  complexity, and (4) being present in a sufficient quantity.   Foremost among the criteria for immunogenicity is the  antigen’s foreignness. A self-antigen that fulfills all these cri-  teria except foreignness does not normally elicit an immune  response. Thus most individuals are tolerant to their own anti-  gens. The immune system has an exquisite ability to distinguish  self (self-antigens) from non-self (foreign antigens). Tolerance,  once thought to be a state of nonresponsiveness in which the  immune system passively allowed self-antigens to persist, is  now known to have a variety of mechanisms. In some cases,  a state of central tolerance exists, in which lymphocytes with  receptors against self-antigens have been eliminated. In other  cases, tolerance is peripheral tolerance and part of the adap-  tive immune response. Rather than merely tolerating some self-  antigens, the immune system actively prevents their recognition  by lymphocytes and antibodies. The response to self-antigens  may be actively regulated by specialized T lymphocytes called  T-regulatory (Treg) cells (see Figure 8-2). Some pathogens have  a survival advantage by their capacity to mimic self-antigens  and avoid inducing an immune response.   Molecular size also contributes to an antigen’s immunoge-  nicity. In general, large molecules (those bigger than 10,000 dal-  tons), such as proteins, polysaccharides, and nucleic acids, are  most immunogenic. Low-molecular-weight molecules, such  as amino acids, monosaccharides, fatty acids, and the purine  and pyrimidine bases, tend to be unable to induce an immune  response. Many small molecules can function as haptens: anti-  gens that are too small to be immunogens by themselves but  become immunogenic in combination with larger molecules  that function as carriers for the hapten. For example, the anti-  gens of penicillin and poison ivy are haptens, but they initiate  allergic responses only after binding to large-molecular-weight  proteins in the allergic individual’s blood or skin. Antigens that  induce an allergic response are also called allergens.   Chemical complexity affects immunogenicity. The best  immunogens contain a diversity of chemically different com-  ponents. For instance, a large synthetic protein consisting only  of alanine amino acids would not be very immunogenic, despite  its size and foreignness. However, if other amino acids, such as  tyrosine, tryptophan, or phenylalanine, were inserted into the  structure, the degree of immunogenicity would increase greatly.   Finally, antigens that are present in extremely small or large  quantities may be unable to elicit an immune response and  therefore by definition are also nonimmunogenic. In many  cases, high or low extremes of antigen quantities may induce a  state of tolerance rather than immunity.   Even if an antigen fulfills all these criteria, the quality and  intensity of the immune response may still be affected by a vari-  ety of additional factors. For example, the route and vehicle of  antigenic entry or administration are critical to the immuno-  genicity of some antigens. This has important clinical impli-  cations. The most common routes for clinical administration  of antigen, such as vaccines, are intravenous, intraperitoneal,  subcutaneous, intranasal, and oral. Each route preferentially    stimulates a different set of lymphocyte-containing (lymphoid)  tissues and therefore results in the induction of different types  of cell-mediated or humoral immune responses. For some vac-  cines, the route may affect the protectiveness of the immune  response so that the individual is protected if immunized by one  route, but may remain susceptible to infection if administered  through a different route. Immunogenicity of an antigen also  may be altered by being delivered along with substances that  stimulate the immune response; these substances are known  as adjuvants. Finally, the genetic makeup of a host can play a  critical role in the immune system’s ability to respond to many  antigens; some individuals appear to be unable to respond to  immunization with a particular antigen, whereas they respond  well to other antigens. For instance, a small percentage of the  population fails to produce a measurable immune response to  the most common vaccines, despite multiple injections. Many  other factors can modulate the immune response. These include  the individual’s age, nutritional status, genetic background, and  reproductive status, as well as exposure to traumatic injury, con-  current disease, or the use of immunosuppressive medications.    Antigen is directly recognized by three molecules: circulating  antibody and antigen receptors on the surface of B lymphocytes  (B-cell receptor, or BCR) and T lymphocytes (T-cell receptor,  or TCR) (Figure 8-5).    An antibody, or immunoglobulin, is a serum glycoprotein pro-  duced by plasma cells in response to a challenge by an immuno-  gen. The term immunoglobulin is used to denote all molecules  that are known to have specificity for antigen, whereas the term  antibody is generally used to denote one particular set of immu-  noglobulins with specificity against a known antigen. There are  five molecular classes of immunoglobulins (IgG, IgA, IgM, IgE,  and IgD) that are characterized by antigenic, structural, and  functional differences (Figure 8-6). Within two of the immu-  noglobulin classes are several distinct subclasses including four  subclasses of IgG and two subclasses of IgA.   Classes. IgG is the most abundant class of immunoglobulins;  they constitute 80% to 85% of those circulating in the body and  account for most of the protective activity against infections  (Tables 8-3 and 8-4). As a result of selective transport across the  placenta, maternal IgG is also the major class of antibody found  in blood of the fetus and newborn. Four subclasses of IgG have  been described: IgG1, IgG2, IgG3, and IgG4.   IgA can be divided into two subclasses, IgA1 and IgA2. IgA1  molecules are found predominantly in the blood, whereas IgA2  is the predominant class of antibody found in normal body  secretions. The IgA molecules found in bodily secretions are  dimers anchored together through a J chain and “secretory  piece.” This secretory piece is attached to the IgAs inside muco-  sal epithelial cells and may function to protect these immu-  noglobulins against degradation by enzymes also found in the  secretions.   IgM is the largest of the immunoglobulins and usually exists  as a pentamer that is stabilized by a J (joining) chain. It is the    FIGURE 8-5 Antigen-Binding Molecules. Antigen-binding molecules include soluble antibody (A, B, C) and cell surface  receptors (D). A, The typical antibody molecule consists of two identical heavy chains and two identical light chains connected  by interchain disulfide bonds (- between chains in the figure). Each heavy chain is divided into three regions with relatively  constant amino acid sequences (CH1, CH2, and CH3) and a region with a variable amino acid sequence (VH). Each light chain  is divided into a constant region (CL) and a variable region (VL). The hinge region (Hi) provides flexibility in some classes  of antibody. Within each variable region are three highly variable complementary-determining regions (CDR1, CDR2, CDR3)  separated by relatively constant framework regions (FRs). B, Fragmentation of the antibody molecule by limited digestion with  the enzyme papain has identified three important portions of the molecule: an Fc and two identical Fab fragments. Both Fab    ragments bind antigen. As the antibody folds (C), the CDRs are placed in proximity to form the antigen-binding site. D, The    antigen receptor on the surface of B cells (BCR complex) is a monomeric antibody with a structure similar to that of circulating  antibody, with an additional hydrophobic transmembrane region (TM) that anchors the molecule to the cell surface. The active  BCR complex contains molecules (Iga and IgB) that are responsible for intracellular signaling after the receptor has bound  antigen. The T-cell receptor (TCR) consists of an a-chain and a B-chain joined by a disulfide bond. Each chain consists of a con-  stant region (Ca and Cf) and a variable region (Vo. and V@). Each variable region contains CDRs and FRs in a structure similar  0 that of antibody. The active TCR is associated with several molecules that are responsible for intracellular signaling. These  include CD3, which is a complex of y (gamma), ¢ (epsilon), and 8 (delta) subunits, and a complex of two ¢ (zeta) molecules. The  ¢ molecules are attached to a cytoplasmic protein kinase (ZAP70) that is critical to intracellular signaling. (C from Patton KT,    Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2012, Mosby.)    first antibody produced during the initial, or primary, response  to antigen. IgM is synthesized early in neonatal life, and its syn-  thesis may be increased as a response to infection in utero.   Information on the role of IgD is limited. This class of  immunoglobulins is found in very low concentrations in the  blood, where they do not appear to have a known function.  IgD is located primarily on the surface of developing B lym-  phocytes, where they function as one type of B-cell antigen  receptor.    IgE is the least concentrated of any of the immunoglobu-  lin classes in the circulation. It appears to have very specialized  functions as a mediator of many common allergic responses  (see Chapter 9) and in the defense against parasitic infections.   Molecular Structure. Structural analysis ofimmunoglobulins  began with Porter’s early studies on the effects of the enzyme  papain on IgG.2 The nomenclature of antibody structure  originated from that work. Limited digestion with the enzyme  papain cleaved IgG into three fragments, two of which were    FIGURE 8-6 Structure of Different Immunoglobulins. Secretory IgA, IgD, IgE, IgG, and IgM. The black circles attached    IgG IgG! 146,000  IgG2 146,000 280-300  IgG3 165,000 90-100  IgG4 146,000 50  IgM 970,000 120-150  IgA1 160,000 280-300  IgA2  slgA ; 385,000  IgD 184,000  IgE 190,000    identical. The two identical fragments were found to retain  the ability to bind antigen, and each was termed an antigen-  binding fragment (Fab).* The third fragment crystallized when  separated from the Fab portions and was termed the crystalline  fragment (Fc) (see Figure 8-5).   What Porter learned about the structure of IgG still applies  not only to this class of immunoglobulins but also to each of the  other classes. The Fab portions of an immunoglobulin contain  the recognition sites (receptors) for antigenic determinants and  confer the molecule’s specificity toward a particular antigen.  The Fc portion is responsible for most of the biologic functions    of antibodies, including activation of the complement cascade  and opsonization by binding to Fc receptors on the surface of  the cells of the innate immune system.   The basic structure of the antibody molecule consists of  four polypeptide chains—two identical light (L) chains and  two identical heavy (H) chains (see Figure 8-5). Within the  same molecule, the two heavy chains are identical and the two  light chains are identical. The class of antibody is determined  by which heavy chain is used: gamma (IgG), mu (IgM), alpha  (IgA), epsilon (IgE), or delta (IgD). The light chains of an  antibody molecule are of either the kappa (k) or the lambda  (A) type. The light and heavy chains are held together by two  major forces: noncovalent bonds and disulfide linkages. A set of  disulfide linkages between the heavy chains occurs in the hinge  region and in some instances lends a degree of molecular flex-  ibility at that site so that the Fab regions can move.   Light and heavy chains are further subdivided into constant  (C) and variable (V) regions. The constant regions have rela-  tively stable amino acid sequences within a particular immuno-  globulin class or subclass. Thus the amino acid sequence of the  constant region of one IgG1 should be almost identical with the  sequence of the same region of another IgG1, even if they react  with different antigens. Conversely, among different antibodies,  the sequences of the variable regions are characterized by a large  number of amino acid differences. Therefore, two IgG1 mol-  ecules against different antigens may have many differences in  the amino acid sequence of their variable regions. The variable  region can be further subdivided because most of the region’s  variability in amino acid sequence is localized in three areas of  the variable region. These three areas were once called hypervari-  able regions, but are now called complementary-determining    Fe, Crystalline fragment; /g, immunoglobulin; PMN, polymorphonuclear neutrophil; s/gA, secretory immunoglobulin A; -, lack of activity; +, relative    regions (CDRs). The four regions separating the CDRs have  relatively stable amino acid sequences and are called frame-  work regions (FRs).   The combined amino acid sequences of the variable regions  of both the heavy (Vj) and light (V,) chains determine the  conformation of the antigen-binding site and therefore the  antigenic specificity of the immunoglobulin molecule. Most  proteins will naturally fold and take on secondary or tertiary  structures. As the immunoglobulin molecules fold, the FRs  control the accuracy of folding in the variable region, and  the CDRs in both variable regions are moved into proximity,  resulting in an antigen-binding site formed by the three CDRs  of the heavy chain and the three CDRs of the light chain. The  chemical nature of the particular amino acids in those sites,  as well as the topography of the site, determines the specific-  ity toward a particular antigen. The antigen that will bind most  strongly must have complementary chemistry and topography  with the binding site formed by the antibody. The antigen fits  into this binding site with the specificity of a key into a lock and  is held there by noncovalent chemical interactions (Figure 8-7).  In some cases the substitution of a single critical amino acid in  a CDR may have a significant effect on the shape of the binding  site and thus the specificity of the antibody molecule.   Because the heavy and light chains are identical within the  same antibody molecule, the two binding sites are also identi-  cal and have specificity for the same antigen. The number of  functional binding sites is called the antibody’s valence. Most  antibody classes (i.e., IgG, IgE, IgD, and circulating IgA) have  a valence of 2, but secretory IgA has a valence of 4. IgM, being  a pentamer, has a theoretical valence of 10, but can simultane-  ously use only about five binding sites because a large antigen  binding to one site blocks antigen binding to another site.    The B-cell receptor (BCR) complex is located on the surface of  B lymphocytes (see Figure 8-5). Its role is to recognize antigen,    FIGURE 8-7 Antigen-Antibody Binding. The specificity required for anti-  body binding with an antigen is determined by the shape and chemistry of the six  complementary-determining regions (CDRs) in the combining site on the variable  region of the antibody. This figure indicates two different antibodies (Fab portions  of antibody 1 and antibody 2) that have different sets of CDRs and therefore dif-  ferent specificities. As indicated, the antigenic determinant that reacts well with  antibody 1 is unable to react with antibody 2 because of differences in the antibody  combining site. C, Constant; CH, constant region of the heavy chain; CL, constant  region of the light chain; Fab, antigen-binding fragment, V, variable; VH, variable  heavy chain, VL, variable light chain.    but unlike circulating antibody, the receptor must communi-  cate that information to the cell’s nucleus. Therefore, the BCR  complex consists of antigen-recognition molecules and acces-  sory molecules involved in intracellular signaling (Iga and  Ig8). BCRs on the surface of immunocompetent B cells are  membrane-associated IgM (mIgM) and IgD (mIgD) immuno-  globulins that are produced from the same genes that are used  by plasma cells to produce soluble antibodies. As a BCR, how-  ever, mlgM is a monomer rather than the pentamer primarily  found in the blood.    The BCR signaling complex consists of two Iga and Igf het-  erodimers that are closely associated with the BCR and contain  tyrosine kinase signaling activity. The antibody portion of the  BCR complex is responsible for recognition and binding to an  antigen, but by itself cannot provide the intracellular signals  required to activate the B cell and complete its maturation and  the production of antibodies. That message is conveyed by the  Iga and Igp heterodimers.   T lymphocytes use a similar but distinct array of proteins in  their recognition and response to antigens. The T-cell receptor  (TCR) complex is composed of an antibody-like transmem-  brane protein (TCR) and a group of accessory proteins (col-  lectively referred to as CD3) that are involved in intracellular  signaling (see Figure 8-5). Similar to activation of the B lym-  phocyte, the TCR is responsible for recognition and binding to  the antigen, whereas the accessory proteins are responsible for  the intracellular signaling necessary for activation and differ-  entiation of the T cell. Each of the individual components of  the TCR complex is important, and several severe defects in the  T-cell immune response have been related to mutations in indi-  vidual components of the complex (see Chapter 9).    For an effective immune response, most antigens must be pro-  cessed within cells and expressed on the surface of those cells  in a very specific manner. Some types of antigen are managed  only by highly specialized cells: antigen-presenting cells, or  APCs. Other types of antigens can be processed and presented  by almost any type of cell. Several sets of cell surface molecules  have the responsibility for appropriately presenting antigen.  These molecules are described below.   An essential set of recognition molecules are members of the  major histocompatibility complex (MHC). Most antibody and  cellular immune responses are dependent on antigen presenta-  tion by APCs. Additionally, the role of T-cytotoxic cells in kill-  ing virally infected cells depends on presentation of the viral  antigen on the infected cell’s surface. Antigen presentation is  the primary role of molecules of the MHC.   MHC molecules are glycoproteins found on the surface of  all human cells except red blood cells. They are divided into  two general classes, class I and class I, based on their molecular  structure, distribution among cell populations, and function in  antigen presentation. MHC class I molecules are heterodimers  composed of a large a-chain along with a smaller chain called  f2-microglobulin. MHC class I molecules are also heterodimers  with both a- and B-chains. The general properties of each of the  MHC classes are summarized in Figure 8-8.   Molecules of the two MHC classes are encoded from differ-  ent genetic loci that are located as a large complex of genes on  the short arm of human chromosome 6 (see Figure 8-8). The  MHC also contains other genes that control the quality and  quantity of an immune response, which are commonly referred  to as class III MHC genes. The primary MHC class I genes    consist of three closely linked loci on this chromosome labeled  A, B, and C. The primary MHC class II genes are located within  the D region, which actually consists of three separate and inde-  pendent loci: DR, DP, and DQ.   The class I and class II MHC loci are the most genetically  diverse (polymorphic) of any human genetic loci. Within the  human population, the number of possible different alleles (i.e.,  forms of the gene) expressed by each locus is astounding: 649  at the A locus, 1029 at the B locus, 350 at the C locus, 643 at the  DR locus (a and f), 125 at the DQ locus (@ and f), and 154 at  the DP locus (a and §). These numbers are based on the poly-  morphism of observed DNA sequences and may not reflect dif-  ferences in function. Clearly, not every allele is expressed in the  same individual. Humans have two copies of each MHC locus  (one inherited from each parent) that are codominant so that  molecules encoded by each parent’s genes are expressed on the  cell surface. Within an individual, each locus will be expressing  only one allele. For instance, each person will have only two  different A proteins (one from each parent). However, with the  tremendous number of possible alleles that can be expressed, it  is likely that any two unrelated individuals will have different  sets of MHC molecules on their cell surfaces so that each of us  is distinct.   Transplantation. The diversity of MHC molecules becomes  clinically relevant during organ transplantation. Cells in  transplanted tissue or organs from one individual will have  a different set of MHC surface antigens than those of the  recipient; therefore, the recipient can mount an immune  response against the foreign MHC antigens, resulting in  rejection of the transplanted tissue. As a result of studies of  transplantation, the human MHC molecules are also referred  to as human leukocyte antigens (HLAs), and the different  MHC genetic loci are commonly called HLA-A, HLA-B, HLA-  C, HLA-DR, HLA-DQ, and HLA-DP. To minimize the chance  of tissue rejection, the donor and recipient are often tissue typed  beforehand to identify differences in HLA antigens. The more  similar two individuals are in their HLA tissue type, the more  likely a transplant from one to the other will be successful.   Although a large number of alleles exist at the molecular level,  the diversity is considerably less at the antigenic level: there are  approximately 67 different HLA-A antigens, 149 HLA-B anti-  gens, and 39 HLA-C antigens. Because of the large number of  different alleles, it is highly unlikely that a perfect “match” can  be found in the general population between a potential donor  and the recipient.   The specific combination of alleles at the six major HLA loci  on one chromosome (A, B, C, DR, DQ, and DP) is termed a  haplotype. Each individual has two HLA haplotypes, one from  the paternal chromosome 6 and another from the maternal  chromosome. Because the different HLA loci within the MHC  are in such close proximity to one another, haplotypes are not  usually disrupted by recombination and are thus inherited  intact. Each parent passes on one HLA haplotype to each of his  or her offspring, meaning that children usually share one hap-  lotype with each parent (Figure 8-9). Odds dictate that children  will share one haplotype with half of their siblings and either no  haplotypes or both haplotypes with a quarter of their siblings.    FIGURE 8-8 Genetics and Structure of Antigen-Presenting Molecules. Three sets of molecules are primarily respon-  sible for antigen presentation: MHC class |, MHC class II, and CD1. The MHC molecules are encoded from the MHC region  on chromosome 6, which contains information for class | and class II molecules, as well as for several other molecules that  participate in the innate or immune responses. These include several complement proteins (C’) and cytokines (Cyto), which are  referred to as MHC class Ill molecules. Three principal class | molecules, HLA-A, HLA-B, and HLA-C, are presented here, but  this region contains information for the a-chains of several other molecules, including HLA-E, HLA-F, and HLA-G. The MHC  class | products complex with 62-microglobulin, which is encoded by a gene on chromosome 15. The MHC class | molecules  present small peptide antigens in a pocket formed by the a1 and a2 domains of the a-chain. The conformation of the mol-  ecule is stabilized by 82-microglobulin (82M) as well as by intrachain disulfide bonds (-S-S-). The a- and B-chains of class I  molecules are also encoded in this region: HLA-DR, HLA-DP, and HLA-DO. In some cases, multiple genes for «- and B-chains  are available. The MHC class II molecules present peptide antigens in a pocket formed by the a1 domain of the a-chain and  the B1 domain of the B-chain. The genes for CD1 molecules are encoded on chromosome 1, which contains genes for five  a-chains (CD1A-E), and the «-chains complex with B2-microglobulin to present lipid antigens in a pocket formed by the a1 and  a2 domains. All three sets of antigen-presenting molecules are anchored to the plasma membrane by hydrophobic regions on  the ends of the a- and B-chains. MHC, Major histocompatibility complex.    FIGURE 8-9 Inheritance of HLA. HLA alleles are inherited in a codominant fashion so that both maternal and paternal  antigens are expressed. Specific HLA alleles are commonly given numbers to indicate different antigens. In this example, the  mother has linked genes for HLA-A3 and HLA-B12 on one chromosome 6 and genes for HLA-A10 and HLA-B5 on the second  chromosome 6. The father has HLA-A28 and HLA-B7 on one chromosome and HLA-A1 and HLA-B35 on the second chromo-  some. On one particular chromosome, the HLA antigens are firmly linked, with crossovers occurring in only 1% of individu-  als. The children from this pairing may have one of four possible combinations of maternal and paternal HLA. HLA, Human    Thus the chance of finding a match among siblings is much  higher (25%) than that from the general population.   It should be noted, however, that although HLA alleles are  the primary contributor to rejection of a transplant, a number  of other antigens also have a role in determining tissue com-  patibility. Some of these are encoded on other chromosomes  and are inherited independently of HLA antigens. This means  that although two people have the same HLA makeup, a graft or  transplant still may be rejected because of differences between  other antigens. It is preferable to obtain a graft or transplant  from a closely related individual, such as a sibling, because the  chance of sharing both the same HLA antigens and other unde-  termined antigenic differences encoded outside the MHC is  much greater.    Another set of antigen-presenting molecules are members of  the CD1 group. CD1 molecules have very low genetic polymor-  phism, a structure similar to MHC class I, and are found pri-  marily on APCs and cells in the thymus. Unlike MHC molecules  that present proteins, the CD1 molecules appear to specialize in  presenting lipid antigens contained in lipoproteins, glycolipids,  and other molecules. These antigens are commonly important  factors in infections with bacteria of the Mycobacterium spp.  (e.g., Mycobacterium tuberculosis that causes tuberculosis and  Mycobacterium leprae that causes leprosy), which have a very  large amount of lipid in their cell membranes.    The efficient development of an immune response requires sev-  eral antigen-independent interactions between cells. The inter-  actions between specific cellular receptors and their ligands  result in intracellular signaling events that are independent of    MHC class II on APC  MHC class | on APC  CD58 (LFA-3) on APC  CD80 (B7-1) on APC  ICAM-1 on APC  CD40 on B cell    APC, Antigen-presenting cell; /CAM, intercellular adhesion molecule;  LFA, lymphocyte function associated antigen; WHC, major histocom-  patibility complex; 7c, cytotoxic cell; Th, helper T cell.    the TCR or BCR complexes but are necessary complements to  the antigen-specific signal. Several of these molecules are listed  in Box 8-1.   As discussed in Chapter 7, cytokines are low-molecular-weight  proteins, or glycoproteins, that function as chemical signals  between cells. A large number of cytokines are secreted by  APCs and lymphocytes and provide both positive and nega-  tive regulation of the immune response. The effects of particu-  lar cytokines depend on binding to specific cellular receptors,  which are linked to intracellular signaling pathways. The lym-  phocyte may respond in many ways. One of the most common  responses is an increase in the production of proteins, many of  which are other cytokines or cytokine receptors. Many cyto-  kines also cause a lymphocyte to proliferate and differentiate.  The participation of cytokines is essential to the development  of an adequate immune response, and in general, the precise  combination of cytokines influences the ultimate response of    KEY CYTOKINES AND RECEPTORS THAT INFLUENCE THE IMMUNE RESPONSE  PRIMARY FUNCTION    Macrophages, some virally infected cells  Th1 cells, NK cells, Tc cells    Tumor Necrosis Factor (TNF)  TNF-a (cachectin) Macrophages  TNF-B (lymphotoxin) — Tc cells   Induces B-cell proliferation and differentiation; up-regulates MHC class II expression;  induces class-switch to IgE   Induces B-cell proliferation and differentiation into plasma cells; induces acute-phase  proteins in inflammatory response   Major cytokine for induction of B- and T-cell proliferation and differentiation in  central lymphoid organs   Increases inflammation; increased influx of neutrophils and macrophages; increased  epithelial cell chemokine production    Antiviral; increases expression of MHC class |; activates NK cells  Increases expression of MHC class II; activates macrophages and NK cells    IL-1—like properties; induces cellular proliferation  Kills some cells; increases phagocytosis by macrophages and neutrophils    Trimers (a-, B-, and y-chains) IL-2, IL-4, IL-7, IL-9, IL-15  Class Il receptors IFN-at, -B, and -y  TNF receptors TNF-a, TNF-B, CD40, Fas    IL-3 and IL-5 share a common c-chain; IL-6 and IL-11  share a common f-chain    APCs, Antigen-presenting cells; MHC, major histocompatibility complex; NK, natural killer; 7c, cytotoxic cells; Th, helper T cells.    a given cell. Specific deficiencies in the immune response that  result from genetic mutations that lead to defective cytokine  production or defective cytokine receptors are discussed in  Chapter 9. Table 8-5 provides information about key cyto-  kines and receptors that are known to influence the immune  response.    It has been suggested that more than 10° different antigenic  determinants may be recognized by receptors on an individu-  al’s immunocompetent B cells. A similar number may be recog-  nized by T-cell receptors. However, each T or B cell has only a  single receptor specificity that recognizes only one antigen, and    each is present before that individual is ever exposed to foreign  antigen. Thus before the individual is exposed to any foreign  antigen, millions of different T- and B-cell antigen recep-  tors must be constructed to recognize any potential antigenic  determinant.   Several theories were proposed to explain how such a great  diversity of recognition could be produced. The process occurs  in two phases: the generation of clonal diversity, during which  all the necessary receptor specificities are produced; and clonal  selection, during which antigen selects those lymphocytes with  compatible receptors, expands their population, and causes  differentiation into antibody-secreting plasma cells or mature  T cells (Table 8-6).*° The generation of clonal diversity takes  place in the primary (central) lymphoid organs (i.e., thymus    To produce large numbers of T and B lymphocytes with the   maximum diversity of antigen receptors  When does it occur? Primarily in the fetus  Where does it occur?    Central tolerance induced as autoreactive cells are deleted  Immunocompetent T and B cells that can react with antigen  but have not seen antigen, and migrate to the secondary    Select, expand, and differentiate clones of T and B cells against  a specific antigen   Peripheral lymphoid organs, including lymph nodes, spleen, and  other lymphoid tissues   Plasma cells that produce antibody, effector T cells that help  (Th), kill targets (Tc), or regulate immune responses (Treg);  memory B and T cells    APCs, Antigen-presenting cells; /L, interleukin; Tc, cytotoxic T cells; Th, helper T cells; Treg, regulatory T cells.    and bone marrow), is driven by hormones, does not require  foreign antigen, and results in the generation of immature but  immunocompetent T and B cells with receptors that can rec-  ognize virtually any antigenic molecule. Both T and B cells are  derived from common precursor cells (lymphoid stem cells)  that arise either in the liver (in the fetus) or in the bone mar-  row (ofa child or adult). These precursor cells are distinct from  the precursor cells that give rise to cells of the innate immune  system. The immunocompetent T and B cells migrate from the  primary lymphoid organs to secondary (peripheral) lymphoid  organs (e.g., spleen, lymph nodes, adenoids, tonsils, Peyer  patches), where they await antigen. Clonal selection is initi-  ated by antigen and results in a mature and specific immune  response against that antigen.   Although generation of clonal diversity primarily occurs  in the fetus, it probably continues to a low degree throughout  most of adult life. Clonal selection usually begins at birth and  proceeds throughout the life of the individual as new antigens  are encountered, although it can begin as early as the eighth  week of gestation in humans.   As a result of this process, T and B lymphocytes have the  capacity to react against virtually any antigen found in nature.  This endless array of possible antibodies and TCRs certainly  cannot be constructed from the amount of deoxyribonucleic  acid (DNA) that is in the nucleus of a human lymphocyte.  The enormous repertoire of specificities is instead made pos-  sible by rearrangement of existing DNA during T- and B-cell  development in the primary lymphoid organs. Loci in the  DNA that encode for the variable regions of immunoglobu-  lins and TCRs are recombined in a unique way to generate  receptors that collectively can recognize and bind to any pos-  sible antigen. The DNA in the nucleus of a developing T and  B cell is actually cut and spliced (repaired), a process known  as somatic recombination, so that after this manipulation,  the progeny of a single lymphocyte will synthesize identical  immunoglobulins or TCRs. Those variable regions, however,  are cut and spliced differently from those of another lympho-  cyte, making each cell unique and therefore able to react with  different antigens. The particular process for B and T cells is  discussed next.   The central lymphoid organ for T-cell development is the thy-  mus, which is an organ located near the heart. Precursor cells  (lymphoid stem cells) arise in early embryonic life from the  yolk sac and fetal liver and later from the bone marrow. They  migrate to the thymus and enter the subcapsular region. As the  cells move through the thymic cortex to the medulla, they are  instructed by interactions with various thymic cells (epithelial  cells, macrophages, and dendritic cells) and thymic hormones  to undergo proliferation and progressive development of the  characteristics of immunocompetent T cells’ (Figure 8-10).  Changes include development of the T-cell receptor complex  and expression of characteristic surface molecules. Many T cells  randomly develop TCRs against self-antigens, but are deleted  during this process. The final antigen-reactive T cells are  released into the blood and take up residence in the secondary  lymphoid organs to await antigen.   Like antibody, the TCR reacts with antigen (see Figure 8-5).  Although the structure of the TCR closely resembles a Fab por-  tion of antibody, the TCR uses different protein chains than  are used for antibody. The most common TCR contains a- and  6-chains, each of which has a variable region and a constant  region. Within each variable region are three CDR regions sepa-  rated by FR regions.   The great amount of variable region diversity necessary for  identifying the huge number of antigens found in nature is pro-  duced by random recombination of multiple genes to encode  the variable regions of both the a- and f-chains. In the germ-  line genes, the information for the amino acid sequence of the  a-chain variable region is found on chromosome 14 in two sep-  arated, but closely associated, locations: a set of V region genes  and a set of J region genes (Figure 8-11). The TCR a-chain locus  has multiple (at least 50) V genes and multiple (at least 50) J  genes. During somatic recombination in a developing T cell,  one of the possible V genes is randomly selected and spliced to  one of the J genes, with the intervening DNA being removed.  This DNA rearrangement process is controlled by two enzymes    FIGURE 8-10 T-Cell Development in the Thymus. During the generation of clonal diversity in the fetus, lymphoid stem  cells undergo several stages of cellular division and differentiation in a central lymphoid organ (the thymus) under the control  of hormones but without the influence of foreign antigen. A simplified scheme for that process is presented here. The differ-  entiation process is characterized by the up-regulation of many important surface molecules (only some of which are shown)  and the random development of a huge number of different T-cell receptors against all possible antigens that the adult may  encounter. The lymphoid stem cell enters the subcapsular region of the thymus, where it begins to undergo differentiation.  One of the first surface changes is the appearance of the molecule CD2, which is a marker for all T cells. In the cortex of the  thymus, the developing cell encounters epithelial cells that guide most of the early differentiation process. The pre—T cell  begins expressing the surface receptor for the cytokine IL-7, which is produced by the epithelial cell along with other thymic  hormones to drive the T-cell differentiation process. At this stage the T cell begins constructing the T-cell receptor (TCR) by first  rearranging and expressing the TCR B-chain (more detail is provided in Figure 8-11) and expressing CD3 molecules. Although  the TCR a-chain has not yet been produced, the f-chain is expressed on the surface as a pre-TCR (pTCR) using a protein that  acts as a surrogate for the a-chain. Because of the randomness of the process, some pTCRs are produced with specificities  toward self-antigens. Many of these undergo negative selection and are deleted (clonal deletion) by apoptosis induced through  interactions with self-antigens presented by the epithelial cells. Survivors of negative selection move toward the thymic cortex  and begin expressing the TCR a-chain, the normal TCR, and both CD4 and CD8 on their surfaces. These CD4+, CD8+ “double-  positive” cells encounter medullary epithelial cells that express both MHC class | and MHC class II molecules. The phenotype  of the developing T cell is positively selected so that interaction between CD4 and MHC class II selects for retention of CD4  expression, whereas interaction between CD8 and MHC class | favors the CD8 phenotype. Thus two populations of “single-  positive” immunocompetent T cells leave the thymus: one cell is CD4+, CD8- (destined to be a helper T [Th] cell) and the other  is CD4-, CD8+ (destined to be a cytotoxic T [Tc] cell).    produced by genes RAG-1 and RAG-2 (recombination activat-  ing genes). These enzymes cut double-stranded DNA at spe-  cific recognition sites (recombinant signal sequences) and then  repair the break, resulting in excision of the DNA between the  selected V and J genes. At transcription, the genetic information  for the a-chain variable region is still separated from the gene  for the a-chain constant region. This product is transcribed    into messenger ribonucleic acid (mRNA) that contains infor-  mation for the variable region (VJ) separated by a span of RNA  from the information for the a-chain constant region. An  RNA-processing step removes the intervening span, bringing  the message for the variable and constant regions together into  a final mRNA product that is translated into the intact a-chain  protein. The random selection and pairing of 50 V and 50 J    FIGURE 8-11 DNA Rearrangement of Genes for Antigen-Binding Molecules. During the generation of clonal diver-  sity, a tremendous number of different antigen-binding molecules are produced. These include the B-cell receptor (BCR), which  consists of a membrane-bound antibody molecule, and the T-cell receptor (TCR). The process by which receptor diversity is  created is identical for all antigen-binding molecules and is summarized in this figure. Maximum diversity with minimum use of  DNA is accomplished by random rearrangement of sets of genes that encode different portions of the variable regions. A, The  variable regions of the light chain of antibody and the a-chain of the TCR independently rearrange two sets of genes: Vregion  genes and Jregion genes. The light chain uses its own set of genes, and the a-chain uses a completely different set. In neither  case is the exact number of Vor Jregion genes known; therefore, in this figure they are numbered from 1 to an unknown value    n). In a particular cell's DNA, one Vgene is randomly selected and moved to a position immediately adjacent to a randomly  selected J gene. In this example, V3and J3 were selected. The DNA between the selected genes is enzymatically removed and  he DNA repaired, so that the rearranged DNA in this example is missing the portion found in the germline DNA between V3  and J3. This product is transcribed into a precursor ribonucleic acid (RNA) that contains information for the rearranged WJ pair,  a span containing other unselected J regions, and information for the appropriate constant region (C gene) of the molecule. The  RNA between the VJ and the C regions is not translated; therefore, it is removed by RNA processing to produce a messenger  RNA (mRNA) that is translated. B, The variable region of the antibody heavy chain and the TCR B-chain results from a simila  DNA rearrangement, with the added diversity contributed by a group of D region genes. The joining of D and J occurs first,  with the removal of intervening DNA. In this example, D3 and J4 were chosen. This is followed by rearrangement of the Vgene    (e.g., V4) and formation of a VDJ region in the rearranged DNA. The precursor RNA contains information for the VDu, the inter-  vening portion of DNA, and the appropriate constant region. After RNA processing, an mRNA is formed for the intact antibody  heavy chain or the TCR B-chain. Once the DNA is rearranged and spliced in a given B or T cell, all of the antigen receptors  produced by that cell employ the same V; D, and J segments and have the same specificity.    genes by a large number of developing T cells can result in more  than 2500 possible a-chains.   Ina similar fashion, the TCR B-chain locus on chromosome  7 has three sets of genes that rearrange to encode the variable  region of that chain: at least 20 V genes, 13 J genes, and 2 inter-  vening and relatively short D genes that add further diversity.  Using the RAG-1 and RAG-2 enzymes, a developing T cell  randomly selects a set of V, D, and J genes for DNA recom-  bination. The VDJ rearranged segment is transcribed with a  6-chain constant region, the intervening RNA is removed dur-  ing processing, and the final mRNA is translated into an intact  6-chain.®   The a- and B-chains are joined by that cell and inserted into  the membrane to make an antigen-specific TCR. The enor-  mous number of possible combinations of a-chain V and J  regions along with the B-chain V, D, and J regions enables the  generation of a population of T cells with a large diversity of  TCRs (estimated at 1.3 x 10° possible combinations). For both  chains, the V region genes encode the amino acid sequences  that include CDR1 and CDR2 and their appropriate FR regions.    The J regions contain information for CDR3 and FR4. The TCR  6-chain D regions encode a short amino acid sequence found  in the CDR3 and greatly increases the diversity of the B-chain  CDR3. Imprecise joining increases the diversity of the CDR3  regions of both the a- and B-chains even further. For example,  the sites of VJ and VDJ joining may shift slightly resulting in an  amino acid being inserted or deleted from the protein.   Although the af TCR is the preferred antigen receptor, some  T cells use alternative genes: gamma (y) (chromosome 7) and  delta (5) (chromosome 14, in the middle of a-chain genes).  T cells with y6 TCRs appear to migrate to unique areas of the  body (the epithelial areas in the skin, reproductive tract, intes-  tine, respiratory tract) and have different and less well under-  stood functions than the T cells with af TCRs.   Differentiation of T cells in the thymus also results in changes  in a variety of important surface molecules. As the developing T  cells move through the thymic cortex, they initiate the expres-  sion of the molecule CD2 on the cell surface. CD2 is a marker    for T cells and is expressed on virtually every subpopulation of  cells that have undergone development in the thymus. Within  the cortex, the cells begin rearranging the variable region genes  necessary for forming a functional T-cell receptor. The T-cell  receptor undergoes several stepwise changes until the final of  TCR is formed. Concurrently, the TCR accessory molecules  (collectively called CD3) are expressed. The cell also begins  making two important surface proteins, CD4 and CD8, which  are concurrently expressed on the developing cell’s surface at  this stage.? These CD4+, CD8+ cells are often called “double-  positive” cells. Much of T-cell development is controlled by  hormones and cytokines in the thymus, and an early step in  maturation is expression of the receptor for interleukin-7 (IL-  7R), which is a major cytokine that drives the differentiation  process. After entering the medulla of the thymus, the double-  positive cells become “single-positive.” That is, some of the  cells suppress production of the CD8 molecule and remain only  CD4+, whereas others suppress CD4 production and remain  CD8+.'° This branch in the differentiation pathway leads to  two groups of cells with different functional characteristics:  CD4 cells tend to recognize antigen presented by MHC class II  molecules and develop into helpers in the later clonal selection  process (T-helper cells), whereas CD8 cells recognize antigen  presented by MHC class I molecules and become mediators  of cell-mediated immunity and kill other cells directly  (T-cytotoxic cells).!!    During the random rearrangement of VJ and VDJ genes to pro-  duce the T-cell receptor, some combinations result in specifici-  ties that recognize self-antigens. If some of these autoreactive T  cells were allowed to progress further in development and leave  the thymus, a severe immunologic reaction against the individ-  ual’s own tissues could result. One stage at which tolerance for  self-antigens is maintained is the deletion of autoreactive T cells  in the thymus, which is referred to as central tolerance.   A variety of self-antigens are expressed by thymic cells. Many  thymic cells express MHC class I or MHC class II molecules.  During the T-cell’s double-positive stage, if a TCR strongly  reacts with MHC class I or class I, the T cell will undergo apop-  tosis, referred to as clonal deletion. A large spectrum of other  self-antigens is expressed on the surface of thymic macrophages,  dendritic cells, and especially epithelial cells.!* If a developing  T-cell’s TCR binds strongly with a self-antigen, it is deleted.  Although this process of negative selection induces more than  95% of T cells to undergo apoptosis in the thymus, a limited  number of autoreactive clones persist and must be controlled  by other means in the peripheral lymphoid organs (peripheral  tolerance).   The destiny of the double-positive cells with TCRs specific  for foreign antigens (which are not expressed in the thymus)  is determined by their interaction in the thymus with MHC  antigens. If their surface CD4 molecules bind to MHC class II  molecules on the thymic cells, the T cell will become CD4 single-  positive. However, if their surface CD8 reacts with MHC class I  molecules, the cells will become CD8 single-positive. This posi-  tive selection process results in about 60% of immunocompetent    T cells being CD4+ and 40% being CD8+ when they leave the  thymus.!°   Although the thymus is the central lymphoid organ for T-cell  development, humans do not appear to have a discrete organ  for B-cell development. In chickens, B lymphocytes undergo  differentiation in an organ called the bursa of Fabricius. In  humans, portions of the bone marrow function as a bursal-  equivalent tissue for B-cell development.'*   Regardless of the lack of a discrete organ, B-cell differentia-  tion undergoes a very similar process to that described above  for T cells.!° Lymphoid stem cells in the bone marrow interact  with stromal cells through a variety of intercellular adhesion  molecules (Figure 8-12). As the stem cell begins to mature, it  progressively develops a variety of necessary surface markers,  the earliest being CD45R and the IL-7 receptor. IL-7, produced  by the stromal cells, is critical in driving the further differentia-  tion and proliferation of the B cell. The next stage in develop-  ment is formation of the B-cell receptor.    The BCR is an antibody that is anchored to the plasma mem-  brane. The process by which BCR diversity is generated is vir-  tually identical to the process in T cells and also requires the  genetic rearrangement of V, D, and J genes. The segments of  DNA that encode either kappa  (chromosome 2) or lambda  (A) (chromosome 22) light chains contain about 70 V and 5 J  segments, whereas the heavy-chain locus on chromosome 14  contains about 80 V, 30 D, and 6 J regions. The locus for the  antibody heavy chain also contains multiple sequential regions  for different constant regions, with the gene for the mu (1)  constant region being closest to the VDJ region, and the delta  (5) constant region gene being next in sequence (Figure 8-13).  These are followed by the constant region genes for other classes  and subclasses. In the developing B cell, the initial RNA tran-  script contains information for the VDJ recombination, the p  constant region, and the 6 constant region. Transcription is sig-  naled to stop immediately after the 6 constant region. During  the following RNA processing step to form a final mRNA prod-  uct, the cell can alternatively process some mRNAs to retain the  uu constant region only or process other mRNA molecules to  remove the p constant region and retain the 6 constant region.  Thus one cell can use multiple mRNA molecules and alternative  RNA processing to simultaneously produce two different heavy  chains, p and 4, both of which have the same variable region.  The developing B cell rearranges and expresses the heavy  chain, which is followed by the rearrangement of either the  k or the A light chain so that only one type is produced. The  light chains are assembled with two p heavy chains to form a  monomeric IgM antibody or with two 6-chains to form an IgD  antibody. Because each heavy chain used the same VDJ rear-  rangement and the same light chain, the variable regions and  therefore the specificities of the IgM and IgD are identical. At  this stage of B-cell development, both antibodies have hydro-  phobic, or sticky, “tails” that result in insertion into the plasma    FIGURE 8-12 B-Cell Development in the Bone Marrow. During the generation of clonal diversity, lymphoid stem cells  enter portions of the bone marrow that serve as the central lymph organ for B-cell development. Interactions with a series  of bone marrow stromal cells guide the proliferation and differentiation process through direct cell-to-cell contact and the  production of cytokines and hormones by the stromal cells, but without the presence of foreign antigen. A simplified scheme  for that process is presented here. As with T-cell development, the differentiation process of B cells is characterized by the  up-regulation of many important surface molecules (only some of which are shown) and the random development of a huge  number of different B-cell receptors. The early B cell (pro—B cell) binds to a membrane-bound cytokine (stem cell factor) on the  stromal cell and initiates expression of the surface molecule CD45R and begins to rearrange the DJ regions of the antibody  heavy-chain gene. As the cell progresses to the pre—B-cell stage, it concludes DNA rearrangement of the heavy chain (VDJ)  and begins expressing cytoplasmic mu (u) heavy chain. The p- chain is incorporated into a pre—B-cell receptor (pBCR) using a  surrogate protein in place of the light chain. The cell also up-regulates the IL-7 receptor (IL-7R), which interacts with IL-7 pro-  duced by the stromal cells to drive the remaining steps in differentiation. Some pBCRs have specificities toward self-antigen.  Many of these encounter self-antigen expressed on the stromal cells and undergo negative selection (clonal deletion). The  surviving cells (immature B cells) rearrange the light-chain DNA (VJ) and express a BCR consisting of light chain and the  u-heavy chain (surface IgM [slgM]). In the mature B cell, changes in processing of the heavy-chain precursor RNA result in  co-expression of slgM and IgD (slgD) (see Figure 8-13 for more details).    membrane and the co-expression of IgM and IgD receptors on  the cell surface.    As with T cells, B-cell differentiation is also characterized by the  development of a variety of important surface molecules. These  include CD21 (a complement receptor) and CD40 (adhesion  molecule required for later interactions with Th).   During the very earliest stages of formation of the BCR in  the bone marrow, a large number of autoreactive B cells are  eliminated if exposed to self-antigen.!° It is estimated that    more than 90% of developing B cells are induced to undergo  apoptosis.    As described in the previous chapter, successful invasion by a  pathogen will initially elicit an inflammatory response as a host  attempts to destroy and clear the invading microorganism. In  addition to carrying out their roles as inflammatory effector  cells, some of the cells involved in innate immunity are respon-  sible for communicating with immature B and T lymphocytes  to initiate specific and longer-acting acquired immunity. This    FIGURE 8-13 Genetics of the B-Cell Receptor. Most mature immunocompe-  tent B cells express both surface IgM and IgD as the B-cell receptor. In the germline  DNA, the heavy-chain gene complex consists of a series of VD, J, and constant  region genes. In humans, each class and subclass of antibody has a unique con-  stant region gene arranged in the indicated order. Switch regions occur preceding  every constant region gene, except mu (1) (IgM) and delta (5) (IgD). After successful  DNA rearrangement of the VDJ regions, a ribonucleic acid (RNA) molecule is tran-  scribed that contains the information from the VDJ, intervening DNA, the p con-  stant region, and the 6 constant region. Precursor RNA molecules are alternatively  processed to produce messenger RNAs (mRNAs) containing either p or 8. Initially,  RNA processing favors the p chain and production of surface IgM (see Figure 8-12),  but as the B cell matures, both mRNA molecules are produced.    intercellular communication occurs via direct cellular contact  in peripheral lymphoid tissues and is essential for the specificity  of the adaptive immune response.    The secondary lymphoid organs include the spleen, lymph  nodes, adenoids, tonsils, Peyer patches (intestines), and the  appendix (see Figure 8-3). Immunocompetent lymphocytes  enter the secondary lymphoid organs through the blood and  enter specialized small veins, called high endothelial venules  (HEVs), where they bind to the endothelium through a family  of adhesion molecules. The lymphocytes migrate from the ves-  sels into the lymphoid tissues, which contain B- and T-cell-rich  areas. B lymphocytes that encounter antigen in the secondary  lymph organs usually undergo a process of differentiation and  proliferation that results in the formation of specialized germi-  nal centers in these organs (Figure 8-14).!7    Most antigens do not react directly with T or B cells, but require  processing and presentation in the appropriate fashion. This is  the duty of APCs.   Pathogens that penetrate the external barriers and enter  the tissues or bloodstream encounter a variety of phagocytic  cells and are therefore likely to be ingested and destroyed. If  the infectious agent is in the tissues, they may elicit an inflam-  matory response that results in the infiltration of macrophages    FIGURE 8-14 Histology of a Secondary Lymphoid Organ. A, The lymph node contains areas (primary follicles) that  are rich in immunocompetent B cells (stained green), and T cells (stained red) in the paracortex. B, A lymph node is organized  into an outer cortex and an inner medulla. C, In response to antigen, B cells undergo proliferation, resulting in the formation  of secondary follicles with germinal centers. (Modified from Kumar V et al: Robbins & Cotran pathologic basis of disease,    into the site. Additionally, the infectious agent or fragments of  the microorganism may be removed by the lymphatics, which  drain to the lymph nodes. The lymph nodes are extremely rich  in dendritic cells and macrophages, which phagocytose the  material and function as APCs for T and B lymphocytes in the  lymph nodes. Pathogens entering through the bloodstream  may be removed by phagocytic cells in the spleen and other  lymphoid tissues. In either case, the phagocytic cells that digest  invading pathogens are also responsible for processing antigens  from the pathogen and displaying or presenting those antigens  on the phagocyte’s surface to neighboring lymphocytes in order  to initiate the adaptive immune response against that specific  pathogen.   Many cells have the capacity to present antigen to some  degree, but dendritic cells, macrophages, and B lymphocytes  are so efficient at antigen presentation that they are considered  “professional” APCs. Each of these three APCs is responsible for  the presentation of antigens of different types and from different    sources. B cells present antigen to Th cells that facilitate develop-  ment of the humoral immune response. Macrophages are very  effective in presenting antigen to memory Th cells in order to  initiate a rapid response to antigens (i.e., secondary immune  response). The dendritic cells are perhaps the most effective in  presenting antigen to naive immunocompetent Th cells. Den-  dritic cells develop from bone marrow precursor cells, either  of myeloid or of lymphoid lineage (at least two populations of  dendritic cells have been described). They migrate to the periph-  eral tissues (e.g., skin, intestinal tract) and to the secondary lym-  phoid organs. Immature dendritic cells at a site of inflammation  function as phagocytes, and the process of phagocytosis can  initiate differentiation and directed migration to the secondary  lymphoid organs, particularly the lymph nodes (Figure 8-15).!®  Thus dendritic cells can carry processed antigen from a site of  inflammation to the T-cell-rich areas of the lymph nodes.   Both antigen processing and presentation are necessary  for an adaptive immune response to occur. Although B and T    FIGURE 8-15 The Role of the Dendritic Cell in Capturing Antigen. Immature dendritic cells in the tissues encounter  and phagocytose antigen, which results in the production of inflammatory cytokines and a loss of adhesive interactions with  neighboring cells. The maturing dendritic cell migrates through the lymphatic vessels to a regional lymph node, where it pres-  ents the antigen to immunocompetent T cells to initiate the clonal selection process. (Redrawn from Kumar V, Abbas A, Fausto  N: Robbins & Cotran pathologic basis of disease, ed 8, Philadelphia, 2010, Saunders.)    lymphocytes are immunocompetent before they have “seen” an  antigen on the surface of an APC, they are considered “naive”  until they have actually done so. The processing and presen-  tation of antigens to naive lymphocytes result in activation of  an acquired immune response only if (1) the antigen is of the  appropriate type; (2) the lymphocytes are prepared to recog-  nize the presented antigen; and (3) the antigen is presented  appropriately.    In general, the immune system responds to two types of anti-  gens: exogenous and endogenous. Using infection as a model,  exogenous antigens are carried on microorganisms that are  trapped and killed by phagocytic cells; therefore, they come  from outside the cell. Endogenous antigens are synthesized  within a cell. These include viral antigens because viruses infect    cells and use the normal cellular protein-synthesizing machin-  ery to translate the viral genes into viral proteins. Endogenous  antigens also may include those uniquely produced by cancer-  ous cells. When many cells undergo malignant change, they  begin producing unique proteins that are specific to cancer cells  and are presented as foreign antigens on the cell surface.  Exogenous and endogenous antigens are preferentially pre-  sented by different classes of MHC molecules: class I MHC  molecules generally present endogenous antigens, and class II  molecules prefer exogenous antigens (Figure 8-16).!° Because  class I MHC molecules are expressed on all cells, except red  blood cells, any change in that cell attributable to viral infec-  tion or malignancy may result in foreign antigen being pre-  sented by MHC class I on that cell’s surface. Class H MHC  molecules are co-expressed with MHC class I molecules on a  more limited number of cells that have APC function, including    FIGURE 8-16 Antigen Processing. Antigen processing and presentation are required for initiation of most immune  responses. Foreign antigen may be either endogenous (cytosolic protein) or exogenous (e.g., bacterium). Endogenous antigenic  determinants (antigenic peptides) are produced by cellular proteasomes and transported by TAP proteins into the endoplasmic  reticulum (ER) where the MHC and CD1 molecules are being assembled. In the ER, antigenic peptides bind to the a-chains of  the MHC class | molecule, and the complex is transported to the cell surface. In the ER, the a- and B-chains of the MHC class  || molecules are also being assembled, but the antigen-binding site is blocked by a small molecule (invariant chain) to prevent  interactions with endogenous antigenic peptides. The MHC class Il-invariant chain complex is transported to lysosomes,  where exogenous antigenic fragments have been generated as a result of phagocytosis. In the lysosomes the invariant chain  is digested and replaced by exogenous antigenic peptides, after which the MHC class II—antigen complex is inserted into the  cell membrane. CD1 is also assembled in the ER, but its antigen-binding site is specific for lipid antigenic determinants and  does not bind endogenous antigenic peptides. The CD1 molecule is transported to the lysosomes and may encounter and  bind antigenic lipids produced by phagocytic digestion of engulfed bacteria. The CD1-antigen complex is transported to the  cell membrane and presents lipid antigens. MHC, Major histocompatibility complex; 7AP transporter associated with antigen  processing.    macrophages, dendritic cells, B lymphocytes, activated T lym-  phocytes, and some endothelial cells.   Thus, the term antigen processing relates to the process  by which exogenous and endogenous antigens are linked with  the appropriate MHC molecules. Endogenous antigens are  usually components of proteins synthesized in the cytosol.  They are degraded in the cytosol by proteasomes into small  peptides and transported by TAP (transporter associated  with antigen processing) proteins (TAP-1 and TAP-2) into  the endoplasmic reticulum, where MHC class I and class II  molecules are assembled.”° The class I MHC molecules have  open antigen-binding sites so that antigen, the class I MHC  a-chain, and a §2-microglobulin molecule form a stable com-  plex that is transported through the Golgi apparatus to the  plasma membrane. The antigenic peptides presented by class  I MHC molecules are usually very small, 8 to 10 amino acids  in length.   MHC class II molecules are also assembled in the endo-  plasmic reticulum but do not bind with endogenous antigen  because the antigen-binding site is blocked by a small protein  called invariant chain. Exogenous antigens are internalized by  phagocytosis and small antigenic molecules produced by diges-  tion in the lysosomes. The MHC class Il complexes of the class  Il a- and 6-chains, with invariant chain, are transported to the  lysosomes containing exogenous antigens. In the lysosomal  environment, the invariant chain is digested and replaced by  antigenic molecules that are usually slightly larger (in excess of  12 amino acids in length) than those presented by MHC class  I molecules.   CD1 presents a variety of lipid-containing antigens that are  usually derived from phagocytosis and digestion of infectious  microorganisms with very high lipid content in their cell mem-  branes. Therefore, CD1 complexes with antigen in the lyso-  somes, in a fashion similar to MHC class II. The “pocket” that  holds antigen for presentation by CD1 is generally more nar-  row and deeper than that described for MHC molecules, and it  is lined with many hydrophobic amino acids that interact with  lipid.   Regardless of whether an antigen primarily induces a cellular  or humoral immune response, a subpopulation of T lympho-  cytes, T-helper cells (Th cells), is usually necessary for the pro-  cess. As indicated by the name, this group of T cells helps the  antigen-driven maturation of both B and T cells. They perform  this task by facilitating and magnifying the interaction between  APCs and the immunocompetent lymphocytes. This extremely  important role involves three distinct steps: (1) the Th cell  directly interacts with the APC through a variety of antigen-  specific and antigen-independent receptors; (2) the Th cell  undergoes a differentiation process during which a variety of  cytokine genes are activated; and (3) depending on the pattern  of cytokines expressed, the mature Th cell interacts with either  immunocompetent B or T cells to enhance their response to  antigen, which results in differentiation into either plasma cells  or effector T cells, such as T-cytotoxic cells. Th cells are criti-  cal to most immune responses, and a variety of major Th-cell    defects that lead to severely diminished immune responses are  discussed in later chapters.    Cells that are destined to become Th cells emerge from the  thymus with characteristic cell surface markers. They have a  functional a6 TCR complex and express the surface molecule  CD4 and lack CD8. These are generally referred to as precur-  sor Th cells, or sometimes Thp cells (Figure 8-17). As described  previously, the TCR recognizes antigen and the CD4 molecule  confines antigen presentation to MHC class II molecules; thus  CD4+ cells are class II restricted. In order to undergo matura-  tion, the Th cell must receive three independent signals: (1)  antigen binding through the combined interaction of the TCR  complex and CD4, (2) co-stimulatory signals through a variety  of intercellular adhesion molecules, and (3) activation of spe-  cific cytokine receptors. If the appropriate signaling pathways  are activated, the cell will differentiate through multiple inter-  mediate stages into functional Th cells.   The complex of an antigenic peptide presented by an MHC  class II molecule is recognized by multiple molecules on the  Th-cell surface. The TCR binds directly to the antigen, whereas  CD4 independently binds to a different site on the MHC class  II B-chain. This co-recognition of the MHC-antigen complex  by the TCR and CD4 brings CD4 into proximity with the CD3  components of the TCR complex, which initiates a series of  enzymatic interactions among other molecules associated with  the cytoplasmic portions of CD3 and CD4, such as the protein  kinases p56!“ and ZAP70. These molecules activate a signaling  pathway from the TCR to the Th-cell nucleus.   The antigenic signal alone is inadequate and may even inac-  tivate the Th cell if co-stimulatory signals are not present.?!  Co-stimulatory molecules are necessary for proper differen-  tiation to occur. A variety of molecular interactions have been  described, but the most critical appears to involve B7 on the  APC and CD28 on the Th cell. Other interactions occur between  CD48 on the APC and CD2 on the Th cell and between a variety  of other adhesion molecules. In each case, the Th-cell molecule  sends an activation signal to the nucleus. An additional signal  is provided by cytokine. At this early stage of Th-cell differen-  tiation, IL-1 secreted by the APC provides this signal through  interaction with the IL-1 receptor on the Th cell.”   The initial differentiation response by the Th cell includes  the production of the cytokine IL-2 and up-regulation of IL-2  receptors. IL-2 is secreted and acts in an autocrine (self-stimu-  lating) fashion to induce further maturation and proliferation  of the Th cell. Without IL-2 production, the Th cell cannot effi-  ciently mature into a functional helper cell.”° At this point, Th  cells undergo one of several different differentiation pathways  into Th subsets.    The most clearly characterized Th-cell subsets are Th1 and Th2  cells, and the newly described Th17 cells (see Figure 8-17).  These subsets have different functions: Th1 cells help develop  cellular immunity, Th2 cells help develop humoral immunity,  and Th17 cells increase the inflammatory response. A fourth    TNF-B p> Cellular  IL-2 immunity  IFN-y  IL-4  IL-5 => Humoral  IL-6 immunity  IL-17  IL-21 => Inflammation  IL-22  Suppress  Pg => sla ae  ponse    FIGURE 8-17 Development of T-Cell Subsets. The most important step in clonal selection is the production of popula-  tions of helper T (Th) cells (Th1, Th2, and Th17) and regulatory T (Treg) cells that are necessary for the development of cellular  and humoral immune responses. In this model, APCs (probably multiple populations) may influence whether a precursor Th  cell (Thp cell) will differentiate into a Th1, Th2, Th17, or Treg cell. Differentiation of the Thp cell is initiated by three signal-  ing events. (1) The antigen signal is produced by the interaction of the T-cell receptor (TCR) and CD4 with antigen presented  by MHC class II molecules. A set of co-stimulatory signals is produced from interactions between adhesion molecules (e.g.,  CD80 and CD28) (not shown). A third signal is produced by the interactions of cytokines (particularly interleukin-1 [IL-1]) with  appropriate cytokine receptors (IL-1R) on the Thp cell. (2) The Thp cell up-regulates IL-2 production and expression of the  IL-2 receptor (IL-2R), which act in an autocrine fashion to accelerate Thp-cell differentiation and proliferation. (3) Commit-  ment to a particular phenotype results from the relative concentrations of other cytokines. IL-12 and IFN-y produced by some  populations of APCs favor differentiation into the Th1-cell phenotype; IL-4, which is produced by a variety of cells, favors  differentiation into the Th2-cell phenotype; IL-6 and TGF-B (T-cell growth factor) facilitate differentiation into Th17 cells; IL-2  and TGF-6 induce differentiation into Treg cells. The Th1 cell is characterized by the production of cytokines that assist in the  differentiation of cytotoxic T (Tc) cells, leading to cellular immunity, whereas the Th2 cell produces cytokines that favor B-cell  differentiation and humoral immunity. Th1 and Th2 cells affect each other through the production of inhibitory cytokines: IFN-  y will inhibit the development of Th2 cells, and IL-4 will inhibit the development of Th1 cells. Th17 cells produce cytokines  that affect phagocytes and increase inflammation. Treg cells produce immunosuppressive cytokines that prevent the immune  response from being excessive. APC, Antigen-presenting cell; /FN, interferon; MHC, major histocompatibility complex; 7GF  transforming growth factor.    subset, Treg cells, is discussed later in this chapter. The Th sub-  sets differ considerably in the spectrum of cytokines produced  by each, as well as the expression of surface cytokine receptors  and intercellular adhesion molecules. Th1 cells produce IL-2,  tumor necrosis factor-beta (TNF-f), and interferon-gamma  (IFN-y);74 Th2 cells produce IL-4, IL-5, IL-6, and IL-13,*° and  Th17 cells produce IL-17, IL-21, and IL-22.”° As will be seen in  the next portions of this chapter, the Th1 cytokines affect Tc-  cell development, and the Th2 cytokines are needed for B-cell  maturation, including class-switch. Th17-cell cytokines affect  inflammatory responses, particularly infiltration of neutrophils  and macrophages and production of antimicrobial proteins and  chemokines by epithelial cells. Members of the IL-17 cytokine    family induce epithelial cell chemokines and neutrophil infiltra-  tion, and IL-22 more specifically affects epithelial cell antimicro-  bial protein production.’” Thus Th17 cells control many aspects  of inflammation, including chronic inflammation.** Th1, Th2,  and Th17 cells also have different cytokine receptors, so that  IFN-y produced by Th1 cells will bind to receptors on Th2 and  Th17 cells and suppress their function. Likewise, Th2 cells pro-  duce IL-4, which suppresses Thl and Th17 cells through their  IL-4 receptors. Thus in some instances the immune response  favors antibody formation, with suppression of a cell-mediated  response, whereas in other instances the opposite is true. For  example, antigens derived from viral or bacterial pathogens and  those derived from cancer cells are hypothesized to induce a    greater number of Th! cells relative to Th2 cells, whereas anti-  gens derived from multicellular parasites and allergens are  hypothesized to result in production of more Th2 cells. Many  antigens (e.g., tetanus vaccine), however, produce excellent  humoral and cell-mediated responses simultaneously.   How a Th cell is guided into becoming a Thl, Th2, or Th17  cell is not fully known. Some evidence indicates that different  subpopulations of APCs influence the choice by secreting dif-  ferent profiles of cytokines that may favor one route of differen-  tiation over another (see Figure 8-17).    When an immunocompetent B cell encounters an antigen for  the first time, only those cells with specific BCRs complemen-  tary to that antigen’s determinant sites are stimulated to prolif-  erate and differentiate (clonal selection), resulting in multiple  copies of that particular B cell. The differentiated B cell becomes  a plasma cell and can be found in the blood, secondary lym-  phoid organs (primarily spleen and lymph nodes), and some  inflammatory sites. Each plasma cell is a factory for antibody  production and is dedicated to the secretion of a single class  or subclass of antibody with one variable region and therefore  specificity against one antigenic determinant.    The immune response to antigenic challenge has classically  been divided into two phases—the primary and secondary  responses—that can be most easily demonstrated by serologic  tests that measure plasma concentrations of antibody over time  (Figure 8-18). On initial exposure to most antigens, there is a  latent period, or lag phase, during which B-cell differentiation  and proliferation occur. After approximately 5 to 7 days, IgM  antibody specific for that antigen can be detected in the circula-  tion. The lag phase is a result of the time necessary for clonal  selection, including processing and presentation of antigens,    induction of Th cells, interactions between immunocompetent  B cells and Th cells, and maturation and proliferation of the  B cells into plasma cells and memory cells.   This is the initial response, or primary immune response.  Typically, IgM will be produced first, followed by IgG against  the same antigen. The quantity of IgG produced may be about  equal to or less than the amount of IgM production. If no fur-  ther exposure to the antigen occurs, the circulating antibody  is catabolized (broken down) and measurable quantities fall.  The individual’s immune system, however, has been primed.  A second challenge by the same antigen results in the second-  ary (anamnestic) immune response, which is characterized  by the more rapid production of a larger amount of antibody  than that produced by the primary response. The rapidity of  the secondary immune response is the result of the presence of  memory cells that do not require further differentiation. IgM  may be transiently produced in the secondary response and the  quantity may be about the same as that produced in the primary  response. IgG production is increased considerably, making it  the predominant antibody class of the secondary response. It is  often present in concentrations several times larger than those  of IgM, and levels of circulating IgG specific for that antigen  may remain elevated for an extended period of time. If the anti-  genic challenge is in the form of a vaccine or occurs through  natural infection, the level of protective IgG may remain ele-  vated for decades.   The existence of a prolonged and protective secondary  immune response explains how vaccinations provide protection  against certain pathogenic microorganisms. Edward Jenner, an  English physician of the late eighteenth century, performed  the first well-documented vaccine trial.??°° Although some of  the stories about Jenner’s experiments are fanciful, it is known  that Jenner recognized that milkmaids were protected from the  deadly smallpox virus if they had previously developed cowpox,  a bovine equivalent of smallpox that causes only mild disease    FIGURE 8-18 Primary and Secondary Immune Responses. Antigen responses are dominated by two classes of immu-  noglobulins, IgM and IgG. IgM predominates on initial exposure to the antigen in the primary response, with IgG appearing  later. After the host's immune system is primed, another challenge by the same antigen induces the secondary response in    in humans. Jenner took material from a cowpox pustule on the  hand of an infected milkmaid and injected it into the arm of an  8-year-old boy. After the boy’s initial inflammatory reaction to  the injection subsided, Jenner injected the boy again, this time  with material from a smallpox pustule. Fortunately, the experi-  ment was a success because Jenner is reported to have rein-  jected smallpox virus into the boy at least 20 times without the  child becoming ill. In Jenner’s experiment, the antigens on the  cowpox virus and the smallpox virus were sufficiently similar  that the cowpox antigen functioned as an altered or attenuated  smallpox antigen. The antibodies and lymphocytes that rec-  ognized and destroyed cowpox also were able to recognize the  smallpox virus, thereby protecting the immunized child against  smallpox. In 1798, Jenner used the term vaccination (vacca =  cow) to describe his technique.    As with most aspects of immunity, a sequence of cellular inter-  actions is required to produce an effective antibody response  (Figure 8-19). The immunocompetent B cell is also an APC and  expresses surface IgM and IgD BCRs. Unlike the T-cell receptor  that can only “see” processed and presented antigen, the BCR  can react with soluble antigen. Antigen binding to the BCR  complex activates intracellular kinases, in a fashion similar to  the TCR receptor complex. In many instances, circulating anti-  gen, either on macromolecules or on the surface of a pathogen,    will have activated the complement system through the alterna-  tive or lectin pathways. Thus complement receptors on the B  cell, such as CD19 and CD21, act as co-receptors to bind anti-  gen.*! Asa result of signaling from the BCR complex and other  surface co-receptors, the antigen-bearing macromolecule inter-  nalizes, degrades in the lysosomes, and complexes with MHC  class II molecules for presentation on the cell surface, where it is  recognized by a Th? cell through the TCR and CD4. The inter-  cellular bridge created through antigen induces the Th2 cell to  up-regulate additional surface receptors and secrete cytokines.  Direct interaction between CD40 on the B-cell surface and the  CD40 ligand (CD40L, also called CD154) on the Th? cell, as well  as the interaction of B7 on the B cell and CD28 on the Th cell,  and exposure of the B cell to Th2-cell cytokines (particularly  IL-4) induce proliferation of the B cell and maturation into a  plasma cell.*? A major component of maturation is class-switch.    The immunocompetent B cell uses IgM and IgD as recep-  tors. During the clonal selection process, however, each B cell  has the option of changing the class of antibody to a secreted  form of one of the four IgG subclasses, one of the two IgA sub-  classes, or IgE, or continuing to produce IgM but changing to a  secreted form, usually a pentamer. This process is called class-  or isotype-switch. During this process the variable region of the  antibody heavy chain is conserved, and the light chain remains    FIGURE 8-19 B-Cell Clonal Selection. Immunocompetent B cells undergo proliferation and differentiation into antibody-  secreting plasma cells. Three signals are necessary. The antigen signal is provided by the B cell itself. A B cell can recognize  soluble antigen directly through the B-cell receptor and co-receptors, such as complement receptors (CD21), which usually  involve accessory molecules such as CD19 (not shown). Antigen is internalized and processed for presentation by MHC class  || molecules, which interact with the T-cell receptor (TCR) and CD4 on Th2 cells. Co-stimulatory signals are provided through  adhesion molecules, particularly CD40 and CD40L (CD154). The cytokine signal is provided by Th2 cytokines (particularly IL-4)  binding to appropriate cytokine receptors (IL-4R) on the B cell. Additional cytokines influence switch to particular classes or    FIGURE 8-20 Genetics of Class-Switch. During clonal selection, most B cells  switch from expression of surface IgM and IgD to a different class or subclass of  antibody. A first set of DNA rearrangements during the generation of clonal diver-  sity resulted in formation of the VDJ region. The class-switch process involves a  second DNA rearrangement during which the VDJ region is moved to a switch  region (orange ovals) immediately preceding the new class/subclass of antibody.  In this example, the B cell undergoes class-switch to a y1 heavy chain and secre-  tion of an IgG1 antibody. The intervening DNA between the VDJ and the selected  switch region is excised, and the DNA is repaired (DNA after second rearrange-  ment) and transcribed into a precursor ribonucleic acid (RNA). The RNA is pro-  cessed to a messenger RNA (mRNA) with information for the new heavy chain.    unchanged from that used in the BCR; therefore, the antigenic  specificity also remains unchanged.   The mechanism of class-switch involves another DNA rear-  rangement, during which the VDJ region encoding the heavy-  chain’s variable region is moved to another site on the DNA  that is adjacent to the gene for a different constant region under  the control of activation-induced cytidine deaminase (AICD)  (Figure 8-20). The DNA is cut and mended with removal of  the DNA that was between the VDJ site and the new constant  region. Specific recognition sites (switch regions) precede each  constant region gene, and the particular constant region cho-  sen for class-switch appears to be, at least partially, under the  control of specific Th2 cytokines. For instance, IL-4 and IL-13  appear to preferentially stimulate switch to IgE, and transform-  ing growth factor-beta (TGF-B) and IL-5 appear to play major  roles in class-switch to IgA.   A few antigens can bypass the need for Th cells and can  directly stimulate B-cell maturation and proliferation. These  are called T-independent antigens (Figure 8-21). They are mostly  bacterial products that are large and are likely to have repeating  antigenic determinants (multiple identical antigenic determi-  nant sites) that bind and cross-link several B-cell receptors. The  accumulated intracellular signal is adequate to induce differenti-  ation to a plasma cell but is not adequate to induce class-switch.  The CD40-CD4O0L interaction is a necessary component of the  signal that leads to class-switch. Therefore, T-independent anti-  gens usually induce a relatively pure IgM primary and secondary  immune response.   During the clonal selection process, B cells differentiate into  antibody-producing plasma cells and into a set of long-lived  memory cells. During the differentiation of B cells into plasma    FIGURE 8-21 Activation of a B Cell by a T-Cell-Independent Antigen.  Molecules containing repeating identical antigenic determinants may interact  simultaneously with several receptors on the surface of the B cell and induce the  proliferation and production of immunoglobulins, mainly IgM.    cells, the CDR portions of the antibody variable region are  prone to somatic point mutations that lead to changes in single  amino acids. Some of these changes produce better antibodies  that bind more strongly (higher affinity) to the antigen. The  presence of antigen creates a positive selective pressure toward  the developing B cells that express the higher-affinity antibody,  which results in a process called affinity maturation, in which  the quality of the circulating antibody improves over time.  Plasma cells may migrate to special regions of the spleen, lymph  nodes, and mucosal-associated lymphoid tissues that support  the plasma cell’s long-term survival and function so that an ade-  quate level of protective antibody is available in the circulation  for decades after vaccination or resolution of infection.**   The memory cells remain inactive until subsequent exposure  to the same antigen.** On reexposure, these memory cells do  not require much further differentiation and will therefore dif-  ferentiate rapidly into new plasma cells.    Activation of the cell-mediated arm of the immune response  begins with the binding of antigen to specific T-cell recep-  tors. Through a variety of intercellular collaborations that are  mediated by specific cellular receptors and cytokines, the naive  T cell proliferates and differentiates into a functional (effec-  tor) T cell. The two main effector functions of activated T  cells are (1) direct killing of foreign and/or abnormal cells and  (2) assistance and/or activation of other cells, such as macro-  phages. The first function is carried out by a subclass of T cells,  termed T-cytotoxic lymphocytes (Tc cells, or CTLs). Activation  of macrophages is performed by a special subset of Th cells.  Additional T cells develop into cells that regulate the immune  response in order to avoid inadvertently attacking self-antigens  or to avoid overactivation of the immune response. This mixed  population of cells is termed T-regulatory (Treg) cells. Finally,  T-memory cells are also produced to help induce secondary  cell-mediated immune responses.*°    During the clonal selection phase of the cell-mediated immune  response, immunocompetent T cells in the peripheral lymphoid    FIGURE 8-22 Tc-Cell Clonal Selection. The development of effector cytotoxic T (Tc) cells during clonal selection results  from three cooperative signaling events provided by antigen, co-stimulatory adhesion molecules, and cytokines. The immu-  nocompetent Tc cell “sees” antigen presented by MHC class | molecules on the surface of a virally infected or cancerous  “abnormal” cell. The antigen—MHC class | complex is recognized simultaneously by the T-cell receptor (TCR), which binds to  antigen, and CD8, which binds to the MHC class | molecule. The proximity of signaling molecules associated with the cyto-  plasmic portions of CD8 and the TCR result in intracellular signaling. A separate signal results from the interaction of several  groups of adhesion molecules (e.g., CD80 and CD28 in this example). The third signal is provided by the interaction of cytokine,  particularly IL-2 from Th1 cells, and the appropriate receptor. MHC, Major histocompatibility complex.    organs must recognize antigen that has been processed and pre-  sented by MHC class I molecules (Figure 8-22). The antigen is  usually an endogenous antigen expressed on the surface of cells  infected with a virus or cells that have become malignant. The  T cells have a functional «6 TCR complex and express the sur-  face molecule CD8, rather than CD4. The presence of the CD8  molecule confines antigen recognition to MHC class I mol-  ecules; therefore, CD8+ T cells are class I restricted. The TCR  binds directly to the antigenic peptide, whereas CD8 indepen-  dently binds to a different site on the MHC class I a-chain. This  co-recognition of the MHC-antigen complex by the TCR and  CD8 brings CD8 into proximity with the CD3 components of  the TCR complex, which initiates a series of enzymatic interac-  tions among other molecules associated with the cytoplasmic  portions of CD3 and CD4, as was described for Th-cell acti-  vation. These molecules activate a signaling pathway from the  TCR to the T-cell nucleus.   To undergo maturation, the T cell must receive independent  signals from a variety of co-stimulatory intercellular adhesion  molecules and specific cytokine receptors. If the appropriate sig-  naling pathways are activated, the cell will proliferate and differ-  entiate through multiple intermediate stages into functional Tc  cells. The co-stimulatory signals for Tc-cell maturation are virtu-  ally the same as has been described for Th-cell maturation: B7 on    the cell-presenting antigen and CD28 on the T cell, CD48 on the  antigen-presenting cell and CD2 on the T cell, and a variety of  other adhesion molecules. Development of Tc cells also requires  cytokines, especially IL-2, produced by the Th1 cell.    The result of these cellular interactions is the production of  active Tc cells with the capacity to identify antigens on the sur-  face of infected or malignant cells and then to destroy those  cells. As with B cells, some of the T cells that become activated  in response to antigen presentation will not become effectors  that destroy infected targets, but instead develop into a popula-  tion of T-memory cells. These cells have the capacity to rapidly  respond to further exposure to the same antigen.   A group of molecules has the ability to bind the variable por-  tion of the TCR $-chain outside of its normal antigen-specific  binding site, as well as the a-chain of MHC class II molecules  outside of their antigen-presentation sites (Figure 8-23). Thus  these molecules are not digested and processed by an APC to be  presented to an immune cell. This binding results in adherence  of the TCR and MHC class II molecules, independent of anti-  gen recognition, and provides an activation signal for Th-cell    FIGURE 8-23 Superantigens. The T-cell receptor (TCR) and an MHC class  ll molecule normally simultaneously interact with a processed antigen to induce  T-cell differentiation. Superantigens, such as some bacterial toxins, bind directly  to the TCR and the MHC class II molecules. Superantigens activate Th cells inde-  pendently of TCR antigen specificity. MHC, Major histocompatibility complex; V  variable; Va, variable region of the a-chain; V@, variable region of the 6-chain.    activation and proliferation. The normal antigen-specific rec-  ognition between Th cells and APCs results in activation of rela-  tively few cells: only those cells with specific TCRs against that  antigen. The type of binding described here results in activation  of large populations of T lymphocytes, regardless of antigen  specificity. Thus these molecules have been referred to as supe-  rantigens (SAGs).   SAGs induce an excessive production of cytokines, includ-  ing IL-2, IFN-y, and TNF-a. The overproduction of inflamma-  tory cytokines results in symptoms of a systemic inflammatory  reaction, including fever, low blood pressure, and, potentially,  fatal shock. Some examples of SAGs are the bacterial toxins  produced by Staphylococcus aureus and Streptococcus pyogenes  (including the superantigens that cause toxic shock syndrome  and food poisoning).°° Some viruses are also able to produce  superantigens, although the exact nature of these antigens is  unclear.   The chief function of circulating antibodies is to protect the  host from infection. Protection can be afforded by antibody in  several ways, either directly or indirectly (Figure 8-24). Directly,  antibody can cause neutralization (inactivating or blocking the  binding of an antigen to a receptor), agglutination (clumping  insoluble particles that are in suspension), or precipitation    FIGURE 8-24 Direct and Indirect Functions of Antibody. Protective activities of antibodies can be direct (through the  action of antibody alone) or indirect (requiring activation of other components of the innate immune response, usually through  the Fe region). Direct means include neutralization of viruses or bacterial toxins before they bind to receptors on the surface  of the host's cells. Indirect means include activation of the classical complement pathway through C1, resulting in formation  of the membrane attack complex (MAC), or by increased phagocytosis of bacteria opsonized with antibody and complement  components bound to appropriate surface receptors (FcR and C3bR).    (making a soluble antigen into an insoluble precipitate) of  infectious agents or their toxic products. Indirectly, antibod-  ies activate several components of innate immunity, including  complement and phagocytes.   Direct Effects. To cause infection, many pathogens must  attach to specific receptors on the host’s cells. For instance,  viruses that cause the common cold or the influenza virus  must attach to specific receptors on epithelial cells. Some  bacteria, such as Neisseria gonorrhoeae that causes gonorrhea,  must attach to specific sites on epithelial cells. Antibodies may  protect the host against infection by covering the portions  of the microorganism that it needs to bind to the host cell.  Neutralization, or prevention of attachment to the host cell,  thereby prevents infection of the host.   Protection against many viral infections can be elicited effec-  tively by vaccination with inactivated or attenuated (weakened)  viruses to induce neutralizing antibody production at the site  of typical viral entrance into the body. A good indication of the  degree of protection against viral infection is the level of circu-  lating antibodies found in the blood. The level of circulating  antibodies is referred to as an antibody titer. However, many  viruses (e.g., measles, herpes) are inaccessible to antibodies  after initial infection because they do not circulate in the blood-  stream but instead remain inside infected cells, spreading by  direct cell-to-cell contact. Neutralizing antibodies against this  type of virus are most effective in preventing the initial infec-  tion. Other viruses, such as polio and influenza, spread through  the blood, are more susceptible to the effects of circulating anti-  bodies, and can be controlled by antibodies even after the initial  infection.   The symptoms of some infectious diseases result directly  from toxins produced by infecting bacteria. For instance, the  symptoms of tetanus or diphtheria are mediated by specific  toxins. To cause disease, most toxins must bind to surface mol-  ecules on the individual’s cells. Protective antibodies can bind  to the toxins, prevent their interaction with cells, and neutral-  ize their biologic effects. Detection of the presence of an anti-  body response against a specific toxin (antibodies referred to  as antitoxins) can aid in the diagnosis of diseases. For example,  group A streptococcal bacteria produce a toxin, streptolysin  O, that destroys cells, particularly erythrocytes and leukocytes.  The infected individual produces an antibody that can neu-  tralize this toxin (antistreptolysin O) and also be detected in  laboratory tests as a useful diagnostic tool for group A strep-  tococcal infections. Antibodies that neutralize bacterial toxins  can be induced to confer immunity against bacterial pathogens  by means of immunization. To prevent harming the recipient  of immunization, bacterial toxins are chemically inactivated  to destroy their harmful properties but still retain immunoge-  nicity. These are referred to as toxoids. Examples of bacterial  pathogens for which immunization with toxoids can provide  immunologic protection include those that cause diphtheria  and tetanus.   Indirect Effects. Antibody can be protective by interacting  with or activating components of nonspecific inflammation.  Indirect effects are mediated by the Fc portion of the antibody  molecule and include opsonic activity resulting in enhanced    phagocytosis and activation of the complement system that  may lead to complement-mediated destruction of the pathogen  or increased opsonic activity through deposition of C3b.   In their role as opsonins, antibody and C3b make the patho-  gen more susceptible to phagocytosis through binding to Fc or  C3b receptors on the phagocyte’s surface. Opsonization is often  necessary for efficient bacterial clearance because many bacte-  ria have an outer capsule that deters recognition by phagocytes  unless it is coated with an antibody or complement protein.  Bacterial surface molecules are usually complex and have mul-  tiple accessible antigenic determinants, enabling them to bind  several different antibodies simultaneously. When an antigen  reacts with the Fab regions of antibody, the Fe portion of that  antibody is recognized and binds to Fc receptors on the surfaces  of inflammatory cells. Engagement of Fc receptors results in  their activation, making phagocytosis of the opsonized bacte-  rium more efficient.    The immune response that protects the entire body is produced  by the systemic immune system. A distinct set of lymphoid  tissues makes up another, partially independent, immune sys-  tem at the external surfaces of the body. This system is called  the secretory (mucosal) immune system (Figure 8-25). Most  humoral immune responses occur when antibodies or B cells  encounter antigens in the blood, but sometimes this encounter  occurs in other body fluids. Antibodies are present in bodily  secretions such as tears, sweat, saliva, mucus, and breast milk,  where they can protect the body against antigens that have not  yet penetrated the skin or mucous membranes.   Antibodies in secretions are produced by plasma cells of the  secretory (mucosal) immune system. The B cells of these two  systems follow a different pattern of migration after they leave  the bone marrow.°” B lymphocytes of the systemic immune sys-  tem travel through the spleen and most lymph nodes, whereas  those of the secretory immune system travel through a differ-  ent group of lymphoid tissues including the lacrimal and sali-  vary glands and the lymphoid tissues of the breasts, bronchi,  intestines, and genitourinary tract. Immunoglobulins that are  secreted at these sites are called secretory immunoglobulins  and act locally rather than systemically.   Local protection is necessary to combat antigens (chiefly  infectious microorganisms) that are inhaled, swallowed, or oth-  erwise come into contact with external body surfaces. Once they  have taken up residence in the external layers of the body, harm-  ful microorganisms can cause local disease or possibly penetrate  the barriers described in Chapter 7 to cause systemic disease.  Alternatively, the microorganisms may fail to cause disease in  the individual, either because the microorganisms are passed  out of the body without any ill effects or because the infection is  thwarted by the systemic immune system. In the latter case the  individual may continue to “carry” the infectious agent in the  mucosal areas, thereby enabling its spread to other individuals.  The major function of the secretory immune system is to halt  viral and bacterial invasion before local or systemic disease can  develop and to prevent a carrier state that may result in spread  of the infection to others.    FIGURE 8-25 Secretory Immune System. Lymphocytes from the mucosal-associated lymphoid tissues circulate through-  out the body in a pattern separate from other lymphocytes. For example, lymphocytes from the gut-associated lymphoid tissue  circulate through the regional lymph nodes, the thoracic duct, and the blood and return to other mucosal-associated lymphoid  tissues rather than to lymphoid tissue of the systemic immune system.    IgA is the dominant secretory immunoglobulin, although  IgM and IgG also are present in secretions.** The primary role  of IgA is to prevent the attachment and invasion of pathogens  through mucosal membranes, such as those of the gastrointes-  tinal, pulmonary, and genitourinary tracts.°? To induce protec-  tive immunity against some pathogens that enter through these  routes, local immunization seems to be preferable to inducing  only systemic immunity. For instance, two different vaccines  have been used against polio. The Sabin vaccine was admin-  istered orally as an attenuated (i.e., inactivated so as to render  relatively harmless) live virus. This route caused a transient,  limited infection and induced effective systemic immunity  and secretory immunity, preventing both the disease and the  establishment of a carrier state. The Salk vaccine, on the other  hand, consisted of killed viruses that were administered intra-  dermally. It induced adequate systemic protection but did not  generally prevent an intestinal carrier state.   Because B lymphocytes of the secretory/mucosal immune  system travel through breast-associated lymphoid tissue,  most antigens to which the mother has been exposed gastro-  intestinally (e.g., poliovirus) induce secretion of specific IgAs,  IgMs, and IgGs into the breast milk. Antibodies in the milk    may provide protection against these infectious disease agents  to the nursing newborn. Although colostral antibodies (i.e.,  found in colostrum of breast milk) provide the newborn with  passive immunity against gastrointestinal infections, they do  not provide systemic immunity because they do not cross the  newborn’s gut into the bloodstream after the first 24 hours of  life. Passive systemic immunity is provided by maternal anti-  bodies that passed across the placenta into the fetus before  birth.   The mechanisms and functions of antigen-antibody bind-  ing are the same in the secretory immune system as they are  in the systemic immune systems; that is, binding neutralizes  or opsonizes the antigen, preventing it from harming the host.  The major differences between the two systems include (1) the  order of utilization—the secretory immune response is part of  the body’s first-line defense, whereas the systemic response is  the body’s final defense; (2) the lymphocytes of each system  follow different paths of migration and pass through differ-  ent secondary lymphoid tissues; and (3) the secretory response  occurs locally and externally (in body secretions), whereas the  systemic response occurs systemically and internally (in blood  and tissues).    FIGURE 8-26 IgE Function. Soluble antigens from a parasitic infection are processed by local antigen-presenting cells  (APCs) and presented to Th2 cells (1), which respond by producing cytokines that favor class-switch to IgE production (2).  B cells bind soluble parasite antigen, and some switch to producing IgG, whereas others switch to IgE. The secreted IgE  molecules bind to IgE-specific receptors (FceR) on the mast cell surface (3). Additional soluble parasite antigen cross-links  IgE-FceR complexes on the mast cell surface (4), leading to mast cell degranulation and release of many proinflammatory  products, including eosinophil chemotactic factor of anaphylaxis (ECF-A) (5). Eosinophils have receptors for ECF-A (ECFR) and  are stimulated to increase adherence to the vessel walls and initiate diapedesis (6) and invasion of the surrounding tissue. The  eosinophil also responds by increasing the density of surface receptors for IgG (FcyR) and complement component C3b (C3bR)  (7). IgG had previously attached to the antigens on the parasite’s surface and activated the complement cascade (C’ activation)  ina failed attempt to damage the parasite. The eosinophil attaches to the parasite’s surface through Fc and C3b receptors (8).  Once bound to the parasite, the eosinophil releases its lysosomal enzymes onto the parasite, damaging its outer membrane (9).   IgE is a special class of antibody that is designed to help pro-  tect the individual from infection with large parasitic worms.  However, when IgE is produced against relatively innocuous  environmental antigens, it is also the primary cause of common  allergies (e.g., hay fever, dust allergies, bee stings). The role of  IgE in allergies is discussed in Chapter 9.   Large multicellular parasites usually invade mucosal tissues  (Figure 8-26). In response to parasitic antigens, a variety of dif-  ferent antibody classes are produced with many B cells class-  switching to IgE-secreting plasma cells under the direction of  Th2 cells primarily producing IL-4 and IL-13.*° IgG, IgM, and  IgA bind to the surface of parasites, activate complement, gener-  ate chemotactic factors for neutrophils and macrophages, and  serve as opsonins for those phagocytic cells. The influx of neu-  trophils and macrophages progressively leads to development    of a granulomatous response around the parasite. Unique to  parasitic infections, the eosinophil is a primary cell in the gran-  uloma. The influx of eosinophils results from IgE-triggered  mast cell degranulation. Mast cells in the tissues have very high  affinity Fc receptors for IgE, which rapidly bind IgE to the mast  cell surface.*! Soluble macromolecules with multiple antigenic  determinants are released from the parasite, react with the IgE-  Fc receptors, and initiate mast cell degranulation (see Chapter  7). Eosinophil chemotactic factor of anaphylaxis (ECF-A) is  released from mast cell granules and attracts eosinophils to the  site of infection, as well as up-regulates surface receptors for IgG  and complement component C3b. Eosinophil attachment to the  parasite results in degranulation, releasing a variety of very toxic  proteins that are at unusually high concentrations in eosino-  philic granules, major basic protein (binds to heparin sulfate pro-  teoglycans), eosinophil cationic protein (a member of the RNase    A family), and others. These can cause extensive damage to the  parasite if an adequate number of eosinophils are involved.   T-Cytotoxic Lymphocytes. T-cytotoxic lymphocytes (Tc cells)  are responsible for the cell-mediated destruction of such targets  as tumor cells or cells infected with viruses. To perform this  function, the Tc cell must directly adhere to the target cell  through antigen presentation in association with MHC class I  molecules and appropriate adhesion molecules (Figure 8-27).    Most Tc-cell killing requires the af TCR complex and CD8 and  is therefore class I restricted. Because of the cellular distribution  of MHC class I molecules, Tc cells can recognize antigen on the  surface of almost any type of cell that has been infected by a  virus or has become cancerous.   After attachment to a target cell, killing can occur by at least  two different mechanisms that induce apoptosis: through the  actions of perforin and granzyme or by direct receptor interac-  tions. Perforins and granzymes are contained in the Tc-cell lyso-  somal granules, which are released onto the surface of the target  cell. Perforin acts in a fashion similar to C9 of the complement    FIGURE 8-27 Cell Killing Mechanisms. Several cells have the capacity to kill abnormal (e.g., virally infected, cancerous)    arget cells. Cytotoxic T (Tc) cells recognized endogenous antigen presented by MHC class | molecules (ce// on upper left). The  intercellular interaction is enhanced through a variety of co-stimulatory adhesion molecules (not shown). The Tc cell mobilizes  multiple killing mechanisms that induce apoptosis of the target cell, including the secretion of perforin that creates pores for  he entrance of granzymes into the target cell and stimulation of Fas molecules on the target cell surface by Fas ligand (FasL)  on the Tc cell. Natural killer (NK) cells (ce//s on right) use the same mechanisms to kill target cells through activation receptors  hat recognize “abnormal surface changes.” NK cells specifically kill targets that have down-regulated expression of surface   HC class | molecules. Targets expressing MHC class | molecules inactivate NK cells through a variety of inactivation recep-  ors (cell on upper right). Several cells, including macrophages and NK cells, can kill by antibody-dependent cellular cytotoxicity  ADCC). IgG antibody binds to foreign antigen on the target cell. Cells involved in ADCC (ce// on lower left) bind IgG through Fe  eceptors (FcRs) and initiate killing. The insert is a scanning electron microscopic view of Tc cells (L) attacking a much larger  umor cell (Tu). MHC, Major histocompatibility complex. (Insert from Abbas A, Lichtman A: Cellular and molecular immunology,    cascade and penetrates, polymerizes, and forms pores in the tar-  get cell’s plasma membrane. The granzymes enter the target cell  through the perforin-lined pores and activate cellular enzymes  (caspases) that are involved in apoptosis, resulting in death of  the target. Additionally, target cell apoptosis can be induced  directly through the stimulation of specific receptors on the cell  surface. For instance, Tc cells express a surface molecule called  Fas ligand, which is very similar to TNF-a and reacts with a pro-  tein called Fas (CD95) on the target cell surface. Activation of  Fas signals the target cell to undergo apoptosis.   Other Cells That Kill Abnormal Cells. A variety of other cells  kill targets in a fashion similar to Tc lymphocytes. Prominent  among these cells are natural killer (NK) cells (see Chapter 7). In  many ways, NK cells complement the effects of Tc cells. In some  instances, a virally infected or cancerous cell will “protect” itself  by down-regulating MHC class I molecule expression. Without  surface MHC class I molecules, a cell becomes resistant to Tc-cell  recognition and killing. NK cells are a special group of lymphoid  cells that are similar to T cells but do not undergo maturation  in the thymus and lack antigen-specific receptors. Instead, they  express Fc receptors (CD16) for IgG and a variety of NK-specific  cell surface receptors (similar to pattern recognition receptors,  see Chapter 7) that identify protein changes on the surface of  cells that have been infected or are in other ways abnormal.”  After attachment, the NK cell kills its target in a manner similar  to that of Tc cells. However, NK cells also express another set  of receptors, inhibitory receptors, which bind to MHC class I  molecules.** If the target cell continues to express MHC class I,  the NK cell will bind to the class I molecule, and an inhibitory    signal will result. Thus NK cells do not inadvertently kill MHC  class I—bearing cells. If these cells are infected or malignant, yet  still express MHC class I, they remain sensitive to Tc-cell killing.  Thus Tc cells kill abnormal cells that continue to express MHC  class I, whereas NK cells kill abnormal cells that have suppressed  MHC class I expression.   NK cells, as well as some macrophages, can specifically kill  targets through use of antibody. These cells express Fc recep-  tors on their surface. If a pathogen or abnormal cell expresses  a foreign antigen that elicits IgG antibody, which binds to the  antigen, the NK cell can attach to the IgG through Fc receptors  and activate its normal killing mechanisms. This is referred to as  antibody-dependent cell-mediated cytotoxicity (ADCC) (see  Figure 8-27).   Another population of NK-like cells has been identified,  NK-T cells.“4 NK-T cells are produced in the thymus and more  closely resemble Tc cells. However, they express TCRs that have  very limited variability and recognize antigens presented by CD1.    Under conditions of chronic inflammation, T cells produce  cytokines that activate macrophages (see Chapter 7). Mac-  rophage activation is usually accomplished by Th1 cells that  recognize antigen and produce cytokines (particularly IFN-y)  that, in cooperation with microbial products (e.g., LPS), stimu-  late the macrophage to become a more efficient phagocyte and  increase production of proteolytic enzymes and other antimi-  crobial substances (Figure 8-28). IFN-y-induced macrophage  activation is also achieved by NK cells and CD8+ T-cytotoxic    FIGURE 8-28 Activation of a Macrophage by a T Cell. A population of T cells that helps immune and inflammatory  responses (helper T cells or Th1 cells) produces cytokines that activate macrophages. Optimal macrophage activation also  requires close contact among the cells, which is mediated by a variety of adhesion molecules expressed on the surface of each  cell (CD40L and CD40 shown here). CD40L, CD40 ligand; /FN-y, interferon-gamma; /FN-yA, receptor for interferon gamma.  (Micrograph in A courtesy Dr. Noel Weidner, Department of Pathology, University of California, San Diego. B from Fawcett  DW: Bloom and Fawcett: a textbook of histology, ed 12, New York, 1994, Chapman & Hall. With kind permission of Springer    cells. Additional signals (e.g., the CXC chemokine macrophage  migration inhibitory factor) retain macrophages at inflamma-  tory sites and increase intercellular adhesion between the Th1l  cell (CD40L) and the macrophage (CD40).   One form of peripheral tolerance to self-antigens occurs in Treg  cells, a subpopulation of CD4+ T cells (see Figure 8-17).° As  with Th cells, Treg cells are activated by antigen presented in the  context of class IT MHC and differentiation under the control  of specific cytokines, primarily TGF-B and IL-2, during which  they express CD25 (the a-chain of the IL-2 receptor) and are  frequently designated CD4+, CD25+ Treg cells.*° The role of  Treg cells is to control or limit the immune response to protect  the host’s own tissues against autoimmune reactions. Treg cells  produce very high levels of TGF-B and IL-10, an immunosup-  pressive cytokine, which generally decrease Thl and Th2 activ-  ity and suppress antigen recognition and Th-cell proliferation.  The role of Treg cells and other regulatory cells (e.g., CD25  cells, CD8+ regulatory cells, and Breg cells) is under intense  investigation to determine the degree of their heterogeneity of  derivation, function, and specificity.    The normal human infant is immunologically immature at birth.  Although cell-mediated immunologic capabilities begin develop-  ing early in gestation and probably are completely functional at  birth, antibody production is clearly deficient. In the last trimester,  the fetus appears capable of producing a primary immune response  (almost entirely IgM) to antigenic challenge in utero but is unable  to produce a significant IgG response. Although some IgA can be  detected, the capacity to produce IgA is underdeveloped.   To protect the child against infectious agents both in utero  and during the first few postnatal months, a system of active  transport facilitates the passage of maternal antibodies into the  fetal circulation (Figure 8-29). In the placenta, maternal and  fetal blood is separated by a layer of specialized cells termed tro-  phoblasts. Immunoglobulins are too large to diffuse across this  cellular layer so the trophoblastic cells actively transport immu-  noglobulins from the maternal to the fetal circulation. Active  transport of maternal IgG is mediated by surface receptors that  are specific for the Fc portion of free IgG but not for IgM, IgE,  or IgA. Active transport sometimes results in higher antibody  titers in umbilical cord blood than in maternal blood. (Active  transport mechanisms are discussed in Chapter 1.)   At birth, total IgG levels in the umbilical cord are near adult  levels (Figure 8-30). When the source of maternal antibodies is  severed at birth, antibody titers in the newborn begin to drop  as maternal antibody is catabolized. Thus antibody titers drop  rapidly as the neonate’s production of IgG is beginning to rise.  The rate of catabolism is usually more rapid than the rate of pro-  duction so that the total immunoglobulin levels reach a mini-  mum at 5 to 6 months in the normal child, occasionally causing  transient hypogammaglobulinemia (insufficient quantities of  circulating immunoglobulins). Many normal infants experience  recurrent mild respiratory tract infections at this age.    FIGURE 8-29 Transport of IgG Across the Syncytiotrophoblast. The human  placenta is covered with a specialized multinucleated cell, the syncytiotrophoblast.  Transport of maternal IgG across the syncytiotrophoblast and into the fetal circula-  tion is an active process. Maternal IgG binds to Fc receptors on the surface of the  syncytiotrophoblast and is internalized by the process of endocytosis. Receptors  on the syncytiotrophoblast are specific for the Fe portion of IgG and do not bind  other classes of immunoglobulins. Interaction of IgG with Fc receptors protects the  antibody from lysosomal digestion during transport of the vacuole across the cell  (i.e., transcytosis). On the fetal side of the syncytiotrophoblast, IgG is released by  exocytosis (see Chapter 1).    FIGURE 8-30 Antibody Levels in Umbilical Cord Blood and in Neonatal  Circulation. Early in gestation maternal IgG begins crossing the placenta and  enters the fetal circulation as shown in Figure 8-29. At birth, the fetal circulation  may contain nearly adult levels of IgG, which is almost exclusively from the mater-  nal source. The fetal immune system has the capacity to produce IgM and small  amounts of IgA before birth (not shown). After delivery, maternal IgG is rapidly  catabolized and neonatal IgG production increases.    Immune function decreases in old age as a result of changes  in both lymphocyte function and relative lymphocyte pop-  ulations. Individuals older than 60 years of age generally  exhibit decreased T-cell activity as demonstrated by labora-  tory assays of T-cell function, as well as in vivo reductions in  cell-mediated responses to infections. The thymus, where T  cells begin their development, reaches its maximum size at    sexual maturity and then begins involuting until thymic size  is only 15% of its maximum by middle age. Thymic capac-  ity to mediate T-cell differentiation decreases with this atro-  phy.’” Although the total number of circulating T cells does  not decrease with age, there is a shift in the populations of  T-cell subtypes.**    B-cell function is also altered with age as shown by decreases  in specific antibody production in response to antigenic chal-  lenge, with concomitant increases in circulating immune com-  plexes and in circulating autoantibodies (antibodies against  self-antigens). A decrease in the number of circulating memory  B cells is also observed.   1. Compared with the innate inflammatory response, the adap-  tive immune response is slower, is specific (rather than non-  specific or general), and has “memory” that makes it much  longer lived.   2. The adaptive immune response is most often initiated by  cells of the innate system. These cells process and present  portions of invading pathogens (i.e., antigens) to lympho-  cytes in peripheral lymphoid tissue.   3. The adaptive immune response is mediated by two differ-  ent types of lymphocytes—B lymphocytes and T lympho-  cytes. Each has distinct functions. B cells are responsible  for humoral immunity that is mediated by circulating anti-  bodies, whereas T cells are responsible for cell-mediated  immunity, in which they kill targets directly or stimulate the  activity of other leukocytes.   4. Adaptive immunity can be either active or passive depending  on whether immune response components originated in the  host or came from a donor.   1. Antigens are the molecules that can react with components of  the adaptive immune system, including antibodies and lym-  phocyte surface receptors. Immunogens are antigens that can  initiate the adaptive immune response. To be immunogenic,  an antigen must be of the correct type, size, and complexity and  be present in sufficient quantities. Haptens are small-molecu-  lar-weight antigens that are not themselves immunogenic.   2. Both B and T lymphocytes bind antigen through cognate  receptor complexes on their surfaces. These receptor com-  plexes (i-e., the BCR and TCR complexes, respectively) work  in conjunction with accessory proteins to produce lympho-  cyte activation.   3. The antigen-binding molecule of the BCR is antibody.  Antibodies are composed of four polypeptide chains—two  identical heavy chains and two identical light chains—held  together by disulfide bonds. Each heavy chain has a variable  region and a large constant region. Each light chain has a  variable region and a short constant region. The class of anti-  body is determined by which constant regions make up their  heavy chains, giving each class a slightly different molecular  structure. The classes include IgG (the most prevalent), IgA  (mostly in secretions), IgE (the most rare), IgD, and IgM (the  first and largest immunoglobulin produced). The parts of  antibody that bind antigen are called the Fab, and the part  that reacts with cells and molecules of the innate system is    called the Fc. Antigen binds to hypervariable regions (com-  plementary-determining regions, or CDRs) of both the  heavy and the light chains.   4. For most antigens to elicit an immune response, they must  be presented to lymphocytes by molecules on the surface of  antigen-presenting cells. Endogenous protein antigens are  presented by class I molecules of MHC. Exogenous protein  antigens are presented by class II MHC molecules. Lipid  antigens are presented by CD1.   5. The MHC is a cluster of genes found on human chromosome  6. The products of these genes are also called HLA antigens.  The MHC genes are highly polymorphic, having many dif-  ferent possible alleles. An individual will carry only two  alleles at each locus, one from each parent. The particular  combination of alleles a given individual carries defines his  or her MHC haplotype.   6. For an immune response to develop, a variety of cells must  interact through surface adhesion molecules.   7. During their interactions, cells must communicate with each  other through soluble cytokines. In addition to their roles  in the innate immune response, cytokines have multiple  functions in the adaptive immune response including both  positive and negative regulation of B-cell and T-cell matura-  tion. In general, it is the precise combination of cytokines  influencing a given cell that ultimately determines that cell’s  response.   1. The generation of clonal diversity occurs in the primary lym-  phoid organs (thymus for T cells, bone marrow for B cells) in  the fetus.   2. An individual’s population of T cells and B cells has the col-  lective ability to respond to virtually any antigen. This ability  results from genetic rearrangement of various genes to form  the variable regions for the TCR and BCR. Rearrangement  of V and J genes results in the variable regions of the TCR  a-chain and the BCR light chain, and rearrangement of V, D,  and J genes result in the variable regions of the TCR 6-chain  and the BCR heavy chain.   3. Differentiation of B cells and T cells in the primary lymphoid  organs results in expression of several characteristic surface  markers, such as CD4 on helper T cells, CD8 on cytotoxic  T cells, and CD21 and CD40 on B cells.   4. During generation of clonal diversity, B cells and T cells that  produce receptors against self-antigens are eliminated by a  process of central tolerance.    Cells leaving the primary lymphoid organs are immunocom-  petent (capable of reacting to antigen) and enter the circula-  tion and secondary lymphoid organs.    Clonal selection is the process by which antigen selects lym-  phocytes with complementary TCRs or BCRs and induces  an immune response with the production of specific anti-  body or cytotoxic T cells, or both.    and presented by an APC in the context of the appropri-  ate molecule, either MHC class I, MHC class II, or CD1  molecules.    Precursor Th cells interact with APCs through the TCR-CD4  complex, a variety of adhesion molecules, and cytokines,  especially IL-1, and develop into either Thl or Th2 subsets.  Th1 cells are responsible for helping to activate macrophages  and cytotoxic T cells, whereas Th2 cells are responsible for  helping to activate B cells.    . Another set of Th cells, Th17 cells, provides help in develop-    ing inflammation, particularly attraction of neutrophils and  macrophages and induction of chemokine and antimicrobial  protein production by epithelial cells.    by the BCR, processing of the antigen, and presentation by  MHC class II antigens to Th2 cells. Interactions between the  B cells and Th2 cells through adhesion molecules (e.g., CD40  and CD40L) are also required. Depending on the particu-  lar combination of cytokines produced by the Th2 cell, the  B cells can undergo class-switch from making IgM antibody  to making and secreting either IgA, IgE, or IgG.    primary and secondary. These differ in the relative amounts  of IgG produced—the secondary response having a much  higher proportion of IgG relative to IgM. The two responses  also differ in the speed with which each occurs after antigen  challenge—the secondary response being much more rapid  than the primary response because of the presence of mem-  ory cells in the secondary phase.    antigen to proliferate and differentiate either into plasma cells  that function as factories for the synthesis of large amounts  of antibody that is specific for the recognized antigen or into  memory B cells.    CD8 of antigen presented by MHC class I. Appropriate inter-  cellular adhesion molecules and cytokines, such as IL-2 from  Thl cells, are also necessary for efficient differentiation. T  cells become CTLs or memory T cells.    that can bind to the TCR of the Th cell outside the normal  antigen-binding site and to class II MHC on the APCs,  resulting in activation of a large number of Th cells and  excessive production of proinflammatory cytokines that may    cause shock and death of the patient. Examples of these anti-  gens, called superantigens, include the bacterial toxins that  can cause toxic shock syndrome and food poisoning.    The antibodies that are produced by B cells affect antigens  by several different mechanisms that can be categorized as  either direct or indirect. Direct mechanisms are mediated  by the antigen-binding portions of antibodies (the Fab por-  tions containing the variable regions). This binding results  in neutralization of the biologic activity of antigens and pos-  sibly removal of the antigen by agglutination or precipita-  tion. Indirect mechanisms depend on both the Fab and the  non-antigen-binding portion of antibodies (the Fc portions  containing the constant regions), which interact with com-  ponents of innate immunity.    out the body, whereas antibodies of the secretory (mucosal)  immune system—primarily immunoglobulins of the IgA  class—are associated with bodily secretions and function to  prevent pathogenic infection on epithelial surfaces.    . Cytotoxic T cells (Tc cells) adhere directly to antigen pre-    sented by MHC class I on target cells (virus-infected cells or  cancer cells) through the TCR, CD8, and a variety of adhe-  sion proteins. This contact results in killing of the target by  apoptosis through the release of perforin and granzymes  and/or direct stimulation of apoptotic receptors on the target  (e.g., Fas).    . NK cells kill targets in a fashion similar to that of Tc cells.    However, NK cells recognize target cells that do not express  MHC class I.    . With infections that are resistant to cells of innate immunity,    some Th1 cells produce cytokines that activate macrophages  to become more efficient phagocytes.    The human neonate has a poorly developed immune  response, particularly in the production of IgG. The fetus and  neonate are protected in utero and during the first few post-  natal months by maternal antibody that was actively trans-  ported across the placenta.    until they disappear altogether by about 10 months of age.  The neonate begins producing IgG at birth, and the child’s  antibodies reach protective levels after about 6 months of age.    T-cell activity is deficient in older adults, and a shift in the  balance of T-cell subsets is observed. These changes may  result in increased susceptibility to infection.    although older adults tend to have increased levels of circulat-  ing autoantibodies.    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As part of your Pageburst Digital Book, you can access the following Integrated Resources:  Animations    http://evolve.elsevier.com/McCance/  * Review Questions and Answers  * Online Course: Module 6    Hypersensitivity: Allergy, Autoimmunity,  and Alloimmunity, 262  Mechanisms of Hypersensitivity, 263  Antigenic Targets of Hypersensitivity Reactions, 270  Autoimmune and Alloimmune Diseases, 277    The immune system is a finely tuned network that protects the  host against foreign antigens, particularly infectious agents.  Sometimes this network breaks down, causing the immune sys-  tem to react inappropriately. Inappropriate immune responses  may be (1) exaggerated against environmental antigens  (allergy); (2) misdirected against the host’s own cells (autoim-  munity); (3) directed against beneficial foreign tissues, such as  transfusions or transplants (alloimmunity); or (4) insufficient  to protect the host (immune deficiency). All of these can be seri-  ous or life threatening. Exaggerated immune responses (allergy)  are the most common, but usually the least life threatening.    HYPERSENSITIVITY: ALLERGY,  AUTOIMMUNITY, AND ALLOIMMUNITY  Hypersensitivity is an altered immunologic response to an    antigen that results in disease or damage to the host. Hyper-  sensitivity reactions can be classified in two ways: by the source    Deficiencies in Immunity, 281  Initial Clinical Presentation, 281  Primary Immune Deficiencies, 281  Secondary Immune Deficiencies, 289  Evaluation and Care of Those with Immune Deficiency, 292  Replacement Therapies for Immune Deficiencies, 293    of the antigen that the immune system is attacking (allergy,  autoimmunity, alloimmunity; Table 9-1) and by the mecha-  nism that causes disease (types I, I, III, and IV; see Table 9-3).  The term allergy originally denoted both facets of the immune  response: immunity, which is beneficial, and hypersensitivity,  which is harmful. Allergy has now come to mean the deleteri-  ous effects of hypersensitivity to environmental antigens, and  immunity means the protective responses to antigens expressed  by disease-causing agents.   Autoimmunity is a disturbance in the immunologic toler-  ance of self-antigens. The immune system normally does not  strongly recognize the individual’s own antigens. Healthy indi-  viduals of all ages, but particularly older adults, may produce  low quantities of antibodies against their own antigens (auto-  antibodies), without development of overt autoimmune disease.  Therefore, the presence of low quantities of autoantibodies does  not necessarily indicate a disease state. Autoimmune diseases  occur when the immune system reacts against self-antigens to    *The frequency of each reaction is indicated in a range from rare  to very common . An example of each reaction is given.    such a degree that the person’s own tissues are damaged by  autoantibodies or autoreactive T cells. Many clinical disorders  are associated with autoimmunity and are collectively referred  to as autoimmune diseases (Table 9-2).   Alloimmunity (also termed isoimmunity) occurs when the  immune system of one individual produces an immunologic  reaction against tissues of another individual. Alloimmunity  can be observed during immunologic reactions against transfu-  sions, transplanted tissue, or the fetus during pregnancy.   The mechanism that initiates the onset of hypersensitivity,  whether it consists of allergy, autoimmunity, or alloimmu-  nity, is not completely understood. It is generally accepted that  genetic, infectious, and possibly environmental factors contrib-  ute to hypersensitivity. Most diseases caused by hypersensitivity  develop because of the interactions of at least three variables:  (1) an original “insult,” which alters immunologic homeostasis  (a steady state of tolerance to self-antigens or lack of immune  reaction against environmental antigens); (2) the individual’s  genetic makeup, which determines the degree of the resultant  immune response from the effects of the insult; and (3) an  immunologic process that causes the symptoms of the disease.    Diseases caused by hypersensitivity reactions can be character-  ized also by the particular immune mechanism that results in  the disease (see Table 9-1). These mechanisms are apparent  in most hypersensitivity reactions and have been divided into  four distinct types: type I (immunoglobulin E [IgE]—mediated)  hypersensitivity reactions, type II (tissue-specific) hyper-  sensitivity reactions, type III (immune complex—mediated)  hypersensitivity reactions, and type IV (cell-mediated) hyper-  sensitivity reactions (Table 9-3).! This classification is artificial  and seldom is a particular disease associated with only a single  mechanism. The four mechanisms are interrelated, and in most  hypersensitivity reactions, several mechanisms can be at work  simultaneously or sequentially. Some of the mechanisms are  secondary to the disease and not directly involved in the patho-  logic process, whereas others are the primary cause of tissue  destruction.   Hypersensitivity reactions require sensitization against a par-  ticular antigen that results in primary and secondary immune    responses. An individual is sensitized when an adequate amount  of antibodies or T cells is available to cause a noticeable reaction  on reexposure to the antigen. Some individuals become sensi-  tized quite rapidly (after an apparent single exposure to the  antigen), whereas others require multiple exposures that may  occur over years. After sensitization has been achieved, hyper-  sensitivity reactions can be immediate or delayed, depending  on the time between reexposure to the antigen and the onset  of clinical symptoms. Reactions that occur within minutes to  a few hours are termed immediate hypersensitivity reactions.  Delayed hypersensitivity reactions may take several hours to  appear and are at maximum severity days after reexposure to  the antigen.   The most rapid and severe immediate hypersensitivity  reaction is anaphylaxis. Anaphylaxis occurs within minutes  of reexposure to the antigen and can be either systemic (gen-  eralized) or cutaneous (localized). Symptoms of systemic  anaphylaxis include itching, erythema, headaches, vomiting,  abdominal cramps, diarrhea, and breathing difficulties. In  severe cases, contraction of bronchial smooth muscle, laryngeal  edema, and vascular collapse may result in respiratory distress,  decreased blood pressure, shock, and death. Examples of sys-  temic anaphylaxis are allergic reactions to bee stings, peanuts,  and fish. Cutaneous anaphylaxis causes the less severe symptom  of local inflammation.    Type I reactions are mediated by antigen-specific IgE and the  products of tissue mast cells* (Figure 9-1). Most common aller-  gies (e.g., pollen allergies) are type I reactions. In addition, most  type I reactions occur against environmental antigens and are  therefore allergic. Because of this strong association, many  healthcare professionals use the term allergy to indicate only  IgE-mediated reactions. However, IgE can contribute to a few  autoimmune and alloimmune diseases, and many common  allergies (e.g., poison ivy) are not mediated by IgE.   In some individuals, exposure to an environmental antigen  causes primarily IgE production. Repeated exposure to the anti-  gen usually is required to elicit enough IgE so that the person  becomes “sensitized.” IgE has a relatively short life span in the  blood because it rapidly binds to very-high-affinity Fc receptors    Endocrine System  Hyperthyroidism (Graves disease)  Autoimmune thyroiditis  Primary myxedema  Insulin-dependent diabetes  Addison disease   Mixed connective tissue disease  Polyarteritis nodosa (necrotizing vasculitis)  Scleroderma (progressive systemic sclerosis)  Felty syndrome   Surface antigens on steroid-producing cells; microsomes of adrenal cortex  Interstitial cells; corpus luteum   Surface antigens on chief cells (epithelial cells of gland)  Prolactin-producing cells; growth hormone—producing cells   Cardiac tissue (subsarcolemmal membrane); cross reaction with group A  streptococcal antigen    Antigens of lacrimal gland, salivary gland, thyroid, and nuclei of cells;  immunoglobulin G (IgG)  Antigens of the iris, ciliary body, and choroid   Numerous antigens in nuclei, organelles, and extracellular matrix  Ribonucleoprotein and numerous other nucleoproteins    CLASS OF PRINCIPAL  RATE OF ANTIBODY EFFECTORCELLS COMPLEMENT EXAMPLES  NAME DEVELOPMENT INVOLVED INVOLVED PARTICIPATION OF DISORDERS    on the plasma membranes of mast cells (see Figure 9-1). The  subclass IgG4 also has specific receptors on the mast cell and  may contribute to the type I mechanism. Antibody that binds  to mast cells is termed cytotropic antibody (able to bind to  cell surfaces) or reagin (skin-sensitizing antibody). Unlike Fc  receptors on phagocytes, which bind IgG that has reacted with  antigen, the Fc receptors on mast cells bind with IgE that has  not previously interacted with antigen.   If further exposure of a sensitized individual to the antigen  occurs, one molecule of antigen may bind simultaneously to  two molecules of IgE-Fc receptor complexes on the mast cell’s  surface (cross-link) resulting in activation of intracellular sig-  naling pathways and mast cell degranulation (see Figure 9-1,  B, and Chapter 7). The antigen that triggers cross-linking must  have at least two antigenic determinants on the same mole-  cule. Sometimes an IgE-mediated response is beneficial to the  host, as is the case of some immune reactions against parasites.  (This mechanism is described in Chapter 8 and illustrated in  Figure 8-26.)   The products of mast cell degranulation can modulate  almost all aspects of an acute inflammatory response. (The  effects of biochemical mediators released by mast cells are  illustrated in Figure 7-11). The most potent mediator is hista-  mine, which affects several key target cells. Acting through the  HI receptors, histamine contracts bronchial smooth muscles,  causing bronchial constriction; increases vascular permeability,  causing edema; and causes vasodilation, increasing blood flow  into the affected area (see Figures 7-3 and 7-12). The interac-  tion of histamine with H2 receptors results in increased gastric    acid secretion and a decrease of histamine released from mast  cells and basophils. The action of histamine through H2 recep-  tors suggests an important negative-feedback mechanism that  stops degranulation. That is, the released histamine inhibits  release of additional histamine by interacting with H2 recep-  tors on the mast cells. Histamine also may affect control of the  immune response through H2 receptors on most cells of the  immune system. Another important activity of histamine is  enhancement of the chemotactic activity of other factors, such  as eosinophil chemotactic factor of anaphylaxis (ECF-A), which  attracts eosinophils into sites of allergic inflammatory reactions  and prevents them from migrating out of the inflammatory  site. (The role of the eosinophil in inflammation is discussed  in Chapter 7.)   Type II hypersensitivity reactions are generally characterized by  a specific cell or tissue being the target of an immune response.  In addition to major histocompatibility locus antigens (HLAs;  discussed in Chapter 8), most cells have other antigens on their  surfaces. Some of these other antigens are called tissue-specific  antigens because they are expressed on the plasma membranes  of only certain cells in specific tissues. Platelets, for example,  have groups of antigens that are found on no other cells of the  body. The symptoms of many type II diseases are determined by  which tissue or organ expresses the particular antigen. Environ-  mental antigens (e.g., drugs or their metabolites) may bind to  the plasma membranes of specific cells (especially erythrocytes  and platelets) and function as targets of type II reactions.    FIGURE 9-1 Mechanism of Type | lgE—Mediated Reactions. A, Th2 cells are activated by antigen-presenting dendritic  cells to produce cytokines, including IL-3, IL-4, IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF). IL-3,    IL-5, and GM-CSF attract and promote the survival of eosinophi  IgE-producing plasma cells. The IgE coats the surface of the m  cell's plasma membrane (sensitization). Further exposure to the  signals from the cytoplasmic portion of the IgE Fc receptors. These signals initiate two parallel and interdependent processes:  mast cell degranulation and discharge of preformed mediators  and production of newly formed mediators such as arachidonic metabolites (leukotrienes, prostaglandins). Many local type |  hypersensitivity reactions have two well-defined phases. The initial phase is characterized by vasodilation, vascular leakage,  and, depending on the location, smooth muscle spasm or glandular secretions. These changes usually become evident within  5 to 30 minutes after exposure to the antigen. The late phase occurs 2 to 8 hours later without additional exposure to the  antigen. The late phase has more intense infiltration of tissues with eosinophils, neutrophils, basophils, monocytes, and Th    ls. Other cytokines (e.g., IL-4) induce B cells to class-switch to  ast cell by binding with IgE-specific Fc receptors on the mas  same allergen cross-links the surface-bound IgE and activates    cells and tissue destruction in the form of mucosal epithelial cell damage.    The five general mechanisms by which type II hypersen-  sitivity reactions can affect cells are shown in Figure 9-2. All  of these mechanisms begin with antibody binding to tissue-  specific antigens or antigens that have attached to particular  tissues. First, the cell can be destroyed by antibody (IgG or  IgM) and activation of the complement cascade through the  classical pathway. Formation of the membrane attack complex  (C5-9) damages the membrane and may result in lysis of the    cell (see Figure 9-2, A). For example, erythrocytes are destroyed  by complement-mediated lysis in individuals with autoimmune  hemolytic anemia (see Chapter 28) or as a result of an alloim-  mune reaction to ABO-mismatched transfused blood cells.  Second, antibody may cause cell destruction through phago-  cytosis by macrophages. IgG and also C3b of the complement  system are opsonins that bind to receptors on the macrophage  (see Figure 9-2, B). Phagocytosis of the target cell follows.    FIGURE 9-1, cont'd B, Activation of mast cells leading to degranulation of preformed mediators (primary mediators) and  synthesis of newly formed (de novo) mediators (secondary mediators). ECF, Eosinophilic chemotactic factor; NCF neutrophil    (Phagocytosis is illustrated in Figures 7-15 and 7-16.) For  example, antibodies against platelet-specific antigens or against  red blood cell antigens of the Rh system coat those cells at low  density, resulting in their preferential removal by phagocytosis  in the spleen, rather than by complement-mediated lysis.  Third, antibody and complement may attract neutrophils.  Either antigen expressed normally on the vessel walls or soluble  antigen in the circulation (e.g., released from cells within the  body or from infectious agents or by way of drugs or medica-  tions) that has been deposited on the surface of endothelial cells  may bind antibody (see Figure 9-2, C). The antibody initiates  the complement cascade, resulting in the release of C3a and  C5a, which are chemotactic for neutrophils, and deposition of  complement component C3b. Neutrophils bind to the tissues  through receptors for the Fc portion of antibody (Fc recep-  tor) or for C3b and attempt to phagocytose the tissue. Because  the tissue is large, phagocytosis cannot be completed; even so,  neutrophils release their granules onto the healthy tissue. The  components of neutrophil granules, as well as the several toxic  oxygen products produced by these cells, will damage the tissue.  The fourth mechanism is antibody-dependent cell-  mediated cytotoxicity (ADCC) (see Figure 9-2, D). This mech-  anism involves a subpopulation of cytotoxic cells that are not    antigen specific (natural killer [NK] cells). Antibody on the  target cell is recognized by Fc receptors on the NK cells, which  release toxic substances that destroy the target cell.   The fifth mechanism does not destroy the target cell, but  rather causes it to malfunction. In this mechanism of type II  injury, the antibody is usually directed against antigenic deter-  minants associated with specific cell surface receptors, and the  symptoms of the disease are a result of a direct effect of anti-  body binding alone (see Figure 9-2, E). The antibody reacts  with the receptors on the target cell surface and modulates the  function of the receptor by preventing interactions with their  normal ligands, replacing the ligand and inappropriately stimu-  lating the receptor, or destroying the receptor. For example, in  the hyperthyroidism (excessive thyroid activity) of Graves dis-  ease, autoantibody binds to and activates receptors for thyroid-  stimulating hormone (TSH) (a pituitary hormone that controls  the production of the hormone thyroxine by the thyroid). In  this way the antibody stimulates the thyroid cells to produce  thyroxine.° Under normal conditions, the increasing levels of  thyroxine in the blood would signal the pituitary to decrease  TSH production, which would result in less stimulation of the  TSH receptor in the thyroid and a concomitant decrease in  thyroxine production. Because the level of anti-TSH receptor    FIGURE 9-2 Mechanisms of Type II, Tissue-Specific, Reactions. Antigens on the target cell bind with antibody and  are destroyed or prevented from functioning by A, complement-mediated lysis (an erythrocyte target is illustrated here);  B, clearance (phagocytosis) by macrophages in the tissue; C, neutrophil-mediated immune destruction; D, antibody-dependent  cell-mediated cytotoxicity (ADCC) (apoptosis of target cells is induced by granzymes and perforin produced by natural killer  [NK] cells and interactions of Fas ligand [FasL] on the surface of NK cells with Fas on the surface of target cells); or E, modula-  tion or blocking the normal function of receptors by antireceptor antibody. This example of mechanism E depicts myasthenia  gravis in which acetylcholine receptor antibodies block acetylcholine from attaching to its receptors on the motor end plates  of skeletal muscle, thereby impairing neuromuscular transmission and causing muscle weakness. C7, Complement component  C1; C3b, complement fragment produced from C3, which acts as an opsonin; C5a, complement fragment produced from C5,  which acts as a chemotactic factor for neutrophils; Fey receptor, cellular receptor for the Fc portion of IgG; FcR, Fc receptor.    antibody is not controlled by the pituitary, increasing amounts  of thyroxine in the blood have no effect on antibody levels, and  thyroxine production continues to increase despite decreasing  amounts of TSH (see Chapter 22).    Mechanisms of Type Ill Hypersensitivity. Most type III  hypersensitivity diseases are caused by antigen-antibody  (immune) complexes that are formed in the circulation and  deposited later in vessel walls or extravascular tissues (Figure  9-3). The primary difference between type II and type III  mechanisms is that in type II hypersensitivity antibody binds to  the antigen on the cell surface, whereas in type II the antibody  binds to soluble antigen that was released into the blood or  body fluids, and the complex is then deposited in the tissues.  Type III reactions are not organ specific, and symptoms have  little to do with the particular antigenic target of the antibody.  The harmful effects of immune complex deposition are caused  by complement activation, particularly through the generation  of chemotactic factors for neutrophils. The neutrophils bind to  antibody and C3b contained in the complexes and attempt to  ingest the immune complexes.   They are often unsuccessful because the complexes are  bound to large areas of tissue. During the attempted phagocy-  tosis, large quantities of lysosomal enzymes are released into the  inflammatory site instead of into phagolysosomes. The attrac-  tion of neutrophils and the subsequent release of lysosomal  enzymes cause most of the resulting tissue damage.    Immune complexes can be of various sizes, depending on the  relative amounts of antigen and antibody. Fairly large immune  complexes are cleared rapidly from the circulation by tissue  macrophages, whereas very small complexes eventually are fil-  tered from blood through the kidneys, without any pathologic  consequences. Intermediate-sized immune complexes (formed  at a ratio of antigen to antibody that has a slight excess of anti-  gen) are likely to be deposited in certain target tissues, where  they have severe pathologic consequences, such as inflamma-  tion in the kidneys (glomerulonephritis), the vessels (vasculi-  tis), or the joints (arthritis or degenerative joint disease).   Immune Complex Disease. The nature of the immune  complexes may change during the progression of the disease,  with resultant changes in the severity of the symptoms.  Immune complex formation is dynamic as variations in the  ratio of antigen to antibody, the class and subclass of antibody,  and the quantity and quality of circulating antigen occur. Thus  complexes formed early in a disease process may differ from  those formed later, and several types of immune complexes  may be present simultaneously. With the tremendous potential  heterogeneity of immune complexes, it is not surprising that  immune complex diseases are characterized by a variety  of symptoms and periods of remission or exacerbation of  symptoms.   Because many immune complexes activate complement very  effectively, complement levels in the blood may decrease dur-  ing active disease. At times the individual’s blood may become  hypocomplementemic (i.e., contains below normal amounts of  complement activity). During type I, II, or IV hypersensitivity    FIGURE 9-3 Mechanism of Type III, Immune Complex—Mediated, Reactions. Immune complexes form in the blood  from circulating antigen and antibody. Both small and large immune complexes are removed successfully from the circulation  and do not cause tissue damage. Intermediate-sized complexes are deposited in certain target tissues in which the circulation  is slow or filtration of the blood occurs. The complexes activate the complement cascade through C1 and generate fragments  including C5a and C3b. C5a is chemotactic for neutrophils, which migrate into the inflamed area and attach to the IgG and  C3b in the immune complexes. The neutrophils attempt unsuccessfully to phagocytose the tissue and in the process release a  variety of degradative enzymes that destroy the healthy tissues. Fcy receptor is the cellular receptor for the Fc portion of IgG.    reactions, complement levels are unaffected, or some com-  ponents of the complement cascade, such as C3, may even be  increased.   Two prototypic models of type III hypersensitivity help  explain the variety of diseases in this category. Serum sickness  is a model of systemic type III hypersensitivities, and the Arthus  reaction is a model of localized or cutaneous reactions.   Serum Sickness. The systemic prototype of immune com-  plex—mediated disease is called serum sickness because it was  initially described as being caused by the therapeutic admin-  istration of foreign serum, such as horse serum that contained  antibody against tetanus toxin.° Foreign serum generally is not  administered to individuals today, although serum sickness  reactions can be caused by the repeated intravenous adminis-  tration of other antigens, such as drugs, and the characteristics  of serum sickness are observed in systemic type HI autoim-  mune diseases. Serum sickness—type reactions are caused by  the formation of immune complexes in the blood and their  subsequent generalized deposition in target tissues. Typically  affected tissues are the blood vessels, joints, and kidneys. Other  symptoms include fever, enlarged lymph nodes, rash, and pain  at sites of inflammation.   A form of serum sickness is Raynaud phenomenon, a con-  dition caused by the temperature-dependent deposition of  immune complexes in the capillary beds of the peripheral cir-  culation. Certain immune complexes precipitate at tempera-  tures below normal body temperature, particularly in the tips  of the fingers, toes, and nose, and are called cryoglobulins. The  precipitates block the circulation and cause localized pallor and  numbness, followed by cyanosis (a bluish tinge resulting from  oxygen deprivation) and eventually gangrene if the circulation  is not restored.   Arthus Reaction. An Arthus reaction is the prototypic  example of a localized immune complex—mediated inflamma-  tory response.’ It is caused by repeated local exposure to an  antigen that reacts with preformed antibody and forms immune  complexes in the walls of the local blood vessels. Symptoms of  an Arthus reaction begin within 1 hour of exposure and peak  6 to 12 hours later. The lesions are characterized by a typical  inflammatory reaction, with increased vascular permeability,  an accumulation of neutrophils, edema, hemorrhage, clotting,  and tissue damage.    Type IV: Cell-Mediated Hypersensitivity Reactions  Whereas types I, II, and III hypersensitivity reactions are medi-  ated by antibody, type IV reactions are mediated by T lym-  phocytes and do not involve antibody (Figure 9-4). Type IV  mechanisms occur through either cytotoxic T lymphocytes (Tc  cells) or lymphokine-producing Th1 and Th17 cells. Tc cells  attack and destroy cellular targets directly. Thl and Th17 cells  produce cytokines that recruit and activate phagocytic cells,  especially macrophages. Destruction of the tissue is usually  caused by direct killing by toxins from Tc cells or by the release  of soluble factors, such as lysosomal enzymes and toxic reactive  oxygen species (ROS), from activated macrophages.   Clinical examples of type IV hypersensitivity reactions  include graft rejection and allergic reactions resulting from    contact with such substances as poison ivy and metals. A type  IV component also may be present in many autoimmune dis-  eases. For example, T cells against type II collagen (a protein  present in joint tissues) contribute to the destruction of joints in  rheumatoid arthritis; T cells against a thyroid cell surface anti-  gen contribute to the destruction of the thyroid in autoimmune  thyroiditis (Hashimoto disease); and T cells against an antigen  on the surface of pancreatic beta cells (the cell that normally  produces insulin) are responsible for beta-cell destruction in  insulin-dependent (type 1) diabetes mellitus.®   A type IV hypersensitivity reaction in the skin was thoroughly  described first by Ehrlich in 1891 and led to the development of  a diagnostic skin test for tuberculosis.’ The reaction follows an  intradermal injection of tuberculin antigen into a suitably sen-  sitized individual and is called a delayed hypersensitivity skin test  because of its slow onset—24 to 72 hours to reach maximum  intensity. The reaction site is infiltrated with T lymphocytes and  macrophages, resulting in a clear hard center (induration) and a  reddish surrounding area (erythema).    Antigenic Targets of Hypersensitivity Reactions  Allergy  Allergy is a hypersensitivity response against an environmen-  tal antigen (allergen). Although the most common allergies  are type I hypersensitivities, any of the other three mechanisms  may cause allergic responses.!°   Typical allergens that induce type I hypersensitivity include  pollens (e.g., ragweed), molds and fungi (e.g., Penicillium  notatum), foods (e.g., milk, eggs, fish), animals (e.g., cat dan-  der, dog dander), cigarette smoke, components of house dust  (e.g., fecal pellets of house mites), and almost anything else we    Activated  macrophage  FIGURE 9-4 Mechanism of Type IV, Cell-Mediated, Reactions. Antigens  from target cells stimulate T cells to differentiate into cytotoxic T cells (Tc cells),  which have direct cytotoxic activity, and helper T cells (Th1 cells) involved in  delayed hypersensitivity. The Th1 cells produce lymphokines (especially interferon-  gamma [IFN-y]) that activate the macrophage through specific receptors (e.g., IFN-  y receptor [IFN-yR]). The macrophages can attach to targets and release enzymes  and reactive oxygen species that are responsible for most of the tissue destruction.    may encounter in our environment. Allergens that primar-  ily elicit type IV allergic hypersensitivities include plant resins  (e.g., poison ivy, poison oak), metals (e.g., nickel, chromium),  acetylates, and chemicals in rubber, cosmetics, detergents, and  topical antibiotics (e.g., neomycin). Type I] and type III allergic  hypersensitivities are relatively rare but may include antibiotics  (e.g., penicillin, sulfonamides) and soluble antigens produced  by infectious agents (e.g., hepatitis B).   Usually a sensitization process involving multiple exposures  to the allergen occurs before adequate amounts of antibody or  T cells are available to elicit a hypersensitivity response. In some  instances, exposure to a particular allergen may not be apparent  in the case of allergens that are drugs, additives, or preservatives  in food. For example, an individual may become sensitized by  drinking milk that contains trace amounts of penicillin used for  treating cows for mastitis. Thus, the first therapeutic exposure  to penicillin may cause an unexpected hypersensitivity reaction.  Additionally, penicillin shares a B-lactam structure with cepha-  losporin, so that one antibiotic may be sensitive against another.   Genetic Predisposition. Certain individuals are genetically  predisposed to develop allergies, particularly type I allergies,  and are called atopic.!' In families in which one parent has an  allergy, allergies develop in about 40% of the offspring. If both  parents have allergies, the incidence in the offspring may be as  high as 80%. (Principles of genetic inheritance are discussed in  Chapter 4.)    Atopic individuals tend to produce higher quantities of  IgE and to have more Fc receptors for IgE on their mast cells.  The airways and the skin of atopic individuals are also more  responsive to a wide variety of both specific and nonspecific  stimuli than are the airways and skin of individuals who are  not atopic. Multiple genes have been associated with the atopic  state, including polymorphisms in a large variety of cytokines  that regulate IgE synthesis (e.g., interleukin [IL]-4, IL-5, IL-12,  IL-13) and cellular receptors.    The clinical manifestations of type I reactions are attributable  mostly to the biologic effects of histamine. Tissues most com-  monly affected contain large numbers of mast cells and are  sensitive to the effects of histamine released from them. These  tissues are found in the gastrointestinal tract, the skin, and the  respiratory tract (Figure 9-5 and Table 9-4). The particular  symptoms frequently reflect the main portal of entry for the  allergen. For instance, pollens and other airborne allergens usu-  ally cause respiratory symptoms.   Effects of allergens on the mucosa of the eyes, nose, and respi-  ratory tract include conjunctivitis (inflammation of the mem-  branes lining the eyelids), rhinitis (inflammation of the mucous  membranes of the nose), and asthma (constriction of the bron-  chi).!* Symptoms are caused by vasodilation, hypersecretion of  mucus, edema, and swelling of the respiratory mucosa. Because    FIGURE 9-5 Type! Hypersensitivity Reactions. Manifestations of allergic reactions as a result of type | hypersensitivity  include itching, angioedema (swelling caused by exudation), edema of the larynx, urticaria (hives), bronchospasm (constriction  of airways in the lungs), hypotension (low blood pressure), and dysrhythmias (irregular heartbeat) because of anaphylactic  shock, and gastrointestinal cramping caused by inflammation of the gastrointestinal mucosa. Photographic inserts show a  diffuse allergic-like eye and skin reaction on an individual. The skin lesions have raised edges and develop within minutes or  hours, with resolution occurring after about 12 hours. (Inserts from Male D et al: /mmunology, ed 8, St Louis, 2013, Mosby.)    the mucous membranes lining the respiratory tract (accessory  sinuses, nasopharynx, and upper and lower respiratory tracts)  are continuous, they are all adversely affected. The degree to  which each is affected determines the symptoms of the disease.   Gastrointestinal allergies are caused primarily by allergens  that enter through the mouth—usually foods or medicines.  Symptoms include vomiting, diarrhea, or abdominal pain and  may be severe enough to result in malabsorption or protein-  losing enteropathy, if the reactions are prolonged or recurrent.  Foods most often implicated in gastrointestinal allergies are  milk, chocolate, citrus fruits, eggs, wheat, nuts, peanut butter,  and fish.!* When food is the allergen, the active immunogen  may be a product of food breakdown by digestive enzymes.   Urticaria, or hives, is a dermal (skin) manifestation of type  I allergic reactions (see Figure 9-5). The underlying mechanism  is the localized release of histamine and increased vascular per-  meability, resulting in limited areas of edema. Urticaria is char-  acterized by white fluid-filled blisters (wheals) surrounded by  areas of redness (flares). The wheal and flare reaction is usually  accompanied by itching. Not all urticarial symptoms are caused  by allergic (immunologic) reactions. Some, termed nonimmu-  nologic urticaria, result from exposure to cold temperatures,  emotional stress, medications, systemic diseases, hyperthyroid-  ism, or malignancies (e.g., lymphomas).   If possible, avoidance of the allergen is the best method to  limit allergic responses. Approximately 30% of laboratory    *An order of fungi that is stimulated by warmth to grow and proliferate.  Modified from Bellanti JA: Immunology III, Philadelphia, 1985, Saunders.    animal handlers have allergies to animal dander and must use  face masks or other devices to avoid contact.   Although some type I allergic responses can be controlled  by blocking histamine receptors with antihistamines, the pri-  mary mechanism of control is the autonomic nervous system.  The autonomic nervous system includes biochemical mediators  (e.g., epinephrine, acetylcholine) that, like the mediators of the  inflammatory response, have profound effects on cells. These  mediators bind to appropriate receptors on mast cells and the  target cells of inflammation (e.g., smooth muscle), thereby con-  trolling (1) the release of inflammatory mediators from mast  cells and (2) the degree to which target cells respond to inflam-  matory mediators (see Chapter 7).    An example of a life-threatening allergy is an anaphylactic reac-  tion to a bee sting. Bee venoms contain a mixture of enzymes  and other proteins that may serve as allergens. About 1% of chil-  dren may have an anaphylactic reaction to bee venom. Within  minutes they may develop excessive swelling (edema) at the bee  sting site, followed by generalized hives, itching, and swelling in  areas distal from the sting (e.g., eyes, lips), and other systemic  symptoms including flushing, sweating, dizziness, and head-  ache. The most severe symptoms may include gastrointestinal  (e.g., stomach cramps, vomiting), respiratory (e.g., tightness in  the throat, wheezing, difficulties breathing), and vascular (e.g.,  low blood pressure, shock) reactions. Severe respiratory and  vascular reactions may lead to death.   If a child has had a previous anaphylactic reaction to bee  stings, the chance of having another is about 60%. During the  reaction the administration of antihistamines has little effect  because histamine has already bound H1 receptors and initiated  severe bronchial smooth muscle contraction. Most individuals  carry self-injectable epinephrine. Autonomic nervous system  mediators, such as epinephrine, bind to specific receptors on  smooth muscle and reverse the effects of histamine and result  in muscle relaxation. Similar anaphylactic reactions have been  described against peanuts and other nuts, shellfish, fish, milk,  eggs, and some medications.    Allergic reactions can be life threatening; therefore, it is essen-  tial that severely allergic individuals be made aware of the spe-  cific allergen against which they are sensitized and instructed  to avoid contact with that material.!* Several tests are available,  including food challenges, skin tests with allergens, and labora-  tory tests for measurements of total IgE and allergen-specific  IgE in the blood.*   Reactivity to a particular food allergen may be tested by  controlled administration of small doses of the suspected aller-  gen in order to evoke a mild allergic response. This approach  can be dangerous if the individual has a history of anaphylac-  tic responses. A safer approach is injection of an allergen into  (intradermal) or onto (epicutaneous or prick test) the skin. If  the individual is allergic to a particular allergen, a local wheal  and flare reaction may occur within a few minutes at the site of  injection. The diameter of the flare reaction is usually indicative    of the individual’s degree of sensitivity to that allergen. In the  most severely allergic individuals, even the extremely small  amounts of allergen used for the skin test may evoke a systemic  anaphylaxis. Skin test is also contraindicated if the individual is  using medications that may affect the test or has diffuse derma-  titis, which would make the reaction difficult to interpret.   A variety of laboratory tests can detect IgE antibodies in  serum. These assays have various commercial acronyms,  depending on whether they are radioimmunoassays (RIAs;  reactivity detected by measuring a radioactive reagent) or  enzyme immunoassays (EIAs or ELISA [enzyme-linked immu-  nosorbent assay]; reactivity detected by measuring a color  change caused by an enzyme-labeled reagent). One set of assays  measures circulating levels of total IgE, with atopic individu-  als usually having elevated levels. Other assays are capable of  measuring circulating levels of specific IgE antibodies against  selected allergens. The amount of IgE against a specific aller-  gen correlates well with the degree of skin test reactivity and  the severity of clinical symptoms related to the same allergen,  although the laboratory text is less sensitive.   Desensitization. Clinical desensitization to allergens can be  achieved in some individuals. Minute quantities of the allergen  are injected in increasing doses over a prolonged period. The  procedure may reduce the severity of the allergic reaction in the  treated individual. However, this form of therapy is associated  with a risk of systemic anaphylaxis, which can be severe and life  threatening. This approach works best for routine respiratory  allergens!° and biting insect allergies (80% to 90% rate of  desensitization over 5 years of treatment). Food allergies have  been very difficult to suppress, but some promising trials are  underway to evaluate desensitization by oral or sublingual  administration of increasing amounts of allergen.'”   The mechanisms by which desensitization occurs may be  several, one of which is the production of large amounts of so-  called blocking antibodies, usually circulating IgG. A blocking  antibody presumably competes in the tissues or in the circu-  lation for binding with antigenic determinants on the allergen  so that the allergen is “neutralized” and is unable to bind with  IgE on mast cells. Sublingual desensitization (another approach  that works best with some food allergies) produces sIgA and  circulating IgG that may prevent the allergen from access-  ing mast cells. Desensitization injections also may stimulate  the generation of clones of T-regulatory lymphocytes, which  inhibit hypersensitivity by suppressing the production of IgE or  modifying the Th1/Th2 interactions in favor of production of  anti-inflammatory cytokines.   Other approaches to suppressing type I allergic responses  have been tested, with some preliminary success. An example is  injection of anti-IgE antibody directed against the Fc portion of  the IgE in order to decrease binding of IgE to mast cells.   Type IV Allergic Hypersensitivities. The allergens that  induce a type IV allergic reaction are mostly haptens that react  with normal self-proteins in the skin. When presented in this  fashion, these antigens are recognized by pattern recognition  receptors (PRRs) on antigen-presenting cells in the skin  and induce a cell-mediated response.'* (Pattern recognition  receptors are discussed in Chapter 7.) The primary result is    an allergic contact dermatitis that is confined to the area of  contact with the allergen. The best-known example is poison  ivy (Figure 9-6). The antigen in that instance is a plant catechol,  urushiol, that reacts with normal skin proteins and evokes a cell-  mediated immune response.   As noted, type I hypersensitivity reactions may result in a  skin reaction (e.g., hives formed during an allergic reaction to  a particular food). The distribution of the lesions may suggest  whether the reaction is caused by immediate (type I) or delayed  (type IV) hypersensitivity mechanisms.!’ Immediate hypersen-  sitivity reactions, termed atopic dermatitis, are usually charac-  terized by widely distributed lesions, whereas contact dermatitis  (delayed hypersensitivity) consists of lesions only at the site of  contact with the allergen, such as a metal allergy to jewelry (see  Figure 9-6).   Types Il and Ill Allergic Hypersensitivities. Type II  allergic hypersensitivities are usually against allergic haptens  that bind to the surface of cells and elicit an IgG or IgM  response. For instance, allergic reactions against many drugs  (e.g., penicillin, sulfonamides) occur after the drug binds to  proteins on the plasma membranes of a person’s cells and  becomes immunogenic.”? The immune system attacks the  allergen on the cell membrane and destroys the cell as well.  In allergic reactions to penicillin, the immunogenic antigen is  a metabolite of penicillin catabolism that binds to the plasma  membranes of erythrocytes or platelets and induces an antibody  response that destroys the cells (type II hypersensitivity), causing  anemia or thrombocytopenia. Type II allergic reactions also  can occur against antigens of infectious diseases. For instance,  encephalitis secondary to a rubella infection may result from  damage to cells of the nervous system by an immune response  against rubella virus antigen on the cell’s plasma membrane.   Type III allergic reactions occur after the formation of  immune complexes containing soluble allergens. For instance,  Arthus reactions may be observed after injection, ingestion, or  inhalation of allergens. Skin reactions can follow subcutane-  ous or intradermal inoculation with drugs, fungal extracts, or  antigens used in skin tests. Gastrointestinal reactions, such as  gluten-sensitive enteropathy (celiac disease), follow ingestion of  antigen, usually gluten from wheat products (see Chapter 41).  Allergic alveolitis is a type II acute hemorrhagic inflammation  of the air sacs (alveoli) of the lungs resulting from inhalation of  fungal antigens, usually particles from moldy hay (farmer’s lung)  or pigeon feces (pigeon breeder’s disease)*! (see Chapter 35).  Circulating drugs (e.g., penicillin) or antigens produced from  infectious diseases (e.g., hepatitis B, streptococcal infection)  may form circulating immune complexes that are deposited in  the circulation (vasculitis) or the kidneys (glomerulonephritis).    Breakdown of Tolerance. Self-antigens are usually in a state  of tolerance, or immunologic homeostasis, with the host’s own  immune system. Central tolerance develops in humans during  the embryonic period as autoreactive lymphocytes are either  eliminated or suppressed in the primary lymphoid organs during  differentiation and proliferation of immature T or B lymphocytes  (see Figures 8-10 and 8-12). Clones of cells with antigen receptors    FIGURE 9-6 Development of Allergic Contact Dermatitis, a Delayed Hypersensitivity Reaction. A, Shown here is  the development of allergy to catechols from poison ivy. No dermatitis results from the primary contact because the antigens  (catechols) are sensitizing the immune response and producing memory T cells. Secondary contact, however, quickly activates  a type IV, cell-mediated reaction that causes dermatitis. B, This contact dermatitis was caused by a delayed hypersensitiv-  ity reaction that led to vesicles and scaling at the sites of contact. (From Damjanov |, Linder J: Anderson's pathology, ed 10,    for self-antigens are deleted. Peripheral tolerance is maintained  in the secondary lymphoid organs through the action of  T-regulatory lymphocytes or antigen-presenting dendritic cells.  Autoimmunity is a breakdown of tolerance in which the body’s  immune system begins to recognize self-antigens as foreign.  In most autoimmune conditions the mechanism of tolerance  breakdown is unknown, although several potential mechanisms  have been suggested.   Sequestered Antigen. The induction of central tolerance  requires that the self-antigen be present in the fetus and exposed  to the developing fetal immune system. Some self-antigens may    not normally encounter the immune system in either fetal or  adult life, but are sequestered or hidden from the immune system  in immunologically privileged sites, so named because foreign  tissues can be transplanted into these sites with less chance of  immunologic rejection. For example, several sites (e.g., anterior  chamber of the eye, the brain) are separated from the circulation  by barriers (blood-ocular and blood-brain barriers) that offer  protection against many immune cells and lead to relatively poor  lymphatic drainage. Lymphocytes that enter these sites encoun-  ter tissue that expresses Fas ligand (FasL) and tumor necro-  sis factor (TNF)-related apoptosis-inducing ligand (TRAIL).    These molecules induce the lymphocytes to undergo apop-  tosis, thus protecting the tissue. Self-antigens in these sites are  not normally seen by the immune system and are therefore not  immunogenic. However, if the barriers are damaged, antigenic  sensitization can occur, and the resultant antibodies and lympho-  cytes can enter the site and cause additional damage to the tissue.  For instance, physical trauma to one eye may result in release  of sequestered antigen into the blood or lymphatics, resulting in  immunologic injury to the other eye (sympathetic uveitis).   Infectious Disease. A long-standing hypothesis is that for-  eign antigens from infectious microorganisms can initiate  autoimmune disease through a process of molecular mimicry.  Some antigens of infectious agents so closely resemble (mimic)  a particular self-antigen that antibodies or T cells produced to  protect against the infection also recognize the self-antigen as  foreign (cross-reactive antibody or T cell). The relationship  between many autoimmune diseases and predisposing infec-  tions, such as enterovirus infection and type 1 diabetes, is being  investigated.*? However, the only clearly defined example so far  is acute rheumatic fever that may occur after a group A strepto-  coccal sore throat (see following).   Neoantigen. In certain situations a neoantigen that induces  an allergic reaction may also lead to autoimmunity. Many neo-  antigens (new antigens) are haptens that become immunogenic  after binding to self-proteins. The immune reaction against the  neoantigen may lead to an immunologic reaction against nor-  mal antigenic determinants on the protein. Other new antigenic  determinants may result from posttranslational modifications of  a normal protein so that one or more amino acids are chemically    altered (e.g., addition or removal of amino acid side groups,  phosphorylation) without affecting the protein’s function.’  Many experimental autoimmune diseases (e.g., experimental  autoimmune thyroiditis) can be initiated by immunization with  molecules containing neoantigenic determinants.   Forbidden Clone. During differentiation and proliferation  of lymphoid stem cells into immature T and B lymphocytes (see  Figures 8-10 and 8-12), some lymphocytes produce receptors  that react with self-antigens. Many autoreactive lymphocytes  interact with self-antigens and other co-stimulatory molecules  on the surface of thymic epithelial cells and are induced to  undergo clonal deletion by a process of apoptosis. Thus lym-  phocytes reactive against self-antigen are prevented, or “for-  bidden,” from maturing. Autoimmunity may result from the  survival of a forbidden clone and its proliferation later in life.   Defective Peripheral Tolerance. Tolerance to some self-  antigens is controlled in the secondary lymphoid organs.  This process is controlled by a variety of cells, including  antigen-presenting dendritic cells and members of a family of  T-regulatory lymphocytes (Treg cells) that normally suppress  immune responses against self. Defects in particular regulatory  cells may result in expansion of clones of autoreactive cells and  the development of autoimmune disease. Systemic lupus ery-  thematosus, which is characterized by the production of a large  array of autoantibodies, may be caused by a general breakdown  in the regulatory network.   Original Insult. Although many theories exist, the initial  cause of most autoimmune diseases is unknown (see What’s  New? Maternal Microchimerism and Autoimmune Disease).    A rapidly growing body of evidence suggests that we are in a state of micro-  chimerism (Mc); possessing a small number of cells originating from another  individual.' The placenta, which was once considered a cellular “barrier,” is  more porous than suspected and routinely allows bidirectional passage of both  maternal and fetal cells. Passage results during normal pregnancy, as well as  spontaneous miscarriages and elective terminations,? and includes a broad  spectrum of cells, ranging from erythrocytes and mature white blood cells, to  stem cells at various stages of differentiation. Most gravid women (having been  pregnant) have detectable fetal cells (fetal Mc) in their blood and many organs  (e.g., white blood cells, hepatocytes, kidney tubular epithelium, neurons and glia,  cardiomyocytes, endothelial cells, thyrocytes, intestinal epithelium, and islet  6 cells), which apparently originated as fetal stem cells that differentiated in  the maternal tissues. As early as 6 weeks gestation, maternal Mc is apparent in  fetal blood and tissues (e.g., thymus, lung, heart, pancreas, liver, spleen, kidney,  adrenal gland, ovary, testis, and brain).? Maternal Mc originates predominately  from maternal cells, but may also include cells from one’s grandmother, a non-  identical twin, or older siblings, all of which were harbored in the mother's blood  tissues. Both maternal and fetal Mc persists for decades after pregnancy.  The long-term implications of Mc may include both detrimental and beneficial  effects. Fetal cells express both maternal and paternal HLA antigens and are  recognized as partially foreign by maternal immune cells. Most studies of mater-  nal Mc use assays for the presence of the Y chromosome in maternal blood or  organs. Many autoimmune diseases are associated with increased numbers of  male cells in the diseased organs (e.g., scleroderma, dermatomyositis, Sjogren  syndrome, thyroiditis, primary biliary cirrhosis, hyper- and hypothyroidism, and    systemic lupus erythematosus) suggesting that Mc may contribute to the eti-  ology of these diseases.' Maternal Mc in the offspring also may affect their  risk for autoimmune disease. Increased levels of maternal cells in the child's  blood have been reported in cases of juvenile inflammatory myopathy, neonatal  lupus syndrome, type 1 diabetes, and biliary atresia. Maternal cells were found  as myocytes in the myocardium of infants with fatal neonatal lupus-associated  heart block and as insulin-producing cells in the pancreas of diabetics.' It cannot  yet be determined whether the foreign cells are initiators of autoimmune dam-  age or whether injury to the tissue results in increased proliferation. Thus these  observations remain intriguing but of unknown significance.  Beneficial effects of Mc are also observed. Treg cells may control immunologic  tolerance to maternal cells. A significantly greater success rate of liver transplanta-  tion was observed with maternal or sibling donors than paternal donors. Thus Mc  may modulate the immune response and minimize rejection of organs from selected  donors. Fetal Mc occurs in several regions of the brain, but at a significantly lower  incidence and concentration in women with Alzheimer’s disease than those without  neurologic disease.° Whether Mc is protective or not remains unknown.    References  . Nelson JL: Trends Immunol 33(8):421—427, 2012.  . Peterson SE et al: Human Reprod 27(9):2607—2612, 2012.  . Boyon C et al: Fur J Obset Gynecol Reprod Biol 158(2):148-152, 2011.  . Nijagal A, Fleck S, Mackenzie TC: Chimerism 3(2):37—-39, 2012.  . Chan WFN et al: Plos ONE7(9):e45592. doi:10.1371/journal.pone.0045592,  2012.    It is suspected that some autoimmune diseases are initiated  by infections that have resolved without leaving evidence that  would lead to identification of the particular infectious agent.  The evidence for an infectious causation is clear for only one  autoimmune disease: acute rheumatic fever. In a small number  of individuals with group A streptococcal sore throats, the M  proteins in the bacterial capsule induce antibodies that also  react with proteins in the heart valve, damaging the valve.   Additionally, some streptococcal skin or throat infections  result in the release of bacterial antigens into the blood and the  formation of circulating immune complexes. The complexes  may deposit in the kidneys and initiate an immune complex  glomerulonephritis (inflammation of the kidney). Thus capsu-  lar antigens of the group A Streptococcus may mimic (antigenic  mimicry) normal heart antigens resulting in a type II autoim-  mune hypersensitivity (rheumatic fever), whereas in another  person this infection may release bacterial antigen (an environ-  mental antigen) into the blood, resulting in a type III allergic  hypersensitivity (poststreptococcal glomerulonephritis).   Genetic Factors. Genetic factors that contribute to  autoimmunity are easier to identify than the original insult that  initiates the disease. It is fairly well established that autoimmune  diseases can be familial. Affected family members may not  all develop the same disease, but several members may have  different disorders characterized by a variety of hypersensitivity  reactions, including autoimmune and allergic.   Associations with particular autoimmune diseases have  been identified for a variety of major histocompatibility com-  plex (MHC) alleles (see Chapter 8) or non-MHC genes. The  specific HLA alleles of susceptible and resistant individu-  als have been analyzed for almost every known disease, and  almost universally individuals with certain diseases are more  likely than the general population to have a specific HLA allele  or set of alleles. Some associations are strong; others are more  tenuous (Table 9-5). The reason some HLA alleles are asso-  ciated with inappropriate immune function is unclear, but it  may directly involve the ability of particular HLA molecules to  present antigen or the use of particular HLAs as receptors for  disease-causing microorganisms. These genes may determine  an individual’s susceptibility to specific infectious agents or  the capacity of that individual to mount an immune response  against specific antigens. Therefore, an individual of a specific  HLA type may have inappropriate or exaggerated immune  responses against a microorganism, resulting in a hypersen-  sitivity reaction.   A large variety of non-MHC genes also have been identified  as risk factors for the development of specific autoimmune dis-  eases. Most of these genes encode for inflammatory cytokines or  co-stimulatory molecules found on the cell surface.    Alloimmunity occurs when an individual’s immune system  reacts against antigens on the tissues of other members of  the same species. The two clinically relevant examples of this  reactivity are (1) several transient neonatal diseases (in which  the maternal immune system becomes sensitized against anti-  gens expressed by the fetus) and (2) transplant rejection and    transfusion reactions (in which the immune system of a recipi-  ent of an organ transplant or blood transfusion reacts against  antigens on the donor cells).   Transient Neonatal Alloimmunity. Because the fetus is a  hybrid between the mother and father, it expresses paternal  antigens that are not found in the mother. Occasionally these  fetal antigens cross the placenta and elicit an immune response  in the mother (e.g., production of alloantibodies against the  fetal antigens). The maternal alloantibody may be transported  across the placenta into the fetal circulation, bind to the fetal  cells, and produce alloimmune disease in the fetus and neonate.  The mother’s immune system produces the antibody, but  because her cells do not express the target antigen, she has no  symptoms of the disease.   Neonatal alloimmune disease may be secondary to mater-  nal autoimmune diseases in which the mother produces an IgG  autoantibody specific for maternal self-antigens that are found  on fetal cells as well. Therefore, symptoms of the same auto-  immune disease may affect mother and child, even though the  autoantibody is being produced only by the mother’s immune  system. This form of disease usually occurs only in association  with type II (tissue-specific) hypersensitivity reactions. It does  not occur in association with IgE-mediated (type I) reactions,  immune complex—mediated (type III) reactions, or cell-medi-  ated (type IV) reactions because the immunologic factors (IgE,  immune complexes, T cells) that cause these reactions do not  readily cross the placenta and enter the fetal circulation in suf-  ficient quantity.    TABLE 9-5 EXAMPLES OF ASSOCIATIONS  BETWEEN SPECIFIC HLA  ALLELES AND DISEASE    Acute anterior uveitis B27  Addison disease DR3  Ankylosing spondylitis B27  Behcet syndrome B51  Celiac disease DR3  Chronic active hepatitis DR3  Dermatitis herpetiformis DR3  Diabetes (type 1) DR3  DR4  DR3/DR4  Goodpasture syndrome DR2  Graves disease DR3  Hashimoto disease DR11  Multiple sclerosis DR2  Myasthenia gravis DR3  Pemphigus vulgaris DR4  Postgonococcal arthritis B27  Reiter syndrome B27  Rheumatoid arthritis DR4  Sjégren syndrome DR3  Systemic lupus erythematosus DR3    HLA, Human leukocyte antigen; RA, the approximate relative risk,  which is the frequency of a disease in individuals with the particular  HLA allele compared with individuals without that allele.    Symptoms of the alloimmune disease may be present in  utero or immediately after birth and may be fatal to the fetus or  neonate. At birth, maternal circulating antibody can no longer  enter the child, and if symptoms are successfully treated, the  disease will disappear as the maternal antibody is catabolized.  Examples of maternal immunologic hypersensitivity diseases in  which the child can be affected include the following antibody-  mediated diseases:   1. Graves disease—an autoimmune disease in which mater-  nal antibody against the receptor for TSH causes neonatal  hyperthyroidism   2. Myasthenia gravis—an autoimmune disease in which mater-  nal antibody binds with receptors for neural transmitters  on muscle cells (acetylcholine receptors), causing neonatal  muscular weakness (see Chapter 18)   3. Immune thrombocytopenic purpura—both autoimmune  and alloimmune variants in which maternal antiplatelet  antibody destroys platelets in the fetus and neonate (see  Chapter 29)   4. Alloimmune neutropenia—in which maternal antibody  against neutrophils destroys neutrophils in the neonate   5. Systemic lupus erythematosus—autoimmune disease in  which diverse maternal autoantibodies induce anomalies  (e.g. congenital heart defects) in the fetus or cause preg-  nancy loss   6. Rh and ABO alloimmunization (e.g., erythroblastosis  fetalis)—in which maternal antibody against erythrocyte  antigens induces anemia in the child (see Chapter 30)    Many examples of autoimmune or alloimmune diseases  have been described. Several basic principles are exemplified  by two examples: systemic lupus erythematosus (an autoim-  mune disease) and tissue rejection (i.e., transplant rejection  or transfusion reaction) (an alloimmune phenomenon). Most  of the classic autoimmune diseases, including disorders of  the endocrine system (autoimmune thyroiditis and Graves  disease), hematologic system (the hemolytic and pernicious  anemias), nervous system (myasthenia gravis), and connec-  tive tissue in joints (rheumatoid arthritis), are discussed in  Unit I of this book.    Systemic lupus erythematosus (SLE) is a chronic, multisystem,  inflammatory disease and is one of the most common, complex,  and serious of the autoimmune disorders.”* SLE is characterized  by the production of a large variety of autoantibodies against  nucleic acids, erythrocytes, coagulation proteins, phospholip-  ids, lymphocytes, platelets, and many other self-components.  The most characteristic autoantibodies produced in SLE are  against nucleic acids (e.g., single-stranded deoxyribonucleic  acid [DNA], double-stranded DNA), histones, ribonucleopro-  teins, and other nuclear materials.   Deposition of circulating immune complexes containing  antibody against DNA produces tissue damage in individu-  als with SLE. DNA and DNA-containing immune complexes  have a high affinity for glomerular basement membranes and    therefore may be selectively deposited in the glomerulus (Figure  9-7). (Kidney structures are described in Chapter 37.) The pres-  ence of DNA in the circulation increases from cellular damage in  response to trauma, drugs, or infections and is usually removed  in the liver. Removal of circulating DNA is slowed in the pres-  ence of immune complexes, thereby increasing the potential for  deposition in the kidney. (The liver’s role in removing waste  products from the blood is discussed in Chapter 40.) Deposi-  tion of immune complexes composed of DNA and antibody  also causes inflammatory lesions in the renal tubular basement  membranes, brain (choroid plexus), heart, spleen, lung, gastro-  intestinal tract, skin (see Figure 9-7), and peritoneum.   SLE, as with most autoimmune diseases, occurs more often  in women (approximately a 10:1 predominance of females),  especially in the 20- to 40-year-old age group. Blacks are affected  more often than whites (about an eightfold increased risk).  A genetic predisposition for the disease has been implicated on  the basis of increased incidence in twins and the existence of  autoimmune disease in the families of individuals with SLE.   A transient lupus-like syndrome that is indistinguish-  able both clinically and in the laboratory from spontaneously  occurring SLE can develop from the prolonged use of medica-  tions, particularly hydralazine (an antihypertensive agent) and    FIGURE 9-7 Deposition of IgG in the Kidney and Skin of Individuals with  Lupus. These photographs of tissue were obtained from individuals with lupus  and stained with fluorescent anti-IgG. A, Section from a kidney showing a glom-  erulus with deposits of IgG (arrow, indicating bright areas of staining). B, Section  of the skin showing deposition of IgG along the dermal-epidermal junction (arrow,  indicating bright green staining). (A courtesy Dr. Helmut Rennke, Department of  Pathology, Brigham and Women’s Hospital, Boston; B courtesy Dr. Richard Son-  theimer, Department of Dermatology, University of Texas Southwestern Medical  School, Dallas.)    procainamide (an antidysrhythmic drug). In genetically suscep-  tible individuals, certain environmental agents, such as ultra-  violet light, and several infectious agents may trigger lupus-like  immune reactions.   Clinical manifestations of SLE include arthralgias or arthritis  (90% of individuals), vasculitis and rash (70% to 80% of indi-  viduals), renal disease (40% to 50% of individuals), hemato-  logic abnormalities (50% of individuals, with anemia being the  most common complication), and cardiovascular diseases (30%  to 50% of individuals). As with most autoimmune diseases, the  disease process develops slowly (up to 10 years from occurrence  of the first autoantibody until diagnosis)? and is characterized  by frequent remissions and exacerbations. Because the signs  and symptoms affect almost every body system and tend to be  intermittent, SLE is extremely difficult to diagnose. This has led  to the development of a list of 11 common clinical findings. The  serial or simultaneous presence of at least four of them indicates  that the individual has SLE”*:   3. Photosensitivity (skin rash developed as a result of  exposure to sunlight)  Oral or nasopharyngeal ulcers  Nonerosive arthritis of at least two peripheral joints  Serositis (pleurisy, pericarditis)  Renal disorder (proteinuria of 0.5 g/day or cellular casts)  Neurologic disorders (seizures or psychosis)  Hematologic disorders (hemolytic anemia, leukopenia,  lymphopenia, or thrombocytopenia)   10. Immunologic disorders (positive lupus erythemato-  sus [LE] cell preparation, anti—double-stranded DNA,  anti-Smith [Sm] antigen, false-positive serologic test  for syphilis, or antiphospholipid antibodies [anticardio-  lipin antibody or lupus anticoagulant] )   There is no cure for SLE or most other autoimmune diseases.  The goals of treatment are to control symptoms and prevent  further damage by suppressing the autoimmune response.  Nonsteroidal anti-inflammatory drugs, such as aspirin, ibupro-  fen, or naproxen, reduce inflammation and relieve pain. Corti-  costeroids are often prescribed for more serious active disease.  Immunosuppressive drugs (e.g., methotrexate, azathioprine, or  cyclophosphamide) are used to treat severe symptoms involv-  ing internal organs. Ultraviolet light can worsen symptoms  (known as flares), and protection from sun exposure is help-  ful. Prolonged use of certain drugs can cause transient SLE-like  symptoms, and the medication history is important for diag-  nostic evaluation.   Other therapeutic approaches have been attempted for SLE  and other autoimmune diseases. Several decades ago prepara-  tions of intravenous immune globulin (IVIg), which was rou-  tinely used to replenish antibodies in persons with antibody  deficiencies, were administered to children with autoimmune  thrombocytopenia (an autoimmune disease in which platelets  were destroyed by an autoantibody).”’ IVIg therapy resulted  in a rebound of platelet levels and temporary resolution of the  thrombocytopenia. IVIg is currently being used for a variety of    autoimmune diseases, including SLE. More recently, mono-  clonal antibodies and other reagents have specifically targeted  and suppressed B and T cells that are participating in autoim-  mune responses.”® This approach has been somewhat successful  in SLE, rheumatoid arthritis, and other autoimmune diseases.  Improved outcomes may be available in the future with the  continued advances in medical research and the use of stem cell  treatments.    Red blood cells (erythrocytes) express several important surface  antigens, known collectively as the blood group antigens, which  can be targets of alloimmune reactions. More than 80 different  red cell antigens are grouped into several dozen blood group  systems, each determined by a different locus or set of loci. The  most important of these, because they provoke the strongest  humoral alloimmune response, are the ABO and Rh systems.   ABO System. Human blood transfusions were carried out  as early as 1818, but they were often unsuccessful. Sometimes  after a transfusion, the recipient’s red blood cells would clump  together, thereby blocking the capillaries and causing death in  some instances. In 1901, Karl Landsteiner reported that this  reaction was related to the ABO antigens located on the surface  of erythrocytes.   The ABO blood group consists of two major carbohydrate  antigens, labeled A and B (Figure 9-8). These two carbohydrate  antigens are codominant, which means that both A and B can  be simultaneously expressed, resulting in an individual having  any one of four different blood types. The erythrocytes of per-  sons with blood type A have the type A carbohydrate antigen  (i.e., carry the A antigen), those with blood type B carry the B  antigen, those with blood type AB carry both A and B antigens,  and those of blood type O carry neither the A nor the B antigen.  A person with type A blood also has circulating antibodies to  the B carbohydrate antigen. If this person receives blood con-  taining B antigens (i.e., blood from a type AB or B individual),  a severe transfusion reaction occurs and the transfused eryth-  rocytes are destroyed by agglutination (Figure 9-9) or com-  plement-mediated lysis. Similarly, a type B individual (whose  blood contains anti-A antibodies) cannot receive blood from  a type A or AB donor. Type O individuals, who have neither  A nor B antigen but have both anti-A and anti-B antibodies,  cannot accept blood from any of the other three types. These  naturally occurring antibodies, called isohemagglutinins, are  immunoglobulins of the IgM class and are induced by simi-  lar antigens expressed on naturally occurring bacteria in the  intestinal tract.   Because individuals with type O blood lack both types of  antigens, they are considered universal donors, meaning that  anyone can accept their red blood cells. Similarly, type AB  individuals are considered universal recipients because they  lack both anti-A and anti-B antibodies and can be transfused  with any ABO blood type. When large volumes of whole blood  (ie., cells plus plasma) are transfused, however, antibodies in  the donor’s blood can bind to antigenic determinants on the  recipient’s erythrocytes, causing agglutination of the recipient’s  own cells. Agglutination and lysis cause harmful transfusion    FIGURE 9-8 ABO Blood Types. This figure shows the antigens and antibodies associated with the ABO blood groups.  The surfaces of erythrocytes of individuals with blood group O have the core H antigenic carbohydrate. Their sera contain IgM  antibodies against both A and B carbohydrates. In individuals of the blood group A, some of the H antigens have been modified  into A antigens by the addition of N-acetylgalactosamine (NAGA). The sera of these individuals have IgM antibodies against  the B antigen. In individuals with blood group B, some of the H antigens have been modified into B antigens by the addition of  galactose (Gal). These individuals have IgM antibodies against the A antigen in their sera. In individuals of the blood group AB,  some of the H antigens have been modified into both the A and B antigens. These individuals do not have antibody to either A    FIGURE 9-9 Mismatched Transfused Blood Cells. Agglutination of erythro-  cytes caused by anti-A blood-typing serum. (Copyright Ed Reschke.)    reactions that can be prevented only by complete and careful  ABO matching between donor and recipient.   Rh System. The Rh blood group is the most polymorphic  system of red cell antigens, consisting of at least 50 separate  antigens. At least five major antigens and a large number of rare  variants have been identified and are expressed primarily on    erythrocytes. The major antigens are contained on two proteins  encoded from two closely linked genes, RHD and RHCE. The  RhD protein expresses the dominant antigen, which determines  whether an individual is Rh-positive or Rh-negative. Individuals  who express the D antigen on the RhD protein are Rh-positive,  whereas individuals who do not express the D antigen  are Rh-negative. The letter d is used to indicate lack of D.  Rh-positive individuals can have either a DD or a Dd genotype,  whereas Rh-negative individuals have the dd genotype. About  15% of North American whites are Rh-negative, whereas the  Rh-negative genotype is much less common among members of  other ethnic groups. Rh-negative individuals can make anti-D if  exposed to Rh-positive erythrocytes, but because the letter d is  used to indicate the lack of the D antigen and does not represent  a different antigen, Rh-positive individuals do not produce an  antibody against d. The second protein, RhCE, expresses two  different antigens, C and E, each of which has two different  alleles (C or ¢ E or e). Therefore, four potential haplotypes of  C and E antigens are commonly observed: CE, Ce, cE, and ce.  IgG anti-D alloantibody produced by Rh-negative mothers  against erythrocytes of their Rh-positive fetuses was the primary  cause of Rh maternal-fetal incompatibility and the resulting  hemolytic disease of the newborn (see Chapter 30). However,    over the past several decades, the incidence of mothers with high  titers of anti-D antibody has decreased dramatically because of  the use of prophylactic anti-D immunoglobulin. By mecha-  nisms that are still not completely understood, administration  of anti-D antibody within a few days of exposure to RhD-pos-  itive erythrocytes completely prevents sensitization against the  D antigen. Because hemolytic disease of the newborn related  to the D antigen has been controlled, alloantibodies against the  other Rh antigens (usually C, c, or E) have become more impor-  tant. In general, these alloantibodies are associated with a less  severe hemolytic disease.   A form of autoimmune hemolytic anemia is often caused by  autoantibodies against Rh antigens, especially e. This variant is  caused by IgG antibodies that react with erythrocytes at nor-  mal body temperature (thus called warm autoimmune hemo-  lytic anemia) and increase phagocytic destruction of the red  blood cell. This characteristic differentiates the warm variant  from another form of autoimmune hemolytic anemia, which is  caused by IgM autoantibodies that react optimally with eryth-  rocytes in the cooler portions of the body (e.g., fingers, toes)  and is referred to as cold autoimmune hemolytic anemia.    Transplantation of organs commonly is complicated by an  immune response against antigens—primarily HLA—on the  donated tissue. Most of our knowledge on the transplantation  of organs is based on renal transplant studies. The primary  mechanism of the rejection of transplanted organs is a type IV  cell-mediated reaction. Two randomly chosen individuals are  almost certainly antigenically different to some degree. Organ  transplants between them could be rejected in approximately 2  weeks without the extensive use of immunosuppressive drugs.   After the donor and recipient are matched for ABO antigens,  antigens of the HLA system are the principal targets of the rejec-  tion reaction; HLA matching of donor and recipient enhances  the probability of acceptance of the graft. Not all HLA loci are  equally important; matching at the HLA-DR locus appears to be  the most critical for graft acceptance, and matching at HLA-A  and HLA-B of slightly lesser importance. (These loci are dis-  cussed in Chapter 8.)   Transplant rejection may be classified as hyperacute, acute,  or chronic, depending on the amount of time that elapses  between transplantation and rejection. Hyperacute rejection is  immediate and rare. When the circulation is reestablished to  the grafted area, the graft may immediately turn white (the so-  called white graft) instead of a normal pink. Hyperacute rejec-  tion usually occurs in recipients with preexisting antibody to  antigens in the graft. The antibodies may have resulted from  rejection of a previous graft or from prior blood transfusions  that contained platelets and white blood cells with foreign HLA.  Additionally, about half of women who have had multiple  pregnancies have circulating antibodies against their husband’s  HLA antigens. As the circulation to the graft is established, anti-  bodies bind to the vascular endothelial cells in the grafted tissue  and activate the inflammatory response, including the coagula-  tion cascade, which results in stasis of blood flow into the tissue  (Figure 9-10). (Coagulation is described in Chapters 7 and 27.)    FIGURE 9-10 Examples of Hyperacute and Acute Rejection of Renal  Allografts. A, Hyperacute antibody-mediated damage to the blood vessel of a  renal allograft. The blood vessel is thickened, and the lumen (arrow) is obstructed  by proliferating fibroblasts and macrophages. B, Acute cellular rejection of a renal  allograft with intense mononuclear cell infiltrate (arrow). €, Acute cellular rejection  stained with immunoperoxidase reagent (brown) against T cells, which are infiltrat-  ing the tissue. (A courtesy Dr. Ihsan Housini, Department of Pathology, University  of Texas Southwestern Medical School, Dallas; B and € courtesy Dr. Robert Colvin,  Department of Pathology, Massachusetts General Hospital, Boston.)    Biopsies of the graft often show deposits of antibody (IgG and  IgM), complement, and neutrophils. This condition is rare  because of effective pretransplantation cross-matching during  which a recipient is tested for antibodies against the HLA anti-  gens of the potential donor.   Acute rejection is primarily a cell-mediated immune response  that occurs within days to months after transplantation. This  type of rejection occurs when the recipient develops an immune  response against unmatched HLAs after transplantation. Sensi-  tization is usually initiated by the recipient’s lymphocytes inter-  acting with the donor’s dendritic cells within the transplanted  tissue, resulting in induction of recipient Th1 and Tc cells against  the donor’s antigens. The Th1 cells release cytokines that acti-  vate infiltrating macrophages, and the Tc cells directly attack  the endothelial cells in the transplanted tissue. A biopsy of the  rejected organ usually shows an infiltration of lymphocytes and  macrophages characteristic of a type IV reaction. Immunosup-  pressive drugs may delay or lessen the intensity of acute rejection.   Another form of acute rejection, acute antibody-mediated  rejection, has recently been recognized and accounts for about    10% of acute rejections. This form of rejection is mediated by  antibody and complement.’ The predominant antibodies are  against HLA antigens or, on occasion, autoantigens in the graft  (e.g., vimentin, angiotensin receptor), but, unlike those anti-  bodies that cause hyperacute rejection, are not present at the  time of transplantation. Sensitization takes 2 weeks or longer  and results in the accumulation of antibody, complement, neu-  trophils, and thrombi in the vasculature of the graft (a type II  hypersensitivity reaction).   Chronic rejection may occur after a period of months or  years of normal function. It is characterized by slow, progressive  organ failure. Chronic rejection may be caused by inflamma-  tory damage to endothelial cells lining blood vessels as a result  of a weak cell-mediated immunologic reaction against minor  histocompatibility antigens on the grafted tissue.°? Antibodies  against HLA and other antigens also may cause chronic rejec-  tion through activation of complement or antibody-dependent  cellular cytotoxicity (ADCC) with NK cells.*!    Disorders resulting from immune deficiency are the clinical  sequelae (results) of impaired function of one or more com-  ponents of the immune or inflammatory response, includ-  ing B cells, T cells, phagocytes, and complement (Table 9-6).  An immune deficiency is the failure of these mechanisms of  self-defense to function at their normal capacity, resulting in  increased susceptibility to infections. Primary (congenital)  immune deficiency is caused by a genetic anomaly, whereas  secondary (acquired) immune deficiency is caused by another  illness, such as cancer or viral infection, or by normal physi-  ologic changes, such as aging. Acquired forms of immune defi-  ciency are far more common than the congenital forms.    The clinical hallmark of immune deficiency is a tendency to  develop unusual or recurrent, severe infections. Preschool and  school-age children normally may have 6 to 12 infections per  year, of which 3 or 4 are ear infections, and adults may have 2 to  4 infections per year. Most of these are not severe and are lim-  ited to viral infections of the upper respiratory tract, recurrent  streptococcal pharyngitis, or mild otitis media.   Potential immune deficiencies are considered if the indi-  vidual has had severe, documented bouts of pneumonia, otitis  media, sinusitis, bronchitis, septicemia, or meningitis or infec-  tions with opportunistic microorganisms that normally are not  pathogenic or usually confined to one site (e.g., Pneumocystis  jirovecii, disseminated Candida infection, cytomegalovirus  [CMV]).*? Infections are generally recurrent with only short  intervals of relative health, and multiple simultaneous infec-  tions are common. Individuals with primary immune defi-  ciencies often have eight or more ear infections, two or more  serious sinus infections, and two or more pneumonias, recur-  rent abscesses or infections in unusual sites, or persistent fungal  infections (particularly thrush in an individual at least 1 year  old) within a year. Recurrent internal infections, such as menin-  gitis, osteomyelitis, or sepsis, are common. Prolonged antibiotic    use is commonly ineffective by oral or injected routes and may  necessitate intravenous administration. Additional symptoms  may include failure to thrive and chronic diarrhea. A familial  history of immune deficiency may be found in some types of  primary deficiency.   The type of recurrent infections that manifest may indi-  cate the type of immune defect. Deficiencies in T-cell immune  responses are suggested when recurrent infections are caused by  certain viruses (e.g., varicella, vaccinia, herpes, cytomegalovi-  rus), fungi and yeasts (e.g., Candida, Histoplasma), or certain  atypical microorganisms (e.g., P. jirovecii). B-cell deficiencies  and phagocyte deficiencies, however, are suggested if the indi-  vidual has documented, recurrent infections with microorgan-  isms that require opsonization (e.g., encapsulated bacteria) or  viruses against which humoral immunity is normally effective  (e.g., rubella). Some complement deficiencies resemble defects in  antibody or phagocyte function, but others are commonly asso-  ciated with disseminated infections with bacteria of the genus  Neisseria (Neisseria meningitidis and Neisseria gonorrhoeae).   Much of our current understanding of the development  of the immune system and the interactions of the cells in the  immune response was developed by studying congenital and  acquired immune deficiencies or, as they have been called,  “experiments of nature.” Many immune deficiencies result from  selective alteration or removal of one component of the immune  system. We can understand the importance of that component  by observing the effect of its removal on the remainder of the  immune response.    Most primary immune deficiencies are the result of a single  gene defect*’ (Figure 9-11). Generally, the mutations are spo-  radic and not inherited: a family history exists in only about  25% of individuals. The sporadic mutations occur before birth,  but the onset of symptoms may be early or later, depending on  the particular syndrome. In approximately 60% of the cases  symptoms of immune deficiency appear within the first 2 years  of life, whereas other immune deficiencies are progressive, with  the onset of symptoms appearing in the second or third decade  of life. The most common symptoms include sinusitis (68%  of individuals), pneumonia (51%), ear infections (51%), diar-  rhea (30%), and bronchitis (55%), with the incidence varying  depending on the specific syndrome.   Many immune deficiencies also are associated with other  characteristic defects, some of which appear to be unrelated  to the immune system yet may be inherently life threatening.  Examples include eczema and thrombocytopenia (in Wiskott-  Aldrich syndrome); cardiac anomalies, low levels of calcium in  the blood, and structural anomalies of the face (in DiGeorge  syndrome); or a severe lack of muscular coordination and dila-  tion of the small blood vessels (in ataxia-telangiectasia). These  associated symptoms can be useful diagnostically. For instance,  the principal immunologic defect in DiGeorge syndrome is the  partial or complete absence of T-cell immunity. However, this  syndrome is also characterized by severe congenital structural  defects of the heart and low levels of calcium, which may result  in seizures.   MHC class | deficiency  MHC class II deficiency  Wiskott-Aldrich syndrome  Ataxia-telangiectasia    Mannose-binding lectin deficiency  Properdin, factor D or B deficiency  Factor H, factor | deficiency    Little or no class-switch to IgG or IgA, with  overproduction of IgM    Defective switch to an IgG subclass  Defective switch to IgA  Defective switch to >1 antibody class    Complete; lack of white blood cells  Complete; few or no T, B, or NK cells  Partial; few T or NK cells    Complete; little or no maturation of T or B cells;  normal NK cells    Abnormal cytotoxic T-cell activity  Abnormal helper T-cell activity  Altered T and B cells; decreased IgM  Altered T and B cells; absent IgA    Defective opsonization  Defective lysosomal granules  Lack of myeloperoxidase  Defective production of H,0,    AICD, Activation-induced cytidine deaminase; WHC, major histocompatibility complex; NADPH, nicotinamide adenine dinucleotide phosphate; NK,  natural killer; RAG, recombination activating gene; SCID, severe combined immune deficiency; TCR/BCR, T-cell receptor/B-cell receptor; ZAP zeta-  chain associated protein.    FIGURE 9-11 Lymphocyte Development Defects. This diagram shows defects in lymphocyte development that may  account for congenital (primary) immune deficiencies. See the text and refer to Figures 8-10 through 8-12 for more detailed  information. Pluripotent stem cell indicates the common stem cells for lymphocytic, granulocytic, and monocytic lineages.  Cytokine receptor defects include X-linked severe combined immunodeficiency (SCID) (IL-2 receptor defect), JAK3 defects,  and IL-7 receptor defects. T-cell receptor (TCR) defects include defects in CD3, CD45, and ZAP-70. Neither common variable  immune deficiency nor chronic mucocutaneous candidiasis is included in this figure because the cause of these defects remains  unknown. See Table 9-6 for further information on each defect. ADA, Adenosine deaminase deficiency; agamma, agamma-  globulinemia; A/CD deficiency, activation-induced cytidine deaminase deficiency; A/, ataxia-telangiectasia; PVP purine nucleo-  side phosphorylase deficiency; s/gM and sigD, surface IgM and IgD, respectively; WAS, Wiskott-Aldrich syndrome.    Individual primary immune deficiencies are very rare. For  instance, only 30 to 50 new cases of severe combined immune  deficiency are diagnosed in the United States yearly. How-  ever, approximately 150 different genetic defects resulting in  immune deficiencies have been identified. Together, primary  immune deficiencies are more common than cystic fibrosis,  hemophilia, childhood leukemia, or many other well-known  diseases. An estimated 50,000 cases of clinically significant  primary immune deficiency have been reported in the United  States. The gender distribution depends on the specific disease,  but in general those diagnosed within the first 2 years of life  have a male preponderance (5:1) because many are X-linked,  whereas those diagnosed later are evenly distributed. The three  most commonly diagnosed deficiencies are common variable  immune deficiency (34%), selective IgA deficiency (24%), and  IgG subclass deficiency (17%).   Primary immune deficiencies are classified into five groups,  based on which principal component of the immune or inflam-  matory systems is defective. This chapter uses the five clas-  sifications proposed by the National Institutes of Health.**  B-lymphocyte deficiencies result from defects in B-cell  immune responses. T-cell immunity rarely depends on com-  petent B-cell responses; thus T-cell immune responses are not  affected in pure B-lymphocyte deficiencies. T-lymphocyte  deficiencies are defects in the development and function of T  lymphocytes. Because T-helper cells are obligatory in the devel-  opment of many B-lymphocyte responses, antibody production  is often diminished in these conditions, although the B cells  are fully capable of producing an adequate antibody response.  Many textbooks disagree on the classification of several specific  immune deficiencies because of the difficulty in distinguishing  between primary B-cell defects and those that are secondary  to a primary T-cell defect. The classifications described below  define T-cell defects as those with a clear defect in T-cell immu-  nity, with normal B-cell immune responses. Combined T- and  B-lymphocyte deficiencies result from inherent defects that  directly affect the development of both T and B lymphocytes.  Some combined deficiencies result in major defects in both T-  and B-cell immune responses, whereas others are “partial” and  more adversely affect T cells than B cells. The partial combined  deficiencies include many conditions that may be classified as  T-cell defects in other textbooks. Complement deficiencies  and phagocytic deficiencies frequently present like antibody  deficiencies because of the close interactions among antibody,  complement, and phagocytes.   A defect in B-cell development results in lower levels of circulat-  ing immunoglobulins and increased susceptibility to infections  in which antibodies are the primary protective mechanism.*°  The condition in which immunoglobulin levels are lower than  normal is termed hypogammaglobulinemia. The condition  in which they are totally or almost totally absent is termed  agammaglobulinemia. (Normal lymphocyte development is  discussed in Chapter 8.) Recurrent infections range from life  threatening to mild, depending on the severity of the defi-  ciency. Characteristic infections include encapsulated bacteria    (e.g., Streptococcus pneumoniae or Haemophilus influenzae) that  may cause pneumonia or sepsis and other microorganisms that  cause infections of the sinuses, ears, and gastrointestinal tract.   The most severe B-lymphocyte deficiency is Bruton’s agam-  maglobulinemia, also referred to as X-linked agammaglobulin-  emia. Somewhat less than a third of the mutations are sporadic.  This condition results from mutations in the gene for Bruton’s  tyrosine kinase (Btk)—an enzyme involved in intracellular sig-  naling from several B-cell receptors, including the IgM B-cell  antigen receptor, the IL-5 receptor, and the IL-6 receptor. Inef-  fective signaling results in the arrest of the development in the  bone marrow of early cells in the B-cell lineage into mature B  cells*° (see Figure 9-11). Few or no circulating mature B cells are  present, although T-cell number and function are normal. At 6  months of life the approximate normal serum concentrations  of immunoglobulins are IgG, 400 mg/dl; IgM, 40 mg/dl; and  IgA, 30 mg/dl. In 6-month-old children with Bruton’s agam-  maglobulinemia, serum IgG levels are well below 100 mg/dl and  IgM and IgA are almost absent.   An autosomal recessive form of agammaglobulinemia (auto-  somal agammaglobulinemia) results from other mutations in  the B-cell receptor. The most common is a mutation of the mu  (y) chain of the IgM portion of the receptor. This mutation pre-  vents intracellular signaling after antigen binds to the receptor,  leading to blocked maturation, the absence of antibody produc-  tion, and very severe infections.   Several defects in antibody class-switch have been identified  (see Figure 9-11). X-linked hyper-IgM syndrome results from  a mutation in CD40 ligand, which is expressed on the surface  of T-helper (Th) cells. Th cells stimulate B cells to undergo a  switch in the class of antibody they produce through multiple  Th-—B-cell interactions involving ligands expressed on one cell  binding to specific receptors on the other cell. The ligand-  receptor interaction results in an intracellular signal facilitat-  ing rearrangement of the genes for the antibody variable region  from a site near the constant region gene for the » chain to the  constant region for a different antibody H chain (see Figure  8-20). A critical ligand-receptor interaction occurs between the  receptor CD40 on the B cell and its ligand (CD154 or CD40L)  on the Th cell. A mutation in CD40L results in defective class-  switch, decreased or absent production of IgG and IgA, poor  development of memory B cells, and overproduction of IgM.  T-cell immunity is not affected.   Defects in other components of the Th—B-cell interaction  result in autosomal hyper-IgM syndrome. Mutations in CD40  on B cells result in a similar effect to that described previ-  ously. A defect in a DNA editing enzyme (activation-induced  cytidine deaminase; AICD) also inhibits class-switch. During  class-switch and movement of the H chain genetic information  for the variable region to a different constant region gene, the  double-stranded DNA must be cut and mended. This enzyme is  responsible for cutting and mending the DNA.   Deficiencies in certain subclasses of antibody (IgG subclass  deficiency), particularly IgG2, may result from a defect in  switch to a particular subclass constant region (see Figure 9-11).  The level of IgG2 subclass is often increased in response to poly-  saccharide antigens such as those on the surface of encapsulated    bacteria. Low levels of IgG2 may be responsible for recurrent  risk for pneumonias caused by these bacteria. Whether IgG sub-  class deficiencies are unique immune deficiency conditions is  unclear because many are apparently early indications of the  development of common variable immune deficiency (see fol-  lowing) or are secondary to selective IgA deficiency.   One of the most common primary immune deficiencies is  a selective IgA deficiency. Because many affected individuals  are asymptomatic, the true incidence is uncertain, although  estimates ranging from 1 person in 300 to 1 in 3000 have been  made. Individuals with selective IgA deficiency are able to pro-  duce other classes of immunoglobulins but fail to produce IgA  (see Figure 9-11). Many will have B cells that have undergone  class-switch to IgA, but for unknown reasons, cannot undergo  the terminal steps of differentiation to IgA-secreting plasma  cells. Although many individuals are asymptomatic, others pres-  ent with a history of severe recurring sinus, lung, and gastroin-  testinal infections. They commonly also have chronic intestinal  candidiasis (infection with Candida albicans). (The secretory,  or mucosal, immune system is described in Chapter 8.)   Complications of IgA deficiency include severe atopic dis-  ease and autoimmune diseases; selective IgA deficiency is two  or three times more common in atopic individuals than in oth-  ers. Secretory IgA normally may prevent the uptake of aller-  gens from the environment so that IgA deficiency may lead to  increased allergen uptake and a more intense challenge to the  immune system because of prolonged exposure to environ-  mental antigens. One of the most severe complications of IgA  deficiency is an anaphylactic reaction that can follow adminis-  tration of blood products that contain IgA. Serious anaphylactic  reactions can occur in individuals totally lacking IgA because  the immune system recognizes donor IgA as a foreign antigen.  Initial sensitization can occur in fetal life through exposure to  maternal IgA that leaks across the placenta or later through  the ingestion of maternal IgA in breast milk or bovine IgA in  cow’s milk. Sensitization also can occur with initial administra-  tion of blood products containing IgA. The individual’s primed  immune system then acts against donor IgA on subsequent  exposure.   Common variable immune deficiency is the most com-  monly diagnosed immune deficiency. As the name implies,  the presentation is very heterogeneous. It is characterized by  hypogammaglobulinemia, but the particular class of antibody  that is decreased varies: most have low amounts of IgG, which  may or may not be accompanied by decreased levels of IgA  or IgM, or both, with normal numbers of B cells. Some may  have accompanying T-cell defects. Multiple genetic defects in  terminal differentiation account for this condition, although  the specific defects have not been identified in most people.  The age of onset of symptoms, such as recurrent bacterial  respiratory tract infections, is generally later than most pri-  mary immune deficiencies (late twenties). Secondary com-  plications include arthritis (infectious and noninfectious),  gastrointestinal symptoms (malabsorption, chronic diarrhea),  autoimmune disease (anemia, thrombocytopenia, endocrine  diseases), and cancer (of the lymphoid system, skin, and gas-  trointestinal tract).   Two well-studied examples of T-lymphocyte defects that repre-  sent different ends of the T-cell differentiation process include  DiGeorge syndrome and chronic mucocutaneous candidiasis.  Lymphoid stem cells begin maturing into functional T lympho-  cytes in the thymus. DiGeorge syndrome (congenital thymic  aplasia or hypoplasia) is caused by the lack, or more commonly  partial lack, of the thymus, resulting in greatly decreased T-cell  numbers and function and in life-threatening viral, fungal, and  intracellular bacterial infections*’ (see Figure 9-11). The defect  is attributed usually to deletions on chromosome 22 (some  deletions also have been identified on chromosome 10),*®  about 25% of which are inherited. The deleted region encodes  information for formation of organs that originate from the  third and fourth pharyngeal pouches during the twelfth week  of gestation. In addition to the lack of thymus development,  the individual may present with a partial or complete absence  of the parathyroid gland (resulting in decreased blood cal-  cium levels), major structural defects in the heart and the aorta  (resulting in inadequate blood flow and inadequate oxygen-  ation of the tissues), and abnormal facial characteristics (e.g.,  underdeveloped chin, low-set ears, shortened structure of the  upper lip) (Figure 9-12).   Chronic mucocutaneous candidiasis is a primary defect  of T lymphocytes in response to a specific infectious agent,  the yeast C. albicans. At least seven variants of this condition  have been described. All are characterized by mild to extremely  severe chronic mucocutaneous candidiasis: Candida infections  that involve the mucous membranes, nails, and skin. Invasive  candidiasis is extremely rare. Although most B- and T-cell  immune responses may be normal, most individuals with this  defect cannot react to antigens from Candida. The cause of this  defect is unknown.    The most severe deficiencies usually occur when both the B- and  T-cell immune responses are affected. A great deal of knowledge  about the evolution of bone marrow stem cells into functional  B- and T-cell effectors came from studying children with the    FIGURE 9-12 Facial Anomalies Associated with DiGeorge Syndrome.  Note the wide-set eyes, low-set ears, and shortened structure of the upper lip.  (From Roitt |, Brostoff J, Male D: /mmunology, ed 6, St Louis, 2001, Mosby.)    most severe immune deficiency, severe combined immune  deficiency (SCID). The most severe form of SCID is reticu-  lar dysgenesis (failure of blood cells to develop), in which a  common stem cell for all white blood cells is absent; therefore,  T cells, B cells, and phagocytic cells never develop (see Figure  9-11). Most children with reticular dysgenesis die in utero or  very soon after birth. More typically, a defect occurs after some  stem cells become committed to developing into lymphocytes  (lymphoid stem cells); therefore, most individuals with SCID are  deficient in lymphocyte development, but have normal numbers  of all other white blood cells. SCID often results in few or absent  T and B lymphocytes in the circulation and secondary lymphoid  organs (spleen, lymph nodes). The thymus is usually hypoplastic  (underdeveloped) because of the absence of T cells. Immuno-  globulin levels, especially of IgM and IgA, are absent or greatly  reduced, although IgG levels may be almost normal in the first  months of life because of the presence of maternal antibodies. In  the most severe defects, death occurs at about 1 year of life.   At least 20 different forms of SCID have been identified.  Depending on the specific genetic mutation, the defect may  involve T cells, B cells, and NK cells or may suppress more  severely the function of one cell type, with relatively minor  effects on the others. All three cells are adversely affected (T-,  B-, NK-—) in SCID resulting from a deficiency of adenosine  deaminase (adenosine deaminase [ADA] deficiency), which  is an enzyme involved in purine metabolism (see Figure 9-11).  This defect is autosomal recessive and results in the accumula-  tion of toxic purine metabolites to which rapidly dividing cells,  such as lymphocytes, are especially sensitive. ADA deficiency  accounts for about 16% of all persons with SCID. The devel-  opment of T cells, B cells, and NK cells is arrested very early,  and very few lymphocytic cells are found in the blood. In some  forms of SCID, the defect resides in receptors for cytokines  that are necessary for maturation of lymphocytes (see Figure  9-11). T cells and NK cells are preferentially affected (T—, B+,  NK-—), but often the defect results in the production of imma-  ture B cells that cannot respond well to antigen because of the  lack of Th cells. The most common (44% of those with SCID)  is an X-linked SCID resulting from a defect in the IL-2 recep-  tor gamma (y)-chain (IL-2Ry). This protein is a component of  several receptors for cytokines, including IL-2, IL-4, IL-7, IL-9,  IL-15, and IL-21. These cytokines participate in the early devel-  opment of immunocytes, particularly T and NK cells. Defective  IL-2Ry results in arrested maturation of T and NK cells and the  production of immature B cells. A similar deficiency occurs with  mutation in JAK3 (JAK3 deficiency), which is an enzyme (a  tyrosine kinase) that associates with IL-2Ry in normal cells and  communicates information from the receptor to the nucleus.  Thus cells with defects in JAK3 cannot respond to cytokines that  bind to these receptors on the cell surface. An autosomal form  results from mutations of one of the protein chains (a-chain)  of the IL-7 receptor (IL-7 receptor deficiency). IL-7 appears to  be necessary for the maturation of T cells, so that this deficiency  has relatively normal levels of B cells and NK cells.   Mutations in another purine metabolism enzyme, purine  nucleoside phosphorylase (purine nucleoside phosphorylase  [PNP] deficiency), are less severe than ADA deficiency (see    Figure 9-11). T cells and NK cells appear to be more susceptible to  mutations in PNP so that B-cell function can be relatively normal.   Another form of SCID preferentially affects T cells and B  cells (T—, B—, NK+). T and B lymphocytes possess receptors for  antigen, whereas NK cells do not. Those receptors result from a  process of genetic rearrangement of V and J genes to form the  variable regions of the L chain (B-cell receptor [BCR]) and the  a-chain (T-cell receptor [TCR]) and the V, D, and J genes to  form the variable regions of the H chain (BCR) and the $-chain  (TCR). Successful rearrangement is controlled by two recombi-  nation activating enzymes (RAG-1 and RAG-2). RAG enzymes  cut and repair double-stranded breaks in DNA that are nec-  essary for genetic rearrangement. RAG-1 or RAG-2 deficien-  cies are autosomal recessive and result in arrested lymphocyte  development from blocked recombination of variable regions  of B-cell and T-cell receptors (see Figure 9-11).   Forms of partial SCID, with the defect being primarily of T  cells, arise from mutations in several components of the TCR  complex (see Figure 9-11). Defects in the TCR result in inad-  equate maturation of T cells, with normal B and NK cells. Anti-  body production may be depressed because of the lack of Th  cells. The TCR is a complex organization of proteins that react  with antigen (a- and f-chains), and then provide an intracellu-  lar signal to the nucleus (y-, 6-, and e-chains [collectively called  CD3] and the associated molecules CD45 and ZAP-70). Exam-  ples of these deficiencies include mutations in CD3, CD45, or  ZAP-70. The T-cell defect in each can range from mild to severe  in nature, with normal B lymphocytes.   Even if nearly adequate numbers of B and T cells are pro-  duced, their ability to process and present antigen may be defec-  tive. The bare lymphocyte syndrome is a group of immune  deficiencies characterized by an inability of lymphocytes and  macrophages to present antigen because of defects in class I or  class II MHC antigen expression (see Figure 9-11). MHC class  I deficiency results from mutations in the genes for TAP] or  TAP2, which control the transport of antigenic protein frag-  ments across the endoplasmic reticulum and the formation of  MHC class I/antigen complexes for transportation to the cell  surface (see Figure 8-16). Because MHC class I molecules pref-  erentially present antigen to CD8+ Tc cells, the resultant defi-  ciency is of CD8+ cytotoxic cells, with normal levels of CD4+  helper cells and normal antibody production. MHC class II  deficiency is more severe. A variety of mutations prevent nor-  mal production of MHC class II molecules, which present  antigen to CD4+ helper cells. Because of defective recruitment  of T-helper cells, normal antibody responses are greatly sup-  pressed. Children with this deficiency develop life-threatening  infections and usually die before age 5 years.   Some combined immune deficiencies are secondary to muta-  tions that affect a variety of cells other than immunocytes. For  instance, Wiskott-Aldrich syndrome (WAS; an X-linked reces-  sive disorder) results from sporadic mutations in the WAS pro-  tein (WASP), which is involved in intracellular signaling and  regulation of the organization of the cell’s actin cytoskeleton (see  Figure 9-11). The defects in the cytoskeleton lead to the classic  symptoms of thrombocytopenia (with resultant bleeding dis-  orders), scaly eczema, and defective T and B cells. IgA and IgG    levels are usually normal, but IgM responses are highly depressed.  Antibody responses against antigens that elicit primarily an IgM  response, such as polysaccharide antigens from bacterial cell  walls (e.g., of Pseudomonas aeruginosa, S. pneumoniae, H. influ-  enzae, and other microorganisms with polysaccharide outer cap-  sules), are deficient. Persons with WAS have a very high risk of  lymphoid malignancies (leukemias and lymphomas).   Ataxia-telangiectasia (AT) is an autosomal recessive disorder  resulting from a large variety of sporadic mutations in the ATM  gene, which encodes a protein involved in repair of double-  stranded breaks in DNA. Affected infants often develop ataxia  (unsteady gait), which usually becomes apparent when the child  is learning to walk. The neurologic defect may eventually lead to  confinement in a wheelchair. Telangiectasia (dilation of capillar-  ies) can occur in the eyes and skin, especially on the ears, neck,  and extremities. Both B and T cells are variably affected and unre-  paired double-stranded DNA breaks are commonly observed in  the regions encoding the T-cell and B-cell receptors. About 70%  of those with AT are IgA deficient, occasionally accompanied by  deficiencies in IgG (see Figure 9-11). Individuals with AT are at  high risk for developing leukemias and lymphomas.   Complement activation is a necessary component of protection  against many infectious agents. IgG and complement compo-  nents, such as C3b, are opsonins and facilitate phagocytosis  by neutrophils and macrophages. Defects in the complement    cascade often resemble antibody deficiencies, with recurrent  infections with encapsulated bacteria (e.g., H. influenzae and  S. pneumoniae) that are highly sensitive to opsonin-assisted  phagocytosis. In addition to recurrent infections, deficiencies in  the classical pathway commonly lead to a SLE-like syndrome.  As noted previously, excessive levels of circulating complexes  of antibody, antigen, and complement may lead to type Il  hypersensitivity diseases (immune complex diseases). However,  healthy individuals release small amounts of soluble intracel-  lular antigens into the blood during normal cell turnover. Low  levels of naturally occurring autoantibodies and limited activa-  tion of the classical pathway of the complement system through  C3 facilitate the removal of this debris by phagocytes. Some  complement defects may slow the clearance from the blood of  natural immune complexes, leading to SLE-like symptoms.   C3 deficiency is the most severe complement defect (Figure  9-13). C3 is the component that unites all pathways of comple-  ment activation, and complement component C3b is a major  opsonin. Persons with C3 deficiency are at risk for recurrent  life-threatening infections with encapsulated bacteria at an early  age, as well as a SLE-like syndrome that may be complicated by  kidney disease (glomerulonephritis). C2 deficiency, more so  than Cl or C4 deficiencies, also has an increased risk for recur-  rent respiratory tract infections with encapsulated bacteria (e.g.,  S. pneumoniae, H. influenzae).   Mannose-binding lectin (MBL) deficiency is the pri-  mary defect of the lectin pathway of complement activation.    FIGURE 9-13 Complement Defects. The complement cascade is initiated through three pathways: the classical pathway,  the lectin pathway, and the alternative pathway. Each of the three pathways produces a C3 convertase, which activates C3  leading to the formation of a C5 convertase. The activation of C5 initiates formation of the membrane attack complex (MAC).  For more details, see the text and Figure 7-5. The most severe defect is a C3 deficiency because it blocks all three pathways.  MASP MBL-associated serine protease; MBL, mannose-binding lectin.    The defect results in increased risk of infection with microor-  ganisms that have polysaccharide capsules rich in mannose,  particularly the yeast Saccharomyces cerevisiae and encapsulated  bacteria such as N. meningitidis and S. pneumoniae.   Deficiencies in the alternative pathway also result in recur-  rent infections with encapsulated bacteria. Properdin defi-  ciency is associated with recurrent meningococcal infections  and is X-linked, whereas all other complement deficiencies are  autosomal recessive. Symptoms generally appear in the second  decade of life. Factor I and factor H are major regulators of the  complement cascade and control the level of spontaneous acti-  vation of C3. Factor I deficiency and factor H deficiency can be  severe because they lead to increased spontaneous destruction  of C3 and a secondary C3 deficiency.   Deficiencies of components of the terminal portion of the  complement cascade (C5, C6, C7, C8, or C9 deficiencies) are  associated with increased infections with only one group of bac-  teria—those of the genus Neisseria (N. meningitidis or N. gonor-  rhoeae). Neisseria usually cause localized infections (meningitis  or gonorrhea), but those individuals with terminal pathway  defects have more than an 8000-fold increased risk for sys-  temic infections with atypical strains of these microorganisms.  C9 deficiency is the most common terminal pathway defect,  appears primarily in Japanese populations, and is generally    asymptomatic. The other deficiencies of the terminal pathway  are extremely rare, but are characterized by more aggressive  infections. The risk for systemic infections with Neisseria is also  increased in those with deficiencies of C2, factor D, factor B,  and properdin.   Phagocytosis is generally aided by bacterial opsonization with  IgG or C3b; therefore, defects in phagocytic killing usually result  in recurrent infections with the same group of microorganisms  (encapsulated bacteria) associated with antibody and comple-  ment deficiencies. Phagocytosis is a multistep process that  involves initial adhesion between circulating phagocytes and  the endothelial cells lining the circulation (see Figure 7-15). The  phagocytes exit the circulation and move to a site of infection  by a chemotactic process in response to soluble chemotactic fac-  tors released by the infection. The process of phagocytosis itself  begins with attachment of the phagocyte to the targeted bacte-  ria through the interaction of opsonins on the microorganism  and matched receptors on the phagocyte’s surface. Phagocytic  engulfment results in internalization of the infectious agent and  activation of a variety of oxygen-dependent and oxygen-inde-  pendent killing mechanisms. Deficiencies can arise from muta-  tions that affect one or more of these steps (Figure 9-14).   FIGURE 9-14 Phagocytic Defects. Several genetic defects in the process leading up to and including phagocytosis  result in increased susceptibility to bacterial infections. See the text and refer to Figure 7-15 and Table 7-3 for more detailed  information. The phagocyte leaves the bloodstream and enters the tissue through interactions between leukocyte and endo-  thelial adhesion molecules and the process of diapedesis. The cell is attracted to the inflammatory site by chemotaxis, where  it encounters opsonized bacteria, and attaches to and engulfs the microorganism. Inside the phagocyte the bacteria are killed  and broken down by the combination of lysosomal granule constituents and reactive oxygen products of the hexose-monophos-  phate shunt and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. C3R, C3 receptor, which includes the C3b  receptor (C3bA); Fey, receptor for the Fc portion of IgG; Hz02, hydrogen peroxide; 03, reactive oxygen.    Inadequate numbers of phagocytes, particularly neutro-  phils (severe congenital neutropenias), result in a variety of  recurrent and severe bacterial infections beginning early in life.  Approximately 50% of these individuals have a mutation in the  neutrophil elastase gene (ELA2). Other mutations have been  identified (e.g., WAS gene) in the other 50%. A milder form,  cyclic neutropenia, is autosomal dominant with almost 100%  of affected individuals having a mutation in the ELA2 gene.  Changes in neutrophil levels are cyclic and may remain at or  near normal for 2 to 3 weeks, followed by periods of neutro-  penia lasting a few days to weeks. During the neutropenia, the  individual has increased susceptibility to recurrent bacterial  infections.   Near sites of inflammation, soluble mediators diffuse into  the circulation and induce expression of a variety of adhe-  sion molecules on the phagocyte surface, which interact with  complementary molecules on the endothelial cells to increase  adherence between the phagocyte and the vessel wall and allow  for margination and diapedesis to occur. Leukocyte adhesion  deficiencies (LADs) result from mutations in various phago-  cyte adhesion molecules (see Table 7-3). Leukocyte adhesion  deficiency, type 1 (LAD-1) results from an autosomal recessive  mutation in CD18, which is a B-integrin chain that is shared by  several different receptors. LAD-2 results from a defect in adding  the monosaccharide fucose to carbohydrates on the phagocyte  surface. Surface carbohydrates with fucose are ligands for selec-  tins on the endothelial and leukocyte. These and other defects  in leukocyte adhesion molecules usually result in increased  levels of neutrophils in the blood (leukocytosis) because they  cannot leave the circulation and in increased recurrent bacterial  and fungal infections.   Additional deficiencies diminish the leukocyte’s recognition  of opsonins of the complement cascade (e.g., C3b). Deficiencies  in the complement receptor for C3 (C3 receptor deficiency)  result in recurrent bacterial infections, particularly of the skin.   A variety of defects in killing of microorganisms have been  described. Chédiak-Higashi syndrome results from a defect  in cytoplasmic granules from an autosomal recessive mutation  in the lysosomal trafficking regulator gene (CHS1). The CHS1  protein helps control movement of granules to cellular mem-  branes in preparation for degranulation. As a result of these  mutations, the granules remain in the cytoplasm and form large  aggregates that are readily apparent microscopically. Leuko-  cytes from individuals with Chédiak-Higashi syndrome have  decreased chemotaxis, granular fusion, and bacterial killing.  Platelet granules also may be affected, resulting in prolonged  bleeding, and partial albinism can occur because of defects in  melanocyte granules. Affected children develop recurrent infec-  tions of the skin, respiratory tract, and mucous membranes,  especially with gram-positive bacteria.   The enzyme myeloperoxidase participates in a major mecha-  nism of bacterial killing in phagocytes. Myeloperoxidase is found  in primary granules and catalyzes the formation of acids from  halides (e.g., chloride ion) and hydrogen peroxide (H,O). As a  result of phagocytosis, neutrophils and other phagocytes switch  much of their glucose metabolism to the hexose-monophos-  phate shunt. A byproduct of this pathway is the conversion of    molecular oxygen by nicotinamide adenine dinucleotide phos-  phate (NADPH) oxidase and other enzymes into highly reac-  tive and toxic oxygen derivatives, including hydrogen peroxide.  Two deficiencies in the myeloperoxidase-hydrogen peroxide  killing process have been extensively studied. Myeloperoxidase  deficiency is a relatively mild disorder characterized by a com-  plete or partial deficiency in myeloperoxidase. Individuals do  not have severe recurrent infections because most infectious  bacteria are sensitive to direct killing by many of the toxic oxy-  gen molecules produced by NADPH oxidase. The exception is  the person with concurrent diabetes, who may have recurrent  disseminated candidiasis.   Chronic granulomatous disease (CGD) is a more severe  defect in the myeloperoxidase—hydrogen peroxide system.*? Sev-  eral forms of the disease have been characterized, both X-linked  (about 70% of the individuals) and autosomal recessive, with the  X-linked form being more severe. CGD occurs from a variety of  mutations (at least four have been identified) in portions of the  NADPH oxidase complex, resulting in deficiencies in the pro-  duction of hydrogen peroxide and other oxygen products. Thus  individuals have adequate myeloperoxidase and chloride but lack  the necessary hydrogen peroxide. Individuals with CGD have  recurrent severe pneumonias; tumor-like granulomas in lungs,  skin, and bones; and other infections with some normally rela-  tive innocuous microorganisms, such as Staphylococcus aureus,  Serratia marcescens, Aspergillus spp., and others. These are cat-  alase-positive microorganisms. Infections with more virulent,  but catalase-negative, microorganisms (e.g., S. pneumoniae)  are rare. Most microorganisms produce their own hydrogen  peroxide as a byproduct, which accumulates in the phagocytic  vacuole and can be used by the phagocyte’s myeloperoxidase to  kill the microorganism. Some microorganisms also produce the  enzyme catalase, which breaks down hydrogen peroxide. Thus  catalase-negative microorganisms donate hydrogen peroxide to  the phagocyte’s myeloperoxidase, leading to their own death.  Catalase-positive microorganisms, however, destroy the bacte-  rial hydrogen peroxide and survive and cause infection.    Secondary Immune Deficiencies  Secondary, or acquired, immune and inflammatory deficiencies  are far more common than primary deficiencies.*° These defi-  ciencies are not related to genetic defects, but are complications  of other physiologic or pathophysiologic conditions. Some con-  ditions that are known to be associated with acquired deficien-  cies include:  * Normal physiologic conditions  * Pregnancy  + Infancy  * Aging  + Psychologic stress  + Emotional trauma  + Eating disorders  * Dietary insufficiencies  + Malnutrition caused by insufficient intake of large cat-  egories of nutrients, such as protein or calories  + Insufficient intake of specific nutrients, such as vitamins,  iron, or zinc    * Malignancies  + Malignancies of lymphoid tissues, such as Hodgkin dis-  ease, acute or chronic leukemia, or myeloma  * Malignancies of nonlymphoid tissues, such as sarcomas  and carcinomas  * Metabolic diseases or genetic syndromes  * Diabetes  * Cystic fibrosis  * Alcoholic cirrhosis  * Sickle cell disease    * SLE  + Chromosome abnormalities, such as trisomy 21 (Down  syndrome)   radiation  * Infections  * Congenital infections, such as rubella, cytomegalovirus,  hepatitis B   Although secondary deficiencies are common, many are not  clinically relevant. In many cases, the degree of the immune defi-  ciency is relatively minor and without any apparent increased  susceptibility to infection. Alternatively, the immune system  may be substantially suppressed, but only for a short duration,  thus minimizing the incidence of clinically relevant infections.  Some secondary immune deficiencies, however, are extremely  severe and may result in recurrent life-threatening infections.    The competence of an individual’s immune system varies  throughout life. Pregnancy itself is considered by many to be  an immunocompromised condition. Pregnant women may  have decreased reactivity or altered results in several tests of the  immune system, including skin tests against various antigens,  circulating numbers of T lymphocytes, and other very general  tests. Pregnancy itself, however, is not associated with a marked  change in infections, suggesting that the mother’s immune sys-  tem is not severely altered.   The newborn child is immunologically immature. Although  T-cell immune responses may be normal or near normal,  other components of the immune system (especially antibody  production) are just beginning to mature. Beginning at about  32 weeks of pregnancy, the placenta transports maternal antibod-  ies into the fetal blood to protect the child during the first months    of life (see Figure 8-30). After the delivery, the level of the moth-  er’s antibodies slowly decreases in the newborn so that maternal  antibodies no longer protect the child by about 6 months of life.  By 6 to 8 months, the newborn should be efficiently protected  by antibodies produced by its own B cells. In some infants, the  development of antibody production is delayed, and a transient  low level of antibody may persist for several months (transient  hypogammaglobulinemia of infancy), during which the child  has increased susceptibility to infections. Premature infants are  particularly immunologically immature and are at increased  risk for neonatal infections. The blood of infants born before  32 weeks’ gestation is generally devoid of maternal antibody.   Aging is also associated with a progressive depression in  immune responses. Older adults generally have more severe  bacterial and fungal infections, greater difficulty resolving those  infections, and lower responses to vaccination.   Several meaningful changes occur during aging, although  variations in the degree of change and a corresponding increased  susceptibility to infection can be considerable among individu-  als. The thymus involutes over time, resulting in decreased pro-  duction of fresh T cells. A concurrent depletion of T-memory  cells results in depressed responses to both new and “recall”  antigens. A shift toward Th2 cells also may occur with a resul-  tant decrease in Th1 cytokines. Total numbers of B cells may  decrease. Numbers of NK cells may remain normal, although  their activity is decreased. Similarly, neutrophil numbers may  remain normal, with decreased phagocytosis and killing.    The relationship between emotional stress and depressed  immune function has become an area of intense clinical and  research interest. For many decades anecdotal reports have sug-  gested that increased incidences of infection and malignancy  are associated with periods of both intense stress (e.g., the loss  of a loved one, divorce) and relatively minor stress (e.g., final  examination periods at colleges and universities). In addition,  early studies showed that immune function, as demonstrated  by delayed hypersensitivity skin test results, could be depressed  through posthypnotic suggestion.   We are now beginning to understand the mechanisms of the  relationship between emotional stress and the immune system.  Many lymphoid organs are innervated and can be affected by  nerve stimulation. In addition, lymphocytes have receptors for  many hormones (e.g., sex hormones, neurotransmitters, and  neuropeptides) and can respond to changing levels of these  chemicals with increased or decreased function. For instance,  stress-induced catecholamines affect the expression of adhesion  molecules and the movement of lymphocytes among lymphoid  organs. (Further discussion of the effects of stress on suscepti-  bility to disease is the subject of Chapter 11.)    Nutritional status can have a profound effect on immune func-  tion, and malnutrition is the predominant cause of secondary  immune deficiencies worldwide. Severe deficits in calorie or pro-  tein intake lead to deficiencies in T-cell function and numbers.  The humoral immune response is less affected by starvation,    although complement activity, neutrophil chemotaxis, and bac-  terial killing within neutrophils often are depressed, resulting in  infections with microorganisms that are normally destroyed by  opsonization and phagocytosis.   Deficient zinc intake can profoundly depress both T- and  B-cell function. Zinc is required as a cofactor for at least 70 dif-  ferent enzymes, some of which are found in lymphocytes and  are necessary for their function. Secondary zinc deficiencies may  be associated with malabsorption syndrome (failure to absorb  zinc), chronic renal disease (loss of zinc in the urine), chronic  diarrhea (loss of zinc through the gut), or burns or severe psori-  asis (loss of zinc through the skin). Deficiencies of other enzyme  cofactors, such as vitamins (e.g., pyridoxine, pantothenic acid,  folic acid, and vitamins A, C, E, and B,,), also may result in  severe depressions of B- and T-cell function, phagocytosis, and  complement activity.    Many malignancies are complicated by a wasting syndrome  (cachexia) in the later stages, which can suppress the immune  system secondary to the resultant malnutrition. Additionally,  a very close relationship exists between the immune system  and the development of malignancies. It is generally accepted  that successful malignancies have developed mechanisms to  avoid rejection by the individual’s immune system. Persons  with primary immune deficiencies are usually at greater risk  for developing malignancies, particularly malignancies of lym-  phoid tissues, such as leukemias or lymphomas. Malignancies  aggressively depress the individual’s immune system. The effect  is commonly nonspecific, resulting in a generalized deficiency  of the immune response and a greatly increased susceptibility  to developing life-threatening infections. In fact, many people  with malignancies die from infection rather than from direct  effects of the tumor.   Malignancies of lymphoid tissues, such as Hodgkin disease,  acute or chronic leukemia, or myeloma, result in depletion of  normal lymphocytes and their replacement by the malignant  cells. Thus the number of B or T cells capable of responding to  infections is depleted. Many malignancies, even those of non—  lymphoid tissues, produce cytokines (e.g., transforming growth  factor-beta [TGF-8] and vascular endothelial growth factor  [VEGF]) that nonspecifically suppress the immune responses.    Diabetes suppresses many aspects of the immune and inflam-  matory responses, including phagocytosis and chemotaxis,  lymphocyte proliferation, and glucose metabolism. The effects  of trisomy 21 are less severe, but primarily include diminished  neutrophil function. People with cystic fibrosis have decreased  airway clearance of bacteria, thus increasing the probability of  major respiratory tract infections.    Individuals are constantly exposed to environmental agents that  affect the immune system. UV light from sun exposure or tan-  ning salons induces apoptosis of lymphoid stem cells, increases  production of Treg cells that suppress defenses against cancer,    and increases production of anti-inflammatory cytokines. Ion-  izing radiation affects rapidly dividing cells, including those of  the immune system. At very high doses, the entire immune sys-  tem can be depleted.    Trauma that compromises the epithelial barrier also predis-  poses an individual to infection. Burn victims are susceptible  to severe bacterial infections. Thermal burns appear to be  associated with suppressed neutrophil function (especially  chemotaxis), complement levels, cell-mediated immunity,  and primary humoral responses, although secondary humoral  responses are normal. The mechanism of this immunosuppres-  sion may be twofold. Blood from burned individuals contains  nonspecific immunosuppressive factors (all immune responses  are suppressed, regardless of the antigen involved). In addition,  burn victims also have increased regulatory T-cell function,  which may increase antigen-specific suppression.    Medical treatments themselves may produce suppression of  immune responses. Depression of B- and T-cell formation is  manifested as a progressive increase in infections with opportu-  nistic microorganisms (especially P. jirovecii, cytomegalovirus,  C. albicans, and other fungi), the extent and location of which  are unusual.   Many drugs that are used to fight cancer (e.g., cancer che-  motherapeutic agents) are not specific for cancer cells, but  are designed to attack cells in susceptible stages in their cell  cycles or rapidly proliferating cells, which includes cells of the  immune system as well as malignant cells. The immunosup-  pressive effects of chemotherapeutic drugs are exacerbated by  concurrent treatment with ionizing radiation (x-rays), which  also affect cells that are rapidly making new DNA. Therefore,  a person’s immune response can be profoundly depressed as a  result of the therapy. Other drugs, such as corticosteroids, are  intentionally used to suppress the immune system and control  hypersensitivity diseases (especially autoimmune disease) or  prevent rejection of transplants. Because of their nonspecific  activity, however, immune responses against infectious agents  also can be suppressed, increasing an individual’s susceptibility  to infection. The list of drugs that affect the immune response  is ever increasing and includes analgesics, antithyroid medica-  tions, anticonvulsants, antihistamines, antimicrobial agents,  antilymphocyte antibodies, and tranquilizers.   Surgery and anesthesia also can suppress T- and B-cell func-  tion. Transient, severe lymphopenia is a common postoperative  condition that can last as long as 1 month. Surgery to remove  the spleen (splenectomy) can result in a depressed humoral  response against encapsulated bacteria (especially S. pneu-  moniae, H. influenzae, S. aureus, group A streptococci, and N.  meningitidis), depressed serum IgM levels, and decreased levels  of opsonins.    Many infectious microorganisms are successful at invading  the human body because they have evolved mechanisms for    fighting off specific immune/inflammatory responses against  themselves (discussed in Chapter 10). However, some infec-  tious agents (e.g, human immunodeficiency virus [HIV],  Epstein-Barr virus [EBV], CMV, herpes simplex virus type 6,  measles) can generally suppress the immune response. HIV is  one of the few microorganisms that directly attacks the central  processes involved in the development of an immune response  (discussed in detail in Chapter 10). It infects and destroys the  T-helper cell, which is necessary to provide help for the matu-  ration of both plasma cells and T-cytotoxic cells.*! Therefore,  HIV suppresses the immune response against itself and second-  arily creates a generalized immune deficiency by suppressing  the development of immune responses against other pathogens  and opportunistic microorganisms.   Several viruses (e.g., hepatitis B, rubella, CMV) can establish  congenital infections through transmission from an infected  mother to her child at birth when the child’s immune system  is immature. These children may have suppressed immune  responses, although the degree of the deficiency is not usually  severe; however, as the child’s immune system develops, the  viral antigens may be partially seen as “self” so that a chronic  infection is established.   Routine care of individuals with immune deficiencies must be  tempered with the knowledge that the immune system may  be totally ineffective. Administration of conventional immu-  nizing agents or blood products to these individuals may be  unsafe because of the risk that the immunizing agent will cause  an uncontrolled infection. Attenuated vaccines contain live  but weakened microorganisms (e.g., live polio vaccine; vac-  cines against measles, mumps, and rubella) that can cause dis-  seminated infection. Although the vaccine virus is attenuated  enough to be destroyed by a normal immune system, it can sur-  vive, multiply, and cause severe disease in an immune-deficient  recipient. Additionally, even healthy recipients of vaccines con-  taining live microorganisms can shed those microorganisms for  a short time, increasing the risk of infection to family members  or other close associates who are immune deficient. Even simple  procedures, such as penetrating the skin for routine blood tests,  may lead to fatal septicemia (bacterial infection of the blood) in  the immune-deficient person.   Individuals with immune deficiencies are also at risk for  graft-versus-host disease (GVHD). Mature T cells in a trans-  planted graft (e.g., transfused blood) are capable of a destructive  cell-mediated reaction against unmatched histocompatibility  antigens on the tissues in the graft recipient. Symptoms of an  acute graft-versus-host reaction usually appear within 10 to 30  days after the transplant. The primary targets for GVHD are the  skin (e.g., rash, loss or increase of pigment, thickening of skin),  liver (e.g., damage to bile duct, hepatomegaly), mouth (e.g., dry  mouth, ulcers, infections), eyes (e.g., burning, irritation, dry-  ness), and gastrointestinal tract (e.g., severe diarrhea) and may  lead to death from infections.   GVHD is not a problem when the recipient is immuno-  competent, that is, has an immune system that can control    the donor’s lymphocytes. If, however, the recipient’s immune  system is deficient, the grafted T cells remain unchecked and  attack the recipient’s tissues. Most GVHD is prevented by treat-  ing whole blood with irradiation to kill white blood cells before  transfusion.   The most common presenting symptom of immune defi-  ciencies is recurrent severe infections. Significant information  concerning the nature of the specific immune deficiency can  be obtained by noting the types of infection, as well as certain  characteristics of the affected individual, including gender, age  of disease onset, the presence of any associated anomalies, fam-  ily history, and risk factors associated with secondary immune  deficiencies. Humoral deficiencies are generally characterized by  recurrent sinopulmonaty infections with encapsulated bacteria,  gastrointestinal malabsorption, and poor growth. T-cell defects  generally present with failure to thrive, chronic diarrhea, persis-  tent thrush, and opportunistic infections (e.g., Mycobacterium,  Pneumocystis, Candida, and certain viruses). Phagocytic defects  are usually associated with recurrent abscesses, oral ulcers, and  infections with specific bacteria (e.g., catalase-positive bacte-  ria). Complement defects may be linked to SLE-like disease and  recurrent and disseminated infections with Neisseria spp.   A variety of laboratory tests are available to evaluate specific  immune deficiencies** (Table 9-7). The choice of which par-  ticular tests to perform is determined on the characteristics  described previously. A basic screening test is a complete blood  count (CBC) with a differential. The CBC provides informa-  tion on the numbers of red cells, white cells, and platelets, and  the differential indicates the quantities of lymphocytes, granu-  locytes, and monocytes in the blood. Quantitative determina-  tion of immunoglobulins (IgG, IgM, IgA) is a screening test for  antibody production, and an assay for total complement (total  hemolytic complement, CHs,) is useful if a complement defect  is suspected.   If the nature of the immune deficiency remains uncertain  after the screening tests, additional relatively common tests can  be performed. For instance, subpopulations of lymphocytes  (T or B) can be quantified using characteristic surface mark-  ers, such as surface immunoglobulin for B cells and CD3 for T  cells. T-cell populations can be further subdivided using addi-  tional surface markers, such as CD4 (T-helper cells) or CD8  (T-cytotoxic cells). For antibodies, routine assays are available  to quantify subclasses of IgG, such as IgG2.   An additional level of testing would include determination  of immune responses against specific antigens. Determination  of isohemagglutinins is informative about antigen-specific IgM  production. Antibody responses to vaccines (e.g., tetanus, per-  tussis, measles, diphtheria, hepatitis B) are usually indicative of  IgG responses. T-cell immunity against specific antigens can be  measured by skin tests against antigens to which the individual  had been exposed: “recall antigens.” These include antigens  from vaccines (e.g., mumps, tetanus) or from microorgan-  isms with which the person had a previous active infection  (e.g., Candida). An adequate T-cell immunity results in a posi-  tive delayed hypersensitivity skin test reaction.   If the tests do not identify the immune deficiency, more  esoteric tests are offered by reference laboratories or research    Tests of Cellular Immune Function  Delayed hypersensitivity  especially Candida albicans or tetanus toxoid  T-cell numbers  or expressing membrane CD3 or CD11 antigen  Proliferative response to nonspecific mitogens  (e.g., phytohemagglutinin)    laboratories. These include quantification of individual comple-  ment components, in vitro proliferation (mitogenic response)  of T or B cells to antigens or nonspecific mitogens, and a variety  of tests of phagocyte function (e.g., nitroblue tetrazolium test  [NBT] for hexose-monophosphate shunt activity, specific tests  for phagocytosis, chemotaxis, or bacterial killing).   Individuals with B-cell deficiencies that cause hypogamma-  globulinemia or agammaglobulinemia usually can be treated  successfully with administration of gamma globulins, which are  antibody-rich fractions prepared from plasma pooled from large  numbers of donors. Administration of gamma globulin tem-  porarily replaces the individual’s antibodies. Antibodies from  these preparations are removed slowly from the person’s blood,  with half of the antibodies being removed by 3 to 4 weeks. Thus  individuals must be treated repeatedly to maintain a protective  level of antibodies in the blood.   Commercial gamma-globulin preparations are usually  administered intramuscularly or by intravenous (IV) infu-  sion. The dosage varies among individuals and is primarily  determined by body weight. The schedule and dosage are also  determined according to titers of circulating immunoglobulins  and the incidence of infections in the individual. Commercial  gamma-globulin preparations usually contain small amounts  of IgM and IgA. Individuals with selective IgA deficiency occa-  sionally develop allergic reactions to IgA in gamma-globulin  preparations.*°   Individuals who need larger amounts of IgM or IgA can be  given fresh frozen plasma in monthly IV infusions. Compli-  cations associated with plasma therapy include the potential  transmission of hepatitis or AIDS. The plasma is irradiated to  destroy immunocompetent T cells and to avoid GVHD in indi-  viduals with accompanying T-cell deficiencies. Administration  of fresh frozen plasma is successful in individuals with WAS  (IgM deficient), AT (IgA deficient), or complement component  deficiencies.    Presence of antibody-producing B cells  Capacity to produce specific IgM antibodies  Capacity to produce specific IgG antibodies    Presence of antigen-responsive I cells and skin test cellular  interactions (e.g., lymphokine activity and macrophage function)  Presence of circulating T cells    Capacity of all T cells to divide in response to nonspecific  stimulation (mitogens)  Capacity of antigen-reactive T cells to respond to antigen   Several primary immune deficiencies originate from defects in  lymphoid stem cells that interfere with their development in  the primary lymphoid organs. Some of these (e.g., SCID, WAS,  leukocyte adhesion defect) have benefited from replacement of  stem cells through transplantation of bone marrow, umbilical  cord cells, or other cell populations that are rich in stem cells.   The source of donor cells, particularly bone marrow, may  contain a mixed population of stem cells and more mature  T lymphocytes. In order to avoid GVHD, the preferred donor  would be matched with the recipient for HLA antigens. Sev-  eral other diseases involving depletion of the bone marrow (i.e.,  aplastic anemia, leukemia requiring eradication of tumor cells  in the marrow) also are treated by bone marrow transplanta-  tion. At least 75% of bone marrow transplants between indi-  viduals who are matched for HLA-A, HLA-B, HLA-C, and  HLA-DR are accepted. In immunocompetent recipients, most  rejections of HLA-matched transplants occur because of rec-  ognition of minor histocompatibility antigens by individuals  who have received multiple blood transfusions and are, as a  result, sensitized against those antigens, which are not evalu-  ated in tissue typing. For stem cell transplants, differences in  minor histocompatibility antigens may lead to GVHD. Because  HLA antigens are inherited in a codominant fashion, the pre-  ferred donor would be a relative, especially a sibling. Although  the donor is not tested for minor histocompatibility antigens,  the use of a close relative also would minimize differences at  those loci.   Chronic GVHD appears in 30% to 50% of transplants  between HLA-matched siblings and 60% to 70% of transplants  between unrelated donors. Symptoms may appear about 4 to  7 months after the transplant, but may begin much earlier or  later. Depletion of T cells from bone marrow before trans-  plantation significantly lowers the incidence of both acute and  chronic GVHD. One method of doing this is to infuse the graft  with monoclonal antibody against plasma membrane antigens  found only on mature T cells. Another method is to use fetal  tissue as the graft. For example, fetal liver, which contains stem    cells but not immunocompetent lymphocytes, is sometimes  grafted in place of bone marrow if an HLA-matched donor can-  not be found.   Steroids are commonly used to suppress GVHD in recipi-  ents of bone marrow transplants performed to treat certain  malignancies or primary immune deficiencies. In cases where  steroids are ineffective, promising new data support the use  of mesenchymal stem cells (MSCs).“* Stem cells are relatively  undifferentiated cells and can be obtained from a variety of  sources (e.g., embryos, bone marrow, adult tissues). MSCs are  present in all adult tissues. These particular stem cells undergo  differentiation into other cell types and, more importantly, have  potent immunosuppressive properties. Several recent clinical  trials have demonstrated complete suppression of GVHD in a  large number of recipients of MSCs.*°   One therapy for deficiency diseases in which the individual  lacks a thymus or thymic function (e.g., DiGeorge syndrome,  ataxia-telangiectasia, or chronic mucocutaneous candidiasis)  is reconstitution of thymic function. The procedure involves  transplantation of fetal thymic tissue, which lacks immuno-  competent T cells, or thymic epithelial cells (the cells that pro-  duce the thymic hormones) from which mature T cells have  been removed. In some individuals transplantation increases  the number of circulating mature T cells, but in most cases  improvement is only temporary.   Enzymatic defects that cause SCID (e.g., adenosine deami-  nase deficiency) have been treated successfully with trans-  fusions of glycerol frozen-packed erythrocytes. The donor  erythrocytes contain the needed enzyme and can, at least tem-  porarily, provide sufficient enzyme for normal lymphocyte  function. An alternative method is administration of purified    The administration of soluble materials that affect lymphocyte  function can restore T-cell function, especially in individuals  with WAS or chronic mucocutaneous candidiasis. Successful  for some individuals is the use of transfer factor, a low-molec-  ular-weight nucleoprotein prepared from lymphocyte lysates,  which can confer specific reactivity against certain antigens.  Thymosin, a thymic hormone, also has been used, although  with limited success. Cytokine therapy also has been effective in  some cases of chronic granulomatous disease.    The first successful therapeutic replacement of defective genes  was performed in two girls with SCID caused by an ADA defi-  ciency.*° The normal gene for ADA was cloned and inserted  into a retroviral vector.” The gene for ADA replaced some  retroviral genes, resulting in a virus that carried the normal  human gene but did not cause disease. The virus was used to  infect bone marrow stem cells from these children. The retrovi-  rus inserted the normal ADA gene into the individuals’ genetic  material. The genetically altered stem cells were infused into the  children, resulting in reconstitution of their immune systems.  Gene therapy has now been used to successfully reconstitute the  immune systems in individuals with ADA deficiency, X-linked  SCID, and WAS.*° However, the treatment trials have not been  without some major complications, such as leukemia, that raise  questions concerning the use of retroviral vectors for the inser-  tion of new genes.   1. Inappropriate immune responses are misdirected responses  against the host’s own tissues (autoimmunity); directed  responses against beneficial foreign tissues, such as transfu-  sions or transplants (alloimmunity); exaggerated responses  against environmental antigens (allergy); or insufficient  responses to protect the host (immune deficiency).   2. Allergy, autoimmunity, and alloimmunity are collectively  known as hypersensitivity reactions.   3. Mechanisms of hypersensitivity are classified as type I (IgE-  mediated) reactions, type II (tissue-specific) reactions, type  III (immune complex—mediated) reactions, and type IV  (cell-mediated) reactions.   4, Hypersensitivity reactions can be immediate (develop-  ing within minutes to a few hours) or delayed (developing  within several hours or days).   5. Anaphylaxis, the most rapid immediate hypersensitivity  reaction, is an explosive reaction that occurs within min-  utes of reexposure to the antigen and can lead to cardiovas-  cular shock.    7. Type I (IgE-mediated) reactions are mediated through  the binding of IgE to Fc receptors on mast cells and cross-  linking of IgE by antigens that bind to the Fab portions of  IgE. Cross-linking causes mast cell degranulation and the  release of histamine (the most potent mediator) and other  inflammatory substances.   8. Histamine enhances the chemotaxis of eosinophils into  sites of type I allergic reactions.   9. Atopic individuals tend to produce higher quantities of IgE  and to have more Fc receptors for IgE on their mast cells.   10. Type II (tissue-specific) reactions are caused by five pos-  sible mechanisms: complement-mediated lysis, opsoniza-  tion and phagocytosis, neutrophil-mediated tissue damage,  antibody-dependent cell-mediated cytotoxicity, and modu-  lation of cellular function.   11. Type II (immune complex—mediated) reactions are caused  by the formation of immune complexes that are deposited  in target tissues, where they activate the complement cas-  cade, generating chemotactic fragments that attract neu-  trophils into the inflammatory site. Neutrophils release  lysosomal enzymes that result in tissue damage.    Intermediate-sized immune complexes are the most likely  to have severe pathologic consequences.   Immune complex disease can be a systemic reaction, such as  serum sickness, or a localized response, such as the Arthus  reaction.   Type IV (cell-mediated) reactions are caused by either cyto-  toxic T lymphocytes (Tc cells) or lymphokine-producing  Thl cells.   Typical allergens include pollen, molds and fungi, certain  foods (milk, eggs, fish), animals, certain drugs, cigarette  smoke, and house dust.   Clinical manifestations of allergic reactions usually are con-  fined to the areas of initial intake or contact with the aller-  gen. Ingested allergens induce gastrointestinal symptoms,  airborne allergens induce respiratory tract or skin manifes-  tations, and contact allergens induce allergic responses at  the site of contact.   Autoimmunity is a breakdown of immunologic homeosta-  sis, the immune system’s tolerance of self-antigens. Central  tolerance develops during the embryonic period. Peripheral  tolerance is maintained in secondary lymphoid organs by reg-  ulatory T lymphocytes or antigen-presenting dendritic cells.  Autoimmune disease can be caused by the exposure of  a previously sequestered antigen, the development of a  neoantigen, the complications of infectious disease, the  emergence of a forbidden clone of lymphocytes, or the con-  sequence of ineffective peripheral tolerance.   Alloimmunity is the immune system’s reaction against anti-  gens on the tissues of other members of the same species.  Alloimmune disorders include transient neonatal disease,  in which the maternal immune system becomes sensitized  against antigens expressed by the fetus; transplant rejection;  and transfusion reactions, in which the immune system of  the recipient of an organ transplant or blood transfusion  reacts against foreign antigens on the donor’s cells.   SLE is a chronic, multisystem, inflammatory disease and  is one of the most serious of the autoimmune disorders.  SLE is characterized by the production of a large variety of  autoantibodies.   Hyperacute graft rejection (preexisting antibody) is imme-  diate and rare, acute rejection is cell mediated and occurs  days to months after transplantation, and chronic rejection  is caused by inflammatory damage to endothelial cells as a  result of a weak cell-mediated reaction.   Red blood cell antigens may be the targets of autoimmune  or alloimmune reactions. The most important of these,  because they provoke the strongest humoral immune  response, are the ABO and Rh systems.    Disorders resulting from immune deficiency are the clinical  sequelae of impaired function of components of the immune  or inflammatory response, phagocytes, or complement.  Immune deficiency is the failure of mechanisms of self-  defense to function in their normal capacity.    acquired (secondary). Primary immune deficiencies are  caused by genetic defects that disrupt lymphocyte develop-  ment, whereas secondary immune deficiencies are second-  ary to disease or other physiologic alterations.    to unusual or recurrent severe infections. The type of infec-  tion usually reflects the immune system defect.    of the cell-mediated immune response are fungal and  viral, whereas infections in individuals with defects of the  humoral immune response or complement function are  primarily bacterial.    . Defects in B-cell function are diverse, ranging from a com-    plete lack of the human bursal equivalent function, the lym-  phoid organs required for B-cell maturation (as in Bruton’s  agammaglobulinemia), to deficiencies in a single class of  immunoglobulins (e.g., selective IgA deficiency).    plasia) is characterized by complete or partial lack of the  thymus (resulting in depressed T-cell immunity) and the  parathyroid glands (resulting in hypocalcemia) and the  presence of cardiac anomalies.    . SCID is a total lack of T-cell function and a severe (either    partial or total) lack of B-cell function. SCID can result  from mutations in critical enzymes (ADA deficiency, PNP  deficiency), in cytokine receptors (X-linked SCID, JAK3  deficiency, IL-7 receptor deficiency), or in antigen receptors  (RAG-1/RAG-2 deficiencies, CD45 deficiency, CD3 defi-  ciency, ZAP-70 deficiency). Other combined defects may  result from deficiencies in antigen-presenting molecules  (bare lymphocyte syndrome), cytoskeletal proteins (WAS),  or DNA repair (ataxia-telangiectasia).    defective. The most severe defect is C3 deficiency, which  results in recurrent life-threatening bacterial infections.  Defects in proteins of the membrane attack complex usu-  ally result in unusual disseminated infections with bacteria  of the Neisseria spp.   Defects in phagocyte function, which include insufficient  numbers of phagocytes or defects of chemotaxis, phago-  cytosis, or killing, can result in recurrent life-threatening  infections such as septicemia and disseminated pyogenic  lesions.   Acquired immunodeficiencies are caused by superimposed  conditions, such as aging, malnutrition, infections, malig-  nancies, physical or psychologic trauma, environmental  factors, some medical treatments, or other diseases.  Deficiencies in immunity usually are treated by replace-  ment therapy. Deficient antibody production is treated by  replacement of missing immunoglobulins with commer-  cial gamma-globulin preparations. Lymphocyte deficien-  cies are treated with the replacement of host lymphocytes  with transplants of bone marrow, fetal liver, or fetal thymus  from a donor.   Factor I deficiency, 288  Graft-versus-host disease (GVHD), 292  Hyperacute rejection, 280  Hypersensitivity, 262  Hypocomplementemic, 269  Hypogammaglobulinemia, 284   IL-7 receptor deficiency, 286  Immediate hypersensitivity reaction, 263  Immune deficiency, 281   Leukocyte adhesion deficiency (LAD), 289  Mannose-binding lectin (MBL) deficiency, 287  Mesenchymal stem cell (MSC), 294  MHC class I deficiency, 286    16. Stokes JR, Casale TB: Allergic rhinitis and asthma: celebrating 100 years   Berin MC, Sicherer S: Food allergy: mechanisms and therapeutics, Curr  Opin Immunol 23(6):794—800, 2011.   Kaplan DH, Igyarté BZ, Gaspari AA: Early immune events in the  induction of allergic contact dermatitis, Nat Rev Immunol 12(2):114—-124,    Novak N, Leung DYM: Advances in atopic dermatitis, Curr Opin  Immunol 23(6):778—783, 2011.  Khan DA, Solensky R: Drug allergy, J Allergy Clin Immunol 125(2):    Peden D, Reed CE: Environmental and occupational allergies, J Allergy  Clin Immunol 125(2):S150-S160, 2010.   on type 1 diabetes and viruses: the role of viruses in type 1 diabetes: a  difficult dilemma, Clin Exp Immunol 168(1):5—-11, 2011.   Doyle HA, Mamula MJ: Autoantigenesis: the evolution of protein  modifications in autoimmune disease, Curr Opin Immunol 24(1):    Arbuckle MR et al: Development of autoantibodies before the clinical onset  of systemic lupus erythematosus, N Engl J Med 349(16):1526-1533, 2003.  American College of Rheumatology: Systemic lupus erythematosus, 2012  Available at www.rheumatology.org/practice/clinical/patients/diseases_    Lux A et al: The pro and anti-inflammatory activities of immunoglobulin  G, Ann Rheum Dis 69(Suppl 1):i92-196, 2010.   Lee S, Ballow M: Monoclonal antibodies and fusion proteins and their  complications: targeting B cells in autoimmune diseases, J Allergy Clin  Immunol 125(2):S814—S820, 2010.    1. Gell PGH, Coombs RRA, Lachman PT: Clinical aspects of immunology, 17.  Oxford, England, 1975, Blackwell Scientific.  2. Simons FER: Anaphylaxis, J Allergy Clin Immunol 125(2):S161-S181, 18.  2010.  3. Portier P, Richet C: De l’action anaphylactique de certains venins, 2012.  Comptes Rendus Societie Biologie (Paris) 54:170, 1902. 19.  4. Stone KD, Prussin C, Metcalfe DD: IgE, mast cells, basophils, and  eosinophils, J Allergy Clin Immunol 125(2):S73-S80, 2010. 20.  5. Franklyn JA, Boelaert K: Thyrotoxicosis, Lancet 379(9821):1155—1166, ‘i S126-S137, 2010.  2012. :  6. Pirquet C, Schick B: Serum sickness, Leipzig, Germany, 1905, Franz  Denticke. 22.  7. Arthus M, Breton M: Lésions cutanées produites par les injections de  sérum, Compt Rendus Soc Biol 55:817, 1903.  8. Roep BO, Peakman M: Diabetogenic T lymphocytes in human type 1 23.  diabetes, Curr Opin Immunol 23(6):746-753, 2011.  9. Koch R: Fortsetzung der mitteilungen, ber ein heilmittel gegen 112-118, 2012.  tuberkulose, Deutsche Med Wochenschr 9:101, 1891. 24.  10. Lambrecht BN, Leung DYM: Initiation and maintenance of allergic 2121, 2011.  inflammation: team work at the interface of innate and adaptive 25.  immunity, Curr Opin Immunol 23(6):769-771, 2011.  11. Holloway JW, Yang IA, Holgate ST: Genetics of allergic disease, J Allergy 26.  Clin Immunol 125(2):S81-S94, 2010. an  12. Dykewicz MS, Hamilos DL: Rhinitis and sinusitis, J Allergy Clin Immunol and_conditions/lupus.asp.  125(2):$103-S115, 2010. 27.  13. Burks AW et al: ICON: food allergy, J Allergy Clin Immunol 129(4):  906-920, 2012. 28.  14. Mousallem T, Burks AW: Immunology in the Clinic Review Series;  focus on allergies: immunotherapy for food allergy, Clin Exp Immunol  167(1):26-31, 2011. 29.  15. Hamilton RG: Clinical laboratory assessment of immediate-type    Issa F, Chandrasekharan D, Wood KJ: Regulatory T cells as modulators of    chronic allograft dysfunction, Curr Opin Immunol 23(5):648-654, 2011.  Smith RN, Colvin RB: Chronic alloantibody mediated rejection, Semin  Immunol 24(2):115-121, 2012.   Arkwright PD, Gennery AR: Ten warning signs of primary  immunodeficiency: a new paradigm is needed for the 21st century, Ann  NY Acad Sci 1238:7-14, 2011.   National Institute of Child Health and Human Development, NIH,  DHHS: Primary immunodeficiencyWashington, DC, 2003, Government  Printing Office. Available at www.nichd.nih.gov/publications/pubs/  primary_immuo.cfm. Updated 04/07/2008.    . Vale AM, Schroeder HW Jr: Clinical consequences of defects in B-cell    development, J Allergy Clin Immunol 125(4):778-787, 2010.  Bruton OC: Agammaglobulinemia, Pediatrics 9(6):722—728, 1952.    . DiGeorge AM: Congenital absence of the thymus and its immunologic    consequences. In Bergsma D, McKusick FA, editors: Immunologic  deficiency diseases in man, National Foundation—March of Dimes original  article series, Baltimore, 1968, Williams & Wilkins.   Demczuk S, Aurias A: DiGeorge syndrome and related syndromes  associated with 22q11.2 deletions, Ann Genet 38:59, 1995,   Kuijpers T, Lutter R: Inflammation and repeated infections in CGD: two  sides of a coin, Cell Mol Life Sci 69(1):7-15, 2012.    Chinen J, Shearer WT: Secondary immunodeficiencies, including HIV  infection, J Allergy Clin Immunol 125(2):S195-S203, 2010.   Cohen MS, et al: Acute HIV-1 infection, N Engl J Med 364(20):  1943-1954, 2011.   Oliveira JB, Fleisher TA: Laboratory evaluation of primary  immunodeficiencies, J Allergy Clin Immunol 125(2):S297-S305, 2010.  Rachid R, Bonilla FA: The role of anti-IgA antibodies in causing adverse  reactions to gamma globulin infusion in immunodeficient patients:   a comprehensive review of the literature, J Allergy Clin Immunol  129(3):628-634, 2012.   Toubai T et al: Mesenchymal stem cells for treatment and prevention  of graft-versus-host disease after allogeneic hematopoietic cell  transplantation, Curr Stem Cell Res Therapy 4(4):252-259, 2009.  Blaese RM: Development of gene therapy for immunodeficiency:  adenosine deaminase deficiency, Pediatr Res 33(Suppl 1):S49-S53,  1993,   Onodera M et al: Gene therapy for severe combined immunodeficiency  caused by adenosine deaminase deficiency: improved retroviral vectors  for clinical trials, Acta Haematol 101(2):89—96, 1999.   for primary adaptive immune deficiencies, J Allergy Clin Immunol  127(6):1356-1359, 2011.    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Emerging Infections, 299  Microorganisms and Humans: A Dynamic Relationship, 300  Microorganisms and Infections, 300  Process of Infection, 300  Clinical Infectious Disease, 301  Classes of Infectious Microorganisms, 302  Acquired Immunodeficiency Syndrome (AIDS), 322  Transmission, 322  Pathogenesis, 324    For most of human history infectious disease was the primary  disease-related cause of death; bubonic/pneumonic plague (The  Black Death) of the 14th century killed more than 50 million  people worldwide, the Spanish influenza of 1918 to 1919 killed  between 50 and 100 million people within 2 years, and it was  not uncommon for frequent regional outbreaks of diseases such  as smallpox or cholera to kill hundreds of thousands of people.’  Modern health care has shown great progress in preventing and  treating infectious diseases through the success of public health  initiatives, vaccination programs, and the use of antibiotics. The  greatest progress has occurred in developed countries where  death from infections is most common among those with debili-  tating diseases, nutritional deficiencies, or immunosuppression.  Death from influenza and pneumonia was the eighth leading  cause of death in the United States in 2011.” As a result of these    initiatives, smallpox has been eradicated from the globe (the last  reported case was in 1975 in Somalia), measles is almost eradi-  cated in the Western Hemisphere, and many diseases, such as  tuberculosis and polio, are on the decline. Although the advent  of sanitary living conditions, clean water, uncontaminated food,  vaccinations, and antimicrobials had improved the health in  many countries, infectious disease remains a significant threat  to life in many parts of the world, including India, Africa, and  Southeast Asia. The impact of differences in economic prosper-  ity is significant.** The leading causes of death in high-income  countries were heart disease, stroke, and other cerebrovascular  diseases; cancers of the respiratory tract; and Alzheimer disease  and other dementias, with lower respiratory tract infections  (influenza and pneumonia) the sole infectious cause in the  top 10. In low-income countries, where the implementation of    programs to prevent infection has been less effective, 6 of the  top 10 causes of death are caused by infection: lower respiratory  tract infections (#1), diarrheal diseases (#2), HIV/AIDS (#3),  malaria (#5), tuberculosis (#7), and neonatal infections (#10).   lic health and immunization policies, infectious disease remains  a significant cause of morbidity and mortality because of the  emergence of previously unknown infections, the reemergence  and spread of old infections that were thought to be under con-  trol, and the development of infectious agents that are resistant  to multiple antibiotics. The causes for these occurrences are  numerous and include the following:   + Vast and rapid urbanization in many areas of the world,  resulting in a breakdown in public health programs and a  more rapid spread of infection   * Global travel, allowing more rapid spread of disease from  isolated areas to virtually any point around the world in a  few hours   * Human encroachment into wilderness areas, resulting in  contact with previously sequestered infectious agents   + Practice of prescribing antibiotics excessively or not tak-  ing antibiotics for a complete course of therapy, or, even  when appropriately used, facilitates emergence of antibi-  otic-resistant microorganisms   * Denial of a problem by governments, allowing infections  to spread in an uncontrolled way   Ebola virus Zaire and Sudan  Legionella pneumophila United States  Toxin-producing strains of Staphylococcus spp. _ United States   Borrelia burgdorferi Northeast United States  Escherichia coli0157:H7 United States, Japan  Helicobacter pylori Australia  Human herpesvirus 6 United States  Hepatitis C virus United States  Vibrio cholerae 0139 Indonesia  Hantavirus Korea  Human herpesvirus 8 United States  Hendra virus Australia   Prion, variant of Creutzfeldt-Jakob disease agent United Kingdom  Nipah virus Malaysia  SARS-associated coronavirus China  Granulobacter bethesdensis United States  Bundidugyo ebolavirus Uganda  Saffold virus United States  Avian virus China   * Increased global warming, allowing insect vectors to  spread into and breed in areas that were previously too  cool for them    The emergence of previously unknown infections is not a new  event in human history. However, the current rate may be  unprecedented.’ Within 1 generation, more than 40 previously  unknown infections have arisen, and some examples are pre-  sented in Table 10-1. Several have extremely high mortality rates  of more than 50% including severe acute respiratory syndrome  (SARS) (in those older than 65 years), Ebola virus, Marburg  virus, “mad cow” disease, Nipah virus (up to 75%), and acquired  immunodeficiency syndrome (AIDS) (almost 100% in untreated  persons). However, most either spread very slowly (e.g., AIDS)  or initially appear in relatively isolated areas and are effectively  controlled by quarantine (e.g., Ebola virus). Although none of  these infections has developed into the worldwide scourges por-  trayed in the Hollywood movies Andromeda Strain and I Am  Legend, the potential of reversion to more rapidly spreading vari-  ants is a concern of public health agencies worldwide.  Concurrently, the incidence and spread of at least 20 previ-  ously known infections are increasing. A new strain of chol-  era that arose in Indonesia in 1961 has spread to Africa and  in 1991 to South America. Malaria, dengue fever, and yellow  fever are reemerging in areas where they had been eliminated  or were unknown. The incidence of tuberculosis is increasing  in countries that had reported declines and has risen by almost  33% between the mid-1980s and early 1990s. Diphtheria has    reemerged as a major health issue in Russia. In 1994 plague was  reported in India after being dormant for a generation. War  has led to outbreaks of Marburg hemorrhagic fever during civil  war in Angola during 1975 to 2002 and cholera in the Demo-  cratic Republic of the Congo among Rwandan refugees in 1994;  about 50,000 refugees died from a combination of cholera and  shigella dysentery. The spread of cholera, yellow fever, and epi-  demic meningococcal disease has rebounded. Decreased insect  control programs that were previously successful have led to  spread of vector-borne diseases: African trypanosomiasis, den-  gue hemorrhagic fever, and malaria. Although the United States  is relatively free of most of these diseases, the effects of global  warming and relaxed control of vectors may result in resur-  gence. It should not be forgotten that in 1793 a yellow fever  outbreak in Philadelphia killed 2000 of the city’s 55,000 inhab-  itants and forced the U.S. government to abandon the city until  the outbreak ceased. To date, outbreaks of locally acquired  malaria in the United States have been rare. However, West  Nile Virus, also spread by mosquitoes, appeared initially in the  Western Hemisphere in 1999 in the New York City area and  has spread throughout the continental United States, Canada,  and Mexico.*   Many common and reemerging infections have become  antibiotic and drug resistant. Streptococcus pneumoniae, a com-  mon cause of otitis media, pneumonia, and bacteremia, has  been treated routinely and successfully with penicillin. Now  at least 25% of isolates are penicillin resistant, and some are  resistant to multiple antibiotics. Multiple antibiotic-resistant  forms of Staphylococcus aureus, a primary cause of infections of  wounds, surgical incisions, and catheter insertion, are endemic  in some hospitals. Some forms of this microorganism once were  sensitive only to a single antibiotic, vancomycin, and now have  become vancomycin-resistant. Antimicrobial resistance is now  routinely observed in tuberculosis, diarrheal diseases, hospi-  tal-acquired infections, malaria, meningitis, respiratory tract  infections, sexually transmitted infections (STIs), and human  immunodeficiency virus (HIV).   Added to this collage of microbiologic dangers is the ris-  ing risk of bioterrorism. Agents such as smallpox, anthrax, and  plague are continuing threats to public health and safety. All  healthcare providers should have information about the char-  acteristics and clinical manifestations of these biologic agents.  The theoretical threat of bioterrorism became real in 2001 when  letters containing anthrax were mailed; 22 individuals became  infected and 5 died.    For many microorganisms the human body is a hospitable site  in which to grow and flourish because of its sufficient nutri-  ents and appropriate conditions of temperature and humid-  ity. In many cases a symbiotic relationship exists, in which  both humans and microorganisms benefit (Box 10-1). These  microorganisms make up the normal microbiome—the resident  microorganisms found in different parts of the body, includ-  ing the skin, mouth, gastrointestinal tract, respiratory tract, and   Opportunism: A situation in which benign microorganisms become pathogenic  because of decreased human host resistance    genital tract? (see Chapter 7). For instance, the normal bacte-  rial microbiome of the human gut is provided with nutrients  from ingested food and in exchange produce enzymes that facil-  itate the digestion and use of many of the more complex mol-  ecules found in the human diet, produce antibacterial factors  (e.g., bacteriocins, colicins) that prevent colonization by  pathogenic microorganisms, and produce usable metabolites  (e.g., vitamin K, B vitamins). This beneficial homeostasis is nor-  mally maintained through the physical integrity of the gut and  other mechanisms that sequester these microorganisms on the  mucosal surface.    The symbiotic relationship with the normal flora can be  breached as a result of injury that compromises the physi-  cal protective barriers. Damage to the intestinal tract releases  intestinal bacteria into the bloodstream, potentially leading to  sepsis, shock, and death. Cuts in the skin may allow normally  noninfectious bacteria (e.g., S. aureus) to cause local infections  (e.g., abscesses, boils) and invade further and infect vari-  ous organs. Symbiosis is also maintained by the immune and  inflammatory systems. If those systems are compromised, many  microorganisms will leave their normal sites and cause infec-  tion elsewhere in the body. Individuals with immune deficien-  cies easily become infected with opportunistic microorganisms,  which normally would not cause disease but seize the opportu-  nity to do so when a person’s defensive systems are weakened or  suppressed (see Chapter 9).   Unlike opportunistic infectious agents, true pathogens have  devised means to circumvent the individual’s defenses (dis-  cussed in Chapters 7 and 8) and directly cause infection. Suc-  cessful infection with these agents is usually dependent on  adequate numbers of microorganisms rather than compromise  of the host’s defenses.   From the perspective of the microorganisms that cause dis-  ease, the infectious process undergoes four separate stages of  progression: colonization, invasion, multiplication, and spread.    Infectious microorganisms usually exist in reservoirs, such as  the environment (e.g., contaminated water, soil), animals,  or another human who is infected or in a noninfectious state  within the individual’s normal microbiome. An individual may   Infections contracted from animal reservoirs (zoonotic  infections) may be transmitted by direct contact (e.g., trans-  mission of the rabies virus through bites) or indirectly by means  of vectors (e.g., insects). Mechanical vectors (e.g., housefly)  passively transfer microorganisms from a contaminated site  to an individual. Biologic vectors (e.g., fleas, lice, mosquitoes,  ticks) transmit infectious microorganisms through bites and  stings. Individuals can also become infected by direct expo-  sure to contaminated materials, such as fecal-oral transmis-  sion through food or water (e.g., salmonella food poisoning,  cholera, hepatitis A infection, polio, rotavirus infection) or  soil (e.g., tetanus).   Human-to-human transmission may occur through aero-  solized microorganisms in droplets (e.g., produced by coughing  or sneezing), which is the primary means of transmission for  respiratory tract infections (e.g., agents that cause the common  cold, influenza, streptococcal sore throat, bacterial meningitis).  Other infectious agents require physical contact (e.g., sexual  contact, blood transfusion, direct contact with contaminated  clothes or bandages, entrance through wounds or openings  in the skin). Direct contact is usually required for transmis-  sion of sexually transmitted infections (STIs), hepatitis B virus,  cytomegalovirus (CMV), herpes simplex virus, or warts. Some  microorganisms have the capacity to spread from mother to  child across the placenta (e.g., Treponema pallidum, Listeria  monocytogenes, CMV, Toxoplasma gondit), ascending the birth  canal or during delivery (e.g., group B Streptococcus, Escherichia  coli, Chlamydia trachomatis, Neisseria gonorrhoeae, hepatitis  B virus, HIV, Candida albicans), or through the breast milk  (e.g., S. aureus). This is classified as vertical transmission, whereas  spread from one person to another is horizontal transmission. In  a very few instances, the infectious agent may develop airborne  transmission. Effective airborne transmission may occur by the  prolonged presence of aerosolized droplets released by respira-  tion, exercise, or other body activity and has been observed with  SARS, tuberculosis, norovirus, and smallpox.   After deposition in receptive environments for coloniza-  tion, the microorganism stabilizes the adherence to the tissue  through specific surface receptors. For instance, infectious  agents that cause respiratory tract infections specifically bind  to molecules found on respiratory epithelium. Adherence helps  protect the microorganism from removal by mechanical non-  specific forces, such as coughing of respiratory mucus. The  specificity of adherence results in a particular microorganism  being limited to the locations where infections can occur (tissue  tropism), such as the confinement of common cold viruses to  producing respiratory tract infections.    Once colonization has occurred the infectious agent can invade  the surrounding tissue and, in many cases, other sites in the  individual. Successful infectious agents have developed mecha-  nisms to penetrate the tissues and evade the host’s nonspecific  and specific defenses (inflammation and immunity). Many of  these are discussed throughout this chapter.    Within the warm and nutrient-filled environment of human  tissue, most microorganisms undergo rapid multiplication with  production of many new infectious progeny. Viral pathogens  replicate within infected cells, and some bacteria are intracel-  lular pathogens and replicate in macrophages and other cells.    Many successful pathogens produce localized infections with-  out spread to other regions of the body (e.g., Vibrio cholerae).  Others, however, are highly invasive and may enter the lym-  phatics, blood, and internal organs. Successful spread relies on  a variety of virulence factors, including adhesion molecules,  toxins, and protection against the individual’s inflammatory  and immune systems. Fungi, in particular, are opportunistic.  In an individual with an intact immune system, the microor-  ganism remains localized, whereas the infection may rapidly  spread if the individual’s immune or inflammatory systems are  compromised.    From the perspective of the individual who is infected, the clini-   * Incubation period—the period from initial exposure to the  infectious agent and the onset of the first symptoms, during  which the microorganism has entered the individual, under-  gone initial colonization, and begun multiplying, but is yet  in insufficient numbers to cause symptoms; this period may  last from several hours to years   * Prodromal stage—the occurrence of initial symptoms, which  are often very mild and include a feeling of discomfort and  tiredness   + Invasion period—the pathogen is multiplying rapidly, invad-  ing farther and affecting the tissues at the site of initial coloni-  zation as well as other areas; the immune and inflammatory  responses are being triggered; development of symptoms  specifically related to the pathogen and symptoms related to  the ongoing protective inflammatory response   * Convalescence—in most instances, the individual’s immune  and inflammatory systems have successfully removed the  infectious agent, and symptoms decline; alternatively, the  disease may be fatal or may enter a latency phase with reso-  lution of symptoms until reactivation at a later time  Clinical manifestations of infectious disease vary, depend-   ing on the pathogen, the organ system affected, and the sever-   ity. Effects of infection may be acute, chronic, secondary to  the immune and inflammatory responses, or a consequence of  bacterial toxins or viral injury. Manifestations can arise directly  from the infecting microorganism or its products; however, the  majority of manifestations result from the host’s inflammatory  and immune responses. Infectious diseases typically begin with  the nonspecific or general symptoms of fatigue, malaise, weak-  ness, and loss of concentration. Generalized aching and loss of  appetite are common complaints. However, the hallmark of  most infectious diseases is fever.   Fever is not failure of the body to regulate temperature;  rather, body temperature is being regulated at a higher level than    normal. Body temperature is regulated by nervous system feed-  back to the hypothalamus, which functions as a central thermo-  stat (see Chapter 16). A large number of agents (pyrogens) can  produce fever. In current classification, those pyrogens derived  from outside the host are termed exogenous pyrogens and  those produced by the individual are termed endogenous pyro-  gens. There is little evidence that exogenous pyrogens cause  fever directly. Such pyrogens indirectly affect the hypothalamus  through endogenous pyrogens released by cells of the host. A  number of cytokines have been identified as endogenous pyro-  gens. They are interleukin-1 and interleukin-6 (IL-1 and IL-6,  respectively), interferon (IFN), tumor necrosis factor (TNF),  and others (see Figure 16-8). These cytokines seem to raise the  thermoregulatory set point through stimulation of prostaglan-  din synthesis and turnover in both thermoregulatory (brain)  and nonthermoregulatory (peripheral) tissue. Although it is  generally believed that fever has a beneficial value in infection,  the molecular mechanism behind the beneficial effects has not  been established. Many investigators, however, consider fever  as an adaptive host-defense response.   * Communicability: The ability to spread from one indi-  vidual to others and cause disease: measles and pertussis  spread very easily; HIV is of lower communicability   + Immunogenicity: The ability of pathogens to induce an  immune response   + Infectivity: The ability of the pathogen to invade and mul-  tiply in the host   + Pathogenicity: The ability of an agent to produce dis-  ease—success depends on communicability, infectivity,  extent of tissue damage, and virulence   + Portal of entry: The route by which a pathogenic microor-  ganism infects the host: direct contact, inhalation, inges-  tion, or bites of an animal or insect   * Toxigenicity: The ability to produce soluble toxins or  endotoxins, factors that greatly influence the pathogen’s  degree of virulence   * Virulence: The capacity of a pathogen to cause severe  disease—for example, measles virus is of low virulence;  rabies virus is highly virulent    50 million (a third of Europe's population);  up to 100 million worldwide    Infectious diseases are also classified by their prevalence  and spread within the community.   + Endemic: Diseases with relatively high, but constant, rates  of infection in a particular population   + Epidemic: The number of new infections in a particular  population greatly exceeds the number usually observed   + Pandemic: An epidemic that spreads over a large area,  such as a continent or worldwide (Table 10-2)    Infectious disease can be caused by microorganisms that range  in size from 20 nm (poliovirus) to 10 m (tapeworm). Classes of  pathogenic microorganisms and their characteristics are summa-  rized in Table 10-3 and discussed in detail in the following sections.    Bacteria are prokaryotic unicellular microorganisms with no  nuclei, mitochondria, or membrane-bound organelles. They  are generally divided into several groups.   * “True bacteria” divide by binary fission and may have  a variety of morphologies, including cocci (spherical),  bacilli (rod shaped), vibrios (comma-shaped rods), or  spirilla (twisted, rod shaped). Most disease-causing bac-  teria fall into this classification.   + Filamentous bacteria may have branching, mycelium-  like structures that resemble fungi. Examples include  the mycobacteria Mycobacterium tuberculosis and Myco-  bacterium leprae that respectively cause tuberculosis and  leprosy.   * Spirochetes are flexible spiral filaments that are motile.  Most are anaerobic. Pertinent examples include Borrelia  recurrentis (relapsing fever), T. pallidum (syphilis), and  Borrelia burgdorferi (Lyme disease).   * Mycoplasma lack a rigid cell wall and are small and pleo-  morphic. They are the smallest and most simple members  of the bacteria. Mycoplasma pneumoniae causes atypical  pneumonia, and Mycoplasma genitalium is a suspected  cause of urethritis and pelvic inflammatory disease.   * Rickettsia are strict intracellular parasites that can be  rod-shaped, spherical, or pleomorphic. They are typi-  cally spread by insect vectors and cause Rocky Mountain  spotted fever (Rickettsia rickettsii) and typhus (Rickettsia  prowazekii).    200-1000 nm  300-1200 nm Intracellular  125-350 nm Extracellular  0.8-15 mcg Skin  Mucous membranes  Extracellular  Intracellular  2-200 mcg Skin  Mucous membranes  Extracellular  Intracellular  Mucosal  Extracellular  Intracellular  Extracellular    * Chlamydia are also strict intracellular parasites, but with  more complex intracellular life cycles. The primary chla-  mydial pathogen is Chlamydia trachomatis, which causes  the most common bacterial sexually transmitted infec-    : Ja ‘ é : Inclusion :a\ es i  tion (pelvic inflammatory disease) and eye infections body lmelusion  (conjunctivitis). body  Bacteria are also categorized as gram-negative or gram-pos- Peptidoglycan  itive. Gram-negative bacteria do not retain crystal violet dye in oj layer  the Gram-staining process whereas gram-positive bacteriado A VS Leese $  retain crystal violet dye. Gram-negative bacteria also have a Giteplasmic / membrane  lipopolysaccharide (LPS) coat in the outer membrane, which membrane Rinessine Periplasmic  consists of lipid A, a core polysaccharide, and O antigen. The Surface proteins Chromosome ite    LPS coat is also known as endotoxin (see Figure 10-1 and fur-  GRAM NEGATIVE    ther discussion on p. 306). Common bacterial pathogens are  listed in Table 10-4.   Transmission and Colonization. Transmission of bacterial  infections occurs through the same routes generally described  previously. Many pathogenic bacteria normally reside in  humans without causing disease, for instance, Streptococcus  pyogenes (pharyngitis), S. pneumoniae (pneumonia, meningitis),  Neisseria meningitidis (meningitis), and Haemophilus influenzae  type b (meningitis). In most cases they either are present in  inadequate numbers to cause disease or are effectively controlled  by local protective mechanisms. Others reside in nature and  cause infection after being ingested or entering wounds (e.g., V.  cholerae [cholera] in contaminated water or Clostridium tetani  [tetanus] in contaminated soil).   A large number require human-to-human contact, includ-  ing several that are unstable on environmental surfaces  (e.g., Bordetella pertussis [whooping cough], N. gonorrhoeae  [gonorrhea], T. pallidum [syphilis]). Even the human-to-  human spread of infectious bacteria contracted initially from  environmental reservoirs can be facilitated by certain aspects of   of the bacterial cell wall determines its staining characteristics with Gram stain.    Gram-positive bacteria have a thick layer of peptidoglycan (left). Gram-negative bac-  teria have a thin peptidoglycan layer and an outer membrane of lipopolysaccharide    the disease (e.g., the explosive diarrhea of cholera). Chlamydia,  which may be contracted as an STI, can spread from the mother  to child during childbirth and may establish long-term intracel-  lular persistence in the newborn.    (LPS) (right). B, Example of a gram-positive (darkly stained microorganisms, arrow)  group A Streptococcus. This microorganism consists of cocci that frequently form  chains. €, Example of a gram-negative (pink microorganisms, arrow) Neisseria men-  ingitidis in cerebrospinal fluid. Neisseria form complexes of two cocci (diplococci).   MICROORGANISM CGRAM STAIN __RESPIRATORY PATHWAY _ EXTRACELLULAR __  Respiratory Tract Infections  Upper Respiratory Tract Infections  Corynebacterium diphtheriae (diphtheria) Gram + Facultative anaerobic Extracellular  Haemophilus influenzae Gram - Facultative anaerobic Extracellular  Streptococcus pyogenes (group A) Gram + Facultative anaerobic Extracellular  Otitis Media  Haemophilus influenzae Gram - Facultative anaerobic Extracellular  Moraxella catarrhalis Gram - Aerobic Extracellular  Streptococcus pneumoniae Gram + Facultative anaerobic Extracellular  Lower Respiratory Tract Infections  Bacillus anthracis (pulmonary anthrax) Gram + Facultative anaerobic Extracellular  Bordetella pertussis (whooping cough) Gram - Aerobic Extracellular  Chlamydia pneumoniae Not stainable Aerobic Obligate intracellular  Escherichia coli Gram - Facultative anaerobic Extracellular  Haemophilus influenzae Gram - Facultative anaerobic Extracellular  Klebsiella pneumoniae Gram - Facultative anaerobic Extracellular  Legionella pneumophila Gram - Aerobic Facultative intracellular  Mycobacterium tuberculosis Weak gram + Aerobic Extracellular  Mycoplasma pneumoniae Not stainable Aerobic Extracellular  Neisseria meningitidis (develops into meningitis) Gram - Aerobic Extracellular  Pseudomonas aeruginosa Gram - Aerobic Extracellular  Streptococcus agalactiae (group B; develops into meningitis) Gram + Facultative anaerobic Extracellular  Streptococcus pneumoniae Gram + Facultative anaerobic Extracellular  Yersinia pestis (plague) Gram - Facultative anaerobic Extracellular  Gastrointestinal Tract Infections  Inflammatory Gastrointestinal Tract Infections  Bacillus anthracis (gastrointestinal anthrax) Gram + Facultative anaerobic Extracellular  Clostridium difficile Gram + Anaerobic Extracellular  Escherichia coli 0157:H7 Gram - Facultative anaerobic Extracellular  Vibrio cholerae Gram - Facultative anaerobic Extracellular  Vibrio parahaemolyticus Gram - Facultative anaerobic Extracellular  Invasive Gastrointestinal Tract Infections  Brucella abortus (brucellosis, undulant fever leading to sepsis, Gram - Aerobic Intracellular   heart infection)  Campylobacter jejuni Gram - Microaerophilic Extracellular  Francisella tularensis Gram - Strict anaerobic Facultative intracellular  Helicobacter pylori (gastritis and peptic ulcers) Gram - Microaerophilic Extracellular  Listeria monocytogenes (leading to sepsis and meningitis) Gram + Aerobic ntracellular  Salmonella typhi (typhoid fever) Gram - Anaerobic Extracellular  Shigella sonnei Gram - Facultative anaerobic Extracellular  Food Poisoning  Bacillus cereus Gram + Facultative anaerobic Extracellular  Clostridium botulinum Gram + Anaerobic Extracellular  Clostridium perfringens Gram + Anaerobic Extracellular  Staphylococcus aureus Gram + Facultative anaerobic Extracellular  Sexually Transmitted Infections  Chlamydia trachomatis (pelvic inflammatory disease) Not stainable Aerobic ntracellular  Neisseria gonorrhoeae (urethritis) Gram - Aerobic Facultative intracellular  Treponema pallidum (spirochete; syphilis) Gram - Aerobic Extracellular  Skin and Wound Infections  Bacillus anthracis (cutaneous anthrax) Gram + Facultative anaerobic Extracellular  Borrelia burgdorferi (Lyme disease; spirochete) Gram - Aerobic Extracellular   Brucella abortus (brucellosis, also called undulant fever)  Borrelia burgdorferi (spirochete; Lyme disease)   Rickettsia rickettsii (rickettsia; Rocky Mountain spotted fever)  Rickettsia prowazekii (rickettsia; typhus)    Gram +  Gram -  Gram -  Gram +  Gram -  Gram -  Gram -    Nosocomial Infections  Enterococcus faecalis  Enterococcus faecium  Escherichia coli (cystitis)  Pseudomonas aeruginosa  Staphylococcus aureus  Staphylococcus epidermidis    Gram +  Gram +  Gram -  Gram -  Gram +  Gram +    The establishment of stable colonization requires adhesion.  Many bacteria attach through pili (also called fimbriae), which  are thin rod-like projections from the bacterial surface (see  Figures 10-1 and 10-2). Pathogenic strains of Escherichia coli  involved in urinary tract infections have a variety of different  specific pili-associated adhesion molecules, including man-  nose-binding protein that binds with glycoproteins specifically  expressed on the bladder epithelium and PapG (pyelonephri-  tis-associated protein) adhesin that binds to galactoses of the  human P blood group. PapG is a specific adhesion for urinary  tract epithelium, but PapG variants are specific for other cell  types so that the particular PapG expressed will determine the  preferred site of infection with E. coli. The particular adhesin  may vary depending on growth conditions under which bac-  teria may undergo a “phase change” and shift from one type  to another.   Neisseria spp. bind to urinary tract epithelial cell membrane-  associated cofactor protein (CD46), which is a receptor that  regulates complement and protects cells by helping inactivate  C3b and C4b. Several other microorganisms (e.g., B. pertussis,  Legionella pneumophila, Mycobacterium tuberculosis) bind to the  CR3 complement receptor (a receptor for C3b and C3b break-  down products) on the surface of monocytes/macrophages. B.  pertussis expresses a surface hemagglutinin that recognizes CR3,  whereas L. pneumophila and M. tuberculosis initially absorb  inactivated C3b (C3bi) for use as an adhesin for CR3.    Fac ive anaerobi  Fac ive anaerobi  Fac ive anaerobi  Obligate anaerobic  Facultative anaerobi  Facultative anaerobi    A variety of proteins and carbohydrates not associated with  pili function as adhesion molecules. Flagella (used for motion)  act as adhesions in V. cholerae. Hemagglutinins on B. pertus-  sis, Salmonella spp., and Helicobacter pylori bind to erythro-  cyte surface molecules. Fibronectin is a common component  of mucosal cell surfaces and is frequently used as a receptor.  Several bacteria (S. pyogenes, S. aureus, T. pallidum) have devel-  oped specific adhesion molecules that recognize a particular  amino acid sequence (Arg-Gly-Asp) in fibronectin. Many other  bacteria have developed adhesion molecules that bind to colla-  gen, laminin, and vitronectin, which are plentiful in connective  tissue. A surface polysaccharide (poly-N-acetylglucosamine) is  on nonencapsulated Staphylococcus spp., E. coli that infect the  urinary system. Yersinia pestis, which causes plague, mediates  adherence to the material in catheters and prosthetic devices,  thus increasing the risk of infection of joint replacements and  other implanted materials.   Although discussions of infectious diseases generally focus  on single microorganisms that can be isolated and identified as  part of the diagnostic workup, the microorganism frequently  exists in the individual as part of complex multicellular masses  called biofilms.° Biofilms consist of mixed species of microor-  ganisms, including bacteria, fungi, and viruses.’ Growth of bac-  teria in biofilms offers survival advantage by protection from the  host’s protective responses and exposure to antibiotics. These  structures are associated with chronic and recurrent infections    FIGURE 10-2 Attachment of Escherichia coli Through Pili. A, Transmission electron micrograph showing pili (arrows)    of pathogenic £. coli. B, Scanning electron micrograph of E. coli (orange) attached by pili (arrows) to bladder epithelium (b/ue).  (A courtesy Eric Buckles and Paula J. Fernandes; B modified from Wein A et al: Campbell-Walsh urology, ed 9, Philadelphia,    associated with persistent nasopharyngeal colonization with  staphylococci; otitis media; urinary tract infections secondary  to indwelling catheters; foot ulcers in diabetic persons; infected  burn wounds; vaginitis; osteomyelitis; pneumonia secondary to  cystic fibrosis; and diseases of the oral cavity related to dental  plaque, such as dental caries and periodontitis.” !°   Invasion and Evasion. Invasion results in direct confrontation  with the individual’s primary defense mechanisms against  bacteria, which include the complement system, antibodies,  and phagocytes, such as neutrophils and macrophages (see  Chapters 7, 8, and 9). Bacterial survival and growth depend on  the effectiveness of the body’s defenses and on the bacterium’s  capacity to resist those defenses and obtain nutrients and  multiply. Evasion of the body’s defense mechanisms may result  in infectious microorganisms being transported in the blood  (bacteremia) to infect other organs or even multiplying in the  blood (sepsis).   Efficient pathogens produce a variety of toxic molecules that  may kill the individual’s cells, disrupt the tissue, and protect  against inflammation. Exotoxins are proteins released during  bacterial growth. They are usually enzymes and have highly spe-  cific effects; they include cytotoxins, neurotoxins, pneumotox-  ins, enterotoxins, and hemolysins. Exotoxins can damage cell  membranes, activate second messengers, and inhibit protein  synthesis. For instance, a key component of invasion by N. men-  ingitidis is a toxin that weakens intercellular adhesion between  epithelial cells, thus allowing penetration into the underlying  tissue. Pathogenic strains of streptococci and staphylococci pro-  duce hyaluronidase, lipases, and hemolysins that break down  cells and intercellular matrix. Exotoxins are immunogenic and  elicit the production of antibodies known as antitoxins. Con-  sequently, vaccines are available for many of the exotoxins  (ie., tetanus, diphtheria, and pertussis).   Endotoxins are lipopolysaccharides (LPSs) contained in  the cell walls of gram-negative bacteria and released during lysis  (or destruction) of the bacteria (see Figure 10-1). The inner-  most part of the lipopolysaccharide, lipid A, is made of polysac-  charides and fatty acids and is responsible for the substance’s  toxic effects. Bacteria that produce endotoxins are called    pyrogenic bacteria because they stimulate the release of inflam-  matory mediators and produce fever and the local and systemic  effects of inflammation including septic shock and damage  to multiple organs (Figure 10-3).!' Endotoxin also may be  released from the membrane of the bacteria, either during bac-  terial growth or during treatment with antibiotics. Therefore,  antibiotics cannot prevent the toxic effects of the endotoxin.  Evasion of the individual’s immune and inflammatory systems  is multifaceted, and the most successful pathogens incorporate  several mechanisms (Table 10-5).!2   Rapid Division. Because the primary immune response may  take 3 to 5 days to reach protective levels, some pathogens pro-  liferate at rates that surpass the development of the immune sys-  tem. Cholera causes severe vomiting and watery diarrhea, has a  60% mortality rate, and develops within 2 to 3 days of ingestion  of the bacteria. Some strains of toxin-producing group A strep-  tococci cause destructive skin infections and pneumonia that  may kill an individual within 2 days. Group B streptococci from  the maternal vagina may ascend the birth canal, penetrate fetal  membranes, and infect the fluid surrounding the fetus. This  microorganism may have already established an active infection  of the child’s lungs by the time of birth, resulting in a pneumo-  nia (50% mortality rate in newborns) that is too advanced to be  treated successfully by antibiotics.   Intracellular Survival. Bacteria may hide from the immune  response by growth in sites that are relatively poorly protected  by immune cells, for example, V. cholerae in the gastrointestinal  (GI) tract and Salmonella typhi in the intestinal tract and bili-  ary tract (gallbladder). Even asymptomatic people may undergo  prolonged local colonization and shed infectious microorgan-  isms in urine and feces, thus creating a carrier state.   Survival within cells (intracellular bacteria) affords a dis-  tinct advantage to some bacteria. Many intracellular bacte-  ria can survive and even multiply in macrophages (Brucella,  Listeria, M. leprae, M. tuberculosis) or in other cells (Yersinia,  Shigella, Listeria, E. coli).'° Normally a macrophage would  efficiently kill bacteria by fusing lysosomal granules with the  phagosome to produce a phagolysosome and using oxygen-  dependent and oxygen-independent mechanisms. Successful    FIGURE 10-3 The Many Activities of Lipopolysaccharide (LPS). Bacterial endotoxin (LPS) activates almost every  aspect of inflammation. The release of LPS from gram-negative bacteria triggers successive waves of cytokine production,  including tumor necrosis factor (7NVF), interleukin-1 (/L-1), interleukin-6 (/L-6), and interleukin-8 (/L-8), and secondary mediators  of inflammation, such as nitric oxide (NO) and platelet-activating factor (PAF). At low levels of LPS the effect is local. Moder-  ate levels of LPS cause more systemic inflammatory responses. High levels of LPS may lead to septic shock and death. ARDS,  Acute respiratory distress syndrome; DIC, disseminated intravascular coagulation. (From Kumar V, Abbas A, Fausto N: Robbins  & Cotran pathologic basis of disease, ed 7, Philadelphia, 2005, Saunders; Modified from Abbas AK et al: Cellular and molecular    intracellular bacteria may block killing in several ways. Several  microorganisms are resistant to killing and survive in the  phagolysosome.   Species of Salmonella secrete products that alter the environ-  ment of the phagolysosome. Production of catalase and super-  oxide dismutase (N. gonorrhoeae, Brucella abortus, S. aureus)  destroys toxic oxygen products produced by the hexose-mono-  phosphate shunt.!* S. aureus also produces a cell-bound pig-  ment (carotenoid) that “quenches” singlet oxygen. A second  means of avoiding killing is escape from the phagosome. Several  bacteria secrete lysins (e.g., hemolysin of Shigella, listeriolysin  O and phospholipase C of L. monocytogenes, phospholipase A  of Rickettsia spp.) that break down the phagosome membrane,  and the bacteria are released into the cytoplasm, where they  multiply.!° A third means of avoiding killing is by prevention  of phagosome-lysosome fusion. M. tuberculosis and T. gondii    produce toxins that prevent fusion so that the environment in  the phagosome remains relatively nontoxic.   Protection Against Phagocytosis. Bacteria produce a large  variety of toxins and extracellular enzymes, some of which kill  phagocytic cells (e.g., Pseudomonas aeruginosa exotoxin A).  Staphylococcal hemolysins and toxins from Bacillus anthracis  and B. pertussis decrease phagocytic and chemotactic activities  and may be toxic. Streptococcal products, such as streptolysin  O, bind to cholesterol in the phagocyte’s plasma membrane and  initiate destruction through the internal release of enzymes in  lysosomal granules.   Antiphagocytic capsules are expressed by most bacterial  pathogens involved in pneumonia and meningitis (Figure  10-4). Capsules are mostly polysaccharide, although some very  important proteins may be capsular components, which inhibit  complement activation and phagocytosis. Such coatings inhibit   Intracellular bacteria block granule  fusion, survive in phagolysosomes,  enter and multiply in cytoplasm   Capsules with antiphagocytic and  anticomplement activities, toxins  to kill phagocytes (e.g., o.-toxin  and leukocidin)   Adsorption of fibronectin or IgG  (e.g., protein A), sialic acid capsule   Large diversity of surface molecules,  phase changes in pili or membrane  proteins, strain-to-strain serotype  differences    Proteases degrade complement  (e.g., C3b, C5a), capsules that  prevent complement deposition,  inhibitors of complement  components and convertases    Resistance to lysosomal  enzymes, block granule fusion,  enter and multiply in cytoplasm    Degrade or inactivate C3b,  C3a, and C5a; break down C3  convertase    Release of soluble antigens that  induce “tolerance,” polyclonal  B-cell activation, induction of  anti-inflammatory cytokines,  cytotoxic molecules    Rapid proliferation of viruses  with small genomes  Obligative intracellular life cycle,  latency (e.g., herpes simplex  virus in dorsal root ganglia)  NA   Viral enzymes that produce  translational errors, antigen  shift and drift, diversity of  serotypes    Secretion of viral proteins  to neutralize antibody,  molecules to neutralize  cytokines    Infect and kill immune cells,  inhibit Tc and natural killer  (NK) recognition of major  histocompatibility complex  (MHC), inhibit antigen  presentation    phagocytosis and include the thick polysaccharide covering  of the pneumococcus (S. pneumoniae), the waxy capsule sur-  rounding the tubercle bacillus (M. tuberculosis), the polysac-  charide “slime” capsule of P. aeruginosa, and the M protein  of S. pyogenes. The M protein binds fibrinogen and fibrin and  functions as an adhesin.   Coating with Self-Protein. Some bacterial surface pro-  teins (e.g., protein G of S. pyogenes) bind the Fc portion of the  individual’s antibody, thus forming a protective coat of “self”  protein. Binding through the Fc holds the antibody in an ori-  entation that does not allow complement activation or phago-  cytosis. T. pallidum coats itself with fibronectin. Capsules are  produced that contain sialic acid (E. coli K-12), which closely  resembles the sialic acid on the surface of most human cells,  and hyaluronic acid (group A streptococci), which is the basic  substance in connective tissue.   Antigenic Variation. Antigenic variation allows the patho-  gen to alter surface molecules that express antigens that are the    targets of protective immune responses. Thus as the individual  develops protective levels of antibodies, the pathogen responds  by changing antigens and becoming resistant. The three pri-  mary mechanisms of antigenic variation are mutation, recombi-  nation, and gene switching. Antigenic variation can occur during  the course of an infection in the host or during the spread of  infection through the environment.   Neisseria use pili to adhere to epithelium, and antibody  against these antigens can abrogate adherence. Neisseria under-  goes phase shifts during which pilar antigens are changed by  progressive silencing of 1 set of 10 or 11 available pili genes and  activation of others that express different antigens. The spiro-  chete B. recurrentis (relapsing fever) repeatedly relapses with  spiking fevers as a result of as many as 10 episodes of antigenic  changes over weeks or months. Many other bacteria have a large  number of different antigenic types (serotypes) across the spe-  cies. At least 80 different strains of group A S. pyogenes express  different serotypes of the capsular M protein. S. pneumoniae has   FIGURE 10-4 Bacterial Capsule. Gram stain of a sputum sample from an indi-  vidual with pneumococcal pneumonia (x 1000 magnification). The sputum is rich in  polymorphonuclear (PMN) cells and slightly elongated, gram-negative cocci (Strep-  tococcus pneumoniae). Clear areas (arrows) around the bacteria indicate capsules.  (Modified from Mandell G, Bennett J, Dolin R: Principles and practice of infectious  diseases, ed 7, Philadelphia, 2010, Churchill Livingstone.)    at least 100 different serotypes based on capsular polysaccha-  rides. Multiple serotypes are also found in V. cholerae, S. aureus,  E. coli, N. gonorrhoeae, and others. Although the particular sero-  type is stable on that bacterium, an immune response against  one serotype will result in increased growth of a different sero-  type. Some gram-negative bacteria can revert to “rough” forms  in which serotype-specific carbohydrates are deleted, thus  becoming resistant to antibody and activation of complement.   Degradation of Immune Molecules. Protection is afforded  by the breakdown of molecules of the immune or inflamma-  tory system. An IgA protease produced by meningitis-causing  microorganisms and other related bacteria (N. gonorrhoeae,  N. meningitidis, H. influenzae, S. pneumoniae) cleaves IgA at the  hinge region into ineffective Fc and Fab’, regions.'° A staphy-  lokinase produced by Staphylococcus spp. activates plasmin  (resulting in the breakdown of clots) and degrades IgG and  C3b of the complement system. Pseudomonas produces elastase  (breakdown C3 of the complement system) and a 56-kDa pro-  tease (breaks down C5a).   Salmonella membrane protease degrades nonspecific antimi-  crobial molecules like defensins and cathelicidins. Salmonella  can also alter surface lipid A by changing its fatty acid content  to become resistant to small-molecular-weight antimicrobials.   Neutralization of Immune Molecules. Bacteria may spon-  taneously release surface molecules that bind to and neutralize  antibody. These include endotoxin from gram-negative bacte-  ria, capsular antigens from S. pneumoniae and N. meningitidis,    and protein A from S. aureus. During infection the blood may  contain high levels of complexes between antibody and bacte-  rial antigen. At certain antigen/antibody ratios the complexes  will deposit in the kidney, joints, and other target organs and  initiate type II hypersensitivity reactions (see Chapter 9).   Complement Evasion. Complement is a major component  of the defense against bacterial infection through production  of opsonin (C3b) and chemotactic factors (C3a, C5a) for neu-  trophils. Teichoic acid in the Gram-positive cell wall provides  resistance against complement-mediated lysis. Bacterial regu-  latory proteins (e.g., Borrelia complement-regulator-acquiring  protein, Neisseria porins, and members of the Streptococcus M  protein family) affect complement activation, including desta-  bilization of the C3 convertase complex or degradation of the  opsonin C3b.!”   Immune Suppression. Although more prominent in viral  infections, some bacterial pathogens can broadly suppress  immune responses against their own antigens as well as other  antigens unrelated to the infectious agent. Chronic bacterial  infections, like leprosy (M. leprae) and tuberculosis (M. tuber-  culosis), induce anergy (suppressed response to multiple anti-  gens) in infected hosts. H. pylori can release LPS that binds to  dendritic cells and blocks development of Th1 cells, as well as  produce toxins that block the T-cell IL-2 receptor signaling  pathway, thus inhibiting maturation of Th cells. N. gonorrhoeae  pili antigens bind to adhesion molecules on CD4+ cells and pre-  vent their activation.   Tissue Damage. Bacterial infections damage tissue either  directly by means of bacterial products or indirectly as a result  of inflammation. Many toxins break down tissue directly. These  include a large variety of proteases, lipases, hyaluronidases,  hemolysins, and many others discussed previously. Some bacterial  diseases arise completely from the systemic effects of toxins.  Diphtheria is a respiratory tract infection (Corynebacterium  diphtheriae) with systemic complications caused by toxin  that inhibits messenger ribonucleic acid (mRNA) translation  and causes low blood pressure, necrosis in the heart and liver,  degeneration of myelin sheaths, and death. Gastrointestinal  pathogens (V. cholerae, Salmonella, Shigella, E. coli) may produce  enterotoxins that are cytotoxic and alter the permeability of  intestinal cells leading to diarrheal diseases.   Necrotizing fasciitis, commonly called flesh-eating disease, is  an unusual rapidly progressing bacterial infection of the soft tis-  sue. Group A Streptococcus is the primary cause of this disease,  although mixed infections with other bacterial microorganisms  may cause similar soft tissue damage. The microorganisms usu-  ally invade the subcutaneous tissue from a minor wound infec-  tion. Severe and rapid tissue destruction proceeds from the  combined effects of bacterial toxins and enzymes released from  damaged cells. Rapid surgical débridement is absolutely neces-  sary to limit morbidity and prevent the individual’s death.   Clostridia are anaerobic bacteria that produce some of the  most powerful toxins known. One type of food poisoning is  caused by Clostridium botulinum that produces a paralytic neu-  rotoxin (botulinum toxin) that blocks the release of acetylcho-  line at nerve-muscle synapses and results in flaccid paralysis.  Infection of deep wounds with C. tetani results in release of a    neurotoxin that causes severe muscle spasms, spastic paralysis  of the voluntary muscles, and potentially death. C. perfringens  produces multiple toxins that cause gas gangrene. One of these,  alpha toxin, is a lecithinase that destroys the infected tissue by  digesting cellular plasma membranes. Infection of the colon  with Clostridium difficile results in watery diarrhea from toxins  that damage the mucosa.   Bacterial superantigens are toxins that increase the adher-  ence between major histocompatibility complex (MHC) class  II proteins on antigen-presenting cells and the T-cell receptor.  Because the effect is independent of antigen, a large popula-  tion of T cells is activated and overproduces proinflammatory  cytokines, such as IL-1, IL-6, and TNF-a. Superantigens are  responsible for several diseases, including food poisoning  (enterotoxins of S. aureus and C. perfringens), toxic shock syn-  drome (toxic shock syndrome toxin [TSST] of S. aureus), and  scarlet fever (erythrogenic toxin of S. pyogenes).   Inflammation is the body’s initial response to the presence of  the bacteria. Vascular permeability is increased, allowing blood-  borne substances (e.g., the complement system) involved in  bacterial destruction to access the site of infection. The release  of anaphylatoxins (C5a and C3a) of the complement cascade  may increase the inflammatory response and lead to an increase  in capillary permeability sufficient to permit the escape of large  volumes of plasma, contributing to hypotension and, in severe  cases, cardiovascular shock (see Chapter 48). Many persistent  bacterial infections (e.g., M. tuberculosis) may lead to formation  of granulomas, which diminishes the function of the affected  organ (e.g., the lung).   The release of a sufficient amount of endotoxin can lead to  fatal endotoxic shock (septic shock), which is one of the lead-  ing causes of death in intensive care units. The usual cause is  proliferation of gram-negative bacteria, although shock may  be caused by a few gram-positive bacteria and fungi. Once in  the blood, endotoxins cause the release of vasoactive peptides  and cytokines that affect blood vessels, producing vasodilation,  which reduces blood pressure, causes decreased oxygen deliv-  ery, and produces subsequent cardiovascular shock (see Figure  10-3 and Chapter 48). Endotoxin can activate the coagulation  cascade, leading to the syndrome of disseminated (or diffuse)  intravascular coagulation (see Chapter 27). Additionally, endo-  toxin induces the release of TNF-a (cachectin) by macrophages.  TNF is a potent proinflammatory cytokine that is also called  cachectin because of its role in promoting cachexia in individu-  als with cancer. (Cachexia is discussed in Chapter 12; cytokines  are discussed in Chapters 7 and 8.)   Example of Bacterial Pathogenesis. S. aureus has become a  major cause of hospital-acquired (nosocomial) infections. This  microorganism is a common commensal inhabitant of normal  skin and nasal passages (about 30% of individuals are nasal  carriers) and can be transmitted by direct skin-to-skin contact  or by contact with shared items or surfaces that have become  contaminated from another person’s infection (e.g., towels,  used bandages).?   Skin infections may occur at sites of trauma, such as  cuts and abrasions, and at areas of the body covered by hair  (e.g., back of neck, groin, buttock, armpit, beard area of men).    Most infections are relatively mild and localized, appearing as  red and swollen pustules on the skin, containing pus or other  drainage (Figure 10-5). They can develop into abscesses, boils,  carbuncles, cellulitis, or furunculosis. Invasive disease may  originate from wound infections (e.g., trauma, surgical wounds,  indwelling medical devices, prosthetic joints) and lead to fatal  septicemia and abscesses in internal organs (e.g., lungs, kidney,  bones, skeletal muscle, meninges, or heart).!®   Adherence to tissue is mediated by surface proteins that  attach to connective tissue (laminin, fibrin, fibronectin) and  endothelium. Attachment to collagen occurs in osteomyelitis  and septic arthritis—causing strains, and capsular polysaccha-  ride mediates attachment to prosthetic devices.   Staphylococci also produce very effective polysaccha-  ride capsules that protect against phagocytosis as well as sur-  face protein A that binds IgG by the Fc portion and a surface  coagulase that induces fibrin clotting on the bacterial surface;  both processes mask bacterial antigens under a surface of self-  proteins. Staphylococcal protein A, as well as a protein called  staphylococcal binder of immunoglobulin, is also secreted and  binds and neutralizes IgG.'? Staphylococcus produces proteins  that inhibit complement activity, including C3 and C5 conver-  tases, C5, C2, and the C5a receptor that mediates complement-  induced chemotaxis.”” Many pathogenic strains have increased  resistance to intracellular oxidative killing when engulfed by a  phagocyte.   Invasion is mediated by a variety of toxins, including  membrane-damaging toxins (a-toxin, which forms pores in  membranes; hemolysin, which destroys erythrocytes; §-toxin,  which is a sphingomyelinase; 6-toxin, a detergent-like toxin;  leukocidin, which lyses phagocytes), coagulase (causes clots),  staphylokinase (breaks down clots), exfoliative toxins (causes  separation of epidermis resulting in scalded skin syndrome),  lipase (degrades lipids on skin surface; facilitates abscess for-  mation), and a variety of enterotoxins. Many of the enterotox-  ins are superantigens that are responsible for staphylococcal  food poisoning with diarrhea and vomiting and toxic shock  syndrome. Each infectious strain of S. aureus produces a few  of these toxins so that strains may differ in their capacities  to cause particular diseases; thus, different strains can cause  purulent dermal infections, food poisoning, or toxic shock  syndrome.   Antibiotic resistance has become a major problem with  S. aureus. For several decades pathogenic strains have commonly  produced B-lactamase, an enzyme that destroys penicillin. More  recently staphylococci have developed resistance (methicillin-  resistant Staphylococcus aureus [MRSA]) to broad-spectrum  antibiotics, including methicillin-like antibiotics, which were  widely used to treat penicillin-resistant microorganisms.    Fungi are eukaryotic microorganisms with thick rigid cell walls  and the capacity to form a variety of complex structures (Figure  10-6). Fungi may grow as a mold with branched filaments or as  a meshwork mycelium structure (e.g., Aspergillus spp., causing  aspergillosis), yeast with ovoid or spherical shapes (C. albicans,  which causes candidiasis), or dimorphic with a yeastlike    appearance in tissue and mycelium in culture (e.g., Histoplasma  capsulatum, which causes histoplasmosis, a systemic respira-  tory disease). The cell wall is composed of polysaccharides  that differ from the peptidoglycans of bacteria and are thus are  resistant to bacterial cell wall inhibitors such as penicillin and  cephalosporin. In contrast to bacteria, the cytosol of fungi con-  tains organelles: mitochondria, Golgi apparatus, microtubules,  microvesicles, endoplasmic reticulum, and nuclei. Molds are  aerobic, and yeasts are facultative anaerobes. Common patho-  logic fungi are summarized in Table 10-6.   Fungi are diagnosed by microscopic observation of speci-  mens treated with potassium hydroxide and stained to enhance  visualization of spheres and filaments. Specimens also can be  cultured. Skin tests are available for species of Aspergillus. Many  of the antifungal drugs (e.g., amphotericin B, ketoconazole, flu-  conazole) used to treat deep or systemic infections are toxic to    the host because the fungal cell composition is similar to the  human cell.   Transmission and Colonization. Infection with a fungus is called  mycosis. Most pathogenic fungi (e.g., H. capsulatum, Coccidioides  immitis, Blastomyces dermatitidis) grow as saprophytes in the  environment and are transmitted by inhalation or contamination  of wounds. The majority of medically relevant fungi either exist as  human commensals or cause relatively mild infections (superficial  mycoses) of the skin, nails, hair, and mucous membranes of the  mouth and vagina. These include dermatophytes (e.g., tineas,  which refers to several skin mycoses including ringworm,  athlete’s foot, and others) and yeasts (e.g., Candida, Aspergillus,  Cryptococcus).   Human-to-human transmission is only a concern with der-  matophyte infections. Systemic mycosis caused by pathogenic  fungi generally results from inhalation of spores present in a    FIGURE 10-5 Staphylococcus aureus \nfections. Different strains of S. aureus (gram-positive cocci in sputum from  an individual with pneumonia [center photograph]) cause a variety of infections. The particular infection may depend on the  toxin produced: exfoliative toxin (scalded skin syndrome), enterotoxins A-G (food poisoning), or toxic shock syndrome toxin-1  (TSST-1). (Toxic shock syndrome, carbuncle, impetigo, and wound infection photos from Cohen J, Powderly WG: Infectious  diseases, ed 3, St Louis, 2010, Mosby. Folliculitis photo from Goldman L, Ausiello D: Ceci! medicine, ed 24, Philadelphia, 2012,  Saunders. Center photo and photos of food poisoning and endocarditis from Kumar V et al: Robbins & Cotran pathologic basis  of disease, ed 8, Philadelphia, 2010, Saunders. Furuncle photo from Long S et al: Principles and practice of pediatric infectious  diseases, ed 4, Philadelphia, 2012, Saunders. Scalded skin syndrome and pneumonia photos from Mandell G et al: Principles  and practice of infectious diseases, ed 7, Philadelphia, 2010, Churchill Livingstone.)    contaminated environment and initially presents as a pulmo-  nary infection. Infection that disseminates to other organs can  be life threatening. Systemic mycosis caused by opportunistic  fungi is usually secondary to immunosuppression caused by  genetic defects, infections such as HIV, cancer, and drugs used  to prevent transplant rejection.    MOLDS  Filamentous fungi grow as  multinucleate, branching  hyphae, forming a mycelium  (i.e., ringworm)    YEASTS  Yeasts grow as ovoid or  spherical; single cells multiply  by budding and division (i.e.,  Histoplasma)    FIGURE 10-6 Morphology of Fungi. Fungi may be either mold or yeast forms,  or dimorphic. The photograph shows Candida albicans with both the mycelial and  the yeast forms. (From Goering R et al: Mims’ medical microbiology, ed 5, London,  2013, Saunders.)    Specific adherence to the epithelium is provided by several  polysaccharides on the fungal surface. Glucan, mannan, glyco-  protein, and chitin molecules adhere with host receptors, includ-  ing Toll-like receptors (TLRs), mannose receptors, dectin-1, and  cadherins, respectively. A cell wall adhesion molecule, aggluti-  nin-like sequence 3 (ALS3), on several fungi (e.g., C. albicans)  promotes adherence to epithelial cells as well as silicone, thus  facilitating infection of implants and other medical devices.   In 2006 the opportunist pathogen Pneumocystis carinii was  reclassified as a fungus, and the specific variant that infects  humans was renamed Pneumocystis jiroveci.*! Despite the offi-  cial change in nomenclature, much of the literature will con-  tinue to use P. carinii for some time. As with many fungi and  protozoa, Pneumocystis has two life-cycle forms: a trophic form  and the cyst form. Two surface proteins, glycoprotein A (gpA)  and major surface glycoprotein (MSG), mediate attachment to  alveolar epithelial cells.   Invasion and Evasion. The host defense against fungal infec-  tion includes the fungistatic properties of neutrophils and mac-  rophages. T lymphocytes are crucial in limiting the extent of  infection and producing cytokines to further activate macro-  phages. Human host defense against the inhaled spores begins  with the mucous layer and the ciliary action in the respiratory  tract, which then remove the fungus or facilitate phagocytosis  by local macrophages. Pathogenic fungi have developed means  to circumvent these mechanisms (see Table 10-5).??   Intracellular Survival. Fungal virulence and resistance to  the individual’s protective mechanisms is a complex process  that requires the expression of multiple genes at different stages  and different sites of infection. Pathologic fungi are generally  dimorphic (e.g., H. capsulatum, B. dermatitidis, C. immitis) and  readily adapt to the host environment, responding to tempera-  ture variations, low oxygen environment, more alkaline pH,  and other conditions in the host tissue by undergoing changes    Tinea pedis (athlete's foot)  Tinea cruris (jock itch)  Tinea corporis (ringworm)  Cutaneous candidiasis   Lesions in most areas of skin, mucous  membranes, thrush, vaginal infection    in morphology and switching from avirulent mold forms to  virulent yeast forms. Similar conditions also trigger yeasts (e.g.,  C. albicans) to switch from the yeast form to its more virulent  hyphal form.   The more virulent morphologies allow fungi to survive in mac-  rophages after phagocytosis. After phagocytosis by macrophages,  the yeast form of Histoplasma replicates in phagosomes and pha-  golysosomes. Some yeast may produce proteins that inhibit the  activity of lysosomal proteases. The macrophage either may be  destroyed as a result of membrane modification by the fungus or,  in the case of fungi like Histoplasma, may harbor the fungus in  granulomas. Breakdown of the granulomas over time may result  in release of viable fungi and recurrence of the infection.   Protection Against Phagocytosis. Encapsulated yeast cells  (e.g., Cryptococcus neoformans) are more resistant to phago-  cytosis than unencapsulated yeast. The cryptococcal polysac-  charide capsule is antiphagocytic by blocking recognition by  macrophages and may also be immunosuppressive by inhibiting  migration of leukocytes into the site of fungal infection. Asper-  gillus fumigatus and many other fungi produce toxic metabo-  lites (e.g., gliotoxin) that inhibit macrophage and neutrophil  phagocytosis. Molecules like gliotoxin may also be immu-  nosuppressive, including suppression of mast cell activation,  degranulation, and secretion of leukotrienes and cytokines.   Antigenic Variation. Altered antigen expression affords pro-  tection against the developing immune responses, although this  defense strategy is rarely used by fungal pathogens. Pneumo-  cystis contains approximately 80 different goA and MSG genes,  only 1 of which is expressed at a time. Modulation of these anti-  gens may provide resistance against immune destruction.   Immune Suppression. Several yeasts stimulate the pro-  duction of immunosuppressive cytokines, resulting in down-  regulation of some aspects of the host’s immune response. The  yeast C. neoformans suppresses inflammation by inhibiting pro-  duction of the proinflammatory cytokines TNF-a and IL-12  and inducing production of the anti-inflammatory cytokine  IL-10. The overall result is suppression of macrophage function  and protection against killing.   Tissue Damage. Fungal infections damage tissue directly  by secretion of enzymes and indirectly by initiation of an  inflammatory response. Secreted enzymes, such as proteases,  phospholipases, and elastases, damage cells and intercellular  matrix, leading to necrosis. Many molds secrete mycotoxins  when grown in environmental locations, such as on nuts, beans,  and grains. Ingestion of this toxin affects muscle coordination,  causes tremors, and may be fatal. Some fungal toxins may cause  cancer; aflatoxins produced by some Aspergillus are especially  carcinogenic.   The typical immune and inflammatory reaction against fungal  infections involves a cell-mediated response with infiltration of T  cells and macrophages, as well as neutrophils. The inflammatory  site is rich in proinflammatory cytokines. Fungal infections can  be very difficult for these systems to eradicate, leading to pro-  gressively increasing production of cytokines. Thus, as the host’s  response increases so do the destructive effects on surrounding  healthy tissue. In cases of persistent infection, granulomas form  and compromise the normal function of the infected tissue.    Example of Fungal Pathogenesis. Candida albicans is the  most common cause of fungal infections in humans. It is an  opportunistic yeast that isa commensal in the normal microbiome  of many healthy individuals, residing in the skin, gastrointestinal  tract, mouth (30% to 55% of healthy individuals), and vagina  (20% of healthy women) and normally under the control of  local defense mechanisms, including members of the bacterial  microbiome that produce antifungal agents. In healthy individuals,  particularly those whose normal microbiome has been disturbed  by antibiotic therapy (e.g., diminished levels of Lactobacillus in the  vaginal microbiome), Candida overgrowth may occur resulting  in vaginitis or oropharyngeal infection (thrush). In those with an  intact immune system the infection remains localized.   In immunocompromised individuals, particularly those  with diminished levels of neutrophils (neutropenia), dissemi-  nated infection may occur. Candida is the most common fun-  gal infection in people with cancer (particularly acute leukemia  and other hematologic cancers), transplantation (bone mar-  row and solid organ), and HIV/AIDS. Almost 90% of people  with AIDS have Candida at least one time during the disease,  although infection is usually contained locally (thrush or vagi-  nitis) because of adequate numbers of neutrophils (Figure  10-7). Invasive candidiasis may also be secondary to indwelling    FIGURE 10-7 Candida albicans. A, Gram stain of sputum showing chains  of elongated budding yeasts of C. albicans producing pseudohyphae (x1000).  B, Oral candidiasis (thrush). (A from McPherson R, Pincus M: Henry's clinical diag-  nosis and management by laboratory methods, ed 22, Philadelphia, 2012, Saunders;  B courtesy Dr. Stephen Raffanti.)    catheters, intravenous lines, or peritoneal dialysis, which pro-  vides direct entrance into the blood.   Disseminated candidiasis may involve several internal  organs, including abscesses in the kidney, brain, liver, and  heart, and is characterized by persistent or recurrent fever,  gram-negative shock-like symptoms (hypotension, tachycar-  dia), disseminated intravascular coagulation (DIC), and death.  The mortality rates of sepsis or disseminated candidiasis are in  the range of 30% to 40%.?°   Like most pathogenic yeasts, Candida undergoes morpho-  logic changes from unicellular yeast to filamentous hyphal  forms under conditions of neutral to alkaline pH, elevated  temperature, and changes in host serum factors. Switching of  morphology results in altered profiles of surface antigens and  increased resistance to immunologic destruction as well as  altered tissue adhesion specificity.** Candida expresses diverse  surface adhesion molecules that permit adherence to materials  in implants, epithelium, extracellular matrix (fibronectin, lam-  inin, collagen), and leukocytes and facilitate invasion into tis-  sue. One surface adherence molecule is a glycoprotein, INT 1p  (integrator complex subunit 1), which specifically binds to inte-  grins. EAP1 (enhanced adhesion to plastic) is a glycoprotein  that permits Candida to bind to epithelial cells and a variety of  synthetic materials found in implants.   Candida secretes several enzymes that function as viru-  lence factors and contribute to tissue destruction. Acid pro-  teases and phospholipases damage the cell membrane and  enhance invasive capacity. Secreted aspartic proteinases (Saps)  increase the virulence of Candida by destroying cell membranes    and removing surface molecules, including from cells of the  immune and inflammatory systems.   Candida may suppress the host’s immune system. Produc-  tion of the cytokine granulocyte-monocyte colony-stimulating  factor (GM-CSF) suppresses monocyte/macrophage function,  including the production of components of the complement  cascade. Decreased production of C3 results in less opsoniza-  tion (C3b) and production of chemotactic activity (C3a) for  phagocytes.    Parasitic organisms establish symbiosis with another species  in which the parasite benefits at the expense of the other spe-  cies. Parasites range from unicellular protozoal to large worms.  Parasitic worms (helminths) include intestinal and _ tissue  nematodes (e.g., hookworm, roundworm), flukes (e.g., liver  fluke, lung fluke), and tapeworms. A protozoan is a eukary-  otic, unicellular microorganism with a nucleus and cytoplasm.  Pathogenic protozoa include malaria (Plasmodium), amoebae  (e.g. Entamoeba histolytica, which causes amoebic dysentery),  and flagellates (e.g., Giardia lamblia, which causes diarrhea;  Trypanosoma, which causes sleeping sickness). Although less  common in the United States, parasites and protozoa are com-  mon causes of infections worldwide, with a significant effect on  the mortality and morbidity of individuals in developing coun-  tries. Important parasites of humans are listed in Table 10-7.  Transmission and Colonization. Parasitic and protozoal  infections are rarely transmitted from human to human. The  predominant means is through vectors in which the organism    Dysentery, liver abscess  Diarrhea  Sores on skin, progression to liver, spleen   Generalized, blood, lymph nodes,  progressing to cardiac and central  nervous system (CNS)    spends part of its life cycle. Examples include the transmission  of malaria (Plasmodium spp.) by mosquitoes, trypanosomes  (Trypanosoma cruzi, which causes Chagas disease in South  America; Trypanosoma brucei, which causes sleeping sickness  in Africa) by the tsetse fly, and Leishmania spp. by sand fleas.  Many of the protozoal infectious agents (e.g., E. histolytica,  G. lamblia) are encountered in contaminated water or food and  transmission is by ingestion.   The initial attachment depends on whether the microor-  ganism is injected into the bloodstream by a vector or whether  entrance is through the gastrointestinal tract. Microorganisms  in the bloodstream frequently have surface lectins that react  with carbohydrates on specific cells. Malarial parasites attach  to erythrocytes that express Duffy blood group antigens. Thus  Duffy-negative individuals are resistant to malaria. T. cruzi can  infect both CD4-negative and CD8-positive T cells through a  T-cell surface receptor. Several parasites express surface glyco-  proteins that facilitate preferential entrance into monocytes/  macrophages using various receptors, including the receptors  for complement component C3b (Leishmania spp.). Leishmania  expresses a surface glycoprotein (gp63) that is necessary for its  entrance into macrophages. The gp63 molecule binds comple-  ment components (C3b, C3bi) and uses the macrophage com-  plement receptors. E. histolytica expresses two surface proteins  that react with the disaccharide galactose/N-acetylgalactosamine  on epithelium.   Invasion and Evasion. An effective immune response varies  depending on the particular parasite or protozoa. Intercellular  pathogens are susceptible to cell-mediated immunity and  activation of macrophages by T cells. Other organisms are more  sensitive to antibody, particularly used in antibody-dependent  cell-mediated cytotoxicity (ADCC) by macrophages and  natural killer (NK) cells. Many helminth infections are sensitive  to damage by eosinophils, which are attracted by IgE-mediated  mast cell degranulation and release of eosinophil chemotactic  factor of anaphylaxis (ECF-A). Evasion of the individual’s  defenses is accomplished by several means (see Table 10-5).?°   Intracellular Survival. Leishmania spp. are obligative intra-  cellular parasites of monocytes/macrophages. They are pro-  tected from being killed in the phagosome and phagolysosome  in which they multiply. Protection may be afforded by a surface  protein that inhibits fusion of lysosomes to the phagosome,  thus decreasing the amount of degradative enzymes within the  phagolysosome. Toxoplasma spp. may be protected by entrance  into a variety of cells, including macrophages. The probability  of survival is increased by inhibiting fusion of lysosomes with  the phagosome. Many of the intracellular organisms are sensi-  tive to macrophage activation by T cells. T. cruzi bypasses the  effects of macrophage activation by escaping from the phago-  some and growing in the macrophage cytoplasm.   Protection Against Phagocytosis. Because many unicellu-  lar parasites survive within macrophages, the development of  antiphagocytic capsules does not seem to be a major protective  strategy. In some cases, a surface glycocalyx may function in a  similar fashion as capsules to mask surface antigens from bind-  ing antibody. Some organisms produce toxins to protect them-  selves against phagocytosis; E. histolytica releases phospholipase   Coating with Self-Proteins. Pathogens that coat themselves  with human proteins may be disguised and “fool” the immune  system. Schistosomes and trypanosomes mask their antigens by  absorbing IgG by the Fc portion of the molecule.   Antigenic Variation. In general, those organisms that  undergo part of their life cycle in humans or may assume mul-  tiple morphologic forms will also undergo antigenic changes  related to the stage in the life cycle or morphology. Some proto-  zoa have developed very complex alterations in surface antigens  using gene switching. Infection with African trypanosomes  may lead to fatal neurologic disease. During infection protective  antibody is produced against surface antigens called variable  surface glycoproteins (VSGs). The parasite remains extracellu-  lar and an IgG or IgM response will successfully kill most of the  microorganisms. However, a small percentage will undergo a  gene shift that results in a change in VSG.”° The existing anti-  bodies will not recognize the new VSG, and the level of schisto-  somes will rebound, causing recurrent disease. The schistosome  has genetic information (about 10% of the genome) for hun-  dreds of variations in VSG, which are expressed one at a time.  Thus the organism undergoes periodic shifts in VSG expres-  sion, resulting in periodicity of parasites in the blood. A similar  process occurs in some helminths (Trichinella spiralis).   Degradation of Immune Molecules. If a microorganism is  sensitive to a particular component of the immune or inflam-  matory system, a survival advantage is obtained by production  of enzymes that specifically degrade that component. Schisto-  somes secrete an enzyme that diminishes the effectiveness of  IgG by specifically removing a critical peptide. E. histolytica  secretes a protease that can degrade IgG and IgA.   Neutralization of Immune Molecules. Large parasitic  organisms may release a large amount of soluble antigen to  neutralize antibody.   Complement Evasion. Complement activation is effective  against several parasites. Some parasites (e.g., Echinococcus spp.,  Leishmania spp.) produce complement regulatory proteins  that affect complement function by destabilizing C3 conver-  tase or promoting degradation of C3b. Trypanosomes produce  complement regulatory factors, including a surface gp63-like  molecule, that confer resistance to complement. E. histolytica  produces complement regulatory factors that inactivate C3a  and C5a, thus inhibiting phagocyte chemotaxis activity.   Immune Suppression. Parasites may produce both patho-  gen-specific and nonspecific immune suppression. The release  of large amounts of soluble antigen may induce specific toler-  ance to the pathogen as well as induce dysfunctional macro-  phage antigen processing. The function of immune cells is  directly blocked by secretion of cytotoxic molecules (T. spira-  lis), selective inhibitors of T-cell function (schistosomes), or  inducers of polyclonal B-cell activation (B-cell mitogen released  by trypanosomes).   E. histolytica induces T-cell hyporesponsiveness by induc-  tion of IL-4 and IL-10 that down-regulate maturation of Th  cells. The VSG molecules of African trypanosomes stimulate  macrophages to overproduce TNF-a and CD8-positive cells to    secrete high levels of interferon-gamma (IFN-y), which impairs  T-cell responses.?’ Leishmania has developed an interesting  approach to circumventing antigen processing by macrophages.  This pathogen adsorbs IgG, which binds to the macrophage Fc  receptor, resulting in the hyperproduction of IL-10 and sup-  pression of IL-12 from infected macrophages. IL-10 prevents  macrophage responses to IFN-y, allowing the parasites to sur-  vive even in the immunologically intact individual.   Tissue Damage. Tissue damage may result directly by parasitic  infestation in the tissue or be secondary to the individual’s  immune and inflammatory responses. The particular process  depends a great deal on burden of parasites infesting the  site and sensitivity of the particular site to damage. Large  infestations may lead to physical loss of function in a tissue or  organ. For instance, a large number of intestinal parasites (e.g.,  the roundworm Ascaris lumbricoides, tapeworms, Giardia spp.)  compete for and prevent uptake of nutrients, leading to various  forms of malabsorption, blocked uptake of fats, or anemia from  malabsorption of B,, or from large amounts of blood loss.  Filarial parasites (e.g., Wuchereria bancrofti and Brugia malayi,  which causes elephantiasis) block the lymphatics and cause  accumulation of lymph in tissues. The larvae of tapeworms  (e.g., Taenia solium) encyst in and prevent normal function of  organs (e.g., muscle, liver, eye), which is particularly dangerous  in the human brain.   Toxins released from parasites may cause significant irrevers-  ible organ damage. Proteolytic enzymes from E. histolytica are  very cytolytic, leading to ulceration of intestinal walls, bloody  diarrhea, amoebic dysentery, dehydration, and death in infants  and young children. T. cruzi (causes Chagas disease) secretes  proteases and phospholipases that damage the myocardium  and intestinal smooth muscle and secretes a small-molecular  —weight neurotoxin that affects the anatomic nervous system  and causes fever.   The infected individual’s immune and _ inflammatory  responses result in considerable histopathology. Schistosomia-  sis results in the deposition of eggs in organs (e.g., the liver),  which leads to formation of granulomas and tissue destruction  through fibrosis. Some parasitic products (T. brucei, malarial  parasites) activate macrophages to overproduce cytokines, which  leads to exacerbated inflammation. The IgE produced against  parasitic worms is protective, but can also stimulate excessive    degranulation of mast cells and even anaphylactic shock. Poly-  clonal B-cell activation leads to the production of a broad  spectrum of autoantibodies that may precipitate autoimmune  diseases. Overproduction of antigens by some pathogens (e.g.,  malaria, trypanosomiasis, schistosomiasis) may lead to exces-  sive levels of pathogenic circulating immune complexes and  initiation of type III hypersensitivity reactions (see Chapter 9)  in the kidneys and vasculature.   Example of Parasitic Pathogenesis. Malaria is one of  the most common infections worldwide. The World Health  Organization (WHO) estimated in 2010 that there were  219 million cases of malaria worldwide and that malaria  accounted for an estimated 666,000 deaths, 90% of which  are in Africa, mostly among children.** Malaria is caused  by four species of Plasmodium parasites that infect humans:  Plasmodium falciparum (accounts for most fatalities),  Plasmodium vivax and Plasmodium ovale (both of which are  more benign), and Plasmodium malariae. The four strains  differ in disease severity and incidence of fever. Infection with  P. falciparum, the most severe form, results in severe chills,  high fever, sweating, headache, muscle pains, vomiting, severe  anemia, pulmonary edema, and many other complications.  Neurologic complications may result from infected red blood  cells (RBCs) adhering to endothelium in capillaries of the brain.  The individual may develop cardiovascular collapse, shock,  coma, and death.   Transmission is through the bite of an infected female  Anopheles mosquito, where the microorganism grows in the  salivary gland. The infectious form enters the bloodstream, sur-  vives in the liver, and invades parenchymal cells. After several  rounds of division, the liver cell ruptures, and several thou-  sand parasites enter the blood, where they infect red blood cells  (Figure 10-8). Multiplication occurs in RBCs, resulting in the  release of daughter parasites that reinfect other erythrocytes.   P. vivax and P. ovale malaria can remain dormant in the  liver for years, protected from the immune system by intracel-  lular residence. The parasite in the blood avoids destruction by  phagocytes in the spleen by expressing adhesion proteins that  cause adherence and sequestration along the walls of the small  vessels. Additionally, P. falciparum undergoes gene switch-  ing among about 60 different antigenic variants of antigens  expressed on the surface of infected erythrocytes (P. falciparum    acteristic band from trophozoite of Plasmodium malariae containing intracellular pigment hemozoin. (From Kliegman R et al:    erythrocyte membrane protein, PfEMP). Malaria induces a  form of immune suppression. Numbers of CD4 and CD8 T  cells are diminished and lymphocytes from individuals infected  with P. falciparum do not proliferate in the presence of PPEMP  antigen in vitro.   Malarial parasites have developed broad drug resistance  including chloroquine, the previous mainstay of the preventive  and therapeutic arsenal of antimalarial drugs.”’ Most resistance  originates from mutations in the target genes (antigenic varia-  tion). Resistance to drugs that cause cellular damage appear to  result from increased activity, or even novel development, of  drug transporters that eliminate the drugs from the parasitic  organism.    Viruses are extremely simple microorganisms and do not  possess any of the metabolic organelles found in prokaryotes  (e.g., bacteria) or eukaryotes (e.g., human cells). The basic viral  structure (virion) consists of nucleic acid protected by a pro-  tein shell, the capsid. The capsid may take many characteristic  shapes: helical, icosahedral, or large pleiomorphic (poxvirus)  (Figure 10-9). Some viruses also have a protective envelope sur-  rounding the capsid, which consists of the plasma membrane  from the previously infected cell.   Viruses are classified by the format of nucleic acid in the  virion, which may be RNA or deoxyribonucleic acid (DNA)    and either single-stranded (ss) or double-stranded (ds), and by  whether the virus uses the enzyme reverse transcriptase (RT)  for replication. Thus seven classifications are used: dsDNA  (e.g., herpesvirus, smallpox virus), ssDNA (parvovirus), dsRNA  (rotavirus), ssRNA +sense (+sense functions as mRNA) (e.g.,  hepatitis A and C viruses, SARS virus, poliovirus, rhinovirus),  ssRNA-sense (e.g., Ebola virus, Marburg virus, Nipah virus,  influenza virus, and viruses that cause measles, mumps, and  rabies, hantavirus, Lassa virus), ssRNA +sense with RT (e.g.,  HIV), and dsDNA with RT (e.g., hepatitis B virus).   Viral diseases are the most common afflictions of humans  and include the common cold, the “cold sore” of herpes sim-  plex virus, several forms of hepatitis, HIV, and several types of  cancer. Examples of human diseases caused by specific viruses  are listed in Table 10-8.   Transmission and Colonization. Viruses are obligatory  intracellular parasites; thus transmission is usually from one  infected individual to an uninfected individual or from an  animal reservoir (zoonotic infection). Transmission may be  direct or through a vector, such as mosquitoes. Human-to-  human transmission may take many forms, including aerosols  of respiratory fluids, contact with infected blood, or sexual  contact.   The viral life cycle is completely intracellular and involves  several steps: attachment to the target cell (determines host  range and tropism), penetration (by endocytosis or membrane    FIGURE 10-9 Electron Micrographs of Representative Viral Structures. A, Rotavirus: particles with a double shell  and a characteristic “wheel-and-spoke” appearance. B, Epstein-Barr virus: icosahedral enveloped DNA virus. €, Adenovirus:  particles with characteristic icosahedral structures. D, Paramyxovirus: spherical enveloped RNA virus. RNA is seen spilling  out of the disrupted virus. (A from Long S, Pickering L, Prober C: Principles and practice of pediatric infectious diseases, ed  3, Philadelphia, 2005, Saunders; B and D photos courtesy Science Source; © Photo Researchers, Inc., New York, NY; € from  Mandell GL, Bennett JE, Dolin R: Mandell, Douglas, and Bennett’ principles and practice of infectious diseases, ed 7, Phila-    fusion), uncoating (release of viral nucleic acid from the viral  capsid by viral or host enzymes), replication (synthesis of viral  proteins and mRNA), assembly (formation of new virions), and  release (by lysis, budding) (Figure 10-10).   Attachment involves specific interactions between surface  proteins on the virus and receptors on the cell to be infected. The  specificity of the virus for these receptors and the distribution of  receptors throughout the individual’s tissues dictate the range  of host cells that a particular virus can infect. For example, HIV    has a glycoprotein (gp120) that attaches to the CD4 molecule  expressed on helper T cells, monocytes, and microglia. Rota-  virus recognizes sialic acid and other constituents of epithelial  junctions. Epstein-Barr virus (EBV, which causes mononucleo-  sis) binds to complement receptor 2 (CR2) on B lymphocytes.  Once bound, the virion penetrates the plasma membrane  by receptor-mediated endocytosis, by envelope fusion with the  plasma membrane, or by directly crossing the plasma mem-  brane. Within the cytoplasm the virus uncoats the protective    AIDS, Acquired immunodeficiency syndrome; DNA, deoxyribonucleic acid; ds, double-stranded; H/V, human immunode    Yellow fever virus  Dengue virus  West Nile virus  Rubella virus  SARS    nucleic acid; AT, reverse transcriptase; SARS, severe acute respiratory syndrome; ss; single-stranded.    nucleocapsid and releases viral genetic information. Most RNA  viruses directly produce mRNA, which is translated into viral  proteins, and genomic RNA, which is eventually packaged into  new viruses. One particular family of viruses, retroviruses (e.g.,  HIV), carries the enzyme reverse transcriptase that creates a  double-stranded DNA version of the virus. The DNA “provi-  rus” enters the cell’s nucleus, where it becomes integrated into  the host cell’s chromosomal DNA. DNA viruses also enter the  nucleus and are transcribed into mRNA before protein trans-  lation. Some DNA viruses also may integrate into the infected  cell’s chromosomal DNA.   The translation of viral-specific mRNA results in viral pro-  teins that self-assemble. New virions are released from the cell  for transmission of the viral infection to neighboring uninfected  cells. Enveloped viruses are released through budding, in which  shed viral particles are enveloped in the plasma membrane  from the surface of the infected cell. Nonenveloped viruses  commonly are released in large numbers concurrent with the  destruction of the cell. Viral DNA that has become integrated  with host DNA is transmitted to the daughter cells during mito-  sis. By this process, viral genes can become part of the genetic  information of the cell and its progeny.   Invasion and Evasion. The primary defense mechanisms  against viruses include antibody that prevents viral entrance into  a cell and cellular immunity that recognizes antigenic changes  on the surface of infected cells. Nonspecific defense includes  production of a- and f-interferons that block intracellular  viral replication. However, many viruses are highly successful  pathogens and have developed a variety of mechanisms for  bypassing immune rejection (see Table 10-5, p. 308).   Rapid Division. Some viruses, particularly those with small  genomes, rapidly proliferate after the initial infection and  by doing so produce a large number of virions more quickly  than the immune system can develop. Norovirus and rotavi-  rus (causes of severe diarrhea and vomiting) and Ebola virus,  Marburg virus, and hantavirus (causes of hemorrhagic fever)  have very short incubation periods. By the development of an  effective adaptive immune response in 4 or 5 days, the virus has  spread and caused severe clinical disease.    Replication  FIGURE 10-10 Stages of Viral Infection of an Infected Cell.    Intracellular Survival. As obligative intracellular pathogens,  viruses hide within cells and away from normal inflammatory  or immune responses. Viral agents that spread from cell to cell  after the initial infection must encounter the immune response,  which in most cases cures the infection. Thus most viral infec-  tions are self-limiting.   Ifa symbiotic relationship is maintained between the cell and  the virus, persistent unapparent infection may result (latency).  The infected cell will be functional, and the virus persists until  it is activated to replicate (e.g., the recurrent coldsores of her-  pes simplex virus infection).°*° Latent viruses usually possess  latency-associated transcript (LAT) genes that control persis-  tence indefinitely. Reactivation usually results from expression  of lytic genes that lead to increased viral expression and destruc-  tion of the infected cell. Latency is characteristic of several  chronic viral infections (e.g., HIV, hepatitis B and C viruses).   The interferon response is particularly effective against many  viral infections, and viral survival mechanisms have evolved to  mitigate the antiviral effects of interferon. The V and P proteins  of the measles virus may function as regulators of transcription  and prevent the synthesis of interferon, as well as the induc-  tion of protective genes by interferon.*! In a similar fashion, the  influenza virus produces a family of viral proteins that inhibit  the pathways leading to the production of interferon and to  activation of interferon-activated protective genes.**   Coat with Self-Proteins. Enveloped viruses are the prime  examples of how this mechanism may succeed. The viral cap-  sid is completely surrounded by a cellular plasma membrane  that is highly similar to that of an uninfected cell. Only a few  critical differences exist. In order to infect another cell the  viron expresses envelope proteins (SU and TM proteins) that  are critical for the intercellular fusion process. These proteins  are virus-specific and targets for protective immune responses.  Other viruses, such as the hepatitis C virus, bind on their sur-  face normal proteins from the infected host, such as lipopro-  teins, that mask the viral epitopes from circulating antibody.°?   Antigenic Variation. One of the classic examples of anti-  genic variation is influenza. This virus undergoes frequent anti-  gen shifts and drifts, which are described in detail within the  following section titled Example of Viral Pathogenesis. Other  viruses (e.g., HIV) add antigenic diversity by incorporating fre-  quent functional translational errors. Some viral enzymes are  designed to create small errors in reading mRNA leading to  minor changes in the viral proteins. These changes are not at  functionally critical sites, but may provide resistance to specific  and nonspecific defense mechanisms.   In a manner similar to bacteria, some viruses have multi-  ple stable antigenic serotypes. A person who recovers from an  infection with one serotype may not have protective immunity  against other serotypes of the same virus. At least 100 serotypes  of rhinovirus can cause the “common cold,” which explains  why individuals can catch many colds throughout their lives.  HIV and hepatitis C virus also have multiple serotypes.   Neutralization of Immune Molecules. As with other patho-  gens, the secretion of large amounts of soluble viral antigen may  lead to neutralization of antibody and formation of immune  complexes. With infections such as hepatitis B significant levels    of circulating immune complexes may form and be deposited in  target tissues, such as the kidneys.   Some viruses also have the capacity to neutralize cytokines,  such as IL-1 and TNF-a. Cells infected with vaccinia virus pro-  duce a protein that can bind to IL-1. These molecules are fre-  quently called cytokine decoys.   Complement Evasion. Several viruses induce expression of  regulators of complement activation. Cellular complement inhib-  itors are incorporated into the envelope of some viruses (e.g.,  HIV-1, vaccinia). Cytomegalovirus (CMV) induces complement  inhibitors on the surface of infected cells. Herpes simplex virus  expresses a cell surface protein (glycoprotein C-1) that binds and  inhibits C3b, as well blocks the membrane attack complex.   Immune Suppression. HIV and other viruses have devel-  oped the capacity to infect and kill immune cells, thus protect-  ing themselves, but also leading to a broad immunosuppression  against other antigens. This process is discussed more thor-  oughly in the section on AIDS.   Some viruses have developed mechanisms for interfering  with antigen processing and presentation by major histocompat-  ibility complex (MHC) class I molecules. Endogenous antigens,  such as viral antigens, are normally degraded by proteasomes,  transported by transporters with antigen processing (TAP)  proteins into the endoplasmic reticulum, and complexed with  MHC class I molecules for expression on the cell surface and  presentation to appropriate cells of the immune response (see  Chapter 8). Many of the herpesviruses and retroviruses prevent  steps in this process. For instance, Epstein-Barr virus inhibits  degradation by the proteasomes. Herpes simplex virus can pre-  vent binding of the antigenic peptide to MHC class I. Inhibition  of antigen presentation by MHC class I prevents the generation  of effective T-cell immune responses.   Human CMV has developed a unique modification of affect-  ing MHC processing. NK cells are the principal defenders against  tumor cells or virally infected cells that have down-regulated  MHC expression and are therefore not recognized by T-cytotoxic  cells. NK cell function is suppressed by targets with surface class  I MHC molecules. CMV is capable of preventing antigen presen-  tation by MHC class I and stimulates the expression of a MHC-  like molecule that cannot present antigen but is recognized as  a suppression signal by NK cells. Thus CMV-infected cells are  protected from both T-cytotoxic cells and NK cell killing.   Tissue Damage. Once inside the infected cell, viruses may  have many harmful effects, including the following:   * Cytopathic effects resulting from inhibition of cellular  DNA, RNA, or protein synthesis, disruption of lysosomal  membranes, resulting in release of “digestive” lysosomal  enzymes that can kill the cell (cell lysis)   * Fusion of infected, adjacent cells, thereby producing multi-  nucleated giant cells (herpesviruses and paramyxoviruses  [measles virus, mumps virus, respiratory syncytial virus])   + Transformation of infected cell into cancerous cells,  resulting in uninhibited and unregulated growth   + Alteration of the antigenic properties, or “identity,” of the  infected cell, causing the immune system to attack the cell  as if it were foreign    Example of Viral Pathogenesis. Influenza is an ssRNA  (—strand) with a segmented genome (seven or eight pieces  of ssRNA) (Figure 10-11). It is transmitted through aerosols  or body fluids and is highly infectious. The virions attach to  respiratory epithelial cells and enter by endocytosis. Symptoms  begin 1 to 4 days after infection and may include chills, fever,  sore throat, muscle aches, severe headaches, coughing, weakness,  generalized discomfort, nausea, and vomiting, and may lead to  pneumonia; it can be fatal, particularly in young children and  older adults. The normal rate of infectivity is about 5% to 15%,  with a mortality rate of about 0.1%, and in most cases recovery  occurs in 1 to 2 weeks. Yearly seasonal influenza outbreaks  result in about 250,000 to 500,000 deaths worldwide.   The influenza virion expresses two surface proteins that are  essential to virulence. The hemagglutinin (HA) protein is a gly-  coprotein that is necessary for entrance into cells by binding to  glycan receptors, which are richly expressed on the surface of  respiratory epithelium.** The surface neuraminidase (NA) is an  enzyme that is necessary for release of new virions from infected  cells by cleaving cellular sialic acids (a common component of  mammalian cell membranes).   Antibodies against the HA and NA antigens are responsible  for protection against influenza infection. Infections are sea-  sonal and protection gained from 1 year’s infection does not  totally protect against influenza in the following year because  the HA and NA antigens undergo yearly change. Usually anti-  genic variation is relatively minor (antigenic drift) and results  from mutations. Individuals frequently have partial protection  resulting from the previous year’s infection, which lessens the  effects of the disease. Two groups of influenza virus, influenza  A and influenza B, infect humans, and the yearly vaccine against  influenza virus is a trivalent mixture of inactivated proteins  from two influenza A subtypes and one influenza B subtype.  Influenza B almost exclusively infects humans, mutates at a  much lower rate than influenza A, and has reduced rate of anti-  genic change. Influenza B, however, has antigenically distinct  subtypes based on HA (16 forms) and NA (9 forms) antigens  and is infectious to birds and mammals. Currently subtypes  HI1N1, H1N2, and H3N2 are the primary causes of influenza  worldwide. Information regarding subtype H5N1 (avian influ-  enza) is summarized in What’s New? Avian Influenza.   Periodically influenza A undergoes major antigenic changes  (antigenic shifts) (see Figure 10-11). Shifts occur in animals  coinfected by a human and an avian strain of influenza.°°  Because the genome is segmented, the segments can undergo  recombination during which the human virus obtains a new  HA or NA antigen. When such changes occur, previous protec-  tion may not exist, resulting in a major pandemic and much  more severe disease. In 1918 an antigenic shift occurred in the  western United States (first reported in Fort Riley, Kansas)  resulting in an influenza A virus with an HIN] serotype (called  Spanish flu). The virus spread worldwide throughout 1918 and  1919. Symptoms were unusually severe, resulted from excessive  production of cytokines, and included deaths from secondary  bacterial pneumonia, massive hemorrhages, and pulmonary  edema. Spanish flu possessed an extremely high rate of infec-  tivity (up to 50%) and mortality (killed 20% or more of those    FIGURE 10-11 Antigenic Shifts in Influenza Virus. One theory proposes that antigenic shifts occur when a human  influenza virus (blue) and an avian influenza virus (red) coinfect a species that is permissive for both. The eight ssRNA strands  are co-expressed in the same infected cell, resulting in mixing of the strands so that a hybrid virus can be produced. The  hybrid virus indicated here contains all the genetic information of the original virus that infected humans, but contains a new  hemagglutinin (HA}containing stand from the avian virus. This virus expresses a new HA antigen and will be less susceptible  to residual immunity that normally provides partial protection against yearly influenza infections.    Influenza viruses infect a wide variety of species, including humans, different  strains of birds, and swine. The species specificity of a particular variant of  influenza is determined by the amino acid sequence of the hemagglutinin (HA)  molecule on the viral surface. Influenza viruses have a relatively high mutation  rate that can result in minor changes in the HA and change the species specific-  ity. As a result, an influenza virus strain that primarily infects birds may, after a  mutation, become efficiently infectious for humans.   Various strains of a highly pathogenic avian influenza A (H5N1) have arisen in  the past few years. These strains were first reported in 1996 in China. The most  pathogenic variants have a near 100% mortality rate in domestic poultry and have  spread globally, killing tens of millions of birds. The global spread may be a result  of collateral nonfatal infection of wild migrating birds, such as ducks and geese.   In 1997, the first human infections with the H5N1 avian virus were reported  in Hong Kong involving 18 cases, 6 of whom died. From 2003 through 2012,  the WHO has reported a total of 608 confirmed H5N1 cases and 359 deaths  across 15 countries worldwide. So far, human infections occur primarily in those  individuals who have been in close contact with infected birds (especially those  who have handled sick, dead, or frozen poultry). Human-to-human transmission  is rare. No cases have been identified among short-term travelers visiting coun-  tries affected by outbreaks. The H5N1 strain infects the lungs and targets type  2 alveolar pneumocytes and macrophages. It also passes throughout the body    to the gastrointestinal tract, brain, liver, and blood cells and can be transmitted  transplacentally from the mother to the fetus. Symptoms include fever, cough,  sore throat, muscle aches, eye infections (conjunctivitis), pneumonia, acute  respiratory distress, and other severe and life-threatening complications. Diag-  nosis is made by detection of viral ribonucleic acid (RNA) obtained through throat  swabs. The mortality rate in human infections is about 60%. Host immunogenic  variation may play a role in the outcome of the immune response.   The concern is that further mutations may lead to a strain that spreads and  infects humans more efficiently, resulting in a rapid pandemic. These concerns  are not unfounded. Highly pathogenic H5N1 strains have undergone continued  evolution and expansion of host range with increasing mortality rates among  wild birds and infectivity for other mammals, including dogs and cats. In 2007,  a H5N1 strain was clearly transmitted from an infected individual to six other  members of the same Indonesian family group. The virus was further transmit-  ted from one of those six, an infected child, to the child's caregiver. Seven of the  eight individuals died.   Whether highly pathogenic variants of H5N1 avian influenza virus eventually  mutate into a major human pathogen remains to be seen. Prevention efforts rely  on the development, distribution, and use of vaccines. Antiviral agents are used  for active infection and prophylaxis of those who have been exposed to the virus.  Candidate genes influencing susceptibility are being identified.    Data from Chmielewski R, Swayne DE: Annu Rev Food Sci Technol 2:37-57, 2011; Juno J, Fowke KR, Keynan Y: Clin Dev Immuno! 2012:797180,  2012; Steel J: BioDrugs 25(5):285-298, 2011; Van Kerkhove MD et al: PLoS One 6(1):e14582, 2011, review, erratum in PLoS One 7(1), 2012; Wata-  nabe Y et al: Trends Microbiol 20(1):11-20, 2012; World Health Organization: Cumulative number of confirmed human cases of avian influenza/  (H5N1) Reported to WHO, 2012. Available at www.who. int/influenza/human_animal_interface/H5N1_cumulative_table_archives/en/index.html.    infected) and resulted in an estimated 40 million deaths world-  wide. A unique aspect of this influenza pandemic concerned  the age of the most susceptible populations.°° Most mortalities  secondary to influenza generally occur in the very young or very  old. Although those two age groups were at risk, a startling high  mortality rate was observed in adults between ages 20 and 39.  Strain variations caused by antigenic drift occur within both HA  and NA, and some may further affect virulence of that virus.  The 1918 HIN1 serotype also possessed several mutations in  the HA that resulted in a far greater virulence than the currently  circulating H1N1 type. Studies have demonstrated that survi-  vors of the 1918 pandemic still have protective levels of anti-  bodies against that particular virus, confirming that protection  against a particular influenza strain may be lifelong.    The most notable form of secondary or acquired immune defi-  ciency caused by an infectious agent is acquired immunode-  ficiency syndrome (AIDS). AIDS is a viral disease caused by  the human immunodeficiency virus (HIV). HIV infects and  depletes a portion of the immune system (Th cells), making  individuals extremely susceptible to life-threatening infections  and malignancies.   Despite major efforts by healthcare agencies around the  world, HIV/AIDS remains the major cause of worldwide mor-  bidity and mortality. Although aggressive antiretroviral therapy  and public health campaigns have stabilized the number of  new cases and deaths in the United States from HIV/AIDS,  the number of cases and deaths continues to increase rapidly  worldwide. Surveillance reports from the Centers for Disease  Control and Prevention (CDC) estimates that more than a mil-  lion (1,148,200) adults and adolescents were living with HIV  infection in the United States in 2010, of whom 18% were  undiagnosed, and that approximately 50,000 new HIV infec-  tions occur yearly.*” Most new infections (61%) occurred in  gay or bisexual men. The number of new AIDS diagnoses in  the United States increases by more than 30,000 per year (esti-  mated at about 35,000 in 2011). The estimated number of  AIDS-related deaths in 2010 was 15,529. Cumulatively since  1981 more than a million individuals (1,155,792) have been  diagnosed with AIDS in the United States, of which almost  636,000 have died as a result, and more than 490,000 are still  living with AIDS. In the United States, AIDS is predominantly  related to a history of male-to-male sexual contact: about 50%  of the newly diagnosed cases were attributed to male-to-male  sexual contact, 30% to high-risk heterosexual contact, and 14%  to injected drug abuse. About 25% of new cases were diagnosed  in females, primarily (74%) contracted through high-risk het-  erosexual contact.   Sub-Saharan Africa is still the epicenter of the AIDS pan-  demic. In 2009, the World Health Organization (WHO) esti-  mated that 22.5 million people living with HIV infection (68%  of the global total) resided in sub-Saharan Africa. South Africa  continues to have the largest estimated number of infected  individuals (5.6 million), and Swaziland has the highest adult    prevalence (26%) of HIV infection in the world.** Women  remain at greatest risk of infection: of all women infected  with HIV globally, 76% of them reside in sub-Saharan Africa.  Throughout the region, women, especially those aged 15 to 19,  are the majority of HIV-infected individuals. HIV infection  among women aged 20 to 24 in South Africa is approximately  21%, compared to 7% in age-matched men. It is estimated that  the incidence of new HIV infections in women in the region  exceeds those in men by 1.3 times. It is estimated that AIDS is  responsible for almost 50% of all deaths in South Africa and  71% of deaths among individuals in the 15- to 40-year age  group. It is the leading cause of maternal deaths and is respon-  sible for 35% of deaths in children younger than 5 years of age.  As a result, the average life expectancy is now 54 years, whereas  it would be at least 64 without AIDS. More than half of the cur-  rent 15-year-olds are not expected to live to age 60.   The outlook for the future is not all bleak. Through the work  of the WHO and other groups, as well as the implementation  of aggressive AIDS awareness programs and greatly increased  access to antiretroviral therapy in many sub-Saharan African  countries, the incidence of HIV infection and death caused  by AIDS is falling across the region. The HIV infection rate in  the total region fell by more than 25% between 2001 and 2009.  Between 2004 and 2009, the number of AIDS-related deaths  decreased by 20%.    Transmission  HIV is a blood-borne pathogen present in body fluids (e.g.,  blood, vaginal fluid, semen, breast milk) with the typical routes  of transmission: blood or blood products, intravenous drug  abuse, heterosexual and homosexual activity, and maternal-  child transmission before or during birth. As of 2009, an esti-  mated 8640 children in the United States developed AIDS after  contracting HIV infection from their mothers across the pla-  centa, through contact with infected blood during delivery, or  through the milk during breast-feeding. Without treatment,  symptoms usually develop within 6 months of life, and life  expectancy is generally less than 3 years. However, adequate use  of prenatal antiviral therapy has reduced maternal-child trans-  mission dramatically; only 12 new cases were reported in 2009.  As with all blood-borne infections, healthcare providers are at  increased risk of contracting the infection from an individual’s  blood.*? The first reported case of occupational HIV infection  was an emergency department nurse who became infected in  1986. The route of infection was probably through cuts in her  hand that came into contact with contaminated blood through  a gauze pad she was holding on a person’s open wound. The  infectivity of HIV is relatively low compared to other major  blood-borne contaminants; from a single needle stick of con-  taminated blood the probability of acquiring an HIV infection is  0.3%, compared to 3% for hepatitis C and 30% for hepatitis B.*°  Tens of thousands of healthcare workers have become infected  with HIV, but as of May 2011, only 57 cases of confirmed HIV  infection and 143 possible cases were contracted by occupational  exposure, and no new cases of occupational HIV infection have  been identified since 1999.*! Since initiation of widespread edu-  cational programs on universal precautions published by the   ¢ Matrix (p17)  Undergoes myristylation that  helps target gag polyprotein  to lipid rafts, promoting virus  assembly at cell surface   ¢ Cleaved in endoplasmic  reticulum to gp120 (SU)  and gp41 (TM)   * gp120 mediates CD4  and chemokine receptor  binding, while gp41  mediates fusion    on —_ ~]  pol vpr rev tat  Polymerase Viral Protein R (p15) Regulator of Viral Transcriptional  e Encodes a variety ¢ Promotes G2 Gene Expression (p19) Activator (p14)  of viral enzymes, cell cycle arrest ¢ Promotes nuclear e¢ Enhances RNA  including PR (p10), ¢ Facilitates HIV export of incompletely Pol IlI-mediated  RT and RNAse H infection of spliced viral RNAs elongation of  (p66/51), and IN (p32) macrophages integrated viral  all processed by PR DNA  FIGURE 10-12 The Structure and Genetic Map of HIV-1. The HIV-1 virion consists of a core of two identical strands  of viral RNA molecules of viral enzymes (reverse transcriptase [RT], protease [PR], integrase [IN]) encoated in a core capsid  structure consisting primarily of the structural viral protein p24. The capsid is further encased in a matrix consisting primarily  of a viral protein, p17. The outer surface is an envelope consisting of the plasma membrane of the cell from which the virus  budded (lipid bilayer) and two viral glycoproteins: a transmembrane gp41 and a noncovalently attached surface protein, gp120.  The HIV-1 genome contains regions that encode the structural proteins (gag), the viral enzymes (pol), and the envelope proteins  (env). The gag region is translated into a large precursor (Pr559°9) that is cut by the HIV protease into smaller proteins that  construct the capsid and matrix. The env region is translated into a gp160 precursor protein that is cut by a host-cell protease  into the gp120 and gp41 envelope proteins. The genome of complex retroviruses, like HIV-1, often contains a variety of small  regions that regulate expression of the virus. (Modified from Kumar V et al: Robbins & Cotran pathologic basis of disease, ed 8,  Philadelphia, 2010, Saunders.)    CDC only 3 new cases have been reported. Nurses (42% of total  cases) and clinical laboratory technicians (28% of cases) are by  far the most commonly exposed healthcare workers. In the event  of occupational exposure to HIV-contaminated specimens,  post-exposure prophylaxis with antiretroviral medications may  be appropriate.    HIV-1 was initially isolated by researchers at the Pasteur Institute  as the lymphadenopathy/AIDS virus (LAV), a discovery for which  they received the 2008 Nobel Prize in Medicine.** A second major  and less virulent variant, HIV-2, was identified later and is found  mostly in western Africa. HIV is a member of the retrovirus fam-  ily, which carries genetic information in the form of two copies    Fusion of HIV membrane  with host cell membrane;  entry of viral genome    of RNA (Figure 10-12). Retroviruses use a viral enzyme, reverse  transcriptase, to convert RNA into double-stranded DNA (Fig-  ure 10-13). Using a second viral enzyme, an integrase, the new  DNA is inserted into the infected cell’s genetic material, where  it may remain dormant. If the cell is activated, translation of the  viral information may be initiated, resulting in the formation of  new virions, lysis and death of the infected cell, and shedding of  infectious HIV particles. If, however, the cell remains relatively  dormant, the viral genetic material may remain latent for years,  and is probably present for the life of the individual.   The primary surface receptor on HIV is the envelope glyco-  protein gp120, which binds to the molecule CD4, found primarily  on the surface of helper T cells (see Figure 10-13).*? Several other  necessary co-receptors have been identified on the target cells,    FIGURE 10-13 Life Cycle and Possible Sites of Therapeutic Intervention of HIV-1. HIV infection begins when a  virion, or virus particle, binds to CD4 and chemokine co-receptors on a susceptible cell. The HIV virion has viral proteins gp41  and gp120 on its surface (envelope), which interact with CD4 and the CCR5 co-receptor and initiate fusion between the viral  envelope and the plasma membrane, resulting in the core of the virus being injected into the cytoplasm. Uncoating occurs in  the cytoplasm, during which the core proteins are removed, and the viral RNA is released into the infected cell’s cytoplasm.  The viral RNA is converted to a double-stranded DNA provirus by the action of the viral reverse transcriptase. The provirus  migrates into the nucleus and is integrated into the cell’s own DNA. The provirus may remain latent. If the infected cell is acti-  vated (e.g., by cytokines), the provirus may be transcribed and translated into viral protein precursors. The precursor proteins  are modified by viral (gag proteins) and cellular (env proteins) proteases into smaller proteins that are used to package the viral  RNA into new virions that bud from the cell. The HIV-1 life cycle is susceptible to blockage at several sites. Some agents could  block the attachment and entrance of the virus (entrance inhibitors). Reverse transcriptase inhibitors (e.g., azidothymidine  [AZT]) prevent the reverse transcription of viral RNA into DNA. Drugs also may be able to inhibit the viral integrase (integrase  inhibitors) and prevent insertion of the provirus into the host's chromosomes. Protease inhibitors specifically inhibit the viral  protease and prevent the processing of the gp160 into viral capsid and matrix proteins. (Modified from Kumar V, Abbas A,  Fausto N: Robbins & Cotran pathologic basis of disease, ed 7, Philadelphia, 2005, Saunders.)    particularly the chemokine receptors CXCR4 and CCRS5. Dif-  ferent strains of HIV-1 are selective for the CKCR4 or CCR5 co-  receptors, which influences the tropism for different target cells.  Strains that prefer the CXCR4 co-receptor tend to be T-cell tropic,  usually found later in an infection, and cause infected cells to fuse  and form a multinucleate syncytium. Strains that react better with  the co-receptor CCR5 are macrophage-tropic, usually cause the  primary HIV infection, and do not cause syncytium formation.   * Dendritic cells (depending on the level of chemokine  receptors the cell expresses)   * Macrophages (express low levels of CD4, but high amounts  of heparin sulfate proteoglycans [syndecan] and other  molecules [CCR5] that bind to gp120 and adsorb HIV)   * CD8-positive Tc cells (low rate of infection, but CD4 can  be expressed by activated CD8-positive Tc cells)    Initially, the lymphoid areas of the mucosal surfaces are the pri-  mary sites of infection (Figure 10-14). Dendritic cells and mucosal  T cells probably spread the infection to other peripheral lymphoid  organs (especially follicular dendritic cells in the lymph nodes,  which infect T cells).“° Infection also may involve the thymus and  bone marrow, including the bone marrow stromal cells. Cells in  the central nervous system (e.g., astrocytes and monocytes), the  gastrointestinal tract (particularly in the rectum and ileum), and  other anatomic sites act as reservoirs in which HIV can be rela-  tively protected from antiviral drugs.*” The virus is also found in  T cells and macrophages in semen and in the renal epithelium.   The major immunologic finding in AIDS is the striking  decrease in the number of CD4+ Th cells (Figure 10-15). Indi-  viduals who are not HIV infected typically have 800 to 1000  CD4+ cells/uL of blood, with a range from 600 to 1200/pL.  Numbers of CD8+ Tc cells are usually normal or slightly ele-  vated. The decrease in CD4+ cell numbers results in a reversal  of the normal CD4/CD8 T-cell ratio (normally about 1.9) to  lower than 0.9 and often near zero.   HIV causes destruction of Th cells by a variety of means.  Production of new HIV virions can be directly cytopathic to the  infected cell, causing lysis (breakdown of the cell) or inducing    FIGURE 10-14 Distribution of Tissues That Can Be Infected by HIV. Infection is closely linked to the presence of CD4  receptors or chemokine co-receptors on host tissue, particularly T cells and macrophages. (Modified from Weber JN, Weiss  RA: HIV infection: the cellular picture, in the science of AIDS: readings from Scientific American, New York, 1989, Freeman.)    6 9 12 2 4 6 8 10 12  B Weeks Years    FIGURE 10-15 Typical Course of Progression from HIV Infection to AIDS in Untreated Persons. A, Within weeks  after infection, the person may experience symptoms of acute HIV syndrome. During this early period the virus progressively  infects mucosal T cells and dendritic cells, propagates, and spreads to the lymphoid organs, with a sharp decrease in the  number of circulating CD4+ Th cells. The resulting immune response usually induces a period of clinical latency, during which  viral replication and T-cell destruction continue in the lymph nodes, although the individual is generally asymptomatic. As the  disease progresses, the person may develop HIV-related disease (constitutional symptoms}—a variety of symptoms of acute  viral infection that do not involve opportunistic infections or malignancies. When the number of CD4+ cells is critically sup-  pressed, the person becomes susceptible to a variety of opportunistic infections and cancers. The length of time for progres-  sion from HIV infection to AIDS may vary considerably from person to person. B, Antibody and Tc cell (cytotoxic T lymphocytes    CTLs]) levels change during the progression to AIDS. During the initial phase antibodies against HIV-1 are not yet detectable  (window period), but viral products, including p24 antigen, viral RNA, and infectious virus, may be detectable in the blood a few  weeks after infection. Most antibodies produced against envelope proteins in the early phase are absorbed onto viral particles  in the blood and are not detectable by most routine assays. During the latent phase of infection antibody levels against p24  and other viral proteins, as well as HlV-specific CTLs, generally increase, then remain constant until the development of AIDS.  As the immune system becomes severely depressed and excess viral antigen is released into the blood, measurable antibody  evels decrease. Disease progression usually ends in the death of the untreated individual. (A redrawn from Fauci AS, Lane HC:  Human immunodeficiency virus disease: AIDS and related conditions. In Fauci AS et al, editors: Harrison's principles of internal    medicine, ed 14, New York, 1997, McGraw-Hill; B from Kumar V, Abbas A, Fausto N: Robbins & Cotran pathologic basis of    apoptosis. Additionally, HIV-infected cells express new surface  antigens and are targets for Tc-mediated lysis.   However, it is not unusual for a large majority (>98%) of  peripheral CD4+ Th cells to not be infected with HIV-1, although  a significant amount (10% to 50%) show signs of apoptosis.  Therefore, HIV-1 killing is probably an indirect rather than  direct effect. HIV-infected cells shed soluble viral envelope pro-  tein, gp120, which can induce apoptotic cell death of uninfected  T lymphocytes, neurons, and monocytes through interaction  with cell surface receptors. The interaction between viral enve-  lope protein on the surface of infected cells and its receptors on  neighboring uninfected cells also can result in intercellular fusion  and syncytium formation. The syncytia undergo apoptosis after a  phase of latency. Envelope protein present on the surface of HIV-  1-infected cells also can create partial fusion (hemifusion, mem-  brane damage) that results in death of the uninfected cell. The  presence of HIV virions and soluble viral antigen can result in a  chronic activation of uninfected T cells with HIV-specific T-cell  receptors (TCRs). Because activated T cells more efficiently sup-  port HIV replication, the most susceptible cells are those with  TCRs against HIV, which undergo antigen-driven activation  and infection. This observation may not bode well for successful  vaccine development if the induced and supposedly protective  CD4+ cells are also the most susceptible targets for HIV.    As a result of these processes the level of T cells decreases  (particularly T-memory cells, which seem more susceptible to  HIV infection), thymic production of new T cells is decreased,  and the secondary lymphoid organs (particularly the lymph  nodes) are damaged.    Depletion of CD4+ cells has a profound effect on the immune  system, causing a severely diminished response to a wide array  of infectious pathogens and malignant tumors (Box 10-2).   At the time of diagnosis, the individual may manifest one of  several different conditions: serologically negative (no detect-  able antibody), serologically positive (positive for antibody  against HIV) but asymptomatic, early stages of HIV disease, or  AIDS (see Figure 10-15).   The presence of circulating antibody against the HIV indi-  cates infection by the virus, although many of these individu-  als are asymptomatic. Antibody appears rather rapidly after  infection through blood products, usually within 4 to 7 weeks.  After sexual transmission, however, the individual can be  infected yet seronegative for 6 to 14 months or, in at least one  case, for years. In addition, in the late stages of the disease,  some individuals become seronegative because of a deficient  immune system.    BOX 10-2 AIDS-DEFINING OPPORTUNISTIC  INFECTIONS AND NEOPLASMS  FOUND IN INDIVIDUALS WITH  HIV INFECTION    Protozoal and Helminthic Infections  Cryptosporidiosis or isosporiasis (enteritis)  Toxoplasmosis (pneumonia or central nervous system [CNS] infection)   Pneumocystosis (pneumonia or disseminated infection)  Candidiasis (esophageal, tracheal, or pulmonary)  Cryptococcosis (CNS infection)    Mycobacteriosis (atypical, e.g., Mycobacterium avium-intracellulare,  disseminated or extrapulmonary; Mycobacterium tuberculosis,  pulmonary or extrapulmonary)   Cytomegalovirus (pulmonary, intestinal, retinitis, or CNS infections)  Herpes simplex virus (localized or disseminated)   B-cell non-Hodgkin lymphomas  Primary lymphoma of the brain  Invasive cancer of the uterine cervix    Adapted from Kumar V et al: Robbins & Cotran pathologic basis of  disease, ed 8, Philadelphia, 2010, Saunders.    The period between infection and the appearance of antibody  is referred to as the window period (see Figure 10-15). Although  the individual may not have antibody, he or she may have virus  growing, have virus in the blood and body fluids, and be infec-  tious to others. Early symptoms are relatively nonspecific to HIV  and include fatigue, fever, muscle aches, and headaches.   Those with the early stages of HIV disease (early stage disease  or clinical latency) are usually asymptomatic. The early stage may  last as long as 10 years in untreated people, during which viral  load increases and numbers of CD4+ cells progressively decrease.  Some estimates are that approximately 99% of untreated HIV-  infected individuals would eventually progress to AIDS.   The currently accepted definition of AIDS relies on both labo-  ratory tests and clinical symptoms. The most common labora-  tory test is for antibodies against HIV proteins (particularly p24).  If the individual is seropositive, the diagnosis of AIDS is made in  association with various clinical symptoms (see Box 10-2). The  symptoms include atypical or opportunistic infections and can-  cers, as well as indications of debilitating chronic disease (e.g.,  wasting syndrome, recurrent fevers) (Figure 10-16). Most com-  monly, new cases of AIDS are diagnosed initially by decreased  CD4+ T-cell numbers at or below 200 cells/uL.    The current regimen of antiretroviral therapy (ART) for treat-  ment of HIV infection is a combination of drugs.** As of 2012,  more than 20 antiretroviral drugs that fell into 6 different mecha-  nisms were available for ART. Classes of antiretroviral agents  included inhibitors of the enzyme reverse transcriptase (nucleo-  side reverse transcriptase inhibitors [NRTIs] and non-nucleoside  reverse transcriptase inhibitors [NNRTIs]), inhibitors of the viral  protease (protease inhibitors [PIs]), inhibitors of fusion between  HIV and the cell membrane (fusion inhibitors), inhibitors of HIV  binding to CCR3 (CCR5 antagonists), and inhibitors of the viral  integrase enzyme (integrase strand transfer inhibitors [INSTIs]).  Several preferred and alternative therapeutic regimens are recom-  mended, depending on the particular individual. In general, the  combination includes at least three drugs: two NRTIs and one  from another class (NNRTI, PI, INSTI, or CCR5 antagonist) (see  Figure 10-13). Death from AIDS-related diseases has been reduced  significantly since the introduction of ART; without treatment an  individual may live only 9 to 10 months after diagnosis of AIDS,  whereas those who respond well to ART may survive for several  decades. However, many people do not respond to ART therapy,  those who do respond are not “cured,” and resistant variants to  these drugs have been identified. Many individuals who initiate  antiretroviral therapy will still have a shortened life expectancy  secondary to HIV-associated persistent immune activation.  Although the capacity of the immune system to respond to spe-  cific pathogens is greatly diminished, HIV infection nonspecifi-  cally activates T cells and monocytes resulting in greatly increased  production of inflammatory cytokines and an increased risk for  developing chronic and potentially fatal morbidities, such as car-  diovascular disease, renal disease, diabetes, and liver disease.*”   Drug therapy for AIDS is difficult because, like most retrovi-  ruses, the AIDS virus incorporates into the genetic material of  the host and may never be removed by antimicrobial therapy.  Therefore, drug administration to control the virus may have  to continue for the lifetime of the individual. Additionally, HIV  may persist in regions where the antiviral drugs are not as effec-  tive, such as the central nervous system (CNS).   To date, the development of an effective vaccine is the only  hope for preventing the spread of HIV infection. Most com-  mon antiviral vaccines (e.g., rubella, mumps, influenza) induce  protective antibodies that block the initial infection. Only one  vaccine (rabies) is used after the infection has occurred. That  approach is successful because the rabies virus proliferates and  spreads very slowly. Whether an HIV vaccine would be effec-  tive in either preventing or treating HIV infection is problem-  atic, and the results of recent vaccine trials have for the moment  dampened enthusiasm. The USPSTF recommends that clini-  cians screen adolescents and adults aged 15 to 65 years for HIV  infection. Those younger or older who are at increased risk  should also be screened.*”*   The clinical diagnosis of HIV in children is very often a diffi-  cult task (Box 10-3). The presence of passive maternal antibody  limits the use of HIV antibody testing in infants in the high-risk    FIGURE 10-16 Clinical Symptoms of AIDS. A, Severe weight loss and anorexia. B, Biopsy-proven Kaposi sarcoma    lesions. €, Perianal vesicular and ulcerative lesions of herpes simplex infection. D, Deterioration of vision from cytomegalo-  virus retinitis leading to areas of infection; unless treated the progressive impairment will lead to blindness. (A and D from  Taylor PK: Diagnostic picture tests in sexually transmitted diseases, London, 1995, Mosby; B and € from Morse SA, Holmes  KK, Ballard RC, editors: Atlas of sexually transmitted diseases and AIDS, ed 4, London, 2011, Saunders.)    category up to 18 months of age. In this age group, diagnosis of  HIV infection must be made by assays to measure viral DNA or  RNA in the blood. For children older than 18 months, the diag-  nosis of HIV infection is confirmed by the presence of specific  antibodies to the virus.   HIV directly invades most major organ systems, including  the CNS. Therefore, the clinical manifestations vary greatly  from child to child. The initial signs and symptoms may be  nonspecific and subtle, and they may progress slowly or rapidly  to an acute, life-threatening condition. A definite diagnosis of  HIV is made by obtaining a personal history, performing viro-  logic testing, and assessing clinical manifestations. Monitoring  CD8+ T lymphocytes and monocytes, in addition to CD4+ Th  lymphocytes, has been suggested for predicting risk for progres-  sive encephalopathy. Decreases in the number of CD8+ Tc lym-  phocytes diminish defenses against viral infection and facilitate  infected monocytes to cross the blood-brain barrier.    A particularly vulnerable site of HIV infection in infants and  children is the CNS. HIV encephalopathy is more common in  the advanced stages. Because survival of children with HIV has  been prolonged with effective treatment, the incidence of pro-  gressive encephalopathy has increased. The 1994 classification  from the CDC requires one of the following progressing find-  ings to be present for at least 2 months, in the absence of a con-  current illness other than HIV that could explain the following  findings:   + Failure to attain or loss of developmental milestones, or  loss of intellectual ability, verified by standard develop-  mental scale or neuropsychologic tests   + Impaired brain growth or acquired microcephaly dem-  onstrated by head circumference measurements or brain  atrophy demonstrated by computed tomography (CT) or  magnetic resonance imaging (MRI) with serial imaging  required in children less than 2 years of age   Children who have no signs or symptoms considered to be the result of HIV infec-  tion or who have only one of the conditions listed in Category A   Children with two or more of the conditions listed below but none of the condi-  tions listed in Category B or C:   Recurrent or persistent upper respiratory tract infection, sinusitis, or otitis media   Children who have symptomatic conditions other than those listed for Category  A or C that are attributed to HIV infection; examples of conditions in clinical  Category B include but are not limited to:   Anemia (<8 g/dl), neutropenia (<1000 mm?), or thrombocytopenia (<100,000  mms) persisting =30 days    Candidiasis or oropharyngeal infection (thrush) persisting (=2 months) in children  >6 months of age   Herpes simplex virus (HSV), recurrent stomatitis (more than two episodes within  1 year)   HSV bronchitis, pneumonitis, or esophagitis with onset before 1 month of age   Herpes zoster (shingles) involving at least two distinct episodes or more than  1 dermatome    Category C: Severely symptomatic  Children who have any condition listed in the 1987 surveillance case definition of  acquired immunodeficiency with the exception of LIP    Data from Centers for Disease Control and Prevention: MMWR Morb Mortal Wkly Rep 43(12):1, 1994.   It may be difficult to completely differentiate the effect of  HIV infection on the CNS from the effect of prenatal and peri-  natal exposure. In addition, other insults may accompany HIV  in a young child and affect growth and development, such as  drug exposure, prematurity, chronic illness, and a chaotic social  atmosphere. The pathogenesis of HIV encephalopathy in chil-  dren is poorly understood, but the presence of inflammatory  mediators may be a contributing factor.   A growing number of investigational protocols are available  for treatment of children with HIV. In general, treatment is  focused on the preservation and maintenance of the immune  system, aggressive response to opportunistic infections, and  support and relief of symptomatic occurrences and administra-  tion of ART.°°    An extremely effective means of countering infectious micro-  organisms is rigorous use of environmental infection control  measures, including control of insect vector populations, estab-  lishment of modern sanitation facilities, provision of clean    water and uncontaminated food supplies, and other measures.  Additionally, prophylactic or interventive procedures have been  developed to prevent pathogens from initiating disease (vac-  cines) or to subdue the pathogen once the disease process has  started (antimicrobials). Vaccine development has focused suc-  cessfully on preventing the most severe and common infections  (Table 10-9). With the initial success of antibiotic therapy, there  was no perceived need for vaccination against many common  and non-life-threatening infections. The increasing problem  of antibiotic-resistant pathogens, however, forced a reappraisal  of that strategy, and a greater emphasis is being placed on the  development of new vaccines.    Although effective means of safeguarding populations from  exposure to infectious disease are well-known, lack of imple-  mentation or breakdowns in application of these initiatives has  led to the reemergence of some infectious diseases.   John Snow, a British physician, is considered the “father of  epidemiology.”°! Industrialization in England in the nineteenth  century resulted in rapid expansion of London’s population  that outgrew city services. An outbreak of cholera in the Soho  area of London in 1854 resulted in more than 600 deaths. Snow  discovered that the outbreak centered around one particular  public water pump, which got water from a well that had been    TABLE 10-9 REDUCTION IN VACCINE-  PREVENTABLE DISEASES  IN THE UNITED STATES    From National Institute of Allergy and Infectious Disease, National  Institutes of Health: Vaccine, Vaccine Benefits, Updated May 11, 2010  available at http://www.niaid.nih.gov/topics/vaccines/understanding/  pages/vaccinebenefits.aspx. Accessed February 25, 2013.   *Average number of reported cases over multiple years before initia-  tion of vaccine (Centers for Disease Control and Prevention: MMWR  Morb Mortal Wkly Rep 48[12]:243-248, 1999, Morb Mortal Wkly Rep  57[11]:289-291, 2008).    dug 3 feet from a cesspool (open sewage was common in Lon-  don at that time). After the pump was closed, the rate of new  cholera cases rapidly diminished. Snow’s observation stimu-  lated the development of the construction of clean water sup-  plies and sewers throughout the city.   Sewage removal and other public health initiatives (e.g., rou-  tine trash collection, disposal of garbage by incineration or in  landfills) are now the expected norm in developed countries.  The quality of water and food, as well as disposal of human  and animal waste, remains poor in many developing coun-  tries. Rapid urbanization as well as other problems (e.g., pov-  erty, overcrowding, mass relocation of people because of war,  rapid destruction of forests) has put pressure on already inad-  equate systems.°* A 1991 outbreak of cholera in Peru resulted  in an estimated 10,000 deaths and was attributed to inadequate  sanitation.   Additionally, previously successful programs designed to  control the breeding of insect vectors have been reversed.  Despite an international emphasis on draining standing water  that provides breeding grounds for mosquitoes, large unman-  aged areas still abound. A very successful international mos-  quito eradication program resulted in decreasing incidence of  mosquito-borne diseases. Some regions were declared “free” of  mosquito-borne diseases. However, since the international ban  on DDT (dichlorodiphenyltrichloroethane) for agricultural  work and limitation of its use for control of disease vectors,  mosquitoes and mosquito-related diseases have rebounded in  previously disease-free areas. In northern India, heavy rains  in the 1990s resulted in an increase in standing water that was  not drained because of the lack of government-provided public    health information and inadequate insecticides to control mos-  quitoes. Since 1996, recurrent and increasingly severe outbreaks  of dengue fever (caused by dengue virus, which is related to  yellow fever virus and West Nile virus) have occurred in this  region. In the 2006 outbreak 10,344 cases were reported, with  162 deaths. This problem is exacerbated by the development of  insecticide-resistant mosquitoes.    Since the first use of penicillin during World War II, antibiotics  have had the greatest effect on controlling infection. Antibiotics  are natural products of fungi, bacteria, and related microorgan-  isms and kill or inhibit the growth of other microorganisms.  Numerous chemicals or antimicrobials have been identified  that either prevent the growth of microorganisms or directly  destroy them. Antibiotics generally act by preventing the func-  tion of enzymes or cell structures that are unique to the infect-  ing agent. Because viruses use the enzymes of the host’s cells,  there has been far less success in developing antiviral antibiotics.   Immediately after antibiotics became widely used, antibiotic-  resistant microorganisms were observed. By 1944 an adequate  supply of penicillin allowed its widespread use to treat infections.  In 1946 a hospital in Britain reported that 14% of all S. aureus  infections were penicillin resistant. By 1950 the same hospital  reported an increase to 59% and to greater than 89% in the 1990s.  Over the past few decades healthcare providers have observed  increasing incidences of drug-resistant malaria, tuberculosis, gon-  orrhea, salmonellosis, shigellosis, and staphylococcal infections  (see What’s New? Drug-Resistant Tuberculosis). S. pneumoniae,  which causes pneumonia, meningitis, and acute otitis media (ear  infections), was once routinely susceptible to penicillin. Since the  1980s, however, the incidence of penicillin-resistant microorgan-  isms has risen to greater than 30% in some populations.   The goal of antibiotic therapy is elimination of the patho-  genic microorganism. Some antibacterial antibiotics are bac-  tericidal (kill the organism), whereas others are bacteriostatic  (inhibit growth until the organism is destroyed by the individ-  ual’s own protective mechanisms). The mechanisms of action  of most antibiotics are (1) inhibition of the function or pro-  duction of the cell wall, (2) prevention of protein synthesis,  (3) blockage of DNA replication, or (4) interference with folic  acid metabolism.   Antibiotic resistance is usually a result of one of four gen-  eral mechanisms resulting from genetic mutations that can be  transmitted directly to neighboring microorganisms by plas-  mid exchange.** One mechanism microorganisms commonly  develop is the capacity to inactivate antibiotics. For example,  resistance to penicillin, cephalosporins, and other B-lactam-  containing antibiotics results from the production of an enzyme  (f-lactamase) that breaks down the structure of the antibiotic.*°  Other forms of resistance result from modification of the target  molecule. Azidothymidine (AZT) is a family of antivirals that  suppresses the enzymatic activity of reverse transcriptase, a viral-  specific enzyme responsible for the replication of viral RNA and  the production of a DNA copy. HIV frequently mutates and  produces an AZT-resistant reverse transcriptase. Some bacteria  have gained the capacity to produce penicillin-binding proteins    Tuberculosis (TB) is one of the oldest known human diseases. Evidence of  molecular biomarkers of infection with the etiologic agent of TB, the bacterium  Mycobacterium tuberculosis, dates to the earliest Egyptian dynastic period  (about 3500-2650 BCE) and even earlier. (/. tuberculosis was not discovered  as the cause of TB until 1882 by Robert Koch, who won the 1905 Nobel Prize  for his work.   The bacterium primarily attacks the lungs and spreads from person to per-  son through droplets, released into the air during coughing or sneezing. Few  individuals (approximately 10%) with adequate immune responses develop  overt disease; however, most will not completely destroy the microorganisms  and will develop a chronic asymptomatic infection that can be activated if the  immune system is suppressed, such as associated with aging, progressive  genetic immunodeficiency, immunosuppressive medication, HIV infection, and  other conditions. If the individual is inmunocompromised upon initial exposure  to M. tuberculosis, the probability of developing clinical, rather than chronic, TB  is near 50%.   For centuries TB was a major cause of death throughout the world. The spread  of the disease was limited by the recognition in the 19th century that TB was  caused by a contagion, which led to separation of infected individuals in isola-  tion wards and sanatoriums. The advent of antibiotic use after World War II  increased optimism that TB could be controlled. The rapid spread of AIDS in the  1980s, however, resulted in a rebound in the incidence of TB. The World Health  Organization (WHO) estimated that in 2010 8.8 million individuals (1.1 million  of whom were HIV-infected) contracted TB and 1.4 million (350,000 of whom  were HIV-infected) died of TB. Most deaths from TB occurred in Southeast Asia,  Africa, and the Western Pacific.   In 1993, the WHO declared a TB “global emergency” and initiated a global TB  control program. Although the number of new cases of TB has declined slowly,  the global incidence decreased by 1% to 3% annually since 2002; since 1990,  deaths fell by 40% globally; and record low rates of TB have been achieved  in the United States and most of Western Europe. However, the goals of the  program will not be met. /V. tuberculosis developed resistance to the limited  battery of available anti-tuberculosis drugs. Development of drug resistance has  been increased in many countries by provision of incomplete or erratic therapy by  poorly trained physicians, substandard quality of real or counterfeit medications,    lack of expert testing for drug-resistant strains, and other inadequacies in  healthcare systems.   Drug resistance has been classified as multidrug-resistant (MDR) TB and  extensively drug-resistant (XDR) TB. MDR TB is defined as resistance to the two  first-line drugs isoniazid and rifampicin. XDR TB is defined as MDR TB that is also  resistant to second-line drugs, including all fluoroquinolones and at least one of  three injectable drugs (capreomycin, kanamycin, or amikacin). Both classes of  drug resistance occur in individuals with untreated TB who were infected from  others with a drug-resistant strain or those who were poorly treated initially  and developed recurrence with a drug-resistant strain. In most countries, accu-  rate estimates of drug resistance are difficult to obtain because of inadequate  aboratory testing facilities. In Azerbaijan, a careful study reported that 22.3% of  new and 55.8% of previously treated TB cases were MDR. A recent study from  China, where an estimated 1 million new cases of TB occur yearly, estimated  hat 1 in 10 infected persons have MDR TB and 1 in 120 have XDR TB. Drug-  resistant TB is difficult to treat because anti-tuberculosis drugs are expensive  and have several side effects and because MDR TB may require up to 2 years of  reatment with success rates of 70% or less; XDR TB may be incurable in many  individuals.   The situation has become worse. Reports from India of 12 individuals with  TB that is resistant to all approved first- and second-line drugs have sparked  concern in both the medical and lay communities. These reports are not the first  of such cases; earlier reports of similar broadly resistant TB had occurred in 15  cases in Iran in 2009 and in two cases in Italy in 2007. The term totally drug-  resistant (TDR) TB has been used unofficially to describe this disease. Will TDR  TB become a predominant form in the future, and how will it be contained? Many  new anti-tuberculosis drugs are in the developmental pipeline, but efficacy, side  e  Vv    fects, cost, and other important considerations remain unknown. An effective  accine would be the ideal solution, but only one vaccine is currently available.  The bacille Calmette-Guérin (BCG) vaccine was developed a century ago using an  attenuated strain of the bovine form of TB (Mycobacterium bovis) and is admin-  istered to children in many countries. Although it protects against disseminated  infection and death in children, there is no protection against chronic infection or  pulmonary TB in adults. At least a dozen new vaccines are in development, but  will take years to be approved, even if one is found to be effective.    Data from Arya SC, Agarwal N: Int J Tuberc Lung Dis 16(6):852, 2012; Brennan MJ, Thole J: Tuberculosis 92(Suppl 1):S6-S13, 2012; Chaisson  RE, Nuermberger EL: N Eng/ J Med 366(23):2223-2224, 2012; Donoghue HD: Clin Microbiol Infect 17(6):821-829, 2011; Loewenberg S: Lancet  379(9812):205, 2012; Migliori GB et al: Clin Infect Dis 54(9):1379-1380, 2012; Rappuoli R, Aderem A: Nature 473(7348):463-469, 2011; Ravi-  glione M et al: Lancet 379(9829):1902-1913, 2012; Udwadia ZF et al: Clin Infect Dis 54(4):579-581, 2012; Zumla A et al: J Infect Dis 205(Suppl    2):S228-S240, 2012; Zumia A et al: Nat Rev Drug Disc 11(3):171-172, 2012.    that block penicillin from binding to sites in the bacterial cell  wall, and other bacteria have modified antibiotic-sensitive bind-  ing sites on the ribosomes and developed resistance to antibiotics  that interfere with protein synthesis. A third mechanism of resis-  tance results from alteration of metabolic pathways that may be  sensitive to antibiotics to alternative, more antibiotic-resistant  pathways. Some bacteria have gained resistance to sulfonamide  by converting from use of environmental para-aminobenzoic  acid for conversion to folic acid, which is an antibiotic-sensitive  step in nucleic acid synthesis, to the direct use of environmental  folic acid. A fourth mechanism is mediated by multidrug trans-  porters in the microorganism’s membrane. These transporters  affect the rate of intracellular accumulation of the antimicro-  bial by preventing entrance or, more commonly, increasing  active efflux of the antibiotic. Antibiotic-resistant strains of    M. tuberculosis are protected from aminoglycosides and tetracy-  cline by the transporters with antigen processing (TAP) protein  (a mycobacterial multidrug efflux pump).   Many microorganisms are now resistant to multiple anti-  biotics. Methicillin-resistant Staphylococcus aureus (MRSA)  incorporates several different mechanisms of resistance. MRSA  produces a f-lactamase (penicillinase). Penicillinase-resis-  tant antibiotics (e.g., methicillin) can be used as a substitute,  but MRSA carrying the gene mecA is also methicillin resistant  because of a lower affinity for B-lactams. Resistance to the  glycopeptide antibiotic vancomycin is controlled by the gene  vanA, which results in alterations in peptidoglycans and loss of  the vancomycin-binding site.   Why have multiple antibiotic—resistant microorganisms  appeared? Overuse of antibiotics can lead to the destruction    of the normal microbiome, allowing the selective overgrowth  of antibiotic-resistant strains or pathogens that had previously  been kept under control. For example, after treatment with the  antibiotic clindamycin, the normal intestinal microbiome can  become compromised, allowing the overgrowth of Clostridium  difficile and the development of pseudomembranous colitis.°°  Also, lack of compliance concerning the necessity of complet-  ing the therapeutic regimen with antibiotics allows the selective  resurgence of microorganisms that are more relatively resistant  to the antibiotic.   With the development of multiple antibiotic—resistant  strains, creativity in addressing this challenge must be rekin-  dled. Antibiotics should no longer be used for minor infections,  such as mild to moderate sinusitis.°’ New antibiotics may solve  a portion of the problem or may exacerbate it further as patho-  gens develop resistance to new antibiotics as well. Available  antibiotics that prove to be no longer effective must be replaced  with alternative forms of therapy, including the increased devel-  opment and use of vaccines and other therapies.    Contracting and surviving an infectious disease is the most  effective means of developing lifelong immunity against a par-  ticular pathogen. However, some infections cause a great deal  of morbidity and mortality. The purpose of vaccination is to  induce active immunologic protection before exposure to the  risks of infection. For each vaccine an initial immunization pro-  tocol is developed to produce large numbers of memory cells  and a sustained protective secondary immune response in the  greatest number of individuals. In general, vaccine-induced  protection does not persist as long as infection-induced immu-  nity; thus, booster injections may be necessary to maintain pro-  tection throughout life. The Centers for Disease Control and  Prevention maintain the most current immunization schedules  for people of all ages. The schedules can be reviewed at www.  cdc.gov/vaccines/recs/schedules/default.htm.   Mass vaccination programs have led to major changes in the  health of the world’s population. In the early 1950s an estimated  50 million cases of smallpox occurred each year, with about 15  million deaths. The World Health Organization (WHO) con-  ducted a smallpox immunization campaign from 1967 to 1977  that resulted in the global eradication of smallpox by 1979. The  1988 immunization initiative against polio resulted in a 99%  decrease in that disease. In 1960, 2525 cases of paralytic polio  were reported in the United States, but no cases of naturally  acquired polio have been reported since 1979. In 1994, polio  was declared officially eradicated in all the Americas. The goal  of the WHO is to eradicate polio worldwide by 2022.°* Similar  trends occurred for each disease against which an effective vac-  cine has been developed.   Development of a successful vaccine depends on many  factors. These include characterizing the desired protective  immune response (e.g., antibody, T cell), identifying the appro-  priate antigen to induce that response (i.e., immune responses  against some antigens on an infectious agent are ineffective  or even increase the risk for infection), determining the most  effective route of administration (e.g., injected, oral, inhaled),    optimizing the number and timing of vaccine doses to induce  protective immunity in a large proportion of the at-risk popula-  tion, and deciding the most effective, yet safe, form in which to  administer the vaccine. For instance, most vaccines against viral  infections (e.g., measles, mumps, rubella, varicella [chicken-  pox], rotavirus) contain live viruses that are weakened (attenu-  ated) to continue expressing the appropriate antigens but are  unable to establish more than a limited and easily controlled  infection. The limited proliferative capacity of attenuated live  viruses appears to afford better long-term protection than using  purified viral antigen. Two exceptions are the vaccines against  hepatitis B, which uses a recombinant viral protein, and hepati-  tis A, which is an inactivated (killed) virus.   Even attenuated viruses can, however, establish life-threat-  ening infections in vaccine recipients whose immune system is  congenitally deficient or suppressed (see Chapter 9). Two dif-  ferent vaccines were developed against polio. The Sabin vaccine  is an attenuated virus that is administered orally (oral polio  vaccine [OPV]). It provides systemic protection and induces a  secretory immune response to prevent growth of the poliovirus  in the intestinal tract. The live attenuated vaccine causes polio  in some children who have unsuspected immune deficiencies  (about 1 case in 2.4 million doses). The Salk vaccine is a com-  pletely inactivated virus administered by injection (inactivated  polio vaccine [IPV]). It induces protective systemic immunity  but does not provide adequate secretory immunity. There-  fore, even if the individual is protected from systemic infection  the “wild-type” poliovirus can transiently infect the intestinal  mucosa, be shed, and spread to others.*? When polio was epi-  demic, the live oral vaccine was preferred; however, about eight  cases of paralytic polio per year in the United States resulted  from the vaccine strain proliferating in individuals with inad-  equate immune systems. As a result, the CDC currently recom-  mends vaccination with the killed virus.   Some common bacterial vaccines are killed microorganisms  or extracts of bacterial antigens. The vaccine against pneumo-  coccal pneumonia consists of a mixture of capsular polysac-  charides from 10 strains of S. pneumoniae. Of the more than  90 known strains of this microorganism, only these 10 cause  the most severe illnesses. However, the capsular vaccine is not  very immunogenic in young children. A “conjugated” vac-  cine is available that contains capsular polysaccharides from  seven strains that are conjugated to carrier proteins in order to  increase immunogenicity. A similar vaccine is available for Hae-  mophilus influenzae type B (Hib).   Some bacterial diseases are caused by potent toxins that  act locally or systemically. These include diphtheria, cholera,  and tetanus. Vaccination against the toxins is achieved using  toxoids—purified toxins that have been chemically detoxified  without loss of immunogenicity. Pertussis (whooping cough)  vaccine was changed from a killed whole cell vaccine to an acel-  lular vaccine that contained the pertussis toxin and additional  bacterial antigens.   With so many available vaccines there has been an effort to  mix vaccines in order to minimize the number of required injec-  tions. One of the first licensed vaccine mixtures was DPT, which  now usually contains diphtheria (D) and tetanus (T) toxoids and    acellular pertussis vaccine (aP). More recent mixtures include  DTaP with inactivated poliovirus, either with Hib conjugate to  tetanus toxoid or with hepatitis B vaccine.   Common problems include access to vaccination programs  in less developed countries or compliance of the susceptible  population even when vaccination programs are available.°°  Depending on the microorganism, a certain percentage of the  population (usually about 85%) should be immunized in order  to achieve protection of the total population. This is referred to  as herd immunity. If this level of immunization is not achieved,  outbreaks of infection can occur. For instance, an effective mea-  sles (rubeola) vaccine was made available in 1963 and resulted  in a dramatic decrease in the number of measles cases.°! Many  parents became complacent and did not obtain measles vacci-  nation for their preschool children. As a result, a large increase  in the number of cases and deaths in 1989 and 1990 occurred,  which initiated a reemphasis on complete immunization before  children could start school. More recently resistance to immu-  nization with measles has increased, and in early 2008 the num-  ber of measles cases in the United States increased by about  fourfold. In several European countries immunization pro-  grams have been disrupted by anti-vaccine groups. As a result  the incidence of pertussis (whooping cough) increased by 10  to 100 times compared with neighboring countries that main-  tained a high incidence of immunization.   The refusal to vaccinate has generally been based on poten-  tial vaccine dangers. As with any medicine, complications can  arise. In the case of vaccines, these include pain and redness at  the injection site, fever, allergic reactions to vaccine ingredi-  ents, infection associated with attenuated viruses in immuno-  deficient individuals, and others. For instance, rotavirus is the  most common cause of diarrheal disease in children globally,  and more than 500,000 children die each year from severe acute  diarrhea.’ A rotavirus vaccine approved more than a decade  ago was found to increase the risk for a life-threatening bowel  obstruction resulting from twisting of the intestines, and the  vaccine was recalled.°* New rotavirus vaccines are available that  are safe from adverse events." A commonly discussed fear is  related to the presence of the preservative thimerosal in vac-  cines. Thimerosal is a mercury-containing compound that has  been used as a preservative since the 1930s. Although no cases  of mercury toxicity have been reported secondary to vaccina-  tion, thimerosal was removed from all vaccines in 2001, with    the exception of inactivated influenza vaccines.“ In 2003,  groups in northern Nigeria claimed that the oral polio vaccine  was unsafe, which led to suspension of polio immunization in  two states and reduction of immunization in other states. The  result was a 36% increase in cases of polio and thousands of  cases of paralysis, including in previously polio-free areas.    Passive immunotherapy is a form of countermeasure against  pathogens in which preformed antibodies are given to the indi-  vidual. This form of therapy has been used for decades. Horse  serum-containing antibodies were given to treat diphtheria,  pneumococcal pneumonia, tetanus, and other diseases in the  early twentieth century. However, because of foreign proteins  in the serum, many individuals developed an immune reaction  against the horse proteins and an immune complex—mediated  serum sickness. Passive immunotherapy with human immu-  noglobulin has been approved for several infections, including  hepatitis B and hepatitis A. Treatment of potential rabies infec-  tion after a bite combines passive and active immunization. The  rabies virus proliferates very slowly. Individuals who have been  bitten receive a onetime injection with human rabies immuno-  globulin, or more recently with monoclonal antibody, to further  slow viral proliferation, followed by multiple injections with a  killed viral vaccine to induce greater protective immunity.°° For  several other diseases more specific therapy with monoclonal  antibodies is being evaluated, and a monoclonal antibody against  respiratory syncytial virus has been approved for therapy.   In the past, vaccines and therapeutic antibodies were devel-  oped for only the most deadly pathogens. With the increase  in antibiotic-resistant microorganisms, the development and  widespread use of new vaccines and antibodies against these  microorganisms must be considered. For example, otitis media,  a purulent ear infection, is caused primarily by Streptococcus,  Haemophilus, and Staphylococcus. This infection routinely has  been treated successfully with antibiotics; however, the increase  in multiple antibiotic-resistant microorganisms may force a  reevaluation of the use of childhood immunization as an alter-  native to preventing this disease. Other vaccines used now only  to a limited degree may be used more widely in the future, and  others may be developed soon, including vaccines against chol-  era, typhoid, malaria, West Nile virus, hantavirus, SARS, and  several other diseases.   1. Deaths from infections are the eighth (influenza and pneu-  monia) and tenth (sepsis) leading causes of death in the  United States and account for about one third of deaths  worldwide.   2. Infectious disease is a significant cause of death and morbid-  ity because of the reemergence of old infections thought to  be controlled, the emergence of previously unknown infec-  tions, and the development of infections resistant to mul-  tiple antibiotics.    3. The current rate of emergence of previously unknown infec-  tions may be unprecedented. More than 40 unknown infec-  tions have arisen within 1 generation.   4. Although most infections are controlled, some uncontrolled  infections have high mortality rates including SARS, Ebola virus,  Marburg virus, “mad cow disease,” Nipah virus, and AIDS.   5. Many common and reemerging infections have become  antibiotic and drug resistant. At least 25% of S. pneumoniae  infections are penicillin resistant and some are resistant to  multiple antibiotics.    Resistant forms of S. aureus, a primary cause of infections  of wounds, surgical incisions, and catheters, are endemic in  some hospitals.   Antimicrobial resistance is routinely observed in tuberculo-  sis, diarrheal diseases, hospital-acquired infections, malaria,  meningitis, respiratory tract infections, STIs, and HIV.    The human body is a hospitable site for microorganisms  to grow and flourish. These microorganisms make up the  normal microbiome of the body.   The beneficial homeostasis between humans and microor-  ganisms is maintained through the physical integrity of the  gut and other mechanisms that sequester these microor-  ganisms on the mucosal surface.    The symbiotic relationship with the normal microbiome  can be altered by injury, compromising protective barriers.    can circumvent an individual’s defenses and directly cause  infection. Successful infection with these agents usually  requires adequate numbers of microorganisms rather than  compromised immune defenses.    contaminated soil, contaminated water, breast milk), ani-  mals, or another human.    adherence to tissue through surface receptors. Once coloniza-  tion occurs, the infectious agent can invade surrounding tissue.    isms undergo rapid multiplication. Viral pathogens repli-  cate within infected cells, and some bacteria are intracellular  pathogens and replicate in macrophages and other cells.  Many pathogens produce only localized infections. Others  are, however, highly invasive.   Successful spreading requires a variety of virulence factors,  including adhesion molecules, toxins, and the ability to  evade immunity.   Clinical infectious disease occurs in four distinct stages: (a)  incubation period, (b) prodromal state, (c) invasion period,  and (d) convalescence.   The hallmark of most infectious diseases is fever. Body tem-  perature is regulated at a higher than normal level.   A large number of agents (pyrogens) can produce fever.  Current classifications include endogenous (e.g., cyto-  kines) and exogenous agents. However, the evidence for    exogenous agents is limited and they indirectly affect the  hypothalamus through endogenous pyrogens.   Several factors influence the capacity of a pathogen to cause  disease, including communicability, immunogenicity,  infectivity, mechanisms of action, pathogenicity, entry por-  tal, toxigenicity, and virulence.   Infectious diseases also are classified by their prevalence and  spread as endemic, epidemic, and pandemic.   Classes of infectious microorganisms include bacterial, fun-  gal, parasitic, protozoal, and viral.   Bacteria are divided into several groups: “true bacteria,” fila-  mentous, spirochetes, mycoplasma, rickettsia, and chlamydia.  Stable colonization of bacteria requires adhesion. Many  bacteria attach through pili, also called fimbriae.   Invasion by bacteria results in direct confrontation with an  individual’s defense mechanisms, including complement,  antibodies, and phagocytes (neutrophils, macrophages).  Evasion of these defenses can result in bacteremia and sepsis.  Efficient pathogens can produce a variety of toxic mol-  ecules that may kill the individual’s cells, disrupt tissue,  and protect themselves against inflammation. Exotoxins  are released by bacteria during bacterial growth and can  damage cell membranes, activate second messengers, and  inhibit protein synthesis.   Endotoxins are contained in the cell walls of gram-nega-  tive bacteria and released during lysis of the bacteria. Bac-  teria that produce endotoxins are called pyrogenic bacteria  because they activate inflammation and produce fever.  Bacteria can protect against phagocytosis by producing tox-  ins and extracellular enzymes that destroy phagocytic cells.  Some bacteria can coat the Fc portion ofan individual’s anti-  body, preventing complement activation or phagocytosis.  Antigenic variation allows the pathogen to alter surface  molecules that express antigens that are the targets of pro-  tective immune responses. The pathogen thus becomes  resistant.   Other self-protective mechanisms for bacteria and other  pathogens include degradation of immune molecules, neu-  tralization of immune molecules, complement evasion, and  immune suppression.   Tissue damage from bacterial infections is either directly by  bacterial products or indirectly from infection.   S. aureus has become a major cause of hospital-acquired  (nosocomial) infections. Antibiotic resistance also has  become a major problem with S. aureus.   Fungal infection is called mycosis. Most pathologic fungi  are from the environment and transmitted by inhalation or  contamination of wounds.   In 2006, the opportunistic pathogen P. carinii was reclassi-  fied as a fungus and the specific variant that infects humans  was renamed P. jiroveci.   C. albicans is the most common cause of fungal infections  in humans. It resides in the skin, gastrointestinal tract,  mouth, and vagina. Local defense mechanisms, including  members of the bacterial microbiome, produce antifungal    agents. The infection remains localized in individuals with  an intact immune system.   Parasitic organisms establish a symbiosis with another spe-  cies, whereby the parasite benefits. They range from uni-  cellular protozoa to large worms. Although less common  in the United States, parasites and protozoa are common  causes of infection worldwide.   Parasitic and protozoal infections are rarely transmitted from  human to human. Infection mainly spreads through vectors  and includes malaria by mosquito bites, trypanosomes by  the tsetse fly, and Leishmania spp. by sand fleas. Others are  found in contaminated water or food (e.g., G. lamblia).  Malaria is one of the most common infections worldwide.  It is transmitted through the bite of an infected Anopheles  mosquito. The parasite enters the bloodstream, survives  in the liver, and invades parenchymal cells. After several  rounds of division, the liver cell ruptures and thousands of  parasites enter the blood, infecting red blood cells.   Viruses are classified by the format of nucleic acid in the  virion (RNA or DNA), either single stranded (ss) or dou-  ble stranded (ds), and whether it uses the enzyme RT for  replication.   Viral diseases are the most common affliction of humans  and include the common cold, the “coldsore,” hepatitis,  HIV, and several types of cancer.   Viruses are intracellular parasites. The viral life cycle is com-  pletely intracellular and involves several stages: attachment,  penetration, uncoating, replication, assembly, and release.  New virions are released from the cell for transmission of  the viral infection to neighboring, uninfected cells.   The primary defense mechanisms against viruses include  antibody and cellular immunity. Nonspecific defenses include  a- and §-interferons that block intracellular replication.  Successful viruses use a variety of mechanisms for bypassing  immune rejection, including rapid division, intracellular  survival, coating with self-proteins, antigenic variation, neu-  tralization, complement evasion, and immune suppression.  Viruses inside the infected cell have several harmful effects,  including inhibition of DNA, RNA, or protein synthe-  sis; disruption of lysosomal membranes, resulting in lytic  enzyme release; promotion of cell apoptosis; fusion of adja-  cent cells (i.e., giant cells); transformation into a neoplastic  cell; and alteration of antigenic properties (ie., decreasing  immune effectiveness).   HIV infects and depletes a portion of the immune system  (Th cells), making individuals susceptible to life-threaten-  ing infections and malignancies.   HIV/AIDS remains a major cause of death worldwide.  Aggressive antiretroviral therapy and public health cam-  paigns have stabilized the number of new cases and deaths  in the United States from HIV/AIDS, but the cases and  deaths continue to increase rapidly worldwide.    . In 2009, 50% of newly diagnosed cases of AIDS in the    United States were attributed to male-to-male sexual con-  tact, 30% to high-risk heterosexual contact, and 14% to  injected drug abuse. About 25% of newly diagnosed cases  were female, with about 74% contracted through high-risk  heterosexual contact.    Women have the highest risk of infection. Because of AIDS,  the average life expectancy in South Africa has dropped  from 64 years to 54 years.    . HIV is a blood-borne pathogen present in body fluids (e.g.,    blood, vaginal fluid, semen, breast milk) with typical routes  of transmission: blood or blood products, intravenous drug  abuse, heterosexual and homosexual activity, and mater-  nal-child transmission before or during birth.    . At the end of 2009, an estimated 8640 children in the    United States developed AIDS after contracting HIV infec-  tion from their mothers (e.g., across the placenta, through  contact with infected blood during delivery, or through  ingestion of infected breast milk).    infections from another person’s blood. However, as of May  2011, only 57 cases of confirmed HIV infection and 143  possible cases were contracted by occupational exposure.  HIV is a member of the retrovirus family, which carries  genetic information in the form of two copies of RNA.  An enzyme, reverse transcriptase (RT), converts RNA  into a double-stranded DNA. Another enzyme, an inte-  grase, inserts the new DNA into the infected cell’s genetic  material. On activation, translation of the viral informa-  tion may be initiated, forming new virions, resulting in  lysis and death of the infected cell, and shedding infectious  HIV particles.   The primary surface receptor on HIV is the envelope gly-  coprotein gp120, which binds to the CD4 molecule found  mostly on the surface of T-helper cells. Several other impor-  tant co-receptors have been identified.   The major immunologic finding in AIDS is the striking  decrease in the number of CD4 Th cells.   The presence of circulating antibody against HIV indi-  cates infection by the virus, although many individuals are  asymptomatic.   The current treatment for HIV infection is a combination  of drugs called antiretroviral therapy (ART).    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Stressful experiences include daily  hassles, major life events (e.g., loss of family member, loss of  job), abuse, trauma, work-life balance, and many other events.  For example, the pressure to remain in contact despite illness,  travel, vacation, and other events that used to provide socially  acceptable temporary absences is now customary in the Ameri-  can, and indeed global, culture. This prevalent assumption of  constant availability is a newly identified stressor contributing  to the more global and better studied stressors of work-related  and relationship stressors. When added to other well-identified  stressors such as financial problems, the result may be potential  suffering from the so-called stress-related disorders.   When thinking about stress, one must consider the factors  producing a perception of stress. Stress begins with a stimulus  that the brain perceives as stressful, which in turn promotes  adaptational and survival-related physiologic responses. These  responses can become dysregulated and cause pathophysiologic    Neuroendocrine Regulation, 344  Stress and the Immune System, 353  Stress, Personality, Coping, and Illness, 355  Coping, 357  AGING and Stress: Stress-Age Syndrome, 358    conditions.' Another way to think about stress involves short-  or long-term stressors and a discussion of the physiologic  responses to these different types of events. Today most  researchers feel that acute stress is considered to be immunoen-  hancing (protective) while chronic stress is now thought to be  immunosuppressive (destructive).!    Walter B. Cannon used the term stress to encompass both physi-  ologic and psychologic ideas as early as 1914.* He applied the  engineering concept of stress and strain in a physiologic context  and believed that emotional stimuli also were capable of caus-  ing stress. In 1946, Hans Selye popularized these same findings,  viewing stress as a biologic phenomenon.’ Originally, Selye  inadvertently discovered the biologic syndrome of stress while  he was attempting to discover a new sex hormone by injecting  crude ovarian extracts into rats.° He repeatedly found that three  structural changes occurred: (1) enlargement of the cortex of the    FIGURE 11-1 Neural Recognition and Response to Real or Predicted Stressors.    adrenal gland, (2) atrophy of the thymus gland and other lym-  phoid structures, and (3) development of bleeding ulcers in the  stomach and duodenal lining. Selye soon discovered that these  manifestations were not specific to injected ovarian extracts but  also occurred after he exposed the rats to other noxious stim-  uli, such as cold, surgical injury, and restraint. He called these  stimuli stressors. Selye concluded that this triad or syndrome of  manifestations represented a nonspecific response to noxious  stimuli, naming it the general adaptation syndrome (GAS).  He identified three successive stages of the GAS: (1) the alarm  stage or reaction, in which the central nervous system (CNS) is  aroused and the body’s defenses are mobilized (e.g., “fight or  flight”) (Figure 11-1); (2) the stage of resistance or adaptation,  during which mobilization contributes to “fight or flight”; and  (3) the stage of exhaustion, where continuous stress causes the  progressive breakdown of compensatory mechanisms (acquired  adaptations) and homeostasis. Exhaustion marks the onset of  certain diseases (diseases of adaptation).   Initially one becomes alarmed by a stressor that activates  the hypothalamus and sympathetic nervous system (see Fig-  ures 11-1 and 11-2). The resistance or adaptation phase begins  with the actions of the hormones cortisol, norepinephrine, and  epinephrine. Exhaustion (also known as allostatic overload; dis-  cussed later) occurs if stress continues and adaptation is not suc-  cessful, ultimately causing impairment of the immune response,  heart failure, and kidney failure, leading to death.   From a physiologic perspective, what is emerging across the  disciplines involved—molecular biology, immunology, neurol-  ogy, endocrinology, and behavioral science—is a more holistic  and complex model that involves biochemical relationships of  the CNS, autonomic nervous system (ANS), endocrine system,  and immune system that cause the stress responses identified by  Selye. More simply, these relationships are often cited together  as the hypothalamic-pituitary-adrenal (HPA) axis (Figure  11-3). The reader may find it helpful to become familiar with  the ANS function content in Chapter 15, p. 470.   In sequence, the hypothalamus secretes corticotropin-  releasing hormone (CRH), which binds to specific receptors  on pituitary cells that, in turn, produce adrenocorticotropic  hormone (ACTH). ACTH is then transported through the  blood to the adrenal glands located on the top of the kidneys.  After binding to specific receptors on the adrenal glands, the  glucocorticoid hormones (primarily cortisol; from the adre-  nal cortex) are released. Cortisol initiates a series of metabolic    changes discussed in the section Glucocorticoids: Cortisol;  however, overall, these hormones are thought to enhance  immunity during acute stress and suppress immunity during  chronic stress because of prolonged exposure and increased  concentration.!    Selye believed that stressors cause a general or nonspecific  response. However, research in the past 50 years has shown the  remarkable sensitivity of the central nervous system and endo-  crine system to psychologic influences (emotion is included  in psychologic and social stress and acts through psychologic  mechanisms). Thus, although Selye’s identification of the GAS  is regarded as tremendously important and the cornerstone  of stress research, the idea that stress is a purely physiologic  response is vastly oversimplified. In the mid-1950s, stud-  ies showed that activation of the adrenal cortex occurred in  humans in response to psychologic stressors,’ in monkeys with  conditioned emotional responses,’ and in humans subjected to  a stressful interview technique.° In the early 1960s, researchers  found that plasma cortisol levels in groups of subjects increased  while they watched war movies and decreased while they viewed  Disney nature films.”* Mason later demonstrated that the ini-  tiation of the GAS depended on psychologic factors surround-  ing the stressors.’ He also showed that various factors, such as  degrees of discomfort or unpleasantness or suddenness of the  stress, could account for the presence or absence of physiologic  stress responses.”   The term stress has been used persistently and widely across  many disciplines despite numerous disagreements over its  definition. Nevertheless, in recent years stress has been more  usefully defined as a transactional or interactional concept.  Transactionally, stress is viewed as the state of affairs arising  when a person relates to (i.e., interacts or transacts with) situ-  ations in certain ways. People are not disturbed by situations  per se but by the ways they appraise and react to situations. In  general, a person experiences stress when a demand exceeds  a person’s coping abilities, resulting in reactions such as  disturbances of cognition, emotion, and behavior that can  adversely affect well-being. Moreover, psychologic stressors  can elicit reactive or anticipatory stress responses. The reac-  tive response is a physiologic response derived from psycho-  logic stressors. For example, the stress of an examination may    ; ; y ; Decreased glucose Increased  “Variable changes in B-endorphins, growth hormone, and prolactin uptake in skeletal gluconeogenesis  (see text).    muscle and adipose  tEffects may be dependent on amount of cortisol and nature of the P  stressor.    +Caused by protein catabolism in muscle, adipose tissue, skin, bones,  lymphoid tissue. Increased blood glucose    FIGURE 11-3 Hypothalamic-Pituitary-Adrenal (HPA) Axis. The response to  stress begins in the brain. The hypothalamus is the control center in the brain for  many hormones including corticotropin-releasing hormone (CRH). ACTH, Adreno-  corticotropic hormone.    produce an increased heart rate and dry mouth in the unpre-  pared student. The anticipatory response occurs when physi-  ologic responses develop in anticipation of disruption of the  optimal steady-state, also known as homeostasis. These antic-  ipatory responses can be generated either by species-specific  innate programs, such as reacting to the presence of preda-  tors and unfamiliar situations, or by experience-dependent  memory programs created by conditioning.'® Anticipatory  responses are learned responses under fine control by regions  located in the brain’s limbic system. These regions are those  most frequently associated with learning and memory and  include the hippocampus, amygdala, and prefrontal cortex. In  order for these regions to elicit a stress response, the paraven-  tricular nucleus (PVN) of the hypothalamus must be stimu-  lated. The limbic structures rarely interact directly with the  PVN and are believed to influence the stress response through  intermediary neurons, some of which are primarily used for  the reactive response.   In a conditional response one learns that specific stimuli  (i.e., objects or situational context) are associated with danger,  and as such anticipation of subsequent encounters with the    stimulus produces a physiologic stress response. For example,  a child that is abused by a parent may experience a physiologic  stress response in anticipation of further abuse when the par-  ent enters the room. Under some circumstances these memory  programs may become so strong that psychologic disorders,  such as phobias, develop. In a similar fashion, some persons  develop posttraumatic stress disorder (PTSD) in response to  the memory, as opposed to the anticipation of traumatic events.  PTSD is characterized by flashback memories, sleep distur-  bances, depression, and other symptoms. These symptoms have  the potential to greatly interfere with normal activities such as  employment and frequently disrupt personal relationships and  quality of life.   Today there is evidence implicating stress as a precipitat-  ing factor for some diseases and conditions and as an exacer-  bating factor, worsening symptoms and outcomes, in others,  such as atherosclerosis, irritable bowel syndrome, ulcers,  asthma, autoimmune disorders, anxiety, delayed wound  healing, chronic pain and fatigue syndromes, reproductive  dysfunction, diabetes, and depression.” '! In addition, evi-  dence published since 2000 generally supports a relationship  between stress and human immunodeficiency virus (HIV)  progression. !   Psychologic stress may cause or exacerbate (worsen) sev-  eral disease states, including many of the diseases implicated  as the leading causes of death in the United States (Table  11-1). For example, stress-induced chronic inflammation is  suggested as being important in the functional decline that  leads to frailty, disability, and untimely death; cardiovascu-  lar disease; and infectious diseases.'*"!° Additionally, impor-  tant effects of acute emotional stress, such as the death of a  loved one, on the heart muscle include three areas: (1) left  ventricular contractile dysfunction, (2) myocardial ischemia,  and (3) disturbances of heart rhythm (see What’s New? Acute  Emotional Stress and Adverse Heart Effects). Other examples  include research linking stress to the recurrence of genital  herpes virus in women with HIV.!? As evidence has mounted  concerning the important role that stress plays in certain  disease processes, research has focused on the mechanisms  responsible for these mind-body interactions. Along with a  greater understanding of the relationship between the human  stress response and disease, new strategies for treatment of  stress-related disorders are emerging. It has recently been  demonstrated that the interactions among social, psychologic,  biologic, and behavioral factors are inherent in the causes and  courses of many diseases. Molecular biologists, immunolo-  gists, neurologists, clinicians, and behavioral scientists are  now exploring the role of the other half of the mind-body  (dualistic) model—that is, the mind. What is emerging is a  more holistic and complex model of health and disease states.  This model involves the biochemical relationships of the cen-  tral and autonomic nervous systems, the endocrine system,  and the immune system and their relationships to stress-  elicited coping behaviors, such as smoking and poor diet, that  can also modify the integrity of the immune system. Discover-  ies of these complex links have led to the creation of the field  of psychoneuroimmunology.   e Individuals with coronary heart disease may develop myocardial ischemia  during mental or acute emotional stress even though their exercise results  are negative.   e Systemic vascular resistance increases during periods of mental or acute  emotional stress with concomitant increased myocardial oxygen demand.    Left Ventricular Dysfunction  This condition is more evident in older women.  After acute emotional stress or trauma, there is an increase in sudden chest  pain and shortness of breath.    Left ventricular dysfunction is more common in the cardiac apex.  Alterations occur possibly because of increases in the levels of catechol-  amines. Increased stress in daily life is associated with enhanced HPA axis  response, a higher cortisol awakening response, and higher mean day and  evening cortisol levels.   e Intense or unusual acute stress precipitates about 20% of serious ventricu-  lar dysrhythmias or sudden cardiac death.   e Altered brain activity may lead to changes in ventricular repolarization and  electrical instability of the cardiac muscle.    Data from Critchley HD et al: Brain 128(Pt 1):75-85, 2005; Ramach-  andruni S et al: J Am Coll Cardiol 47(5):987-991, 2006; Soufer R:  Circulation 110(13):1710-1713, 2004; Wittstein IS et al: N Engl J Med  352(6):539-548, 2005; Ziegelstein RC: JAMA 298(3):324-329, 2007.  Kumari M et al: Psychoneuroendocrinology, 35(7):1091-1099, 2010.   Psychoneuroimmunology (PNI) is the study of how the con-  sciousness (psycho), brain and spinal cord (neuro), and the  body’s defenses against infection and abnormal cell division  (immunology) interact. Psychoneuroimmunology assumes that    all immune-mediated diseases result from interrelationships  among psychosocial, emotional, genetic, and behavioral factors  with the neurologic, endocrine, and immune systems.'!!”!° The  immune system is integrated with other physiologic processes  and is sensitive to changes in CNS and endocrine functioning,  such as those that accompany psychologic states. Stressors can  elicit the stress response or stress system through the action of  the nervous and endocrine systems. Stressors include infection,  noise, decreased oxygen supply, pain, malnutrition, heat, cold,  trauma, prolonged exertion, radiation, responses to life events  (including anxiety, depression, anger, fear, loss, and excitement),  obesity, old age, drugs, disease, surgery, and medical treatment.  Although the field of PNI is relatively new, and a body of sci-  entific literature is present, the subject of PNI has caused strenu-  ous scientific debate, especially with respect to the causal role of  personality in cancer mortality and morbidity.'’ For example,  mouse models suggest a strong link between stress and breast  cancer progression, yet this effect has not been consistently  found in humans.!??° What is certain, however, is that hor-  mones released by the stress response influence many metabolic  systems and corresponding physiologic events, even if the mech-  anisms and subsequent physiologic events are yet to be fully  understood. Further, sufficient data now exist to conclude that  immune modulation by psychosocial stressors or interventions  leads directly to health outcomes.*!*’ The strongest support  to date for the link between psychosocial stressors and health  outcomes remains in studies of infectious disease and wound  healing.°**? However, a very recent meta-analysis of 10 studies  conducted among persons living in England found that any level  of psychologic distress is associated with increased mortality  and increased risk of death from cardiovascular disease, exter-  nal causes, and cancer (albeit only at higher levels of distress);  68,000 persons were used in this study and personal factors, such  as age, smoking, and alcohol use, were adjusted accordingly.“    FIGURE 11-4 Stress Interactions Are Nonlinear and Complex. Nonlinearity means that when one mediator is  increased or decreased, the subsequent compensatory changes in other mediators depend on time and level of change, caus-  ing multiple interacting variables. The inevitable consequences from adapting to daily life over time include changes in behav-  ioral responses. For example, these changes include sleeping patterns, tobacco use, alcohol consumption, physical activity,  and social interactions. These behavioral patterns are a part of the allostatic overload with chronic elevations in cortisol  level, sympathetic activity, and proinflammatory cytokines, and a decrease in parasympathetic activity. (From McEwen BS:  Eur J Pharmacol 583[2-3]:174-185, 2008.) DHEA, Dehydroepiandrosterone.    The stress response is initiated by the central nervous system and  endocrine system (see Figure 11-1). Specifically, corticotropin-  releasing hormone (CRH) is released from the hypothalamus,  and influences the sympathetic nervous system, the pituitary  gland, and the adrenal gland (see Figure 11-2). CRH is also  released peripherally at inflammatory sites called peripheral, or  immune, CRH. The activation of these systems redirects adap-  tive energy to the CNS and stressed body sites.   Where the stress response begins depends on whether the  stressor is perceived or real. Perceived stressors elicit an antic-  ipatory response that usually begins in the limbic system of  the brain, the area responsible for emotions and cognition.  The limbic system indirectly elicits both an endocrine stress  response by stimulating neural pathways responsible for  receiving sensory information and a central stress response  by directly stimulating the locus ceruleus (LC) to release nor-  epinephrine (see Figure 11-1). Norepinephrine release pro-  motes arousal, increased vigilance, increased anxiety, and  other protective emotional responses. Real stressors elicit a  reactive response that can begin either in the limbic system  or in regions of the brain receiving specific sensory informa-  tion (see Figure 11-1). This information is then relayed to the    PVN. The PVN stimulates the LC and both central and endo-  crine stress responses.    Central Stress Response  Better understanding is emerging regarding the physiology  involved in meeting the demands and challenges of daily life.  Some refer to these challenges as “stressors,” and the chroni-  cally stressed person may use the term “stressed out.” The  physiology is complex, involving both protection and damage.  As previously mentioned, glucocorticoids from the adrenal cor-  tex in response to ACTH from the pituitary gland (see Figure  11-3) comprise the major stress hormones along with the cat-  echolamines epinephrine and norepinephrine. Other central  hormones/mediators also play a role including the proinflam-  matory and anti-inflammatory cytokines that are regulated by  glucocorticoids and catecholamines (Figure 11-4).?!  Catecholamines can increase proinflammatory cytokine pro-  duction, causing, for example, increased heart rate and blood  pressure. Glucocorticoids are known to inhibit this proinflam-  matory production; however, inhibition depends on dose and  cell or tissue type.*° More simply, glucocorticoids can also pro-  mote inflammation depending on dose and cell type.*! The  increased understanding of these effects suggests the possibility  that chronic and dysfunctional HPA axis stimulation (as may    FIGURE 11-5 Physiologic and Behavioral Stress Responses. Stress processes arise from bidirectional communication  patterns between the brain and other physiologic systems (autonomic, immune, neural, and endocrine). Importantly, these bidi-  rectional mechanisms are protective, promoting short-term adaptation (allostasis). Chronic stress mechanisms, however, can lead  to long-term dysregulation and promote behavioral responses and physiologic responses that lead to stress-induced disorders/    diseases (allostatic load) that compromise health. (From McEwen Bs: Eur J Pharmacol 583[2-3]:174-185, 2008.)    occur during chronic inflammation) increases inflammation  in the brain and other tissue, possibly contributing to other  diseases including osteoporosis, metabolic disease (diabetes,  obesity), and cardiovascular disease.** Additionally, these inter-  actions are nonlinear and are very complex.    The parasympathetic system balances the sympathetic nervous  system and, thus, also influences adaptation or maladaptation  to stressful events. The parasympathetic system also has anti-  inflammatory effects. The parasympathetic system opposes the  sympathetic (catecholamine) responses, for example, by slowing  the heart rate.°! Researchers evaluate the relative balance of the  parasympathetic and sympathetic nervous systems using a tech-  nique known as heart rate variability (the measurement of R wave  variability from heartbeat to heartbeat).   Allostasis is considered an adaptive physiologic response  to stressful events (e.g., fight or flight).*! Chronic or dysregu-  lated allostasis (long-term or chronic exaggerated responses  to stress) can lead to disease. Allostatic load (Figure 11-5) is  the individualized cumulative amounts of stressors that exist  in our lives and that influence our physiologic responses. Allo-  static load includes our genetic makeup, our lifestyle (including  damaging health behaviors), daily events, and dramatic events  (such as disasters).?!*° Over time this load exacts a toll on our  bodies (i.e., “wear and tear”). Because the brain is a key player in  deciding what is stressful, it is influential in determining when  we have reached allostatic overload. Moreover, these responses  are individualized in that what would be considered normal  for one person is considered extremely stressful for another.*°    Under conditions of allostatic overload, the parasympathetic  system may decrease its restraint of the sympathetic system,  resulting in increased or prolonged inflammatory responses.”!*!  Physiologically, in response to acute and chronic stress some  regions of the brain (the hippocampus, amygdala, and prefron-  tal cortex) may respond by undergoing structural remodeling,  which can alter behavioral and physiologic responses (such as  cognitive impairment or depression).”! Key mediators involved  in allostatic overload (exaggerated pathophysiologic responses  to stress) include the glucocorticoid cortisol, catecholamines  (released from sympathetic nervous system activation), and  proinflammatory cytokines; in addition, there is a decline in  parasympathetic activity. A prevalent example is sleep depri-  vation resulting from excessive stress. Sleep deprivation has  significant damaging effects including elevated evening cortisol  level; elevated insulin and blood glucose levels; increased blood  pressure; reduced parasympathetic activity; increased levels of  proinflammatory cytokines; and increased concentrations of  the gut hormone ghrelin, which increases appetite. Altogether,  these alterations can lead to increased caloric intake, depressed  mood, cognitive problems, and a host of other responses from  insomnia.**    The sympathetic nervous system (SNS) is aroused during the  stress response and causes the medulla of the adrenal gland  to release catecholamines (80% epinephrine and 20% norepi-  nephrine) into the bloodstream. The adrenal medulla is actually  an extension of the SNS because preganglionic fibers from the  splanchnic nerve terminate in the medulla, where they innervate   Acute and chronic stress inhibits several  components of innate immunity, particularly  decreasing number of natural killer cells   Depend on availability of type 1/  proinflammatory cytokines, presence or  absence of antigenic stressors, and peripheral  corticotropin-releasing hormone (CRH)    Data from Elenkov IJ, Chrousos GP: Ann N Y Acad Sci 966:290-303,  2002; Granner DK: Hormones of the adrenal medulla. In Murray RK  et al, editors: Harper's biochemistry, ed 25, New York, 2000.   *Some of these responses require glucocorticoids (e.g., cortisol) for  maximal activity (see text for explanation).    the chromaffin cells that produce the catecholamine hormones.  Simultaneously, hypothalamic CRH stimulates the pituitary  gland to release a variety of hormones, including antidiuretic  hormone and oxytocin from the posterior pituitary gland, and  prolactin, endorphins, growth hormone (GH), and adrenocor-  ticotropic hormone (ACTH) from the anterior pituitary gland.  ACTH stimulates the cortex of the adrenal gland to release  cortisol (see Figure 11-2).   Circulating catecholamines essentially mimic direct sympathetic  stimulation. Catecholamines cannot cross the blood-brain bar-  rier and are synthesized locally in the brain. In response to stress,  the chromaffin cells of the adrenal medulla produce large quan-  tities of epinephrine and small amounts of norepinephrine.  Once released, catecholamines circulate bound to the plasma  protein albumin. The physiologic effects of the catecholamines  on organs and tissues are summarized in Table 11-2. Norepi-  nephrine regulates blood pressure by constricting smooth  muscle in all blood vessels. During stress, norepinephrine raises  blood pressure by constricting peripheral vessels; it dilates the   Q2 Smooth muscle relaxation (gastrointestinal tract); smooth  muscle contraction (some vascular beds); inhibition  of lipolysis, renin release, platelet aggregation, and  insulin secretion   Stimulation of lipolysis; myocardial contraction (increased  rate, increased force of contraction)   Increased hepatic gluconeogenesis; increased hepatic  glycogenolysis; increased muscle glycogenolysis;  increased release of insulin, glucagon, and renin;  smooth muscle relaxation (bronchi, blood vessels,  genitourinary tract, gastrointestinal tract)    pupils of the eye, causes piloerection, and increases sweat gland  action in the armpits and palms (see Figure 11-2).   Epinephrine is rapidly transported to and acts on several  organs, but it is metabolized quickly, making it short-acting.  Metabolically, epinephrine causes transient hyperglycemia  (high blood glucose level), decreases glucose uptake in the  muscles and other organs, and decreases insulin release from  the pancreas. This is accomplished by activating enzymes whose  actions promote glucose formation (gluconeogenesis) and gly-  cogen breakdown (glycogenolysis) in the liver, while inhibiting  glycogen formation. This prevents glucose from being taken  up by peripheral tissue and preserves it for the CNS. Further,  very little adrenal norepinephrine reaches distal tissue; thus, the  effects caused by norepinephrine during the stress response are  primarily elicited from the SNS.*°*”   Epinephrine has a greater influence on cardiac action and  is the principal catecholamine involved in metabolic regula-  tion. Epinephrine enhances myocardial contractility (inotro-  pic effect), increases the heart rate (chronotropic effect), and  increases venous return to the heart, all of which increase cardiac  output and blood pressure. Epinephrine dilates blood vessels of  skeletal muscle, allowing for greater oxygenation. Epinephrine in  the liver and skeletal muscles is rapidly metabolized and dilates  blood vessels supplying skeletal muscles, allowing for more oxy-  genation. Epinephrine also mobilizes free fatty acids and choles-  terol by stimulating lipolysis, freeing triglycerides and fatty acids  from fat stores, and by inhibiting the degradation of circulating  cholesterol to bile acids. The metabolic actions of epinephrine  aid the metabolic actions of cortisol, which are similar.   Table 11-2 summarizes other well-known effects of adrenal  catecholamines. All of these effects prepare the body to take  physical action: to fight or flee. Stressors commonly associated  with catecholamine release by the adrenal medulla include exer-  cise, thermal changes, and acute emotional states.   The catecholamines stimulate two major classes of receptors:  a-adrenergic receptors and B-adrenergic receptors. These two  classes are divided further into two subclasses: (1) a, and a,  and (2) 6; and 8. Table 11-3 summarizes the actions of the two  subclasses of adrenergic receptors. Epinephrine binds to and    Diminishes peripheral uptake and utilization of glucose; promotes gluconeogenesis in liver metabolism cells; enhances    Increases protein synthesis in liver and decreases protein synthesis (including immunoglobulin synthesis) in muscle,    lymphoid tissue, adipose tissue, skin, and bone; increases plasma level of amino acids; stimulates deamination in liver    High levels of cortisol used in drug therapy suppress inflammatory response; inhibit proinflammatory activity of many  growth factors and cytokines; however, over time some individuals may develop tolerance to glucocorticoids, causing    Lipolysis in extremities and lipogenesis in face and trunk  Treatment levels of glucocorticoids are immunosuppressive; thus, they are valuable agents used in numerous diseases;    the T-cell or innate immunity system is particularly affected by these larger doses of glucocorticoids with suppression  of Th1 function or innate immunity; stress can cause a different pattern of immune response; these nontherapeutic  levels can suppress innate (Th1) and increase adaptive (Th2) immunity—the so-called Th1 to Th2 shift; several factors  influence this complex physiology and include long-term adaptations, reproductive hormones (i.e., overall, androgens  suppress and estrogens stimulate immune responses), defects of hypothalamic-pituitary-adrenal axis, histamine-  generated responses, and acute vs. chronic stress; thus stress seems to cause a Th2 shift systemically whereas locally,  under certain conditions, it can induce proinflammatory activities and by these mechanisms may influence onset or  course of infections and autoimmune/inflammatory, allergic, and neoplastic diseases    activates both a- and f-adrenergic receptors. Norepinephrine  at physiologic concentrations binds primarily to a-adrenergic  receptors.*®   Catecholamines can modify the numbers of cells of the  immune system circulating in the blood.” Injection of epi-  nephrine into healthy human subjects is associated with a tran-  sient increase of the number of lymphocytes (e.g., T cells and  natural killer [NK] cells) in the peripheral blood. Specifically,  the levels of T cytotoxic and NK cells increase, whereas little  change occurs in B lymphocytes. The main change involves the  NK cells.*? Qualitatively, lymphocyte responsiveness of T and  B lymphocytes is reduced. Similar quantitative and qualitative  changes are found 5 to 6 minutes after exposure to a psycho-  logic or physical stressor.°° However, the effects of acute eleva-  tion of catecholamine levels on the alteration of lymphocyte  function are short-lived, lasting only about 2 hours.*!    The adrenal cortex is activated during stress by ACTH (see Figure  11-2), which increases adrenocortical secretion of glucocorticoid  hormones, primarily cortisol (hydrocortisone is a synthetically pro-  duced but chemically identical version of cortisol). These steroid  molecules reach all tissues, including the brain, easily penetrate  cell membranes, and react with numerous intracellular glucocor-  ticoid receptors. Because they spare almost no tissue or organ and  influence a large proportion of the human genome, they exert sig-  nificant diverse biologic actions.?* The feedback mechanisms of    Decreases proliferation of fibroblasts in connective tissue (thus delaying healing)  Maintains normal contractility and maximal work output for skeletal and cardiac muscle    Maintains normal blood pressure; permits increased responsiveness of arterioles to constrictive action of adrenergic  stimulation; optimizes myocardial performance   Somehow modulates perceptual and emotional functioning; essential for normal arousal and initiation of daytime activity    the HPA axis sense and determine the circulating glucocorticoid  levels, whereas other tissues passively accept the actions of circu-  lating glucocorticoids.” Chronic dysregulation of the HPA axis,  especially elevated cortisol level, has been linked to a wide variety  of disorders including obesity, sleep deprivation, lipid abnormali-  ties, hypertension, diabetes, atherosclerosis, loss of bone density,  hippocampal atrophy, and cognitive impairment.”   Cortisol circulates in the plasma, both protein bound and free.  The main plasma-binding protein is called transcortin or cor-  ticosteroid-binding globulin. The unbound, or free, fraction is  approximately 8% of the total plasma cortisol and is biologically  active.*® Cortisol mobilizes substances needed for cellular metab-  olism. One of the primary effects of cortisol is the stimulation of  gluconeogenesis, or the formation of glucose from noncarbohy-  drate sources, such as amino acids or free fatty acids in the liver.  In addition, cortisol enhances the elevation of blood glucose level  promoted by other hormones, such as epinephrine, glucagon,  and growth hormone. This action by cortisol is said to be permis-  sive for the actions of other hormones. Cortisol also inhibits the  uptake and oxidation of glucose by many body cells. The overall  action of cortisol increases blood glucose concentration, thereby  enabling the body to combat the stressor. The physiologic effects  of cortisol are summarized in Table 11-4.   Cortisol also affects protein metabolism. It has an anabolic  effect; that is, it increases the rate of synthesis of proteins and  ribonucleic acid (RNA) in the liver. The anabolic effect of cor-  tisol, however, is countered by its catabolic effect on protein    The signs and symptoms of Cushing syndrome (e.g., excess glucocorticoids  [GCs]) include truncal obesity, relatively thin extremities, a “moon face,”  and a “buffalo [neck] hump.” In such individuals the possibility of associ-  ated hypertension is high as well as increased risk of infection and metabolic  syndrome or frank type 2 diabetes. In addition, the likelihood of an elevated  ratio of intra-abdominal subcutaneous fat mass to nonabdominal fat mass is  high because the glucocorticoids mediate the redistribution of stored calories  into the abdominal region. The specific increase in abdominal fat stores is a  consequence of elevated levels of glucocorticoids combined with increased  insulin action. However, the increased levels of glucocorticoids need not be  present in the circulation, but can be generated locally in fat by conversion  of inactive cortisone to active cortisol through the action of the isoenzyme  11-B-hydroxysteroid dehydrogenase (11-B-HSD) type-1. This conversion is  referred to as “pre-receptor” metabolism of cortisol. The active steroid is  secreted directly to the liver through the portal vein. In vitro insulin synthesis    and secretion from the pancreas are inhibited by the glucocorticoids. How-  ever, increasing levels of glucocorticoids in vivo are associated with increasing  insulin secretion possibly because of an anti-insulin effect on the liver, which  appears to be vulnerable to the negative effects of glucocorticoids on insu-  lin action. Hepatic insulin resistance is strongly associated with abdominal  obesity.   Recent data reveal that the plasma concentration of inflammatory mediators,  such as tumor necrosis factor-alpha (TNF-c) and interleukin-6 (IL-6), is increased  in the insulin-resistant states of obesity and type 2 diabetes. Two mechanisms  might be involved in the pathogenesis of inflammation: (1) glucose and macronu-  trient intake (i.e., which can be mediated through chronic stress) causes oxida-  tive stress; and (2) the increased concentrations of TNF-o and IL-6 associated  with obesity and type 2 diabetes might interfere with insulin signal transduction.  This interference might promote inflammation. Chronic overnutrition (obesity)  might thus be a proinflammatory state with oxidative stress.    Stress, Inflammation, Obesity, and Type 2 Diabetes. The induction of reactive oxygen species (ROS) generation and  inflammation through the proinflammatory transcription factor, NF-kf, activates most proinflammatory genes. Macronutri-  ent intake, obesity, free fatty acids, infection, smoking, psychologic stress, and genetic factors increase the production  of ROS. Interference with insulin signaling (insulin resistance) leads to hyperglycemia and proinflammatory changes.  Proinflammatory changes increase the levels of TNF-c and IL-6, and also lead to the inhibition of insulin signaling and  insulin resistance. Inflammation in pancreatic beta cells leads to beta-cell dysfunction, which in combination with insulin    Data from Dallman MF et al: Endocrinology 145(6):2633-2638, 2004; Dandona P, Aljada A, Brandyopadhyay A: Trends Immunol 25(1):4—7, 2004;  Kim SP et al: Diabetes 52:2453-2460, 2003; Masuzaki H et al: Science 94:2166-2170, 2001; Padgett DA, Glaser R: Trends Immunol 24(8):444-448,    stores in other tissues. Protein catabolism acts to increase  levels of circulating amino acids, and chronic exposure to  excess cortisol can severely deplete protein stores in muscle,  bone, connective tissue, and skin. Further, cortisol acts to  reduce protein synthesis in nonhepatic tissues, a loss for which  dietary protein cannot compensate. Some evidence suggests  that cortisol depresses transport of amino acids into muscle  cells while enhancing their uptake into the liver. Finally, cor-  tisol promotes gastric secretion in the stomach and intestines,  potentially causing gastric ulcers. This could account for the  gastrointestinal ulceration observed by Selye. This is in opposi-  tion to norepinephrine, which reduces gastric secretion.    Cortisol also has a powerful effect that reverses the insulin-  induced suppression of hepatic gluconeogenesis, as well as basal  levels of cortisol that stimulate the activity of hepatic enzymes  responsible for glycogen and glucose production. The increased  amino acid uptake into liver and the increased levels of glucose-  producing enzymes favor the production of glucose. Although  diseases of excess cortisol secretion, such as Cushing disease,  produce characteristics of type 2 (non—insulin-dependent) dia-  betes mellitus, recent studies found that chronic stress also may  facilitate the development of type 2 diabetes.°?°* Glucocorti-  coids contribute to the development of metabolic syndrome  and the pathogenesis of obesity (Box 11-1). The mechanism    for this action is under investigation, but it is believed that  the development of diabetes is secondary to cortisol-induced  obesity. Cortisol promotes lipogenesis in certain regions of the  body and to a lesser extent promotes lipolysis in other regions  by increasing the actions of lipolytic hormones, such as cat-  echolamines and growth hormone. Chronic cortisol excess  induces lipogenesis in the abdomen, trunk, and face, resulting  in central obesity. Finally, glucocorticoids may affect fetal pro-  gramming of the HPA axis by causing an adverse intrauterine  environment because of alterations in cortisol secretion during  pregnancy.**    Cortisol secretion during stress exerts beneficial effects by inhib-  iting initial inflammatory effects, for example, vasodilation and  increased capillary permeability.** Cortisol also promotes reso-  lution and repair. These actions are mainly accomplished by  facilitating the effects of glucocorticoid receptor (GR), namely,  the transcription of genetic material (through DNA binding)  within leukocytes.** Because GR is so widely expressed, glu-  cocorticoids influence virtually all immune cells. However,  whether cortisol-induced effects are adaptive or destructive may  depend on the intensity, type, and duration of the stressor; the  tissue involved; and the subsequent concentration and length of  cortisol exposure. Finally, glucocorticoids have been shown to  induce T-cell apoptosis.°?   Cortisol acts to suppress the activity of Thl1 cells, which  leads to a decrease in innate immunity and to the proinflam-  matory response. Cortisol also stimulates the activity of Th2  cells, which leads to an increase in adaptive immunity and the  anti-inflammatory response. Epinephrine and norepinephrine  have a similar effect: a decrease in Th1 activity and an increase  in Th2 activity.   Initially, immune responses are regulated by cells of innate  immunity called antigen-presenting cells (APCs), such as  monocytes/macrophages, dendritic cells, and other phagocytic  cells, and by Th1 and Th2 lymphocytes (cells involved in adap-  tive immunity). These cells secrete chemical messengers, called  cytokines, that regulate innate and adaptive immune responses.  Cytokines are a group of chemicals such as interferons, inter-  leukins, and tumor necrosis factors that can stimulate or inhibit  various components of the immune system. Antigen-present-  ing cells also release cytokines that induce T cells to differenti-  ate into Th1 cells. Th1 cells and APC cytokines work together  to stimulate the activity of cytotoxic T cells, natural killer cells,  and activated macrophages—the major components of innate  immunity. These cytokines also stimulate the synthesis of nitric  oxide and other inflammatory mediators that increase chronic  delayed-type inflammatory responses. Because of this effect,  these cytokines are sometimes referred to as proinflammatory  cytokines.   The cytokines secreted by the Th2 cells act to inhibit Th1 cells  and can promote adaptive immunity by stimulating the growth  and activation of mast cells and eosinophils, as well as the dif-  ferentiation of B-cell immunoglobulins. Thus, these cytokines  are sometimes referred to as anti-inflammatory cytokines*°  (Figure 11-6). Moreover, cytokines can act synergistically,    antagonistically, or reciprocally. However, the roles of cytokines  are highly complex and much remains unknown. Regardless, the  decrease in Th] activity and increase in Th2 activity is sometimes  called a Th1 to Th2 shift. Individuals experiencing a Th1 to Th2  shift are more likely to experience allergic responses, infections,  and temporary worsening of autoimmune conditions such as  arthritis.   The preceding description of the effect of stress hormones  on the Th1-Th2 balance may not be accurate for certain local  responses.*»°° It has been documented that the release of cat-  echolamines (epinephrine and norepinephrine) can cause cer-  tain epithelial cells of the lung to release cytokines that promote  recruitment of leukocytes, potentially enhancing inflammation  and worsening lung function. This paradoxical stress-induced  potentiation of inflammation in the lungs may explain why  “acute respiratory distress syndrome” often develops in indi-  viduals with major infections associated with profound activity  of the stress response.°’   Stress hormones, especially glucocorticoids (cortisol), have  been used therapeutically as powerful anti-inflammatory/  immunosuppressive agents for years. The synthetic forms of glu-  cocorticoid hormones (exogenous types of anti-inflammatory  glucocorticoids administered for a pharmaceutical reaction) are  poorly metabolized when compared to endogenous glucocorti-  coids, leading to a longer half-life and no circadian rhythm for  these compounds. Moreover, these synthetic compounds bind  to different targets, so each has a unique effect.*! Therapeutic  levels of glucocorticoids inhibit the accumulation of leukocytes  at the site of inflammation and inhibit the release of substances  involved in the inflammatory response (i.e., kinins, plasmino-  gen-activating factor, prostaglandins, and histamine) from the  leukocytes. Glucocorticoids inhibit fibroblast proliferation and  function at the site of an inflammatory response. This inhibition  accounts for the poor wound healing, increased susceptibility to  infection, and decreased inflammatory response that often are  noted in individuals with chronic glucocorticoid excess.   Paradoxically, elevated levels of glucocorticoids and catechol-  amines (epinephrine and norepinephrine)—both endogenous  and exogenously administered—may decrease innate immunity  and increase autoimmune responses. These effects can accen-  tuate inflammation in general and potentially increase neuro-  nal death (e.g., in stroke victims).°' This may help explain the  seemingly contradictory stress response of immunosuppression  and increased risk of infection (decreased innate immunity)  with a heightened antibody response and autoimmune disease  (increased adaptive immunity).   Corticotropin-releasing hormone (CRH) influences the  immune system indirectly by the activation of cortisol (gluco-  corticoids) and catecholamines. CRH is secreted by the hypo-  thalamus and also peripherally at inflammatory sites (called  peripheral or immune CRH).”>”> Peripheral (immune) CRH  is proinflammatory, causing an increase in vasodilation and  vascular permeability.°° Therefore, it appears that mast cells  are the target of peripheral CRH. Mast cells release histamine,  which is a well-known mediator of acute inflammation and  allergic reactions (see Figure 11-6). Recent evidence has indi-  cated that immune cells may have histamine receptors and that    FIGURE 11-6 Effect of Corticotropin-Releasing Hormone (CRH)—Mast Cell—Histamine Axis, Cortisol, and Cat-  echolamines on the Th1/Th2 Balance—Innate and Adaptive Immunity. Adaptive immunity provides protection against  multicellular parasites, extracellular bacteria, some viruses, soluble toxins, and allergens. Innate immunity provides protection  against intracellular bacteria, fungi, protozoa, and several viruses. Type 1 cytokines or proinflammatory cytokines include IL-12,  interferon-gamma (IFN-y), and tumor necrosis factor-alpha (TNF-a). Type 2 cytokines or anti-inflammatory cytokines include IL-10  and IL-4. Solid lines (black) represent stimulation, whereas dashed lines (blue) represent inhibition (i.¢., Th1 and Th2 are mutually  inhibitory, IL-12 and IFN-y inhibit Th2, and vice versa; IL-4 and IL-10 inhibit Th1 responses). Stress and CRH modulate inflammatory/  immune and allergic responses by stimulating cortisol (glucocorticoid), catecholamines, and peripheral (immune) CRH secretion and  by changing the production of regulatory cytokines and histamines. CRH (peripheral, immune), Corticotropin-releasing hormone; /L,  interleukin; VE, norepinephrine; NK, natural killer cell; 7c, cytotoxic T cell; 7h, helper T cell; dashed lines, decreased (inhibited); solid  lines, increased (stimulation). (Redrawn from Elenkov lJ, Chrousos GP: Trends Endocrinol Metab 10[9]:359-368, 1999.)    histamine may have an effect similar to catecholamines. This  finding suggests that histamine induces acute inflammation  and allergic reactions while suppressing Th] activity (decreas-  ing innate immunity) and promoting Th2 activity (increasing  adaptive immunity).°”°? A number of stress factors initiate  CRH production, including high levels of interleukin-1 (IL-1)  and IL-6. Increased CRH secretion results in an increase in  cortisol secretion. Cortisol in turn inhibits further cytokine  release by macrophages and monocytes. The observation that  IL-1 can elicit changes in the nervous and endocrine systems  by stimulating CRH production in the hypothalamus is part of  a growing body of evidence demonstrating immune-induced  regulation of the CNS. The release of the immune inflamma-  tory mediators IL-6, tumor necrosis factor-alpha (TNF-a),  and interferon is triggered by bacterial or viral infections,  cancer, and tissue injury that in turn initiate a stress response  through the HPA pathway. Enhanced systemic production of  these cytokines also induces other CNS and behavior changes  seen frequently during the acute phase of an infectious episode,    acting either directly in a distant, systemic “endocrine” way  or indirectly through the mediation of neuropeptides. These  effects include pyrogenesis (fever), induction of slow-wave  sleep, and anorexia, all of which are adaptive responses to  infection and possibly cancer. Slow-wave sleep is associated  with enhanced release of growth hormone (GH) and a reduc-  tion in levels of cortisol, which is beneficial for tissue repair  and enhanced immune response.   In summary, stress can activate an excessive immune  response and, through cortisol and catecholamines, suppress  the Th1 response, causing a Th1 to Th2 shift. Locally, stress can  exert proinflammatory or anti-inflammatory effects depending  on the chemicals that are released in the local environment and  the way that the cells of the local environment respond to those  chemicals. Moreover, different types of stressors may have vari-  able effects on the immune response. Thus systemic responses  to stress may cause a decrease in innate immunity and enhance  adaptive immunity, whereas local responses to stress, under cer-  tain conditions, can induce proinflammatory activities that    may influence the onset and cause of infectious, autoimmune/  inflammatory, allergic, and neoplastic diseases.    The immune system is integrated with other physiologic pro-  cesses and is sensitive to changes in CNS and endocrine func-  tioning, such as those that accompany psychologic states. For  example, neuropeptide Y (NPY), a sympathetic neurotrans-  mitter, has been shown to be a stress mediator. Because NPY  is a growth factor for many cells, it is implicated in atheroscle-  rosis and tissue remodeling.*? Other hormones that influence  the stress response are listed in Table 11-5. Neuropeptides and  hormones have a significant effect on the immune response.  Whether this effect on immune function is suppressive or poten-  tiating depends on the type of factor secreted, with some factors  enhancing activity, some suppressing activity, and some doing  both, depending on the concentration and length of exposure,  the target cell, and the specific immune function studied.  Hormones of the Female Reproductive System. Cortisol exerts  inhibiting effects by suppressing levels of luteinizing hormone  (LH), estradiol, progesterone, and possibly testosterone.°°!  The HPA axis exerts powerful, multilevel effects on the female  reproductive system. Stress generally inhibits the female  reproductive system (Figure 11-7), primarily through the HPA  axis by (1) suppression of hypothalamic gonadotropin-releasing  hormone (GnRH) secretion by CRH and CRH stimulation of  6-endorphin release; (2) inhibition of GnRH, pituitary LH, and  ovarian estradiol (E,) secretion by cortisol; and (3) cortisol-  induced target tissue resistance by estradiol.°%°? The locus  ceruleus—norepinephrine (LC/NE) system provides positive input  to the reproductive system, which is frequently altered by the  stress-activated HPA axis. Sexual stimulation and GnRH neuron  activation, however, may cause the gonadal axis to be resistant to  suppression by the HPA axis. Through estradiol, the reproductive  system provides positive input to both components of the stress  system by stimulating CRH secretion and inhibiting reuptake  and catabolism of catecholamines. Table 11-6 presents potential  pathologic effects of central and peripheral CRH in women.  Estrogen stimulates the HPA axis. In addition, HPA axis  responsiveness is greater in women than that in men.°? Estro-  gen directly stimulates the CRH gene promoter and the cen-  tral noradrenergic (norepinephrine) system, which may help  explain adult women’s slight hypercortisolism, increases in  affective anxiety and eating disorders, mood cycles, and vulner-  ability to autoimmune and inflammatory disease, all of which  follow estradiol concentration fluctuations. Estradiol down-  regulates glucocorticoid receptor binding in the anterior pitu-  itary, hypothalamus, and hippocampus—this tends to increase  HPA activity by interfering with glucocorticoid-negative feed-  back, whereas progesterone opposes these effects. Thus altera-  tions in estradiol levels during normal menses, perimenopause  (including increases as well as decreases), and menopause alter  the regulatory feedback loop, and adaptations over time develop  as a new equilibrium is established in the relationship (see  Figure 11-7). Over time, these changes increase the incidence of  mood alterations, eating disorders, anxiety, depression, weight  alterations, and inflammatory and immune disorders.    The adipocyte-derived peptide hormone leptin interacts  directly and indirectly with the adrenal and gonadal axes; leptin  levels are higher in women than in men. Leptin regulates appe-  tite (satiety) and energy balance. It also inhibits the HPA axis at  both hypothalamic and adrenocortical levels. In addition, leptin  positively influences the female reproductive axis by inhibition  of the HPA axis and arcuate proopiomelanocortin (POMC)  neuronal system and through activation of the LC/NE system.  By promoting satiety and sympathetic system outflow, leptin  is thought to provide the peripheral signal to a central mecha-  nism regulating the size of body fat stores.°° Thus leptin may be  significant in control of the onset of puberty because of its rela-  tionship to the amount of fat mass, in the adaptive activation of  the HPA axis, and in inhibition of gonadal function that takes  place in cases of starvation and anorexia nervosa.°°*   Endorphins and Enkephalins. Endorphins and enkephalins  (endogenous opiates) are released into the blood as part of the  response to stressful stimuli. They are proteins found in the brain  that have pain-relieving capabilities. Stressful stimuli include  traumatic injury and an acute, intense stress situation, such  as first-time parachute jumping. In inflamed tissue, immune  cell-derived endorphins activate endorphin receptors on  peripheral sensory nerves, leading to pain relief or analgesia.°°  Hemorrhage increases B-endorphin levels, which appear to  inhibit blood pressure increase or delay compensatory changes  that would increase blood pressure.’? Thus endogenous opiates  modulate blood pressure instability and neuroendocrine and  cytokine responses to blood losses.7!”7   In a number of conditions or activities in which endog-  enous opiate activity is increased, subjects not only experi-  ence insensitivity to pain but also report increased feelings of  excitement, positive well-being, or euphoria. In addition, cells  of the immune system synthesize and release opioids when the  lymphoid cells are activated.’? T and B lymphocytes and mono-  nuclear phagocytic cells have receptors for opioids. Endorphins  may play a role in the excitement and exhilaration produced by  dancing, contact sports, and combat. There is little direct evi-  dence, however, documenting the endorphin system in most of  these activities.   Growth Hormone (Somatotropin). Growth hormone (GH) is  released from the anterior pituitary gland and is produced by  lymphocytes and mononuclear phagocytic cells.’* GH affects  protein, lipid, and carbohydrate metabolism and counters  the effects of insulin. It is involved in tissue repair and may  participate in the growth and function of the immune system.  Receptors for GH are present on lymphoid cells.”° This finding  suggests a role for GH in regulating phagocytic function and  possibly antigen presentation. GH levels increase in the blood  after a variety of acutely stressful stimuli, such as cardiac  catheterization, electroshock therapy, gastroscopy, surgery,  fever, and physical exercise. Psychologic stimuli associated with  increased levels of GH include taking examinations, viewing  violent or sexually arousing films, anticipating exhausting  exercise, and performing certain psychologic tests. However,  prolonged activation of the stress response (chronic stress)  leads to suppression of GH and other growth factor effects on  target tissues.”° (This is not to be confused with a congenital    Produced by sensory nerve terminals found  in and released from lymphoid cells and  hypothalamus   Found in neurons of central nervous system  (CNS) and in peripheral nerves    Found in spinal cord motor neurons and  in sensory neurons near dendritic cells  of skin and in primary and secondary  lymphoid tissues   Present in neurons of CNS and in neurons  throughout body; co-localized in nerve  terminals in lymphatic tissues with  norepinephrine   Produced by a neuropeptide classified  as tachykinin (increases heart rate  subsequent to lowering blood pressure)  found in brain, as well as nerves  innervating secondary lymphoid tissues    1. Amico JA et al: J Neuroendocrinol 16(4):319-324, 2004.  2. Rabin BS: The nervous system—immune system connection. In Stress, immune function, and health: the connection, New York, 1999, Wiley-Liss.    . Rohleder N et al: J Neuroimmunol 126(1-2):69-77, 2002.  . Marucha PT, Kiecolt-Glaser JK, Favagehi M: Psychosom Med 60(3):362—365, 1998.  . Chesnokova V, Melmed S: Endocrinology 143(5):1571-1574, 2002.  . Guezennec CY et al: /nt J Sports Med 16(6):368-372, 1995.   . Repka-Ramirez MS, Baraniuk JN: Clin Allergy Immunol 17:1-17, 2002.  . Maestroni GJ: Adv Exp Med Biol 460:396, 1999.   . Petito JM, Huang Z, McCarthy DB: J Neuroimmuno! 54:81, 1994.    Activates endorphin (opiate) receptors on peripheral sensory nerves, leading to pain relief or analgesia  Hemorrhage increases levels to inhibit blood pressure or delay compensatory changes that would increase  blood pressure!  Affects protein, lipid, and carbohydrate metabolism  Counters effects of insulin  nvolved in tissue repair  ay participate in growth and function of immune system?  Levels increase after a variety of stressful stimuli (cardiac catheterization, electroshock therapy, gastroscopy,  surgery, fever, physical exercise)  ncreased levels associated with psychologic stimuli (taking examinations, viewing violent or sexually arousing  films, certain psychologic performance tests)  Prolonged stress (chronic stress) suppresses growth hormone  ncreases in response to many stressful stimuli (including procedures such as gastroscopy, proctoscopy, pelvic  examination, and surgery}?  Requires more intense stimuli than those leading to increases in catecholamine or cortisol levels  Levels show little change after exercise  Promotes bonding and social attachment  n animals associated with reduced hypothalamic-pituitary-adrenal (HPA) activation levels and reduced anxiety*  Regulates male secondary sex characteristics and libido  Levels decrease after stressful stimuli (anesthesia, surgery, marathon running, mountain climbing)®  Decreased by psychologic stimuli; however, some data indicate that psychologic stress associated with  competition (e.g., pistol shooting) increases both testosterone and cortisol levels, especially in athletes older  than 45 years®  arkedly reduced in individuals with respiratory failure, burns, and congestive heart failure’  Decreased levels occur during aging and are associated with a lower cortisol responsiveness to stress-induced  inflammation?  Works in concert with oxytocin, exerting a calming effect during stressful situations?  ncreases during stress response; release is suppressed by light and increased in the dark; receptors have  been identified on lymphoid cells, possibly higher density of receptors on T cells than B cells; suppression of  lymphocyte function by trauma was reversed by melatonin'®  atural killer (NK) function and immunoglobulin synthesis are decreased by SOM; growth hormone secretion  decreased by SOM    VIP increases during stress; VIP-containing nerves are located in both primary and secondary lymphoid tissues,  around blood vessels, and in gastrointestinal tract; VIP receptors are on both T and B cells; VIP may influence  lymphocyte maturation; cytokine production by T cells is modified by VIP; B cells and antibody production are  influenced by VIP   CGRP receptors are present on T and B lymphocytes; thus it is likely that CGRP can modulate immune function;  CGRP may enhance acute inflammatory response because it is a vasodilator; maturation of immune B  lymphocytes is inhibited by CGRP; IL-1 is inhibited by CGRP, which is important for activation of T cells; it has  been shown to interfere with lymphocyte activation   Lymphocytes have receptors for NPY and thus may modulate their function;'' several lines of evidence suggest  that NPY is a neurotransmitter and neurohormone involved in stress response; increased levels of NPY  occur in plasma in response to severe or prolonged stress; it may be responsible for stress-induced regional  vasoconstriction (splanchnic, coronary, and cerebral); it may also increase platelet aggregation?   SP increases in response to stress; receptors for SP are found on membranes of both T and B cells, mononuclear  phagocytic cells, and mast cells; proinflammatory activity induces release of histamine from mast cells during  stress response; causes smooth muscle contraction, causes macrophages and T cells to release cytokines,  and increases antibody production    FIGURE 11-7 Stress and the Female Reproductive System. Interactions of the reproductive system with the hypotha-    lamic-pituitary-adrenal (HPA) axis and locus ceruleus—norepinephrine system (LC/|  express proopiomelanocortin (POMC) peptides. Stress generally inhibits the fema    HPA by (1) suppressing hypothalamic gonadotropin-releasing hormone (GnRH) secretion by corticotropin-releasing hormone    (CRH) and CRH-induced B-endorphins; (2) inhibiting GnRH, pituitary luteinizing ho  tion by cortisol; and (3) enhancing cortisol-induced target tissue resistance to es    system to stimulate the stress system by stimulating CRH secretion and inhibiting  ACTH, Adrenocorticotropic hormone; FSH, follicle-stimulating hormone. Dashed li    rmone (LH), and ovari  radiol. The LC/NE system provides positive  input to the reproductive system, which can be overridden by the stress-activated HPA. Estradiol can    refer to direct stimulatory pathways. (Adapted from Chrousos GP et al: Ann Intern Med 129[3]:229-240, 1998.)    GH deficiency, which leads to short stature, decreased muscular  strength, and bone density pathology.) When under stress,  chronic glucocorticoid stimulation decreases the release of  GH from the pituitary gland, resulting in potentially decreased  skeletal muscle, increased bone catabolism, reduced oxygen  uptake, increased fat production, worsening sleep patterns,  decreased force of cardiac contractions, decreased thyroid  function, and poorer mood state. In other words, glucocorticoids  antagonize the beneficial actions of GH.’”   Prolactin. Prolactin is released from the anterior pituitary  gland as well as numerous extrapituitary tissue sites. It is  necessary for lactation and breast development. Prolactin  receptors are present in many different tissues, including the  liver, kidney, intestine, and adrenals. Prolactin is also produced  by lymphoid cells.’* Prolactin levels in plasma increase as a  result of a variety of stressful stimuli, including gastroscopy,  proctoscopy, pelvic examination, and surgery. The level of  prolactin also rises during parachute jumping, during motion  sickness, after taking examinations, and after receiving various  sexual stimuli, for example, stimulation of the nipple or areola  in women. Unlike GH, prolactin levels show little change after  exercise. Like GH, however, a prolactin level increase appears  to require more intense stimuli than those leading to increases  in catecholamine or cortisol levels. Immune cells also are  influenced by prolactin. Prolactin acts as a second messenger    for IL-2 and is known to have a positive influence on B-cell  activation and differentiation. Several classes of lymphocytes  have receptors for prolactin, suggesting a direct effect of  prolactin on immune function.   Oxytocin. Oxytocin is well known as a hormone produced  in high levels by the hypothalamus during childbirth and  lactation. It is also produced during orgasm in both sexes and  has been shown to promote bonding and social attachment.  Oxytocin also has antistress properties, as has been shown  in animal experiments in which elevations in endogenous  oxytocin level were associated with reduced HPA activation  levels and reduced anxiety.”? Oxytocin in some tissues works in  concert with estrogen; these two hormones have a calming effect  during stressful situations.®° In contrast, another hormone  closely resembling oxytocin, vasopressin, acts in concert with  testosterone to increase blood pressure and heart rate, thus  enhancing the “fight or flight” stress response. Thus different  effects of stress on males and females may be explained, in part,  by gender-related hormonal profiles that dictate to some extent  the characteristics, quality, and outcomes of the stress response.   Testosterone. Testosterone, a hormone secreted by Leydig  cells, regulates male secondary sex characteristics and libido.  Testosterone levels decrease after stressful stimuli. This  decrease in testosterone level occurs after stimuli such as ether  or anesthetic administration, surgery, marathon running,    TABLE 11-6 POTENTIAL PATHOLOGIC  EFFECTS OF CENTRAL AND  PERIPHERAL CORTICOTROPIN-  RELEASING HORMONE (CRH)  IN WOMEN    ncreased secretion of placental CRH  Decreased secretion of placental CRH  Decreased secretion of ovarian CRH    Data from Chrousos GP et al: Ann Intern Med 129(3):229-240; Kalantaridou  SN et al: J Reprod Immunol 62(1-2):61-68, 2004.   *New line of investigation: Filipcik P et al: Cel! Mol Neurobiol 32(5):  837-845, 2012.    and mountain climbing. The mechanism causing decreased  levels of testosterone is thought to be exerted by cortisol and  B-endorphin.   Psychologic stimuli also lead to a decrease in testosterone  levels. Men engaged in rigorous combat training and those  engaged in the first several weeks of officer candidate school  experience significant drops in testosterone levels.*!** However,  other data have shown that the psychologic stress associated  with some types of competition (e.g., pistol shooting) increases  both testosterone and cortisol levels, especially in athletes older  than 45 years.®? Moreover, individuals with acute illness, such  as respiratory failure, burns, and congestive heart failure, show  a marked reduction in plasma testosterone level.**   The direct immunologic effects of sex hormones contribute  to the sexual dimorphism seen in the incidence of autoimmune  disease®? and the greater susceptibility to sepsis and mortality  in males following injury.*° Estrogens generally are associated    with a depression of T-cell-dependent immune function and  an enhancement of B-cell functions, and androgens suppress  both T- and B-cell responses.** In injury, however, males pro-  duce greater amounts of proinflammatory cytokines, a profile  that is associated with poor outcome.*” Additionally, androgens  appear to induce a greater degree of immune cell apoptosis  following injury, a mechanism that may elicit a greater immu-  nosuppression in injured males vs. females.®* (A list of other  hormones, including melatonin, substance P, neuropeptide Y,  calcitonin gene-related peptide, somatostatin, and vasoactive  intestinal peptide, is contained in Table 11-5.)    Many immune-related conditions and diseases are associated  with stress. Several conditions with variable pathophysiologic  characteristics appear to have a common origin®®”® relating  to chronic inflammatory processes. These conditions include  cardiovascular disease, osteoporosis, arthritis, type 2 diabe-  tes mellitus, chronic obstructive pulmonary disease (COPD),  other diseases associated with aging, and some cancers; all are  characterized by the prolonged presence of proinflammatory  cytokines.®””! It is important to remember that inflammation is  associated with impairment of normal tissue function. Athough  inflammation is a normal response and considered beneficial, an  excessive inflammatory response can damage tissue. Stress and  negative emotions are associated directly with the production of  increased levels of proinflammatory cytokines, providing a possi-  ble link between stress, immune function, and disease.”””? Stress  and negative emotions are associated directly with the produc-  tion of increased levels of proinflammatory cytokines, provid-  ing a possible link between stress, immune function, and disease  (see What’s New? Psychosocial Stress and Progression to Coro-  nary Heart Disease). Research is now focused on the regulatory  interactions between the immune system and the nervous and  endocrine systems, which may represent mechanistic pathways  for stress-associated immune-mediated diseases. The immune,  nervous, and endocrine systems communicate through similar  pathways using hormones, neurotransmitters, neuropeptides,  and immune cell products.*” The complexity of this system can  be daunting. Various components of immune system responses  can be affected by neuroendocrine-produced factors involved in  the stress reaction. Conversely, immune cell-derived cytokines  and other products affect neurocrine and endocrine cells.”*   The immune, nervous, and endocrine systems commu-  nicate through similar pathways involving hormones, neu-  rotransmitters, neuropeptides, and immune cell products.  Immune system responses are potentially affected by all known  neuroendocrine-produced factors involved in the stress reac-  tion. Conversely, immune cell-derived cytokines and other  products have effects on neurocrine and endocrine cells. Several  pathways regulate communication among these systems with  both direct and indirect patterned effects (Figure 11-8).   The stress response directly influences the immune system  through hypothalamic and pituitary peptides and through  products of the sympathetic branch of the ANS. These fac-  tors include CRH, ACTH, endorphins, substance P, epineph-  rine, norepinephrine, dopamine, serotonin, histamine, GH,    The link between stress and coronary heart disease was proposed as early as  the 1970s; however, it was only recently that evidence and proposed mecha-  nisms for development of the disease were identified. Much work continues  to focus on elucidating the interaction between stress and cardiovascular  disease.   Studies show that persons with highly reactive personality types and who  experience high levels of anxiety with stress are much more likely to progress  from prehypertension to hypertension and then to develop cardiac disease, spe-  cifically coronary heart disease, than those who have better coping abilities.  Further long-term psychologic stress, such as that experienced in a strained  marriage or an unhappy work environment, not only was shown to speed the  progression of hypertension and coronary heart disease but also is correlated  with higher mortality rates from coronary heart disease.   Trait anger, defined as a stable personality trait characterized by frequency,  intensity, and duration of anger, also was shown to be a factor in the develop-  ment of coronary heart disease at higher rates than in the general population.  Individuals with trait anger also experienced more strokes. Hostile individuals  with advanced cardiovascular disease may be particularly susceptible to stress-  induced increases in sympathetic activity and inflammation.    One popular mechanism for the interaction between psychosocial stress and  cardiovascular disease suggests that stress triggers an inflammatory response  that, over time, increases the chances of developing coronary heart disease. The  primary mechanisms proposed are chronically elevated cortisol levels and dys-  regulation of the circadian rhythm for cortisol release. Further, chronic stress  alters hypothalamic-pituitary-adrenal (HPA) function, resulting in an abnormal  stress response pattern. This alteration in HPA activity was found in persons  with coronary heart disease along with increased levels of inflammatory mark-  ers. The elevation in levels of inflammatory markers seen with chronic stress is  important because these markers were shown to interact with lipids, specifi-  cally low-density lipoprotein (LDL), to increase the production of atherosclerotic  plaques.   Because coronary heart disease is one of the major causes of death in indus-  trialized countries, development of successful interventional programs is of high  priority. Programs in which dietary changes, exercise, stress management, and  positive support systems are implemented continue to show positive results for  slowing the progression of heart disease and decreasing the risk factors for dis-  ease development. Further, individuals in these programs experience improvement  in depression, stress, and overall mental health.    Data from Brydon L et al: J Psychosom Res 68(2):109-116, 2010; Chida Y, Steptoe A: Hypertension 55:1026-1032, 2010; Davidson KW: Cleve  Clin J Med 75(Supp! 2):S15-S19, 2008; Richardson S et al: Am J Cardio! 110(12):1711-1716, 2012; Shamaei-Tousi A et al: Cell Stress Chaperones  12(4):384-392, 2007; Steptoe A, Brydon L: Neurosci Biobehav Rev 33:63-70, 2009; Vizza J et al: J Cardiopulm Rehabil Prev 27(6):376-383, 2007.    FIGURE 11-8 Nervous System-Endocrine System—Immune System  Interactions. Interconnections of pathways of communication among the immune,  nervous, and endocrine systems.    vasoactive intestinal polypeptide (VIP), B-endorphin, methi-  onine-enkephalin, leucine-enkephalin, and somatostatin.  Direct suppressive effects of CRH have also been reported on  two immune cell types possessing CRH receptors—the mono-  cyte/macrophage and CD4 (T helper) lymphocyte.” Release of  endogenous opiates occurs during stress, and these peptides are  known to have concentration-dependent, enhancing or sup-  pressive effects on various immune cells.°° Immune cells have  been shown to have surface receptors for epinephrine, sero-  tonin, ACTH, CRH, endorphins, GH, and prolactin, as well as  intracellular steroid receptors.    Products of the sympathetic branch of the ANS also influ-  ence immune cell behavior. There is direct innervation of the  thymus, spleen, lymph nodes, and bone marrow,”’ and histo-  chemical studies have verified the presence of cholinergic and  adrenergic nerve terminals in the lymphoid organs and tissues.  There is evidence for the interaction of norepinephrine released  from nerve endings with lymphocytes and macrophages in the  spleen. This finding implicates the presence of a route of com-  munication between the ANS and immune system through  direct delivery of chemical mediators that alter immune cell  behavior in a paracrine (cell to adjacent cell) fashion in the  microenvironment of the lymphoid organ.   The pineal gland regulates the immune response and medi-  ates the apparent effects of the circadian rhythm on immunity.  Blockage of production of melatonin (by continuous light or  by pharmacologic means) results in suppression of the immune  response, whereas administration of melatonin reverses these  effects. This immunomodulation pathway may affect immune  changes found with dysregulation of circadian rhythm, a com-  mon occurrence among older adults, acutely ill persons, and  stressed individuals.’* Melatonin also modulates seasonal  changes in immune function and affects tumor development.”   In summary, stress-induced immune changes affect many  immune cell functions, including decreased natural killer cell  and T-cell cytotoxicity and impaired B-cell function.'! These  impairments in immune function may have health conse-  quences for stressed individuals, including increased risk of  infection and some types of cancer.!°!0! The complex and bidi-  rectional communication among systems involves common use  of signal molecules and their receptors, which in turn regulates  the behavior of cells in each system. Thus the most recent find-  ings are that (1) there are direct effects of CNS neuropeptides on    immune cells; (2) stress-induced endocrine products influence  immune cell and neurologic cell function; and (3) immune cell  products (cytokines) affect nervous and endocrine cell function  through direct and indirect pathways.    It is not entirely clear why cortisol secretion during stress is  beneficial. It has been suggested that gluconeogenesis prompted  by cortisol ensures an adequate source of glucose (energy) for  body tissues, and nerve cells in particular. The pooling of amino  acids from catabolized proteins may ensure amino acid avail-  ability for protein synthesis in certain cells. The redistribution  of protein to sites where replacement is critical, such as muscle  or cells of damaged tissue, would be beneficial. Short-term,  cortisol-induced alterations in immune cell distribution (e.g.,  traffic) patterns may be adaptive, with a decrease in peripheral  blood cell numbers as effector cells locate to sites of injury or  inflammation. In addition, decreased immune cell activity by  cortisol may be beneficial in some situations because it prevents  immune-mediated tissue damage by prolonged cell exposure  to high levels of certain cytokines. Whether cortisol-induced  effects are adaptive or destructive may depend on the intensity,  type, and duration of the stressor, and the subsequent concen-  tration and length of cortisol exposure that target cells of the  individual experience.   Extreme physiologic stressors, such as severe burn injury, rep-  resent a predictable stimulus for the stress responses described  previously. A less severe and defined event or situation, how-  ever, can bea stressor for one person and not for another. Many  stressors, such as fasting or temperature changes, do not neces-  sarily cause a physiologic stress response if psychologic factors  are minimized. Stress itself is not an independent entity but a  system of interdependent processes that are moderated by the  nature, intensity, and duration of the stressor and the percep-  tion, appraisal, and coping efficacy of the affected individual,  all of which in turn mediate the psychologic and physiologic  response to stress. Further, adjustment to repetitive stressors is  known to be individualized, based on a person’s appraisal of a  situation.'"? Illustrating the influence of an individualized stress  appraisal on physiologic processes, a meta-analysis of the rela-  tionships between stressors and immunity found that a higher  perception of stress was associated with reduced T-cytotoxic  (Tc) cell cytotoxicity although not with levels of circulating Th  or Tc lymphocytes.!°°   Psychosocial distress may be predictive of psychologic and  physical health outcomes. In psychologic distress the individ-  ual feels a general state of unpleasant arousal after life events  that manifests as physiologic, emotional, cognitive, and behav-  ioral changes. Periods of depression and emotional upheaval  often are associated with adverse life events and place the  affected individual at risk for immunologic deficits, increasing  the risk of ill health.'°* An older meta-analysis of studies dem-  onstrates the longstanding relationship between depression and  reduction in lymphocyte proliferation and NK cell activity.!°  Multiple moderating factors may be important in immune  modulation in depressed individuals, including comorbidities    such as alcoholism. Examples of triggering mechanisms include  bereavement, academic and job-related pressures, life events  (positive and negative changes), and aging. Adverse life events  having the most negative effect on immunity are characterized  as uncontrollable, undesirable, and overtaxing the individual’s  ability to cope.   Studies have strengthened the association of stress with  potential for illness in humans (see What’s New? Telomeres,  Disease, and Childhood Stress). One study examined medi-  cal students who were immunized with hepatitis B vaccine  on the third day of a stressful examination period; the time to  seroconversion and level of antibody titer to the vaccine were  measured later. The students with the most rapid seroconver-  sion and the highest titers also reported being less stressed and  had a good social support system (which may reduce stress).!°°  Even more convincing is a study in which the psychologic stress  status was determined in healthy individuals after experimen-  tally controlled exposure to a respiratory tract virus by nasal  inoculation. Individuals reporting more stress had an increased  incidence of clinical cold and respiratory symptoms compared  with subjects reporting less stress, and other infections, includ-  ing HIV, were shown to be potentially influenced by psychoso-  cial factors. !07"-110   Animal studies have found that stress contributes to the ini-  tiation, growth, and metastasis of certain tumors.!'! Studies of  mechanisms in humans reveal stress affects important processes  in cancer including antiviral responses, deoxyribonucleic acid    Shortening of the tips of chromosomes, or telomeres, is a potential physi-  ologic mechanism linked to stress, cellular aging, and disease mortality.  In experimental animal studies, telomere-deficient mice have been used  to study telomere loss and shortening and associated tissue atrophy, stem  cell depletion, organ system failure, and impaired tissue injury responses.  Accumulating evidence reveals telomere damage as a stimulus for age-  associated organ damage and disease risk. In humans, an emerging field is  the discovery of mechanisms that mediate the effects of childhood stress  on late-life disease, morbidity, and mortality. For example, recent evidence  from the Environmental-Risk Longitudinal Twin Study found that children who  experienced two or more kinds of violence exposure (i.e., maternal domestic  violence, frequent bullying victimization, physical maltreatment by an adult)  showed significantly more telomere erosion between age 5 at baseline and  age 10 at follow-up measurements. This was observed even after adjusting  for gender, socioeconomic status, and body mass index. In addition, investiga-  tors in 2004 compared telomere lengths in white blood cells of mothers of  chronically ill children compared to those from mothers of healthy children.  The longer the mother was a care provider for her child, the shorter were her  telomeres. For mothers with the most self-reported stress, telomere shorten-  ing was equivalent to at least a decade of aging. In addition, a study of 4441  women aged 41 to 80 provided support for an association between adverse  experiences during childhood and shorter telomere length in adulthood.    Data from Armanios M, Blackburn EH: Nat Rev Genet 13(10):693-704,  2012; Blackburn EH, Epel ES: Nature 490(7419):169-171, 2012:   Epel ES et al: Proc Natl Acad Sci U S A 101(49):17312-17315, 2004;  Jaskelioff M et al: Nature 469(7328):102-106, 2011; Shalev | et al:  Mol Psychiatry 2012 Apr 24 [Epub ahead of print]; Surtees PG et al:    FIGURE 11-9 Health Outcome Determination in Stressful Life Situations Is Moderated by Numerous Factors.  Whether an individual experiences distress or illness depends on the subject's appraisal of the event and the coping strategies  used during the stressful period. Models A and B reflect possible outcomes in stressed healthy and symptomatic individuals.  Model € illustrates the dynamic clinical setting in which the diagnosis of a serious illness and subsequent medical interven-  tions may be perceived as stressful challenges and have potentially detrimental influences on physical outcome.    (DNA) repair, and aspects of cellular aging.'!' The role of epi-  genetics and stress is a new and developing field with strong  implications for the intersection between stress and disease.  A very recent study suggests that breast cancer bone metasta-  ses may be influenced by chronic stress by increasing the levels  of Receptor Activator of Nuclear Factor kB Ligand (RANKL)  that are expressed by osteoblasts, a known chemoattractant for  RANK-expressing breast cancer cells.!!* However, the overall  evidence is mixed from prospective studies linking stress with  cancer incidence and progression. Stress may be more likely  to influence progression and recurrence of cancer; however,  the critical prospective studies have been mostly unsupport-  ive.!* Studies examining impairments in antiviral immunity  and chronic activation of hormonal responses (e.g., HIV-  related tumors, hepatocellular carcinoma, and cervical cancer)  may be more successful designs for defining the stress-related  mechanisms.!!!   Previous and current evidence is showing a relationship  between immune stimulation and heart disease.'!> The rela-  tionship between stress and cardiovascular health may be  mediated by stress-induced changes in immune function,  which may potentiate proinflammatory processes and per-  mit alterations that lead to heart disease!!* (see What’s New?  Acute Emotional Stress and Adverse Heart Effects [p. 342] and  What’s New? Psychosocial Stress and Progression to Coro-  nary Heart Disease [p. 354]). A new study of heart disease and  inflammation demonstrates that monocytes and splenic mac-  rophages invade atherosclerotic plaques after an initial myo-  cardial infarction (heart attack), rendering them unstable and  as such contribute to secondary heart attacks.'!°    In the past decade a significant amount of evidence has accu-  mulated linking severe psychosocial stress resulting from negative  life events to a chronic syndrome with mental and physical conse-  quences. Posttraumatic stress disorder (PTSD) has been described  in many populations.'!*!'® A cascade model has been proposed  to describe the pathogenesis and clinical course illustrating the  clinical, epidemiologic, neurobiologic, and psychosocial com-  ponents of PTSD.''° The study of PTSD has contributed to the  knowledge concerning mechanisms involved in the chronic stress  and disease relationship. Recently an appreciation of the associa-  tion of chronic stress with high levels of cortisol production and  paradoxical biounavailability (i-e., bound to plasma protein and  therefore not bioavailable) of cortisol has been gained.!”°   The interaction with healthcare providers in a clinical setting,  the diagnosis of a major illness, and the execution of various  clinical procedures (e.g., blood draws, injections, examinations,  surgical procedures) also may represent significant negative life  events to many individuals (Figure 11-9) (for example, mam-  mography and the activation of the HPA axis).   The influence of repetitive but episodic stress on cancer  survivors demonstrates a connection between events such as  mammography and activation of the HPA axis. Early research  with breast cancer survivors by Cordova and colleagues!?!  demonstrated a link between sympathetic activity and HPA  axis activation, noting that some women reported symptoms  of PTSD (heart palpitations, panic, shakiness, nausea) dur-  ing thoughts of recurrence triggered by events such as finding  themselves near the hospital where they received initial treat-  ment.!?! HPA axis activation also influences organs and tissues  that enable bidirectional communication processes (feedback    loops) between neuroendocrine and immune processes.”*  For example, among breast cancer survivors 3 to 5 years post  diagnosis, elevated baseline cortisol levels and blunted corti-  sol reactivity were reported in response to the anticipation of  a real, regularly scheduled mammogram, and alterations in  cortisol level and heart rate variability were reported in women  simulating the threat of cancer with a controlled laboratory  stressor.'?*!?5 Further, Ma and colleagues!” reported that the  threat of cancer recurrence (using a simulated mammography  event as a stressor to elicit thoughts of cancer recurrence) elic-  ited greater alterations in heart rate variability when compared  with another simulated controlled stressor. These studies sug-  gest activation of the autonomic nervous system to events, such  as mammography, that occur repeatedly throughout breast  cancer survivorship, although the timing of onset of these auto-  nomic activation responses to a stressor is unclear. Similar ANS  activation may occur in association with events particular to the  management of many other types of chronic illnesses as well as  interactions with the healthcare system.   These additional stresses may affect the course of illness  as well as interfere with the efficacy of the medical interven-  tion. Identifying and reducing stress in the clinical setting have  particular applicability in both disease prevention and illness  management. In addition to medical procedures, patient-  provider communication also provides an important area for  future research. Recent studies of cancer communication and  patient-provider interaction have demonstrated a link between  communication events and emotional outcomes, such as uncer-  tainty and mood state in breast cancer survivors. !**!° Although  a logical extension, it remains to be seen if these emotional out-  comes affect physiologically based health outcomes caused by  activation of the HPA axis and subsequent immune processes.    Coping  Personality characteristics are associated with individual dif-  ferences in appraisal and response to stressors.'*° The coping  response of individuals may exaggerate or moderate physical  consequences of the stress response. Coping is defined as the  process of managing stressful demands and challenges that are  appraised as taxing or exceeding the resources of the person.!*’  One response may be a negative change in behavior resulting  in potentially adverse health effects (e.g., increased smoking,  change in eating habits). Serious disturbances of the sleep-wake  cycle are observed in many people under stress and in many  clinical settings. Further, sleep disturbances may exacerbate the  pathophysiologic status of certain patient populations.!?*!°°  Investigators have reported that sleep deprivation and circa-  dian disruption, even in young, otherwise healthy individuals,  have detrimental influences on respiratory and immune system  function. Even partial sleep deprivation was associated with  reduced NK cell activity in healthy subjects, and only recently  have seriously ill patients been assessed for adequacy and struc-  ture of sleep during recovery.!7°   Coping can be considered as adaptive or maladaptive. Adap-  tive coping strategies, especially those that are problem focused  and those that encourage seeking social support, are beneficial  during stressful experiences. The extent to which an individual    responds to distress, using effective positive coping strategies,  determines the degree of successful moderation of the stress  challenge. Conversely, ineffective negative coping attempts may  exacerbate the effects of distress on health, thus augmenting  the potential for illness. Mediating factors that may influence  stress susceptibility or resilience include age, socioeconomic  status, gender, social support status, personality and lifestyle,  self-esteem, genetics, life events, past experiences, and current  health status.'°! Evidence suggests that effective intervention  may result in greater stress resilience and improved psychologic  and physiologic outcomes. In a study of nursing home residents  randomly assigned to control or social support intervention  groups, improved psychologic measures and immune function  (NK cell activity) were observed in the experimental group at  6 weeks.!*? In another study, women with recurrent metastatic  breast cancer were given either routine follow-up (routine care)  or weekly support group sessions. Survival in the support treat-  ment group was an average of 19 months longer than in the  routine care group, suggesting a mediating influence of addi-  tional support for these women.*>!°?   The importance of social support for seriously ill individu-  als has focused attention on the health and well-being of family  members who function as caregivers (see What’s New? Partner’s  Survival and Spouse’s Hospitalizations and/or Death). Signifi-  cant stress manifested as depression, anxiety, and fatigue has  been noted in family caregivers of those with cancer, Alzheimer  disease, and burn trauma.!*4 Individuals and caretakers exhib-  ited suppression of various measures of immune function, with  improved function associated with better perceived social sup-  port.!°>"!97 Gender-based coping differences may be attributed,  in part, to the hormonal milieu of the individual, with females  more likely to offer social support, a behavior with an oxytocin/  estrogen association.”    A Harvard study shows that a spouse’s chances of dying increase not only  when the partner dies but also when that partner becomes seriously ill. The  9-year follow-up study consisted of 518,240 elderly couples. Mortality after  the partner's hospitalization varied according to the spouse's diagnosis. For  elderly people whose spouse had been hospitalized, the short-term risk of  dying approaches that of an elderly person after his or her spouse's death.  A wife's hospitalization increased her husband's chances of dying within 1  month by 35%; a husband's hospitalization increased his wife's chances of  dying by 44%. Likewise, a wife's death increased her partner's 1-month mor-  tality risk by 53%, and a husband's death raised his partner's risk by 61%.  The researchers commented that a spouse's illness or death can increase a  partner's mortality by causing severe stress and removing a primary source of  emotional, psychologic, practical, and financial support.   From a recent review, longitudinal studies put the long-term excess risk of  death associated with widowhood compared to marriage at about 15%, and  estimates of short-term effects during the first few months immediately post-  bereavement range from 50% to 90%. However, there is substantial heteroge-  neity in the magnitude of effects reported in different studies.    Data from Christakis NA, Allison PD: N Engl J Med 354(7):719-730,  2006; Moon JR et al: PLoS One 6(8):e23465, 2011.    Interventions to prevent or manage stress-related psycho-  logic or physical problems include both short- and long-term  coping strategies. Stress management consists of educational  components specific to the individual’s problems and relaxation  techniques, which may include meditation, imagery, massage,  and biofeedback. These approaches may be used on an individ-  ual or a support group basis. Incorporation of these approaches  into clinical training facilitates their use in the clinical arena.  Research should focus on the efficacy of such approaches with  various populations.    A set of neurohormonal and immune alterations, as well as tis-  sue and cellular changes, sometimes develops with aging. These  changes, which recently have been defined as stress-age syn-  drome, include the following:!*))1°8  + Alterations in the excitability of structures of the limbic  system and hypothalamus  + Increase of the blood concentrations of catecholamines,  antidiuretic hormone (ADH), ACTH, and cortisol  + Decrease of the concentrations of testosterone, thyroxine,  and others  + Alterations of opioid peptide concentration   Some of the alterations are adaptational, whereas others are  potentially damaging. These stress-related alterations of aging  can influence the course of developing stress reactions and  lower adaptive reserve and coping.!°?   Interventions to potentially prevent or manage stress-related  psychologic or physical problems include both short- and long-  term coping strategies. Educational components are specific to  the individual’s problems. Relaxation techniques may include  meditation, mindfulness, imagery, massage, yoga, and biofeed-  back. These approaches may be used on an individual or group  basis. Incorporation of these approaches into clinical training  facilitates their use in the clinical arena. Future research should  focus on the efficacy of such approaches with various populations.   In summary, it is clear that the mind and body are connected  through a multitude of complex physical and emotional inter-  actions. Understanding the complexity of these interactions is a  challenge for many researchers. Areas of promise include investi-  gating relationships between the potential for illness with respect  to stressors, as well as developing effective stress management  techniques and approaches that can be easily and cost-effectively  employed.   2. In general, a person experiences stress when a demand  exceeds a person’s coping abilities.   3. Hans Selye identified three structural changes in rats sub-  jected repeatedly to noxious stimuli (stressors): enlarge-  ment of the cortex of the adrenal gland, atrophy of the  thymus gland and other lymphoid tissues, and ulceration of  the gastrointestinal tract.   4. Selye believed that the three changes were caused by a non-  specific physiologic response to any long-term stressor. He  called this response the general adaptation syndrome (GAS).   5. The GAS occurs in three stages: the alarm stage, the stage  of resistance or adaptation, and the stage of exhaustion.  Diseases of adaptation develop if the stage of resistance or  adaptation does not restore homeostasis.   6. Selye identified three components of physiologic stress: the  stressor, the physiologic or chemical disturbance produced  by the stressor, and the body’s adaptational response to the  stressor.   7. We now know that, while important, the physiologic view  of stress as outlined in the GAS is an oversimplified model  of stress responses. We currently view the stress response as  the product of the interaction of the mind and body.    Concepts of Stress  1. Psychologic stress may cause or exacerbate (worsen) several  disease states. Stress is related to the severity of symptoms  and the outcomes of diseases and conditions. Research is   2. Stress has been defined as the state of affairs arising when a  person relates to (i.e., interacts or transacts with) situations  in a certain way. The way a person appraises and reacts to  situations has a profound impact on stress.   3. The nonspecific physiologic response consists of interac-  tion among the sympathetic branch of the autonomic ner-  vous system (ANS) and other neural signals that activate  the endocrine system, known as the HPA axis.   4. The nonspecific physiologic response is a common residual  response and can be elicited with diverse agents such as  cold, heat, x-rays, adrenaline, insulin, tubercle bacilli, and  muscular exercise. Although the reactions of these stages  are nonspecific, evidence supports the coexistence of highly  specific, adaptive reactions to any of these agents.   5. As with a physically mediated stress response, psychologic  stressors can elicit a reactive stress response; that is, a physi-  ologic response can be derived from psychologic stressors.   6. Another type of psychologic-mediated stress response is the  anticipatory response.   7. Inaconditioned response, the organism learns that specific  stimuli are associated with danger and anticipation of sub-  sequent encounters with that particular stimulus produces  a physiologic stress response (e.g., PTSD).   8. Psychoneuroimmunology (PNI) is the study of the interac-  tion of consciousness (psycho), the brain and spinal cord  (neuro), and the body’s defense against external infection  and abnormal cell division (immunology).    Psychoneuroimmunology assumes that all immune-related  disease is multifactorial. The immune system is integrated  with other physiologic processes and is sensitive to changes  in CNS and endocrine functioning, such as those that  accompany psychologic states.   CRH is released centrally from the brain and peripherally at  inflammatory sites.    The stress response is initiated by the CNS and endocrine  system. Where the stress response begins depends on  whether the stressor is perceived or real.    ally begins in the limbic system of the brain. The limbic  system elicits an endocrine stress response indirectly by  stimulating neural pathways responsible for receiving sen-  sory information and elicits a central response directly by  stimulating the LC to release LC/NE.    . Real stressors elicit a reactive response that can begin either    in the limbic system or in the brain in response to specific  sensory information. This information is then relayed to  the PVN. The PVN stimulates the LC and both central and  endocrine stress responses.    stimulation of the adrenal medulla to secrete catecholamines  (norepinephrine and epinephrine) and _stressor-induced  stimulation of the hypothalamus to secrete CRH, which in  turn stimulates the pituitary to secrete ACTH, which then  stimulates the adrenal cortex to secrete steroid hormones,  particularly cortisol.    . In general, the catecholamines prepare the body to act, and    cortisol mobilizes energy stores (e.g., glucose) and other  substances needed to fuel the action.    system. Epinephrine increases cardiac output and increases  blood flow to the heart, brain, and skeletal muscles by dilat-  ing vessels that supply these organs. It also dilates the airways,  thereby increasing delivery of oxygen to the bloodstream.    nephrine. Norepinephrine constricts blood vessels of the  viscera and skin; this has the effect of shifting blood flow  to the vessels dilated by epinephrine. Norepinephrine also  increases mental alertness.    vation of glucocorticoids (cortisol) and catecholamines.  Peripheral CRH is proinflammatory, causing vasodilation  and vascular permeability. It appears that the mast cells are  the target of peripheral CRH.    Cortisol’s chief effects involve metabolic processes. By  inhibiting the use of metabolic substances while promoting  their formation, cortisol mobilizes glucose, amino acids,  lipids, and fatty acids and delivers them to the bloodstream.  Cortisol’s effect on the immune system is concentration  and location dependent and may include either stimulation  or inhibition of the immune system.   The nervous, endocrine, and immune systems communi-  cate through the common use of signal molecules and their  receptors, which in turn regulate the behavior of cells in  each system during stress challenge.   There are direct and indirect pathways of influence  among the nervous, endocrine, and immune systems.  Neuropeptides have direct effects on immune cells, as  well as indirect influences through neuromediated endo-  crine modulation of immune function. Endocrine prod-  ucts (cortisol) also influence nerve cell behavior. Immune  cell products affect both nerve and endocrine cell func-  tion, reflecting an adaptive role for the immune system  as a “signal” organ to alert other systems of threatening  stimuli.   Other hormones are affected by the stress response and  include increased circulating levels of (-endorphins,  growth hormone, and prolactin and a decrease in antidi-  uretic hormone level with extreme stress. Concentrations of  luteinizing hormone, estradiol, progesterone, and possibly  testosterone decrease during the stress response.    Stress is a system of interdependent processes that are mod-  erated by the nature, intensity, and duration of the stressor  and the coping efficacy of the affected individual, all of  which in turn mediate the psychologic and physiologic  response to stress.    immune function, and evidence strengthens the association  of stress with potential for illness in humans.   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Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:  Case Study    Cancer Characteristics and Terminology, 363  Tumor Classification and Nomenclature, 364  The Biology of Cancer Cells, 368   The Genetic Basis of Cancer, 372  Cancer-Causing Mutations in Genes, 372  Oncogenes and Tumor-Suppressor Genes: Accelerators   and Brakes, 373  Gene Changes That Occur in Cancer, 375  Guardians of the Genome, 379  Types of Genes Misregulated in Cancer, 380  Inflammation, Immunity, and Cancer, 382    Cancer is a leading disease, cause of death, and source of mor-  bidity of adults in the Western world. The incidence of can-  cer increases markedly with advancing age and is strongly  affected by gender, lifestyle, ethnicity, infection, and genetics.  Over the past 35 years intensive research has led to a signifi-  cantly enhanced understanding of this complex and frighten-  ing disease. We now understand that cancer is a collection of  more than 100 different diseases, caused by an accumulation of  genetic and epigenetic alterations. Environment, heredity, and  behavior interact to modify the risk of developing cancer and  the response to treatment. Improvements in treatment strate-  gies and supportive care, coupled with new, often individualized    Cancer Invasion and Metastasis, 387  Only Rare Cells in a Cancer Are Able to Metastasize, 388  Detachment and Invasion, 388  Survival and Spread in the Circulation, 389  Selective Adherence in Favorable Sites, 389  Escape from the Circulation and Development  of a New Microenvironment, 390  Clinical Manifestations and Treatment of Cancer, 392  Clinical Manifestations of Cancer, 392  Cancer Treatment, 395    therapies based on advances in our fundamental understanding  of the basic pathophysiology of malignancy, have contributed  to an increasing number of effective options for these diverse,  often lethal, disorders collectively called cancer.    Any discussion of cancer must start with a definition of what  it is and what it is not. Although most readers may have an  intuitive understanding of this disorder, composing an exact  definition that encompasses this broad category is more chal-  lenging. In general, a tumor is an abnormal growth resulting  from uncontrolled proliferation and serves no physiologic  function.   Are poorly differentiated; may not be  the tissue from which they arose able to determine tissue of origin    The term cancer derives from the Greek word for crab, karki-  noma, which the physician Hippocrates used to describe the  appendage-like projections extending from tumors. The word  tumor originally referred to any swelling that was caused by  inflammation, but is now generally reserved for describing a  new growth, or neoplasm. Not all tumors or neoplasms, how-  ever, are cancer. The term cancer refers to a malignant tumor  and is not used to refer to benign growths, such as lipomas or  hypertrophy of an organ. Yet it is important to recognize that  benign neoplasms also can be life threatening if they enlarge  in critical locations. For example, a benign meningioma at the  base of the skull may cause symptoms by compressing adjacent  normal brain tissue. The definitions of benign vs. malignant are  presented in the following text and in Table 12-1.    Proper identification of a cancer is important for many reasons.  Different lesions will have different causes, different rates and  patterns of progression, and different responses to treatment.  Cancer classification starts with knowing the site of origin  and microscopic appearance of the lesion, but can extend to a  detailed description of critical genetic changes in the cancer.   Benign tumors, which are not referred to as cancers, are  usually encapsulated and well differentiated. They retain some  normal tissue structure and do not invade the capsules sur-  rounding them or spread to regional lymph nodes or distant  locations. Benign tumors are generally named according to the  tissues from which they arise, and include the suffix “-oma.” For  example, a benign tumor of the smooth muscle of the uterus is a  leiomyoma, and a benign tumor of fat cells is a lipoma.   Some tumors initially described as benign can progress to  cancer and then are referred to as malignant tumors. These  tumors are distinguished from benign tumors by their more  rapid growth rates and specific microscopic alterations, includ-  ing loss of differentiation and absence of normal tissue orga-  nization. One of the hallmarks of cancer cells, as seen under  the microscope, is anaplasia, the loss of cellular differentiation,  irregularities of the size and shape of the nucleus, and the loss  of normal tissue structure. Malignant tumors may present with  different degrees of encapsulation; some lack a capsule, and  even if a capsule is apparent, its integrity has been compromised  so that tumor cells can grow to invade nearby blood vessels,    lymphatics, and surrounding structures. The most important  and most deadly characteristic of malignant tumors is their  ability to spread far beyond the tissue of origin, a process known  as metastasis (Figures 12-1 and 12-2; see Table 12-1).   In general, cancers are named according to the cell type  from which they originate. Cancers arising in epithelial tissue  are called carcinomas, and if they arise from or form ductal  or glandular structures are named adenocarcinomas. Hence,  a malignant tumor arising from breast glandular tissue is a  mammary adenocarcinoma. Cancers arising from connective  tissue usually have the suffix sarcoma. For example, malignant  cancers of skeletal muscle are known as rhabdomyosarcomas.  Cancers of lymphatic tissue are called lymphomas, whereas  cancers of blood-forming cells are called leukemias. However,  many cancers, such as Hodgkin disease and Ewing sarcoma,  are named for historical reasons that do not follow this naming  convention. Table 12-2 presents the nomenclature and classifi-  cation of selected tumors.    Carcinoma in situ (often abbreviated CIS) refers to preinvasive  epithelial malignant tumors of glandular or squamous cell ori-  gin. Cancers develop incrementally, as they accumulate specific  genetic lesions. Careful surveillance for cancer often detects  abnormal growths in epithelial tissues that have atypical cells  and an increased proliferation rate compared with normal sur-  rounding tissues. These early stage cancers are localized to the  epithelium and have not penetrated the local basement mem-  brane or invaded the surrounding stroma (see Figure 12-1).  Based on these characteristics, they are not malignant but are  often called carcinoma in situ (CIS). CIS is recognized in a  number of sites, including the cervix, skin, oral cavity, esopha-  gus, and bronchus. In glandular epithelium, in situ lesions occur  in the stomach, endometrium, breast, and large bowel. In the  breast, ductal carcinoma in situ (DCIS) fills the mammary ducts  but has not progressed to local tissue invasion. DCIS lesions are  readily treatable, although the optimal therapeutic approach is  controversial. CIS lesions can have one of the following three  fates: they can remain stable for a long time, they can prog-  ress to invasive and metastatic cancers, or they can regress and  disappear. CIS can vary from low-grade to high-grade dyspla-  sia, with the high-grade lesions having the highest likelihood  of becoming invasive cancers. The time that such preinvasive  lesions remain in situ before becoming invasive is unknown.!  Some carcinomas of the cervix appear as preinvasive lesions  in situ for several years before they progress to invasive carci-  noma and metastatic tumors (see Figure 12-1). Knowing how  to best treat low-grade CIS lesions is challenging because the  proportion that progress to cancer vs. the proportion that will  never cause clinical problems is usually not known. Although  most persons prefer removal of any CIS as opposed to “watch-  ful waiting,” this topic continues to be a source of great debate.   Because our knowledge about the molecular alterations in  cancer can influence the choices of therapy, it becomes increas-  ingly important for clinicians to accurately molecularly clas-  sify each cancer. The classification, and hence the treatment    FIGURE 12-1 Progression from Normal to Neoplasm in the Uterine Cervix. A sequence of cellular and tissue changes  progressing from low-grade to high-grade intraepithelial neoplasms (also called carcinoma in situ) and then to invasive cancer  is seen often in the development of cancer. In this example of the early stages of cervical neoplastic changes, the presence of  anaplastic cells and the loss of normal tissue architecture signify the development of cancer. The high rate of cell division and  the presence of local mutagens and inflammatory mediators all contribute to the accumulation of genetic abnormalities that  lead to cancer. (From Alberts B et al: Molecular biology of the cell, ed 5, New York, 2002, Garland.)    decisions, of cancers was originally based on gross and light  microscopic appearance and is now commonly accompa-  nied by immunohistochemical analysis of protein expression.  Increasingly, this is supplemented by a more extensive molecu-  lar analysis of the tumors. Sometimes a single gene is examined  (for example, to determine if there is a characteristic chromo-  somal translocation diagnostic of chronic myelogenous leu-  kemia [CML]), and sometimes a panel of genes and proteins  are examined (e.g., in breast cancer) to determine if the tumor  expresses estrogen receptor, progesterone receptor, and the  epidermal growth factor (EGF) receptor HER2, or if there are  mutations in specific genes that include response to therapy. In  a research setting, and increasingly in clinical settings, expres-  sion and mutation analysis of a large number of genes can be  measured using polymerase chain reaction (PCR), microarray,  or advanced DNA sequencing technology. These analyses can  be used to classify tumors more precisely and may predict the  most effective therapy. This detailed analysis of each tumor is a  form of personalized medicine that offers therapy based on a  very detailed knowledge of each individual’s characteristics and  their specific cancer.2 This enhanced molecular characteriza-  tion subdivides cancers into therapeutically and prognostically  relevant smaller groups. As an example, breast cancers can now  be subclassified into more than four types (luminal A, luminal    B, basal-like, and others) based on their expression of specific  markers, such as estrogen receptor, HER2/Neu, and other spe-  cific genes and proteins. Each subtype has a different response  to therapy and a different prognosis (Figure 12-3).    During surveillance or diagnosis of cancer as well as following  therapy, specific biochemical markers of tumors have proven  to be helpful. These tumor markers are substances produced  by both benign and malignant cells that either are present in  or on tumor cells or are found in blood, spinal fluid, or urine  (Table 12-3). Some tumor markers have been known for many  decades. For diseases associated with a tumor marker, there  is indeed a “blood test for cancer.” Tumor markers include  hormones, enzymes, genes, antigens, and antibodies. Liver and  germ cell tumors secrete a protein known as alpha fetoprotein  (AFP) into the blood, and prostate tumors secrete prostate spe-  cific antigen (PSA) into the blood. If the tumor marker itself has  biologic activity, then it can cause symptoms, a phenomenon  known as a paraneoplastic syndrome. For example, the adre-  nal medulla normally secretes the catecholamine epinephrine  (adrenaline). Benign tumors of the adrenal medulla (pheo-  chromocytoma) can produce catecholamines (e.g., adrena-  line) in vast excess, leading to rapid pulse rate, high blood   So ESE RL SSS %  FIGURE 12-2 Loss of Cellular and Tissue Differentiation During the Development of Cancer. The cells of a benign  neoplasm (B) resemble those of the normal colonic epithelium (A), in that they are columnar and have an orderly arrangement.  Loss of some degree of differentiation is evident in that the neoplastic cells do not show much mucin vacuolization. Cells of  the well-differentiated malignant neoplasm (C) of the colon have a haphazard arrangement and although gland lumina are  formed, they are architecturally abnormal and irregular. Nuclei vary in shape and size, especially when compared with those  in A. Cells in the poorly differentiated malignant neoplasm (D) have an even more haphazard arrangement, with very poor  formation of gland lumina. Nuclei show greater variation in shape and size compared with the well-differentiated malignant  neoplasm in C. Cells in anaplastic malignant neoplasms (E) bear no relation to the normal epithelium, with no recognizable  gland formation. Tremendous variation is found in the size of cells and their nuclei, with very intense staining (hyperchromatic  nuclei). Not knowing the site of origin would make it impossible to classify this tumor by microscopic appearance alone. Well-  differentiated tumors often resemble their cell of origin, as shown in the example of a benign tumor of smooth muscles (F).  (From Stevens A, Lowe J: Pathology, ed 2, London, 2000, Mosby.)    pressure, diaphoresis (i.e., sweating), and tremors. Detection  of elevated blood or urine levels of catecholamines helps to  confirm the diagnosis, and treatment of the disease relieves the  symptoms. Tumor markers can be used in three ways: (1) to  screen and identify individuals at high risk for cancer; (2) to  help diagnose the specific type of tumor in individuals with    clinical manifestations relating to their tumor, as in adrenal  tumors or enlarged liver or prostate; and (3) to follow the clini-  cal course of a tumor. For example, a falling PSA level after  radiation or surgical therapy for prostate cancer indicates suc-  cessful treatment, and a later rise in the PSA level may indicate  a recurrence.    Tumors of Epithelial Origin  Squamous cells Squamous cell papilloma  Basal cells =  Glandular or ductal epithelium Adenoma  Cystadenoma   Transitional cells Transitional cell papilloma  Bile duct Bile duct adenoma  Liver cells Hepatocellular adenoma  Melanocytes Nevus  Renal epithelium Renal tubular adenoma  Skin adnexal glands    Plasma cells  Lymphoid  Nongranular leukocytes and prelymphocytes  Proliferating lymphocytes and monocytes  Proliferating immature precursor monocytes  Solid tumors of lymph tissue (thymus, spleen,  lymph nodes)  Neural and retinal tissue  Nerve sheath Neurilemoma, neurofibroma  Nerve cells Ganglioneuroma  Retinal cells (cones) —_—  Connective tissue  Fibrous tissue Fibromatosis (desmoid)  Fat Lipoma  Bone Osteoma  Cartilage Chondroma  Muscle  Smooth muscle Leiomyoma  Striated muscle Rhabdomyoma  Endothelial and related tissues  Blood vessels Hemangioma    Modified from Murphy GP et al: American Cancer Society's textbook of clinical oncology, ed 2, New York, 1995, American Cancer Society.    *Note: This list is intended to provide only an introduction to tumor nomenclature.   B Time (years)  FIGURE 12-3 Molecular Markers Aid in Cancer Classification and Treat-  ment Choices. A, Cancers can be classified based on gene expression patterns.  In this breast cancer study, gene expression was measured in tumors from 115  patients. Each row is a different gene, and each column is a different patient sam-  ple. Red denotes high gene expression; green signifies low gene expression. Using  this molecular subtyping method, breast cancer can be subdivided into at least four  molecular subtypes—luminal A, luminal B, HER2, and basal. The group on the far  right is normal breast tissue. B, Molecular classification predicts overall survival. In  this group of women, breast cancer molecular subtypes were determined by gene  expression profiles in a group of women with similar stage tumors, as in (A). The  olecular subtype is a good predictor of response to chemotherapy and survival.  This molecular subtyping method can help select the best therapy for women. (A  from Sorlie T et al: Proc Nat! Acad Sci U S A 100[14]:8418-8423, 2003; B from  Parker JS et al: J Clin Oncol 27[8]:1 160-1167, 2009.)    There are several significant problems in using tumor  marker assays to screen populations of healthy individuals for  cancer. Testing large populations will always detect a few nor-  mal individuals with test results at the high end of the normal  distribution (the “false positives”), which can lead to expen-  sive and invasive additional tests, and unnecessary concern.  Similarly, some individuals with disease will have test results in  the normal range (“false negatives”). Furthermore, some non-  malignant conditions also can produce tumor markers. The  presence of an elevated tumor marker therefore may suggest a  specific diagnosis, but it is not used alone as a definitive diag-  nostic test. Identification of ideal sensitive and specific tumor  markers that are elevated early in the course of common cancers  remains a high priority because the early detection of cancer  often improves the treatment outcome.   Cancer cells behave differently than normal cells in several  important ways. Transformation refers to the process by  which a normal cell becomes a cancer cell. Autonomy refers to  the cancer cell’s independence from normal cellular controls  and is part of the transformational process. These differences  are most readily seen in specialized laboratory assays, especially  those examining the growth patterns of normal and cancerous  cells in laboratory incubators. Transformed cells lack many  of the normal “social controls” seen in nontransformed cells.  They often have markedly decreased requirements for external  growth factors. Normal cells cease to divide when they fill a  petri (or tissue culture) dish. Transformed cells, unlike normal  cells, lack contact inhibition and continue to crowd, eventually  piling up on each other (Figure 12-4). Normal cells usually will  not grow unless they are attached to a firm surface (like a petri  dish). However, cancer cells are often anchorage independent;  that is, they continue to divide even when suspended in a soft  agar gel. Normal cells have a limited life span in the labora-  tory; they may divide in a petri dish 10 or 50 times, but then  they cease growing. Cancer cells usually are immortal in that  they seem to have an unlimited life span and will continue to  divide for years under appropriate laboratory conditions. One  of the most commonly used laboratory cell lines, HeLa cells,  was derived from a cervical cancer specimen obtained in 1951  that continues to grow and divide in laboratories around the  world.’ Cancerous cells can be assayed in mice as well; when  normal human cells are injected into a special type of mouse  (genetically engineered to lack an immune system to prevent  rejection of human cells) they will not grow. However, cancer-  ous cells from humans can continue to grow and even metas-  tasize in these mice.   Cancer cells often show defects in the normal process of  differentiation; that is, the process of acquiring a specialized  function and organization, such as evolving into a muscle cell  (see Chapter 43) or a nerve cell (see Chapter 15). Anaplasia  is the absence of differentiation (see Figure 12-2) and means  literally “without form.” In clinical specimens, anaplasia is  recognized by a loss of organization and a marked increase  in nuclear size with evidence of ongoing proliferation. In    Non-cancerous cells are  anchorage dependent and  only proliferate when  attached to a surface.    Normal cells suspended  in soft agar cannot attach  and therefore cannot  proliferate.    200-kDa glycoprotein  Glycopeptide hormone B-chain  33-kDa glycoprotein  Epinephrine and precursors  Catecholamine metabolites    When these cells form a  complete monolayer, they  stop dividing due to  contact inhibition.    Cancer cells do not exhibit  contact inhibition, and  continue to divide, piling  up on each other.    FIGURE 12-4 Cancerous Cells Show Abnormal Growth in the Laboratory. Cancer cells, unlike most normal cells (A),  usually continue to grow and pile on top of one another after they have formed a confluent monolayer in culture (loss of contact    inhibition) and (B) can grow without being attached to a surface,    contrast to normal cells, which are uniform in size and shape,  anaplastic cells are of variable size and shape, or pleomor-  phic. For example, a benign muscle tumor (benign myoma)  will retain the ability to make muscle, whereas in a malignant  muscle tumor (rhabdomyosarcoma), new muscle formation is  seen only rarely, and even then appears highly disorganized.  Thus the muscle cancer cells appear undifferentiated. The  most malignant tumors tend to have the most anaplasia and  be the least differentiated.    Cancer cells live in a distinct milieu from normal cells and  have different nutritional requirements from nonproliferating  cells. The successful cancer cell divides rapidly, with the conse-  quent requirement for the building blocks of new cells. Cancers  often must grow in a hypoxic and acidic environment. Cancers  also are parasites, able to selectively extract nutrients from the  bloodstream without any evolutionary pressure for balanced  metabolism. Nonmalignant cells in the presence of adequate  oxygen normally generate adenosine triphosphate (ATP) by  mitochondrial oxidative phosphorylation (OXPHOS), generat-  ing 36 ATP molecules from each glucose molecule that is bro-  ken down to water and carbon dioxide. Only in the absence of  sufficient oxygen do normal cells perform anaerobic glycolysis,    generating only two ATP molecules per molecule of glucose,  with lactic acid as a byproduct. However, even in the presence of  oxygen, cancer cells perform glycolysis, not OXPHOS* (Figure  12-5). Although this aerobic glycolysis was originally postulated  as some form of cancer-specific mitochondrial dysfunction, it is  now apparent that this is instead a highly regulated and benefi-  cial adaptation for cancer cells. This shift from OXPHOS to gly-  colysis allows lactate and its metabolites to be used for the more  efficient production of lipids and other molecular building  blocks needed for rapid cell growth. Furthermore, many cancer  genes promote this switch to aerobic glycolysis. Alterations in  a number of cancer genes, including receptor tyrosine kinases,  AKT, PTEN, TP53, and MYC, inhibit OXPHOS and promote  the activity of glycolytic and related metabolic pathways that  support the rapid growth of cancers.*°   Clinically the high glucose utilization of a cancer can be  exploited for its detection. !8F-Fluorodeoxyglucose (FDG) is  incorporated into cells in the same way as glucose, with two key  differences. Because it is missing a key hydroxyl group it cannot  be broken down by glycolysis and, thus, FDG accumulates in  cells. Because it is tagged with !8F, it can be imaged by positron  emission tomography (a PET scan). Small metastatic tumor  masses that are consuming huge amounts of glucose can readily  be detected with this imaging method (Figure 12-6).    FIGURE 12-5 Cancers Have Altered Metabolism. Normal tissues use oxidative phosphorylation (OXPHOS) to turn glu-  cose into CO, and energy (in the form of ATP). Cancers take a different approach; even in the presence of oxygen, they do not  use OXPHOS. Instead, they consume large quantities of glucose to make cellular building blocks, supporting rapid proliferation.  ATP Adenosine triphosphate. (From Van der Heiden MG, Cantley LC, Thompson CB: Science 324:1029-1033, 2009.)    FIGURE 12-6 Intense Glucose Requirement Aids in Diagnosis of Meta-  static Non-Small Cell Lung Cancer. This 54-year-old woman had a non-small  cell lung cancer (NSCLC) resected from the left upper lobe. Five years later,  these studies were obtained. The positron emission tomography (PET) scan using  18-fluorodeoxyglucose (FDG) shows metastatic lesions in the brain, right shoul-  der, and mediastinal and cervical lymph nodes, as well as in the liver, left pelvis,  and proximal femur. PET whole-body image (left): Representative coronal image  from the whole-body FDG-PET/CT—fused image of the same patient (right). The  fused image consists of the computed tomography (CT) image with the metabolic  information superimposed in color. The pattern of spread is most likely from the  primary tumor to the large mediastinal lymph nodes, followed by lymphatic spread  to cervical nodes. Blood-borne dissemination produced the bone, brain, and liver  metastases. Normally, only the heart, brain, and bladder show a strong signal in  PET scans. (Images courtesy John Hoffman, MD, Huntsman Cancer Institute, Salt  Lake City, UT.)   Many tissues, most notably the skin, intestines, and blood-  forming cells, continuously renew themselves. The human gut  sheds and replaces hundreds of grams of cells each day. This  ongoing proliferation of these tissues with a high turnover rate  depends on their regeneration from a small fraction of cells  known as adult stem cells. Adult stem cells have two essential  characteristics: first, they self-renew (that is, some fraction of  the cell divisions creates new stem cells); and second, they are  multipotent, or have the ability to differentiate into multiple  different cell types. In the bone marrow, it is estimated that  only 0.05% (1 in 20,000) of the blood-forming cells are stem  cells, yet this small pool of stem cells can be stimulated to divide  and to repopulate all the mature bone marrow-derived cells  in approximately 2 weeks after bone marrow transplantation.  As few as 10 stem cells are sufficient to entirely repopulate the  entire bone marrow of a mouse in bone marrow transplantation  experiments. Similarly, the absorptive and goblet cells lining the  intestine have a life span of less than 1 week, after which they  undergo cell death, or apoptosis, and slough into the intestinal  lumen. They too must be replenished by ongoing proliferation  of intestinal stem cells. A key feature of stem cells is that they  can divide asymmetrically (i.e., during division, the cytoplasmic  contents are unevenly distributed between the daughter cells);  they can give rise to another stem cell and one daughter cell  that ultimately terminally differentiates into diverse cell types,  depending on the needs of the tissue (Figure 12-7). Multipotent  bone marrow stem cells can self-renew and differentiate into all  types of bone marrow-derived cells, such as red cells, lympho-  cytes, and neutrophils. Certain adult stem cells have a broader  range of potential fates. For example, mesenchymal stem cells    FIGURE 12-7 Postulated Multiple Lineage—Specific Differentiation of Mesenchymal Stem Cells. Differentiation  occurs progressively as the offspring of stem cells commit to various lineages. Mesenchymal stem cells can renew themselves  and give rise to multiple tissue types. (Modified from Caplan A, Bruder S: 7rends Mol Med 7[6]:259—264, 2001.)    are able to differentiate into multiple types of cells, such as  blood vessels, neurons, and muscle cells. Theoretically, such a  stem cell might be able to give rise to all cell types in the body,  and as such, could be useful in regeneration of diseased tissues.   Many cancers, like normal tissues, are heterogeneous, with  differences in cell shape, size, behavior, and protein expres-  sion. There are two models to explain this heterogeneity within  tumors. In the clonal evolution model, all the cancer cells divide  regularly, and heterogeneity arises from proliferation, muta-  tion, epigenetic changes, differences in local environment, and  natural differentiation of cells. In this model, most of these  cells are still robust cancer cells, capable of forming complex  tumors in experimental animals. In contrast, in the cancer stem  cell model, heterogeneity arises because there is a rare cancer  stem cell whose offspring do not have stem cell properties, but  undergo a limited number of divisions while generating het-  erogeneity through epigenetic and environmental alterations.  However, similar to the adult tissue stem cells, only the cancer  stem cell, if transplanted, is postulated to be capable of form-  ing complex and heterogeneous tumors. The typical cancer  stem cell experiment separates cancer cells into different pools    depending on some measurable characteristic such as cell sur-  face proteins, and then assays how many cells must be injected  into an experimental mouse to form a cancer. In some cases,  these tumor-initiating cells are very rare, with only 1 in 10,000  human colon cancer cells able to re-form a complex and het-  erogeneous colon cancer in mice (Figure 12-8).° However,  these tumor-initiating cells are not always rare; in human mela-  nomas, one in four cells can initiate a complex tumor in the  appropriate mouse model.’ This is an experimentally difficult  area of research, because human cancers are examined in mice  where there are multiple barriers to transplantation, including  immune responses, as well as species differences in the various  growth factors, cytokines, and microenvironment that can all  influence the results. Therefore most progress is likely to be  made by studying cancer stem cells arising in mouse tumors  rather than human tumors.   Enthusiasm for the cancer stem cell model arises, in part,  from its therapeutic potential. Most of the drugs now used in  treating cancer can kill a large fraction of cancer cells but may  not touch the cancer stem cell. If less than 1 in 100,000 cells ina  cancer is responsible for perpetuating a cancer, then perhaps we    FIGURE 12-8 Concept of Cancer Stem Cells. A, Only rare cells within a cancer can initiate cancer regrowth. In labora-  tory experiments it takes as many as 100,000 breast cancer cells injected into a mouse mammary fat pad to form a new cancer.  If the breast cancer cells are sorted, one rare subtype (shown here in red) is much more proficient at forming new cancers. B,  Conventional chemotherapy can destroy the bulk of a cancer. However, if the cancer stem cells (red cells) are not destroyed,  the cancer may regrow. If therapies can be devised that kill the cancer stem cells, then durable long-term responses may be    should be looking for drugs that target those rare cells instead of  using more toxic drugs that initially shrink tumors but do not  lall the cancer stem cells.    Before the advent of modern molecular biology, many differ-  ent causes of cancer were postulated, based on epidemiologic  studies as well as investigations of specific carcinogens and  viruses. We now understand that changes in the genes of the  cancer cell cause the cell to become cancerous. As our knowl-  edge of cancer biology continues to increase so too does our  understanding of the many ways that heritable changes in  cells can contribute to cancer. These changes include deoxyri-  bonucleic acid (DNA) mutations, but also include changes in  DNA and histone chemical modification (epigenetic changes),  and, most recently recognized, changes in non—coding micro-  ribonucleic acid (miRNA) expression (also see Chapters 4, 6,  and 13). Although the word mutation is used extensively here,  it can also refer to heritable changes in gene and non-coding  RNA expression (epigenetics) that do not involve changes in  DNA sequence.   Cancer is predominantly a disease of aging. Perhaps the most  revealing epidemiologic data are presented in Figure 12-9. The  incidence of most cancer, that is, the fraction of individuals in  each age group who develop cancer, increases dramatically with  age. The best explanation for these epidemiologic data is that  each individual acquires a number of genetic “hits” or muta-  tions over time. When sufficient mutations have occurred, can-  cer develops. These epidemiologic data are consistent with the   Age  FIGURE 12-9 Marked Increases in Cancer with Age. The graph depicts the  number of cases of colon cancer diagnosed per 100,000 women in England and  Wales in 1 year. The incidence of cancer increases dramatically with advancing  age. These data suggest that accumulation of genetic and epigenetic alterations  over time increases the risk of developing cancer. The slope of the curve suggests  that five to seven mutations must occur before full-blown cancer develops. (Modi-  fied from Alberts B et al: Molecular biology of the cell, ed 4, New York, 2002,  Garland.)    FIGURE 12-10 Clonal Proliferation Model of Neoplastic Progression. During clonal proliferation, progressively  altered populations of cells arise over time. As genetic and epigenetic changes occur, different subclones (indicated by dif-  ferent color cells) coexist for a time. Clones that grow the fastest out-compete other clones, producing increasingly more  malignant, and abnormal-appearing, growths. The sequential accumulation of mutations has been well studied in the progres-  sion from a normal colon cell to a benign intestinal polyp to a malignant colon cancer. One of the earliest mutations in colon  cancer is loss of the tumor-suppressor gene APC. Additional mutations, often in the oncogene ras, activation of COX-2, and  loss of the tumor suppressors DCC and 7P53 occur as the lesion progresses from a benign polyp to an invasive carcinoma.  APC, Adenomatous polyposis coli; COX-2, cyclooxygenase-2; DCC, deleted in colon cancer. (Modified from Mendelsohn | et al:  The molecular basis of cancer, ed 2, Philadelphia, 2001, Saunders; Kumar V, Cotran RS, Robbins SL: Basic pathology, ed 6,    observation of mutations in early and advanced cancers and  with data obtained from the study of experimental cancers cre-  ated in the laboratory—the accumulation of four to seven spe-  cific hits over time is required to cause a full-blown cancer.®    As a cell accumulates specific mutations, it can acquire, step-  by-step, the characteristics of a cancer cell, for example,  anchorage-independent growth, lack of contact inhibition, and  immortality. That mutant cell may then have a selective advan-  tage over its neighbors; its progeny can accumulate faster than  its nonmutant neighbors. This is referred to as clonal prolif-  eration or clonal expansion (Figure 12-10). As a clone with a  mutation proliferates, it may become an early stage tumor, for  example, a carcinoma in situ or a benign colonic polyp. Addi-  tional heritable changes can occur in these early lesions that  permit progression to more advanced tumors. The process of  tumor development is a form of darwinian evolution; cells with  a genetic change that confers a survival advantage out-compete  their neighbors. The progressive accumulation of distinct  advantageous (from the point of view of the cancer cell, not the  individual!) mutations leads from normal cells to fully malig-  nant cancers.   One organ in which this correlation of genetic and clini-  cal progression has been especially well studied is the colon.’  The colon is accessible to inspection with a colonoscope, and  so neoplastic lesions of varying size can readily be detected and  removed. Intestinal polyps are benign neoplasms and the first  stage in development of colon cancer. Small polyps tend to have  only a few detectable mutations. Large polyps have more muta-  tions, whereas frank colon cancers have even more mutations.    This type of genetic information provided the framework for  the now widely accepted concept that it is the stepwise accu-  mulation of alterations in specific genes that is required for the  development of cancer (see Figure 12-10).    Passengers and Drivers  The previous discussion refers to the heritable changes in cells  as being key in the development of cancer. New technologies  that provide massive amounts of information about chro-  mosome and gene structure allow us to see multiple altera-  tions in cancer cells. These methods include massively parallel  high-throughput DNA sequencing (the process by which the  sequence of nucleotides along a strand of DNA is determined),  high-density single-nucleotide polymorphism (SNP), and  chromosome copy number analysis (CNA). These approaches  confirm that there are a small number of very common genetic  alterations in cancer and a very large number of alterations that  individually are rare.!° It is clear that some mutations can con-  tribute to cancer progression (e.g., mutations in p53 or RAS).  These mutations are driver mutations; they drive the progres-  sion of cancer. Conversely, not all mutations in cancer contrib-  ute to the malignant phenotype. Some are just random events,  and are referred to as passenger mutations; they are just along  for the ride. The increasing amount of cancer genome analysis  data poses the following question: how do we determine which  mutations are drivers and which are passengers?   What Are the Driver Mutations? To understand how genetic  mutations cause cancer, first it is important to distinguish between    oncogenes and tumor-suppressor genes. Table 12-4 compares  the two types of cancer genes. Oncogenes are mutant genes that  in their normal nonmutant state direct synthesis of proteins that  positively regulate (accelerate) proliferation. Conversely, tumor-  suppressor genes encode proteins that in their normal state   Requires loss of function  of both alleles to  increase cancer risk    negatively regulate (halt, or “put the brakes on”) proliferation.  Hence, they also have been referred to as anti-oncogenes.   In its normal, nonmutant state, an oncogene is referred to as  a proto-oncogene. An example of a proto-oncogene would be a  growth factor (e.g., epidermal growth factor) or a growth factor  receptor (e.g., epidermal growth factor receptor). Other positive  regulators of proliferation are in the signal transduction pathway  that transmits the signal from the growth factor receptor to the  cell nucleus. Normally, Ras is a proto-oncogene (Figure 12-11).   Oncogene Addiction. There are a number of common driver  mutations in cancer. Cancers that arise because of these mutations  often depend on these mutant genes and proteins for their  continued growth and survival. If the mutations and abnormal  proteins can be returned to their normal states, the cancers often  stop growing and even regress. The cancers are addicted to their  mutant cancer genes, a concept known as oncogene addiction.  This also provides a key example of how targeted cancer therapy  can work—for example, if the oncogene is a protein kinase (e.g.,  BCR-ABL, EGFR, HER2, or BRAF) that can be inhibited by a  drug, then the cancer can be deprived of the function of the  oncogene. Treating the addiction treats the cancer.!!    FIGURE 12-11 Many Growth Factors Signal Through the RAS Protein. When a normal cell is stimulated through a  growth factor binding to its receptor, inactive RAS exchanges GDP for GTP, becoming active. Active (GTP-bound) RAS sends  growth signals throughout the cell by interacting with a number of signaling proteins, including RalGDS, RAF, PLCe, and PI3K.  RAS is normally inactivated when it hydrolyzes GTP to GDP. Oncogenic Ras has a mutation that blocks hydrolysis of GTP,  thereby locking RAS in the active configuration. GDP Guanosine diphosphate; GAP guanosine triphosphate-activating protein;  GTP guanosine triphosphate; MAPK, mitogen-activated protein kinase; P/3K, phosphoinositide 3-kinase; PLCe, phospholipase  C-epsilon; RAF serine/threonine-specific protein kinase; Ra/GDS, Ral guanine nucleotide dissociation stimulator; Ras, RAS  protein. (Adapted from Kumar V, Abbas AK, Aster J: Robbins basic pathology, ed 9, Philadelphia, 2013, Saunders.)    The activation and inactivation of various genes is key in the  development of cancer. The following three types of DNA  changes occur in cancer: small DNA changes, large DNA  changes, and epigenetic changes.    Point Mutations. Several types of genetic events can activate  oncogenes (Box 12-1 and Figure 12-12). Perhaps the most  common events are small-scale changes in DNA such as point  mutations, the alteration of one or a few nucleotide base pairs  (see Chapter 4). This type of mutation can have profound effects  on the activity of proteins. A point mutation in the ras gene  converts it from a regulated proto-oncogene to an unregulated  oncogene, an accelerator of cellular proliferation. Activating   5. Gene silencing (DNA methylation, histone modification, microRNAs)  6. Exogenous sequences (tumor viruses)    point mutations in ras are found in many cancers, especially  pancreatic and colorectal cancer.'* Specialized tests, such as  direct DNA sequencing, can detect such point mutations in  clinical samples.   Chromosome Translocations and Copy Number Variation.  Chromosome translocations are large changes in chromosome  structure in which a piece of one chromosome is translocated to  another chromosome. Translocations can activate oncogenes in  one of two distinct mechanisms. First, a translocation can cause  excess and inappropriate production of a proliferation factor.  One of the best examples is the t(8;14) translocation found in  many Burkitt lymphomas;!* t(8;14) designates a chromosome  that has a piece of chromosome 8 fused to a piece of chromosome  14 (see Chapter 29). Burkitt lymphoma is an aggressive cancer of  Blymphocytes. The myc proto-oncogene found on chromosome  8 is normally activated at low levels in proliferating lymphocytes  and is deactivated in mature lymphocytes. The MYC protein  is part of the positive signal for cell proliferation. If accidental  formation of the t(8;14) translocation occurs, the myc gene is  aberrantly placed under the control of a B-cell immunoglobulin  gene (Ig) present on chromosome 14. The Ig gene is very  active in maturing B lymphocytes. The t(8;14) translocation  alters the control of myc; its normal low level is switched to  high levels, as directed by an Ig gene promoter. MYC protein,  when inappropriately high, drives proliferation and blocks    FIGURE 12-12 Oncogene Activation Mechanisms. Cellular genes may become cancerous oncogenes as a result of (A)  point mutations that alter one or a few nucleotide base pairs, causing the production of a protein that is activated as a result  of the altered sequence (e.g., ras); (B) amplification of the cellular gene, resulting in higher levels of protein expression (e.g.,  N-myc in neuroblastoma); or (C) chromosomal translocations that either lead to the juxtaposition of a strong promoter, causing  increased protein expression (c-myc in Burkitt lymphoma), or produce a novel fusion protein that is derived from gene frag-  ments normally present on different chromosomes (Bcr-Ab/ in chronic myeloid leukemia). (From Haber DA: Molecular genetics    FIGURE 12-13 N-myc Gene Amplification in Neuroblastoma. The \V-myc gene is detected in human neuroblastoma  cells using a technique called FISH (fluorescent in situ hybridization). A, A single pair of N-myc genes are detected in normal  cells and in low-grade neuroblastoma. B, Multiple, amplified copies of the N-myc gene are detected in some cases of neuro-  blastoma. Amplification of the -myc gene is strongly associated with a poor prognosis in childhood neuroblastoma. (Courtesy  Arthur R. Brothman, PhD, FACMG, University of Utah School of Medicine, Salt Lake City, UT.)    differentiation. Hence, the t(8;14) translocation causes cancer  of maturing B cells (see Figure 12-12, C).   Second, chromosome translocations also can lead to produc-  tion of novel proteins with growth-promoting properties. In a  different type of leukemia, chronic myeloid leukemia (CML),  a specific chromosome translocation is almost always present.  This translocation, t(9;22), was first identified in association  with CML in Philadelphia in 1960 and so is often referred to  as the Philadelphia chromosome." This translocation fuses two  chromosomes in the middle of two different genes, bcr on chro-  mosome 9 and abl on chromosome 22. The result is production  of a BCR-ABL fusion protein containing the first half of BCR  and the second half of ABL. BCR-ABL is a misregulated protein  tyrosine kinase that promotes growth of myeloid cells. Imatinib,  a drug that specifically targets this tyrosine kinase, represents  the first successful chemotherapy targeted against the product  of a specific oncogenic mutation. Imatinib and related tyrosine  kinase inhibitors (TKIs) are highly effective in the treatment of  CML and, because of their specificity, lack the toxic side effects  noted with nonspecific anticancer drugs.'° However, imatinib  is not effective in cancers that do not have the t(9;22) trans-  location or related mutations. In modern personalized cancer  therapy, knowledge of the specific genetic alteration can dictate  the optimal drugs for the individual.   Just as single nucleotides can be gained or lost, larger regions  of DNA encompassing entire genes can be gained or lost, a phe-  nomenon known as copy number variation (CNV).'° CNV can  be inherited and accounts for a significant fraction of human  genetic diversity. CNV also can occur in the course of cancer  development, where it can amplify oncogenes or delete tumor-  suppressor genes.   Gene Amplification. Another type of genetic abnormality that  can activate oncogenes is gene amplification (see Figures 12-12,  B, and 12-13). Amplifications are the result of duplication of a  small piece of a chromosome over and over again, so that instead  of the normal two copies of a gene, tens or even hundreds of  copies are present (see Chapter 4). Gene amplification results    TABLE 12-5 SOME FAMILIAL CANCER  SYNDROMES CAUSED  BY LOSS OF TUMOR-  SUPPRESSOR GENE  FUNCTION    Li-Fraumeni syndrome  Familial melanoma p16lk4a (CDKN2A)  Neurofibromatosis Neurofibromin (NF1)  Familial adenomatous polyps APC    in increased expression of an oncogene, or in some cases, drug  resistance genes. The N-myc oncogene is amplified in 25% of  childhood neuroblastoma cases and confers a poor prognosis.!”  The epidermal growth factor receptor erbB2 is amplified in  20% of breast cancers.!* Individuals whose cancers have erbB2  amplification respond well to drugs specifically targeted to this  oncogene.”    Tumor-suppressor genes are genes whose major function is to  negatively regulate cell growth and prevent mutations. Tumor  suppressors may normally slow the cell cycle, inhibit prolifera-  tion resulting from growth signals, or stop cell division when  cells are damaged. Examples of several tumor suppressors  are given in Table 12-5. One of the first discovered tumor-  suppressor genes, the retinoblastoma (Rb) gene, normally  strongly inhibits the cell division cycle (see Chapter 1). When  it is inactivated, the cell division cycle can proceed unchecked.  Rb is mutated in childhood retinoblastoma, and in many lung,  breast, and bone cancers as well.   Whereas oncogenes are activated in cancers, tumor suppres-  sors must be inactivated to allow cancer to occur (see Table  12-5 and Figure 12-14). A single genetic event can activate an    FIGURE 12-14 Silencing Tumor-Suppressor Genes by Epigenetic Alterations. Tumor-suppressor genes can be turned off  by a variety of mechanisms. A, In this example, the first hit is a point mutation in a tumor-suppressor gene (white box), followed by  either epigenetic silencing or chromosome loss of the second allele (red box). B, Genes can normally be silenced by a variety of inter-  acting processes including DNA methylation, histone modifications, nucleosome remodeling, and microRNAs (not shown). A number  of cellular enzymes contribute to these modifications, including DNA methyltransferases (DN/MTs), histone deacetylases (HDACs),  histone methyltransferases (H//Ts), and complex nucleosomal remodeling factors (NUAFs). Gene silencing is essential for normal  development and differentiation. C, Histone modification and promoter methylation regulate gene expression. Genes are transcribed  when chromatin is modified by addition of acetyl (Ac) groups to specific lysine groups in histones. Gene expression can be turned  off when specific acetyl groups are removed by HDACs or when the CpG-rich promoter regions of genes are modified by direct DNA  methylation (by DNA methyltransferase). In addition, small endogenous RNA molecules (microRNAs or miRNA) can bind to mRNA and  reduce gene expression. D, Changes in promoter methylation turn cancer genes off and on. Oncogenes can be turned on by promoter  hypomethylation, and tumor-suppressor genes can be turned off by promoter hypermethylation. Each of these changes can produce  selective growth and survival advantage for the cancer cell. (B adapted from Jones PA, Baylin SB: Ce// 128:683-692, 2007; C from  Gluckman PD et al: V Eng/ J Med 359[1]:66, 2008; D from Shames DS, Minna JF, Gazdar AF: Curr Mol Med 7:85—102, 2007.)    oncogene because it can act in a dominant manner in the cell.  However, we have two copies, or alleles, of each gene, one from  each parent. It therefore takes two hits to inactivate the two  alleles of a tumor-suppressor gene. The first allele of a tumor  suppressor is often inactivated by point mutations. For example,  the Rb gene may be inactivated on one chromosome by a point  mutation (e.g., the copy inherited from the father). Because  the other copy of the retinoblastoma gene (in this example, the  one from the mother) is intact, a functional RB protein can still  be made and therefore the cell division cycle can be regulated  appropriately. If the remaining gene is mutated or silenced,  then all RB function is lost and another step toward cancer  occurs (see Chapter 4).   Loss of Heterozygosity. For the function of a tumor  suppressor to be lost, both chromosomal copies (alleles)  of the gene must be inactivated. This is because they act in a  recessive manner at the level of the cell. Although it may seem  intuitive that simple inactivating mutations might disrupt both  alleles, in fact this is not what usually happens.” Instead, the  first allele (in the preceding example, the paternal copy) is  inactivated by simple mutation, but the second allele (in this  example, the maternal copy) is lost because entire regions of the  maternal chromosome are epigenetically silenced or a piece of  the chromosome is simply lost (see Figure 12-14, A). Because  humans have two chromosomes, one from each parent, they are  always heterozygous for nearby multiple genetic markers; loss of  one copy (allele) of a chromosome region in a tumor is referred  to as loss of heterozygosity, or LOH. Loss of heterozygosity,  like silencing, can unmask inactivating mutations in recessive  tumor-suppressor genes. For example, the Rb gene resides on  chromosome 13, in a region referred to as q14 (13q14). Most  individuals with Rb mutations have a subtle mutation in one  allele and have lost the other copy of Rb through loss of the  13q14 chromosome region on the other chromosome.    Epigenetic Silencing. Abnormal gene silencing is emerging  as a major cause of cancer. Gene expression can be regulated  in a heritable manner (i.e., passed from a parent to a child or  from a single cell to its progeny) by an “epigenetic” mechanism  called silencing. Inheritance of silencing occurs during cell  division and does not require mutations or changes in DNA  sequence (also see Chapter 6). More simply, the same DNA  sequence can produce dramatically different phenotypes  depending on chemical modifications that alter the expression  of genes. Epigenetic silencing is caused by reversible chemical  modification (methylation [addition of a methyl group] or  acetylation [addition of an acetyl group]) of histones and  related chromatin components, as well as methylation of  cytosine residues in DNA (known as DNA methylation) (see  Figure 12-14, Figures 6-2, 6-3, and Chapter 16). Whole regions  of chromosomes are normally shut off by silencing, so that the  pattern of gene expression is different than that seen in other  cells with the same genes. In this way, the progeny of liver cells  remain liver cells, and skin cells remain skin cells. Notably,  global changes in epigenetic silencing can turn these cells back  into stem cells.7!    Changes in gene silencing contribute to the development  of cancer.”* Many cancers have increased methylation of DNA  in the promoter region of tumor-suppressor genes (in CpG  islands or C-cytosine and G-guanine, p-phosphodiester bond,  rich sequences that are often located near promoter regions;  see Chapters 4 and 13). They also have associated changes  in the modification of histones in the chromatin, including  methylation of lysines 9 and 27 in histone H3. In addition,  overexpression of chromosome silencing proteins known  as the polycomb complex, and loss of expression of histone  deacetylases (enzymes that remove acetyl groups from his-  tone proteins) SIRT1 is seen in human cancers. These changes  in chromatin-modifying genes alter the promoter regions of  genes leading to their silencing. The boundaries of the nor-  mally silenced regions can also spread in cancer cells, thereby  inactivating previously active genes. In either case, silencing  can shut off critical tumor-suppressor genes in the absence  of mutations in the gene. Early in the development of cancer,  these changes in gene expression can lead to a selective advan-  tage for affected cells, perhaps leading to their immortaliza-  tion and clonal expansion. Silencing of tumor suppressors  may be a faster way to create cancer cells than mutational or  genetic loss of tumor suppressors.*> Conversely, loss of silenc-  ing can contribute to inappropriate expression of oncogenes.  Chemotherapeutic drugs that can regulate gene silencing,  including histone deacetylase (HDAC) inhibitors and 5-aza-  cytidine (which reverses the effects of DNA methyltransfer-  ases [DNMTs]), have proven effective in reactivating silenced  tumor-suppressor genes in the treatment of selected cancers**  (see Figure 12-14).   MicroRNAs, Oncomirs, and Non-coding RNAs. Changes  in gene regulation can affect not just single genes, but also  entire networks of signaling. Gene expression networks can  be regulated by changes in microRNAs (miRNAs, or miRs)  and other non-coding RNAs (ncRNAs). miRNAs are short  (approximately 22 nucleotides) RNAs derived from introns of  protein coding genes or transcribed as independent genes from  regions of the genome previously believed to have no function  (erroneously called junk DNA). The human genome encodes  more than 1000 miRs. miRs regulate diverse signaling pathways;  the miRs that stimulate cancer development and progression are  termed oncomirs. miRs decrease the stability and expression of  other genes by pairing with mRNA in a process that involves  the RNA-induced silencing complex, or RISC. A single miR  can have multiple mRNA targets. Changes in miR abundance  can therefore affect the expression of many genes, making miRs  both powerful regulators and challenging subjects to study.?°  Beyond miRs, longer RNAs without apparent protein coding  capacity also are implicated in cellular regulation with an  emerging appreciation of their role in cancer.”°   miRs can play both positive and negative roles in cancer.  The importance of miRs in cancer was first shown in chronic  lymphocytic leukemia (CLL), where a chromosome region  encoding miR15 and miR16 was found to be deleted in a large  number of individuals. Decreased expression of these two  miRs is seen in many cases of CLL, as well as in prostate and  several other cancers, and results in increased expression of a    number of oncogenes. Conversely, increased expression of a  cluster of miRs (17-18-19-20-92) is seen in some lymphomas  and solid tumors, causing the decreased expression of a num-  ber of tumor-suppressor genes. miR expression can be easily  assessed with microarray technology, leading to the realization  that substantial changes in miR expression are seen in many  cancers.    The previous discussion of mutations leads naturally to the  question of how mutations occur in the first place. The integ-  rity of genetic information can be compromised at several  points: during each round of DNA synthesis, during each mito-  sis when chromosomes are segregated to daughter cells, and  when external mutagens (e.g., chemicals and radiation) alter  or disrupt DNA. Multiple mechanisms have evolved to protect  and repair the genome.”’ These repair mechanisms are directed  by caretaker genes, genes that are responsible for the mainte-  nance of genomic integrity. Caretaker genes encode proteins  that are involved in repairing damaged DNA, such as occurs  with errors in DNA replication, mutations caused by ultraviolet  or ionizing radiation, and mutations caused by chemicals and  drugs. Loss of function of caretaker genes leads to increased  mutation rates. If DNA damage is severe, the cell undergoes  programmed cell death, or apoptosis, rather than simply divid-  ing with damaged DNA.   Inherited mutations can disrupt the caretaker genes that  protect the integrity of the genome. Examples include the dis-  order xeroderma pigmentosum (XP); affected individuals have  defects in the repair of ultraviolet light-induced DNA damage  and should avoid direct sunlight exposure. They have a very  high incidence of skin cancer. Hereditary nonpolyposis colorec-  tal cancer (HNPCC) results from an inherited defect in repair-  ing DNA base pair mismatches that occur occasionally during  DNA replication. Affected individuals have an increased rate of  small insertions and deletions in DNA, leading to a high rate  of colon and other cancers.’® Finally, there are inherited muta-  tions that threaten the integrity of entire chromosomes. Bloom  syndrome, caused by mutations in a DNA helicase, and Fanconi    aplastic anemia, caused by loss of function of a multiprotein  complex required for repair of DNA double-stranded breaks,  are autosomal recessive disorders in which affected individuals  demonstrate marked chromosomal instability. Chromosome  breaks, aberrant fusions, and chromosome loss are common.  As a consequence, these individuals have a high risk of develop-  ing cancer at an early age.   The rate of individual gene mutation is probably too low to  account for the acquisition of many new mutations during the  evolution of a malignant cancer clone. In addition to abnormal  epigenetic silencing, chromosome instability (often referred to  as CIN) also appears to be increased in malignant cells.” The  underlying mechanism of this instability is not clear but may be  caused by malfunctions in the cellular machinery that regulates  chromosome segregation at mitosis.°” Chromosome instabil-  ity results in a high rate of chromosome loss, as well as loss of  heterozygosity and chromosome amplification. Each of these  events can accelerate the loss of tumor-suppressor genes and  the overexpression of oncogenes.    Genetic events are the primary basis of carcinogenesis. Most of  the genetic and epigenetic alterations that cause cancer occur  within the somatic tissues during the lifetime of the individual.  As previously discussed, the frequency of genetic changes can  be increased by exposure to mutagens, that is, agents causing  mutations, and by defects in DNA repair. Because these genetic  events occur in somatic cells as opposed to germ cells, they are  not transmitted to future generations. Even though they are  genetic events they are not inherited! It is possible, however, for  cancer-predisposing mutations to occur in germline cells (cells  that produce gametes). Mutations present in germline cells  result in the transmission of cancer-causing genes from one  generation to the next, producing families with a high incidence  of specific cancers. These inherited mutations that predispose  to cancer are almost invariably found in tumor-suppressor  genes (see Table 12-5).   Although rare, such “cancer families” demonstrate that  inheritance of a mutated gene can cause cancer (Figure 12-15).    FIGURE 12-15 Familial Colon Cancer Pedigree. Darkened symbols represent individuals diagnosed with colon cancer.  One of the individuals in the first generation must have carried a mutation in the APC gene. (From Jorde LB et al: Medical    FIGURE 12-16 Hallmarks of Cancer. Cancers acquire alterations in specific pathways during their evolution. The six key  pathways that must be altered are shown at the top of the circle, and supporting pathways are shown at the bottom of the  circle. Mutation in key genes often alters several pathways; for example, 053 mutations alter both angiogenesis and evasion  of apoptosis. Y= Inhibits. (From Luo J, Solimini NL, Elledge SJ: Ce// 136:823-837, 2009.)    Inheritance of one mutant allele in these families predisposes  a person to a specific form of cancer.*! Individuals who inherit  the germline mutant allele will inevitably suffer loss of the nor-  mal allele by loss of heterozygosity (LOH) or epigenetic silenc-  ing (see Figure 12-14) in some cells and eventually develop  the tumor. Examples of human cancers that can be inherited  are retinoblastoma, a childhood cancer of the eye that can be  caused by germline mutations in one allele of the Rb gene;  Wilms tumor, a childhood cancer of the kidney (W?1); neurofi-  bromatosis (Nf1); inherited breast cancer (BRCA1); and famil-  ial polyposis coli or adenomas of the colon (APC). A specific  tumor-suppressor gene has been found in each of these cancers.  In many cases, these tumor-suppressor genes also are inacti-  vated in sporadic (as opposed to inherited) cancers. For exam-  ple, inherited mutations in the APC gene are rare and account  for only a few percent of all colon cancers. However, 85% of  sporadic colon cancers also have acquired mutations of APC,  which occurred over time in the individual. Characterization  of cancer-causing genes and other genetic factors helps identify  individuals prone to developing cancer (see Figure 12-15) and  contributes to our understanding of sporadic cancers. Individu-  als known to carry mutations in tumor-suppressor genes (for  example, women with a germline BRCA1 mutation) are offered  targeted cancer screening to facilitate early cancer detection and  therapy.°?    Types of Genes Misregulated in Cancer  Alterations in Progrowth and Antigrowth Signals  We now understand that multiple genetic hits are required for the  evolution of full-blown cancer. One key question is, what types of  genes must be altered to cause a cancer? In 2000, a highly influen-  tial paper by Hanahan and Weinberg” proposed six specific path-  ways that must be misregulated for cancer to develop (see Figures  12-10, 12-11, and 12-16). First, cancer cells must have mutations  that enable them to proliferate in the absence of external growth  signals. To achieve this, some cancers acquire the ability to secrete  growth factors that stimulate their own growth, a process known  as autocrine stimulation (also see Chapter 1). Other cancers  have an increase in growth factor receptors; for example, in breast  cancer, the epidermal growth factor (EGF) receptor HER2/neu  is up-regulated, and likely sends growth signals into the cell even  when growth factors are at very low levels. Inhibitors of HER2  and other EGF receptors that block this pathway are effective in  treating selected breast and lung cancers.** Alternatively, the sig-  nal cascade from the cell surface receptor to the nucleus may be  mutated in the “on” position. Up to one third of all cancers have  an activating mutation in the gene for an intracellular signaling  protein called RAS. This mutant RAS stimulates cell growth even  when growth factors are missing (see Figure 12-11).    FIGURE 12-17 Tumor-Induced Angiogenesis. Malignant tumors secrete angiogenic factors and tissue-remodeling  matrix metalloproteinases (MMPs) that actively induce formation of new blood vessels. New blood vessels are formed from  both local endothelial cells and circulating precursor cells recruited from the bone marrow. Circulating platelets can also release  regulatory proteins into the tumor. bFGF and bFGFR, Basic fibroblast growth factor and its receptor, respectively; POGF and  PDGFR, platelet-derived growth factor and its receptor, respectively; VEGF and VEGFR, vascular endothelial growth factor and  its receptor, respectively. (Adapted from Folkman J: Nat Rev Drug Discov 6[4]:273-286, 2007.)    membranes, and with soluble factors all normally signal cells to  stop proliferating. These mechanisms can put a halt to unregu-  lated cell growth. In addition, this normal antigrowth signal must  be inactivated or ignored. Common mutations that subvert the  antigrowth signal include inactivation of the tumor-suppressor  retinoblastoma or, conversely, activation of the protein kinases  that drive the cell cycle, the cyclin-dependent kinases (see Chap-  ter 1). Next, cells have a mechanism that causes them to self-  destruct when growth is excessive and cell cycle checkpoints have  been ignored. This self-destruct mechanism, called apoptosis,  is triggered by diverse stimuli, including normal development  and excessive growth (see Chapter 2). The pathway to apoptosis  is disabled in advanced cancers. The most common mutations  conferring resistance to apoptosis occur in the TP53 gene.    Angiogenesis  If cancers are to grow larger than a millimeter in diameter,  they need their own blood supply to deliver oxygen and    nutrients. However, in adults new blood vessel growth is  normally limited to areas of wound healing and to the uterus  during the proliferative phase of the menstrual cycle. Tiny  cancers lack the ability to grow new blood vessels and may  never grow larger than a grain of sand. More advanced can-  cers can, however, secrete multiple factors that stimulate new  blood vessel growth (called neovascularization or angiogen-  esis). The angiogenic factors, such as vascular endothelial  growth factor (VEGF), platelet-derived growth factor (PDGF),  and basic fibroblast growth factor (bFGF), by recruiting new  vascular endothelial cells and initiating the proliferation of  existing blood vessel cells, allow small cancers to become large  cancers.*° Therapies directed against new vessel growth are in  clinical use; these agents include bevacizumab, a monoclonal  antibody that inhibits VEGF; erlotinib, sorafenib, and suni-  tinib, inhibitors of the VEGF and PDGF receptor tyrosine  kinases; and thalidomide, which decreases vascular prolifera-  tion*® (Figure 12-17).    Telomerase  enzyme  FIGURE 12-18 Control of Immortality: Telomeres and Telomerase. Nor-  mal adult somatic cells cannot divide indefinitely because the ends of their chro-  mosomes are capped by telomeres. In the absence of the telomerase enzyme,  telomeres become progressively shorter with each division until, when they are  critically short, they signal to the cell to stop dividing. In germ cells, adult stem  cells, and cancer cells the telomerase gene is “switched on,” producing an enzyme  that rebuilds the telomeres. Thus, like germ cells, the cancer cell becomes immor-    A hallmark of cancer cells is their immortality. Usually the only  cells in the body that are “immortal” are germ cells (those that  generate sperm and eggs) and stem cells. Other cells in the body  are not immortal and can divide only a limited number of times  (known as the Hayflick limit) before they cease dividing. One  major block to unlimited cell division (i.e., immortality) is the  size of a specialized structure called the telomere. Telomeres are  protective ends, or caps, on each chromosome and are placed  and maintained by a specialized enzyme called telomerase (Fig-  ure 12-18). As you might expect, telomerase is usually active  only in germ cells (in ovaries and testes) and in stem cells. All  other cells of the body lack telomerase. Therefore, when non-  germ cells begin to proliferate abnormally, their telomere caps  become smaller and smaller with each cell division. Short  telomeres normally signal the cell to cease cell division. If the  telomeres become critically small, the chromosomes become  unstable and fragment, and then the cells die. Cancer cells,  when they reach a critical age, activate telomerase somehow in  order to restore and maintain their telomeres and thereby make  it possible to divide over and over again.*’ Because telomerase  is specifically activated in cancer cells, and potentially in cancer  stem cells, it is an attractive therapeutic target.°*   Finally, it appears genetic differences exist between cells that  successfully metastasize and those that do not.*” Specific genes  regulate the ability to metastasize. Decreased cell-to-cell adhe-  sion, the secretion of various proteases that digest surrounding    barriers, and the ability to grow in new locations all contribute  to successful metastasis“ (discussed later in this chapter).    With the advent of research studies on cancer in inbred mice  (genetically identical) in the 1950s, immunologists recognized  that many cancers expressed antigens on the cell surface that  were not normally expressed on the surface of non—cancer cells  from the same tissue. Similar tumor-associated antigens are  also expressed on human cancer cells. Two hypotheses arose  from these observations. First, immunologists predicted that  many developing malignancies were suppressed by an efficient  immune surveillance system by which cells expressing tumor-  associated antigens were identified, and the resultant immune  response destroyed developing malignant cells. Second, when  tumors do develop, their tumor-associated antigens could be  targets of effective immunotherapy. Immunotherapy could be  either active by immunization with tumor antigens to elicit or  enhance the immune response against a particular cancer, or  passive by injecting the cancer patient with antibodies or lym-  phocytes directed against the tumor-associated antigens.    The immune system is indeed important in protecting us  against cancers caused by specific viral infections. A broad spec-  trum of viruses has been associated with cancer in animals, and  several viruses have been associated with human cancer.*!  In humans, human papillomavirus (HPV), Epstein-Barr virus  (EBV) (also known as HHV4), Kaposi sarcoma herpesvirus  (KSHV) (also known as HHV8), and hepatitis B and C viruses  (HBV, HCV) are associated with about 15% of all human can-  cers worldwide (Table 12-6). Cancer of the cervix and hepato-  cellular carcinoma account for approximately 80% of the cases  of virus-linked cancer.   Virtually all cervical cancer is caused by infection with  specific types of HPV, which infects basal skin cells and com-  monly causes warts. There are more than 120 HPV types, but  only about 40 can infect human mucosal tissue, and only a  few (HPV16, -18, -31, and -45) are associated with the highest  risk for developing cervical, anogenital, and penile cancer (see  Chapters 10 and 26). Most HPV infection is handled effectively  and rapidly by the immune system and does not cause cancer.  Cancer is more common in people with prolonged infection  with HPV (a decade or more), during which the viral DNA  becomes integrated into the genomic DNA of the infected basal  cell of the cervix and directs the persistent production of viral  oncogenes. Early oncogenic HPV infection is readily detected  by the Papanicolaou (Pap) test, an examination of cervical epi-  thelial scrapings. Early detection of cellular atypia in a Pap test  alerts healthcare providers to the possibility of cervical carci-  noma in situ, which can be effectively treated. The Pap test is  probably the most effective cancer screening test developed to  date. Vaccines protecting against the common oncogenic HPV  types (HPV16 and HPV18 [types that cause 70% of cervi-  cal cancers] and HPV6 and HPV11 [types that cause 90% of  genital warts]) were approved for clinical use beginning in    Modified from Mendelsohn J et al, editors: The molecular basis of cancer, ed 2, Philadelphia, 2001, Saunders.  KSHV/HHV8, Kaposi sarcoma—associated herpesvirus/human herpesvirus-8; HPV, human papillomavirus; HTLV-1, human T-cell lymphotropic    2006; if these vaccines are administered to young women and  men before an initial HPV infection, this is likely to prevent  many cases of cervical cancer.*?   EBV and HHV8 are members of the Herpesviridae family.*  More than 90% of adults have been infected with EBV, usually  as children and without symptoms. EBV infection during ado-  lescence may cause infectious mononucleosis. The virus infects  B lymphocytes and stimulates their proliferation; the infection  usually remains latent throughout the individual’s life. In indi-  viduals who are immunosuppressed because of HIV infection  or because of drugs given for an organ transplant, persistent  EBV infection can lead to the development of B-cell lympho-  mas. Development of B-cell lymphomas in persons with organ  transplants is known as post-transplant lymphoproliferative  disorder (PTLD).*° One effective therapy for PTLD is, if possi-  ble, to decrease or stop the administration of immunosuppres-  sant drugs and allow the immune system to attack the virus.  EBV infection also is associated with Burkitt lymphoma in  areas of endemic malaria and with nasopharyngeal carcinoma,  a cancer endemic in Chinese populations in Southeast Asia.*°*”  HHVS8 is linked to the development of Kaposi sarcoma, a can-  cer that was once seen primarily in older men but now occurs  in a markedly more virulent form in immunocompromised  individuals, especially those with acquired immunodeficiency  syndrome (AIDS).*° HHV8 also has been linked to several rare  lymphomas.   Human T-cell lymphotropic virus type 1 (HTLV-1) is an  oncogenic retrovirus linked to the development of adult T-cell  leukemia and lymphoma (ATLL).“? HTLV is transmitted ver-  tically (that is, inherited by children from infected parents)  and horizontally (e.g., by breast-feeding, sexual intercourse,  blood transfusions, and exposure to infected needles). Infection  with HTLV may be asymptomatic, and only a small fraction  of infected individuals develop ATLL, often many years after  acquiring the virus.   Chronic hepatitis B infections are common in parts of Asia  and sub-Saharan Africa and confer up to a 200-fold increased  risk of developing liver cancer. Chronic hepatitis C infections  have become increasingly recognized in Western countries.  Up to 80% of liver cancer cases worldwide are associated with  chronic hepatitis caused either by HBV or by HCV. The initial  infection with hepatitis B or C is not associated with cancer;  instead, it is acquisition of a chronic viral hepatitis that markedly  increases cancer risk.*° In both cases, it appears that a lifetime of    chronic liver inflammation predisposes to the development of  hepatocellular carcinoma. Widespread use of the HBV vaccine  is expected to significantly decrease the incidence of chronic  hepatitis B and hence hepatocellular carcinoma. Unfortunately,  a vaccine for HCV is not yet available.   The immune surveillance hypothesis would predict that  compromise of the immune system, either by administration  of immunosuppressive drugs or by development of genetic  or acquired immunodeficiencies, would result in increased  incidences of all types of cancer. However, defective immune  responses generally only increase the risk for lymphoid can-  cers, many of which are associated with viral infections.°! For  instance, individuals taking chronic powerful immunosuppres-  sive drugs, such as those given for kidney, heart, or liver trans-  plant, have a much higher risk of developing viral-associated  cancers, with a 10-fold increased risk of non-Hodgkin lym-  phoma (caused by Epstein-Barr virus) and up to a 1000-fold  increased risk of Kaposi sarcoma (caused by human herpesvirus  8 [HHV8]). The same immunosuppressed individuals, how-  ever, have only a slight increase in the risk of common cancers  such as lung and colon cancer (and this could well be because  of increased inflammation at those sites), and no increase in  the risk of breast or prostate cancer.°*»* Although the immune  system is indeed important in protecting us against cancers  caused by specific viral infections, it does not effectively protect  us against most common cancers.    Although the immune surveillance theory remains controver-  sial the general opinion remained that an immune or inflam-  matory response to malignancy is a detrimental condition that  successful tumors have evolved methods of evading. We now  realize that the relationship between a cancer and the immune  and inflammatory systems is much more complex. Inflamma-  tory and immune responses may create a local environment  in which cells can develop into a malignant phenotype and  may even benefit progression and spread of malignancies.”  In fact, chronic inflammation has been recognized for close to  150 years as being an important factor in the development of  cancer.°° Epidemiologic studies strongly support the conclu-  sion that chronic inflammation predisposes to cancer. Chronic  inflammations may result from many causes; for example, solar  irradiation, asbestos exposure (mesothelioma), pancreatitis,  and infection (Table 12-7). Additionally, some organs appear to   Vulvar squamous cell carcinoma  Pancreatic carcinoma  Esophageal carcinoma  Salivary gland carcinoma  MALT lymphoma   Bladder, liver, rectal carcinoma; follicular lymphoma of the spleen  Gastric adenocarcinoma, MALT    Modified from Coussens LM, Werb Z: Nature 420(6917):860-867, 2002; Dalgleish AG, O'Byrne KJ: Adv Cancer Res 84:231-276, 2002; Shacter E,    HIV, Human immunodeficiency virus; HPV, human papillomavirus; MALT, mucosa-associated lymphoid tissue.    be more susceptible to the oncogenic effects of chronic inflam-  mation; for example, the gastrointestinal (GI) tract, prostate,  thyroid gland, pancreas, urinary bladder, pleura, and skin.  Individuals who have suffered with ulcerative colitis for  10 years or more have up to a 30-fold increase in the risk of devel-  oping colon cancer. Chronic viral hepatitis caused by hepatitis  B virus (HBV) or hepatitis C virus (HCV) infection markedly  increases the risk of liver cancer. One large study found a 66%  increase in the risk of lung cancer among women with chronic  asthma, an inflammatory disease of the airways (see Chapter 35).  Inflammation and cancer have much in common.*° In  both cancer and inflammation (e.g., after injury and during  infection), inflammatory cells, including neutrophils, lym-  phocytes, and macrophages, migrate to the site of injury and  release cytokines and growth and survival factors that stimu-  late local cell proliferation and new blood vessel growth to  promote wound healing by tissue remodeling (Figure 12-19)  (see Chapter 5). These factors combine in chronic inflam-  mation to promote continued proliferation.°’ In addition,  inflammatory cells release compounds such as reactive oxy-  gen species (ROS) and other reactive molecules that can  promote mutations and block the cellular response to DNA  damage. Notably, an increased abundance of the enzyme  cyclooxygenase-2 (COX-2), which generates prostaglandins  during acute inflammation, has been associated with colon  and some other cancers. Meta-analyses of multiple clinical  studies have concluded that long-term high-dose use of non-  steroidal anti-inflammatory drugs (NSAIDs), such as aspirin,    that inhibit COX-2 can reduce the risk of colon cancer by as  much as 20% (see Chapter 5).°°   A specific example is the association between gastric inflam-  mation induced by infection with the bacterium Helicobacter  pylori (H. pylori) and the risk for gastric cancer. H. pylori is a  bacterium that infects more than half of the world’s population.  Chronic infection with H. pylori is an important cause of peptic  ulcer disease and is strongly associated with gastric carcinoma,  a leading cause of cancer deaths worldwide. It is also associated  with a less common cancer, gastric mucosa—associated lymphoid  tissue (MALT) lymphomas. H. pylori infection is often acquired  in childhood and disproportionately affects lower socioeco-  nomic classes. Although most infections are asymptomatic, pro-  longed chronic inflammation can lead to increased gastric acid  secretion, atrophic gastritis, and duodenal ulcers, or to benign  cellular proliferation that can, in a small fraction of individuals,  progress to dysplastic changes and finally frank gastric adeno-  carcinoma. H. pylori infection can both directly and indirectly  produce genetic and epigenetic changes in infected stomachs,  including mutations in p53 and alterations in the methylation  of specific genes.°”°° Eradication of H. pylori from infected indi-  viduals before the development of dysplasia may prevent the  development of cancer.°! However, there is no expert consensus  on the value of population screening and treatment strategies.    Once cells with malignant phenotypes have developed, addi-  tional complex interactions occur between the tumor and the    FIGURE 12-19 Wound Healing vs. Invasive Tumor Growth. A, Wounds simulate a local inflammatory response. With  tissue injury, a blood clot with activated platelets forms, releasing multiple factors that stimulate wound healing. Chemotactic  factors such as transforming growth factor-beta and platelet-derived growth factor, derived from activated platelets, initiate  granulation tissue formation, activation of fibroblasts, and secretion of proteolytic enzymes (including matrix metalloprotein-  ases) necessary for remodeling of the extracellular matrix. Signaling from many cell types in the wound, including stromal  cells, facilitates healing. Once the wound is healed, the signals presumably stop. B, Invasive carcinomas act as disorganized  wounds. Neoplastic cells produce angiogenic factors, cytokines, and chemokines that are mitogenic and/or chemoattrac-  tants for numerous cells. In return, activated fibroblasts and infiltrating inflammatory cells also secrete proteolytic enzymes,  cytokines, and chemokines, which are mitogenic for neoplastic cells as well as for endothelial cells involved in neoangiogen-  esis. These factors, which in the normal situation promote wound healing, now can stimulate tumor growth and angiogen-  esis, induce fibroblast migration and maturation, and promote metastatic spread through the venous or lymphatic networks.    surrounding stroma and cells of the immune and inflamma-  tory systems (Figure 12-20). Normal tissues contain a com-  plex mixture of cell types, including fibroblasts, vascular cells,  adipocytes, mesenchymal cells (including mesenchymal stem  cells), inflammatory cells, and immune cells, and a supporting  extracellular matrix. Cancers disrupt this environment, initiate  or enhance inflammation, and in turn recruit local and distant  cells (macrophages, lymphocytes, and other cellular compo-  nents of inflammation). The acute inflammatory response  related to infection, instead of cancer, undergoes several phases;  the initial phase is protective and focused on destruction of the  contaminating infectious agents, whereas the later phases are  focused on the initiation and progression of healing, as well as  preventing the development of autoimmune responses against  the normal cellular debris of tissue destruction and regen-  eration (see Chapter 7). Successful tumors appear capable of  manipulating cells of the inflammatory and immune responses  towards the phenotypes associated with wound healing and tis-  sue regeneration, which is a process that includes induction of  cellular proliferation, neovascularization, and local immune    suppression. These activities benefit cancer progression, as well  as increase resistance to chemotherapeutic agents.”   One of the key cells that promote tumor survival is the  tumor-associated macrophage, or TAM.°? Many tumors pro-  duce cytokines and chemokines that are chemotactic factors  for monocytes/macrophages (for example, colony-stimulating  factor-1 [CSF-1; also known as macrophage colony stimulating  factor or M-CSF], vascular endothelial growth factor [VEGF],  the chemokine ligand 2 [CCL2; also known as monocyte che-  motactic protein-1 or MCP-1]). These chemotactic factors,  especially CCL2, are commonly expressed by human tumors  (for example, levels of CCL2 in human breast and cancers of the  esophagus are related to the degree of macrophage infiltration  and progression of the tumor). Thus monocytes are attracted  from the blood and into the tumor, where they mature into  macrophages. Monocytes have the capacity to differentiate into  several macrophage phenotypes, depending upon the condi-  tions in the microenvironment. The classical pro-inflammatory  macrophage (M1) is the primary macrophage in the acute  inflammatory response and is responsible for removal and    FIGURE 12-20 Cancers Live in a Complex Microenvironment. This diagram represents aspects of the complex micro-  environment of a high-grade epithelial neoplasm. The tumor cells produce angiogenic factors that induce neovascularization  and invasion by inflammation-related cells from neighboring tissue and from the blood. Individual cancer cells have undergone  diverse phenotypic changes, including the formation of cancer stem cells (CSCs). Cytokines and chemokines produced by vas-  cular endothelial cells (ECs) directly affect the proliferation and spread of cancer cells. Cancer-associated fibroblasts originate  from fibroblasts associated with blood vessels or invasion from surrounding tissues and produce factors that primarily affect  tumor cell proliferation and breakdown of the underlying extracellular matrix. Circulating monocytes invade the tumor and dif-  ferentiate into tumor-associated macrophages (macrophages) (TAMs) of the M2 phenotype. TAMs produce factors that affect  most other cells in the microenvironment. T lymphocytes infiltrate the tumor in the form of CD8+ cytotoxic cells (Tc) and CD4+  regulatory cells (Treg). The Tc cells are suppressed through the combined effect of cytokines and chemokines produced by Treg    destruction of infectious agents. During healing, however, a  different phenotype (M2) produces anti-inflammatory media-  tors to suppress ongoing inflammation and induce cellular pro-  liferation, angiogenesis, and wound healing.°? TAMs appear to  phenotypically mimic the M2 phenotype. The transition to the  M2 phenotype is under control of Th2 cytokines (for exam-  ple, tumor necrosis factor-alpha [TNF-a], colony-stimulating  factor-2 [CSF2; also known as granulocyte/macrophage colony  stimulating factor or GM-CSF], interleukin-4 [IL-4], IL-10,  IL-13).   TAMs have diminished cytotoxic response, and develop the  capacity to block cytotoxic T-cell and NK cell functions and  produce cytokines that are advantageous for tumor growth  and spread. TAMs secrete cellular growth factors (for example,  TGF-6 and fibroblast growth factor [FGF-2]) that favor tumor  cell proliferation, angiogenesis, and tissue remodeling, similar  to their activities in wound healing. They also secrete angiogen-  esis factors (for example, VEGF) that induce neovascularization  and matrix metalloproteinase (MMP) that degrade intercellular  matrix. The overall effect is increased tumor growth, increased  oxygen delivered to the tumor, invasion of the blood vessels,  and invasion through the degraded matrix into the local tis-  sue. Most tumors have large numbers of TAMs, whose pres-  ence frequently correlates with reduced survival (for instance,  in individuals with breast cancer, some forms of lung cancer,    and Hodgkin lymphoma). Therapies targeting the nonmalig-  nant TAMs are effective at slowing cancer progression.°°   Many tumors also have an abundance of tumor-infiltrating  lymphocytes. Although the immune cells frequently found in  tumors were once thought to be futile attempts at an antitu-  mor response, instead it appears that cancers actively recruit an  immune and stromal response to assist in remodeling of tissues,  formation of new blood vessels, and promotion of metastasis®°  (see Figure 12-20) cells are generally in low amounts in tumors.  The predominant lymphocytes are regulatory T (Treg) cells.°’  Treg cells are CD4+ cells that differentiate under the control  of specific cytokines, primarily TGF-$, and express CD25 (the  a-chain of the IL-2 receptor) and are thus frequently designated  CD4+, CD25+ Treg cells. The role of Treg cells during wound  healing is to control or limit the immune response to protect  the host’s own tissues against autoimmune reactions. Their role  in tumors is manipulated to prevent a destructive antitumor  immune response and provide cytokines that facilitate tumor  cell proliferation and spread.°® Treg cells and TAMs, as well as  stromal cells, produce very high levels of TGF-B and IL-10, an  immunosuppressive cytokine, which generally decrease Thl  and Th2 activity, suppress antigen recognition and cell prolif-  eration by Th cells, and suppress the capacity of CD8+ cytotoxic  T (Tc) cells to recognize, proliferate in response to antigen,  and kill tumor cells. Increased levels of Treg cells in blood and    lymph nodes and also infiltrating the tumor correlate with poor  outcomes in breast and GI tumors.”   In several conditions the release of immunosuppressive fac-  tors into the tumor microenvironment increases resistance of  the tumor to chemotherapy and radiotherapy.”” In advanced  non-small cell lung cancer an elevated ratio of Treg to Tc cells  is related to a poor response to platinum-based chemotherapy.  Other cytokines appear to increase the cancer cells’ resistance  to apoptosis. For example, the Th2 cytokine IL-4 increases the  resistance of thyroid cancer to chemotherapy; IL-6 produced by  adipocytes and fibroblasts activates survival pathways in breast  cancer leading to resistance to radiotherapy; and adipocytes  enhance the transcription of the anti-apoptotic factor Bcl-2 in  leukemia cells.”!   A major component of wound healing is angiogenesis—  the process of establishing new blood vessels within the tissue  undergoing repair. Access to a blood supply is a major benefit to  the growth and spread of cancer. Vascular endothelial growth  factor (VEGF), an extremely potent inducer of angiogenesis, is  secreted by most cells in the tumor microenvironment, includ-  ing tumor-infiltrating monocytes, endothelial cells, adipocytes,  cancer-associated fibroblasts, and some tumor cells. Tumor  cells may also have VEGF receptors. VEGF may, thus, induce  increased resistance to chemotherapy. For instance, in soft  tissue sarcomas VEGF induces increased expression of anti-  apoptotic proteins (survivin, Bcl-2) and activation of Pi3K/Akt-  mediated survival pathways. The use of angiogenic inhibitors  targeting VEGF signaling can inhibit angiogenesis and diminish  tumor growth.   Tumor growth and progression is enhanced by, and perhaps  is dependent upon, interactions with cells in the microenviron-  ment. Suppression of tumor-enhancing inflammatory/immune  responses may provide powerful adjunctive approaches to  traditional antitumor therapeutic regimens, such as chemo-  therapy and radiation therapy.’* Tumor-infiltrating cells, such  as TAM and Treg cells, express cell-specific surface markers.  Antibodies directed against those markers can induce apopto-  sis of these cells. Additionally, the effects of specific cytokines,  chemokines, and other tumor-enhancing mediators produced  in the tumor microenvironment may be neutralized by specific  antagonists.”> These are also usually in the form of monoclo-  nal antibodies. For instance, TNF-a antagonist has been used  effectively in rheumatoid arthritis to inhibit production and  neutralize the effects of TNF-a, including reduction of angio-  genesis, leukocyte infiltration, and production of metallopro-  teinases. Trials are currently underway to assess the effects of  TNF-a antagonists on the progress of cancer. Other antago-  nists are under investigation, including those against IL-1,  TGF-8, CSF-1 (M-CSF), VEGF, IL-6, IL-10, and metallopro-  teinases. Chemokine antagonists are also under development.  A potential complication of adjunctive therapy directed against  cellular or molecular products of inflammation concerns the  importance of these constituents in normal inflammatory/  immune responses. If the proposed antagonists were admin-  istered systemically, suppression of responses elsewhere in the  body may increase the individual’s susceptibility to infection.  Delivery systems that concentrate the antagonists proximal to    the tumor environment may be the most effective means of  administration.    Metastasis is the spread of cancer cells from the site of the  original tumor to distant tissues and organs through the body.  Metastasis is a defining characteristic of cancer, contributes  significantly to the pain and suffering from cancer, and is the  major cause of death from cancer. Cancer that has not metas-  tasized can often be cured by a combination of surgery, che-  motherapy, and radiation. These same therapies are frequently  ineffective against cancer that has metastasized. For example,  in appropriately treated women with low-stage breast cancer,  the 5-year survival rate is often greater than 90%.” Tragically,  less than 30% of women with metastatic breast cancer are alive  5 years after diagnosis.’”” A growing body of basic and clinical  research is defining the biologic principles of metastasis, with  the hope that this improved understanding will lead to novel  diagnostic approaches and better therapies to prevent and treat  metastatic cancers.’°   Invasion, or local spread, is a prerequisite for metastasis and  is the first step in the metastatic process. In its earliest stages  local invasion may occur by direct tumor extension. Eventu-  ally, however, cells migrate away from the primary tumor and  invade the surrounding tissues. Mechanisms important in  local invasion include recruitment of macrophages and other  cell types to the primary tumor, where they promote digestion  of connective tissue capsules and other structural barriers by  secreted proteases; changes in cell-to-cell adhesion, often by  changes in the expression of cell adhesion molecules such as  cadherins and integrins, making the cancer cells more slippery  and mobile; and increased motility of individual tumor cells’  (Figure 12-21). Tumors that are encased in a capsule, such as  breast ductal carcinoma, must breakdown the capsule in order  to initiate local spread.”® The capsule consists of layers of epi-  thelial cells and myoepithelial cells in contact to the tumor and  contained by a basement membrane (see Figure 24-43). The  myoepithelial cells may be tumor suppressive; they produce  proteins that are tumor suppressors (e.g., TGF-a, IL-6), as  well as angiogenesis inhibitors and proteinase inhibitors.”” The  mechanism of capsular dissolution is unclear, but may result  from production of enzymes by the tumor or the influx of leu-  kocytes.*° Information about mechanical stress and associated  tumor cell response is contained in What’s New? Mechanical  Stress and Tumors.   To transition from local to distant metastasis, the cancer cells  must also be able to invade local blood and lymphatic vessels, a  task facilitated by stimulation of neoangiogenesis and lymphan-  giogenesis by factors such as VEGF. Finally, a successful meta-  static cell must be able to survive in the circulation, attach in an  appropriate new microenvironment, and multiply to produce  an entire new tumor, similar to the characteristics of a cancer  stem cell. Different cancers have different patterns of spread,  determined by a combination of factors. Cancers often spread  first to regional lymph nodes through the lymphatics and then  to distant organs through the bloodstream. A cancer’s ability    Cells, whether in isolation or in tissues, often face and respond to a wide variety  of external stimuli. These environmentally induced changes, called perturba-  tions, can be chemical or physical and responses can be physiologic, such as  cellular homeostatic activities or tissue development movements, or pathologic,  such as malignant transformation or inflammation. Cellular responses to chemi-  cal signals have been studied in great detail, but the elements involved in the  recognition of physical stresses (e.g., hypoxia, osmotic shock, ionizing radiation,  or mechanical stretching) and the mechanisms related to cell responses to these  stimuli remain barely analyzed. These responses include a variety of conserved  adaptive behaviors, such as wound healing, cell migration, extravasation, secre-  tion, and necrotic or apoptotic death.'   Mechanical stress is a key physical stimulus sensed by cells. At the cellu-  lar level, mechanical cues or stressors can modulate almost all aspects of cell  behavior, including growth, differentiation, migration, gene expression, protein  synthesis, and apoptosis, many of them of important clinical interest (e.g., can-  cer metastasis, stem cell proliferation, and differentiation and wound healing).  Mechanical cues control specific physiologic processes, such as sound sensa-  tion, by cells of the inner ear or blood flow across the endothelium.? Impor-  tantly in some cases, organs and tissues adapt their structures and functions in  response to acute or chronic mechanical stress (e.g., pressure overload causes  cardiovascular hypertrophy and muscle disuse results in atrophy).   For tumor biology, the cell surface integrin family act as critical mechano-  sensors.° Integrin-mediated cell adhesion and signaling are crucial events for  numerous cell fates and include morphogenesis, differentiation, cell growth, the  immune response, and cell survival.’ /ntegrins function as noncovalent trans-  membrane receptors that are organized in focal adhesions (FAs) and link the  extracellular matrix (ECM) to the actin cytoskeleton; they do not directly inter-  act with actin filaments. A number of actin-binding proteins, including talin,  a-actinin, and filamin, have been identified as intermediates.° Integrins can  mediate the sensing of mechanical properties of the ECM by changing their affin-  ity, conformation, clustering, and recruitment and by transducing these signals to    to establish a metastatic lesion in a new location requires that  the cancer both attach to specific receptors and survive in the  specific environment. Because metastasis requires successful  completion of each and every step, there may be many oppor-  tunities to interrupt this potentially lethal pathway.    Metastasis is a highly inefficient process. A landmark clinical  review examined a group of women with advanced ovarian  cancer.*! These unfortunate women had accumulated a large  amount of peritoneal fluid filled with malignant ovarian cancer  cells (malignant ascites). To relieve the pressure caused by the  ascites, the fluid was surgically shunted into the venous circula-  tion. This palliative procedure relieved the abdominal pressure  but had the side effect of moving millions of ovarian cancer cells  an hour directly into the bloodstream. Despite this direct injec-  tion of billions of cancer cells into the circulation, these women  unexpectedly had no increased number of metastases when they  died. The conclusion from this clinical study is that most cancer  cells cannot successfully cause metastases, a conclusion that has  been supported by many other clinical and laboratory studies.**  The reason lies both in the seed and in the soil. Cancer cells  (the seeds) must surmount multiple physical and physiologic    the activation of downstream signaling cascades. The molecular architecture of  FAs suggests that mechanical force is, itself, essential for focal adhesion forma-  tion and maintenance. From stretch-induced recruitment, talin may serve as a  molecular ruler that specifies focal adhesion molecular architecture.®   Investigators are studying the relationships of cues from the microenvironment  and tumor behavior. For example, recent work showed the mechanical tone of  nontumorigenic host epithelium directs the phenotype of tumor cells.’ Investiga-  tors established a three-dimensional ex vivo model of both normal and malignant  mammary epithelial growth to test the importance of the ECM in regulating local  migration of tumor cells and dissemination.® From their studies, they determined  that breaks in the basement membrane could induce invasion and dissemination  from the resulting direct contact between cancer cells and collagen 1.8 Uncon-  trolled growth in a confined space generates compressive forces. To understand  how this may affect tumor behavior, investigators from various fields, includ-  ing chemical engineering and radiation oncology, found that compressive stress  accumulated during tumor growth can enable coordinated migration of cancer  cells by stimulating formation of leader cells and enhancing cell—substrate adhe-  sion.2 This novel mechanism represents a potential target for the prevention of  cancer cell migration and invasion. Overall, the research on mechanical stress  and associated tumor cell response is just beginning.   . Shimaoka M, Springer TA: Nat Rev Drug Discov 2:703-716, 2003.   . Boghaert E et al: Proc Nat! Acad Sci U S A 109(48):19632—19637, 2012.   . Nguyen-Nqoc KV et al: Proc Nat! Acad Sci U S A 109(39):E2595-E2604, 2012.  . Tse JM et al: Proc Nat! Acad Sci U S A 109(3):911-916, 2012.    barriers in order to spread, survive, and proliferate in distant  locations, and the destination (the soil) must be receptive to the  growth of the cancer. It has been suggested that the metastatic  cell must, like a decathlon champion, be successful in every  event to allow a cancer to spread.*?   How do cancer cells develop the ability to metastasize? The  same heritable changes that occur to cause the primary cancer,  including gene mutations, deletions, translocations, epigenetic  silencing, and changes in miRNA expression, all work to pro-  vide genetic heterogeneity in the tumor cells as they proliferate.  As this diversity increases, this increases the number of cells in  the cancer mass with new abilities that can facilitate metastasis.    In order for cells to move away from their normal niche, they  must be able to detach from the stroma and migrate. Cells are  normally attached to extracellular matrix (ECM). To facilitate  cancer spread, many tumors and their associated inflammatory  cells secrete proteases and protease activators, such as the matrix  metalloproteinases (MMPs) and plasminogen activators. Active  proteases digest the extracellular matrix and basement mem-  branes, creating pathways through which cells can move, while  releasing bioactive peptides as digestion products that further   FIGURE 12-21 Multistep Nature of Metastasis. (From Gupta GP, Massagué  J: Cell 127[4]:697—708, 2006.)    stimulate tumor growth and mobility. However, the produc-  tion of metalloproteinases alone is inadequate to explain the  metastatic process.   The process by which neoplastic cells dissociate from the  primary tumor, spread into the lymphatics and blood vessels,  and establish macrometastases in foreign microenvironments is  a fascinating, and yet not fully understood, utilization of path-  ways that are more commonly observed in embryonic and fetal  development. Carcinomas originate from highly differentiated  and polarized epithelial cells that form structured sheets stabi-  lized by multiple adherences to neighboring cells and to a base-  ment membrane (an extracellular meshwork of collagens and  other connective tissue proteins) along the cells’ basal surface.  Although the degree of malignant transformation resulting in  a primary tumor may be adequate for local expansion of the  tumor, neoplastic cells in the primary carcinoma usually retain  some epithelial-like characteristics that prevent dissociation  from the extracellular matrix and preclude successful metasta-  sis to distal sites. A greater degree of cellular “dedifferentiation”  is necessary to produce the “seeds” that can separate from the    primary tumor and flourish in a potentially hostile secondary  site. This results from a programmed transition of the still par-  tially epithelial-like carcinoma to a more undifferentiated mes-  enchymal-like phenotype (epithelial-mesenchymal transition  [EMT]) (Figure 12-22).°° A similar process occurs with tumors  of endothelial origin (endothelial-mesenchymal transition).**   EMT is a process that occurs normally in embryonic devel-  opment (for example, cell movement related to morphogenesis  during gastrulation and neural crest formation) and implan-  tation, as well as wound healing and tissue repair. Generally,  cells that have transitioned into a mesenchymal-like phenotype  have suppressed expression of adhesion molecules with a loss  of polarity, increased migratory capacity, elevated resistance  to apoptosis, and the potential to redifferentiate into other  cell types. These properties permit the tumor cells to dissoci-  ate from the primary tumor and be transported to a distal site.  The degree of dedifferentiation may be variable, but most cells  undergoing EMT acquire stem cell traits that facilitate initial  growth in a new microenvironment.®? The EMT is not a stable  transition; the metastatic tumor tends to regain some charac-  teristics of the primary tumor, thus reverting to some extent to  its epithelial origins.   The transition to a mesenchymal-like phenotype is, in most  cases, driven by cytokines and chemokines produced within the  tumor microenvironment (see Figure 12-22). IL-8 is an effec-  tive driver of carcinoma cells into EMT. TGF-f induces loss of  E-cadherin (an integral component of tight junctions) and B,-  integrin in mammary gland tumor cells. The loss of E-cadherin  in particular allows cells to detach from extracellular matrix and  migrate more readily.   Genetic changes associated with the EMT are under the con-  trol of a variety of transcription factors, for example, Snail, Slug,  and Twist.*° Most are repressors of transcription, so that expres-  sion of adhesion molecules such as E-cadherin is greatly dimin-  ished. The translational factor Slug also represses transcription  of Bcl-2 antagonists, resulting in increased Bcl-2 expression and  increased resistance to apoptosis.    Normal cells, when separated from their ECM, undergo anotkis,  a form of apoptosis (see Chapter 2). The process of EMT fre-  quently results in increased resistance to apoptosis. In addition,  tumor cells that have already adapted to a hypoxic environment  have already been selected for resistance to apoptosis, often by  loss of normal cell death pathways. For example, neuroblas-  tomas with loss of the pro-apoptotic caspase-8 genes are able  to avoid apoptosis after loss of integrins, and are more able to  metastasize than the same cells with normal levels of caspase-8.  Accordingly, individuals whose neuroblastomas have low levels  of caspase-8 have a poor prognosis*” (see Chapter 2).    After release from the ECM and digestion of basement mem-  branes, cancer cells gain access to the circulation through  new tumor-associated blood vessel growth or angiogenesis  (described earlier), also known as neovascularization. Mobile  tumor cells are able to enter the circulation, perhaps facilitated    FIGURE 12-22 Epithelial-Mesenchymal Transition (EMT). Tumors of epithelial origin usually retain epithelial-like  characteristics that preclude spread into adjacent tissues and metastasis to distal sites. As seen in this diagram, cells within  carcinoma in situ or non-invasive carcinoma (not shown) retain adhesion to adjacent cells and the underlying basement mem-  brane (BM). The process of transition to mesenchymal-like cells is driven by cytokines within the tumor microenvironment and  induction of a family of EMT-inducing transcription factors. The outcome included dedifferentiation of the tumor cell, poten-  tially to a cancer stem cell phenotype, loss of adhesion-related molecules, breakdown of the BM, and increased resistance to  apoptosis, which result in a locally invasive carcinoma and release into the bloodstream or lymphatic vessels of cells capable  of relocalization, redifferentiation (potentially through a reverse mesenchymal-to-epithelial transition process; MET), and for-  mation of a metastasis. CSC, Cancer stem cell. (From Craene BD, Berx G: Nat Rev Cancer 13[2]:97—110, 2012.)    by the leaky newly made vessels and attraction of the cells  because of chemoattractants coming from these new vessels.  Once in the circulation, metastatic cells must be able to with-  stand the physiologic stresses of travel in the blood and lym-  phatic circulation, including high shear rates and exposure to  immune cells. One mechanism is for tumor cells to bind to  blood platelets, giving them a protective coat of nonmalignant  blood cells that both shields the tumor cells and creates a small  tumor embolus, or cancer clot, that can promote cancer cell  survival in distant locations.   The patterns of metastasis are dictated by the interaction  between the cancer cells and the microenvironments in which  they land. Two distinct mechanisms give rise to patterns of  distant spread. First, cancer cells spread through vascular and  lymphatic pathways, as well as natural tissue planes. The neo-  vascularization of a cancer offers malignant cells direct access  into the venous blood, and draining lymphatics can carry  malignant cells to regional lymph nodes. Single cells, clumps,  and even tumor fragments can disseminate by these routes.  Anatomic patterns of lymphatic and venous blood flow help  determine how colon cancers spread to the liver, liver cancers  spread through the portal vein to the lungs, lung cancers spread  through the systemic circulation to the brain, and breast can-  cer spreads through lymphatics to axillary lymph nodes (Figure  12-23). There is also a major yet poorly understood selectivity of    different cancers for different sites. Thus metastatic breast can-  cer often spreads through the bloodstream to bones but rarely  to kidney or spleen, whereas lymphomas often spread to the  spleen but uncommonly spread to bone. In a key study, Schack-  ert and Fidler®® injected different types of cancer cells into the  carotid artery of mice. Despite identical blood flow—mediated  distribution of the cancer cells, each cancer cell type produced  cancers in very different parts of the brain. This tissue selectiv-  ity is likely caused by specific interactions between the cancer  cells and specific receptors on the small blood vessels in different  organs (Table 12-8). Experimental metastasis studies in mice are  beginning to reveal additional molecular reasons for this tissue  specificity (Figure 12-24). Examples include interaction between  0361 integrins binding to laminin-5 receptors in the lung, and  the chemokine receptor CXCR4 on breast cancer cells promot-  ing homing to lung tissues expressing the ligand CXCL12.*?   As the study with women with ovarian cancer illustrates, pump-  ing millions of cancer cells in the bloodstream does not nec-  essarily cause metastatic disease. Cancer cells may arrive in a  new location and survive but not proliferate to form a clini-  cally relevant metastasis. The tumor cells that do not make the  transition from simple survival to robust proliferation in a new    FIGURE 12-23 Patterns of Metastatic Spread. A, Sites of hematogenous metastasis. Blood-borne tumor metastasis  leads to growth of secondary tumors in several main sites. The macroscopic appearance of bone metastasis is shown in B, where  lesions are seen in vertebrae. C, Numerous metastases from a neoplasm of the stomach are seen in the brain. D, The liver is the  most common site for metastases from tumors in the gastrointestinal tract that arose from a colonic neoplasm. E, Metastatic  tumor has replaced both adrenal glands, as is commonly seen with spread from lung and breast tumors. F, The lung is the most  common site for blood-borne metastases from tumors outside the spinal tract, particularly mesenchymal tumors.    COMMON SITE OF DISTANT  PRIMARY TUMOR _ MAJOR ANATOMIC PATHWAY METASTASIS   Inferior vena cava, right ventricle, pulmonary artery Lungs  Testicular Lymphatics to periaortic area to subclavian veins to right ventricle Lungs, liver, brain    Prostate Regional lymphatics and veins, which drain to Batson plexus of presacral veins Bones (especially lumbar spine), liver   Breast Axillary, transpectoral, and internal mammary lymphatics Bones, lung, brain, liver   Ovarian Direct extension, peritoneal seeding, mesenteric veins Peritoneal surfaces, diaphragm, omentum, liver   Melanoma Regional lymphatics In transit lymphatics, lung, liver, brain,  gastrointestinal tract    location are said to be in a state of dormancy. This dormancy __ of the factors that allow proliferation of cancer cells in the new  may account for the observation that solitary tumor cells canbe — environment may be cancer’s recruitment of normal cells from  detected in the blood years after a complete clinical remission —_ local and circulating bone marrow stem cells. One developing  in individuals, and that many people with detectable microme- _ concept is that successful metastatic tumor cells secrete factors  tastases will not develop clinically obvious metastases.**? One _ that recruit circulating mesenchymal stem cells to the metastatic    FIGURE 12-24 Clues Regarding How the Patterns of Metastatic Spread Are Determined. Different cancer cells  from the same cancer can spread to different locations. This is because tumors are heterogeneous mixtures of cells, with  variations in the genes that are turned on and off. Different anatomic locations favor different types of cells. Studies with mice  illustrated here show that expression of specific factors such as adhesion molecules, chemokines, and host factors such as  blood-brain barrier disruption can favor the spread of specific cancer cells to different locations. In this example, cancer cells  were visualized by genetically tagging cells with firefly luciferase for bioluminescent imaging. (From Gupta GP, Massagué J:    site (see Figure 12-17). These newly recruited stem cells then  differentiate into tumor-supporting stroma and new blood ves-  sels. One area of research is aimed at understanding why some  micrometastases remain dormant; new therapies might block  their progression to clinically important disease.   Cancer can be discovered in many ways: after screening tests,  from routine exams, and after investigation of symptoms (see    What’s New? Screening Mammography: Why It Has Not Lived  Up to Expectations). The symptoms a cancer produces are as  diverse as the types of cancer. The location of the cancer can  determine symptoms by physical pressure, obstruction, and  loss of normal function, or a cancer can cause problems far  away from its source by pressing on nerves or secreting bioac-  tive compounds. Whatever the initial complaint, once the diag-  nosis is suspected and a tumor has been identified, it is essential  that tumor tissue be obtained to establish a definitive diagnosis  and correctly classify the disease. Various methods of obtaining  tissue are described in Table 12-9.   Once tissue is obtained, it is examined microscopically by  the pathologist for the histologic hallmarks of cancer detailed    Screening mammograms illustrate many of the difficulties that arise from pop-  ulation-based screening tests. The goal of screening tests is early and accurate  detection of a treatable disease without causing false alarms (a low false-  positive rate) or missing a diagnosable disease (a low false-negative rate). We  also do not want to detect disease or conditions that are insignificant and do not  require treatment, known as overdiagnosis. Recently, investigators examined the  extent of overdiagnosis of breast cancer. Various databases were examined to  study breast cancer trends between 1976 (just before screening mammography  was introduced) and 2008. During this interval the incidence of ductal carcinoma  in situ (DCIS) and localized disease (early stage cancers) doubled from 112 to  234 per 100,000 women, an increase of 122 cases per 100,000 women.! During  the same interval, the annual incidence of late stage cancers decreased mini-  mally from 102 to 94 per 100,000 women, a decrease of 8 per 100,000 women.  The higher increase in early stage cases compared to late stage cases (112 vs.  8 per 100,000) suggests substantial overdiagnosis.* The investigators estimate  that, as a result of breast cancer overdiagnosis, more than 1 million U.S. women  have been presumably treated unnecessarily (overtreatment) with approaches  including surgery, radiotherapy, and chemotherapy during the last 30 years.!  These authors also conclude that the improvement in breast cancer mortality  during those years is mainly because of treatment and not screening. This ques-  tion, however, is debated. The Cochrane reviewers analyzed tumor sizes and  stages and reported that screening has not lowered the rate of advanced can-  cers and recent observational studies of breast cancer mortality have failed to  find an effect related to mammography screening.’ Results from the Norwegian  screening program found 15% to 25% of cases of breast cancer are overdiag-  nosed.’ The Nordic Cochrane Center found that 13 years of breast screening had  no measurable effect on breast cancer mortality in Norway.° An independent  expert panel in the United Kingdom estimated the risks and benefits of screen-  ing for breast cancer in women 50 to 70 years of age invited for mammography  every 3 years in the UK. They found for every 180 women who are screened, 1  life is saved but 3 women are diagnosed and treated for cancer that would not  otherwise have become apparent in their lifetimes.® A study involving women  from 30 European countries showed that the mean decrease in breast cancer  mortality between 1989 and 2005 among women less than 50 years of age was  37%; the corresponding decrease was 21% among women aged 50 to 69 years.’  The declines in mortality, however, began before the start of organized screen-  ing programs in many countries and may possibly be the result of tamoxifen  treatment.’ Another study compared three pairs of similar neighboring countries  where screening was introduced 10 to 15 years apart.® The pairs were Northern  Ireland and the Republic of Ireland, the Netherlands and Belgium, and Sweden  and Norway. There was no relationship between the start of screening mam-  mography and reduction in breast cancer mortality.   Authors state that most publications on mammography screening have exam-  ined the effects on mortality separately from harms, such as overtreatment.?  The Canadian Task Force on Preventive Health Care has new recommendations  for screening for breast cancer in women at average risk aged 40 to 74 years."  These new guidelines are cautious, advising against routine screening in women  aged 40 to 49 years. This Task Force recommends screening women aged 50  to 69 years every 2 to 3 years, admitting that this is a weak recommendation  based on moderate-quality evidence, and screening women aged 70 to 74 years    in the beginning of this chapter. The classification of the cancer  can be further facilitated by a variety of clinically available tests,  including immunohistochemical stains, flow cytometry, elec-  tron microscopy, chromosome analysis, and nucleic acid-based  molecular studies.    on the same schedule based on low-quality evidence.'' This Task Force sug-  gested that women who do not place a high value on a small reduction in breast  cancer mortality from screening and those who are concerned about false-posi-  tives on mammography and overdiagnosis may decline screening.'° The United  States Preventive Services Task Force (USPSTF) recommendations include  following:  e The USPSTF recommends biennial screening mammography for wom  aged 50 to 74 years.  Grade: B Recommendation  The decision to start regular, biennial screening mammography before  age of 50 years should be an individual one and take the woman's context  into account, including the woman’s values regarding specific benefits and  harms.  Grade: C Recommendation  The USPSTF concludes that the current evidence is insufficient to assess  the additional benefits and harms of screening mammography in women  75 years or older.  Grade: | Statement  The USPSTF recommends against teaching breast self-examination (BSE).  Grade: D Recommendation  The USPSTF concludes that the current evidence is sufficient to assess the  additional benefits and harms of clinical breast examination (CBE) beyond  screening mammography in women 40 years or older.  Grade: | Statement  The USPSTF concludes that the current evidence is insufficient to assess  the additional benefits and harms of either digital mammography or mag-  netic resonance imaging (MRI) instead of film mammography as screening  modalities for breast cancer.  Grade: | Statement  Overall, considering benefits, overdiagnosis, overtreatment, and potential  harms, including unnecessary surgery, radiotherapy, increased number of  biopsies, and administration of toxic drugs, a// of which may contribute  to the biology of breast carcinogenesis, there will be continued debate  regarding the role of screening mammography in decreasing breast cancer  mortality.   . Jgrgensen KJ, Brodersen J, Gatzsche PC: Int J Cancer 132(7):1725-1726,  2013.   . Canadian Task Force on Preventive Health Care et al: CMAJ  183(17):1991—2001, 2011.    If the diagnosis of cancer is established, it is critical to deter-  mine if the cancer has spread, known as the stage of the cancer.  Staging initially involves determining the size of the tumor, the  degree to which it has locally invaded, and the extent to which  it has spread (metastasized) (Figure 12-25). Specific molecular    Removal of a portion of a lesion  Core needle biopsy  tomography (CT)  Fine needle aspiration  structure  Exfoliative cytology    Complete removal, usually with a margin of normal tissue  Often performed with direct vision, or guided with ultrasound or computed  Obtains dissociated cells for cytologic study but does not preserve tissue    Cells shed from the surface, for example, from cervix, sputum (lung) or urine   Full resection (e.g., mastectomy, partial colectomy)  Lymph node biopsy, muscle mass biopsy    T = Primary tumor; the number equals  size of tumor and its local extent.    N = Lymph node involvement; a higher  number means more nodes are  involved.    FIGURE 12-25 Tumor Staging by the TNM System. Example of staging for breast cancer.    tests are increasingly used in staging as well. Diverse schemes  are used for staging different tumors. In general, a four-stage  system is used, with carcinoma in situ regarded as a special case.  Cancer confined to the organ of origin is stage 1; cancer that  is locally invasive is stage 2; cancer that has spread to regional  structures, such as lymph nodes, is stage 3; and cancer that has  spread to distant sites, such as a liver cancer spreading to the  lung or a prostate cancer spreading to bone, is stage 4. One  common scheme for standardizing staging is the World Health  Organization’s TNM system: T indicates tumor spread, N indi-  cates node involvement, and M indicates the presence of distant  metastasis (see Figure 12-25). The prognosis generally wors-  ens with increasing tumor size, lymph node involvement, and  metastasis (Table 12-10). Staging also may alter the choice of  therapy, with more aggressive therapy being delivered to more  invasive disease.    Paraneoplastic syndromes are symptom complexes that are  triggered by a cancer but are not caused by direct local effects    TABLE 12-10 CANCER SURVIVAL  DEPENDS ON TUMOR TYPE  AND STAGE OF DISEASE    Comment: Estimated percentage of individuals surviving 5 years for  selected tumors, by stage at diagnosis. Additional factors such as age,  molecular lesions, histologic subtypes, and type of treatment modify  the outcome as well.    of the tumor mass. They are most commonly caused by bio-  logic substances released from the tumor (e.g., hormones) or  by an immune response triggered by the tumor. For example, a  small fraction of carcinoid tumors release hormones, including  serotonin, into the bloodstream that cause flushing, diarrhea,    Nerve and Muscle Syndrome  Myasthenia  Disorders of central and peripheral nervous systems    Osseous, Articular, and Soft Tissue Changes  Hypertrophic osteoarthropathy and clubbing of the fingers    From Kumar V, Abbas AK, Fausto N: Pathologic basis of disease, ed 7, Philadelphia, 2005, Saunders.  ACTH, Adrenocorticotropic hormone; /L, interleukin; TGF, transforming growth factor; TNF, tumor necrosis factor.    wheezing, and rapid heartbeat. A number of cancers trigger an  antibody response that attacks the nervous system, causing a  variety of neurologic disorders that can precede other symp-  toms of cancer by months.”!   Although infrequent, paraneoplastic syndromes are signifi-  cant because they may be the earliest symptom of an unknown  cancer and, in affected individuals, can be serious, often irre-  versible, and sometimes life-threatening. Table 12-11 presents  the classifications of paraneoplastic syndromes. Other clinical  manifestations of cancer are summarized in Box 12-2.    The diagnosis of cancer has a profound effect on individuals  and their families. Responses range from depression to resigned  fatalism to an aggressive no-holds-barred pursuit of therapy.  The choice of therapy should be based on a full consideration of  the individual’s diagnosis, prognosis, and therapeutic options  by the individual, the family, and the medical team. Many types  of cancer can be effectively treated with chemotherapy, radio-  therapy, surgery, and combinations of these modalities. Care-  givers must recognize that many individuals seek additional    Pain: There is little or no pain during the early stages of malignant disease.  Significant pain can occur in many individuals who are terminally ill with can-  cer. Direct pressure, obstruction, invasion of a sensitive structure, stretching  of visceral surfaces, tissue destruction, infection, and inflammation all can  cause pain.   Fatigue: The most frequently reported symptom of cancer and cancer treatment.  The exact mechanisms that produce fatigue are poorly understood. Suggested  causes include sleep disturbances, various biochemical changes secondary  to disease and treatment, numerous psychosocial factors, level of activity,  nutritional status, and other environmental and physical factors.   Cachexia: A syndrome that includes many symptoms including anorexia, early  satiety (filling), weight loss, anemia, asthenia (marked weakness), taste alter-  ations, and altered protein, lipid, and carbohydrate metabolism. It is the most  severe form of malnutrition associated with cancer and results in wasting,  emaciation, and decreased quality of life. Cytokines and metabolites from the  tumor may contribute to cachexia.   Anemia: Commonly associated with malignancy, with 20% of persons diag-  nosed with cancer having hemoglobin concentrations less than 9 g/dl (normal  value = 15 g/dl). Mechanisms of anemia include chronic bleeding (resulting in  iron deficiency), severe malnutrition, cytotoxic chemotherapy, and malignancy  in blood-forming organs. Chronic bleeding and iron deficiency can accompany  colorectal or genitourinary malignancy. Iron also is malabsorbed in individuals  with gastric, pancreatic, or upper intestinal cancer.   Leukopenia and Thrombocytopenia: Causes can include many chemothera-  peutic drugs because they are toxic to the bone marrow, often causing granu-  locytopenia and thrombocytopenia. Granulocytopenia also can result from  radiation therapy if it encompasses significant areas of the bone marrow.    Thrombocytopenia is a major cause of hemorrhage in people with cancer and  is often treated with platelet transfusions. Thrombocytopenia is a disorder of  disseminated intravascular coagulation that occurs in individuals with acute  promyelocytic leukemia and severe infections.   Infection: The most significant cause of complications and death in patients  with malignant disease. When the absolute granulocyte count falls below  500 cells per yl, the risk of serious microbial (bacterial and fungal) infection  increases. Advanced disease can predispose to infection and immunosup-  pression from the underlying cancer and the radiotherapy and chemotherapy  used to treat it. (Factors that predispose individuals with cancer to infection  are summarized in Table 12-12.) The prevalence of hospital-acquired (nosoco-  mial) infections increases because of indwelling medical devices, inadequate  wound care, and the introduction of microorganisms from visitors and other  individuals.   Gastrointestinal Tract (Gl): The Gl tract relies on rapidly growing cells to pro-  duce an effective barrier to trauma and infection and to provide an absorp-  tive surface for nutrients. Chemotherapy and radiation therapy may cause a  decreased cell turnover, thereby leading to oral ulcers (stomatitis), malab-  sorption, and diarrhea. The disruption of barrier defenses also increases the  risk for infection, especially invasion by a person's own Gl flora.   Hair Loss (Alopecia) and Skin: Results from chemotherapy effects on hair  follicles. It is usually temporary, although hair may regrow with a different  texture initially. Not all chemotherapeutic agents cause alopecia. Decreased  renewal rates of the epidermal layers in the skin may lead to skin break-  down and dryness, altering the normal barrier protection against infection.  Radiation therapy may cause skin erythema (redness) and contribute to  breakdown.    Data from Miller AH et al: J Clin Oncol 26(6):971-982, 2008; Pachman DR et al: J Clin Oncol! 30(30):3687-3695, 2012.    non-science-based explanations and therapies and often use  alternative therapies, either concurrently or sequentially. Alter-  native therapies can be biologically harmless or harmful; rarely  is there any evidence they are medically effective and in the  worst cases they can be expensive, delay the use of effective ther-  apies, and produce unknown side effects. A challenge for the  medical team is to provide the same level of psychosocial com-  fort and support that alternative therapies can provide, while  also providing scientifically rational evidence-based therapies.    The era of modern chemotherapy began with the observation in  World War II that mustard gas exposure caused suppression of  the bone marrow. Related compounds, such as nitrogen mus-  tard and cyclophosphamide, were then tested and produced  clinical responses in hematologic malignancies, including lym-  phomas. Also in the late 1940s, based on the remarkable clinical  observation that the vitamin folic acid could increase leukemia  growth, anti—folate drugs were developed (leading ultimately to  methotrexate) that produced remissions in previously untreat-  able leukemias.”   All chemotherapeutic agents take advantage of specific  vulnerabilities in target cancer cells. Antimetabolites, such as  methotrexate and L-asparaginase, block normal growth path-  ways in all cells, but leukemia and other cancer cells are exqui-  sitely sensitive to folic acid and asparagine deprivation, whereas  nonmalignant cells are far less sensitive. Similarly, some cancer    cells are highly sensitive to DNA-damaging agents, such as  cyclophosphamide and anthracyclines, because of the onco-  genic mutations that accelerate the cell cycle and DNA syn-  thesis. Cellular checkpoints prevent normal cells treated with  microtubule-directed drugs, such as vincristine and the taxanes,  from undergoing mitosis, whereas cancer cells treated with  these agents lack normal checkpoints, continue through mito-  sis, and undergo mitotic catastrophe (see Chapter 1).   Single chemotherapeutic agents often shrink cancers, but  these drugs given alone rarely if ever provide a cure. Hence, che-  motherapy drugs are usually given in combinations designed  to attack a cancer from many different weaknesses at the same  time and to limit the dose and therefore the toxicity of any  single agent. Cancers contain a very large number of cells, and  commonly a small fraction of those cells may be resistant to a  particular drug. However, those cells are likely to be sensitive to  the second or third drug in a chemotherapy cocktail. Schedul-  ing of drug administration is also very important, with many  studies showing cancers are more likely to develop drug resis-  tance if there are significant delays between planned courses of  chemotherapy.   The newest highly targeted agents used to treat cancer  exploit specific vulnerabilities uncovered by molecular analy-  sis in specific diseases. These new drugs are still used in com-  bination with conventional chemotherapy and to be effective  they must be used in diseases in which the molecular target  is present. For example, imatinib is a competitive inhibitor of    Far-advanced cancer often results in immobility and general debility that worsens with age.  Elderly persons are predisposed to nutritional inadequacies.    Sites and circumstances favorable to growth of microorganisms (obstruction, serous or blood effusion, ulceration) can be    Metastasis to bone marrow may cause leukopenia or other defects in immunity.    Thrombocytopenia (bleeding, breaks in skin integrity) can occur.  Late effect: Chronic lung disease from Pneumocystis jiroveci pneumonia can develop during therapy.    Humoral and cellular immune defects (anergy, altered immunoglobulin production) result.  Late effect: Splenectomy in children can cause increased susceptibility to infection.  Invasive procedure interrupts first lines of defense.    Radical nature of surgery (removal of large blocks of tissue in lengthy procedures) causes hemorrhage, decreased tissue  perfusion, creation of dead spaces, devitalization of tissues.   Nutritional derangements (especially important in head and neck surgery) may result.   Lymph node dissection may predispose patient to local infection and impair containment to area.    Data from Donovan MI, Girton SF: Cancer care nursing, ed 2, New York, 1984, Appleton-Century-Crofts; Murphy GP, Lawrence W, Lenhard RE:    tyrosine kinases, primarily the BCR-ABL tyrosine kinase. It is  highly effective in treating CML and gastrointestinal stromal  tumor (GIST) but ineffective in virtually all other cancers. Sev-  eral monoclonal antibodies directed against cellular receptors  or cell surface antigens are in use or being evaluated. These  include antibodies against the CD20 antigen expressed on  some B-cell lymphomas, the epidermal growth factor (EGF)  receptor on colon cancers and head and neck cancers, and the  HER2 EGF receptor on breast cancer. Fortunately, because  these drugs are so tightly targeted they have much less toxicity  than conventional chemotherapies that have targets in virtu-  ally all cells.   Chemotherapy can be used for several distinct purposes.  Induction chemotherapy seeks to cause shrinkage or disap-  pearance of tumors. In Hodgkin disease, for example, chemo-  therapy alone can be used in some cases to cure the disease.  In other settings, chemotherapy may shrink the tumor and  improve symptoms without ultimately providing a cure.  Adjuvant chemotherapy is given after surgical excision of  a cancer with the goal of eliminating micrometastases. Neo-  adjuvant chemotherapy is given before localized (surgical    or radiation) treatment of a cancer. As with induction che-  motherapy, the effectiveness, or lack thereof, of neoadjuvant  therapy can be measured (for example, with follow-up scans).  Neoadjuvant therapy can shrink a cancer so that surgery may  spare more normal tissue. For example, in the bone can-  cer osteogenic sarcoma, neoadjuvant therapy often converts  a large tumor mass into a much smaller mass, allowing the  surgeon to perform a limb-sparing excision rather than an  amputation.    Radiation therapy is used to kill cancer cells while minimiz-  ing damage to normal structures. Ionizing radiation damages  cells by imparting enough energy to cause molecular damage,  especially to DNA. The damage may be lethal, in which the cell  is killed by radiation; potentially lethal, in which the cell is so  severely affected by radiation that modifications in its envi-  ronment will cause it to die; or sublethal, in which the cell can  subsequently repair itself. Cellular compartments with rapidly  renewing cells are, in general, more radiosensitive. Effective cell  killing by radiation also requires good local delivery of oxygen,    something not always present in large cancers. Radiation pro-  duces slow changes in most cancers and irreversible changes in  normal tissues as well. Because of these irreversible changes,  each tissue has a maximum lifetime dose of radiation it can tol-  erate. Radiation is well suited to treat localized disease in areas  that are hard to reach surgically, for example, in the brain and  pelvis. A number of radiation delivery methods are available,  with external beam being the most common. Radiation sources,  such as small !?°I-labeled capsules (also called seeds), can also be  temporarily placed into body cavities, a delivery method termed  brachytherapy. Brachytherapy is useful in the treatment of cer-  vical, prostate, and head and neck cancers.   Radiation therapy and chemotherapy may affect the gam-  etes, leading to varying degrees of decreased fertility and pre-  mature menopause. These effects are dose and age dependent,  with the prepubertal gonad thought to be more resistant to  damage. The potential for harm also is dependent on the agent  used, with the alkylating category of chemotherapies carrying  the greatest risk. Craniospinal irradiation for central nervous  system tumors also may affect the hypothalamus or pituitary  gland, with subsequent secondary gonadal failure because  of lack of production of gonadotropin-releasing hormone,  luteinizing hormone, and follicle-stimulating hormone. The  potential for reproductive harm should be addressed before  therapy, if possible, with provisions made for sperm or embryo  banking.   Surgery plays many roles in the care of individuals with cancer.  The multiple approaches to obtaining tissue for diagnosis have  been discussed. Surgery is often the definitive treatment of can-  cers that do not spread beyond the limits of surgical excision. It is  also indicated for the relief of symptoms, such as those caused by  tumor mass obstruction. In selected high-risk diseases, surgery  plays a role in the prevention of cancer. For example, individuals  with familial adenomatous polyposis because of germline muta-  tions of the APC gene have close to a 100% lifetime risk of colon  cancer, so a prophylactic colectomy is indicated. Similarly,  women with BRCA1/2 mutations have a markedly increased  risk of breast and ovarian cancer, and often choose prophylac-  tic mastectomy or bilateral salpingo-oophorectomy (removal of  ovaries and fallopian tubes), or both.”   Key principles apply specifically to cancer surgery, including  obtaining adequate surgical margins during a resection to pre-  vent local recurrences, placing needle tracks and biopsy incision  scars (that may be contaminated with cancer cells) carefully  so they can be removed in subsequent incisions, avoiding the  spread of cancer cells during surgical procedures through care-  ful technique, and paying attention to obtaining adequate tissue  specimens during biopsies so that the pathologist can be confi-  dent of the diagnosis. Additionally, the surgeon provides criti-  cal staging information by inspection, sampling, and removal of  local and regional lymph nodes during procedures.   1. Benign tumors are usually encapsulated and well differenti-  ated and do not spread to distant locations.   2. Malignant tumors, compared with benign tumors, have  more rapid growth rates, specific microscopic alterations  (anaplasia, loss of differentiation), absence of normal tissue  organization, and no capsule; they invade blood vessels and  lymphatics and have distant spread.   3. Carcinomas arise from epithelial tissue, and leukemias  are cancers of blood-forming cells. CIS refers to prein-  vasive epithelial tumors of glandular or squamous cell  origin.   4. Localized cancer is considered low stage, whereas cancer  that has spread regionally and distantly is termed stage 3 and  stage 4, respectively.   5. Cancer cells are characterized by anaplasia, or loss of differ-  entiation, and autonomy, or independence, from normal cel-  lular controls.   6. In the adult, undifferentiated cells not committed to a spe-  cific function are known as pluripotent cells, precursor cells,  or adult stem cells. Cancerous growth depends on derange-  ments of cell differentiation.   7. Tumor markers are substances (ie., hormones, enzymes,  genes, antigens, antibodies) found in cancer cells and in  blood, spinal fluid, or urine. They are used to screen and  identify individuals at high risk for cancer, to help diagnose  specific types of tumors, and to follow the clinical course of  cancer.   1. Genetic events are the primary basis of carcinogenesis.  Mutations in cancer-causing genes accumulate with age,  causing the increasing risk of cancer with advanced age.   2. Epidemiologic and molecular data suggest it takes five or six  distinct mutations in different signaling pathways to pro-  duce cancer. Mutations activate growth-promotion path-  ways, block antigrowth signals, prevent apoptosis, turn on  telomerase and new blood vessel growth, and allow tissue  invasion and distant metastasis.   3. In rare families, cancer is inherited in an autosomal domi-  nant fashion as a result of mutations in tumor-suppressor  genes such as TP53, RB1, and BRCAI.   4. Proto-oncogenes encode for growth factors (e.g., PDGF),  growth factor receptors (e.g., HER2), signal transducers (e.g.,  RAS), and nuclear growth-promoting proteins (e.g., MYC).   5. Three key genetic mechanisms have a role in human car-  cinogenesis: (a) activation of proto-oncogenes resulting in  hyperactivity of growth-related gene products (such genes  are called oncogenes); (b) mutation of genes resulting in loss  or inactivity of gene products that normally would inhibit  growth (such genes are called tumor-suppressor genes); and  (c) mutation of genes resulting in overexpression of prod-  ucts that prevent normal cell death, or apoptosis, thus  allowing continued growth of tumors.   6. Tumor-suppressor genes encode for proteins that act as  inhibitors of growth factor stimulation. Tumor-suppressor  gene proteins block specific phases of the cell cycle, induce   Carcinogenesis, or the development of cancer, involves  both inactivation of tumor-suppressor genes (usually by  loss of heterozygosity, or by “silencing”) and activation of  oncogenes.   Epigenetic changes in genes by DNA methylation and cova-  lent histone modification can mimic mutation by heritably  inactivating tumor-suppressor genes.   Like many normal adult tissues, cancers can contain rare  stem cells. To fully eradicate a cancer, it may be necessary to  target the cancer stem cell.   Caretaker genes are responsible for maintaining genomic  integrity. Inherited mutations can disrupt caretaker genes  and cause chromosome instability.   A number of viruses can cause cancer. Human cervical can-  cer is caused by papillomavirus infection. Kaposi sarcoma  is caused by infection with HHV8, a member of the Her-  pesviridae family. Chronic hepatitis infection with HBV or  HCY is the leading cause of liver cancer.   Defects in the immune system increase the risk of viral-  associated cancers but have a minimal effect on the risk of  other cancers.   Active inflammation predisposes to cancer by stimulating  a wound-healing response that includes proliferation and  new blood vessel growth.   Vaccinations can prevent hepatitis B—associated liver cancer  and many human papillomavirus-caused cervical cancers.  Chronic H. pylori—associated inflammation causes stomach  cancer and a rare lymphoma.   Metastasis is the major cause of death from cancer.  Cancers metastasize by several routes, including direct  invasion and spread through lymphatics and veins.  Metastasis is a complex process that requires cells to have  many new abilities, including the ability to invade, survive,  and proliferate in a new environment and recruit new blood  vessel growth.   Carcinomas undergo a process of epithelial-mesenchymal  transition (EMT) during which many epithelial-like charac-  teristics are lost (e.g., polarity, adhesion to basement mem-  brane) resulting in increased migratory capacity, increased  resistance to apoptosis, and dedifferentiation to a stem cell—  like state that favors growth in foreign microenvironments  and establishment of metastatic disease.    Clinical manifestations of cancer include fatigue, pain,  cachexia, anemia, leukopenia, thrombocytopenia, and  infection.   Paraneoplastic syndromes are rare symptom complexes often  caused by release of active substances from or stimulation of  an immune response by a cancer that causes symptoms not  directly produced by the local effects of the cancer.   Pain is generally associated with the late stages of can-  cer. It can be caused by pressure, obstruction, invasion of a  structure sensitive to pain, stretching, tissue destruction, and  inflammation.   Fatigue is the most frequently reported symptom of cancer  and cancer treatment.   Cachexia (loss of appetite, early satiety, weakness, inability to  maintain weight, taste alterations, altered metabolism) leads  to protein-calorie malnutrition and progressive wasting.  Anemia associated with cancer usually occurs because of  malnutrition, chronic bleeding and resultant iron deficiency,  chemotherapy, radiation, and malignancies in the blood-  forming organs.   Leukopenia is usually a result of chemotherapy (which is  toxic to bone marrow) or radiation.   Infection may be caused by leukopenia, immunosuppres-  sion, or debility associated with advanced disease. It is the  most significant cause of complications and death.    Cancer is treated with surgery, radiation therapy, chemother-  apy, and combinations of these modalities.   The theoretic basis of chemotherapy is the vulnerability of  tumor cells in various stages of the cell cycle. The goal of che-  motherapy is to eradicate enough tumor cells so the body’s  natural defenses can eradicate remaining cells.   Modern chemotherapy uses combinations of drugs with dif-  ferent targets and different toxicities.   A new generation of specific targeted drugs attacks targets  identified by the molecular analysis of cancers.   Ionizing radiation causes cell damage, so the goal of radia-  tion therapy is to damage the tumor without causing exces-  sive toxicity or damage to undiseased structures.   Surgical therapy is used for nonmetastatic disease, for which  cure is possible by removing the tumor, and asa palliative mea-  sure to alleviate symptoms.    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Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Animations  Model for Activation of the ras Gene  Pathogenesis of Metastasis  Protooncogene Regulation of Cellular Function  Six Hallmarks of Cancer    Genetics, Epigenetics, and Tissue, 403  Incidence and Mortality Trends, 409  Incidence Trends, 409  Mortality Trends, 410  In Utero and Early Life Conditions, 410  Environmental-Lifestyle Factors, 413  Tobacco Use, 413  Diet, 414    Although cancer arises from a complicated and an interact-  ing web of multiple etiologies, avoiding high-risk behaviors  and exposure to individual carcinogens, or cancer-causing  substances, will prevent many types of cancer (Figure 13-1).!°  Research has shown that lifestyle behaviors, dietary and envi-  ronmental factors (such as exposure to ultraviolet radiation and  infections), and occupational exposure contribute to the num-  ber of cancer cases and deaths.*° In this context, any of the fol-  lowing factors can contribute to the development of cancer”:  * Lifestyle choices, such as nutritional intake, smoking, or  alcohol use  + Environmental conditions, including exposure to sun-  light, natural and medical radiation, workplace expo-  sures, and involuntary or unknown exposures  * Lack of physical exercise and overweight/obesity   The question of estimating the environmentally attributable  risk for cancer is deceptive because such estimates vary tremen-  dously as a result of the definition of the environment used.  Therefore, another way of examining what portion of cancer  risk is attributable to the environment involves asking, “What is  not attributable to the environment?”!” In this context, it is usu-  ally those cancers caused by highly penetrant genes; inherited  mutations very rarely predispose us to cancer.!!"!4 The Inter-  national Agency for Research on Cancer (IARC) completed a  review of the more than 100 chemicals, occupations, physical    FIGURE 13-1 Key Causes of Cancer. Tobacco, diet and alcohol, obesity, lack of physical activity, hormones, infections,  ionizing radiation, occupational hazards, reproductive factors, and ultraviolet light are key causes of cancer.    agents, biologic agents, and other agents classified as carcino-  genic to humans.’ Simplified tables with a list of classifications  by cancer sites with sufficient or limited evidence in humans are  contained in Table 13-1.    Cancers are caused by environmental-lifestyle behaviors and  by exposures and genetic factors. Cancer is driven by genetic  alterations and epigenetic abnormalities (see Chapter 12).!>'®  These changes are mitotically and meiotically heritable!’”° (see  Chapter 4). Although driver and passenger genetic alterations  are key, a wealth of data now indicate the importance of epi-  genetic processes, especially those with resultant gene silencing  (not broken, but mute) of key regulatory genes (see Chapters  6 and 12 and Figure 13-2).   There has been intense scrutiny of the biology of aberrant  gene silencing and associated environmental factors. Much  research has focused on the abnormal appearance of an epi-  genetic alteration—DNA methylation (the addition of a methyl  group [CH;])—in the proximal promoter regions of associated  genes (see Figure 13-2, B). Some of these genes are known as  key tumor-suppressor genes.!*!°7! The promoter DNA hyper-  methylation and gene silencing (ie., epigenetic alterations)    cause a loss of function and this loss facilitates tumor initiation  and progression!*'®?! (see Chapter 11).   Cancer development and progression involves the tissue micro-  environment or stroma (see Chapter 12). The microenvironment  participates in a complex signaling process that facilitates tumor  promotion and metastasis because stromal tissue has various  immune cells. Extensive clinical and experimental evidence shows  that infiltrating immune cells cause chronic inflammation and,  therefore, create a permissive tumor-progressing environment.  Chronic inflammation also can precede and presumably initi-  ate malignant change, as for example in inflammation-induced  colon cancer.” It is well documented that chronic inflammation  induced by bacteria, viruses, autoimmune processes, and toxins  promotes common types of cancer, including colon, liver, and  lung cancer. Inflammation can be caused by numerous environ-  mental factors, for example, inhaling tobacco smoke, asbestos  fibers, or fine particles in the air from diesel engine exhaust and  industrial sources. These sources are major factors in lung and  other respiratory tract cancers.?>** Cancer development in the  presence of chronic inflammation involves the continuous pres-  ence of cytokines, chemokines, reactive oxygen species (ROS),  oncogenes, cyclooxgenase-2 (COX-2), 5-lipoxygenase (5-LOX),  and matrix metalloproteinases (MMPs) as well as the activation of    TABLE 13-1 LIST OF CLASSIFICATIONS BY CANCER SITES WITH SUFFICIENT OR LIMITED    Lip, Oral Cavity, and Pharynx  Lip  Oral cavity Alcoholic beverages  Betel quid with tobacco  Betel quid without tobacco  Human papillomavirus type 16  Tobacco, smokeless  Tobacco smoking  Salivary gland X-radiation, y-radiation  Tonsil Human papillomavirus type 16  Pharynx Alcoholic beverages  Betel quid with tobacco  Human papillomavirus type 16  Tobacco smoking  Nasopharynx Epstein-Barr virus  Formaldehyde  Salted fish, Chinese-style  Wood dust  Digestive tract, upper Acetaldehyde associated with consumption of alcoholic beverages   Esophagus Acetaldehyde associated with consumption of alcoholic beverages  Alcoholic beverages  Betel quid with tobacco  Betel quid without tobacco  Tobacco, smokeless  Tobacco smoking  X-radiation, y-radiation    Colon and rectum Alcoholic beverages  Tobacco smoking  X-radiation, y-radiation  Anus Human immunodeficiency virus type 1  Human papillomavirus type 16  Liver and bile duct Aflatoxins  Alcoholic beverages  Clonorchis sinensis  Estrogen-progestogen contraceptives  Hepatitis B virus  Hepatitis C virus  Opisthorchis viverrini  Plutonium  Thorium-232 and its decay products  Tobacco smoking (in smokers and in smokers’ children)  Vinyl chloride  Gallbladder Thorium-232 and its decay products  Pancreas Tobacco, smokeless  Tobacco smoking   Nitrate or nitrite (ingested) under conditions that  result in endogenous nitrosation   Radium-226 and its decay products  Radium-228 and its decay products  Tobacco smoking   Bis(chloromethyl) ether; chloromethy! methyl ether (technical grade)  Cadmium and cadmium compounds   Radium-224 and its decay products  Radium-226 and its decay products  Radium-228 and its decay products  X-radiation, y-radiation   Human papillomavirus types 5 and 8 (in individuals  with epidermodysplasia verruciformis)    TABLE 13-1 LIST OF CLASSIFICATIONS BY CANCER SITES WITH SUFFICIENT OR LIMITED  EVIDENCE IN HUMANS—cont’d   Human papillomavirus 16  Diethylstilbestrol (exposure in utero)  Human papillomavirus 16  Diethylstilbestrol (exposure in utero)  Estrogen-progestogen contraceptives  Human immunodeficiency virus type 1    Human papillomavirus types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59    Aristolochic acids, plants containing phenacetin  Phenacetin, analgesic mixtures containing  Tobacco smoking    Human papillomavirus types 26, 53, 66, 67, 68, 70,  73, 82  Tetrachloroethylene    Human immunodeficiency virus type 1  Human papillomavirus type 18  Androgenic (anabolic) steroids   Arsenic and inorganic arsenic compounds  Cadmium and cadmium compounds  Rubber production industry    Arsenic and inorganic arsenic compounds  Cadmium and cadmium compounds  Printing processes   Leukemia and/or lymphoma Azathioprine  Benzene  Busulfan  1,3-Butadiene  Chlorambucil  Cyclophosphamide  Cyclosporine  Epstein-Barr virus  Etoposide with cisplatin and bleomycin  Fission products, including strontium-90  Formaldehyde  Helicobacter pylori  Hepatitis C virus  Human immunodeficiency virus type 1  Human T-cell lymphotropic virus type 1  Kaposi sarcoma herpesvirus  Melphalan  MOPP (vincristine-prednisone-nitrogen mustard-procarbazine mixture)  Phosphorus-32  Rubber production industry  Semustine (methyl-CCNU)  Thiotepa  Thorium-23 and its decay products  Tobacco smoking  Treosulfan  X-radiation, y-radiation    Adapted from Cogliano VJ et al: J Nat! Cancer Inst 103:1-13, 2011. Available at http://jnci.oxfordjournals.org/content/early/2011/12/11/jnci.djr483.    Note: This table does not include factors not covered in the IARC Monographs, notably genetic traits, reproductive status, and some nutritional    FIGURE 13-2 Epigenetic Modulation and Modifications. A, Overview of the potential role of epigenetic modulation by  dietary and other environmental factors in cancer development. B, Epigenetic modulations’ model according to current knowledge.  The different types of chemical modifications, such as methylation or acetylation, of promoter regions and/or other regulatory  DNA sequences outside the gene can have severe impact on gene transcription and translation and a resultant high modulation of  gene expression and product (protein) functionality. (From World Cancer Research Fund/American Institute for Cancer Research:  Food, nutrition, physical activity, and the prevention of cancer: a global perspective, Washington, DC, 2007, AICR.)    Investigators are working hard to understand and connect  the complex and intricate relationships between genotype, phe-  notype, and the environment in order to understand a person’s  chances of developing cancer (see Figure 13-2, A and B). The  root cause of cancer is more than inherited or acquired genetic    mutations and involves epigenetic changes that frequently precede  and induce cancer-causing genetic mutations.*> The past decade  has highlighted the major role epigenetic processes play in can-  cer initiation, progression, and treatment.”° Additionally, if these  early epigenetic alterations can be detected and reversed, cancer    may be prevented. In the 1980s, cancer biologist Stephen Baylin  hypothesized that if a tumor-suppressor gene is hypermethylated  its activity would decrease or stop entirely. Firm evidence came  in 1994 when Baylin and oncologist James Herman showed that  20% of the individuals with the noninherited form of renal cell  carcinoma (RCC) did not have a mutation in von Hippel-Lindau  and their genes were silenced not by a mutation but rather by epi-  genetic hypermethylation.”° These and many other investigators’  stunning experiments and observations have changed the biology  of cancer dramatically! The paradigm shift from a genetic to an epi-  genetic model is critical for prevention strategies because these changes  are potentially reversible and may precede genetic mutations. Inves-  tigators are linking epigenetic abnormalities to mutations in genes  that control DNA methylation, the packaging and the function  of DNA in chromatin, and metabolism’? (see Chapter 12). We  know that environmental contaminants can damage the immune  system, altering signaling processes that facilitate tumor prolif-  eration. At the interface of environment and genetics is chronic  inflammation. Inflammation has been linked with increased  DNA methylation, an epigenetic alteration. A notable example is  found in persons with ulcerative colitis, who can develop colon  cancer at an age younger than the 60- to 70-year average. The epi-  genetic changes that occur in colon cancer, including DNA hyper-  methylation and gene silencing, are accelerated and appear in the  inflamed tissue before the actual cancer.’”-?    Cancer is reported to become a major cause of morbidity and  mortality in the coming decades in all regions of the world  (What’s New? Global Cancer Transitions).*° In the National  Cancer Institute’s 2011 annual report to the nation, trends  were reported for all cancers combined, for childhood can-  cers, and for the top 15 cancers for each of the major racial    and ethnic groups by gender.*! The report also presents inci-  dence of malignant and nonmalignant brain tumors in chil-  dren and adults by race, gender, age group, and histologic  type. Overall, cancer incidence rates for all racial and eth-  nic groups combined decreased by 0.8% per year during the  most recent study period, 2003 to 2007. A significant decrease  of 0.6% per year was noted in women and a nonsignificant  decrease of 0.8% per year was noted in men influenced by a  nonsignificant increase in prostate cancer incidence (2005 to  2007).°! The most frequently diagnosed cancers, prostate and  breast, showed possible changing trends. Cancer of the prostate  showed a nonsignificant annual increase of 3.0% for the period  2005 to 2007 after a significant decrease for the period 2001  to 2005. Breast cancer showed a decrease from 1999 to 2007  after a sharp decrease in 2002 to 2003; the lower rates thereafter  remained stable. The cancer rates among children (from birth  to age 19 years) showed an increase of 0.6% per year for the  entire period of 1992 to 2007. The long-term increase in cancer  incidence rates in children is possibly related to increases in  lymphoid leukemias and a smaller increase in other childhood  cancers?! (see Chapter 14).   From the period 2003 to 2007, 5 of the 15 most common can-  cers among men—lung and bronchus (lung), colorectal, oral  and pharynx (oral), stomach, and malignant brain tumors—  showed a significant decrease. Significant increases among men  in the period 2003 to 2007 included melanoma of the skin,  kidney and renal pelvis (kidney), pancreas, and liver and intra-  hepatic bile duct (liver). Cancers that had neither an increase  nor a decrease in the period 2003 to 2007 included prostate (see  preceding paragraph), bladder, esophageal cancers, leukemia,  myeloma, and non-Hodgkin lymphoma.   Significant, increasing trends among women were noted in  three of the four cancers increasing in men (kidney, pancreas,  and melanoma of the skin); leukemia and thyroid cancer also  increased.*! Significant decreasing trends occurred with cancers    The United Nations has estimated that the global population will reach 7 billion  by 2012 and 8.3 billion by 2030. Population aging and growth will be greatest  in low- and middle-income countries. Researchers used four levels of a Human  Development Index [HDI] (low, medium, high, and very high), as an indicator of life  expectancy, education, and gross domestic product per head, to present an over-  view of global patterns of cancer incidence and mortality. This important report is  the first of its kind to present this global overview. These statistics may translate  toa global incidence of 20.3 million new cancer cases by 2030 (compared with an  estimated 12.7 million cases in 2008) and a predicted 13.2 million cancer-related  deaths worldwide by 2030, an increase from the 7.6 million cancer-related deaths  in 2008. In both high HDI and very high HDI regions, four cancers (female breast,  lung, colorectal, and prostate cancers) explain almost half of the overall cancer  burden. In medium HDI regions, lung and female breast cancers are the most com-  mon types of cancer along with stomach and liver cancers. In low HDI regions,  female breast and liver cancers also are common, as well as the infection-related  cancers cervical cancer and Kaposi sarcoma. In these low HDI regions, cervical  cancer was more common than both breast cancer and liver cancer. Across 184    countries, 9 different cancers were most commonly diagnosed in men, including  the 3 most common—prostate, lung, and liver cancers. Breast and cervical can-  cers were the most common in women. In medium HDI and high HDI settings, the  decreases in incidence of cervical and stomach cancers seem to be offset by the  rising increases in incidence of female breast, prostate, and colorectal cancers.  The reduction in infection-related cancers appears to be offset by simultaneous  increases in cancers related to the “western lifestyle” and changes in tobacco  consumption and the effect on lung and other cancers.  Targeted interventions can substantially reduce the incidences of cancers  worldwide and include primary prevention strategies to decrease or eliminate  certain lifestyle factors—including tobacco avoidance and cessation of smok-  ing, reduction in the number of obese individuals, reduction in alcohol intake,  increase in physical activity, and implementation of vaccination programs for liver  and cervical cancer as well as effective early detection programs for colorectal,  breast, and cervical cancer. Reductions in mortality could be implemented that  increase access to curative treatment because provision of palliative care for  those individuals dying of cancer will help to reduce population inequities.    Data from Bray F et al: Lancet Oncol 13(8):790-801, 2012; Ferlay J et al: Int J Cancer 127:2893-2917, 2010.    of the breast, lung, colon or rectum, uterus, cervix, bladder, and  oral cavity. No significant trends were observed in non-Hodgkin  lymphoma, ovarian cancer, and malignant brain tumors.°!   This current analysis shows the relative stability of long-  term trends of malignant brain tumors of the neuroepithelial  tissue. From the period 1980 to 2007, brain tumors increased  1.9% per year during 1980 to 1987 followed by a decrease of  0.4% per year during the remaining 20 years. Yet, marked dif-  ferences occurred for histologic groups of brain tumors because  of changing diagnostic methods, pathologic coding schemes,  and classifications. Better classifications have enabled progress  in understanding the pathogenesis of malignant gliomas.*! The  trends in nonmalignant tumors are not now known because  they only became reportable on a national level in 2004.°!    Since the mid-1970s, cancer death rates have decreased for  children. Long-term (1975 to 2007) trends in death rates con-  tinued to decrease in children, although at a slower rate in the  recent decade*! (see Chapter 14). Death rates from the periods  1998 to 2007 and from 2003 to 2007 continued to decrease for  7 of the top 15 cancer types in both men and women (colorec-  tal, brain, stomach, and kidney cancers; non-Hodgkin lym-  phoma; leukemia; and myeloma).°*! Decreasing death rates  for men also included lung, prostate, and oral cavity, and for  women breast and bladder cancers. Overall, however, death  rates continued to increase for cancers of the liver and pan-  creas among men and women, for uterine cancer in women,  and for melanoma of the skin in men.*! Importantly, lung can-  cer death rates in women showed a significant decrease during  the period 2003 to 2007, following long-term increases during  the period 1975 to 2003.    From studies of the etiology of certain cancers, it is widely  accepted that a long latency period precedes the onset of adult  cancers. Accumulating data suggest early life events influence  later susceptibility to certain chronic diseases.** Throughout in  utero development, the placenta plays a major role in control-  ling growth and development.°’ Because the placenta is a reg-  ulator of the intrauterine environment and can be influenced  by exposures throughout pregnancy,*’ much research is being  done with DNA methylation linking environmental cues to pla-  cental pathologies and adult life (Figure 13-3).   Children may be affected by prenatal exposures, parental  exposures before conception, and exposure to breast milk.  Developmental plasticity is the degree to which an organism’s  development is contingent on its environment. It requires stable  gene expression that in part appears to be modulated by epigen-  etic processes such as DNA methylation and histone modifi-  cation (Figure 13-4).°* Sensitivity to environmental-lifestyle  factors influences the mature phenotype and is dependent  on the interactions of both the genome and the epigenome.  Abnormal DNA hypermethylation in cancer is noted in many  genes important to embryonic development.” Although the  developing embryo is protected from the physical and chemical    toxins or dangers of the outside environment by the uterine  environment, elements of the maternal diet, drugs, or acci-  dentally ingested and/or inhaled toxins can be delivered to  the embryo through the maternal circulation.** Known envi-  ronmental effects include drugs, such as valproic acid (VPA,  an anti-epileptic),*° or the effects of high maternal alcohol  consumption.°°°7   Perhaps one of the best examples of early life events and  future cancer is the chemical exposure to diethylstilbestrol  (DES), a synthetic estrogen. This medication was prescribed  between 1938 and 1971 to attempt to prevent multiple preg-  nancy-related problems, such as miscarriage, premature birth,  and abnormal bleeding.** By the 1950s it became clear that DES  interfered with the development of the reproductive system in  the fetus and it did not prevent miscarriage. Recent data sug-  gest that DES-associated increase in clear cell adenocarcinoma  is elevated throughout a woman’s reproductive years.*’ More  recent studies have revealed that daughters of women who took  DES during pregnancy may have a slightly increased risk of  breast cancer before age 40 (ie., 1.9 times the risk compared  with unexposed women at age 40).*° For every 1000 DES-  exposed women ages 45 to 49 it is estimated that 4 will be diag-  nosed with breast cancer.   Research from animal studies has demonstrated a relation-  ship between DES exposure and an increased rate of a rare  type of testicular cancer (rete testis) and prostate cancer.*)? In  terms of in utero exposures, testicular cancer has been linked to  exposure to abnormal levels of estrogen,” and testicular cancer  is a risk factor for men with undescended testicles, a factor in  some studies correlated with DES exposure. However, studies  in humans determining the risk of testicular or prostate cancer  and DES exposure are unclear and continuing.“   Additionally, investigators are studying diet during preg-  nancy. Recently, a striking experiment in mice demonstrated  how extra vitamin doses during pregnancy in the mother’s diet  changed the fur color of her pups.*° This was the first study to  show maternal nutrition and subsequent phenotype changes.  The nutrients (Bj, folic acid, choline, and betaine) silenced  the gene that rendered mice fat and yellow but did not alter its  DNA sequence. Silencing, or switching the gene off, linked pre-  natal diet to such diseases as diabetes, obesity, and cancer. These  concepts, called the developmental basis of health and disease,  are defining the hypothesis of disease onset. Subsequently, the  focus of disease prevention and intervention needs to include  the decades before onset—that is, during the in utero and neo-  natal periods.   In summary, epidemiologic and animal studies reveal that  small changes in the developmental environment can alter phe-  notypic changes, resulting in individual responses in adulthood.  Continuing evidence indicates that epigenetic mechanisms are  responsible for tissue-specific gene expression during cellular  differentiation and that these mechanisms modulate develop-  mental phenotypic changes. The phenotypic effects of epigen-  etic modifications during development may need long latency  periods, such as in cancer, thus manifesting later in life. In  addition, epigenetic effects may help explain transgenerational  effects (Tables 13-2 and 13-3).    FIGURE 13-3 Pro- and Anti-Cancer Effects. (From World Cancer Research Fund/American Institute for Cancer Research:  Food, nutrition, physical activity, and the prevention of cancer: a global perspective, Washington, DC, 2007, AICR.)    It should be noted that lifestyle habits are modifiable and  that changing them can translate to reduced cancer risk, but a  critical question is whether we are intervening early enough in  life to achieve benefits.! Protective measures in very young and  young people—for example, avoiding sun exposure during peak  hours (10 aM to 3 pM) and covering the skin whenever possible,    increasing physical exercise, and avoiding high-risk sexual prac-  tices, will reduce cancer incidence. Understanding that it takes  years to develop tumors, cancer prevention beginning early in  life will help reduce the burden of cancer on individuals and  society! (see What’s New? Preventing Cancer—Protecting the  Health of Current and Future Generations).    FIGURE 13-4 Fetal Vulnerability to External and Internal Environments.  The fetus is particularly vulnerable to changes in the external and internal envi-  ronments, which can have immediate and lifelong consequences. Such environ-  mentally induced changes can occur at multiple levels, including molecular and  behavioral. Ultimately these alterations may be epigenetic, inducing mitotically  heritable alterations in gene expression without changing the DNA. (Adapted from  Crews E, McLachlan JA: Endocrinology 147[6 Suppl]:S4—S10, 2006.)    Essentials for preventing cancer include eliminating smoking, decreasing obe-  sity, promoting exercise, eliminating infections, and avoiding an unhealthy  diet.   Interventions targeting lifestyle behaviors for cancer prevention are crucial.  Continued efforts are needed to educate students and clinicians to target  high-risk patients and promote prevention in pregnant women and in women,  men, and children.   Additionally, efforts must also focus more broadly than just smoking, lifestyle  behaviors, and chemopreventive interventions.   Establish a national cancer prevention strategy and redirect accordingly both  research and policy agendas.   Create a more integrated, coordinated, and transparent system for promulgat-  ing and enforcing environmental contaminant policy and regulations, driven  by science and free of political or industry influence.   Set tangible goals for reducing or eliminating toxic environmental exposures  in cancer causation.   The Kids Safe Chemical Act is an important first step toward a precautionary  chemicals’ management policy.   Shift the burden of proving safety to chemical manufacturers before new  chemical approval.   Increase concordance of exposure measures and standards to facilitate inter-  agency and international regulatory policy and enforcement.    Increase information sharing among the public, researchers, regulatory agen-  cies, industry, and other appropriate groups.   Involve environmental and public health advocates in developing environmen-  tal cancer research, policy agendas, and information dissemination.  Strengthen research on workplace exposures and on the impact of in utero  and childhood exposures that appear to have multigenerational effects.  Accelerate the development of new research models and endpoints to better  quantify exposures at individual, occupational, and population levels.  Scientists disagree about cancer risk attributable to various environmental  exposures. The unequal burden of exposure to known and suspected carcino-  gens must be addressed.   Cancer risk should include geographic areas and vulnerable populations  (including, but not limited to, children, migrant and other farm workers, cancer  “hotspots,” socioeconomic differences).   Actions to minimize radiation exposure from medical sources include the edu-  cation of healthcare providers, radiology technicians, and the public about  the extent of radiation exposure from commonly used imaging and nuclear  medicine examinations. Radiation dose—lowering techniques and inspection  of radiation-emitting equipment must be implemented.   Healthcare providers, especially physicians, nurse practitioners, and physi-  cians’ assistants, should routinely query patients about their previous and  current workplace and home environments.   Public health messages need development and dissemination to raise aware-  ness of environmental cancer risks.    *Data from 2008-2009 Annual Report, President's Cancer Panel: Reducing environmental cancer risk. What we can do now (Suzanne H. Reuben  for the President's Cancer Panel), U.S. Department of Health and Human Services, NIH, NCI, April 2010.    Cigarette smoking is carcinogenic and remains the most impor-  tant cause of cancer. Tobacco accounts for nearly one in five  deaths,*° yet it is the single most preventable cause of death  and disease in the United States.*’ The risk is greatest in those  who begin to smoke when young and continue throughout life.  Globally, tobacco use accounts for 80% of the worldwide lung  cancer burden in males and about 50% in females.***? Male  lung cancer death rates are decreasing in most Western coun-  tries and increasing in China and several other Asian and Afri-  can countries. However, the highest lung cancer incidence rates  are still found in North America, Northern Europe, and Aus-  tralia/New Zealand.°° Rates in females are increasing in many  countries including Spain, France, Belgium, and the Nether-  lands and are now plateauing in the United States, Canada, and  the United Kingdom. Overall, lung cancer rates in females lag  behind males where females started smoking later than males.°°  Half of all long-term smokers die prematurely from smoking-  related causes, and for every person who dies from tobacco use  another 20 people suffer with at least 1 serious tobacco-related  illness.°! The prevalence of current smoking among U.S. adults  declined from 24.7% in 1997 to 18.9% in 2011.°* Non-Hispanic  white adults were the most likely to be current smokers fol-  lowed by non-Hispanic black adults and Hispanic adults.°*  Forms of tobacco used in the United States include ciga-  rettes, cigars, pipes, and imported nonconventional cigarettes  (e.g., bidis and clove cigarettes). Besides lung cancer, tobacco  use increases the risk for cancers of the mouth, lips, nasal cav-  ity and sinuses, larynx, pharynx, esophagus, stomach, pancreas,  kidney, bladder, uterus, cervix, colorectum, and ovaries as well  as acute leukemia.*° The relationship between breast cancer and  smoking has been the subject of much controversy and conflict-  ing epidemiologic reports published since 2002, partially from  confounding with alcohol use. Reanalyses of evidence from  recent cohort studies suggest an increased risk of breast cancer  related to smoking independent of alcohol use.*’ In younger  premenopausal women an increased risk of breast cancer was  related to exposure to passive smoke.°’ Biologic mechanistic  studies also support a positive association between cigarette  smoking and breast cancer.’ A 2009 Report from the Canadian  Expert Panel on Tobacco Smoke and Breast Cancer Risk con-  cluded from epidemiologic and toxicologic studies and biologic  understandings that both pre- and postmenopausal breast can-  cers are consistent with causality.°* In addition, smoking causes  even more deaths from vascular diseases (e.g., coronary heart  disease, peripheral vascular disease, abdominal aortic aneu-  rysm), respiratory diseases (e.g., emphysema, bronchitis, airway  obstruction), and other diseases than from cancer.  Secondhand smoke, also called environmental tobacco  smoke (ETS), is the combination of sidestream smoke (burn-  ing end of a cigarette, cigar, or pipe) and mainstream smoke  (smoke exhaled by the smoker). More than 4000 chemicals have  been identified in mainstream tobacco smoke (250 chemicals as  toxic),°° of which 60 are considered carcinogenic.°° Nonsmok-  ers who live with smokers are at greatest risk for lung cancer    as well as numerous noncancerous conditions.°” One in vitro  study supported a relationship between nicotine and genotoxic  effects in fetal cells.°* Other studies are emerging on the rela-  tionship of both maternal and paternal smoking and in utero  effects. Smoking during pregnancy causes lower birth rates, an  increased incidence of spontaneous abortion and preterm birth,  increased placental pathology, and increased stillbirth rates.°”   Cigar or pipe smoking, or both, is strongly and causally  related to cancers of the oral cavity, oropharynx, hypophar-  ynx, larynx, esophagus, lung, and probably the pancreas.” Pipe  smokers have an increased risk of dying from cancers of the lung,  throat, esophagus, larynx, pancreas, and colorectum.*! Smoking  bidi, a small amount of tobacco wrapped in the leaf of another  plant (used in South Asia), delivers higher amounts of nicotine  per gram of tobacco and comparable or greater amounts of tar  compared with cigarettes.°* Bidi smokers have the same risks of  cancers and higher risks of heart attacks and chronic bronchitis  than those found in nonsmokers.°? Several types of cancers have  been linked to hookah or water pipe smoking.“   United Kingdom researchers reported for the first time that  starting smoking results in epigenetic changes associated with  the development of cancer.°? These researchers showed that  smoking increased DNA methylation. Figure 13-5 illustrates a  working model of carcinogenesis by cigarette smoke. Measures    FIGURE 13-5 Working Model of Carcinogenesis by Cigarette Smoke. The  major inducer of both lung cancer and COPD is cigarette smoke. Nonsmokers may  develop these diseases caused by other environmental or genetic/epigenetic fac-  tors. Cigarette smoke induces an inflammatory response and causes an increase in  reactive oxygen species (ROS), causing oxidative stress. Oxidative stress is a risk  factor for many diseases because it can alter many cellular proteins. A combination  of immune-inflammatory signals and epigenetic events may increase the risk for  individuals with COPD developing lung cancer. (From Adcock IM et al: Respiration  81[4]:265-284, 2011.)   Foods containing folate  Foods containing lycopene  Foods containing selenium  Red meat    FIGURE 13-6 Summary of Convincing and Probable Judgments. (From World Cancer Research Fund/American Insti-  tute for Cancer Research: Food, nutrition, physical activity, and the prevention of cancer: a global perspective, Washington,    that prevent young adults from starting smoking would sub-  stantially avoid future disease burden. A strong public health  approach is one that prevents young people from starting smok-  ing and helps others stop smoking.   Understanding dietary factors that increase the risk for cancer  can be difficult. The ways in which diet affects one’s likelihood  of developing cancer are complicated by the variety of foods  consumed, the many constituents of foods, the metabolic con-  sequences of eating, and the temporal changes in the patterns  of food use. Cancer risks in older adults may depend as much  on diet in early life as on current eating practices. In addition,  studies in humans targeting diet and disease associations face a  variety of challenges including measurements of specific nutri-  ents, food types, and dietary patterns.   Dietary sources of carcinogenic substances include com-  pounds produced in the cooking of fat, meat, or protein, and  naturally occurring carcinogens associated with plant food sub-  stances, such as alkaloids or mold byproducts. Figure 13-6 is  a summary of convincing and probable judgments related to  food and physical activity risk factors and the prevention of  cancer. Dietary components can act directly as mutagens or  interfere with mutagen elimination. Abundant evidence exists    FIGURE 13-7 Basis for the Study of Food, Nutrition, Obesity, Physical  Activity, and the Cancer Process. The genetic message in the DNA code is  translated to RNA, and then into protein synthesis, and so determines metabolic  processes. Research methods, called “-omics,” address these different stages.  (Adapted from World Cancer Research Fund/American Institute for Cancer  Research: Food, nutrition, physical activity, and the prevention of cancer: a global  perspective, Washington, DC, 2007, AICR.)    that nutritional factors in many processes are related to cancer  development (Figure 13-7).   Research is ongoing to understand the complexity of genom-  ics, epigenomics, transcription factors (transcriptomics), pro-  teomics, and metabolic factors (metabolomics) and the way  that modifying any one, or more, influences cancer risk. Nutri-  genomics is the study of nutrition on the phenotypic variability    FIGURE 13-8 Food, Nutrition, Obesity, Physical Activity, and Cellular  Processes Linked to Cancer. Food, nutrition, and physical activity can influence  fundamental processes shown here, which may promote or inhibit cancer devel-  opment and progression. (Adapted from World Cancer Research Fund/American  Institute for Cancer Research: Food, nutrition, physical activity, and the prevention  of cancer: a global perspective, Washington, DC, 2007, AICR.)    of individuals based on genomic differences (see Figure 13-7).  Investigators are focusing on the sequence and functions of  genes, single nucleotide polymorphisms (SNPs), and amplifica-  tions and deletions within the DNA sequences as modifiers of  the response to foods and drinks and their components.   What we eat, how much we weigh, and how much we move  influence our risks of developing cancer. Mounting evidence is  clear—everyday choices impact our chances of getting or pre-  venting cancer. Ongoing tedious and comprehensive investiga-  tive work is linking diet, body weight, and exercise to risk of  specific cancers.   Nutrition. Important cellular processes affected by nutrition  include the cell cycle; the balance between cell proliferation and  cell death (e.g., apoptosis); cell differentiation; genes, including  oncogenes and tumor-suppressor genes; cell signaling; gene  expression; cellular microenvironment that influences gene  expression; epigenetic regulation; hormonal regulation; DNA  damage and repair; carcinogen metabolism; and inflammation  and immunity (Figure 13-8).   Gene expression is influenced by epigenetic processes like  DNA methylation or acetylation (addition of an acetyl group)  (see Chapters 6 and 12). Dietary sources of methyl groups  including folate, methionine, betaine, serine, and choline are  primary potential donors as modulators of DNA methylation  (Figure 13-9).   B vitamins, coenzymes in one-carbon metabolism (vitamins  By, Bg, By), also are modulators of DNA methylation. To  date there are limited human studies of the effects of methyl  donor supply on methylation of specific genomic sequences.®°  However, a recent study®’ found that periconceptional mater-  nal supplementation with 400 micrograms (mcg) of folic acid/  day was associated with increased methylation in offspring aged    FIGURE 13-9 Dietary Factors, DNA Methylation, and Cancer. Cer-  tain dietary factors (see Table 13-5) may supply methyl groups (+CH3) that can  be donated through S-adenosylmethionine (SAM) to many acceptors in the cell  (DNA, proteins, lipids, and metabolites). Donation and removal (demethylation)  are affected by numerous enzymes, including DNA methyltransferase (DNM7).  Increased DNMT activity occurs in many tumor cells. Hypermethylation can inhibit  or silence tumor-suppressor genes (see Chapter 12), and DNA methylation inhibi-  tors as anticancer agents can block DNMT, thus reactivating tumor-suppressor  genes. DNA hypomethylation can reactivate and mutate genes, including cancer-  causing oncogenes. SAH, S-Adenosylhomocysteine.    17 months. In the Waterland study, methylation effects were  found to be similar in all tissues examined, suggesting that the  mechanism may alter markings in stem cells early in embryo-  genesis before tissue differentiation, and persist into adult life.*”  Choline deficiency in pregnancy results in hypermethylation  of genomic DNA and of the IGF2 gene.°* Several studies have  reported that severe folate deficiency (which increases risk of  hepatocellular cancer) induces hypomethylation of the p53  tumor-suppressor gene.°’ In vitro studies have shown that  several bioactive food components, including tea polyphenols  and bioflavonoids, inhibit DNA methyltransferase (DNMT-  1)-mediated DNA methylation in a dose-dependent manner”  (see Figure 13-9). Acetylation and deacetylation are mediated  by enzyme histones (see Figure 6-1), histone acetyl transferase  (HAT), and histone deacetylation (HDAC). Dietary compo-  nents have been identified that act as regulators of gene expres-  sion by epigenetic mechanisms.’! For example, there is strong  evidence for the epigenetic effects of organosulfur compounds  from garlic and of isothiocyanates from cruciferous vegeta-  bles.”! Interest in reservatrol is growing because of its demon-  strable role in possibly delaying age-related diseases, including  cancers.’* Butyrate produced in the colon by bacterial fermen-  tation of non-starch polysaccharide (fiber), diallyl disulfide  from garlic and other allium vegetables, and sulforaphane from    cruciferous vegetables can act as histone deacetylase inhibitors  to maintain DNA stability or modify transcription.”   MicroRNAs (miRNAs) expression in response to diet may be  involved in several cancers.** Several dietary factors, including  macronutrients (fat, protein, and alcohol) and micronutrients  (folate and vitamin E), alter the expression of many miRNAs in  animals and humans® (see Chapter 12).   Bioactive components have a profound effect on differentia-  tion and a major area of investigation is on the differentiation of  cancer stem cells. Cancer stem cells have been isolated and iden-  tified in hematopoietic and epithelial cancers, including cancers  of the brain, breast, ovary, prostate, colon, and stomach.°+7°  Stem cells are found among most adult tissues, where they  maintain and regenerate tissues. Stem cells can remodel organs  in response to physiologic triggers—adaptive resizing.’* Cancer  stem cells utilize several developmental mechanisms for self-  renewal and these mechanisms appear to be fundamental to the  initiation and recurrence of tumors. Even if chemotherapy or  radiation eliminates cancer cells, it is only when the cancer stem  cells are destroyed that a full recovery is achievable.’> Repopu-  lation with radioresistant or chemoresistant stem cells may sig-  nificantly contribute to therapy resistance. Evidence from both  drug and bioactive food constituents shows modifications in  cancer stem cell self-renewal capabilities; for example, retinoic  acid may promote differentiation of breast cancer stem cells.”°  Adequate consumption of specific food compounds, including  vitamins A and D, genistein, green tea, epigallocatechin gal-  late (EGCG), sulforaphane, theanine, curcumin, choline, and    DNA repair aided by  retinoids/vitaminA,  vitamin D, folate,  coenzyme Qj, selenium    possibly many others, may suppress cancer stem renewal.’  Uncontrolled self-renewal process may be initiated by abnor-  mal developmental signals that come from the extracellular  microenvironment known as “niches.” The loss of regulation  in self-renewal signals, including Wnt, Notch, and hedgehog  pathways, is a characteristic of cancer stem cells.”° Various food  bioactive components can modulate the signaling pathway.   A variety of food constituents may influence DNA repair“  (Figure 13-10). Observational studies suggest that malnutri-  tion can reduce DNA repair from damage.’° In vivo studies  have demonstrated that healthy adults consuming kiwi fruits,  cooked carrots, or supplemental coenzyme Qj improved their  DNA repair.°* Consumption of lycopene-rich vegetable juice  was associated with significantly decreased damage to the DNA  of lung epithelial cells in healthy adults.””   Humans are constantly exposed to a variety of compounds  termed xenobiotics (Greek xenos, “foreign”; bios, “life”) that  include toxic, mutagenic, and carcinogenic chemicals. Many of  these chemicals are found in the human diet. Most xenobiot-  ics are transported in the blood by lipoproteins and penetrate  lipid membranes. These chemicals can react with cellular mac-  romolecules, such as proteins and DNA, or can react directly  with cell structures to cause cell damage.’* The body has two  main defense systems for counteracting these effects: (1) detox-  ification enzymes and (2) antioxidant systems (see Chapter  2). Enzymes that activate xenobiotics are called phase I acti-  vation enzymes and are represented by the multigene cyto-  chrome P-450 family, aldehyde oxidase, xanthine oxidases, and    M phase  M checkpoint  ensures each  daughter cell gets  correct DNA    Gp checkpoint stops cycle if  DNA is damaged or unreplicated  Cell can either repair DNA or  undergo apoptosis    Apoptosis promoted by  curcumin, quercetin, rutin,  polyphenols (resveratrol,  epigallocatechin gallate), vanilloids,  lycopene, organosulfur  compounds, isothiocyanates _    FIGURE 13-10 Cell Cycle and Nutrition Regulation. Nutrition may influence the regulation of the normal cell cycle,  which ensures correct DNA replication. Gp represents the resting phase, G, the growth and preparation of the chromosome  for replication, S the synthesis of DNA, G, the preparation of the cell for division, and M mitosis. (Adapted from World Cancer  Research Fund/American Institute for Cancer Research: Food, nutrition, physical activity, and the prevention of cancer: a global    peroxidases. Phase II detoxification enzymes then protect fur-  ther against a large array of reactive intermediates and nonacti-  vated xenobiotics.“ These enzymes are located predominantly  in the liver and provide clearance of compounds through the  portal circulation, thereby preventing the potentially carcino-  genic agent(s) from entering the body through the gastrointes-  tinal tract and portal circulation. They also occur in the skin  epithelia and can be induced in other extrahepatic tissue, such  as the lung. They represent a potential target to influence car-  cinogen metabolism. Isothiocyanates from cruciferous vegeta-  bles induce the expression of phase II detoxification enzymes.  Food and nutrition modify carcinogen metabolism and may  modify carcinogenesis. Some examples include selenium, allyl  sulfur, sulforaphane, and isoflavonoids. The enzyme CYP3A4  is involved in the metabolism of many drugs and is sensitive  to foods.®* Interactions, for example, have been reported for  grapefruit juice, red wine, garlic, and drugs.   Glutathione-S-transferases (GSTs) are enzyme housekeepers  involved in the metabolism of environmental carcinogens and  reactive oxygen species. Individuals who lack these enzymes  may be at higher risk for cancers because of decreased capac-  ity to dispose of activated carcinogens. For example, the fungi  that produce aflatoxins can grow on certain crops like peanuts  and certain cereal (grains) are carcinogens activated by phase  I enzymes in the liver that can produce DNA adducts. Indi-  viduals lacking these enzymes are at higher risk of colon can-  cer. Diets high in isothiocyanates (from cruciferous vegetables)  may decrease this risk.” Individuals who consume diets high  in red meat and processed meat and who carry certain genetic  polymorphisms have an increased risk of developing colorectal  cancer.°+*° Processed meats include those preserved by preser-  vatives or by smoking, curing, or salting. The European Pro-  spective Investigation into Cancer and Nutrition (EPIC) study,  which included 478,040 people from 10 countries, reports  that the most convincing data are from meats, including sau-  sages, bratwursts, frankfurters, and hot dogs, all of which have  nitrites, nitrates, or other preservatives. These N-nitroso com-  pounds can increase nitrogenous residues in the colon and  cause DNA damage.***! Dietary components either can be acti-  vated into potential carcinogens through metabolic processes  or can be inactivated and prevent DNA damage.” High intake  of red meat may result in the synthesis of higher levels of heme  iron; iron can activate oxidative stress and inflammation in the  colon. A new report suggests meat may have certain thermore-  sistant oncogenic bovine viruses (e.g., polyoma-papilloma) or  possible single-stranded DNA viruses.** Certain single nucleo-  tide polymorphisms (SNPs) in the N-acetyltransferase gene  alter the activity of the enzyme involved in the activation of het-  erocyclic amines from cooking meat at high temperatures and  may increase the risk of colon cancer.   Other foods that alter the metabolism of carcinogens and  induce GSTs include cruciferous vegetables, especially brussels  sprouts and red cabbage. Red cabbage leads to changes in meat-  derived mutagens in urine.®* Flavonoids found in plants may  alter carcinogen metabolism, and dietary indole-3-carbinol  inhibited spontaneous occurrence of endometrial adenocarci-  nomas in rats.°*    Chronic inflammation and immune function may help  explain patterns of cancer around the world. People who are  undernourished or live in poverty may have impaired immune  status, which can be a factor in cancers caused by infectious  agents, for example, cancers of the liver and cervix.°* Undernu-  trition can include deficiencies in vitamin A, riboflavin, vitamin  By», folic acid, vitamin C, selenium, and zinc, and these nutri-  ent deficiencies may be related to chronic inflammation and  immune alterations. The cytokine interleukin-6 (IL-6) can act  as either a proinflammatory or an anti-inflammatory cytokine;  consequently, it can enhance both innate and adaptive immu-  nity as well as stimulate or suppress tumor growth.   In summary, epidemiologic and laboratory evidence suggests  that diet has important consequences for cancer development  and perhaps its rate of progression.?!** Diet affects many path-  ways to cancer including cell cycle control, differentiation, DNA  repair, gene silencing, inflammation, apoptosis, and carcinogen  metabolism. Many of these processes are likely influenced, if not  regulated, by DNA methylation, an epigenetic mechanism that  affects gene function. As illustrated in Figure 13-2, it is possible  that many environmental factors interact with the genome to  produce altered epigenetic markers that change the expression  of cancer-causing genes, tumor-suppressor genes, and onco-  genes. Future research is needed to define robust biomarkers  of cancer risk.   Obesity. Obesity in most developed countries (and in urban  areas of many developing countries) has been increasing rapidly  over the past 20 years. Obesity in the United States is an epidemic  and constitutes a startling setback to major improvements  in other areas of health during the past century.** Childhood  obesity also is increasing. Numerous health conditions are linked  to obesity and physical inactivity. The substantial suffering and  long-term human and societal costs of obesity underlie the  urgency to accelerate progress in obesity prevention.** This will  require a comprehensive approach including the involvement  of knowledgeable healthcare personnel, the provision of  appropriate education from schools, the access to healthy food  and beverage choices, and the promotion of physical activity.   Studies have significantly improved the understanding of the  relationship between overweight/obesity, energy balance and  cancer risk, cancer recurrence, and survival (Figure 13-11).°4°>-*7  Consensus now exists that obesity is a risk factor for cancers of  the endometrium, colorectum, kidney, esophagus, breast (post-  menopausal), and pancreas. Evidence is evolving of the asso-  ciation between obesity and cancers of the thyroid, gallbladder,  liver, and ovary as well as aggressive types of prostate cancer  and non-Hodgkin lymphoma.***>*” Importantly, obesity is  recognized as a poor prognostic factor for several cancers.°*°?  Worrisome are the effects of obesity on incidence and the poor  outcomes in individuals with cancer because of the rising obe-  sity epidemic.”!   The only globally accepted criteria for overweightness and  obesity are based on body mass index (BMI). Widely accepted  standards based on BMI criteria for overweightness and obe-  sity are recommended by the WHO” and supported by other  panels and federal agencies (WHO classifications are shown in  Table 13-4).    FIGURE 13-11 Weight and Risk of Dying from Cancer. A, As a man’s body mass index (BMI) rises above the normal  range (18.5 to 24.9), his risk of dying of colorectal, esophageal, kidney, and other cancers also rises. For example, the risk of  dying from colorectal cancer is 10% higher for men who are overweight (BMI 25 to 29.9) than for men of normal or lower BMI.  For the most obese men (BMI 35 or higher) the risk is almost double (84%). B, As a woman's BMI rises above the normal range  (18.5 to 24.9), her risk of dying of breast, kidney, uterine, and other cancers rises. For example, the risk of dying from breast  cancer is 34% higher for women who are overweight. For the most obese women (BMI >40), the risk of dying from breast  cancer is double. The risk of kidney disease is almost five times higher, and the risk of uterine cancer is six times higher. (Data  from Calle EE et al: N Eng/ J Med 348:1625-1638, 2003.)    TABLE 13-4 WHO® CLASSIFICATION OF Worldwide estimates are 1.5 billion adults are overweight  BODY MASS INDEX (BMI)    (BMI =25 to 29.9 kg/m?) and 500 million are obese (BMI  230 kg/m?).”* There is considerable concern for children with   23-2919 Grade 1 overweight Overweight model based on energy balance and energy expenditure was   *The cutoffs are somewhat arbitrary, although they are derived from comprised of: (1) the resting metabolic rate (RMR), the energy   epidemiologic studies of BMI and overall mortality. It is important to required for normal body functions, which constitutes the   understand that within each category of BMI there can be substantial majority of energy needs; (2) the thermic effect of food, or the  individual variation in total and visceral adiposity and in related meta- : :   WHO, World Health Organization. (3) physical activity, a moderate and modifiable part of energy    expenditure. This model does not include body composition  (i.e., lean tissue, adipose tissue) or the dynamic state of body    FIGURE 13-12 Obesity, Insulin Resistance, Inflammation, and Cancer. A proposed model of the role of insulin  resistance, obesity, genetic susceptibility, and environmental factors and cancer. This model suggests insulin resistance and  inflammation as driving forces for cancer development. FFA, Free fatty acids; /GFBPs, IGF-binding proteins; /L-6, interleukin-6;  PAI-1, plasminogen activator inhibitor 1; ROS, reactive oxygen species; SHBG, sex hormone-binding globulin; 7G, triglycerides;  TNF-a, tumor necrosis factor-alpha; VEGF, vascular endothelial growth factor. (Adapted from Arcidacono B et al: Exp Diabetes    composition. Because lean mass determines resting metabolic  rate it is unknown whether obesity itself drives cancer progres-  sion or whether components of energy balance (i.e., too much  consumed or too little expended) have a greater impact, and  therefore it is uncertain which factors hold more promise for  cancer control and prevention.®°   Overall, the putative mechanisms whereby obesity drives the  progression of cancer are not completely known and the pro-  cess is complex. Earlier studies linked levels of circulating free  hormones (e.g., estradiol) and hormonally driven cancers as an  important mechanism. (Chapters 22 and 24 contain discussions  on hormones and cancer risk.) Research now includes other  mechanisms whereby energy balance may affect: (1) genomic  instability, (2) dysregulated growth signaling and cellular ener-  getics, (3) inhibition of apoptosis and immune surveillance,  and (4) angiogenesis. Additionally, numerous signaling path-  ways and factors are involved in the acceleration of cancer. Data  now exist for several factors including energy-driven signaling  from insulin, insulin-like growth factor 1 (IGF-1), phospha-  tidylinositol] 3-kinase, and AMP-activated protein kinase and  many others.®° These pathogenic effects of insulin might be    mediated by insulin receptors in the preneoplastic or neoplas-  tic target cells, or could be caused by alterations in endogenous  hormone metabolism secondary to hyperinsulinemia. Insulin  resistance increases with body fatness, particularly with abdom-  inal fatness, and the pancreas compensates by increasing insulin  production. Hyperinsulinemia is associated with a risk of can-  cers of the colon, endometrium, and possibly kidney and pan-  creas.°! Like sex steroids, leptin produced by adipose cells also  can stimulate premalignant and malignant cell types.   Insulin promotes the synthesis and biologic activity of insulin-  like growth factor 1 (IGF-1), a peptide hormone that has mitotic  and anti-apoptotic effects.”° Intense investigation is ongoing on  the relationship between IGF-1 and the development of cer-  tain cancers (Figure 13-12). For example, a pooled reanalysis of  world-wide prospective data showed IGF-1 is associated with an  increased risk for prostate cancer.”° Insulin also can promote the  synthesis and biologic availability of the male and female sex hor-  mones, including estrogens, progesterone, and androgens” (see  Figure 13-6).   Parts of the insulin resistance syndrome have been well  studied in both breast and colon cancer.?° As an example, in    individuals with nondiabetic breast cancer, higher levels of fast-  ing insulin were associated with a twofold to threefold increase  in risk of mortality.°*’? One biologic basis for this effect is the  overexpression of insulin receptors, especially the fetal insulin  receptor (IRa) on breast cancer cells.!°° Similar findings are  reported for colon cancer and suggest that adiposity, physi-  cal activity, and diet influence insulin and IGF levels that can  stimulate growth and inhibit apoptosis of micrometastases—  possibly a cause of recurrence.!°! It has recently been reported  that postmenopausal diabetic women treated with insulin had  a significantly higher risk of lung cancer.!°? This relationship  needs much further investigation. Additionally, the Women’s  Health Initiative (WHI) investigators report that diabetes sever-  ity assessed by duration or need of pharmacologic care had  stronger links to risk of liver, pancreatic, and rectal cancer.!°° A  first review of epidemiologic studies revealed diabetes mellitus  as an independent risk factor for colon and rectal cancer.!°* The  biologic mechanisms between diabetes mellitus and cancer risk  are currently unknown.   The survivorship literature is growing and data suggest that  increasing BMI is related to less favorable outcomes for recur-  rence, survival, and comorbidities (e.g., cardiovascular disease,  diabetes, wound healing).*° A meta-analysis of more than 40  studies of women diagnosed with breast cancer showed a mod-  est but significant increase in all-cause and breast cancer—  specific mortality in obese vs. nonobese women.!°° Obesity has  been consistently associated with prostate cancer mortality in  cohort studies.*>!°° Emerging data on colorectal cancer so far  show mixed findings.   Adipose tissue can have greater effects on the physiology  of other tissue (see Chapter 41). The metabolic function of  adipose tissue is derived in part because it can secrete many  proteins, collectively called adipokines.!”’ Adipose tissue is a  source of inflammatory modulators, and increasing evidence  indicates that obesity is casually linked to inflammation (Figure  13-13),108109   The adipokine leptin enhances the production of inflamma-  tory factors and tumor necrosis factor-alpha (TNF-a).®°° These  inflammatory factors also are modulated by sex hormones (e.g.,  estradiol and testosterone) and growth factors, especially vas-  cular endothelial growth factor (VEGF). Importantly, increased  adiposity is correlated with lower levels of adiponectin that nor-  mally induces apoptosis, thus increasing cell proliferation.®°  Lower levels of adiponectin also give rise to insulin resistance—  a state characterized by the reduced metabolic response of tis-  sues to insulin and to compensatory hyperinsulinemia.   Adipokines have both proinflammatory and anti-inflammatory  activities and their balance can contribute to the initiation and pro-  gression of obesity-induced metabolic changes that can affect other  organs (including the brain, heart, vasculature, liver, and muscle)  and increase the risk of cancer, cardiovascular disease, and meta-  bolic disturbances.!°”   Cancers have altered metabolism. Normal tissues use oxida-  tive phosphorylation (OXPHOS) to convert glucose into CO,  and energy (i.e., ATP). Some cancers use a different approach;  they consume large quantities of glucose—aerobic glycolysis—  to make cellular building blocks (Warburg effect), supporting    rapid proliferation!'!®!!' (see Chapter 12). However, this con-  cept has been challenged because some tumors use oxidative  phosphorylation.!'* New research reveals that cancer cells can  use oxidative stress as a “weapon” to extract recycled nutrients  from cancer-associated fibroblasts in the stromal tissue. The  oxidative stress changes the normal fibroblast cancer-associated  fibroblasts (CAFs). This transition seems to cause the aging of  the stromal environment, or senescence. Autophagic senescent  fibroblasts then produce high-energy nutrients resulting in ana-  bolic tumor growth. This two-compartment tumor metabolism  is sometimes called the Reverse Warburg effect. It is possible  that this simple model of metabolism by the cancer could  explain why chronological aging is one of the most important  factors for the development of cancer. Emerging data indicate  that cellular signaling and metabolism are tightly linked.'!!  Several signaling pathways implicated in cell proliferation also  regulate metabolic pathways. Signaling pathways activated by  hormones and growth factors stimulate the metabolic activity  of cells to promote proliferation or differentiation.'!' Metabo-  lism affects key cellular processes by regulating signaling, gene  expression, and metabolic processes.!!!   Recent studies reveal a link between glucose availability and  protein acetylation, an epigenetic change.''! Importantly, in  the context of constant glucose levels, metabolite levels seem  to oscillate in a circadian way within cells and tissues.'!! Food  metabolism and circadian cycles are linked and impairment of  clock regulation (e.g., disrupted night sleep and light; shift work)  results in dysregulated metabolism.'!’ Circadian rhythms per-  vade mammalian biology (Figure 13-14). They manifest and  permeate temporal organization in behavioral, physiologic,  cellular, and neuronal processes.''* This ancient timekeeper  interacts with multiple cell systems, including signaling mecha-  nisms, and the cell cycle, thus impacting disease. Evidence is  emerging that circadian mechanisms are linked to cell prolifera-  tion and its control at the DNA (epigenetic), RNA, and protein  levels. Circadian disruption accelerates malignant growth.'"4 In  addition to nutrient levels oscillating metabolically, circadian  rhythms appear to affect detox cycles.!!*:!!4 Mutations in inter-  nal clock genes alter glucose and lipid metabolism and affect the  function of the kidney.!!°   Alcohol Consumption. Alcohol is classified by the International  Agency for Cancer Research as a human carcinogen. Excessive  alcohol plays a contributory role in several common cancers.°°  Overall, there are strong data describing alcohol as a cause  of cancers of the mouth, pharynx, larynx, esophagus, liver,  colorectum, and breast (Table 13-5).°4°!!© The evidence does  not show any “safe limit” of intake, and the effect is from ethanol  regardless of the type of drink.   Animal studies show chronic alcohol intake is associated  with reduced genomic DNA methylation in the colon.!!” Alco-  hol and cancers of the esophagus and liver also involve epi-  genetic alterations.!!*!!° The molecular actions of ethanol are  believed to include site-specific changes to histone modifica-  tions and alterations of one-carbon metabolism causing meth-  ylation changes.°°? MicroRNA expression has recently been  linked to alcohol consumption in a case-control study of head  and neck cancer (i.e., head and neck squamous cell carcinoma    FIGURE 13-13 Adipose Tissue, Obesity, Inflammation, Insulin, and Cancer. A, Changes in adipose tissue and obesity. Adipose tissue is composed of adipocytes  and stromal-vascular tissue (pre-adipocytes, macrophages, other inflammatory cells, endothelial cells). With obesity there is an increase in the size and number of adipocytes  and increases in the inflammatory and vascular compartment (endothelial). B, Adipokine and inflammatory signaling in obesity. Overall, adiponectin inhibits proliferation and  metastasis. Circulating leptin can bind to the leptin receptor or IL-6 and activate JAK signaling and STAT signaling. STAT3 can function as an oncogenic transcription factor.  Inflammatory cells in adipose tissue produce IL-6 and TNFo. as well as other cytokines. IL-6 activates JAK-STAT signaling which promotes proliferation and metastasis. TNFa  activates NF-«B through the degradation of the inhibitor of «B kinase (IkB). NF-«B is now free to translocate to the nucleus where it inhibits apoptosis and promotes prolif-  eration and metastasis. Obesity increases circulating insulin and possibly IGF-1 and IGF-2. Binding of insulin, IGF-1 and IGF-2 results in phosphorylation of IRS proteins that  can activate downstream signaling, such as ERK pathways. The oncogenic pathways MYC (oncogene) and ETS (oncogene) are activated by ERK. Activation of PI3K pathways  causes AKT (serine/threonine protein kinase) phosphorylation and mTOR activation promoting protein synthesis and cell growth. AKT also activates MDM? that degrades p53  preventing cell cycle checkpoints and apoptosis. €, A summary of increased inflammation, increased availability of lipids and other macromolecules, insulin, and changes in  adipokine signaling may contribute to the conversion of normal epithelial cells to an invasive tumor. ERK, extracellular signal-regulated kinase; /GF insulin-like growth factor;  IL-6, interleukin-6; /RS, insulin receptor substrate; JAK, Janus tyrosine kinase; m7OR, mammalian target of rapamycin; MDMZ, mouse double minute2 homolog; mammalian  target of rapamycin; NFB, nuclear factor «B; PA/7, plasminogen activator inhibitor-1; P/3K, phosphoinositide 3-kinase; STAT, activator of transcription signaling; 7NFc., tumor  necrosis factor alpha. (Adapted from Kandekar MJ et al: Molecular mechanism of cancer development in obesity, Nat Rev Cancer 11[12]:886-895, 2011.)    Adapted from World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR): Second expert report: food, nutrition, physical  activity, and the prevention of cancer: a global perspective, London, 2007, Author.    FIGURE 13-14 Regulation of Metabolism by the Circadian Clock. Periph-  eral clocks, such as that in the liver, are regulated by the master clock present in  the suprachiasmatic nucleus (SCN). The liver clock can regulate multiple metabolic  pathways by various mechanisms. These mechanisms include regulation of rate-  limiting steps, control of metabolite levels, interaction of nutrient sensors, and  modulation of nuclear sensors. (Adapted from Sahar S, Sassone-Corsi P: Trends  Endocrinol Metab 23[1]:1-8, 2011.)    [HNSCC]).!?° The risk may be modified by alcohol dehydroge-  nase genes.!*! Alcohol is now an established risk factor for breast  cancer in women and has been linked to genome-wide leuko-  cyte DNA hypomethylation.'”* Alcohol interacts with smoke,  increasing the risk of malignant tumors, possibly by acting as a  solvent for the carcinogenic chemicals in smoke products.  Other mechanisms involved in alcohol-related carcinogenesis  include the effect of acetaldehyde, the first metabolite of ethanol  oxidation; the induction of cytochrome P-450 2E1 (genetic vari-  ant CYP2E1) leading to the generation of reactive oxygen species  (ROS); the development of increased procarcinogen activation  (e.g., nitrosamines) and the modulation of cellular regeneration    *In the judgment of the Panel (WCRF/AICR), the factors listed modify the risk of cancer. Judgments are graded according to the strength of the  The judgments for men and women are different because there are fewer data for women. Increased risk is only apparent above a threshold of  *Cirrhosis is an essential precursor of liver cancer caused by alcohol. The International Agency for Research on Cancer has graded alcohol as a    class 1 carcinogen for liver cancer. Alcohol alone only causes cirrhosis in the presence of other factors.  ’The evidence was sufficient to judge that alcoholic drinks are unlikely to have an adverse effect on the risk of kidney cancer; it was inadequate to    Adapted from World Cancer Research Fund/American Institute for  Cancer Research (WCRF/AICR): Second expert report: food, nutrition,  physical activity, and the prevention of cancer: a global perspective,  London, 2007, Author.   *In the judgment of the Panel (WCRF/AICR), physical activity! modi-  fies the risk of the cancers. Judgments are graded according to the  strength of the evidence.   *Much of the evidence grouped colon cancer and rectal cancer is  together categorized as “colorectal cancer.” The Panel judges that the  evidence is stronger for colon cancer than for rectal cancer.    (cell cycle); and the manifestation of nutritional deficiencies (e.g.,  retinol, retinyl esters, folic acid, other vitamins). Nutritional  deficiencies may result in altered mucosal integrity, enzyme and  metabolic dysfunction, and other structural abnormalities.   Physical Activity. Studies suggest that regular exercise  decreases the risk of breast cancer, colon cancer, and  endometrial cancer, independent of weight changes. The World  Cancer Research Fund summarized the effects as convincing for  cancers of the colon and probable for postmenopausal breast  cancer and endometrial cancer™ (Table 13-6).   The effect of physical activity on the risk of rectal can-  cer is much less certain,®”'* and one study shows an inverse    520,000 (32.0%)  490,000 (30.2%)  470,000 (28.9%)  96,000 (5.9%)  39,000 (2.4%)  660 (0.0%)  2,000 (0.1%)  6,000 (0.4%)   Human T-cell lymphotropic virus type 1  Opisthorchis viverrini and Clonorchis sinensis  Schistosoma haematobium    Data from de Martel C et al: Lancet Oncol 13(6):607-615, 2012.  *Numbers are rounded to two significant digits.    80,000 (19.4%)  120,000 (29.2%)  190,000 (46.2%)  16,000 (3.9%)  4,100 (1.0%)  1,500 (0.4%)    600,000 (29.5%)  610,000 (30.0%)  660,000 (32.5%)  110,000 (5.4%)  43,000 (2.1%)  2,100 (0.1%)    tData are number of new cancer cases attributed to a particular infectious agent (proportion of the total number of new cases attributed    relationship.'** Evidence of a reduction in breast cancer risk  in postmenopausal women was associated with higher levels  of activity (dose-response effect).°'7° A recent meta-analysis  concluded that physical activity seems to be related to a reduc-  tion in the risk of endometrial cancer independent of body  weight.!”° Several biologic mechanisms suggest physical activity  may protect against cancers of the breast and endometrium, by  decreasing insulin and IGF levels, decreasing obesity, altering  inflammatory mediators, decreasing levels of circulating sex  hormones and metabolic hormones, improving immune func-  tion, and enhancing cytochrome P-450 activity, thus modifying  carcinogen activation.®!?7"'°° For colon cancer, physical activ-  ity increases gut motility, which reduces the length of transit  time that the bowel lining is exposed to potential mutagens.!””  Other mechanisms of protection may include a reduction in  insulin resistance, reduced body fatness, and changes in steroid  hormone metabolism.“ A randomized trial found that after  12 months of moderate-intensity exercise, postmenopausal  women had significantly decreased levels of serum estrogens.!>!  Physical activity also helps prevent type 2 diabetes, which  has been associated with risk of cancer of the colon and pan-  creas.!**!52 However, evidence that physical activity protects  against pancreatic cancer is limited.   Many questions are unanswered regarding frequency, inten-  sity, and duration of exercise. Much of the literature suggests  that between 3.5 and 4 hours of vigorous activity per week are  necessary to optimize protection for colon cancer.!*° There is  likely a dose-response relationship for colon cancer and breast  cancer, and 30 to 60 minutes per day of moderate to vigorous  intensity is proposed to decrease breast cancer risk.'** A recent  12-month randomly controlled trial supported the Institute  of Medicine and Department of Agriculture guidelines of 60  minutes per day of moderate to vigorous physical activity for  decreasing weight, BMI, and amounts of body fat and intra-  abdominal fat.'** Several reports suggest that physical activity  after a cancer diagnosis is associated with better cancer-specific  sequelae and improved overall survival time with early-stage  breast, prostate, and colorectal cancers.*° Further research is  needed on cancer outcomes and physical activity.   Infection is an important contributor to cancer worldwide and  the population attributable fraction (PAF) indicated that 16.1%  of cancers diagnosed in 2008 were caused by infection, or about  2 million new cases.!*° Infection and cancer rates vary widely  by region: with a 7.4% rate for more developed regions and a  22.9% rate for less developed regions.!*° The highest PAF is for  sub-Saharan Africa with a rate of 32.7%. Agents classified by the  IARC were used in this report because the strength of published  evidence is controversial.!°° The four top notable infections and  new cancer cases include human papillomavirus (HPV), Heli-  cobacter pylori (H. pylori), hepatitis B virus (HBV), and hepati-  tis C virus (HCV) (Table 13-7). According to the investigators  these results probably are conservative and underestimate the  true burden of infection-associated cancers.'°° Most of the fol-  lowing discussion will be about human papillomavirus (HPV);  however, hepatitis B and hepatitis C can infect the liver and  together account for the large majority of liver cancer cases (see  Chapter 41). It has been estimated that H. pylori accounts for  about 75% of all stomach cancers.!*° Epstein-Barr virus (EBV)  is linked to cancers of the nasopharynx, Hodgkin disease, and  non-Hodgkin lymphoma. Human herpesvirus type 8 is linked  to Kaposi sarcoma and human T-cell lymphotropic virus type 1  is linked to leukemia and lymphoma.   Human papillomavirus (HPV) is the most common sexually  transmitted virus in the United States. At least 50% of sexu-  ally active people will have genital HPV at some time in their  lives.!°7 HPVs are a group of more than 150 related viruses.  More than 40 of these viruses can easily spread from direct skin  contact or through vaginal, rectal, or oral sex.!° Low-risk HPVs  do not cause cancer but can cause skin warts, called condylo-  mata acuminata. High-risk, or oncogenic, HPVs can cause can-  cer. Even though about a dozen HPVs are identified, HPV types  16 and 18 are responsible for the majority of cancers.!°* How-  ever, most high-risk HPV infections may cause cytologic abnor-  malities or abnormal cell changes that disappear unexpectedly.  Persistence of infection with high-risk HPV is a prerequisite for  the development of cervical intraepithelial neoplasia (CIN) (see    Figure 24-19), lesions, and invasive cervical cancers.!°? Almost  all cervical cancers are caused by HPV infections, with HPV  types 16 and 18 responsible for about 70% of all cases.!40!4!  HPV can cause anal cancer, with about 85% of all cases caused  by HPV-16.!°° HPV types 16 and 18 also have been found to  be responsible for almost half of vaginal, vulvar, and penile  cancers.'*” Recently, HPV infections have been found to cause  cancer of the oropharynx (soft palate, base of the tongue, ton-  sils).!°°> More than half of the oropharyngeal cancers diagnosed  in the United States are linked to HPV-16.'* The incidence of  HPV-associated oropharyngeal cancer has increased during  the past 20 years, especially among men, and it has been esti-  mated that by 2020 HPV will cause more oropharyngeal can-  cers than cervical cancers in the United States.'“4 Factors that  may increase the risk of developing cancer following a high-risk  HPV infection include smoking, decreased immunity, having  many children (for increased risk of cervical cancer), long-term  oral contraceptive use (for increased risk of cervical cancer),  poor oral hygiene (for increased risk of oropharyngeal cancer),  and chronic inflammation."!   HPVs infect epithelial cells that cover the inside and out-  side surfaces of the body, including the skin, throat, genital  tract, and anus. Because HPVs are not thought to enter the  bloodstream, having an HPV infection in one part of the body  should not cause an infection in another part of the body.!°*  Once an HPV virus enters an epithelial cell, the virus begins  to make proteins that can interfere with normal functions in  the cell, enabling the cell to grow in an uncontrolled manner,  and to avoid apoptosis.'°* These infected cells are often recog-  nized by the immune system and eliminated. Sometimes, how-  ever, infected cells are not destroyed and a persistent infection  results. As the persistently infected cells continue to grow, they  may develop mutations that promote even more cell growth,  leading to the formation of a high-grade lesion and, ultimately,  a tumor.!°* Investigators believe that it can take between 10 and  20 years from the time of an initial HPV infection until tumor  formation. However, even high-grade lesions do not always  lead to cancer.!°*    A discussion of the relationship between viruses, bacteria, and  cancer is contained in Chapter 12 and appropriate chapters  in Unit I. Other microorganisms involved in carcinogenesis  include parasites such as Opisthorchis viverrini and Schistosoma  haematobium. Their specific roles in carcinogenesis are thought  to be related to cofactors or carcinogens, or both.   Much of the knowledge of the effects of ionizing radiation (IR)  on human cancer has stemmed from observations of the Hiro-  shima and Nagasaki atomic bomb (A-bomb) exposures, par-  ticularly the Life Span Study. These data provide estimates of  human cancer risk over the dose range from 20 to 250 centigray  (cGy) for low linear energy transfer (LET) radiation, such as  x-rays or y-rays. Other evidence is derived from groups exposed  for medical reasons, underground miners exposed to radon gas,  and other occupational exposures (Table 13-8). The atomic    Data from Jones JA, Casey RC, Karouia F: lonizing radiation as a car-  cinogen. In McQueen E, editor: CA comprehensive toxicology, ed 2, St  Louis, 2010, Elsevier.   AB, Atomic bomb survivors; AS, ankylosing spondylitis patients; PM,  postpartum mastitis patients; TC, tinea capitis patients; TH, individuals  receiving thorotrast; RP radium dial painters; UM, underground min-  ers; RD, radiologists.    bomb exposures in Japan caused acute leukemias in adults and  children and increased frequencies of thyroid and breast car-  cinomas. Lung, stomach, colon, esophageal, and urinary tract  cancers and multiple myeloma have been added to the list. At  Nagasaki and Hiroshima, leukemia incidence in individuals 15  years or younger reached its peak 6 to 7 years after the explo-  sions and has steadily declined since 1952. People 45 years and  older at the time of exposure had a latent period of 20 years  before developing acute leukemia.   Recently, standard models and evaluations of age of exposure  to radiation and radiation-induced cancer risks have been ques-  tioned.'4?"!48 Epidemiologic data from Japanese atomic bomb  survivors and from children exposed to radiation for medical  intervention suggest that excess relative risks (ERRs) for radia-  tion-induced cancers at a given age are exceptionally higher for  individuals exposed during childhood than for those exposed at  older ages.'*? These data also are published by the International  Commission on Radiological Protection (ICRP) and the National  Academy of Sciences Committee on the Biological Effects of Ion-  izing Radiation (BEIR Committee).!°° What is at question is the  ERRs of radiation exposure in adulthood and radiation-induced  cancer risk. Recent analyses of Japanese bomb survivors suggest  that the ERR for cancer induction decreases with increasing age  at exposure only until exposure ages of 30 to 40 years; with radia-  tion exposure at older ages, the ERR does not decrease further and  for many individual cancer sites (liver, colon, lung, stomach, and  bladder) the ERR may actually increase in all solid cancers com-  bined.!46!45:149151 These new data present a challenge to our con-  ceptual understanding of the mechanisms of cancer induction.!“*  Biologic models of cancer development all predict that ERRs should  decrease continuously with increasing age of radiation exposure.  Recent models, however, of radiation carcinogenesis show IR  acts not only as an initiator of premalignant cell clones but also    Interventional fluoroscopy  (medical) (7%)  FIGURE 13-15 Pie Chart Showing Sources of Exposure to lonizing Radiation. Percent contribution of various sources  of exposure to the total collective effective dose (1,870,000 person-Sv) and the total effective dose per individual in the U.S.  population (6.2 mSv) for 2006. Percent values have been rounded to the nearest 1%, except those <1%. Sv, Sievert. (From  NCRP: 2009 Ionizing radiation exposure of the population of the United States, NCRP Report No. 160, Bethesda, Md, Author.)    as a promoter of preexisting premalignant cell alterations.!4%!48-!5!  Promotion is used here to mean the process by which an initi-  ated cell clonally expands. Therefore promotional processes from  radiation can result in increasing excess lifetime cancer risks with  increasing age at exposure. From these new data investigators pro-  pose that radiation-induced cancer risks after exposure in middle  age may be almost twice as high as previously estimated.!4*  Human exposure to IR includes emissions from x-rays, radio-  isotopes, and other radioactive sources (Figure 13-15). Health  risks involve not only neoplastic diseases but also cardiovascular  disease and stroke following high doses in therapeutic medicine  and lower doses in A-bomb survivors (BEIR VII).!52:!55 Late effects  of radiation in A-bomb survivors show persistent elevations in the  levels of inflammatory markers, implying immunologic damage  may be the cause of later cardiovascular effects.!°4 Investigators  for the first time using a model of umbilical vein endothelial cells  showed that low doses (0.05 Gy) of x-rays induce DNA damage  and apoptosis in endothelial cells. These data will need contin-  ued research.!°“* Cardiac and blood vessel damage may manifest  years after completion of radiation therapy.!°° Other risks include  somatic mutations that may contribute to other diseases (e.g.,  respiratory diseases, birth defects, and eye maladies) and, from  animal studies, inherited mutations that may affect the incidence  of diseases in future generations. An important summary point in  BEIR VII'*? is the concern from medical exposure, for example,  computed tomography (CT) (see What’s New? CT Scans and  Issues). In 2009 the National Council on Radiation Protection  and Measurements!°° reported Americans were exposed to more    than seven times as much IR from medical procedures compared  to the 1980s (Figure 13-16). In Europe, 20 millisieverts (mSv) is  the annual allowable occupational exposure of radiation, and in  the United States the annual allowable occupational exposure is  50 mSv.!°” The increase in imaging is likely driven by several fac-  tors, including improvements in the technology, that have led to  increased clinical applications, patient demand, physician demand,  defensive medical practices, and medical uncertainty.!°*>°  Evidence, usually epidemiologic, shows cancer associated  with exposure to IR (see Table 13-8). Evidence includes animal  models and in vitro studies as well as exposed groups includ-  ing atomic/nuclear survivors, survivors of industrial accidents  and the Techa River basin in Siberia, and medical diagnos-  tic/therapeutic data. The studies of exposed groups are large  enough to allow epidemiologists to derive detail concerning the  dose and quality, age at exposure, and other factors on cancer  incidence in a large variety of organs.'°? From data collected  over several decades, exposed cohorts reveal that IR is a potent  carcinogen.!® Additionally, reports of occupational exposures  may have increased the incidence of certain types of cancer, for  example, underground miners and lung cancer.!°! Certain med-  ical conditions, especially those with a genetic basis, predispose  individuals to ionizing radiation—induced injury.!°° The most  well-known condition is ataxia-telangiectasia (AT), a rare (1 in  300,000 people) condition in which individuals have a strong  sensitivity to IR. Additionally, individuals with BRCA1/BRCA2  pathway mutations have increased radiosensitivity caused by  insufficient DNA repair and cell cycle control mechanisms. !°   Currently, almost all of the available epidemiologic data are generated from   people exposed to background radiation, such as the Japanese survivors of   The effects of low-dose radiation (LDR) are mainly based on the linear non-   1. No injurious effects are detected at a dose less than 100 mSv for adults  and less than 50 mSv for children.   4. Cancer may not develop until there is accumulated genetic damage.   1. The bystander effect and associated chromosomal effects have not been  fully studied.   Carcinogenesis is considered the most serious consequence of LDR and it   The hereditary effect is the variation of damage that could occur in germ cells.   the hereditary effect? The ICRP estimated the hereditary effect as 0.2%/Sv.   Approximately 5% to 10% of individuals are hypersensitive to radiation, for   The accumulative effects of LDR from repeated CT scans may lead to buildup   The proportion of annual CT scans in some developed countries increased   rom 6.1% (1970-1979) to 48% (1991-1996). In the last 25 years, usage of CT   has increased 12 times in the United Kingdom and more than 20 times in the   he range of low-dose radiation and CT. About 0.6% and 1.5% of the cumula-   ive cancer risk could be attributed to diagnostic x-rays in England and Ger-   many, respectively. About 3.2% of new cancer cases in Japan are considered   he result of two examinations every year. It is estimated that about 29,000   cancers could be related to CT scans in the United States every year; scans   the abdomen and pelvis are the most common.®:'S Other estimates indicate   hat CT scan-induced cancer risk is about 0.7%,° CT angiography risk is about   low doses and low dose rates of radiation from CT is estimated at 5%/Sv.'   he mathematical extrapolation of LNT to LDR may not be accurate because   CT scans can save lives, improve diagnostic accuracy, limit medical proce-   Researchers report that certain CT scans are unnecessary and a survey   revealed that about 77% of lumbar spine, 36% of head, 37% of abdomen,   20% of nasal sinuses, and 3% of cervical spine CT scans should have been   It is probable that at least 25% of CT scans are not clinically warranted.    Radiation from CT scans can activate antioxidants, such as superoxide dis-  mutase (SOD), DNA repair mechanisms, and the immune system, to recognize  mutated cells.'4    Repeated CT scanning can alter the balance between antioxidant and oxidant  systems and increase the number of ROS.   ROS can lead to DNA single- and double-strand breaks, DNA interstrand  cross-linking, and eventually the formation of apurinic and apyrimidinic  sites.   A quantitative marker of LDR-induced double-strand breaks is a member of  the histone H2A family, H2AX, which becomes phosphorylated within 1 to 3  minutes of DNA damage and forms foci at the break sites. '®:'7   Continuous DNA damage can lead to chromosomal aberration, chromosomal  damage in cell progeny, and elevated levels of y-H2AX. Such alterations  might lead to genomic instability and currently there are reported increases in  the number of cases of non-Hodgkin lymphoma and breast cancer. '®7   With the increase in multi-slice CT (MSCT), the radiation dose is gradually  increasing. The 64-slice CT to do heart scanning included exposures of other  tissues: heart, 32.4 mSv; breast, 39.1 mSv; lung, 33.2 mSv; and spinal cord,  29.8 mSv.21.22   Organ doses relevant to most CT usage are between 5 and 100 mSV; the expo-  sure is a very small but well-established individual cancer risk, particularly for  patients without significantly reduced life expectancy.2°2°   Epigenetics including DNA methylation and miRNA expression could be espe-  cially helpful in understanding the biology of radiation-induced genomic insta-  bility (RIGI).    About 600,000 children under the age of 15 have abdominal and head CT  scans in the United States every year, and It is estimated that about 500 chil-  dren might eventually die from CT-induced cancer.°   Children are more sensitive to radiation and their carcinogenic risks are about  4 times those of an adults’ risk (a 1-year-old infant is 10 to 15 times more  prone to develop cancer than an adult).2’   CT-induced cancer risks were 3% (10 years old) and 2% (15 years old) in chil-  dren who received abdominal and pelvic CT scans for renal calculi detection.”  German investigators have planned to conduct a historic cohort study to  investigate cancer incidence from CT exposure in children younger than age  bee    Surveys are being done to understand the radiation knowledge of patients  and healthcare workers.   A survey reported more than 70% of patients underestimated the radiation  dose from CT scans and had very limited understanding of radiation-induced  cancer risks.°   Another survey revealed about 7% of patients were informed about the ben-  efits and risks before having a CT scan and 53% of radiologists and 91%  of emergency department physicians believed CT scans would not increase  cancer risks.°!   About 43% of hospital imaging departments made technologic adjustments  for pediatric patients.°2   About 33% of CT imaging departments indicated they had adjusted the tube  current down to less than 100 milliamperes (mA) when they performed helical  CT scans of the chest on 4-year-old children.*°   A German study revealed physicians overestimated the radiation exposure  from conventional x-rays but underestimated the exposures from CT scans.**    1. Shumei MA et al: /nt J Radiat Biol, December 2012. [Epub ahead of print.].  2. Dauer LT et al: Radiat Prot Dosimetry 140(2):103—-136, 2010.   . Huda W et al: AUR Am J Roentgenol 196(2):W159-165, 2011.   . Berrington de Gonzalez A et al: Gastrointest Endosc Clin North Am  20(2):279-291, 2010.   . Berrington de Gonzalez A: AUR Am J Roentgenol! 196(4):816-823, 2011.   . Berrington de Gonzalez A et al: Arch Intern Med 169(22):2071—2077, 2009.   . Feinendegen LE, Pollycove M, Sondhaus CA: Toxicol Med 2(3):143-171,  2004.   . Sharma A, Singh K, Almasan A: Methods Mol Biol 920:613-626, 2012.    FIGURE 13-16 CT Scans in the United States. NCRP estimates that 67 mil-  lion CT scans (compared to 3 million in 1980), 18 million nuclear medicine proce-  dures, and 17 million interventional fluoroscopy procedures were performed in the    United States in 2006. (From NCRP: 2009 Ionizing radiation exposure of the popula-  tion of the United States, NCRP Report No. 160, Bethesda, Md, Author.)    . Novik KL et al: Cancer Epidemiol Biomarkers Prev 16(6):1098—1106, 2007.  . Streffer C: Mutat Res 568(1):79-87, 2004.   . Meer AB et al: J Am Coll Radiol 9(4):245-250, 2012.   . Smith-Bindman R et al: Arch Intern Med 169(22):2078—2086, 2009.  . Brenner DJ, Shuryak |, Einstein AJ: Radiology 261:193-198, 2011.  . Brenner DJ, Hall EJ: N Eng! J Med 357:2277-2284, 2007.   . Pearce MS et al: Lancet, 2012 Jun 7. [Epub ahead of print.]   . Linton 0, Mettler FA: AUR Am J Roentgenol 181(2):321-329, 2003.  . Sodickson A et al: Radiology 251(1):175-184, 2009.   . Merzenich H et al: BMC Health Serv Res 12:47, 2012.    Studies conducted jointly by the U.S. Air Force and NASA  from 1963 to 1969 studied the relative biologic effectiveness  (RBE) of different types of radiation exposures on rhesus mon-  keys and mice.'®? Long-term follow-up studies of the exposed  animals showed an induction of solid tumors and leukemia  and the extent of life-shortening depended on dose and not on  proton energy level.!® The general characteristics of radiation  carcinogenesis were determined from studies done after World  War II, mainly from rats and mice.'°° However, together with  epidemiologic studies of humans, these animal studies elucidated  radiation carcinogenesis.'°*!® The BEIR VII report that focused  on low-level radiation determined that the radiation-induced life  shortening observed in mice is reflective in humans of radiation-  induced cancer mortality.!°° These studies are important because  they show that IR is universally carcinogenic to animals and  humans and that there are wide differences in radiation responses  according to species, organ, and radiation distribution.!   The universal nature of radiation as a carcinogen relates to  its ability to penetrate cells and deposit energy in tissues at ran-  dom. By the 1980s, using in vitro models, the general character-  istics of IR-induced carcinogenesis were well established.!°” The  past two decades have focused on specific cellular and molecu-  lar mechanisms that relate to the induction of cancer, includ-  ing dose-response relationships for chromosome aberrations,  cell transformation, gene expression (genetic and epigenetic),  alternative targets, mutagenesis in somatic cells, and the bio-  logic effects that occur in nonirradiated cells (i.e., nontargeted  effects) and effects on the microenvironment.!© Through much  of the twentieth century, radiobiology was thought to be a rela-  tively simple science and was dominated by physicists. Now, with  biologists entering the field, it has become apparent that radio-  biology is not so simple and involves much more understand-  ing beyond a DNA-centric model, including alternative targets,  such as membranes, repair, and rescue within a biologic sys-  tem.!°* Because models and underlying assumptions are incom-  plete, investigators are working hard to understand induced  repair, adaptive responses, hormesis, low-dose hypersensitivity,    FIGURE 13-17 Free Radicals. Free radicals formed by water nearby and around DNA cause indirect effects. These effects  have a short life of single free radicals. Oxygen can modify the reaction, enabling longer lifetimes of oxidative free radicals.    nontargeted effects, signaling, exosomes, and long-term persis-  tence of radiation damage and clonal heterogeneity.!   Part of the biologic response of radiation-induced cancer is  oncogene activation. Although evidence suggests that inter-  individual differences in radiation responses may be attributed  to certain genes, IR can activate oncogenes, resulting in uncon-  trolled cell growth!® (see Chapter 12). Tumor-suppressor  genes also are sensitive to IR. Several tumor-suppressor genes  have been identified that are deactivated by IR that promotes  carcinogenesis.!? Recent research has shown that cells can  detect and respond epigenetically, altering gene expression after  low doses of radiation.'®° Gene expression can change as a func-  tion of radiation dose and radiation type.'©   IR is a mutagen and carcinogen; it can penetrate cells and tissues  and deposit energy in tissues at random in the form of ioniza-  tions (e.g., removal of an electron from the target atom). Impor-  tantly, arising from IR is the localized release of large amounts  of energy that can break a chemical bond (electron volts [eV] is  the energy per ionizing event). Damage from IR can occur either  directly from biologic macromolecules (e.g., DNA) or indirectly,  in the medium from which organelles are suspended in mostly  water, and irreversibly from ionizations that can attack by water-  based free radicals (e.g., H:, OH*) (radiolysis).!°? Electromag-  netic radiations, such as x-rays and y-rays, damage by reactive  species produced by ionizations elsewhere in the cell and thus  have indirect action. The biologic effects of indirect action  include cell killing (days), mutation (generation), and carcino-  genesis (years). IR affects many cell processes, including gene  expression, mitochondrial function disruption, cell cycle arrest,  and cell death. IR is a potent DNA-damaging agent, causing  cross-linking, nucleotide base damage, and single (SSBs)- and  double-strand breaks (DSBs) (Figure 13-17). Damage to DNA  and disrupted cellular regulation processes can lead to carcino-  genesis.!’°!”* The double-strand break (DSB) is considered the  important lesion in the induction of both chromosomal abnor-  malities and gene mutations. Repair of radiation-induced DNA  double-strand breaks in human fibroblasts is consistent with a    continuous spectrum of repair probability!”*'”> (Figure 13-18).  The misrepair of DSBs could lead to substantial chromosomal  instability.'”° Importantly, DSBs are probably repaired by the  nonhomologous end-joining (NHEJ) pathway.!°? Another  pathway is by homologous recombination (HR); for example,  BRCAI and BRCA2 are tumor-suppressor genes and one of  their functions is DNA repair by HR.!’”'7 These two mecha-  nisms of DSB repair act at different phases of the cell cycle.  Irradiated human cells unable to execute the NHEJ pathway are  supersensitive to the introduction of large-scale mutations and  chromosomal aberrations.!   Cell transformation describes the total changes associated with  loss of normal homeostatic control.!°° The majority of studies  on cell transformation in vitro have been quantitative, using  rodent-derived models. Few human-derived assays have been  conducted. Overall, the exposure to high-LET radiation results  ina higher transformation frequency than exposure to low-LET  radiation.'°° There is no tendency, however, for the response  per unit dose to decrease at low doses or low dose rates, and a  number of studies have shown an enhanced effect.!°°    Nontargeted Effects  A long-held assumption is that cellular alterations—mutations  and malignant transformation—occur only in cells directly  radiated. There is clear evidence indicating that cells not directly  traversed by a radiation particle, but in the vicinity of a cell that  has been exposed to or received signals from irradiated cells,  can participate in the damage response.'”? The DNA damage  response (DDR) is a coordinated series of events that allows  DNA damage detection, signaling that includes cell cycle check-  point activation, and repair.!®°'*! Emerging and important  data indicate that the DDR should be considered not only at the  DNA level but also in the chromatin of cell nuclei where DNA  envelopes histone proteins.'®” Additionally, the importance of  the plasticity of the microenvironment is becoming integrated  into the radiation response.   It is now known that cells not directly exposed to radia-  tion, but instead the progeny of cells that were irradiated  many cell divisions previously, may express a high level of gene    FIGURE 13-18 Simplified Model of the Effects of Radiation on Tumor Microenvironment. Tumor cells that are not  hypoxic cells (i.¢., called normoxic) are more sensitive to radiation and hence more susceptible to cell death (apoptosis) and  mitotic catastrophe or destruction. In some cases, however, pro-apoptotic mechanisms can cause the release of cytokines  that promote tumor regrowth and recurrence. Hypoxic cells are resistant to radiation therapy and more likely lead to tumor  recurrence. Continuous radiation (especially fractionated) can lead to reoxygenation, which can improve radiation-induced cell  killing or promote release of reactive oxygen species (ROS) and angiogenesis and/or induce tumor cell movement to blood ves-  sels; both mechanisms can result in tumor regrowth and recurrence. Decreased cytokine production and destruction of blood  vessels from continued administration of high doses of radiation can increase tumor cell killing. In certain situations, however,  irradiation is associated with the production of an aggressive phenotype of the remaining cells that survive radiation therapy.  This failure is caused by the release of protective cytokines and/or growth factors (GF), recruitment of macrophages, altered  perfusion of blood, and hypoxia that increase angiogenesis or blood vessel growth, resulting in tumor regrowth and recurrence  and/or metastasis. Importantly, the effects of radiation on tumor microenvironment depend on many factors. (Adapted from    cKenna WG, Muschel RJ: The impact of tumor microenvironment on cancer treatment and its modulation by direct    and indirect antivascular strategies, Cancer Metastasis Rev 31(3-4):823-842, 2012. [Epub ahead of print.])    mutations, cell lethality, and chromosomal aberration. Alto-  gether these effects are called genomic instability. Effects in  the distant progeny are also called transgeneration inheritance  or effects (see p. 410). The directly irradiated cells also can  lead to genetic effects in so-called bystander cells or innocent  cells (called bystander effects) even though they themselves  received no direct radiation exposure.'”? The bystander effect  has been demonstrated in three-dimensional human tissues!**  and recently in whole animal organisms.'** Signaling commu-  nication is thought to occur from direct physical connection  between cells or gap junctions, called gap junctional intercellu-  lar communication (GJIC). Other mechanisms, however, may  be involved. Numerous intercellular and intracellular signaling  pathways are implicated in the bystander response and these  effects have been shown to be transmitted to their descendents.  The bystander and genomic instability effects also have been  termed nontargeted effects.    IR causes acute and persistent short- and long-term effects.  Acute exposure to IR can cause damage to several organ sys-  tems, especially those with highly proliferative cells such as the  hematopoietic system, the skin, and the gastrointestinal sys-  tem!*? (see Chapter 2). Investigators have postulated that radia-  tion’s carcinogenic potential persists because of nontargeted  radiation effects that alter cell and tissue signaling and change  the microenvironment.'”°!*! Figure 13-18 provides a simplified  model of the effects of radiation on tumor microenvironment.  With improvement in cancer survival the long-term risks of a  second cancer from treatment become more important.!?*  Radiation-induced cancer in humans has latent periods,  usually 5 to 10 years but can be decades.!°'°? British investiga-  tors reported the following results: for solid cancers, radiation-  related excess risk starts to appear about 5 years after exposure  in therapeutically irradiated groups, and for leukemia, it starts    to appear within 5 years of exposure.!”4 Using U.S. Surveillance  Epidemiology and End Results (SEER) data, the estimated  excess of second cancers that could be related to radiotherapy  is about 8%; data from the United Kingdom, which included  diagnostic procedures and excluded therapeutic irradiation,  yielded an estimation of 15%,!97)!%4    New studies on low doses of radiation have resulted in three  paradigm shifts: (1) bystander effects have been observed in  which nonhit cells may respond as well as hit cells; (2) radiation-  induced changes in gene expression at very low radiation doses    Several models include the linear no-threshold (LNT) relationship,  in which any dose, including very low doses, has the potential  to cause mutations (see A). Another model, the linear-quadratic  relationship, proposes there is a risk mathematical term that is  directly proportional to the dose (linear term) and another term  proportional to the square of the dose (quadratic term) (see B).  The threshold model proposes a threshold dose below which  radiation may not cause cancer in humans (see €). Proponents of    alter response pathways, some of which appear to involve adap-  tive or protective responses; and (3) early changes in the initiation  phase of radiation-induced cancer were thought to be induced by  gene mutation and chromosomal aberrations only; however, it  is now understood that genomic instability that leads to the loss  of genetic control appears to have a major role in the develop-  ment of cancer.!”° Constant debate involves risk estimates for  human exposure at low-dose, low-LET ionizing radiation (0 to  100 mSv or less than 0.1 Gy). Accurate measurements of risks  from low doses and low dose rates of radiation are statistically  difficult because they require such large populations that theo-  retic models are used to estimate response curves (Box 13-1).    this model argue that such thresholds are derived, for example,  from the ability to repair damage caused by lower doses of radia-  tion. There is some evidence that low doses may actually produce  a higher level of risk per unit of dose, which is called the supra-  linear hypothesis (see D). E, Stochastic or random probability is  a major model for understanding low-dose radiation. Currently,  the shape of the response curve for the low-dose region is really  unknown.    Theoretic Models for Estimating Risk of Low-Dose lonizing Radiation. Collective population dose is expressed as a person-rem (roentgen equivalent, man).  Estimating a collective dose then enables an application of a “constant risk factor” to obtain a statistical estimate of the number of additional cancers (above back-  ground radiation) from that exposure. These computations apply to low doses—low dose rates only (A). Many propose the best fit is the linear no-threshold (LNT)  model (B). The most common alternative to the LNT model is the linear-quadratic model. The quadratic term is the square of the dose. The linear term is equal to zero  (C). The threshold model is a threshold below which there is no increase in cancer risk. Proponents of this model argue that because some toxic chemicals/materi-  als exhibit such thresholds, radiation must also have a threshold. Their arguments are related to repair of the radiation damage caused by lower doses of radiation  (D). Some evidence exists that low levels of radiation produce a higher level of risk per unit dose, which is called the supralinear model. The stochastic model is  where effects are random and the events cannot be predicted (E). (Adapted from Makhijani A, Smith B, Thorne MC: Science for the vulnerable: setting radiation and  multiple exposure environmental health standards to protect those at most risk, Takoma Park, Md, 2006, Institute for Energy and Environmental Research.)    Data from Hoel DG: Ann N Y Acad Sci 1076:309-331, 2006; Preston DL et al: Radiat Res 160:381-407, 2003.    Extrapolations from high dose or high dose rate down to very  low doses and very low dose rates using these mathematical mod-  els may underestimate or overestimate cancer risks at low doses.  Consequently, animal studies are also ongoing to experimentally  understand the biology of low-dose radiation and low dose rates  of radiation. The risks of low doses of radiation are controver-  sial and the uncertainties associated with the best estimates are  great.!°° The risk of neoplastic transformation in bystander cells  remains unclear.    Ultraviolet sunlight causes basal cell carcinoma and squamous  cell carcinoma (ie., photocarcinogenesis), two common skin  cancers found in white individuals (see following discussion  about melanoma). Exposure to ultraviolet radiation (UVR)  can emanate from natural and artificial sources; however, the  principal source of exposure for most people is sunlight. With  further depletion of the stratospheric ozone layer, people and  the environment will be exposed to higher intensities of UVR.  The degree of damage in skin depends on the intensity and  wavelength content (i.e., ultraviolet A [UVA] or ultraviolet B  [UVB]; ultraviolet C possess the highest energy but does not  penetrate the atmosphere) and the depth of penetration. UV  radiation is known to cause specific gene mutations; for exam-  ple, squamous cell carcinoma involves mutation in the TP53  gene, basal cell carcinoma in the patched gene, and melanoma  in the CDKN2A/p16 gene.!”” In addition, UV light induces the  release of TNF-a in the epidermis, which may reduce immune  surveillance against skin cancer.!°®   Skin exposure to UVR and ionizing radiation, as well as  chemical (xenobiotic) agents/drugs, produces ROS in large  quantities that can overwhelm tissue antioxidants and other  oxygen-degrading pathways.'”? Uncontrolled release of ROS  is an important contributor to skin carcinogenesis.'”? Healthy  genes are needed to coordinate the levels of antioxidants and  decrease harmful ROS. Imbalances in ROS and antioxidants can  lead to oxidative stress, tissue injury, and direct DNA damage.  ROS can induce a number of transcription factors (e.g., acti-  vator protein 1 [AP-1] and NF-«B)?°° and increase regulating  genes that induce inflammation.?°!7” Inflammation is a critical  component of tumor progression. The pathophysiology of skin  carcinogenesis is discussed further in Chapter 46.   Basal cell carcinoma (BCC) commonly occurs on the  head and neck. Individuals with these tumors generally have  fair complexions, light-colored eyes, and fair hair. They tend  to sunburn rather than tan and live in areas of high sunlight  exposure. Usually these cancers arise on areas of the body that  receive the greatest sun exposure, although they are not nec-  essarily restricted to these skin sites. Squamous cell carcinoma  (SCC) is found more commonly in men who work outdoors.  These tumors are distributed over the head, neck, and exposed  areas of the upper extremities (see Chapter 46).   The incidence of melanoma in the United States (from the  most recent SEER data) has been increasing annually at a rate of  about 2.8% from 1981 to 2008.2”. Because mortality rates have  not risen as rapidly, however, controversy exists as to whether  the incidence increase is a true increase in clinically significant    melanoma or is a result of overdiagnosis.”°* Overdiagnosis  may include lesions that are histologically malignant but bio-  logically benign.2°° Melanomas most commonly affect whites,  and the lower incidence of melanoma in darker-skinned indi-  viduals is thought to be the result of higher melanin densities in  these individuals.” Established risk factors for melanoma are  genetic and phenotypic traits; increasing age; fair skin and hair  color; the presence of >20 nevi, 23 atypical nevi, or freckling; an  increased likelihood of burning with sun exposure; a history of  immunosuppression, previous psoralen UVA treatment, solar  keratoses, squamous cell carcinoma, or xeroderma pigmento-  sum; and a family history of dysplastic nevi or melanoma.?°70%   Environmental exposures important in melanoma include  history of three or more episodes of sunburn, periodic excessive  sunlight exposure (e.g., vacations with intense exposure), pos-  sibly long-term continuous sunlight exposure,””? and UV expo-  sure at tanning salons.*°” Other environmental factors, such as  ozone depletion and latitudes closer to the equator, also may be  related.?°” Sun exposure and the risk of melanoma remain com-  plex. Melanomas can appear suddenly without warning but can  arise from or near a mole (melanocytic nevus). When detected  in the early stages, melanoma is highly curable.?'? About 20%  of melanomas, however, are diagnosed at nonlocalized and  advanced stages.”!” According to Sekulic and colleagues,*!! the  failure of current diagnostic methods to accurately predict indi-  vidual risk of disease progression and outcome challenges the  ability to diagnose melanoma in early stages. Recent progress  in understanding the molecular alterations in melanoma will  likely advance its diagnosis, prognosis, and treatment.   Until 1998 a direct causal relationship between UVB light and  melanoma in humans had not been established. Grafted new-  born human foreskin (xenograft) onto RAG-1—immunodeficient  mice showed such a relationship.*'? Melanocytic hyperplasia  occurred in 73% of UVB-treated xenografts. One graft treated  with 9,10-dimethylbenz[a]anthracene (DMBA) and UVB light  developed a human malignant melanoma. This was the first  experiment to show that exposure to both UVB light and an  exogenous carcinogen could result in a new malignant mela-  noma. Recent evidence shows UV signature mutations in human  melanoma.*!>?!* (For further specific pathophysiology discus-  sion, see Chapter 46.)   Increased understanding of the intricate cellular interactions  in melanoma will further our knowledge of melanoma etiology  and pathogenesis. This knowledge is essential for early detec-  tion and treatment.    Health risks associated with radiofrequency electromagnetic  radiation (RF-EMR) are very controversial. RF-EMR is in the  frequency range of 30 kHz to 300 GHz. Electromagnetic fields  (EMFs) generated by RF sources couple with the body and  result in induced electric and magnetic fields with associated  currents inside tissue.?!> Exposure to electric and magnetic  fields is widespread. Electric fields are shielded or weakened  by walls and other objects; however, magnetic fields are not.?!°  EMRs are a type of nonionizing, low-frequency radiation with-  out enough energy to pull electrons from their orbits around    atoms and ionize (charge) the atoms. Microwaves, radar,  mobile and cell phones, mobile phone base stations, appli-  ances, power frequency radiation associated with electricity and  radio waves, fluorescent lights, computers, and other electric  equipment create EMRs of varying strength. The major debate  for more than four decades has focused on the association of  exposure to EMR and resultant health consequences, including  cancer. Scientific evidence is accumulating although hampered  by the availability of methods to accurately measure exposure,  the lack of a clear dose-response relationship, and the difficulty  in reproducing effects. In addition, with competing priorities  such as convenience, financial interest, and health necessity, a  consensus of the risk/benefit ratio of EMR exposure may be dif-  ficult to achieve, and safety standards significantly vary, up to  1000 times among countries.”!”7!* In 1998, the National Insti-  tute of Environmental Health Sciences Electric and Magnetic  Fields Working Group?!’ recommended that low-frequency  electromagnetic fields (EMFs) be classified as possible carcin-  ogens. Overall, there is limited evidence that magnetic fields  cause childhood leukemia’!° (see Chapter 14). Studies of mag-  netic field exposure from power lines and electric blankets in  adults reveal little evidence of an association with leukemia,  brain tumors, or breast cancer.?!©   Most exposure to EMF from occupational sources comes  from near-field sources; the highest exposure to the general  population comes from transmitters close to the body, such  as hand-held devices like mobile telephones.?!> Epidemio-  logic evidence for an association between EMF and cancer has  been derived from case-control, cohort, and time-trend stud-  ies. The most extensively studied exposure is from use of wire-  less telephones (mobile and cordless); other exposures include  occupational settings and sources from the general environ-  ment?!> (also see Chapter 14). The one cohort study and five  case-control studies judged by the WHO International Agency  for Research on Cancer Monograph Working Group to offer  potentially useful information about associations between wire-  less phones and glioma, with time-trend analyses, did not show  an increased rate of brain tumors after the increase in mobile  phone use. However, these studies had limitations because most  of the analyses examined trends only in the early 2000s.”!° The  INTERPHONE study,””’ a multicenter case-control study, is the  largest study so far that studies the relationship between mobile  phone use and brain tumors—glioma, acoustic neuroma, and  meningioma. The pooled analyses included 2708 glioma cases  and 2972 controls. The odds ratios (ORs) in terms of time spent  on the phone showed that the highest time spent on the phone  (>1640 hours of use) was related to glioma risk (OR 1.40; 95%  confidence interval [CI] 1.03-1.89). There was a suggestion of  increased risk of tumors on the same side of the head as the  phone use (ipsilateral exposure) in the temporal lobe, where  radiofrequency (RF) EMF exposure is highest.?!> The OR for  glioma increased with increasing RF dose for exposure 7 years  or more before diagnosis, and there was no association with esti-  mated dose for exposure less than 7 years before diagnosis.7!° A  Swedish investigative group performed a pooled analysis of two  similar studies between the relationship of glioma, acoustic neu-  roma, and meningioma manifestation and mobile and cordless    phone use.””! Study participants who used a mobile phone for  more than 1 year had an OR for glioma of 1.3 (95% CI 1.1-1.6).  The OR increased with increasing time since first use and with  total call time, 3.2 (2.0-5.1) for more than 2000 hours of use.?!>  Ipsilateral use of the phone was associated with higher risk.”!°  Similar findings were reported for cordless phones.*!> Although  the INTERPHONE and Swedish studies were judged suscep-  tible to bias, the Working Group concluded that the findings  could not be dismissed because of bias alone and a causal rela-  tionship between phones and glioma is possible.?!> The Work-  ing Group concluded there is “limited evidence in humans” for  the carcinogenicity of RF-EMF based on associations between  glioma and acoustic neuroma and exposure to RF-EMF from  wireless phones.”!° The Working Group reviewed animal stud-  ies and concluded there is “limited evidence” in experimental  animals for the carcinogenicity of RF-EMF.?!°   The Working Group also reviewed numerous studies’ end-  points relevant to mechanisms of carcinogenicity from RF-  EMF.?!° The mechanisms included genotoxicity, effects on  immune function, gene and protein expression, cell signaling,  oxidative stress, and apoptosis. Additionally, studies on the  possible effects of RF-EMF on the blood-brain barrier were  analyzed. Overall, the Working Group reported there was  evidence of RF-EMF on some of these endpoints, but they  provided weak mechanistic evidence of RF-EMF-—induced  cancer in humans.*!? The outcome of the Working Group  was to classify RF-EMF as “possibly carcinogenic to humans”  (Group 2B).   There are no studies of adults who have used cell phones as  children or adolescents. Concern is for children in whom the  effects may be compounded because of increased vulnerability  to radiation and their longer use of cell phones into adulthood.  Ongoing unbiased research is desperately needed. Absolute  proof of causation may be hindered because of the ethical ques-  tions of exposing individuals to potentially harmful interven-  tions.?”? Chapter 14 discusses cancer in children.   An estimated 80,000 synthetic chemicals are used in the United  States. Of those, only about 7% have been tested for their health  effects.’*> It is disturbing that another 1000 are manufactured  each year. Exposure to chemicals occurs every day—they are  present in air, soil, food, water, household products, toys, per-  sonal care products, workplaces, and homes. The number of  known carcinogens in experimental animals is large. It is sus-  pected that most of these chemical carcinogens are potentially  carcinogenic in humans but documentation is lacking. Table  13-1 provides a summary of the chemicals according to suffi-  cient or limited evidence in humans by cancer site. Known and  probable carcinogenic agents are updated by the International  Agency for Research on Cancer (IARC). Chemical carcinogene-  sis involves the classical genotoxic mechanisms and exposure to  genotoxic carcinogens might also involve a variety of nongeno-  toxic effects in cells.** Recently, a number of studies reported  that the carcinogenic effects induced by several chemicals,  including 2-acetylaminofluorene, tamoxifen, trichloroethylene,    aflatoxin B,, ochratoxin, nickel, and chromium, do not follow  a classic genotoxic carcinogenesis model, but rather involve a  spectrum of cellular alterations encompassing epigenetic altera-  tions.?”> These epigenetically reprogrammed cells show an  epigenetic profile similar to that frequently observed in cancer  cells, including altered histone patterns, hypomethylation of  DNA repetitive elements, alterations in proto-oncogenes, and  hypermethylation of tumor-suppressor genes. Altered epigen-  etic status confers genome instability and loss of controlled  growth signals, typically observed in cancer cells.?*°   A substantial percentage of cancers of the upper respira-  tory passages, lung, bladder, and peritoneum are attributed to  occupational factors; however, fewer studies of nonsmokers  exist.2*” One notable occupational factor is asbestos, which  increases the risk of mesothelioma and lung cancer. Asbestos  was used in homes and buildings built before the 1970s to  insulate ceiling tiles, flooring, and pipe covers. In Western  Europe, the epidemic of mesothelioma in building workers  and other workers born after 1940 did not become appar-  ent until the 1990s because of long latency. No exposure to  asbestos is without risk and a large number of countries still  use, export, and import asbestos-containing products (see  Table 13-1).   Carcinoma of the bladder has been linked with the manu-  facture of dyes, rubber, paint, and aromatic amines, especially  6-naphthylamine and benzidine. Benzol inhalation is linked to  leukemia in shoemakers and in workers in the rubber cement,  explosives, and dyeing industries. Other notable occupational  hazards include heavy metals (e.g., high-nickel alloy, chromium  VI compounds, inorganic arsenic), silica, polycyclic aromatic  hydrocarbons, sulfuric acid, and chloromethyl ether. Studies of  occupational exposure to diesel exhaust indicate an increased  risk of lung cancer.”*® Disentangling data related to lung cancer,  air pollution, and occupational risks is complex, especially in  combination with active and passive smoking and the interplay  of environmental factors and genetic polymorphisms at mul-  tiple loci.    In the United States, two types of air pollution are most impor-  tant and widespread: ozone and particle pollution.”?? Other  important air pollutants include carbon monoxide, lead, nitro-  gen dioxide, sulfur dioxide, mercury, arsenic, benzene, form-  aldehyde, and acid gases.?*? Ozone is an extremely reactive  gas molecule composed of three oxygen atoms. It is the main  ingredient in smog air pollution. The ozone layer found in the  upper atmosphere (the stratosphere) is called ozone (O3), or  good ozone, and protects life on earth by absorbing UV radia-  tion emitted from the sun. The heavy use of propellants, such  as aerosols, has decreased the size of the good ozone layer,  leading to the banning of chlorofluorocarbons. The accumu-  lating ozone at the lower atmospheric level or ground level is  a toxic air pollutant. This ground-level ozone is a gas formed  by reactions with nitrogen oxides, volatile organic compounds  (VOCs), and sunlight. This gas mixture is emitted from motor  vehicle exhausts and industrial emissions. Nasty combinations  of mixtures cause damage (i.e., ROS and inflammation) to lung    tissue, especially in people with preexisting lung diseases. These  mixtures can also affect healthy people when combined with  other air pollutants, such as sulfur dioxide. Sulfur dioxide is  produced by power plants burning oil and coal, copper smelt-  ing, and paper mills. Fine or ultrafine particles, those less than  10 micrometers in diameter, are considered the most harmful.  Fine or ultrafine particles are easily absorbed by the lungs and  phagocytosed by macrophages and neutrophils that release tis-  sue-damaging inflammatory mediators. Acute exposure to die-  sel exhaust that contains fine particles is linked to lung, throat,  and eye irritations; asthma attacks; and myocardial ischemia.**°  Importantly, according to the WHO diesel exhaust is carcino-  genic and causes lung cancer.”*'! Long-term exposure to other  sources of air pollution may cause lung cancer.”** Evidence  for cancers, other than lung cancer and childhood cancer, is  inconsistent.?°?   Indoor pollution generally is considered worse than outdoor  pollution, partly because of cigarette smoke. Environmental  tobacco smoke (ETS; passive smoking) can cause the forma-  tion of reactive oxygen free radicals and thus DNA damage.  The IARC has classified ETS as a human carcinogen. Another  significant indoor air pollutant is radon gas. Radon is a natural  radioactive gas derived from the radioactive decay of uranium  that is ubiquitous in rock and soil; it can become trapped in  houses and gives rise to radioactive decay products known to  be carcinogenic to humans. The most hazardous houses can  be identified by testing and then by being modified to prevent  further radon contamination. Exposure levels are greater from  underground mines than from houses. Most of the lung cancers  associated with radon are bronchogenic; however, small cell  carcinoma does occur with greater frequency in underground  miners. Radon increases the risk of lung cancer in underground  miners whether they smoke or not.   In China, some regions report very high levels of lung cancer  in women who spend much of their time indoors. Exposures  from heating and cooking combustion sources (e.g., oil vapors,  volatile toxicants) are identified as risk factors for lung can-  cer.”*+55 In addition, domestic coal use and ETS increase the  risk of lung cancer in women and men.”°°   Inorganic arsenic (known as a carcinogen since the late  1960s), found principally in underground water (from 1000 to  4000 mcg/L), is found in many regions of the world. Accord-  ing to the IARC, strong evidence indicates an increased risk of  bladder, skin, and lung cancers following consumption of water  with high levels of arsenic (generally greater than 200 mcg/L).?°”  Evidence for cancers of the liver, colon, and kidney is weaker.  Other sources of inorganic arsenic are related to occupational  exposures.   The central hypothesis, based on rat studies, for the mecha-  nisms related to particle-induced lung carcinogenesis is that  insoluble particles cause pulmonary inflammation (e.g., cyto-  kine release, ROS), which leads to oxidative stress and oxidation  of DNA, proliferative response, and tissue remodeling pro-  gressing toward fibrosis and tumor development. Additional  research is needed to understand the surface chemistry and lung  tissue remodeling in relation to insoluble particles, lung carci-  nogenesis, and other respiratory problems.    Cancer arises from a complicated and an interacting web of  multiple causes. Avoiding high-risk behaviors and exposures  to individual carcinogens, or cancer-causing substances, will  prevent many types of cancer.    such as exposure to ultraviolet radiation and occupational car-  cinogens, contribute to the number of cancer cases and deaths.    type, phenotype, high-risk lifestyle behaviors, the environ-  ment, and carcinogenesis. The root cause of cancer is more  than inherited or acquired genetic mutations and involves  epigenetic changes that frequently precede and induce cancer-  causing genetic mutations.    ing process that facilitates tumor promotion and metastases  because stromal tissue has immune cells. Chronic inflamma-  tion from infiltrating immune cells can be caused by numerous  environmental factors, for example, inhaling tobacco smoke.    Cancer is reported to become a major cause of morbidity  and mortality in the coming decades in all regions of the  world.    . Overall, cancer incidence rates in the United States for all    racial and ethnic groups combined decreased by 0.8% per  year during the most recent study period, 2003 to 2007.    . Death rates from the periods 1998 to 2007 and 2003 to 2007    continued to decrease for 7 of the top 15 cancer types in both  men and women (colorectal, brain, stomach, and kidney  cancers; non-Hodgkin lymphoma; leukemia; and myeloma).  Decreasing death rates for men also included lung, prostate,  and the oral cavity, and for women breast and bladder can-  cers. Death rates continued to increase for cancers of the  liver and pancreas among men and women, uterine cancer  in women, and melanoma of the skin in men.    Accumulating data suggest early life events influence later  susceptibility to certain chronic conditions, including cancer.    development is contingent on its environment. It requires  stable gene expression that in part appears to be modulated  by epigenetic processes such as DNA methylation, histone  modification, and microRNAs.    in the developmental environment can alter phenotypic  changes, resulting in individual responses in adulthood.    Cigarette smoking is carcinogenic and the most important  cause of cancer. The risk is greatest in those who begin to  smoke when young and continue throughout life.    Cigarette smoking accounts for one of every five deaths each  year in the United States. Yet it is the single most preventable  cause of death and disease.    . Smoking tobacco is linked to cancers of the lung, lower uri-    nary tract, upper aerodigestive tract, liver, kidney, pancreas,  cervix, and uterus and to myeloid leukemia.    carcinogenic. Nonsmokers who live with smokers are at  greatest risk for lung cancer, as well as other noncancerous  conditions. In utero effects from maternal or paternal smok-  ing and subsequent disease are being investigated.    . Cigar or pipe smoking is strongly and causally related to    cancers of the oral cavity, oropharynx, hypopharynx, lar-  ynx, esophagus, lung, and possibly the pancreas. Bidi smok-  ing can cause cancers of the respiratory and digestive tracts  and also increase the risk of heart attacks and chronic  bronchitis.    Dietary sources of carcinogenic substances include com-  pounds produced in the cooking of fat, meat, or pro-  tein, and naturally occurring carcinogens associated  with plant food substances, such as alkaloids or mold  byproducts.    nutrition and genomics, epigenomics, transcription fac-  tors (transcriptomics), proteomics, and metabolic factors  (metabolomics) and the effect on cancer risk of modifying  one or more of these factors.    genes that should be active or activate genes that should be  silent. The expression of microRNAs in response to diet  may be involved in several cancers.    DNA damage and repair, stem cell renewal, hormonal  axes, the balance of cellular proliferation and cell death,  the microenvironment, cell signaling, inflammation, and  immunity.    . Undernutrition can be a factor in cancers caused by infec-    tious agents, for example, cancers of the liver and cervix.  Future research is needed to define robust biomarkers of  cancer risk.    Obesity has been increasing in most developed countries  and in urban areas of developing countries.    the relationship between overweight/obesity, energy bal-  ance and cancer risk, cancer recurrence, and survival.    . Consensus now exists that obesity is a risk factor for can-    cers of the endometrium, colorectum, kidney, esophagus,  breast (postmenopausal), and pancreas. Evidence is evolv-  ing of the association of obesity with cancers of the thyroid,  gallbladder, liver, and ovary and also with aggressive types  of prostate cancer and non-Hodgkin lymphoma.    . Obesity is recognized as a poor prognostic factor for several    the progression of cancer are not completely known and  the process is complex.    ever, research now includes other mechanisms whereby  energy balance may affect (a) genomic instability, (b)  dysregulated growth signaling and cellular energetics, (c)  inhibition of apoptosis and immune surveillance, and (d)  angiogenesis.    acceleration of carcinogenesis. Data now exist for several fac-  tors, including energy-driven signaling from insulin, insulin-  like growth factor 1 (IGF-1), phosphatidylinositol 3-kinase,  and AMP-activated protein kinase and many others.  Adipose tissue is a source of inflammatory modulators and  increasing evidence indicates that obesity is causally linked  to inflammation   Cancers have altered metabolism. Tumors consume large  quantities of glucose to make cellular building blocks,  called the Warburg Effect. Yet, some tumors do use oxida-  tive stress as a weapon to extract recycled nutrients from  cancer-associated fibroblasts in stromal tissue (Reverse  Warburg Effect).   Food metabolism and circadian cycles are linked and  impairment of inner clock regulation results in dysregu-  lated metabolism.   Overall, there are strong data supporting alcohol as a cause  of cancers of the mouth, pharynx, larynx, esophagus, liver,  colorectum, and breast.    Infection is an important contributor to cancer worldwide  and the population attributable fraction (PAF) was 16.1% of  cancers diagnosed in 2008 were caused by infection, or about  2 million new cases.    . Infection and cancer rates vary widely by region, with a 7.4%    rate for more developed regions and 22.9% rate for less devel-  oped regions. The highest PAF is for sub-Saharan Africa with  a rate of 32.7%.    HPV, Helicobacter pylori (H. pylori), hepatitis B virus, and  hepatitis C virus.    . Hepatitis B and C can infect the liver and together account    . It has been estimated that H. pylori accounts for about 75% of    types of HPV are required for the development of most cer-  vical cancers. HPV types 16 and 18 cause the majority of  cancers.    . HPV types 16 and 18 also have been found to cause almost    half of vaginal, vulvar, and penile cancers. Recently, HPV  infections have been found to cause cancer of the orophar-  ynx (soft palate, base of the tongue, tonsils).    . Factors that may increase the risk of developing cancer fol-    lowing a high-risk HPV infection include smoking, decreased  immunity, having many children (for increased risk of cervi-  cal cancer), long-term oral contraceptive use (for increased  risk of cervical cancer), poor oral hygiene (for increased risk  of oropharyngeal cancer), and chronic inflammation.    . HPVs infect epithelial cells that cover the inside and outside    surfaces of the body, including the skin, throat, genital tract,  and anus.    Physical activity reduces the risk for breast cancer, colon  cancer, and endometrial cancer, independent of weight  changes.    include decreasing insulin and IGF levels, decreasing obe-  sity, increasing free-radical scavenger systems, changing  inflammatory mediators, decreasing the levels of circulating  sex hormones and metabolic hormones, improving immune  function, and enhancing cytochrome P-450 function, thus  modifying carcinogen activation and increasing gut motility.    ity program after a cancer diagnosis is associated with better  cancer-specific outcomes and overall survival with early-  stage breast, prostate, and colorectal cancers.    quency, intensity, and duration of exercise required for opti-  mal health benefits.    1. Much of the knowledge of the effects of ionizing radiation    (IR) on human cancer has stemmed from observations of  the Hiroshima and Nagasaki atomic bomb exposures, par-  ticularly the Life Span Study. Other evidence is derived from  groups exposed for medical reasons, underground miners  exposed to radon gas, and other occupational exposures.    2. The atomic bomb exposures in Japan caused acute leu-  kemias in adults and children and increased frequencies  of thyroid and breast carcinomas. Lung, stomach, colon,  esophageal, and urinary tract cancers and multiple myeloma  have been added to the list.   3. Recent models of radiation carcinogenesis show ionizing  radiation (IR) acts not only as an initiator of premalignant  cell clones but also as a promoter of preexisting premalig-  nant cell alterations.   4, Health risks from IR involve cancers, cardiovascular dis-  eases, respiratory diseases, birth defects, and eye maladies.   5. In 2009 the National Council on Radiation Protection and  Measurements reported Americans were exposed to more  than seven times as much IR from medical procedures  compared to IR exposure in the 1980s.   6. Ionizing radiation is a mutagen and carcinogen and can  penetrate cells and tissues and deposit energy in tissues at  random in the form of ionizations.   7. The past two decades have focused on cellular and molec-  ular mechanisms that relate to the induction of cancer,  including dose-response relationships for chromosome  aberrations and for cell transformation; gene expression  (genetic and epigenetic); alternative targets, such as mem-  branes; mutagenesis in somatic cells; the biologic effects  that occur in nonirradiated cells (i.e., nontargeted effects);  and effects on the microenvironment.   8. Because models and underlying assumptions of IR and cell  damage are incomplete, investigators are working hard to  understand induced repair, adaptive responses, hormesis,  low-dose hypersensitivity, nontargeted effects, signaling,  exosomes, and long-term persistence of radiation damage  and clonal heterogeneity.   9. A long held assumption is that cellular alterations—muta-  tions and malignant transformation—occur only in cells  directly radiated. It is now known that radiation may induce  a type of genomic instability to the progeny of the directly  irradiated cells over many cell generations and can affect  so-called innocent bystander cells.   10. Epigenetic events after radiation include alterations in  pathways affecting cell adhesion, extracellular matrix inter-  actions, and cell-to-cell communication.   1. Ultraviolet radiation (UVR) causes basal cell carcinoma and  squamous cell carcinoma. The principal source of UVR is  sunlight.   2. The degree of damage in skin depends on the intensity and  wavelength content—ultraviolet A (UVA) or ultraviolet B  (UVB).   3. UVR is known to cause specific gene mutations; for exam-  ple, squamous cell carcinoma involves mutation in the TP53  gene, basal cell carcinoma in the patched gene, and mela-  noma in the p16 gene.   4. Skin exposure to UVR produces ROS in large quanti-  ties that can overwhelm tissue antioxidants and other    oxygen-degrading pathways. Imbalances in ROS can lead to  oxidative stress, tissue injury, and direct DNA damage.    . ROS can induce a number of transcription factors (e.g., acti-    vator protein 1 [AP-1] and NF-«B) and increase the levels of  regulating genes that induce inflammation. Inflammation is  a critical component of tumor progression.    . The incidence of melanoma in the United States has been    increasing annually at a rate of about 2.8% from 1981 to  2008. Because mortality rates have not risen as rapidly, how-  ever, controversy exists as to whether the incidence increase  is a true increase in clinically significant melanoma or is a  result of overdiagnosis.    . The relationship between sun exposure and the risk of mela-    in melanoma will enhance knowledge of melanoma etiology  and pathogenesis. This knowledge is essential for early detec-  tion and treatment.    Health risks associated with electromagnetic radiation  (EMR) are controversial. Exposure to electric and magnetic  fields is widespread. EMRs are a type of nonionizing and  low-frequency radiation.    body and result in induced electric and magnetic fields with  associated currents inside tissue.    stations, appliances, power frequency radiation associated  with electricity and radio waves, fluorescent lights, computers,  and other electric equipment create EMRs of varying strength.    and cancer are limited because of inadequate methods to  accurately measure exposure, lack of clear dose-response  relationships and reproduction of effects, financial interests,  and other priorities such as convenience.    from near-field sources; the highest exposure to the general  population comes from transmitters close to the body, such  as hand-held devices like mobile telephones.    Monograph Working Group reported that the INTER-  PHONE and Swedish studies were judged susceptible to bias,  the findings could not be dismissed because of bias alone, and  a causal relationship between phones and glioma is possible.    . The outcome of the Working Group was to classify RF-EMF    as “possibly carcinogenic to humans” (Group 2B). The mech-  anisms included genotoxicity, effects on immune function,  gene and protein expression, cell signaling, oxidative stress,  apoptosis, and, possibly, the blood-brain barrier.    . There are no studies of adults who have used cell phones as    children or adolescents. Concern is for children in whom the  effects may be compounded because of increased vulner-  ability to radiation and their longer use of cell phones into  adulthood.    An estimated 80,000 synthetic chemicals are used in the  United States. Of those, only about 7% have been tested for  their health effects and another 1000 are synthesized each  year.    . Chemicals are present in air, soil, food, water, personal care    is large. It is suspected that most of these chemical carcino-  gens are potentially carcinogenic in humans but documenta-  tion is lacking.    mechanisms, and exposure to genotoxic carcinogens also  might involve a variety of nongenotoxic effects, including  epigenetic alterations in cells.    induced by several chemicals do not follow a classic geno-  toxic carcinogenesis model, but rather involve a spectrum of  cellular alterations encompassing epigenetic alterations.    passages, lung, bladder, and peritoneum are attributed to  occupational factors; however, fewer studies of nonsmokers  exist.    8. Disentangling data related to lung cancer, air pollution, and  occupational factors is complex, especially in combination  with active and passive smoking, environmental factors, and  multiple interacting genes.   1. In the United States, two types of air pollution are most  important and widespread: ozone and particle pollution.  Other important air pollutants include carbon monoxide,  lead, nitrogen dioxide, sulfur dioxide, mercury, arsenic, ben-  zene, formaldehyde, and acid gases.   3. Ground-level ozone is a gas formed by reactions with nitro-  gen oxides, volatile organic compounds (VOCs), and sun-  light. This gas mixture is emitted from motor vehicle exhausts  and industrial emissions.   4. Fine or ultrafine particles are easily absorbed by the lungs  and phagocytosed by macrophages and neutrophils that  release tissue-damaging inflammatory mediators.   5. The indoor air pollution environmental tobacco smoke (ETS;  passive smoking) can cause the formation of reactive oxygen  free radicals and thus DNA damage. The IARC has classified  ETS as a human carcinogen.   6. Strong evidence indicates an increased risk of bladder, skin,  and lung cancers following consumption of water with high  levels of arsenic (generally greater than 200 mcg/L).    Adipokine, 420 Environmental tobacco smoke (ETS), 413 Radiofrequency electromagnetic radiation (RD-EMR),  Asbestos, 433 Genomic instability, 429 431   Carcinogen, 402 Insulin-like growth factor 1 (IGF-1), 419 Reverse Warburg Effect, 420    1. Colditz GA, Wolin KY, Gehlert S: Applying what we know to accelerate  cancer prevention, Sci Transl Med 4(127): 127rv4, 2012.   2. National Cancer Institute (NCI): 2008-2009 Annual Report President’s  Cancer Panel: Reducing environmental cancer risk. What we can do  now, Washington, DC, 2010, U.S. Department of Health and Human  Services.   3. Parkin DM, Boyd L, Walker LC: The fraction of cancer attributable  to lifestyle and environmental factors in the UK in 2010, Br J Cancer  105(Suppl 2):$77—S81, 2011.   4. 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In 2012, approximately 12,060 children (from birth to 14 years  of age) in the United States will be diagnosed with cancer, and  approximately 1340 will die from the disease, one third of these  from leukemia.!   The types of malignancies in children are vastly different  from those that affect adults. The most common types of can-  cer among adults include prostate, breast, lung, and colon.  Children (birth to 14 years of age) with leukemias and brain  tumors account for 61% of childhood cancers; neuroblastoma  and soft tissue or bone sarcomas are less common. Although  many adult cancers have associated lifestyle factors that  could theoretically be avoided, such as smoking and lifetime    exposure to sun, very few environmental factors have been  linked to pediatric malignancies. Yet more data are emerging  that the developing child may be affected by parental expo-  sures before conception, exposures in utero, and the contents  of breast milk.*”   The incidence of cancer among adolescents and young adults  represents only 2% of all invasive cancers. However, the malig-  nancy rate in this age group (15- to 39-year-olds) is three times  higher than that in children younger than 15 years. Each year  about 70,000 adolescents and young adults will be diagnosed  with cancer. The following are the most common cancers diag-  nosed among the 15- to 39-year-old population in the United  States? (these cancers are discussed in the appropriate chapters):    Most childhood cancers originate from the mesodermal  germ layer that gives rise to connective tissue, bone, cartilage,  muscle, blood, blood vessels, gonads, kidney, and the lymphatic  system. Thus the more common childhood cancers are leuke-  mias, sarcomas, and embryonic tumors. Embryonic tumors  originate during intrauterine life. These tumors contain abnor-  mal cells that appear to be immature embryonic tissue, unable  to mature or differentiate into fully developed functional cells.  Embryonic tumors are diagnosed early in life (usually before 5  years of age). Embryonic tumors often contain the term blast  cell in their name, which refers to the immature nature of the  cells.   Leukemia is the most common malignancy in children and  the most common type of leukemia is acute lymphoblastic leu-  kemia (ALL), which represents approximately 75% of all pediat-  ric leukemia cases. Although the presenting signs of the various  types of leukemia may be similar, the treatment and response to  treatment of childhood leukemias vary greatly (see Chapter 30).   CNS tumors are the most common types of solid tumors  in children and account for 27% of all childhood cancers! (see  Chapter 20). Not all brain tumors are diagnosed malignant by  histologic studies, but even a benign tumor can have devastat-  ing effects, depending on the anatomic location. The treatment  for brain tumors in children often presents difficulties because  therapies, such as radiation, may have debilitating effects on the  developing brain, particularly in children younger than 3 years  of age.   Lymphoma, including non-Hodgkin lymphoma and Hodg-  kin lymphoma, is a malignancy that occurs in children and  adults. However, the subtypes of lymphoma and treatments in  the two populations often differ (see Chapter 30).   Many pediatric solid tumors usually develop only in children  but in very rare instances may occur in adults. These tumors  include neuroblastoma, Wilms tumor, rhabdomyosarcoma,  retinoblastoma, osteosarcoma, and Ewing sarcoma.   Childhood cancers are most often diagnosed during peak  times of physical growth. In general, they are extremely fast  growing, with 80% having distant spread (metastases) at diag-  nosis. Overall, cancer is 10% to 25% more common in white  than in black children. Boys are more likely to develop cancer  than girls.    The causes of cancer in children are largely unknown. A few  environmental factors are known to predispose a child to can-  cer, but causal factors have not been established for most child-  hood cancers. A number of host factors, many of which are  genetic risk factors or congenital conditions, have been impli-  cated in the development of childhood cancer (Table 14-1).  It is most likely the interaction of many factors that produces  cancer, a concept referred to as multiple causation or multi-  factorial etiology. According to this premise, cancer develops  because of the predisposing characteristics of the person and  the interaction with environmental causes.   The multiple causation concept is useful when the results of  epidemiologic studies are interpreted. For example, laboratory    and epidemiologic studies may indicate that exposure to a cer-  tain chemical can cause leukemia, but not all children exposed  to that chemical will develop leukemia. Additional studies will  be needed to determine what other factors must interact with  chemical exposure to cause the disease.    TABLE 14-2 SELECTED ONCOGENES  AND TUMOR-SUPPRESSOR  GENES ASSOCIATED WITH  CHILDHOOD CANCER    Data from Dome JS, Coppes MS: Curr Opin Pediatr 14(1):5-11, 2002;  Linblom A, Nordenskjold M: Semin Cancer Biol 10(4):251-254, 2000;  Tischkowitz M, Rosser E: Eur J Cancer 40:2459-2470, 2004; Look A,  Kirsch IR: Molecular basis of childhood cancer. In Pizzo PA, Poplack DG,  editors: Principles and practices of pediatric oncology, ed 6, Philadelphia,  2011, Lippincott Williams & Wilkins.    Oncogenes and tumor-suppressor genes are associated with the  development of childhood cancer (Table 14-2; also see Chap-  ter 12). Proto-oncogenes code for proteins that help to regulate  normal cell growth and differentiation. If mutated, proto-onco-  genes become oncogenes that help to turn normal cells into  cancer cells. Changes produced by specific oncogenes cause  the cell cycle to become dysregulated. An example of an onco-  gene identified in pediatric cancer is N-myc, which is involved  in neuroblastoma and glioblastoma. Tumor-suppressor genes  arise from genes that normally suppress cancer cell prolifera-  tion but have lost their suppressor function, thus leading to  uncontrolled growth. Some childhood cancers identified with  tumor-suppressor genes include osteosarcoma, leukemia, rhab-  domyosarcoma, retinoblastoma, and Wilms tumor.*   Other genetic factors involve chromosomal aberrations or  single-gene defects. These chromosomal abnormalities include  aneuploidy, amplifications, deletions, translocations, and sus-  ceptibility to breakage, known as fragility. A well-known chro-  mosomal abnormality is the Philadelphia chromosome found in  chronic and acute myelogenous leukemias.° Chromosomal dele-  tions are often observed in retinoblastoma and osteosarcoma.    A collaborative study conducted at 20 different centers in the United States  examined how DNA in medulloblastoma in children differs from the DNA in  adult cancers. The investigators found that the tumors in children had 5 to  10 times fewer mutations than the tumors in adults. However, although the  tumors in the children had fewer mutations, more than one third were known    to disrupt gene function, which is a much higher percentage than that found  in adult tumors.   The findings from this study suggest that childhood cancer is very differ-  ent than adult cancers. As scientists better understand which genes are most  important for causing and preventing cancer, they will be able to more readily  identify the type of cancer a person has and also develop targeted therapies.    Some chromosomal defects and congenital malformations  are associated with the development of pediatric cancer. Tri-  somy 21 (Down syndrome) is the most common genetic defect  linked to the development of acute leukemia. Children with  Down syndrome have a 10- to 20-fold increased risk of devel-  oping acute lymphoblastic and myelogenous leukemias and a  higher risk for developing acute megakaryocytic leukemia. The  risk is highest between 1 and 4 years of age.° Wilms tumor is  associated with several congenital syndromes: aniridia, or con-  genital absence of the iris of the eye; ambiguous genitalia and  mental retardation (AGR), neurofibromatosis, and Beckwith-  Wiedemann syndrome.’ Retinoblastoma, a malignant embry-  onic tumor of the eye, occurs as an inherited defect or as an  acquired mutation (see Chapter 20).   Several single-gene defects have been associated with the  subsequent development of childhood cancers. Fanconi anemia  and Bloom syndrome, two autosomal recessive conditions, are  risk factors for the development of acute lymphocytic leukemia  (ALL) (see Chapter 30).   Although not determined to be genetically transmitted, a  child who has a sibling with leukemia has a risk for the develop-  ment of leukemia that is two to four times greater than that for  children with healthy siblings. The occurrence of leukemia in  monozygous twins is estimated as being as high as 25%.   In families with a history of Li-Fraumeni syndrome (LFS)  (an autosomal dominant disorder involving the p53 tumor-sup-  pressor gene), the risk of developing cancer as a child or adult is  significantly higher than that seen in the unaffected population.  Children and adults in these families are at risk for soft tissue sar-  coma, breast cancer, leukemia, osteosarcoma, melanoma, and  cancer of the colon, pancreas, adrenal cortex, and brain. Individu-  als with LFS are at increased risk for developing multiple primary  cancers.® Overall, cancers in children are very different than adult  cancers and are associated with far fewer genetic mutations (see  What’s New? Far Fewer Genetic Mutations in Pediatric Cancer).   Although many adult cancers are associated with environmen-  tal agents, few childhood tumors share a similar strong asso-  ciation. Because of the lengthy latency period required between    TABLE 14-3 DRUGS THAT MAY INCREASE RISK OF CHILDHOOD CANCER  DRUG CLASS    exposure and development of cancer, presumably early expo-  sure to carcinogens does not result in cancer until the child is  an adult. A recent meta-analysis of 1426 cases of neuroblastoma  failed to show an association between paternal occupational  exposure to pesticide and development of disease.”    Prenatal exposure to some drugs and pesticides has been  linked to childhood cancers. The most well-described drug is  diethylstilbestrol (DES), which was prescribed by physicians  to prevent spontaneous miscarriage (in women with previ-  ous miscarriage). In 1971, DES was identified as a transpla-  cental chemical carcinogen because a small percentage of the  daughters of the women who took DES developed adenocar-  cinomas of the vagina and cervix. Since then, other studies  have attempted to identify drugs taken by pregnant women  that may cause cancer in their offspring, but no other drugs  have been found. Prior research suggested an association  between antenatal x-ray exposure and childhood cancer, but  studies have not been replicated or supported in recent lit-  erature. In 2006 the Office of the U.S. Surgeon General sug-  gested evidence of a causal relationship between childhood  leukemia, lymphoma, and brain tumors and prenatal or  postnatal environmental tobacco smoke exposure; the results  have suggested an association between parental exposure to  pesticides before or during pregnancy.’ A recent study sug-  gested that the risk of leukemia and lymphoma increased  when the mother was exposed to pesticides in the prena-  tal period and the risk of brain tumors was correlated with  paternal exposure (occupational or household use) either  before or after birth.!°   Childhood exposure to ionizing radiation, drugs, or viruses has  been associated with the risk of developing cancer. Retrospective  research has shown a significant correlation between radiation-  induced malignancies from radiotherapy (cancer treatment) or  from radiation exposure from diagnostic imaging.'! Few stud-  ies have followed children for a long enough period of time to  determine whether there is an increased risk of cancer in adult-  hood, although there are current studies with more rigorous  methodology to assess this risk!* (see What’s New? CT Scans  in Childhood Appear to Increase Cancer Risk). In addition to  the drug and environmental agents that are known to cause  cancer in adults and therefore also are risks for exposure dur-  ing childhood, a few drugs may particularly increase cancer risk  during childhood (Table 14-3). Exposures during childhood    The findings from a recent study of 176,587 children suggest that those who  had 2 or 3 computed tomography (CT) scans of the head before age 22 years  were 3 times as likely to develop brain cancer as those in the general popula-  tion, and the risk of developing leukemia was 3 times as great in those who  received 5 to 10 CT scans. Previous studies have speculated that there may be  increased risk from repeated CT scans, but this large study was the first to pro-    vide direct evidence. Although the risk remains low, it amounts to 1 additional  case of brain cancer for every 30,000 children scanned or to 1 additional case  of leukemia for every 10,000 persons who were scanned. Although it remains  important for children to receive CT scans to detect head injuries, the results  of this study suggest that children should only be scanned when necessary  and also with the lowest dose of radiation possible.    to unspecified residential pesticides and insecticides have been  associated with childhood leukemia."   The relationship between childhood cancer and exposure to  radon" and electromagnetic fields has been the focus of many  epidemiologic studies, yet no conclusive evidence has been  observed. In 2007 a task group of scientific experts convened by  the World Health Organization (WHO) reported that it could  not confirm the existence of any health consequences from  exposure to low-level magnetic fields.!°   The strongest association between viruses and the develop-  ment of cancer in children has been the relationship between  exposure to Epstein-Barr virus (EBV) and development of  Burkitt lymphoma, nasopharyngeal carcinoma, and Hodgkin  disease. Children with acquired immunodeficiency syndrome  (AIDS) have an increased risk of developing non-Hodgkin lym-  phoma and Kaposi sarcoma. However, with the use of highly  active antiretroviral therapy in the developed world, the inci-  dence of AIDS-related malignancies has declined dramatically'®  (see Chapter 10).    More than 80% of children diagnosed with cancer are cured.  Mortality rates have declined from 6.5 per 100,000 in 1969 to  2.2 per 100,000 in 2008, largely because of advances in treat-  ment and increased participation in clinical trials.   Some of the factors leading to improved cure rates in pedi-  atric oncology include the use of combination chemotherapy    and multimodal treatment for childhood solid tumors. Addi-  tionally, development of research centers for comprehensive  childhood cancer treatment, cooperation among treatment  institutions, and development of cooperative study groups  enable the most efficient advancement of treatment regimens.  Currently, clinical trials are being conducted by the Children’s  Oncology Group (COG) at more than 180 hospitals across the  United States and are funded by the National Cancer Institute    through CureSearch® for Children’s Cancer. Side effects of  treatment are better managed as a result of improvements in  nursing and supportive care, recognition of the psychologic  effects of cancer treatment, and continued follow-up to track  trends in the late effects of cancer treatment. Young children  are particularly prone to long-term sequelae of cancer therapy.  Clinical trials are continually focusing on more effective, tar-  geted therapies with fewer side effects.   1. Cancer in children is rare, but is still the leading cause of  death from disease in this population.   2. Leukemias and brain tumors account for 61% of cancer in  children from birth to 14 years of age, with neuroblastoma  and soft tissue or bone sarcomas less common.   3. The most common cancers among the adolescent and young  adult populations (15 to 39 years of age) are Hodgkin lym-  phoma, leukemia, germ cell tumors (particularly testicular),  central nervous system (CNS) tumors, non-Hodgkin lym-  phoma, thyroid cancer, melanoma, sarcomas, and breast,  cervical, liver, and colorectal cancers.   1. Itis most likely the interaction of many factors produces can-  cer in children, a concept referred to as multiple causation or  multifactorial etiology.   2. Oncogenes and tumor-suppressor genes have been associ-  ated with childhood malignancies.    3. Chromosomal aberrations or single-gene defects including  aneuploidy, amplifications, deletions, translocations, and  fragility are associated with the development of childhood  cancer.   4. Wilms tumor and retinoblastoma are pediatric malignancies  that are linked in a familial manner.   5. Childhood exposure to ionizing radiation, drugs, or viruses  has been associated with the risk of developing cancer.   1. More than 80% of children diagnosed with cancer are cured.   2. Mortality rates have declined significantly in the past 40  years largely because of advances in treatment and increased  participation in clinical trials.   3. Young children are particularly prone to long-term sequelae  of cancer therapy. It is imperative that more effective, targeted  therapies with fewer side effects be found.    1. American Cancer Society: Cancer facts and figures 2012, Atlanta,  2012, Author.   2. Wigle DT et al: Epidemiologic evidence of relationships between  reproductive and child health outcomes and environmental  chemical contaminants, J Toxicol Environ Health B Crit Rev 11(5-6):  373-517, 2008.   3. National Cancer Institute: Adolescents and young adults with  cancer. Available at www.cancer.gov/cancertopics/aya/types.  Retrieved July 29, 2012.   4. Plon SE, Malkin D: Childhood cancer and heredity. In Pizzo PA,  Poplack DG, editors: Principles and practice of pediatric oncology,  ed 6, Philadelphia, 2011, Lippincott Williams & Wilkins,  pp li-37-   5. Alvarnez JC et al: Acute lymphoblastic leukemia, J Natl Comp  Canc Netw 10(7):858—-914, 2012.   6. Margolin JF et al: Acute lymphoblastic leukemia. In Pizzo PA,  Poplack DG, editors: Principles and practice of pediatric oncology, ed 6,  Philadelphia, 2011, Lippincott Williams & Wilkins, pp 518-565.   7. Fernandez C et al: Renal tumors. In Pizzo PA, Poplack DG, edi-  tors: Principles and practice of pediatric oncology, ed 6, Philadel-  phia, 2011, Lippincott Williams & Wilkins, pp 861-885.    8. Tabori U, Malkin D: Risk stratification in cancer predisposition  syndromes: lessons learned from novel molecular developments  in Li-Fraumeni syndrome, Cancer Res 68(7):2053—2057, 2008.   9. Moore A, Enquobahrie DA: Paternal occupational exposure to  pesticides and risk of neuroblastoma among children: a meta  analysis, Cancer Causes Control 22(11):1529-1536, 2011.   10. Vinson F et al: Exposure to pesticides and risk of childhood  cancer: a meta analysis of recent epidemiological studies, Occup  Environ Med 68(9):694—702, 2011.   11. Buka [et al: Trends in childhood cancer incidence: review of envi-  ronmental linkages, Pediatr Clin North Am 54(1):177—203, 2007.   12. Linet MS et al: Cancer risks associated with external radiation from  diagnostic imaging procedures, CA Cancer J Clin 62:75-100, 2012.   13. Turner MC, Wigle DT, Krewski D: Residential pesticides and  childhood leukemia: a systematic review and meta-analysis, Envi-  ron Health Perspect 118(1):33—41, 2010.   14. Tong J et al: Environmental radon exposure and childhood leu-  kemia, J Toxicol Environ Health B Crit Rev 15(5):332-347, 2012.   16. Pajand O et al: Detection of Epstein-Barr virus DNA in plasma and  lymph node biopsy samples in pediatric and adult patients with  Hodgkin lymphoma, Pediatr Hematol Oncol 28(1):10-15, 2011.    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Overview and Organization of the Nervous  System, 447  Cells of the Nervous System, 448  Neurons, 448  Neuroglia and Schwann Cells, 449  Nerve Injury and Regeneration, 450  Nerve Impulse, 451  Synapses, 451  Neurotransmitters, 452  Central Nervous System, 454  Brain, 454  Spinal Cord, 460  Motor Pathways (Tracts), 463  Sensory Pathways, 464  Protective Structures, 464  Blood Supply, 467  Peripheral Nervous System, 469  Autonomic Nervous System, 470    The human nervous system is a remarkable structure that  is responsible for the body’s ability both to interact with the  environment and to regulate activities involving our internal  organs, muscles, and glands. The nervous system drives the  other systems of the body. It is a network composed of complex  structures that transmit electrical and chemical signals between  the body’s many organs and tissues and the brain.    Anatomy of the Sympathetic Nervous System, 470  Anatomy of the Parasympathetic Nervous  System, 473   Tests of Nervous System Function, 477  Skull and Spine Roentgenograms, 477  Computed Tomography, 478  Magnetic Resonance Imaging, 478  Magnetic Resonance Angiography, 478  Positron-Emission Tomography Scan, 478  Brain Scan, 478  Cerebral Angiography, 480  Myelography, 480  Echoencephalography (Ultrasound), 480  Electroencephalography, 480  Evoked Potentials, 480  Cerebrospinal Fluid Analysis, 480    Although the nervous system functions as a unified whole,  structures and functions of the nervous system have been  divided to facilitate comprehension. Structurally, the ner-  vous system is divided into the central nervous system and    the peripheral nervous system. The central nervous system  (CNS) consists of the brain and spinal cord, enclosed within  the protective cranial vault and vertebrae, respectively. The  peripheral nervous system (PNS) is composed of the cra-  nial nerves, which project from the brain and pass through  foramina (openings) in the skull, and the spinal nerves, which  project from the spinal cord and pass through intervertebral  foramina of the vertebrae. Peripheral nerve pathways are dif-  ferentiated into afferent pathways (ascending pathways) that  carry sensory impulses toward the CNS and efferent path-  ways (descending pathways) that innervate effector organs,  such as skeletal, cardiac, and smooth muscle, as well as glands,  by transmitting motor impulses away from the CNS. Organs  innervated by specific components of the nervous system are  called effector organs. Cranial nerves are viewed most correctly  as modified spinal nerves. Some cranial nerves function simi-  larly to spinal nerves, whereas others have specialized sensory  tasks, such as smell, taste, sight, and hearing.   Functionally, the PNS can be divided into the somatic ner-  vous system and the autonomic nervous system. The somatic  nervous system consists of motor and sensory pathways regulat-  ing voluntary motor control of skeletal muscle. The autonomic  nervous system (ANS) also consists of motor and sensory com-  ponents and is involved with regulation of the body’s internal  environment (viscera) through involuntary control of organ  systems. The ANS is further divided into sympathetic and para-  sympathetic divisions. Today we understand that some aspects  of the ANS can be controlled through mental practice with or  without biofeedback techniques.    The two basic types of cells that comprise nervous tissue  are neurons and neuroglial cells. The neuron is the primary  information/communication cell of the nervous system.  Working in parallel systems, neurons can scan the environ-  ment, integrate many systems at higher cognitive levels, and  initiate body responses to maintain homeostasis. The neuro-  glial cells are found in the CNS and PNS and can provide  structural support and nutrition for neurons, remove debris,  increase the speed of nerve impulses, and play a significant  role, along with neurons, in processing and storing informa-  tion (i.e., memory).!    Neuronal structure varies considerably throughout the CNS.  Neurons vary in size from micrometers to several meters long  and have from one to many cell processes. Even the shapes and  complexity of the processes can vary considerably. Neurons are  specialized cells that share many of the same metabolic activi-  ties and constituents as other types of cells. The fuel source for  the neuron is predominantly glucose; insulin, however, is not  required for cellular glucose uptake in the CNS. Neurons con-  tain many cellular constituents, namely, neurotubules, neuro-  filaments, neurofibrils, and Nissl substances. Neurofilaments  and neurofibrils are composed of structural proteins and are  responsible for structural support within the cell and movement    of neuron processes, as seen in amoebae and white blood cells.  Microtubules also are made of protein and are believed to  be involved in the transport of cellular products. Nissl sub-  stances consist of endoplasmic reticulum and ribosomes and  are involved in protein synthesis. The CNS is formed with more  neurons than it needs, and those neurons that do not become  involved in functional systems die. Some neurons continue to  divide after birth. Olfactory neurons in the nose continue to  divide throughout life.   A neuron (Figure 15-1) has three components: a cell body  (soma) and the thin processes of the cell—the dendrites and  axons. Most cell bodies are located within the CNS. Dense,  packed cell bodies in the CNS are called nuclei. Cell bodies in  the PNS are usually found in groups called ganglia or plexuses.  The dendrites are extensions that carry nerve impulses toward  the cell body. The dendritic zone is the receptive portion of  a neuron that receives a stimulus and continues further con-  duction. Axons are long, conductive projections from the cell  body that carry nerve impulses away from the cell body. The  axon hillock is the cone-shaped, organelle-free area where the  axon leaves the cell body. In large nerves, axons are bundled  together as fascicles. The initial segment of the axon has the  lowest threshold for stimulation, and as a result, action poten-  tials begin there.   A typical neuron has only one axon, which may be cov-  ered with a segmented layer of lipid material called myelin,  which acts as an insulating substance. This entire membrane is  referred to as the myelin sheath; the thin membrane between  the myelin sheath and the endoneurium, a delicate connec-  tive tissue around each axon in the PNS (see Figure 15-1, C), is  the neurilemma (Schwann sheath). The neurilemma and the  myelin sheath are interrupted at regular intervals by the nodes  of Ranvier. Myelin acts as an insulator that allows ions to flow  between segments rather than along the entire length of the  membrane, resulting in increased velocity of neuronal conduc-  tion. This mechanism is referred to as saltatory conduction.  If the Schwann cells are loosely wrapped around the axon, it  is referred to as unmyelinated, and conduction velocity is not  increased. Axons are capable of extensive branching, which  occurs at the nodes of Ranvier. Two major principles of infor-  mation processing in the nervous system are divergence and  convergence. Divergence refers to the ability of these branch-  ing axons to influence many different neurons. Convergence  is the term applied to branches of numerous neurons converg-  ing on and influencing one or a few neurons. Disorders of the  myelin sheath (demyelinating diseases), such as multiple scle-  rosis and Guillain-Barré syndrome, demonstrate the important  role myelin plays in nerve function (see Chapter 18). Besides  depending on the myelin coating, conduction velocities also are  influenced by the diameter of the axon. Larger axons transmit  impulses at a faster rate.   Neurons are structurally classified on the basis of the num-  ber of processes (projections) extending from the cell body.  There are four basic types of cell configuration: (1) unipolar, (2)  pseudounipolar, (3) bipolar, and (4) multipolar (Figure 15-2).  Unipolar neurons have one process that branches shortly  after leaving the cell body. One example is found in the retina.    Node of Axon  Ranvier :  Neurilemma  (sheath of Schwann cell) Cell  membrane  C of axon    FIGURE 15-1 Structure of a Typical Neuron. A, Many dendrites carry nerve impulses to the cell body, and from the cell  body the nerve impulses are conducted along a single, long axon. Long axons are encased at intervals by a myelin sheath. B,  Photomicrograph of a neuron. €, A segment of myelinated fiber in cross section, showing myelin sheath composed of several  layers of myelin, which insulate the axon. D, Axons bundled into fascicles. (A and C from Thibodeau GA, Patton KT: Structure  and function of the human body, ed 12, St Louis, 2004, Mosby; B, copyright Edward Reschke; D from Patton KT, Thibodeau GA:    Pseudounipolar neurons (some authors call them unipolar)  have one process that has its dendritic portion extending away  from the CNS and its axon portion projecting into the CNS (see  Figure 15-2, C). The configuration is typical of sensory neu-  rons in both cranial and spinal nerves. Bipolar neurons have  two distinct processes arising from the cell body. This type of  neuron connects to rod and cone cells of the retina. Multipo-  lar neurons are the most common and have multiple dendrites  and a single axon. A motor neuron is typically multipolar.  Functionally, there are three types of neurons (with their  direction of transmission and typical configuration noted in  parentheses): (1) sensory (afferent, mostly pseudounipolar),  (2) associational (interneurons, multipolar), and (3) motor  (efferent, multipolar). Sensory neurons carry impulses from  peripheral sensory receptors to the CNS (Box 15-1). Associa-  tion neurons (interneurons) transmit impulses from neuron  to neuron, for example, from sensory to motor neurons, and    are also involved in cognitive function. Motor neurons trans-  mit impulses away from the CNS to an effector organ. In skel-  etal muscle the end processes form a complex neuromuscular  (myoneural) junction.    Neuroglia comprise the general classification of cells that sup-  port the neurons of the CNS. They make up approximately  half of the total brain and spinal cord volume and are 5 to 10  times more numerous than neurons. Different types of neuro-  glia serve different functions. Astrocytes, for example, fill the  spaces between neurons and surround blood vessels in the CNS  (see What’s New? Astrocytes). Oligodendrocytes function to  deposit myelin within the CNS. Oligodendroglia are the CNS  counterpart of the Schwann cells. Ependymal cells line the  cerebrospinal fluid (CSF)-—filled cavities of the CNS. Microglia  remove debris (phagocytosis) in the CNS. Characteristics and    Neuroglial (glia) cells have been considered the g/ue that exists between or  around neurons. Until recently, neurons have been considered the major play-  ers in the nervous system and glia just minor support cells. Astrocytes, the most  abundant glial cells in the nervous system, were believed to be simple nutrient  support “housekeeping” cells for neurons, and it was thought they helped form  the blood-brain barrier. Recent reports on astrocytes portray a “partnership”  with glial cells. Astrocytes (1) can be a source for new neurons; (2) build a  structural framework around neurons, forming glia-vascular units to provide the  specific blood flow (nutrients) that a neuron requires; (3) may regulate synaptic  formation and maintenance, which helps consolidate memories; and (4) have  a two-way interaction with neurons at synapses through the release of glial  neurotransmitters that could facilitate either excitation or inhibition of neuron  activity at the pre- and postsynaptic membranes. Alterations in astrocyte func-  tion play a significant role in brain malfunctions including hepatic encephalopa-  thy, seizures, Alzheimer disease, and brain tumor invasiveness.    Data from Parpura V et al: J Neurochem 21(1):4—27, 2012; Ranson BR,  Ransom CB: Methods Mol Biol 814:3-7, 2012; Stantello M, Cali C,  Bezzi P: Adv Exp Med Biol 970:307-331, 2012; Steindler DA: Methods  Mol Biol 814:9-22, 2012.    FIGURE 15-2 Structural Classification of Neurons. (From Patton KT,  Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)   Chemoreceptors (flavors, odors, oxygen levels, osmolarity of body fluids, and  carbon dioxide levels in the blood)    FIGURE 15-3 Types of Neuroglial Cells. A, Astrocyte attached to brain capil-  lary; B, microglial cell; €, ependymal cells that form sheets to line fluid cavities in  brain; D, oligodendrocyte wrapped around CNS nerve fiber forming myelin. (From  Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    functions of neuroglia and Schwann cells are summarized in  Figure 15-3 and Table 15-1.   The Schwann cell, or neurolemmocyte, is a glial cell that  wraps around and covers axons in the peripheral nervous  system. Schwann cells form and maintain the myelin sheath,  and the nodes of Ranvier form the spaces on either side of the  Schwann cell. If the myelin layer is tightly wrapped many times  around the axon forming nodes of Ranvier, it increases conduc-  tion velocity and the neuron is referred to as myelinated (see  Figure 15-1).    When an axon is severed, a typical sequence of events, known  as wallerian degeneration, occurs. In the axon distal to the cut,  the myelin sheath shrinks and disintegrates and this axon por-  tion degenerates and disappears. The myelin sheaths re-form   Appear to be the scar-forming cells of the CNS,  which may be the foci for seizures   Appear to work with neurons in processing  information and memory storage   Serve as a lining for ventricles and choroid  plexuses involved in production of  cerebrospinal fluid    into Schwann cells that align in a column between the cut and  the effector organ.   At the proximal end of the injured axon, similar changes  occur, but only back as far as the next node of Ranvier. The cell  body responds to trauma by swelling and then dispersing the  Nissl substance (chromatolysis). During the repair process the  cell increases metabolic activity, protein synthesis, and mito-  chondrial activity. Approximately 7 to 14 days after the injury,  new terminal sprouts project from the proximal segment and  may enter the remaining Schwann cell pathway. (Figure 15-4  contains a representation of these events.) This process, how-  ever, is limited to myelinated fibers and generally occurs only in  the PNS. The regeneration of axonal constituents in the CNS is  limited by increased scar formation and the different nature of  myelin formation by the oligodendrocyte.   Nerve regeneration depends on many factors, such as loca-  tion of the injury, the type of injury, the inflammatory responses,  and the process of scarring. The closer the injury is to the cell  body of the nerve, the greater the chances that the nerve cell will  die and not regenerate. A crushing injury allows recovery more  fully than does a cut injury. Crushed nerves sometimes recover  fully, whereas cut nerves often form connective tissue scars that  block or slow regenerating axonal branches.    Neurons generate and conduct electrical and chemical impulses  by selectively changing the electrical portion of their plasma  membranes and influencing other nearby neurons by the release  of chemicals (neurotransmitters). A neuron in its unexcited  state maintains a resting membrane potential (see Chapter 1).  When the membrane potential is raised sufficiently, an action  potential is generated (see Figure 1-35), and the nerve impulse    FIGURE 15-4 Repair of a Peripheral Nerve Fiber. When cut, a damaged  motor axon can regrow to its distal connection only if the neurilemma remains  intact (to form a guiding tunnel) and if scar tissue does not block its pathway. (From  Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    then flows to all parts of the neuron. The action potential  response occurs only when the stimulus has sufficient strength;  if it is too weak, the membrane remains unexcited. This prop-  erty is sometimes termed the all-or-none response.   Neurons are not physically continuous with one another. The  region between adjacent neurons is called a synapse. Impulses  are transmitted across the synapse by chemical (see Figures  15-5 and 15-14) and electrical conduction (Chapter 1); only  chemical conduction is discussed here. The neurons that con-  duct a nerve impulse are named according to whether they  relay impulses toward the synapse (presynaptic neurons) or  away from the synapse (postsynaptic neurons). Four basic  types of connections occur in regions of contact between the  presynaptic and postsynaptic neurons. These are between axons  (axo-axonic), from axon to cell body (axo-somatic), from axon  to dendrite (axo-dendritic), and from dendrite to dendrite  (dendro-dendritic).   Impulses are transmitted across the synapse by chemical  conduction. The conducting substance is called a neurotrans-  mitter and it is often formed in the neuron, transported to the  synaptic knobs (boutons) of the presynaptic neuron’s axon,  and stored in synaptic vesicles within the knobs. Action poten-  tials in the presynaptic neuron cause the synaptic vesicles to  release their neurotransmitter(s) through the plasma mem-  brane into the synaptic cleft (the space between the neurons),  where they bind to specific neurotransmitter (protein) recep-  tor sites on the plasma membrane of the postsynaptic neuron    FIGURE 15-5 Neuronal Transmission and Synaptic Cleft. The electrical impulse travels along the axon of the first  neuron to synapse at synaptic knobs. The chemical transmitter is secreted into the synaptic space to depolarize the membrane  (dendrite or cell body) of the next neuron in the pathway. Details illustrate the synaptic knob (axon terminal) of a presynaptic  neuron, the plasma membrane of a postsynaptic neuron, and a synaptic cleft. At step (1)—the arrival of an action potential at  the synaptic knob—voltage-gated Ca** channels open and allow extracellular Ca** to diffuse into the presynaptic cell. At step  (2) the Ca** triggers the rapid exocytosis of neurotransmitter molecules from vesicles in the knob. At step (3) neurotransmitter  diffuses into the synaptic cleft and binds to receptor molecules in the plasma membrane of the postsynaptic neuron. The  postsynaptic receptors directly or indirectly trigger the opening of stimulus-gated ion channels, initiating a local potential in  the postsynaptic neuron. At step (4) the local potential may move toward the axon, where an action potential may begin. (From  Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    (see Figure 15-5). Neurons can synthesize more than one neu-  rotransmitter, and postsynaptic membranes can contain more  than one type of transmitter-specific receptor.    A neurotransmitter is defined as a chemical that “must be  synthesized in the neuron, become localized in the presynap-  tic terminal (synaptic bouton), be released into the synaptic  cleft, bind to a receptor site (binding site) on the postsynap-  tic membrane of another neuron or effector where it affects  ion channels, and last, be removed by a specific mechanism  from its site of action.” More than 46 neurotransmitters,  including norepinephrine, acetylcholine, dopamine, histamine,    gamma-aminobutyric acid (GABA), and serotonin, have been  identified.** Many of these transmitters have more than one  function. For example, norepinephrine in the brain probably  helps regulate mood, functions in dream sleep, and maintains  arousal. Several neurotransmitters are amino acids, includ-  ing GABA, glutamic acid, and aspartic acid. Small chains of  amino acids, such as enkephalins and endorphins, also func-  tion as neurotransmitters. They (neuropeptides) are involved  in the perception and integration of pain, as well as in emo-  tional experiences. Neurotransmitter and neuromodulator  substances are listed in Table 15-2.   Because the neurotransmitter is normally stored on one side  of the synaptic cleft and the receptor sites are on the other side,    Many parts of the brain, spinal cord,  neuromuscular junction of skeletal  muscle, and many ANS synapses    Many areas of the brain and spinal cord;  also in some ANS synapses  Many areas of the brain and spinal cord    Alzheimer disease (a type of dementia) is associated with a  decrease in the number of acetylcholine-secreting neurons.  Myasthenia gravis (weakness of skeletal muscles) results  from a reduction in the number of acetylcholine receptors.   Is involved with mood, anxiety, and sleep induction. Levels  of serotonin are elevated in schizophrenia (delusions,  hallucinations, withdrawal).   Parkinson disease (depression of voluntary motor control)  results from destruction of dopamine-secreting neurons.  Drugs used to increase dopamine production induce  vomiting and schizophrenia.   There is no clear indication of histamine-associated  pathologic conditions. Histamine is involved with arousal  and attention and links to other brain transmitter systems.    Drugs that increase GABA function have been used to treat  epilepsy by inhibiting excessive discharge of neurons.  Glycine receptors are inhibited by strychnine.    Spinal cord, brain, and sensory neurons  associated with pain, Gl tract    used to treat amyotrophic lateral sclerosis. These drugs might  prevent overexcitation from seizures and neural degeneration.    Morphine and heroin bind to endorphin and enkephalin  receptors on presynaptic neurons and reduce pain by  blocking the release of neurotransmitter.   Substance P is a neurotransmitter involved in pain  transmission pathways. Blocking release of substance P by  morphine reduces pain.    From Seeley R, Stephens TD, Tate P: Anatomy and physiology, ed 7, New York, 2006, McGraw-Hill.  ANS, Autonomic nervous system; CNS, central nervous system; G/, gastrointestinal; PNS, peripheral nervous system.    chemical synapses operate in one direction. Therefore, action  potentials are transmitted along a multineuronal pathway in one  direction. The binding of the neurotransmitter at the receptor  site changes the permeability of the postsynaptic neuron and,  consequently, its membrane potential. Two possible scenarios  can then follow: (1) the postsynaptic neuron may be excited  (depolarized; excitatory postsynaptic potentials [EPSPs]),  or (2) the postsynaptic neuron’s plasma membrane may be  inhibited (hyperpolarized; inhibitory postsynaptic potentials  [IPSPs]). Cannabinoid transmitters are released from postsyn-  aptic neurons that modulate neurotransmitter release from pre-  synaptic neurons.*° (Chapter 1 contains a review of electrical  impulses and membrane potentials.)   Usually, a single EPSP cannot induce a neuron’s action  potential and the propagation of the nerve impulse. Whether an  action potential occurs depends on the number and frequency    of potentials the postsynaptic neuron receives—a concept  known as summation. Temporal summation (time relation-  ship) refers to the effects of successive, rapid impulses received  from a single neuron on the same synapse. Spatial summation  (spacing effect) is the combined effects of impulses from a  number of neurons on a single synapse at the same time. Facili-  tation refers to the effect of EPSPs on the plasma membrane  potential. The plasma membrane is facilitated when summa-  tion brings the membrane closer to the threshold potential and  decreases the stimulus required to induce an action potential.  The effect that a neurotransmitter has on the plasma membrane  potential depends on the balance of these effects. The mecha-  nisms of convergence, divergence, summation, and facilitation  allow for the integrative processes of the nervous system.   Two points could be helpful in understanding the com-  plexity of brain physiology. First, the aforementioned    neuromodulators appear to function to raise or lower the  membrane potentials of neurons. These chemicals facilitate  or inhibit the effect of neurotransmitters. Second, recipro-  cal synapses between dendrites—that is, one dendrite being  able to depolarize or hyperpolarize the membrane potential    Cerebral hemispheres  Cerebral cortex  Rhinencephalon  Basal ganglia  Epithalamus  Thalamus  Hypothalamus  Subthalamus  Corpora quadrigemina  (tectum)  Cerebral peduncles  Tegmentum  Red nucleus  Substantia nigra  Basis pedunculi  Hindbrain Metencephalon Cerebellum  (rhombencephalon) Pons  Myelencephalon Medulla oblongata  Spinal cord Spinal cord    of another dendrite through the use of neurotransmitters—  demonstrate that the interactions between neurons are far  more complicated than postulated by simple on-off models  of brain function.   The human brain enables individuals to reason, function intel-  lectually, express personality and mood, and interact with the  environment. The brain is a pinkish gray organ that weighs  approximately 3 pounds and has the consistency of tofu or cus-  tard. It receives approximately 15% to 20% of the total cardiac  output. The three major divisions of the brain, based on embry-  ologic origin, are: (1) the forebrain, formed by the two cere-  bral hemispheres; (2) the midbrain, which includes the corpora  quadrigemina, tegmentum, and cerebral peduncles; and (3) the  hindbrain, which includes the cerebellum, pons, and medulla  (Table 15-3). The midbrain, medulla oblongata, and pons make  up the brainstem, which connects the hemispheres of the brain,  cerebellum, and spinal cord. A collection of nuclei (nerve cell  bodies) within the brainstem collectively constitute the reticu-  lar formation (Figure 15-6). The reticular formation is a large  network of connected tissue nuclei that regulate vital reflexes,  such as cardiovascular function and respiration. The reticular  formation is essential for maintaining wakefulness and in con-  junction with the cerebral cortex is referred to as the reticular  activating system. Some nuclei within the reticular formation  are involved in motor movements.!    FIGURE 15-6 Reticular Activating System. System consists of nuclei in the brainstem reticular formation plus fibers  (axons) that conduct to the nuclei from below and fibers that conduct from the nuclei to widespread areas of the cerebral  cortex. Functioning of the reticular activating system is essential for consciousness. (From Patton KT, Thibodeau GA: Anatomy  & physiology, ed 8, St Louis, 2013, Mosby.)    Superior Precentral gyrus Central (rolandic) sulcus  frontal  Middle gyrus Postcentral gyrus  frontal    temporal  gyrus  A  Precentral gyrus  (primary  somatic motor)  Brodmann area 4  Postcentral gyrus  Premotor Central (primary somatic    Primary auditory  Cc Brodmann areas 41, 42  FIGURE 15-7 Cerebral Hemispheres. A, Left hemisphere of cerebrum (/atera/ view). B, Functional areas of the cerebral  cortex (midsagittal view). C, Functional areas of the cerebral cortex (lateral view).    In general, many major divisions of the brain are associated  with specific functions, such as the occipital lobe and vision,  but attributing specific functions to definite regions of the  brain is not entirely accurate. Many activities, such as motor  movements and memory, may actually be performed in several  regions. Understanding functional specificity is very useful to  clinical personnel, especially when attempting to localize patho-  logic conditions in the nervous system. A neurologist often can  localize the site of a tumor, stroke, or bullet wound in an indi-  vidual just by performing a neurologic examination.   Many attempts have been made to ascribe function to various  regions of the cerebral cortex. (Figure 15-7, B and C, illustrates  these regions and identifies some functional areas.) Another basic  CNS principle, plasticity, holds that the CNS is capable of change.  For example, children with brain damage may experience “relo-  cation” of some functional areas to other parts of the brain. This  propensity for plasticity decreases with age, which explains why  older individuals tend not to recover from brain injuries as well as  younger individuals. This varying balance between specificity and  plasticity makes understanding brain functions difficult.    Telencephalon. The telencephalon consists of the cerebrum  (the largest portion of the brain), which includes the cerebral  cortex and basal ganglia. The surface of the cerebrum is  characterized by numerous convolutions called gyri (see Figure  15-7, A). The gyri greatly increase the cortical surface area.  Grooves between adjacent gyri are called sulci. Deeper grooves    are referred to as fissures. The cerebral cortex contains the  cell bodies and dendrites of neurons, which often are referred  to as gray matter. Gray matter is organized into columns  perpendicular to the surface that receive, integrate, store, and  transmit information. White matter lies beneath the cerebral  cortex and is composed of myelinated nerve fibers, which send  neuron “messages” throughout the nervous system and body.   The two cerebral hemispheres are separated by the longi-  tudinal fissure. The surface of each hemisphere is divided into  lobes that take their names from the region of the skull under  which each of them lies. The posterior margin of the frontal  lobe is the central sulcus (fissure of Rolando, central fissure); it  borders inferiorly on the lateral sulcus (sylvian fissure, lateral  fissure) (see Figure 15-7, A). The prefrontal area is responsible  for goal-oriented behavior (i.e., ability to concentrate), short-  term or recall memory, and elaboration of thought and inhibi-  tion on the limbic (emotional) areas of the CNS. The premotor  area (Brodmann area 6) (see Figure 15-7, C) is involved in  programming motor movements. This area also contains the  neurons that contribute to the basal ganglia system (extrapy-  ramidal system—efferent pathways outside the pyramids of the  medulla oblongata). The frontal eye fields (the lower portion of  Brodmann area 8), which are involved in controlling eye move-  ments, are located in the middle frontal gyrus.   The primary motor area (Brodmann area 4) is located  along the precentral gyrus forming the primary voluntary  motor area, which has a somatotopic organization that often is  referred to as a homunculus (little man) (Figure 15-8). Electrical    FIGURE 15-8 Primary Somatic Sensory (A) and Motor (B) Areas of the Cortex. (From Patton KT, Thibodeau GA:  Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    stimulation of specific areas of this cortex causes specific mus-  cles of the body to move. The medial part of the cortex in the  longitudinal fissure (midline space between the two cerebral  hemispheres) affects the lower limb and foot, whereas on the  lateral surface, the superior third controls the torso and arm,  the middle third the hand, and the lowest third the face and  mouth/throat. The axons traveling from the cell bodies in and  on either side of this gyrus project fibers (axons) that form the  corticospinal tracts (pyramidal system) that descend down the  spinal cord. Cerebral impulses control function on the opposite  side of the body, a phenomenon called contralateral control  (Figure 15-9, A). The Broca speech area (Brodmann areas 44,  45) is rostral to the inferior edge of the premotor area (Brod-  mann area 6) on the inferior frontal gyrus. It is usually on the  left hemisphere and is responsible for the motor aspects of  speech. Damage to this area, commonly as a result of a cere-  brovascular accident (stroke), results in the inability to form, or  difficulty in forming, words (expressive aphasia or dysphasia)  (see Chapter 18).   The parietal lobe lies within the borders of the central, pari-  etooccipital, and lateral sulci. This lobe contains the major area  for somatic sensory input, located primarily along the postcen-  tral gyrus (Brodmann areas 3, 1, 2), which is adjacent to the  primary motor area. Communication between the motor and  sensory areas (and among other regions in the cortex) is pro-  vided by association fibers (i.e., axons from association fibers).  Much of this region is involved in sensory association (stor-  age, analysis, and interpretation of stimuli). (Figure 15-8 shows  the distribution of functions associated with both the primary  motor area and the primary sensory area of the cerebral cortex.)   The occipital lobe lies caudal to the parietooccipital sulci  and superior to the cerebellum. The primary visual cortex  (Brodmann area 17) is located in this region and receives input  from the retinas. Much of the remainder of this lobe is involved  in visual association (Brodmann areas 18, 19). The temporal  lobe lies inferior to the lateral sulcus and is composed of the  superior, middle, and inferior temporal gyri. The primary audi-  tory cortex (Brodmann area 41) and its related association area  (Brodmann area 42) lie deep within the lateral sulcus on the  superior temporal gyrus. The Wernicke area (posterior por-  tion of Brodmann area 22) is located on the superior temporal  gyrus. This area is responsible for reception and interpretation  of speech, and dysfunction may result in receptive aphasia or  dysphasia. The Wernicke area, along with adjacent portions of  the parietal lobe, constitutes a sensory speech area. The temporal  lobe also is involved as a major area for long-term memory and  secondary functions, such as balance, taste, and smell.   Another cerebral area, the insula, lies hidden from view deep  in the lateral sulcus. Lying directly beneath the longitudinal fis-  sure is a massive white matter pathway called the corpus cal-  losum (commissural fibers). The corpus callosum connects  the two cerebral hemispheres and is essential in the coordina-  tion of activities between hemispheres, especially specific tasks  that may be present in only one hemisphere (see Figures 15-7,  C, and 15-15). As a last resort, part or all of the corpus callo-  sum is cut to prevent the spread of epileptic loci (site of seizure  activity) through the corpus callosum to the opposite cerebral    hemisphere. Epileptic loci often are found in the temporal lobe  (see Chapters 17 and 20). This procedure, evolved in the well-  known split-brain studies, results initially in temporary aphasia  and paralysis.   Inside the cerebrum are numerous tracts (white matter)  and nuclei (gray matter). The major cerebral nuclei are called  basal ganglia and include the corpus striatum and amygdala.  The corpus striatum consists of the lentiform nucleus (lens  shaped), the putamen and globus pallidus, and the ram’s horn—  shaped caudate nucleus. The internal capsule is a thick white-  matter region in which afferent and efferent pathways, to and  from the cerebral cortex, pass through the center of the cerebral  hemispheres. The corpus striatum appears striped because of  the rostral connections between its gray matter and the white  matter of the internal capsule.   Functionally, the basal ganglia include, in addition to the  corpus striatum, the subthalamic nucleus of the diencephalon  and the substantia nigra of the mesencephalon. The basal gan-  glia plus their interconnections with the thalamus, premotor  cortex, red nucleus, reticular formation, and spinal cord are  part of the basal ganglia system (extrapyramidal system). The  basal ganglia system is believed to exert a fine-tuning effect on  motor movements. Parkinson disease and Huntington disease  are conditions associated with defects of the basal ganglia (Box  15-2). They are characterized by various involuntary or exag-  gerated motor movements (see Chapter 17).   The limbic system, first described in 1878 by Broca, is com-  posed of the Papez circuit (amygdala, parahippocampal gyrus,  hippocampus, fornix, mamillary body of the hypothalamus,  thalamus, and cingulate gyrus), septal area, habenula, nucleus  accumbens, and other portions of the hypothalamus, and  related autonomic nuclei. It is an extension or modification of  the olfactory system (rhinencephalon). Its principal effects are  believed to be involved with primitive behavioral responses, vis-  ceral reaction to emotion, feeding behaviors, biologic rhythms,  and the sense of smell. Expression of affect (emotional and  behavioral states) is mediated by extensive connections with the  limbic system and prefrontal cortex. The limbic system has as  one of its major functions the consolidation of memory through  a reverberating circuit (see Chapter 17 and Figure 17-9).   Diencephalon. The diencephalon, surrounded by the  cerebrum, is made up of four divisions: epithalamus, thalamus,  hypothalamus, and subthalamus (see Table 15-3 and Figure  15-7, B). The epithalamus forms the roof of the third ventricle  (a brain cavity) and composes the most superior portion of the  diencephalon. It has connections between the limbic system  and other parts of the brain. The pineal body (a component of  the epithalamus) secretes melatonin, which maintains circadian  rhythms and the sleep-wake cycle (see Chapters 16 and 21). The  largest component of the diencephalon is the thalamus. It is  approximately the size and volume of the thumb from the tip  to the first joint. It borders and surrounds the third ventricle,  and it is a major integrating center for afferent impulses to the  cerebral cortex, except for olfaction. The perception of various  sensations occurs at this level but requires cortical processing  for interpretation. The thalamus also serves as a relay center for  sensory aspects of motor information from the basal ganglia    FIGURE 15-9 Examples of  Somatic Motor and Sensory  Pathways. A, Motor: 1, the pyra-  midal pathway through the lateral  corticospinal tract and 2, the  extrapyramidal pathways through  the rubrospinal and reticulospinal  tracts. Note that the pyramidal  tracts decussate (cross over) to  control the opposite side of the  body. B, Sensory: 1, pathways of  the medial lemniscal system that  conducts information about dis-  criminating touch and kinesthesis  and 2, the spinothalamic pathway  that conducts information about  pain and temperature. (From Pat-  ton KT, Thibodeau GA: Anatomy &  physiology, ed 8, St Louis, 2013,  Mosby.)    Surgical treatment can provide gratifying relief from the disabling symptoms  of Parkinson disease (PD) when pharmaceutical therapies are no longer effec-  tive or as an adjunct to pharmacotherapy. The forms of surgical intervention  include deep brain stimulation (globus pallidus internus to improve motor  symptoms and nucleus ventralis intermedius to improve tremor), ablation  (thalamotomy, unilateral pallidotomy, and subthalamotomy), stem cell and  fetal dopamine neuron replacement therapy, and gene therapy (mainly o  striatum to restore dopaminergic function). Deep brain stimulation with pl  ment of brain electrodes is currently the surgical gold standard for treatment  of PD because it results in symptom control with minimal tissue destruction.  However, an ablation technique can be the preferable option for other indi-  viduals. Functional imaging during the procedures is contributing to the under-  standing of how these treatments affect neuronal activity. Stem cell grafts of  dopamine neurons are being studied, but a number of problems still remain  to be resolved, including poor cell survival of the grafted neurons and rein-  nervation into the host striatum. Gene therapy strategies include activation of  dopamine-synthesizing enzyme genes in the subthalamic nucleus. Controlled  trials are in progress and are showing some promise.    Data from Fasano A, Daniele A, Albanese A: Lancet Neuro! 11(5):429—  442, 2012; Freed CR, Zhou W, Breeze RE: Neurotherapeutics 8(4):549-  561, 2011; Kahn E et al: J Neuro! Neurosurg Psychiatry 83(2):164-170,  2012; Lindvall O, Bjorklund A: Neurotherapeutics 8(4):539-548, 2011;  Obeso | et al: /nt Rev Psychiatry 23(5):467-475, 2011; Politis M,  Lindvall O: BMC Med 10:1, 2012; Schuepbach WM et al: N Eng! J Med  368(7):610-616. 2013.    and cerebellum to appropriate cortical motor areas. Cerebral  cortical information also projects to the thalamus, creating  reverberating circuits.   The hypothalamus forms the base of the diencephalon.  Hypothalamic function falls into two major areas: (1) mainte-  nance of a constant internal environment and (2) implementa-  tion of behavioral patterns. Integrative centers control function  of the ANS, regulation of body temperature, function of the  endocrine system, and regulation of emotional expression.  (Temperature regulation is discussed in Chapter 16.) The hypo-  thalamus exerts its influence through the endocrine system, as  well as through neural pathways (Box 15-3). (For endocrine  functions of the hypothalamus and pituitary, see Chapter 21.)   The subthalamus flanks the hypothalamus laterally. The  subthalamus contains the subthalamic nucleus, which is part  of the basal ganglia system (p. 456).    The midbrain (mesencephalon) (see Table 15-3) is composed  of three structures: the corpora quadrigemina, or tectum  (composed of the superior and inferior colliculi); the tegmen-  tum (containing the red nucleus and substantia nigra); and the  basis pedunculi. (The tegmentum and basis pedunculi are col-  lectively termed the cerebral peduncles—see Figure 15-9, A.)  The superior colliculi are involved with voluntary and  involuntary visual motor movements (e.g., the ability of the  eyes to track moving objects in the visual field). The infe-  rior colliculi accomplish similar motor activities but involve  movements affecting the auditory system (e.g., positioning    the head to improve hearing). The inferior colliculus is also  a major relay center along the auditory pathway. The red  nucleus is a major motor output center that is influenced by  the cerebellum. The inferior-most portion of the basal ganglia  is the substantia nigra, which synthesizes dopamine, a neu-  rotransmitter and precursor of norepinephrine. Its dysfunc-  tion is associated with Parkinson disease (see Chapter 17) and  drug addiction (see What’s New? Nucleus Accumbens, Dopa-  mine, and Drug Addiction). The basis pedunculi are made up  of efferent fibers of the corticospinal, corticobulbar, and corti-  copontocerebellar tracts.   Other notable structures of this region are the nuclei and  tracts of the third and fourth cranial nerves. The cerebral aque-  duct (aqueduct of Sylvius), which carries cerebrospinal fluid  (CSF), also traverses this structure. The obstruction of this  aqueduct is often the cause of hydrocephalus.    Metencephalon. The major structures of the metencephalon  are the cerebellum and the pons. The cerebellum (see Figure  15-7, A and B) is composed of two cerebellar hemispheres  covered with small convolutions called folia. Each hemisphere  is divided by the primary fissure into two lobes (anterior and  posterior) that are connected by a midline structure called the  vermis, meaning worm.   The cerebellum is responsible for conscious and unconscious  muscle synergy and for maintaining balance and posture. This  is accomplished through extensive neural connections from the  spinal cord and medulla oblongata through the inferior cer-  ebellar peduncle and with the midbrain and higher structures  through the superior cerebellar peduncle. The two cerebellar  hemispheres receive massive cerebral cortical input through the  middle cerebellar pedunculi. These connections allow extensive  sampling of visual, vestibular, and proprioceptive data from  other regions of the CNS and periphery. Damage to the cer-  ebellum is characterized by ipsilateral (same side) loss of equi-  librium, balance, and motor coordination. The cerebellum has  ipsilateral control of the body, in contrast to the cerebral cortex,  which has contralateral (opposite side) control of the body.   The pons (bridge) is easily recognized by its bulging appear-  ance below the midbrain and above the medulla oblongata.  Primarily, it transmits information from the cerebellum to  the brainstem nuclei and relays motor information from the    A small nucleus (see accompanying figure) in the septal area of the frontal lobe  has become a center of intense research. The nucleus accumbens is considered  to be the principal site of action for addictive drugs and the anatomic basis of  positive reinforcement and reward. The nucleus accumbens has input from the  mesencephalon (ventral tegmental area) and many other neural areas. Mesen-  cephalon neurons project dopamine to the nucleus accumbens and can affect its    activity. Other neurotransmitters involved in this positive feedback system are  gamma-aminobutyric acid (GABA), serotonin, and glutamate. Opiates can inter-  fere with this system by allowing excessive amounts of dopamine to travel to the  nucleus accumbens, contributing to drug craving and addiction. Research is in  progress to discover pharmaceutical agents that target specific neurotransmitter  receptors for the treatment of drug addiction.    Data from Gardner EL: Adv Psychosom Med 30:22-60, 2011; Lee BR, Dong Y: Neuropharmacology 61(7):1060-1069, 2011; Morales M, Pickel VM:  Ann N Y Acad Sci 1248:71-88, 2012; Hikida T et al: Proc Nat! Acad Sci U S A 110(1):342-347, 2013.    cerebral cortex to the contralateral cerebellar hemisphere. The  pons is an important center for the control of respiration (i.e.,  rate and relationship of inspiration to expiration). The nuclei of  cranial nerves V through VIII are located in this structure.   Myelencephalon. The medulla oblongata comprises the  myelencephalon and is the lowest portion of the brainstem.  Reflex activities, such as heart rate, respiration, blood  pressure, coughing, sneezing, swallowing, and vomiting,  are controlled in this area. The nuclei of cranial nerves IX  through XII (see Table 15-6 for discussion) are located in  this region. The lowest portion of the reticular formation is  found here as well.   A major portion of the descending motor pathways (i.e.,  corticospinal tracts) crosses to the contralateral side, or decus-  sates, at the inferior medulla oblongata (see Figure 15-9, A).  These pathways, together with other areas of decussation in the  CNS, are the basis for the phenomenon of contralateral control.    The spinal cord is the portion of the CNS that lies within the  vertebral canal and is surrounded and protected by the ver-  tebral column. The spinal cord has many functions, which  include being a long nerve tract that connects the brain and  body, conducting somatic and autonomic reflexes, provid-  ing motor pattern control centers, and serving as a sensory  and motor modulation center. It continues from the medulla  oblongata and ends inferiorly at the level of the first or sec-  ond lumbar vertebra in adults (Figure 15-10). The end of the  spinal cord, the conus medullaris, is cone shaped (Figure 15-11).  Spinal nerves continue from the end of the spinal cord and  form a nerve bundle called the cauda equina. The thin filament  anchor from the conus medullaris to the coccyx is the filum  terminale (see Figure 15-10).   Grossly, the spinal cord is divided into sections (8 cer-  vical, 12 thoracic, 5 lumbar, 5 sacral, and 1 coccygeal) that    Filum terminale  FIGURE 15-10 Spinal Cord Within Vertebral Canal and Exiting Spinal  Nerves. Posterior view of brainstem and spinal cord in situ with spinal nerves  and plexus. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis,  2013, Mosby.)    correspond to paired nerves (see Figure 15-10). A cross sec-  tion of the spinal cord (see Figures 15-11 and 15-12) is  characterized by a butterfly-shaped inner core of gray matter  (containing nerve cell bodies). The central canal lies in the  center of this region and extends through the spinal cord from  its origin in the fourth ventricle. The gray matter of the spi-  nal cord is divided into three regions with specific functional  characteristics. These regions include the posterior horn  (dorsal horn), which is composed primarily of interneurons  and axons from sensory neurons whose cell bodies lie in the  sensory ganglion (dorsal root ganglion). At the tip of the pos-  terior horn is the substantia gelatinosa, a structure involved  in pain transmission (see Chapter 16). The intermediolateral  gray horn (lateral horn) contains cell bodies involved with    FIGURE 15-11 Spinal Nerves and Coverings of the Spinal Cord. Note how  the dura mater extends to cover the spinal nerve roots and nerves. (Modified from  Thibodeau GA, Patton KT: Structure and function of the body, ed 14, St Louis, 2012,  Mosby.)    the ANS. The anterior horn (ventral horn) contains the nerve  cell bodies for efferent pathways leaving the spinal cord by way  of spinal nerves. The terms anterior and posterior are preferred  by many authors for describing human spinal cord anatomy,  whereas dorsal and ventral are the common zoologic (veteri-  nary) terms.    FIGURE 15-12 Major Tracts of the Spinal Cord. The major ascending (sensory) tracts, shown only on the left here, are  highlighted in blue. The major descending (motor) tracts, shown only on the right, are highlighted in red. (From Patton KT,  Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    Surrounding the gray matter is white matter that forms  ascending and descending pathways called spinal tracts and  short ascending and descending integrative pathways. Spinal  tracts are named to denote their beginning and ending points.  For example, the spinothalamic tract carries nerve impulses  from the spinal cord to the thalamus in the diencephalon. The  white matter is subdivided into columns. These consist of the  anterior column (ventral column), lateral column, and poste-  rior column (dorsal column), that is, the fasciculus gracilis and  fasciculus cuneatus. (Figure 15-12 identifies the location and  principal activities of the major spinal tracts.)   Neural circuits in the spinal cord, when activated, display  specific sets of motor responses. Reflex arcs form basic units that  respond to stimuli and provide protective circuitry for motor  output. Structures mandatory for a simple reflex arc (mono-  synaptic reflex) are a receptor, an afferent (sensory) neuron, an  efferent (motor) neuron, and an effector muscle or gland. The  afferent neuron is a pseudounipolar neuron, with its cell body in  the sensory ganglion. A simple reflex arc contains only two neu-  rons (e.g., knee jerk reflex). Most reflex arcs include one or more  interneurons or association neurons between the afferent and  efferent neurons (polysynaptic reflex). (Figure 15-13 illustrates  a reflex arc.) The transmission time for polysynaptic reflexes is  slower than that for monosynaptic reflexes because there are  two or more synaptic delays. The afferent neuron of the reflex  arc simultaneously sends sensory information to the effector  organ and to higher CNS centers (see Figure 15-8, B; also see  Figure 16-3). The motor effects from reflex arcs generally occur  before perception of the event in the higher centers of the brain.  Much of the regulation of the internal environment is mediated    by polysynaptic ANS reflexes (e.g., cardiac muscle and smooth  muscle contraction/relaxation and glandular responses).   Afferent pathways transmit information from peripheral  receptors and the information ultimately terminates in the cere-  bral or cerebellar cortex, or both. Efferent pathways primarily  relay information from the cerebrum to the brainstem or spinal  cord (see Figure 15-9, A). Upper motor neurons (i.e., corticospi-  nal and corticobulbar tracts) are the classification of motor path-  ways completely contained within the CNS (see Figure 17-31).  Their primary roles include directing, influencing, and modifying  reflex arcs, lower-level control centers, and motor (and some sen-  sory) neurons. Generally, upper motor neurons form synapses  with interneurons, which then form synapses with lower motor  neurons before projecting into the periphery. Lower motor neu-  rons (i.e., cranial and spinal efferent neurons) are responsible for  direct influence on muscles. Their cell bodies lie in the gray mat-  ter of the spinal cord, but their processes extend into the PNS (see  Figure 15-9, A and Figure 17-32). Destruction of upper motor  neurons usually results in initial paralysis followed within days  or weeks by partial recovery, whereas destruction of the lower  motor neurons often leads to permanent paralysis, unless periph-  eral nerve damage is followed by nerve regeneration. (Injury to  motor neurons is discussed in Chapter 18.)   Muscle activity (i.e., stimulation and contraction) is regu-  lated by nerve impulses. Motor neurons innervate one or more  muscle cells, forming motor units consisting of a neuron and  the skeletal muscles it stimulates. The junction between the  axon of the motor neuron and the plasma membrane of the  muscle cell is called the neuromuscular (myoneural) junction  (Figure 15-14). The skeletal muscle neuromuscular junction is    FIGURE 15-13 Cross Section of Spinal Cord Showing Simple Reflex Arc. (From Patton KT, Thibodeau GA: Anatomy    FIGURE 15-14 Neuromuscular Junction. This figure shows how the distal end of a motor neuron fiber forms a synapse,  or “chemical junction,” with an adjacent muscle fiber. Neurotransmitters (specifically, acetylcholine /Ach/) are released from  the neuron’s synaptic vesicles and diffuse across the synaptic cleft where they stimulate receptors in the motor end-plate  region of the sarcolemma. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)   The four clinically relevant motor pathways (tracts) are the  lateral corticospinal, corticobulbar (upper motor neurons of  cranial nerves), basal ganglia, and vestibulospinal pathways.    The corticospinal (see Figure 15-9, A) and corticobulbar (see  Figure 17-31) are essentially the same tract and consist of a  two-neuron chain. The cell bodies originate in and around the  precentral gyrus; pass through the corona radiata of the cere-  brum, the internal capsule, and the middle three fifths of the  basis pedunculus, pons, and pyramid; decussate (cross con-  tralaterally) in the medulla oblongata; and form the lateral    corticospinal tract of the spinal cord (see Figure 15-12). The  lateral corticospinal tract axons (upper motor neurons) leave  the tract to go to specific interneurons or motor neurons in  the anterior horn. The lateral corticospinal tract has the same  somatotopic organization as the body. These spinal motor neu-  rons project to specific motor units and are lower motor neu-  rons. The corticobulbar (bulbar refers to brainstem) tract can  be thought of as the part of the corticospinal tract that inner-  vates the cranial motor nuclei for eye, face, tongue, throat, and  neck movement. This tract innervates all the cranial motor  nuclei bilaterally except for the facial (spinal), accessory, and  hypoglossal nuclei, which receive primarily contralateral inner-  vation. These tracts are involved in precise motor movements.  The basal ganglia are part of a system that drives the reticular  descending tracts. (Figure 15-12 shows only one of the two  reticulospinal tracts.) These tracts modulate motor movement  by inhibiting and exciting spinal activity. The vestibulospinal  tract is an extrapyramidal tract and arises from the lateral ves-  tibular nucleus in the pons and causes the extensor muscles of  the body to rapidly contract, most dramatically witnessed when  a person starts to fall backward.    The three clinically important spinal afferent pathways are  the posterior (dorsal) column, anterior spinothalamic, and  lateral spinothalamic (see Figure 15-12; also see Figures 16-2  and 16-3). The posterior (dorsal) column pathway has a  somatotopic organization (looks like your body) with the fas-  ciculus gracilis and fasciculus cuneatus, respectively, carrying  lower body and upper body fine touch, two-point discrimi-  nation, and proprioceptive information (i., epicritic). The  posterior column is formed by a three-neuron chain. The first  neuron of the chain is the primary afferent neuron. It is also the  sensory neuron of the reflex arc. After entering the spinal cord  it sends its axon ipsilaterally up the spinal cord in a specific part  of the posterior column and synapses in one of three posterior  column nuclei in the hindbrain. A basketball center has primary  afferent neurons that run from the great toe up to the pons,  which could be more than 6 feet long. The second-order neu-  ron has its cell body in one of the three posterior column nuclei  and sends its axon contralaterally and ascends to a specific  nucleus of the thalamus and synapses. The third-order neuron,  originating in the thalamus, continues the tract into the internal  capsule, corona radiata, and postcentral gyrus (Brodmann areas  3, 1, 2) (see Figure 15-7, C). The anterior and lateral spinotha-  lamic tracts are responsible for vague touch and for pain and  temperature, respectively (see Figure 15-9, B). These modalities  are referred to as protopathic.   Today the anterior and lateral spinothalamic tracts are com-  bined by many neuroanatomists into the anterolateral system  because these modalities are difficult to localize into finite tracts  in the spinal cord. These tracts also form a three-neuron chain.  However, the primary afferent neurons synapse in the posterior  horn of the spinal cord, not just at the level they enter the inter-  vertebral foramen but in a number of spinal segments above  and below their point of entry. This is an example of divergence.  The axons of the second-order neurons in the posterior horn    cross to the contralateral side in the spinal cord in the lateral  column, and ascend to the same thalamic nucleus as the pos-  terior column pathway and continue on with the posterior col-  umn pathway to the postcentral gyrus.    Protective Structures  Cranium  The cranium is composed of eight bones. The cranial vault  functions to enclose and protect the brain and its associated  structures. The galea aponeurotica, which is a thick, fibrous  band of tissue overlying the cranium between the frontal and  occipital muscles, affords added protection to the bony struc-  ture of the skull. The subgaleal space has venous connections  with the dural sinuses, and with increased intracranial pressure,  blood can be shunted to this space, thus reducing pressure in  the intracranial cavity. The subgaleal space is also a common  site for placement of wound drains after intracranial surgery.  The floor of the cranial vault is irregular and contains many  foramina (openings) that act as exit sites for cranial nerves,  blood vessels, and the spinal cord. The cranial floor is divided  into three fossae (depressions). The frontal lobes lie in the ante-  rior fossa; the temporal lobes and base of the diencephalon lie  in the middle fossa (temporal fossa); and the cerebellum lies in  the posterior fossa. These terms are commonly used anatomic  landmarks to describe the location of intracranial lesions.   Surrounding the brain and spinal cord are three protective  membranes: the dura mater, the arachnoid, and the pia mater.  Collectively they are called the meninges (Figure 15-15). The  dura mater (meaning literally “hard mother”) is composed of  two layers, with the venous sinuses formed between them. The  outermost layer forms the periosteum (endosteal layer) of the  skull, and the inner dura, or meningeal layer, is responsible for  the formation of rigid, double-thickness membranous plates  that serve to support and separate various brain structures.   One of these membranous plates (see Figure 15-15), the falx  cerebri, dips between the two cerebral hemispheres along the  longitudinal fissure. The falx cerebri is anchored anteriorly to  the base of the brain at the crista galli of the ethmoid bone. The  tentorium cerebelli is a membrane that separates the cerebel-  lum below from the cerebral structures above. The tentorium  may become involved during periods of increased intracranial  pressure caused by an injury to the brain. An injury within the  cranial cavity tends to shift intracranial contents, and as struc-  tures shift, they tend to be compressed against these rigid mem-  branes, resulting in damage or destruction. A common example  is tentorial herniation.   Below the dura mater lies the arachnoid membrane, char-  acterized by its filmy, weblike structure. It loosely follows the  contours of the cerebral structures but lies over the sulci.   The subdural space lies between the dura and arachnoid.  Many small bridging veins that have little support traverse  the subdural space. Their disruption results in a subdural  hematoma (see Chapter 18 and Figures 18-5 and 18-6). The  subarachnoid space, which contains CSF, lies between the  arachnoid and the pia mater (see Figure 15-15). Damage to    FIGURE 15-15 Coverings of the Brain. Frontal section of the superior portion of the head, as viewed from the front. The  bony and the membranous coverings of the brain can be seen. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8,    intracranial vessels can lead to a condition called subarachnoid  hemorrhage, which frequently results in signs of meningeal  irritation, such as neck stiffness, positive Kernig sign, and low  back pain.   Unlike the dura mater and arachnoid, the delicate pia mater  (see Figure 15-15) closely adheres to the surface of the brain and  spinal cord and even follows the sulci and fissures. It provides sup-  port for blood vessels serving brain tissue. The choroid plexuses,  structures that produce cerebrospinal fluid (CSF), arise from the  pia mater. The spinal cord is anchored to the vertebrae by exten-  sions of the meninges called denticulate ligaments. The meninges  continue beyond the end of the spinal cord to the lower portion of  the sacrum. CSF, contained within the subarachnoid space, also  circulates down to the large lumbar cistern, which extends from  the second lumbar vertebra to the second sacral vertebra. Cisterns  are expanded areas of the subarachnoid space. The cerebellom-  edullary cistern (cisterna magna) and the pontine cistern are two  other important cisterns.   The meninges form potential and real spaces important to  understanding functional and pathologic mechanisms. For  example, between the dura mater and skull lies a potential space  termed the epidural space (see Figure 15-15). In the spinal  canal is a real epidural space filled with fatty tissue and a venous  plexus. The arterial supply to the meninges consists of blood  vessels that lie within grooves in the skull. As a result of trauma,  the skull can be fractured and the blood vessels disrupted. The  ruptured vessels can lead to an accumulation of blood within  the epidural space, called an epidural hematoma (see Chapter 18  and Figure 18-4). Persons with alcoholism often fall and injure  their head, resulting in an epidural hematoma. An inflamma-  tion of the meninges (meningitis) also can have life-threatening  implications because of the relative proximity to the brain. (See  Chapter 18.)    Cerebrospinal Fluid and the Ventricular System  Cerebrospinal fluid (CSF) is a clear, colorless fluid similar to  blood plasma and interstitial fluid. The intracranial and spinal  cord structures float in CSF and are thereby partially protected  from jolts and blows. The buoyant properties of the CSF also  prevent the brain from tugging on meninges, nerve roots, and  blood vessels. (Constituents of CSF are listed in Table 15-4.)  Between 125 and 150 ml of CSF, approximately the quantity of  a small cup of coffee, is circulating within the ventricles (small  cavities) and subarachnoid space at any given time. Approxi-  mately 600 ml of CSF is produced daily.   The choroid plexuses in the lateral, third, and fourth ven-  tricles produce the major portion of CSF. (Ventricles are  illustrated in Figures 15-15 and 15-16.) These plexuses are char-  acterized by a rich network of blood vessels, supplied by the pia    FIGURE 15-16 Flow of Cerebrospinal Fluid. A, Ventricles highlighted in blue within a translucent brain ina left lateral  view. B, Flow of cerebrospinal fluid. The fluid is produced by filtration of blood by the choroid plexus of each ventricle, and from  the ventricles flows to the subarachnoid space and then to the blood. (From Patton KT, Thibodeau GA: Anatomy & physiology,    mater, that lie in close contact with ventricular ependymal cells  that secrete and absorb CSF.   The CSF exerts pressure within the brain and spinal cord.  When a person is lying down, CSF pressure is approximately 120  to 180 mm of water pressure, or approximately 9 to 14 mmHg  pressure. CSF flow is a result of a pressure gradient between  the arterial system and the CSF-filled cavities. Beginning in the  lateral ventricles, the CSF flows through the interventricular  foramen (foramen of Monro) into the third ventricle and then  passes through the cerebral aqueduct (aqueduct of Sylvius)  into the fourth ventricle. From the fourth ventricle, the CSF  may pass through either the paired lateral apertures (foramina  of Luschka) into the pontine cisterns, located along the basal  pons, or the midline median aperture (foramen of Magendie)  into the cerebellomedullary cistern before communicating with  the subarachnoid spaces of the brain and spinal cord. The CSF  does not, however, accumulate. Instead, it is reabsorbed into  the venous circulation through the arachnoid villi, primar-  ily located superior to the falx cerebri in the superior sagittal  sinus. The arachnoid villi protrude from the arachnoid space,  through the dura mater, and lie within the blood flow of the  venous sinuses. CSF is reabsorbed by means of a pressure gradi-  ent between the arachnoid villi and the cerebral venous sinuses.  The villi function as one-way valves directing CSF outflow into  the blood but preventing blood flow into the subarachnoid  space. Thus CSF is derived from the blood, and after circulating  throughout the CNS, it returns to the blood.   Samples of CSF are withdrawn for diagnostic purposes either  (1) by inserting a needle between the third and fourth lumbar  vertebrae into the lumbar cistern (subarachnoid space)—a pro-  cedure called lumbar puncture—or (2) by placing an intraven-  tricular catheter. Spinal anesthesias (blocks) are administered  in a manner similar to the lumbar puncture.   The vertebral column (Figure 15-17) is composed of 33 verte-  brae: 7 cervical, 12 thoracic, 5 lumbar, 5 fused sacral, and 4 fused  coccygeal. Between each interspace (except the fused sacral and    FIGURE 15-17 Vertebral Column. A, Right lateral view. B, Anterior view.  (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013,  Mosby.)    spine & “Cavity for  B spinal cord  FIGURE 15-18 A, Lumbar Vertebra, Superior View. B, Intervertebral Disk.  (A from Patton KT, Thibodeau GA: Anatomy & physiology, ed 6, St Louis, 2007,    Mosby; B from Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis,  2013, Mosby.)    coccygeal vertebrae) is an intervertebral disk (Figure 15-18). At  the center of the intervertebral disk is the nucleus pulposus, a  pulpy mass of elastic fibers. The intervertebral disk functions to  absorb shocks, preventing damage to the vertebrae. The inter-  vertebral disk is also a common source of back problems. If too  much stress is applied to the vertebral column, the disk contents  may rupture and protrude into the spinal canal, causing com-  pression of the spinal cord or nerve roots. The disks also can  degenerate.   The brain receives approximately 20% of the cardiac output,  or 800 to 1000 ml of blood flow per minute. Carbon dioxide  serves as a primary regulator for blood flow within the CNS.  It is a potent vasodilator in the CNS, and its effects ensure an  adequate blood supply.   The brain derives its arterial supply from two systems: the  internal carotid arteries and the vertebral arteries (Figure  15-19). The internal carotid arteries, anteriorly, supply a pro-  portionately greater amount of blood flow. They originate from  the common carotid arteries, enter the cranium through the  base of the skull, and pass through the cavernous sinus. After  giving off some small branches, they divide into the anterior  and middle cerebral arteries (Figure 15-20). The vertebral  arteries, posteriorly, originate as branches off the subclavian  arteries, pass through the transverse foramina of the cervical    Superficial  temporal artery  Posterior  auricular artery  Occipital artery  Maxillary artery  Ascending  pharyngeal artery    Superior thyroid artery  Vertebral artery  Common carotid artery  Subclavian artery  Brachiocephalic artery    FIGURE 15-19 Major Arteries of the Head and Neck. (From Patton KT,  Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    vertebrae, and enter the cranium through the foramen mag-  num. They join at the junction of the pons and medulla oblon-  gata to form the basilar artery. The basilar artery divides at the  level of the midbrain to form paired posterior cerebral arteries.  Three major paired arteries perfuse the cerebellum and brain-  stem and originate from the posterior arterial supply: the pos-  terior inferior cerebellar artery, off the vertebral artery; and the  anterior inferior cerebellar and superior cerebellar arteries, off  the basilar artery. The basilar artery also gives rise to small pon-  tine arteries. The large arteries on the surface of the brain and  their branches are called superficial arteries (conducting arter-  ies). The small branches that project into the brain are termed  projecting arteries (nutrient arteries). Occluding any of these  vessels can cause neurologic signs and symptoms that are often  diagnostically unique.   The arterial circle (circle of Willis) (see Figure 15-20) is a  structure credited with the ability to compensate for reduced  blood flow from any one of the major contributors (collateral  blood flow). The arterial circle is formed by the posterior cere-  bral arteries, posterior communicating arteries, internal carotid  arteries, anterior cerebral arteries, and anterior communicating  artery. The anterior cerebral, middle cerebral, and posterior  cerebral arteries leave the arterial circle and extend to various  brain structures. (Table 15-5 and Figure 15-21 illustrate struc-  tures served, functional relationships, and pathologic consider-  ations related to occlusion of cerebral arteries.)   Cerebral venous drainage does not parallel (lie side by side) its  arterial supply, whereas the venous drainage of the brainstem and  cerebellum does parallel the arterial supply of the structures. The  cerebral veins are classified as superficial veins and deep cerebral  veins. The veins drain into venous plexuses and dural sinuses    Cerebellum  A  FIGURE 15-20 Arteries at the Base of the Brain. The arteries that compose the circle of Willis are the two anterior  cerebral arteries, joined to each other by the anterior communicating two short segments of the internal carotids, off of which  the posterior communicating arteries connect to the posterior cerebral arteries. (From Patton KT, Thibodeau GA: Anatomy &  physiology, ed 8, St Louis, 2013, Mosby.)    Basal ganglia; corpus callosum; medial surface of cerebral hemispheres;  superior surface of frontal and parietal lobes    Hemiplegia on contralateral side of body, greater in  lower than in upper extremities    Anterior cerebral artery  Middle cerebral artery Frontal lobe; parietal lobe; temporal lobe (primarily cortical surfaces)    Posterior cerebral artery Part of diencephalon and temporal lobe; occipital lobe    FIGURE 15-21 Areas of the Brain Affected by Occlusion of the Anterior, Middle, and Posterior Cerebral Artery  Branches. A, Inferior view. B, Lateral view.   FIGURE 15-22 Large Veins of the Head. Deep veins and dural sinuses are   projected on the skull. Note connections (emissary veins) between the superficial   and deep veins. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8,  St Louis, 2013, Mosby.)    The blood-brain barrier (BBB) is a term used to describe cellular structures  that selectively inhibit certain substances in the blood from entering the inter-  stitial spaces of the brain or cerebrospinal fluid (CSF). This term emphasizes  the impermeability of the nervous system to large and potentially harmful mol-  ecules. Astrocytes wrap their foot processes around the epithelial cells of brain  capillaries, contributing to the formation of the BBB. Tight junctions between  capillary endothelial cells form a barrier that regulates the passage of ions (e.g.,  sodium and potassium) that could interfere with nerve transmission, prevent  toxins from entering the brain, and promote transport of nutrients and removal  of metabolites. Compromise of the BBB contributes to passage of molecules  and immune cells into the brain causing disease. The BBB has substantial impli-  cations for drug therapy because certain types of antibiotics and chemothera-  peutic drugs show a greater propensity than others for crossing the barrier. BBB  permeability can be affected by hormones, neurotransmitters, and inflamma-  tory mediators. Inhibiting these endogenous chemicals with drug therapy may  reduce brain edema and slow the onset of degenerative brain diseases.    Data from Caraglia M et al: Curr Cancer Drug Targets 12(3):188-196,  2012; Cristante E et al: Proc Nat! Acad Sci U S A 110(3):832-941, 2013;  De Rosa G et al: Curr Drug Metab 13(1):61-69, 2012; Muldoon LL et al:  J Cereb Blood Flow Metab 33(1):13-21, 2013; Rosenberg GA: J Cereb  Bood Flow Metab, 2012 [Epub]; Van Sorge NM, Doran KS: Future  Microbiol 7(3):383-394, 2012.    (formed between the dural layers) and eventually join the inter-  nal jugular veins at the base of the skull (Figure 15-22). Adequacy  of venous outflow can have a significant effect on intracranial  pressure. For example, in individuals with head injury, turning  or letting the head fall to the side partially occludes venous return  and can increase intracranial pressure because of decreased flow  through the jugular veins.  The blood-brain barrier is discussed in Box 15-4.    The spinal cord derives its blood supply from branches off the  vertebral arteries and from branches from various regions of  the aorta (Figure 15-23). The anterior spinal arteries and the  paired posterior spinal arteries branch off the vertebral artery    at the base of the cranium and descend alongside the spinal  cord. Arterial branches from vessels exterior to the spinal cord  follow the spinal nerve through the intervertebral foramina,  pass through the dura, and divide into the anterior and poste-  rior radicular arteries.   The radicular arteries eventually reconnect to the spinal  arteries. Branches from the radicular and spinal arteries form  plexuses whose branches penetrate the spinal cord, supplying  the deeper tissues. Venous drainage parallels the arterial supply  closely and drains into venous sinuses located between the dura  and periosteum of the vertebrae.    The cranial and spinal nerves, including their branches and gan-  glia, constitute the PNS. A peripheral nerve (cranial or spinal) is  composed of individual axons/dendrites, with most wrapped in  a myelin sheath. These individual fibers are arranged in bundles  called fascicles (see Figure 15-1 and Figure 15-24, B). The cover-  ings provide structural support, a blood supply, and interstitial  compartments necessary for the delivery of essential electrolytes  to support nerve impulse conduction.   The 31 pairs of spinal nerves derive their names from the  vertebral level from which they exit. There are eight cervical spi-  nal nerves. The first cervical nerve exits above the first cervical  vertebra, and the rest of the spinal nerves exit below their cor-  responding vertebrae. From the thoracic region (and inferiorly)  nerves correspond to the vertebral level above their exit (see  Figure 15-10).   Spinal nerves contain both sensory and motor neurons and  are called mixed nerves. They arise as rootlets from the anterior  and posterior horn cells of the spinal cord. These two spinal  nerve roots converge in the region of the intervertebral fora-  men to form the spinal nerve (see Figure 15-11). Shortly after  converging, the spinal nerve divides into anterior and poste-  rior rami (branches). The anterior rami (except the thoracic)  initially form plexuses (networks of nerve fibers), which then  branch into the peripheral nerves. Instead of forming plexuses,  the thoracic nerves pass through the intercostal spaces and  innervate regions of the thorax.   The main spinal nerve plexuses innervate the skin and the  underlying muscles of the limbs. The brachial plexus, for  example, is formed by the last four cervical nerves (C5-C8)  and the first thoracic nerve (T1). The brachial plexus inner-  vates the nerves of the arm, wrist, and hand. The lumbar  plexus (L2-L4) and sacral plexus (L5-S5) contain nerves that  innervate the anterior and posterior portions of the lower  body, respectively (see Figure 15-10).   The posterior rami of each spinal nerve, with their many  processes, are distributed to a specific area in the body. Sen-  sory signals thus arise from specific sites associated with a spe-  cific spinal cord segment. Specific areas of cutaneous (skin)  innervation at these spinal cord segments are called derma-  tomes. The dermatomes of various spinal nerves are distrib-  uted in a fairly regular pattern, although adjacent regions  between dermatomes can be innervated by more than one  spinal nerve Figure 15-24, D.    FIGURE 15-23 Arteries of the Spinal Cord. A, Arteries of cervical cord exposed (posterior view). B, Arteries of spinal  cord diagrammatically shown in horizontal section. (From Rudy EB, editor: Advanced neurological and neurosurgical nursing,    Like spinal nerves, cranial nerves are categorized as periph-  eral nerves. Most of these are mixed nerves (like the spinal  nerves), although some are purely sensory or motor. Cranial  nerves arise from nuclei in the brain and brainstem. (Figure  15-24, A, illustrates their location, and Table 15-6 describes  structural and functional characteristics.)    Components of the ANS are located in both the CNS and the  PNS; however, the ANS is considered part of the efferent divi-  sion of the PNS, even though visceral afferent neurons are an  important part of this system. Many neurons of the ANS travel  in spinal nerves and in certain cranial nerves. The widespread  activity of this system indicates that its components are distrib-  uted over the entire body. The peripheral autonomic nerves  carry mainly efferent fibers. The motor component of the ANS  is a two-neuron system consisting of preganglionic neurons  (myelinated) and postganglionic neurons (unmyelinated).  This arrangement contrasts with the somatic nervous system, in  which a single motor neuron travels from the CNS to the inner-  vated structure. Visceral afferent neurons have their cell bodies  in some sensory and cranial ganglia and their fiber processes  traveling in peripheral nerves. The CNS has autonomic areas  in the intermediolateral horns of the spinal cord, cardiovascu-  lar and respiratory centers in the reticular formation, and both  sympathetic and parasympathetic areas in the hypothalamus.  CNS pathways interconnect all these areas.   The ANS coordinates and maintains a steady-state among  visceral (internal) organs, such as regulation of cardiac muscle,  smooth muscle, and the glands of the body. This system is con-  sidered an involuntary system because one generally cannot will    these functions to happen. The ANS is separated structurally  and functionally into two divisions: (1) the sympathetic ner-  vous system (Figure 15-25) and (2) the parasympathetic ner-  vous system (Figure 15-26).   The sympathetic nervous system functions to mobilize energy  stores in times of need (e.g., in the fight-or-flight response)  (see Chapter 11 and Figure 11-2). The sympathetic division  receives its innervation from cell bodies located from the first  thoracic (T1) through the second lumbar (L2) regions of the  spinal cord and is therefore called the thoracolumbar division.  The preganglionic axons of the sympathetic division form syn-  apses shortly after leaving the spinal cord in the sympathetic  ganglia. These preganglionic axons travel several different  ways: (1) directly synapsing with postganglionic neurons in the  sympathetic chain ganglion at their level, (2) traveling up or  down the sympathetic chain ganglion before forming synapses  with a higher or lower postganglionic neuron (divergence), or  (3) passing through the sympathetic chain ganglion postgan-  glionic neurons within collateral ganglia (see Figure 15-25).  Some preganglionic axons form pathways called splanch-  nic nerves, which lead to collateral ganglia surrounding the  abdominal aorta. The collateral ganglia are named according  to the branches of the aorta nearest them, namely, the celiac,  superior mesenteric, and inferior mesenteric. These postgan-  glionic neurons leave the collateral ganglia and innervate the  viscera below the diaphragm.   Preganglionic sympathetic neurons that innervate the adre-  nal medulla also travel in the splanchnic nerves and do not syn-  apse before reaching the gland. The secretory cells in the adrenal  medulla are considered modified postganglionic neurons.    FIGURE 15-24 Cranial and Peripheral Nerves and Skin Dermatomes.  A, Ventral surface of the brain showing attachment of the cranial nerves.  B, Peripheral nerve trunk and coverings. €, Scanning electron micrograph of a freeze-  fractured preparation of peripheral nerve D, Dermatome distribution of front and  back of body surface. (A, B, and D from Patton KT, Thibodeau GA: Anatomy and  Physiology, ed 8, St Louis 2013, Mosby).    Fibers arise from nasal olfactory  epithelium and form synapses  with olfactory bulbs that transmit  impulses to temporal lobe   Fibers arise from retina of eye to form  optic nerve, which passes through  sphenoid bone; two optic nerves  then form optic chiasma (with partial  crossover of fibers) and eventually  end in occipital cortex    Fibers emerge from posterior midbrain  and exit from skull to run to eye   Fibers emerge from pons and form  three divisions that exit from skull  and run to face and cranial dura mater    Fibers leave pons and travel through  temporal bone and extend to face    Fibers run from inner ear (hearing and  equilibrium receptors in temporal bone)  to enter brainstem just below pons    Fibers emerge from midbrain and leave  skull and extend to pharynx, salivary  glands, and tongue    Fibers emerge from medulla, pass through  skull, and descend through neck region  into thorax and abdominal region    Fibers arise from medulla and superior  spinal cord and extend to muscles of  neck and back    Fibers arise from medulla and exit from  skull and extend to tongue    Contains motor fibers to inferior oblique and  to superior, inferior, and medial rectus  extraocular muscles that direct eyeball;  levator muscles of eyelid; smooth muscles  of iris and ciliary body; and proprioception  (sensory) to brain from extraocular muscles   Proprioceptor and motor fibers for superior  oblique muscle of eye (extraocular muscle)   Both motor and sensory for face; conducts  sensory impulses from mouth, nose, surface  of eye, and dura mater; also contains motor  fibers that stimulate chewing muscles    Contains motor fibers to lateral rectus muscle  and proprioceptor fibers from same muscle  to brain   Mixed: (1) supplies motor fibers to muscles  of facial expression and to lacrimal and  salivary glands, and (2) carries sensory  fibers from taste buds of anterior part of  tongue    Purely sensory; vestibular branch transmits  impulses for sense of equilibrium; cochlear  branch transmits impulses for sense of  hearing   Mixed: (1) motor fibers serve pharynx (throat)  and salivary glands, and (2) sensory fibers  carry impulses from pharynx, posterior  tongue (taste buds), and pressure receptors  of carotid artery   Fibers carry sensory and motor impulses  for pharynx; a large part of this nerve is  parasympathetic motor fibers, which supply  smooth muscles of abdominal organs;  receives sensory impulses from viscera   Provides sensory and motor fibers for  sternocleidomastoid and trapezius muscles  and muscles of soft palate, pharynx, and  larynx   Carries motor fibers to muscles of tongue and  sensory impulses from tongue to brain    Person is asked to sniff aromatic  substances, such as oil of cloves and  vanilla, and to identify them    Vision and visual field tested with an  eye chart and by testing point at which  person first sees an object (finger)  moving into visual field; inside of eye is  viewed with ophthalmoscope to observe  blood vessels of eye interior   Pupils examined for size, shape, and  equality; pupillary reflex tested with a  penlight (pupils should constrict when  illuminated); ability to follow moving  objects    Tested in common with cranial nerve III  relative to ability to follow moving objects   Sensations of pain, touch, and temperature  tested with safety pin and hot and cold  objects; corneal reflex tested with a wisp  of cotton; motor branch tested by asking  subject to clench teeth, open mouth against  resistance, and move jaw from side to side   Tested in common with cranial nerve III  relative to ability to move each eye  laterally   Anterior two thirds of tongue tested for  ability to taste sweet (sugar), salty, sour  (vinegar), and bitter (quinine) substances;  symmetry of face checked; subject asked  to close eyes, smile, whistle, and so on;  tearing tested with ammonia fumes   Hearing checked by air and bone  conduction by use of a tuning fork;  vestibular tests: Barany and caloric tests    Gag and swallow reflexes checked; subject  asked to speak and cough; posterior one  third of tongue may be tested for taste    Same as for cranial nerve IX (IX and X are  tested in common) because they both  serve muscles of the throat    Sternocleidomastoid and trapezius muscles  checked for strength by asking subject to  rotate head and shrug shoulders against  resistance    FIGURE 15-25 Sympathetic Division of the Autonomic Nervous System. CG, Celiac ganglion; C/G, ciliary ganglion;  IMG, inferior mesenteric ganglion; OG, otic ganglion; PP pelvic plexus; SCG, superior cervical ganglion; SG, submandibular  ganglion; SMG, superior mesenteric ganglion; SpG, sphenopalatine ganglion. (Redrawn from Rudy EB, editor: Advanced  neurological and neurosurgical nursing, St Louis, 1984, Mosby.)    Because preganglionic sympathetic fibers are all myelinated,  nerve conduction to the adrenal medulla is quick, and innerva-  tion causes the rapid release of epinephrine and norepineph-  rine. Epinephrine and norepinephrine are mediators of the  fight-or-flight response (see Chapter 11).    The parasympathetic nervous system functions to conserve and  restore energy. The nerve cell bodies of this division are located  in the cranial nerve nuclei and in the sacral region of the spi-  nal cord, and therefore constitute the craniosacral division.  Unlike the sympathetic division, the preganglionic fibers in the  parasympathetic division travel to ganglia close to the organs  they innervate before forming synapses with the relatively short  postganglionic neurons (see Figure 15-26). Parasympathetic    nerves arising from nuclei in the brainstem travel to the vis-  cera of the head, thorax, and abdomen within cranial nerves—  including the oculomotor (III), facial (VII), glossopharyngeal  (IX), and vagus (X) nerves.   Preganglionic parasympathetic nerves that originate from  the sacral region of the spinal cord run either separately or  together with some spinal nerves. The preganglionic axons join  to form the pelvic nerve, which innervates the viscera of the  pelvic cavity. These preganglionic axons synapse with postgan-  glionic neurons in terminal ganglia located close to the organs  they innervate.    FIGURE 15-26 Parasympathetic Division of the Autonomic Nervous System. C/G, Ciliary ganglion; OG, otic ganglion;  PN, pelvic nerve; PP pelvic plexus; SG, submandibular ganglion; SpG, sphenopalatine ganglion; VN, vagus nerve. (From Rudy  EB, editor: Advanced neurological and neurosurgical nursing, St Louis, 1984, Mosby.)    same neurotransmitter released by somatic efferent neurons  (Figure 15-27). These fibers are characterized by cholinergic  transmission. Most postganglionic sympathetic fibers release  norepinephrine (adrenaline) and thus are considered to func-  tion by adrenergic transmission. A few postganglionic sym-  pathetic fibers, such as those that innervate the sweat glands,  release acetylcholine.   The action of catecholamines (epinephrine, norepineph-  rine, dopamine) varies with the type of neuroreceptor stim-  ulated. It should be remembered that catecholamines also  are released by the adrenal medulla gland that physiologi-  cally and biochemically resembles the sympathetic nervous  system. Mainly two types of adrenergic receptors exist: a-  and $-adrenergic receptors. Cells of the effector organs may  have only one or both types of adrenergic receptors. The a-  adrenergic receptors have been further subdivided according  to the action produced: a-adrenergic activity is associated  mostly with excitation or stimulation; a-adrenergic activ-  ity is associated with relaxation or inhibition. Most of the    a-adrenergic receptors on effector organs belong to the a,-  adrenergic class. The B-adrenergic receptors are classified  as B,-adrenergic receptors (which facilitate increased heart  rate and contractility and cause the release of renin from the  kidney), Bz-adrenergic receptors (which facilitate all of the  remaining effects attributed to $-adrenergic receptors), and  63-adrenergic receptors (mediate lypolysis and thermogenesis  and are up-regulated in cardiovascular disease).°   Norepinephrine stimulates all a-adrenergic and B ;-adrenergic  receptors and (3-adrenergic receptors, and only certain B)-  adrenergic receptors. The primary response from norepineph-  rine, however, is stimulation of the a-adrenergic receptors that  cause vasoconstriction. Epinephrine strongly stimulates all four  types of receptors and induces general vasodilation because of  the predominance of B-adrenergic receptors in muscle vascula-  tures. (Table 15-7 summarizes the effects of neuroreceptors on  their effector organs.)   Dopamine is a precursor of norepinephrine and epinephrine  and is a brain neurotransmitter synthesized in the substantia    FIGURE 15-27 Autonomic Nervous System and Type of Neurotransmitters Secreted by Preganglionic and  Postganglionic Fibers. Note that all preganglionic fibers are cholinergic (Ach). A somatic nerve is used for comparison.    Increase automaticity and propagation velocity  Increase automaticity and propagation velocity  Increase contractility    Constriction, dilation  Constriction  Dilation, constriction  Constriction (sligh  Constriction, dilati  Constriction  Constriction, dilati  Constriction  Constriction, dilati    Liver 1, Bo  Gallbladder and ducts By  Pancreas  Acini a  Islet cells 2, Bo  Intestine  Motility and tone 4, A, By, Be  Sphincters Oy  Secretion Oy  Adrenal medulla =    Modified from Brunton LL et al, editors: Goodman & Gilman's the pharmacological basis of therapeutics, ed 12, New York, 2010, McGraw-Hill;  Yagiela JA et al: Pharmacology and therapeutics for dentistry, ed 6, St Louis, 2011, Mosby.    nigra and the ventral tegmental areas of the brain There are five  types of dopamine receptors distributed throughout the brain,  D,, D2, D3, Dy, and D; They have varying functions including  pleasure, motivation, cognition, memory, learning, and fine  motor control (see What’s New? Nucleus Accumbens, Dopa-  mine, and Drug Addiction, p. 460).   Many body organs are innervated by the sympathetic and  parasympathetic nervous systems. The two divisions frequently  cause opposite responses; for example, sympathetic stimula-  tion of the gastrointestinal (GI) tract causes decreased peri-  stalsis, whereas parasympathetic stimulation of the GI tract  increases peristalsis. In general, sympathetic stimulation pro-  motes responses that are concerned with the protection of the  individual. For example, sympathetic activity increases blood  glucose levels and temperature and raises blood pressure. In  emergency situations a generalized and widespread discharge  of the sympathetic system occurs. This is accomplished by an  increased firing frequency of sympathetic fibers and by activa-  tion of sympathetic fibers normally silent and at rest (fibers to  the sweat glands, pilomotor muscles, and the adrenal medulla,  as well as vasodilator fibers to muscle). Regulation of vasomo-  tor tone is considered the single most important function of the  sympathetic nervous system. (Figure 15-28 illustrates some of  the most important functions of the sympathetic nervous sys-  tem; also see Figure 11-2.)    Increased parasympathetic activity promotes rest and tran-  quility and is characterized by reduced heart rate and enhanced  visceral functions leading to digestion. Stimulation of the vagus  nerve in the GI tract increases peristalsis and secretion, as well  as relaxation of sphincters. Activation of parasympathetic fibers  in the head, provided by cranial nerves II, VH, and IX, causes  pupillary constriction, tear secretion, and increased salivary  secretion. Stimulation of the sacral division of the parasympa-  thetic system contracts the urinary bladder and facilitates the  process of genital erection.   The parasympathetic system lacks the generalized and  widespread response of the sympathetic system. Specific  parasympathetic fibers are activated to regulate particu-  lar functions. Although the actions of the parasympathetic  and sympathetic systems usually are antagonistic, there are  exceptions. Changes in the shape of the lens (for near vision)  require only oculomotor parasympathetic activity. Most of  the blood vessels involved in the control of blood pressure  are innervated by sympathetic nerves. Peripheral vascular  resistance is increased and decreased by the relative activity of  the sympathetic division without a counteracting parasympa-  thetic component. To decrease blood pressure, therefore, it is  more important to block or paralyze the continuous (tonic)  discharge of the sympathetic system than to promote para-  sympathetic activity.    Glycogenolysis Glycolysis | | Breakdown  in the liver in muscle of adipose  tissue    FIGURE 15-28 Some Important Functions of the Sympathetic Nervous System. A, Regulation of vasomotor tone.  B, Regulation of strenuous muscular exercise (fight-or-flight response). (See also Chapter 11 and Figure 11-2 for more detail    The CNS mechanisms involved in the aging process are  extremely complex, and many questions concerning the neu-  rologic effects of aging have yet to be answered. Some of the  identified mechanisms associated with aging are pathologic, but  the distinction between these mechanisms and those that are a  part of the normal aging process remains somewhat ambigu-  ous. Box 15-5 contains information on the structural, cellular,    cerebrovascular, and functional changes that occur in the ner-  vous system with aging.   Roentgenograms (x-ray films) of the skull or spine from mul-  tiple angles (views) are used primarily to localize bony defects,  bone density, erosion, or calcified structures. The pineal gland   Decreased brain weight and size, particularly frontal regions  Fibrosis and thickening of the meninges    Decrease in the number of neurons, not consistently related to changes in  mental function   Formation of intracellular neurofibrillary tangles; significant accumulation in  cortex associated with Alzheimer dementia    Cerebrovascular Changes with Aging  Arterial atherosclerosis (may cause infarcts and scars)  Increased permeability of the blood-brain barrier  Decreased vascular density    Data from Brown WR, Thore CT: Neuropathol App! Neurobiol 37(1):56-74, 2011; Crowley K: Neuropsychol Rev 21(1):41-53, 2011; Glorioso C,  Sibille E: Prog Neurobiol 93(2):165-181, 2011; Hof PR, Mobbs C: Neuroscience of aging, Oxford, 2009, Academic Press; Jang YC, Van Remmen H:  Exp Gerontol! 46(2-3):193-198, 2011; Kumar A, Foster TC: Neurophysiology of old neurons and synapses. In Riddle DR, editor: Brain aging: models,  methods, and mechanisms, Boca Raton, FL, 2007, CRC Press; Nyberg L et al: Trends Cogn Sci 16(5):292-305, 2012.    in older people becomes calcified and is useful as an internal  brain landmark. X-ray films are probably the most commonly  used radiologic studies.    Computed tomography (CT) creates two-dimensional recon-  structions from multiple radiologic images (x-rays) using  computer-assisted analysis. It is capable of demonstrating fine  distinctions in shape, size, and densities of a variety of tissues  based on differential absorption of x-rays. CT imaging is a nonin-  vasive procedure used in evaluating cranial and spinal structures,  as well as hemorrhages, tumors, and distortions in the brain  caused by pressure differences. A variety of contrast media also  are commonly used in conjunction with this procedure to aid in  enhanced delineation of selected structures. Spiral or helical CT  uses a multidetector scanner mounted on a rotating gantry to pro-  vide several axial images for imaging a large continuous anatomic  area in a matter of seconds. Helical CT angiography uses contrast  media for detection of aneurysms or ruptured aneurysms.    Magnetic resonance imaging (MRI) is a commonly used test-  ing modality. It uses a static magnetic field, instead of x-rays,  to orient physiologic atomic particles. Disruption of this orien-  tation by excitation of the particles using serial radiofrequency  pulsations provides the image data. The specific tissue reaction  is computer-analyzed to give an image of exquisite detail, simi-  lar to that provided by CT. The MRI also provides reconstruc-  tion of images in three views at right angles (i.e., axial, sagittal,  coronal). MRI is reported to have none of the adverse effects  associated with radiation examinations. Magnetic resonance  spectroscopy can be completed at the same time as a standard  MRI by analyzing the chemical composition of proton (hydro-  gen) or phosphorus-based molecules and is useful for evaluating  the chemical composition and function of various regions of the    brain. Functional MRI (fMRI) detects changes in blood oxygen-  ation and flow and can be used to produce maps showing the  parts of the brain that are functioning during a mental process.    A newer addition to MRI is magnetic resonance angiography  (MRA). Special imaging techniques allow the visualization of  blood vessels in great detail. MRA is likely to become indis-  pensable, alone or in conjunction with cerebral angiography,  in detecting and localizing pathologic lesions of the circulatory  system of the brain.    The positron-emission tomography (PET) scan uses CT  imaging to detect the emission of positive electrons from trace  amounts of radioactive substances injected into the bloodstream  or administered as inhaled gases. With radioactive decay, radio-  active substances emit a positron. As they are distributed in  tissues, they display characteristic patterns that indicate physi-  ologic and metabolic processes, for example, glucose and oxy-  gen uptake, cerebral blood flow, neural and neurotransmitter  function, and the effects of drugs. As a research tool, PET is  being used to visualize the specific brain sites that are involved  in the processing of information in the brain.    The brain scan images radionuclide substances (technetium  [°™Tc]) that have been introduced into the bloodstream.  For example, visualization of tissue uptake of the radioactive  agent provides an indication of blood-brain barrier integrity  (increased uptake of the agent indicates disruption). This scan-  ning technique also can identify abnormalities in blood flow  dynamics and cellular metabolic function. The brain scan is  particularly helpful in detecting abnormal vascularity resulting  from neoplasms, abscesses, and vascular lesions.    Pressure (initial 120-180 mm H,0 (9-14 mmHg) <60 mm H,0 Faulty needle placement  readings) Dehydration  Spinal block along subarachnoid space  Block of foramen magnum  >200 mm H,0 Muscle tension  Abdominal compression  Brain tumor  Subdural hematoma  Brain abscess  Brain cyst  Cerebral edema (any cause)  Hydrocephalus  Color (turbidity) Clear, colorless Cloudy Increased cell count  Increased microorganisms  Yellow Xanthochromic (caused by red blood cell [RBC] pigments)  High protein content  Smoky Presence of RBCs  Red blood cells Blood-tinged Traumatic tap  Grossly bloody Traumatic tap  Subarachnoid hemorrhage  White blood cells 0-6/mms >10/mms (cell counts range from Occurs in many conditions:  <100/mm% to many thousands Bacterial infections of meninges  depending on causative factor; all Viral infections of meninges  are abnormal findings) Neurosyphilis  Tuberculous meningitis  Metastatic neoplastic lesions  Parasitic infections  Acute demyelinating diseases  Following introduction of air or blood into subarachnoid space  Protein* 15-45 mg/dl (1% of serum <10 mg/dl Little clinical significance  protein)  >60 mg/dl Occurs in many conditions:  Complete spinal block  Guillain-Barré syndrome  Carcinomatosis of meninges  Tumors close to pial or ependymal surfaces or in  cerebellopontine angle  Acute and chronic meningitis  Meningeal hemorrhage  Demyelinating disorders  Degenerative diseases  Glucose (CSF: 0.6: approximately 60% of blood ~~ <0,4: <40 mg/dl Acute bacterial meningitis  Serum Ratio) glucose level - 50-55 mg/dl) >0,6: >60mg/dl Tuberculous meningitis  Meningeal carcinomatosis  Acute viral meningitis  >100 mg/dl Diabetes  Chloride 700-750 mg/dl <625 mg/dl Hypochloremia  116-130 mEq/L <110 mEq/L Tuberculous meningitis  >800 mg/dl Not of neurologic significance; correlates with blood levels  of chloride    Data from Rudy EB, editor: Advanced neurological and neurosurgical nursing, St Louis, 1984, Mosby; Marx JA editor in chief: Rosen’s emergency  medicine, Philadelphia, 2010, Saunders.  *Note: If CSF contains blood, this will raise the protein level.    Isotope cisternography is another radionuclide imaging  technique that uses brain scan imaging to detect CSF flow,  CSF resorption, and integrity of CSF pathways. The radionu-  clide agent in this case is injected directly into the subarach-  noid space. Under normal conditions the agent passes over  the cortical surface and is resorbed through the arachnoid  villi. Demonstration of the agent in the ventricular system  after a specific period of time indicates CSF obstruction; that  is, the CSF backflows from the subarachnoid space into the  ventricles.   Angiography is a radiologic technique that demonstrates cere-  brovascular blood flow. This technique commonly is performed  by the introduction of a small catheter into the femoral artery.  The catheter is then passed to the level of the cerebral circula-  tion and through the aorta, and a contrast dye is injected. Serial  x-ray films are then taken. These films demonstrate flow of the  dye through the cerebral vasculature and provide informa-  tion on patency, location, size, and flow pattern of the vessels.  Another technique used in cerebral angiography is the retro-  grade (reverse flow) injection of the dye through catheterization  of a brachial, axillary, subclavian, or femoral vein.   A myelogram demonstrates intraspinal anatomy by the intro-  duction of a radiographic dye into the lumbar subarachnoid  space or the cerebellomedullary cistern (cisterna magna). The  dye is allowed to flow in a cephalic direction, as in the case of a  lumbar injection, or inferiorly in a cerebellomedullary cistern  puncture. X-ray films are then obtained. The distribution of the  dye delineates spinal cord and nerve root structure and integrity.    Echoencephalography, or ultrasound, is a safe, noninvasive  procedure using sound waves that are deflected at differing    rates, depending on the density of the tissue. Information is  processed and displayed on an oscilloscope screen. It is useful  primarily in the detection of structural characteristics of intra-  cranial space—occupying mass lesions and the determination of  ventricular dimensions, especially in newborns.   The electroencephalograph (EEG) is a recording of electrical  impulses, arising from the cortical surface of the brain, which  is detected by scalp electrodes. The recording of brain wave  patterns is analyzed for alterations or localization (or both) of  specific electrical activity. This test is especially useful in detect-  ing and localizing foci that initiate seizure activity. It is also an  important technique in determining, from a person’s brain  activity, whether the person is legally “brain dead.”    Evoked potentials (EPs) are a method of detecting electrical  brain activity that results from a stimulus—primarily auditory,  visual, or peripheral sensory. Electrical activity is computer for-  matted to display changes in trends. The primary uses of EPs  include perioperative detection of sensory pathway integrity  and disease- or drug-related sensory dysfunction.   CSF generally is obtained from the lumbar or cisternal sub-  arachnoid space by means of a hollow needle that allows pas-  sive flow. The lumbar puncture is performed most often at the  L3-L4 interspace (below the level of the spinal cord at L1-L2).  Cisternal puncture is performed by the insertion of a needle  into the cerebellomedullary cistern using an approach from the  back of the neck in the region of the foramen magnum. CSF  pressure is commonly measured during these procedures. The  CSF can be analyzed also for gross characteristics and constitu-  ents (color, blood cells, electrolytes, and protein) and cultured  for microorganisms (Table 15-8).   1. The divisions of the nervous system have been categorized  as either structural (CNS and PNS) or functional (somatic  nervous system and ANS).   2. The CNS is contained within the brain and spinal cord.   3. The PNS is composed of cranial and spinal nerves that carry  impulses toward the CNS (afferent) and away from the CNS  (efferent) to target organs or skeletal muscle.   1. The neuron and neuroglial cells make up nervous tissue.  The neuron is specialized to transmit and receive electrical  and chemical impulses, and the neuroglial cell provides sup-  portive functions. The neuron is further divided into uni-  polar, pseudounipolar, bipolar, and multipolar categories,  according to structure and particular mechanics of impulse  transmission.    2. The neuron is composed of a cell body, one or more den-  drites, and an axon. A myelin sheath around selected axons  forms an insulation that allows quicker nerve impulse con-  duction, referred to as saltatory conduction.   3. Neurons have four basic types of cell configuration: (a) uni-  polar, (b) pseudounipolar, (c) bipolar, and (d) multipolar.  The three function types of neurons are sensory, associa-  tional, and motor.   4. Neuroglial cells (“nerve glue”) support the CNS and comprise  approximately half of the total brain and spinal cord volume.   5. Nerve injury triggers a sequence of events known as wal-  lerian degeneration. The degree of nerve regeneration that  occurs depends on many factors.   1. The region between adjacent neurons is the synapse, and  the region between the neuron and muscle is the myoneural  junction.    2. Neurotransmitters are responsible for chemical conduc- 9. The paired carotid and vertebral arteries supply blood to  tion across the synapse and myoneural junction. The nerve the brain and connect to form the circle of Willis. The  impulse is predominantly regulated by a balance of IPSPs major branches projecting from the circle of Willis are the  and EPSPs, temporal and spatial summation, and conver- anterior, middle, and posterior cerebral arteries. Drain-  gence and divergence. age of blood from the brain is accomplished through the   venous sinuses and jugular veins.  Central Nervous System 10. Blood supply to the spinal cord originates from the verte-    The brain is contained within the cranial vault and is divided  into three distinct regions: (a) forebrain, (b) midbrain, and  (c) hindbrain.    2. The forebrain comprises the two cerebral hemispheres 1. The PNS functions to relay information from the CNS  and allows conscious perception of internal and external to muscle and effector organs through cranial and spinal  stimuli, thought and memory processes, and voluntary nerve tracts arranged in fascicles (multiple fascicles bound  control of skeletal muscles. The deep portion of the fore- together form the peripheral nerve).  brain is termed the diencephalon and processes incoming 2. The 31 pairs of spinal nerves contain sensory and motor    sensory data. The center for voluntary control of skeletal  muscle movements is located along the precentral gyrus in  the frontal lobe, whereas the center for perception is along  the postcentral gyrus in the parietal lobe. The Broca area  (rostral to the postcentral gyrus) and the Wernicke area  (superoposterior temporal lobe) are major speech centers.    . The midbrain is primarily a relay center for some motor    and sensory tracts, as well as a center for auditory and visual  reflexes.    sory data from the periphery and motor impulses from the  cerebral hemispheres for the purpose of coordination and    The ANS is responsible for the maintenance of a steady-  state in the internal environment. Two opposing systems  constitute the ANS: (a) the sympathetic nervous system  responds to stress by mobilizing energy stores and pre-  pares the body to defend itself, and (b) the parasympa-  thetic nervous system conserves energy and the body’s  resources.    refinement of skeletal muscle movement. 1. Major structural changes with aging include a decrease in  5. The spinal cord contains the majority of nerve fibers con- number of neurons and a decrease in brain weight and size.   necting the brain with the periphery. Reflex arcs are com- 2. Decreased amounts of myelin, deposition of lipofuscin,   pleted in the spinal cord and influenced by the higher and the presence of senile plaques, multiple neurofibrillary   eral corticospinal, corticobulbar, basal ganglia, and 3. Cerebral atherosclerosis, decreased vascular density, and   vestibulospinal. increased permeability of the blood-brain barrier occur  7. The three clinically important afferent pathways are the with aging.   posterior column, anterior spinothalamic, and lateral 4, Functional changes with aging include diminished sensory    . The CNS is protected by the scalp, bony cranium, menin-    ges, vertebral column, and CSF. The CSF is formed from  blood components in the choroid plexuses of the ventricles  and is reabsorbed in the arachnoid villi (located in the dural  venous sinuses) after circulating through the brain and spi-  nal cord.    Tests of nervous system function include x-ray films, CT,  MRI and MRA, PET, brain scan, cerebral angiography,  myelography, echoencephalography, electroencephalogra-  phy, EPs, and analysis of CSF.   Central nervous system (CNS), 448  Central sulcus (fissure of Rolando), 456  Cerebellomedullary cistern (cisterna magna), 465  Cerebellum, 459   Corpora quadrigemina (tectum), 459  Corpus callosum (commissural fiber), 457  Corpus striatum, 457   Inferior mesenteric branch of aorta, 470  Inhibitory postsynaptic potential (IPSP), 453  Inner dura (meningeal layer), 464    Posterior horn (dorsal horn), 461  Posterior spinal artery, 469  Postganglionic neuron, 470  Postsynaptic neuron, 451  Precentral gyrus, 456   Primary motor area, 456  Primary voluntary motor area, 456  Projecting artery (nutrient artery), 467  Protopathic, 464   Reticular activating system, 454  Reticular formation, 454  Roentgenogram (x-ray film), 477  Sacral plexus, 469   Saltatory conduction, 448  Schwann cell (neurolemmocyte), 450  Sensory ganglion (dorsal root ganglion), 461  Sensory neuron, 449   Spiral (helical) CT, 478  Splanchnic nerve, 470  Subarachnoid space, 464  Subdural space, 464   Substantia gelatinosa, 461  Substantia nigra, 459  Subthalamic nucleus, 459  Subthalamus, 457   Superior mesenteric branch of aorta, 470  Superior sagittal sinus, 466  Sympathetic ganglia, 470  Sympathetic nervous system, 470  Synapse, 451   Vertebral column, 466  Vestibulospinal pathway, 463  Wallerian degeneration, 450  Wernicke area, 457    Haines DE: Fundamental neuroscience for basic and clinical applications,  ed 3, Philadelphia, 2012, Churchill Livingstone.   Kandel ER et al: Principles of neural science, ed 5, New York, 2012,  McGraw-Hill.   Purves D et al: Neuroscience, ed 4, Sunderland, 2008, Sinauer Associates.    . Kolb B, Whishaw IQ: An introduction to brain and behavior, ed 3, New York,    . Dessy C, Balligand JL: Beta3-adrenergic receptors in cardiac and vascular    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Animations  Autonomic Neurotransmitters  Brain Anatomy and Function, Part 1: Brain Lobes  Brain Anatomy and Function, Part 2: The Limbic System  Brain Anatomy and Function, Part 3: Substantia Innominata  Brain Anatomy and Function, Part 4: Ventricles, Thalamus, Hypothalamus  Cranial Nerves  Divisions of the Nervous System  Reflex Arcs  The Autonomic Nervous System as a Whole  The Synapse    Pain, 485  Theories of Pain, 485  Neuroanatomy of Pain, 485  Pain Modulation, 487  Clinical Descriptions of Pain, 491  PEDIATRICS and Perception of Pain, 495  AGING and Perception of Pain, 495  Temperature Regulation, 495  Hypothalamic Control of Temperature, 496  PEDIATRICS and Temperature Regulation, 498  AGING and Temperature Regulation, 498  Pathogenesis of Fever, 498  Benefits of Fever, 498  Disorders of Temperature Regulation, 500    Alterations in sensory function may involve dysfunctions of  the general or the special senses. Dysfunctions of the general  senses include chronic pain and altered temperature regulation.  Somatosensory alterations include tactile, proprioceptive, and  vestibular dysfunction. Dysfunctions of the special senses include  visual, auditory, olfactory, and gustatory (taste) dysfunction.  Pain is a unique sensory experience that, although universally  described as unpleasant, is nonetheless essential to our survival.  Pain provides protection by signaling the presence of disease  or injury. Unlike pain, which need not be a part of everyday  life, temperature is carefully monitored and regulated within  clearly defined normal limits. Like pain, however, variations in    Sleep, 502  Non-Rapid Eye Movement (NREM) Sleep, 502  Rapid Eye Movement Sleep, 503  PEDIATRICS and Sleep Patterns, 503  AGING and Sleep Patterns, 504  Sleep Disorders, 504  Sleep Disorders Associated with Mental, Neurologic, or  Medical Disorders, 505  Somatosensory Function and the Special Senses, 506  Touch, 506  Proprioception, 506  Vision, 507  AGING and Vision, 509  Hearing, 514  AGING and Hearing, 515  Olfaction and Taste, 517  AGING and Olfaction and Taste, 518    temperature can signal disease. Fever is a common manifesta-  tion of dysfunction and is often the first symptom observed in  an infectious or inflammatory condition.   Sleep is a normal, cyclic process that restores the body’s energy  and maintains normal functioning. Sleep is so essential to physi-  ologic and psychologic function that sleep deprivation causes a  wide range of clinical manifestations. Prolonged deprivation or  disruption of sleep ultimately leads to serious dysfunction.   The special senses of vision, hearing, touch, smell, and taste  are the means by which individuals perceive stimuli that are  essential for interacting with the environment. Special sensory  receptors are connected to specific areas of the brain through    the afferent pathways of the peripheral and central nervous sys-  tem (CNS). Each of the special senses thus involves a connected  system of organs and tissues that receives stimuli and sends sen-  sory messages to areas of the CNS, where they are processed and  guide behavior.    Pain is one of the body’s most important adaptive and protective  mechanisms and all definitions suggest it is a complex phenom-  enon and cannot be characterized as only a response to injury. A  widely accepted definition of pain is that drafted by the Interna-  tional Association for the Study of Pain (IASP) and accepted by  the American Pain Society and the World Health Organization:  “Pain is an unpleasant sensory and emotional experience associ-  ated with actual or potential tissue damage or described in terms  of such damage.”’ Waddell defines pain as “...a symptom, not  a clinical sign, diagnosis or disease....”* A clear understanding  of the complexities of the pain experience—specifically one that  encompasses an individual’s emotions, cognition, motivation,  prior history, and even issues of secondary gain—is needed to  manage pain and to further understand the pain processes. “The  inability to communicate verbally does not negate the possibility  that an individual is experiencing pain and is in need of appro-  priate pain-relieving treatment. Pain is always subjective.”    The theories of pain include the specificity theory, pattern the-  ory, gate control theory, and neuromatrix theory.   Specificity theory proposes that injury activates specific pain  receptors and fibers that project to the brain. Intensity of pain is  directly related to the amount of associated tissue injury (ie.,  pricking one’s finger with a needle would cause minimal pain,  whereas cutting one’s hand with a knife would produce more  pain). The theory is useful when applied to specific injuries and  the acute pain associated with them. It does not account for  chronic pain or cognitive and emotional elements that contrib-  ute to more complex types of pain.°   Pattern theory describes the role of impulse intensity and  the repatterning of the central nervous system (CNS). The pat-  tern theory is limited because it does not account for all types of  pain experiences.*°   Gate control theory (GCT) integrates and builds upon fea-  tures of the other theories to explain the complex multidimen-  sional aspects of pain perception and pain modulation.’ Pain  transmission is modulated by a balance of impulses conducted  to the spinal cord where cells in the substantia gelatinosa func-  tion as a “gate.” The spinal gate regulates pain transmission to  higher centers in the CNS. Large myelinated A-delta fibers and  small unmyelinated C fibers respond to a broad range of painful  stimuli (mechanical, thermal, and chemical). These fibers ter-  minate on interneurons in the substantia gelatinosa (laminae in  the dorsal horn of the spinal cord). Nociceptive transmissions  on these fibers “open” the spinal gate and increase the percep-  tion of pain. Closure or partial closure of the spinal gates can  occur from non-nociceptive stimulation (i.e., from touch sen-  sors in the skin). These signals are carried on non-nociceptive    larger A-beta fibers and decrease pain perception. This is why  rubbing a painful area may alleviate some of the discomfort.  Other efferent CNS pathways descend to the spinal cord and  may close, partially close, or open the gate modulating the pain  experience. The gate control theory, bolstered by progress in  understanding neuronal pathways in the peripheral and central  nervous systems, has greatly advanced our understanding of  pain. As good as the GCT has been, however, there are observa-  tions about pain in paraplegics that “do not fit the theory.”  Neuromatrix theory proposes that the brain produces pat-  terns of nerve impulses drawn from various inputs, including  genetic, psychologic, and cognitive experiences.° The qualities  we normally feel from the body, including pain, also can be felt  in the absence of inputs from the body (as noted with phan-  tom limb pain). In other words, stimuli may trigger the patterns  but do not produce them. Neuromatrix patterns are normally  activated by sensory inputs from the periphery, but may origi-  nate independently in the brain with no external input.’ The  neuromatrix theory illustrates the plasticity (adaptable change  in structure and function) of the brain. It does not supplant  our understanding of the gate theory, and what we have learned  about peripheral inflammation, spinal modulation, and mid-  brain descending control of pain. The neuromatrix theory  expounds upon the gate control theory by explicating a body-  self that provides a holistic, integrated, dynamic consideration  of pain. However, there are many different kinds of pain and  no single theory is adequate to explain the complex dynamics  of the pain experience. Continuing research is advancing our  understanding of the neural mechanisms of pain.*?    The integrated function of three portions of the nervous system  is responsible for the sensation and perception of pain:   1. The afferent pathways, which begin in the peripheral ner-  vous system (PNS), travel to the spinal gate in the dorsal  horn and then ascend to higher centers in the central ner-  vous system (CNS).   2. The interpretive centers located in the brainstem, mid-  brain, diencephalon, and cerebral cortex.   3. The efferent pathways that descend from the CNS to the  dorsal horn of the spinal cord modulate pain.   The processing of potentially harmful (noxious) stimuli  through a normally functioning nervous system is called noci-  ception. Nociception involves four phases: transduction, trans-  mission, perception and modulation.   Pain transduction begins when tissue is damaged by expo-  sure to chemical, mechanical, or thermal noxious stimuli and  is converted to electrophysiological activity. This causes activa-  tion of nociceptors,    Nociceptors are free nerve endings in the afferent peripheral  nervous system that selectively respond to different chemi-  cal, mechanical, and thermal stimuli. Nociceptors are located  throughout the body (Table 16-1) but are not evenly distributed  so the relative sensitivity to pain differs according to their location.  The variable nature and distribution of nociceptors affects relative    sensitivity to pain in different areas of the body. For example, fin-  gertips have more nociceptors than the skin of the back, and all  skin has many more nociceptors than the internal organs. Unlike  sensory neurons of the special senses of vision, gustation, and  olfaction (discussed later), which are required to detect only one  type of sensory stimulus (e.g., light for the sense of vision), pri-  marty nociceptive afferents have the remarkable ability to detect a   Engorged or inflamed mucosa, distention or  spasm of smooth muscle, traction on mesenteric  attachment   Ischemia, injuries of connective tissue sheaths,  necrosis, hemorrhage, prolonged contraction,  injection of irritating solutions   Traction, inflammation, or displacement of arteries,  meningeal structures, and sinuses; prolonged  muscle contraction    wide range of stimuli. To do this, nociceptors are equipped with  an array of transduction channels that can sense different forms  of noxious stimulation and at different intensities. In addition  to the previously well studied voltage-gated potassium, sodium,  and calcium channels, there are multiple types of transmembrane  receptors (called transient receptor potential [TRP] channels),  which reside on “naked nerve endings” and respond to a variety  of physical, chemical, and thermal stimuli.!°   Nociceptors (primary order neurons) are categorized accord-  ing to the stimulus to which they respond and by the properties  of the axons associated with them. A-delta (AS) fibers are lightly  myelinated, medium-sized fibers that are stimulated by severe  mechanical deformation (mechanonociceptors) or by mechani-  cal deformation and/or extremes of temperature (mechanother-  mal nociceptors). Ad fibers rapidly transmit sharp, well-localized  “fast” pain sensations. These fibers are responsible for causing  reflex withdrawal of the affected body part from the stimulus  before a pain sensation is perceived. The smaller unmyelinated  C fibers are polymodal and are stimulated by mechanical, ther-  mal, and chemical nociceptors. The unmyelinated C fibers slowly  transmit dull, aching, or burning sensations that are poorly local-  ized and longer lasting. A-beta (AB) fibers are large myelinated  fibers that transmit touch and vibration sensations. They do not  normally transmit pain but play a role in pain modulation."   Pain transmission is the conduction of pain impulses along  the Aé and C fibers into the dorsal horn of the spinal cord and  to the brainstem, thalamus, and cortex (Figure 16-1).    FIGURE 16-1 Pain Fibers That Terminate Primarily in Laminae II and V of the Dorsal Horn. The myelinated Aé fibers  (fast localized pain) synapse on a second set of neurons that carry the signal to the thalamus via the neospinothalamic tracts.  The C fibers (slow pain) synapse on laminae II and V interneurons that connect with neurons in laminae II, IV, and V and carry  the pain signal to the reticular formation and midbrain via the paleospinothalamic tract. The axons of the spinothalamic tracts  cross over the spinal cord to ascend in the anterior and lateral spinal cord white matter.   The cell bodies of primary-order neurons or pain-transmitting  neurons reside in the dorsal root ganglia just lateral to the spine  along the sensory pathways that penetrate the posterior part of  the cord. Once the axons of the Aé and C fibers enter the cord  they synapse with interneurons (second-order neurons) that may  branch into ascending or descending collaterals for one or two  cord segments in neuronal projections called the dorsolateral  tract. Eventually all of the primary afferents terminate on inter-  neurons in the marginal layer (laminae I) or substantia gelati-  nosa (laminae II) of the spinal cord (Figure 16-2).   Two classes of interneurons or second-order neurons are  found in the dorsal horn: (1) excitatory interneurons, which relay  nociceptive transmissions to projection cells, to other interneu-  rons, or to motor cells concerned with local reflexes such as the  pain withdrawal reflex; and (2) inhibitory interneurons, which  modulate nociceptive transmission. The synaptic connections  between cells of primary and second-order neurons located in  the substantia gelatinosa and other spinal laminae function as  a “pain gate.” The “gate” in the spinal cord regulates the trans-  mission of pain impulses that ascend to the brain for further  processing and interpretation (see gate control theory, p. 485).   From the dorsal horn, nociception continues on the axons  of projection neurons as they cross the midline of the cord and  ascend to various areas of the brain. These ascending fibers are    Spinal cord  FIGURE 16-2 Nociception Pathways. Aé and C fibers comprise the primary,  first-order sensory afferents coming into the gate at the dorsal horn of the spinal  cord. Second-order neurons cross the cord (“decussate”) and ascend to the thala-  mus as part of the spinothalamic tract. Third-order afferents project to higher brain  centers of the limbic system, the frontal cortex, and the primary sensory cortex of  the postcentral gyrus of the parietal lobe.    organized into tracts or funiculi that are found in the white  matter of the spinal cord, and are named according to their  location in the cord and to where they project—either to the  higher cord and brainstem or to the diencephalon (thalamus  and hypothalamus) and limbic structures. Most nociceptive  information travels by means of ascending columns in the lat-  eral spinothalamic tract (also called the anterolateral funiculus)  (Figure 16-3).   Although the organization of all of the ascending tracts is  complex, the principal target for nociceptive afferents is the  thalamus (the major relay station of sensory information in  general). Several other spinal cord projection systems convey  nociceptive information directly or indirectly to the reticular  formation of the brainstem and the periaqueductal gray (PAG)  matter of the midbrain.   From the thalamus, brainstem, and midbrain, third-order  neurons project to portions of the CNS and cortex involved in  the processing and interpretation of pain and neuroendocrine  responses (e.g., the response to fright or to surgical stress).!*  The extensive cortical networks that detect and react to pain are  referred to as the “pain matrix.” '*!   Pain perception is the conscious awareness of pain. Inter-  pretation of pain is influenced by many factors including cul-  tural preferences, male and female roles, and life experience,  including past pain experiences and current expectations. Three  systems interact to produce the perception of pain and indi-  vidual responses to pain. The sensory-discriminative system  is mediated by the somatosensory cortex and is responsible  for identifying the presence, character, location, and intensity  of pain. The affective-motivational system determines an  individual’s conditioned avoidance behaviors and emotional  responses to pain. It is mediated through the reticular forma-  tion, limbic system, and brainstem with projections to the pre-  frontal cortex. The cognitive-evaluative system overlies the  individual’s learned behavior concerning the experience of pain  and can modulate perception of pain. It is mediated through  the cerebral cortex.    Pain modulation is the physiologic process of suppressing  or facilitating pain. Pain modulation involves many differ-  ent mechanisms that increase or decrease the transmission of  pain signals throughout the nervous system. Depending on the  mechanism, modulation can occur before, during, or after pain  is perceived.'>    Several mechanisms modulate pain both at the level of the spi-  nal cord and in the brain (Figure 16-4). Segmental inhibition  of pain occurs when Af fibers (which synapse in the dorsal  horn along with their nociceptive Ad and C fiber counterparts)  close the pain gates through an inhibitory interneuron. These  afferent AB fibers carry non-noxious low-threshold mechani-  cal information gained by touch, vibration, and pressure. For  example, hitting your thumb with a hammer and holding the  thumb or putting it into your mouth provides distractive input  that lessens the pain.    Medulla  Spinal nucleus  Spinothalamic of cranial nerve V  aa Neuron in dorsal    FIGURE 16-3 Central Nervous System Pathways That Mediate the Sensations of Pain and Temperature. VPL,  Ventral posterior lateral thalamic nuclei; VPM, ventral posterior medial thalamic nuclei.    FIGURE 16-4 Diagram Representing the Central Mechanisms of Pain  Modulation. A noxious peripheral stimulus activates both segmental and top-  down (corticofugal and bulbospinal heterosegmental) modulatory mechanisms,  which either accentuate or inhibit afferent pain transmission to the brain. The most  important and widespread source of top-down (corticofugal) modulation arises  from the cortex. Both thalamic and prethalamic nociceptive relays are under the  influence of this top-down control. The dorsal horn of the spine is also under the  influence of the caudal medulla through diffuse noxious inhibitory control (DNIC).  (Modified from Villanueva L, Fields HL: The pain system in normal and pathological  states: a primer for clinicians, Seattle, 2004, IASP Press.)    Descending modulation of pain arises from many brain areas.  Powerful heterosegmental control of nociception probably origi-  nates from the cortex because almost all nociceptive relays within  the CNS are under so-called top-down (corticofugal) modulation  that often occurs even in the absence of painful stimuli.'°   Diffuse noxious inhibitory controls (DNICs) are spinal-  medullary-spinal pathways that are activated when peripheral  pain stimulation remote from the pain site relieves pain (counter-  irritation). It may be the basis for pain relief with acupuncture  or deep massage. Several ascending and descending bulbospinal  pathways (between the medulla and spinal cord) respond simul-  taneously to the noxious stimulus and participate in DNICs.!”   Expectancy-related cortical activation can exert control over  analgesic systems of the brainstem to attenuate or intensify pain.  In other words, cognitive expectations (also known as the placebo  effect or nocebo [adverse] effect) can cause real, measurable, often  powerful physiologic effects that share some of the same descend-  ing corticofugal pathways as the pain modulation systems.!*!”   The entire complex of modulatory pathways represents an  integration of peripheral sensory axon terminals, spinal inter-  neurons, and top-down control pathways that converge on the  spinal dorsal horns. The result is to modify, dampen, or aug-  ment nociceptive transmission, depending on the many factors  existing both within and without the organism.””    Inhibitory Transmitters  Gamma-aminobutyric acid (GABA)  Glycine  Descending pain modulators  Norepinephrine—a.,-receptors  Serotonin (5-hydroxytryptamine)  Opioids (u, 5, « receptors)  Endorphins ) Released from  Enkephalins PAG and NRM  Dynorphins and other areas  of the brain    AMPA, a-Amino-3-hydroxy-5-methyl-4-isoxazole-propionate; ATP adeno-  sine triphosphate; NMDA, N-methyl-b-aspartate; NAM, nucleus raphes  magnus; PAG, periaqueductal gray.    A wide variety of biogenic amines and other neurotransmitters  act to modulate control over the transmission of pain impulses  in the periphery, spinal cord, and brain. Pain neurotransmit-  ters can be classified as inflammatory, pain excitatory, or pain  inhibitory (Box 16-1). In the periphery, local injury and inflam-  mation can result in direct or indirect excitation or inhibition  of nociceptors.   Direct excitation occurs when nociceptors respond with a  threshold depolarization initiated by the application of heat,  radiation, toxic chemicals, or tissue trauma. Indirect excita-  tion occurs when tissue injury results in inflammation and the  release of inflammatory mediators including prostaglandins  (PGE, and PGI,), tumor necrosis factor-alpha (TNF-a), nitric  oxide, bradykinins, histamine, and other cytokines (see Chapter  7). Activity within the nociceptors or damage to them causes  them to release peptides and neurotransmitters, such as tachy-  kinins (e.g., substance P and neurokinins), calcitonin gene—  related peptide (CGRP), and adenosine triphosphate (ATP),  which promote the spread of pain locally and further contribute  to vasodilation, increased vascular permeability, and degranu-  lation of even more mast cell cytokines. The resultant “inflam-  matory soup” serves to lower the threshold for nociceptive  depolarization and increases the magnitude of the response to  noxious stimulation, known as hyperalgesia. The consequence  of some or all of these mechanisms is known as peripheral  sensitization. Normally peripheral sensitization phenomena  extinguish themselves as the tissue heals and inflammation sub-  sides. However, when primary afferent function is altered in an  enduring way by injury or disease, hyperalgesia may persist and  cause chronic pain.    FIGURE 16-5 Descending Pathway and Endorphin Response. The biologic receptors of the enkephalins and endor-  phins are located close to known pain receptors in the periphery and ascending and descending pain pathways.    Excitatory Neurotransmitters. Glutamate is the most  common excitatory neurotransmitter in the brain and spinal  cord. Glutamate activates two different kinds of receptors:  AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionate)  receptors, which are very fast, and NMDA (N-methyl-p-  aspartate) receptors, which are implicated in memory and  long-term potentiation of synapses. Both of these receptors  lead to nerve membrane excitation and depolarization of the  cell. Glutamate receptors mediate many spinal and central  responses to painful stimulation.*! High levels of glutamate  and aspartate have been found in the periaqueductal gray  (PAG) as well as at the synapses of first-order nociceptors with  ascending spinothalamic tract neurons. Repeated stimulation  of nociceptive afferents results in an activity-dependent  increase in the excitability of neurons in the dorsal horn of the  cord. Glutamate, which accumulates in the dorsal horn, results  in the displacement of a magnesium ion that serves to inhibit  the NMDA receptor. With the loss of the blocking magnesium  ion, receptor “wind-up” or sensitization in the CNS to further  nociception becomes evident. This is known as central  sensitization (increased excitability of neurons). Although  central sensitization is triggered in dorsal horn neurons by  activity in peripheral nociceptors, innocuous activation of  fibers carrying low-threshold mechanoreception (light touch)  will activate second-order nociceptive neurons, giving rise  to allodynia (the induction of pain by normally nonpainful  stimuli) and hypersensitivity. Changes in microglia, astrocytes,  gap junctions, membrane excitability, and gene transcription  also contribute to central sensitization.** Thus both peripheral  and central sensitization can lead to chronic pain syndromes.    Inhibitory Neurotransmitters. Gamma-aminobutyric acid  (GABA) and glycine have major inhibitory effects in the spinal  cord and brain.”* For example, dorsal horn laminae interneurons  are rich in GABA (GABA-A, GABA-B, etc.) and function to  inhibit release of pain neurotransmitters. Loss of GABAnergic  interneurons in the dorsal horn after nerve injury may cause loss  of pain inhibition, resulting in chronic pain.” Glycine receptors  inhibit pain and also have anti-inflammatory, cytoprotective,  and immune modulating effects. Norepinephrine and  5-hydroxytryptamine (serotonin) contribute to pain modulation  (inhibition) in the medulla and pons.   Endogenous opioids are a family of morphine-like neuropep-  tides that inhibit transmission of pain impulses in the spinal cord,  brain, and periphery. Their receptors also play a role in various  central nervous system, gastrointestinal system, immune system,  and other organ system disorders.” There are four types of opioid  neuropeptides: (1) enkephalins, (2) endorphins, (3) dynorphins,  and (4) endomorphins. These substances are neurohormones that  act as neurotransmitters by binding to one or more G-protein—  coupled opioid receptors. Three distinct types of opioid receptors  are found in the body: mu (y) meaning morphine (with subtypes  , and py), kappa (k) (with subtypes k, and k,), and delta (8). A  fourth receptor is nociceptin-opioid peptide (NOP) receptor. Its  ligand is nociceptin and it is homologous to dynorphin.   Each receptor type binds differently with the various types of  opioids. Agonist activity at the opioid receptors by endogenous  opioids inhibits the release of excitatory neurotransmitters such  as substance P in the dorsal horn (blocking the transmission of the  painful stimulus) or in other areas of the brain such as the PAG  or the rostral ventromedial nuclei in the brainstem (Figure 16-5).    Opioids from the midbrain release adrenergic and serotonergic  descending pathways from GABAnergic inhibition and decrease  pain. Leukocytes release opioids and participate in peripheral  pain control. Because leukocyte opioids do not cross the blood-  brain barrier, they do not have central nervous system side effects  such as respiratory depression, somnolence, or addiction.”°   Perhaps the best known and the most prevalent of these  natural opioids are the enkephalins. There are two types of  enkephalins: methionine-enkephalin (Met-enkephalin) and leucine-  enkephalin (Leu-enkephalin), and their ratio is 4:1, respectively.  They were the first endogenous opioids extracted in research.  Enkephalins, like the other endogenous opioids, can be identi-  fied immunohistochemically. They are found concentrated in  the hypothalamus, the PAG matter, the nucleus raphe magnus  of the medulla, and the dorsal horns of the spinal cord.   Endorphins were first discovered in the human PAG with  B-endorphin being the best studied of the group. The synthe-  sis and activity of B-endorphin are concentrated in the hypo-  thalamus and the pituitary gland. B-Endorphin is purported to  produce a greater sense of exhilaration, or “high,” than all of  the other endorphin types. It is a strong p-receptor agonist and  is generally believed to provide substantial natural pain relief.   Dynorphins (the most potent of these endogenous neu-  rohormones) are found in the hypothalamus, the brainstem,  the PAG-rostral ventromedial medulla (PAG-RVM) system,  and the spinal cord. Dynorphins and nociceptin, which bind  strongly to k-receptors located in the dorsal horn of the spinal  cord and in areas of the brain, generally serve to impede pain  signals but can, in certain circumstances, incite pain through  mechanisms of up-regulation.’”   Endomorphins have potent analgesic, gastrointestinal  (GI), and anti-inflammatory effects. Endomorphin-1 and  endomorphin-2 are peptides isolated from the brain and the  spinal cord and show the highest affinity and selectivity for the  H-opiate receptor.?®?   In addition to analgesic effects, endogenous opioids are  involved in a variety of other functions throughout the body  including modulation of stress and anxiety, feeding behavior,  cough suppression, immune and inflammatory responses, and  alcohol intake.*” Endogenous opioids of one type or another are  found to bind to almost all tissues in the body and thus affect  numerous biologic functions.”    Pain threshold is the point at which a stimulus is perceived as  pain and it does not vary significantly among people or in the  same person over time. Intense pain at one location, however,  may cause an increase in the threshold in another location. For  example, a person with severe pain in one knee is less likely to  experience chronic back pain that is less intense. This phenom-  enon is called perceptual dominance. Because of perceptual  dominance, pain at one site may mask other painful areas.*!  Pain tolerance is the duration of time or the intensity of  pain that an individual will endure before initiating overt pain  responses and is generally decreased with repeated exposure  to pain. Pain tolerance is influenced by the person’s cultural  perceptions, expectations, role behaviors, physical and mental    I. Neurophysiologic pain  A. Nociceptive pain  1. Somatic  2. Visceral  3. Referred  B. Neuropathic (non-nociceptive)  1. Central pain (lesion/dysfunction in brain or spinal cord)  2. Peripheral pain (lesion/dysfunction in peripheral nervous system  [PNS})   . Neurogenic pain  A. Neuralgia (pain in the distribution of a nerve)  B. Constant    Adapted from Derasari MD: Taxonomy of pain syndromes: classifica-  tion of chronic pain syndromes. In Raj PP, editor: Practical manage-  ment of pain, ed 3, St Louis, 2000, Mosby.    health, gender, fatigue, anger, boredom, apprehension, and  sleep deprivation. Tolerance may be increased by alcohol con-  sumption, persistent use of pain medication, hypnosis, warmth,  distracting activities, and strong beliefs or faith.°?   Pain can be described in a variety of ways, including duration  (acute vs. chronic), inferred neurophysiologic mechanisms  (nociceptive vs. non-nociceptive [i.e., neuropathic]), etiology,  and region affected. Because of the complex nature of pain,  however, many terms overlap and more than one approach is  often used. The broad categories of pain are summarized in Box  16-2. Some of the most common clinical pain presentations are  summarized in the following sections.    Acute pain is a protective mechanism that alerts the individual  to a condition or experience that is immediately harmful to  the body and mobilizes the individual to take prompt action  to relieve it. Acute pain is transient, usually lasting seconds to  days, and sometimes up to 3 months.*? It begins suddenly and is    relieved after the chemical mediators that stimulate pain recep-  tors are removed. Stimulation of the autonomic nervous system  results in physical manifestations including increased heart rate,  hypertension, diaphoresis, and dilated pupils. Anxiety related  to the pain experience, including its cause, treatment, and prog-  nosis, is common and there is expectation of limited duration.   Acute pain arises from cutaneous and deep somatic tissue, or  from visceral organs and can be classified as (1) acute somatic,  (2) acute visceral, and (3) referred.   Somatic pain is superficial, arising from connective tissue,  muscle or bone, and skin. It is either sharp and well local-  ized (especially fast pain carried by Aé fibers) or dull, aching,  throbbing, and poorly localized as seen in polymodal C fiber  transmissions.   Visceral pain refers to pain in internal organs and the lin-  ing of body cavities with an aching, gnawing, throbbing, or  intermittent cramping quality. It is transmitted by sympathetic  afferents and is poorly localized because of the lesser number  of nociceptors in the visceral structures. Visceral pain is associ-  ated with nausea and vomiting, hypotension, restlessness, and,  in some cases, shock. It often radiates (spreads away from the  actual site of the pain) or is referred.   Referred pain is pain that is felt in an area removed or dis-  tant from its point of origin—the area of referred pain is sup-  plied by the same spinal segment as the actual site of pain.  Impulses from many cutaneous and visceral neurons converge  on the same ascending neuron, and the brain cannot distin-  guish between the two. Because the skin has more receptors, the  painful sensation is experienced at the referred site instead of  the site of origin. Referred pain can be acute or chronic. Figure  16-6 illustrates common areas of referred pain and their associ-  ated sites of origin.    Chronic pain is usually defined as lasting at least 3 months and  lasting well beyond the expected healing time following the ini-  tial onset of tissue damage or injury. Chronic or persistent pain  serves no purpose and is poorly understood. It often appears  to be out of proportion to any observable tissue injury. It may    be ongoing (e.g., low back pain) or intermittent (e.g., migraine  headaches). Changes in the peripheral and central nervous sys-  tems that cause dysregulation of nociception and pain modula-  tion processes (peripheral and central sensitization) are thought  to lead to chronic pain.   The following mechanisms have been implicated in the ini-  tiation and entrenchment of chronic pain states**°>:   + Alterations in the dorsal root ganglion in response to periph-   Neuroimaging studies have demonstrated brain changes in  individuals with chronic pain that may lead to cognitive defi-  cits and decreased ability to cope with pain.*°*” It is thought  to be due, in part, to the stress of coping with continuous pain  and may be reversible when pain is controlled.***? Chronic pain  often does not respond to usual therapy. Because it is not yet  possible to predict when acute pain will develop into chronic  pain, early and individualized prevention and treatment of  acute pain is encouraged.*°4!   Physiologic responses to intermittent chronic pain are simi-  lar to those associated with acute pain, whereas persistent pain  allows for physiologic adaptation, producing normal heart rate  and blood pressure. This leads many to mistakenly conclude  that people with chronic pain are malingering because they do  not appear to be in pain. As chronic pain progresses, certain  behavioral and psychologic changes often emerge, including  depression, difficulty eating and sleeping, preoccupation with  the pain, and avoidance of pain-provoking stimuli.” The desire  to relieve pain and the need to hide it become conflicting drives  for those with chronic pain, who fear being labeled complain-  ers.*>* Comparison of acute and chronic pain is summarized  in Tablel6-2. Common chronic pain conditions are listed in  Table 16-3.   Chronic Pain Syndromes. Specific (i.e., intervertebral disk  degeneration) and non-specific low back pain (not attributable  to a specific pathologic source) are global, common, chronic,  and disabling pain conditions. The prevalence of non-specific  low back pain is about 23% with 11% to 12% of those affected  being disabled.***° Prevalence estimates and definition of risk  factors vary among studies depending on the definition of low  back pain used. Acute back pain is relatively rare and many  individuals of all ages have chronic recurrent back pain. Both  cortical and spinal alterations in pain processing are associated  with low back pain. Treatment is often ineffective and the  personal and societal burden is great.447   Myofascial pain syndrome (MPS) is associated with injury  to muscle, fascia, and tendons and includes myositis, fibrosi-  tis, myofibrositis, myalgia (see Chapter 44 for fibromyalgia),    TABLE 16-2 COMPARISON OF ACUTE AND CHRONIC PAIN  CHARACTERISTIC ACUTE PAIN CHRONIC PAIN   Pain identification Painful and nonpainful areas less easily differentiated: change in  sensations becomes more difficult to evaluate    Increased pulse rate, elevated blood pressure, increased  respiratory rate, diaphoresis, dilated pupils   Continuous or intermittent; intensity may vary or remain constant  Suffering usually increases over time   Results from poor muscle tone, inactivity, muscle strain, or sudden, vigorous exercise   Examples include myositis, fibrositis, myofibrositis, myalgia, and muscle strain—conditions that involve injury to the muscle  and fascia   Chronic pain that can occur with disruption or cutting of sensory nerves   Can be pain attributed to advance of disease, associated with treatment, or attributed to coexisting disease entities   Common types include severe burning pain triggered by various stimuli, such as cold, light touch, or sound, and reflex  sympathetic dystrophies (occur after peripheral nerve injury and are characterized by continuous, severe, burning pain  associated with vasomotor changes and muscle wasting)   Increased sensitivity and decreased pain threshold to tactile and painful stimuli   Pain is diffuse, modified by fatigue and emotion, and mixed with other sensations   Loss of ability to identify source of pain on one side of the body   Painful stimuli on that side produce discomfort, anxiety, moaning, agitation, and distress but no attempt to withdraw from  the stimulus   Pain experienced in amputated limb after stump has completely healed; may be immediate or occur months later   Trigger points—small hypersensitive regions in muscle or connective tissues that, when stimulated, produce pain in a  specific area    and muscle strain. These conditions involve myofascial trigger  points within a taut band of skeletal muscle. The pain may be  the result of low-threshold mechanosensitive afferents project-  ing to sensitized dorsal horn neurons and the development of  peripheral and central sensitization.*? Neuroaxonal degenera-  tion with alterations in neuromuscular transmission may occur.  Compression of the trigger point causes referred pain, motor  dysfunction, and autonomic responses. During the early stages  of the disorder the pain is localized, but as the disorder pro-  gresses it becomes deep, aching, and more generalized. These,  like many other chronic conditions, begin as a result of poor    muscle tone, inactivity, muscle or tendon strain, or sudden vig-  orous exercise and can evolve into a chronic pain state.   Chronic postoperative pain occurs in some individuals and  includes complex regional pain syndrome, phantom limb pain,  chronic donor site pain, post-thoracotomy pain syndrome,  postmastectomy pain syndrome, and joint arthroplasty pain.  Plastic changes in the peripheral nervous system (PNS) and  CNS contribute to allodynia and hypersensitivity. Multimodal  approaches to analgesia are needed for pain management  including adequate management of preoperative pain and post-  operative management of acute pain.*!°°    Cancer pain is often chronic and associated with neuropa-  thies. The categories include*!: (1) pain attributed to tumor  growth and advance of the disease, (2) pain associated with  treatment of the disease, and (3) pain attributed to coexisting  entities (e.g., osteoarthritis) that are unrelated to the disease.  Cancer and immune cells can release mediators that sensitize  primary afferent nociceptors in the area of the tumor. Infec-  tion and inflammation, increasing pressure of a growing tumor  on nerve endings, tissue destruction, distention of visceral sur-  faces, and obstruction of ducts and intestine also cause pain.”  Alterations in the dorsal horn and other central pain process-  ing pathways lead to central sensitization and chronic pain.°?  Therapeutic approaches to the management of cancer pain have  advanced significantly in recent years, particularly in palliative  care and hospice programs. Frequent assessment of pain, man-  agement of breakthrough pain, and implementation of indi-  vidualized interdisciplinary therapeutic strategies (including  pharmacotherapeutic, anesthetic, neurosurgical, psychologic,  and rehabilitative techniques along with frequent evaluations)  are essential to optimal cancer pain management.°?    Neuropathic pain results from primary injury to the peripheral  or central nervous system and is not the result of pain signaling  from peripheral tissues or organs. Chronic neuropathic pain  leads to long-term plastic changes along somatosensory path-  ways from the periphery to the cortex and abnormal processing  of sensory information by the PNS and CNS. The pathogenesis  of neuropathic pain syndromes includes both peripheral and  central mechanisms of pain sensitization.”   Peripheral neuropathic pain is caused by peripheral nerve  trauma, diabetic or alcohol abuse—induced neuropathy, carci-  noma, nutritional deficiencies, and human immunodeficiency  virus (HIV). When injured nerves become hyperexcitable, they  generate ectopic discharges, resulting in spontaneous firing of  some neurons with low thresholds for mechanical, chemical,  or thermal stimuli. Pain sensation can occur in the absence of  a stimulus and may be evoked by movement (incident pain),  and hypersensitivity and/or allodynia may be present in the  involved body part.   Central neuropathic pain is caused by a lesion or dys-  function in the CNS (brain or spinal cord). Alterations of  the sensory pathways and impairment of descending inhibi-  tory mechanisms contribute to the pain. Examples of central  causes of neuropathic pain include brain or spinal cord trauma,  tumors, vascular lesions, multiple sclerosis, Parkinson disease,  postherpetic neuralgia (PHN), phantom limb pain, and reflex  sympathetic dystrophy.   Neuropathic pain is often paroxysmal with hyperesthesia  and paresthesias (tingling sensations of pins and needles), burn-  ing, shooting, or stabbing sensations. Neuropathic pain is often  described as “gnawing” and miserable. No single diagnostic test  for neuropathic pain (or for pain in general) is available, and  differentiating some neuropathies from other chronic somatic  pain syndromes can be difficult.°>°°   Lesions resulting in loss of sensory input to the dorsal  column of the spinal cord from a part of the body are called    deafferentation. Deafferentation pain syndromes are neuropa-  thies that result from lesions in the peripheral nervous system  (i.e., complex regional pain syndrome type II, postherpetic neu-  ralgia, phantom limb pain, tumor infiltration of nerve tissue;  damage from radiation, chemotherapy, brachial plexus avul-  sion, or surgical sectioning of a nerve) or lesions in the central  nervous system that interrupt the spinothalamic pathways at  any level of the nervous system (1.e., thalamic lesions or stroke).  Deafferentation pain syndromes are associated with hyperex-  citability of the somatosensory thalamus and cortex.°’ Deaffer-  entation pain, which is poorly controlled by many analgesics,  is usually described as a constant, dull, viselike ache, accom-  panied by paroxysms of burning or electric shock-like sensa-  tions. There may be loss of temperature sensation. The pain  may manifest over a large and diffuse area or be well-defined  and circumscribed. It is usually irritating and constant, can be  difficult to treat, and can cause considerable suffering.°**?   Hemiagnosia pain is a form of central pain associated with  stroke that produces paralysis and hypersensitivity/allodynia  on one half of the body. In this painful condition, often a con-  comitant loss of ability to identify the source of pain through  normal sensory pathways occurs. The result is a confusing pre-  sentation in which even mild stimulation of the affected side of  the body produces discomfort, anxiety, moaning, agitation, and  distress, with a diminished ability to withdraw from the offend-  ing stimulus.   Phantom limb pain is pain that an individual feels in an  amputated limb after the stump has completely healed. Non-  painful phantom limb sensations occur in almost all amputees,  but the sensations usually fade with time. This is distinguished  from the syndrome of phantom limb pain, a chronic pain occur-  ring in 80% to 100% of amputees.°°! It is more likely to appear  in individuals who experienced pain in the limb before ampu-  tation. Theories about the cause of phantom limb pain include  regeneration or hyperactivity of injured or cut peripheral nerves,  scar tissue or neuroma formation in the cut peripheral nerves,  spinal cord deafferentation, and alterations in the thalamus and  cortex. It has been proposed that CNS integration, including  reorganization and plastic changes of the somatosensory cor-  tex, results in the perception of pain from receptors associated  with the amputated limb even though the limb itself is no lon-  ger present.®* The absence of inhibitory effects of sensory input  from the missing peripheral body part may cause increased  autonomous activity of dorsal horn neurons with pain trans-  mission. The cause is likely multifactorial, contributing to the  difficulty of prevention or effective treatment.   Sympathetically mediated pain (SMP) is another type  of neuropathic pain that can occur after peripheral nerve or  extremity injury. The diseases formerly called reflex sympathetic  dystrophy and causalgia, both thought to arise from sympathetic  nervous system imbalance, are now called complex regional  pain syndromes (CRPSs) type I (associated with injury but no  apparent nerve injury) and type II (evidence of nerve injury).  CRPS develops 1 to 2 weeks after an extremity injury (e.g., a  fracture without identifiable nerve injury) (type I) or an injury  to the brachial plexus or the median, sciatic, or other periph-  eral nerves (type II). The exact pathophysiologic mechanism is    unclear. A combination of injury and the presence of inflam-  matory cytokines and neuropeptides may lead to peripheral  nociceptive sensitization and physiologic change in pain trans-  mission and autonomic and motor systems.™ The severe, dif-  fuse, burning, and persistent pain occurs in the extremity or area  supplied by the injured nerve. Hypersensitivity and allodynia  are common. Discoloration and changes in the texture of the  skin may appear in the affected area. Vasomotor changes usu-  ally begin with vasodilation and are followed by vasoconstric-  tion and cool, cyanotic, and edematous extremities. Swelling  and stiffness of proximate joints may occur. Hair loss is usually  noted and there are changes in skin color and temperature.  In the evaluation and management of neuropathic pain, as  well as all other chronic pain states, psychologic components  (e.g., depression or anxiety), sleep disturbances, work-related  issues of impairment and disability, treatment expectations, the  availability of social support from family and friends (or lack  thereof), and legal compensation should not be overlooked.    Infants and children have the anatomic and functional ability to  perceive pain. Pain pathways and cortical and subcortical cen-  ters for pain perception, as well as neurochemicals associated  with pain transmission and modulation, are functional in pre-  term and newborn infants. The nociceptor system is functional  in fetuses by 20 to 24 weeks of gestation although the cortical  experience may be minimal.°”°* Repetitive, painful experiences  and prolonged exposure to analgesic drugs in infants, in chil-  dren, and during the neonatal period may permanently alter  synaptic and neuronal organization®’ and fetal pain may have  an enduring effect on behavior and pain perception.””7!   Facial expression, crying, body movements, and lack of con-  solability are the most consistent expressions of pain in infants.  The painful facial expression includes lowered brows drawn  together; presence of a vertical bulge and furrows in the fore-  head between the brows; broadened nasal root; tightly closed,  scourged eye fissures; and angular, tongue cupping, squarish  mouth and chin quiver (Figure 16-7). Physiologic responses  include increases in heart rate, blood pressure, and respiratory  rate although these measures lack sensitivity and specificity.  There may be flushing or pallor, sweating, and decreased oxy-  gen saturation.’* Toddlers also express pain with crying, facial  expression, and body language (tensed body, guarding, and  hands holding body). Older children, between ages 5 and  18 years, tend to have a lower pain threshold than do adults.  Children, like adults, have highly individual responses to pain.  Any behavioral and physiologic indicators of pain must be care-  fully and accurately assessed’? and adequately treated for chil-  dren of all ages.”*7°    Studies on pain perception in the older adult population have  yielded conflicting evidence. Some studies show an increase in  pain threshold with aging; others show no change.’°’® The var-  ied results are probably a function of independent variation in    FIGURE 16-7 Painful Facial Expression of Infants. (From Hockenberry MJ:  Wong's nursing care of infants and children, ed 7, St Louis, 2003, Mosby.)    the sensory-discriminative, motivational-affective, and cognitive-  evaluative components of the pain experience. In general,  studies confirm that an increase in the pain threshold occurs  in some older adults. This change may be caused by periph-  eral neuropathies and changes in the thickness of the skin or  cognitive impairment. (Neuropathies are discussed in Chapter  18.) A decrease in pain tolerance is also evident in some older  adults, and women appear to be more sensitive to pain than are  men/’®°° (see What’s New? Pain and Gender). Pain in the older  adult is also influenced by liver and renal function, including  alterations in metabolism of drugs and metabolites and age-  associated brain changes. Pain must be accurately assessed in  relation to its effect on cognitive function, coexisting disease,  drug interactions, other reactions to treatment, and an indi-  vidual’s ability to express pain and safety.*? Poorly managed  pain can result in depression, inactivity, and failure to maintain  activities of daily living.*!    In all homeothermic animals, temperature regulation is  achieved through precise balancing of heat production, heat  conservation, and heat loss. In humans, body temperature is  maintained around 37° C (98.6° F) and rarely exceeds 41° C  (105.8° F). The normal range is 36.2° to 37.7° C (97.2° to 99.9°  F), but all parts of the body do not have the same temperature.  The extremities, for example, are generally cooler than the  trunk. The temperature at the core of the body (as measured  by rectal temperature) is generally 0.5° C higher than the sur-  face temperature (as measured by oral temperature) and has  minimal fluctuations. The internal temperature varies normally  in response to activity, environmental temperature, and daily    Gender differences in the experience of pain and the response to analgesics  have been studied in both animal and human research. Women report higher  pain levels or have less tolerance for pain stimuli, such as heat, cold, pressure,  and electrical stimulation. The differences may be related to mechanisms of  excitatory and inhibitory control. Gender differences exist also in the preva-  lence of painful chronic diseases; for example, women are more affected by  intestinal cystitis, fibromyalgia, and rheumatoid arthritis, and men are more  affected by cluster headache. Pain symptoms differ for men and women for  diseases such as coronary artery disease, irritable bowel syndrome, appendi-  citis, and cancer. Sex hormones are known to have an effect on the mecha-  nisms and outcomes of opiate analgesia, and in rodents, morphine analgesia  is more effective in males than in females. Pain sensitivities in women also  vary across the phases of the menstrual cycle. Recent human and animal stud-  ies suggests that x-opioid receptor analgesia is greater in women than in men  and may reflect a difference in endogenous pain circuits mediated by different  opiate receptor subtypes and influenced by effects of estrogen and proges-  terone. Gender differences with respect to pain also are influenced by role  socialization, cognitive factors, and culture. Continuing research is needed to  further understand gender differences in the operation of pain mechanisms  and the development of more specific pain management strategies.    Data from Leresche L: Clin Orthop Relat Res 469(7):1871-1877, 2011;  Mogil JS, Bailey AL: Prog Brain Res 186:141-157, 2010; Palmeira   CC, Ashmawi HA, Posso Ide P: Rev Bras Anestesiol 61(6):814-828,  2011; Popescu A et al: Pain 150(2):309-318, 2010; Racine M et al: Pain  153(3):602-618, 2012; Racine M et al: Pain 153(3):619-635, 2012;  Rasakham K, Liu-Chen LY: Life Sci 88(1-2):2-16, 2011.    fluctuation of circadian rhythm (the pattern of each 24-hour  day). Oral temperatures generally fluctuate within 0.2° to 0.5°  C during a 24-hour period. Women tend to have wider fluc-  tuations that follow the menstrual cycle, with a sharp rise in  temperature just before ovulation. In both genders the daily  fluctuating temperature peaks around 6 pm and is at its low-  est during sleep.** Maintenance of body temperature within the  normal range is necessary for life.    Temperature regulation (thermoregulation) is mediated by  the hypothalamus. Peripheral thermoreceptors in the skin and  abdominal organs (unmyelinated C fibers and thinly myelinated  A6é fibers) and central thermoreceptors in the spinal cord and  other central locations provide the hypothalamus with infor-  mation about skin and core temperatures. If these temperatures  are low or high, the hypothalamus responds by triggering heat  production, heat conservation, or heat loss mechanisms. The  endocrine system also operates to control body temperature.**  Increased heat production is initiated by a series of hormonal  mechanisms involving the hypothalamus and its connections  with the endocrine system. The heat-producing mechanism  begins with a hypothalamic hormone, thyroid-stimulating  hormone-releasing hormone (TSH-RH). In turn, TSH-RH  stimulates the anterior pituitary to release TSH, which acts on  the thyroid gland, stimulating release of thyroxine (T,), one of  the thyroid hormones. This hormone then acts on the adrenal  medulla, causing the release of epinephrine (a catecholamine    and vasopressive hormone) into the bloodstream (see Chapter  21). Epinephrine causes vasoconstriction (improves thermal  insulation), stimulates glycolysis, and increases metabolic rates,  thus increasing heat production. Heat is distributed by the cir-  culatory system.   The hypothalamus also triggers heat conservation. The  mechanisms of heat conservation involve stimulating the sym-  pathetic nervous system, which is responsible for stimulating  the adrenal cortex, increasing skeletal muscle tone, initiating  the shivering response, and producing vasoconstriction. The  hypothalamus also functions in raising body temperatures by  relaying information to the cerebral cortex. Awareness of cold  provokes voluntary responses such as increasing body move-  ment and wearing protective clothing.   The hypothalamus responds to warmer core and peripheral  temperatures by reversing the same mechanisms. The TSH-RH  pathway is shut down. The sympathetic pathway is prompted  to produce cutaneous vasodilation, decreased muscle tone, and  increased sweat production. Hypothalamic stimulation of the  cerebral cortex provokes voluntary behavior to reduce heat pro-  duction and promote heat loss.*4   Mechanisms of heat production, heat loss, and heat conser-  vation maintain body temperature within a narrow range of 98°  F (36.6° C) and 100° F (37.7° C) when the ambient temperature  is between 68° F (20° C) and 130° F (54.4° C).    Chemical Reactions of Metabolism. The chemical reactions  that occur during the ingestion and metabolism of food and  those required to maintain the body at rest (basal metabolism)  require energy and produce heat. These processes occur in the  body core (primarily the liver) and are in part responsible for  the maintenance of core temperature.   Skeletal Muscle Contraction. Skeletal muscles produce heat  through two mechanisms: (1) gradual increase in muscle tone  and (2) production of rapid muscle oscillations (shivering—  which does not occur in neonates). Both increasing muscle tone  and shivering are controlled by the posterior hypothalamus and  occur in response to cold. As peripheral temperature drops,  muscle tone increases and shivering begins. Shivering is a fairly  effective method for increasing heat production because no  work is performed and all the energy produced is retained as  heat.®°   Chemical Thermogenesis. Chemical thermogenesis, also  called nonshivering thermogenesis or adrenergic thermogenesis,  results from the release of epinephrine and norepinephrine.  Epinephrine and norepinephrine produce a rapid, transient  increase in heat production by raising the body’s basal  metabolic rate. Chemical thermogenesis seems to be different  from hormone-triggered increases in the basal metabolic rate.  Chemical thermogenesis produces a quick, brief rise in basal  metabolic rate, whereas the hormone thyroxine triggers a slow,  prolonged rise. Chemical thermogenesis occurs in brown adipose  tissue. Brown adipose tissue is rich with mitochondria and  blood vessels and is essential for nonshivering thermogenesis.  White and brown adipocytes are found together in visceral  and subcutaneous tissue. White adipocytes store energy and    brown adipocytes produce heat. Adipocytes demonstrate  transdifferentiation and such plasticity allows direct conversion  of one cell type into the other. With chronic cold exposure  white-to-brown conversion increases thermogenesis, whereas  excessive food consumption induces brown-to-white conversion  to meet the need for energy storage.*°    Heat loss is achieved through many mechanisms: (1) radiation,  (2) conduction, (3) convection, (4) vasodilation, (5) decreased  muscle tone, (6) evaporation, (7) increased pulmonary venti-  lation, (8) voluntary measures, and (9) adaptation to warmer  climates.   Radiation. Radiation refers to heat loss through  electromagnetic waves. These waves emanate from surfaces  with temperatures higher than the surrounding air temperature.  Thus if the temperature of the skin is higher than that of the air,  the skin and therefore the body lose heat to the air.   Conduction. Conduction refers to heat loss by direct  molecule-to-molecule transfer from one surface to another.  Through conduction, the warmer surface loses heat to the  cooler surface. Thus the skin loses heat through direct contact  with cooler air, water, or another surface. In the same manner,  the core of the body loses heat to the cooler body surface.   Convection. Convection is the transfer of heat through  currents of gases or liquids. It greatly aids heat loss through  conduction by exchanging warmer air at the surface of the body  with cooler air in the surrounding space. Convection occurs  passively as warmer air at the surface of the body rises away  from the body and is replaced by cooler air, but the process may  be aided by fans or wind. (The combined effect of conduction  and convection by wind is conventionally measured as the  windchill factor.)   Vasodilation. Peripheral vasodilation increases heat loss  by diverting core-warmed blood to the surface of the body.  As the core-warmed blood passes through the periphery, heat  is transferred by conduction to the skin surface and from  the skin to the surrounding environment. Because heat loss  through conduction depends on the surrounding temperature,  it is minimal to nonexistent if the surrounding air or water is  warmer than the body surface.   Vasodilation occurs in response to autonomic stimula-  tion under the control of the hypothalamus. It is useful in  instances of moderate temperature elevation. As core tempera-  ture increases, vasodilation increases until maximal dilation is  achieved. At that point the body must use additional heat loss  mechanisms.   Decreased Muscle Tone. To decrease heat production,  muscle tone may be moderately reduced and voluntary muscle  activity curtailed. These mechanisms explain in part the  “washed-out” feeling associated with high temperatures and  warm weather. Decreased muscle tone and reduced activity  have a limited effect on decreasing heat production, however,  because muscle tone and heat production cannot be reduced  below basal body requirements.   Evaporation. Evaporation of body water from the surface of  the skin and the linings of the mucous membranes is a major    source of heat reduction. Insensible water loss (in the absence  of perceptible sweating) accounts for a loss of about 600 ml of  water per day. Heat is lost as surface fluid is converted to gas,  so that heat loss by evaporation is increased if more fluids are  available at the body surface. To speed this process, fluids are  actively secreted through the sweat glands. As much as 2.2 L of  fluid per hour may be lost by sweating. Electrolytes are lost with  the water. Therefore, loss of large volumes through sweating  may result in decreased plasma volume, decreased blood  pressure, weakness, and fainting. (Alterations in fluid balance  are discussed in Chapter 3.)   Like other heat reduction mechanisms, stimulation of sweat-  ing occurs in response to sympathetic neural activity and depends  on a favorable temperature difference between the body and  the environment. In addition, heat loss through evaporation is  affected by the relative humidity of the air. If the humidity is low,  sweat evaporates quickly, but if the humidity is high, sweat does  not evaporate and instead remains on the skin or drips off.   Increased Pulmonary Ventilation. Exchanging air with  the environment through the normal pulmonary ventilation  provides some heat loss, although it is minimal in humans. As  air is inhaled, the air draws heat from the upper respiratory  tract. The air is further warmed in the alveoli by blood in the  microcirculation. This warmed air then is exhaled into the  environment. This normal process occurs faster at higher body  temperatures through an increase in ventilatory rates. Thus  hyperventilation is associated with hyperthermia. (Normal  pulmonary function is discussed in Chapter 34.)   Adaptation to Warmer Climates. The body of an individual  who moves from a cooler to a much warmer climate undergoes  a period of adjustment, a process that takes several days to  weeks. At first the individual experiences feelings of lassitude,  weakness, and faintness with even moderate activity. Body  temperatures rise with any work. Within several days, however,  the individual experiences an earlier onset of sweating, the  volume of sweat is increased, and the sodium content is  lowered. Heart rate is decreased and stroke volume increased  so that cardiac output remains unchanged. Extracellular fluid  volume increases, as does plasma volume. These physiologic  adaptations result in improved warm weather functioning and  decreased symptoms of heat intolerance. People’s work output,  endurance, and coordination increase, and their subjective  feelings of discomfort decrease.*’    The body conserves heat and protects core temperature through  two important mechanisms: (1) involuntary vasoconstriction  mediated by the sympathetic nervous system and (2) volun-  tary mechanisms.*® To preserve core temperature, the skin and  periphery are used as an insulating cover.*”    Vasoconstriction. By constricting peripheral blood vessels,  centrally warmed blood is shunted away from the periphery  (where radiation, conduction, and convection would allow heat  loss) to the core of the body, where heat can be retained. This  mechanism takes advantage of the insulating layers of the skin  and subcutaneous fat to protect core temperature.   Voluntary Mechanisms. In response to lower body  temperatures, individuals typically “bundle up,” “keep  moving,” or “curl up in a ball.” Bundling up involves dressing  with several layers of clothes that allow air to be trapped between  the skin and the clothing, thus providing an additional layer of  insulation. Keeping moving, stamping feet, clapping hands,  jogging, and other types of physical activity increase skeletal  muscle activity and thus promote heat production. Curling up  in a ball decreases the amount of skin surface available for heat  loss through radiation, convection, and conduction.    Infants and older adults require special attention to mainte-  nance of body temperature. Term infants produce sufficient  body heat, primarily through the metabolism of brown fat,  but they are unable to efficiently conserve heat because of the  infant’s small body size, greater ratio of body surface area to  body weight with heat loss through conduction and convection,  and inability to shiver. Infants have a thin layer of subcutaneous  fat and thus are not as well insulated as adults.*? Therefore, it is  important to keep infants warm with hats, clothing, and blan-  kets. Children also have a greater ratio of body surface area to  body weight, lower sweating rate, higher peripheral blood flow  in the heat, and a greater extent of vasoconstriction in the cold  than adults. They can acclimatize to changes in environmental  temperatures, but do so at a lower rate than that seen in adults.”    Older adults have poor responses to environmental tempera-  ture extremes as a result of slowed blood circulation, structural  and functional changes in the skin, an overall decrease in heat-  producing activities, and the presence of disease (i.e., congestive  heart failure, chronic lung disease, diabetes mellitus, or periph-  eral vascular disease). Cold stress in older adults also decreases  coronary perfusion.’! Other factors affecting thermal regula-  tion in the older adult population include decreased shivering  response (delayed onset and decreased effectiveness), slowed  metabolic rate, sedentary lifestyle, decreased vasoconstric-  tor and vasodilator responses, diminished or absent sweating,  desynchronization of circadian rhythm, undernutrition, and  decreased perception of heat and cold.?*-*   Fever (febrile response or pyrexia) is a temporary resetting of  the hypothalamic thermostat to a higher level in response to  endogenous or exogenous pyrogens.”> The pathophysiologic  mechanism of fever begins with the introduction of exogenous  pyrogens or endotoxins produced by pathogens (Figure 16-8).    The most frequently encountered exogenous pyrogens are the  lipopolysaccharide complex in the cell wall of gram-positive  bacteria and viruses. Endogenous pyrogens, including pros-  taglandin E, (PGE}), interleukin-1 (IL-1), IL-6, tumor necro-  sis factor-alpha (TNF-a), and interferon-y, are produced by  phagocytic cells as they destroy microorganisms within the  host. The endogenous pyrogens act on the preoptic nucleus of  the hypothalamus. An integrated behavioral, endocrine, and  autonomic nervous system response is then initiated. Centers in  the hypothalamus and brainstem signal an increase in heat pro-  duction and heat conservation to raise body temperature to the  new set point. Peripheral vasoconstriction occurs with shunting  of blood from the skin to the body core. Epinephrine release  increases metabolic rate, and muscle tone increases. Decreased  release of vasopressin reduces the volume of body fluid to be  heated. Shivering also may occur. The individual dresses more  warmly, decreases body surface area by curling up, and may go  to bed in an effort to get warm. Body temperature is maintained  at the new level until the fever “breaks.”   During fever, arginine vasopressin (AVP), a-melanocyte-  stimulating hormone (a-MSH), and corticotropin-releasing  factor are released from the brain, and systemic anti-  inflammatory cytokines (i.e., IL-1 receptor agonist and IL-10)  can act as endogenous cryogens or antipyretics to help dimin-  ish and control the febrile response.” This antipyretic effect  constitutes a negative-feedback loop (see Figure 16-8). The  antipyretic effect may help explain fluctuations in the febrile  response. When the fever breaks, the set point is returned to  normal. The hypothalamus responds by signaling a decrease  in heat production and an increase in heat reduction mecha-  nisms. The result is decreased muscle tone, peripheral vaso-  dilation, flushed skin, and sweating. The individual feels very  warm, replaces warm clothing with cooler clothes, throws off  the covers, and stretches out. Once the body has returned to  a normal temperature, the individual feels more comfortable  and the hypothalamus adjusts thermoregulatory mechanisms  to maintain the new temperature.    Moderate fever aids responses to infectious processes through  several mechanisms.”° A raised body temperature kills many  microorganisms and has adverse effects on the growth and rep-  lication of others. Higher body temperatures decrease serum  levels of iron, zinc, and copper, all of which are needed for bac-  terial replication. The body switches from burning glucose to a  metabolism based on lipolysis and proteolysis, thereby depriv-  ing bacteria of a food source. Anorexia and somnolence reduce  the demand for muscle glucose.?”* Increased temperature also  causes lysosomal breakdown and autodestruction of cells, thus  preventing viral replication in infected cells. Acute-phase pro-  teins produced by the liver during inflammation bind cations  necessary for bacterial reproduction. Heat increases lymphocytic  transformation and motility of polymorphonuclear neutrophils,  thus facilitating the immune response. Phagocytosis is enhanced,  and production of antiviral interferon may be augmented.”  Because fever is a beneficial response to infection, suppress-  ing fever with antipyrogenic medications should be reviewed    Acute-phase  response and  other organ systems  (e.g., liver, bone marrow,  adrenals, muscles)    FIGURE 16-8 Pathogenesis of Fever and Acute-Phase Response. Certain disease states, through the elaboration of  exogenous pyrogens, stimulate monocytes and macrophages to produce endogenous pyrogens such as IL-1, IL-6, TNF-c,, and  interferon-y. These pyrogenic cytokines act at the endothelial surface of the circumventricular organ of the preoptic area of  the anterior hypothalamus (PO/AH) to induce the production of PGE, which elevates the body's thermal set point. Physiologic  and behavioral responses may be invoked to raise body temperature to a new set point. This febrile response must be con-  sidered in the context of an overlapping acute-phase response as a global nonspecific response to the original insult. Intrinsic  central antipyretics and systemic antipyretics exert their effects by decreasing levels of PGE,, thus decreasing the “set point”  and lowering body temperature. The red dotted line represents a negative feedback response. cAMP Cyclic adenosine mono-  phosphate; /FN, interferon; /L-1, /L-6, interleukin-1, interleukin-6; PGE,, prostaglandin Ey; TNF-a, tumor necrosis factor-alpha.  (Modified from Armstrong D, Cohen J: /nfectious diseases, ed 2, St Louis, 2004, Mosby.)    carefully.!°° Such treatment should be used only if the fever is  high enough to produce serious side effects such as nerve dam-  age or convulsion.   Infection and fever responses in older adults and in chil-  dren may vary from those in the adult. Older individuals  may have decreased or no fever response to infection. The  absence of fever responses to infection and therefore the ben-  eficial aspects of fever production may explain the increase  in morbidity and mortality rates seen in very old individu-  als.'°! In contrast, children develop higher temperatures than  do adults for relatively minor infections. Febrile seizures  may occur with temperatures greater than 39° C (102.2° F),  although most children do not develop febrile seizures until  temperatures are much higher. Febrile seizures are more pre-  dominant in boys before age 5 years, and genetic factors con-  tribute to susceptibility.'°* Febrile seizures are generally brief  and self-limiting, lasting less than 5 minutes in 40% of chil-  dren and less than 20 minutes in 75% of children. Although  in most instances there appear to be no long-term effects on  the child, a small percentage of children (1% to 2%) may  develop epilepsy.!°° Prolonged febrile seizures are associated  with the development of temporal lobe epilepsy in children  and are probably associated with functional changes in neu-  rons and neural networks. !0#!0°   Fever of unknown origin (FUO) is a fever with a body  temperature greater than 38.3° C (101° F) that remains undi-  agnosed after 3 days of hospital investigation or two or more  outpatient visits. The clinical categories of FUO include classic,  nosocomial, neutropenic, and HIV associated.!°°   Internal body temperature is maintained within a narrow range.  Alterations in the regulation of heat production or heat loss can  be life-threatening.   Hyperthermia is elevation of the body temperature without  an increase in the hypothalamic set point. Hyperthermia can  produce nerve damage, coagulation of cell proteins, and death.  At 41° C (105.8° F), nerve damage produces convulsions in the  adult. At 43° C (109.4° F), death results. Hyperthermia is not  mediated by pyrogens, and may be associated with brain injury  or applied therapeutically.   Therapeutic hyperthermia is a form of local, regional, or  whole-body induced hyperthermia used to destroy pathologic  microorganisms or tumor cells by facilitating the host’s natural  immune process or tumor blood flow.!”   Accidental hyperthermia includes: (1) heat cramps, (2) heat  exhaustion, (3) heat stroke, and (4) malignant hyperthermia.!°*   Heat Cramps. Heat cramps are severe spasmodic cramps in  the abdomen and extremities that follow prolonged sweating  and associated sodium loss. Heat cramps usually appear in  individuals who are not accustomed to heat or in those who  are performing strenuous work in very warm climates. Fever,  rapid pulse rate, and increased blood pressure often accompany  the cramps. Treatment involves administration of dilute salt  solutions through oral or parenteral routes.    Heat Exhaustion. Heat exhaustion, or collapse, is a result of  prolonged high core or environmental temperatures. These high  temperatures cause the appropriate hypothalamic response of  profound vasodilation and profuse sweating. Over a prolonged  period the hypothalamic responses produce dehydration,  decreased plasma volumes, hypotension, decreased cardiac  output, and tachycardia. The individual feels weak, dizzy,  nauseated, and faint. The symptoms of heat exhaustion cause  the individual to stop work, lie down, and rest. Ceasing activity  decreases muscle work, causing decreased heat production.  Lying down redistributes vascular volume. The individual  should be encouraged to drink warm fluids to replace fluid lost  through sweating.   Heat Stroke. Heat stroke is a potentially lethal result of a  breakdown in control of an overstressed thermoregulatory  center.!°? The brain cannot tolerate temperatures greater than  40.5° C (104.9° F). When core temperature reaches or exceeds  40.5° C (104.9° F), the brain may be preferentially cooled by  maximal blood flow through the veins of the head and face,  specifically the forehead. Sweat production on the face is  maintained even during dehydration. Evaporation of the sweat  cools the blood in the veins of the face and forehead; the blood  then is returned to the endocranial venous network and sinus  cavernosus, cooling the blood in the cerebral arterial vessels that  lie in proximity. Fanning the face enhances this mechanism. In  this way the brain can be maintained temporarily at 40° C (104°  F), even when core temperatures are higher. In instances of  very high core temperatures (40° to 43° C [104° to 109.4° F]),  the cardiovascular and thermoregulatory centers may cease to  function appropriately. Sweating ceases, and the skin becomes  dry and flushed. The individual may be irritable, confused,  stuporous, or comatose. Visual disturbances may occur.   As heat loss through the evaporation of sweat ceases, core  temperatures increase rapidly. High core temperatures and  vascular collapse produce cerebral edema, degeneration of the  CNS, swollen dendrites, renal tubular necrosis, and multiple  organ failure. Death results unless immediate, effective treat-  ment is initiated. Individuals who recover from heat stroke may  have permanent damage to the thermoregulatory center and  thus may have difficulty tolerating environmental temperature  changes. A systemic inflammatory response syndrome (SIRS)  that ensues following heat-induced tissue injury may cause the  long term sequelae associated with heat-injured tissue.!!°   Treatment includes removing the person from the warm  environment, if possible, and using a cooling blanket or cool  water bath or ice packs on the head, neck, groin, and axil-  lae.!°° Care must be taken to prevent too rapid cooling of the  surface, which causes peripheral vasoconstriction and prevents  core cooling. Children are more susceptible to heat stroke than  adults because (1) they produce more metabolic heat when  exercising, (2) they have a greater surface area to body mass  ratio, and (3) their sweating capacity is less than that of adults.   Malignant Hyperthermia. Malignant hyperthermia is  a potentially lethal hypermetabolic complication of a rare  inherited muscle disorder. The condition is precipitated by  the administration of volatile anesthetics and neuromuscular-  blocking agents. There is wide variability in incidence ranging    from 1:5000 to 1:50,000. Malignant hyperthermia is caused  by either increased myoplasmic calcium release or decreased  calcium uptake with muscle contraction. This allows intracellular  calcium levels to rise, producing sustained, uncoordinated  muscle contractions, which in turn increase muscle work,  oxygen consumption, and lactic acid production. As a result  of these contractions, acidosis develops and temperature  rises (body temperature may rise 1° C [1.8° F] every 5  minutes); approximately 5% of those who develop malignant  hyperthermia do not survive.''!! Malignant hyperthermia occurs  most often in children and young adults immediately after the  induction of anesthesia. Sympathetic responses and acidosis  produce tachycardia and cardiac dysrhythmias, followed by  hypotension, decreased cardiac output, and, eventually, cardiac  arrest. Increasing temperature, acidosis, hyperkalemia, and  hypoxia produce coma-like symptoms in the CNS (including  unconsciousness, absent reflexes, fixed pupils, apnea, and  sometimes a flat electroencephalogram [EEG]). Oliguria and  anuria are common, probably resulting from shock, ischemia,  and low cardiac output.!!*   Treatment includes withdrawal of the provoking agents  and administration of dantrolene sodium (a skeletal relaxant  that inhibits calcium release during muscle contraction). Pro-  cainamide (Pronestyl) is used to treat cardiac dysrhythmias.  Sodium bicarbonate is used for acidosis. Hyperkalemia can  be treated with insulin and glucose. Body temperature can be  decreased through use of ice bags, a cooling blanket, and iced  saline lavage.    Hypothermia (core body temperature less than 35° C [95° F])  is caused by prolonged exposure to cold. Hypothermia pro-  duces vasoconstriction, shivering, alterations in microcircula-  tion, coagulation, and ischemic tissue damage. In a controlled  situation, such as a surgical procedure, most tissues can tolerate  temperatures as low as 33° C (91.4° F). In severe hypothermia  (less than 28° C [82.4° F]), ice crystals forming on the inside of  the cell cause cells to rupture and die. Tissue hypothermia slows  the rate of chemical reactions (tissue metabolism), increases the  viscosity of the blood, slows blood flow through the microcir-  culation, facilitates blood coagulation, and stimulates profound  vasoconstriction. Hypothermia may be accidental or therapeu-  tic. In accidental hypothermia, high-energy phosphates (e.g.,  ATP) are depleted, and in therapeutic hypothermia, ATP stor-  age is preserved,!!%!!4   Accidental Hypothermia. Accidental hypothermia is  generally the result of sudden immersion in cold water or  prolonged exposure to cold environments.!'* At particular risk  for accidental hypothermia are young persons and older adults,  because thermoregulatory mechanisms are altered in these  two groups. Also at risk are individuals with conditions that  diminish the ability to generate heat. Such conditions include  hypothyroidism, hypopituitarism, decreased liver function,  malnutrition, Parkinson disease, and rheumatoid arthritis.  Other risk factors include chronic increased vasodilation  and decreased thermoregulatory control caused by cerebral  injuries, ketoacidosis, uremia, and drug overdoses. In acute    hypothermia, peripheral vasoconstriction shunts blood away  from the cooler skin to the core in an effort to decrease heat  loss, which produces peripheral tissue ischemia. Intermittent  reperfusion of the extremities (the Lewis phenomenon) helps  preserve peripheral oxygenation. Intermittent peripheral  perfusion continues until core temperatures drop dramatically.   The hypothalamic center stimulates shivering in an effort to  increase heat production. Severe shivering occurs at core tem-  peratures of 35° C (95° F) and continues until core temperature  drops to about 30° to 32° C (86° to 89.6° F). Prolonged shiv-  ering can lead to exhaustion of liver glycogen stores. Thinking  becomes sluggish and coordination is decreased at 34° C (93.2°  F). As hypothermia deepens, paradoxical undressing may occur  as hypothalamic control of vasoconstriction is lost and vasodi-  lation occurs with loss of core heat to the periphery. The hypo-  thermic individual therefore feels suddenly warm and begins to  remove clothing.!!   At 30° C (86° F), the individual becomes stuporous, heart  rate and respiratory rate decline, and cardiac output is dimin-  ished. Cerebral blood flow is decreased. Metabolic rate declines,  further decreasing core temperature. Sinus node depression  occurs with slowing of conduction through the atrioventricular  node. In severe hypothermia (core temperature of 26° to 28° C  [78.8° to 82.4° F]), pulse and respirations may be undetectable.  Acidosis is moderate to severe. Coagulopathy, ventricular fibril-  lation, and asystole are common.'!° Surface cooling may cause  frostbite and fat necrosis.   If hypothermia is mild, passive rewarming may be sufficient.  If core temperature is greater than 30° C (86° F), active rewarm-  ing also may be required. Active rewarming uses warm-water  baths, warm blankets, heating pads, and warm oral fluids when  the individual is fully alert. Core rewarming may be accom-  plished through administration of warm intravenous (IV) solu-  tions, warm gastric lavage, warm peritoneal lavage, inhalation  of warmed gases, and, in extreme cases, exchange transfusions,  warming blood in a pump oxygenator circuit, and mediastinal  lavage.!!°   Rewarming generally should proceed no faster than a few  degrees per hour. Short-term complications of rewarming  include acidosis, rewarming shock, and dysrhythmias. Long-  term complications include congestive heart failure, hepatic  and renal failure, abnormal erythropoiesis, myocardial infarc-  tion, pancreatitis, and neurologic dysfunctions.   Therapeutic Hypothermia. Therapeutic hypothermia is used  to slow metabolism and preserve ischemic tissue after brain  trauma or during brain surgery, after cardiac arrest, and in  neonatal hypoxic encephalopathy.''’ Hypothermia protects  the brain by reduction in metabolic rate, ATP consumption,  oxidative stress, and the critical threshold for oxygen delivery;  modulation of excitotoxic neurotransmitters and calcium  antagonism; preservation of protein synthesis and the blood-  brain barrier; decreased edema formation; and modulation of  the inflammatory response.!!®!!°    Major body trauma has varying effects on temperature regu-  lation, depending on the body systems involved. Five types    of traumatic injury that usually affect temperature regulation  are: (1) CNS trauma (discussed in Chapter 18), (2) accidental  injury, (3) hemorrhagic shock, (4) major surgery, and (5) ther-  mal burns.   Central Nervous System Trauma. CNS trauma that causes  CNS damage, inflammation, increased intracranial pressures,  or intracranial bleeding typically produces a temperature  greater than 39° C (102.2° F). This temperature, often referred  to as neurogenic or central fever, appears with or without relative  bradycardia and is not caused by infection. The temperature is  sustained, does not induce sweating, and is highly resistant to  antipyretic therapy. !?°   Accidental Injuries. Mild accidental injuries may produce a  slight elevation in core temperature. Moderate to severe injuries  result in peripheral vasoconstriction with decreased surface and  core temperatures. Core temperature is thought to be inversely  related to the severity of the injury and may be a result of  decreased oxygen transport to the tissues. In severe injuries,  shivering is absent and some alteration in thermoregulation is  evident.!7!   Hemorrhagic Shock. Loss of blood volume in hemorrhage  triggers peripheral vasoconstriction and hypoxia, contributing  to hypothermia. Risk for subsequent decreases in core  temperature occurs when hemorrhagic shock is treated with  unwarmed, volume-expanding solutions and surgery. Volume  expansion with warmed solutions is recommended to prevent  the deleterious effects of hypothermia on cardiac output,  cardiac rhythm, and the immune system.   Major Surgery. Major surgery often induces significant  hypothermia through exposure of body cavities to the relatively  cool operating room environment, irrigation of body cavities  with room temperature solutions, infusion of room temperature  intravenous solutions, use of drugs that impair thermoregulatory  mechanisms, and inhalation of unwarmed anesthetic agents.  Anesthesia induces hypothermia, reduces platelet function, and  impairs the coagulation cascade, contributing to transfusion  requirements and postoperative complications. Use of warmed  irrigating and intravenous solutions and perioperative forced  air and skin warming procedures reduces intraoperative  hypothermia and postoperative complications. !7*   Thermal Burns. Large burn injuries produce significant  hypothermia because of the loss of the skin barrier to fluid  evaporation and the loss of control of the microcirculation in  the skin. Severe burns also compromise the normal insulation  of the skin and subcutaneous tissues. (Burns are discussed in  Chapter 48.)    Sleep is an active, multiphase, complex brain process that pro-  vides restorative functions and promotes memory consolida-  tion. Several areas of the brain are associated with sleep and  sleep-wake cycles. A small group of hypothalamic nerve cells,  the suprachiasmatic nucleus (SCN), controls the timing of  the sleep-wake cycle and coordinates this cycle with circadian  rhythms (24-hour rhythm cycles) in other areas of the brain and  body tissues using electrical, endocrine, and metabolic signaling    FIGURE 16-9 Electroencephalogram (EEG) Stages of Wakefulness and  NREM Sleep. Awake, Low-voltage fast activity; stage NT, falling asleep; stage  N2, light sleep with sleep spindles; stage N3, slow delta waves. Rapid eye move-  ment (REM) sleep looks similar to awake and stage N1 sleep. Sleep spindles are  bursts of brain activity associated with onset of sleep.   and NREM sleep succeed each other in 90- to 110-minute inter-   vals in a predictable pattern.'** Four to six cycles occur during   a normal sleep period in an adult. NREM sleep is divided into   three stages based on changes in the EEG pattern (Figure 16-9)   Awake—Wakefulness with eyes closed and predominated by  alpha waves (8 to 25 Hz)   N3—Low-frequency (1 to 3 Hz) high-amplitude delta waves  with occasional sleep spindles—also known as slow-wave  sleep; no slow eye movements (15% to 20% of sleep time)   REM sleep—time of most dreaming (20% to 25% of sleep  time)    NREM (slow-wave) sleep accounts for 75% to 80% of sleep time  and is initiated by the withdrawal of neurotransmitters from the  reticular formation and by the inhibition of arousal mechanisms  in the cerebral cortex. During NREM sleep, respiration is con-  trolled by metabolic processes.!*° The basal metabolic rate is  decreased by 10% to 15%. Temperature is decreased 0.5° to 1° C  (0.9° to 1.8° F). Heart rate decreases by 10 to 30 beats per minute.  Respiration, blood pressure, and muscle tone all decrease. Knee-  jerk reflexes are absent. Pupils are constricted. During stages N1  and N2, cerebral blood flow to the brainstem and cerebellum is  decreased. During stage N3, cerebral blood flow to the cortex is  decreased.'*” Growth hormone is released during stage N3, and  levels of corticosteroids and catecholamines are depressed.   Rapid eye movement (REM) sleep accounts for 20% to 25% of  sleep time and is characterized by desynchronized, low-voltage,  fast activity that occurs for 5 to 60 minutes about every 90 min-  utes beginning after 1 to 2 hours of NREM sleep. The brain is  quite active in REM sleep with vivid dreaming. REM sleep is  also known as paradoxic sleep because the EEG pattern is simi-  lar to the normal awake pattern. Alternating periods of REM  and NREM sleep occur throughout the night, with lengthen-  ing intervals of REM sleep and fewer intervals of deeper stages  of NREM sleep toward morning. REM sleep is characterized  by bursts of conjugate rapid eye movement in all directions;  atonia of antigravity muscles; suppressed temperature regu-  lation; alteration in heart rate, blood pressure,!*”!*° and res-  piration; penile erection in men and clitoral engorgement in  women; and a high rate of memorable dreams. Steroids are  released in short bursts. During REM sleep, respiratory control  is thought to be largely independent of metabolic requirements  and oxygen variation. Loss of normal voluntary muscle control  in the tongue and upper pharynx may produce some respira-  tory obstruction. Cerebral blood flow to both hemispheres is  increased. REM sleep is controlled by the pontine reticular  formation.   An individual progresses through REM and NREM sleep ina  predictable cycle while asleep. The first cycle of the night begins  with stage N1. The individual then progresses through stages  N2, N3, and REM sleep. A new cycle, beginning with stage N2,  follows each REM sleep. With each successive cycle, the amount  of time spent in stage N3 sleep decreases and the amount of  time spent in REM sleep increases (Figure 16-10). The individ-  ual who is awakened begins the next cycle with stage N1.   The hypothalamus as a major sleep center secretes hypo-  cretins (orexins), neuropeptides that promote wakefulness  and REM sleep as well as appetite, energy consumption, and  pleasure or reward. In addition to the hypocretins, acetylcho-  line and glutamate are important waking factors. The preoptic  area of the hypothalamus promotes sleep through inhibitory  modulation of multiple arousal systems with involvement of  the inhibitory neurotransmitter GABA.'”° The reticular for-  mation is primarily responsible for generating REM sleep and  projections from the reticular formation and other areas of the  mesencephalon and brainstem produce NREM sleep.!?’   Many neurotransmitters are associated with excitatory and  inhibitory sleep mechanisms. Sleep-promoting neurotrans-  mitters include prostaglandin D), L-tryptophan, serotonin,  adenosine, melatonin, GABA, and growth hormones. Awake-  promoting neurotransmitters include hypocretin (orexin),  acetylcholine, and glutamate.'*° Their mechanism of action  is complex and not clearly understood. Growth hormone is  associated with initiation of sleep, and cortisol levels rise in the  morning just before waking.'*! Acetylcholine and somatostatin  play a role in stages of sleep transition. Forced awakenings in  the middle of the night may result in increased difficulty return-  ing to sleep or may alter the normal progression of sleep, or  both.!°°!>? The purpose of sleep is unknown, although restor-  ative processes, particularly neuronal repair and generation of  new neural pathways, have been proposed.'°’ Loss of REM sleep    FIGURE 16-10 Normal Sleep Cycles. Rapid eye movement (REM) sleep  occurs cyclically throughout the night at intervals of approximately 90 minutes  in all age groups. REM sleep shows little variation in the different age groups,  whereas stage N3 sleep decreases with age. In addition, older adults awaken fre-  quently and show a marked increase in total time awake.    impairs learning and memory. Sleep is important enough that  people spend about one third of their life sleeping.    The sleep patterns of the newborn and young child vary from  those of the adult in total sleep time, cycle length, and percent-  age of time spent in each sleep cycle.'** Newborns sleep about  16 to 17 hours per day. About 53% of that time is spent in active  sleep (REM sleep), 23% in quiet sleep (NREM sleep), and the  remainder in an indeterminate phase. The infant sleep cycle  is approximately 50 to 60 minutes long, with 20 minutes of  NREM sleep and 10 to 45 minutes of REM sleep, in contrast  to the adult sleep cycle. Newborns enter REM sleep immedi-  ately on falling asleep.'*° At about 1 year of age, an infant spends  approximately 45% of total sleep time in quiet sleep and 41%  in REM sleep. Total sleep time decreases slightly from birth to 1  year. Bottle-fed infants that do not share sleeping space with the  mother increase maximum sleep time from 4 to 5 hours to 8 to  10 hours by 4 months of age. They begin to “sleep through the  night.” Infants who are breast-fed for up to 2 years and share  sleeping space with the mother continue to sleep in short bouts  and wake frequently to nurse.'°? In the young child, the sleep    cycle length is 45 to 60 minutes, in contrast to 90 to 100 minutes  in the adult. The child assumes the adult sleep pattern at some  point during the first 2 to 5 years of life.!°° Sleep for infants  and children is important for growth and neurocognitive devel-  opment. Sleep disorders are common in children and include  insomnia and obstructive sleep apnea syndrome (OSAS). OSAS  is related to adenotonsillar inflammation (i.e., enlargement of  the adenoids and tonsils) or to obesity.!°”!°* Sudden infant  death syndrome (SIDS) is presented in Chapter 36.    The sleep pattern of the older adult differs from that of the  younger adult or child. Total sleep time is decreased, and the  older individual takes longer to initiate and maintain asleep.  Older adults tend to go to sleep earlier in the evening and  awaken more frequently during the night and earlier in the  morning. REM and slow-wave sleep decreases. Changes in  the older adult’s sleep pattern may be associated with changes  in lifestyle, presence of chronic disease, lack of daily routine,  desynchronization of circadian rhythm, and use of medica-  tions.'*? Growth hormone and cortisol levels are diminished in  the older adult and may affect sleep patterns.'** The alteration  in sleep pattern typically appears about 10 years later in women  than in men. Older adults are less able than younger individuals  to tolerate sleep deprivation.!*°   The average length of sleep time has declined over the years  for both children and adults.'*!)!** Daily sleep loss accumulates  as a sleep debt that becomes evident in reduced neurobehav-  ioral capability that, in turn, results in decline of executive func-  tion and lapses in vigilance.'**!“* Individuals responsible for  public health and safety, including but not limited to healthcare  workers, often work night shifts and long hours that make them  prone to sleep-related errors.!4>!4°   Sleep disorders can be primary or secondary and can occur as  a result of many medical and psychiatric conditions. The focus  of this section is on primary sleep disorders. The classification  of primary sleep disorders is complex and a system has been  produced by the American Academy of Sleep Medicine!’ that  includes four general classifications: (1) dyssomnias (intrinsic  and extrinsic sleep disorders and circadian rhythm sleep dis-  orders); (2) parasomnias (arousal and sleep-wake transition  disorders and REM sleep disorders); (3) sleep disorders associ-  ated with mental, neurologic, or other medical disorder; and (4)  proposed sleep disorders. The most common dyssomnias and  parasomnias are presented here.    The dyssomnias are sleep disorders related to difficulty in  initiating or maintaining sleep or the presence of excessive  sleepiness. The most common dyssomnias include insomnia,  obstructive sleep apnea syndrome, restless leg syndrome, circa-  dian rhythm disorder, and hypersomnia.   Insomnia is the inability to fall or stay asleep and is more  common in women.'** Primary insomnia may be transient,    lasting a few days, and related to travel across time zones, dis-  rupted sleep schedules, or acute stress. Secondary insomnia is  associated with drug or alcohol abuse, chronic pain disorders,  or chronic depression, obesity, and aging.'*? Drugs known to  produce insomnia include amphetamines, steroids, central  adrenergic blockers, bronchodilating agents, and caffeine.!°   Obstructive sleep apnea syndrome (OSAS) is a disorder of  breathing during sleep related to upper airway obstruction that  is associated with reduced blood oxygen saturation and hyper-  capnia. The typical classification of the severity of this disease  uses the Apnea Hypopnea Index (AHI). This index represents  how many apnea (total airway closure) or hypopnea (partial  airway closure) episodes occur per night—the number of which  is then divided by the night’s total sleep time to give an aver-  age number of apnea or hypopnea episodes per hour. The AHI  severity scale is as follows:   Normal: fewer than 5 episodes of abnormal sleep episodes  per hour   Mild: between 5 and 15 episodes of abnormal sleep epi-  sodes per hour   Moderate: between 15 and 30 episodes of abnormal sleep  episodes per hour   Severe: more than 30 episodes of abnormal sleep episodes  per hour   The prevalence of OSAS associated with accompanying day-  time sleepiness is common with an occurrence of approximately  3% to 7% for adult men and 2% to 5% for adult women,!*! or  approximately 10 million adults in the United States. Some esti-  mates suggest between 12 and 20 million people in the United  States have diagnosable OSAS.'*” Risk factors include obesity,  male gender, menopause, and age.!**   OSAS is increasingly prevalent in our rapidly expanding  older adult population.'°*!*° Premenstrual women may be  protected from sleep-disordered breathing because the female  hormone progesterone is a respiratory stimulant.'°° The longer  pharyngeal airway in males also may contribute to increased  risk for OSAS. Obese individuals often have a short, thick neck;  pharyngeal airway collapse; impaired respiratory mechan-  ics; and depressed respiratory control, particularly during  sleep.'°’ Obesity hypoventilation syndrome (obesity, daytime  hypoventilation, and sleep-disordered breathing not related to  other causes) may be related to leptin resistance because leptin  is also a respiratory stimulant.!*°   OSAS is, as reflected in the preceding discussion of AHI, char-  acterized by repetitive increases in resistance to airflow within  the upper airway with loud snoring, gasping, intervals of apnea  lasting from 10 to 30 seconds, fragmented sleep, and chronic  daytime sleepiness. The obstruction is caused by the soft palate  or base of the tongue, or both, collapsing against the pharyngeal  walls because of decreased muscle tone especially during REM  sleep. In the supine position, the tongue may fall farther back,  obstructing the airway. The level of negative intrathoracic pres-  sure is the most likely stimulus for arousal, possibly mediated by  mechanoreceptors in the upper airway. Potentially fatal cardiac  and vascular illnesses associated with OSAS include hyperten-  sion, pulmonary hypertension, heart failure, nocturnal cardiac  dysrhythmias, myocardial infarction, and ischemic stroke.!°”    The pathophysiologic consequences of mechanical and  neurochemical responses present during apneic episodes may  be causal factors in the cardiovascular disease commonly seen  in OSAS. Such hypoxia-induced vascular dysfunction impairs  blood flow regulation and compromises tissue perfusion and  oxygen delivery during episodes of OSAS. The combination of  intermittent hypoxia and hypercapnia, increased number of  arousals, increased sympathetic tone, altered baroreflex control  during sleep, oxidative stress, hormonal changes, and cardio-  vascular changes induced by increased negative intrathoracic  pressure contribute to these complications.'®° OSAS also con-  tributes to the development of metabolic syndrome, which is  associated with cardiovascular disease mortality'®! (see Chap-  ter 22). Many individuals are not aware of their heavy snoring  and nocturnal arousals and may remain undiagnosed. Fatigue,  decline in cognitive function, car accidents, and poor work per-  formance are common.   Diagnosis of OSAS is confirmed with polysomnogra-  phy. Treatments include continuous positive airway pressure  (CPAP), dental devices that modify the position of the tongue  or jaw, upper airway surgical reconstruction, and weight reduc-  tion.'©* Treatment with CPAP utilizes positive air pressure to  maintain an open airway and has been shown to result in a  reversal of abnormalities associated with OSAS, including sys-  temic and pulmonary hypertension and decreased cardiovascu-  lar disease mortality.'°° 1°   Restless leg syndrome (RLS) is a common sensorimotor dis-  order associated with unpleasant sensations (prickling, tingling,  crawling) that occurs at rest and is worse in the evening or at  night. There is a compelling urge to move the legs for relief,  with a significant effect on sleep and quality of life. The disor-  der is more common in women, older adults, and individuals  with iron deficiency. RLS has a familial tendency and is associ-  ated with a circadian fluctuation of dopamine in the substan-  tia nigra. Iron is a cofactor in dopamine production, and some  individuals respond to iron administration as well as dopamine  agonists, 109166   Hypersomnia is excessive daytime sleepiness and is com-  monly associated with voluntary sleep deprivation. There may  also be an underlying sleep disorder such as OSAS or narcolepsy.  Individuals may fall asleep while driving, working, or even con-  versing, resulting in significant concerns for safety. Treatment is  symptomatic with reinforcement of good sleeping habits.   Narcolepsy is characterized by hypersomnia, cataplexy (brief  spells of muscle weakness), hallucinations, and sleep paraly-  sis. The disorder is associated with hypothalamic hypocretin  (orexin) deficiency and may be related to immune-mediated  destruction of hypocretin-secreting cells. There is a genetic  component to the disorder in animals.!°”   Circadian rhythm sleep disorders are common disorders of  the sleep-wake schedule and include rapid time-zone changes  (jet-lag syndrome), alterations in sleep schedule with an advance  or a delay of 3 hours or more in sleep time, or changes in total  sleep time from day to day. These changes in the timing of  established sleep schedules have been shown to desynchronize  circadian rhythm.'®* Degree of vigilance, performance of psy-  chomotor tasks, and subjective reports of levels of arousal are   decrease in accuracy, an increase in accident proneness, and an  increase in likelihood of poor work performance.'® For similar  reasons, people suffering from jet-lag syndrome require sev-  eral days to adapt to a new time zone. Travel across time zones  requires 2 days to adjust the sleep-wake schedule, 5 days to  adjust the body temperature cycle, and 8 days to adjust cortisol  level secretion. Transmeridian travel requires up to 10 days to  adjust the body clock when traveling from east to west. Timed  bright light exposure and administration of exogenous mela-  tonin provide some success in retiming or resetting the body  clock before or after time-zone shifts.!7!!/2   1. A marked impact on performance through decreases in  cognitive functions and specific effects on brain regions  that support cognitive function   3. Declines in attention and vigilance with distinct intrain-  dividual variability   4, Abnormal activation in the prefrontal cortex, parietal  lobes, thalamus, and temporal lobes as shown by func-  tional neuroimaging    Parasomnias are complex behaviors related to awakening from  REM sleep or partial arousal from NREM sleep and disorders  of sleep stage transitions. Three types of parasomnias include  arousal disorders such as confusional arousals, sleepwalking  (somnambulism), night terrors (dream anxiety attacks), rear-  ranging furniture, eating food, violent behavior, bruxism (teeth  grinding), and sleep enuresis; sleep-wake transition disorders  such as rhythmic movements (head banging), sleep talking, and  nocturnal leg cramps; and disorders associated with REM sleep  such as sleep paralysis and nightmares, sleep apnea, and SIDS.  SIDS affects children primarily in the first 2 years of life and  may be related to central sleep apnea (a disorder of thalamic  breathing control) episodes (see Chapter 36). Parasomnias are  more common in children and may be familial.!7°!77   Many mental and physical disorders are associated with altera-  tions in sleep (secondary sleep disorders). Many disorders pro-  duce alterations in the quantity and quality of sleep or affect  sleep stages, including mental disorders (e.g., depression and  anxiety), disorders of neurocognitive function (e.g., dementia  or Parkinson disease), and physical disorders (e.g., alterations  in thyroid hormone levels, pain, and many acute and chronic  diseases). In other instances, sleep stages may contribute to    disease (sleep-provoked disorders) such as chronic obstructive  pulmonary disease (COPD), asthma, cardiac ischemia, diabetes  mellitus, and gastroesophageal reflux.   REM sleep behavior disorder is loss of normal skeletal muscle  atonia during REM sleep and may cause injury from acting-  out of dreams. It is more common in older adult men and is  associated with Parkinson disease and other neurodegenerative  diseases. '7®   Individuals who are depressed have difficulty falling asleep  and exhibit less slow-wave sleep, less time spent in REM sleep,  early awakening, and less total sleep time. In addition, depressed  individuals move through the sleep stages more quickly than do  individuals who are not depressed. The same neurotransmitters  that may be disturbed in depression also regulate sleep.!7>'”°   Coronary artery disease is most affected during REM sleep.  During REM, dreams may provoke nocturnal angina, increased  heart rate, and electrocardiogram (ECG) changes. In adults,  attacks of bronchial asthma may occur at any time during the  night. The attacks cause the individual to spend more of the  sleep period awake and thus result in a decrease in stage N3  sleep time. In children, bronchial asthma attacks are uncom-  mon during the first one third of the night, when stage N3 sleep  predominates, and occur more frequently during the final two  thirds of the night. Stage N3 sleep time is decreased overall in  the child with bronchial asthma. In addition to these changes,  asthmatic individuals may experience bronchial spasm during  REM sleep. 8°"!   People with COPD experience significantly lowered oxygen  tension and increases in carbon dioxide retention during sleep.  The lowered oxygen tension is most significant in the tonic  phase of REM sleep when voluntary neuromuscular control,  including intercostal muscle function, is depressed. Pulmonary  spasm and transient pulmonary hypertension result. These  changes are particularly evident in the “blue bloater” individual  and may contribute to early pulmonary hypertension and cor  pulmonale in these people.!**:!**   Because blood glucose levels vary during sleep, individuals  with uncontrolled diabetes may need to pay careful attention  to blood glucose levels. Studies show that people with duodenal  ulcers secrete 3 to 20 times more gastric acid during REM sleep  than do people without duodenal ulcers. This increased gastric  acid secretion often produces nocturnal epigastric pain.    The somatosensory system includes the peripheral receptors  and central nervous system pathways that detect internal and  external information, which is then processed and interpreted  by the brain. This system includes touch, proprioception and  vestibular function, and the special senses—sight, hearing,  smell, and taste.   Touch is not a uniform sensory experience. The sensation of  touch involves the fusion of several qualities, including modal-  ity, intensity, location, and duration of the sensory stimulus.    Receptors sensitive to touch are present in the skin. Meissner  and pacinian corpuscles are rapidly adapting receptors, whereas  Merkel disks and Ruffini endings are slowly adapting touch  receptors. Touch receptors are most numerous in the skin of  the fingers and lips and are more scarce in the skin of the trunk.  Specific sensory input is carried to the higher levels of the CNS  by the dorsal column of the spinal cord and the anterior spino-  thalamic tract.   Much of the development of the cutaneous senses takes place  before birth, but structural growth of the cutaneous senses con-  tinues into early adulthood at a reduced rate. Then a gradual  decline occurs.'®° Studies have documented loss in tactile sensi-  tivity with advancing age.'*°!®” This occurs simultaneously with  an increase in the size of pacinian corpuscles and a decrease in  the number of corpuscles.   Abnormal tactile perception may be caused by alterations at  any level of the nervous system, from the receptor to the cere-  bral cortex. Any factor that interrupts or impairs reception,  transmission, perception, or interpretation of touch also alters  tactile sensation. Trauma, tumor, infection, metabolic changes,  vascular changes, and degenerative diseases thus may cause tac-  tile dysfunction, which may involve heightened or diminished  tactile perceptions.   In addition, most tactile sensations evoke affective responses  that determine whether the sensation is unpleasant, pleasant,  or neutral. Cerebral and hypothalamic centers influence this  response. Sedative drugs and prefrontal injury, which interrupt  connections between the prefrontal cortex and subcortical cen-  ters, diminish the interpretation of tactile sensations.   Perception and awareness of the position of the body and its  parts depend on impulses from the inner ear and from recep-  tors in joints and ligaments. The role of muscle, tendon, and  cutaneous receptors is indefinite. Sensory data are transmitted  to higher centers, primarily through the dorsal columns and  the spinocerebellar tracts, with some data passing through the  medial lemnisci and thalamic radiations to the cortex. These  stimuli are necessary for the coordination of movements, the  grading of muscular contraction, and the maintenance of  equilibrium.   A progressive loss of proprioception has been reported in  older adults with increased risk for falls and injury.!** Proprio-  ceptive dysfunction may be caused by alterations at any level of  the nervous system. As with tactile dysfunction, any factor that  interrupts or impairs the reception, transmission, perception,  or interpretation of proprioceptive stimuli also alters proprio-  ception. Two common causes of proprioceptive dysfunction  are vestibular dysfunction and neuropathy.   Specific vestibular dysfunctions are vestibular nystagmus  and vertigo. Vestibular nystagmus is the constant, involun-  tary movement of the eyeball caused by ear disturbances. This  condition occurs when the semicircular canal system is over-  stimulated. Vertigo (dizziness) is the sensation of spinning  that occurs with inflammation of the semicircular canals in the  ear. The individual may feel either that he or she is moving in  space or that the world is revolving. Vertigo often causes loss of    balance. Vertigo and nystagmus may occur in a variety of con-  ditions, including labyrinthitis, vestibular neuritis, acute toxic  labyrinthitis, benign paroxysmal positional vertigo, migrainous  vertigo, and Ménieére disease.'*?   Méniére disease (endolymphatic hydrops) is an idiopathic  episodic vestibular disorder resulting from abnormalities in  the quantity, composition, and pressure of the endolymph in  the middle ear.!°° The individual with Méniére disease expe-  riences vertigo, hearing loss, tinnitus, and aural fullness and  may have proprioceptive dysfunction. Standing or walking  may be impossible because of loss of balance. Méniére syn-  drome, or secondary endolymphatic hydrops, is secondary to  other conditions that alter the production or absorption of  endolymph.   Peripheral neuropathies also can cause proprioceptive dys-  functions. Neuropathies may be caused by a variety of con-  ditions and commonly are associated with renal disease and  diabetes mellitus. Although the exact sequence of events is  unknown, neuropathies are thought to be caused by a meta-  bolic disturbance of the neuron itself. The result is a diminished  or absent sense of body position or position of body parts. Gait  changes often occur. (Neuropathies are further discussed in  Chapter 18.)   The eyes are complex sense organs responsible for vision.  Within a protective casing, each eye has receptors, a lens sys-  tem for focusing light on the receptors, and a system of nerves  for conducting impulses from the receptors to the brain. Visual  dysfunction may be caused by abnormal ocular movements or  alterations in visual acuity, refraction, color vision, or accom-  modation. Visual dysfunction also may be the secondary effect  of another neurologic disorder.    Protective external eye structures include the eyelids (palpe-  brae), conjunctivae, and lacrimal apparatus (Figure 16-11).  The eyelids are used to control the amount of light reaching the  eyes, and the conjunctivae line the eyelids. Tears released from  the lacrimal apparatus bathe the surface of the eye and prevent  friction, maintain hydration, and wash out foreign bodies and  other irritants.   Infection and inflammatory responses are the most com-  mon conditions affecting the supporting structures of the eyes.  Blepharitis is an inflammation of the eyelids caused by Staphy-  lococcus or seborrheic dermatitis. Redness, edema, tearing, and  itching are common symptoms."”!   An external hordeolum (stye) is an infection of the seba-  ceous glands of the eyelids, and an internal hordeolum is an  infection of the eyelid margin. A chalazion is a noninfectious  lipogranuloma of the meibomian (oil-secreting) gland and may  be associated with an internal hordeolum. These conditions  present with redness, swelling, and tenderness and are treated  symptomatically.!°? Entropion is a common eyelid malposition  in which the lid margin turns inward against the eyeball. There  are both surgical and nonsurgical treatments to reposition the  lid margin.    FIGURE 16-11 Lacrimal Apparatus. Fluid produced by lacrimal glands (tears)  streams across the eye surface, enters the canals, and then passes through the  nasolacrimal duct to enter the nose. (From Patton KT, Thibodeau GA: Anatomy &  physiology, ed 8, St Louis, 2013, Mosby.)   Conjunctivitis is an inflammation of the conjunctiva  (mucous membrane covering the front part of the eyeball).  Conjunctivitis may be caused by bacteria, viruses, allergies,  or chemical irritations. The inflammatory response produces  redness, edema, pain, and lacrimation. Treatment is related  to cause.!°?   Acute bacterial conjunctivitis (pinkeye) is highly conta-  gious and often is caused by gram-positive organisms (Staphy-  lococcus, Haemophilus, Proteus), although other bacteria may  be involved. The onset is acute, characterized by mucopuru-  lent drainage from one or both eyes. In children younger than  6 years, Haemophilus infection often leads to otitis media  (conjunctivitis-otitis syndrome). Preventing spread of the  organism with meticulous handwashing and use of separate  towels is important. The disease often is self-limiting and  resolves spontaneously in 10 to 14 days. Antibiotic eyedrops  usually are effective.   Viral conjunctivitis is caused by an adenovirus. Symp-  toms vary from mild to severe. Some strains of virus cause  conjunctivitis and pharyngitis (pharyngoconjunctival fever),  and others cause keratoconjunctivitis. Both diseases are con-  tagious, with watering, redness, and photophobia. Treatment  is symptomatic.   Allergic conjunctivitis is associated with a variety of anti-  gens, including pollens. Ocular itching is associated with pho-  tophobia, burning, and gritty sensations in the eye. Treatment  is symptomatic and may include antihistamines, low-dose cor-  ticosteroids, mast cell stabilizers, and vasoconstrictors.   Chronic conjunctivitis is the result of any persistent conjunc-  tivitis. The cause requires identification for effective treatment.    Trachoma (chlamydial conjunctivitis) is caused by Chla-  mydia trachomatis. It often is associated with poor hygiene and  is the leading cause of preventable blindness in the world. The  severity of the disease varies, but it can involve inflammation  with scarring of the conjunctiva and eyelids causing distorted  lashes to abrade the cornea, leading to corneal scarring and  blindness. Chlamydial organisms are sensitive to local or sys-  temic antibiotics. The World Health Organization aims to elim-  inate trachoma as a public health problem by 2020 using the  SAFE Strategy: Surgery for inturned lashes, Antibiotics, Facial  cleanliness, and Environmental improvement.!”4   Keratitis. Keratitis is an inflammation of the cornea that  can be noninfectious or caused by bacteria, viruses, or fungus.  Bacterial infections often cause corneal ulceration and require  intensive antibiotic treatment. Staphylococcus aureus is the  most common bacterial infection. Type 1 herpes simplex virus  can involve the cornea and conjunctiva. Predisposing factors  include contact lens use, trauma, and penetrating keratoplasty  (corneal grafting). Common symptoms include photophobia,  pain, and lacrimation. Severe ulcerations with residual scarring  require corneal transplantation.!”°    The wall of the eye is formed of three layers: sclera, choroid, and  retina (Figure 16-12). The sclera is the thick, white, outermost  layer. It becomes transparent at the cornea, the portion of the  sclera in the central anterior region that allows light to enter  the eye. The choroid is the deeply pigmented middle layer that  prevents light from scattering inside the eye. The iris, part of the  choroid, has a round opening, the pupil, through which light  passes. Smooth muscle fibers control the size of the pupil so  that in close vision and bright light the pupil constricts and in  distant vision and dim light the pupil dilates.   The retina is the innermost layer of the eye, and contains mil-  lions of rods and cones, special photoreceptors that convert light   FIGURE 16-12 Structure of the Eyeball and Cell Layers of the Retina. A, Horizontal section through the left eyeball.  The eye is viewed from above. B, Pigmented and sensory layers of the retina. (From Patton KT, Thibodeau GA: Anatomy &  physiology, ed 8, St Louis, 2013, Mosby.)    energy into nerve impulses. Rods mediate peripheral and dim  light vision and are densest at the periphery. Cones, densest in  the center of the retina, are color and detail receptors. The pho-  toreceptive rods and cones are distributed over the entire retina,  except where the optic nerve leaves the eyeball. Lack of rods and  cones in this area results in the optic disc, or blind spot. Lateral to  each optic disc is the fovea centralis, a tiny area that contains only  cones and provides the greatest visual acuity (see Figure 16-12).  The optic nerve (second cranial nerve) is composed of reti-  nal cell axons. As shown in Figure 16-13, nerve impulses pass  through the optic nerves after leaving the retinas. At the optic  chiasm the fibers from the inner (nasal) halves of the retinas  cross to the opposite side, where they join fibers from the outer  (temporal) halves of the retinas to form the optic tracts. The  fibers of the optic tracts synapse in the dorsal lateral geniculate  nucleus, and from there the geniculocalcarine fibers pass by way  of the optic radiation (or geniculocalcarine tract) to the primary  visual cortex in the occipital lobe of the brain. Some fibers ter-  minate in the suprachiasmatic nucleus (located above the optic  chiasm) and are involved in regulating the sleep-wake cycle.  Light entering the eye is focused on the retina by the lens—  a flexible, biconvex, crystal-like structure. In youth the lens is  transparent and has the consistency of hardened jelly. The flex-  ibility of the lens allows a change in curvature with contraction  of the ciliary muscles. This is called accommodation and it  allows the eye to focus on objects at different distances. Anterior  to the lens are the iris and the aqueous chamber, which is filled  with aqueous humor. The aqueous humor helps to maintain the  pressure inside the eye and provides nutrients to the lens and  cornea. Aqueous humor is free-flowing fluid, secreted by the  ciliary processes and reabsorbed into the canal of Schlemm. If  drainage is blocked, pressure within the eye increases (as it does  with glaucoma). Posterior to the lens is the vitreous chamber and  it is filled with a gel-like substance called vitreous humor. Vit-  reous humor helps prevent the eyeball from collapsing inward.    FIGURE 16-13 Visual Fields and Defects That Accompany Damage to the  Right Visual Pathways. 1, Optic nerve: blindness. 2, Lateral optic chiasm: grossly  incongruous, incomplete (contralateral) homonymous hemianopsia. 3, Central optic  chiasm: bitemporal hemianopsia. 4, Optic tract: incongruous, incomplete homony-  mous hemianopsia. 5, Temporal loop of the optic radiation: congruous partial or  complete (contralateral) homonymous superior quadrantanopia. 6, Parietal (supe-  rior) projection of the optic radiation: congruous partial or complete homonymous  inferior quadrantanopia. 7, Complete parieto-occipital interruption of the optic  radiation: complete congruous homonymous hemianopsia with psychophysical  shift of the foveal point, often sparing central vision and resulting in “macular spar-  ing.” 8, Incomplete (subtotal) damage to the visual cortex: congruous homonymous  scotomas, usually encroaching at least acutely on central vision. (From Goldman  C, editor: Goldman's Cecil medicine, ed 24, vol 2, Philadelphia, 2012, Saunders.)    The central retinal artery provides blood to the inner retinal  surface. Nutrients and oxygen are supplied to the outer surface  of the retina by the choroid, a vascular layer that lies between  the retina and sclera. Six extrinsic eye muscles, attached to the  outer surface of each eye, allow gross eye movements and per-  mit the eyes to follow a moving object (Figure 16-14).    Changes in the visual and motor components of the eye caused  by aging begin at an early age, particularly in the lens of the  eye. Changes caused by aging are summarized in Table 16-4.  Structural changes combined with chronic diseases, including  dementias and diabetes mellitus, result in a decline in visual  acuity and extraocular motor muscle function.!°°!%”    Alterations in Ocular Movements. Abnormal ocular  movements occur as a result of oculomotor, trochlear, or    FIGURE 16-14 Extrinsic Muscles of the Right Eye, Superior View. (From  Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    abducens cranial nerve dysfunction (see Table 15-6). The  three types of eye movement disorders are (1) strabismus, (2)  nystagmus, and (3) paralysis of individual extraocular muscles.   Strabismus is the deviation of one eye from the other when  a person is looking at an object; it results in failure of the two  eyes to simultaneously focus on the same image and therefore  loss of binocular vision. The deviation may be upward, down-  ward, inward, or outward, resulting from a weak or hypertonic  muscle in one of the eyes. Strabismus may be caused by a neu-  romuscular disorder of the eye muscle, diseases involving the  cerebral hemispheres, or thyroid disease.!°* The primary symp-  tom of strabismus is diplopia (double vision). Strabismus in  children requires early intervention to prevent the development  of amblyopia (reduced vision in the affected eye without ocu-  lar pathology and with full optical correction). Surgery may be  helpful to both children and adults with strabismus.!”   Nystagmus is an involuntary unilateral or bilateral rhyth-  mic movement of the eyes and can occur in infants (congenital)  or adults (acquired). It may be present at rest, or it may occur  with eye movement. The two major forms of nystagmus are  pendular nystagmus and jerk nystagmus. Pendular nystagmus  is characterized by a regular alternating forward and backward  movement of the eyes in which both phases of the movement  are equal in length. In jerk nystagmus one phase of the eye  movement is faster than the other. Nystagmus may be caused  by an imbalance in the normally coordinated reflex activity of  the inner ear, vestibular nuclei (connecting the vestibular nerve  with vestibulospinal tracts), cerebellum, medial longitudinal  fascicle (connecting the mesencephalon with the upper portion  of the spinal cord), or nuclei of the oculomotor, trochlear, and  abducens cranial nerves (see Table 15-6). Drugs, retinal disease,  and diseases involving the cervical cord also may produce nys-  tagmus. Acquired untreated nystagmus can lead to loss of visual  acuity.20   Paralysis of specific extraocular muscles may cause a variety  of abnormalities, including limited abduction, abnormal clo-  sure of the eyelid, ptosis (drooping of the eyelid), and diplopia.    Formation of a gray ring at the edge of cornea (arcus senilis)  Decrease in size and volume caused by thickening of lens    Reduction in number of rods at periphery, loss of rods and   Occasionally exerts pressure on Schlemm canal and may lead to  increased intraocular pressure and glaucoma   Decrease in refraction with increased light scattering and  decreased color vision (green and blue); decreased dark  adaptation; cataracts   Increase in the minimum amount of light necessary to see an object    *The rate at which consecutive visual stimuli can be presented and still be perceived as separate.    The abnormalities occur as a result of unopposed muscle activ-  ity. Trauma or pressure in the area of the cranial nerves may  cause paralysis of specific extraocular muscles. Diseases such as  diabetes mellitus and myasthenia gravis also may affect specific  extraocular muscles.   Alterations in Visual Acuity. Visual acuity is the ability to  see objects in sharp detail. With advancing age the eye’s lens  becomes less flexible and less adjustable. In addition, the  sclera changes shape, causing light to fall on the macula (an  opaque portion of the cornea). Thus visual acuity declines  with age. Visual acuity also may change or diminish for many  other reasons. Specific causes of visual acuity changes include:  (1) amblyopia, (2) scotoma, (3) cataracts, (4) papilledema,  (5) dark adaptation, (6) glaucoma, (7) retinal detachment, and  (8) macular degeneration.   Amblyopia (lazy eye) is a reduction or dimness of vision for  unknown reasons. It does not result from a change in refraction  (i.e., deviation of light rays) or from any visible changes in the  eye. Amblyopia is associated with strabismus and anisometro-  pia (refractive error in one eye differs from that of the other  eye); with diseases such as diabetes mellitus, renal failure, and  malaria; and with toxic substances such as alcohol and tobacco.  Amblyopia is the most common cause of vision loss in children  and is usually treated either by patching the unaffected eye for  extended times to ensure a period of use of the affected eye or  by administering atropine eyedrops.*”! Refractive errors are  treated with corrective lenses.   A scotoma is a circumscribed defect of the central field of  vision. It can be a sequel to demyelinating optic neuritis, an  inflammatory lesion of the optic nerve frequently associated  with optico-spinal multiple sclerosis (see Chapter 18). Age-  related macular degeneration is associated with scotoma. Less  common causes include the compression of one optic nerve  by a retroorbital tumor, neuromyelitis optica (autoantibody-  related inflammation of the optic nerve and spinal cord), per-  nicious anemia, and toxic or metabolic causes such as methyl  alcohol poisoning and use of tobacco. The precise mechanisms    for these conditions causing a scotoma are uncertain, but the  result is always a serious impairment in visual acuity.7°?   A cataract is a cloudy or opaque area in the ocular lens and  leads to visual loss when located on the visual axis. The incidence  of cataracts increases with age as the lens enlarges. Cataracts  develop because of alterations of metabolism and transport of  nutrients within the lens. Although the most common form of  cataract is degenerative, cataracts also may occur congenitally  or as a result of infection, radiation, trauma, drugs, or diabetes  mellitus. Cataracts cause decreased visual acuity, blurred vision,  glare, and decreased color perception. Cataracts are treated by  removal of the entire lens and replacement with an intraocular  artificial lens.”°   Dark adaptation also affects visual acuity. Low illumina-  tion causes impaired visual acuity, particularly in older adults.  The average 80-year-old person needs more than twice as much  light as a 20-year-old person to see equally well. Changes in the  quantity and quality of rhodopsin, a substance found in the rods  and responsible for low-light vision, are thought to be respon-  sible for reduced dark adaptation in older adults.?°* Vitamin A  deficiencies can cause the same phenomenon in individuals of  any age.   Glaucoma is a leading cause of visual impairment and blind-  ness. It is characterized by intraocular pressures greater than the  normal pressures of 12 to 20 mmHg maintained by the aqueous  fluid. Family history is a risk factor, and glaucoma can be inher-  ited.? The types of glaucoma are summarized in Table 16-5  and Figure 16-15. Open-angle glaucoma is the most common.  Chronic increased intraocular pressure causes death of retinal  ganglions and optic nerve degeneration with loss of peripheral  vision, followed by central vision impairment and blindness.  Extremely high pressures can cause blindness within days or  hours. Loss of visual acuity results from pressure on the optic  nerve, which is believed to block the flow of cytoplasm from  neuronal bodies in the retina to peripheral optic nerve fibers  entering the brain. Lack of nutrients, ischemia, cytotoxic fac-  tors, and altered immune mechanisms may lead to death of the    Obstruction of outflow of aqueous humor at  trabecular meshwork or Schlemm canal;  myopia may be a risk factor   Form of open-angle glaucoma with  symptomless damage to the optic nerve and  gradual vision loss when intraocular pressure  is within normal range (12-20 mmHg)   Forward displacement of iris toward cornea  with narrowing of iridocorneal angle and  obstruction to outflow of aqueous humor from  anterior chamber   Acute closure of iridocorneal angle with a  sudden rise in intraocular pressure, producing  pain, redness, and visual disturbances   Open- or closed-angle obstruction caused by,  for example, uveitis, hemorrhage, rupture of  lens or tumors   Malformation of trabecular meshwork and  excess extracellular matrix in outer meshwork    involved neurons.*°° Acute pain may result and there is loss of  peripheral vision and progression to blindness. Early detection  and treatment prevent optic neuropathy and visual impair-  ment. Glaucoma often is treated with pharmaceutical eyedrops  to reduce secretion or increase absorption of aqueous humor.  Surgery may be needed to open the spaces of the trabeculae  and reduce intraocular pressure. Neuroprotective therapies are  being evaluated.?°”   Retinal detachment is a common cause of visual impairment  and blindness. Risk factors include retinal holes and vitreoreti-  nal traction. Fluid (exudate, hemorrhage, or liquid vitreous)  separates the photoreceptors from the retinal pigment epithe-  lium. The separation deprives the outer retina of oxygen and  nutrients because the diffusion distance is increased. Commu-  nication is also disrupted between the pigment epithelium and  photoreceptors. Rhegmatogenous retinal detachment (retinal  breaks caused by vitreoretinal traction) is the most common  form of retinal detachment. Causes include intracapsular cata-  ract extraction, severe myopia, lattice degeneration, vitreoreti-  nal traction, and trauma. Contraction of fibrous membranes  can cause tractional separation of the retinal layers as occurs in  proliferative diabetic retinopathy. Treatment involves surgical  retinal reattachment.7°°   Age-related macular degeneration (AMD) is a process in  which “drusen” or retinal waste products accumulate within  the deep retinal layers. There are two forms of AMD: wet and  dry. The dry or atropic form of AMD is most prevalent and  involves loss of retinal pigment epithelium and photoreceptors  with overall atrophy of cells. The wet exudative form (neovas-  cular AMD) is the more severe form and involves proliferation  of abnormal choroidal vessels, which leak and bleed, causing  retinal detachment. Hypertension, cigarette smoking, cataract   FIGURE 16-15 Glaucoma. 1, Open-angle glaucoma. The obstruction to aque-  ous flow lies in the trabecular meshwork. 2, Closed-angle glaucoma. The iris  presses against the lens, blocking aqueous flow into the anterior chamber and    surgery, diabetes mellitus, higher plasma fibrinogen levels, and  genetic predisposition are risk factors for AMD.*”’ Symptoms  include blurred vision, loss of central vision, difficulty reading,  and poor night vision. AMD is the major cause of blindness in  individuals older than 50 years. Progress is being made in anti-  angiogenic and vascular endothelial growth factor treatments.  Understanding genetic factors contributing to AMD will assist  with identifying a biomarker for the disease.*!°   Alterations in Accommodation. Accommodation is the  process whereby the thickness of the lens changes with  contraction of the ciliary muscles. Accommodation is needed  for clear vision and is mediated through the oculomotor nerve  (cranial nerve III). Pressure, inflammation, and disease of the  oculomotor nerve may alter accommodation. Symptoms include  diplopia, blurred vision, and headache. Loss of accommodation  in older adults is termed presbyopia, a condition in which the  ocular lens becomes larger, firmer, and less elastic. The major  symptom is reduced near vision, causing the individual to hold  reading material at arm’s length. Correction of presbyopia  is accomplished through reading glasses or bifocal lenses,  accommodative intraocular lenses, or surgical treatment.?!!   Alterations in Refraction. Alterations in refraction are the  most common visual problem. Errors in refraction are caused  by irregularities of the corneal curvature, the focusing power  of the lens, and the length of the eye. The major symptoms of  refraction alterations are blurred vision and headache. Three  types of refraction alterations are myopia, hyperopia, and  astigmatism (Figure 16-16).   In myopia (nearsightedness), light rays are focused in front  of the retina when a person is looking at a distant object, result-  ing in blurred vision. A concave lens is needed for correction.    FIGURE 16-16 Alterations in Refraction. A, Myopic eye. Parallel rays of light  are brought to a focus in front of the retina. B, Hyperopic eye. Parallel rays of light  come to a focus behind the retina in the nonaccommodative eye. C, Simple myopic  astigmatism. The vertical bundle of rays is focused on the retina; the horizontal  rays are focused in front of the retina and the image is blurred. (From Stein HA,  Stein RM, Freeman MI: The ophthalmic assistant: a text for allied and associated  ophthalmic personnel, ed 9, Philadelphia, 2013, Saunders.)    Myopia requires frequent changes of eyeglasses while the eye-  ball is lengthening in childhood. Myopia is a risk factor for reti-  nal detachment and cataract formation.   In hyperopia (farsightedness), light rays are focused behind  the retina when a person is looking at a near object. Hyperopia  is corrected with a convex lens. Astigmatism is caused by an  unequal curvature of the cornea. In astigmatism, light rays are  bent unevenly and do not come to a single focus on the retina.  Astigmatism may coexist with myopia, hyperopia, or presby-  opia. Correction is accomplished with a cylinder lens.   Alterations in Color Vision. Normal sensitivity to color  diminishes with age because of the progressive yellowing of  the lens that occurs with aging. All colors become less intense,  although color discrimination for blue and green is most greatly  affected. Color vision deteriorates more rapidly for individuals  with diabetes mellitus than for the general population. The  deterioration is thought to be an accelerated version of senile  color vision deterioration.   Abnormal color vision also may be caused by color blind-  ness, an inherited trait. Color blindness is generally an X-linked  recessive characteristic affecting 8% of the male population and    0.5% of the female population. Although many forms of color  blindness exist, most commonly the affected individual cannot  distinguish red from green.?!?7!°   Neurologic Disorders Causing Visual Dysfunction. Various  neurologic disorders may cause visual dysfunction. Vision may  be disrupted at many points along the visual pathway, causing  a variety of defects in fields of vision. Visual changes do not  always cause defects or blindness in the entire visual field;  hemianopia is the term that describes defective vision in half of  a visual field. (Figure 16-13 illustrates the many areas along the  visual pathway that may be damaged and the associated visual  changes.) Because of the anatomy of the optic nerves, injury to  the optic nerve causes ipsilateral (same side) blindness but a  normal contralateral (opposite side) visual field. Injury to the  optic chiasm (the X-shaped crossing of the optic nerves), often  caused by atherosclerotic ischemia or external compression  from trauma or aneurysm, can cause a variety of defects,  depending on the location of injury. These defects vary because  at the optic chiasm, nerve fibers from the medial half of each  retina separate from the lateral half and enter the opposite optic  tract.   Because of the normal structure of the visual pathways,  destruction of one optic tract causes homonymous hemianop-  sia (complete loss of vision in the inner half of one eye and the  outer half of the other). Thus, if an injury to the left optic tract  occurs, the individual is blind in the right eye’s medial (inner)  field and the left eye’s lateral (outer) field. If the compression of  the optic tract is asymmetric, an incongruous (or uneven) hom-  onymous defect results. Injury to one optic radiation (an ocu-  lar pathway in the internal capsule, temporal lobe, or occipital  lobe) also causes a homonymous (same field) defect. A major  injury in the optic radiation causes homonymous hemianop-  sia. A lesser injury may cause an upper quadrant homonymous  defect. Generally the defects are the same size in both eyes.  When the homonymous hemianopsia is caused by an occipi-  tal lobe lesion, the area of hemianopsia is split. Although visual  acuity may remain unimpaired, reading is difficult because of  the inability to group words.   Papilledema is edema of the optic nerve at its point of  entrance into the eyeball. Papilledema is caused by increased  intracranial pressure (e.g., brain tumors, intracranial hemor-  rhage, hydrocephalus). The subarachnoid space of the brain is  continuous with the optic nerve sheath. As cerebrospinal fluid  (CSF) pressure increases, the pressure is transmitted to the  optic nerve and the optic nerve sheath compresses the nerve  and impedes axoplasmic transport. This leads to accumulation  of axoplasmic substances at the level of the lamina cribrosa (a  meshlike structure in the sclera where the retinal nerves exit the  eye and form the optic nerve), resulting in the characteristic  swelling of the optic disc. Obliteration of the physiologic cup (a  bright area normally located in the center of the optic disc) fol-  lows. Later the optic disc becomes raised above the level of the  surrounding retina, and the margins become blurred and indis-  tinct. With severe swelling, hemorrhage and patches of white  exudate (caused by nerve infarcts) surround the disc margins.  The edematous nerves compress the small retinal veins, caus-  ing venous stasis and engorgement. Headache is common and    FIGURE 16-17 Retinoblastoma. The tumor occupies a large portion of the  inside of the eye globe. (From Damjanov |: Pathology for the health professions,  ed 3, St Louis, 2006, Saunders. Courtesy Dr. Walter Richardson and Dr. Jamsheed  Khan, Kansas City, Kansas.)    there may be no visual changes, blurred vision, or constriction  of visual fields.   Retinoblastoma. Retinoblastoma is a rare congenital eye  tumor of young children that originates in the retina of one or  both eyes (Figure 16-17). Retinoblastoma demonstrates both  an inherited and an acquired form. Retinoblastoma rarely is  diagnosed after the child is 5 years of age. The inherited form  of the disease generally is diagnosed during the first year of  life and often involves multiple tumors and sometimes both  eyes (40%).7!4 The acquired disease is commonly diagnosed  in children 2 to 3 years of age and involves unilateral disease.  Although retinoblastoma is the most common pediatric  intraocular tumor, only about 300 cases are diagnosed in the  United States each year and 1 in 4 cases involves both eyes.”!°   PATHOPHYSIOLOGY. Approximately 40% of retinoblastomas are  inherited as an autosomal dominant disorder caused by muta-  tions in the RBI tumor-suppressor gene. The remaining 60%  are acquired. In the early 1970s Knudson proposed the “two-  hit” hypothesis to explain the occurrence of hereditary and  acquired forms of the disease. This hypothesis predicts that two  separate transforming events or “hits” must occur in a normal  retinoblast cell to cause the cancer. Further, it proposes that in  the inherited form the first hit or mutation occurs in the germ  cell (inherited from either parent), and the mutation is con-  tained in every cell of the child’s body. Only a second, random  mutation in a retinoblast cell is necessary to transform that cell  into cancer. Multiple tumors are observed in the inherited form  because these second mutations are likely to occur in several of  the approximately 1 to 2 million retinoblast cells. In contrast,  the acquired form of retinoblastoma requires that two indepen-  dent hits or mutations occur in the same somatic cell (after the  egg is fertilized) for transformation to cancer. This is much less  likely to happen.?!° Figure 16-18 illustrates the two-mutation  model for these two patterns of mutation.   The gene location in which the initial retinoblastoma muta-  tion occurs is on the long arm of chromosome 13, band q14.7!°  The gene responsible for retinoblastoma, a tumor-suppressor  gene, is called the RB gene. The first hit inactivates one allele  of the RB gene, and the second hit inactivates the other allele  of the gene. Without the normal functioning of the RB gene,  production of protein growth regulators that control retinal cell  growth is lacking. Because the gene is inactivated, lack of cell  growth control results in unregulated proliferation and tumor  development. Epigenic effects are under investigation.?!™    Retinoblastoma grows as one or more tumors in the ret-  ina and extends into the vitreous humor. Free-floating, small  tumors in the vitreous humor may attach to the surface of  the retina in multiple areas and proliferate (Figure 16-19).  The tumor also can invade the optic nerve by infiltrating the  cribriform plate of the ethmoid bone or can spread through  the sheath around the nerve. In either case the tumor can gain  access to the subarachnoid space and the CNS. The tumor  spreads into the choroid in 25% of children with retinoblas-  toma. Because the choroid is highly vascular, metastasis by  means of hematogenous spread is possible. When hematog-  enous spread occurs, metastatic sites include the bone marrow,  long bones, lymph nodes, and liver. If the tumor invades the  orbit, lymphatic spread is possible. Spontaneous regression  occurs, although infrequently, and may be caused by the tumor  outgrowing its blood supply.   CLINICAL MANIFESTATIONS. The two most frequent symptoms  of retinoblastoma are leukokoria, a white pupillary reflex also  called cat’s-eye reflex caused by the mass behind the lens (see  Figure 16-17), and strabismus. At that point, the tumor is large  enough that a light shone into the eye is reflected back by the  tumor, making the pupil appear white. Note that an ophthalmo-  logic examination is not necessary to detect this tumor but only  a simple examination of the pupils with a flashlight. If leukoko-  ria is noted, the child should be referred for a complete dilated  ophthalmologic exam. Other signs and symptoms include a red,  painful eye and limited vision. Any of these signs and symptoms  in a child younger than 4 years of age warrants careful ophthal-  mologic examination of both eyes. Similarly, any newborn with  a known genetic risk for retinoblastoma should have routine  ophthalmologic examinations.   EVALUATION AND TREATMENT. Diagnostic evaluation for reti-  noblastoma includes documentation of family history; com-  plete ophthalmologic examination; and metastatic studies that  include bone marrow aspiration, lumbar puncture for spi-  nal fluid examination, bone scan, and additional ultrasound,  radiologic, and CT studies of the orbit and brain. Because of  the potential hereditary risk to a child’s siblings, all siblings  younger than 4 years also should receive ophthalmologic  evaluations.   Retinoblastoma is a treatable tumor, and dual priorities are  saving the child’s life and restoring useful vision. Early diag-  nosis and new chemotherapeutic agents have led to a more  conservative approach to treatment. Chemoreduction of the  tumor occurs with intravenous chemotherapy to reduce tumor  volume. Focal treatments using hyperthermia, laser photoco-  agulation, or cryotherapy then destroy residual tumor. Large  or multiple tumors, indicating more advanced disease, require  external beam or plaque radiotherapy and in some cases enu-  cleation (removal) of the eye. Every attempt is made to pre-  serve vision in at least one eye without jeopardizing the child’s  survival.?!7   The prognosis for most children with retinoblastoma is  excellent, with a greater than 90% long-term survival, although  children with bilateral or metastatic disease at diagnosis have  a poor prognosis. Approximately 75% of children have useful  vision in the treated eye.    FAMILIAL FORM PATHOGENESIS OF SPORADIC FORM  RETINOBLASTOMA  Somatic cells  of parents  N f Mutant  Ofna RB gene  gene    FIGURE 16-18 The Two-Mutation Model of Retinoblastoma Development. In inherited (familial) retinoblastoma,  mutations of the AB locus on chromosome 13q14 lead to neoplastic proliferation of retinal cells. The first mutation is transmit-  ted through the germline of an affected parent. The second mutation occurs somatically in a retinal cell, leading to develop-  ment of the tumor. In sporadic retinoblastoma, development of a tumor requires two somatic mutations. (From Kumar V, Cotran  RS, Robbins SL: Robbins basic pathology, ed 8, Philadelphia, 2010, Saunders.)    FIGURE 16-19 Bilateral Retinoblastoma. Presence of white mass consist-  ing of detached retina and neoplastic tissue immediately behind lens in each eye.  (From Kissane JM, editor: Anderson's pathology, ed 8, St Louis, 1985, Mosby.)   The external auditory canal is surrounded by the bones of the  cranium. Its opening (meatus) is just above the mastoid process  (Figure 16-20), which contains air-filled sinuses called mastoid  air cells. These promote conductivity between the external and  the middle ear.   The ear is divided into three areas: (1) the external ear, involved  only with hearing; (2) the middle ear, involved only with hear-  ing; and (3) the inner ear, involved with both hearing and  equilibrium. The external ear is composed of the pinna (auri-  cle), which is the visible portion of the ear, and the external  auditory canal, a tube that leads to the middle ear (see Figure  16-20). Sound waves entering the external auditory canal hit    FIGURE 16-20 The Ear. External, middle, and inner ear structures. (Anatomic structures are not drawn to scale. Middle  and inner ears enlarged for better visualization here.) (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis,    the tympanic membrane (eardrum) and cause it to vibrate.  The tympanic membrane separates the external ear from the  middle ear.   The middle ear is composed of the tympanic cavity, a small  chamber in the temporal bone. Three ossicles (small bones)  transmit the vibration of the tympanic membrane to the inner  ear. The three ossicles are termed the malleus (hammer), incus  (anvil), and stapes (stirrup). When the tympanic membrane  moves, the malleus moves with it and transfers the vibration to  the incus, which passes it on to the stapes. The stapes presses  against the oval window, a small membrane of the inner ear.  The movement of the oval window sets the fluids of the inner  ear in motion (Figure 16-21).   The eustachian (pharyngotympanic) tube connects the  middle ear with the thorax. Normally flat and closed, the eusta-  chian tube opens briefly when a person swallows or yawns, and  it equalizes the pressure in the middle ear with atmospheric  pressure. Equalized pressure permits the tympanic membrane  to vibrate freely. Through the eustachian tube the mucosa of the  middle ear is contiguous with the mucosal lining of the throat.   The inner ear is a system of osseous labyrinths (bony, maze-  like chambers) filled with a fluid called perilymph. The bony  labyrinth is divided into the cochlea, the vestibule, and the  semicircular canals (see Figure 16-21). Suspended in the peri-  lymph is a membranous labyrinth that basically follows the  shape of the bony labyrinth. The membranous labyrinth is filled  with a thicker fluid called endolymph.   Within the cochlea is the organ of Corti, which contains  hair cells (hearing receptors). Sound waves that reach the  cochlea through vibrations of the tympanic membrane, ossicles,  and oval window set the cochlear fluids into motion. Receptor  cells on the basilar membrane are stimulated when their hairs  are bent or pulled by the movement. Once stimulated, hair cells    transmit impulses along the cochlear nerve (a division of the  vestibulocochlear nerve) to the auditory cortex of the temporal  lobe in the brain (see Figure 16-21), where interpretation of the  sound occurs. Directional hearing is controlled by the angle of  the sound source to both ears and by the axonal delay in con-  duction in groups of neurons.   The semicircular canals and vestibule of the inner ear contain  equilibrium receptors. In the semicircular canals the dynamic  equilibrium receptors respond to changes in direction of move-  ment. Within each semicircular canal is the crista ampullaris,  a receptor region composed of a tuft of hair cells covered by a  gelatinous cupula. When the head is rotated, the endolymph in  the canal lags behind and moves in the direction opposite to the  head’s movement. The hair cells are stimulated, and impulses  are transmitted through the vestibular nerve (a division of the  vestibulocochlear nerve) to the cerebellum.   The vestibule in the inner ear contains maculae, receptors  essential to the body’s sense of static equilibrium. As the head  moves, otoliths (small pieces of calcium salts) move in a gel-  like material in response to changes in the pull of gravity. The  otoliths pull on the gel, which in turn pulls on the hair cells  in the maculae. Nerve impulses in the hair cells are triggered  and transmitted to the brain (see Figure 16-21). Thus the ear  not only permits the hearing of a large range of sounds but also  assists with maintaining balance through the sensitive equilib-  rium receptors.    Auditory changes caused by aging are common and incre-  mental. Changes in hearing with aging are summarized in  Table 16-6. Approximately one third of people older than 65  years have hearing loss caused by genetic and environmental    FIGURE 16-21 The Inner Ear. A, The bony labyrinth (orange) is the hard outer wall of the entire inner ear and includes  semicircular canals, vestibule, and cochlea. Within the bony labyrinth is the membranous labyrinth (purple), which is sur-  rounded by perilymph and filled with endolymph. Each ampulla in the vestibule contains a crista ampullaris that detects  changes in head position and sends sensory impulses through the vestibular nerve to the brain. B, The inset shows a section  of the membranous cochlea. Hair cells in the organ of Corti detect sound and send the information through the cochlear nerve.  The vestibular and cochlear nerves join to form the eighth cranial nerve. (From Patton KT, Thibodeau GA: Anatomy & physiol-  ogy, ed 8, St Louis, 2013, Mosby.)    Loss of auditory neurons  in spiral ganglia of organ  of Corti    Inability to hear high-frequency sounds  (presbycusis, sensorineural loss); interferes  with understanding speech; hearing may  be lost in both ears at different times   Inability to hear high-frequency sounds  (presbycusis, sensorineural loss); interferes  with understanding speech; hearing may  be lost in both ears at different times   Inability to hear at all frequencies, but  more pronounced at higher frequencies  (cochlear conductive loss)   Equal loss of hearing at all frequencies  (strial loss); inability to disseminate  localization of sound   Equal loss of hearing at all frequencies  (strial loss); inability to disseminate  localization of sound    factors.*'> Changes may occur in the structural and functional  components of the peripheral or central auditory system. Loss  of hearing for sounds in the high-frequency range (presbycu-  sis) is most common and interferes with understanding speech,  particularly high-frequency consonant sounds (e.g., s, sh, f).  Hearing may be lost in both ears but not at the same time. Older    adults from rural areas have less hearing loss than those in noisy  cities. The ability to discriminate localization of sound varies  with high and low frequencies and diminishes with age.?!? In  the low-frequency range, sound localization is a function of the  timing of sound arrival between the two ears; localization of  high-frequency sounds is a function of sound intensity. Because  older adults tend to lose high-frequency hearing first, they may  have difficulty localizing high-frequency sounds.   Otitis Externa. Ear infections can occur in the ear canal (otitis  externa) or in the middle ear (otitis media). Otitis media is the  leading cause of healthcare visits and drug prescriptions throughout  the world with 50% occurring in the under 5-year age group.””°   Otitis externa is the most common infection of the outer  ear usually caused by bacteria and less commonly a fungus.””!  The most frequently found microorganisms are Pseudomonas,  Escherichia coli, and Staphylococcus aureus. Infection usually  follows prolonged exposure to moisture (swimmer’s ear). The  earliest symptoms are inflammation with swelling and clear  drainage progressing to purulent drainage with obstruction of  the canal. Tenderness and pain with earlobe retraction accom-  pany inflammation.   Otitis Media. Otitis media is an infection of the middle ear  and is the most common infection of infants and children.  Most children have one episode by 3 years of age. The most  common pathogens are Streptococcus pneumoniae, Haemophilus  influenzae, and Moraxella catarrhalis. Respiratory viruses also  may have an etiologic role.’ Predisposing factors include    allergy, sinusitis, submucous cleft palate, adenoidal hypertrophy,  and immune deficiency. Breast-feeding is a protective factor.   Acute otitis media (AOM) is associated with ear pain, fever,  irritability, inflamed tympanic membrane, and fluid in the mid-  dle ear. The tympanic membrane progresses from erythema to  opaqueness with bulging as fluid accumulates. An increasing  prevalence of AOM is caused by methicillin-resistant microor-  ganisms. Otitis media with effusion (OME) is the presence of  fluid in the middle ear without symptoms of acute infection.  Treatment includes antimicrobial therapy for AOM, particu-  larly in children 2 years and younger.   Chronic otitis media is persistent or recurring infection of the  middle ear. Placement of tympanostomy tubes is considered when  bilateral effusion persists for 3 months and for significant hearing  loss.?’? Mastoidectomy combined with tympanostomy tubes may  be required when there is cholesteatoma (skin growth into the  middle ear associated with perforation of the eardrum).’** Compli-  cations include mastoiditis, brain abscess, meningitis, and chronic  otitis media with hearing loss. Speech, language, and cognitive dis-  abilities may be affected by persistent middle ear effusions.    Between 5% and 10% of the general population have a hear-  ing impairment. The major categories of auditory dysfunction  are conductive hearing loss, sensorineural hearing loss, mixed  hearing loss, and functional hearing loss.   Conductive Hearing Loss. Conductive hearing loss occurs  when a change in the outer or middle ear impairs sound from  being conducted from the outer to the inner ear. Conductive  hearing loss occurs when there is interference in air conduction.  Conditions that commonly cause a conductive hearing loss  include impacted cerumen, foreign bodies lodged in the ear  canal, benign tumors of the middle ear, carcinoma of the external  auditory canal or middle ear, eustachian tube dysfunction,  otitis media, acute viral otitis media, chronic suppurative otitis  media, cholesteatoma, and otosclerosis (impaired mobility of  the stapes footplate in the presence of dense sclerotic bone).   Symptoms of conductive hearing loss include diminished  hearing and soft speaking voice. The voice is soft because often  the individual hears his or her voice, conducted by bone, as  loud. In addition, although the cause is unknown, the individ-  ual often hears better in a noisy environment than in a quiet  one (a condition called paracusia willisiana). Treatment of the  underlying cause generally improves hearing and a hearing aid  can improve quality of life.?7°   Sensorineural Hearing Loss. A sensorineural hearing loss  is caused by impairment of the organ of Corti or its central  connections. The hearing loss may be gradual or sudden.  Conditions that commonly cause sensorineural hearing loss  include congenital and hereditary factors, noise exposure,  aging, Méniére disease, ototoxicity, and systemic disease  (syphilis, Paget disease, collagen diseases, diabetes mellitus).  Congenital and neonatal sensorineural hearing loss may be  caused by maternal rubella, ototoxic drugs, prematurity,  traumatic delivery, erythroblastosis fetalis, and congenital  hereditary malfunction. Diagnosis often is made when delayed  speech development is noted.    Presbycusis is age-related hearing loss usually in the high  frequencies. It is the most common form of sensorineural hear-  ing loss and is especially common in older adutls.”!* Presbycusis  may occur because of atrophy of the basal end of the organ of  Corti, a loss in the number of auditory receptors, changes in  vasculature, or stiffening of the basilar membranes. Because of  the slow progression of hearing loss, onset of symptoms is grad-  ual. In addition, drug ototoxicities (drugs that cause destruc-  tion of auditory function) have been observed after exposure  to a variety of chemicals, for example, antibiotics such as strep-  tomycin, neomycin, gentamicin, and vancomycin; diuretics  such as ethacrynic acid and furosemide; and chemicals such as  salicylate, quinine, carbon monoxide, nitrogen mustard, arse-  nic, mercury, gold, tobacco, and alcohol. Because of increased  concentrations of antibiotics in the endolymph, these drugs  generally cause damage to the cells of the cristae and maculae  (located in the inner ear) or the cells of the organ of Corti. The  increased concentration of drugs in the endolymph is preferen-  tially toxic to the cells.   Diuretics affect hearing primarily by altering the sodium-  potassium balance, causing extracellular fluid accumulation  and changes in the microstructure of secretory cells. Qui-  nine, mercury, and lead affect the neural pathways of hearing,  including the spinal ganglia, the eighth cranial nerve, and the  cochlear nucleus. The site of action for the other chemicals,  including alcohol and tobacco, has not yet been determined.  In most instances the drugs and chemicals listed previously  initially cause tinnitus (ringing in the ear), followed by a pro-  gressive high-tone sensorineural hearing loss. Care is aimed at  prevention of further hearing loss because the loss is usually  permanent.   Mixed Hearing Loss. A mixed hearing loss is caused by a  combination of conductive and sensorineural losses.   Functional Hearing Loss. A functional hearing loss occurs  for no organic reason. The individual does not respond to voice  and appears not to hear. Functional hearing loss is thought to  be caused by emotional or psychologic factors. It occurs only  rarely.    Olfaction (smell) dysfunction and taste (gustation) dysfunc-  tion may occur separately or jointly. The strong relationship  between smell and taste creates the sensation of flavor. If either  sensation is impaired, the perception of flavor is altered. (Olfac-  tory structures are illustrated in Figure 16-22.)   Olfaction is a function of cranial nerve I (olfactory) and part  of cranial nerve V (trigeminal). The receptor cells for smell are  located in the olfactory epithelium. Seven primary classes of  olfactory stimulants have been identified: (1) camphoraceous,  (2) musky, (3) floral, (4) peppermint, (5) ethereal, (6) pungent,  and (7) putrid.   Olfactory dysfunctions include hyposmia, anosmia, hallu-  cinations, and parosmia. Hyposmia is the impaired sense of  smell, and anosmia is the complete loss of smell. Both condi-  tions are associated with aging, neurodegenerative and nasal/  sinus disorders, and head trauma.??° When hyposmia or  anosmia occurs bilaterally, it is usually the result of rhinitis    FIGURE 16-22 Olfaction. Location of olfactory epithelium, olfactory bulb, and neuronal pathways involved in olfaction. A,  Midsagittal section of the nasal area shows the locations of major olfactory sensory structures. B, Major olfactory integration  centers of the brain. (Modified from Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    (inflammation of nasal mucosa), sinusitis, nasal polyps, or  excessive smoking. Unilateral hyposmia or anosmia may indi-  cate compression of one olfactory bulb (a bulblike portion of  the olfactory nerves) or nerve tract (olfactory nerve pathway),  possibly by tumor or head trauma. Olfactory hallucinations  arise from hyperactivity in cortical neurons and involve smell-  ing odors that are not really present. They are associated with  temporal lobe seizures and rarely with schizophrenia. Paros-  mia, an abnormal or perverted sense of smell, may occur with  severe depression.?””   Taste is a function of multiple nerves in the tongue, soft pal-  ate, uvula, pharynx, and upper esophagus, including cranial  nerves VII (facial) and IX (glossopharyngeal). The primary sen-  sations of taste are sour, salty, sweet, bitter, and umami (savori-  ness). Taste buds sensitive to each of the primary sensations are  located on the circumvallate, fungiform, and foliate papillae in  specific areas of the tongue. Taste receptors also are found on  airway smooth muscle (bitter) and in the gastrointestinal tract  (bitter and sweet). Their function is not for taste. In the lung  they stimulate bronchodilation and in the gastrointestinal tract  they may participate in metabolic and digestive regulation.?”°”"   Alterations in taste can be caused by injury, medications,  oral infections, or aging. A change in taste also may be attrib-  utable to impairment of smell associated with injury near the  hippocampus.   Hypogeusia is a decrease in taste sensation, and ageusia is  the absence of taste. Ageusia affecting the entire tongue may  follow head injury. Damage to the glossopharyngeal nerve (cra-  nial nerve IX, which innervates the posterior one third of the  tongue) causes the loss of the ability to detect bitterness. This  loss occurs because the receptors for bitter are located on the    base of the tongue. Damage to the facial nerve (cranial nerve  VII, which innervates the anterior two thirds of the tongue)  causes loss of the ability to detect sour, sweet, and salty tastes.  Only bitter tastes can be detected. These losses occur because  sour, sweet, and salt receptors are located on the anterior por-  tion of the tongue. Parageusia is a perversion of taste in which  substances possess an unpleasant flavor. Parageusia occasion-  ally develops for no apparent reason in older adults and is com-  mon in individuals receiving chemotherapy for cancer. In both  cases, parageusia often leads to anorexia and malnutrition.    Sensitivity to odors declines steadily with aging.*°°>!* A study  of odor identification indicates an increasing ability from child-  hood to adolescence and then a decline after 60 years of age. The  sense of smell begins to degenerate with loss of olfactory sensory  neurons and loss of cells from the olfactory bulbs. Loss of olfac-  tory sensitivity and odor identification may diminish appetite  and food selection and thus may lead to malnutrition. Safety  also may be compromised by an inability to smell spoiled food  or hazardous gases.””°   The decline in taste sensation is more gradual than that of  smell and is associated with loss of olfaction. Higher concentra-  tions of flavors are required, and older adults have difficulty  differentiating combinations of flavors. Taste changes with  aging are associated with decline in the number of fungiform  papillae on the tongue, and changes in taste receptor func-  tion.”*! Taste also may be affected by decreased salivary gland  secretion. Amylase, contained in saliva, facilitates perception  of sweet flavors.    Pain is a protective and a complex phenomenon composed  of sensory experiences (time, space, intensity) and emotion,  cognition, and motivation.    . The gate control theory of pain describes the modulation of    pain in the dorsal horn of the spinal cord by sensory affer-  ent stimulation and central descending impulses that influ-  ence the “pain gate” within the substantia gelatinosa of the  spinal cord.    brain produce patterns of pain but the stimuli may origi-  nate independently in the brain with no external input.    . The portions of the nervous system responsible for the sen-    sation and perception of pain may be divided into three  areas: (a) the afferent fibers, (b) the afferent pathways, and  (c) the CNS.    . The afferent system is composed of nociceptors, AS and C    fibers (first-order neurons); the dorsal horn of the spinal  column (second-order neurons); and afferent neurons in  the spinothalamic tract (third-order neurons).    . Nociceptors detect a wide range of stimuli and respond to    mechanical and thermal, sharp, localized pain. Unmyelin-  ated polymodal C fiber transmission is slower and conveys  diffuse burning and aching sensations. These primary-  order neurons terminate on second-order neurons.    transmission: projection cells, excitatory interneurons, and  inhibitory interneurons. The second-order neurons are  located in the spinal cord laminae and function as a pain  gate to regulate pain transmission.    marily in the lateral spinothalamic tract to projection cen-  ters including the thalamus, reticular formation, and PAG  matter.   Third-order neurons carry information to the sensory cor-  tex and reticular and limbic systems for pain processing and  interpretation.   Efferent pathways from the PAG are responsible for modu-  lation or inhibition of afferent pain signals. The thalamus,  cortex, and postcentral gyrus perceive, describe, and local-  ize pain. The reticular formation and limbic system control  the emotional and affective response to pain.   Pain can be modulated by segmental inhibition, which is the  peripheral stimulation of nociceptors by touch, vibration, or  pressure resulting in closure of the spinal cord pain gate. The  higher brain center also can influence painful stimuli (het-  erosegmental control of nociception) as well as inhibition  from the caudal medulla (diffuse noxious inhibitory con-  trols). Thus pain can be modulated with stimulation from  the periphery or by descending impulses from the brain.  Pain neurotransmitters can be classified as inflammatory,  excitatory, and inhibitory modulators of pain. Inflamma-  tory neurotransmitters are usually excitatory.    Pain threshold is the point at which pain is perceived. Pain  threshold does not vary significantly among people or  within the same person over time.   Pain tolerance is the duration of time or the intensity of  pain that an individual will endure before initiating overt  pain response. Tolerance varies widely among individuals  and in the same individual over time.   Classifications of pain include nociceptive pain (with a  known physiologic cause), non-nociceptive pain (neuro-  pathic pain), acute pain (signal to the person of a harm-  ful stimulus), and chronic pain (persistence of pain of  unknown cause or unusual response to therapy).   Acute pain may be (a) somatic (superficial), (b) visceral  (internal), or (c) referred (present in an area distant from  its origin).   Somatic pain arises from connective tissue, muscle, bone,  and skin and is sharp and localized.   Visceral pain is from internal organs and is transmitted by  sympathetic afferents and is poorly localized.   Referred pain usually arises from the viscera and terminates  in an area of the spinal cord that is conjoined with fibers  originating in the skin and other areas and thereby pro-  duces the perception of pain at the referred site.  Physiologic responses to acute pain include increased heart  rate, respiratory rate, and blood pressure; pallor or flush-  ing; dilated pupils; and diaphoresis. Blood glucose level is  elevated; gastric secretion and motility are decreased; and  blood flow to the viscera and skin is decreased.   Chronic pain generally lasts at least 3 months and may be per-  sistent, for example, low back pain or intermittent migraine  headache pain, myofascial pain syndromes, chronic postop-  erative pain, and chronic pain associated with cancer.  Neuropathic pain is usually chronic, results from nerve  trauma or disease, and leads to abnormal peripheral and  central pain processing. Types of neuropathic pain include  deafferentation pain, sympathetically maintained pain,  central pain, and phantom pain.   Newborns and young children have the anatomic and func-  tional ability to perceive pain. Pain experienced by infants  may have prolonged effects on brain organization and  responses to pain.   Older individuals may or may not have an increased pain  threshold. In all age groups, women appear to be more sen-  sitive to pain than are men.   Pain in older adults is influenced by liver and renal func-  tion, including alterations in the metabolism of drugs and  metabolites.    Temperature regulation (thermoregulation) is achieved  through precise balancing of heat production, heat con-  servation, and heat loss. Body temperature is maintained  around 37° C (98.6° F).   Temperature regulation is mediated by the hypothala-  mus. Peripheral thermoreceptors in the skin and central    thermoreceptors in the hypothalamus, spinal cord, and  abdominal organs provide the hypothalamus with informa-  tion about skin and core temperatures.    vasodilation, decreased muscle tone, evaporation of sweat,  increased ventilation, and voluntary mechanisms.    . Fever is triggered by the release of pyrogens from leukocytes    and other cells involved in the immune response (endog-  enous pyrogens) and bacteria (exogenous pyrogens). Fever  is both a symptom of a disease and a normal immunologic  mechanism.    higher level. When a fever breaks, the set point is returned  to normal.    Higher temperatures kill many microorganisms and  decrease serum levels of iron, zinc, and copper that are  needed for bacterial replication.    tenance of body temperature. Because of their greater body  surface area to mass ratio and decreased subcutaneous fat,  infants do not conserve heat well. Older individuals have  poor responses to environmental temperature extremes as a  result of slowed blood circulation, structural and functional  changes in skin, and an overall decrease in heat-producing  activities.   Hyperthermia (marked warming of core temperature)  can produce nerve damage, coagulation of cell proteins,  and death. Forms of accidental hyperthermia include  heat cramps, heat exhaustion, heat stroke, and malignant  hyperthermia. Heat stroke and malignant hyperthermia are  potentially lethal developments.   Hypothermia (marked cooling of core temperature) slows  the rate of chemical reaction (tissue metabolism), increases  the viscosity of the blood, slows blood flow through the  microcirculation, facilitates blood coagulation, and stimu-  lates profound vasoconstriction. Hypothermia may be acci-  dental or therapeutic.    Sleep may be divided into REM and NREM stages, each of  which has its own series of stages. While asleep, an indi-  vidual progresses through the three stages of NREM (slow-  wave) sleep and REM sleep in a predictable cycle.    mitters from the afferent formation and by the inhibition  of arousal mechanisms in the cerebral cortex. REM sleep is  controlled by mechanisms in the hypothalamus and pon-  tine reticular formation.    During sleep the body is actively engaged in restoring  and repairing itself. Sleep deprivation can cause profound  changes in personality and functioning.    . The sleep patterns of the newborn and young child vary from    those of the adult in total sleep time, cycle length, and per-  centage of time spent in each sleep cycle. Older adults expe-  rience a total decrease in sleep time.    sleep disorders associated with mental, neurologic, or other  medical disorder, and (d) proposed sleep disorders.    alterations in the quantity and quality of sleep or affect sleep  stages. These are referred to as secondary sleep disorders. In  some instances sleep stages produce alterations in certain dis-  ease states. These are referred to as sleep-provoked disorders.    The sensation of touch involves the fusion of several quali-  ties, including modality, intensity, location, and duration of  the sensory stimulus.    . Receptors sensitive to touch are present in the skin; these    include Meissner and pacinian corpuscles and Merkel disks  and Ruffini endings. The sensory response is conducted to  the brain through the dorsal column and anterior spinotha-  lamic tract.    at any level of the nervous system, from the receptor to the  cerebral cortex.    of the body and its parts. Proprioceptors are located in the  inner ear, joints, and ligaments. Proprioceptive stimuli are  necessary for balance, coordinated movement, and grading  of muscular contraction.    at any level of the nervous system. Two common causes of  proprioceptive dysfunction are vestibular dysfunction and  neuropathy.    tect the eye. Infections are the most common disorders;  they include blepharitis, conjunctivitis, chalazion, and  hordeolum.    allergic. Redness, edema, pain, and lacrimation are com-  mon symptoms. Trachoma (chlamydial conjunctivitis) is    the leading cause of blindness in the world and is associated  with poor sanitary conditions.   Keratitis is a bacterial or viral infection of the cornea that  can lead to corneal ulceration. Photophobia, pain, and tear-  ing are common symptoms.   The wall of the eye has three layers: sclera, choroid, and ret-  ina. The retina contains millions of photoreceptors known  as rods and cones that receive light through the lens and  then convey signals to the optic nerve and subsequently to  the visual cortex of the brain.   The eye is filled with vitreous and aqueous humor, which  prevent it from collapsing.   Structural eye changes caused by aging or chronic disease  result in decreased visual acuity.   The major alterations in ocular movement include strabis-  mus, nystagmus, and paralysis of the extraocular muscles.  Alterations in visual acuity can be caused by amblyopia,  scotoma, cataracts, papilledema, macular degeneration,  retinal detachment, and glaucoma.   Alterations in accommodation develop with increased  intraocular pressure, inflammation, and disease of the ocu-  lomotor nerve. Presbyopia is loss of accommodation caused  by loss of lens elasticity with aging.    . Alterations in color vision occur with disorders of the cor-    . Trauma or disease of the optic nerve pathways, or optic    radiations, can cause blindness in the visual fields. Homon-  ymous hemianopsia is caused by damage of one optic tract.  Retinoblastoma is a congenital eye tumor that has a heredi-  tary and a nonhereditary form.    The ear is composed of external, middle, and inner struc-  tures. The external structures are the pinna, auditory canal,  and tympanic membrane. The tympanic cavity (contain-  ing three bones: malleus, incus, and stapes), oval window,  eustachian tube, and fluid comprise the middle ear and  transmit sound vibrations to the inner ear.    rinths that transmit sound waves through the cochlea to the  division of the eighth cranial nerve (i.e., vestibulocochlear).  The semicircular canals and vestibule help maintain bal-  ance through the equilibrium receptors.   Approximately one third of all people older than 65 years  have hearing loss.   Otitis externa is an infection of the outer ear. Otitis media,  an infection of the middle ear, is common in children and  can be acute or chronic.   Acute otitis media is an infection of the middle ear associ-  ated with ear pain, fever, an inflamed tympanic membrane,  and fluid in the middle ear.   Hearing loss can be classified as conductive, sensorineural,  mixed, or functional.   Conductive hearing loss occurs when sound waves cannot  be conducted through the middle ear.   Sensorineural hearing loss develops with impairment of  the organ of Corti or its central connections. Presbycusis is  age-related hearing loss and is the most common form of  sensorineural hearing loss.    11. Loss of hearing with no known organic cause is a functional    1. The perception of flavor is altered if olfaction or taste dys-   Hyposmia is a decrease in the sense of smell, and anosmia  is the complete loss of smell. Inflammation of the nasal  mucosa and trauma or tumors of the olfactory nerve lead to  a diminished sense of smell.   Hypogeusia is a decrease in taste sensation, and ageusia is  the absence of taste. Loss of taste buds or trauma to the  facial or glossopharyngeal nerves decreases taste sensation.   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Boyce JM, Shone GR: Effects of ageing on smell and taste, Postgrad Med  J 82(966):239-241, 2006.    231a. Methven L et al: Ageing and taste, Proc Nutr Soc 71(4):556—-565, 2012.    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Alterations in Cognitive Systems, 527  Alterations in Arousal, 528  Alterations in Awareness, 535  Data Processing Deficits, 539  Seizure Disorders, 550   Alterations in Cerebral Hemodynamics, 555  Increased Intracranial Pressure, 555  Cerebral Edema, 557  Hydrocephalus, 558    A person achieves functional adequacy (competence) through  complex integrated processes. Three major neural systems  account for this functional adequacy: cognitive systems, sensory  systems, and motor systems. Alterations in any or all of these  affect functional adequacy. Alterations in cognitive and sensory  systems and motor function are associated with many central  and peripheral nervous system injuries and pathologies. The  purpose of this chapter is to present the concepts and processes  of these alterations as an approach to understanding the mani-  festation of neurologic dysfunction. Some specific diseases are  also presented (1.e., Parkinson disease, Huntington disease, and  amyotrophic lateral sclerosis) because they fit best here. The  manifestations of these concepts and processes are integrated  with specific central and peripheral nervous system disorders  and are presented in Chapter 18. Alterations in sensory func-  tion are presented in Chapter 16.   The neural systems essential to cognitive function are: (1)  attentional systems that provide arousal and maintenance of  attention over time; (2) memory and language systems by which    Alterations in Neuromotor Function, 559  Alterations in Muscle Tone, 559  Alterations in Movement, 561  Extrapyramidal Motor Syndromes, 573  Alterations in Complex Motor Performance, 574    information is communicated; and (3) affective or emotive sys-  tems that mediate mood, emotion, and intention. These core sys-  tems are fundamental to the processes of abstract thinking and  reasoning. The products of abstraction and reasoning are orga-  nized and made operational through the executive attentional  networks. The normal functioning of these systems manifests  through the motor system in a behavioral array viewed by oth-  ers as being appropriate to human activity and successful living.  Nervous system disorders can be acquired (ie., from trauma,  infection, or related to systemic disease) or have a genetic basis.    Full consciousness is a state of awareness both of oneself and  of the environment and appropriate responses to that envi-  ronment. The fully conscious individual responds to external  stimuli with a wide array of responses. Any decrease in this  state of awareness and varied responses is thus a decrease in  consciousness.    Consciousness has two distinct components: arousal (state  of awakeness) and awareness (content of thought). Arousal is  mediated by the reticular activating system, which regulates  aspects of attention and information processing and maintains  consciousness (see Figure 15-6). Cognitive cerebral functions  require a functioning reticular activating system. Awareness  encompasses all cognitive functions and is mediated by atten-  tional systems, memory systems, language systems, and execu-  tive systems.    Alterations in level of arousal may be caused by structural, met-  abolic, or psychogenic (functional) disorders.   PATHOPHYSIOLOGY. Structural alterations in arousal are  divided according to original location of the pathologic condi-  tion or lesion: supratentorial (above the tentorium cerebelli);  infratentorial (subtentorial, below the tentorium cerebelli);  subdural (below the dura mater [see Figure 17-17]); extrace-  rebral (outside the brain tissue); and intracerebral (within the  brain tissue). Structural alterations can be caused by infectious,  vascular, neoplastic, traumatic, congenital (developmental),  degenerative, genetic, and metabolic disorders.   Supratentorial disorders produce changes in arousal by  either diffuse or localized dysfunction. Diffuse dysfunction  may be caused by disease processes affecting the cerebral cor-  tex or the underlying subcortical white matter (e.g., encepha-  litis). Disorders outside the brain but within the cranial vault  (extracerebral) also can produce diffuse dysfunction, including  neoplasms, closed-head trauma with subsequent bleeding, and  subdural empyema (accumulation of pus). Localized dysfunc-  tion is generally caused by masses that directly impinge on dien-  cephalic structures (ie., thalamus and hypothalamus) or that  secondarily compress these structures in the process of hernia-  tion. Disorders within the brain substance (intracerebral)—  bleeding, infarcts, emboli, and tumors—function primarily    Corneal reflex (cranial nerves V, VII) Symmetric response  Grimace to pain (cranial nerve VII) Symmetric response  Motor function movement Symmetric  Tone Symmetric  Posture Symmetric    Equal and reactive; may be large (e.g., atropine),  pinpoint (e.g., opiates), or midposition and fixed  (e.g., glutethimide [Doriden])    as masses. Such localized destructive processes directly impair  function of the thalamic or hypothalamic activating systems.   Infratentorial disorders produce a decline in arousal in one of  two ways: (1) there may be a direct destruction of the reticular  activating system (RAS) and its pathways, or (2) the brainstem  may be destroyed either by direct invasion or by indirect impair-  ment of its blood supply. The most common cause of direct  destruction is cerebrovascular disease. Demyelinating diseases,  neoplasms, granulomas, abscesses, and head injury also may  cause brainstem destruction by tissue compression. This com-  pression may occur because of (1) direct pressure on the pons  and midbrain, producing ischemia and edema of the neurons  of the RAS; (2) upward herniation of the cerebellum through  the tentorial notch, thus compressing the upper midbrain and  diencephalon; or (3) downward herniation of the cerebellum  through the foramen magnum, compressing and displacing the  medulla oblongata.   Metabolic alterations in arousal are caused by alterations in  delivery of energy substrates (e.g., hypoxia, electrolyte distur-  bances, or hypoglycemia) or alterations in neuronal excitability  caused by drugs and toxins (both exogenous and endogenous  [e.g., liver or renal failure] ). All the systemic diseases that even-  tually produce nervous system dysfunction are part of this met-  abolic category.   Psychogenic alterations in arousal (unresponsiveness),  although uncommon, may signal general psychiatric disorders  (see Chapter 19). Despite apparent unconsciousness, the person  actually is physiologically awake and the neurologic examina-  tion reflects a normal response.   CLINICAL MANIFESTATIONS AND EVALUATION. Patterns of clini-  cal manifestations assist in determining the extent of brain  dysfunction and serve as indexes for identifying increasing or  decreasing central nervous system (CNS) function. Distinctions  are made between metabolic and structurally induced manifes-  tations (Table 17-1). The types of manifestations suggest the   Gaze paresis, nerve Ill palsy, medial longitudinal  fasciculus (MLF) syndrome (internuclear  ophthalmoplegia)   Asymmetric and/or nonreactive; may be midposition  (midbrain injury), pinpoint (pons injury), large (tectal  injury)    cause of the altered arousal state (Table 17-2). Five categories  of neurologic function are critical to the evaluation process: (1)  level of consciousness, (2) pattern of breathing, (3) pupillary  changes, (4) oculomotor responses, and (5) motor responses.    Level of consciousness is the most critical clinical index of ner-  vous system function or dysfunction. Changes can indicate  either improvement or deterioration of the individual’s condi-  tion and state of awakeness. A person who is alert and oriented  to self, others, place, and time is considered to be functioning at  the highest level of consciousness, which implies full use of all  the person’s cognitive capacities. From this normal alert state,  levels of consciousness diminish in stages from confusion to  coma, each of which is clinically defined (Table 17-3).    Respiratory patterns help to evaluate level of brain dysfunc-  tion and level of coma. Rate, rhythm, and pattern of breathing  should be assessed. The breathing patterns can be categorized  as hemispheric or brainstem breathing patterns (Table 17-4 and  Figure 17-1).   With normal breathing, a neural center in the forebrain  (cerebrum) produces a rhythmic breathing pattern. When  consciousness decreases, lower brainstem centers regulate the  breathing pattern by responding only to changes in Paco, lev-  els. This irregular breathing pattern is called posthyperventila-  tion apnea (PHVA).   Cheyne-Stokes respiration is an abnormal rhythm of  breathing (periodic breathing) with alternating periods of  hyperventilation and apnea (crescendo-decrescendo pattern).    Neurologic signs at any given time point to one anatomic area (e.g., diencephalon, mesencephalon, medulla)    Confusion and stupor commonly precede motor signs  Motor signs usually are symmetric  Pupillary reactions usually are preserved    Asterixis, myoclonus, tremor, and seizures are common  Acid-base imbalance with hyperventilation or hypoventilation is common    Pupils reactive or dilated (cycloplegics)  Oculocephalic reflexes are unpredictable; oculovestibular reflexes are physiologic (nystagmus is present)  Motor tone is inconsistent or normal    Loss of ability to think rapidly and clearly; impaired judgment and decision making   Beginning loss of consciousness; disorientation to time followed by disorientation to place and impaired memory;  lost last is recognition of self   Limited spontaneous movement or speech; easy arousal with normal speech or touch; may not be oriented to  time, place, or person   Mild to moderate reduction in arousal (awakeness) with limited response to the environment; falls asleep unless  stimulated verbally or tactilely; answers questions with minimum response   A condition of deep sleep or unresponsiveness from which the person may be aroused or caused to open eyes  only by vigorous and repeated stimulation; response is often withdrawal or grabbing at stimulus   Coma No verbal response to the external environment or to any stimuli; noxious stimuli such as deep pain or suctioning   Deep coma Associated with unresponsiveness or no response to any stimulus   Normal After a period of hyperventilation that lowers the arterial Response of the nervous system to an external  carbon dioxide pressure (Paco), the individual continues to stressor—not associated with injury to the CNS  breathe regularly but with a reduced depth.   Posthyperventilation apnea Respirations stop after hyperventilation has lowered the Associated with diffuse bilateral metabolic or  Pco, level below normal. Rhythmic breathing returns when structural disease of the cerebrum  the Pco, level returns to normal. (Usually an intact cerebral  cortex will trigger breathing within 10 seconds regardless  of Pco.)   Cheyne-Stokes respirations Breathing pattern has a smooth increase (crescendo) in the Bilateral dysfunction of the deep cerebral or  rate and depth of breathing (hyperpnea), which peaks and diencephalic structures; seen with supratentorial  is followed by a gradual smooth decrease (decrescendo) in injury and metabolically induced coma states  the rate and depth of breathing to the point of apnea when unrelated to neurologic dysfunction; may see also  the cycle repeats itself. The hyperpneic phase lasts longer in CHF  than the apneic phase (represents an amplitude change).    Brainstem Breathing Patterns  Central reflex hyperpnea (central A sustained deep rapid but regular pattern (hyperpnea) May result from CNS damage or disease that  neurogenic hyperventilation) occurs, with a decreased Paco and a corresponding involves the lower midbrain and upper pons; seen  increase in pH and increased Poy. after increased intracranial pressure and blunt  head trauma  Apneusis A prolonged inspiratory cramp (a pause at full inspiration) Indicates damage to the respiratory control  occurs. A common variant of this is a brief end-inspiratory mechanism located at the pontine level; most  pause of 2 or 3 seconds, often alternating with an end- commonly associated with pontine infarction  expiratory pause. but documented with hypoglycemia, anoxia, and  meningitis  Cluster breathing A cluster of breaths has a disordered sequence with Dysfunction in the lower pontine and high  irregular pauses between breaths. medullary areas  Ataxic breathing Completely irregular breathing occurs, with random shallow Originates from a primary dysfunction of the lower  and deep breaths and irregular pauses. Often the rate is pons or upper medulla  slow.  Gasping breathing pattern (agonal gasps) A pattern of deep “all-or-none” breaths is accompanied bya _ Indicative of a failing medullary respiratory center  slow respiratory rate.    FIGURE 17-1 Abnormal Respiratory Patterns with Corresponding Level of Central Nervous System Activity.    Metabolic imbalance or deep bilateral hemisphere lesion such as  hydrocephalus or thalamic hemorrhage    Full consciousness Eyes at rest, still (cortical gaze centers inhibit spontaneous Eyes move as the head turns  roving eye movements) Oculocephalic responses not elicited or inconsistently elicited (frontal  gaze centers inhibit brainstem reflexes that fix gaze straight ahead)  Oculovestibular (caloric) stimulation produces nystagmus  Cortical dysfunction Conjugate, horizontal, roving eye movements may well Gaze fixed straight ahead regardless of head position—positive doll’s  or disruption of be present (cortical gaze centers no longer inhibit these eyes reaction (normal oculocephalic reflexes are no longer inhibited by  efferent pathways brainstem-generated roving eye movements) frontal gaze centers)  Diffuse anoxic “Ocular dipping’—slow, dysrhythmic downward movement Nystagmus is no longer induced by caloric stimulation (normally a cold-  damage to cortex followed by faster, upward movement water stimulus produces deviation of the eyes opposite the irrigated ear;  a warm-water stimulus deviates the eyes to the same [ipsilateral] side)  With an injury that depresses cortical gaze center function, the eyes (and  often the entire head) deviate or appear to look toward the side of the  injured hemisphere  With an injury that irritates (stimulates) the neurons of the cortical gaze  center, the eyes (and often the entire head) deviate away from the  injured hemisphere (all fibers from the frontal gaze centers decussate  and therefore control the function of the contralateral pontine gaze  center, which moves the eyes in the ipsilateral direction)  Mesencephalon Roving eye movements cease and the eyes become immobile — Oculovestibular reflexes become inconsistent and abnormal  dysfunction and directed ahead (roving eye movements require an intact —_Loss of Bell phenomenon (upward deviation of eyes on stimulation)  brainstem) (requires intact eye movement pathways from the mesencephalon to  Eyes may turn down and inward pons)  Pontine dysfunction Loss of spontaneous blinking (requires an intact pons)  “Ocular bobbing—brisk, conjugate, downward movement of  eyes with loss of horizontal eye movements    The pathophysiology of Cheyne-Stokes respiration involves a  hyperventilatory response to carbon dioxide stimulation. In  the damaged brain, higher levels of Paco, (hypercapnia) are  required to stimulate ventilation, and the response is hyperven-  tilation. As a result, the Paco, level decreases to below normal  and breathing stops (PHVA) until carbon dioxide reaccumu-  lates and stimulates hyperventilation. In cases of opiate or seda-  tive drug overdose, the respiratory center is depressed and the  rate of breathing gradually decreases until respiratory failure  occurs.   Central neurogenic hyperventilation is a respiratory pat-  tern of sustained hyperventilation caused by a lesion in the cen-  tral pons. Apneustic respirations have prolonged inspiratory  and expiratory phases caused by injury to the pons or upper  medulla. Cluster respirations are characterized by periods or  clusters of rapid respirations of near equal depth resulting from  trauma or compression to the medulla or from chronic opioid  abuse. Ataxic respirations are irregular respirations with pro-  longed periods of apnea associated with damage to the medulla  (see Figure 17-1).   Brainstem areas that control arousal are adjacent to areas that  control the pupils. Pupillary changes thus are a valuable guide  to evaluating the presence and level of brainstem dysfunction  (Figure 17-2).   Some drugs affect pupils and must be considered in the eval-  uation of pupillary responses in comatose states. Large doses of  atropine, scopolamine, amphetamines, mydriatics, and cyclo-  plegics can fully dilate and fix pupils. Sedatives (e.g., glutethi-  mide) in sufficient amounts to produce a coma cause the pupils  to become midposition or moderately dilated (4 to 5 mm in  diameter), unequal, and frequently fixed to light. Opiates (her-  oin and morphine) and barbiturates, as well as extensive pon-  tine damage, cause pinhole pupils (1 mm). Severe barbiturate  intoxication may produce fixed pupils.   Severe ischemia and hypoxia produce bilaterally wide  (5 mm) and fixed pupils usually caused by severe midbrain  damage. Occasionally the pupils remain small (1 to 2.5 mm) or  midposition even in the presence of profound hypoxia. Hypo-  thermia also may cause fixed pupils.    Resting, spontaneous, and reflexive eye movements and ocu-  lovestibular (caloric) reflexes change at various levels of brain  dysfunction (Table 17-5). Persons with metabolically induced  coma, except in cases of barbiturate-hypnotic and phenytoin  (Dilantin) poisoning, generally retain ocular reflexes, however,  even when other signs of brainstem damage, such as central  neurogenic hyperventilation, are present.   The presence of brisk oculocephalic reflexes and roving eye  movements, as well as the failure to elicit nystagmus with instil-  lation of cold or warm water into the external ear canal, indi-  cates a decrease in consciousness (loss of cortical influence) but  an intact brainstem (Figures 17-3 and 17-4).   Destructive or compressive injury to the brainstem causes  specific abnormalities of the oculocephalic and oculovestibular    FIGURE 17-3 Test for Oculocephalic Reflex Response (Doll's Eyes Phe-  nomenon). A, Normal response—eyes turn together to side opposite from turn  of head. B, Abnormal response—eyes do not turn in conjugate manner. C, Absent  response—eyes do not turn as head position changes. (A and C from Rudy EB:  Advanced neurological and neurosurgical nursing, St Louis, 1984, Mosby.)    reflexes. For example, a skewed deviation, in which one eye  diverges downward and the other looks upward, indicates  brainstem dysfunction. Destructive or compressive disease  processes that involve an oculomotor nucleus or nerve cause  the involved eye to deviate outward, producing a resting dys-  conjugate lateral position of the eyes (each eye diverges later-  ally). Unilateral abducens paralysis (paralysis of cranial nerve  VI) results in an upward deviation of the ipsilateral eye. With  bilateral abducens paralysis, the eyes come together (converge).  Reflexive eye movements may be suppressed by drugs, most  commonly phenytoin, tricyclics, and barbiturates. Occasion-  ally alcohol, phenothiazines, and diazepam may alter reflex eye  movements.    Assessment of motor responses helps to evaluate the level of  brain dysfunction and determine the side of the brain that is  maximally damaged. The pattern of response noted may be  (1) purposeful (a defensive or withdrawal movement of limbs  to noxious stimuli); (2) inappropriate, or not purposeful (gen-  eralized motor movement, posturing, grimacing, or groan-  ing); or (3) not present (unresponsive, no motor response).    FIGURE 17-4 Test for Oculovestibular Reflex (Caloric Ice-Water Test). A, Normal response—conjugate eye move-  ments. B, Abnormal response—dysconjugate or asymmetric eye movements. C, Absent response—no eye movements.    FIGURE 17-5 Pathologic Reflexes. A, Grasp reflex. B, Snout reflex. C, Palmo-  mental reflex. D, Suck reflex.    Purposeful movement requires an intact corticospinal system.  Nonpurposeful movement is evidence of severe dysfunction of  the corticospinal system.   Motor signs indicating loss of cortical inhibition are com-  monly associated with decreased consciousness. These signs  include contralateral or bilateral (depending on whether the  process is localized or diffuse) reflex grasping, reflex suck-  ing, snout reflex, palmomental reflex, and rigidity (paratonia)  (Figure 17-5). Abnormal flexor and extensor responses, par-  ticularly in the upper extremities, are defined in Table 17-6 and  illustrated in Figure 17-6.   Vomiting, yawning, and hiccups are complex reflex-like  motor responses that are integrated by neural mechanisms  in the lower brainstem. These responses may be produced  by compression or diseases involving tissues of the medulla  oblongata (e.g., infection, neoplasm, infarct, or other more  benign stimuli to the vagal nerve). Most CNS disorders pro-  duce nausea and vomiting. Vomiting without nausea indicates  direct involvement of the central neural mechanism (or pyloric  obstruction). Vomiting often accompanies CNS injuries that  (1) involve the vestibular nuclei or its immediate projections,  particularly when double vision (diplopia) also is present;  (2) impinge directly on the floor of the fourth ventricle; or  (3) produce brainstem compression secondary to increased  intracranial pressure.    Outcomes of alterations in arousal fall into two categories: extent  of disability (morbidity) and mortality. Outcomes depend on the  cause and extent of brain damage and the duration of coma.  Some individuals may recover consciousness and an original  level of function, some may have permanent disability, and  some may never regain consciousness and experience neuro-  logic death. Two forms of neurologic death—brain death and  cerebral death—result from severe pathologic conditions and  are associated with irreversible coma. Other possible outcomes  include a vegetative state, a minimally conscious state, akinetic  mutism, or locked-in syndrome. Extent of disability has four  subcategories: recovery of consciousness, recovery of residual  cognitive function, recovery of psychologic function, and recov-  ery of vocational function.   Brain death (total brain death) occurs when irreversible  brain damage is so extensive that the brain has no potential  for recovery and no longer can maintain the body’s internal  homeostasis. State laws define brain death as irreversible cessa-  tion of function of the entire brain, including the brainstem and  cerebellum. The brain is autolyzing (self-digesting) or already  autolyzed on postmortem examination.   Clinical criteria for brain death include the absence of dis-  cernible evidence of cerebral hemisphere function or function of  the brainstem’s vital centers for an extended period. There is no  detectable function above the level of the foramen magnum so  there is whole brain death. In addition, the abnormality of brain  function must result from structural or known metabolic disease  and not be caused by a depressant drug, alcohol poisoning, neuro-  muscular blockage, or hypothermia. An isoelectric, or flat, electro-  encephalogram (EEG) (electrocerebral silence) for a period of 6 to  12 hours in a person who is not hypothermic and has not ingested  depressant drugs indicates that no mental recovery is possible.  This usually means that the brain is already dead. A task force to  determine brain death in children recommended the same criteria  as those used for adults! but with a longer observation period.    Slowly developing flexion of the arm, wrist, and fingers  with abduction in the upper extremity and extension,    extremity  Decerebrate posturing/rigidity: upper and lower  extremity extensor responses (Figure 17-6)    Opisthotonos (hyperextension of the vertebral column)  with clenching of the teeth; extension, abduction,    In acute brain injury, shivering and hyperpnea may  accompany unelicited recurrent decerebrate spasms    Extensor responses in the upper extremities  accompanied by flexion in the lower extremities    Data from Goetz CG: Textbook of clinical neurology, ed 3, Philadelphia, 2007, Saunders; Nadeau SE et al: Medical neuroscience, Philadelphia, 2004,    FIGURE 17-6 Decorticate and Decerebrate Responses. A, Decorticate  response (flexor posturing): bilateral flexion of elbows and wrists with shoulder  adduction in upper extremities. Extension, internal rotation of lower extremities.  B, Decerebrate response (extensor posturing): all four extremities in rigid exten-  sion, internal rotation of shoulders with hyperpronation of forearms. ©, Decorti-  cate response on right side of body and decerebrate response on left side of body:  the most pronounced response differences are in the upper body. (From Rudy EB:  Advanced neurological and neurosurgical nursing, St Louis, 1984, Mosby.)    3. No spontaneous respiration (apnea)—a Paco, that rises  above 60 mmHg without breathing efforts, providing  evidence of a nonfunctioning respiratory center (apnea  challenge)   4. No brainstem function (ocular responses to head turn-  ing or caloric stimulation; dilated, fixed pupils; no gag or  corneal reflex)   hemispheres exclusive of the brainstem and cerebellum. Brain  damage is permanent and sufficiently severe that the individual  is unable to ever respond behaviorally in any significant way    to the environment. The brainstem may continue to maintain  internal homeostasis (normal respiratory and cardiovascular  functions, normal temperature control, and normal gastro-  intestinal function). The person does not follow commands,  speak, or have voluntary movement.   The recovery spectrum after severe brain injury includes: (1)  coma, (2) vegetative state, (3) akinetic mutism, (4) minimally  conscious state, and (5) locked-in syndrome (Table 17-7). The  survivor of cerebral death may remain in a coma or emerge into  a vegetative state. In coma (a state of unarousable neurobe-  havioral unresponsiveness) the eyes are usually closed with no  evidence of eye opening either spontaneously or in response to  external stimuli. The person does not follow commands, does  not verbalize or mouth words, and has no goal-directed or voli-  tional behavior. There are no sustained visual pursuit move-  ments beyond a 45-degree arc.   A persistent vegetative state (VS) is complete unaware-  ness of the self or surrounding environment and complete  loss of cognitive function. The Multi-Society Task Force on  Persistent Vegetative States (MSTF) identified the diagnostic  criteria for VS as: (1) periods of eye opening (spontaneous  or following stimulation); (2) the potential for subcortical  responses to external stimuli, including generalized physi-  ologic responses to pain, such as posturing, tachycardia, and  diaphoresis, and subcortical motor responses, such as grasp  reflex; (3) return of so-called vegetative (autonomic) func-  tions, including sleep-wake cycles and normalization of respi-  ratory and digestive system functions; and (4) occasional  roving eye movements without concomitant visual tracking  ability.° The person’s eyes open spontaneously or following  stimulation, or both. There may be random hand, extrem-  ity, or head movements. The individual maintains blood  pressure and breathing without support. Brainstem reflexes  (pupillary, oculocephalic, chewing, swallowing) are intact.  No discrete localizing motor responses are present, and the  individual does not speak any comprehensible words or fol-  low commands.’    TABLE 17-7 COMPARATIVE CLINICAL FEATURES OF ALTERATIONS IN LEVELS OF AROUSAL   Persistent vegetative state Eyes open spontaneously; no visual tracking;  sleep-wake cycle resumes or state of  chronic wakefulness; arousal often  sluggish   Eyes open spontaneously; normal to  abnormal sleep-wake cycle; arousal level  ranges from obtunded to normal   Inconsistent evidence of perception,  communication ability, or purposeful  motor activity; visual tracking often  intact    Cannot speak or move muscles except  vertical eye movement and blinking    Data from Giacino JT et al: Neurology 58(3):349-353, 2002; Owen AM: Ann N Y Acad Sci 1125:225-238, 2008.    In a minimally conscious state (MCS), an individual dem-  onstrates minimal but defined behavioral evidence of self or  environmental awareness.°® The clinical features include:  (1) following simple commands, (2) manipulating objects,  (3) responding with gestural or verbal “yes/no” responses,  (4) demonstrating intelligible verbalization, and (5) blinking  and smiling that occur in a meaningful relationship to the elic-  iting stimulus and are not attributable to reflexive activity.   Akinetic mutism (AM) is a neurobehavioral state character-  ized by a severe disturbance in behavioral drive (motivation).  Generally, these individuals evidence eye opening with visual  tracking and have little or no spontaneous speech or following of  commands. Little movement is present. This is not attributable  to decreased wakefulness or motor weakness or impairment.  The pathology involves damage to the frontal lobe or cingulate  gyrus (a component of the limbic system) (also see p. 538).?   With locked-in syndrome there is complete paralysis of vol-  untary muscles with the exception of eye movement. Content of  thought and level of arousal are intact but the efferent pathways  are disrupted (injury at the base of the pons with the reticular  formation intact, often caused by basilar artery occlusion).'°  Thus the individual cannot communicate either through speech  or through body movement but is fully conscious, with intact  cognitive function. The upper cranial nerves (I through IV)  often are preserved, so that the person possesses vertical eye  movement and blinking as a means of communication.    Awareness (content of thought) encompasses all cognitive  functions, including awareness of self, environment, and affec-  tive states (i.e., moods). Awareness is mediated by the core net-  works (selective attention and memory) under the guidance of  executive attention networks (i.e., the networks that involve  abstract reasoning, planning, decision making, judgment, error  correction, and self-control). Each attentional function is not  localized in a single brain area but is a network of intercon-  nected brain circuits.    Pulvinar nucleus  of thalamus:  engagement of move component of  selective attention selective attention   nication: language and pragmatics. In Hoeman SP, editor: Rehabilitation nursing:  prevention, intervention, & outcomes, ed 4, p 508, St Louis, 2008, Mosby.)    Selective attention (orienting) refers to the ability to select  specific information to be processed from available, compet-  ing environmental and internal stimuli and to focus on those  stimuli.'! Frontal and parietal regions of the right hemisphere  contribute to selective attention. The engage component is  mediated by the pulvinar nucleus of the thalamus (Figure 17-7).  The disengagement mechanism is mediated by the right pari-  etal lobe. The move component is mediated by the superior col-  liculi for visual orienting. A weak orienting network results in a  neglect syndrome.   Sensory inattentiveness is a form of neglect and may be  visual, auditory, or tactile. The person with sensory inattentive-  ness is able to recognize individual sensory input from the dys-  functional side when asked to do so but ignores (i.e., neglects,  extinguishes) the sensory input from the dysfunctional side    FIGURE 17-8 Cortical Areas of the Left (Dominant) Hemisphere. (From Patton KT, Thibodeau GA: Anatomy & physiol-    when stimulated from both sides. This phenomenon is called  extinction. The entire complex of denial of dysfunction, loss  of recognition of one’s own body parts, and extinction is some-  times referred to as the unilateral neglect syndrome and is  common after stroke.   An isolated (pure) selective attention deficit (orientation),  which manifests as a neglect syndrome, rarely, if ever, occurs  clinically because typically other deficits also are present. A  neglect syndrome may appear temporarily as a result of seizure  activity or a postictal state. Temporary or permanent deficits  may occur with contusions or subdural hematomas, encepha-  litis, and ischemic stroke. Progressive neglect deficits may be  found with gliomas or metastatic tumor and in Alzheimer and  Pick diseases.   Memory is the recording, retention, and retrieval of knowl-  edge. Two types of memory exist: declarative and nonde-  clarative (Figure 17-10). Declarative memory involves the  learning and remembrance of episodic memories (personal his-  tory, events, and experiences) and semantic memories (facts and  information). Declarative memory is mediated by domain-  specific cortical areas of the association areas. This includes:  (1) areas of the temporal, parietal, and occipital lobes (Figure  17-8), where long-term memories are thought to be stored;  and (2) domain-independent areas of the medial temporal lobe  (i.e., hippocampus), the diencephalon (thalamic structures and  hypothalamus), and the basal forebrain (located ventral to the  striatum and produces acetylcholine) (Figure 17-9), where it is  thought distinct domain-specific features of an experience are  related or bound.!?   Nondeclarative memory (nonconscious), also called  reflexive, procedural, or implicit memory, is the memory for  actions, behaviors (habits), skills, and outcomes.!* It is not  a language memory but a motor memory. Nondeclarative  memory involves the construction of the motor pattern for  the motor performance so that the action, behavior, or skill    becomes increasingly more automatic. The striatum of the  basal ganglia supports this learning across trials (stimulus-  response learning), as well as probabilistic classification learn-  ing, which supports outcome prediction." All skills and habits  are stored in this memory network. Cerebellar memory was  originally thought to be related to only motor learning but  it is now believed to involve nonmotor functions of cogni-  tion, emotion, and memory.!° Emotional memory is mediated  by the amygdala (located on the inner surface of the tempo-  ral lobe) (see Figure 17-9). The amygdala attaches positive  (e.g., pleasure) or negative (e.g., fear) dispositions to stimuli  in the absence of conscious recollection of the circumstances  of the emotional experience. Additionally, the amygdala  modulates the event memory during and after the event  (memory-enhancing effect).'° The reflex pathways mediate  nonassociative learning (e.g., habituation [decreased response  to a stimulus] and sensitization [increased response to a stim-  ulus]) (see Figure 17-10).   Dysmnesia is a disorder of the domain-independent declar-  ative memory network. Dysmnesia is defined as the loss of  past memories (retrograde amnesia) coupled with an inability  to form new memories (anterograde amnesia) despite intact  attentional networks. The hippocampus and other tempo-  ral lobe structures are often involved. Isolated (pure) domain-  independent dysmnesia is caused by only a limited number  of conditions, such as transient global dysmnesia (episodic  global dysmnesia), amnestic stroke, and Korsakoff psychosis  (amnestic or dysmnesic syndrome), as well as after temporal  lobectomy. Many disorders may temporarily or permanently  produce domain-independent dysmnesia that accompanies  other deficits of the cognitive systems.!© A temporary domain-  independent dysmnesia is found during complex partial seizures  that persist for a time in the postictal state, in postconcussive  states, and in mild posttraumatic brain injury states. A per-  manent domain-independent dysmnesia may be seen in several    FIGURE 17-9 Midline Cortical and Deep Areas of the Cerebral Hemisphere.    disorders including subarachnoid hemorrhage or moderate or  severe posttraumatic brain injury states; carbon dioxide poi-  soning and other hypoxic or anoxic states; Wernicke encepha-  lopathy, viral encephalitis, and granulomatous meningitides;  tumors; and Alzheimer and Pick diseases.   A pure auditory or visual domain-specific declarative mem-  ory deficit manifests as an isolated agnosia (see Table 17-9). An  isolated (pure) domain-specific declarative memory deficit of    tactile sensations rarely occurs clinically because selective atten-  tion would likely be affected as well. A temporary auditory,  visual, or tactile pattern recognition (remote memory) deficit  may appear as a result of seizure activity or a postictal state.  A temporary or permanent deficit can occur with temporal,  occipital, or parietal lobe contusion; with subdural hematoma  or ischemic stroke; and in encephalitis. A progressive domain-  specific declarative memory deficit may occur in temporal,    occipital, or parietal gliomas; in metastatic tumors; and in  Alzheimer and Pick diseases.   The prefrontal areas mediate several cognitive functions,  called executive attention functions (planning, problem solving,  goal setting). The vigilance system provides the person with the  ability to maintain a sustained state of alertness for searching  and scanning activities and involves the right frontal areas and  the locus ceruleus (LC) (located in the rostral pons) (see Figure  17-7). Through the neurotransmitter norepinephrine from the  LC, the speed of the orienting (selective attention) network is  increased and the detection function of the anterior cingulate  gyrus (see Figure 17-9) is decreased.   Detection is the recognition of the object’s identity and  the realization that the object fulfills a desired goal (i.e., target  selection among competing, complex contingencies). There  is conscious execution of an instruction, ensuring that the  instructions are followed. The anterior cingulate cortex inhib-  its automatic responses so that a less routine response can be  given. The basal ganglia and cingulate, as well as other frontal  areas, function in color, motion, and form detection.   The anterior cingulate plus the ventrolateral and dorsolat-  eral prefrontal cortex (see Figure 17-7) are involved in the rep-  resentations of information in the absence of a stimulus, such  as spatial position of visual events in memory when the event  is removed from view (i.e., working memory [short-term rep-  resentation memory]). Control of activation of such memories  is also in these areas. This gives the person control over infor-  mation processing. These temporary storage areas permit the  brain to retrieve instructions and other information needed to  guide behavior. A person holds and manipulates information in  working memory for a short period of time.   Isolated (pure) vigilance deficit, detection deficit and  working memory deficits are uncommon because these defi-  cits generally are present simultaneously. Akinetic mutism is  a condition where a person can neither speak nor move and  it exemplifies a detection deficit from disease or injury to the  frontal lobe. The person orients to external stimuli and can fol-  low with his or her eyes but does not initiate other voluntary  activity. There are no goals generated and no plans for carry-  ing out the goals. The combination of vigilance, detection,  and working memory deficits, accompanied by other deficits  of the cognitive systems, is much more common. Whether the  deficits are temporary or permanent depends on the cause and  severity of injury. Deficits caused by CNS-depressant drugs, by  seizure activity, and (it is hoped) by neurosurgical procedures  involving retraction of the frontal lobes are temporary. Deficits  in postconcussive and mild traumatic brain injury states may  prove to be temporary and resolve over time. Permanent defi-  cits are more likely to be found with frontal lobe contusions,  moderate or severe posttraumatic brain injury states, ischemic  frontal lobe stroke, and neurosurgery that required frontal  lobe resection. Progressive deficits in vigilance, detection, and  working memory functions are caused by frontal lobe gliomas,  frontal lobe infarcts associated with hypertensive vascular dis-  ease, and late stages of Alzheimer and Pick diseases. People with  schizophrenia have difficulty in clearing working memory of  information that is irrelevant to the task. Additionally, recently    encountered visual material that is no longer in plain view can-  not be preserved in working memory.   Higher-level thought involves the same neural areas used  for sensory-specific computations, but when used voluntarily  in thought, these areas are activated from the detection and  work memory networks (top-down processing from the pre-  frontal cortex) rather than from bottom-up automatic process-  ing (from the medial temporal lobe) beginning in sensory areas  with a specific sensory stimulus. There is a voluntary search  for a feature. By reordering component computation, a person  produces novel thoughts.   PATHOPHYSIOLOGY. Individuals with a disease affecting the  superior colliculi (positioned below the thalamus) have a  disturbance in the move component of selective attention,  which manifests as a slowness in orienting attention.'” Peo-  ple with parietal lobe disease may experience selective atten-  tion deficits related to disengagement from a stimulus. Those  with right parietal lobe dysfunction also may experience a  unilateral neglect syndrome, the prototype of a selective  attention disorder. People with a disease affecting the pulvi-  nar of the thalamus (posterior part of the thalamus) have a  disturbance in the engage component of selective attention  (see Figure 17-9).   A disorder in vigilance may be produced by disease in the  right frontal areas. A pathologic condition in the frontal areas  also may produce detection and working memory deficits.  Impaired higher-level thought may result from a pathologic  process in the cortical association areas of the parietal, tempo-  ral, and occipital lobes.   The exact pathophysiologic mechanisms of the various dis-  orders of cognitive systems are not fully known. Researchers are  studying the defects in the elementary operations (components)  of each cognitive system. In the past, pathophysiology related to  the memory systems was the most studied component.   As a highly general statement, the primary pathophysiologic  mechanisms that operate in cognitive system disorders are:  (1) direct destruction because of direct ischemia and hypoxia  or indirect destruction as a result of compression and (2) the  effects of toxins and chemicals or metabolic derangement. Dis-  inhibition resulting in overactivity, such as seen in some drug  withdrawal states, is a pathologic mechanism that can produce  detection deficits or a hypervigilant state. The pathophysiologic  processes are summarized in Figure 17-11.   CLINICAL MANIFESTATIONS. Clinical manifestations of selective  attention deficits; domain-independent and domain-specific  declarative deficits; and vigilance, detection, and working mem-  ory deficits are presented in Table 17-8.   EVALUATION AND TREATMENT. Immediate medical manage-  ment is directed at diagnosing the cause and treating reversible  factors. Rehabilitative measures for cognitive system deficits  generally are either compensatory or restorative in nature and  have been greatly facilitated by computer technology and other  electronic-assisted devices. Approaches based on behavioral  techniques tend to be compensatory, whereas process-oriented  approaches, it is hoped, are restorative.   Selective attention and executive attention deficits mas-  querade as other cognitive deficits. Differential diagnosis of    other cognitive deficits is blocked, and learning potential  is largely obscured, by the presence of an attention deficit.  Therefore, diagnosis and treatment of attention deficits are  fundamental.    Data processing deficits include specific disorders of awareness  (content of thought): agnosias, dysphasias, acute confusional  states, and dementias including Alzheimer disease.   Agnosia is a defect of pattern recognition—a failure to recog-  nize the form and nature of objects. The disorder involves the  loss of recognition through one sense, although the object or  person may still be recognized by other senses. Agnosia can be  tactile, visual, or auditory. For example, an individual may be  unable to identify a safety pin by touching it with a hand but  able to name it when looking at it. Agnosia may be as minimal    as a finger agnosia (failure to identify by name the fingers of  one’s hand) or more extensive, such as a color agnosia.  Agnosia is produced by dysfunction in the primary sensory  area or in the interpretive areas of the cerebral cortex (temporo-  occipital area) (see Figure 17-8). The types of agnosia and the  associated area that is most commonly involved with each are  presented in Table 17-9. Although agnosia most commonly is  associated with cerebrovascular accidents, it may arise from any  pathologic process that injures these specific areas of the brain.    Dysphasia  Dysphasia is impairment of comprehension or production of  language (semantic processing). With dysphasia, comprehen-  sion or use of symbols, in either written or verbal language, is  disturbed or lost. Aphasia is loss of comprehension or produc-  tion of language.   Dysphasias usually are associated with cerebrovascular acci-  dents involving the middle cerebral artery or one of its many    branches. The language disorders, however, may arise from a  variety of injuries and diseases—vascular, neoplastic, traumatic,  degenerative, metabolic, or infectious. Dysphasia results from  dysfunction in the left cerebral hemisphere, most commonly  in the frontotemporal region, particularly around the insula  (insular cortex) deep within the lateral sulcus. Genes located  on several chromosomes have been linked to language develop-  ment and disorders.!* Most language disorders are caused by  acute processes that either resolve or cause a chronic residual  deficit. Some language disorders are caused by degenerative dis-  orders that make the dysfunction progressive.   Dysphasias have been classified anatomically and function-  ally. Other classifications are linguistic and describe fluency,  volume, or quantity of speech. Pure forms of any language  dysfunction, however, are rare. Expressive dysphasias are  characterized primarily by expressive deficits, but a verbal  comprehension (auditory-receptive element) deficit may be  present. Receptive dysphasias may have expressive deficits.    (Table 17-10 compares types of dysphasias; Table 17-11 illus-  trates some of the language disturbances.)   Dysphasias referred to as transcortical dysphasias (transcor-  tical sensory dysphasia, mixed transcortical dysphasia, isolated  speech center) involve the ability to repeat (called echolalia) and  recite. Speech is fluent but with striking paraphrases. The indi-  vidual cannot read and write, and comprehension is impaired.   Transcortical dysphasias are caused by hypoxia from prolonged  hypotension, carbon monoxide poisoning, or other mechanisms  that destroy the border zone (watershed area) of the anterior,  middle, and posterior cerebral arteries (see Figure 15-20). Blood  supply is marginal in this region. Hypoxia in this area occasionally  may isolate the posterior speech areas or all the speech areas from  the remainder of the cortex, although both areas remain intact.  The sensory and motor speech areas therefore are functional,  but connections with other sensory or motor areas are impaired.  Information from the remaining areas of the cortex cannot be  transmitted to the Wernicke area to be transformed into language.    Inability to focus attention; decreased eye, head, and body  movements associated with focusing on the stimuli;  decreased search and scanning; faulty orientation to stimuli  causing safety problems   Domain-independent declarative Left hemisphere: disorientation to time, situation, place, name,  person (verbal identification); impaired language memory  (e.g., names of objects); impaired semantic memory   Right hemisphere: disorientation to self, person (visual), place  (visual); impaired episodic memory (personal history); impaired  emotional memory   Left hemisphere: inability to retrieve personal history, past  medical history; unaware of recent current events   Right hemisphere: inability to recognize persons, places,  objects, music, etc. from the past   Inability to categorize (identify similarities and differences), sort;  inability to form concepts; inability to analyze relationships;  misinterpretation; inability to interpret proverbs   Inability to perform deductive reasoning (convergent reasoning);  inability to perform inductive reasoning (divergent reasoning);  inability to abstract; concrete reasoning demonstrated;  delusions    Executive Attentional Network  Vigilance Failure to search and scan environment  Detection Lack of initiative (anergy); lack of ambition; lack of motivation;  flat affect; no awareness of feelings; appears depressed,  apathetic, and emotionless; fails to appreciate deficit;  disinterested in appearance; lacks concern about childish or  crude behavior  Responds to immediate environment but no new ideas; grooming  and social graces are lacking  Severe Motionless, lack of responding to even internal cues; does not  respond to physical needs; does not interact with surroundings    Inability to use feedback regarding behavior; failure to  recognize omissions and errors in self-care, speech, writing,  and arithmetic; impaired cue utilization; overestimation of  performance    Failure to shift response set; failure to change behavior when  conditions change; cue utilization may be impaired    Failure to make plans; inability to produce a complete line of  reasoning; inability to make up a story; appears impulsive   Failure to initiate behavior; failure to maintain behavior; failure  to discontinue behavior; slowness to alternate response for the  next step; motor perseveration    Person reports inability to focus attention, failure  to perceive objects and other stimuli (history of  injuries, falls, and safety problems)    Person reports disorientation, confusion, “not  listening,” “not remembering”; reports by others  of person being disoriented, not able to remember,  not able to learn new information    Reports by others of frequent misinterpretation  of data; failure to conceptualize or generalize  information   Reports by others of predominantly concrete  thinking; lack of understanding of everyday  situations, healthcare regimens, delusional  thinking   Reports by others of laziness or apathy, flat affect or  lack of emotional expression, failing to exhibit or  be aware of feelings    Reports by others of lack of ambition, motivation, or  initiative, failure to carry out adult tasks, lack of  social graces and new ideas   Reports by others of failure to groom or toilet self,  unawareness of surroundings and own physical  needs   Reports by others of not changing behavior when  requested; unawareness of limitations; does not  recognize and correct errors in dressing, grooming,  toileting, eating; fails to recognize speech and  arithmetic errors; careless speech   Reports by others of failure to use feedback;  inability to incorporate feedback (does not correct  when feedback is given)   Reports by others of not knowing where to begin,  inability to carry out sequential acts (maintain a  behavior), inability to cease a behavior    TABLE 17-9 TYPES OF AGNOSIA (CONCEPT DISORDERS)  TYPE OF AGNOSIA DEFINITION    Tactile agnosia (astereognosis) nability to recognize objects by touch  Spatial agnosia ncapacity to find one’s way around familiar places; disturbance of  perception of space (disorders of [1] topographic [extrapersonal]  orientation or [2] topographic and geographic memory [construction])  Gerstmann syndrome Loss of spatial orientation of fingers, body, sides, and numbers  Finger agnosia (digital agnosia) nability to identify the names of one’s fingers  Right-left confusion nability to distinguish right from left  Agraphia nability to write  Acalculia nability to perform mathematic calculations  Visual agnosia  Object agnosia nability to recognize objects and pictures  Prosopagnosia nability to recognize faces  Color agnosia nability to understand colors as qualities of objects; faulty color concepts  and inability to evoke color images in the absence of color blindness;  specific types: (1) “hue” problem, (2) color anomia (cannot name color)    Body image agnosias (may be spatial)  Anosognosia  Autotopagnosia  relationships among various parts    Word blindness (alexia/dyslexia)  Auditory agnosia (pure word deafness)  Amusia (music deafness)    Acute confusional states (ACSs) (also may be known as acute  organic brain syndromes) are transient disorders of awareness.  They are associated with cerebral dysfunction secondary to drug  intoxication, alcohol or drug withdrawal, metabolic disorders  (hypoglycemia, thyroid storm), nervous system disease, trauma  or surgery (following anesthesia), febrile illnesses or heat stroke,  and electrolyte imbalance; in addition, ACSs may be associated  with systemic diseases (such as heart, kidney, or liver failure), head  injury, anesthesia administration, or the presence of certain focal  cerebral lesions.!? The complex of symptoms is characterized by  deficits in attention and coherence of thoughts and actions. Often  the symptoms are associated with an altered level of arousal, global  cognitive dysfunction, perceptual disturbances, sleep-wake cycle  disruption, affective disturbance, and emotional liability. Hospi-  talized older individuals are at greatest risk for ACS.   PATHOPHYSIOLOGY. Acute confusional states arise from disrup-  tion of a widely distributed neural network involving the reticular  activating system of the upper brainstem and its projections to the  thalamus, basal ganglion, and specific association areas of the cortex  and limbic areas. Delirium (hyperkinetic confusional state) is an  acute state of brain dysfunction associated with right middle tem-  poral gyrus or left temporo-occipital junction disruption.*! These  areas receive extensive input from the limbic areas and modulate  motivational and affective aspects of attention. Several neurotrans-  mitters are involved, including increased levels of acetylcholine,  dopamine, and serotonin, and increased or decreased levels of  gamma-aminobutyric acid (GABA). Inflammatory cytokines,  including interleukins, interferon, and tumor necrosis factor-alpha  (TNF-a), may contribute to delirium by altering the blood-brain  barrier permeability and further affecting the neurotransmission  and subsequent neurobehavioral and cognitive symptoms.”    Ignorance or denial of existence of the disease  Loss of ability to identify the body, in whole or in part, or to recognize    Excited delirium syndrome (ExDS), also known as agitated  delirium, is a type of hyperkinetic delirium that can lead to sud-  den death. The exact signs and symptoms are difficult to precisely  define. There is altered mental status, combativeness, aggressive-  ness, tolerance to significant pain, rapid breathing, sweating,  severe agitation, elevated temperature, noncompliance or poor  awareness to direction from police or medical personnel, lack  of fatiguing, unusual or superhuman strength, and inappropri-  ate clothing for the current environment. Hypoglycemia, thyroid  storm, certain kinds of seizures, cocaine or methamphetamine  intoxication, and/or catecholamine-induced fatal arrhythmias  are associated with ExDS. Individuals with ExDS are at high risk  for sudden death and represent a true medical emergency.*   Hypokinetic confusional states (hypokinetic delirium) are  more likely associated with right-sided frontal—basal ganglion  disruption.*! These areas modulate motor exploratory aspects  of attention. Most metabolic disturbances that produce a con-  fusional state interfere with neuronal metabolism or synaptic  transmission. Many drugs and toxins also interfere with neu-  rotransmission function at the synapse. Cholinergic pathways  critical for attention and arousal are often disrupted.   CLINICAL MANIFESTATIONS. The predominant feature of an acute  confusional state is impaired or lost detection. Symptoms can fluc-  tuate and include confusion, inability to focus or maintain atten-  tion, delusions, and hallucinations. Because of dysfunction of the  anterior cingulate gyrus (see Figure 17-9 and Figure 15-7, B), the  ability to focus, sustain, or shift attention is seriously impaired  or completely lost. The person is highly distractible and unable  to concentrate on incoming sensory information or on any par-  ticular mental or motor task, and loses coherence of thought and  actions. The person may persist in thoughts or actions that are no  longer appropriate (perseveration) and be unable to monitor the    VERBAL READING  TYPE EXPRESSION COMPREHENSION REPETITION NAME COMPREHENSION WRITING LOCATION OF LESION CAUSE OF LESION    Receptive  Wernicke Fluent: able to produce Impaired (disturbance Impaired Impaired Impaired Impaired Left posterosuperior Occlusion of inferior division  dysphasia, verbal language but in understanding all temporal lobe (Wernicke of left middle cerebral  sensory language is meaningless; language) area) artery, temporal abscess  words are often  inappropriate; words  with similar sounds  or words with similar  meaning are substituted  for the correct words;  words that are not part  of the language may be  present; these neologisms  may be so extensive  as to make the speech  entirely incomprehensible;  because the person has  no means to monitor the  language for correctness,  errors are not recognized;  intonation, accent,  cadence, rhythm, and  articulation are normal  Global Nonfluent, produces little Impaired or completely —_ Impaired; Impaired Reading out Impaired; Frontotemporal lobe (left Occlusion of the left middle  (sensorimotor speech; at best speaks a lost; person not able to loud—impaired or produces sylvian region); anterior cerebral artery of left  receptive- few words or phrases understands only the repeat completely lost little and posterior speech internal carotid artery;  expressive) simplest things said Reading silently written areas extensively trauma, infection, tumors,  intact language impaired other mass lesions, and  hemorrhage may be the  cause    characteristics; knows  what he or she wants to  say but cannot find words;  may even use desired  word in another context  but still cannot isolate  word when needed  Nonfluent    in supramarginal gyrus,  disruption of the large  bundle of fibers that  arise from the temporal  lobe and pass posteriorly  around the sylvian    occlusion of the ascending  parietal or posterior  temporal branch of the  middle cerebral artery,  angular branch of middle  cerebral artery    Occlusion of left anterior  cerebral artery or anterior  border zone vascular  infarct   The car would spit sweetly down  the road. (The car sped swiftly  down the road.)   The onset of an acute confusional state usually is abrupt  rather than insidious. Later there are top-down processing prob-  lems, including misperceptions, delusions, and hallucinations.  Obsessions, compulsive behavior, and rituals may be evident.   Delirium is associated with autonomic nervous system over-  activity and typically develops over 2 to 3 days, most commonly  in critical care units, after surgery, or during withdrawal from  central nervous system depressants (e.g., alcohol or narcotic  agents). Delirium initially manifests as difficulty in concentrat-  ing, restlessness, irritability, insomnia, tremulousness, and poor  appetite. Some persons experience seizures. Unpleasant, even  terrifying, dreams or hallucinations may occur. In a fully devel-  oped delirium state, the individual is completely inattentive and  perceptions are grossly altered with delusions or hallucinations.  The person appears distressed and often perplexed; conversation  is incoherent. Frank tremor and high levels of restless movement  are common. Violent behavior may be present. The individual  cannot sleep, is flushed, and has dilated pupils, a rapid pulse rate  (tachycardia), temperature elevation, and profuse sweating (dia-  phoresis). Delirium typically abates suddenly or gradually in 2 to  3 days, although delirium states occasionally persist for weeks.   In hypokinetic acute confusional states (hypokinetic/hypo-  active delirium), the individual exhibits decreases in mental  function. Alertness is decreased, as are attention span, accurate  perception, and interpretation of the environment. Forgetful-  ness is prominent. Reactions to the environment are slowed and    Urinary tract infection,  thyroid disorders, hypoxia,  hypoglycemia, toxicity,  fluid-electrolyte imbalance,  renal insufficiency, trauma,  multiple medications    Adapted from Caplan JP, Rabinowitz T: Med Clin North Am 94(6):1103-  1116, ix, 2010.    indecisive. The individual dozes frequently. Hypoactive ACS can  be mistaken for depression or dementia although individuals  may have underlying depression or dementia with an incident  of ACS.   EVALUATION AND TREATMENT. An ACS is an acute medical  problem. The initial goal is to establish that the individual  is confused, and to identify the cause and contributing fac-  tors. Hypokinetic delirium will need to be differentiated from  depression. An underlying dementia may be present (Table  17-12). A complete history and physical examination, as well as  laboratory tests, is needed including an electrocardiogram and  blood, urine, cerebral spinal fluid (CSF), and radiologic studies.  Several assessment scales are available to guide evaluation.”   Once the cause is established, treatment is directed at con-  trolling the primary disorder. In an acute confusional state,  all drugs that may be contributing to or causing the condition  are discontinued unless the problem is the result of drug with-  drawal. Supportive measures are designed to enhance coping  skills and to minimize the individual’s need for altered cortical  functions. Supportive and protective management also involves  maintaining the person’s intact cortical functions by promot-  ing use of these functions. Delirium is preventable in some  individuals.?>7°   Dementia is the progressive failure (an acquired deteriora-  tion) of many cerebral functions that includes impairment of  intellectual function with a decrease in orienting, memory,    Potentially Reversible  Causes of Dementia  Infection  Encephalitis  Meningitis  Neurosyphilis  Normal Pressure Hydrocephalus  Chronic Subdural Hematoma  Nutritional Deficiencies  Vitamin B, (thiamine) deficiency  Vitamin B;» (cobalamin)  deficiency  Nicotinic acid (pellagra)  deficiency  Chronic Drug Intoxication  Alcohol*  Sedatives  Metabolic Disorders  Thyroid abnormalities  Chronic hepatic encephalopathy  Cerebral vasculitis  Sarcoidosis  Some Types of Tumors  Frontal and temporal lobe  Pseudodementia of depression    Irreversible Causes  of Dementia  Neurodegenerative Disorders  Alzheimer disease*  Dementia with Lewy bodies  Frontotemporal dementia  Pick disease  Huntington disease  Parkinson disease  Vascular Disease  Vascular dementia*  Multi-infarct  Strategic single infarct  Binswanger disease” (diffuse  white matter disease)  Amyloid angiopathy  Infection  Creutzfeldt-Jakob disease (CUD)  Postencephalitic dementia  Dementia associated with HIV    language, executive attentional functions, and alterations in  behavior. The greatest risk factor is age.?”? More than 26 mil-  lion people in the world have Alzheimer disease and by 2050 the  number is expected to triple with nearly 50% requiring a high  level of care.?*   Dementias can be classified according to etiologic factors  (e.g., trauma, tumors, vascular disorders, infections) and to  associated clinical and laboratory signs. Dementing processes  have been grouped as cortical, subcortical, or both. Box 17-1  lists the potentially reversible and irreversible causes of demen-  tia. Alzheimer disease (AD) is the most common cause followed  by vascular disease, then dementia associated with Lewy bod-  ies (i.e., Parkinson disease).’” In people younger than 60 years,  frontotemporal dementia (FTD) rivals AD in terms of fre-  quency.” Disruption in cerebral neural circuits is present. The  culmination of a progressive dementing process is nerve cell  degeneration and brain atrophy involving the cerebral cortex,  diencephalon, and basal ganglia.   PATHOPHYSIOLOGY. Mechanisms leading to dementia include:  (1) neurodegeneration, possibly caused by genetics, inflamma-  tion, or biochemical alterations; (2) atherosclerosis, multiple  foci of infarction throughout the thalami, basal ganglia, cerebral  projection pathways, and associated areas; (3) trauma, lesions in  the cerebral convolutions (mainly frontal and temporal), corpus  callosum, and mesencephalon; and (4) compression, increased  intracranial pressure, and chronic hydrocephalus. Genetic pre-  disposition associated with neurodegenerative diseases is sum-  marized in Table 17-13. CNS infections, including the human  immunodeficiency virus (HIV) and Creutzfeldt-Jakob disease    (human prion disease or transmissible spongiform encephalop-  athies), are associated with dementia in addition to changes in  motor function (i.e., ataxia, rigidity, and shuffling gait). Progres-  sive dementias produce nerve cell degeneration and brain atrophy.   CLINICAL MANIFESTATIONS. A summary of the clinical manifesta-  tions of the degenerative dementias is presented in Table 17-14.   EVALUATION AND TREATMENT. Establishing the cause for a  dementing process may be complicated, but anyone evidencing  the clinical manifestations of dementia should be evaluated with  laboratory and neuropsychologic testing and brain imaging.   If a specific treatable cause is identified, the appropri-  ate treatment is initiated. For example, an infectious process  requires the appropriate antibiotic, and a potentially resectable  mass may require neurosurgery. Nutritional deficiencies are  corrected. If the cause is metabolic, the imbalance is corrected  or the metabolic disorder is treated, or both.   Unfortunately no specific treatment or cure exists for most  progressive dementias. The goal is to discover the pathogenetic  mechanisms underlying dementia and to delay the conver-  sion of cognitive decline and mild cognitive impairment to full  dementia. Therapy is directed at maintaining and maximizing  the remaining capacities, restoring functions if possible, accom-  modating to lost abilities, and controlling behavioral changes.°°  Delusions, paranoia, and hallucinations often respond to neu-  roleptic medications. If coexisting depression is suspected, a  trial of antidepressants is appropriate. Assisting the family to  understand the dementing process and to learn ways to assist  the demented individual is an essential component of support-  ive management.    Alzheimer disease (dementia of Alzheimer type [DAT],  senile disease complex) is the leading cause of dementia and  one of the most common causes of severe cognitive dysfunc-  tion in older adults. Nonhereditary, or sporadic, late-onset AD  (70% of cases) is the most prevalent form. It is estimated that  5.4 million Americans have AD and by 2050 the numbers are  expected to range from 11 to 16 million.*! The greatest risk  factors are age and family history. Other proposed risk fac-  tors include diabetes, midlife hypertension, hyperlipidemia,  midlife obesity, smoking, depression, cognitive inactivity or  low educational attainment, female gender, estrogen deficit  at the time of menopause, physical inactivity, head trauma,  elevated serum homocysteine and cholesterol levels, oxidative  stress, and neuroinflammation (Figure 17-12). Proposed pro-  tective factors include lifelong activity, the presence of apoE2  and antioxidant substances, estrogen replacement at the time  of menopause, low-calorie diet, and use of nonsteroidal anti-  inflammatory agents. Statins are being investigated for their  role in preventing AD.°?"**   PATHOPHYSIOLOGY. The exact cause of AD is unknown and there  is no clear understanding of this complex disease process. Early-  onset familial Alzheimer disease (FAD) is autosomal dominant  and has been linked to three gene defects: amyloid precursor  protein (APP) gene on chromosome 21, presenilin 1 (PSEN1)  on chromosome 14, and PSEN2 on chromosome 1.°?° Late-  onset AD may be associated with chromosome 19 involved with   Prion (20) (up to 15% of  cases carry these dominant  mutations)    Amyloid plaques,  neurofibrillary tangles;  neuronal and synaptic loss  in the brain    Data from Premi E, Padovani A, Borroni B: Adv Exp Med Biol 724:114-127, 2012; Sikorska B et al: Adv Exp Med Biol 724:76-90, 2012; Wijsman  EM et al: PLoS Genet 7(2):e1001308, 2011; Zimprich A: Curr Opin Neurol 24(4):318-323, 2011.  APP. Amyloid precursor protein; PRNP prion protein; PrPS©, prion protein scrapie form; PSEN, presenilin.    Memory loss, disorientation to place and  time, loss of facial recognition   Language loss with talking less and  speech becoming hesitant or loss  of understanding of language, may  precede memory loss; spares drawing    Initially normal; progressive cognitive, language,  abstraction, and judgment impairment  Depression, anxiety, decreased cognitive function    Loss of empathy (emotional blunting), apathy,  increased inappropriate or decline in personal or  social conduct, loss of judgment and reasoning,  hyperorality, euphoria, depression    Apathy, loss of interest early; impaired cognition,  judgment, and memory occur later    Often but not always sudden, usually within 3  months of a stroke; variable; apathy, falls, focal    Usually motor slowing, spasticity;  can be normal or may have  symptom improvement with  stroke recovery    CBD, Cortical basal degeneration; FTP. frontotemporal dementia; PPA, primary progressive aphasia; PSP progressive supranuclear palsy.    Loss of synaptic plasticity and neural transmission  Cholinergic dysfunction  Loss of neuronal repair and remodeling  Neurodegeneration    FIGURE 17-12 Proposed Risk Factors and Pathogenesis of Alzheimer Disease. Apo, Apolipoprotein E; APP amy-  loid precursor protein; BP blood pressure. (Data from Barnes DE, Yaffe K: The projected effect of risk factor reduction on  Alzheimer's disease prevalence, Lancet Neuro! 10[9]:819-828, 2011; de la Monte SM: Contributions of brain insulin resistance  and deficiency in amyloid-related neurodegeneration in Alzheimer's disease, Drugs 72[1]:49-66, 2012; Daviglus ML et al: Risk  factors and preventive interventions for Alzheimer disease: state of the science, Arch Neuro! 68[9]:1185—-1190, 2011; Hasan  MK, Mooney RP: The predisposing factors, biological markers, neuroimaging techniques and medical complications associated    the apolipoprotein E gene-allele 4 (apoE4).*’ Sporadic AD is the  most common and does not have a specific genetic association;  however, the cellular pathologic mechanisms are the same as  those seen in early- and late-onset AD. Pathologic alterations  in the brain include the formation of neuritic plaques contain-  ing a core of amyloid beta protein, the formation of neurofibril-  lary tangles, and the degeneration of basal forebrain cholinergic  neurons with loss of acetylcholine. Failure to process and clear  amyloid precursor protein results in the accumulation of toxic  fragments of amyloid beta protein that leads to formation of  diffuse neuritic plaques, disruption of nerve impulse transmis-  sion, and death of neurons. Amyloid also is deposited in cere-  bral arteries, causing an amyloid angiopathy and disturbance  in blood flow (Figure 17-13). The tau protein, a microtubule-  binding protein, in neurons detaches and forms an insoluble  filament called a neurofibrillary tangle, which contributes to  neuronal death. Tangles are flame shaped (Figure 17-14). Senile  plaques and neurofibrillary tangles are more concentrated in  the cerebral cortex and hippocampus (important for memory).  The loss of neurons results in brain atrophy with decreases in    FIGURE 17-13 Altered Cerebral Blood Flow in Alzheimer Disease. Single  photon emission computerized tomography scan showing reduction of temporopa-  rietal blood flow (right) compared with normal blood flow (left). (From Perkin GD  et al: Atlas of clinical neurology, ed 3, Philadelphia, 2011, Saunders.)    FIGURE 17-14 Major Histopathologic Changes in Alzheimer Disease.  Beta-amyloid protein deposits (plaques) in the neutrophil (long arrows) and neuro-  fibrillary tangles (short arrows). (From Kumar V, Abbas AK, Aster J: Robbins basic  pathology, ed 9, Philadelphia, 2013, Saunders.)    weight and volume. The sulci widen and the gyri thin, especially  in the frontal and temporal lobes, and the ventricles enlarge to  fill the space (Figure 17-15). Loss of acetylcholine and other  neurotransmitters contributes to the decline of memory and  attention and the decline of other cognitive functions associated  with AD. Neuroinflammation is evident in the pathophysiology  of AD but the exact mechanisms are still being determined.°*  Alterations in intracellular calcium levels are functionally linked  to presenilin mutations, apoE4 expression, amyloid plaques, tau  tangles, and synaptic dysfunction. Aging and injury may result  in changes that contribute to the development and progres-  sion of this disease. Such changes include oxidative stress and  neuroinflammation, decreased oxygen and glucose transport,  molecular changes in vascular smooth muscle and in the blood-  brain barrier, and mitochondrial defects that alter cell metabo-  lism and processing of proteins, including amyloid (apoE4).°?"*!   CLINICAL MANIFESTATIONS. AD has a long preclinical and  prodromal course while pathophysiologic changes can occur  decades before the appearance of the clinical dementia syn-  drome. The disease progresses from mild short-term memory  deficits and culminates in total loss of cognition and executive  functions. Initial clinical manifestations are subtle and nonspe-  cific and often attributed to forgetfulness, emotional causes, or  other illness. The individual becomes progressively more for-  getful over time, particularly in relation to recent events. Mem-  ory loss increases as the disorder advances, and the person  becomes disoriented and confused. The ability to concentrate  declines. Abstraction, problem solving, and judgment gradu-  ally deteriorate. A failure in mathematic calculation ability,  language, and visuospatial orientation occurs. Dyspraxia may  appear. The mental status changes induce behavioral changes,  including irritability, agitation, and restlessness. Mood changes  also result from the deterioration in cognition. The person may  become anxious, depressed, hostile, emotionally labile, and  prone to mood swings. Motor changes may occur if the poste-  rior frontal lobes are involved. The individual exhibits rigidity  (paratonia, gegenhalten), with flexion posturing, propulsion,  and retropulsion. Weight loss can be significant (see Nutrition    FIGURE 17-15 Alzheimer Disease. The brain decreases in volume and  weight, the sulci widen, and the gyri thin, especially in the temporal and frontal  lobes. The ventricles enlarge to fill the space. (From Kumar V, Cotran RS, Robbins  SL: Robbins basic pathology, ed 7, p 843, Philadelphia, 2007, Saunders.)    Weight loss is a major concern for older adults with Alzheimer disease and  it may precede onset of the classic motor symptoms. Weight loss may be  a result of (1) increased incidence of infection, (2) increased energy output  because of constant pacing, (3) olfactory and taste changes making food less  appealing, (4) inadequate food intake, and (5) decreased independence and  difficulty in self-feeding. Dementia may lead to memory loss, social isolation,    depression, and poor food intake with resultant weight loss. Individuals may  forget or refuse to eat, fail to communicate the need to eat, throw or hide  food, eat spoiled food or nonfood substances, eat favorite foods to the exclu-  sion of other foods, take a long time to eat, have difficulty in preparing foods,  and be unable to feed themselves. Reduced lean body mass has been associ-  ated with brain atrophy and declining cognitive performance. Oral nutritional  supplementation can improve nutritional status.    Data from Burns JM et al: Arch Neurol 67(4):428-433, 2010; Pivi  GA et al: Nutr J 26(10):98, 2011; Soto ME et al: J Alzheimers Dis  28(3):647-654, 2012.    & Disease: Diet and Alzheimer Disease). Great variability in  age of onset, intensity and sequence of symptoms, and loca-  tion and extent of brain abnormalities occurs among individu-  als with AD. Table 17-15 presents the clinical findings in each  stage of AD.   EVALUATION AND TREATMENT. The specific diagnosis of AD is  made by postmortem examination.” The clinical history, cog-  nitive testing, course of the illness, laboratory tests, and brain  imaging are used for diagnostic evaluation. The course of the  disorder is highly variable, usually developing over 5 years or  more. Genetic susceptibility tests for PSEN1, PSEN2, and APP  are used to screen for early-onset AD.**   There are no disease-arresting therapies available for AD.  Cholinesterase inhibitors (ChE-Is) are used in mild to moder-  ate AD to enhance cholinergic transmission. Drugs for moder-  ate to severe AD block the activity of glutamate (an excitatory  neurotransmitter and modulator of neuroplasticity) and work  as an noncompetitive N-methyl-p-aspartate (NMDA) receptor  (a glutamate receptor) antagonist.“*    event (episodic memory)  and new information  (semantic memory)  Possibly depression (vs.  apathy); mild anxiety    forgetfulness; easy  to get lost; may dress  inappropriately; may  have hallucinations    Little cognitive ability; language  not clear; personality change;  does not recognize family  members; wandering; repetitive  behavior    Adapted from National Conference of Gerontological Nurse Practitioners and the National Gerontological Nursing Association, Counseling Points    1(1):6, 2008.  ADL, Activities of daily living; ADL, instrumental activities of daily living.    Treatment of AD also is directed at decreasing impaired  cognitive function by implementing compensation techniques  (such as memory aids), maintaining cognitive functions that  are not impaired, and retaining or improving the general state  of hygiene, nutrition, and health. Environmental management,  counseling, education, pharmacotherapy, and health promo-  tion measures provide the foundation on which a comprehen-  sive individualized treatment program is built.*°    Frontotemporal dementia (FTD), previously known as Pick  disease, is a rare, severe degenerative disease of the frontal  and anterior frontal lobes that produces death of tissue and  dementia. Age of onset is less than 60 years. Three different  clinical presentations have been described: behavioral variant  frontotemporal dementia (bvFTD), semantic dementia (SD),  and progressive nonfluent aphasia (PNFA) (see What’s New?  The Frontotemporal Disorders). Each clinical presentation is  associated with a distinct region of brain atrophy and patterns  of cellular atrophy. There is an autosomal dominant pattern    Although marked by progressive damage to the anterior temporal or frontal  lobes of the brain, or both, specific subtypes of frontotemporal degeneration  (FTD) have been identified with distinct clinical presentations associated with  the brain area most affected. Behavioral variant FLTD (bvFTD, Pick disease, or  frontal variant FTD) has a predominant behavioral presentation characterized  by loss of empathy and increasingly inappropriate social behavior. The right  frontal lobe is most affected by bvFTD. A predominant language presenta-  tion known as primary progressive aphasia (PPA) can manifest as a nonflu-  ent/agrammatic PPA with the person talking less and the speech becoming  hesitant or with a progressive deterioration in understanding language and  recognizing objects. The left language areas are most affected in this subtype.  A third variant is marked by deteriorating ability to retrieve (recall) words and  is associated with left temporal areas. A predominant movement presentation  occurs in corticobasal syndrome (CBS) characterized by decreased movement  unilaterally and rigidity accompanied by a tremor initially and in progressive  supranuclear palsy (PSP) characterized by gait and balance problems and  inability to coordinate eye movements.    Data from Gorno-Tempini ML et al: Neurology 15:76(11):1006-1014,  2011; Sieben A et al: Acta Neuropathol 124(3):353-372, 2012.    of inheritance in 30% to 50% of cases. The majority of cases  involve mutations of genes encoding tau protein or progranu-  lin (may be important for nerve repair). The disease is diffi-  cult to distinguish clinically and pathologically from Alzheimer  disease.*°    Seizure disorders represent a manifestation of disease and not  a specific disease entity. A seizure is a sudden, transient disrup-  tion in brain electrical function caused by abnormal excessive  hypersynchronous discharges of cortical neurons.*” Epilepsy  is the recurrence of seizures and a type of seizure disorder for  which no underlying correctable cause for the seizure can be  found. The term convulsion is sometimes applied to seizures  and refers to the tonic-clonic (jerky, contract-relax) movement  associated with some seizures. Seizures in children are pre-  sented in Chapter 20.    Any condition that changes the neuronal environment may  produce seizure activity; therefore, in theory, anyone can have  a seizure. The seizure threshold of some individuals, however,  is genetically lower.   Diseases or other processes that involve the nervous system  may cause a seizure disorder. The onset of seizures may point to  the presence of an ongoing primary neurologic disease. Etiologic  factors in seizures include: (1) cerebral lesions, (2) biochemical  disorders, (3) cerebral trauma, and (4) epilepsy. Conditions that  may produce a seizure are metabolic defects, congenital mal-  formations, genetic predisposition, perinatal injury, postnatal  trauma, myoclonic syndromes, infection, brain tumor, and vas-  cular disease.   Seizures also may be precipitated by hypoglycemia; fatigue  or lack of sleep; emotional or physical stress; fever; large  amounts of water ingestion (hyponatremia); constipation; use  of stimulant drugs; withdrawal from depressant drugs or alco-  hol; hyperventilation (respiratory alkalosis); and some envi-  ronmental stimuli, such as blinking lights, a poorly adjusted  television screen, loud noises, certain odors, or merely being  startled. Immediately before or during menses women may  have increased seizure activity.**    Seizures are classified in different ways—by clinical manifesta-  tions, site of origin, EEG correlates, or response to therapy.*?°  Types of seizures are presented in Table 17-16. Generalized  seizures, 30% of seizures, involve neurons bilaterally, often    do not have a local (focal) onset, and usually originate from  a subcortical or deeper brain focus. Generalized seizures result  from cellular, biochemical, or structural abnormalities of a  widespread nature.‘”? With a generalized seizure, conscious-  ness always is impaired or lost. Focal seizures (partial seizures)    TABLE 17-16 TYPES OF SEIZURES AND CLINICAL MANIFESTATIONS  TYPE CLINICAL MANIFESTATIONS    . With jacksonian march  (jacksonian seizure—the  seizure activity spreads  in an orderly fashion to  adjacent areas)    . With special sensory or  somatosensory symptoms  (focal sensory seizure); less  common than focal motor  seizures; any age may be  affected   1. Simple partial onset fol-  lowed by impairment of  consciousness—common  seizures found in children  and adults but in most per-  sons occurs before 20 years  of age   Motor movement elicited by the seizure activity depends on the anatomic-physiologic portion of the  irritated cortex, but motor seizures most often begin in the face and hands   Focal seizures begin with slow, repetitive jerking of the body part, which increases in strength and  rate over 5 to 15 seconds   The seizure can cease spontaneously, with a gradual decrease in clonic movement   Seizure activity spreads to adjacent areas after the initial clonic movement increases; motor  movements, for example, begin in the fingers of one side and spread to the hand, wrist, forearm,  arm, face, and finally the lower extremity on the same side of the body    Turning movement of hand and eyes to the side opposite the irritative focus occurs   Often it is associated with contractions of the trunk and extremities   Sensory experience is subjective and confined to the primary sensory modalities (somesthetic,  visual, auditory-vestibular, or olfactory)   If sensory seizure begins on the hand area of the sensory cortex, the person experiences numbness,  tingling, or “pins and needles” phenomena. Other sensory experiences include burning, a  crawling sensation, or a feeling of movement of the body part    The person is able to interact with the environment with purposeful, although inappropriate,  movements; although the body muscles stiffen, the person does not fall and may even  continue the complex activity in which he or she was involved, such as driving (perseverative  automatisms); the person may appear “wide eyed”   Awide variety of sensory experiences precede the automatism and include illusions; formed hallucinations;  primitive visceral, olfactory, and gustatory sensations; and affective and cognitive symptoms   Most characteristic event of a temporal lobe seizure is the automatism; common examples of  automatisms are lip smacking, chewing, facial grimacing, swallowing movements, and patting,  picking, or rubbing oneself or one’s clothing   Temporal lobe seizures generally last 11 seconds to 8 minutes (average 2 minutes) and are  followed by several minutes of postictal confusion   Characterized by lapses in consciousness that rarely last longer than 10 seconds. Often associated  with additional subtle signs and symptoms such as clonic movements, changes in postural tone,  automatisms, and autonomic changes   Lapses in consciousness occur almost always accompanied by motor signs, especially changes in  tone and lasts from 10 to 25 seconds   Postcentral  gyrus (parietal  lobe) with  involvement  of the primary  sensory area    Characterized by sudden uncontrollable jerking movements of one or more extremities or the entire body — Multifocal   Person often is flung violently to the ground; injury is a real possibility   Characterized by repetitive clonic jerks of constant amplitude and diminishing frequency   Loss of postural tone without evidence of clonicity, with flexion of the upper limbs and extension of  the lower limbs   Assumes an abnormal posture for seconds or minutes without losing consciousness   A prodromal period of irritability and tension may precede a tonic-clonic seizure by several hours or  days; however, usually seizures begin without warning   Characteristically tonic-clonic seizures begin with a sudden loss of consciousness and brief flexion;    the person falls to the ground and the body stiffens in an opisthotonos position with legs and,  usually, arms extended; the jaw snaps shut; a shrill cry may be heard as a result of forceful  exhalation of air through the closed vocal cords as the thoracic muscles initially contract; the  bladder and, less often, the bowel may evacuate; during the tonic phase, the person is apneic  with subsequent cyanosis; pupils are dilated and unresponsive to light   The tonic phase lasts less than 1 minute (average 10-15 seconds)   The clonic phase is characterized by flexion spasms of the whole body interrupted by muscular  relaxation; muscular contractions are accompanied by strenuous hyperventilation; the face is  contorted; the eyes roll, and there is excessive salivation with frothing from the mouth; profuse  sweating and a rapid pulse rate are evident. The tongue is often bitten.   The clonic jerking subsides in frequency and amplitude over a period of about 30 seconds    After the clonic phase, the person is in a stupor or coma for about 5 minutes; the extremities are  limp; breathing is quiet; and the pupils begin to respond to light  When the person awakens, he or she may be confused and disoriented with complaints of    Tonic-clonic seizures may occur at any time of day or night, whether the person is awake or asleep  The frequency of recurrence may vary from hours to weeks, months, or years    Characterized by sudden loss of postural muscle tone; the tone loss may be mild, resulting ina    Ill. Unclassified epileptic seizures  A. Neonatal seizures Occurs within first 28 days of life    Neck and trunk flexion and arm abduction with a jackknife pattern    Epileptic spasms occur in clusters recurring every 5 to 40 seconds    involve neurons only unilaterally, often have a local (focal)  onset, and originate from discrete areas usually associated  with structural abnormalities localized to the cortical brain  tissue, thereby having a superficial focus. Consciousness may  be maintained as long as the seizure activity is limited to one  hemisphere in simple partial seizures, but partial seizures may  become generalized to involve neurons of the other hemisphere  and the deeper brain nuclei. This process is called secondary  generalization. Consciousness is lost at the point of general-  ization. In complex partial seizures, consciousness is impaired;  that is, the person is unable to respond normally to exogenous  stimuli. Sixty percent of seizures are either complex partial sei-  zures or seizures with secondary generalization.  PATHOPHYSIOLOGY. Seizures occur when there is disruption in  the balance of excitation and inhibition of electrical impulses.*!  The primary abnormality may be a membrane defect leading    to instability in resting potential, abnormalities of potassium  conductance or calcium channels, defects of the gamma-  aminobutyric acid (GABA) inhibitory system, or an abnor-  mality in excitatory transmission enhancement, particularly of  the N-methyl-p-aspartate type (NMDA). In animal models, a  defect in the GABA inhibitory system is the mechanism caus-  ing generalized seizures. Three groups of physiologic mecha-  nisms are involved in seizures and epilepsies: (1) mechanisms of  seizure initiation and propagation (excitation and inhibition),  (2) mechanisms of epileptogenesis, and (3) genetics.°?   Seizure initiation is characterized by two simultaneous  events in a group of neurons: (1) high-frequency bursts of  action potentials and (2) hypersynchronization. The burst activ-  ity is produced by a relatively long-lasting depolarization of the  neuron caused by an influx of extracellular calcium that opens  the voltage-dependent sodium channel. The influx of sodium    generates repetitive action potentials.” The firing of involved  neurons becomes increasingly greater in frequency and ampli-  tude. With sufficient neuronal activation, recruitment of sur-  rounding neurons occurs through a variety of mechanisms.  The discharge spreads or propagates to adjacent normal neu-  rons through corticocortical synapses. If uninhibited at this  point, the cortical excitation spreads through interhemispheric  tracts to the contralateral cortex and through projection path-  ways to the subcortical areas of the basal ganglia, thalamus, and  brainstem. The excitation spread to the subcortical, thalamic,  and brainstem areas corresponds to the tonic phase (phase  of muscle contraction associated with increased muscle tone)  and is associated with loss of consciousness. Autonomic clinical  manifestations also may emerge at this point, and apnea may  be present for a few seconds. The excitation is further projected  downward to the spinal cord neurons through the corticospinal  and reticulospinal pathways.   The clonic phase (phase of alternating contraction and  relaxation of muscles) begins as inhibitory neurons in the cor-  tex, anterior thalamus, and basal ganglia begin to inhibit the  cortical excitation. This inhibition causes an interruption in  the seizure discharge, producing an intermittent contract-relax  pattern of muscle contractions. The intermittent clonic bursts  gradually become more and more infrequent until they finally  cease. At this point the epileptogenic neurons are exhausted and  the neuronal membranes probably are hyperpolarized.   The maintenance of seizure activity demands a 250% increase  in the concentration of adenosine triphosphate (ATP). Cerebral  oxygen consumption is increased by 60%. Although cerebral  blood flow also increases approximately 250% during seizure  activity, available glucose and oxygen are readily depleted. With  a severe seizure the brain tissue may require more ATP than can  be produced by the tissues from the available oxygen and glu-  cose. A deficiency of ATP, phosphocreatine, and glucose then  occurs, and lactate accumulates in the brain tissues. Severe sei-  zures thus may produce secondary hypoxia, acidosis, and lactate  accumulation, all of which are imbalances that may result in  progressive brain tissue injury and destruction. Cellular exhaus-  tion and destruction are consequences of these events.   Epileptogenesis refers to the transformation of a normal  neuronal network into one that is chronically hyperexcitable  (epileptogenic focus).°° A delay of months to years often occurs  between the initiating injury and the first seizure. Some forms  of epileptogenesis involve structural changes in the neuronal  network. Reorganization or “sprouting” of surviving neurons  (plasticity) also has been found to affect the excitability of the  network.   If a seizure focus is active for a prolonged period, a second-  ary focus, called a mirror focus, may develop in normal tissue.  This process apparently is caused by the interhemispheric com-  munication, inasmuch as the mirror focus is located in the con-  tralateral cortical area. Seizure threshold in some individuals is  genetically lower. Research is in progress to identify alterations  in gene transcription that affect seizure threshold.*+°   Status epilepticus in adults is a state of continuous seizures  lasting more than 5 minutes, or rapidly recurring seizures before  the person has fully regained consciousness from the preceding  seizure, or a single seizure lasting more than 30 minutes. Status    epilepticus can arise from abnormal persistence of excessive  excitation or ineffective recruitment of inhibition.°° The person  is still in a postictal state (a state that follows an epileptic sei-  zure and returns to baseline) when the next seizure begins. Sta-  tus epilepticus most often results from abrupt discontinuation  of antiseizure medications but also may occur in untreated or  inadequately treated persons with seizure disorders. The situ-  ation is a medical emergency because of the resulting cerebral  hypoxia. Mental retardation, dementia, other brain damage,  and even death are serious threats. Aspiration also is a great risk.   The term epilepsy, meaning “to be seized by a force from with-  out,” generally is applied to conditions in which there is no under-  lying correctable cause for the seizures. The seizure activity recurs  without treatment because of a primary underlying brain abnor-  mality. Epilepsy therefore is a general term for the primary condi-  tion that causes the symptoms of seizures.* It is now considered to  be the result of the interaction of complex genetic mutations with  environmental effects that cause abnormalities in brain wiring, an  imbalance in the brain’s neurotransmitters, or the development of  abnormal nerve connections after injury.°® Epilepsy is estimated to  affect about 2.7 million people in the United States with 150,000  new cases of epilepsy reported in 2010.°’ Incidence is highest in  early childhood and declines to plateau in adulthood. However,  incidence rises again in older people to early childhood levels.   Epileptic syndromes are epileptic disorders characterized by  specific clusters of signs and symptoms.” Two categories are  based on clinical history, EEG manifestations, and etiology and  include: (1) localization (focal) related (e.g., temporal lobe epi-  lepsy) and (2) generalized. Localization-related epilepsies and  syndromes are typified by seizures that originate from a local-  ized cortical region and are characterized by seizures that have  a focal or partial onset. Generalized epilepsies are characterized  by seizures with initial activation of neurons within both cere-  bral hemispheres.   Epilepsy syndromes are further subdivided into idiopathic,  symptomatic, or cryptogenic. Idiopathic epilepsy refers to  syndromes that arise spontaneously without a known cause,  presumably having a genetic basis. The genetic basis may be  through a specific inherited trait in which the seizures are  the principal expression of the genetic defect (e.g., childhood  absence epilepsy). In two thirds of cases, the etiology of the  epilepsy is not identified. Symptomatic epilepsy denotes epi-  lepsies with an identified cause. One third of seizures can be  classified as symptomatic (provoked or secondary). Some  symptomatic epilepsies also have a genetic basis in which the  inherited trait is expressed in a neurologic or systemic disor-  der that is associated with seizures (e.g., neurofibromatosis).  The term cryptogenic epilepsy describes syndromes that are  presumed to be symptomatic but have no known etiology, and  occur in persons with or without abnormalities on neurologic  examination. Box 17-2 presents the international classification  of epilepsies, and Table 17-17 groups the etiology of recurrent  seizures by age group.   CLINICAL MANIFESTATIONS. The clinical manifestations asso-  ciated with seizure depend on the type of seizure (see Table  17-16). Two types of symptoms often signal an impending  generalized tonic-clonic seizure: an aura, a partial seizure that  immediately precedes the onset of a generalized tonic-clonic    Neonates (<1 month) Acute CNS infection (e.g., sepsis, meningitis,  encephalitis)  Cortical malformation  Drug withdrawal or toxicity  Genetic disorders  Intracranial hemorrhage and trauma  Kernicterus  Metabolic disturbances (e.g., hypoglycemia,  hypocalcemia, hypomagnesemia, pyridoxine  deficiency)  Perinatal hypoxic and ischemic encephalopathy  Infants and children Degenerative disorders (e.g., tuberous sclerosis,  (1 month to 12 yr) neurofibromatosis, Tay-Sachs disease)  Febrile seizures  Genetic disorders (e.g., metabolic, degenerative,  primary epilepsy syndromes)  Idiopathic  Infantile spasms  Trauma  Children (5-11 yr) Early onset and childhood absence seizures  Meningoencephalitis  Adolescents (12-18 yr) | Acute CNS infection (e.g., sepsis, meningitis,  encephalitis)  Brain tumor  Genetic disorders  Idiopathic  Illicit drug use (e.g., cocaine, amphetamines)  Trauma  Young adults Alcohol or drug withdrawal (e.g., barbiturates,  (18-35 yr) benzodiazepines)  Brain tumor  Idiopathic  Illicit drug use (e.g., cocaine, amphetamines)  Trauma  Older adults (>35 yr) Alcohol or drug withdrawal (e.g., barbiturates,  benzodiazepines)  Brain tumor  Cerebrovascular disease (e.g., stroke, aneurysm,  arteriovenous malformations)  CNS degenerative diseases (e.g., Alzheimer  disease, multiple sclerosis)  Idiopathic  Metabolic disorders (e.g., uremia, hepatic failure,  electrolyte abnormalities, hypoglycemia)    |. Localization related (focal, partial)  A. Idiopathic  1. Benign childhood epilepsy with centrotemporal spikes  2. Childhood epilepsy with occipital paroxysms  3. Primary reading epilepsy  B. Symptomatic  1. Temporal lobe epilepsy  2. Frontal lobe epilepsy  3. Parietal lobe epilepsy  4. Occipital lobe epilepsy  5. Chronic progressive epilepsia partialis continua of childhood  C. Cryptogenic defined by:  1. Seizure type  2. Clinical features  3. Etiology  4. Anatomic localization  . Generalized  A. Idiopathic  1. Benign neonatal familial convulsions  . Benign neonatal convulsions  . Benign myoclonic epilepsy in infancy  . Childhood absence epilepsy  . Juvenile absence epilepsy  . Juvenile myoclonic epilepsy  . Epilepsies with grand mal seizures on awakening  . Other generalized idiopathic epilepsies  . Cryptogenic or symptomatic  1. West syndrome  2. Lennox-Gastaut syndrome  3. Epilepsy with myoclonic-astatic seizures  4.  3),    Epilepsy with myoclonic absences  Other symptomatic generalized epilepsies  . Symptomatic  onspecific etiology  . Early myoclonic encephalopathy  . Early infantile epileptic encephalopathy with suppression bursts  . Undetermined epilepsies  A. Generalized and focal features  1. Neonatal seizures  2. Severe myoclonic epilepsy in infancy  3. Epilepsy with continuous spike wave during slow-wave sleep  4. Acquired epileptic aphasia  . Special syndromes  A. Situation-related seizures  1. Febrile convulsions  2. Isolated seizures or isolated status epilepticus  3. Seizures occurring only when there is an acute or toxic event Data from Goetz CG, editor: Textbook of clinical neurology, ed 3,  attributable to factors such as alcohol, drugs, eclampsia, nonke- Philadelphia, 2007, Saunders; Nabbout R, Dulac O: Curr Opin Neurol  21(2):16106, 2008; Neubauer BA, Gross S, Hahn A: Dtsch Arzteb! Int  105(17):319-327, 2008; Waterhouse E, Towne A: Cleve Clin J Med  From the Commission on Classification and Terminology of the Inter- 72(Suppl 3):S26—S37, 2005.  national League Against Epilepsy: Epilepsia 30:389-399, 1989. Used CNS, Central nervous system; yr, year(s).  with permission of International League Against Epilepsy.    A partial seizure experienced as a peculiar sensation  preceding the onset of a generalized seizure or  complex partial seizure that may take the form of  gustatory, visual, or auditory experience; a feeling of  dizziness or numbness; or just “a funny feeling”   Early clinical manifestations, such as malaise, headache,  or a sense of depression, that may occur hours to a few  days before the onset of a seizure   A state of muscle contraction in which there is excessive  muscle tone    seizure; and a prodroma, an early manifestation that may occur  hours to days before a seizure (Table 17-18). Both manifesta-  tions may become familiar to the person experiencing recurrent  generalized seizures and so may help in preventing injuries dur-  ing the seizure.   EVALUATION AND TREATMENT. Health history is the most criti-  cal aspect in diagnosing a seizure disorder and establishing the  cause and onset. The health history is supplemented by the  physical examination and laboratory tests of blood and urine  (blood glucose, serum calcium, blood urea nitrogen, urine  sodium, and creatinine clearance measurements) to iden-  tify any systemic diseases known to have seizures as a clinical  manifestation. Brain imaging and cerebrospinal fluid (CSF)  examination are useful for identifying any neurologic diseases  associated with seizures. The EEG is useful in assessing the type  of seizure and may help determine its focus. Combined EEG  and functional magnetic resonance imaging (MRI) are useful  in identifying neural networks involved in epileptic activity.°!   Treatment for a seizure disorder is first to correct or control  its cause, if possible. If this is not possible, the major means  of management is the judicious administration of antiseizure  medications. The therapeutic goal is complete suppression  of seizure activity without intolerable side effects of the drug  or drug resistance. Dietary treatments (e.g., ketogenic diet)  are effective for some individuals with epilepsy.®? Surgical  interventions can improve seizure control and quality of life  in people with drug-resistant epilepsy.°? Vagus nerve stimu-  lation can reduce seizure frequency in persons with drug-  resistant partial seizures.°* Educational programs may reduce  seizure frequency and improve psychologic functioning but  it is not known if behavioral and psychologic treatments are  beneficial.    An injured brain reacts with structural, chemical, and patho-  physiologic changes called secondary brain injuries (see Chap-  ter 18). The primary injury is the original trauma and the    Cerebral blood volume (CBV) is the amount of blood in the intracranial vault  at a given time (normally about 10%). Most of this CBV is in the low-pressure  venous system. CBV is determined by autoregulatory mechanisms that control  cerebral blood flow (CBF). CBF is the flow of blood through the brain and is  normally maintained at a rate that matches local oxygen need and removal  of metabolic wastes. CBF is sensitive to concentrations of carbon dioxide,  hydrogen ion, and oxygen. CBF decreases 3% for every 1-mmHg decrease in  CO, pressure attributable to vasoconstriction. CBF increases at a Pao, of less  than 50 mmHg; CBF is stable (maintained) at a Pao, of greater than 80 mmHg.   CBF to the brain is maintained at a rate that matches local metabolic needs  of the brain, about 750 to 900 ml/minute (15% to 20% of the cardiac output).  Blood flow to neuronal cell bodies of gray matter is about three to four times  greater than that to white matter because of the increased metabolic activ-  ity. CBF is calculated as follows: CBF + CPP (cerebral perfusion pressure)/  CVR (cardiovascular resistance). CPP is the net pressure gradient required to  perfuse the cells of the brain. CPP is calculated as follows: CPP = mean arterial  pressure (MAP) — intracranial pressure (ICP). Normal CPP is 60 to 100 mmHg.  The CPP determines the CBF. As the CPP decreases to 70 to 80 mmHg in the  injured brain, vasodilation occurs, which increases the CBV, also increasing  the ICP. An increased ICP will decrease CPP.   Cerebral oxygen saturation is measured in the internal jugular vein (Sjo2)  at the jugular bulb and reflects the amount of oxygen still bound as the blood  leaves the cranial vault. Cerebral extraction of oxygen (CEo,) is calculated  using the formula Sad — Sjo2/Sa0, x 100. Normal CEo, is 20% to 24%; normal  Sj02 is 55% to 70%. When oxygen demand exceeds oxygen supply, extraction  increases, increasing the Sjo7. A CEo2 less than 24% or an Sjoy greater than  75% indicates cerebral hyperemia. Acid-base balance and temperature influ-  ence oxyhemoglobin dissociation (see Figure 34-16).    Data from Arshi B, Mack WJ, Emanuel B: Neural Res Int 2013:987934,  2013; Brady KM et al: Anesth Analg 108(4):1278-1283, 2009; Verweij  BH, Amelink GJ, Muizelaar JP: Prog Brain Res 161:111-124, 2007.  CO», Carbon dioxide; PaOz, arterial oxygen pressure; SaO,, oxygen  saturation in arterial blood; SjO2, oxygen saturation in the jugular vein.    secondary injury is a consequence of ischemia often related to  cerebral hemorrhage and edema. Critical features of these inju-  ries include alterations in cerebral blood flow, intracranial pres-  sure, and oxygen delivery. Several relevant features of cerebral  hemodynamics relate to cerebral oxygenation (Box 17-3).  Alterations in cerebral blood flow may be related to three  injury states: (1) cerebral oligemia (inadequate cerebral per-  fusion), (2) cerebral perfusion pressure (CPP) in the normal  range (60 to 100 mmHg) but with an elevated intracranial  pressure (ICP), and (3) cerebral hyperemia (excessive cerebral  blood volume). In the treatment algorithms, oxygen saturation  measured in the internal jugular vein (Sjo) is categorized as  less than 55%, greater than 55% but less than 70%, or greater  than 75%. After Sjo, is categorized, the ICP must be added to  the equation as less than 20 mmHg or greater than 20 mmHg.  Depending on the Sjoy and ICP values, treatment algorithms  are implemented that address not only ICP but also CPP. The  therapeutic goal is to balance ICP and Sjo,. Target values for  relevant clinical parameters are presented in Table 17-19.    Intracranial pressure normally is 5 to 15 mmHg, or 60 to 180  mm H,O. Increased intracranial pressure (IICP) may result    from an increase in intracranial content (as occurs with tumor  growth), edema, excess CSF, or hemorrhage. It necessitates an  equal reduction in volume of the other cranial contents. The  most readily displaced content is CSF. If intracranial pressure  remains high after CSF displacement out of the cranial vault,  cerebral blood volume and blood flow are altered.   In stage 1 of intracranial hypertension, vasoconstriction and  external compression of the venous system occur in an attempt  to further decrease the intracranial pressure. Thus, during the  first stage of intracranial hypertension, ICP may not change  because of the effective compensatory mechanisms and there  may be few symptoms (Figure 17-16). Small increases in vol-  ume, however, cause an increase in pressure, and the pressure  may take longer to return to baseline. This can be detected with  ICP monitoring.   In stage 2 of intracranial hypertension, there is continued  expansion of intracranial contents. The resulting increase in    TABLE 17-19 THERAPEUTIC  MANAGEMENT GOALS  FOR INDIVIDUALS WITH  ALTERED CEREBRAL  HEMODYNAMICS    ICP may exceed the brain’s compensatory capacity to adjust.  The pressure begins to compromise neuronal oxygenation,  and systemic arterial vasoconstriction occurs in an attempt to  elevate the systemic blood pressure sufficiently to overcome  the IICP. Clinical manifestations at this stage are usually subtle  and transient, including episodes of confusion, restlessness,  drowsiness, and slight pupillary and breathing changes (see  Figure 17-16).   In stage 3 of intracranial hypertension, the ICP begins to  approach arterial pressure, the brain tissues begin to experience  hypoxia and hypercapnia, and the individual’s condition rap-  idly deteriorates. Clinical manifestations include decreasing lev-  els of arousal or central neurogenic hyperventilation, widened  pulse pressure, bradycardia, and pupils that become small and  sluggish (see Figure 17-16).   Dramatic sustained rises in ICP are not seen until all com-  pensatory mechanisms have been exhausted. Then dramatic  rises in ICP occur over a very short period. Autoregulation,  the compensatory alteration in the diameter of the intracranial  blood vessels designed to maintain a constant blood flow dur-  ing changes in cerebral perfusion pressure, is lost with progres-  sively increased ICP. Accumulating carbon dioxide may still  cause vasodilation locally, but without autoregulation this vaso-  dilation causes the hydrostatic (blood) pressure in the vessels to  drop and blood volume to increase. The brain volume is thus  further enhanced, and ICP continues to rise. Small increases  in volume cause dramatic increases in ICP, and the pressure  takes much longer to return to baseline. As the ICP begins to  approach systemic blood pressure, cerebral perfusion pres-  sure falls and cerebral perfusion slows dramatically. The brain  tissues experience severe hypoxia, hypercapnea, and acidosis.    STAGES OF BEGINNING DECOMPENSATION  COMPENSATION DECOMPENSATION (HERNIATION)  STAGE 1 STAGE 2 STAGE 3 STAGE 4 DEATH  Mental Awake and Episodes of | Beginning inabilityto | |  status alert | confusion stay awake continuing on to progressively deeper coma  Restlessness | ———  | |  etna Small, reactive pupils i@® Ce) @ @  Pupils Equaland | Equaland |! progressing to slowing of response to light Bilateral |  reactive | reactive | Ipsilateral dilation ae and  | > Cc) | and fixation Isceuitern |  Breathing Normal ' Normal Normal, may slow some then progressing to |  (eupnea) | (eupnea) | jCheyne-Stokes breathing !  | | | Central neurogenic hyperventilation  apneustic off  160) Systolic ataxic breathing  Blood 120: ae  pressure 80.2 Sse |  | |  160 | | | |  120 | | :  Pulse 30 | | Slight |  | Full and bounding irregularity  |  Temperature Patterns vary \    FIGURE 17-16 Clinical Correlates of Compensated and Uncompensated Phases of Intracranial Hypertension.  (From Beare PG, Myers JL: Principles and practice of adult health nursing, ed 3, St Louis, 1998, Mosby.)    FIGURE 17-17 Brain Herniation. Herniations can occur both above and  below the tentorial membrane. Supratentorial: 1, uncal (transtentorial); 2, central:  3, cingulate; 4, transcalvarial (external herniation through an opening in the skull).  Infratentorial: 5, upward herniation of cerebellum; 6, cerebellar tonsillar moves  down through foramen magnum.    In stage 4 of intracranial hypertension, brain tissue shifts  (herniates) from the compartment of greater pressure to a  compartment of lesser pressure and IICP in one compart-  ment of the cranial vault is not evenly distributed throughout  the other vault compartments (see Figures 17-16 and 17-17).  With this shift in brain tissue, the herniating brain tissue’s  blood supply is compromised, causing further ischemia and  hypoxia in the herniating tissues. The volume of content  within the lower pressure compartment increases, exerting  pressure on the brain tissue that normally occupies that com-  partment, and impairing its blood supply. Small hemorrhages  often develop in the involved brain tissue. Obstructive hydro-  cephalus may develop. The herniation process markedly and  rapidly increases intracranial pressure. Mean systolic arterial  pressure soon equals ICP and cerebral blood flow ceases at  this point. The types of herniation syndromes are outlined  in Box 17-4.    Cerebral edema is an increase in the fluid content of brain  tissue, a net accumulation of water within the brain (Figures  17-18 and 17-19). Cerebral edema causes an increase in extra-  cellular or intracellular tissue volume after brain insult from  trauma, infection, hemorrhage, tumor, ischemia, infarct, or  hypoxia. The harmful effects of cerebral edema are caused by  the distortion of blood vessels, the displacement of brain tis-  sues, and the eventual herniation of brain tissue from one brain  compartment to another.   Three types of cerebral edema are (1) vasogenic edema,  (2) cytotoxic (metabolic) edema, and (3) interstitial edema.  Vasogenic edema is clinically the most important type. It is  caused by the increased permeability of the capillary endothe-  lium of the brain after injury to the vascular structure. The result   1. Uncal herniation. This occurs when the uncus or hippocampal gyrus, or both,  shifts from the middle fossa through the tentorial notch into the posterior  fossa, compressing the ipsilateral third cranial nerve, the contralateral third  cranial nerve, and the mesencephalon. Uncal herniation generally is caused  by an expanding mass in the lateral region of the middle fossa. The classic  manifestations of uncal herniation are a decreasing level of consciousness,  pupils that become sluggish before fixing and dilating (first the ipsilateral,  then the contralateral pupil), Cheyne-Stokes respirations (which later shift  to central neurogenic hyperventilation), and the appearance of decorticate  and then decerebrate posturing.   . Central herniation. This is the straight downward shift of the diencephalon  through the tentorial notch. It may be caused by injuries or masses located  around the outer perimeter of the frontal, parietal, or occipital lobes; extra-  cerebral injuries around the central apex (top) of the cranium; bilaterally  positioned injuries or masses; and unilateral cingulate gyrus herniation.  The individual rapidly becomes unconscious; moves from Cheyne-Stokes  respirations to apnea; develops small, reactive pupils and then dilated,  fixed pupils; and passes from decortication to decerebration.   . Cingulate gyrus herniation. This occurs when the cingulate gyrus shifts  under the falx cerebri. Little is known about its clinical manifestations.   . Transcalvarial herniation. The brain shifts through a skull fracture or a sur-  gical opening in the skull. This type of external herniation may occur during  a craniectomy—surgery in which a flap of skull is removed, preventing the  piece of skull from being replaced.   The most common syndrome is cerebellar tonsillar. The cerebellar tonsil shifts  through the foramen magnum because of increased pressure within the pos-  terior fossa. The clinical manifestations are an arched stiff neck, paresthesias  in the shoulder area, decreased consciousness, respiratory abnormalities, and  pulse rate variations. Occasionally the force produces an upward transtento-  rial herniation of a cerebellar tonsil or the lower brainstem. There is increased  ICP but no specific set of clinical manifestations associated with infratentorial  herniation (see Figure 17-17).    FIGURE 17-18 Cerebral Edema. This coronal section of cerebrum demon-  strates marked compression in the lateral ventricles (/ong arrows) and flattening  of gyri (short arrows) from extensive bilateral cerebral edema. Edema increases  intracranial pressure, leading to herniation. (From Klatt EC: Robbins and Cotran  atlas of pathology, ed 2, Philadelphia, 2010, Saunders.)    FIGURE 17-19 Cerebral Edema, Gross. The surface of the meninges of the  brain with cerebral edema shows widened, flattened gyri  with narrowed sulci  (©). (From Klatt EC: Robbins and Cotran atlas of pathology, ed 2, Philadelphia,  2010, Saunders.)    is a disruption in the blood-brain barrier (selective permeabil-  ity of brain capillaries). Plasma proteins leak into the extracel-  lular spaces, drawing water to them, and the water content of  the brain parenchyma increases. Vasogenic edema begins in the  area of injury and spreads with preferential accumulation in the  white matter of the ipsilateral side because the parallel myelin-  ated fibers separate more easily. Edema then promotes more  edema because of ischemia from increasing pressure.   Clinical manifestations of vasogenic edema include focal  neurologic deficits, disturbances of consciousness, and a severe  increase in intracranial pressure. Vasogenic edema resolves by  slow diffusion.   In cytotoxic (metabolic) edema, toxic factors directly affect  the cellular elements of the brain parenchyma (neuronal, glial,  and endothelial cells), causing failure of the active transport sys-  tems. The blood-brain barrier is not disrupted. The cells lose  their potassium and gain larger amounts of sodium. Water fol-  lows by osmosis into the cell so that the cells swell. Cytotoxic  edema occurs principally in the gray matter and may increase  vasogenic edema.   Interstitial edema is seen most often with noncommunicat-  ing hydrocephalus (see following section and Chapter 20). The  edema is caused by transependymal movement of CSF from  the ventricles into the extracellular spaces of the brain tissues.  The brain fluid volume thus is increased predominantly around  the ventricles. The hydrostatic pressure within the white matter  increases, and the size of the white matter is reduced because of  the rapid disappearance of myelin lipids.    The term hydrocephalus refers to various conditions char-  acterized by an excess of fluid within the cerebral ventricles,  subarachnoid space, or both (see Figures 15-15 and 15-16).  Hydrocephalus occurs because of interference with CSF flow  caused by increased fluid production, obstruction within the  ventricular system, or defective reabsorption of the fluid. A  papilloma (i.e., epithelial tumor) may, in rare instances, cause  overproduction of CSF (Figure 17-20).    Noncommunicating hydrocephalus (obstructive) (internal or  intraventricular hydrocephalus) is caused by obstruction within  the ventricular system. Impaired absorption of CSF from the  subarachnoid space occurs when an obstructive process dis-  rupts the flow of CSF through the subarachnoid space. The fluid  is prevented from reaching the convex portion of the cerebrum,  where the arachnoid granulations are located.   Communicating hydrocephalus (nonobstructive) (extra-  ventricular) results from impaired absorption of CSF in the  absence of obstruction between the ventricles and subarach-  noid space. The most common causes of communicating  hydrocephalus are subarachnoid hemorrhage, developmental  malformation, head injury, neoplasm, inflammation (i.e., men-  ingitis), high venous pressure in the sagittal sinus, and increased  CSF secretion by the choroid plexus.   Hydrocephalus ex vacuo is a form of communicating hydro-  cephalus that arises from cerebral atrophy. CSF fills the unoc-  cupied space. The amount of CSF is increased, but the fluid is  not under pressure.   Normal-pressure hydrocephalus (low-pressure, adult, or  occult hydrocephalus) is a form of communicating hydrocephalus  that occurs mostly in late middle age. The ventricles are enlarged  and the cerebrospinal fluid pressure is minimally elevated. This  form of hydrocephalus is idiopathic or occurs secondarily as a  complication of head injury or subarachnoid hemorrhage.   Acute hydrocephalus may develop in several hours in per-  sons who have sustained head injuries. Acute hydrocephalus  contributes significantly to increased ICP.   PATHOPHYSIOLOGY. The obstruction of CSF flow associated  with hydrocephalus produces dilation of the ventricles proxi-  mal to the obstruction. Obstructed CSF is under pressure,  causing atrophy of the cerebral cortex and degeneration of  the white matter tracts. There is selective preservation of gray  matter. When excess CSF fills a defect caused by atrophy, a  degenerative disorder, or a surgical excision, this fluid is not  under pressure; therefore, atrophy and degenerative changes  are not induced.   CLINICAL MANIFESTATIONS. Most cases of hydrocephalus  develop gradually and insidiously over time. Acute hydrocepha-  lus presents with signs of rapidly developing increased intracra-  nial pressure. The person deteriorates rapidly into a deep coma  if not promptly treated. Normal-pressure hydrocephalus has a  long-term presentation and develops slowly over time. A triad  of symptoms, including declining memory with loss of cogni-  tive function (frontal lobe and subcortical dementia); unsteady,  broad-based gait; and urinary urgency and incontinence from  detrusor overactivity, are common and make diagnosis difficult  to differentiate from other causes of dementia. Additional clini-  cal manifestations are apathy, inattentiveness, and indifference  to self, family, and the environment.°”   EVALUATION AND TREATMENT. The diagnosis is made on the  basis of clinical history and physical examination, evaluation of  CSF pressure and volume, and results of brain imaging. Hydro-  cephalus can be treated by surgery to resect cysts, neoplasms, or  hematomas or by ventricular bypass into the normal intracra-  nial channel or into an extracranial compartment using a shunt.    FIGURE 17-20 Comparison of Normal and Hydrocephalic Brains. A, Sagittal; B, axial; and €, coronal planes as seen  in magnetic resonance imaging (MRI). (From Haines DE, editor: Fundamental neuroscience for basic and clinical applications,    Excision or coagulation of the choroid plexus is needed occa-  sionally when a papilloma is present.    Movements are complex patterns of activity controlled by the  cerebral cortex, the pyramidal system, the extrapyramidal sys-  tem, and the muscle motor units. Dysfunction in any of these  areas can cause motor dysfunction. General motor dysfunc-  tions are associated with changes in muscle tone, movement,  and complex motor performance.°*?   Normal muscle tone involves a slight resistance to passive  movement. The resistance is smooth, constant, and even  throughout the range of motion. Abnormalities of muscle tone  are presented in Table 17-20.   In hypotonia (decreased muscle tone), passive movement  of a muscle occurs with little or no resistance to stretching.  Hypotonia is a symptom of alterations in nervous control of  muscles. It is thought to be caused by decreased muscle spindle    Thought to be caused by decreased muscle spindle  activity as a result of decreased excitability of neurons   Occurs typically when nerve impulses necessary for  muscle tone are lost    Results when the lower motor unit reflex arc  continues to function but is not mediated or  regulated by higher centers   Exact mechanism unclear; appears to arise from an  increased excitability of the alpha motor neurons  to any input because of absence of the descending  inhibition of the pyramidal systems    Passive movement of a muscle mass with little or no resistance  Difficult to detect; extremity is floppy and allows excessive movement when displaced  Muscles may be rapidly moved without resistance   A gradual increase in tone causing increased resistance until tone suddenly is  reduced, which results in clasp-knife phenomenon   Selective distribution (predominates in flexors of upper extremities and extensors of  lower extremities and in pronators compared with supinators)   Resistance to passive movement, which varies in direct proportion to force applied    Muscle resistance to passive movement of a rigid limb that is uniform in both    Gamma  cerebral cortex, decreasing the inhibition of alpha  and gamma motor neurons    activity secondary to decreased excitability of neurons. Hypoto-  nia caused by pure pyramidal tract damage (a rare occurrence)  produces hypotonia and weakness. Hypotonia contributes to  the ataxia and intention tremor in cerebellar damage and mani-  fests with minimal weakness and normal or slightly exagger-  ated reflexes. Hypotonia, often described as flaccidity (a state  in which the muscle may be moved rapidly without resistance),  occurs when nerve impulses necessary for muscle tone are lost,  such as in spinal cord injury or cerebrovascular accident.   Individuals with hypotonia report that they tire easily (asthe-  nia) or are weak, signs that can be observed during their activity  attempts. They may have difficulty rising from a sitting posi-  tion, sitting down without using arm support, or walking up  and down stairs, as well as an inability to stand on their toes.  Because of their weakness, accident proneness during locomo-  tion and self-care activities is common. Inasmuch as the joints  become hyperflexible in hypotonic states, people with hypoto-  nia may be able to assume positions that require extreme joint  mobility. The joints may appear loose, and the knee jerks are  pendulous.   The muscle mass atrophies because of decreased input  entering the motor unit. Muscle cells gradually are replaced by    Increased muscular tone relatively independent of degree of force used in passive  movement; does not vary throughout the passive movement   e uniform resistance may be interrupted by a series of brief jerks resulting in    paired relaxation characterized by extensor rigidity of skeletal muscle after the  contraction  paired relaxation of skeletal muscle after the contraction    connective tissue and fat. The muscles are flabby on palpation  and are flat in appearance. Fasciculations may be present in  some cases.    In hypertonia (increased muscle tone), passive movement of a  muscle occurs with resistance to stretch and is caused by upper  motor neuron damage. Four types of hypertonia are described:  spasticity, gegenhalten (paratonia), dystonia, and rigidity.   Spasticity results from hyperexcitability of the stretch  reflexes (overactivation of the alpha motor neurons) and  is associated with damage to the motor, premotor, and  supplementary motor areas, as well as lateral corticospinal  tract damage (Figure 17-21). Spasticity is accompanied by  increased deep tendon reflexes (hyperreflexia) and the spread  of reflexes (clonus).   Gegenhalten (paratonia) is resistance to passive movement  that increases with velocity of movement. Dystonia is increased  involuntary muscle contraction, manifested as sustained,  involuntary twisting movements. It is caused by slow muscle  contraction and may be caused by a failure in appropriate  reciprocal inhibition of the muscles (Figures 17-22 and 17-23).    FIGURE 17-21 Left-Sided Hemifacial Spasm. (From Perkin GD: Mosby's  color atlas and text of neurology, London, 1998, Mosby-Wolfe.)    Injury to the putamen or its outflow tracts also is associated  with hemidystonia.   Rigidity produced by tonic reflex activity mediated by  gamma motor neurons may be continuous or intermittent.  The involved muscles are firm and tense; the increase in muscle  movement is even and uniform throughout the range of passive  movement. Four types of rigidity are described: plastic, or lead-  pipe; cogwheel; gamma; and alpha (see Table 17-20).   Individuals with hypertonia may tire easily (asthenia) or  be weak. Passive movement and active movement are equally  affected, except in gegenhalten, in which more active than  passive movement is possible. As a result of hypertonia and  weakness, accident proneness during locomotion and self-care  activities is common.   The muscles may atrophy because of decreased use. How-  ever, hypertrophy occasionally may occur in some diseases.  Hypertrophy results from overstimulation of muscle fibers.  Overstimulation occurs when the motor unit reflex arc remains  intact and functioning but is not inhibited by higher centers.  The loss of inhibition and the constant state of excitation cause  continual muscle contraction, resulting in enlargement of the  muscle mass. The muscles are firm on palpation (Figure 17-24).    Movement requires a change in the contractile state of muscles.  Abnormal movements may occur when a variety of CNS dys-  functions alter muscular innervation. The neurotransmitter  dopamine has a role in motor function. Some movement dis-  orders (e.g., the akinesias) result from too little dopaminergic  activity, whereas others (e.g., chorea, ballism, tardive dyski-  nesia) result from too much dopaminergic activity. Still oth-  ers are not related primarily to dopamine function. Movement  disorders are not associated necessarily with mass, strength, or  tone but are neurologic dysfunctions with either an excess of    FIGURE 17-22 Dystonic Posturing of the Hand and Foot. (From Perkin GD:  Mosby’ color atlas and text of neurology, London, 1998, Mosby-Wolfe.)    Perkin GD et al: At/as of clinical neurology, ed 3, Philadelphia, 2011, Saunders.)    movement or a lack of voluntary movement. Muscle strength is  quantitatively evaluated on a scale of 0 to 4+ or 0 to 5, in which  4+ or 5 is normal and 0 indicates an inability to move against  gravity (Table 17-21).   Hyperkinesia (excessive movements), dyskinesias (unnatural  movements), and abnormal involuntary movements represent  excess movement. Huntington disease is the hallmark of excess  movement. Hypokinesia (decreased amplitude of movement),  bradykinesia (decreased speed of movement), and akinesia    FIGURE 17-24 Pseudohypertrophy of the Calf Muscles. (From Perkin GD  et al: Atlas of clinical neurology, ed 3, Philadelphia, 2011, Saunders)    TABLE 17-21 UK MEDICAL RESEARCH  COUNCIL CLASSIFICATION  OF MUSCLE POWER  GRADE DEFINITION  0 Total paralysis—no muscle contraction  1 Flicker of contraction—no joint movement  2 Movement with gravity eliminated  3 Movement against gravity but not resistance  4 Movement against resistance but incomplete  5) Normal power against resistance    Data from Vanhoutte EK et al: Brain 135(Pt 5):1639-1649, 2012.  UK, United Kingdom.    (absence of voluntary movement) are terms that represent lack  of voluntary movement. Parkinson disease is the hallmark of  lack of movement.    Hyperkinesia (excessive movement) represents the second  broad category of abnormal movements. Within this category  are a number of specific hyperkinesia syndromes (Table 17-22).  Also included in the general category of hyperkinesias are dys-  kinesias, that is, abnormal involuntary movements.   Paroxysmal dyskinesias are abnormal, involuntary move-  ments that occur as spasms. The type of dyskinesia varies  depending on the specific disorder.   Tardive (slow onset) dyskinesia is the involuntary move-  ment of the face, trunk, and extremities. Although the condi-  tion occurs occasionally in individuals with Parkinson disease,  it usually occurs as a side effect of prolonged use of first- or sec-  ond-generation antipsychotic drugs.’”” The antipsychotic drugs  cause denervation hypersensitivity, thereby mimicking the effect  of excessive dopamine. The most common symptom of tardive  dyskinesia is rapid, repetitive, stereotypic movements. The  most characteristic movements of tardive dyskinesia include  continual chewing with intermittent protrusions of the tongue,  lip smacking, and facial grimacing. Stereotypic movements are  believed to be a form of excessive dopaminergic activity.    There is growing evidence that Tourette syndrome (TS) occurs worldwide and,  has common features across all races and cultures. No specific genetic muta-  tions have been found. The hallmark of TS is the presence of multiple motor  and vocal tics. The tics may be simple, involving only an individual muscle  group (for example, eye blinking or a grunt), or complex, requiring coordi-  nated movement of muscle groups (for example, head banging or repeating  of another person's words). Sensory tics involve unpleasant sensations in the  face, head, and neck areas. Onset of TS is typically between the ages of 2  and 15 years, is more common in males, and is probably underdiagnosed. The  tics lessen in adulthood. The syndrome has a complex, multifactorial etiology  with as yet to be determined genetic, environmental, immune, and hormonal  factors. The pathophysiology of TS is unclear and currently under study. There  is evidence of basal ganglia dysfunction and, in some cases, altered dopami-  nergic neurotransmission. TS is often diagnosed in association with anxiety,  depression, attention-deficit/hyperactivity disorder (ADHD), and obsessive-  compulsive disorder.    Data from Bloch M, State M, Pittenger C: Curr Opin Neurol 24(2):119-  125, 2011; Deng H, Gao K, Jankovic J: Nat Rev Neurol 8(4):203-213,  2012; Jankovic J, Kurlan R: Mov Disord 26(6):1149-1156, 2011; State  MW: Curr Opin Genet Dev 21(3):302-309, 2011.    Other movement disorders under this category are (1)  complex repetitive movements, including automatism, stereo-  type, complex tics (e.g., Tourette syndrome [see What’s New?  Tourette Syndrome]), compulsions, perseverations, and man-  nerisms; (2) positivism (excessive reactions to certain stimuli);  and (3) paroxysmal excessive activity, including cataplexy and  excessive startle reaction.   Huntington disease (HD), also known as chorea, is a relatively  rare, autosomal dominant disease with high penetrance. The  onset of HD is usually between 25 and 45 years of age, when  the trait may already have been passed to the person’s children.  The disorder has a prevalence rate of approximately 2 to 8 per  100,000 persons and occurs in all races.’!   PATHOPHYSIOLOGY. The genetic defect of HD is on the short  arm of chromosome 4. There is an abnormally long polyglu-  tamine tract in the huntingtin (htt) protein that is toxic to  neurons and is caused by a cytosine-adenine-guanine (CAG)  trinucleotide repeat expansion (40 to 70 repeats instead of 9 to  34). Age of symptom onset is related to the length of the repeat  sequences and mechanisms of toxicity. Repeat lengths greater  than 60 cause the juvenile form of the disease.’   The principal pathologic feature of HD is severe degenera-  tion of the basal ganglia, particularly the caudate and putamen  nuclei and the frontal cerebral cortex. The degeneration of the  basal ganglia leaves enlarged lateral ventricles (Figure 17-25).  Expression of the huntingtin gene produces tangles of protein  that collect in brain cells and chains of glutamine on the abnor-  mal molecules that adhere to each other.”> The mechanism of  neuronal death is unknown. The excitotoxic theory of striatal  and cortical degeneration proposes that the mutated hunting-  tin protein produces excitotoxic pathways meditated by gluta-  mate function that also induce concomitant dysregulation of    Nonrepetitive muscular contractions, usually of the extremities  of the face; random pattern of irregular, involuntary rapid  contractions of groups of muscles; disappears with sleep,  decreases with resting; increases with emotional stress and  attempted voluntary movement   Disorder of distal-muscle postural fixation; slow, twisting,  sinuous, irregular movements most obvious in the distal  extremities, more rhythmic than choreiform movements and  always much slower; movements accompany characteristic  hand posture; slowly fluctuating grimaces   Disorder of proximal-muscle postural fixation with wild flinging  movement of the limbs; movement is severe and stereotyped,  usually lateral; does not lessen with sleep; ballism is  most common on one side of the body, a condition termed  hemiballism   State of prolonged, generalized, increased activity that is largely  involuntary but may be subject to some voluntary control; not  highly stereotyped but rather manifests as continual changes in  total body posture or in excessive performance of some simple  activity, such as pacing under inappropriate circumstances    Special type of hyperactivity; mild compulsion to move (usually  more localized to legs); severe frenzied motion possible;  movements are partly voluntary and may be transiently  suppressed; carrying out the movement brings a sense of relief;  a frequent complication of antipsychotic drugs   Regular, rhythmic, slow flexion-extension contraction; involves  principally the metacarpophalangeal and wrist joints; alternating  movements between thumb and index finger described as “pill  rolling”; disappears during voluntary movement    Rapid, rhythmic tremor affecting fingers, lips, and tongue;  accentuated by extending the body part; enhanced physiologic  tremor    Tremor of fingers, hands, and feet; absent at rest but accentuated  by extension of body part, prolonged muscular activity, and  stress    Series of shocklike, nonpatterned contractions of a portion of a  muscle, entire muscle, or group of muscles that cause throwing  movements of a limb; usually appear at random but frequently  triggered by sudden startle; do not disappear during sleep    Associated with excess concentration of or a supersensitivity to  dopamine within basal ganglia    Occurs most commonly as a result of injury to the putamen of the  basal ganglion; exact pathophysiologic mechanism is not known    Results from injury (vascular disease) to the subthalamic nucleus  (one of the nuclei that comprise the basal ganglia); thought to be  caused by reduced inhibitory influence in the nucleus, a release  phenomenon; hemiballism results from injury to the contralateral  subthalamic nucleus   Loss of inhibitory influence of dopamine in the basal ganglia,  causing instability of basal ganglia feedback circuit within the  cerebral cortex    Caused by transient inhibition of muscles that maintain posture;  thought to be related to accumulation of products normal  detoxified by the liver   Occurs in conditions associated with disturbed metabolism  toxicity, as in thyrotoxicosis (hyperthyroidism), alcoholism, and  chronic use of barbiturates, amphetamines, lithium, amitriptyline  (Elavil); exact mechanism responsible unknown    Occurs in disease of the dentate nucleus (one of the deep  cerebellar nuclei responsible for efferent output) and the  superior cerebellar peduncle (a stalklike structure connected to  the pons); caused by errors in feedback from the periphery and  errors in preprogramming goal-directed movement   Results from lesions involving the dentatorubrothalamic tract (a  spinothalamic tract connecting the red nucleus in the reticular  formation and the dentate nucleus in the cerebellum)   Associated with an irritable nervous system and spontaneous  discharge of neurons; structures associated with myoclonus  include the cerebral cortex, cerebellum, reticular formation, and  spinal cord    FIGURE 17-25 Huntington Disease. On the right is a normal brain with a  normal caudate (C); on the left is a brain from an individual with Huntington disease  showing severe atrophy of the caudate (A) and an enlarged lateral ventricle. (From  Stevens A, Lowe J, Scott |: Core pathology, ed 3, London, 2009, Mosby.)    dopaminergic function. The huntingtin protein also may alter  mitochondrial function, which in turn activates apoptotic path-  ways and causes neuronal death. Neurotrophic factors also may  be depleted, leading to loss of neurons.’**”°   Early in the disease, selective loss of the striatal GABA/  dopamine-enkephalin pathway to the lateral aspect of the  pallidum occurs. The striatum of the basal ganglia normally  contains a preponderance of GABAergic (GABA-secreting)  neurons, including the pathway between the basal ganglia and  substantia nigra (pallidonigral pathway-express dopamine  D,-receptors, dynorphin, and substance P). Basal ganglia and  nigral depletion of GABA, an inhibitory neurotransmitter, is  the principal biochemical alteration in HD. Degeneration of  the GABAergic pallidonigral pathway causes GABA depletion  in the substantia nigra with decreased inhibitory GABA activity  on dopaminergic neurons in the substantia nigra and a relative  excess of dopaminergic activity in the basal ganglia feedback  circuit within the cerebral cortex. A relative excess of dopami-  nergic activity in this circuit, as in HD, is manifested by hypo-  tonia and hyperkinesia (involuntary, fragmentary movements  such as chorea). Loss of excitatory glutamate may liberate the  pathway from the thalamus to the premotor cortex, impairing  modulation of movement later in the course of the disease. Pro-  ducing energy for brain activity is difficult and there is resultant  buildup of lactic acid.   CLINICAL MANIFESTATIONS. The classic manifestations of HD  are abnormal movements that occur without conscious effort,  emotional lability, and progressive dysfunction of cognitive  processes (dementia). Any one of these features may mark the  onset of the disease. Cognitive impairment may precede motor  symptoms by up to 15 years.’° Chorea is the most common  type of abnormal movement and begins in the face and arms,  eventually affecting the entire body. It can be combined with  athetosis (twisting and writhing). Symptoms of frontal lobe  dysfunction include executive attention deficits and short-term  memory loss (working memory); reduced capacity to plan,  organize, and sequence, as well as bradyphrenia (slow think-  ing); and apathy. Restlessness, disinhibition, and irritability are    common. Affectively, euphoria or depression or both may be  present. Progression of the disease is fatal.   EVALUATION AND TREATMENT. The diagnosis of HD is based on  family history, clinical presentation of the disorder, and genetic  testing. No known treatment is effective in halting the degen-  eration or progression of symptoms. Chorea is treated with  dopamine receptor—blocking or dopamine receptor—depleting  agents. Medication and nonmedical care for depression and  aggressive behavior may be required. Efforts are in progress to  identify biomarkers for early diagnosis and to monitor disease  progression.’”””   Hypokinesia (decreased movement) is loss of voluntary move-  ment despite preserved consciousness and normal peripheral  nerve and muscle function. Types of hypokinesia include aki-  nesia, bradykinesia, and loss of associated movement.   Akinesia. Akinesia is an absence, poverty, or lack of control  of associated and voluntary muscle movements. There is a  disturbance in the time it takes to perform a movement. Akinesia  is related to dysfunction of the extrapyramidal system, as in  parkinsonism. Pathogenesis is related to either a deficiency of  dopamine or a defect of the postsynaptic dopamine receptors,  which occurs in parkinsonism (see Parkinson disease below).   Bradykinesia. Bradykinesia is slowness of voluntary move-  ments. There is a disturbance in the time it takes to perform a  movement. In bradykinesia all voluntary movements become  slow, labored, and deliberate. Bradykinesia consists of: (1) diffi-  culty in initiating movements, (2) difficulty in continuing move-  ments smoothly, and (3) difficulty in performing synchronous  (at the same time) and consecutive tasks. Difficulty in initiating  movements ranges from slight hesitancy to severe freezing (tran-  sient, helpless immobility). Each intended movement requires  effort. Difficulty in continuing motions smoothly causes jerky,  irregular, rapid movements, which then decrease in rate and  amplitude until they stop. The individual is scarcely aware of the  cessation. Difficulty in performing synchronous and consecu-  tive tasks means that each motor act is performed separately. The  individual is unable to integrate two acts or to change from one  motor pattern to the next with a single smooth motion.   Loss of Associated Movement. In hypokinesia the normal,  habitually associated movements that provide skill, grace, and  balance to voluntary movements are lost. Decreased associated  movements accompanying emotional expression cause an  expressionless face, a statue-like posture, absence of speech  inflection, and absence of spontaneous gestures. Decreased  associated movements accompanying locomotion cause  reduction in arm and shoulder movements, in hip swinging,  and in rotary motion of the cervical spine.    Parkinson disease (PD) is a complex motor disorder accom-  panied by systemic nonmotor and neurologic symptoms. The  main disease feature is degeneration of the basal ganglia (corpus  striatum, globus pallidus, subthalamic nucleus, and substan-  tia nigra) involving the dopaminergic (dopamine-secreting)  nigrostriatal pathway. Nigrostriatal disorders produce a    Secondary Parkinsonism  Neurodegenerative disorders (sporadic or genetic)  Disorders associated with alpha-synuclein pathology  Multiple system atrophies (glial and neuronal inclusions)  Nigrostriatal degeneration  Olivopontocerebellar atrophy  Shy-Drager syndrome  Motor neuron disease with PD features  Dementia with Lewy bodies (cortical and brainstem neuronal inclusions)  Disorders associated with primary tau pathology (“tauopathies”)  Progressive supranuclear palsy  Corticobasal degeneration  Frontotemporal dementia  Disorders associated with primary amyloid pathology (“amyloidopathies”)  Alzheimer disease with parkinsonism  Genetically mediated disorders with occasional parkinsonian features  Wilson disease  Hallervorden-Spatz disease  Chédiak-Higashi syndrome  SCA-3 spinocerebellar ataxia  X-linked dystonia-parkinsonism (DY7T3)  Fragile X permutation associated with ataxia-tremor-parkinsonism syndrome  Huntington disease (Westphal variant)  Prion disease    Miscellaneous acquired conditions  Vascular parkinsonism: atherosclerosis, amyloid angiopathy  Normal pressure hydrocephalus  Catatonia  Cerebral palsy  Repeated head trauma (“dementia pugilistica” with parkinsonian features)  Infectious and postinfectious diseases  Postencephalitic PD  Creutzfeldt-Jakob disease  Neurosyphilis  Metabolic conditions  Hypoparathyroidism or pseudohypoparathyroidism with basal ganglia  calcifications  Non-wilsonian hepatolenticular degeneration  Multiple sclerosis  Neoplastic disease  Drugs  Neuroleptics (typical antipsychotics)  Selected atypical antipsychotics  Antiemetics (e.g., compazine, metoclopramide)  Dopamine-depleting agents (reserpine, tetrabenazine)  a-Methyldopa  Lithium carbonate  Valproic acid  Fluoxetine  Toxins  1-Methyl-1,2,4,6-tetrahydropyridine (MPTP)  Manganese  Cyanide  Methanol  Carbon monoxide  Carbon disulfide  Hexane    Data from Delong MR, Juncos IL: Parkinson's disease and other extrapyramidal movement disorders. In Fauci AS et al, editors: Harrison's prin-  ciples of internal medicine, ed 17, p 2553, New York, 2008, McGraw-Hill; Lang A: Parkinsonism. In Goldman L, Ausiello D, editors: Cecil medicine,    syndrome of abnormal movement called parkinsonism (Par-  kinson syndrome, parkinsonian syndrome).   Etiologic classification of parkinsonism includes primary par-  kinsonism and secondary parkinsonism (Box 17-5). The onset  of PD occurs after 40 years of age, with mean onset of 60 years of  age.’’ PD is one of the most prevalent of the primary CNS dis-  orders and a leading cause of neurologic disability in individuals  older than 60 years. Approximately 60,000 people in the United  States are diagnosed each year and an estimated 10 million peo-  ple worldwide are living with PD. Men are 150% more likely to  have PD than women.* The familial form represents about 10%  of PD; however, the majority of cases are sporadic or idiopathic.   PATHOPHYSIOLOGY. The pathogenesis of primary PD is  unknown. Several PD genes have been identified, the most sig-  nificant of which are listed in Table 17-13 (p. 547). The hallmark  pathologic features of PD are loss of dopaminergic pigmented  neurons in the substantia nigra (SN) pars compacta with dopa-  minergic deficiency in the putamen portion of the striatum (the  striatum includes the putamen and caudate nucleus) (Figure  17-26). Dopamine loss in other brain areas including the brain-  stem, thalamus, and cortex also occurs.*! Degeneration of the    FIGURE 17-26 Atrophic Substantia Nigra (A) Compared with Normal  Control (B). (From Perkin GD et al: Atlas of clinical neurology, ed 3, Philadelphia,  2011, Saunders.)    dopaminergic nigrostriatal pathway to the basal ganglia results  in underactivity of the direct motor pathway (normally facili-  tates movement) (Figure 17-27) and overactivity of the indirect  motor loop (normally inhibits movement). This results in inhibi-  tion of the motor cortex manifested with bradykinesia and rigid-  ity. The subthalamic nucleus (STN) overactivity also influences  the limbic system,” accounting for emotional signs and symp-  toms. Neuronal loss within the cerebral cortex is found in half of  individuals with PD. Mechanisms of cell dysfunction and death    FIGURE 17-27 Reduced Fluorodopa in Parkinson Disease. Positron-emission tomography scan showing reduced fluo-  rodopa uptake in the basal ganglia consistent with neurodegeneration (right) compared with a normal control (left). (From  Perkin GD et al: Atlas of clinical neurology, ed 3, Philadelphia, 2011, Saunders.)    include mitochondrial dysfunction, oxidative stress, altered pro-  tein handling, and inflammatory changes with autophagy and  apoptosis.°?   Lewy bodies, fibrillar intracellular eosinophilic inclusions,  and high concentrations of alpha-synuclein, ubiquitin, tau  protein, tuberculin, and other proteins are found in the sub-  stantia nigra (SN), locus ceruleus (LC), and other areas of the  brain. They are a marker for neuronal degeneration.** Degen-  eration of the LC, which contains noradrenergic neurons, also  occurs in PD. Norepinephrine is thought to be neuroprotec-  tive and loss of LC neurons may be associated with a wors-  ening of disease progression and the behavioral symptoms  of PD.** Molecular events thought to be associated with the  neurodegeneration of PD include mitochondrial dysfunction,  oxidative stress, abnormal folding and accumulation of alpha-  synuclein, abnormal phosphorylation, and dysfunction of the  ubiquitin proteasome system (regulates intracellular protein  processing)®>*° (Figure 17-28).   CLINICAL MANIFESTATIONS. Onset of symptoms is insidious  and symptoms appear after a 70% to 80% loss of pigmented  nigral neurons and a 60% to 90% loss of striatal dopamine.*”  The classic motor manifestations of PD are resting tremor,  bradykinesia/akinesia (poverty of movement), rigidity  (muscle stiffness), and postural abnormalities. These mani-  festations may develop alone or in combination; however,  as the disease progresses, all four are usually present to at  least some degree. There is no true paralysis. A modified  Hoehn and Yahr scale*® can be used to assess progression of  symptoms:    In early stages of the disease, reflex, sensory, and mental sta-  tus are usually normal. Nonmotor symptoms associated with PD  include hyposmia, fatigue, pain, autonomic dysfunction, sleep frag-  mentation, depression, and dementia with or without psychosis.°?   Parkinsonian tremor, the most conspicuous and most vari-  able symptom, is usually the first motor symptom to appear.  It is a tremor at rest, disappearing briefly during the course of  a voluntary movement and reappearing when the limb is held  in a stationary position. Intensity and amplitude of the tremor  vary. The arm is more affected than the leg. Most individuals  with PD have this tremor and tremors are increased by stress  and anxiety.    Parkinsonian tremor appears to result from instability of  feedback from the basal ganglia to the cerebral cortex caused  by loss of the inhibitory influence of dopamine in the basal  ganglia. Increased oscillation in the normal feedback cycles of  the motor outflow feedback circuit when the muscles are at  rest produces the tremor. When the individual performs vol-  untary movements, the tremor becomes temporarily blocked,  presumably because other motor control signals arriving in the  thalamus override the abnormal basal ganglia signals. As the  disorder worsens, tremor may lessen as rigidity supervenes.  The postural tremor is associated with damage to the cerebel-  lofugal pathway to the red nucleus, a pathway that subserves  communication from muscle spindles to the thalamus and  motor cortex.   Parkinsonian rigidity is an increased resistance to the pas-  sive movement of a joint that impedes active and passive move-  ment. The first symptoms of rigidity may be painful muscle  cramps in the toes or hands. More commonly the limb feels stiff,  heavy, tired, or aching. Plastic rigidity is constant throughout  the entire range of motion and is felt as lead-pipe resistance  during passive movement. Cogwheel rigidity, brief palpable  jerks, is accompanied by tremor. The mechanism underlying  rigidity is unclear, but there is increased resting muscle activity  of antagonistic muscle groups with enhancement of the long-  latency component of the stretch reflex.”   Parkinsonian bradykinesia is poverty of associated and  voluntary movements. It is the most prevalent and crippling  symptom and often is overlooked in the early stages. The patho-  physiology underlying the bradykinesia is an overactive sub-  thalamic nucleus (STN) that inhibits the motor thalamus and  motor cortex.”” It is associated with dopamine deficiency and  failure of the mechanism programming movement patterns  manifested as a defect in the voluntary production of smooth  motions at different speeds.”   All striated muscles—extremity, trunk, ocular, facial—are  affected eventually, including muscles of mastication (chew-  ing), deglutition (swallowing), and articulation. Micrographia  (small handwriting) is present. Extreme underactivity in the  individual with PD makes the person appear stiff, even when  resistance to passive movement cannot be felt. Bradykinesia  is a separate phenomenon from rigidity and may be severe  even in the presence of rigidity. Individuals state that they feel  “wooden” (as though moving against resistance) and complain  of rapid, severe fatigue.   Hypokinesia, or decreased frequency or absence of associ-  ated movements, is one of the earliest symptoms. Individuals  with PD sit and lie motionless for long periods without the little  shifts an unaffected person makes to prevent discomfort and  stiffness. Bradykinesia, or slowness of voluntary movements, is  characterized by difficulty initiating, continuing, or synchro-  nizing movements. Both associated and voluntary movements  are interspersed by freezing (an inability to continue move-  ment). Freezing may be precipitated by (1) increasing the effort  to move, (2) turning, and (3) initiating certain types of tactile  and visual contact.   Postural Abnormalities. Three types of postural abnormalities  occur in individuals with PD: (1) disorders of postural fixation,    et al: Atlas of clinical neurology, ed 3, Philadelphia, 2011, Saunders.)    (2) disorders of equilibrium, and (3) disorders of righting. The  disorder of postural fixation associated with PD is involuntary  flexion of the head and neck. The individual is unable to  maintain an upright position of the trunk while standing or  walking. Postural abnormalities of the hands and feet also  occur. Postural abnormalities are caused by a loss of normal  postural reflexes, muscular rigidity, axial dystonia, weakness  caused by myopathy, and impaired proprioception.”!   Disorders of equilibrium result from loss of postural stabil-  ity. The person with PD is unable to make the appropriate pos-  tural adjustment to tilting or falling and falls like a post when  starting to tilt. The festinating gait (short, accelerating steps) of  the person with PD is an attempt to maintain an upright posi-  tion while walking (Figure 17-29). Individuals also are unable  to right themselves when changing from a reclining or crouch-  ing position to a standing position and when rolling over from  a supine to a lateral or prone position.   Autonomic and Neuroendocrine Symptoms. Autonomic  and neuroendocrine dysfunctions in PD produce nonmotor  symptoms that are distressing but not incapacitating. The  basal ganglia influence hypothalamic function (autonomic and  neuroendocrine) through pathways connecting the hypothalamus  with the basal ganglia and cerebral cortex. Common autonomic  symptoms in PD include inappropriate diaphoresis, gastric  retention, constipation, and urinary retention. Cardiac  sympathetic denervation is common and causes neurogenic  orthostatichypotension. Asymptomattributed to neuroendocrine  dysfunction is seborrhea. Hypothalamic hypersecretion of  hormone-releasing factors acting on the anterior pituitary causes    hypersecretion of androgenotropic hormones, producing sebum  hypersecretion by sebaceous glands. The resulting seborrhea is  characterized by oily skin with seborrheic dermatitis along the  hairline and in chin-nasal creases.”   Cognitive-Affective Symptoms and Dementia. Approximately  30% to 40% of people with PD have a depression that is now  believed to be an inherent part of the pathologic state of the  disease (an endogenous depression), not a response to the  situation.”*** Mild cognitive impairment not associated with  either dementia or depression is associated with dopaminergic  dysmodulation. Bradyphrenia (slowness of thinking) also is  present. These disorders may appear early in the course of the  disease and may progress to dementia. Bradyphrenia is caused  by disruption of the caudal basal ganglion connections and  outflows. The clinical manifestations are slowness of thinking,  poverty of thought (diminished imagination and insight),  and difficulty formulating thoughts (decreased ability to  conceptualize, plan, decide, or improvise).”°   Of individuals treated on an outpatient basis for PD, 30%  have a dementia, and 80% of those with PD requiring insti-  tutional care have dementia as well.?° Dementia is more com-  mon in individuals older than 70 years. Pathologically, in those  with dementia, findings include loss of cholinergic cells in  the basal nucleus of Meynert (nucleus basalis); neuronal loss,  senile plaques, and neurofibrillary tangles in the neocortex; and  amyloid changes in small blood vessels. Lewy bodies (alpha-  synuclein inclusions) are distributed diffusely in many neurons,  making this a Lewy body dementia.”” The individual evidences  disorientation; confusion; memory loss; distractibility; and  difficulty with concept formation, abstraction, calculations,  thinking, and judgment. Although the symptoms fluctuate,  they progressively worsen. Anxiety disorders, impulse-control  disorders, and punding (a disorder of stereotypical motor  behavior in which there is intense fascination with repetitive  handling and examining of mechanical objects) are recognized  features of PD.   Other nonmotor symptoms are common in PD including  sensory dysfunction with anosmia, ageusia, pain, paresthesias,  fatigue and weight loss, sweating, urinary and gastrointesti-  nal dysfunction, and eye tremor.”®”? Sleep disorders are com-  mon including disturbances in the sleep-wake cycle, excessive  daytime sleepiness, obstructive sleep apnea, and restless leg  syndrome. !0”   Influence of Symptoms. Early in the disease, people often  experience a sleep benefit; that is, symptoms decrease with sleep.  Symptoms also fluctuate in an on-off pattern. Stress influences  symptoms adversely, but the underlying mechanism is unclear.  The person’s mental status may be further compromised by the  side effects of the medication taken to control symptoms.   The combination of all the parkinsonian symptoms gives the  individual a characteristic appearance: a wide-eyed, unblink-  ing, staring expression with the facial muscles smoothed out  and almost immobile. Saliva frequently drools from the corners  of the slightly open mouth. The skin of the face is frequently  greasy. The gait is pathognomonic: the individual walks with  slow, short, shuffling steps; the arms are flexed, abducted, and  held stiffly at the side; and the trunk is bent slightly forward. The    person may break into a run spontaneously or when pushed  forward or backward. Because of the disorder of postural fixa-  tion, the tendency is to fall to the side. Postural instability, sleep  disorders, and difficulty concentrating are some of the most  depressing symptoms for people with PD.!°!   EVALUATION AND TREATMENT. The diagnosis of primary PD is  made on the basis of the four cardinal symptoms: (1) resting  tremor, (2) cogwheel rigidity, (3) akinesia, and (4) postural  instability. This group of symptoms has the acronym TRAP.!°?  The exclusion of other causes of parkinsonism and a combi-  nation of imaging techniques, clinical evaluations, biochemical  markers, and genetic tests support the diagnosis of PD.!°%!%+  Early nonmotor symptoms of PD can precede motor symptoms  and their identification may assist early diagnosis and guide  disease-modifying strategies.!°°!°° Median time between diag-  nosis and death is between 7 and 15 years. Disease progression  varies with age of disease onset, comorbidities, quality of care,  and among different populations. !0°!07   The aim of drug therapy is to restore striatal dopamine lev-  els using oral drugs such as levodopa (L-dopa), a precursor of  dopamine (dopamine does not cross the blood-brain barrier),  dopamine agonists that directly stimulate dopamine recep-  tors, anticholinergic drugs, antihistamines, and amantadine;  L-dopa is effective in reducing symptoms in early PD but can  cause motor fluctuations, “off” periods, and dyskinesia in the  long term. Monoamine oxidase B inhibitors, which inhibit the  breakdown of endogenous dopamine, may improve symptoms,  reduce motor fluctuations, and delay the need for L-dopa but  can cause adverse effects. Adding catechol-O-methyltransferase  (COMT) inhibitor prolongs the half-life of dopamine (COMT  metabolizes dopamine in the synapse). Dopamine agonists to  L-dopa or a dopamine agonist alone may reduce “off” time or  improve symptoms but can also increase disability.'°° Surgery  may be considered in later stages of PD. Thalamotomy and  pallidotomy are surgical options. Deep brain stimulation is an  approach to controlling medically resistant motor symptoms  and 1-dopa-related peak dose dyskinesia.!°? Gene- and cell-  based therapies hold promise for future treatment.!!° Dysphagia  and general immobility are special problems of the individual  with PD requiring preventive, symptomatic, supportive, and  rehabilitative management, such as physiotherapy and speech  therapy.”? Nursing interventions, occupational therapy (OT),  physical therapy (PT), and speech, language, and swallowing  therapy are effective and safe for improving functional status.    Paresis and paralysis are symptoms of upper and lower motor  neuron syndromes (Table 17-23).   Paresis (weakness) is impairment of motor function, that is,  partial paralysis with incomplete loss of muscle power. Paralysis is  loss of motor function, that is, inability of a muscle group to over-  come gravity. The characteristics of paresis or paralysis are related  to involvement of either the upper or the lower motor neurons.   Upper Motor Neuron Syndromes. Upper motor neuron  paresis/paralysis is known also as spastic paresis/paralysis and  different terms are used to describe the specific disorders.  Hemiparesis or hemiplegia is paresis or paralysis, respectively,    Increased muscle stretch reflexes (clasp-knife spasticity; resistance to passive  flexion that releases abruptly to allow easy flexion)   Asymmetric and may involve one limb only in beginning to become generalized  as disease progresses   2. Motor system disease  3. Polyneuritis (varied locations)  4. Amyotrophic lateral sclerosis    . Inflammations  . Degenerative diseases  (Parkinson disease)  7. Amyotrophic lateral sclerosis    FIGURE 17-30 Disturbances in Motor Function. Disturbances in motor function are classified pathologically along  upper and lower motor neuron structures. It should be noted that neoplasms occur at more than one site in an upper motor  neuron (above right). A few pathologic conditions, such as amyotrophic lateral sclerosis, involve upper and lower motor neuron  structures. Other lesion sites include myoneural junctions and primary muscles, making it possible to classify conditions as  neuromuscular and muscular, respectively. CVA, Cerebrovascular accident.    of the upper and lower extremities on one side. Diplegia is the  paralysis of both upper and lower extremities as a result of cerebral  hemisphere injuries. Paraparesis or paraplegia refers to weakness  or paralysis, respectively, of the lower extremities. Quadriparesis  or quadriplegia refers to paresis or paralysis of all four extremities.  Paraparesis or paraplegia and quadriparesis or quadriplegia may  be caused by dysfunction of the spinal cord. Upper cord damage    results in quadriparesis or quadriplegia, and lower cord damage  preserves upper extremity function and causes paraparesis or  paraplegia (spinal cord injury is discussed in Chapter 18).   Upper motor neuron paresis/paralysis is associated with a  pyramidal motor syndrome. The pyramidal motor syndrome  is a series of motor dysfunctions that result from interrup-  tion of the pyramidal system (Figures 17-30 and 17-31). The    FIGURE 17-31 Structures of the Upper Motor Neuron, or Pyramidal, System. Pyramidal system fibers are shown to  originate primarily in the cells in the precentral gyrus of the motor cortex; to converge at the internal capsule; to descend to  form the central third of the cerebral peduncle; to descend farther through the pons, where small fibers supply cranial nerve  motor nuclei along the way; to form pyramids at the medulla, where most of the fibers decussate; and then to continue to  descend in the lateral column of the white matter of the spinal cord. A few fibers descend without crossing at the medulla level.    injury may be in the cerebral cortex, the subcortical white mat-  ter, the internal capsule, the brainstem, or the spinal cord. The  clinical manifestations reflect overactivity and include excessive  movements, such as clonus and spasms, occurring regularly  as a result of loss of higher motor control. The distribution of  clinical manifestations varies, depending on the location of the  lesion, although certain features are constant. There is great  variation depending on the suddenness of onset and the age of  the individual.   Spinal shock is the complete cessation of spinal cord func-  tion below the lesion. When the pyramidal system is destroyed  below the level of the pons, spinal shock occurs. It is charac-  terized by complete flaccid paralysis, absence of reflexes, and  marked disturbances of bowel and bladder function. The rea-  sons for spinal shock are not fully understood, but a major  factor is the sudden destruction of the efferent pathways. If    destruction occurs more slowly, spinal shock may not develop  (see Chapter 18).   If the pyramidal system is interrupted above the level of the  pons, the hand and arm muscles are greatly affected. Paralysis  rarely involves all the muscles on one side of the body, however,  even when the hemiplegia results from complete damage to the  internal capsule. Bilateral movements, such as those of the eye,  jaw, and larynx, are affected only slightly, if at all. Predomi-  nantly the limbs are affected. Because of their bilateral control,  trunk muscles are much less influenced.   Paralysis associated with a pyramidal motor syndrome rarely  remains flaccid for a prolonged time. After a few days or weeks,  a gradual return of spinal reflexes marks the end of spinal shock.  Reflexes then become hyperactive, and muscle tone is increased  significantly, particularly in antigravity muscles. Spasticity is  common, although rigidity occasionally occurs. Most often,    FIGURE 17-32 Component Structure of a Lower Motor Neuron, Including  Motor (Efferent) and Sensory (Afferent) Elements. 7op, Anterior horn cell (in  anterior gray column of spinal cord and its axon), terminating in motor end plate as  it innervates extrafusal muscle fibers in the quadriceps muscle. Detailed enlarge-  ment: Sensory and motor elements of the gamma loop system. The gamma efferent  fiber is shown innervating the polar, or end, region of the muscle spindle (sensory  receptor of skeletal muscle). Contraction of muscle spindle fibers stretches the  central portion of the spindle and causes the afferent spindle fiber to transmit the  impulse centrally to the cord. Muscle spindle afferent fibers in turn synapse on the  anterior horn cell and are transmitted by way of gamma efferent fibers to skeletal  (extrafusal) muscle, causing it to contract. Muscle spindle discharge is interrupted  by active contraction of extrafusal muscle fibers.    passive range of motion causes the “clasp-knife” phenomenon,  probably because of the activation of the two varieties of stretch  receptors: (1) the muscle spindles and (2) the Golgi tendon  organ. (Muscle function is discussed in Chapter 43.) With pyra-  midal motor syndrome, predominantly the flexors of the arms  and the extensors of the legs are affected.   Lower Motor Neuron Syndromes. Lower (primary, alpha)  motor neurons are the large motor neurons in the anterior  (ventral) horn of the spinal cord and the motor nuclei of the  brainstem. The axons from these nerve cell bodies bring nerve  impulses from upper motor neurons to the skeletal muscles  through the anterior spinal roots or cranial nerves (Figure  17-32). Lower motor neuron syndromes impair voluntary and  involuntary movement. The degree of paralysis or paresis is  proportional to the number of lower motor neurons affected.  If only a portion of the motor units that supply a muscle  is affected, only partial paralysis or paresis results. If all the  motor units are affected, a complete paralysis results. Other  clinical manifestations also are proportional to the degree of  dysfunction, but the precise manifestations depend on the  location of the dysfunction in the motor unit and in the CNS.   Small motor (gamma) neurons, which function to main-  tain muscle tone and protect the muscle from injury, also are    necessary for normal motor movement. These neurons depend  on input from the muscle spindle (arriving through an affer-  ent limb rising to the cord). Dysfunction in this motor system  impairs tone and reduces the tendon reflexes, causing hypo-  reflexia. The muscle is lax and soft, with a decrease in normal  tone, or hypotonia, which impairs voluntary and involuntary  motor movements. The muscles become susceptible to damage  from hyperextensibility because the normal protective mecha-  nisms that prevent muscle fiber injury are impaired. The degree  of tone loss and the loss of tendon reflexes are proportional to  the dysfunction in these reflex motor units.   Generally in a pathologic process the large and small motor  neuron systems are equally affected. Therefore, the paresis and  paralysis caused by a disorder of the lower motor neurons are  called flaccid paresis/flaccid paralysis because the muscle has  reduced or absent tone and is accompanied by hyporeflexia or  areflexia (loss of tendon reflexes).   A few gamma neuropathies (small motor neuron disorders)  affect only the gamma motor system of the spinal cord. A mani-  festation of these disorders is a marked reduction in the deep  tendon reflexes, which are strikingly out of proportion to the  degree of muscle weakness present.   Denervated muscles (i.e., muscles that have lost their ner-  vous system input) undergo atrophy over weeks to months,  mostly from disuse. Denervated muscles also demonstrate  fasciculations, which are seen as muscle rippling or quivering  under the skin. Occasionally denervated muscles cramp. Fibril-  lation (isolated contraction of a single muscle fiber) also may  occur, although this manifestation is not visible clinically.    Motor neuron diseases result from progressive degeneration of  upper or lower motor neurons in the spinal cord, brainstem, or  cortex. Amyotrophic lateral sclerosis and paralytic poliomyeli-  tis (now almost nonexistent because of the polio vaccine) are  examples of these diseases.   Several pathologic processes may generate motor neuron  diseases, which can be sporadic or inherited. A virally induced  or postinfectious or postvaccination inflammatory process may  injure or destroy anterior horn cells or cranial nerve cell bodies.  Most of these inflammatory processes are mild and are followed  by rapid cellular recovery (see What’s New? Bell Palsy).   In motor neuron disease, muscle strength, muscle tone,  and muscle bulk are affected in the muscles innervated by  the involved motor neurons. The paresis and paralysis associ-  ated with anterior horn cell injury are segmental, but because  each muscle is supplied by two or more roots, the segmental  character of the weakness may be difficult to recognize. When  cranial nerve motor nuclei are affected (these lack nerve roots  and have only small rootlets near the point of exit from the  brainstem), the distribution of the motor weakness follows  that of the peripheral nerve. The weakness may involve distal  muscles, proximal muscles, and the muscles of midline struc-  tures. Hypotonia and hyporeflexia or areflexia are present.   The atrophy associated with motor neuron disease is seg-  mental when the anterior horn cells of the spinal cord are  involved and follows the distribution of the peripheral nerve    The etiology of Bell palsy (facial nerve palsy) remains unknown. There is usually  an inflammatory reaction compressing the facial nerve in the fallopian canal,  particularly in the narrowest labyrinthine segment, followed by demyelinating  neural change. The most distressing symptoms are unilateral facial weakness  and inability to smile or whistle. Bell palsy may be caused by reactivation of  herpesviruses in cranial nerve VII (facial) geniculate ganglia. Herpes simplex    type 1 has been detected in up to 78% of cases and herpes zoster in 30% of  cases. Severe pain with facial palsy and a vesicular rash in the ear or mouth  suggest herpes zoster infection. Ramsay Hunt syndrome (herpes zoster oticus)  is rare but complete recovery is less than 50%. Recovery from Bell palsy is usu-  ally complete. Both disorders may be treated with antivirals, corticosteroids, or  both. Treatment should be individualized according to severity of symptoms.    Data from Arbusow V et al: J Med Virol 82(11):1917-1920, 2010;  Gronseth GS, Paduga R: Neurology 79(22):2209-2213, 2012; Linder  TE, Abdelkafy W, Cavero-Vanek S: Oto! Neuroto! 31(2):319-327, 2010;  Santos Rde F, Brasileiro BF: Gen Dent 59(4):266-271, 2011.    when the motor nuclei of the cranial nerves are affected. The  atrophy may be in distal, proximal, or midline muscles. Fas-  ciculations are particularly associated with primary motor neu-  ron injury, and muscle cramps are common. Mild fatigue is a  common complaint. If the pathologic process is limited to the  primary motor neuron, no sensory changes are evident.   Because degenerative disorders can cause loss of nerve cells  in the anterior horn or motor nuclei, the surviving cells are  small and shrunken and filled with lipofuscin. Lost neurons are  replaced by astrocytes. The roots or rootlets are thin, and the  muscles show denervation and atrophy.   Several brainstem syndromes involve damage to one or more  of the cranial nerve nuclei. These are called cranial nerve palsy  (Table 17-24) and may be caused by vascular occlusion, tumor,  aneurysm, tuberculosis, or hemorrhage.   The anterior horn cells and the motor nuclei of the cra-  nial nerves may be affected secondarily in many severe patho-  logic processes that primarily involve the peripheral nerves.  The condition may extend proximally to affect the nerve  roots or rootlets and the motor neurons themselves, a pro-  cess commonly seen, for example, in Guillain-Barré syndrome  (see Chapter 18). If sufficient numbers of motor neurons are  destroyed, permanent loss of motor function results because  regeneration of the damaged axons requires a living neuronal  cell body.   A group of degenerative disorders principally cause progres-  sive motor cell atrophy. One of these is progressive spinal mus-  cular atrophy, in which the degenerated anterior horn cells of  the spinal cord are the affected motor neurons. This disorder  occurs in adults and closely resembles the familial progressive  muscular atrophies that occur in infants and children and that  are considered inherited metabolic disorders (see Chapter 45).  If the motor nuclei of the cranial nerves are affected instead of  the anterior horn cells, the disorder is labeled progressive bul-  bar palsy, so named because the myelencephalon (medulla and  upper cranial nerves) originally was called the bulb and a degen-  erative process causes a progressively more serious condition.  When any lower motor neuron syndrome involves the cranial    Other cranial nerve signs  Contralateral spastic  hemiparesis/hemiplegia  system Contralateral hyperreflexia  Aneurysm Contralateral extensor plantar  Intramedullary bleedi reflex  Facial Pontine tumor Paresis/paralysis of both  Cerebrovascular dise upper and lower facial  in the vertebrobasi muscles for both voluntary  system movement and emotionally  induced movement  Intramedullary tumor Ipsilateral loss of pain and  temperature sensations of  the face  Cerebrovascular disease Contralateral spastic arm and  in the vertebrobasilar eg paresis/hemiplegia  system Ipsilateral cerebellar signs  Intramedullary tumor Contralateral loss of position  sense and vibration in the  arm and leg  Contralateral spastic  hemiparesis/hemiplegia    nerves that arise from the bulb (i.e., cranial nerves IX, X, and  X11), the dysfunction is called a bulbar palsy.   The clinical manifestations of bulbar palsy include paresis or  paralysis of the jaw, face, pharynx, and tongue musculature. Artic-  ulation is affected, especially articulation of the lingual (r, n, D),  labial (b, m, p, f), dental (d, t), and palatal (k, g) consonants. Mod-  ulation is impaired, making the voice rasping or nasal. Pharyngeal  reflexes are diminished or lost. Palate and vocal cord movement  during phonation is impaired, and chewing and swallowing  are affected. The facial muscles are weak, and the face appears  to droop. The jaw jerk reflex is decreased. Atrophy eventually  becomes apparent, as do fasciculations. All these manifestations  become progressively worse, leading to aspiration, malnutrition,  possible dehydration, and an inability to communicate verbally.    Amyotrophic lateral sclerosis (ALS) (sporadic motor system  disease, sporadic motor neuron disease, motor neuron dis-  ease, Lou Gehrig disease) is a worldwide degenerative disorder  diffusely involving lower and upper motor neurons. Progressive  muscle weakness leads to respiratory failure and death, usually  2 to 5 years from symptom onset. There are no racial, ethnic, or  socioeconomic boundaries. The prevalence rate is about 6 to 8  cases per 100,000. ALS may begin at any time from the fourth  decade of life; its peak occurrence is in the early fifties. Male/  female ratio is 1:4 to 2:5, equalizing at about age 70 years.!!!  The term amyotrophic (without muscle nutrition or progres-  sive muscle wasting) refers to the predominant lower motor    neuron component of the syndrome. Lateral sclerosis, or scar-  ring of the corticospinal tract in the lateral column of the spinal  cord, refers to the upper motor neuron component of the syn-  drome. ALS differs from other motor neuron disorders in that  upper and lower motor neurons are both involved.   Most cases of ALS are sporadic. In familial ALS (5% to 10%  of cases), mutations have been found in 12 different genes with  the superoxide dismutase (SOD1) gene on chromosome 21 the  most common.!!? The defective SOD1 gene leads to an auto-  somal dominant pattern with age-dependent penetrance and  accounts for 15% to 20% of the cases of familial ALS. Mutated  TAR DNA-binding protein 43 (TDP-43) is a major constituent  of the ubiquitinated protein inclusions in ALS, and provides a  possible link between the genetic mutation and cellular pathol-  ogy of motor neuron injury.!!°   PATHOPHYSIOLOGY. The pathogenesis of ALS is not clear.  Apoptotic factors, abnormal synthesis of filament units, defects  in axonal transport, glutamate excitotoxicity, oxidative stress,  growth factors, mitochondrial dysfunction, and neuroinflam-  mation are under study for a possible contribution to the patho-  genesis.'!* The principal pathologic feature of ALS is lower and  upper motor neuron degeneration. The number of large motor  neurons in the spinal cord, brainstem, and cerebral cortex (pre-  motor and motor areas) is reduced, with ongoing degeneration  in the remaining motor neurons. The nuclei of cranial nerves  I, IV, and VI usually are not involved. Death of the motor  neuron results in axonal degeneration and secondary demy-  elination with glial proliferation and sclerosis (scarring) along  the corticospinal tract. Inclusion bodies containing the protein  ubiquitin are found in surviving neurons. However, there also  is widespread neural degeneration of nonmotor neurons in the  spinal cord and motor cortices, as well as in the premotor, sen-  sory, and temporal cortices.!!° Altered astrocytes and microglial  functions are suspected to exist. Lower motor neuron degenera-  tion denervates motor units. Adjacent, still-viable lower motor  neurons attempt to compensate by a process of distal intramus-  cular sprouting, reinnervation, and enlargement of motor units.   CLINICAL MANIFESTATIONS. The initial onset of ALS can be  subtle with cramping or weakness that affects a limb, incoor-  dination, slurring of speech, and difficulty swallowing. Muscle  weakness in ALS exhibits the following characteristics:   3. Gradual involvement occurs in all striated muscles, except  extraocular and heart muscles, and progresses to paralysis  with no remissions.   4. Flaccid and spastic paresis may coexist in a single muscle  group; flaccid paresis may mask spasticity, which is usu-  ally mild.   The lower motor neuron syndrome of flaccid paresis consists  of weakness of individual muscles, progressing to paralysis, asso-  ciated with hypotonia and primary muscle atrophy (i.e., atrophy  caused by denervation). Hypotonia is manifested by (1) decreased  resistance to passive movement, (2) hypoactive or absent deep  tendon reflexes, (3) absent abdominal and cremasteric reflexes,    and (4) absent Babinski sign. Primary atrophy is manifested  by (1) severe, irreversible muscular wasting; (2) fasciculations;  (3) metabolically related changes in the skin and appendages; and  (4) specific electromyographic (EMG) findings. Fasciculations,  along with fibrillations, are prominent features of ALS. Metabolic  changes include: (1) thinning of the skin, (2) thickening of the  nails, (3) loss of body hair, and (4) decreased perspiration.   The upper motor neuron syndrome of spastic paresis con-  sists of weakness of movement patterns, progressing to paral-  ysis, associated with spasticity and, in some cases, atrophy  secondary to disuse. Spasticity is manifested by (1) clasp-knife  phenomenon, evident with passive movement; (2) hyperac-  tive deep tendon reflexes and clonus with severe spasticity; (3)  absent abdominal and cremasteric reflexes; and (4) presence of  Babinski sign. The coexistence of a dementia has been demon-  strated to be higher than previously thought.   EVALUATION AND TREATMENT. The diagnosis of ALS is based pre-  dominantly on medical history and physical examination.'!©  Nerve conduction studies are important to exclude other diagno-  ses. There must be upper and lower motor neuron symptoms not  attributable to other causes. Riluzole (Rilutek), an antiglutamate,  is the standard treatment for ALS and prolongs life for months.  Treatment also is directed at relief of symptoms, prevention of  complications, maintenance of maximal function, and main-  tenance of optimal quality of life. Special problems requiring  preventive and symptomatic management are communication  difficulties caused by dysmasesis and dysphonia, salivation prob-  lems with either thick saliva or excessively thin saliva (sialorrhea),  and dyspnea caused by diaphragmatic and intercostal weakness.  Ventilatory issues become prominent. Supportive and rehabilita-  tion management is directed toward preventing complications of  immobility. Psychologic support of the affected individual and  the family is extremely important in this disorder. ALS is fatal  from respiratory failure usually within 3 years of diagnosis. A  small percentage of individuals live 5 to 10 years or longer.!!”    Because the extrapyramidal system encompasses all the motor  pathways except the pyramidal system, two types of motor  dysfunction comprise the extrapyramidal motor syndromes:  (1) the basal ganglia motor syndromes and (2) the cerebellar  motor syndromes. Unlike pyramidal motor syndromes, both  extrapyramidal motor syndromes result in movement or pos-  ture disturbance without significant paralysis, along with other  distinctive symptoms (Table 17-25).   Basal ganglia motor syndromes are movement disorders that  involve either a paucity or an excess of movements. Stress and  nervous tension typically worsen the symptoms, whereas relax-  ation improves motor performance. Akinesia may occur despite  normal strength. Involuntary movements, such as tremor, cho-  rea, ballism, athetosis, and dystonia, also may occur and prob-  ably are caused by the loss of the normal modulating effects of  the corpus striatum and other parts of the basal ganglia.   Basal ganglia motor syndromes also are characterized by  alterations in muscle tone and posture. Rigidity, together with  the cogwheel phenomenon, is present in all muscle groups but is  most prominent in those that maintain flexed position. Postural    PYRAMIDAL VS. EXTRAPYRAMIDAL MOTOR SYNDROMES  PYRAMIDAL MOTOR SYNDROME EXTRAPYRAMIDAL MOTOR SYNDROME    Paralysis of voluntary movement Little or no paralysis of voluntary movement   Absence of involuntary movements Presence of tremor, chorea, athetosis, or dystonia   Spasticity in muscles (e.g., clasp-knife Plastic (equal throughout movement) rigidity or intermittent (generalized but  phenomenon) predominantly in flexors of limbs and trunk) rigidity (cogwheel rigidity)   Hypertonia present in flexors of arms and Hypotonia, weakness and gait disturbance in cerebellar disease    abnormalities result from the loss of normal postural reflexes. Dys-  functional equilibrium results from the loss of postural stability.   Cerebellar motor syndromes involve the cerebellum and  may result in (1) acute loss of muscle tone; (2) difficulty with  coordination of voluntary movements (ataxia); (3) minor  degrees of muscle weakness, tendency toward fatigue, and  impairment of associated movements; and (4) disorders of  equilibrium, posture, and gait. Cerebellar effects are chiefly  ipsilateral (primarily affecting the same side of the body), so  damage to the right cerebellum generally causes symptoms on  the right side of the body. Predominant symptoms depend on  the area of damage within the cerebellum. The four cerebel-  lar syndromes are the rostral vermis, caudal vermis, cerebellar  hemisphere, and pancerebellum!!® (Table 17-26).   Diagnosis of a cerebellar motor syndrome is based on the  symptoms, but these may vary because of the individual’s  attempts at compensation. Further, the nervous system often  can operate well despite destruction of parts of the cerebellum,  although the mechanisms responsible for this retained function  are not fully understood.    The alterations in complex motor performance include dis-  orders of posture (stance), disorders of gait, and disorders of  expression.    An inequality of tone in muscle groups because of a loss of nor-  mal postural reflexes results in a posturing of limbs. Many reflex  systems govern tone and posture, but the most important factor  in posture control is the stretch reflex, in which stretching of  extensor (antigravity) muscles causes increased extensor tone  and inhibited flexor tone. Four types of disorders of posture  are described: (1) dystonic posture, (2) decerebrate posture,  (3) basal ganglion posture, and (4) senile posture. Equilibrium  and balance are disrupted when postural disorders are present.   Dystonia is the maintenance of an abnormal posture  through muscular contractions. When muscular contractions  are sustained for several seconds, they are called dystonic  movements, such as in choreoathetoid movements associated  with high levels of t-dopa. When contractions last for longer  periods, they are called dystonic postures, such as in torticol-  lis. Dystonic postures may last for weeks, causing permanent  fixed contractures. Dystonia has been associated with basal gan-  glia abnormality, but the exact pathophysiologic mechanisms    Ataxia of stance and gait with varying  degrees of instability of the trunk and  ataxia of legs; anteroposterior body  sway; presence of Romberg sign   Truncal, postural, and gait ataxia;  omnidirectional body sway; Romberg  negative; tendency to fall; saccadic slow  pursuit, nystagmus; inability to suppress  vestibulo-ocular reflex (doll’s eyes)   Severe disturbance in ipsilateral limb  movements; hypotonia in acute situa-  tion; dysmetria (extremity overshooting  its target); decomposition of movement;  kinetic tremor, past-pointing; deviation  of gait; dysarthria   Ataxia of trunk and bilateral limbs;  ataxia of gait and stance; dysarthria;  oculomotor disturbance    Data from Timmann D, Diener HC: Coordination and ataxia. In Goetz  GC, editor: Textbook of clinical neurology, St Louis, 2007, Saunders.    Botulinum toxin, both A and B, is effective in relieving cervical dystonia (spas-    modic torticollis) symptoms in adults and is the mainstay of modern treatment  for focal dystonia. The effectiveness of other drugs (benodiazepines, gamma-  aminobutyric acid [GABA] inhibitors, atypical anticonvulsants, dopaminergic  agonists and antagonists), as well as the effect of surgical interventions or  physical therapies, is not empirically known.    Data from Nijmeijer SW et al: Parkinsonism Relat Disord 18(6):731-736,  2012; Truong D: Neurol Sc 316(1-2):9-14, 2012; Colosimo C, Tiple D,  Berardelli A: Neurotox Res 22(4):265-273, 2012.    are unknown (Box 17-6). One particularly relevant dystonic  posture already discussed in this chapter is decorticate posture  (striatal posture or upper motor neuron dysfunction posture),  which may be unilateral or bilateral in occurrence. Decorticate  posture (also referred to as antigravity posture or hemiplegic  posture) is characterized by upper extremities that are flexed    at the elbows and held close to the body and by lower extremi-  ties that are externally rotated and extended (see Figure 17-6).  Decorticate posture is believed to occur when the brainstem,  which facilitates the antigravity position, is not inhibited by the  motor function of the cerebral cortex. Upper motor neuron  posture is more commonly described as the arm flexed at the  elbow, with a wristdrop; the leg inadequately bent at the knee,  with the hip excessively circumabducted; and the presence of a  footdrop.   Decerebrate posture refers to increased tone in extensor  muscles and trunk muscles, with active tonic neck reflexes.  When the head is in a neutral position, all four limbs are rigidly  extended (see Figure 17-6). The decerebrate posture is caused  by severe injury to the brain and brainstem, resulting in over-  stimulation of the postural righting and vestibular reflexes.   Basal ganglion posture refers to a stooped, hyperflexed  posture with a narrow-based, short-stepped gait. This posture  abnormality results from the loss of normal postural reflexes  and not from defects in proprioceptive, labyrinthine, or visual  function. Dysfunctional equilibrium results from the loss of  postural stability, and thus the individual is unable to make the  appropriate postural adjustment to tilting or loss of balance  and consequently falls. Dysfunctional righting is the inability  to right oneself when changing from a lying or crouching to a  standing position or when rolling from the supine to the lat-  eral or prone position. Dysfunctional postural fixation is the  involuntary flexion of the head and neck, causing the person  difficulty in maintaining an upright trunk position while stand-  ing or walking. Basal ganglion dysfunction accounts for this  posture.   Senile posture is characterized by an increasingly flexed pos-  ture similar to that caused by basal ganglion dysfunction. The  posture is associated with frontal lobe dysfunction, but the pri-  mary pathophysiology is not well described.   Four predominant types of gait disorder are: (1) upper motor  neuron dysfunction gait, (2) cerebellar (ataxic) gait, (3) basal  ganglion gait, and (4) senile (frontal lobe, pseudoparkinsonian)  gait. As with posture, equilibrium and balance are affected with  gait disturbances.   Several upper motor neuron gaits exist. In the presence of  mild upper motor neuron dysfunction, a footdrop may appear  only with fatigue. The individual may complain of hip and leg  pain. A spastic gait, which is associated with unilateral injury,  is manifested by a shuffling gait with the leg extended and held  stiff, causing a scraping over the floor surface. An impaired leg  swing around the body rather than an appropriate lifting and  placing of the leg is noted. The foot may drag on the ground,  and the person tends to fall to the affected side. A scissors    gait is associated with bilateral injury and spasticity. The legs  are abducted, causing them to touch each other. As the person  walks, the legs are still swung around the body but then cross in  front of each other because of adduction. Injury to the pyrami-  dal system accounts for these gaits.   A cerebellar gait manifests as a wide-based gait with the feet  apart and often turned outward or inward for greater stability.  The pelvis is held stiff, and it seems to be independent of the  trunk. The individual staggers when walking. Cerebellar dys-  function accounts for this particular gait.   A basal ganglion gait and a senile gait are both broad-based  gaits. The person walks with small steps and a decreased arm  swing. The head and body are flexed and the arms are semi-  flexed and abducted, whereas the legs are flexed and rigid in  more advanced states. Basal ganglion and frontal lobe dysfunc-  tion, respectively, account for these two gaits.    Disorders of expression involve the motor aspects of commu-  nication and include (1) hypermimesis, (2) hypomimesis, and  (3) dyspraxias and apraxias. Hypermimesis is a disinhibition  phenomenon that most commonly manifests as pathologic  laughter or crying. Pathologic laughter is associated with right  hemisphere injury, and pathologic crying is associated with left  hemisphere injury. The exact pathophysiology is not known.  Hypomimesis manifests as aprosody, or the loss of voice mod-  ulation (pitch, speed, emphasis, emotion). Receptive aprosody  involves an inability to understand emotion in speech and facial  expression, whereas expressive aprosody involves the inability  to express emotion in speech and facial expression. Aprosody is  associated with right hemisphere damage.   Dyspraxia is the partial inability and apraxia is the complete  inability to perform purposeful or skilled motor acts in the  absence of paralysis, sensory loss, abnormal posture and tone,  abnormal involuntary movement, incoordination, or inatten-  tiveness. These are disorders of learned skilled movements.!!”  Dyspraxia and apraxia are associated with left hemisphere vas-  cular disorders, trauma, tumor, degenerative disorders, infec-  tions, and metabolic disorders. The medial premotor cortex,  including the supplementary motor area (SMA), appears to  play a role in skilled movements as does the convexity premo-  tor areas!!? (Table 17-27).   True dyspraxias occur when the connecting pathways  between the left and right cortical areas are interrupted, caus-  ing language-motor and motor representation disconnections  between the hemispheres. Dyspraxias may result from any  pathologic process that disrupts the cortical areas necessary for  the conceptualization and execution of a complex motor act  or the communication pathways within the left hemisphere or  between the hemispheres.    Impairment in selecting, sequencing, and spatial orientation of movements  involved in gestures (spatial and temporal production errors)   Difficulty performing in response to command and imitation; cannot discriminate  well between poorly performed and well-performed acts   Performs poorly to command and imitation but comprehends and discriminates  pantomime   Lesions anterior to the supramarginal gyrus, which  disconnects visual kinesthetic motor engrams  from premotor and motor areas    Greater impairment in performance when imitating movements than when  pantomiming to command; comprehends pantomime and gesture but cannot  perform the movements   Inability to gesture normally to command and required verbal mediation; has  good performance with imitation and actual tools and objects   Inability to carry out an ideational plan or a series of acts in the proper sequence   Cannot recall type of action associated with specific tools, utensils, or objects  (content and tool selection errors; may be unable to recall which tool is  associated with a specific object or may have impaired mechanical knowledge)    1. Full consciousness is an awareness of oneself and the envi-   3. Alterations in level of arousal may be caused by structural,  metabolic, or psychogenic disorders.    memory. With a vigilance deficit, the person cannot main-  tain search and scanning activities. With a detection deficit,  the person is unmotivated and unable to use feedback.  Some specific disorders of awareness (content of thought)  are data processing deficits: agnosias, dysphasias, acute con-  fusional states, and dementias, including AD.    4. Levels of consciousness can diminish in stages from alert visual, or auditory. They are caused by dysfunction in the  and oriented to confusion and coma. primary sensory area or the interpretive areas of the cere-  5. An alteration in breathing pattern and level of coma reflects bral cortex.  the level of hemispheric and brainstem dysfunction. 18. Dysphasia is an impairment of comprehension or produc-  6. Pupillary changes reflect changes in level of brainstem func- tion of language. Dysphasia may be expressive or sensory.  tion, drug action, and response to hypoxia and ischemia. 19. Aphasia is loss of language comprehension or production.  7. Abnormal eye movements, including nystagmus and diver- 20. Wernicke dysphasia is a disturbance in understanding all  gent gaze, reflect alterations in brainstem function. language—verbal and reading comprehension.  8. Level of brain function manifests by changes in generalized 21. Conductive dysphasias result from disruption of temporal  motor responses or the presence of no responses. lobe fibers, with a failure to repeat words but an ability to  9. Loss of cortical inhibition associated with decreased con- initiate speech, writing, and reading aloud.  sciousness includes abnormal flexor and extensor movements. | 22. Anomic dysphasia is an inability to name objects, people, or  10. Brain death represents irreversible total brain damage qualities.  including an inability to maintain cardiac, respiratory, and 23. Transcortical dysphasias involve an ability to repeat and  other vital functions. recite.  11. Arousal returns in the vegetative state and minimally con-  —-.24._ Broca aphasia is an expressive dysphasia of speech and writ-  scious state, but content of thought is absent or markedly ing but with retention of comprehension.  reduced, respectively. 25. Global aphasia involves anterior and posterior speech areas,  12. Alterations in awareness encompass all cognitive functions with expressive and receptive aphasia.  including awareness, selective attention, and memory. 26. Acute confusional states are characterized chiefly by defects  13. With a deficit in selective attention, mediated by the brain- in attention and coherence of thoughts and actions and, in  stem, the parietal lobe structures, and the pulvinar nucleus the case of delirium, an intense autonomic nervous system  of the thalamus, the individual cannot focus on selective hyperactivity.  stimuli and thus neglects those stimuli, causing a neglect 27. Dementia is impairment of intellectual function, memory,    syndrome.  In dysmnesia and amnesia, some memories are not retrieved  and new memories cannot be stored.    and language with alteration in behavior and can be caused  by trauma, vascular disease, infection, and progressive  neurodegeneration.    AD is the most common chronic, irreversible dementia.  Seizures represent abnormal, excessive hypersynchronous  discharges of cerebral neurons with transient alterations in  brain function. Seizures may be generalized or focal. There  are three categories of epileptic syndrome: location-related,  generalized, and cryptogenic (undetermined).    Cerebral oxygenation is a critical management issue.  Cerebral perfusion pressure determines cerebral blood flow.  An injured brain may experience cerebral oligemia, normal  cerebral blood flow but with increased intracranial pres-  sure, or cerebral hyperemia.    excess CSF, hemorrhage, or tumor growth. When intra-  cranial pressure approaches arterial pressure, hypoxia and  hypercapnia produce brain damage.    . Cerebral edema is an increase in the fluid content of the    brain resulting from infection, hemorrhage, tumor, isch-  emia, infarct, or hypoxia.    . The shifting or herniation of brain tissue from one com-    partment to another disrupts the blood flow of both com-  partments and damages brain tissue.    pocampal gyrus shifting from the middle fossa to the poste-  rior fossa; transtentorial herniation with a downward shift  of the diencephalon through the tentorial notch; and shift-  ing of the cingulate gyrus herniation under the falx.    . The most common infratentorial herniation is a shift of the    terized by an excess of fluid within the cranial vault, sub-  arachnoid space, or both. Hydrocephalus occurs because of  interference with CSF flow caused by increased fluid pro-  duction or obstruction within the ventricular system or by  defective reabsorption of the fluid.    Motor dysfunction may be characterized as alterations of  motor tone, movement, and complex motor performance.    the basal ganglia and frontal cerebral cortex with a depletion  of neurons that secrete GABA (an inhibitory neurotransmit-  ter) that causes involuntary, fragmentary movements accom-  panied by emotional lability and progressive dementia.    Types of hypokinesia include akinesia, bradykinesia, and  loss of associated movements.   PD is a common degenerative disorder of the basal ganglia  (corpus striatum) involving degeneration of the dopamine-  secreting nigrostriatal pathway resulting in overactivity by  the subthalamic nucleus, causing tremor, rigidity, and bra-  dykinesia. Involvement of the limbic system causes emo-  tional lability. Progressive dementia may be associated with  an advanced stage of the disease.    . Partial paralysis occurs with only partial loss of alpha motor    neurons, and total paralysis is complete loss of alpha motor  neurons. Loss of gamma motor neurons impairs muscle  tone and decreases deep tendon reflexes.   Motor neuron diseases result from progressive degenera-  tion of upper or lower motor neurons in the spinal cord,  brainstem, or cortex.   Nuclear palsies involve damage to the cranial nerve nuclei.  Bulbar palsies involve cranial nerves IX, X, and XI.   ALS is a motor neuron disease. The pathogenesis of ALS is  not fully known; however, lower and upper motor neuron  degeneration occurs as well as degeneration of the nonmotor  neurons in the cortices and spinal cord. Clinical manifesta-  tions of ALS may include weakness in all muscles that may  begin in a single muscle group, slurring of speech, and dif-  ficulty swallowing. Flaccid paresis progressing to paralysis is  characteristic of the lower motor neuron syndrome.  Extrapyramidal motor syndromes include basal ganglia and  cerebellar motor syndromes.   Basal ganglia disorders manifest with alterations in muscle  tone and posture, including rigidity, involuntary move-  ments, and loss of postural reflexes.   Cerebellar motor syndromes result in loss of muscle tone,  difficulty with coordination, and disorders of equilibrium  and gait.   Alterations in complex motor performance include disor-  ders of posture (stance), disorders of gait, and disorders of  expression.   Disorders of posture include dystonic posture, decerebrate  posture, basal ganglion posture, and senile posture.  Disorders of gait include upper motor neuron gaits, cer-  ebellar gait, basal ganglion gait, and senile gait.   Disorders of expression include hypermimesis, hypomime-  sis, and dyspraxia or apraxia.   Dyspraxia is the partial inability and apraxia is the complete  inability to perform purposeful or skilled motor acts.   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Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Disorders of the Central and Peripheral Nervous  Systems and the Neuromuscular Junction    Central Nervous System Disorders, 581  Traumatic Brain and Spinal Cord Injury, 581  Degenerative Disorders of the Spine, 594  Cerebrovascular Disorders, 598  Headache Syndromes, 607  Infection and Inflammation of the Central    Alterations in central nervous system (CNS) structure and  function are caused by traumatic injury, vascular disorders,  tumor growth, infectious and inflammatory processes, meta-  bolic derangements (including those arising from nutritional  deficiencies and drugs/chemicals), and degenerative processes.  Alterations in peripheral nervous system function involve the  nerve roots (radiculopathies), a nerve plexus, the nerves them-  selves (neuropathies), or the neuromuscular junction.   Traumatic brain injury (TBI) is an alteration in brain func-  tion or other evidence of brain pathology caused by an exter-  nal force.' An estimated 1.7 million people sustain TBI in the  United States each year with approximately 53,000 deaths.    Peripheral Nervous System and Neuromuscular Junction  Disorders, 621  Peripheral Nervous System Disorders, 621  Neuromuscular Junction Disorders, 624  Tumors of the Central Nervous System, 626  Cranial Tumors, 626  Spinal Cord Tumors, 633    Those at highest risk for TBI are children 4 years and younger,  adolescents 15 to 19 years, and adults 65 years and older. Males  have the highest incidence in every age group.” TBI is high-  est among American Indian/Alaska Natives and blacks and in  lower- and median-income families. TBIs are caused by falls  (35%), motor vehicle—-related injuries (17%), and a strike or  blow to the head from or against an object (e.g., workplace or  sports-related injuries [16.5%], assaults [10%], and other and  unknown causes [21%]).°   TBI survival is improving because of advancements in safety  measures (e.g., passive seat restraints, air bags, protective head  gear), reduced transport time to hospitals or trauma centers,  and improved on-scene and follow-up medical management.  Prevention and management of secondary and tertiary brain  injuries also have improved outcomes. TBI is capable of pro-  ducing physical, intellectual, emotional, social, and vocational  changes.    SEVERITY OF BLUNT TRAUMA, TRAUMA STATE INDUCED,  AND ONSET AND PERSISTENCE OF CLINICAL MANIFESTATIONS    Paraplegia (associated  with injury to top of head)  Blindness (associated  with occipital injury)  Delayed development of  unresponsiveness (vasomotor  or vasovagal syncopal episode)    Acute contusional swelling  Acute subdural hematoma  Subacute subdural hematoma*  Subdural hygroma (fluid    *May be seen after moderate head injury, especially in elderly people.    Traumatic brain injury can be caused by closed (blunt)  trauma and open (penetrating) trauma. Closed (blunt) trauma  is more common and involves either the head striking a hard  surface or a rapidly moving object striking the head. The dura  mater remains intact, and brain tissues are not exposed to the  environment. Most closed (blunt) trauma is mild (75% to 90%)  and causes mild concussion and classic cerebral concussion (see  pp. 587-588 and Table 18-1). Open (penetrating) trauma occurs  when a break in (penetration of) the dura mater results in expo-  sure of the cranial contents to the environment.   The Glasgow Coma Scale (GCS) is used to assess severity of  injury.* The hallmark of a severe TBI is loss of consciousness for  6 hours or more. TBI classifications using the GCS are: (1) mild  TBI with GCS score of 13 to 15, associated with mild concus-  sion; (2) moderate TBI with GCS score of 9 to 12, associated  with structural injury such as hemorrhage or contusion; and  (3) severe TBI with GCS score of 3 to 8, associated with cog-  nitive and/or physical disability or death. Age and admission  GCS score are important diagnostic factors in TBI.° Mild TBI is  characterized by five features: a GCS score between 13 and 15, a  brief period of unconsciousness or dazed consciousness, post-  traumatic amnesia, negative neuroimaging studies, and recov-  ery within weeks to months without sequelae or the need for  specific medical intervention.    Three mechanisms produce brain damage: primary, sec-  ondary, and tertiary injury. Primary injury is caused by the  impact and involves neural injury, primary glial injury, vascular  responses, and shearing and rotational forces. Secondary injury  is an indirect consequence of the primary injury and includes  a cascade of cellular and molecular brain events (Figure 18-1).  Tertiary injury can develop days or months later as a conse-  quence of systemic complications, such as pneumonia, fever,  infections, and immobility, which contribute to further brain  injury or delays in repair.   Primary Brain Injury. Primary brain injuries can be classified  as focal, affecting one area of the brain, or diffuse (diffuse  axonal injury [DAI]), involving more than one area of the brain  (see Table 18-1). Both types of injury can be associated with the  same initiating event and can occur with brain trauma or stroke  syndromes (see Figure 18-1). Focal brain injury accounts for  more than two thirds of head injury deaths; DAI accounts for  less than one third. However, more severely disabled survivors,  including those in an unresponsive state or reduced level of  consciousness, have DAI.   Focal Brain Injury. Focal brain injuries are specific,  grossly observable brain lesions that occur in a precise location  (e.g., cortical contusions, epidural hemorrhage, subdural hema-  toma, intracerebral hematoma). Focal brain injuries can occur    ———————— | Secondary Injury  Hypotension (decreased cerebral perfusion  pressure)  Hypoxia  Cerebral ischemia  Impaired autoregulation of blood flow  Cerebral edema  Increased intracranial pressure  Excitotoxicity  Oxidative stress  Vascular injury and  blood-brain barrier dysfunction  Inflammation  Neuronal death    Primary Injury  Focal (direct impact)  Scalp laceration  Skull fracture  Hemorrhage:  Epidural hematoma  Subdural hematoma  Intracerebral hematoma  Subarachnoid hemorrhage  Diffuse  (acceleration/deceleration rotational)  Concussion: mild to severe    Opening of Na*, K* and Ca** channels Release of excitotoxic amino acids    Mitochondrial dysfunction - energy failure and apoptosis  Formation of reactive oxygen molecules, lipid peroxidation and oxidative injury    Activation of inflammatory mediators - leukocyte infiltration/microglia activation  Microvascular injury - failure of BBB (vasogenic edema)    with both blunt and open brain trauma and can be associated  with skull fractures.   Focal brain injury results from compression of the skull at the  point of impact and rebound effects. The focal injury may be a  coup injury (directly below the point of impact) or contrecoup  (on the pole opposite the site of impact) (Figure 18-2). Objects  (e.g., baseball bat, weapon) striking the front of the head usually  produce only coup injuries (contusions and fractures) because  the inner skull in the occipital area is smooth. Objects striking the  back of the head usually result in both coup and contrecoup inju-  ries because of the irregularity of the inner surface of the frontal  bones. Objects striking the side of the head may produce coup or  contrecoup injuries. The force of impact (translational accelera-  tion) typically produces localized brain contusions. Injury to the  vault, other vessels, and supporting structures can produce epi-  dural hemorrhage and subdural and intracerebral hematomas.   Contusions (blood leaking from an injured vessel)  (Figure 18-3) are found most commonly in the frontal lobes,    particularly at the poles and along the inferior orbital surfaces;  in the temporal lobes, especially at the anterior poles and along  the inferior surface; and at the frontotemporal junction. Con-  tusion severity varies with the amount of impact energy trans-  mitted by the skull to underlying brain tissue. The smaller  the area of impact, the greater the severity of injury because  the force is concentrated into a smaller area. Brain edema  forms around and in damaged neural tissues, contributing to  increasing intracranial pressure (ICP). Within the contused  areas are infarction and necrosis, multiple hemorrhages, and  edema. The tissue has a pulpy quality. The maximum effects  of injury related to contusion, bleeding, and edema peak 18 to  36 hours after severe head injury.   Contusions cause changes in attention, memory, execu-  tive attentional function (motivation, goal selection or forma-  tion, planning, self-monitoring, and use of feedback), affect,  emotion, and behavior. Less commonly, contusions occur in  the parietal and occipital lobes. Focal cerebral contusions are    FIGURE 18-2 Coup and Contrecoup Brain Injury Following Blunt Trauma.  1, Coup injury: impact against object; a, site of impact and direct trauma to brain;  b, shearing of subdural veins; ¢, trauma to base of brain. 2, Contrecoup injury:  impact within skull; a, site of impact from brain hitting opposite side of skull; b,  shearing forces through brain. These injuries occur in one continuous motion—the  head strikes the wall (coup) and then rebounds (contrecoup). (Modified from Rudy  EB: Advanced neurological and neurosurgical nursing, St Louis, 1984, Mosby.)    FIGURE 18-3 Cerebral Contusions. The temporal poles are discolored by  areas of hemorrhage (arrows). Such lesions represent “bruises” on the surface of  the brain caused by violent contact between the delicate brain parenchyma and  the hard inner surface of the skull. (From Kumar V, Cotran RS, Robbins SL: Robbins  basic pathology, ed 7, Philadelphia, 2003, Saunders.)    superficial, involving just the gyri. Hemorrhagic contusions  may coalesce into a large, confluent intracranial hematoma.  The clinical manifestations of a contusion may include imme-  diate loss of consciousness (generally accepted to last no longer  than 5 minutes); loss of reflexes, which results in the individual  falling to the ground; transient cessation of respiration; brief  period of bradycardia; and decrease in blood pressure (lasting  30 seconds to a few minutes). A momentary increase in cere-  brospinal fluid (CSF) pressure and changes on electrocardio-  gram (ECG) and electroencephalogram (EEG) recordings have  been demonstrated to occur on impact. Vital signs may stabi-  lize to normal values in a few seconds. Reflexes return next and  the person begins to regain consciousness. Returning to being  fully awake and alert can vary from minutes to days. Regaining    FIGURE 18-4 Epidural Hematoma, CT Image. Note the large right epidural  hematoma with a lens-shaped outline as the smooth dura becomes indented  against the underlying cortex on the right lateral aspect of the cerebrum. The epi-  dural hematoma is confined within an area bounded by cranial sutures where the  dura is firmly adherent to the skull. Note the mass effect with effacement of the  lateral ventricles and the shift of midline to the left (arrows). In this case the indi-  vidual fell from a height and struck the right side of his head, severing the middle  meningeal artery. This epidural hematoma collected within hours. C7, Computed  tomography. (From Klatt EC: Robbins and Cotran atlas of pathology, Philadelphia,  2006, Saunders.)    a full level of consciousness may be extremely slow and residual  deficits may persist. In some persons, full level of consciousness  never returns.   Evaluation is based on history, level of consciousness using the  Glasgow Coma Scale, imaging studies (e.g., computed tomog-  raphy [CT], magnetic resonance imaging [MRI], and positron-  emission tomography [PET]), and assessment of vital parameters  (e.g., ICP and EEG). Large contusions and lacerations with  hemorrhage may be excised surgically.° Otherwise, treatment is  directed at controlling ICP and managing symptoms.   Extradural hematomas (bleeding between the dura mater  and the skull [i-e., epidural hematomas or epidural hemor-  rhages]) represent 1% to 2% of major head injuries and occur  in all age groups, but most commonly in those 20 to 40 years  of age. Extradural hematomas are caused most commonly by  motor vehicle accidents (MVAs) and occasionally by falls and  sporting accidents. A temporal fracture causes 90% of temporal  lobe extradural hematomas. Direct frontal lobe trauma is asso-  ciated with frontal extradural hematomas. Posterior extradural  hematomas are associated with a fracture across the transverse  sinus from an occipital blow.   An artery is the source of bleeding in 85% of extradural  hematomas (Figure 18-4); 15% result from injury to the menin-  geal vein or dural sinus. Ninety percent of individuals also have  a skull fracture. The temporal fossa is the most common site  of extradural hematoma caused by injury to the middle men-  ingeal artery or vein. The resulting shift of the temporal lobe  medially precipitates uncal and hippocampal gyrus herniation    FIGURE 18-5 Subdural Hematoma, Gross, and Bridging Veins, Gross. A large subdural hematoma (A) is seen in the  frontoparietal region. A subdural hematoma forms after head trauma that severs the bridging veins from dura to brain, shown  in the right panel (B), where the dura has been reflected to reveal the normal appearance of the bridging veins that extend  across to the superior aspect of the cerebral hemispheres. Older adults and the very young are at greater risk because their  cerebral veins are more vulnerable to injury. Because the bleeding is venous, blood collects over hours to weeks, with variable  onset of symptoms. Because the blood collects beneath the dura, a subdural hematoma can be seen to cross the region of  cranial sutures. (From Klatt EC: Robbins and Cotran atlas of pathology, Philadelphia, 2006, Saunders.)    through the tentorial notch. Extradural hemorrhages are found  occasionally in the subfrontal area (especially in the young and  older adult populations), caused by injury to the anterior men-  ingeal artery or a venous sinus, and in the occipital-suboccipital  area, which results in herniation of the posterior fossa contents  through the foramen magnum. CT and MRI showa lens-shaped  mass over the surface of the cortex.   Individuals with classic temporal extradural hematomas (i.e.,  over the temporal lobe) experience loss of consciousness at the  time of injury, followed by a lucid period that lasts from a few  hours to a few days in one third of individuals (if bleeding from  a vein). As the hematoma accumulates, a headache of increasing  severity, vomiting, drowsiness, confusion, seizure, and hemipa-  resis may develop. Level of consciousness may dwindle rapidly  as temporal lobe herniation begins. Clinical manifestations of  temporal lobe herniation also include ipsilateral pupillary dila-  tion and contralateral hemiparesis.   The diagnosis of an extradural hematoma is usually made by  CT or MRI. In some instances, diagnosis is made by history and  clinical findings, because time for a CT or MRI is not available.  The prognosis is usually good if intervention is initiated before  bilateral dilation of the pupils. Surgical therapy is evacuation  of the hematoma through burr holes, followed by ligation of  the bleeding vessel or vessels. Extradural hematomas are almost  always medical emergencies.   Subdural hematomas arise in 10% to 20% of TBIs. MVAs  are the most common cause of subdural hematomas; 50% of  subdural hematomas are associated with skull fractures. Falls,  especially in older adults or in those with long-term alcohol  abuse, are associated with chronic subdural hematomas.   Acute subdural hematomas rapidly develop (within 48 hours)  and usually are located at the top of the skull (the cerebral    convexities). On CT they appear as a high-density mass. Bilateral  hematomas occur in 15% to 20% of persons. Subacute subdural  hematomas develop more slowly, often over 48 hours to 2 weeks.  On CT they appear as a mixed-density mass. Chronic subdural  hematomas (commonly found in older adults and those who  abuse alcohol and have some degree of brain atrophy with a  subsequent increase in the extradural space) develop over weeks  to months. Tearing of the bridging veins is the major cause of  rapidly developing and subacutely developing subdural hema-  tomas, although torn cortical veins or venous sinuses and con-  tused tissue may be the source. These subdural hematomas act  as expanding masses, giving rise to increased ICP that eventu-  ally compresses the bleeding vessels (Figures 18-5 and 18-6). The  displacement of brain tissue can result in a herniation syndrome.   In acute, rapidly developing subdural hematomas the expand-  ing clots directly compress the brain, giving rise to the clinical  manifestations. As the ICP rises the bleeding veins are com-  pressed and thus bleeding is self-limiting, although cerebral  compression and displacement of brain tissue can cause tem-  poral lobe herniation.   An acute subdural hematoma classically begins with head-  ache, drowsiness, restlessness or agitation, slowed cognition,  and confusion. These symptoms worsen over time and prog-  ress to loss of consciousness, respiratory pattern changes, and  pupillary dilation (the symptoms of temporal lobe herniation).  These manifestations are more pronounced than focal mani-  festations such as dysphasia, dyspraxia, or hemiparesis. Other  clinical manifestations may include homonymous hemianopsia  (defective vision in either the right or the left field), dysconju-  gate gaze, and gaze palsies.   The pathogenesis of a chronic subdural hematoma is dif-  ferent. The existing subdural space gradually fills with blood.    FIGURE 18-6 Chronic Subdural Hematoma. Compression of underlying  brain and lateral ventricle. (From Kissane JM, editor: Anderson’ pathology, ed 9,  St Louis, 1993, Mosby.)    A vascular membrane forms around the hematoma in approxi-  mately 2 weeks. Further enlargement takes place in some per-  sons, but the mechanism of this enlargement is unclear.   Presenting manifestations of chronic subdural hematomas  vary. Of those affected, 80% have chronic headaches and ten-  derness over the hematoma on percussion. Most appear to have  a progressive dementia accompanied by generalized rigidity  (paratonia).   Whereas most acute and subacute subdural hematomas are  treated with clot evacuation through a burr hole, chronic subdu-  ral hematomas (and some that are subacute) require a craniot-  omy to evacuate the gelatinous blood. The membrane around a  chronic subdural hematoma is then dissected away from the dura  mater and arachnoid membranes. A technique for percutaneous  drainage for chronic subdural hematomas has proved successful.   Intracerebral hematomas occur in 2% to 3% of head inju-  ries and are usually associated with MVAs and falls from some  distance. Intracerebral hematomas may be single or multiple,  and they are associated with contusions. Although most com-  monly located in the frontal and temporal lobes, intracerebral  hematomas may occur in the hemispheric deep white matter.  Small blood vessels are traumatized by penetrating injury or  shearing forces. The intracerebral hematoma then acts as an  expanding mass, resulting in increased ICP and compression of  brain tissues with resultant edema and ischemia (Figure 18-7).  Delayed intracerebral hematomas may appear 3 to 10 days after  the head injury.   A decreasing level of consciousness is associated with an  intracerebral hematoma. Coma or a confusional state from  other injuries, however, can make the cause of this increasing  unresponsiveness difficult to detect. Contralateral hemiple-  gia also may occur. As the ICP rises, clinical manifestations of  temporal lobe herniation may appear. In delayed intracerebral  hematoma, the presentation is similar to that of hypertensive  brain hemorrhage: sudden, rapidly progressive decreased level  of consciousness with pupillary dilation; breathing pattern  changes; hemiplegia; and bilateral positive Babinski reflexes.    FIGURE 18-7 Acute Intracerebral Hemorrhage. A fresh hematoma has dis-  rupted and expanded the left cerebral hemisphere, causing the midline structures  to shift to the right. Uncontrolled hypertension is an important cause of this cata-  strophic lesion. (From Kumar V, Cotran RS, Robbins SL: Robbins basic pathology, ed 7,  Philadelphia, 2003, Saunders.)    Evacuation of a singular intracerebral hematoma has only  occasionally been helpful, mostly for subcortical white matter  hematomas. Otherwise, treatment is directed at reducing the  ICP to maintain cerebral perfusion pressure and allowing the  hematoma to reabsorb slowly. Secondary brain injury is com-  mon (see p. 588).   Open brain trauma produces both focal and diffuse injuries  and includes compound skull fractures and missile injuries (e.g.,  bullets, rocks, shell fragments, knives, and blunt instruments).  A compound fracture opens a communication between the cra-  nial contents and the environment and should be investigated  whenever there are lacerations of the scalp, tympanic mem-  brane, a sinus, an eye, or mucous membranes. Such fractures  may involve the cranial vault or the base of the skull (basilar  skull fracture). A basilar skull fracture can involve the temporal,  sphenoid, and occipital bones. The cranial nerves may be dam-  aged and the meninges torn, causing leakage of cerebrospinal  fluid from the ear and nose, or both. Severity of brain damage is  related to the severity of skull fracture. Infection is a significant  complication. Injury incurred from bone fragments is mainly  a tangential injury (injury caused by direct contact) and occa-  sionally a penetrating injury. Bone fragments may lacerate or  contuse brain tissues or blood vessels.   The mechanisms of open brain trauma are crush injury  (laceration and crushing of tissue touched by the missile) and  stretch injury (damage of blood vessels and nerves not directly  contacted, occurring as a result of stretching). Crush injury is the  laceration and crushing of whatever tissue the missile touches,  with the amount of crush related to the degree of fragmenta-  tion, deformity, size, and shape. The tangential injury is injury  to the coverings of the brain (scalp and brain lacerations) and  also may include skull fractures and meningeal and cerebral lac-  erations. When driven into the brain substance, projectiles and  debris from scalp and skull injury produce a penetrating brain  injury. Occasionally projectiles are so forceful that they exit the    cranial vault in addition to entering it, producing a through-  and-through injury (e.g., high-velocity bullets). Primary dam-  age is localized along the path of the penetrating object, and  direct tissue disruption along the projectile tract results.   Stretch injury involves blood vessels and nerves that are  damaged without direct contact as a result of the amount of  tissue stretched secondary to shape, deformation, and striking  velocity. Air compressed in front of a bullet exerts an explosive  effect on entry, producing extreme distant tissue damage and an  immediate primary increase in ICP; a cavity many times greater  than the size of the bullet is produced because the brain tissue  is propelled away from the tract. The cavity and pressure pro-  duce contrecoup injuries. The intracranial volume is increased  directly by the projectile and the debris. The temporary cavity  collapses back onto itself, leaving a smaller, permanent cavity.  Intracranial bleeding occurs into the permanent cavity and may  cause the cavity to expand. Edema in and around the injured  brain tissue rapidly develops; edema and bleeding contribute  markedly to increased ICP. This second rise in ICP to 60 to 100  mmHg may last 2 to 5 minutes. Because of acute ischemic dam-  age to the tract, necrosis of tissue begins. Within hours after  bullet-induced injury, tissue within 1 cm adjacent to the tract  disintegrates. Demyelination of white matter affected by hem-  orrhage and edema occurs by the second day. Clinical mani-  festations such as unconsciousness, flaccidity, or decerebrate  posture (see Chapter 17) are associated with high mortality.   Most victims lose consciousness with open-head injury. The  depth of the coma and the length of the unresponsive state are  related to the location of injury, extent of damage, and amount  of bleeding. The diagnosis of a compound fracture is made  through physical examination, skull radiographs, or both. The  diagnosis of a basilar skull fracture is made on the basis of clini-  cal findings. Skull radiographs often do not demonstrate the  fracture, although intracranial air or air in the sinuses on radio-  graph, CT, or MRT is indirect evidence of a basilar skull fracture.   A compound linear fracture is débrided nonsurgically in  cooperative adults and surgically in children and uncoopera-  tive adults. Cranioplasty with insertion of bone or an artificial  graft may be necessary but often is delayed until antibiotics have  been given. Antibiotics are administered after surgery. Open-  head injury often requires surgery to débride the traumatized  tissues to prevent infection and to remove blood clots to help  reduce the ICP. ICP also is managed with dehydrating agents,  osmotic diuretics, or a combination of these drugs. Broad-spec-  trum antibiotics are administered to prevent infection. Use of  prophylactic antibiotics is controversial because studies have  failed to demonstrate that they reduce the rate of infection.” Bed  rest and close observation for meningitis and other complica-  tions are prescribed for a basilar skull fracture.   Diffuse Brain Injury. Diffuse brain injury (diffuse axonal  injury [DAI]) involves widespread areas of the brain. Damage  to delicate axonal fibers and white matter tracts that project to  the cerebral cortex causes concussion. Mechanical effects from  high levels of acceleration and deceleration (whiplash) and  rotational and twisting movements are the primary mecha-  nisms of injury, producing strains and distortions within the  brain (see Figure 18-2). Asa result of the skull’s motion caused    FIGURE 18-8 Diffuse Axonal Injury. Gross photograph demonstrating char-  acteristic hemorrhage lesions within the corpus callosum. (Courtesy Walter Kemp,  MD, Department of Pathology, University of Texas Southwestern Medical School,  Dallas. From Kumar V, Cotran RS, Robbins SL: Robbins basic pathology, ed 7, Phila-  delphia, 2003, Saunders.)    by its attachment to the neck, striking the head causes rota-  tional forces that can trigger shearing forces on brain tissues.  Stretching and tearing of nerve fibers result in axonal damage.  The most severe axonal injuries are located more peripheral to  the brainstem, causing extensive cognitive and affective impair-  ments, as seen in survivors of traumatic brain injury from  vehicular crashes. Axonal damage reduces the speed of infor-  mation processing and response and disrupts the individual’s  attention span.   Pathophysiologically, axonal damage can be seen only  with an electron microscope and involves numerous axons  alone or axonal injury in conjunction with actual tissue tears  (Figure 18-8). Areas where axons and small blood vessels are  torn appear as small hemorrhages, located particularly in  the corpus callosum and dorsolateral quadrant of the rostral  brainstem at the superior cerebellar peduncle. Increasingly  more damaged axons are visible 12 hours to several days after  the injury and secondary brain injury also is occurring (see  p. 588). The severity of diffuse injury correlates with how  much shearing force was applied to the brain. DAI is not  associated with intracranial hypertension immediately after  injury; however, secondary brain injury causes acute brain  swelling from increased intravascular blood flow within the  brain, vasodilation, and increased cerebral blood volume.   Several categories of diffuse brain injury exist: mild concus-  sion, classic concussion, mild DAI, moderate DAI, and severe  DAI (see Table 18-1 and Figure 18-1).   Mild concussion (mild traumatic brain injury) is charac-  terized by immediate but transitory clinical manifestations. CSF  pressure rises, and ECG and EEG changes occur without loss of  consciousness. The Glasgow Coma Scale score is 13 to 15.8 The  initial confusional state lasts from 1 to several minutes, possi-  bly with amnesia for events preceding the trauma (retrograde  amnesia). Anterograde amnesia also may exist transiently. Per-  sons may experience head pain and complain of nervousness  and “not being themselves” for up to a few days. Three grades  have been described:    Grade I: Transient confusion and disorientation accompa-  nied by amnesia (momentary); no loss of consciousness;  symptoms resolve within 15 minutes   Grade II: Transient confusion and retrograde amnesia that  develops after 5 to 10 minutes (memory loss involves only  events occurring several minutes before injury); symp-  toms last more than 15 minutes   Grade II: Any loss of consciousness (seconds or minutes);  confusion and retrograde and anterograde amnesia remain  present from impact and persist for several minutes   Classic cerebral concussion (Grade IV) is any loss of con-  sciousness (can last up to 6 hours) accompanied by retrograde  and anterograde amnesia. Transient cessation of respiration  can occur with brief periods of bradycardia, and a decrease in  blood pressure lasting 30 seconds or less occurs. Vital signs sta-  bilize within a few seconds to within normal limits. This is a  phenomenon of physiologic, neurologic dysfunction without  substantial anatomic disruption. A confusional state persists  for hours to days. The individual experiences head pain, nau-  sea, and fatigue. Attentional and memory system impairments  may persist for weeks to months and may include inability to  concentrate and forgetfulness. Mood and affect changes may  persist for weeks to months and may include nervousness,  anxiety reactions, depression, irritability, fatigability, and  insomnia. There are two forms of Grade IV classic cerebral  concussion: uncomplicated classic cerebral concussion (with-  out focal injury) and complicated classic cerebral concussion  (accompanied by focal injury [e.g., a cerebral contusion that  yields focal signs]).   Some of the effects of a concussion may persist for weeks or  months, depending on the severity of the injury. Approximately  15% to 30% of persons have a postconcussive syndrome that  includes headache, nervousness or anxiety, irritability, insom-  nia, depression, inability to concentrate, forgetfulness, and  fatigability.’ Treatment entails reassurance, symptomatic relief,  and close observation for 24 hours with follow-up care for per-  sistent symptoms.   DAI produces prolonged traumatic coma lasting more than  6 hours because of axonal disruption. Three forms of DAI exist:  mild, moderate, and severe. In mild diffuse axonal injury, post-  traumatic coma lasts 6 to 24 hours. Death is uncommon but  residual cognitive, psychologic, and sensorimotor deficits may  persist. Mild DAI is a relatively uncommon lesion, occurring  in 8% of all severe head injuries and 19% of all cases of DAI.  In mild DAI 30% of persons display decerebrate or decorticate  posturing (see Figure 17-6); they may experience prolonged  periods of stupor or restlessness.   In moderate diffuse axonal injury, widespread physiologic  impairment exists throughout the cerebral cortex and dien-  cephalon. Actual tearing of some axons in both hemispheres  occurs. Basal skull fracture, a focal injury, is commonly asso-  ciated with moderate DAI. Prolonged coma lasting more than  24 hours is present but prominent brainstem signs do not exist  with moderate DAI. Recovery often is incomplete in 93% of  those individuals who survive. Moderate DAI is the most com-  mon type of DAI and is found in 20% of severe head injuries  and 45% of all cases of DAI.    In moderate DAI, the GCS score is 4 to 8 initially and 6 to  8 by 24 hours following the injury. Thirty-five percent of vic-  tims have transitory decerebration or decortication. The person  often remains unconscious for days or weeks and on awaken-  ing is confused. He or she experiences a long period of post-  traumatic anterograde and retrograde amnesia and often has  permanent deficits in memory, selective attention, vigilance,  detection, working memory, data processing, vision or percep-  tion, and language, as well as mood and affect changes ranging  from mild to severe.   Severe diffuse axonal injury involves severe mechanical dis-  ruption of many axons in both cerebral hemispheres and those  extending to the diencephalon and brainstem. Severe DAI rep-  resents 16% of all severe head injuries and 36% of all cases of  DAI. With an initial GCS score of 3, the mortality is 78%;° with  an initial score between 3 and 8, the mortality is 36%; 16% of  persons have either a moderate or a severe disability and 5%  survive in a coma (unresponsive) state.°   Severe DAI is associated with brainstem signs that disap-  pear in a few weeks. The person experiences immediate auto-  nomic dysfunction that resolves in a few weeks. Increased ICP  appears 4 to 6 days after injury. Pulmonary complications occur  frequently, with profound sensorimotor and cognitive system  deficits. Severely compromised coordinated movements and  verbal and written communication, inability to learn and rea-  son, and inability to modulate behavior also are evident.   High-resolution CT scans and MRIs assist in the diagnosis  of focal and diffuse brain injuries.>'° The goal of treatment is to  maintain cerebral perfusion and oxygenation and promote neu-  roprotection. Implementation of traumatic brain injury guide-  lines decreases deaths and improves neurologic outcome.!!!?  Specifically, the evidence is inconclusive about the effectiveness  of hyperventilation and mild hypothermia. Hypertonic saline  or mannitol is used selectively to manage increased intracra-  nial pressure (IICP).!° Barbiturates have not been shown to  be effective in reducing intracranial pressure or preventing  adverse outcomes after TBI. The Corticosteroid Randomisa-  tion After Significant Head Injury (CRASH) trial showed cor-  ticosteroids increase mortality with acute TBI, so these drugs  are no longer used. Antiepileptic drugs may be recommended  to reduce the onset of early and late seizures. Prophylactic anti-  biotics have not been shown to reduce the risk of meningitis or  death with a skull fracture. Progesterone is under investigation  and may improve neurologic outcome.’ Extensive research is  underway to discover effective therapeutic interventions. Fluid  and nutrition management has emerged as critically important  in the care of individuals with severe brain injuries.'°   Secondary Brain Injury. Secondary neuronal injury occurs  when there is brain or spinal cord trauma and in stroke  syndromes. It occurs within hours to days of the primary injury.  Secondary brain injury is the result of both systemic and  intracranial processes and is an indirect result of primary brain  injury. Systemic hypotension, hypoxia, anemia, hypoglycemia,  hyperglycemia, and hypercapnia contribute to secondary  brain insults. Mechanisms of secondary injury include altered  cerebral blood flow, ischemia, inflammation, cerebral edema,  decreased cerebral perfusion pressure (CPP), IICP, and brain    herniation. Molecular alterations occur with stretching and  tearing of axonal membranes and ischemia (see Figure 18-1).  The complex pathophysiology of secondary brain injury  underlies the functional, cognitive, and behavioral changes  associated with brain injury and the motor and sensory losses  associated with spinal cord injury.   Cerebrovascular autoregulation (constriction or dilation  in response to increases or decreases in CPP) is impaired after  brain injury and may be transient or persistent with alterations  in CO, reactivity (i.e, CO, vasodilation). Vasospasm com-  monly occurs, contributing to brain hypoperfusion, and is  caused by chronic depolarization of vascular smooth muscle,  release of endothelin (vasoconstrictor), and decreased availabil-  ity of nitric oxide (vasodilator).   Widespread release of excitatory neurotransmitters (e.g.,  glutamate and aspartate) causes calcium and sodium influx  that is neurotoxic (excitotoxicity). Mitochondrial loading with  calcium leads to mitochondrial failure, anaerobic metabolism,  lactic acid production, and increased levels of reactive oxygen  species (ROS), phospholipases, and other enzymes. ROS and  phospholipase damage proteins and the phospholipid com-  ponents of cell and organelle membranes, causing cell swell-  ing, vacuolization, and, ultimately, necrotic or programmed  cell death (apoptosis). Energy metabolism is depressed with  alteration of gene expression. These events lead to failure of the  capillary blood-brain barrier and vasogenic edema. The influx  of sodium attracts water and results in intracellular cytotoxic  edema in neurons, astrocytes, and microglia irrespective of the  integrity of the vascular endothelial wall. Edema increases intra-  cranial pressure, contributing to tissue hypoxia and cerebral  ischemia.!°!7   Both primary and secondary injuries cause inflammation  (see Chapter 7), which occurs immediately and persists for  weeks. Inflammation is critical for wound healing; immune cells,  including neutrophils, macrophages, and T-cell lymphocytes,  need to infiltrate injured tissue and clear debris, thus promoting  formation of scar tissue. However, an overactive response leads  to occlusion of the microvasculature with leukocytes and plate-  lets. The release of inflammatory cytokines (e.g., tumor necrosis  factor-alpha [TNF-a], interleukins, and interferons), prote-  ases, free radicals, prostaglandins, and complement alters the  blood-brain barrier and causes vasoconstriction, brain edema,  increased intracranial pressure, reduced cerebral perfusion, and  ischemia, aggravating secondary brain injury.!”"!®   Intracranial hemorrhage, whether traumatic or related to  a stroke syndrome, may contribute to secondary brain injury.  The bleeding is often accompanied by increased ICP, ischemia,  oxidative damage, and vasogenic and cytotoxic edema as pre-  viously described. In addition, the vascular injury can cause  activation of platelets, which contribute to vasoconstriction in  large arteries and vasodilation in small arteries. Activated plate-  lets also trigger the release of free radicals from granulocytes,  enhancing oxidative stress. Vascular injury causes coagulation  disorders from release of increased amounts of tissue factor  from endothelial cells, which initiates the coagulation cascade  and overwhelms the normal factors that control coagulation.  Free heme and free iron are released from red blood cells and    There currently are no pharmacologic agents approved for the treatment of  TBI. Animal studies and phase II clinical trials, using intravenous progesterone  for treatment of moderate to severe brain trauma, have shown preliminary  benefits for improved outcome and decreased mortality. Progesterone is lipid  soluble; readily crosses the blood-brain barrier; is safe for administration  in both men and women; is inexpensive; and is known for its multiple anti-  inflammatory, anti-apoptotic, trophic growth-promoting, and neuropro  tive properties. Unlike other steroid hormones, progesterone is synthesi  directly in the brain by oligodendrocytes and in excitatory neurons, so it can be  considered a “neurosteroid” beyond its role as a sex hormone. A phase III clini-  cal trial is now evaluating progesterone for moderate-to-severe TBI in 1140  individuals with final results to be reported in 2015. Additionally, the SyNA\  trial is evaluating intravenous progesterone in 1200 individuals with severe  closed-head trauma in 100 to 120 medical centers throughout the world. These  long-term, multicenter studies will contribute evidence to confirm the safety,  efficacy, and generalizability of using progesterone for treatment of TBI.    Data from BHR Pharma, LLC: SyNAPSe: the global Phase 3 study of  progesterone in severe traumatic brain injury, © 2012, BHR Pharma,  LLC, a Besins Healthcare Co. Available at www.synapse-trial.com/;  Feeser VR, Loria RM: J Neuroimmunol 237(1-2):4-12, 2011; National  Institutes of Health: Clinical trials Gov: progesterone for the treatment  of traumatic brain injury (ProTECT I/l). Available at http://clinicaltrials.  gov/ct2/show/record/NCT00822900; Stein DG: Neuroscience 191:  101-106, 2011.    both cause the induction of free radicals, lipid peroxidation,  and nerve damage.!”   The management of secondary brain trauma is related to pre-  vention and includes removal of hematomas and management  of hypotension, hypoxemia, anemia, intracranial pressure, body  temperature, ventilation, fluid replacement, and nutrition.  Research is in progress to find specific pharmacologic interven-  tions and neuroprotective agents that limit the progression of  secondary injury and to identify biomarkers to guide preven-  tion, prognosis, and treatment”?! (see What’s New? Progester-  one for Treatment of Traumatic Brain Injury [TBI]).   Genetics of Head Injury. Certain genes are up-regulated  and others are down-regulated after head trauma. The  attention of researchers has been focused predominantly on  the apolipoprotein E (apoE) gene and its various alleles. Certain  alleles have been correlated with increased susceptibility to and  severity of head injury. Other alleles have been associated with  improved or diminished recovery after head injury. The clinical  significance of these findings is not clearly known.?*”*    The number of spinal cord injuries (SCIs) in the United States  is approximately 273,000, with 12,000 new cases annually; of  these, 80.7% are males, mostly young adults. The average age  is 40.7 years. Since 2010 the causes include vehicular (36.5%),  falls (28%), violence (14%), and sports (9%). The extent of  injury has been 41% incomplete quadriplegia, 16% complete  quadriplegia, 18.7% incomplete paraplegia, and 18% complete  paraplegia.”*    FIGURE 18-9 Hyperextension Injuries of the Spine. Hyperextension can  result in fracture or nonfracture injuries with spinal cord damage.    FIGURE 18-10 Hyperflexion Injury of the Spine. Hyperflexion produces  translation (subluxation) of vertebrae, which compromises the central canal and  compresses spinal cord parenchyma or vascular structures.    PATHOPHYSIOLOGY. Primary spinal cord injury occurs with  the initial mechanical trauma and immediate tissue destruc-  tion. Vertebral fractures or dislocations can cause bone frag-  ments or connective tissues to compress and damage nerve  fibers. Vertebral injuries result from acceleration, deceleration,  or deformation forces at impact. These forces cause compres-  sion, traction, or shearing of tissues. The bones, ligaments,  joints, and neural tissue of the vertebral column may be dam-  aged by hyperextension, hyperflexion, vertical compression, or  rotation (Figures 18-9 through 18-12). Vertebral fracture and  often compression of one or more elements, dislocation of its  elements, or both fracture and dislocation can occur (see Fig-  ure 15-17 for the structure of the vertebral column). Vertebral  injuries can be classified as (1) simple fracture, a single break  usually affecting transverse or spinous processes; (2) com-  pressed (wedged) vertebral fracture, in which a vertebral body    FIGURE 18-11 Axial Compression Injuries of the Spine. In axial compres-  sion the spinal cord is contused directly by retropulsion of bone or disk material  into the spinal canal.    is compressed anteriorly; (3) comminuted (burst) fracture, in  which a vertebral body is shattered into several fragments; and  (4) dislocation.   Vertebrae fracture readily with direct and indirect trauma.  When the supporting ligaments are torn, the vertebrae move  out of alignment, and dislocations occur. A horizontal force  moves the vertebrae straight forward; if the individual is in  a flexed position at the time of injury, the vertebrae are then  in an angulated position. Flexion and extension injuries may  result in dislocations. (Mechanisms of vertebral injury are pre-  sented in Table 18-2.) Vertebral injuries occur mostly at ver-  tebrae C1-C2 (cervical), C4-C7, and T1-L2 (thoracic-lumbar)  (see Figure 15-17). These are the most mobile portions of the  vertebral column. The cord occupies most of the vertebral canal  in the cervical and lumbar regions. The size makes the cord in  these areas more easily injured. The primary spinal cord injuries  are summarized in Table 18-3. Noncontiguous vertebral inju-  ries are common. Further, primary injury occurs if an injured    Fracture and dislocation of posterior elements such  as spinous processes, transverse processes,  laminae, pedicles, or posterior ligaments   Bruising of the neural tissue causing swelling and  temporary loss of cord-mediated functions   Pressure on the cord causing ischemia to tissues;  must be relieved (decompressed) to prevent  permanent damage to the spinal cord   Tearing of the neural tissues of the spinal cord;  may be reversible if only slight damage is  sustained by the neural tissues; may result in  permanent loss of cord-mediated functions if  spinal tracts are disrupted   All tracts in the spinal cord are completely  disrupted; all cord-mediated functions below the  transection are completely and permanently lost   Some tracts in the spinal cord remain intact,  together with functions mediated by these  tracts; has the potential for recovery although  function is temporarily lost   Preserved motor function without useful purpose;  sensory function may or may not be preserved   Bleeding into the neural tissue because of  blood vessel damage; usually no major loss of  function    spine is not adequately immobilized. Primary spinal cord injury  may occur in the absence of vertebral fracture or dislocation  from longitudinal stretching of the cord with or without flexion  and/or extension of the vertebral column. The stretching causes  altered axon transport, edema, myelin degeneration, and retro-  grade or wallerian degeneration.    Results from forces of acceleration-deceleration  and the sudden reduction in the anteroposterior  diameter of the spinal cord   Results from sudden and excessive force that propels  the neck forward or causes an exaggerated lateral  movement of the neck to one side   Results from a force applied along an axis from the top of  the cranium through the vertebral bodies    Secondary spinal cord injury is a pathophysiologic cascade  of vascular, cellular, and biochemical events that begins within  a few minutes after injury and continues for weeks. The edema,  ischemia, excitotoxicity, inflammation, oxidative damage, and  activation of necrotic and apoptotic cell death signaling events  are similar to those previously described for secondary brain  injury.?° By 5 minutes after injury, venules of the gray matter are  congested and distended by erythrocytes. In 15 to 30 minutes,  small hemorrhages occur with extravasation of erythrocytes  into perivascular spaces of postcapillary and muscular venules.  Microscopic hemorrhages appear in the central gray matter and  pia arachnoid that increase in size within 2 hours. Edema in the  white matter impairs the microcirculation of the cord. Within  4 hours, numerous swollen axis cylinders develop. Localized  hemorrhaging and edema are followed by loss of autoregula-  tion, vasospasm, impaired venous drainage, and reduced vascu-  lar perfusion with development of ischemic areas. There is myelin  disruption, axonal degeneration, and necrosis. The microscopic  hemorrhages and edema are maximal at the level of injury and  for two cord segments above and below it. Impaired perfusion  is aggravated by systemic responses including neurogenic or  hemorrhagic shock, and arrhythmias.*°   Cord swelling increases an individual’s degree of dysfunc-  tion; therefore distinguishing the functions to be lost perma-  nently from those that are impaired just temporarily becomes  difficult. In the cervical region, cord swelling may be life threat-  ening because of the possibility of resulting impairment of  diaphragm function (phrenic nerves exit C3-C5) and vegeta-  tive functions mediated by the medulla oblongata. Within the  first few days of injury, progressive axonal changes occur and  necrotic zones develop. Progressive cavitation and coagulation  necrosis at the site of injury are termed posttraumatic infarction.   Circulation in the white matter tracts of the spinal cord  returns to normal in about 24 hours, but gray matter circula-  tion remains altered. Phagocytes appear 36 to 48 hours after  injury. Proliferation of microglia and changes in astrocytes  occur. Red cells then begin to disintegrate, and resorption of  hemorrhages begins. Degenerating axons are engulfed by mac-  rophages in the first 10 days after injury. A cyst with fluid forms.  The traumatized cord is replaced by acellular collagenous tissue  (a scar), usually in 3 to 4 weeks. Meninges thicken as part of the  scarring process.    CLINICAL MANIFESTATIONS. Immediately after cord injury, nor-  mal activity of spinal cord cells at and below the level of injury  ceases because of loss of the continuous tonic discharge from the  brain or brainstem and inhibition of suprasegmental impulses,  thus causing spinal shock. Spinal shock is characterized by  a complete loss of reflex function, flaccid paralysis, sensory  deficit, and loss of bladder and rectal control in all segments  below the level of the lesion. Disruption of central communica-  tion with sympathetic spinal nerves causes a transient drop in  blood pressure, poor venous circulation, and disturbed thermal  regulation. This damage causes faulty control of diaphoresis  (sweating) and heat radiation through capillary dilation. The  hypothalamus cannot regulate body heat through vasocon-  striction and increased metabolism; therefore, the individual’s  body temperature assumes the temperature of the air. Spinal  shock may persist for as short a time as a few days or as long as  3 months. Indications that spinal shock is terminating include  the reappearance of reflex activity, hyperreflexia, spasticity, and  reflex emptying of the bladder.    Neurogenic shock occurs with cervical or upper thoracic cord  injury and may be seen in addition to spinal shock. Neurogenic  shock is caused by the absence of sympathetic activity through  loss of supraspinal control and unopposed parasympathetic  tone mediated by the intact vagus nerve. Symptoms include  vasodilation, hypotension, bradycardia, and hypothermia.   Continued loss of motor and sensory function depends on  the extent and level of injury. All motor, sensory, reflex, and  autonomic functions cease below any transected area and may  cease below concussive, contused, compressed, or ischemic  areas (Table 18-4). Paralysis of the lower half of the body with  both legs involved is termed paraplegia. Paralysis involving all  four extremities is termed quadriplegia (tetraplegia). In com-  plete quadriplegia the level of injury is above C6, and all upper  extremity function is lost. In incomplete quadriplegia, function  at or above C6 is preserved, leaving the shoulder, upper arm,  and some forearm muscle control intact. With acceleration  injuries the greatest stress point is C4-C5. With a deceleration  force the greatest stress point is at C5-C6.    Loss of pain, temperature, touch, pressure, and proprioception below level of injury  Pain at site of injury caused by a zone of hyperesthesia above the injury    Loss of vasomotor tone in lower body parts; low and unstable blood pressure    Loss or extreme depression of genital reflexes such as penile erection and bulbocavernous reflex  Dry and pale skin, possible ulceration over bony prominences   Bowel and bladder impairment less severe than that seen with complete cord transection   Preservation of ability to perspire in some portions of the body below level of injury   Brown-Séquard syndrome (associated with penetrating injuries, hyperextension and flexion, locked facets, and compression fractures)  1. Ipsilateral paralysis or paresis below level of injury  2. Ipsilateral loss of touch, pressure, vibration, and position senses below level of injury  3. Contralateral loss of pain and temperature sensations below level of injury   Central cervical cord syndrome (acute cord compression between bony bars or spurs anteriorly and thickened ligamentum flavum    |. Motor deficits in upper extremities, especially hands; more dense than in lower extremities    Burning hand syndrome (variant of central cord syndrome; half of cases have an underlying spine fracture/dislocation present)  1. Severe burning paresthesias and dysesthesias in the hands and/or feet  Anterior cord syndrome (compromise of anterior spinal artery by occlusion or pressure effect of disk)    2. Loss of pain and temperature sensations below level of injury  3. Touch, pressure, position, and vibration senses intact    Posterior cord syndrome (associated with hyperextension injuries with fractures of vertebral arch)    Conus medullaris syndrome (compression injury at 112 from disk herniation or burst fracture of body of 112)    1. Flaccid paralysis of legs  2. Flaccid paralysis of anal sphincter  3. Variable sensory deficits    Cauda equina syndrome (compression of nerve roots below L1 caused by fracture and dislocation of spine or large    1. Lower extremity motor deficits  2. Variable sensorimotor dysfunction  3. Variable reflex dysfunction   Syndrome of neuropraxia (seen as post—athletic injury, associated with congenital spinal stenosis)  1. Dramatic but transient neurologic deficits including quadriplegia   Horner syndrome (injury to preganglionic sympathetic trunk or postganglionic sympathetic neurons of superior cervical ganglion)  1. Ipsilateral pupil smaller than contralateral pupil    Emergence of Babinski reflexes, possibly progressing to a triple reflex; possible development of still later flexor spasms  Reappearance of ankle and knee reflexes, which become hyperactive  Contraction of reflex detrusor muscle, leading to urinary incontinence    Mass reflex with flexion spasms, profuse sweating, piloerection, and bladder and occasional bowel emptying may be evoked by  an autonomic stimulation of skin or from a full bladder    Eventual development of extensor reflexes, first in muscles of hip and thigh, later in leg  Possible paresthesias below level of transaction: dull, burning pain in lower back, abdomen, buttocks, and perineum    Return of spinal neuron excitability occurs slowly. Depend-  ing on the degree of damage, either of the following can occur:  (1) motor, sensory, reflex, and autonomic functions return to  normal; or (2) autonomic neural activity in the isolated segment  develops. The sequence of hyperactivity phases, which vary  in length, may include: (1) minimal reflex activity, (2) flexor  spasms, (3) alternation between flexor and extensor spasms,  and (4) predominant extensor spasms.   The initial clinical manifestations associated with acute spi-  nal cord injury are: (1) rapid loss of voluntary movements in  body parts below the level of injury, (2) sensations in the lower  extremities and possibly lower trunk (depending on the level of  injury), and (3) spinal and autonomic reflexes below the level of  injury. The duration of this areflexic state is highly variable. In  most persons, reflex activity returns in 1 to 2 weeks.   Gradually reflexes return and become increasingly easier to  elicit. A pattern of flexion reflexes emerges first, involving the  toes and later the feet and legs. Reflex voiding and bowel elimi-  nation appear. Flexor spasms accompanied by profuse sweating,  piloerection, and automatic bladder emptying (together called a  mass reflex) may develop. The ability to sweat when overheated  may be disrupted, and extensor spasms may develop, usually  after full development of flexor spasms. Sometimes after several  months, episodes of autonomic hyperreflexia occur.    Autonomic hyperreflexia (dysreflexia) is a syndrome of  sudden, massive reflex sympathetic discharge associated with  spinal cord injury at level T5-T6 or above. Supraspinal con-  trol of the sympathetic nervous system is disrupted, causing an  imbalance between the sympathetic and the parasympathetic  nervous systems. The pathophysiology of hyperreflexia involves  the stimulation of sensory receptors below the level of the cord  lesion. The sensory input ascends the spinal cord and activates  the thoracolumbar sympathetic nerves. The intact sympathetic  nervous system reflexively responds with vasoconstriction of  the muscular, splanchnic, and cutaneous vascular beds. The  paroxysmal increase in blood pressure causes baroreceptors in  the cerebral vessels, the carotid sinus, and the aorta to stimu-  late parasympathetic vasodilation above the level of the cord  lesion. The heart rate decreases but not enough to overcome the  hypertension. The visceral and peripheral vessels do not dilate  because efferent impulses cannot pass through the injured cord  (Figure 18-13).   Autonomic hyperreflexia is characterized by debilitating  symptoms: paroxysmal hypertension (up to 300 mmHg sys-  tolic), bradycardia (30 to 40 beats/minute), a pounding head-  ache, blurred vision, sweating above the level of the lesion with  flushing of the skin, nasal congestion, nausea, and piloerection  caused by pilomotor spasm. The symptoms may develop singly    or in combination (syndrome) and often are associated with  somatic (distended bladder or rectum) or sensory stimulation.  The condition is life threatening and requires immediate treat-  ment because cerebrovascular accident (CVA) is possible. The  head of the bed should be elevated and the stimulus should be  determined and removed. Emptying of the bladder or bowel  usually relieves the syndrome. Medical treatment may include  topical nitroglycerin paste above the level of the lesion, calcium  channel blockers (e.g. nefedipine), or a-adrenergic recep-  tor blocking agents.*” Prevention of autonomic hyperreflexia  with bowel and bladder management programs is an effective  approach.   EVALUATION AND TREATMENT. Diagnosis of spinal cord injury is  made on the basis of physical examination and imaging (e.g.,  MRI). For a suspected or confirmed vertebral fracture or dis-  location, regardless of the presence or absence of spinal cord  injury, the immediate intervention is immobilization of the  spine to prevent further injury. Decompression and surgical  fixation may be necessary and performed early. Corticosteroids  may be given at the time of injury to decrease secondary cord  injury and continued for 24 to 48 hours, depending on time of  initiation following injury. Therapeutic hypothermia has shown    some encouraging evidence for improved outcomes, particu-  larly for cervical cord injuries, but more research is needed.”®  Several clinical trials are in progress that address treatment of  acute spinal cord injury, including cell-based therapies, immune  modulators, vasculature selective treatments, and functional  electrical stimulation.’ Nutrition, lung function, skin integrity,  and bladder and bowel management must be addressed. Plans  for rehabilitation require early consideration. Impairments are  permanent because endogenous repair events fail to restore the  damaged axonal circuits.*?*!   Degenerative disk disease (DDD) is a common finding in  individuals 30 years of age and older. It is, in part, a process of  normal aging and includes a genetic component and environ-  mental interactions that may increase susceptibility to lumbar  disk disease by disrupting normal building and maintenance  of cartilage.°* Causes include biochemical (e.g., inflammatory  mediators) and biomechanical alterations (e.g., mechanical  loading and compression) of the intervertebral disk tissue.  Diminished blood supply and loss of disk proteoglycans cause    center of medulla, vagus nerve  stimulated; impulse sent to SA node;  results in bradycardia    subsequent disk dehydration and alterations in disk structure  and function. Splits in the annulus fibrosis can permit her-  niation of the nucleus pulposus, compressing nerves or plac-  ing strain on the spine. Fibrocartilage replaces the gelatinous  mucoid material of the nucleus pulposus as the disk changes  with age. There may be shrinkage of the nucleus pulposus that  produces prolapse or folding of the annulus with secondary  osteophyte formation at the margins of the adjacent vertebral  body. The pathologic findings in DDD include disk protrusion,  spondylolysis or subluxation (or both), degeneration of verte-  brae (spondylolisthesis), and spinal stenosis.°*    Symptoms result from either (1) protrusion of the disk or  annulus or (2) narrowing of the spinal canal or intervertebral fora-  men by osteophytes. A congenital narrow canal or congenitally  short pedicles may be present. Posterior disk protrusion in the  cervical, thoracic, and lumbar regions leads to spinal cord com-  pression causing myelopathy (pathology in the spinal cord). Pos-  terolateral disk protrusions, with or without a contribution from  the vertebral body or apophyseal joint osteophytes, lead to nerve  root compression causing radiculopathy (nerve root damage).   Thoracic disk disease is rarely symptomatic. Lumbosacral  disk disease (lumbar spondylosis) involves degeneration of the    FIGURE 18-14 Motor, Sensory, and Reflex Changes in Lumbosacral Root  Disorders. (From Perkin DG et al: Atlas of clinical neurology, ed 3, Philadelphia,  2011, Saunders.)    lower two lumbar disks in 90% of persons. There may be (1) lat-  eral disk protrusion (10% of cases), manifesting as pain referred  to the anterior thigh and leg; (2) posterolateral disk protrusion;  or (3) central disk protrusion, manifesting with pain, lower  extremity weakness, impaired sphincter function, and saddle  anesthesia. Clinical manifestations of posterolateral protrusions  (Figure 18-14) include pain in the back, the sacroiliac joint, and  the medial aspect of the buttock and upper thigh; radicular pain  exacerbated by movement and straining (medial calf suggests  L5, lateral calf suggests S1 root compression); sensory symp-  toms that are common and segmental in distribution; focal  tenderness on palpation of the back; limited range of motion  in the back and scoliosis secondary to paravertebral spasms;  restricted straight-leg raising (root at or below L5); positive  femoral stretch test (roots of L2, L3, or L4); and focal signs that  are determined by the root affected.   Spondylolysis. Spondylolysis is a degenerative process  of the vertebral column and associated soft tissue. It is  characterized by a structural defect of the spine involving the  lamina or neural arch of the vertebra. The most common site  affected is the lumbar spine. This defect occurs in the portion  of the lamina between the superior and inferior articular  facets called the pars interarticularis. Mechanical pressure may  cause a forward displacement of the deficient vertebra called  spondylolisthesis.    Heredity plays a significant role, and spondylolysis is asso-  ciated with an increased incidence of other congenital spinal  defects. As a result of torsional and rotational stress, “micro-  fractures” occur at the affected site and eventually cause dis-  solution of the pars interarticularis.   Spondylolisthesis. Spondylolisthesis is an osseous defect of  the pars interarticularis allowing a vertebra to slide forward in  relation to the vertebra below, commonly occurring at L5-S1.  It is more prevalent in adolescent athletes.** Spondylolisthesis  is graded from 1 to 4 on the basis of the percentage of slip that  has occurred. Individuals with grade 3 or 4 are considered for  operative decompression or stabilization, or both. Grades 1 and  2 usually are managed symptomatically and with nonsurgical  methods.   Cervical spondylolysis is facet hypertrophy and disk degen-  eration with narrowing in the cervical spine predominantly at  C5-C6 and C6-C7.*> It may present as a cervical radiculopa-  thy or a cervical myelopathy. Clinical manifestations of cervical  radiculopathy include neck or occipital pain as well as pain in  the medial aspects of the scapula, the shoulder, or arm. Sen-  sory symptoms, such as tingling or numbness, follow a derma-  tomal pattern; weakness follows the pattern of innervation of  the affected nerve root. Occipital or suboccipital headache is  another symptom. Clinical manifestations of cervical myelopa-  thy include difficulty walking, altered sensation in the feet, and  sphincter disturbances (occurs late).   Spinal Stenosis. In spinal stenosis the spinal canal may be  congenitally narrowed or narrowed by a bulging annulus, a facet  hypertrophy, or a thick/ossified posterior longitudinal ligament  entrapping a single nerve involving many roots. It is classified as  acquired (more common) or developmental (such as occurs in  achondroplastic dwarfism). It is categorized by area of the spine  affected: cervical, thoracic, or lumbar. Surgical decompression  is recommended for those with long-term symptoms and those  who remain unresponsive to medical management.    The annual incidence of, or percentage of population affected  with, low back pain ranges from 6.3% to 15.4%. Men and  women are affected equally; however, women report low back  symptoms more often after the age of 60 years. About 1% to  2% of individuals with acute low back pain are disabled.*° Sev-  eral risk factors have been identified in the pathogenesis of low  back pain. They include involvement caused by occupations  that require repetitious lifting in the forward bent-and-twisted  position, exposure to vibrations caused by vehicles or industrial  machinery, psychosocial workplace factors, and obesity. Osteo-  porosis increases the risk of spinal compression fractures and  may be the reason older adult women report more symptoms  than men. Genetic predispositions for low back pain include  isthmic spondylolisthesis (vertebra slides forward or slips in  relation to a vertebra below), spinal osteochondrosis, and spinal  stenosis associated with achondroplasia.°*”   PATHOGENESIS. Most cases of low back pain are idiopathic or  nonspecific, and clinicians are unable to provide a precise diag-  nosis for most individuals with this disorder.** Local processes  may be involved in low back pain, including tension caused by    tumors or disk prolapse, bursitis, synovitis, rising venous and  tissue pressures (found in degenerative joint disease), abnormal  bone pressures, problems with spinal mobility, inflammation  caused by infection (as in osteomyelitis), bony fractures, liga-  mentous sprains, and inflammation of the lumbar facet joints.  Pain can be referred from viscera or the posterior peritoneum.  Other causes of low back pain include bone diseases, such as  osteoporosis or osteomalacia, and hyperparathyroidism.*?   Anatomically, low back pain must come from innervated  structures, but deep pain is widely referred and varies from per-  son to person. The nucleus pulposus has no intrinsic innerva-  tion; however, when extruded or herniated through a prolapsed  disk, it irritates the dural membranes and is responsible for pain  referred to the associated segmental area (see Figure 18-14). The  interspinous bursae can be a source of low back pain between  L3, L4, L5, and S1, but also may affect L1, L2, and L3 spinous  processes, depending on the closeness of the adjacent pair of  spines. The anterior and posterior longitudinal ligaments of  the spine and the interspinous and supraspinous ligaments  are abundantly supplied with pain receptors, as is the ligamen-  tum flavum. All of these ligaments are vulnerable to traumatic  tears (sprains) and fracture. The role of muscle injury in the  production of low back pain remains uncertain, even though  sprains and strains are the most common diagnoses. The mus-  cle spasms that often are produced during sieges of low back  pain are thought to be produced by as yet unknown sensory  or motor-reflex pathways. The most commonly encountered  causes of low back pain include lumbar disk herniation, degen-  erative disk disease, spondylolysis, spondylolisthesis, and spi-  nal stenosis. (For a discussion of disk herniation and rupture,  see following text.) Chronic low back pain can cause central  sensitization (see Chapter 16) and abnormal endogenous pain  modulation.   CLINICAL MANIFESTATIONS. Low back pain affects the area  between the lower rib cage and gluteal muscles and often radi-  ates into the thighs. About 1% of individuals with acute low  back pain have sciatica or pain in the distribution of the sciatic  nerve or lumbar and sacral nerve roots. Sciatica often is accom-  panied by neurosensory and motor deficits, such as weakness.  Major or progressive motor or sensory deficit, cauda equina  syndrome (new-onset bowel or bladder incontinence or urinary  retention, loss of anal sphincter tone, saddle anesthesia), history  of cancer metastatic to bone, and suspected spinal infection can  be associated with chronic low back pain.   EVALUATION AND TREATMENT. Diagnosis of low back pain is  made by personal history; physical examination; electromyog-  raphy (EMG), epidurography, diskography, and imaging (MRI  and CT) for specific clinical conditions; and nerve conduction  studies. Most individuals with acute low back pain benefit froma  nonspecific short-term treatment regimen including nonsteroi-  dal anti-inflammatory medications, exercises, physical therapy,  and education. Individuals with chronic low back pain (pain  for more than 3 months) can be treated with anti-inflammatory  and muscle relaxant medications, exercise programs, massage,  topical heat, spinal manipulation, cognitive-behavioral therapy,  and interdisciplinary care.*’ Surgical treatments for identified  pathologic conditions include diskectomy and spinal fusions.    FIGURE 18-15 Disk Bulge, Protrusion, and Herniation. Sagittal T2-weighted  image demonstrates examples for all stages of disk pathology. Viewing from rostral  to caudal, a disk bulge (arrow), a small and more prominent protrusion (arrowheads),  and a herniation (double arrowhead) are seen. (From Daroff RB et al: Brad/ey’s neu-  rology in clinical practice, Philadelphia, 2012, Saunders.)    Radiotherapy is used for treatment of facet-related pain after  diagnostic nerve block. Evaluation of treatment outcomes  should include pain, function, and quality of life.*°    Herniation of an intervertebral disk is a displacement of the  disk material (nucleus pulposus or annulus fibrosis) beyond  the intervertebral disk space (Figure 18-15). Men are more  affected than women, with the highest incidence in the 30- to  50-year age group. The lumbosacral disks (L4-L5, L5-S1) are  most commonly affected. Disk herniation occasionally occurs  in the cervical area, usually at C5-C6 and C6-C7. Herniations at  the thoracic level are extremely rare. Risk factors for herniation  include weightlifting sports and certain work activities, such  as repeated lifting. Rupture of an intervertebral disk usually  is caused by trauma or degenerative disk disease, or both. The  injury may occur immediately, within a few hours, or months  to years after injury.   PATHOPHYSIOLOGY. In a herniated disk the ligament and pos-  terior capsule of the disk usually are torn, allowing the gelati-  nous material (the nucleus pulposus) to extrude. This extrusion  compresses the nerve root, compromising the vascular supply  and causing inflammatory-like changes. Occasionally the injury  tears the entire disk loose, and it protrudes onto the nerve root  or compresses the spinal cord. One or more nerve roots may  be compressed. This multiple nerve root compression is found  especially at the L5-S1 level, where the cauda equina may be  compressed. Large amounts of extruded nucleus pulposus  or complete disk herniation (i.e., of both the capsule and the  nucleus pulposus) may compress the spinal cord.    CLINICAL MANIFESTATIONS. The location and size of the hernia-  tion into the spinal canal, together with the amount of space  that exists inside the spinal canal, determine the clinical mani-  festations associated with the injury. A herniated disk in the  lumbosacral area is associated with pain that radiates along the  sciatic nerve course over the buttock and into the calf or ankle.  The pain occurs with straining, including coughing and sneez-  ing, and usually on straight-leg raising. Other clinical manifes-  tations include limited range of motion of the lumbar spine;  tenderness on palpation in the sciatic notch and along the sci-  atic nerve; impaired pain, temperature, and touch sensation in  the L5-S1 or L4-L5 dermatomes of the leg and foot; decreased  or absent ankle jerk reflex; and mild weakness of the foot.   With the herniation of a lower cervical disk, paresthesias and  pain are present in the upper arm, forearm, and hand in the  affected nerve root distribution. Neck and nerve root pain may  be increased by neck motion and straining, including cough-  ing and sneezing. Neck range of motion is diminished. Slight  weakness and atrophy of biceps or triceps may occur; the biceps  or triceps reflex may decrease. Occasionally signs of corticospi-  nal and sensory tract impairments appear. These include motor  weakness of the lower extremities, sensory disturbances in the  lower extremities, and presence of a Babinski reflex.   EVALUATION AND TREATMENT. Diagnosis of a herniated inter-  vertebral disk is made on the basis of the history and physical  examination, EMG results, imaging procedures when there are  signs of systemic disease, and nerve conduction studies. Radio-  logic evidence of disk herniation does not reliably correlate with  symptoms or predict low back pain. Many individuals with disk  herniation on imaging have no symptoms.*! Clinical improve-  ment occurs in most people over weeks to months. The herni-  ated disk portion on serial imaging tends to regress over time.*”  There is little evidence to support drug treatments, including  the use of analgesics, antidepressants, or muscle relaxants.*°  Randomized controlled trials are needed to evaluate conser-  vative therapy (e.g., nonsteroidal anti-inflammatory drugs  [NSAIDs], bed rest, epidural injections of nonsteroidals, activ-  ity, acupuncture, massage, exercise, heat, or ice).*4*° A surgical  approach is indicated if there is evidence of progressive neu-  rologic deficit (e.g., weakness, decreased deep tendon reflexes,  and bladder/bowel reflexes) or cauda equina syndrome (saddle  anesthesia, decreased or absent reflexes in the lower extremities,  and neurogenic bowel or bladder dysfunction).*°    Cerebrovascular disease is the most frequently occurring neu-  rologic disorder. More than 50% of persons admitted to gen-  eral hospitals with neurologic problems have cerebrovascular  disease. Any abnormality of the brain caused by a pathologic  process in the blood vessels is referred to as a cerebrovascular  disease. Included in this category are lesions of the vessel wall  (e.g., aneurysm or malformations) and strokes or cerebrovas-  cular accidents.    The incidence of new and recurrent stroke is 795,000, and  approximately 185,000 of these are recurrent. Strokes are the    third leading cause of death in the United States, resulting in  about 134,148 deaths. The incidence of stroke is about two  times higher in blacks than whites. Stroke tends to run in fami-  lies. Of all strokes, 87% are ischemic (thrombotic or embolic),  10% are intracerebral hemorrhagic, and 3% are subarachnoid  hemorrhagic.*” No identifiable cause can be established by con-  ventional diagnostic tests in many ischemic strokes and they are  classified as “undetermined” or “cryptogenic.” Strokes in chil-  dren are presented in Chapter 20.   The mildest outcome of a cerebrovascular accident (CVA)  is so minimal as to be almost unnoticed. The most severe  outcomes are hemiplegia, coma, and death. Strokes are clas-  sified according to pathophysiology: ischemic (thrombotic or  embolic) is the most common, global hypoperfusion (as in  shock), or intracerebral hemorrhage.*” Hypertension is the  single greatest risk factor for stroke.** Risk factors for stroke  include the following’:   4. High total cholesterol or low high-density lipoprotein  (HDL) cholesterol level, elevated lipoprotein-A level   PATHOPHYSIOLOGY. Thrombotic strokes (cerebral thrombo-  sis) arise from arterial occlusions caused by thrombi formed in  the arteries supplying the brain or in the intracranial vessels.  The development of a cerebral thrombosis most frequently is  attributed to atherosclerosis and inflammatory disease pro-  cesses (arteritis) that damage arterial walls. Increased coagu-  lation can lead to thrombus formation. Conditions causing  inadequate cerebral perfusion (e.g., dehydration, hypotension,  prolonged vasoconstriction from malignant hypertension)  increase the risk of thrombosis. Over 20 to 30 years, atheroma-  tous plaques (stenotic lesions) tend to form at branchings and  curves in the cerebral circulation. The smooth stenotic area can  degenerate, forming an ulcerated area of vessel wall. Platelets  and fibrin adhere to the damaged wall, and clots form, gradually  occluding the artery. The thrombus may enlarge both distally  and proximally in the vessel. Portions of the clot detach and  travel up the vessel to distant sites where occlusion occurs, pro-  ducing a stroke syndrome.    Transient ischemic attacks (TIAs) are transient episodes  of neurologic dysfunction (weakness, numbness, sudden con-  fusion, loss of balance, loss of vision, sudden severe headache)  resulting from focal cerebral ischemia. However, use of brain  imaging techniques (e.g., diffusion-weighted imaging) in per-  sons with symptoms lasting less than 24 hours often reveals a  brain infarction that requires treatment intervention to pre-  vent stroke. About 30% of individuals experiencing a TIA will  have a stroke within 1 year. Risk stratification for early stroke is  enhanced when imaging is combined with a risk stratification  score (e.g., the ABCD2 score, which considers age, neurologic  symptoms, symptom duration, and diabetes).°!   Embolic stroke involves fragments that break from a throm-  bus formed outside the brain or in the heart, aorta, or com-  mon carotid artery. Other sources of embolism include fat,  air, tumor, bacterial clumps, and foreign bodies. The embolus  usually involves small vessels and obstructs at a bifurcation or  other point of stenosis, thus causing ischemia. An embolus may  obstruct the lumen entirely and remain in place or shatter into  fragments and become part of the vessel’s blood flow. Risk fac-  tors for an embolic stroke are atrial fibrillation (15% to 25%  of strokes), left ventricular aneurysm or thrombus, left atrial  thrombus, recent myocardial infarction, rheumatic valvular  disease, mechanical prosthetic valve, nonbacterial thrombotic  endocarditis, bacterial endocarditis, patent foramen ovale, and  primary intracardiac tumors.*” In persons who experience an  embolic stroke, a second stroke usually follows at some point  because the source of emboli continues to exist. Embolization  is usually in the distribution of the middle cerebral artery (the  largest cerebral artery).   Cerebral Infarction. Cerebral infarction results when an area  of the brain loses blood supply and becomes ischemic because  of vascular occlusion (embolic or thrombotic). The pathologic  manifestation is either (1) a global process that affects neurons  most susceptible to ischemia (pyramidal and striatal neurons),  Purkinje cells of the cerebral hemispheres, and the border zones  at the very end of the circulation of the artery; or (2) a focal pro-  cess with a central zone of infarction surrounded by a zone of  reversible ischemia, the ischemic penumbra, which if perfused  in 1 hour will survive. Proposed pathogenesis may include: (1)  abrupt vascular occlusion (e.g., embolus), (2) gradual vessel  occlusion (e.g., atheroma), and (3) vessels that are stenosed but  not completely occluded. Cerebral thrombi and cerebral emboli  are the most common causes of occlusion, but atherosclerosis  and hypotension are the dominant underlying processes.   Cerebral infarctions are ischemic. In ischemic infarcts (pale  infarcts, “white stroke”), cytotoxic ischemic events and inter-  action between blood elements and blood vessels combine to  produce brain injury. The affected area becomes slightly dis-  colored and softens about 6 to 12 hours after the occlusion.  Necrosis, swelling around the insult, and mushy disintegration  have appeared by 48 to 72 hours after infarction. At a micro-  scopic level, neuronal cell bodies change, myelin sheaths and  axis cylinders are interrupted and disintegrate, and loss of oli-  godendrites and astrocytes occurs. Secondary cellular and bio-  chemical events contribute to neuronal injury and death (see  Secondary Brain Injury, p. 588).    A syndrome of luxury perfusion (increased blood flow to the  brain but decreased O, uptake by cerebral tissue) in areas adja-  cent to the infarct develops first from the loss of autoregulation.  The vascular bed in this area dilates. Later, capillary sprouting  (neovascularization) supports this luxury perfusion syndrome.   In hemorrhagic infarcts (“red strokes”), bleeding occurs into  the infarcted area as a result of restoration of blood flow. Reper-  fusion occurs when the embolus fragments, or lysis or compres-  sive forces lessen, allowing blood flow to be reestablished into  the infarcted area. Most hemorrhagic infarcts are located in the  cerebral cortex. Unfortunately, reperfusion can compromise  recovery by accelerating the sequence of metabolically damag-  ing events including oxidative stress (reperfusion injury).   Lacunar Stroke. A lacunar stroke (lacunar infarct) is a  microinfarct smaller than 1 cm in diameter and involves occlu-  sion of the small perforating arteries, predominantly in the  basal ganglia, internal capsules, and pons. Lacunar infarcts are  caused by lipohyalinosis, subintimal lipid-loading foam cells,  and fibrinoid materials that thicken the arterial walls. The small  arterioles lengthen, become tortuous, and develop subintimal  dissections and microaneurysms. They are associated with  hyperlipidemia, smoking,* hypertension, and diabetes melli-  tus. Because of the subcortical location and small area of infarc-  tion, these strokes may have pure motor and sensory deficits.   CLINICAL MANIFESTATIONS. Because neurons surrounding  the ischemic or infarcted areas undergo changes that disrupt  plasma membranes, cellular edema results, causing compres-  sion of capillaries. Most persons survive an initial hemispheric  ischemic stroke unless massive cerebral edema develops. Mas-  sive brainstem infarcts, caused by basilar thrombosis or embo-  lism, are almost always fatal.   Clinical manifestations of thrombotic or ischemic stroke  vary, depending on the artery obstructed. Different sites of  obstruction create different occlusion syndromes (Table 18-5).   EVALUATION AND TREATMENT. Treatment of ischemic stroke is  focused on (1) restoring brain perfusion in a timeframe that  does not contribute to reperfusion injury, (2) counteracting  the ischemic cascade pathways, (3) lowering cerebral meta-  bolic demand so that the susceptible brain tissue is protected  against impaired perfusion, (4) preventing recurrent ischemic  events, and (5) promoting tissue restoration. Thrombolysis  (ie., tissue-type plasminogen activator [tPA]) given within 3  and up to 4.5 hours of onset of symptoms reduces dependency  at 6 months when the diagnosis of ischemic stroke has been  confirmed and contraindications are eliminated. Endovascular  intra-arterial thrombolysis can be used to treat those who can-  not receive tPA.>4 Because of the short time window of efficacy,  some individuals are not eligible for tPA therapy and antiplate-  let agents are administered. Aspirin, clopidogrel, or aspirin  plus extended-release dipyridamole have been shown to effec-  tively reduce death and dependency at 6 months when initiated  within 48 hours. Systemic anticoagulants (unfractionated hepa-  rin, low-molecular-weight heparin, or fondaparinux) are used  to prevent venous thromboembolism, particularly in immobi-  lized individuals.°° Acute ischemic stroke frequently presents  with hypertension, but the systemic blood pressure should not  be treated unless the systolic pressure exceeds 220 mmHg or the    Anterior and Central Circulation  Note: The internal carotid artery enters the circle of Willis and supplies the lateral anterior and central portions of the cerebral hemispheres through the middle  cerebral artery and the paramedial frontal lobe superior to the corpus callosum through the anterior cerebral artery; penetrating branches serve the deeper layers  of the hemispheres.  Internal carotid If collateral circulation is intact, commonly no  infarction has occurred; if infarcted, location is    Arterial pressure may be low in the retina  Bruit over the internal carotid artery  Possible retinal emboli  e History of transient ischemic attacks (TIAs)  e Positive noninvasive studies    Middle cerebral artery (MCA) Cortical motor area (face, arm, leg) and/or posterior + © Motor: contralateral hemiparesis or hemiplegia, greater in face   Cortical sensory area (face, arm, leg) and/or  posterior limb of internal capsule   Main stem (complete occlusion is uncommon, thus  areas affected differ and collateral circulation  may alleviate signs or symptoms); medial aspect  of frontal lobes, caudate nucleus, and corpus  callosum are supplied by the ACA   Speech: expressive (motor) disorder with anomia (left  hemisphere most commonly affected) with nonfluent aphasia  and some comprehension defects   Perception: transient visual and sensory neglect on the left  if a right lesion   Motor: when present, a mild contralateral hemiparesis,  greater in leg; with bilateral occlusion of ACA, cerebral  paraplegia in both legs can occur   Motor: contralateral paralysis or paresis (greater in foot and  thigh); mild upper extremity weakness   Sensory: mild contralateral lower extremity deficiency with  loss of vibratory and/or position sense, loss of two-point  discrimination   Speech: may have transcortical motor and sensory aphasia if  left hemisphere    Note: The posterior circulation includes the posterior cerebral artery, the vertebral arteries, and the basilar artery; the anatomic territory covered includes  the posterior aspects of the hemispheres, the central areas of the thalamus and midbrain, and the brainstem; occlusion of the vessels is most commonly  by emboli; effects of infarct in these vessels and their penetrating vessels can be specific or devastatingly global: many complex syndromes have been    Medulla and spinal cord tracts, anterior spinal  artery and penetrating branches (medial  medullary syndrome)    impaired contralateral proprioception; flaccid weakness or  paralysis of the tongue and/or dysarthria    TABLE 18-5 STROKE SYNDROMES SECONDARY TO OCCLUSION OR STENOSIS — cont'd  LOCATION/VESSEL AREA OF BRAIN INFARCTED SIGNS AND SYMPTOMS NOTED    Basilar artery (three sets of branches) Midline structures of pons (paramedian branches); e Motor: contralateral hemiparesis or hemiplegia, ipsilateral  three general areas of infarction are common: lower motor neuron facial palsy, “locked-in syndrome”  (1) medial inferior pontine syndrome, (2) medial Sensory: contralateral loss of vibratory sense, sense of  midpontine syndrome, and (3) medial superior position with dysmetria, loss of two-point discrimination,  pontine syndrome impaired rapid alternating movements  Corticospinal and corticobulbar tracts in pons, Visual: inferior pontine: diplopia; impaired abduction of ip-  sensory tracts of medial and lateral lemnisci, silateral eye: internuclear ophthalmoplegia; medial superior:  vestibular nuclei, inferior and middle cerebellar diplopia, internuclear ophthalmoplegia, skewed deviation  peduncles, cranial nerve nuclei and/or fibers, Motor: upper motor neuron type of weakness: paralysis in  cerebellar connections in tectum, descending combinations involving face, tongue, throat, and extremities;  sympathetic pathways, central brainstem, pontine dysphagia, facial weakness, dysmetria, ataxia (either trunk or  tegmentum (vertebrobasilar syndrome) extremities), weak mastication muscles  Sensation: combinations of impaired sensation (vibratory,  two-point, position sense, pain, temperature), facial hypes-  thesia, anesthesia of cranial nerve V  Posterior cerebral artery (PCA) Central territory (thalamic area, dentothalamic Motor: contralateral hemiplegia with possible dysmetria,  tract, cerebral peduncle, red nucleus, subthalamic dyskinesia, hemiballism or choreoathetosis, dystaxia, cer-  nucleus, and cranial nerve III) ebellar ataxia, and tremor; contralateral upper motor neuron  palsy; several syndromes are associated: (1) Weber: cranial  nerve III palsy and contralateral hemiplegia; (2) thalamoperfo-  rate syndrome: superior crossed cerebellar ataxia or inferior  crossed cerebellar ataxia with cranial nerve Ill palsy (Claude  syndrome); (3) decerebrate attacks  Sensory: contralateral sensory loss of all modalities without  agraphia  Function: prosopagnosia (inability to recognize familiar  faces), topographic disorientation, memory deficits, alexia,  inability to read, color anomia  Level of consciousness: in bilateral PCA syndromes,  coma with absent doll’s eyes reflex or loss of alertness may  occur; if tegmentum of midbrain near hypothalamus and third  ventricle is damaged, akinetic mutism may occur    Small Vessel Disease  Note: Small penetrating vessels in brain parenchyma that supply areas near the basal ganglia are most vulnerable to infarction although any small vessels can  occlude deep in the brain and cause injury, producing neurologic signs or symptoms; such infarcts are commonly called /acunes (small pit or hollow), a term that  is changing in meaning; they can be caused by emboli but are most commonly associated with microatheromas; although they can be found in otherwise healthy  people, those with concurrent atherosclerosis, arterial hypertension, and/or diabetes have a higher incidence of this type of infarct.  Internal capsule, most commonly e Motor: contralateral hemiparesis on a single side, with  equal deficit in face, arm, and leg; often unaccompanied by  detectable signs of sensory, visual, and speech loss, depend-  ing on location; old term is “pure motor stroke” although  evidence suggests that other neurologic signs are present but  overlooked because of low intensity  Thalamus, most commonly Sensory: complete or partial loss in face, arm, trunk, and leg  that appears exactly midline; may be accompanied by pain,  hyperesthesias, and uncomfortable sensations (hemisensory  stroke)  Pons e Dysarthria, clumsy hand  Pons, midbrain, capsule or parietal white matter e Hemiparesis, ataxia on same side    diastolic pressure exceeds 120 mmHg. Overly aggressive treat- | promising results, but additional studies are needed to deter-  ment of hypertension can compromise collateral perfusion of mine clinical practice guidelines.  the ischemic penumbra.*° When the pathophysiology of stroke Neuroprotective agents (calcium channel antagonists, citi-    is stabilized, all individuals should receive BP-lowering therapy — coline, gamma-aminobutyric acid [GABA] agonists, glycine  to maintain BP lower than 140/90 mmHg.°”°? Hypothermia antagonists, magnesium, N-methyl-p-aspartate antagonists,  has been used for neuroprotection in ischemic stroke with some _tirilazad) have not been shown to significantly reduce the risk    of poor outcome including death or improve outcomes with  ischemic stroke. New neuroprotective agents are being evalu-  ated.® For acute ischemic stroke, cholesterol reduction using  statins appears to provide neuroprotection and improve both  incidence and survival.°*!   Hemorrhagic Stroke. Hemorrhagic stroke (spontaneous  intracranial hemorrhage [ICH]) is spontaneous bleeding  into the brain. It is the third most common cause of CVA and  accounts for 8% to 18% of CVAs in whites but 30% in blacks  and Asians.°* There are about 40,000 ICHs in the United  States per year.” Risk factors for hemorrhagic stroke include  hypertension, previous cerebral infarct, coronary artery disease,  and diabetes mellitus. The most common causes of spontaneous  primary hemorrhagic strokes are hypertension (56% to  81%), ruptured aneurysms, arteriovenous malformation and  fistula, amyloid angiopathy, and cavernous angioma.®? ICH  can occur secondary to traumatic brain injury, bleeding into  ischemic brain infarction or tumor, or bleeding disorder or  anticoagulation therapy.   PATHOPHYSIOLOGY. A hypertensive hemorrhage is associated  with a significant increase in systolic and diastolic pressure over  several years and usually occurs within the brain tissue. The  pathogenesis of hypertensive cerebral hemorrhage is not fully  understood. Hypertension involves primarily smaller arteries  and arterioles, resulting in thickening of the vessel walls and  increased cellularity of the vessels and hyalinization. Necrosis  may be present. Microaneurysms in these smaller vessels or  arteriolar necrosis precipitates the bleeding.   Hemorrhages are described as massive, small, slit, or pete-  chial. A massive hemorrhage is several centimeters in diameter;  a small hemorrhage is 1 to 2 cm in diameter; a slit hemorrhage  lies in the subcortical area; and a petechial hemorrhage is the  size of a pinhead bleed. The most common sites for hyperten-  sive hemorrhages are in the putamen of the basal ganglia (a  portion of the lentiform nucleus) (40%), the thalamus (15%),  the cortex and subcortex (22%), the pons (8%) (Figure 18-16),  caudate (7%), and cerebellar hemispheres (8%).    With bleeding, a mass of blood is formed and its volume  increases. In massive intracerebral hemorrhage (volume greater  than 150 ml), cerebral perfusion falls to zero and cerebral blood  flow stops, resulting in death. In strokes with less than massive  hemorrhage, adjacent brain tissue is displaced and compressed.  Necrosis around the hematoma is present within 6 hours. Edema  forms and the blood-brain barrier is disrupted. An inflamma-  tory reaction in surrounding brain tissue appears rapidly and  peaks in several days.°* Figure 18-17 illustrates additional detail.  Rupture or seepage of blood into the ventricular system occurs  in many cases.°* The cerebral hemorrhage resolves through  reabsorption. Macrophages and astrocytes appear to dissipate  the blood. A cavity forms, which is surrounded by a dense glio-  sis after removal of the blood.   CLINICAL MANIFESTATIONS. With hemorrhagic stroke, clinical  manifestations vary according to the location and size of the  bleed. Focal neurologic deficits are found in 80% of individuals  experiencing hemorrhagic strokes; altered consciousness occurs  in 50%. Once a deep unresponsive state occurs the immediate  prognosis is grave, and the individual rarely survives. If the per-  son survives, however, recovery of function frequently is possible.   Individuals experiencing intracranial hemorrhage from  a ruptured or leaking aneurysm have one of three sets of  symptoms: (1) onset of an excruciating generalized headache  with an almost immediate lapse into an unresponsive state;  (2) headache, but with consciousness maintained; and (3)  sudden lapse into unconsciousness. If the hemorrhage is con-  fined to the subarachnoid space, there may be no local signs.  If bleeding spreads into the brain tissue, hemiparesis/paraly-  sis, dysphasia, or homonymous hemianopsia may be present.  Warning signs of an impending aneurysm rupture may include  headache, transient unilateral weakness, transient numbness  and tingling, and transient speech disturbance. Warning signs,  however, often are not present.   EVALUATION AND TREATMENT. Clinical guidelines for the man-  agement of spontaneous intracerebral hemorrhage have been  published by the American Heart Association/American Stroke    FIGURE 18-17 Injury Mechanisms Promoted by Intracerebral Hemorrhage. Hemorrhages can induce neuronal injury  through mass effect, particularly in large hematomas that can cause increased intracranial pressure and herniation. Hemor-  rhages may also cause tissue damage through cerebral edema and secondary “neurotoxic” mechanisms caused by activation of  the coagulation cascade and inflammation. Not all potential interactions are shown (e.g., thrombin may potentiate iron-induced  injury; the complement and inflammatory systems overlap and several factors contribute to cerebral edema). CBF Cerebral  blood flow; //CP increased intracranial pressure; ABC, red blood cell. (Data from Mocco J et al: Neurosurg Focus 15:22[5]:E7,  2007; Schubert GA, Thome C: Front Biosci 13:1594—1603, 2008; Xi G, Keep RF, Hoff JT: Lancet Neurol 5[1]:53-63, 2006.)    Association. Diagnosis of hemorrhagic stroke considers the  health history, clinical presentation, laboratory tests, and neuro-  imaging procedures (CT and MRI). Treatment needs to be ini-  tiated within 3 to 4 hours of symptom onset for reversibility of  brain ischemia. Care in multidisciplinary stroke rehabilitation  units appears to be most effective at reducing disability, depen-  dency and length of hospital stay for all stroke syndromes.“   Treatment of a hemorrhagic stroke, regardless of cause, is  focused on: (1) stopping or reducing the bleeding, (2) control-  ling increased ICP, (3) preventing a rebleed, (4) preventing  vasospasm, and (5) promoting tissue restoration. Treatment  for hemorrhagic stroke includes limiting hematoma enlarge-  ment and preventing or controlling seizures and cerebral  edema. Known coagulopathies should be corrected and oral  anticoagulation reversed. Hematoma enlargement is limited  when recombinant activated factor VII is given within 4 hours  of onset but it does not improve outcome and is associated with  thromboembolic complications.® Surgical evacuation does  not appear to be an effective treatment for supratentorial ICHs  but may be indicated for a large posterior fossa hematoma.  Hypertension management is individualized. Elevated blood  pressure can expand the hematoma and low blood pressure can  contribute to ischemia.°*°    Prophylactic treatment of seizures is controversial and when  used it is on a short-term basis (e.g., 3 days).°° Osmotic therapies  (e.g., mannitol) are used for the treatment of increased intra-  cranial pressure and cerebral edema in hemorrhagic stroke.°”  Supportive care is provided for airway management; respira-  tory function; blood pressure control; avoidance of fever; and  maintenance of fluids, glucose, electrolytes, and nutrition.   Intracranial Aneurysm. Intracranial aneurysms (weak bulging  areas of an arterial vessel wall) may result from arteriosclerosis,  congenital abnormality, trauma, inflammation, or infection.  Cocaine use has been linked to aneurysm formation. The size  of the aneurysm may vary from 2 mm to 3 cm. Most aneurysms  are located at bifurcations in or near the circle of Willis, in the  vertebrobasilar arteries, or within the carotid system—85%  to 95% are in the anterior portion of the circle of Willis (see  Figure 15-20 and p. 420). Aneurysms may be single, but in 20%  to 25% of cases, more than one is present. In these instances  the aneurysms may be unilateral or bilateral. The incidence of  rupture is 11 in 100,000 per year. Peak incidence of rupture  is from 50 to 60 years of age. Women have a slightly greater  incidence of aneurysms.   PATHOPHYSIOLOGY. No single pathologic mechanism exists.  A combination of genetic, congenital, and acquired factors    (hypertension) is present.’? Abnormalities in multiple layers  of the blood vessel are found. The endothelial layer is thin, the  internal elastic lamina is not present or fragmented, and the  muscularis layer of the media ends at the aneurysm. Atheroscle-  rotic changes are found. Aneurysm development is attributed  to hemodynamic and wall shear stress and flow turbulence,  particularly at bifurcations, and sites of inflammation and vas-  cular remodeling. They are a symptom of underlying vascular  disease. Hypertension and certain connective tissue disorders in  which there are abnormalities in the extracellular matrix exac-  erbate aneurysm formation.”? The aneurysm wall is composed  of fibrous tissue. Aneurysms may be classified on the basis of  shape and form (Figure 18-18).”!   Saccular aneurysms (berry aneurysms) occur frequently  (in approximately 2% of the population) and are the result of  a combination of a congenital abnormality in the media of the  arterial wall and degenerative changes. The sac grows over time.  A saccular aneurysm may be (1) round with a narrow stalk con-  necting it to the parent artery (Figure 18-19), (2) broad based  without a stalk, or (3) cylindrical. Saccular aneurysms are rare  in childhood; their highest incidence of rupturing or bleeding is  among people 20 to 50 years of age.   Fusiform aneurysms (giant aneurysms), by definition  greater than 25 mm in diameter, make up 5% of all intracra-  nial aneurysms. They occur as a result of diffuse arterioscle-  rotic changes and are found most commonly in the basilar  arteries or terminal portions of the internal carotid arteries.  They act as space-occupying lesions. Mycotic aneurysms  result from arteritis caused by bacterial emboli (e.g. associated  with bacterial endocarditis); these aneurysms are uncommon.  Traumatic (dissecting) aneurysms are caused by a weakening  of the arterial wall by a fracture line, by a penetrating mis-  sile, or after neurosurgical or imaging (e.g., angiographic)  procedures.   What causes an aneurysm to rupture is not known.” Rupture  causes hemorrhage into the subarachnoid space (subarachnoid  hemorrhage) (see p. 605) with rapid spread, producing local-  ized changes in the cerebral cortex and focal irritation of nerves  and arteries. Because of compression, bleeding ceases with the    formation ofa fibrin-platelet plug at the point of rupture. Blood  undergoes reabsorption through arachnoid villi within 3 weeks.   CLINICAL MANIFESTATIONS. Aneurysms are frequently asymp-  tomatic. In routine autopsy, 5% of persons are found to have  one or more intracranial aneurysms. Clinical manifestations  may arise from cranial nerve compression, but the signs vary,  depending on the location and size of the aneurysm. Most  often, cranial nerves III, IV, V, and VI are affected (see Table  15-6). Unfortunately the most common first indication of an  aneurysm is an acute subarachnoid hemorrhage, intracerebral  hemorrhage, or combined subarachnoid-intracerebral hemor-  rhage (see pp. 602 and 605).   EVALUATION AND TREATMENT. Diagnosis before a bleeding epi-  sode is made using arteriographic examination. Intracranial  aneurysms may be found incidently during CT or MRI imaging  for other conditions. After a subarachnoid or an intracerebral  hemorrhage, a tentative diagnosis of an aneurysm that has bled  is based on clinical manifestations, history, and CT and MRI  results. The treatment of choice for an aneurysm is surgical  management. The location and size of the aneurysm and the  person’s clinical status determine whether invasive therapy is  feasible.’*”    Vascular malformations are rare congenital vascular lesions.  They are about one-tenth as common as aneurysms and can  cause hemorrhagic stroke, epilepsy, chronic headache, or focal  neurologic deficits.” Four types of vascular malformation exist:  arteriovenous malformation, cavernous angioma, capillary tel-  angiectasis, and venous angioma. Most are sporadic, although  multiple lesions are observed in families.”° In an arteriovenous  malformation (AVM), arteries feed directly into veins through  a vascular tangle of malformed vessels without a true capillary  bed. AVMs occur as frequently in males as in females, and occa-  sionally are found in families. Although usually present at birth,  AVMs exhibit a delayed age of onset and symptoms most com-  monly occur before 30 years of age. They usually rupture in the    FIGURE 18-19 Berry Aneurysm, Angiogram. In this lateral view with contrast  filling a portion of the cerebral arterial circulation can be seen a berry aneurysm (arrow)  involving the middle cerebral artery of the circle of Willis at the base of the brain.  (From Klatt EC: Robbins and Cotran atlas of pathology, Philadelphia, 2006, Saunders.)    second and third decades of life. Cavernous angiomas (mal-  formations) are sinusoidal collections of blood vessels without  interspersed normal brain tissue. They rarely hemorrhage and  comprise 2% to 4% of hemorrhagic strokes. A capillary telan-  giectasis is dilated capillaries with interspersed normal brain  tissue found deep in the brain, particularly in the brainstem;  hemorrhage is rare. These vascular malformations are associ-  ated with Rendu-Osler-Weber disease (AVM in various areas  of the body). Venous angioma, the most common vascular  malformation found at autopsy (3% of cases), is considered a  subset of developmental venous anomalies that occur second-  ary to arrested development. The result is primitive embryo-  logic veins in a radial pattern feeding a central vein. These rarely  hemorrhage.’°   PATHOPHYSIOLOGY. AVMs are developmental abnormali-  ties that represent persistence of embryonic patterns of blood  vessels, do not have a normal blood vessel structure, and are  abnormally thin (Figure 18-20). The involved vessels are con-  sidered by some researchers to enlarge over time. Their size is  highly variable, from malformations of a few millimeters to  large ones that extend from the cortex to the ventricle. The  large AVMs also may involve the dura mater, including the falx  cerebri and the tentorium cerebelli. The AVM may be fed by  one or several arteries. There is usually high flow through the  feeding arteries and draining veins. These feeder vessels become  tortuous over time and often are dilated. With moderate to  large AVMs, sufficient blood is shunted into the malforma-  tion to deprive surrounding tissue of adequate blood perfusion.  There also are theories that propose sporadic AVMs develop as  a postnatal consequence of an active angiogenic and inflamma-  tory response to some inciting vascular event, such as trauma  or infection.’”   CLINICAL MANIFESTATIONS. Clinical manifestations vary: about  20% of persons with an AVM have a characteristic chronic non-  descript headache, although some experience migraine; about  20% to 25% experience seizure disorders caused by compression.    Initially, the seizures tend to be focal or jacksonian; generaliza-  tion often occurs over time. (Seizures are discussed in Chapter  17.) About 40% to 70% suffer an intracerebral, a subarachnoid,  or a subdural hemorrhage.”* Bleeding from an AVM into the  subarachnoid space causes clinical manifestations identical to  those associated with a ruptured aneurysm. If bleeding is into  the brain tissue, focal signs that develop resemble a stroke-in-  evolution. Ten percent of persons experience hemiparesis or  other focal signs. Hemiparesis usually is caused by compression  or rupture. At times, noncommunicating hydrocephalus (see  Chapters 17 and 20) develops with a large AVM that extends  into the ventricle lining. AVMs account for up to 1% of all sud-  den deaths.’®   EVALUATION AND TREATMENT. A systolic bruit over the carotid  in the neck, the mastoid process, or (in a young person) the  eyeball is almost diagnostic of an AVM. CT, magnetic reso-  nance angiography (MRA), transcranial Doppler (TCD), and  MRI are used in initial diagnosis, followed by an arteriogram  to identify feeding vessels. Treatment options are microsurgery,  embolization, stereotactic radiosurgery (SRS), or combina-  tions of treatment. Observation only depends on age, overall  health, lesion-specific factors (size, location, and angiographic  anatomy), and individual-specific factors. The risk of bleeding  is about 6% in the first year and 2% to 4% each year thereafter  with no intervention.”    With a subarachnoid hemorrhage (SAH), blood escapes from  a defective or injured vasculature into the subarachnoid space  (Figure 18-21). Previous family history of SAH is one of the  strongest predictors of aneurysmal SAH. Heavy alcohol use,  hypertension, smoking, anticoagulation use, and oral contra-  ceptive use are associated with SAH. Individuals at risk for a  SAH are those with a saccular intracranial aneurysm (80% of  cases), intracranial AVM, or hypertension and those who have  sustained head injuries. The mortality is approximately 50%,    FIGURE 18-20 Vascular Malformation, Gross. A vascular malformation represented by a mass of irregular tortuous  vessels over the left posterior parietal region of the brain. (From Klatt EC: Robbins and Cotran atlas of pathology, Philadelphia,    c » = J P.  FIGURE 18-21 Subarachnoid Hemorrhage, Gross. Subarachnoid hemorrhage resulting from rupture of a berry aneu-  rysm. (From Klatt EC: Robbins and Cotran atlas of pathology, Philadelphia, 2006, Saunders.)   PATHOPHYSIOLOGY. When a vessel is leaking, blood oozes  into the subarachnoid space. When a vessel tears, blood under  pressure is pumped into the subarachnoid space. The blood  is extremely irritating to the meningeal and other neural tis-  sues and so produces an inflammatory reaction in these tis-  sues. Additionally, the blood coats nerve roots, clogs arachnoid  granulations (impairing CSF reabsorption), and clogs foramina  within the ventricular system (impairing CSF circulation). ICP  immediately increases to almost diastolic levels. ICP returns  to near baseline in about 10 minutes. Cerebral blood flow and  cerebral perfusion pressure (CPP) decrease. The expanding  hematoma acts like a space-occupying lesion, compressing and  displacing brain tissue. Granulation tissue is formed and scar-  ring of the meninges, with resulting impairment of CSF reab-  sorption and secondary hydrocephalus, often results.   Subarachnoid hemorrhage has a unique pathophysiologic  cascade triggered by the sudden appearance of blood in the  subarachnoid space. Eighty percent of persons with SAH have  infarction on MRI, which is the major cause of death and dis-  ability, and 33% of persons have asymptomatic vasospasm in  the first 2 weeks following an SAH.*!   The cause for cerebral vasospasm (CVS) and delayed  cerebral ischemia (DCI) is unclear. DCI is related to but not  explained by the CVS. Development of CVS requires the pres-  ence of blood and its breakdown products as a consequence of  the SAH. It also appears that oxyhemoglobin is a powerful pre-  cipitator of CVS. It scavenges nitric oxide (a vasodilator), and  its breakdown triggers a free radical cascade that disrupts mul-  tiple blood vessel layers and initiates release of inflammatory  factors. It appears that CVS, disruption of cerebral autoregula-  tion, microthrombi, and spreading cortical depression contrib-  ute to DCI. Autoregulation may be impaired in SAH and the  combination of narrowed blood vessels, because of spasm and  disrupted autoregulation, impairs perfusion, resulting in ische-  mia and infarction.*?    CLINICAL MANIFESTATIONS. Early manifestations associated with  leaking vessels are episodic headache, transient changes in men-  tal status or level of consciousness, nausea or vomiting, focal  neurologic defects including visual or speech disturbances,  cranial nerve palsies, or stiff neck. A ruptured vessel often is  accompanied by a sudden throbbing, “explosive” headache that  is associated with nausea and vomiting, visual disturbances,  motor deficits, and loss of consciousness. These signs can be  related to a dramatic rise in ICP as blood is released directly into  the CSF. Meningeal irritation and inflammation often occur,  causing neck stiffness (nuchal rigidity), photophobia, blurred  vision, irritability, restlessness, and low-grade fever. A positive  Kernig sign (in which straightening the knee with the hip and  knee in a flexed position produces pain in the back and neck  regions) and a positive Brudzinski sign (in which passive flex-  ion of the neck produces neck pain and increased rigidity) may  appear. No localizing signs are present if the bleed is confined  completely to the subarachnoid space.   The Hunt and Hess SAH grading system is based on descrip-  tion of the clinical manifestations (Table 18-6). Rebleeding is a  significant risk with a high mortality (up to 70%). The period  of greatest risk is the first month, with the peak incidence of  rebleeding during the first 2 weeks after the initial bleed.  Rebleeding is manifested by a sudden increase in blood pressure  and ICP, along with a deteriorating neurologic status.   EVALUATION AND TREATMENT. The diagnosis of a subarach-  noid hemorrhage is based on the clinical presentation, imag-  ing results, and cerebrospinal fluid evaluation.**** Treatment is  directed at control of intracranial pressure, prevention of ische-  mia and hypoxia of neural tissues, and prevention of rebleeding  episodes. Antifibrinolytic drugs may be used to stop rebleed-  ing in selected cases. Blood pressure is allowed to remain in the  high normal range or is elevated to that level. Calcium channel  blockers, such as nimodipine, are used to prevent or reverse  vasospasm. Volume expansion or hemodilution through con-  tinuous or bolus administration of hetastarch and administra-  tion of plasma protein factors to maintain a hematocrit of 33%    are used to expand blood volume and augment cerebral perfu-  sion in selected cases. Surgical clipping of the aneurysm may be  done. Endovascular placement of platinum coils and balloon  embolization to occlude the aneurysm are used. Cerebral angio-  plasty can be tried for vasospasm. Evaluation of new treatments  is in progress.*>-*7    Headache is a common neurologic disorder and is usually a  benign symptom. However, it can be associated with serious  disease, such as brain tumor, meningitis, giant cell arteritis,  and cerebrovascular disease. The primary headache syndromes  discussed here are the chronic, recurring type not associated  with structural abnormalities or systemic disease and include  migraine, cluster, paroxysmal hemicrania, and tension head-  aches. Characteristics of the major types of headache syndromes  are summarized in Table 18-7.   Migraine is an episodic neurologic disorder whose marker is  headache lasting 4 to 72 hours. Migraine is more common in  those 25 to 55 years of age, and can occur in young children. The   Neurologic deficit evidenced by cranial nerve  involvement; moderate to severe headache with  more pronounced meningeal signs (e.g., photophobia,  nuchal rigidity)   Drowsiness and confusion with or without focal  neurologic deficits; pronounced meningeal signs    From Cook HA: Aneurysmal subarachnoid hemorrhage: neurosurgical  frontiers and nursing challenges. In Winkleman C, editor: AACN clinical  issues in critical care nursing, Philadelphia, 1991, Lippincott;    incidence of migraine by age 85 years is about 18% in males and  44% in females. Onset after 55 years of age is rare.5* Hormonal  factors account for most of the gender differences. A positive  family history is common as is a genetic predisposition.   Migraine is diagnosed when it is not attributable to any other  disorder and when any two of the following features occur: uni-  lateral head pain, pulsating pain, pain worsening with activ-  ity, moderate or severe pain intensity, and at least one of the  following: nausea or vomiting, or both, or photophobia and  phonophobia.*?   Migraine is a multifactorial disorder caused by a combina-  tion of multiple genetic and environmental factors. Specific  gene associated migraine includes familial hemiplegic migraine,  sporadic hemiplegic migraine, and cerebral autosomal domi-  nant arteriopathy with subcortical infarcts and leukoencepha-  lopathy. Migraine sufferers have an increased risk for epilepsy,  depression, anxiety disorders, and stroke.” Migraine may be  precipitated by triggers. Individuals with migraine are likely to  have a genetically determined reduced threshold for triggers  with further reduced threshold caused by endogenous factors  (e.g., altered sleep patterns [becoming tired or too much sleep],  missed meals, overexertion, weather change, stress or relaxation  from stress, hormonal changes [such as menstrual periods],  excess afferent stimulation [bright lights, strong smells], and  chemicals [alcohol or nitrates] ).°°   The International Headache Society has broadly classified  episodic migraine into two major subtypes: migraine with aura  and migraine without aura.’! In migraine with aura, at least  some of the attacks are temporarily associated with distinct aura  symptoms suggestive of focal brain dysfunction (flashing lights,  visual loss). There are no associated focal neurologic symptoms  in migraine without aura. Two thirds of those with migraines  have migraine without aura. Chronic migraine is a progression  of episodic migraine with a prevalence of about 2%. Criteria for  these headaches include the following: it occurs on more than  15 days per month for at least 3 months; no excessive use of opi-  ate or barbiturate medications is involved; and on more than  8 days per month there is migraine without aura or treatment  provides relief before symptoms develop.”!   The pathophysiologic basis for migraine is complex and not  clearly established. It includes neurologic, vascular, hormonal,  and neurotransmitter components. Migraine pain appears to be  related to activation of the peripheral and central arms of the   Episodic Clusters in time  Usually throbbing Steady Steady  Variable, often unilateral Orbit, temple, cheek Variable  Prodrome, vomiting Lacrimation, rhinorrhea, Horner syndrome None    trigeminal system, cortical spreading depression, and distinct  activity of brainstem nuclei.   The clinical phase of a migraine attack and associated patho-  physiology are as follows”:   1. Premonitory phase: Up to one third of migraine patients  have premonitory symptoms at least some of the time for  several hours before aura or headache onset (e.g., neck  pain, depression, yawning, food cravings); the patho-  genesis is unknown but evidence suggests dopaminergic/  hypothalamic involvement.”   2. Migraine aura: Up to one third of migraine patients  have aura symptoms at least some of the time that may  last 1 hour or sometimes much longer; migraine aura  is defined as a spreading, focal, neurologic disturbance  manifested as visual, sensory, or motor symptoms; the  pathophysiologic mechanism appears to be a cortical  spreading depression (CSD) (focal hyperemia [vasodila-  tion] followed by spreading oligemia [vasoconstriction]),  a reduction in electrical activity, and a decrease in blood  flow that slowly spreads across the cerebral cortex from  the occipital region.*”   3. Headache phase: This phase includes associated symptoms  and may last from 4 to 72 hours (usually about 1 day). The  genesis of migraine pain is unknown and there is debate  about whether the initiating mechanisms are central or  peripheral, vascular or nonvascular.?* Proposed pain  mechanisms include: (1) activation of trigeminal cervical  afferent neurons (arise from the ophthalmic division of  the trigeminal ganglion and in the upper cervical dorsal  roots in the posterior fossa) that innervate cerebral vessel  nociceptors—activation of trigeminal sensory nerves  releases vasoactive peptides that cause a sterile, inflamma-  tory response around vessels in the meninges; (2) abnor-  mal processing of trigeminal pain from the dural vessels  and upper cervical muscles by the diencephalon (thalamus  and hypothalamus), brainstem, or high cervical spinal  cord; (3) central sensitization from an increased response  of thalamic neurons to stimulation—allodynia; (4) dilation  of the terminal branches of the external carotid artery.?”"!"!   4. Recovery phase: This phase may take several hours to days.   Migraine without aura is often located on one side of the  head. In migraine with aura, the most common prodromal  symptoms are visual (scotomas with luminous angles and scin-  tillating edges, and hemianopsia). Sensory deficits and aphasia  also may be present. The aura develops within 5 to 20 minutes  and remits within 60 minutes, followed by headache and other  symptoms, including nausea, vomiting, photophobia, and scalp  tenderness; 10% experience diarrhea.   In susceptible women, migraine occurs most frequently  before and during menstruation and is decreased during preg-  nancy and menopause. Excessive levels of estrogen during  menstruation stimulate receptors in the trigeminal ganglia and  periaqueductal gray that manifest as menstrual migraine.!°  Estrogens also may act directly on vascular smooth muscle,  modulate activity of vasoactive substances at the neurovascular  junction, and activate vasoregulatory responses in the hypo-  thalamus. However, no direct evidence has been found to link    circulating female sex hormones with the frequency and sever-  ity of migraine.   The diagnosis of migraine is made from health history and  physical examination. Clinicians must be skilled in their under-  standing of different types of headaches, risk factors, family his-  tory, and clinical features. Differential diagnosis is confirmed  with CT, MRI, and EEG. A significant number of individuals  with migraine have depression as a comorbidity.   The management of migraine includes education that  migraine is a chronic physiologic, not psychosomatic, disor-  der. Avoidance of triggers, adequate sleep, regular eating habits,  and daily relaxation and meditation can create a headache-  protective environment. With the onset of acute migraine, a  dark room, ice, and sleep can provide relief. The pharmacologic  management of migraine varies with each individual and is  related to the severity of the attack. Drug considerations should  include antiemetics, NSAIDs, ergotamine and dihydroergota-  mine, and serotonin receptor agonists (e.g., sumatriptan).  Triptans, transcutaneous estrogen, and magnesium administra-  tion may help some women with menstrual migraine. Gastric  absorption may be decreased during an attack, and routes of  administration other than oral (e.g., nasal sprays, intravenous,  and rectal) may be used. There are several emerging drugs that  may target the molecular pathophysiology of migraine pain.!°°  The prophylaxis of migraine is considered when attacks can-  not be treated effectively. Several drugs may be considered and  should not be used in combination. Examples include beta-  blockers, a calcium antagonist (flunarizine), serotonin antag-  onists (lisuride, methysergide), NSAIDs, dihydroergotamine  (DHE), valproic acid, and amitriptyline. There are many new  drugs under evaluation.'"*    Cluster headaches are one of a group of disorders referred to  as trigeminal autonomic cephalagia'®° and occur primarily in  men between 20 and 50 years of age. Cluster headache has been  known also as histamine cephalalgia, Horton syndrome, and  erythromelalgia. These uncommon headaches occur in clusters  for a period of days followed by a long period of spontaneous  remission. Cluster headache has an episodic and a chronic form  with extreme pain intensity and short duration. If the cluster of  attacks occurs more frequently without sustained spontaneous  remission, they are classified as chronic cluster headaches (20%  of cases) (see Table 18-7). Triggers are similar to those that  cause migraine headache.   Trigeminal activation occurs but the mechanism is unclear.  There is unilateral trigeminal distribution of severe pain with  ipsilateral autonomic manifestations, including tearing on the  affected side, ptosis of the ipsilateral eye, and congestion of the  nasal mucosa. The pathogenic mechanism for pain is related to  the release of vasoactive peptides, the formation of neurogenic  inflammation, and the activation of the pain matrix. Auto-  nomic dysfunction is characterized by sympathetic underactiv-  ity and parasympathetic activation. The rhythmicity of attacks  is associated with changes in the inferior posterior hypothala-  mus. There may be altered serotonergic nerve transmission, but  at different loci than in migraine headache.!°°    The headache attack usually begins without warning and is  characterized by severe, unilateral tearing; and burning, peri-  orbital, and retrobulbar or temporal pain lasting 30 minutes  to 2 hours. One or several attacks may occur in a day, usually  at the same time of day or night. The same side is affected in  subsequent episodes, and the attack activates the trigeminal-  autonomic reflex. Associated symptoms include lacrimation,  reddening of the eye, nasal stuffiness, eyelid ptosis, and nau-  sea. Pain often is referred to the midface and teeth. Alcohol can  stimulate an attack during a cluster headache in about 50% to  70% of cases, but it is not a triggering factor during remission.   Prophylactic drugs are used to treat cluster headache, as well  as avoidance of triggers. The most effective are calcium chan-  nel antagonists (verapamil), lithium carbonate, topiramate,  valproic acid, gabapentin, and baclofen. Acute attacks are man-  aged with oxygen inhalation and intravenous sumatriptan, or  inhaled ergotamine administration and nerve stimulation.!”   Chronic paroxysmal hemicrania (CPH) is a cluster-type  headache with unilateral head pain that occurs with more daily  frequency (4 to 12 times per day) but with shorter duration (20  to 120 minutes). The remission phases are often shorter. The  attacks are more common in women, usually after pregnancy.  The symptoms are similar to cluster headache. As with cluster  headache, there is an episodic and a chronic form. The patho-  physiology involves a disorder of sympathetic hyperactivity, but  the mechanism is different from that of cluster headache because  there is effective relief of symptoms with indomethacin.!°°    Tension-type headache (TTH) is the most prevalent type of pri-  mary headache. It is not a vascular or migrainous headache. The  average age of onset is during the second decade of life. It is a  mild to moderate bilateral headache with a sensation of a tight  band or pressure around the head. The onset of pain is usu-  ally gradual. Episodic tension-type headache may last for several  hours or several days. It is not aggravated by physical activity.  Chronic tension-type headache evolves from episodic tension-  type headache and represents headache that occurs at least 15  days per month for at least 3 months.?! Many individuals have  both tension-type and migraine headaches.   The pathogenesis of TTH is not clear; however, there is a  probable genetic predisposition. Both a central mechanism and  a peripheral mechanism operate in causing tension headache.  The central mechanism probably involves hypersensitivity  of pain fibers from the trigeminal nerve that leads to central  sensitization. The peripheral sensitization of myofacial sensory  afferents may contribute to muscular hypersensitivity and the  development of chronic TTH.!”? Headache sufferers have more  localized pain and tenderness of pericranial muscles.   Mild headaches are treated with ice, and more severe forms  are treated with aspirin or NSAIDs. Chronic tension-type head-  aches are best managed with a tricyclic antidepressant, such  as amitriptyline. Cognitive-behavioral therapy and relaxation  training reduce symptoms of chronic tension-type headache.  Long-term use of analgesics or other drugs, such as muscle  relaxants, antihistamines, tranquilizers, caffeine, and ergot  alkaloids, should be avoided.!!°    The CNS may be infected by bacteria, viruses, fungi, parasites,  and mycobacteria. Viruses causing acute and chronic CNS  infections are listed in Table 18-8. The infecting microorgan-  isms gain entry to the nervous system by (1) hematogenous  spread through arterial blood or (2) direct extension from  another site of infection.''! Neurologic infections produce dis-  ease by several mechanisms: direct neuronal or glial infection;  mass lesion formation; inflammation with subsequent edema;  interruption of cerebrospinal fluid pathways; neuronal damage,  or vasculopathy; and secretion of neurotoxins (Figures 18-22  through 18-24). Syndromes are acute and subacute bacterial  meningitis, epidural and brain abscess, encephalitis, periph-  eral neuropathy, or neurosyphilis depending on the infecting  microorganism. Signs and symptoms are produced because of  (1) interference with the function of the nervous system tissue  being invaded or compressed or (2) the inflammatory response  produced by the body in response to infection. The cardinal  signs of CNS infection are fever, head or spine pain, and gener-  alized or focal neurologic dysfunction.!!”   Meningitis is inflammation of the brain or spinal cord. Infec-  tious meningitis may be caused by bacteria, viruses, fungi,  parasites, or toxins. (The pathophysiology of infection is dis-  cussed in Chapter 10.) The infection may be acute, subacute, or  chronic with the pathophysiology, clinical manifestations, and  treatment differing for each type of microorganism. In aseptic  meningitis no specific pathogen can be identified and the dis-  ease is treated symptomatically.   Bacterial meningitis is primarily an infection of the pia  mater and arachnoid villi, the subarachnoid space, the ventricu-  lar system, and the CSF. About 1 in 100,000 persons are affected  annually.!!’ Meningococcus (Neisseria meningitidis) and pneu-  mococcus (Streptococcus pneumoniae) are the most common  causes of bacterial meningitis. Meningococcus has been iden-  tified worldwide. Meningococcal meningitis occurs predomi-  nantly in men and boys and in the fall, winter, and spring of the  year. Epidemics of meningococcal meningitis occur in approxi-  mately 10-year cycles, predominantly affecting children and  adolescents. With pneumococcal meningitis, young persons  and those more than 40 years of age are mostly affected. Predis-  posing conditions are otitis or sinusitis (25%), immunocom-  promised status (16%), and pneumonia (12%).!!>!14   Meningitis (viral meningitis, nonpurulent meningitis,  lymphocytic meningitis) is believed to be limited to the menin-  ges. An identifiable bacteria cannot be found in the cerebro-  spinal fluid. The most at-risk populations and the time of year  when occurrences are seen depend on the virus and on the  immune status of the individual. Viral meningitis produces a  variety of symptoms and is caused by a variety of viruses. The  most common are enteroviral viruses (echovirus, coxsackievi-  rus, and nonparalytic poliomyelitis), arboviruses, and herpes  simplex type 2.'!° Treatment is primarily supportive and the  disease usually resolves within 7 to 10 days.    From Lindquist L, Vapalahti O: Lancet 371(9627):1861-1871, 2008; Power C, Noorbakhsh F: Central nervous system viral infections: clinical aspects and pathogenic mechanism. In Gilman S,    editor: Neurobiology of disease, pp 487-488, Burlington, MA, 2007, Elsevier.  CNS, Central nervous system; DNA, deoxyribonucleic acid; HAART, highly active antiretroviral therapy; /V/G, intravenous immunoglobulin; JC, John Cunningham; ND, not determined; RIG,  rabies immune globulin; RNA, ribonucleic acid; SSPE, subacute sclerosing panencephalitis.    FIGURE 18-22 Pathogenesis of Meningitis. (Adapted from Cohen J, Pow-  derly WG: Infectious diseases, ed 2, Mosby, 2004, Edinburgh.)    Fungal meningitis is a chronic, much less common con-  dition than bacterial or viral meningitis. The most common  fungal infections of the nervous system are histoplasmosis,  cryptococcosis, coccidioidomycosis, mucormycosis, candidia-  sis, and aspergillosis. The infection occurs most often in persons  with impaired immune responses or alterations in normal body  flora. It develops insidiously, usually over days or weeks.   Tubercular meningitis is a common and serious form of  CNS tuberculosis especially in persons with acquired immu-  nodeficiency syndrome (AIDS). Miliary tubercles form in the  brain and meninges. At some point the tuberculomas erode  the pia mater, and the mycobacteria enter the CSF, produc-  ing a hypersensitivity reaction that results in a purulent exu-  date involving the basal meninges, cerebrum, and spinal nerves.  Cerebral ischemia and infarction occur from vasculitis. Symp-  toms include headache, low-grade fever, nausea and vomiting,    macrophages: encephalitis viruses,  HIV, CMV HIV, JCV, CMV, HTLV-1  Blood-brain  Ss) barrier  SSSys  Endothelia:   FIGURE 18-23 Viral Infection in the Central Nervous System (CNS). Viruses  infect specific cell types within the CNS depending on the specific properties of the  virus together with individual cell membrane proteins expressed on permissive cell  types. Normally the brain is protected from circulating pathogens and toxins by the  blood-brain barrier. CVV Cytomegalovirus; H/VZ human immunodeficiency virus;  HSV, herpes simplex virus; H7LV-1, human T-cell lymphotropic virus type 1 (causes  T-cell leukemia); JCV, John Cunningham virus (a polyomavirus causing progressive  multifocal leukoencephalopathy); SSPE, subacute sclerosing panencephalitis; VZV.  varicella-zoster virus. (Adapted from Power C, Noorbakhsh G: Central nervous sys-  tem viral infections: clinical aspects and pathogenic mechanisms. In Gilman S, edi-  tor: Neurobiology of disease, p 488, Burlington, MA, 2007, Elsevier.)    FIGURE 18-24 Hematogenous Spread of Viral Pathogens to the Central  Nervous System. (Adapted from Cohen J, Powderly WG: /nfectious diseases,  Mosby, 2007, Edinburgh.)    FIGURE 18-25 Acute Leptomeningitis. The leptomeninges contain abun-  dant creamy, purulent exudate, most prominently over the superior surface of the  cerebrum. The underlying brain is swollen, and the vessels are congested. (From  Kumar V, Cotran RS, Robbins SL: Robbins basic pathology, ed 7, Philadelphia, 2003,  Saunders.)    irritability, difficulty sleeping, and fatigue. These signs and  symptoms increase to confusion, stiff neck, significant behav-  ioral changes, and seizures. Hydrocephalus and cranial nerve  palsies or cerebral infarcts may occur. Recovery rate is 90% with  early diagnosis and treatment with appropriate antituberculosis  therapy.!'°   PATHOPHYSIOLOGY. In bacterial meningitis, a systemic or  bloodstream infection or a direct extension from an infected  area (e.g., from a respiratory tract, ear, or paraspinal infection;  as a result of dental work) is the access route to the subarachnoid  space. The method of CNS entry is through the choroid plex-  uses or areas of altered blood-brain barrier or by hematogenous  spread. Bacteria multiply in the subarachnoid space. The bacte-  ria or their toxins function as irritants and induce an inflamma-  tory reaction by the meninges (pia mater and arachnoid), the  CSF, and the ventricles. The meningeal vessels undergo change,  becoming hyperemic and increasingly permeable. Neutrophils  migrate into the subarachnoid space, producing an exudate that  thickens the CSF and interferes with normal CSF flow around  the brain and spinal cord (Figure 18-25). The exudate has the  potential to obstruct arachnoid villi and produce hydrocepha-  lus and interstitial edema. The amount of purulent exudate  increases rapidly (especially around the base of the brain),  causing further inflammation. The exudate extends into the  sheaths of the cranial and spinal nerves and into the perivas-  cular spaces of the cortex. Meningeal cells become edematous.  The exudate and vasogenic edema increase ICP. The small and  medium-sized subarachnoid arteries, veins, and choroid plex-  uses undergo inflammatory changes and become engorged,  disrupting blood flow and potentially producing thrombosis.  Secondary infection of the brain may occur. The cortical neu-  rons also show some changes, including an increase in the num-  ber of microglia and astrocytes.   In viral meningitis, the virus reaches the CNS by hematog-  enous spread. The virus enters the brain either directly or indi-  rectly, through infected migrating leukocytes, and then infects  vascular endothelial cells. The virus then enters the subarachnoid    space, leading to meningitis. The immune response leads to  release of inflammatory cytokines with increased permeability  of the blood-brain barrier and entry of circulating immuno-  globulins that combat the virus.   Fungi in the nervous system usually produce a granulo-  matous reaction with formations of granulomas or gelatinous  masses. These usually develop in the meninges at the base of  the brain. Fungi also may extend along the perivascular sites  in the subarachnoid space and into the brain tissue, produc-  ing arteritis with thrombosis, infarction, and communicating  hydrocephalus. Meningeal fibrosis develops later in the inflam-  matory process. Cranial nerve dysfunction, caused by compres-  sion, often results from the granulomas and fibrosis.   CLINICAL MANIFESTATIONS. The clinical manifestations of a  bacterial meningitis can be grouped as: (1) inflammation and  irritation—generalized meningeal signs, throbbing headache  that becomes more severe, photophobia that becomes more  severe, nuchal rigidity, positive Kernig and Brudzinski signs;  (2) local tissue dysfunction—cranial nerve palsies, focal neuro-  logic deficits (such as hemiparesis/hemiplegia, ataxia), and sei-  zures; (3) mass effect—decreased level of consciousness, nausea,  vomiting, and increased intracranial pressure; and (4) vascular  compromise. The irritation and damage to the cranial nerves  produced by the inflamed sheaths manifest as follows:   Neck stiffness and pain, and possibly head retraction, reflect  the irritability of spinal accessory and cervical spinal nerves.  Often the vomiting center is irritated, causing projectile vomit-  ing. Confusion and decreasing responsiveness are evidence of  cortical involvement. In meningococcal meningitis, petechial  or purpuric rash involving the skin and mucous membranes  occurs. As ICP increases, papilledema may develop and delir-  ium may progress to the point that the individual becomes  unconscious.   The clinical manifestations of viral meningitis are mild com-  pared with those associated with bacterial meningitis. Mild  generalized throbbing headache, mild photophobia, mild neck  pain, stiffness, fever, and malaise are manifestations of viral  meningitis. Symptoms of aseptic meningitis are similar to those  of viral meningitis.   Fungal meningitis develops slowly and insidiously. The first  manifestations are often those of dementia or communicating  hydrocephalus (see Chapter 17). The individual is characteristi-  cally afebrile.   EVALUATION AND TREATMENT. Diagnosis of bacterial meningi-  tis is based on physical examination and the results of naso-  pharyngeal smear and antigen tests. CSF cultures are required  to diagnose fungal meningitis. Bacterial meningitis and fun-  gal meningitis are treated with appropriate antibiotic therapy,  but resistant strains are an increasing problem. Other sup-  portive measures may be needed. Viral meningitis is managed  pharmacologically with antiviral drugs and corticosteroids in    FIGURE 18-26 Brain Abscess. The abscess is sharply demarcated, indicating  that it has been present for some time. Purulent exudate is visible in the center of  the abscess. Because antibiotics penetrate very poorly into abscesses, surgical  drainage is often necessary to treat such lesions. (From Kumar V, Cotran RS, Rob-  bins SL: Robbins basic pathology, ed 7, Philadelphia, 2003, Saunders.)    addition to supportive care. There are vaccinations to prevent  meningococcal, pneumococcal, and Haemophilus influenzae  meningitis. |!”    Abscesses are localized collections of pus within the parenchyma  of the brain or spinal cord and include subdural and extradural  empyemas. They are rare and develop in about 1 per 100,000  hospital admissions and are more common in males. Abscesses  occur (1) after open trauma and during neurosurgery; (2) from  contiguous spread of infection, such as the middle ear, mastoid  cells, nasal cavity, and nasal sinuses; (3) through metastatic or  hematogenous distribution from distant foci, such as the heart,  lungs, pelvic organs, skin, tonsils, abscessed teeth, osteomy-  elitis (with the exception of cranial bones), and dirty needles  (especially in compromised hosts); and (4) from cryptogenic  (unknown) factors arising without other associated areas of  infections. Streptococci, Staphylococci, and Bacteroides, often in  combination with anaerobes, are the most common bacteria  that cause abscesses; however, yeast and fungi also have been  found in CNS abscesses. Toxoplasma gondii is producing an ever-  increasing number of CNS abscesses in persons with acquired  immunodeficiency syndrome (AIDS). Most CNS abscesses are  located in the frontal and temporal lobes (Figure 18-26). Immu-  nosuppressed persons are particularly at risk.   Brain abscesses are classified as extradural, subdural, or  intracerebral. Extradural brain abscesses (empyemas) are  associated with osteomyelitis in a cranial bone. Subdural brain  abscesses (empyemas) arise from a sinus infection or a vascu-  lar source. Intracerebral brain abscesses arise from a vascu-  lar source. Spinal cord abscesses are classified as epidural or  intramedullary. Epidural spinal abscesses usually originate as  osteomyelitis in a vertebra; the infection then spreads into the  epidural space. (Osteomyelitis is discussed in Chapter 44.)   PATHOPHYSIOLOGY. Microorganisms gain entrance to the  CNS from adjacent sites by direct extension from osteomy-  elitis or spread along the wall of a vein. Infective emboli carry    the microorganisms from distant sites. The virulence of the  pathogen and the immune response of the host are important  determinants of outcome.!!® Brain abscess evolves through  four stages regardless of infecting microorganism except in the  immunosuppressed host, where the process may be incomplete.  The stages are as follows:   1. Early cerebritis (days 1 to 3): A localized inflammatory  process develops in which perivascular infiltration or  inflammatory cells, composed of neutrophils, plasma  cells, and mononuclear cells, surround a central core of  coagulative necrosis; marked cerebral edema surrounds  the area.   2. Late cerebritis (days 4 to 9): The necrotic center is sur-  rounded by an inflammatory infiltrate of macrophages  and fibroblasts; rapid new blood vessel formation occurs  around the abscess; a thin capsule of fibroblasts and retic-  ular fibers gradually develops; the area is still surrounded  by cerebral edema.   3. Early capsule formation (days 10 to 13): The necrotic cen-  ter decreases in size; the inflammatory infiltrate changes  in character and contains an increasing number of fibro-  blasts and macrophages; mature collagen evolves, form-  ing a capsule.   4. Late capsule formation (days 14 and longer): A well-  formed necrotic center surrounded by a dense collag-  enous capsule develops.!!”   A free (nonencapsulated) abscess is associated with a higher  mortality. Existing abscesses also tend to spread and form  daughter abscesses.   Abscesses arising from the ear frequently are located in the  middle or inferior temporal lobe or in the anterolateral cerebel-  lar hemispheres. Abscesses originating from the oral, nasal, or  sinus areas most commonly are located in the frontal and tem-  poral lobes. Abscesses from distant foci often occur in multiple  numbers in the distal portion of the middle cerebral arteries. In  extradural abscesses, pus and granulation tissue accumulate in  the extradural space.   CLINICAL MANIFESTATIONS. Clinical manifestations of brain  abscesses are associated with (1) intracranial infection, such as  fever and increased sedimentation rate; or (2) an expanding  intracranial mass, such as headache, nausea, vomiting, decreas-  ing cognitive abilities, paresis, and seizures. Early clinical mani-  festations of brain abscesses are low-grade fever, headache, neck  pain and stiffness with mild nuchal rigidity, confusion, drowsi-  ness, sensory deficits, and communication deficits. Headache is  the most common early symptom. Later clinical manifestations  may include inattentiveness (distractibility), memory deficits,  decreased visual acuity and narrowed visual fields, papilledema,  ocular palsy, ataxia, and dementia. Symptoms depend on the  location of the abscess. The development of symptoms may be  very insidious, often making an abscess difficult to diagnose.  Extradural brain abscesses are associated with localized pain,  purulent drainage from the nasal passages or auditory canal,  fever, localized tenderness, and neck stiffness; occasionally the  individual experiences a focal seizure. Clinical manifestations of  spinal cord abscesses have four stages: (1) spinal aching; (2) root  pain, which is usually severe, accompanied by spasms of the back    a typical development. Brain biopsy is useful in diagnosis when the virus can be seen by electron microscopy (B) as rounded  particles with a dense core. Virus also can be identified by immunostaining or culture. In early cases, polymerase chain reac-  tion (PCR) can be used to identify viral deoxyribonucleic acid (DNA) in cerebrospinal fluid samples. (From Stevens A, Lowe JS,    muscles and limited vertebral movement because of pain and  spasm; (3) weakness caused by progressive cord compression;  and (4) paralysis.!°   EVALUATION AND TREATMENT. The diagnosis is suggested on  the basis of clinical features and confirmed with MRI or con-  trast-enhanced CT. Surgical aspiration or excision is usually  indicated.!*! Multiple or surgically inaccessible abscesses are  treated with antibiotics, often in conjunction with corticoste-  roid therapy to treat the cerebral edema. In addition, ICP may  require management.!? Because decompression is necessary,  spinal cord abscesses are treated with surgical excision or aspi-  ration. Antibiotic administration and supportive therapy also  are instituted.    Encephalitis is an acute febrile illness, usually of viral origin,  with nervous system involvement. The most common enceph-  alitides are caused by arthropod-borne (mosquito-borne)  viruses and herpes simplex viruses, almost exclusively herpes  simplex type 1 in adults (Figure 18-27). Etiologic agents for  viral encephalitis are presented in Table 18-8. Referred to as  infectious viral encephalitides, encephalitis also may occur as a  complication of systemic viral diseases such as poliomyelitis,  rabies, mononucleosis, rubella, or rubeola. Encephalitis also  may follow vaccination with a live attenuated virus vaccine  if the vaccine has an encephalitis component. Such vaccines  include measles, mumps, rubella; varicella; rotavirus; and yel-  low fever. Typhus, trichinosis, malaria, and schistosomiasis also  are associated with encephalitis. Toxoplasmosis may acutely  reactivate in immunosuppressed hosts when the once-dormant  parasite in cyst form disseminates in brain tissues.   With the exception of the California viral encephalitis,  which is endemic, the arthropod-borne encephalitides occur  in epidemics, varying in geographic and seasonal incidence  (Table 18-9). Eastern equine encephalitis is the most serious  but least common of the encephalitides.!*? West Nile virus is  presented in Box 18-1.    PATHOPHYSIOLOGY. Viruses gain access to the CNS through  the bloodstream, olfactory bulb, or choroid plexus, or through  an intraneuronal route from peripheral nerves.'** Evidence  of meningeal involvement appears in all encephalitides. The  arthropod-borne viral encephalitides cause widespread nerve  cell degeneration. Edema and areas of necrosis with or without  hemorrhage develop. Increased ICP develops and may progress  to herniation. Large degenerative injuries are found in eastern  equine encephalitis, whereas the other arthropod-borne viral  encephalitides have microscopic areas of injury and degenera-  tion. Infectious encephalitis may result from a postinfectious  autoimmune response to the virus or from direct invasion of  the CNS by the virus. Herpes simplex type 1 has a tendency  to infect the inferomedial surfaces of the temporal and frontal  lobes and causes hemorrhagic necrosis.   CLINICAL MANIFESTATIONS. Encephalitis may range from a mild  infectious disease to a life-threatening disorder. The dramatic  clinical manifestations of encephalitis are fever, delirium, or  confusion progressing to unconsciousness, seizure activity, cra-  nial nerve palsies, paresis and paralysis, involuntary movement,  and abnormal reflexes. Signs of marked ICP may be present.   EVALUATION AND TREATMENT. Diagnosis is based on health his-  tory and clinical presentation aided by CSF examination and  culture, serologic examination, white blood cell (WBC) count,  CT scan, or MRI. (Treatment available for the viral encephaliti-  des is listed in Table 18-8.) Supportive therapy is initiated, and  measures to control ICP are paramount.    Approximately 40% to 60% of all persons with AIDS have neu-  rologic complications (see Chapter 10 for the pathophysiology  of AIDS). On postmortem examination, 75% have nervous  system pathologic findings. The CNS pathologic findings result  from (1) the primary human immunodeficiency virus (HIV)  infection; (2) the immune dysregulation of early HIV infection  and progressive immunosuppression in late HIV infections    West Nile (WN) virus, a Flavivirus transmitted predominantly by the Culex mos-  quito, emerged in New York state in 1999. By the end of 2004, human cases had  been found in the 48 contiguous states. Humans and horses, as well as other  mammals, are incidental hosts. Birds and mosquitoes are life cycle hosts. Sum-  mer and fall are peak times of infection incidence. The highest amount of virus  carried by mosquitoes is in early fall. Besides mosquito transmission, WN virus  can be transmitted through blood transfusions and organ transplants. Health  experts believe transmission from mother to unborn child and through breast milk  is possible. Novel strains are emerging increasing the risk for epidemics.   Three clinical forms of West Nile virus have emerged: WN fever, WN encepha-  litis; and WN meningitis, although some individuals have other clinical mani-  festations. Some persons develop WN fever. The febrile illness of acute onset  may be clinically unrecognizable as WN. About 20% of those infected have  mild symptoms that last 4 to 6 days; symptoms generally include fever and may    include weakness, nausea, vomiting, headache, mental status changes, diar-  rhea, rash, and lymphadenopathy. WN encephalitis is marked by disorientation,  stupor, coma, seizures, and movement disorders including tremor, ataxia, extra-  pyramidal signs, and paralysis. WN meningitis is characterized by meningeal  signs of severe headache, high fever, and nuchal rigidity. Myelitis and polyradic-  ulitis also may be present. Myocarditis, pancreatitis, and fulminant hepatitis are  rare. Abnormalities in the brain stem, thalamus, basal ganglia, and cerebellum  are often seen on MAI in people with severe infection—about 1 in 150 develop  nervous system involvement. Identifiable risk factors for this are very young or  advanced age, immunocompromised status, and pregnancy.   A preliminary diagnosis is made if IgM for the virus is found in serum or CSF. A  rapid test became available in 2007. Plaque reduction neutralization assay (PRNA) is  the confirmatory test. Interferon-alpha is used during treatment along with support-  ive care for those with severe infection. Several vaccines are under development.    Data from National Institute of Allergy and Infectious Diseases, Department of Health and Human Services, National Institutes of Health: N/A/D  Research on West Nile Virus, January 2010. Available at www.niaid.nih.gov; Cho H, Diamond MS: Viruses 4(12):3812-3830, 2012; Leis AA, Stokic    resulting in opportunistic infections, neoplasms, and systemic  illness; and (3) the complications of therapy.!*° A variety of  CNS complications of HIV exist (Box 18-2). Multiple CNS  pathologic conditions may be experienced by one person. The  most common neurologic disorder is HIV-associated dementia;  others are peripheral neuropathies, vacuolar (spongy softening)  myelopathy, opportunistic infections of the CNS, neoplasms,  and, less commonly, stroke syndromes.!*°   HIV-infected macrophages/monocytes in blood are  attracted to the brain by up-regulation of proinflamma-  tory mediators such as monocyte chemoattractant protein-1  (MCP-1), tumor necrosis factor-alpha (TNF-a), and adhesion    molecules on endothelial cells. Up-regulation enables transen-  dothelial migration of activated macrophages/monocytes and  causes neuroinflammation. Brain HIV-infected macrophages  and microglia may be a sanctuary site for HIV because drugs  have more difficulty crossing the blood-brain barrier, and  there may be drug-resistant viral mutations and reinfection of  the vascular system.!?”   Human Immunodeficiency Virus-Associated Neurocog-  nitive Disorders (HANDs). A variety of names have been used for  human immunodeficiency virus—associated neurocognitive  disorders (HANDs), including HIV-associated dementia(HAD),  HIV-associated cognitive dysfunction, HIV encephalopathy,    BOX 18-2 NERVOUS SYSTEM COMPLICATIONS OF HIV-1 INFECTIONS  CNS Complications of HIV-1 Infection    Diffuse cerebral disorders  Minor cognitive and motor deficits (MCMDs)  HIV-associated dementia neurocognitive disorder (HAND)  Meningitis  Atypical aseptic meningitis    Nonviral infections  Toxoplasma gondii  Bacterial infections  Neoplasms  Primary CNS neoplasms  Metastatic neoplasms  Cerebrovascular complications  Complications resulting from systemic HIV therapy    Mycobacterial infections  Myelopathy  Spinal vacuolar myelopathy  Focal brain disorders  Opportunistic viral infections  Progressive multifocal leukoencephalopathy  Herpesviruses    subacute encephalitis, HIV-associated dementia complex,  HIV cognitive motor complex, AIDS encephalopathy, AIDS  dementia complex, or AIDS-related dementia. Both adults and  children may be affected with progressive cognitive dysfunction  in conjunction with motor and behavioral alterations. The  syndrome typically develops later in the disease but may be  an early or a singular manifestation. The syndrome is more  prevalent in drug users with HIV.!?8   The neurologic syndromes develop from properties of the  virus, genetic characteristics of the host, and interactions with  the environment (including treatment). At the time of pri-  mary HIV infection, HIV infects the perivascular macrophages,  microglial cells, and astrocytes, particularly in the basal ganglia  and deep white matter. Affected macrophages, macrophage-  derived multinucleated cells, and microglia cause an immune-  mediated demyelination process in white matter. Focal and  diffuse demyelination of white matter and spongy changes of  the spinal cord are present.   HIV-associated neurocognitive disorder is insidious in onset  and unpredictable in its course. Most individuals experience a  steady progression of mental decline characterized by abrupt  accelerations of signs over several months to more than 1 year,  although some experience an abrupt onset or an accelerated  course. The triad of clinical manifestations are neurocognitive  impairment, behavioral disturbance, and motor abnormalities.  Clinical manifestations are summarized in Table 18-10.   Diagnosis is difficult, especially in early stages. The indi-  vidual’s health history, along with physical examination find-  ings and supporting CSF, CT, and MRI data, helps establish  the diagnosis although the brain may appear normal until  there is advanced disease. Specific screening tools have been  developed to assist in diagnosis. Highly active antiretroviral  therapy (HAART) with more efficient CNS drug penetration  has reduced the prevalence and improved survival for severe  HAND, but milder forms of the disease may persist because of   e Cognitive impairments  Short-term memory deficit  Decreased concentration/attention  Confusion and disorientation  Visuospatial perception deficits    e Psychotic symptoms  Hallucinations and delusions  Suspiciousness and delusions  Agitation and inappropriate    Changes in personality or behavior  Apathy, depression  Impaired judgment, erratic  behavior  Social withdrawal  Rigidity of thought  Speech impairment    Generalized systemic symptoms  Fatigue, sleep changes  (hypersomnia)  Anorexia, weight loss  Enuresis  Hypersensitivity to drugs  and alcohol    Data from Clark C: Psychiatric aspects of AIDS, Chapter 71. In Jacob-  son JL, Jacobson AM, editors: Psychiatric secrets, ed 2, Philadelphia,  2001, Hanley & Belfus; Stern TA et al: Massachusetts General Hospital  comprehensive clinical psychiatry, ed 1, St Louis, 2008, Mosby.   HIV Myelopathy. HIV myelopathy involving diffuse  degeneration of the spinal cord may occur with HIV. Vacuolar  myelopathy is believed to be a direct consequence of HIV.  The lateral and posterior columns of the lumbar spinal cord  are affected. A progressive spastic paraparesis with ataxia is  the predominant clinical manifestation. Leg weakness, upper  motor neuron signs, incontinence, and posterior column  sensory loss may be present. Diagnosis is made on the basis of  history, physical findings, and supporting data from diagnostic  procedures. Vacuolar myelopathy is treated supportively and  does not respond to antiretrovirals.!?°   HIV-Associated Peripheral Neuropathy. Some HIV-  associated peripheral neuropathies occur early, may  coincide with seroconversion, are immune-mediated, and  respond to standard immunotherapies. Other peripheral  neuropathies primarily develop with advanced HIV infection  and immunocompromised states and are facilitated by HIV  replication, neurotoxicity from antiretroviral therapies, and  coinfection with opportunistic pathogens.   HIV neuropathy may have one or a combination of several  presentations: a predominantly sensory neuropathy, an auto-  nomic neuropathy, a mononeuritis multiplex, an inflammatory  demyelinating polyneuropathy (e.g., a Guillain-Barré—like syn-  drome), and a myopathy. The peripheral nervous system may  sustain injury in HIV, manifesting as a peripheral neuropathy  or radiculopathy. A progressive radiculopathy of predomi-  nantly the dorsal roots of the lumbar and sacral nerves may  occur, involving severe myelin and axonal loss.   HIV-associated distal symmetric polyneuropathy, a sensory  neuropathy occurring late in the disease, is the most commonly  occurring neuropathy with slowly progressive numbness and  paresthesias and burning sensations in the extremities and  feet. Weakness and decreased or absent distal reflexes may be  present.   The most common myopathy is polymyositis; it may be  present initially or develop later. Inflammation leads to muscle  cell degeneration and necrosis resulting in weakness of extremi-  ties with myalgia and fatigue.   Viral Meningitis and HIV. Some people develop an acute viral  meningitis at approximately the time of seroconversion. This  may well represent the initial infection of the nervous system by  the HIV. Symptoms include headache, fever, and meningismus.   Opportunistic Infections and HIV. Opportunistic infections  may be bacterial, fungal, protozoal, or viral in origin and produce  nervous system disease. Typically bacterial infections are caused  by unusual microorganisms. Cryptococcal infection is the  most common fungal disorder and the third leading cause of  neurologic disease with HIV. In Cryptococcus neoformans, small  granulomas and cysts are found in the cerebral cortex and later  may be present in deep cerebral tissues. The symptoms are vague,  such as fever, headache, malaise, and meningismus. Herpes  encephalitis and herpes varicella-zoster radiculitis may develop.  Papovavirus (especially JC virus) in the immunocompromised  person with HIV may produce a demyelinating disorder called  progressive multifocal leukoencephalopathy (PML). This virus    is found in 90% of healthy persons but is dormant. The virus  reactivates to cause PML in 15% of persons with HIV. Sensory  and motor deficits, aphasia, and apraxia are common clinical  manifestations. The condition is progressive and there is no  effective treatment.!°°   Cytomegalovirus Infection. Cytomegalovirus encephalitis  is common with AIDS but often not diagnosed while a person  is alive. The encephalitis may be present as an acute illness with  encephalitis features accompanied by nystagmus and cranial  nerve signs. Retinitis is found in 50% of those affected.   Parasitic Infection. Toxoplasmosis is the most common  opportunistic infection and occurs in one third of persons with  HIV. CNS toxoplasmosis typically manifests as focal encepha-  litis. Toxoplasma gondii, a protozoan, is thought to reactivate  from latent lesions to produce a well-demarcated necrotizing  process. Lesions may be multiple and exist throughout the cere-  bral hemispheres.   Clinical manifestations of CNS toxoplasmosis are focal but  highly variable and include clumsiness to hemiplegia, aphasia,  seizures, ataxia, cognitive changes, and constitutional symp-  toms. Fever and headache are common. Toxoplasmosis is dif-  ficult to diagnose but is treated effectively with pyrimethamine  and sulfadiazine.   HIV-Associated Central Nervous System Neoplasms.  HIV-associated CNS neoplasms have declined significantly  with HAART, particularly primary CNS lymphoma. Other  neoplasms associated with HIV include systemic non-Hodgkin  lymphoma and metastatic Kaposi sarcoma. Metastasis of a  Kaposi sarcoma to the CNS is uncommon.!*!   Lyme disease, a tick-borne spirochete bacterial infection, is a  common arthropod-borne infection in the United States. It  affects all age groups and involves the peripheral and central  nervous systems. Transmission is most likely in the late sum-  mer or early fall in areas where there are deer, mice, and other  animals that are primary reservoirs for infected ticks. Infected  ticks are endemic in the Midwest, Western wooded and coastal  areas, the mid- to northeast Atlantic, Europe, and eastern Asia.  Lyme disease is caused by Borrelia burgdorferi (B.b.) introduced  by tick bite, requiring about 36 to 72 hours of attachment and  feeding. During feeding the microorganism is transferred from  the gut of the tick to the salivary glands and then into the skin  of the host. B.b. larvae evade immune surveillance by inhibit-  ing complement killing, producing surface proteins that block  phagocytic recognition (antigenic variation), and hiding in the  extracellular matrix. B.b. incubates for 3 to 32 days and then  migrates to the skin, lymph nodes, and other body systems. The  pathologic process progresses through three stages!°?:   Stage I (acute localized): Within 1 month after the bite, the  disease is characterized by a bull’s-eye—like (5 cm in  diameter) burning and centrifugally expanding erythema  migrans rash followed by acute disseminated disease with  general malaise, flulike symptoms (fever, muscle pain),  stiff neck, and headache (seen in 50% to 90% of cases).   Stage II (systemic infection): Skin manifestations continue  with or without acute widespread dissemination of    antibodies and immune complexes and cardiac and neu-  rologic involvement (within a week up to a month). About  10% of cases show cardiac signs and symptoms (palpi-  tations, dizziness, shortness of breath, arrhythmias, and  first-degree heart block). Neurologic signs occur in 10%  to 15% of those affected and include headache, chronic  aseptic (lymphocytic) meningitis, Bell palsy, encephalitis,  and radiculitis. Pathologically, there is meningeal inflam-  mation, perivascular inflammatory cell formation, and  focal demyelination.   Stage LI (chronic stage): The third stage may occur up to 2  years after the bite and involves arthritis and involvement  of brain parenchyma with encephalitis, chronic neuropa-  thy (paresthesias, radiculopathy), and encephalopathy  (cognitive deficits, memory loss).   B.b. infection can be difficult to diagnoses. Treatment of  choice is antibiotic therapy. Minor recurring symptoms are  common in 50% of individuals. Some individuals experi-  ence post—Lyme disease syndrome after antibiotic treatment,  with fatigue, musculoskeletal pain, and short-term memory  difficulty. !°°   Demyelinating disorders are the result of damage to the myelin  nerve sheath. They can occur in either the central (e.g., mul-  tiple sclerosis) or the peripheral (e.g., Guillain-Barré syndrome,  which also involves a polyneuropathy [see p. 622]) nervous  system. Causes of the disorders include genetics, infections,  autoimmune reactions, environmental toxins, and unknown  factors. Multiple sclerosis is the most common and is presented  in the next section.   Multiple sclerosis (MS) is a chronic inflammatory disease  involving degeneration of CNS myelin, scarring or formation  of plaque, and loss of axons. MS is caused by an autoimmune  response to self-antigens in genetically susceptible individuals.  About 0.1% of the population is affected (400,000 persons in  the United States and 2.1 million worldwide).!** Prevalence  rates vary with geographic location (higher in temperate regions  far above the equator) and racial groups (highest in whites,  although it occurs in all races).   The onset of MS is usually between 20 and 40 years of age  with a peak of age 30. Male to female ratio is about 1:2. MS is  the most prevalent CNS demyelinating disorder and a leading  cause of neurologic disability in early adulthood. Life expec-  tancy is not greatly altered by MS and the disease course often  extends over 30 years. The etiology of MS is unknown. Genetic  and environmental factors and interactions are implicated in  disease onset. Although the disorder does not exhibit a defined  inheritance pattern, 15% of those with MS have an affected rela-  tive. Multiple genes affect risk of development of MS. A genetic  link exists in the human leukocyte antigen (HLA) complex,  a large cluster of genes responsible for many immune func-  tions. Several genetic polymorphisms are probably involved.'°°  Vitamin D deficiency, cigarette smoking, and Epstein-Barr  virus infection are environmental risk factors.!*°    The first demyelinating event, or “clinically isolated syn-  drome” (CIS), is a single episode of neurologic dysfunction  lasting greater than 24 hours that can be a prelude to MS. Char-  acteristic episodes include optic neuritis, solitary brainstem  lesions, and transverse myelitis.'°”   PATHOPHYSIOLOGY. MS is a diffuse and progressive CNS dis-  ease that affects white and gray matter. Autoreactive T and B cells  recognize myelin autoantigens and trigger inflammation in the  CNS, leading to the loss of myelin sheaths and nerve conductiv-  ity and subsequently to the death of neurons (Figure 18-28). MS  is described as occurring when a previous infectious insult to the  nervous system has occurred in a genetically susceptible individ-  ual with a subsequent abnormal CNS immune response. Vari-  ous mechanisms cause irreversible tissue damage (inflammation,   ated axons are more fragile and susceptible to further damage and,   begin before symptom onset (early inflammatory demyelination).  The innate and adaptive immune systems are activated in the   following events:  1. Activation of CD4+ and CD8+ T cells; cells cross the   5. Expression of integrins to facilitate adherence and pas-  sage of immune cells into the CNS   6. Promotion of chemokine migration of immune cells into  the CNS that is up-regulated in MS   7. Contribution of B lymphocytes and plasma cells to the  inflammatory response and direct damage to myelin and  axons; B cells are more active in chronic or progressive  forms of MS (B cells produce autoantibodies, secrete  inflammatory cytokines, and activate T cells by present-  ing antigen) !°%!40   8. Activation of complement (promotes inflammation)  during the acute phase; may be neuroprotective during  relapse!*!   9. Presence of cells of inflammation including eosinophils,  neutrophils, and macrophages    As the disease progresses, inflammatory changes in the  CNS increase, and loss of brain volume progresses more rap-  idly.!*7-! The demyelination disrupts sodium, calcium, and  potassium ion channels and calcium influx is proinflammatory  and neurotoxic. Activated microglia and macrophages release  nitric oxide and oxygen free radicals. Activated immune cells  also produce glutamate, a neurotoxin.!“+   MS is characterized not only by focal inflammatory changes  but also by diffuse injury throughout the CNS (MS lesions)  (Figure 18-29). MS lesions may occur anywhere in white or gray  matter. In addition, other neurodegenerative processes that  involve the entire CNS are taking place, including: (1) changes  in gray matter in the cortex, basal ganglia, brainstem, and spi-  nal cord with substantial loss over time; (2) brain atrophy that  begins early in the disease and is highly correlated with disability  and progressive MS; and (3) direct dysfunction of or damage  to oligodendrocytes that manufacture myelin.'4?!4° Normal-  appearing white matter also is highly abnormal microscopically  with the presence of wallerian degeneration, diffuse inflamma-  tion, extensive microglial activation, neurotoxic substances, and  gene activation that disrupt cellular processes.!*° Iron deposits  in both gray and white matter have been found in MS, and the  pathologic significance may be associated with mitochondrial  and oxidative injury.'*” Research is in progress to determine if  chronic cerebrospinal venous insufficiency is a pathogenic fac-  tor in MS."“° In established disease the multifocal, multistaged  feature of MS lesions gives rise to the aphorism that the lesions  are “scattered in space and time.” Symptoms therefore are mul-  tiple and variable among individuals with the disease.   CLINICAL MANIFESTATIONS. A variety of events (e.g., infection,  trauma, or pregnancy) occurring immediately before the onset  or exacerbation of symptoms are regarded as precipitating fac-  tors related to MS. Most of the pregnancy-related exacerbations    FIGURE 18-29 Multiple Sclerosis, Gross. Seen here in periventricular white matter is a large “plaque”  of demyelin-  ation that has a sharp border with adjacent normal white matter. Such plaques have a gray-tan appearance and are typically  associated with the clinical appearance of transient or progressive loss of neurologic function in multiple sclerosis (MS).  Because MS is often multifocal, and the lesions appear in various white matter locations in the central nervous system over  time, the clinical course and findings can be quite varied. (From Klatt EC: Robbins and Cotran atlas of pathology, Philadelphia,    Spinal Type (30% to 40% of Persons)  Spastic ataxia  Deep sensory changes in the extremities  Bladder and bowel symptoms    occur 3 months postpartum, suggesting a relation to the stresses  of labor and the increased fatigue during the postpartum period  rather than to the pregnancy itself.'4? The major classifications  of MS are relapsing-remitting, primary progressive, secondary  progressive, and progressive-relapsing. Initially 90% of persons  present with a relapsing, remitting course; 10% present with  a primary progressive course; and 90% develop a progressive  course in 10 to 20 years after onset of the disease. However,  once walking problems develop, disease progression occurs  quickly regardless of disease type. Usually persons with late MS  have one of the established syndromes—mixed, spinal, or cere-  bellar (Box 18-3). The initial syndrome depends on the portion  of the CNS that is most involved. After years of disease, 50%  of individuals appear to have established syndromes of mixed  involvement.   Optico-Spinal Multiple Sclerosis. Optico-spinal multiple  sclerosis (OSMS) has the manifestations of optic nerve and  spinal cord axonal loss. The condition usually evolves rapidly  over hours to days and is highly suggestive of MS. Involvement  may be unilateral or bilateral. Subjective symptoms are impaired  central vision (blurring, fogginess, haziness) and impaired color  perception. Signs are decreased central visual acuity; central  or paracentral scotoma (area of diminished vision); acquired  color vision deficit, especially to red and green; and defective  pupillary reaction to light. A variety of field defects may occur.  In the acute phase these symptoms may reflect optic papillitis  (inflammation and swelling of the optic disc) or retrobulbar  neuritis with a normal disc. Immune injury damages the optic  nerve and inflammatory edema compresses the blood supply in  the tight optic canal. One third of persons recover completely,  and most others improve significantly.!°°   The brainstem lesions involve cranial nerves III through XII  at the root, nuclear, or corticobulbar (upper motor neuron)  level. Internuclear ophthalmoplegia, nystagmus, and dysarthria  are the most common brainstem symptoms, followed by deaf-  ness, vertigo and vomiting, tinnitus, facial weakness, and facial    sensory deficit. Internuclear ophthalmoplegia is lateral gaze  paralysis caused by involvement of the medial longitudinal fas-  ciculus, the brainstem pathway that coordinates eye movement.  Diplopia and eyeball pain are common complaints. Bilateral  internuclear ophthalmoplegia in a young adult is virtually diag-  nostic of MS.   Cognitive dysfunction has been demonstrated to occur early  in the disease course. The person experiences decreased short-  term memory, recent memory impairment, decreased con-  centration, word-finding problems, and planning difficulties.  Mood alterations are common in MS. Depression is far more  common than euphoria.   Neuromyelitis optica (NO; Devic disease) is a demyelinat-  ing disease that also selectively affects the optic nerve and spinal  cord (usually grouped within three to four vertebrae). It was  previously considered to be a severe variant of MS because of the  similar pathologic features and its resemblance to optico-spinal  MS that occurs in the Asian population. However, aquaporin-4  (AQP4) IgG autoantibodies play a pathogenic role in NO and it  may be a distinct disorder or overlap with OSMS.'°!   Spinal Multiple Sclerosis. The spinal type of MS is the second  most common type, chiefly involving the spinal tracts and  dorsal column. Weakness, numbness, or both in one or more  limbs are initial symptoms in 50% of cases of MS. Subjective  corticospinal (upper motor neuron) symptoms (stiffness,  slowness, weakness) are often unilateral and are a component of  fatigability. Spinal signs are usually bilateral (symmetric), with  lower limbs more often and more severely affected than upper  limbs; spastic paraparesis is probably the most common single  neurologic finding in MS.   Bladder and bowel symptoms occur with major spinal cord  involvement. Urgency and hesitancy generally precede inconti-  nence. Bladder dysfunction most often involves a small, spas-  tic bladder, although occasionally a large, flaccid bladder may  develop with retention problems. Neurogenic impotence often  occurs when sphincter symptoms are present. Bowel inconti-  nence is rare, but constipation is common with severe disease.  Subjective dorsal column symptoms are symmetric paresthesias  (tingling and numbness) in an unpredictable pattern but with a  predilection for lower extremities over upper extremities. Dor-  sal column signs are vibration, position, and two-point discrim-  ination deficits. Sensory complaints often are not substantiated  by objective physical findings but by further diagnostic tests.   Cerebellar Multiple Sclerosis. Nystagmus and ataxia  can present initially and reflect cerebellar and corticospinal  involvement. Cerebellar deficits are usually symmetric, with all  four limbs involved. With combined corticospinal and cerebellar  involvement, the individual has a spastic ataxic gait and ataxia  of the arms. Pure cerebellar symptoms are those of motor  ataxia, hypotonia, and asthenia (weakness). Manifestations  of motor ataxia are decomposition of movement, inability to  perform rapid alternating movements (dysdiadochokinesia),  and dysmetria. Charcot triad describes a combination of  dysarthria, intention tremor, and nystagmus associated with  cerebellar multiple sclerosis. Hypotonia is manifested by  decreased resistance to passive movement, hypoactive deep  tendon reflexes, and pendular knee jerk reflex.    Signs and symptoms indicating disease of  the brain or spinal cord not attributable  to another diagnosis with two or more  episodes lasting at least 24 hours and  occurring at least 1 month apart    Short-lived attacks of neurologic deficits are the temporary  appearance or worsening of symptoms. The mechanism of  these attacks is complete reversible conduction block in par-  tially demyelinated axons. Conditions that cause short-lived  attacks include: (1) minor increases in body temperature or  serum Cat‘? concentration and (2) functional demands exceed-  ing conduction capacity. An increase in body temperature or  serum Ca™* level increases current leakage through demyelin-  ated neurons. Individuals with MS may become dramatically  worse when body temperature is raised. Hypercalcemia induced  by decreased serum pH may aggravate symptoms of MS. Physi-  cal and emotional stress imposes functional demands that may  exceed conduction capacity of affected neurons.   Paroxysmal attacks are sensory or motor symptoms of abrupt  onset and short duration (a few seconds or minutes). These  symptoms include paresthesias, dysarthria and ataxia, and tonic  head turning. The mechanism of paroxysmal attacks is nonsyn-  aptic transmission in which nerve impulses are directly trans-  mitted between adjacent demyelinated axons. These impulses  arise focally and spuriously in the cervical portion of the spinal  cord or in the brainstem. A common paroxysmal symptom,  called Lhermitte sign, is the momentary paresthesia (shock-  like or tingling sensation) that shoots down the trunk or limbs  during active or passive flexion of the neck. Bending the neck  evokes nonsynaptic impulses in demyelinated axons of the  dorsal column in the spinal cord. A person with MS may have  many paroxysmal attacks each day. Inciting events include sen-  sory stimulation, voluntary movement, hyperventilation, and  emotional stress. Paroxysmal attacks tend to persist for weeks or  months and may be followed by progressive symptoms of MS.   EVALUATION AND TREATMENT. The diagnostic criteria for  MS were revised in 2010 and are known as the McDonald  criteria.!°* Clinical examination in combination with MRI, to  demonstrate MS lesions in time and space, and CSF findings are  used to make an early diagnosis (Table 18-11) so that treatment  may begin sooner. Persistently elevated CSF immunoglobulin  G (IgG) index is found in about two thirds of individuals with    MS, and oligoclonal bands of IgG on electrophoresis are found  in more than 90% of persons. Evoked response (ER) studies aid  diagnosis by detecting decreased conduction velocity in visual,  auditory, and somatosensory pathways. MRI is used to assist  diagnosis and assess prognosis although there are limitations to  detecting the full extent of the lesions.!°*   The treatment goal in MS is prevention of permanent neu-  rologic damage. Acute relapses are treated with corticosteroids  to speed recovery. Both oral and injectable disease-modifying  drugs are used to decrease the number of relapses, promote  remyelination and repair, prevent demyelination, suppress  selective B-cell and T-cell function, and prevent disability.'**  Vitamin D supplementation may reduce the risk of MS and  promote a more favorable progression.'°°   Symptom management for fatigue, weakness, vertigo, ataxia,  tremor, heat intolerance, spasticity, bladder dysfunction, bowel  dysfunction, sexual dysfunction, sensory sensations, pain, cog-  nitive difficulties, depression, and psychosocial issues is essen-  tial. Many treatments are only partially effective, particularly  for fatigue and spasticity. Supportive and rehabilitative man-  agement is directed toward preventing the complications of  immobility, especially pressure sores and infections of the pul-  monary and genitourinary systems. Interdisciplinary inpatient  rehabilitation may improve function in the short term.!°°   The axons traveling to and from the brainstem and spinal cord  neuronal cell bodies may be injured by a multitude of disease  processes. Distinct anatomic areas of the axon may be injured  or the spinal nerves may be affected at the spinal roots, at the  plexus before peripheral nerve formation, or at the peripheral  nerves themselves. Cranial nerves do not have roots or plexuses  so are affected only within the nerves. Autonomic nerve fibers  may be injured as they travel within certain cranial nerves or  emerge through the ventral root and plexuses to travel in the  peripheral nerves of the body.   Neuropathies can be classified as (1) generalized symmetric  polyneuropathies, (2) generalized neuropathies, and (3) focal  or multifocal neuropathies. Generalized symmetric polyneu-  ropathies are characterized by symmetric involvement of sen-  sory, motor, or autonomic fibers although, with clinical signs,  one type of fiber may predominate. Generalized symmetric  polyneuropathies further subdivide into distal axonal poly-  neuropathy and demyelinating polyneuropathy. Distal axonal  polyneuropathy affects peripheral axons and is the generalized  peripheral neuropathy commonly seen. The clinical feature  of distal axonal polyneuropathy is involvement of the longest  nerves of the body, those going to the feet, first. Sensory impair-  ment is greater than motor impairment. Symptoms are burning  pain, tingling, and numbness of the feet. Small nerve fiber dam-  age produces decreased pain and temperature sensation, as well  as burning, numbness, and tingling. Large nerve fiber injury  causes decreased light touch, vibration, and position sense.    The two most common causes are diabetes mellitus and alcohol  abuse; occasionally, neurotoxic therapeutic agents also are the  cause. Within the classification of distal axonal neuropathies  is another group of neuropathies called autonomic neuropa-  thy. This neuropathy can involve virtually any sympathetic or  parasympathetic nerve fiber with impairment of cardiovascular,  gastrointestinal, urogenital, thermoregulatory, sudomotor, and  pupillomotor autonomic function. Autonomic neuropathies  have a progressive course and are usually reversible. The myelin  or Schwann cells are affected in demyelinating polyneuropa-  thy, which occurs far less frequently. Weakness is the predomi-  nant sign with far less sensory impairment. Acute and chronic  inflammatory demyelinating neuropathies comprise this group,  of which Guillain-Barré syndrome is the most widely recog-  nized disorder (see below).   Generalized neuropathies affect the cell body of only one  type of peripheral neuron. The dorsal root ganglion cell is  affected in sensory neuropathies, producing numbness that  may begin in a focal or asymmetric distribution or in a distal  symmetric pattern. Sensory neuropathies are seen in leprosy,  some industrial solvent poisonings, some hereditary disorders,  and chloramphenicol toxicity. Motor neuropathies are caused  by anterior horn cell disease, such as amyotrophic lateral sclero-  sis or paralytic poliomyelitis. There is weakness or paralysis that  may be symmetric or asymmetric.   Focal neuropathy or multifocal neuropathies affect sen-  sory and motor fibers in one or more nerves, as is seen in  common compression neuropathies such as carpal tunnel syn-  drome (median nerve compression), ulnar nerve compression  (at the elbow), peroneal nerve compression, or sciatic nerve  compression. Focal neuropathies can involve one or more cra-  nial nerves. Plexus injuries and radiculopathies also fall into  this category.   PATHOPHYSIOLOGY. Although distinct pathophysiologic pro-  cesses are recognized in a neuropathy, these are not disease  specific and may exist simultaneously in any one neuropathy.  Wallerian degeneration, in which the axon and myelin distal  to the site of axonal interruption degenerate, may be present  (see Chapter 15). This type of degeneration is characteristic  of a traumatic nerve injury in which the nerve is severed. In  demyelinating neuropathies the axon may be spared and only  the myelin degenerates. In axonal degeneration distal degen-  eration of the axon occurs first and is followed by degeneration  of the myelin and the axis cylinder. Many pathologic processes  may give rise to neuropathy, and one or more nerves may be  involved.   CLINICAL MANIFESTATIONS. When the axons are affected, muscle  strength, muscle tone, and muscle bulk also are affected. Whole  muscles or groups of muscles are paretic or paralyzed, and the  muscles of the feet and legs often are affected first and more  severely. These long, large axons are thought to (1) be more vul-  nerable to injury because of their size and length, (2) have more  Schwann cells available to be injured, and (3) exhibit a “dying  back” phenomenon caused by difficulty of the nerve cell body  in maintaining the terminal portion of the axon. If unchecked,  the pathologic process tends to involve the hands and arms  because these have the next longest and largest axons.    Tone and the deep tendon reflexes in the affected muscles  generally are decreased in a neuropathy. Atrophy is distributed  according to the peripheral nerves involved. The degree and  distribution of the atrophy probably depend on the extent of  the injury. Fasciculation may be present, especially with asso-  ciated ventral root or motor neuron changes, or both, as in  Guillain-Barré syndrome, diabetic neuropathy, and porphyric  neuropathy. Mild fatigue may be experienced. A few disorders,  notably Guillain-Barré syndrome, produce a pattern of paresis  and paralysis that involves all limbs, the trunk, and the neck.  Peripheral bifacial and other cranial nerve palsies may be seen  with a variety of disorders. Tenderness of the nerve trunks and  associated sensory alterations help to distinguish neuropathy  from amyotrophy. These include paresthesias and dysesthe-  sias as well as decreased or absent primary sensations (e.g., of  temperature, touch, light pain, position, or vibration). Ataxia  of gait or limb may arise from the loss of position and vibra-  tory sensations (i.e., proprioceptive sensory loss) and may be  enhanced by motor weakness.   Reflexes may be altered. Reflex-mediated autonomic ner-  vous system functions, such as sweating and pupillary size, may  be affected. Neuropathies associated with autonomic distur-  bances include diabetes mellitus, alcoholism and related nutri-  tional neuropathies, amyloidosis, porphyria, Guillain-Barré  syndrome, Riley-Day syndrome, and familial sensory neurop-  athy. In many chronic polyneuropathies, the feet, hands, and  spine become deformed. Metabolic changes may arise second-  ary to nerve dysfunction.   EVALUATION AND TREATMENT. The diagnostic workup to deter-  mine the cause of a neuropathy is often extensive. Early diag-  nosis and treatment before irreversible neuronal cell damage  ensues are of paramount importance. Although axonal regrowth  and recovery of function may take months, many neuropathies  can be reversed. The therapeutic management is directed first  at elimination of the cause, if possible. At least the primary dis-  order, such as diabetes mellitus, should be controlled. Further  damage to the axon must be prevented by avoiding (1) trauma  from premature demand for reuse of the nerve, (2) accidents  that cause tissue damage, and (3) hypoxia and ischemia or other  deprivation of essential substrates.   Guillain-Barré Syndrome. Guillain-Barré syndrome (GBS)  (Landry-Guillain-Barré syndrome, idiopathic polyneuritis,  acute inflammatory demyelinating polyradiculopathy, acute  autoimmune neuropathy) is an acquired acute inflammatory  demyelinating or axonal polyneuropathy with four subtypes.  The subtypes and their clinical features are presented in  Table 18-12. These subtypes occur throughout the world, affect  children and adults of both genders and all age groups equally,  and occur in all seasons of the year. The annual incidence rate is  1 to 2 per 100,000 with a 4% to 6% mortality, and a 5% to 10%  morbidity rate (permanent disabling weakness, imbalance, or  sensory loss).!°7   PATHOPHYSIOLOGY. GBS is considered to be an autoimmune  disease triggered by a preceding bacterial or viral infection.  Molecular mimicry (cross-activation of self-epitopes and  pathogen-derived peptides by autoreactive T and B cells) is  associated with the immune injury.!°* It has been recognized    that glycolipids, particularly gangliosides, are immune targets  in the subtypes of GBS. Different gangliosides predominate in  different locations in peripheral nerves and in different nerve  fiber types. Table 18-12 presents the pathology and pathogen-  esis of the four axonal subtypes of GBS. The muscle innervated  by the damaged peripheral nerves undergoes denervation and  atrophy. If the cell body survives, regeneration of the peripheral  nerve takes place and recovery of function is likely. If the cell  body dies from intense root involvement in the inflammatory-  degenerative process, no regeneration is possible. Collateral  reinnervation from surviving axons and regenerating axons  may take place. In this case, motor recovery is less complete and  residual deficits persist.   CLINICAL MANIFESTATIONS. Clinical manifestations may vary  depending on subtype. Typical first manifestations are numb-  ness, pain, paresthesias, or weakness in the limbs. Motor signs  manifest as an acute or subacute progressive paralysis. Proxi-  mal muscles may be involved earlier and more significantly    than distal muscles. The paresis/paralysis may be present in an  ascending pattern involving limbs, respiratory muscles, and  bulbar muscles. Only bulbar muscles may be involved, result-  ing in dysphagia and dysarthria. Weakness usually plateaus or  improves by the fourth week in 90% of cases. After weakness  plateaus, strength improves over a period of days to months,  with the majority of individuals reaching activity levels simi-  lar to their predisease state. If sensory symptoms are present in  the subtype they may include paresthesias/dysthesias (tingling,  burning, shocklike sensations, particularly in the limbs), pain  (throbbing and aching, particularly in the lower back, but-  tocks, and legs), and numbness. Position and vibratory sensa-  tions are more affected than superficial sensation. Respiratory  muscle weakness leads to the need for ventilatory support in  10% to 30% of individuals. Cranial nerve weakness manifests as  facial weakness and bulbar weakness involving chewing, swal-  lowing, and coughing. Autonomic dysfunction may manifest  as tachycardia or, less frequently, bradycardia; hypotension or    Acute inflammatory  demyelinating polyneuropathy  (AIDP accounts for most cases  of GBS)   Some degree of axon loss (all findings most  prominent in the spinal roots and nerve  terminals)   Macrophages invade nodes of Ranvier, leaving the  myelin sheath intact (absence of demyelination)    Similar to AMAN  Absence of demyelination  Evidence of axonal loss in dorsal and ventral roots  Lymphocytic infiltration sparse  Extensive sensory nerve fiber degeneration  Pathologic features similar to those in AIDP,    Deposition of antiganglioside antibodies initially  causes reversible conduction block followed  by axonal degeneration    Selective antibody-mediated attack  on axon (presence of IgG and  complement deposits on axolemma  along with macrophage recruitment)    Antibodies to ganglioside GO1b  measured in serum in 90% of cases    Anti-GQ1b antibodies cross-react  with other gangliosides (typically  GT1a, but in many cases with  GD3, GD1b, and GT1b)    Data from Hardy TA et al: Curr Allergy Asthma Rep 11(3):197-204, 2011; Shahrizaila N, Yuki N: Exo Rev Neurother 11(9):1305-1313, 2011.    hypertension; and loss of or significant increase in sweating in  those more severely affected. Persons may undergo a respira-  tory arrest or cardiovascular collapse, a cause of death. Hypo-  natremia caused by the syndrome of inappropriate antidiuretic  hormone (SIADH) is common, especially in individuals whose  lungs have been ventilated.   EVALUATION AND TREATMENT. Clinical history helps diagnose  GBS and its subtypes. The major diagnostic tests are the exami-  nation of the CSF, nerve conduction studies, and EMG. The  CSF findings include an unusually high protein level (500 mg/  dl) without cellular abnormality. Nerve conduction studies help  identify the subtype. Ventilatory support and management of  the autonomic nervous system dysfunction are two dominant  aspects of the therapeutic management. Intravenous immuno-  globulin, plasmapheresis, or plasma exchanges or combination  therapy within the first 2 weeks of onset of clinical manifes-  tations may be indicated. After the disorder begins to remit,  aggressive rehabilitation should be instituted.'°”   Radiculopathies. Radiculopathies are disorders of spinal  nerve roots. As the spinal roots emerge from or enter the  vertebral canal, they may be injured or damaged by compression,  infection, inflammation, ischemia, or direct trauma whereby  the roots are stretched or torn. Radiculitis (radiculoneuritis)  refers to an inflammatory disorder of the spinal nerve roots.  One or more roots may be affected.   PATHOPHYSIOLOGY. Many different pathologic conditions may  cause tearing, compression, or inflammation of nerve roots.!©°  Roots may be traumatized by a forceful tearing ofa nerve, termed  avulsion, often associated with injuries to the head and shoul-  ders. An acute intervertebral disk prolapse (herniated disk),  degenerative spondyloarthropathies, or a benign tumor may  compress nerve roots. Metastatic tumors of the lung, breast, and  gastrointestinal tract may produce a carcinomatous meningitis,  causing compression and inflammatory changes in nerve roots.  Other causes of inflammatory changes in nerve roots are chronic  meningitis, neurosyphilis, sarcoidosis, and inflammatory arach-  noiditis produced by myelography and lumbar punctures.   CLINICAL MANIFESTATIONS. The strength, tone, and bulk of the  muscles innervated by the involved roots are affected. The pat-  tern and distribution of weakness and atrophy are similar to  those of the amyotrophies. Tone and deep tendon reflexes are  decreased, but rarely absent, because the involved muscles are  usually innervated by two or more spinal roots. Fasciculations  often are present, and mild fatigue may be experienced. Because  pathologic processes usually affect the ventral as well as the dor-  sal roots, sensory alterations are common.   Diseases that involve spinal roots typically produce local  pain; pain on local percussion; pain and paresthesias in the sen-  sory root distribution (called radicular pain and radicular par-  esthesia); increased pain with movement, stretching of the root,  and maneuvers that transiently increase CSF pressure; sensory  loss in a radicular pattern; and spasms of the muscles surround-  ing the vertebral column (i.e., paravertebral muscle spasms).   EVALUATION AND TREATMENT. Diagnostic measures may include  physical examination, spinal films, nerve conduction studies,  EMG, lumbar puncture with CSF examination, myelography,  and biopsy of tumor masses.!°!    Treatment is directed at the cause of the injury and may  take the form of surgical intervention, antibiotic administra-  tion, removal of the injurious agent, corticosteroid use, and  radiation therapy and chemotherapy. Supportive management  may include control of the discomfort, protection from further  injury, prevention of complications, and rehabilitation when  appropriate.   Plexus Injuries. Plexus injuries involve the nerve plexus  distal to the spinal roots but proximal to the formation of the  peripheral nerves. Such injuries may be caused by trauma,  compression (entrapment), or infiltration, or they may be  iatrogenic, caused by positioning during surgery or by an  intramuscular injection. Clinical manifestations include motor  weakness, muscle atrophy, and sensory loss in affected areas.  Paralysis can occur with complete plexus lesions. !°   The diagnosis is made on the basis of history and clinical  manifestations. Therapeutic treatment is directed at removal  of the cause, repair and approximation of nervous tissue, pre-  vention of further injury, control of discomfort, prevention of  complications, and rehabilitation when appropriate. Acetyl-  L-carnitine (ALCAR) or N-acetylcysteine (NAC) can provide  neuroprotection.!®    Transmission of the nerve impulse at the neuromuscular junc-  tion requires the release of adequate amounts of neurotrans-  mitter from the presynaptic terminals of the axon and effective  binding of the released transmitter to the receptors on the mem-  branes of muscle cells (see Figure 15-14). Four neuromuscular  junction disorders (NMJDs), whose pathogenesis is thought to  be autoantibodies, are described: myasthenia gravis, muscle-  specific kinase (MuSK) protein antibody—associated myasthe-  nia gravis, Lambert-Eaton myasthenic syndrome, and acquired  neuromyotonia. In addition, there are rare inherited (con-  genital) myasthenic syndromes that result from mutations in  different key proteins for the acetylcholine receptor, ion chan-  nels, and motor end plates at the neuromuscular junction.'*  Nutritional deficits; certain drugs (e.g., reserpine or methyldopa  [Aldomet]); certain toxins (e.g., botulism); some snake, scor-  pion, or spider venoms; certain plant extracts; and some insecti-  cides also affect the neuromuscular junction. The most common  autoimmune neuromuscular junction disorder (NMJD) is  myasthenia gravis caused by the binding of autoantibodies  to the acetylcholine receptor on the postsynaptic membrane.  MuSK antibody-associated myasthenia gravis is also postsyn-  aptic and is a severe form of the disease.'® Presynaptic autoim-  mune diseases include neurotonia with autoantibodies to the  potassium channels and the rare Lambert-Eaton myasthenic  syndrome with autoantibodies to calcium channels on presyn-  aptic nerve terminals, which presents with muscle weakness and  is commonly associated with small-cell lung carcinoma.'°°    Myasthenia gravis is a chronic autoimmune disease mediated  by acetylcholine receptor (AchR) antibodies that act at the neu-  romuscular junction (Figure 18-30 and Table 18-13). About  20,000 to 70,000 people in the United States have the disease.    Myasthenia gravis is associated with an increased incidence of  other autoimmune diseases, including systemic lupus erythe-  matosus, rheumatoid arthritis, polymyositis, and thyrotoxi-  cosis. (Autoimmune mechanisms are discussed in Chapter 9.)  The etiology of myasthenia gravis is unknown. Some persons  have genetic susceptibility related to variants in AchR genes, as  well as the major histocompatibility genes, and they can present  with varying clinical phenotypes.!°    FIGURE 18-30 Antibodies and Myasthenia Gravis. Acetylcholine receptor  antibodies block the acetylcholine receptor and inhibit the stimulating effect of  acetylcholine on the postsynaptic membrane. Ach, Acetylcholine receptor. (Data  from Juel VC, Massey JM: Orphanet J Rare Dis 2:44, 2007; Mahadeva B, Phillips  LH 2nd, Juel VC: Semin Neurol 28[2]:212-227, 2008; Shigemoto K: Acta Mycol  26[3]:185-191, 2007.)    The subtypes of autoimmune myasthenia gravis are general-  ized AchR, ocular, and neonatal. Generalized AchR myasthenia  gravis is further subdivided based on age and thymic pathology  into the following categories:   Generalized AchR myasthenia involves the proximal mus-  culature throughout the body and has several courses: (1) a  course with periodic remissions, (2) a slowly progressive course,  (3) a rapidly progressive course, or (4) a fulminating course.  Classification by disease severity is as follows:   About 10% to 15% of those with signs and symptoms  of myasthenia gravis often involving severe swallowing and  breathing (bulbar) problems do not have AchR antibodies on  testing. Some of these have MuSK antibodies (an IgG4). This is  now subtyped as MuSK antibody—associated myasthenia gravis.   In neonatal myasthenia, transitory signs of myasthenia  gravis are present in 10% to 15% of infants born to mothers  with myasthenia gravis. The signs appear | to 3 days after birth  and persist for a few days to a few weeks. Myasthenia immuno-  globulin is transferred from the mother to the neonate through  the placenta. Ocular myasthenia, which is more common in  males, involves weakness of the eye muscles and eyelids and  may include swallowing difficulties and slurred speech as well.   PATHOPHYSIOLOGY. Myasthenia gravis results from a defect  in nerve impulse transmission at the neuromuscular junction.  The main defect is T-cell-dependent formation of autoanti-  bodies (an IgG antibody) against receptors at the Ach-binding  site on the postsynaptic membrane. The autoantibodies block  the AchR or cause complement-mediated loss of AchRs from    Complement-mediated destruction  of folds (includes loss of AchR  and sodium channels), increased  turnover, direct block of function    Data from Farrugia ME, Vincent A: Curr Opin Neurol 23(5):489-495, 2010; Pal J et al: J Neuroimmunol! 231(1-2):43-54, 2011.  AchR, Acetylcholine receptor; /g, immunoglobulin; MuSK, muscle-specific kinase; NMJ, neuromuscular junction; VGCC, voltage-gated calcium    the neuromuscular junction (see Figure 18-30).'° The cause  of this autosensitization is unknown. Destruction of receptor  sites occurs, decreasing the number of receptors on the plasma  membrane and causing diminished transmission of nerve  impulses across the neuromuscular junction. Muscle depolar-  ization is incomplete or unsuccessful.   CLINICAL MANIFESTATIONS. Myasthenia gravis typically has an  insidious onset. Clinical manifestations may first appear during  pregnancy, during the postpartum period, or in conjunction  with the administration of certain anesthetic agents. Hallmark  symptoms are exertional fatigue and weakness that worsens  with activity, improves with rest, and recurs with resumption  of activity. The individual often complains of fatigue after exer-  cise and has a recent history of recurring upper respiratory  tract infections. The muscles of the eyes, face, mouth, throat,  and neck usually are affected first. The extraocular (eye) mus-  cles and the levator muscles are most affected. Manifestations  include diplopia, ptosis, and ocular palsies.   The muscles of facial expression, mastication, swallowing,  and speech are the next most involved. The results are facial  droop and an expressionless face; difficulty chewing and swal-  lowing associated with dietary changes and weight loss; drool-  ing; episodes of choking and aspiration; and a nasal, low-volume  but high-pitched monotonous speech pattern.   The muscles of the neck, shoulder girdle, and hip flexors  are affected less frequently. When these muscles do become  involved, however, the person experiences fatigue requiring  periods of rest, weakness of the arms and legs that improves  with rest, and difficulty in maintaining head position. The  respiratory muscles of the diaphragm and chest wall become  weak, and ventilation is impaired. Impairment in deep breath-  ing and coughing predisposes the individual to atelectasis and  congestion. In the advanced stage of the disease, all the muscles  are weak.   Myasthenic crisis occurs when severe muscle weakness  causes extreme quadriparesis or quadriplegia, respiratory insuf-  ficiency with shortness of breath and a markedly decreased tidal  volume and vital capacity, and extreme difficulty in swallowing.  The individual in myasthenic crisis is in danger of respiratory  arrest. Myasthenic crisis usually occurs 3 to 4 hours after the  person takes medication.   Cholinergic crisis may develop secondary to drug over-  dose (anticholinesterase drug toxicity). The clinical picture  resembles that of myasthenic crisis but the weakness occurs 30  to 60 minutes after taking anticholinergic medication. Other  symptoms are also present. Intestinal motility increases and is  associated with episodes of diarrhea and complaints of cramp-  ing; fasciculation, bradycardia, pupillary constriction, increased  salivation, and increased sweating are present. These clinical  manifestations are caused by the smooth muscle hyperactiv-  ity secondary to excessive accumulation of acetylcholine at the  neuromuscular junctions and excessive parasympathetic-like  activity. As in myasthenic crisis, the individual is in danger of  respiratory arrest.   EVALUATION AND TREATMENT. The diagnosis of myasthenia gra-  vis is made on the basis of a response to edrophonium chloride  (Tensilon), results of repetitive single-fiber EMG, and detection    of AchR and MuSK antibodies. The antibodies are found in 80%  of generalized autoimmune myasthenia and 70% of individuals  with ocular myasthenia. With intravenous administration of  Tensilon, immediate improvement in muscle strength usually  persists for 5 to 10 minutes. The EMG is diagnostic in that the  muscle fiber weakens readily. Mediastinal CT and MRI are used  to determine whether a thymoma is present. The progression  of myasthenia gravis is highly variable. In some individuals it  is mild and spontaneously remits. There is usually a series of  relapses, with symptom-free intervals ranging from weeks to  months. Over time the disease can progress, leading to death;  however, current treatments have improved prognosis, includ-  ing ocular myasthenia.   Treatment of myasthenia gravis is individualized. Anticho-  linesterase drugs, corticosteroids, immunosuppressant drugs  (e.g., Rituximab, a chimeric monoclonal antibody against the  protein CD20, primarily found on the surface of B cells), aza-  thioprine, and cyclosporine are used to treat myasthenia gravis  and myasthenic crisis. Plasmapheresis may be lifesaving during  myasthenic crisis, before and after thymectomy, and at the start  of immunosuppressant therapy. For individuals with choliner-  gic crisis, treatment is to withhold anticholinergic drugs until  blood levels fall out of the toxic range while providing venti-  latory support and preventing respiratory complications. Thy-  mectomy is the treatment of choice for a thymoma.!”°    Central nervous system (CNS) tumors include brain and spinal  cord tumors. No proven causative agents for CNS tumors have  been established. Carcinogenesis is discussed in Chapter 12.    Tumors within the cranium can be either primary or metastatic  as follows:   * Primary: Intracerebral tumors originate from brain sub-  stance, including neuroglia, neurons, cells of blood ves-  sels, and connective tissue (Table 18-14). Extracerebral  tumors originate outside substances of the brain and  include meningiomas, acoustic nerve tumors, and tumors  of pituitary and pineal glands.   + Metastatic (secondary): These tumors arise in organ sys-  tems outside the brain and spread to the brain.   Primary brain tumors (both malignant and nonmalignant)  had an estimated incidence rate of 23,130 with 14,080 deaths  in the United States in 2013.!”! The incidence of CNS tumors  increases to age 70 years and then decreases. CNS tumors are  the second most common group of tumors occurring in chil-  dren. Approximately 70% of all intracranial tumors in children  are located infratentorially (see Chapter 20), and in adults 70%  to 75% are located supratentorially. Peripheral nerve tumors  are rare in children and common in adults.   Cranial tumors cause local and generalized clinical manifes-  tations. The local effects are caused by the destructive action  of the tumor itself on a particular site in the brain and com-  pression causing decreased cerebral blood flow. The effects are    Most commonly in frontal lobes deep in  white matter; may arise in brainstem,  cerebellum, and spinal cord    Anywhere in brain or spinal cord,  but predominantly in cerebral  hemispheres    Intramedullary: wall of ventricles, may  arise in caudal tail of spinal cord    Intradural, extramedullary: sylvian  fissure region, superior parasagittal  surface of frontal and parietal lobes,  olfactory groove, wing of sphenoid  bone, superior surface of cerebellum,  cerebellopontine angle, spinal cord    Choroid plexus of ventricular system,  lateral ventricle in children, fourth  ventricle in adults    Pituitary gland; may extend to or invade  floor of third ventricle   Slow growing; marked cellular differentiation; infiltrative;  undergoing malignant progression over time   Poorly differentiated neoplastic cells; extensive  cellular heterogeneity; well-developed microvascular  proliferation; necrosis   More common in children, variable growth rates; more  malignant, invasive form is called ependymoblastoma;  may extend into ventricle or invade brain tissue    Slow growing, circumscribed, encapsulated, sharply  demarcated from normal tissues, compressive in  nature    Usually benign, slow expansion inducing hemorrhage  and hydrocephalus; malignant tumor is rare    At least two distinct  populations of neoplastic  cell types—astrocytes and  oligodendrocytes   Several types: germinoma,  embryonal carcinoma, yolk  sac tumor, choriocarcinoma,  teratoma, mixed germ cell  tumor, with different cell origins    FIGURE 18-32 Origin of Clinical Manifestations Associated with an Intracranial Neoplasm.    varied and include seizures, visual disturbances, unstable gait,  and cranial nerve dysfunction. The generalized effects result  from increased ICP (Figure 18-32). Increased ICP may occur  because of obstruction of the ventricular system, hemorrhages  occurring in and around the tumor, cerebral edema caused by  tumors or expansion of the tumor mass.   Intracranial brain tumors do not metastasize as readily as  tumors in other organs because there are no lymphatic channels  within the brain substance. If metastasis does occur, it is usually  through seeding of cerebral blood, through CSF, during cranial  surgery, or through artificial shunts.   Primary brain tumors constitute about 2% of all cancers in the  United States. Gliomas comprise 50% to 60% of all adult pri-  mary brain tumors and include astrocytomas, oligodendroglio-  mas, mixed oligoastrocytomas, and glioblastoma multiforme.    Gliomas are divided into four grades based on histopathologic  features, cellular density, atypia, mitotic activity, microvascular  proliferation, and necrosis (Table 18-15). Other CNS tumors  include meningiomas, ependymomas, nerve sheath tumors  (schwannomas), and neurofibromas.   Pilocytic astrocytomas are more common in children and  most often present with a median age of 12 years.'”? All other  gliomas generally present after age 30 with secondary glioblas-  tomas occurring more frequently in younger adults and pri-  mary glioblastomas usually presenting in older adults.'7°   Etiology for primary brain tumors is unclear and ionizing  radiation is the only known environmental risk factor. Expo-  sure to radiofrequency electromagnetic fields (cell phones) is  under investigation.'”*   Mutation of the isocitrate dehydrogenase 1 (IDH1) gene, or  less commonly mutation of the related IDH2 gene, has been  identified in the vast majority of World Health Organization    Diffuse, low-grade astrocytoma (fibrillary,  gemistocytic, protoplasmic)  Oligodendroglioma of brain  Anaplastic (malignant) astrocytoma  Anaplastic oligodendroglioma  Glioblastoma (glioblastoma multiforme)    Common in children and young adults and  people with neurofibromatosis type 1;  common in cerebellum   Common in young adults; more common  in cerebrum but can occur in any part   Abnormal microscopic appearance; grows slowly;  infiltrates to adjacent tissue; may recur at higher  grade   Malignant; many cells undergoing mitosis; infiltrates  adjacent tissue; frequently recurs at higher grade   Poorly differentiated; increased number of  cells undergoing mitosis; bizarre microscopic  appearance; widely infiltrates; neovascularization;  central necrosis    Data from American Brain Tumor Association: Brain tumor primer, ed 9, Chicago, IL, 2010, Author. Available at http://neurosurgery.mgh.harvard.edu    /abta/; Louis DN et al: Acta Neuropathol 114(2):97-109, 2007.  *World Health Organization Grading of Central Nervous System Tumors.    (WHO) grades I] and III astrocytic, oligodendroglial, and oli-  goastrocytic gliomas. Silencing of the MGMT gene (methylated-  DNA-protein-cysteine methyltransferase) is found in astrocy-  tomas. Chromosome 1p and 19q deletions are associated with  oligodendrogliomas. Alterations in tumor-suppressor genes  (e.g., mutations, T7P53) are common. Alterations also occur in  growth factor signaling’? and gliomas may arise from cancer-  initiating resident stem cells.!”°   The principal treatment for cerebral tumors is surgical or  radiosurgical excision or surgical decompression if total exci-  sion is not possible. Chemotherapy, radiation therapy, or their  combination may be used. The blood-brain barrier is an obsta-  cle to the delivery of chemotherapeutic agents. New methods are  in progress for penetration of this barrier.'”” Specificity of treat-  ment is advancing with the development of immunotherapy  techniques.'’® (Cancer treatment is discussed in Chapter 12.)   Astrocytoma. Astrocytomas are a type of glioma and the  most common primary CNS tumor (50% of all brain and spinal  cord tumors). Astrocytomas develop from astrocytes and grow  by expansion and infiltration into the normal surrounding  brain tissues. These tumor cells are believed to have lost normal  growth restraint, and thus they proliferate uncontrollably.   One third of astrocytomas are classified at diagnosis as grade  I or grade II. These slow-growing but infiltrative gliomas tend  to form cavities (pseudocysts); however, some are firm, non-  cavitating, avascular, gray-white masses that are difficult to dis-  tinguish from normal white matter of the brain. Although these  tumors may occur anywhere in the brain or spinal cord, they  are located most commonly in the cerebrum, hypothalamus, or  pons. Low-grade astrocytomas in adults tend to have a lateral  or supratentorial location, and they tend to be midline or near  midline in position in children, often in the posterior fossa.   Headache and subtle neurobehavioral changes may be an  early symptom. Approximately half of persons with low-grade  astrocytomas experience a focal or generalized seizure. Onset of  a focal seizure disorder between the second and sixth decades  of life is suggestive of an astrocytoma. Other general or focal  neurologic manifestations develop gradually. Increased ICP is  usually a late clinical manifestation.    Grade I astrocytomas are treated with surgery and follow-up  CT scans. Grade I astrocytomas are treated surgically if they are  accessible or by conventional external radiation, local radiation,  or stereotactic radiosurgery. Following surgery alone, the 5-year  survival rate is 25%; with surgery followed by radiotherapy, the  5-year survival rate is 50%.   Grades II and IV astrocytomas are found predominantly  in the frontal lobes and cerebral hemispheres (Figures 18-33  and 18-34). These tumors also may be located in the brain-  stem. They are found twice as frequently in men as in women.  Grades III and IV astrocytomas are the third most common  cancer in the 15- to 34-year-old age group and the fourth most  common in the 35- to 54-year-old age group.'”? Grades III and  IV astrocytomas are often large and well circumscribed with  a variegated pattern. The peripheral rim is pinkish gray and  solid with a soft, yellow necrotic center and points of hemor-  rhage. Microscopically, there is increased cellularity, vascular  proliferation, cellular pleomorphism, and necrosis. Necrosis is  the main histologic difference between an anaplastic grade HI  tumor and a grade IV glioblastoma multiforme.   Grade IV astrocytomas (glioblastoma multiforme) account  for about 55% of all gliomas. They are highly vascular and  extensively infiltrative with heterogeneity in their molecular  pathology. They may become large enough to extend from the  meningeal surface through the ventricular wall. Fifty percent  of glioblastomas are bilateral or at least occupy more than one  lobe at the time of death. There are reports of grade IV astrocy-  tomas found outside the central nervous system. !°)!®!   The typical clinical presentation for a glioblastoma mul-  tiforme is that of diffuse, nonspecific clinical manifestations,  such as headache, irritability, and personality changes, that  progress to more clear-cut manifestations of increased ICP,  such as headache on position change; papilledema; or vomit-  ing. Of those affected, 30% to 40% experience seizure activity.  Symptoms may progress to definite focal signs, such as hemipa-  resis, dysphasia, dyspraxia, cranial nerve palsies, and visual field  deficits, in addition to the generalized signs from increased ICP.   Diagnosis of high-grade astrocytomas most commonly takes  3 to 6 months from onset of the first clinical manifestations    FIGURE 18-33 Well-Differentiated Infiltrating Astrocytoma. The right tem-  poral lobe contains an infiltrative, homogeneous lesion that has expanded the lobe  and obscured the normal boundaries between gray and white matter (compare to  left temporal lobe). Because of the ill-defined borders, surgical resection rarely  removes all of the tumor in such cases. (From Kumar V, Cotran RS, Robbins SL:  Robbins basic pathology, ed 7, Philadelphia, 2003, Saunders.)    FIGURE 18-34 Glioblastoma Multiforme. In contrast to the well-differentiated  infiltrating astrocytoma in Figure 18-33, this glioblastoma contains irregular areas of  discoloration and cystic change, reflecting the presence of necrosis and hemorrhage.  These lesions are widely infiltrative and associated with considerable mass effect.  Note the shift of midline structures to the right. (From Kumar V, Cotran RS, Robbins  SL: Robbins basic pathology, ed 7, Philadelphia, 2003, Saunders.)    because the person does not recognize the need to consult a  healthcare provider. Survival at 5 years for grades III and IV  astrocytomas is about 5% to 10%.   Oligodendroglioma. A far less commonly occurring glioma  is oligodendroglioma, comprising 2% of all brain tumors and  10% to 15% of all gliomas. Oligodendrogliomas are typically  slow-growing well-differentiated tumors, often with cysts and  calcification present. Most are macroscopically indistinguishable  from other gliomas. They occur most often from 30 to 50 years  of age and are more common in males than females. Their  etiology is unknown. Most oligodendrogliomas are in the  frontal and temporal lobes, often in deep white matter; 20% are  in both hemispheres. They may be found also in other parts of  the cerebrum, third ventricle, brainstem, cerebellum, and spinal  cord. A high incidence of this tumor occurs in young adults  with a history of temporal lobe epilepsy. Approximately half of    FIGURE 18-35 Ependymoma. These tumors may arise in both the intracranial  compartment and the spine. Intracranial tumors typically originate from a ventricu-  lar surface, as in the case of this large lesion arising in the fourth ventricle (arrow).  (From Kumar V, Cotran RS, Robbins SL: Robbins basic pathology, ed 7, Philadelphia,  2003, Saunders)    these tumors generally classified as oligodendrogliomas (a grade  II tumor) are actually oligoastrocytomas (a grade III tumor).'*?  Malignant degeneration occurs in approximately one third of  persons with oligodendrogliomas. If there is extension to the  pia mater (see Figure 15-15) or ependymal wall (epithelial layer  surrounding choroid plexus and separating brain tissue from  cerebrospinal fluid), oligodendrogliomas may metastasize to  distant CNS sites through the ventriculoarachnoid spaces.   More than 50% of individuals experience a focal or gener-  alized seizure as the first clinical manifestation; approximately  half have experienced increased ICP at the time of diagnosis and  surgery, and only one third develop any focal manifestations.  The time from first clinical manifestation to surgical interven-  tion often ranges from 2 to 6 years. Median survival, when  surgery and radiotherapy are both used, is 5 to 10 years and  prognosis is better than for other astrocytomas.!”   Ependymoma. Ependymomas are rare gliomas that arise  from ependymal cells that form the walls of the ventricles or the  spinal canal. They are not encapsulated (Figure 18-35 and see  Table 18-14). They comprise 6% of all primary brain tumors  in adults and 10% in children and adolescents. Intracranial  locations are more common among children and spinal  cord location is more common among adults. The clinical  presentation of spinal ependymoma is neurologic deficit (e.g.,  pain and dysthesias) corresponding to the level of the lesion.  Lateral and third ventricle ependymomas that involve the  cerebral hemispheres present with seizures, visual changes, and  contralateral weakness of a body part on one side of the body.  Etiology for these tumors is unknown.!**   Clinical manifestations and progression of dysfunction asso-  ciated with ependymomas may follow a short or long course.  The interval between first manifestations and surgery may be as  short as 4 weeks with some ependymoblastomas to as long as 7  to 8 years with others.   Ependymomas are treated surgically and with radiotherapy  of the tumor region and operative site (possibly of the entire  brain and spine). The 5-year survival rate is between 20% and    FIGURE 18-36 Meningioma, Gross. Meningioma beneath the dura with com-  pression of underlying cerebral hemisphere. (From Klatt EC: Robbins and Cotran  atlas of pathology, Philadelphia, 2006, Saunders.)    50%. Some persons benefit from a shunting procedure when  the ependymoma has caused a noncommunicating hydroceph-  alus (see Chapter 17 and Chapter 20).    Meningioma. Meningioma constitutes about 30% of all  intracranial tumors. The annual incidence is 6 cases per 100,000,  with a peak incidence in the sixth and seventh decades, and this  tumor is more common in women.!** Predisposing factors  to developing a meningioma are having neurofibromatosis  (NF) type 2 (NEF2, see Nerve Sheath Tumors at right) and  undergoing ionizing radiation after a several-decade latency  period. Genetically, formation of benign meningiomas has been  linked to NF2 gene mutation and chromosome 22q loss along  with DAL-1 loss on chromosome 18. Atypical and anaplastic  meningiomas have been linked to additional gene alterations  involving other multiple chromosomes. !*°   A meningioma is a sharply circumscribed mass that derives  its shape from the space it occupies; the cause is unknown.  These slow-growing, often encapsulated tumors arise from  arachnoidal (meningeal) cap cells in the dural coverings of the  brain. Rarely do meningiomas arise from arachnoid cells of  the choroid plexus of the ventricles. Most are attached to the  dura mater and arise within the intracranial cavity, the spinal  cavity, or, rarely, the orbit (Figure 18-36). A meningioma may  extend to the dural surface and erode the cranial bones or pro-  duce an osteoblastic reaction. Small meningiomas (less than  2 cm in diameter) are often found on postmortem examination  in middle-aged and older adults who had experienced no clini-  cal manifestations and died of totally unrelated causes. A few  meningiomas exhibit malignant, invasive qualities.   Only when meningiomas reach a certain size—at which time  they begin to indent the brain parenchyma—do they begin to  produce clinical manifestations. Focal seizures are frequently  the first manifestation. Other clinical manifestations depend on  the tumor’s location. Clinical features based on site of origin  are as follows:   Because of the extremely slow-growing nature of most  meningiomas, increased ICP is less common than with gliomas.  The most common symptom is seizures (40%). Diagnosis is  made using contrast-enhanced CT, MRI, or both. The primary  treatment is surgical resection. Stereotactic radiotherapy is used  with incomplete resection or recurrence (20% rate). Conven-  tional radiotherapy also is used. Hydroxyurea and somatostatin  are used in cases of tumor recurrence. !*°   Nerve Sheath Tumors. Nerve sheath tumors are either  neurofibromas or schwannomas (neuroma, neurolemma).  Neurofibromatosis (NF) is an inherited autosomal dominant  disorder accounting for 5% of all neuromas and is divided into  two types: NF1 and NF2, which are clinically and genetically  distinct disorders. The gene products are neurofibromin and  merlin (schwannomin), both of which are thought to be tumor  suppressors. |*7   Alterations in chromosomes 17 (17q11.2 for NF1) and 22  (NEF2) are associated with both neurofibromas and schwan-  nomas. NF1 is associated with cutaneous manifestations, iris  hamartomas, and tumors primarily involving the peripheral  nervous system and, occasionally, the CNS.'** NF2 is associated  with cataracts, hearing loss, and tumors primarily in the CNS,  most commonly vestibular schwannoma and meningioma.'*”  Criteria for the diagnosis of neurofibromatosis types 1 and 2  are presented in Box 18-4. The remaining neuromas are benign  tumors that arise from the sheath of Schwann cells surrounding  the axons of the cranial nerves. The tumors most commonly  affect people older than 50 years, women more often than men.  The vestibular division of cranial nerve VIII is most commonly  affected, although neuromas of the acoustic division of cranial  nerves V, VII, VIII, and IX are found (Figure 18-37).   The tumor originates most commonly just distal to the junc-  tion between the nerve root and the brainstem. As the tumor  grows, it extends into the posterior fossa to occupy the cere-  bropontine angle and compress adjacent nerves. Eventually the  brainstem is displaced, and the CSF flow is obstructed.   Initial clinical manifestations may include headache, tinni-  tus, hearing loss, impaired balance, unsteady gait, facial pain,  and loss of facial sensations. Later, vertigo with nausea and  vomiting, a sense of pressure in the ear, and moderate to severe  unsteadiness with rapid position changes may appear. CT or  MRI can establish the diagnosis. Posterior fossa dye studies may  be required. Treatment is by surgical excision and radiotherapy  of the neuroma. Pituitary tumors are discussed in Chapter 22,  and cerebral tumors in children are discussed in Chapter 20.   Brain Metastases. Brain metastases are approximately  10 times more common than primary brain tumors and the  incidence is increasing with improved local control of systemic   Two of the following eight criteria:  Six or more café-au-lait macules greater than 5 mm in greatest diameter  in prepubertal individuals and greater than 15 mm in greatest diameter in  postpubertal individuals (adults)  Multiple axillary or inguinal freckles  One plexiform neurofibroma or two or more neurofibromas of any types  Optic glioma  Two or more Lisch nodules (iris hamartomas)  A distinctive osseous lesion such as sphenoid dysplasia or thinning of the  cortex of long bones with or without pseudoarthrosis    Criteria for the Diagnosis of NF2  Either one of the following criteria:  e Bilateral masses of the eighth cranial nerve seen with appropriate imaging  techniques (e.g., CT or MRI)  e A first-degree relative with NF2 and either:  a. Unilateral mass of the eighth cranial nerve or  b. Two of the following:  1. Neurofibroma  2. Meningioma  3. Glioma  4. Schwannoma  5. Juvenile posterior subcapsular lenticular opacity    From NIH diagnostic criteria for neurofibromatosis. Available at www.  medicalcriteria.com/criteria.neuro_nf.htm. Last modified October 23,  2010. Accessed April 1, 2013.    tumors. The incidence is estimated at up to 250,000 new cases  per year. At autopsy, about 25% of persons with metastases  have brain metastases. Lung and breast cancer are the most  common tumors to have brain metastases within 1 to 3 years,  followed by renal cell carcinoma, gastrointestinal cancer, and  malignant melanomas. Carcinoma of the gallbladder, liver,  thyroid, testes, uterus, ovary, and pancreas also may metastasize  to the brain. Other tumors, besides carcinomas, that metastasize  only occasionally are rhabdomyosarcomas, Ewing tumors,  chorioepithelioma, and lymphoma.!”°   Metastasis of a cancer to the brain parenchyma or the menin-  ges is a late occurrence in the disease process and is believed to  be hematogenous in origin. Two thirds of metastatic tumors  are located within the brain and one third are located in extra-  dural spaces. The cerebral hemispheres are the site of 75% of  metastases, most predominantly in the frontal lobes followed  by the parietal, occipital, and temporal lobes in order of fre-  quency of location. Tumors of the pelvis or retroperitoneal  space have a predilection to metastasize to the cerebellum,  pons, or their coverings.'?! In more than three fourths of per-  sons with metastasis, the metastases are multiple and found in  both the cerebrum and the cerebellum in a scattered distribu-  tion. The metastatic tumors often are located in the meninges  and near the brain surface in the gray matter and subcortical  white matter. These tumors produce little glial cell reaction in    FIGURE 18-37 Acoustic Neuroma (Schwannoma), Gross. A mass lesion  arising in the right vestibular branch of the eighth cranial nerve at the cerebel-  lopontine angle (arrow). (From Klatt EC: Robbins and Cotran atlas of pathology,  Philadelphia, 2006, Saunders.)    the brain tissue but do cause vasogenic, peritumoral edema in  the surrounding brain tissue attributable to blood-brain barrier  incompetence. |”   The brain metastatic process requires a series of sequential  events, called the “metastatic cascade,” as follows:   1. Invasion of primary tumor border  Extravasation of the circulatory system  Survival and persistence/quiescence in the circulation  Extravasation at the distant CNS site  Formation of micrometastasis  . Progressive colonization and growth   Heitatogenous metastasis to the CNS is an inherently inef-  ficient process depending on an interaction between tumor  cells with host defenses and the microenvironment. To produce  brain metastasis, tumor cells must reach the brain vasculature  by attaching themselves to the endothelial cells of the brain  microvessels in the blood-brain barrier, extravasate into the  brain parenchyma, induce blood vessel development (angio-  genesis), and proliferate in response to growth factors. Local  brain invasion, in itself, is a process requiring mechanisms for  cell motility, cell adhesion, enzymatic remodeling of the extra-  cellular components, tumor cell survival, and proliferation.  Cytokines, chemokines, and growth factors have been demon-  strated to participate in the process.!”   The clinical manifestations of parenchymal brain metastasis  are headache, seizures, or alteration in cognition, mental status,  and behavior,'”” although several unusual syndromes do exist.  Carcinomatous encephalopathy causes headache, nervous-  ness, depressed mood, trembling, confusion, and forgetfulness.  In carcinomatosis of the cerebellum, headache, dizziness, and  ataxia are found. Carcinomatosis of the craniospinal menin-  ges (carcinomatous meningitis) manifests with headache,  confusion, and manifestations of cranial or spinal nerve root  dysfunction.   Contrast-enhanced imaging is the most sensitive imaging  procedure for metastatic brain tumors. Prognosis is poor. If one  to three tumors are found, surgical excision is indicated. Radio-  therapy is commonly used to treat solitary as well as multiple  tumors and may be combined with whole brain radiation.!”4   Primary spinal cord tumors are relatively rare, about 2% to 4%  of CNS neoplasms. The most common primary spinal cord  tumors are listed in Box 18-5 and shown in Figure 18-38. Spi-  nal cord tumors are named to reflect their cell type, growth  rate, and structure of origin. They are classified as intramed-  ullary tumors (originating within the neural tissues) or extra-  medullary tumors (originating from tissues outside the spinal  cord). Extramedullary tumors arise from the meninges or roots  (forming intradural tumors) or from epidural tissue or ver-  tebral structures (forming extradural tumors). About 5% of  spinal cord tumors seen in general hospital settings are intra-  medullary, 40% are intradural-extramedullary, and 55% are  extradural.   Metastatic spinal cord tumors are three to four times more  common than primary spinal cord tumors. They are usually  carcinomas from breast, lung, and prostate; lymphomas; or  myelomas; 25% to 70% involve the vertebral body and are asymp-  tomatic. Metastatic spinal cord tumors are extradural in location.  Of extradural tumors, 50% are metastatic and have spread to  the spine through direct extension from tumors of the vertebral  structures or from extraspinal sources extending through the  interventricular foramen or through the bloodstream.   The most common primary extramedullary spinal cord  tumors are neurofibromas and meningiomas. These tumors  are intradural more often than extradural. Neurofibromas are  found most commonly in the thoracic and lumbar regions.  Meningiomas are more evenly distributed throughout the  spine. Other extramedullary tumors in order of frequency of  occurrence are sarcomas, vascular tumors, chordomas, and  epidermoid and similar tumors. Of intradural-extramedullary  tumors, 70% are meningiomas, neurofibromas, or sarcomas.   Intramedullary tumors have the same cellular origins as  brain tumors. Ependymomas are the most common intramed-  ullary tumors. Astrocytomas, glioblastomas, oligodendroglio-  mas, ganglioneuromas, medulloblastomas, hemangiomas, and  hemangioblastomas are more or less equally distributed in fre-  quency of occurrence.!°   PATHOPHYSIOLOGY. Extramedullary spinal cord tumors pro-  duce dysfunction by compression of adjacent tissue, not by  direct invasion. The spinal cord is compressed by the tumor  from without, and destruction of the white matter tracts occurs.  The spinal canal around the cord becomes filled by tumor.   Intramedullary spinal cord tumors produce dysfunction by  invasion and compression. The cord enlarges as a result of the  tumor that is enlarging inside the cord. In addition, distortion    of adjacent white matter tracts occurs. Metastases from spinal  cord tumors occur from seeding through the CSF; medullo-  blastomas and ependymomas establish distant implants in this  manner.   CLINICAL MANIFESTATIONS. The acute onset of clinical manifes-  tations suggests a vascular insult caused by thrombosis of ves-  sels supplying the spinal cord. Clinical manifestations that are  gradual and progressive suggest compression. The clinical man-  ifestations associated with spinal cord tumors fall into three  major categories: (1) a compressive syndrome (sensorimotor  syndrome), (2) an irritative syndrome (radicular syndrome),  and rarely (3) a syringomyelic syndrome.   The compressive syndrome (sensorimotor syndrome) is  associated with compression and is caused less frequently by  invasion and destruction of the spinal cord tracts. Symptoms  are usually gradual and progressive, and initial manifestations  may be asymmetric. With tumors located in the cervical area,  the motor dysfunction usually has the following pattern: ipsi-  lateral arm involvement, followed by ipsilateral and contralat-  eral leg involvement, and finally involvement of the opposite  arm. With thoracic tumors the pattern of motor involvement  is paresis and spasticity of one leg, followed by involvement of  the opposite leg. The sensory clinical manifestations of tingling  paresthesias have a pattern similar to that of the motor signs.  Pain and temperature dysfunctions are found more commonly  than touch, vibration, and proprioceptive changes, although  posterior column signs also are found frequently. Pain is less    well localized than with an irritative syndrome caused by root  involvement. Initially the pain and temperature changes are  contralateral to the motor deficit (Brown-Séquard syndrome,  see Table 18-4, pp. 592-593). Bladder and bowel deficits usually  appear when paresis develops in the legs.   The irritative syndrome (radicular syndrome) combines  the clinical manifestations of a cord compression with radicular  pain, which is pain in the sensory root distribution and indi-  cates root irritation. The segmental manifestations associated  with root irritation include segmental sensory changes that  include paresthesias and impaired pain and touch perception;  motor disturbances, including cramps, atrophy, fasciculations,  and decreased or absent deep tendon reflexes; and ache in the  spine. Tenderness of the spinous processes over the tumor is  present in about half of extramedullary tumors. The segmen-  tal changes may appear months and sometimes years before  the clinical manifestations of compression in benign tumors.  The compressive clinical manifestations include an asymmetric  spastic paresis of the lower extremities with tumors in the tho-  racic or lumbar region, paresis of the arms and legs with tumors  in the cervical area, decreased or absent pain and temperature  perception below the tumor site, posterior column signs, and  spastic bladder.   Because they involve the central gray matter of the cord,  intramedullary spinal cord tumors (notably ependymomas)  may produce a syringomyelic syndrome, or inflammation of  the spinal cord. Inflammation results in the development of    tubular (syrinx) cavities in the spinal cord. Occasionally an  extramedullary tumor may produce the same effect, although  the mechanisms are unknown.   EVALUATION AND TREATMENT. The diagnosis of a spinal cord  tumor is made through bone scan, needle biopsy guided by  CT and positron-emission tomography (PET), or open biopsy.  Involvement of specific cord segments is established. Spinal  tumors are not staged but can be classified as slow growing  (low-grade) or rapidly growing (high-grade).   Treatment varies, depending on the nature of the tumor  and the person’s clinical status. Indications for surgery include  establishment of a tissue diagnosis, neurologic palliation, spinal  stabilization, pain relief, and cancer therapy. Surgical resection  may involve curettage (piecemeal removal of the tumor) or may  be performed en bloc (removal of tumor in one piece). Sur-  gical approaches to the spine include the posterior approach  (decompression laminectomy), lateral approach, anterior  approach (most favored), and combined approaches. Pos-  terior and anterior reconstructive surgery may be necessary.  Oncologic surgical procedures are classified as intralesional,  marginal, wide excision, or radical excision. Indications for  external radiation vs. surgery are a radiosensitive tumor (e.g.,  lymphoma), soft tissue compression without instability, a per-  son who is a poor surgical candidate, paraplegia or advanced  paraparesis of greater than 24 hours’ duration, and an expected  survival of less than 3 to 4 months. Chemotherapy, hormonal  therapy, and pain management protocols may be appropriate.   1. Traumatic brain injury (TBI) is an alteration in brain func-  tion or other evidence of brain pathology caused by an  external force.   2. MVAs are the major cause of traumatic CNS injury. Trau-  matic injuries are classified as closed-head trauma (blunt)  or open-head trauma (penetrating). Closed-head trauma is  the more common type of trauma.   3. Primary brain injury is caused by an impact and can be clas-  sified as focal or diffuse.   4, Focal brain injury includes coup and contrecoup, contu-  sion (bruising of the brain), laceration (tearing of brain tis-  sue), extradural hematoma (accumulation of blood above  the dura mater), subdural hematoma (blood between the  dura mater and arachnoid membrane), intracerebral hema-  toma (bleeding into the brain), and open-head trauma.   5. Open-head trauma involves a skull fracture with exposure  of the cranial vault to the environment. The types of open-  head trauma (compound fracture, perforated fracture) are  linear, comminuted, compound, and basilar skull fracture  (in the cranial vault or at the base of the skull).   6. Diffuse axonal injury (DAI) results from the effects of head  rotation. The brain experiences shearing stresses resulting  in axonal damage ranging from concussion to a severe DAI  state. Categories of diffuse brain injury include mild con-  cussion; classic cerebral concussion; and mild, moderate,  and severe DAI.    7. Secondary neuronal injury occurs as an indirect result of  primary brain injury and is the result of both systemic  and intracranial processes. Secondary injury results from  ischemia, excitotoxicity, inflammation, cerebral edema,  increased intracranial pressure, and brain herniation.   8. Spinal cord injuries occur most often in young men who  sustain various kinds of injuries (recreational or travel  related) and older adults because of preexisting degenera-  tive vertebral disorders.   9. Primary spinal cord injury involves damage to vertebral  or neural tissues from compression, traction, or shearing  forces.   10. Secondary spinal cord injury is related to ischemia, exci-  totoxicity, inflammation, edema, oxidative damage, and  activation of necrotic and apoptotic cell death, and begins  within minutes after injury and continues for weeks.   11. Spinal cord injury often causes spinal shock with cessa-  tion of all motor, sensory, reflex, and autonomic functions  below any transected area. Loss of motor and sensory func-  tion depends on the level of injury.   12. Paralysis of the lower half of the body with both legs  involved is called paraplegia. Paralysis involving all four  extremities is called quadriplegia.   13. Return of spinal neuron excitability occurs slowly. Reflex  activity can return in 1 to 2 weeks in most people with acute  spinal cord injury. A pattern of flexion reflexes emerges,  involving first the toes and then the feet and legs. Eventually    reflex voiding and bowel elimination appear, and mass reflex  (flexor spasms accompanied by profuse sweating, piloerec-  tion, and automatic bladder emptying) may develop.  Autonomic hyperreflexia (dysreflexia) is a syndrome of  sudden massive reflex sympathetic discharge associated  with spinal cord injury at level T5-T6 or above and can  cause life-threatening hypertension.   Immobilization of the spine is the immediate intervention  for a suggested or confirmed vertebral fracture.   The pathologic findings in degenerative disk disease (DDD)  include disk protrusion, spondylosis and/or subluxation,  degeneration of the vertebrae (spondylolisthesis), and spi-  nal stenosis.   Low back pain is pain between the lower rib cage and glu-  teal muscles and often radiates into the thigh.   Low back pain has a high prevalence, affecting 75% to 90%  of the population at some time. Sciatica affects about 1% of  those with low back pain.   Most causes of low back pain are unknown; however, some  secondary causes are disk prolapse, tumor, bursitis, synovi-  tis, DDD, osteoporosis, fracture, inflammation, and sprain.  Diagnosis of injury to the lower back is made on the basis of  physical examination, EMG results, and imaging procedures.  Treatment for low back pain includes use of analgesics and  NSAIDs, exercise, physical therapy, education, and surgery.  Herniation of an intervertebral disk is a protrusion of part  of the nucleus pulposus. Herniation most commonly affects  the lumbosacral disks (L5-S1 and L4-L5). The extruded  pulposus compresses the nerve root, causing pain that radi-  ates along the sciatic nerve.   Clinical improvement occurs in most cases; only 10% have  sufficient pain after 6 weeks to consider surgery. There is  little evidence that drug treatments are effective.  Cerebrovascular disease is the most frequently occurring  neurologic disorder. Any abnormality of the blood vessels  of the brain is referred to as a cerebrovascular disease.  Cerebrovascular disease is associated with two types of  brain abnormalities: (a) ischemia with or without infarc-  tion and (b) hemorrhage.   The most common clinical manifestation of cerebrovascu-  lar disease is a CVA (stroke syndrome), and the most com-  mon risk factor is hypertension.   CVAs are classified according to pathophysiology and  include ischemic (thrombotic, embolic, and global hypo-  perfusion), lacunar, and hemorrhagic strokes.   A transient ischemic attack is a transient episode of neuro-  logic dysfunction resulting from focal cerebral ischemia.  Aspirin, systemic anticoagulation, and thrombolysis improve  outcomes with ischemic stroke. Antiplatelet therapy and  statins decrease recurrence. Endarterectomy is effective if  carotid stenosis is greater than 50%.   Treatment of hemorrhagic stroke includes control of bleed-  ing, prevention of increased intracranial pressure, and pre-  vention of cerebral edema and seizures.   Intracranial aneurysms result from defects in the vascular  wall and are classified on the basis of form and shape. They    are commonly asymptomatic, but the signs vary according  to the location and size of the aneurysm.   Surgical intervention is the treatment of choice before a  cerebral aneurysm ruptures.   An AVM isa tangled mass of dilated blood vessels. Although  sometimes present at birth, AVM exhibits a delayed age of  onset with symptoms ranging from headache and dementia  to seizures and ICH or SAH. Vasospasm and delayed cere-  bral ischemia are serious complications.   Migraine is an episodic disorder whose marker is headache.  Migraine is classified as a headache with and without aura  and is precipitated by a triggering event.   The clinical phases of a migraine attack are the premoni-  tory phase, the migraine aura, the headache phase, and the  recovery phase.   Migraine is associated with activation of the peripheral and  central arms of the trigeminal system, cortical spreading  depression, and distinct activity of brainstem nuclei.  Cluster headaches occur in episodes several times during a  day for a period of days at different times of the year. The pain  is unilateral, intense, tearing, and burning. Associated symp-  toms include ptosis, lacrimation, reddening of the eye, and  nausea. The cause of trigeminal activation is unknown. There  is sympathetic nervous system underactivity and parasympa-  thetic overactivity. The two forms are acute and chronic.  Chronic paroxysmal hemicrania is a cluster headache with  more frequent daily attacks; it occurs primarily in women.  It responds to treatment with indomethacin.   Tension-type headache is the most common type of head-  ache. Both a central mechanism and a peripheral mechanism  are associated with the etiology. The headache is bilateral,  with the sensation of a tight band around the head. The pain  may last for hours or days. There are acute and chronic forms.  Infection and inflammation of the CNS can occur by bacte-  ria, viruses, fungi, parasites, and mycobacteria. The result-  ing infection by bacteria is pus producing, or pyogenic.  Meningitis is inflammation of the brain or spinal cord. Bac-  terial meningitis is primarily an infection of the pia mater  and arachnoid villi and of the fluid of the subarachnoid  space. Viral meningitis is believed to be limited to the menin-  ges. Fungal and tubercular meningitis are less common and  occur in immunosuppressed individuals in particular.   The meningeal vessels become hyperemic, and neutrophils  migrate into the subarachnoid space with bacterial men-  ingitis. An inflammatory reaction occurs, and exudation  ensues and increases rapidly.   The variety of clinical manifestations depends on the type  of meningitis and ranges from throbbing headache to neck  stiffness and rigidity and decreasing responsiveness. Spe-  cific cranial nerve dysfunction is a common occurrence.  Bacterial meningitis and fungal meningitis are treated with  appropriate antibiotic therapy; viral meningitis is treated  with antiviral drugs or corticosteroids and supportive care.  Brain abscesses often originate from infections outside the  CNS. Microorganisms gain access to the CNS from adja-  cent sites or spread along the wall of a vein. A localized    inflammatory process develops with exudate formation,  vessel thrombosis, and leukocyte degeneration. After a few  days the infection becomes delimited, with a center of pus  and a wall of granular tissue.   Clinical manifestations of brain abscesses include head-  ache, nuchal rigidity, confusion, drowsiness, and sensory  and communication deficits. Treatment includes antibiotic  therapy and surgical excision or aspiration.   Encephalitis is an acute febrile illness of viral origin with  nervous system involvement. The most common enceph-  alitides are caused by arthropod-borne viruses and her-  pes simplex virus. Meningeal involvement appears in all  encephalitides.   Clinical manifestations of encephalitis include fever, delir-  ium, confusion, seizures, abnormal and involuntary move-  ment, and increased intracranial pressure.   Most encephalitides are treated by administration of an  antiviral agent or an immune globulin and by control of  intracranial pressure.   The common neurologic complications of AIDS are  HIV-associated neurocognitive disorder (HAND), HIV  neuropathy, HIV myelopathy, opportunistic infec-  tions, cytomegalovirus infection, parasitic infection, and  neoplasms. Pathologically, there may be diffuse CNS  involvement, focal pathologic findings, and obstructive  hydrocephalus. Neurologic involvement associated with  HIV has declined with HAART.   Lyme disease is a tick-borne spirochete bacterial infection  involving the peripheral and central nervous systems that  progresses through three stages of symptoms with acute  and chronic manifestations.   MS is a chronic inflammatory disease involving degenera-  tion of CNS myelin. The cause is unknown and an immune  system dysfunction produces the pathology. The demyelin-  ation is thought to result from a previous viral insult to the  nervous system in a genetically susceptible individual with  a subsequent abnormal immune response in the CNS.   The clinical manifestations of MS involve different types:  relapsing-remitting, primary progressive, secondary progres-  sive, and progressive-relapsing. Optico-spinal MS involves  the optic nerve and cranial nerves III through XII. Spinal MS  primarily involves the spinal tracts and dorsal column with  spastic paresis and bowel and bladder dysfunction. Cerebel-  lar MS manifests with motor ataxia and weakness.   There is no cure for MS. Corticosteroid and immune ther-  apy is used to acutely manage relapses or reduce frequency  of relapses.    Neuropathies are the syndromes that result when the  peripheral nerves are affected. Axon and myelin degenera-  tion may be present. Neuropathies are classified as general-  ized symmetric polyneuropathies, generalized neuropathy,  and focal or multifocal neuropathies.    Therapy for the neuropathies is directed at the primary cause,  such as diabetes mellitus. Axonal regrowth and recovery of  function may take months, but many neuropathies can be  reversed.    tory demyelinating or axonal disorder caused by a humoral  or cell-mediated immunologic response, or both, directed at  peripheral nerves. Four subtypes have been identified and  clinical manifestations depend on the subtype.    . Radiculopathies are disorders of the roots of spinal cord nerves.    The roots may be compressed, inflamed, or torn. Clinical man-  ifestations include local pain or paresthesias in the sensory root  distribution. Treatment may involve surgery, antibiotics, corti-  costeroids, radiation therapy, and chemotherapy.    transmission at the neuromuscular junction. Autoantibod-  ies, complement deposits, and membrane attack complex  destroy the acetylcholine receptor (AchR) sites, causing  decreased transmission of the nerve impulse.    of voluntary muscles, including muscles of the face and throat,  and may involve muscles of the diaphragm and chest wall.    immunotherapy. The progression of the disease is highly vari-  able; in some individuals it is mild and spontaneously remits.    Tumors that occur within the cranium are either primary or  metastatic (secondary). Primary tumors arise from brain tis-  sue and are classified as intracerebral or extracerebral. Meta-  static tumors to the brain arise in organs outside the brain  and are much more common than primary brain tumors.    Gliomas are the most common primary tumor in adults.  The effects are varied; local manifestations include seizures,  visual disturbances, loss of equilibrium, and cranial nerve  dysfunction.    . The principal treatment for brain tumors is surgical or radio-    surgical excision or decompression if total excision is not  possible. Chemotherapy and radiation therapy also are used.    the neural tissues) or extramedullary (outside the spinal  cord). Metastatic spinal cord tumors are usually carcinomas,  lymphomas, or myelomas.    compression of adjacent tissue, not by direct invasion. Intra-  medullary spinal cord tumors produce dysfunction by inva-  sion and compression.    . The onset of clinical manifestations of spinal cord tumors is    gradual and progressive, suggesting compression. Specific  manifestations depend on the location of the tumor; for  example, there may be paresis and spasticity of one leg with  thoracic tumors, followed by involvement of the opposite leg.    of the International and Interagency Initiative toward Common Data:  elements for research on traumatic brain injury and psychological health:   Guillain-Barré syndrome (GBS) (Landry-Guillain-  Barré syndrome, idiopathic polyneuritis, acute  inflammatory polyradiculopathy, acute autoim-  mune neuropathy), 622   Open (penetrating) trauma, 582  Optical-spinal multiple sclerosis (OSMS), 620  Plexus injury, 624   Secondary neuronal injury, 588  Secondary spinal cord injury, 591  Sensory neuropathy, 622   Subarachnoid hemorrhage (SAH), 605  Subdural brain abscess (empyema), 613  Subdural hematoma, 585   Transient ischemic attack (TIA), 599  Traumatic (dissecting) aneurysm, 604  Traumatic brain injury (TBI), 581  Tubercular meningitis, 611    10. 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Chamberlain MC, Barnholtz-Sloan JS: Medical treatment of recurrent  meningiomas, Expert Rev Neurother 11(10):1425-1432, 2011.   Uhlmann EJ, Plotkin SR: Neurofibromatoses, Adv Exp Med Biol  724:266—277, 2012.   Jouhilahti EM et al: The pathoetiology of neurofibromatosis 1, Am J  Pathol 178(5):1932-1939, 2011.   Fox BD et al: Epidemiology of metastatic brain tumors, Neurosurg Clin  North Am 22(1):1-6, v, 2011.   Benjamin RK, Das A, Hochberg FH: Metastatic neoplasms and paraneo-  plastic syndrome. In Goetz CG, editor: Textbook of clinical neurology,   Well JR: Central nervous system metastasis. In Gilman S, editor: Neuro-  biology of disease, Burlington, MA, 2007, Elsevier.   Beasley KD, Toms SA: The molecular pathobiology of metastasis to the  brain: a review, Neurosurg Clin North Am 22(1):7-14, v, 2011.   Lo SS et al: Advances in radiation therapy of brain metastasis, Prog  Neurol Surg 25:96-109, 2012.   Chamberlain MC, Tredway TL: Adult primary intradural spinal cord  tumors: a review, Curr Neurol Neurosci Rep 11(3):320-328, 2011.    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Animations  Arteriovenous Malformation (AVM)  Blood Clot Causing Stroke  Blood Flow to Brain and Infections  Brain Abscess  Cardioembolic Stroke  Epidural Hematoma  Guillain-Barré Syndrome  Pontine Stroke  Posterior Circulation Stroke  Spinal Cord Infarct, Spinal Ischemia  Subarachnoid Hemorrhage  Subdural Hematoma  Transient Ischemic Attacks    Schizophrenia, 642  Etiology and Pathophysiology, 642  Clinical Manifestations, 644  Treatment, 646  Mood Disorders: Depression  and Bipolar Disorder, 647  Etiology and Pathophysiology, 647    Mental illnesses are common and found in different cul-  tures and across the socioeconomic spectrum. When left  untreated, the consequences can be devastating. This chapter  provides an introduction to the neurobiology of schizophre-  nia, mood disorders, and some anxiety disorders. The etiol-  ogy and pathophysiology of mental illnesses are diverse and  complex. Diagnostic criteria are constantly being updated to  more precisely diagnose and effectively treat the disorders.  Every mental disorder manifests a range of symptoms that  vary in intensity. Symptom variations likely reflect individual  differences in neural pathologic brain structures or func-  tions, or both, which affect treatment. Risk factors, such as  exposure to uncontrollable psychosocial stress, may precipi-  tate the onset of mental disorders and point to the challenge  in understanding how diseased genes and environmental fac-  tors interact.   The development of visual and quantitative structural and  functional neuroimaging techniques provides insight into the  pathophysiologic basis of mental disorders. In schizophrenia,  neuroanatomic, functional, and neurochemical alterations   Anxiety Disorders, 654  Panic Disorder, 654  Generalized Anxiety Disorder, 655  Posttraumatic Stress Disorder, 655  Obsessive-Compulsive Disorder, 656    associated with this debilitating illness have uncovered abnor-  mal brain regions along with a host of candidate genes that con-  fer risk. Similarly, in mood and anxiety disorders, brain scans  are revealing structural and functional abnormalities. Nota-  bly, many brain regions implicated in normal cognitive and  emotional processing are found in schizophrenia, mood, and  anxiety disorders. The future lies in unraveling how the highly  interconnected brain structures modulated by neurotransmit-  ters, neuropeptides, and hormones operate in normal to abnor-  mal mental states.   Knowledge of the pathophysiology associated with a specific  mental illness has guided the development of pharmacologic  medications. Although second- and third-generation drugs  with fewer side effects are now available, many individuals con-  tinue to suffer; and to complicate diagnosis and treatment, psy-  chiatric disorders, such as depression and anxiety, often coexist.  Identifying and characterizing diseased genes and environmen-  tal triggers in mental illness will offer hope in developing effec-  tive therapies that alleviate symptoms and lessen or reverse the  pathophysiologic alterations.    Schizophrenia is a serious psychiatric illness that strikes 1%  of the world’s population. The illness is equally prevalent in  males and females and emerges in young adults during the late  teens and early twenties, with a slightly earlier onset in males  than in females. Schizophrenia is the term coined originally by  Eugen Bleuler in 1911 to describe a collection of illnesses char-  acterized by thought disorders, which reflect a break in reality  or splitting of the cognitive from the emotional side of one’s  personality. A schizophrenic individual may exhibit a feeling  of happiness when recollecting a terrible event or emotional  indifference when describing a joyful occasion. Today, disorga-  nized thought in schizophrenia is characterized by positive and  negative symptoms including auditory hallucinations, paranoid  delusions, and cognitive deficits that have devastating effects on  the individual and the individual’s family.   Schizophrenia is a heritable disorder. In monozygotic twins,  the concordance rate varies from 30% to 50%. This variability  may stem from different diagnostic criteria and methodologic  or sampling differences across studies. In dizygotic twins and  siblings the concordance rate decreases to 12%, which is still  considerably higher than the 1% figure found in the general  population.   Nonetheless, schizophrenia is not a simple genetic disor-  der in which inherited disease alleles will always lead to illness.  Schizophrenia likely involves several genes located on different  chromosomes and differs from mendelian disorders, in which  genes are fully penetrant and recognized as the primary cause  of disease (e.g., genes for Huntington disease). As indicated by  the 50% concordance rate in monozygotic twins, the genes for  schizophrenia show reduced penetrance, resulting in individu-  als who carry the disease genes without manifesting the illness.  Further complicating the search for the specific genes that con-  fer risk of schizophrenia is the variability in biologic and phe-  notypic traits among individuals who manifest the illness (see  What’s New? Copy Number Variations Increase in Schizophre-  nia and in Offspring of Older Fathers).   Prenatal and Perinatal Vulnerability Factors. Because the  concordance rate of schizophrenia in monozygotic twins  is never 100% as in mendelian disorders, environmental  factors likely play an important role in increasing the risk  of developing the disorder. A leading hypothesis suggests  that early environmental factors interfere with genetically  programmed neural developmental alterations that eventually  compromise normal brain structures and functions.! An  early brain defect may remain silent and not dramatically  affect the individual until subsequent development requires  adaptive use of brain structures.” Several hypothesized early  environmental factors that may alter brain development and  increase the risk of developing schizophrenia include exposure  to prenatal infection, prenatal nutritional deficiencies, perinatal  complications (such as birth defects and neonatal hypoxia), and  upbringing in an urban environment.°    Copy Number Variations Increase in  Schizophrenia and in Offspring of Older Fathers    Copy number variations (CNVs) involving deletions or duplications of several  million base pairs of DNA sequence of the genome are increasingly recognized  to elevate the risk of serious neurodevelopmental disorders including schizo-  phrenia, autism, epilepsy, and mental retardation. Concerning schizophrenia,  large CNV deletions involving multiple genes show increased penetrance  accompanied with severe phenotypic symptoms of the disease. For example,  CNV deletion at 22q11.2, which consists of 1.5 to 3.0 megabases of DNA, is  reported to increase the risk of schizophrenia by 20- to 30-fold in comparison  to the general population. Research linking 22q11.2 deletion to schizophrenia  as well as other recently identified CNV deletions occurring at distinct loci wil  accelerate our genetic understanding of the pathogenesis of the disease and  have implications for genetic counseling and clinical management.   Of further potential clinical relevance of the role of CNVs in schizophre-  nia, offspring of fathers who are age 50 or more have a twofold to threefold  increased risk of the disease when compared to fathers who are in their twen-  ties. Although the causal mechanisms remain unclear, a recent study using a  mouse model reported that offspring sired by older male mice exhibited an  increase in spontaneously occurring (de novo) CNVs. Six de novo CNVs were  found in the offspring of aged male mice and none from the younger control  group. When the CNVs in the mouse brain were then mapped to the human  genome, three de novo CNVs were found to have genes on human chromo-  somes linked to brain development and schizophrenia. These results suggest  that paternal-age—related mutations in the germline contribute to offspring de  novo CNVs that may underlie schizophrenia.    Data from Bassett AS et al: Am J Psychiatry 167:899-914, 2010;  Flatscher-Bader T et al: Trans/ Psychiatry 1:e34, 2011; Moreno-DeLuca  D, Cubells JF: Curr Psychiatry Rep 13:129-137, 2011.    Neuroanatomic Alterations. Advanced neuroimaging  techniques have revealed evidence of structural brain  abnormalities in schizophrenia.*° A consistent finding is the  enlargement of the lateral and third ventricles and the widening  of frontocortical fissures and sulci (Figure 19-1). Schizophrenics  with cerebral ventricular enlargement often exhibit cognitive  impairments and negative symptoms, and respond poorly to  treatment. Other studies reported a reduction in the thalamus  and temporal lobe areas (e.g., amygdala, hippocampus, and  parahippocampal gyrus).° A reduction in thalamus size may  disrupt neurotransmission between the cortex and primary  sensory and motor areas. Temporal lobe alterations may  contribute to the production of positive schizophrenic  symptoms, such as hallucinations, delusions, and thought  disorder.   Brain imaging studies in adolescents with early onset  schizophrenia reveal progressive loss of cortical gray matter  in temporal lobes, somatosensory and motor cortices, and the  dorsolateral cortex (Figure 19-2). Of clinical concern is the loss  of cortical tissue, which is evident by the time the individual  seeks treatment and continues throughout the course of the ill-  ness despite the use of antipsychotic medication.’ The progres-  sive loss in frontal lobe volume is accompanied by increased  severity of negative symptoms and further reductions in cogni-  tive functioning. These results highlight the ineffectiveness of    FIGURE 19-1 Magnetic Resonance Imaging (MRI) Comparison of Nor-  mal Brain and Brain with Schizophrenia. Three-dimensional MRI reconstruc-  tions showing A, the cerebroventricles (gray regions) and hippocampus (yellow  regions) of a schizophrenic patient, and B, those of a healthy individual. Note the  enlarged cerebroventricles and reduced hippocampal volume of the brain of the  schizophrenic individual. (From Gershon ES, Rieder RO: Sci Am 267:128, 1992.  Original illustrations by Nancy C. Andreason, University of lowa.)    current medications for schizophrenia to attenuate or reverse  the loss of frontal brain tissue.   Brain abnormalities in schizophrenia are believed to origi-  nate in the prenatal period of cell proliferation and migration.  Reelin, an extracellular matrix protein involved in neuronal  migration during development and in synaptic function during  adulthood, is reduced in the prefrontal cortex and hippocam-  pus of schizophrenic individuals.*” Reelin is concentrated in  interneurons that contain gamma-aminobutyric acid (GABA),  the most widespread inhibitory neurotransmitter. Further-  more, in the dorsal prefrontal cortex of schizophrenic brains,  the level of glutamic acid decarboxylase, the major enzyme in    FIGURE 19-2 Accelerated Gray Matter Loss in Brains of Early Onset  Schizophrenic Adolescents. Annual gray matter loss ranging from 2% to 5%  was found in 13- to 18-year-old schizophrenics—compared with age-matched  healthy adolescents. (From Thompson PM et al: Proc Nat! Acad Sci U S A 98:11650,  2001.)   Pathophysiologic changes in the dorsal prefrontal cortex are  believed to contribute to the production of negative symptoms  in schizophrenia (Figure 19-3). In particular, the dorsolateral  prefrontal cortex (DLPFC) (Brodmann areas 9, 10, 46, 47) is  intricately involved in the initiation and maintenance of goal-  directed activities and in solving cognitive problems related to  working memory. Working memory involves the brief storage  and use of information to complete cognitive tasks such as lan-  guage comprehension, learning, and reasoning. Blood flow and  metabolism normally increase in the DLPFC during working  memory processing but not in schizophrenics, who also per-  form poorly in tests of working memory. Thus the dorsolateral  prefrontal cortex appears to be hypoactive in schizophrenia.   The onset of schizophrenia  was initially hypothesized to stem from abnormally high  concentrations of the brain neurotransmitter dopamine. This  dopamine hypothesis of schizophrenia was proposed on the  basis of pharmacologic studies showing that antipsychotic drugs  were potent blockers of brain dopamine receptors. A strong  positive correlation was found between the clinical potencies  of first-generation antipsychotic drugs (e.g., chlorpromazine,  fluphenazine, and haloperidol) and their affinity for the  dopamine D, receptor. In addition, drugs at high doses that  dramatically increased dopaminergic transmission—such as  levodopa (1-dopa), cocaine, and amphetamine—produced  schizophrenic-like psychosis, which was reversed by dopamine  blockers.   A current view of the dopamine hypothesis of schizophrenia  is that brain dopamine pathways are altered in different ways  (Figure 19-4). For example, the negative symptoms and cog-  nitive alterations in schizophrenia are proposed to result from  reduced dopaminergic neurotransmission in the mesocortical  dopamine pathway.!° This hypodopaminergic transmission in  the prefrontal cortex contrasts with the hypothesized hyperdo-  paminergic secretion, in mesolimbic brain regions, which may    FIGURE 19-3 The Prefrontal Cortex. The prefrontal cortex consists of a dor-  solateral (blue) and an orbitofrontal (green) region.    contribute to the production of positive schizophrenic symp-  toms. The mesolimbic dopamine pathway innervates tempo-  ral lobe structures including the hippocampal formation and  amygdala, as well as the nucleus accumbens and anterior cin-  gulate cortex.   Another neurotransmitter system that may underlie the  pathogenesis of schizophrenia is the excitatory neurotrans-  mitter glutamate and its actions on the N-methyl-p-aspartate  (NMDA) receptor subtype. The glutamate hypothesis of  schizophrenia proposes that underactivation of glutamate  receptors contributes to schizophrenia.'! In schizophrenia,  glutamate concentrations in the cerebrospinal fluid (CSF) are  reduced along with a decrease in cortical glutamate synthesis.  Furthermore, in unaffected individuals, blocking the glutamate  NMDA receptor with antagonists, such as phencyclidine (PCP)  and ketamine, facilitates the positive and negative symptoms of  schizophrenia. PCP users report auditory hallucinations and  disorientation, and may become violent from their delusions.    Hippocampus  FIGURE 19-4 The Dopamine System. Dopamine cell bodies are located in  the substantia nigra, where they project to the stratum (nigrostriatal pathway); and  in the ventral tegmental area, where they project to the frontal and cingulate cortex  (mesocortical pathway), the striatum, the hippocampus, and other limbic structures  (mesolimbic pathway). Dopamine nuclei are also located in the hypothalamus and  project to the pituitary.    In monkeys, chronic PCP treatment impairs cognitive perfor-  mance in a test associated with prefrontal cortical damage. '?    The symptoms of schizophrenia are currently divided into three  broad categories of positive, negative, and cognitive symp-  toms (Box 19-1). Positive symptoms frequently occur during a  psychotic episode, when an individual loses touch with reality  and experiences something that should be absent (e.g., halluci-  nations). Negative symptoms are characterized by disruptions in  normal emotional states and expressions. Cognitive symptoms  are fairly common and involve problems with thought pro-  cesses that severely impair the ability to perform routine daily  tasks that involve attention, planning, and social skills. Accord-  ing to the Diagnostic and Statistical Manual of Mental Disorders  (DSM-IV-TR),'° schizophrenia is diagnosed when an individ-  ual exhibits delusions, hallucinations, negative symptoms, or  social/occupational dysfunctions for at least 6 months and at  least two of the common symptoms of the disorder—delusions,  hallucinations, disorganized speech, disorganized or catatonic  behavior, or presence of negative symptoms—must occur for 1  month (or less if successfully treated).    Psychotic dimension refers to hallucinations and delusions and  reflects a person’s confusion or loss of touch with the external  world. Hallucinations and delusions are classified as positive  symptoms and are the most common in schizophrenia.  Hallucinations. A hallucination is a perception experienced  without external stimulation of the sense organs. Sensory  hallucinations can be auditory, tactile, visual, gustatory, and  olfactory. For example, the schizophrenic individual may hear   Delusions of being controlled  Delusions of mind reading  Delusions of reference  Grandiosity    Bizarre Behavior  Aggressive, agitated  Clothing, appearance  Repetitive, stereotyped  Social, sexual behavior   Inability to understand information and  make proper decision to complete a task   Problems with working memory or the inabil-  ity to use recently learned information    The Diagnostic and Statistical Manual of Mental Disorders—or “DSM” —is  published by the American Psychiatric Association, and has been considered  the authoritative guide to diagnosing mental disorders. First published in 1952,  the DSM has undergone several revisions, and not until the 1980 publication  of the DSM-II/ did the manual dramatically impact mental health professionals,  including psychiatrists, clinical psychologists, social workers, and nurses. The  DSM-IIl became known as the “bible of psychiatry” because it introduced a new  set of criteria to standardize the diagnoses of mental disorders by categorizing  symptoms presumably unique to each mental illness, such as schizophrenia and  bipolar disorder. This categorical symptom approach stimulated research on the eti-  ology and pathophysiology of diverse mental disorders and began to impact public  health policy, education, and reimbursement decisions made by insurance compa-  nies. Modest categorical changes were subsequently made in the 1994 edition of  DSM-IV and a text revision of DSM-IV, called DSM-/V-TR, was published in 2000.  The highly anticipated DSM-5 published in 2013 and represents the culmination  of more than 10 years of revision work involving more than 1500 experts in the    psychiatric, psychologic, psychiatric nursing, pediatric, neurologic, social work,  and related disciplines from 39 countries. Users familiar with earlier DSM versions  will encounter two major changes in DMS-5. One major change includes reordering    the chapters based on the relatedness of disorders in terms of similar underlying  vulnerabilities and symptoms. This change in each chapter is intended to align the  DMS-5 with the World Health Organizations International Classification of Diseases,  ed 11, in order to further facilitate communication and diagnosis of disorders.   The second major change is to replace the multiaxial system of diagnosis  with a nonaxial documentation by combining the former Axes |, Il, and III with  separate notations for psychosocial and contextual factors (formerly Axis IV) and  disability (formerly Axis V). Notably, the DSM-5 will not increase the number  of mental disorders; instead, fewer disorders will be found in DSM-5 than in  DSM-IV. However, any change by DSM in the diagnosis of mental health that  defines “normal” behavior will be of concern, especially by advocacy groups an  insurance companies. For example, one controversial change in the DSM-5 wi  be to potentially diagnose any child over the age of 6 who displays irritabili    or frequent angry outbursts with “disruptive mood dysregulation disorder.” This  new diagnosis was included to provide parents or caregivers the opportunity to  plan interventions for children who exhibit problems controlling their emotions.  However, advocacy groups questioned whether such a diagnosis would stigma-  tize children and may lead to unnecessary drug prescriptions. Another change is  a grief and depression diagnosis. Whereas previous DSM versions prevented a  diagnosis of depression in a person grieving the death of a loved one, the DM/S-5  will allow depression diagnoses in the bereaved. The rationale was to provide  those with chronic grief to be diagnosed with, and obtain treatment for, depres-  sion. However, some healthcare professionals questioned whether diagnosing  normal grieving as depression is necessary at all, as in the previous DSM.   Although the new DSM-5 is expected to be used by many clinicians for diagnos-  ing and treating mental disorders, some prominent researchers and clinicians have  begun to question the way mental illnesses are currently viewed by categorizing and  diagnosing symptoms. In particular, the current categorical symptom diagnoses guide  to mental disorders does not guarantee effective treatment. A patient may exhibit  multiple symptoms that overlap with a diagnosis for different disorders and that may  explain why specific clinical treatment will not always relieve or temper mental ill-  ness. What appears to be missing in our present understanding of mental disorders  are the causes and underlying brain mechanisms that trigger the onset of the illness.   To address this issue, Dr. Thomas Insel, Director of the National Institute of  Mental Health, and other prominent scientists are hoping to steer psychiatric  research away from classifying symptoms to a fundamental approach of identify-  ing the genes, molecules, and pathophysiologic brain circuits that cause mental  disorders. To do so, Dr. Insel started a federal project called Research Domain  Criteria to fund research that investigates the biologic basis, and not the symp-  tom categories, of mental disorders. Research projects are beginning to unravel  brain functions that broadly implicate neural systems linked to memory, fear,  anhedonia, and stress, which affect many people with mental illness. Future  treatments that target pathophysiologic neural systems with new drugs or with  cognitive-behavioral methods may be more beneficial to psychiatric patients  than currently available treatments for psychiatric symptoms.    Data from Adam D: Nature 496:416-418, 2013; American Psychiatric Association: www.dsm5.org; Halter MJ et al: J Psychosoc Nurs 51:30-39,  2013; Insel TR et al: Neurosci Biobehav Rev (in press); Stringaris A: J Child Psychol Psychiatr 54:501, 2013.    voices, experience touch or electrical sensations, report images  of animate and inanimate objects, or complain of unpleasant  tastes and odors. These hallucinations may occur alone or  together.   Delusions. A delusion is a persistent belief contrary to the  educational and cultural background of the individual. Delusions  may involve grandiose, nihilistic, persecutory, somatic, sexual,  and religious themes. Paranoid beliefs are common and may  involve spying, conspiracy, persecution, and ridicule. Delusions  also may be referential in that particular stimuli or events  become highly personalized, such as believing a television talk  show host is directing information specifically at them.    Disorganized behavior includes disorganized speech and dis-  organized or bizarre behavior. Incongruity of affect is another  dimension of disorganized behavior.   Disorganized Speech. A common form of disorganized  speech is formal thought disorder, which involves fluent  speech that is difficult to comprehend. The speech often moves  from one topic to another unexpectedly (loose associations)  and illogically and the person becomes easily distracted when  talking.   Another form of disorganized speech is called poverty of  content. Here, the use of vocabularies to convey information  is severely retarded despite a fair amount of spoken words. For  instance, the same phrases are used repeatedly throughout a  conversation.   Disorganized Behavior. Disorganized (or bizarre) behavior  is the conceptual equivalent of disorganized speech. The  individual has difficulty engaging in goal-directed activities.  Repetitive (e.g., stereotyped rocking) or aimless behavior and  poor personal hygiene are exhibited. Another feature is the  incongruity of affect or the manifestation of inappropriate  situational affect as exemplified by hostility without provocation  or childlike silliness in sober situations.    Negative dimensions reflect a deficit in normal functioning  and are characterized by affective flattening, anhedonia, alogia  (poverty of speech), and avolition. Affective flattening is the  near absence of emotional or facial expressions throughout a  conversation or in different situations. In anhedonia, individu-  als are unable to experience emotions such as pleasure or pain  and report a sense of detachment from the environment. Alogia  is the absence of spontaneous speech production for the pur-  pose of answering questions or expressing oneself. Avolition is  a deficit in spontaneous or goal-directed behavior, such as com-  pleting simple daily tasks.    The use of chlorpromazine in the mid-1950s dramatically  altered the treatment of schizophrenia, which previously  required extensive institutional hospitalization. The drug was  especially effective in reducing positive symptoms such as hallu-  cinations and delusions as well as thought disorders and hyper-  activity. The beneficial effects of chlorpromazine and similar   Haloperidol Haldol  Perphenazine Trilafon  Pimozide Orap  Prochlorperazine Compazine  Thioridazine Mellaril  Thiothixene Navane  Trifluoperazine Stelazine    first-generation antipsychotic drugs like haloperidol on positive  symptoms were believed to stem from their ability to block the  dopamine D,-receptor subtype, especially in the overly active  mesolimbic dopamine pathways.   However, D,-receptor blockade, such as in the striatum,  produces a notable neurologic side effect resembling Parkinson  disease—a disorder associated with degeneration of dopamine  cell bodies in the substantia nigra that project to the striatum. A  related side effect of conventional antipsychotics that develops  in 15% to 20% of schizophrenics after several years of treatment  is a condition called tardive dyskinesia. This condition is char-  acterized by tic-like jerky movements, such as smacking the lips  or flicking the tongue, unsteady gait, or rocking back and forth  when seated. Other side effects may include sedation, hypoten-  sion, akathisia (motor restlessness), constipation, weight gain,  amenorrhea, and, less frequently, hepatotoxicity and electro-  cardiographic changes.   Although the majority of schizophrenic individuals obtained  some positive symptom relief from the first-generation or con-  ventional antipsychotics, approximately 20% failed to respond  to D,-blocking drugs (Box 19-2), especially those with pro-  nounced symptoms of apathy, disorientation, and social with-  drawal. However, some of these treatment-resistant individuals  responded to a second generation of drugs that became known as  atypical antipsychotic drugs.'* Atypical antipsychotics also were  shown to have superior efficacy in reducing not only the positive  but also the negative symptoms in comparison with conventional  antipsychotics. For example, clozapine improve some cognitive  functions (such as verbal fluency, verbal learning, and memory)  and some physical functions (such as psychomotor speed). In    addition, the notable neurologic side effects that accompany the  use of the conventional antipsychotics were diminished.   Unlike conventional antipsychotics, atypical drugs appear  to work by blocking a range of neurotransmitter receptors. For  example, clozapine blocks not only D, receptors but also D,,  D3, Dy, and Ds receptors and serotonin (5-hydroxytryptamine,  ie., HT, 5-HT¢, 5-HT7); norepinephrine; and cholinergic and  histamine receptors. Risperidone and ziprasidone have higher  affinity for blocking 5-HT, than D, receptors. The higher  5-HT,/D,-receptor—binding ratio of atypical antipsychotics in  comparison with conventional drugs may reflect a normaliza-  tion of serotonin-dopamine interactions leading to clinical effi-  cacy not observed with D,-receptor blockade alone.   Atypical antipsychotics are not without adverse effects, most  notably metabolic abnormalities including regulation of glu-  cose and lipid levels and weight gain. For example, long-term  clozapine or olazapine treatment increases body weight gain,  which becomes a risk factor for diabetes and cardiovascular  disease. Schizophrenics treated with clozapine also are at risk  of developing agranulocytosis, a potentially lethal blood disor-  der involving the loss of white blood cells and a compromised  immune system.   In conjunction with antipsychotic medication, psychosocial  therapy can facilitate the management of schizophrenia. Psy-  chosocial relationships assist the individual in developing cop-  ing strategies and in identifying stressors and relapse symptoms.  Cognitive-behavioral therapy (CBT), a talking therapy that initi-  ates cognitive and behavioral change based on an individualized  reappraisal of the person’s faulty beliefs, is effective in treating  schizophrenics with stabilized antipsychotic medications.'° An  important benefit of psychosocial and family support is the  encouragement of compliance with antipsychotic medication  that requires a period before the emergence of clinical efficacy.    Mood refers to a sustained emotional state as opposed to brief  emotional feelings, which are termed affective states. Healthy indi-  viduals are normally capable of experiencing a variety of affective  states including euphoria, joy, surprise, fear, sadness, anxiety,  and depression. When emotional states, such as sadness, become  chronic and uncontrollable, individuals may be diagnosed with  a mood disorder called depression. The two major classifications  of mood disorder are: (1) unipolar or major depressive disorder,  also known as major depression or clinical depression, which con-  sists of episodes of depression; and (2) bipolar disorder, which is  further classified into bipolar I and bipolar II disorders. Bipolar I  disorder features manic episodes and at least one major depres-  sive episode and bipolar II disorder is characterized by recurrent  major depressive episodes with one or more hypomanic (milder  than manic) episodes. Box 19-3 presents the major criteria of  depression and bipolar disorder according to the American Psy-  chiatric Association’s DSM-IV-TR.'°   Major (unipolar) depression is the most common mood  disorder and the leading cause of disability in the United States  and throughout the world. Unipolar depression appears in all   Significant (>5%) weight gain or loss ina month  Insomnia or hypersomnia    *Five or more of the symptoms are present in a 2-week period and  at least one of the symptoms is either depressed mood or loss of  interests or pleasure.   ‘Three or more symptoms (four if the mood is only irritable) during a  distinct period of abnormally and persistently elevated, expansive, or  irritable mood occurring for at least 1 week.    age groups including young children. In the United States, the  lifetime prevalence rate of depression is 16.2% of the popula-  tion with a twofold greater risk in women than men after ado-  lescence. In children and adolescents, 2% to 6% suffer from  depression. The prevalence of bipolar disorder ranges from  3% to 5% in the general population. Bipolar I disorder occurs  equally in men and women in comparison with bipolar II disor-  der, which afflicts more women than men. When left untreated,  a number of depressed and bipolar individuals are at risk of  developing a host of medical illnesses, including cardiovascular  disease, obesity, diabetes, and thyroid disease.   Genetic Predisposition and Environmental Influences  Family and twin studies indicate a strong basis for mood disor-  ders. Using DSM-III or DSM-III-R criteria, concordance rates  for bipolar disorder ranged up to 62% and 42% for monozy-  gotic and dizygotic twins, respectively.!° For unipolar disorder,  concordance rates of 62% and 28% were reported in monozy-  gotic and dizygotic twins, respectively. Even among adoptees  with a biologic family history of mood disorders, the incidence  of developing major depression or manic-depressive illness is  higher than among control adoptees. The strong tendency for  mood disorders to run in families has encouraged a search for  the abnormal gene or genes. Interestingly, loci on chromo-  somes 18 and 22 have been linked to both bipolar disorder and  schizophrenia. Bipolar individuals, who may exhibit psychotic  behavior, have deficits in reelin expression linked to genetic    loci, located on chromosome 22, which confers susceptibility to  schizophrenia (see preceding section on schizophrenia, p. 642).  However, the large variation in clinical symptoms suggests  that developmental and environmental factors are as impor-  tant as genetic factors in contributing to the etiology of mood  disorders.   A current view of mood disorders is that the illness stems  from a complex interplay between susceptible genes and envi-  ronmental influences. For example, the interplay between life  stressors and a potentially dysfunctional serotonin (5-HT)  system appears to elevate the risk of depression.'” Researchers  have identified a polymorphic variant of the serotonin trans-  porter (5-HT-T) that exists either as a short (s) allele or as a  long (1) allele. The serotonin transporter serves in the reuptake  of serotonin at the synapse and may moderate the serotonergic  response to stress. However, individuals with two copies of the  s allele were more likely to develop major depression and have  suicidal thoughts in response to stressful events than individu-  als homozygous for the / allele. In addition, among individuals  who carry two s alleles, the risk of a major depressive episode  increased twofold after experiencing four or more stressful  events. This work!” suggests that exposure to both adverse life  events and a genetic alteration in 5-HT function increases the  risk of developing major depression.    Modern theories of mood disorders began with the impor-  tant observations that drugs such as imipramine that elevated  norepinephrine levels within the synapse reduced depression  whereas drugs that depleted monoamine levels (e.g., reser-  pine) increased depression. These studies led to the dominant  monoamine hypothesis of depression, in which a deficit in  the concentration of brain norepinephrine, dopamine, and/  or serotonin is the underlying cause of depression, in con-  trast to mania, which results from elevated concentrations of  monoamines. Three major classes of antidepressant drugs were  initially developed and included monoamine oxidase inhibi-  tors (MAOIs), tricyclic antidepressants (TCAs), and selective  serotonin reuptake inhibitors (SSRIs). These antidepressants  shared the common property, albeit through different mecha-  nisms, that increasing monoamine neurotransmitter levels  within the synapse is the basis for their antidepressant effects  (Figure 19-5).   Additional support for the monoamine hypothesis of depres-  sion came from studies showing a reduction of monoamine  metabolites in the cerebral spinal fluid (CSF) of depressed  people. Other work demonstrated that dietary depletion of  tryptophan, the precursor of serotonin synthesis, or alpha-  methylparatyrosine (AMPT), a drug that inhibits dopamine and  norepinephrine synthesis, produced a rapid return to depres-  sion in individuals successfully treated with antidepressants.'®   Stress and Hypothalamic-Pituitary-Adrenal System Dys-  regulation. The hypothalamic-pituitary-adrenal (HPA) system  plays an essential role in an individual’s ability to cope with  stress (see Chapter 11). However, chronic activation of the HPA    system and elevated glucocorticoid secretion are found in a  large percentage (30% to 70%) of people with major depression,  suggesting that mechanisms responsible for increased HPA  hormone secretion contribute to the pathophysiology of  depression.'!? Notably, antidepressant drugs effective in  normalizing the HPA system are associated with a good clinical  response, whereas persistent dysregulation of the HPA system is  related to continued depression or relapse.   Uncontrollable stress activates not only the HPA system but  also the immune system, which may further contribute to the  development of depression. Psychosocial stress-induced activa-  tion of the immune system increases secretion of proinflamma-  tory cytokines, such as interleukin-1o (IL-1a) and IL-f, tumor  necrosis factor-alpha (TNF-a), and IL-6, which modulates sig-  naling pathways throughout the periphery and brain and aug-  ments further secretion of HPA hormones and monoamine  metabolism. A potential consequence of prolonged cytokine-  induced activation is dysregulation in feedback and feed-  forward control mechanisms of the HPA system, leading to  chronic elevations in cortisol level, as observed in major depres-  sion. Persistent elevations in cortisol level also may induce  immunosuppression that compromises the body’s immune sys-  tems to control inflammation and infectious diseases. Increas-  ing evidence suggests that inflammation is another risk factor  that triggers the onset of depression. For example, inflamma-  tion is a significant contributor to coronary heart disease and  the prevalence of comorbid depression in people with heart  disease is threefold higher than that in the general population.”   Increasing evidence from animal models of stress-induced  depression shows that depression-like behavior is accompanied  by atrophy of neurons in the hippocampus, a reduction in the  development of new hippocampal neurons (i.e., neurogenesis),  and a deficit in hippocampal brain-derived neurotrophic fac-  tor (BDNF) levels.?!:2 Consistent with animal studies, human  postmortem work indicates low hippocampal BDNF levels  in depression. Because the growth factor BDNF supports the  survival of neurons and facilitates neurogenesis from hippo-  campal stem cells, a neurotrophic hypothesis of depression  has been proposed as an extension of the monoamine hypoth-  esis of depression to broadly account for the pathophysiologic  basis of depression. That is, stress-induced depression and the  accompanying reduction in levels of monoamines are caused  by deficits in neurogenesis and BDNF levels. Of clinical rele-  vance, administration of antidepressants to animals reverses the  depression-like state and increases the development of neuro-  genesis and BDNF levels (see What’s New? Hippocampal Neu-  rogenesis and the Glucocorticoid Receptor Play Essential Roles  in Deterring Depression).   Hypothalamic-Pituitary-Thyroid System Dysregulation.  Approximately 20% to 30% of persons with major depression  have an altered hypothalamic-pituitary-thyroid (HPT) system.  These individuals exhibit increased CSF levels of thyrotropin-  releasing hormone (TRH), blunted  thyroid-stimulating  hormone (TSH) response to TRH challenge, and decreased  nocturnal rise in TSH level that normally occurs between  midnight and the early morning hours.’* Persistent blunting  of the TSH response to TRH is associated with an increased    FIGURE 19-5 Schematic Diagrams Showing the Sites of Actions of Antidepressants and Their Effects on Neu-  rotransmitter Levels. A, In healthy individuals an action potential generated in the presynaptic neuron results in neurotrans-  mitter release into the synapse. Some neurotransmitters bind to receptors on the postsynaptic neuron that leads to activation  of second messenger systems (not shown). Neurotransmitters are also removed from the synapse by reuptake into the presyn-  aptic neuron and deaminated by monoamine oxidase (MAO). B, In depressed individuals, neurotransmitter levels are hypoth-  esized to be reduced. The mechanisms responsible for this reduction are not understood. €, MAO inhibitors act by preventing  the degradation of neurotransmitters, such as norepinephrine and serotonin. As a result, neurotransmitter levels are elevated.  D, The tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSA/s) act by reducing the uptake of neu-  rotransmitters from the synapse, leading to increased neurotransmitter levels. TCAs, such as nortriptyline and desipramine,  tend to block norepinephrine reuptake, whereas amitriptyline and imipramine also have effects on serotonin reuptake. SSRIs    Hippocampal Neurogenesis and the Glucocorticoid Receptor Play Essential Roles in Deterring Depression    The hippocampus contains glucocorticoid receptors that play a negative feed-  back role in modulating the inhibition of the HPA hormone system. Chronic  stress induces a persistent elevation in secretion of the glucocorticoid corti-  sol and may precipitate depression as well as a reduction in hippocampa  neurogenesis. However, the specific effects of hippocampal neurogenesis on  depression are not well understood. Two recent studies examined the role o  hippocampal neurogenesis in depression. One study reported that hippocampa  neurogenesis—deficient mice were more likely to exhibit increases in depres-  sion-like behavior and deficits in glucocorticoid negative feedback in com-  parison to control mice. The results suggest an essential role of hippocampa    neurogenesis in dampening stress-induced HPA hormone secretion and buff-  ering the effects of stress on depression. The other study examined whether  hippocampal glucocorticoid receptors are involved in antidepressant-induced  stimulation of neurogenesis. Using human hippocampal progenitor cells, the  antidepressant sertraline was found to increase neuronal differentiation via a  glucocorticoid receptor—-dependent mechanism. Furthermore, drugs that block  the actions of the glucocorticoid receptor reduced the effects of sertraline on  progenitor cell proliferation. The results of this study highlight a role of the glu-  cocorticoid receptor in the antidepressant-induced facilitation of hippocampal  neurogenesis in humans.    Data from Anacker et al: Mol Psychiatry 16:738-750, 2011; Snyder JS et al: Nature 476:458-461, 2011.    FIGURE 19-6 The Serotonin System. Serotonin neurons are located in the  brainstem raphe nuclei. They project diffusely to all regions of the cortex, tem-  porolimbic regions, hypothalamus, basal ganglia, cerebellum, the brainstem, and  spinal cord.    probability of relapse. Abnormalities in thyroid function, such  as increased basal TSH concentrations with normal thyroxine  levels, also are observed in bipolar disorder, especially among  individuals with rapid cycling.    The dorsal and median raphe nuclei, located in the central gray  of the caudal mesencephalon and rostral pons, contain a large  group of serotonin-synthesizing neurons that project exten-  sively to all regions of the cortex, basal ganglia, limbic system,  hypothalamus, cerebellum, and brainstem (Figure 19-6). Post-  mortem and/or brain imaging studies of depressed individuals  revealed a widespread decrease in serotonin 5-HT\, receptor  subtype binding in the frontal, temporal, and limbic cortex  as well as serotonin transporter binding in the cerebral cor-  tex and hippocampus. Mood disorders in some people may  reflect a dysfunctional raphe-serotonin system, which normally  modulates homeostasis, emotionality, and tolerance to aversive  experiences.   A group of norepinephrine-containing cells located in the  locus ceruleus of the rostral pons project to vast areas of the  forebrain, brainstem, and spinal cord (Figure 19-7). The locus  ceruleus—norepinephrine system is implicated in global psycho-  logic processes including attention, vigilance, and orientation  to novel, aversive, or threatening stimuli. Activation of the locus  ceruleus—norepinephrine system is also capable of inhibiting the  raphe-serotonin system, suggesting an indirect role in modu-  lating serotonin functions. Norepinephrine receptor alterations  (e.g., a- and B-adrenergic receptor subtypes) are found in the  frontal cortex of some suicide victims with major depression.  Alterations in norepinephrine systems may be linked to atten-  tion or concentration difficulties as well as sleep and arousal  disturbances in depression.    Hypothalamus  Locus ceruleus  Spinal cord  FIGURE 19-7 The Norepinephrine System. The norepinephrine cell bodies  originate in the locus ceruleus and project throughout the brain, including the hypo-  thalamus, the temporal lobe, the entire cortex, the cerebellum, and spinal cord.    Postmortem and brain imaging studies further reveal struc-  tural and functional abnormalities associated with mood dis-  orders, especially in frontal and limbic regions such as the  amygdala.*+7° Postmortem studies report a reduction in  glial cell numbers in people with unipolar and bipolar disor-  ders. There are also reports of reduced frontal lobe volume in  depressed individuals and decreased or asymmetric temporal  lobe volume in individuals with bipolar illness and depression.  One study showed increased volume of the amygdala in bipolar  illness. In some cases, specific brain abnormalities are associated  with a subtype of depression. For example, late onset depressed  older adults more often exhibit enlarged lateral ventricles than  midlife depressed individuals, depressed older adults with an  early age of illness, or bipolar individuals.   Functional neuroimaging studies indicate decreased cere-  bral blood flow and glucose metabolism in the dorsolateral  and dorsomedial prefrontal cortex of individuals affected by  major depression or bipolar disorder. Dorsolateral prefrontal  abnormalities in depression may be responsible for the retar-  dation in cognitive processing and speech deficits similar to  those found in schizophrenia. Dorsomedial frontal dysfunc-  tion may be associated with mnemonic and attentional impair-  ments that accompany mood disorders. Other frontocortical  regions, including the ventrolateral, ventromedial, and orbital  areas, exhibit increased blood flow and metabolism in unipolar  depression (Figure 19-8). These frontal brain areas have exten-  sive interconnections with the amygdala, and increased blood  flow and metabolism, especially in the right amygdala, is posi-  tively related to negative affect in depressed individuals. These  functional changes in brain activity begin to normalize with  successful antidepressant treatments, suggesting they are state  rather than trait related.   Major depression is characterized by unremitting feelings of  sadness and despair (see Box 19-3). The dysphoric mood or  intensely painful mood is accompanied frequently by insom-  nia, loss of appetite and body weight, and reduced interest in    FIGURE 19-8 Positron-Emission Tomography (PET) Comparison of Brain  Activity in Depression and in Remittance. PET scan showing increased activity  in the left prefrontal cortex in a depressed person but not in the remitted person.  VLPFC, Ventrolateral prefrontal cortex. (From Drevets WC et al: J Neurosci 12:3628,  1992. Copyright ©1992 by the Society for Neuroscience.)    pleasurable activities and interpersonal relationships. Sleep dis-  turbances may include difficulty in initially falling asleep and  awakening in the middle of the night, lying awake for several  hours with an inability to subsequently fall asleep. Individuals  may have reduced motor activity and suffer marked fatigue.  Others complain of restlessness and agitation. Feelings of  worthlessness and guilt are common, and pessimistic or nega-  tive outcomes are often perceived even in routine situations.  The ability to function (e.g., work) and concentrate is greatly  diminished. Depressive episodes may occur or recur suddenly  or gradually and continue from a few weeks to months, and  20% may exhibit a chronic form of depression.   Suicidal risk increases in depression. Factors such as living  alone or being divorced, having a prior history of drug abuse or  suicide attempt, or having depression at midlife or older ages  contribute to suicide in 10% to 15% of depressed individuals.   Manic individuals experience elevated levels of euphoria and  self-esteem and feelings of grandiosity. Energy levels are greatly  enhanced even after only a few hours of sleep each night. The  increased energy, however, does not lead to organized plans and  thoughts. The individual may show poor judgment in spending    money, may become hypersexual, or may make poor business  commitments. Other hallmarks of mania are excessive, rapid,  loud, and pressured speech. The manic person frequently  skips from one topic of conversation to another and is easily  distracted both when speaking and when performing tasks.  Approximately 50% of manic individuals develop psychotic  symptoms, such as delusions or hallucinations, which require  hospitalization. The onset and termination of manic symptoms  (see Box 19-3) are usually abrupt and may last for a few days or  months followed by depression. The risk of recurrence of bipo-  lar disorder is high, especially without immediate treatment.   Approximately 80% of depressed persons will respond to anti-  depressant drugs such as MAOIs, TCAs, and SSRIs (Box 19-4);  psychotherapy; or a combination of both treatment modali-  ties. Although SSRIs have become the standard first-line treat-  ment for major depression, initial selection of an antidepressant  often includes an assessment of the person’s symptoms and age  as well as the side effects, safety, cost, and convenience of the  prescribed medication. For example, medications that produce  sedation may be helpful for the treatment of sleep disturbances.  Approximately 50% of depressed individuals may not show a  favorable response during initial treatment to an antidepres-  sant drug, and 10% to 20% may continue to exhibit symptoms  after 2 years. Individuals who are nonresponsive to a specific  antidepressant during a 2-month period may be given another  antidepressant medication. Atypical antidepressants, such as  nefazodone, trazodone, and mirtazapine, presumably produce  their clinical effects by blocking specific receptors (e.g., 5-HT>,).  A new generation of antidepressants that selectively block sero-  tonin and norepinephrine reuptake is available in the United  States (e.g., venlafaxine) and Europe (i.e., milnacipran, rebox-  etine). At present, there are no criteria to determine whether  selection of the next antidepressant will be efficacious. Among  children and adolescents, only fluoxetine is currently approved  for use in children by the U.S. Food and Drug Administration  (FDA)’° (see What’s New? Comprehensive Treatment of Risk  Factors May Promote Resilience and Rapid Recovery from  Depression).   In bipolar depression, antidepressant medications may lead  to cycle acceleration or induction of mania. However, SSRIs  and bupropion may be less likely to induce these effects than  MAOIs or TCAs.   A number of side effects are reported with MAOIs, TCAs,  and SSRIs. Commonly reported side effects of MAOIs include  sedation or agitation, insomnia, dry mouth, impotence, and  weight gain. MAOIs also may induce acute and heightened  elevations in blood pressure (e.g., hypertensive crisis) after  intake of tyramine-rich foods, such as aged cheeses, sour  cream, pods of broad beans, pickled herring, liver, canned  figs, raisins, and avocados. In addition, MAOI interactions  with TCAs, SSRIs, stimulants, and over-the-counter flu medi-  cations are dangerous and should be avoided. Because of these  adverse side effect issues, MAOIs are used less often than  other antidepressants.    BOX 19-4 FDA-APPROVED MEDICATIONS  USED IN THE TREATMENT OF  DEPRESSION AND ANXIETY  DISORDERS    Monoamine Oxidase Inhibitors  Isocarboxazid Marplan  Phenelzine Nardil  Tranylcypromine Parnate  Selegiline Emsam   Amoxapine Asendin  Clomipramine Anafranil  Desipramine orpramin, Pertofrane  Doxepin Adapin, Sinequan  Imipramine Tofranil    Selective Serotonin Reuptake Inhibitors  Citalopram Celexa  Escitalopram Lexapro  Fluoxetine Prozac  Fluvoxamine Luvox  Paroxetine Paxil  Sertraline Zoloft    TCAs may produce sedation, insomnia, orthostatic hypo-  tension, seizures, and weight gain. Some TCAs have moder-  ate anticholinergic side effects, including constipation, urinary  hesitancy or retention, dry mouth, blurred vision, and memory  impairment. These side effects may be an issue when consid-  ering TCA treatment of older adults, in which case the TCAs  desipramine and nortriptyline may be preferred because of  their reduced anticholinergic, cardiovascular, and sedating  effects.    Common side effects of SSRIs include sleep disturbances  (e.g.. insomnia) and nausea. However, agitation, allergic skin  reactions, dry mouth, anxiety, altered appetite, and sexual dys-  function have been reported. Unlike MAOIs and TCAs, SSRIs  do not have pronounced effects on the cardiovascular or cholin-  ergic systems. SSRIs are potent inhibitors of cytochrome P-450  isoenzymes, which are involved in drug metabolism. Therefore,  SSRIs may lead to dangerous elevations in blood concentrations  of other psychiatric medications when taken together. SSRIs  should not be taken with MAOIs or immediately after discontin-  uing MAOI treatment. A serotonin syndrome characterized by  excitement or autonomic hyperactivity, abdominal pain, rigid-  ity, and hyperthermia may develop, leading to coma or death.   Side effects of atypical antidepressants may include sedation, dry  mouth, weight gain, and constipation. Nefazodone and trazodone  have been associated with hepatic toxicity. Venlafaxine and rebox-  etine lack many of the serious side effects associated with TCAs;  however, sweating, dry mouth, and some sedation may occur.   Electroconvulsive therapy (ECT) is used when individu-  als fail to respond to antidepressants or when they are severely  depressed, pregnant, suicidal, or psychotic. ECT effectively alle-  viates depressive symptoms in about 50% to 80% of people,  who may then begin to respond to antidepressant medications.  Although the mechanism of action of ECT is not clear, the pro-  cedure is known to produce alterations in monoamine systems.  Deep brain stimulation (DBS) is another treatment showing  promise to alleviate major depression in people resistant to cur-  rent antidepressant medications, ECT, and psychotherapy.?”*  The treatment involves implanting electrodes during neurosur-  gery into the subcallosal cingulate gyrus (SCG [Brodmann area  25 and parts of 24 and 32]) and attaching them to an implanted  pulse generator through subcutaneous extension wires. This  SCG region is targeted because abnormal SCG brain activity,  a suggested pathophysiologic cause of major depression, is  reversed by effective antidepressant treatment. A 3- to 6-year  follow-up study of 20 treatment-resistant depressed individu-  als who received DBS in the SCG found that more than half  eventually returned to work and improved their quality of life.’    Bipolar Disorder  FDA-approved treatments are available for bipolar disorders.°°  Individuals with bipolar I disorder are usually treated with lith-  ium, the first choice of treatment to control mania and rapid  cycling and to reduce the risk of suicide. In some cases, lithium  in combination with SSRIs is used to treat bipolar disorder.  In addition to lithium, several medications are used includ-  ing anticonvulsants (e.g., carbamazepine, valproate, gabapen-  tin, lamotrigine, topiramate) or atypical antipsychotics (e.g.,  clozapine, risperidone, ziprasidone, quetiapine, and a combi-  nation of olanzapine with the SSRI fluoxetine). Some bipolar  individuals benefit from thyroid augmentation (levothyroxine).  As in depression, ECT is administered when manic individuals  fail to respond to medication, are pregnant, or have cardiovas-  cular disease.   Frequently reported side effects of lithium treatment include  increased thirst, tremors, diarrhea, and weight gain, which  diminish over time. A potentially serious side effect is lithium    Comprehensive Treatment of Risk Factors May Promote Resilience and Rapid Recovery from Depression    Weak executive function:  weak coping self-efficiency;  negative attention bias;  cognitive inflexibility    Cognitive behavioral therapy  with cognitive reappraisal;  positive emotion exercises,  coping skill development,  and training; well-being  therapy    Strong executive function; high  coping self-efficacy; positive  emotions; realistic optimism;  cognitive flexibility    Dysregulated HPA axis and  SNS in response to stress;  attenuated prefontal cortical  executive function and stress-  induced limbic system  hyperactivity    Genetic and environmental factors, such as uncontrollable stress, interact to  increase the risk of developing major depression. These factors interact in com-  plex ways that are not fully understood to dysregulate neurobiologic systems that  compromise adaptive cognitive, emotional, social, and physiologic/health func-  tions. For example, exaggerated stress-induced arousal of sympathetic and neu-  roendocrine systems may be due, in part, to genetic polymorphisms in serotonin,  endocrine, and neuropeptide systems. However, the extent to which a genetic pre-  disposition contributes to severe depression also may arise from the individual's  inability to cope with stressors, inexperience in exhibiting flexible psychosocial  and emotional skills, and lack of physical health, among others. Identifying and    Neural circuit training; novel  medications (corticotropin-  releasing factor, NPY,  GABA, glutamate)    Effective regulation of HPA axis  and SNS in response to stress;  robust prefrontal cortical executive  function and capacity to regulate  limbic reactivity to stress    addressing these varied genetic and cognitive/behavioral/socioemotional/health  risk factors of depression may open new doors to effective treatment. In particular,  combined treatments or behavioral programs that promote resilience, the ability  to recover from adversity—such as cognitive-behavioral therapy; social support;  and improved diet, sleep, and exercise used in conjunction with current or novel  drug medications that lessen or reverse the neuropathophysiology associated  with heightened activation of stress systems—may quickly lead to remission.  Although, at its early stages, the development of comprehensive resilience pro-  grams holds promise not only for treating depressed individuals but also for proac-  tively serving to diminish or prevent the risk of acquiring stress-related disorders.    Data from Karatsoreos IN, McEwen BS: Trends Cogn Neurosci 15(12):576-584, 2011; Southwick SM, Charney DS: Science 338(6103):79-82, 2012.    toxicity. Lithium is normally removed from the kidneys; how-  ever, when the body is sodium depleted, the kidneys will reab-  sorb sodium along with lithium. Individuals receiving lithium  treatment are advised to avoid physically demanding activities  that may dehydrate the body and to seek medical attention  during fever or other conditions that may increase sweating.  Anticonvulsant treatment may produce unsteadiness, dizziness,  tremors, nausea, and blurry vision.   In addition to pharmacotherapy, psychotherapy can be ben-  eficial for those who have difficulty with psychosocial stressors,  such as low self-esteem, legal problems, fear of recurrence, and  interpersonal conflicts. Treatment is effective when the indi-  vidual becomes aware of the bipolar disorder, copes with psy-  chosocial stressors, engages in drug compliance, and monitors  symptom recurrences.   Unlike treatment of mania in bipolar I disorder, a major  focus in the treatment of bipolar II disorder, the less severe    form of mania, is on the recurrent depressive symptoms. Here,  antidepressants alone (e.g., escitalopram, fluoxetine, venlafax-  ine) are reported to be effective in treating bipolar II disorder.  The treatment of bipolar II in children has raised concerns  because of complications with its diagnosis. For example, bipo-  lar II and attention-deficit/hyperactivity disorder (ADHD)  share the common features of elevated behavioral activity levels,  excessive talking, restlessness, and distractibility. Misdiagnos-  ing bipolar Il for ADHD has negative consequences for treat-  ment because the stimulant drugs Ritalin and Adderall, which  are frequently used to treat ADHD, will potentially exacerbate  the symptoms of a child with bipolar II disorder. On the other  hand, when ADHD is misdiagnosed with bipolar disorder, the  child may begin an ineffective treatment regimen. To reduce  misdiagnosis of children with bipolar and other similar symp-  tomatic characteristics, such as ADHD as well as conduct disor-  der and oppositional defiant disorder, the upcoming DSM-5*!    includes a new category called disruptive mood dysregulation  disorder. This new disorder diagnosis will be used to describe a  young child (6 to 10 years of age) who exhibits only some of the  symptoms of bipolar II, such as frequent temper outbursts, irri-  tability, and bad moods. This category is hoped to exclude chil-  dren from being diagnosed with bipolar disorder and reduce  possible unwarranted treatment with strong medications.**    Fear and anxiety are normal feelings expressed in threatening or  harmful situations. The symptoms may include arousal, tense-  ness, and increased autonomic activity such as heart rate, blood  pressure, and respiration. In addition, individuals often engage  in protective behavioral responses such as flight or avoidance.  These physiologic and behavioral responses allowed humans to  adapt and cope under a variety of situational challenges. How-  ever, when fear and anxiety become too intense and under-  mine the ability to function on a daily basis, the individual may  develop an anxiety disorder. Anxiety disorders are the most  prevalent psychiatric illness, occurring in approximately 10%  to 30% of the general population. Notably, many individuals  with anxiety disorders develop major depression, and the high  comorbidity of anxiety disorders and depression suggests a  common neural pathophysiologic basis linking these two men-  tal illnesses.   The DMS-IV-TR lists eight recognized anxiety disorders:  panic disorder, agoraphobia, generalized anxiety disorder,  social phobia, specific phobia, obsessive-compulsive disorder,  posttraumatic stress disorder, and acute stress disorder. This  section presents an overview of panic disorder, generalized  anxiety disorder, posttraumatic stress disorder, and obsessive-  compulsive disorder.    Panic disorder consists of multiple disabling panic attacks  and is characterized by intense autonomic arousal involving a  wide variety of symptoms, including lightheadedness, a rapid  heart rate (tachycardia), difficulty breathing, chest discomfort,  generalized sweating, general weakness, trembling, abdominal  distress, and chills or hot flashes. Between panic attacks the  individual often worries about future panic attacks and fear of  losing control and dying. Symptoms originally occur spontane-  ously and vary in length from several minutes to an hour.   A notable complication of panic disorder is the development  of agoraphobia or phobic avoidance of places or situations  where escape or help is not readily available. The agoraphobic  individual will avoid being away from home, standing in line or  in a crowd, or traveling in a train, plane, or automobile. Severe  agoraphobic individuals become housebound.   ETIOLOGY AND PATHOPHYSIOLOGY. Genetic factors play a major  role in panic disorder. The risk is nearly 20% among first-  degree relatives and the prevalence of panic disorder is about  1.5% in men and up to 3.0% in women with no family history  of the illness. Some studies suggest that the cholecystokinin  (CCK) receptor gene on chromosome 11p may be linked to  panic disorder.**    The etiology of panic disorder is not known but the abil-  ity to elicit physical symptoms of panic attacks by chemicals,  called panicogens, provides insight into its pathophysiology.  Panic-prone individuals respond to panicogens that include  carbon dioxide, caffeine, cholecystokinin, sodium lactate, and  adrenergic receptor agonists, such as yohimbine. Carbon diox-  ide and sodium lactate, two well-studied panicogens, alter brain  pH balance that panic-prone people are sensitive in detecting.  Brain pH chemosensors are located in the brainstem medulla  and pons, the midbrain serotonergic raphe neurons, the hypo-  thalamus, and the amygdala. Heightened pH sensitivity in the  amygdala may play a key role in generating fearful percep-  tions and activating the cerebral cortex and neural circuits in  the temporal lobe and brainstem, which further facilitate the  production of panic symptoms (see Figures 19-7 and 19-9).*#  Exaggerated activation of physiologic and behavioral arousal  stemming from the noradrenergic locus ceruleus neurons also  may enhance the symptoms of panic. Thus, panic-prone people  appear especially sensitive in detecting pH alterations in brain  sites that modulate fear and arousal.   Panic disorder also may involve the GABA-benzodiazepine  (BZ) receptor system. BZ increases the GABA, ion channel  response to GABA, thereby elevating chloride ion influx and  producing a neuronal inhibitory effect. Brain imaging work  reveals a reduction in BZ receptor binding in brain regions  including the hippocampus, insular, and prefrontal cortex.°°  Drugs that block the benzodiazepine receptor are reported to  increase panic attacks and feelings of anxiety, suggesting an  alteration in inhibitory neuromodulation contributes to panic  disorder.   TREATMENT. Up to 80% of individuals affected by panic dis-  order respond to CBT and antidepressant drugs, either sepa-  rately or in combination. In CBT, the individual learns that the  physical symptoms are not fatal and attempts to exert control  over the anxiety and panic. For example, breathing exercises to    Hippocampus  FIGURE 19-9 The Limbic System. Structures of the limbic system play impor-  tant roles in emotion, learning, and memory. Pathophysiology in limbic structures  is frequently found in mental disorders.    control hyperventilation serve to lessen the intense physiologic  symptoms of panic, such as elevated heart and respiration rates.  Another benefit of CBT is awareness of compliance with drug  medications. However, for individuals with mild agoraphobia,  CBT alone may be effective.   Antidepressants such as SSRIs are considered first-line medi-  cations for panic disorder. Among the SSRIs, paroxetine and  sertraline have received FDA approval specifically for panic  disorder. Venlafaxine, a serotonin-norepinephrine reuptake  blocker, also is effective.   BZs, such as alprazolam and clonazepam, are other medica-  tions for treating panic disorder. These drugs also serve as an  adjunct or augmentation therapy for individuals who do not  fully respond to SSRIs. Short-term effects of BZs include seda-  tion, ataxia, and cognitive impairments. Long-term BZ treat-  ment may lead to physiologic and psychologic dependence.  Abrupt BZ withdrawal induces a withdrawal syndrome of  heightened reemergence of anxiety, insomnia, photophobia,  and diarrhea. A gradual reduction in BZ medication or adjunct  CBT may reduce the reliance and withdrawal symptoms of BZs.    Excessive and persistent worries are the hallmarks of general-  ized anxiety disorder (GAD). The individual worries about  life events such as marital relationships, job performance,  health, money, or social status. The lifetime prevalence rates of  GAD range from 4.1% to 6.6%, with somewhat higher rates in  women than in men. GAD usually emerges in the early twen-  ties, but can occur in childhood. Six major symptoms of GAD  have been identified and include restlessness, muscle tension,  irritability, being easily fatigued, difficulty concentrating, and  difficulty sleeping. The individual startles easily and frequently  suffers from depression and panic attacks. The severity of symp-  toms fluctuates over time and may be linked to the changing  nature of stress. Although GAD tends to be chronic, the symp-  toms may lessen with age. A frequent complication of GAD is  substance abuse, which may result from self-medication with  alcohol or drugs to relieve anxiety symptoms.   ETIOLOGY AND PATHOPHYSIOLOGY. Female twin studies suggest a  concordance rate of 30%, but disease genes linked to specific  chromosomes have yet to be identified. Abnormalities in the  norepinephrine and serotonin systems were reported in GAD.°°  For example, there is a reduction in a,-adrenergic receptor  binding, a decrease in serotonin levels in CSF, and reduced  platelet binding of paroxetine, an SSRI. Another reported alter-  ation in GAD is a reduction of BZ binding in the left temporal  hemisphere.*”   Two functional magnetic resonance imaging (fMRI) stud-  ies have revealed alterations in specific brain regions in adults  and adolescents with GAD. One study in GAD adults showed  increased anticipatory anxiety was associated with elevated cin-  gulate cortex activity and both the heightened anxiety and cin-  gulate cortex activation were reduced after 8 weeks of treatment  with venlafaxine, a serotonin and norepinephrine reuptake  inhibitor.°* This study suggests that a decrease in pathophysi-  ologic cingulate cortex activity is a predictor of GAD treatment  efficacy. In children and adolescents with GAD, brief exposure    to masked angry faces induced heightened right amygdala acti-  vation, which correlated positively with severity of anxiety.°’  This study underscores the role of abnormal amygdala activity  in attentional bias or vigilance to threats in GAD.   TREATMENT. GAD is diagnosed when a person spends at least  6 months worrying excessively and engages in at least three of  the six major symptoms.'? 5-HT/norepinephrine (NE) reup-  take inhibitors, such as venlafaxine or the SSRIs paroxetine and  escitalopram, have become first-line therapeutics for managing  GAD. These medications may produce relief of GAD symptoms  within 1 week and are effective in treating comorbid symptoms  of depression. Buspirone, which has an affinity for serotonin  receptors (5-HT\,), is another treatment option, although the  onset of clinical efficacy may take 2 weeks. The primary side  effects of buspirone, which lessen over time, include dizziness,  headaches, nausea, and mild nervousness. GAD nonresponders  to 5-HT/NE reuptake inhibitors or buspirone may be treated  with BZs. However, because GAD tends to be chronic, and  comorbid with depression or other anxiety disorders,*° BZs are  usually limited to uncomplicated cases of GAD. In addition to  drug therapy, behavioral therapy is used to acquire relaxation  techniques that control anxiety.   Exposure to a terrifying or life-threatening event may produce  posttraumatic stress disorder (PTSD).*! ” Although the disor-  der was initially described in combat situations and called “shell  shock,” “war neurosis,” or “traumatic neurosis,” PTSD does  not develop only from exposure to traumatic experiences in the  battlefield. Any horrific experience involving intense fear, threat  of death, or helplessness, including serious accidents, natural  disasters (such as earthquakes), child abuse, kidnapping, and  violent attacks (such as rape or assault), may induce PTSD. The  disorder may develop within hours of the traumatic experience  or after several months or years. In PTSD, the individual reex-  periences the traumatic event with intrusive flashbacks and per-  sistent nightmares. During a flashback, images, odors, sounds,  and negative emotions are recalled and lead to marked distress.  The duration of the flashback varies from seconds to hours or, in  rare cases, several days. Nightmares of the traumatic experiences  often prevent further sleep. Exposure to cues associated with the  life-threatening event triggers psychologic distress, intense auto-  nomic arousal, and avoidance behavior. The individual shows  emotional numbing or detachment from others and often avoids  activities that may lead to a recollection of thoughts, feelings, or  contact to places or people involved in the trauma. Additional  characteristics of PTSD include irritability, lack of concentra-  tion, hypervigilance, and exaggerated startle response.   The lifetime prevalence rate of PTSD is 7% to 8%. In men,  PTSD is usually found among combat veterans, whereas PTSD  in women is often related to rape or assault. Abused children  also may develop PTSD. Individuals with a history of psychi-  atric illness (major depression, panic disorder) or those lack-  ing strong social support appear more sensitive to the effects of  traumatic stress.   ETIOLOGY AND PATHOPHYSIOLOGY. The primary etiology of PTSD  is exposure to a terrifying life-threatening event and likely    involves stress-induced alterations in several neural structures  and neurotransmitter systems. The amygdala and prefrontal  cortex are highly involved in the pathophysiology of PTSD  because these brain structures normally play important roles in  how fearful memories are stored, retrieved, and extinguished.  Individuals with PTSD who are exposed to trauma-related  stimuli generally exhibit increased activity in the amygdala  and diminished activity in prefrontal cortical areas. Persistent  dysregulation of this fear-based memory system may underlie  chronic PTSD—that is, the failure of prefrontal cortical inhibi-  tion to control amygdala-induced activation of fear compro-  mises the extinction of fear memory.*? Structural brain imaging  studies show that combat-exposed PTSD victims also have a  smaller hippocampus, a brain structure involved in endocrine  functions and memory formation. Pediatric PTSD studies  reveal a more generalized effect of trauma on reducing total  brain volume. Other brain sites exhibiting increased activity in  PTSD are the dorsal anterior cingulate cortex and insula, albeit  similar findings were reported in other anxiety disorders (e.g.,  GAD, obsessive-compulsive disorder [OCD]).**   As in panic disorder, BZ binding is altered in PTSD as indi-  cated by a reduced distribution of BZ receptor binding in the  prefrontal cortex compared with healthy controls.*° This reduc-  tion in prefrontal BZ receptor distribution was not found in  other brain regions.   TREATMENT. PTSD is diagnosed according to the duration  and timing of symptoms (DSM-IV-TR). When the duration of  symptoms is less than 3 months, PTSD is diagnosed as acute  whereas a chronic diagnosis is made when symptoms persist for  3 months or longer or when the delay of onset is longer than  6 months after the trauma. As in GAD, the severity of symp-  toms fluctuates over time. Among war veterans, financial cov-  erage for group or family therapy is supported by the Veterans  Administration. CBT is another therapy used for the individual  to learn to control their anxiety symptoms and the emotionally  distressing memories of the traumatic event.   Chronic PTSD lasting for years may occur in 30% of diag-  nosed individuals. Paroxetine and sertraline are considered  first-line SSRI medications for chronic PTSD because of their  tendency to lessen the recurrent nightmares and flashbacks  and to treat the high accompanied prevalence of depression  and substance abuse. Other antidepressants, such as the TCAs  (amitriptyline and imipramine), have moderate effects and are  second-line drugs; drugs such as nefazodone and bupropion  may provide benefits. BZs may be used in the aftermath of a  traumatic event to control hyperarousal symptoms such as irri-  tability, insomnia, and muscle tension. However, there is no  clear evidence that BZs have clinical efficacy or provide pro-  phylaxis against the development of chronic PTSD, and BZs  should be carefully monitored among individuals with a history  of drug abuse.    Repetitive, intrusive thoughts and/or compulsions are the  hallmarks of obsessive-compulsive disorder (OCD). These  thoughts and acts impair normal functioning and cause  marked distress. Obsessions may involve a preoccupation with    contamination, doubting, religious or sexual themes, or the  belief that a negative outcome will occur if a specific act is not  performed. Compulsions are physical and mental ritualized  acts such as washing, cleaning, checking, counting, organizing,  hoarding, and repeating specific thoughts or prayers. The life-  time prevalence rates of OCD range from 1.2% to 3.3% with  an age of onset between 20 and 25 years. OCD occurs equally  in adult men and women; however, many begin to experience  symptoms during childhood or adolescence.   OCD is diagnosed when obsessions or compulsions cause  severe distress, consume time, or interfere with normal daily  activities.'° In many cases the OCD individual also is diagnosed  with major depression, panic disorder, or GAD.*° Among chil-  dren, tic disorders, attention-deficit/hyperactivity disorder, and  depression coexist with OCD.   ETIOLOGY AND PATHOPHYSIOLOGY. The risk of developing OCD  is about 10% to 12% among first-degree relatives. These first-  degree relatives are also at increased risk (4.6%) of Tourette  syndrome and tics in comparison with control relatives (1%).  Thus OCD and Tourette syndrome may share common genes  and pathophysiology.   Abnormalities of the basal ganglia—frontocortical circuitry  are found in OCD.*” Some studies have shown increased orbi-  tofrontal and thalamic volumes in OCD but not in the caudate  nucleus of the basal ganglia (Figure 19-10). More consistent data  report an increase in orbitofrontal and anterior cingulate corti-  cal activity, which may be responsible for intrusive thoughts,  obsessions, and anxiety, which drive the basal ganglia to engage  in compulsive ritualized acts as a means to alleviate the anx-  ious obsessions. Furthermore, when provoked, OCD individu-  als consistently show increased activity in the orbitofrontal,  anterior cingulate, and caudate nucleus areas of the brain. Of  relevance to prognosis, OCD individuals with very high fronto-  cortical activity are likely to respond poorly to treatment.   Abnormalities in serotonin and dopamine functions may  further contribute to the pathophysiology of OCD. Serotonin    nigra  FIGURE 19-10 Basal Ganglion. Structures of the basal ganglion, which  include the caudate nucleus, putamen, globus pallidus, and substantia nigra, are  important in movement.    agonists exacerbate the symptoms of OCD, and serotonin syn-  thesis is decreased in the prefrontal cortex and caudate nucleus.  Stimulation of the dopamine system also increases repetitive acts,  which may be blocked by dopamine antagonists. However, the  dopamine stimulant—induced compulsions are not accompanied  by anxiety and, therefore, suggest that lack of serotonin control  over the dopamine system may be a primary defect in OCD.   TREATMENT. Because of the chronic nature of OCD, long-term  treatment often involves a combination of pharmacotherapy  and CBT. SSRIs, including citalopram, fluvoxamine, parox-  etine, and sertraline, are the first drugs of choice for OCD.*®  Approximately 70% to 80% of OCD individuals show a partial  positive response that may be further improved by other medi-  cations. For example, clonazepam, a BZ, is found to improve  the effects of fluoxetine and clomipramine therapy. Antipsy-  chotic drugs (e.g., haloperidol and risperidone) in combination  with SSRIs are also effective especially in comorbid OCD and  tic disorders. Normalization of dysfunctional serotonin and  dopamine systems in OCD may be the basis for the therapeutic  effects of SSRIs and dopamine receptor-—related drugs.    CBT and response prevention therapy involve exposure to  cues that elicit distress followed by preventing the individual  from engaging in compulsive rituals for at least an hour or until  the anxiety subsides. Both therapies can produce long-term  symptom remission in adults and children who are able to tol-  erate the exposure-induced anxiety component.   For individuals with severe treatment-resistant OCD, neu-  rosurgery is used to disconnect the basal ganglia from the  frontal cortex.*” This lesioning procedure results in significant  relief of obsessions and compulsions in nearly 50% of individ-  uals and provides further evidence of pathophysiology in the  basal ganglia—-frontocortical circuitry in OCD. An alternative  treatment to ablative neurosurgery is deep brain stimulation,  which also is used for intractable depression.*” Deep brain  stimulation in the anterior limb of internal capsule, striatum/  ventral capsule, nucleus accumbens, subthalamic nucleus, and  inferior thalamic peduncle is effective in alleviating some OCD  symptoms.*”*! Stimulating these brain regions may be reduc-  ing abnormal neuronal firing in the neuroanatomic circuitry  linked to OCD.   1. Schizophrenia is characterized by thought disorders that  reflect a break between the cognitive and the emotional sides  of one’s personality.   2. Schizophrenic symptoms are classified into positive, nega-  tive, and cognitive categories. Positive symptoms include  hallucinations, delusions, formal thought disorder, and  bizarre behavior. Negative symptoms include flattened affect,  alogia, anhedonia, attention deficits, and apathy. Cognitive  symptoms are the inability to perform daily tasks requiring  attention and planning.   3. Schizophrenia has a strong genetic predisposition and envi-  ronmental factors (e.g., viral infection, nutritional deficien-  cies, prenatal birth complications, urban upbringing) may  interfere with genetically programmed neural development  to alter brain structure and function.   4. Brain imaging studies reveal structural brain abnormali-  ties including an enlargement of the cerebroventricles and  widening of the fissures and sulci in the frontal cortex. In  addition, there is a reduction in the volumes of both the thal-  amus, which may disrupt communication among cortical  brain regions, and the temporal lobe, which may be respon-  sible for the manifestations of positive symptoms.   5. In schizophrenia the frontal lobe shows a progressive loss in  volume and a worsening of negative symptoms despite the  use of antipsychotic medications. Blood flow and metabo-  lism are reduced in the dorsolateral prefrontal cortex, which  compromise the ability to engage in goal-directed and cogni-  tive problem-solving behavior.   6. Neurochemical abnormalities in dopamine and glutamate  systems are found in schizophrenia.   7. The first generation of antipsychotic drugs block the dopa-  mine D, receptor. The second generation, called atypi-  cal antipsychotics, block not only D, receptors but also    dopamine, serotonin, and other neurotransmitter receptors.  Antipsychotic medications, however, are not always effective  in treating schizophrenic individuals with severe negative  symptoms. Talk therapies are used to increase drug compli-  ance and to encourage coping strategies.   1. Major depression and bipolar disorder are two common  mood disorders. Major depression is characterized by an  intense and sustained unpleasant state of sadness and hope-  lessness. In bipolar disorder, individuals show recurrent pat-  terns of depression and mania, the latter characterized by  extreme levels of energy and euphoria.   2. Environmental triggers such as psychosocial stress appear to  facilitate the onset of depression in individuals with a genetic  vulnerability.   3. A reduction in brain monoamine neurotransmission is  linked to depression, whereas an elevated monoamine level  is associated with mania.   4. Exposure to uncontrollable stress elevates secretion of the  stress hormone cortisol, which increases both the secretion  of proinflammatory cytokines and the risk of developing  depression. Abnormalities involving thyroid hormones also  are found in depression.   5. Stress-induced depression is accompanied by deficits in  brain-derived neurotrophic factor (BDNF) and neurogen-  esis in the hippocampus. In animal models, stress-induced  depression-like behavior and the accompanying deficits in  hippocampal BDNF and neurogenesis are reversed by anti-  depressant treatment.   6. The frontal lobe and limbic system volumes are reduced in  major depression and bipolar illness. In addition, blood flow  is altered in prefrontal and limbic brain regions that include  the amygdala, a structure implicated in emotional behavior.    7. Pharmacotherapy involves the use of MAOIs, TCAs, SSRIs, 6.  and atypical antidepressants. Manic and bipolar individu-  als are treated with lithium or mood stabilizers. Severely  depressed and manic people may be administered ECT.  Deep brain stimulation is another promising treatment for  intractable depression. 7   1. When normal fear and anxiety mental states persist and 8  become uncontrollable, an individual may develop an anxi-  ety disorder. PD, GAD, PTSD, and OCD are examples of   2. Panic disorder consists of panic attacks characterized by  intense autonomic arousal that occurs spontaneously andis _—10.   fear and anxiety that often continue between panic attacks. 11.  Panic-prone people are sensitive in detecting pH alterations   in the amygdala, a brain structure that modulates fear. An 12.  activated amygdala recruits the cerebral cortex and neural  circuits in the temporal lobe and brainstem, which may fur-   ther exacerbate symptoms of panic. 13.  4. A reduction in BZ receptor binding in brain regions, includ-   may contribute to the pathophysiology of panic disorder. 14.  Panic disorder is generally treatable with CBT and antide-  pressants such as TCAs and SSRIs. BZs are used as an adjunct    GAD is characterized by excessive and persistent worries  about life events. Individuals exhibit varying levels of motor  disturbances, irritability, and fatigue that may be linked to  fluctuations in psychosocial stress. Many GAD individuals  manifest symptoms of depression.   Pathophysiologic changes in the cingulate cortex and amyg-  dala may have prominent roles in stimulating anticipatory  anxiety and attentional bias to threats in people with GAD.  Treatment of GAD usually involves a combination of  behavioral therapy and drug medications, especially sero-  tonin/norepinephrine reuptake inhibitors.   PTSD develops after exposure to a life-threatening or trau-  matic experience. Individuals experience recurring thoughts  and flashbacks and nightmares of the terrifying event.   In PTSD structural and/or functional alterations exist in  the amygdala, prefrontal cortex, and hippocampus, which  likely contribute to dysfunction in an emotional fear mem-  ory system.   Treatment of chronic PTSD is difficult and involves psy-  chotherapy and SSRI pharmacotherapy.   OCD is a chronic illness characterized by irrational obses-  sions and ritualized acts that impair normal functioning  and cause severe distress.   Pathophysiologic alterations in the basal ganglia—fronto-  cortical circuitry and serotonin and dopamine functions  are linked to OCD.   OCD requires long-term treatment consisting of CBT and  drug medication, such as SSRIs and talk therapies. Severe  OCD may require neurosurgery to disconnect the basal  ganglia from the frontal cortex. Deep brain stimulation may  be another option for uncontrollable OCD.    Affective flattening, 646 Dorsolateral prefrontal cortex (DLPFC), 643 Obsessive-compulsive disorder (OCD), 656  Agoraphobia, 654 Dysphoric mood, 650 Panic disorder, 654  Agranulocytosis, 647 Formal thought disorder, 646 Posttraumatic stress disorder (PTSD), 655  Alogia, 646 Gamma-aminobutyric acid (GABA), 643 Poverty of content, 646  Anhedonia, 646 Generalized anxiety disorder (GAD), 655 Psychotic episode, 644  Anxiety disorder, 654 Glutamate hypothesis, 644 Schizophrenia, 642  Avolition, 646 Hallucination, 644 Tardive dyskinesia, 646  Bipolar disorder, 647 Major (unipolar) depression, 647 Thought disorder, 642  Brain-derived neurotrophic factor (BDNF), 648 Manic, 651 Working memory, 643  Delusion, 646 Monoamine hypothesis of depression, 648  Depression, 650 Mood, 647  Dopamine hypothesis, 643 Neurogenesis, 648  REFERENCE S 5. Shenton LD et al: A review of MRI findings in schizophrenia, Schizophr  Res 49(1-2):1—52, 2001.  1. 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Saxena S, Rauch SL: Functional neuroimaging and the neuroanatomy of  obsessive-compulsive disorder, Psychiatr Clin North Am 23(3):563-586,  2000.   Swedo SE, Snider LA: The neurobiology and treatment of obsessive-  compulsive disorder. In Charney DS, Nestler EJ, editors: Neurobiology of  mental illness, ed 2, New York, 2004, Oxford.   Greenberg BD, Murphy DL, Rasmussen SA: Neuroanatomically based  approaches to obsessive-compulsive disorder, Psychiatr Clin North Am  23(3):67 1-686, 2000.   de Koning PP et al: Current status of deep brain stimulation for  obsessive-compulsive disorder: a clinical review of different targets, Curr  Psychiatry Rep 13:274-282, 2011.   Holtzheimer PE, Mayberg HS: Deep brain stimulation for psychiatric  disorders, Annu Rev Neurosci 34:289-307, 2011.    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Structure and Function of the Nervous System in Children, 660  Brain Development, 661  Structural Malformations, 663  Defects of Neural Tube Closure, 663  Craniosynostosis, 666  Malformations of Cortical Development, 667  Alterations in Function: Encephalopathies, 670  Static Encephalopathies, 670    Neurologic disorders in children can occur before birth through  adolescence and include congenital malformations, genetic  defects in metabolism, brain injuries, infection, tumors, and  other disorders that affect neurologic structure and function.  The symptoms, diagnosis, and management of neurologic dis-  orders in children are often different than those of adults. It is  important to note that with better proactive care and advances  in treatment, many of the children with these disorders will live  into adulthood and physicians who care for adults will be seeing  these disorders in adults in increasing numbers.    Embryology is a highly complex and often difficult science to  understand fully. A basic knowledge of this science is essen-  tial because it is the process of embryonic development that  explains many of the malformations that occur in children.  Both genetics and environment shape nervous system devel-  opment. The proper proportions of essential nutrients are nec-  essary for growth and proliferation of the nervous system tissue    Acute Encephalopathies, 674  Cerebrovascular Disease in Children, 677  Perinatal Stroke, 677  Childhood Stroke, 677  Epilepsy, 678  Childhood Tumors, 681  Brain Tumors, 681  Embryonal Tumors, 684    (see Nutrition & Disease: Iron and Cognitive Function). Mater-  nal lifestyle, nutrition, exposure to potential toxins, and state of  health also have a crucial effect on nervous system development  at critical periods of fetal maturation.   The central nervous system (CNS) develops from a dorsal  thickening of the ectoderm known as the neural plate. This  plate appears around the middle of the third gestational week  and unfolds to form a neural groove and neural folds. During  the fourth gestational week the neural groove deepens, its folds  develop laterally, and it closes dorsally to form the neural tube,  epithelial tissue that ultimately becomes the CNS. The neural  tube closes first in the cervical region and then “zippers” in two  directions—cranially and caudally (Figure 20-1).   In the developmental process, some neuroectodermal cells  separate from the neural tube but remain between the tube  and the surface ectoderm, creating the neural crest. This cel-  lular band develops into the cranial and spinal ganglia, more  commonly referred to as the peripheral nervous system. Other  structures associated with the nervous system arise from meso-  derm (somite) and include blood vessels, microglial cells,  dural and arachnoid layers of the meninges, the capsule of    lron deficiency (ID) is the single most significant nutrient deficiency, affecting  15% of the world population and causing anemia in 40% to 50% of children.  lron is essential for neurologic activity, including synthesis of dopamine, sero-  tonin, and catecholamine and, possibly, formation of myelin. Children with ID  have decreased attentiveness, short attention span, and perceptual restric-  tions. ID also may contribute to attention-deficit/hyperactivity disorder. In    some studies, cognitive deficits in iron can be reversed with iron supplements.  In one randomized study, supplementation with iron or zinc, or both, during  infancy did not lead to long-term cognitive improvement in 9-year-old children.  Research is in progress to determine the effects of acute vs. chronic ID and the  relationships between severity of deficiency and cognitive functioning. Altera-  tions in the hippocampus and the brain striatal dopaminergic-opiate system  function have been found in ID.   Khor GL, Misra S: Asia Pac J Clin Nutr 21(4): 476-486, 2012; Lozoff B:  J Nutr 141(4):740S-746S, 2011; Madan N et al: /ndian J Pediatr  78(1):58-64, 2011; Pongcharoen T et al: Am J Clin Nutr 93(3):636-643,  2011; Yadav D, Chandra J: Indian J Pediatr 78(1):65-72, 2011.    FIGURE 20-1 Neural Tube at 3 Weeks of Gestation. Neural folds have  begun to fuse at the cervical level of the future spinal cord. Right, Cross sections  of the neural tube at four different levels; at any given level the embryonic central  nervous system (CNS) goes through a series of stages resembling these four cross  sections. Total length of neural tube at this time is about 2.5 mm.   The cranial end of the neural tube forms the brain, and the  remainder develops into the spinal cord. The lumen of the  neural tube becomes the ventricles of the brain and the cen-  tral canal of the spinal cord (Figure 20-2). On either side of  the neural tube’s inner surface is a longitudinal groove (sulcus  limitans). Anterior to this region (basal plate) the gray matter  differentiates into the nuclei of the lower motor neurons. The  region posterior to the sulcus (alar plate) differentiates into the  sensory nuclei of the spinal cord.   Embryonic development of the nervous system occurs in six  stages: (1) dorsal (posterior) induction, (2) ventral (anterior)    horn  FIGURE 20-2 Sulcus Limitans and Alar and Basal Plates. A, Neural tube  during the fourth week of gestation. B, Embryonic spinal cord during the sixth week  of gestation; dorsal root ganglion cells, derived from the neural crest, send their  central processes into the spinal cord to terminate mainly in alar plate cells; basal  plate cells become motor neurons, whose axons exit in the ventral roots. C, Adult  spinal cord.    induction, (3) proliferation, (4) migration, (5) organization,  and (6) myelination. Figure 20-3 summarizes the embryonic  development of the nervous system and identifies disorders  associated with interference in any of these stages. Many dif-  ferent events happen simultaneously, and critical periods must  pass uninterrupted if the vulnerable fetus is to develop normally.    When an infant is born, the bones of the skull are separated at  the suture lines, thus forming two fontanels or “soft spots”: one  diamond-shaped anterior fontanel and one triangular-shaped  posterior fontanel. The posterior fontanel may be open until  2 to 3 months of age; the anterior fontanel normally closes  by 18 months (Figure 20-4). The fact that the sutures are not  closed allows for increases in head circumference as part of nor-  mal growth for 5 to 8 years after birth; in fact, the head is the  fastest growing body part during infancy. Although basically  all of the neurons that an individual will ever have are pres-  ent at birth, the development of skills, such as walking, talking,  and thinking, depends on these cells making correct connec-  tions with other cells and on myelination of the axons making  those connections. This leads to brain and then to skull growth.  Increased intracranial pressure may result in an increased head  circumference in excess of that expected with normal growth.    Healthcare providers carefully monitor head growth during the  first 5 years of life by measuring head circumference and com-  paring the results with a standardized growth chart. In contrast,  the adult cranium is a closed cavity with sutures firmly holding  the cranial bones together. An adult’s head size will not expand  regardless of intracranial events, e.g., tumor growth, bleeding,  or increased production of cerebrospinal fluid (CSF).   Most neurons are formed during fetal life but the connec-  tions between brain circuits, myelination of those connections,  and dendritic development are most significant after birth.    Human neurologic functioning is primarily at a subcortical  level at birth with many reflex patterns mediated by brainstem  and spinal cord mechanisms that disappear at predictable times  during infancy while brain axons are myelinated and con-  necting pathways develop. Myelination is a process by which  lipid-protein material made by specialized connective tissue  cells (Schwann cells in the peripheral nervous system and oligo-  dendrocytes in the central nervous system) covers the axons of  neurons, allowing electrical signals to travel more quickly (see  Chapter 16). The development of myelin in the brain follows    FIGURE 20-4 Cranial Sutures and Fontanels in Infancy. Fibrous union of  suture lines and interlocking of serrated edges (occurs by 6 months; solid union  requires approximately 12 years).    predictable patterns over time and is most extensive after birth  and throughout childhood. The primitive reflex pathways  require myelination and by 6 months of age they are integrated  and inhibited for progression to voluntary movement. Table  20-1 summarizes the ages at which primitive reflexes appear  and disappear. Testing for the presence or absence of these  reflexes at various times enables the examiner to evaluate the  function and development of the nervous system.   Absence of expected reflex responses at the appropriate age  indicates general depression of central or peripheral motor  function. Asymmetric responses may indicate lesions in the  motor cortex on the opposite side or may occur with fractures  of bones after traumatic delivery or postnatal injury. While the  infant matures, the primitive reflexes disappear in a predictable  order as voluntary motor functions supersede them. Abnormal  persistence of these reflexes is seen in infants with developmen-  tal delays or with central nervous system lesions.    Neural tube defects (NTDs) are caused by an arrest of the nor-  mal development of the brain and spinal cord during the first  month of embryonic development and occur in about 3000  pregnancies in the United States each year. There is a strong  association of fetal death with NTDs, reducing the actual prev-  alence of neural defects at birth. Maternal folate deficiency is  associated with NTDs. The specific mechanism that relates to  how folate supplements prevent these anomalies is unknown  but genes involving folate metabolism and environmental fac-  tors are involved.” In 1996 the United States mandated folate  fortification in many foods and since that time neural tube  defects have decreased by 20% to 30%* (see What’s New?  Reduction of Risks for Neural Tube Defects [NTDs]).   4 months awake  7 months asleep  4 months awake  7 months asleep  6 months    Palmar grasp Birth  Plantar grasp Birth  Tonic neck 2 months  Neck righting 4-6 months  Landau 3 months  Parachute reaction 3 months    Studies indicate that ingestion of multivitamins with folic acid before concep-  tion or early in pregnancy may offer protection against neural tube defects  and reduction of stillbirths caused by NTDs. Folate is a coenzyme essential  for DNA and RNA synthesis and cellular methylation. Recent repeated studies    demonstrate a 60% to 86% reduction of risks for neural tube defects with  periconceptional ingestion of vitamins containing the U.S. recommended daily  allowance of 400 mcg of folic acid. There may also be an increased risk associ-  ated with maternal obesity.    Data from Branum AM, Bailey R, Singer BJ: J Nutr 143(4):486-492,  2013; Centers for Disease Control and Prevention: MMWR Morb  Mortal Wkly Rep 53(36):847-850, 2004; Imdad A, Yakoob MY, Bhutta ZA:  BMC Public Health 11(Suppl 3):S4, 2011; Mastroiacovo P, Leoncini E:  Biofactors 37(4):272-279, 2011; Wolff T et al: Ann Intern Med 150(9):  632-639, 2009.    Defects of neural tube closure are divided into two cat-  egories: posterior defects and anterior midline defects. Poste-  rior defects are more common and will be discussed further  below. These include anencephaly (an, “without”; enkephalos,  “brain”), encephalocele, and a group of disorders collectively  referred to as the myelodysplasias (dys, “bad”; plassein, “to  form”). Although myelodysplasia is defined as a defect in for-  mation of the spinal cord, the term is used to refer to anomalies  of both the vertebral column and the spinal cord. Birth defects  in which there is failure of closure of the vertebrae are known as  spina bifida (split spine). Myelomeningocele is a form of spina  bifida with incomplete development of the spine and protru-  sion of both the spinal cord and meninges through the skin.  Meningocele is a form of spina bifida in which there is protru-  sion of the meninges but the spinal cord remains in the spinal  canal. There is a broad spectrum of abnormalities within each  of these categories depending on the location of the defect, the  tissue involved, and other factors.    Anencephaly is an anomaly in which the soft, bony compo-  nent of the skull and much of the brain are missing. This is a    FIGURE 20-5 Meningoencephalocele of the Occipital Region. (From  Gilbert-Barness: Potters pathology of the fetus, infant and child, ed 2, Philadel-  phia, 2007, Mosby.)    relatively common disorder, with an incidence rate of approxi-  mately 1 per 4859 live births in the United States each year.*  These infants are stillborn or die within a few days after birth.  The pathologic mechanism is unknown. Diagnosis is often  made prenatally using ultrasound or evaluating maternal serum  alpha fetoprotein (AFP).°    Encephalocele refers to a herniation or protrusion of vari-  ous amounts of brain and meninges through a defect in the  skull, resulting in a saclike structure. The incidence rate is  approximately 1 in 10,000 live births in the United States each  year.°   PATHOPHYSIOLOGY. Encephalocele occurs during the first  weeks of pregnancy. When the defect contains only meninges,  it is referred to as a cranial meningocele. Most encephaloceles,  which contain neural tissue as well as meninges, occur in the  occipital area, with the remainder found in the frontal, parietal,  or nasopharyngeal regions.   CLINICAL MANIFESTATIONS. Encephalocele usually is seen at  birth as a midline skull defect through which a large mass pro-  trudes (Figure 20-5). If the defect is located in the nasopharynx,  no external anomaly is visible, but the child may experience  nasal airway obstruction. On examination with a nasal specu-  lum, a smooth, round mass will be visible in the nasal passages.  A frontal encephalocele may extend into the orbit of the eye and  produce proptosis on the affected side.   EVALUATION AND TREATMENT. Diagnosis is based on clinical  manifestations and examination of the meningeal sac. With  cranial meningocele, surgical repair of the cranial defect affords  a good prognosis for most affected infants whose intellectual  and motor functioning is normal. An occipital encephalocele  may be associated with other findings, such as blindness and  cognitive impairment. The size, location, and involvement of  the encephalocele help determine a child’s development and  intellectual outcome.    FIGURE 20-6 Comparison of Normal Spine and Spine with Meningocele  and Myelomeningocele Neural Tube Defects. Diagram depicts section through  normal spine (A), spine with meningocele (B), and spine with myelomeningocele (C).    Meningocele and Myelomeningocele  Meningocele and myelomeningocele are different types of spina  bifida that occur because of an incompletely formed or absent  posterior vertebral arch in the spinal column, allowing protru-  sion of either a saclike cyst of meninges filled with spinal fluid (a  meningocele) or a similar saclike cyst that also has neural tissue,  spinal cord, or nerves in it, in which case it is a myelomeningo-  cele. Both develop during the first 4 weeks of pregnancy when  the neural tube fails to close completely (Figure 20-6). Menin-  goceles occur with equal frequency in the cervical, thoracic, and  lumbar spine areas, whereas 80% of myelomeningoceles are  located in the lumbar and lumbosacral regions, the last regions  of the neural tube to close. Myelomeningocele is much more  common than meningocele and has an incidence rate ranging  from 0.5 to 1 per 1000 pregnancies in the United States.’ It is  thus is one of the most common developmental anomalies of  the nervous system.   PATHOPHYSIOLOGY. Meningocele is a cystlike dilation of men-  inges protruding through a defect in the posterior arch of the  vertebra. The dura mater may be missing and the arachnoid layer    of the meninges bulges beneath the skin. This defect does not  involve the spinal cord. A myelomeningocele results in a cystic  dilation of meninges and protuberance of various amounts of  the spinal cord through the vertebral defect and is associated  with more severe complications than those associated with a  meningocele. Both defects occur during the first 4 weeks of the  gestational period; at the end of this time the neural tube is nor-  mally closed anteriorly and posteriorly.   Because of changes in cerebrospinal fluid (CSF) flow, myelo-  meningoceles also are likely to be associated with a Chiari II  malformation, which is a downward displacement of the cer-  ebellum, brainstem, and fourth ventricle (Figure 20-7). The  Chiari II malformation compresses and essentially stretches the  posterior region of the cerebellum and brainstem downward  through the foramen magnum. The brainstem houses cranial  nerve nuclei and pressure on this region may result in altered  function of these nerves or actual palsies. The Chiari II malfor-  mation is associated with hydrocephalus, an increase in intra-  cranial pressure attributable to obstruction of the flow of CSF;  syringomyelia, an abnormality causing cysts at multiple levels  within the spinal cord; and cognitive and motor deficits.®   Other forms of Chiari malformation include type I, which is  usually asymptomatic; type IH, in which the brainstem or cere-  bellum extends into a high cervical myelomeningocele; and type  IV, which is characterized by lack of cerebellar development.’   Seizures are present in about 30% of children with myelo-  meningocele,'? and visual problems (perceptual and astigma-  tism) and intellectual deficits (ranging from learning problems  to intellectual disability) also are common.!!   CLINICAL MANIFESTATIONS. Myeloceles and myelomeningoceles  are evident at birth as a pronounced skin defect on the infant’s  back (see Figure 20-6). The severity of the clinical presenta-  tion will depend on the amount of tissue involved (generally  the more neural tissue that is included in the sac, the worse the  clinical presentation; some children with meningocele will not  have any functional problems) and the level of the defect (tho-  racic vs. sacral; a sacral defect will cause fewer problems than a  defect higher in the neural axis). The bony prominences of the  unfused neural arches can be palpated at the lateral border of  the defect. The defect is usually covered by a transparent mem-  brane that may have neural tissue attached to its inner surface.  This membrane may be intact at birth or may leak CSF, thereby  increasing the risks of infection and neuronal damage. Until  the defect is closed surgically, CSF may accumulate and cause  increased dilation and enlargement of the sac, which may fur-  ther endanger the nervous system.   Motor and sensory functions below the level of the lesions  are altered. Dysfunction may include degrees of weakness,  paralysis, spasticity, and bowel and bladder dysfunction. These  problems often worsen as the child grows. As the cord ascends  within the vertebral canal, primary scar tissue can tether the  cord. Several musculoskeletal deformities are related to myelo-  meningocele, including clubfoot, dislocation of hip or hips, and  poor spinal alignment. Spinal deformities, such as scoliosis and  kyphosis, are common.   Tethered cord syndrome may develop in children with  myelomeningocele.!* The cord becomes abnormally attached   © 1998, BNI  FIGURE 20-7 Normal Brain and Chiari Type I! Malformation. A, Diagram  of normal brain. B, Diagram of Chiari || malformation with downward displacement  of cerebellar tonsils and medulla through foramen magnum causing compression  and obstruction to flow of CSF. (B modified from Barrow Neurological Institute  of St. Joseph's Hospital and Medical Center, Phoenix, Arizona. Reprinted with  permission.)    or tethered as a result of scar tissue that develops as the cord  transcends the vertebral canal with growth. Traction decreases  blood flow and impairs oxidative metabolism. Symptoms are  related to excessive tension on the lumbosacral cord and can  include scoliosis, altered gait pattern, changes in muscle strength  at or below the lesion, disturbance in urinary and bowel pat-  terns, and back pain. The cord can be untethered surgically. !*  It is possible for a defect to occur without any visible expo-  sure of meninges or neural tissue. There is a cleft in the spine    TABLE 20-2 FUNCTIONAL ALTERATIONS  IN MYELODYSPLASIA  RELATED TO LEVEL OF LESION    Flaccid paralysis of lower extremities; variable  weakness in abdominal trunk musculature;  high thoracic level may mean respiratory  compromise; absence of bowel and bladder  control   Voluntary hip flexion and adduction; flaccid  paralysis of knees, ankles, and feet; may  walk with extensive braces and crutches;  absence of bowel and bladder control   Strong hip flexion and adduction; fair knee  extension; flaccid paralysis of ankles and  feet; absence of bowel and bladder control   Strong hip flexion, extension, and adduction  and knee extension; weak ankle and toe  mobility; may have limited bowel and bladder  function    Data from Farley JA, Dunleavy MJ: Myelodysplasia. In Allen PJ,  Vessey JA, editors: Primary care of the child with a chronic condition,  ed 4, St Louis, 2004, Mosby.    because the posterior vertebral laminae have failed to fuse and  the overlying skin is intact. Because the defect is not apparent  to the unaided eye (i.e., it is “occult” or hidden), the term spina  bifida occulta is used.'? This extremely common defect occurs  to some degree in 10% to 25% of infants. Approximately 80%  of these vertebral defects are located in the lumbosacral regions,  most commonly in the fifth lumbar vertebra and the first sacral  vertebra. Spina bifida occulta usually causes no serious neuro-  logic dysfunctions because the spinal cord and spinal nerves are  generally anatomically and functionally normal, but the spinal  defect can cause hydrocephalus.'*   EVALUATION AND TREATMENT. Diagnosis is based on clinical man-  ifestations and examination of the meningeal sac. Prenatal diag-  nosis of myelomeningocele is possible through ultrasonography.  In the United States, most pregnant women receive triple or quad  screening between 15 and 20 weeks of a pregnancy. The presence  of a neural tube defect may result in an elevated amniotic fluid  AFP level and subsequent maternal serum AFP levels. Additional  testing is then performed if screening tests are positive, including  a detailed ultrasound, which may allow for prenatal diagnosis of  spina bifida. Prenatal diagnosis offers the parents the option to  terminate the pregnancy or become a candidate for fetal intra-  uterine repair.'° Cesarean delivery may be recommended to min-  imize trauma to the open myelomeningocele.!°   In an effort to preserve neuronal function and minimize  damage that may occur from infection and manipulation of the  fragile sac, surgical closure is optimal prenatally or during the  first 72 hours of life, as recommended by the management of  Myelomeningocele Study (MOMS).!” Functional implications  depend on the level and severity of the defect (Table 20-2) and  the presence of associated conditions, such as abnormal renal    structure or function, or both, and the presence of a Chiari I  malformation (see p. 665). These conditions are screened at  birth in any child born with myelomeningocele or meningocele.   Because myelodysplasia affects several other body systems  (e.g., renal, gastrointestinal, musculoskeletal), these infants  require a comprehensive, multidisciplinary approach to treat-  ment. The prognosis depends on the extent of the involvement  at birth and the success of prophylactic and acute treatment for  potential and actual complications that affect the many body  systems. Symptomatic Chiari I] malformations require surgical  decompression and/or placement of cerebrospinal fluid shunts.    Craniosynostosis (craniostenosis) is the premature closure of  one or more of the cranial sutures during the first 18 to 20 months  of an infant’s life. The incidence of craniosynostosis is 1 in 1800  to 2200 live births.'® Males are affected twice as often as females.  Craniosynostosis can occur as part of a syndrome or, more com-  monly, as an isolated defect.!? Nonsyndromic craniosynosto-  sis is classified as simple craniosynostosis when only one suture  is involved and compound or complex craniosynostosis when two  or more sutures are involved. Craniosynostosis prevents normal  skull expansion and causes asymmetric skull growth. Premature  closure of a suture causes failure of the growth of the bone located  at a right angle to the involved suture. Compensatory growth  occurs in regions where the sutures are patent, and this causes  the various cosmetic deformities of head shape. Where sutures  are fused, cerebral growth may exceed the space present. Brain  growth may be restricted, and compression may cause neurologic  symptoms (Figure 20-8). Clinically, however, most children who  present with small heads and developmental delay have micro-  cephaly (see below) caused by defects in brain growth, not com-  pression by prematurely closed sutures.   PATHOPHYSIOLOGY. The exact causes of craniosynostosis are  unknown, but are associated with defects in multiple genes that  control the fibroblast growth factor receptor family.?°   Syndromic craniosynostosis refers to synostosis that occurs  as part of a genetic syndrome. It is associated with various dys-  morphisms involving the face, skeleton, and nervous system  and is usually accompanied by developmental delay.   CLINICAL MANIFESTATIONS. Craniosynostosis is classified  according to head contour or suture involvement. Final skull  contour is determined by the sutures that close, the duration  and order of closure, and the ability of other sutures to com-  pensate by expansion (see Figures 20-8 and 20-9).   Premature closure of the sagittal suture, the most common  form of craniosynostosis, causes elongation of the skull in the  anteroposterior direction. Other anomalies are seen in 25% of  these children. When the coronal suture fuses prematurely, the  brain expands in a lateral direction. This type of craniosynos-  tosis is associated with a 33% to 66% incidence of associated  anomalies.   EVALUATION AND TREATMENT. Craniosynostosis must be differ-  entiated from the more benign skull deformity known as posi-  tional plagiocephaly (flattening of one side of the head), which  is quite common and may be related to the amount of time an  infant spends on his or her back. When the American Academy    FIGURE 20-8 Types and Frequency of Craniosynostosis. Abnormal head configuration resulting from premature clos-  ing of cranial sutures. Normal skull: Bones separated by membranous seams until sutures gradually close. Microcephaly and  craniostenosis: Microcephaly is head circumference more than 2 standard deviations below the mean for age, gender, race,  and gestation and reflects a small brain; craniosynostosis is premature closure of sutures. Scaphocephaly or dolichocephaly  (frequency 56%): Premature closure of sagittal suture, resulting in restricted lateral growth. Brachycephaly: Premature closure  of coronal suture, resulting in excessive lateral growth. Oxycephaly or acrocephaly (frequency 5.8% to 12%): Premature closure  of all coronal and sagittal sutures, resulting in accelerated upward growth and small head circumference. Anterior plagio-  cephaly (frequency 13%): Unilateral premature closure of coronal suture, resulting in asymmetric growth. (From Hockenberry  JH et al: Wong's nursing care of infants and children, ed 9, St Louis, 2011, Mosby.)    of Pediatrics recommended that babies should sleep on their  backs instead of their stomachs, the incidence of positional pla-  giocephaly increased (whereas the incidence of sudden infant  death syndrome decreased). A custom-molded helmet or head-  band applied at about 4 months of age can correct plagioceph-  aly before closure of fontanels and sutures.   Diagnosis of craniosynostosis is made on the basis of physi-  cal examination, head circumference measurements, and  radiologic examination. Surgical treatment is often indicated  for craniosynostosis and is performed when closure of multiple  sutures causes chronic increased intracranial pressure. Surgery  then limits the extent of brain damage. In children with cra-  niosynostosis of one suture, surgery often is performed for cos-  metic purposes.”!    Structural malformations of cortical development are a diverse,  heterogeneous group of disorders caused by abnormal neuronal    cell migration, abnormal neuronal and glial proliferation, and  malformations secondary to abnormal postmigrational neuro-  nal development. The processes of malformation can occur at  any time during fetal development and after birth. There is a  specific genetic defect for some of these disorders; others are  multifactorial or acquired (i.e., intrauterine trauma or infec-  tion). Most increase the risk for seizures that are difficult to con-  trol, developmental delay, and motor dysfunction. Diagnosis is  made by magnetic resonance imaging (MRI), family history,  and clinical information. Genetic testing is done to assess risk  in other family members and to guide prospective therapy.2**°    Reduced proliferation or accelerated apoptosis causes con-  genital microcephaly (microencephaly—small brain), whereas  increased proliferation causes megalencephaly (abnormally  large brain). Microcephaly is a rare defect in brain growth as  a whole (see Figure 20-8). The word microcephaly is derived    FIGURE 20-9 Lateral View of a Child with Scaphocephaly Resulting from  Sagittal Synostosis. Note the frontal bossing, elongation along the anteroposte-  rior (AP) axis, and prominent occiput, all of which are characteristic of this condi-  tion. (From Coran A et al: Pediatric surgery, ed 7, St Louis, 2012, Mosby.)    from the Greek (mikro, “small”; kephale, “head”). Cranial size  is significantly below average for the infant’s age, sex, race,  and gestation. The small size of the skull reflects a small brain  (microencephaly) that is caused by reduced proliferation or  accelerated apoptosis. The condition is not treatable.   True (primary) microcephaly is present at birth and can be  caused by genetic alterations, including autosomal dominant,  autosomal recessive, or X-linked genetic abnormalities, or vari-  ous chromosomal abnormalities. Environmental causes include  toxin or radiation exposure or intrauterine infection during  the period of induction and neural cell migration (Box 20-1).  Secondary microcephaly develops postnatally (the baby’s head  size is normal at birth but then fails to grow as expected) and is  associated with a variety of causes including infection, trauma,  metabolic disorders, maternal anorexia experienced during the  third trimester of pregnancy, and the presence of some genetic  syndromes (e.g., Rett syndrome).”°   Microcephalic brain weight may be as low as 25% of normal,  and the number and size of the cortical gyri may be diminished.  Growth of the frontal lobes is severely stunted, and the cerebel-  lum often is disproportionately large. In microcephaly caused  by perinatal or postnatal disorders, neuronal loss and gliosis  may be present in the cerebral cortex. Children with micro-  cephaly are usually developmentally delayed.    Cortical dysplasias are a heterogeneous group of disorders  caused by defects in neuronal cell migration and subsequent  abnormalities in connections between cells. These disorders  may range from a small area of abnormal tissue (e.g., hetero-  topia, which are pieces of gray matter that did not migrate to  their normal position in the cortex of the brain; or focal cor-  tical dysplasias, where brain organization in one small area is  abnormal) to an entire brain that is smooth without the normal    FIGURE 20-10 Lissencephaly. The absence of cortical gyri defines this  abnormality, seen here in the brain from a full-term infant. (From Kumar V et al:  Robbins & Cotran pathologic basis of disease, ed 8, Saunders, 2010, Philadelphia.)    configuration of gyri and sulci of a developed brain (lissenceph-  aly) (Figure 20-10).    Congenital hydrocephalus is present at birth and characterized  by increased intracranial pressure (ICP). This increase may be  caused by a blockage within the ventricular system in which the  CSF flows, an imbalance in the production of CSF, or a reduced  reabsorption of CSF that results in ventricular enlargement  and increased ICP. The pressure within the ventricular system  dilates the ventricles and pushes and compresses the brain tissue  against the skull. When hydrocephalus develops before fusion    FIGURE 20-11 Hydrocephalus. A block in the flow of cerebrospinal fluid (CSF). A, Patent cerebrospinal fluid circulation.  B, Enlarged lateral and third ventricles caused by obstruction of circulation—stenosis of aqueduct of Sylvius.    of the cranial sutures, the skull has the capacity to increase its  size to accommodate this additional space-occupying volume  and to preserve neuronal function. The overall incidence of  hydrocephalus is approximately 1 to 3 per 1000 live births.”’  The incidence of hydrocephalus, excluding the hydrocephalus  associated with myelomeningocele, is approximately 0.5 to 1  per 1000 live births, with aqueductal stenosis as the cause for  approximately one third of these cases.** (Types of hydrocepha-  lus are discussed in Chapter 17.)   PATHOPHYSIOLOGY. Obstructive hydrocephalus is caused most  commonly by congenital aqueductal stenosis. The cerebral  aqueduct, which connects the third ventricle to the fourth ven-  tricle, is narrowed or replaced by multiple channels that end  blindly. In a small number of children the stenosis is transmit-  ted as an X-linked recessive trait. The Dandy-Walker malfor-  mation is a congenital defect of midline cerebellar structures  and the fourth ventricle in which hydrocephalus is caused by  atresia of the foramina of Luschka or Magendie, which nor-  mally allow the fourth ventricle to empty into the areas sur-  rounding the brain, leading the ventricular flow of CSF into    a “blind pouch.” Other causes of obstructions within the ven-  tricular system that can result in hydrocephalus include brain  tumors, cysts, trauma, arteriovenous malformations, blood  clots, infection, and spina bifida.   CSF travels throughout the ventricular system, surrounds  the brain, and is reabsorbed into the venous system by the  arachnoid villi. Blockage of the arachnoid villi may occur in  conditions such as bacterial or viral meningitis, intraventricu-  lar hemorrhage, and subarachnoid hemorrhage, or may result  from congenital malformations within this area. In this instance  CSF flows or communicates effectively but is unable to be reab-  sorbed, resulting in hydrocephalus.   CLINICAL MANIFESTATIONS. Congenital hydrocephalus is pres-  ent at birth, whereas acquired hydrocephalus usually becomes  apparent in the first weeks to months of life. Symptoms of this  condition depend directly on the cause and rate of hydrocepha-  lus development. Typically, the fontanels enlarge and become  full and bulging (Figures 20-11 and 20-12). The eyes may  assume a staring expression, with sclera visible above the iris, a  finding called sunsetting eyes.    a Ss x SS  MN!  FIGURE 20-12 Child with Enlarged Head Caused by Hydrocephalus.  (From McLaurin DC: Pediatric neurosurgery, ed 2, Philadelphia, 1989, Saunders.)    The infant may have difficulty holding the head upright.  The scalp skin is thin and shiny, and scalp veins may become  prominent. The large cranial vault and the face are dispropor-  tionate, and frontal bossing may be present. The infant’s cry  becomes high pitched as ICP rises; irritability, lethargy, vomit-  ing, and other signs of increased ICP may develop. Dramatic  head growth and enlargement, compression of the optic nerves,  and optic chiasm occur in chronic, untreated hydrocephalus.  However, because of early surgical intervention, these signs of  hydrocephalus rarely are seen in developed countries. When  hydrocephalus develops late in childhood, the head may not  have the capacity to enlarge, and symptoms of increased ICP  occur quickly (see Chapter 17).   The relationship between hydrocephalus and intellectual  disability has been heavily debated. Correlation between the  degree of hydrocephalus and impaired cognitive function often  is a result of additional complications, such as severe congenital  malformations, acute or chronic infections, or progressive brain  tumors. Approximately two thirds of children with uncompli-  cated congenital hydrocephalus treated successfully with shunt-  ing may have normal to borderline intelligence.”   EVALUATION AND TREATMENT. Both cranial ultrasound and  computed tomography (CT) are used to evaluate hydrocepha-  lus. Magnetic resonance imaging (MRI) may add information  about the specific cause of the hydrocephalus. In infancy, head  circumference measurements are obtained and monitored, and  if the head is enlarging too quickly the child is referred for imag-  ing first and then, if needed, to neurosurgery for further evalu-  ation. The treatment is surgical placement of a shunt to divert  the excess CSF from the ventricular cavity to other areas of the  body. Several types of shunts are available. The main objective of  any shunt system is to decrease ICP and preserve neuronal func-  tion. With neurosurgical intervention and follow-up, the 5-year  survival usually is greater than 80%. Most deaths that occur    within this category result from severe congenital malformations  and/or progressive disorders such as brain tumors. Children with  hydrocephalus depend on the internal shunt system to maintain  safe ICPs and therefore are at risk for sudden failure of this sys-  tem, which leads to acute increased ICP and death. Endoscopic  ventriculostomy with choroid plexus cauterization are two newer  procedures performed together and offer hope to replace shunts,  and avoiding shunt blocks, malfunction, and infection.””*    Encephalopathy, a pathology involving the brain, is a general  category of syndromes and diseases that include infections,  ischemia, metabolic and toxic causes, and others. Encephalopa-  thies in children are associated with a great variety of known  and suspected causes. They can be divided into non-progressive  and progressive subtypes. Progressive subtypes can be either  acute or slowly progressive. Rare neurologic disorders with a  genetic basis are summarized in Table 20-3.   Brain injury may occur during gestation or birth or at any time  during childhood growth and development, causing a static  disorder. Static encephalopathy may be a result of trauma near  birth (cerebral palsy); a genetic syndrome (intellectual disabil-  ity); or later trauma, such as a closed-head injury, which may  cause a static encephalopathy with motor and cognitive deficits.  The clinical manifestations of a static encephalopathy depend  on the site and extent of the injury, as well as the age of the child  and stage of development at the time of injury.    Cerebral palsy (CP) is a disorder of movement, muscle tone,  or posture that is caused by injury or abnormal development  in the immature brain, before, during, or after birth up to 1  year of age. CP is one of the most common crippling disorders  of childhood, affecting nearly 500,000 children in the United  States alone. Although the exact incidence is unknown, studies  suggest that the prevalence is approximately 3.3 per 1000 live  births in the United States.°° Although the term cerebral palsy  refers specifically to the motor deficits, associated intellectual  disability, seizures, and other problems also are common in  children with this disorder.   PATHOPHYSIOLOGY. Several factors, alone or in combination,  can produce brain damage that leads to CP (Table 20-4). Pre-  natal factors that affect the developing nervous system may  be endogenous or exogenous. The fetus may be affected by  impaired embryo implantation, chromosomal abnormalities,  infection, trauma, radiation exposure, and toxic substances.  Maternal toxemia, diabetes mellitus, and maternal nutritional  deficiencies can produce neurologic damage in the fetus.  Anoxia, trauma, and infections are the most common factors  that cause injury to the nervous system in the perinatal period.  Low birth weight and birth asphyxia are commonly identified  risk factors for cerebral palsy. Vascular abnormalities, arterial  or venous stasis, and thrombosis can occur as a result of tissue    Loss of function mutation of the  UBE3A gene (ubiquitin protein  ligase) can be acquired from  mother (chromosome 15)   Autosomal recessive; mutation  of the CLN3 gene (ceroid-  lipofuscinosis, neuronal 3)  (chromosome 16)   Autosomal recessive; most  common type is classic caused  by mutation of the BCKDHA gene  (2-oxoisovalerate dehydrogenase  subunit alpha, a mitochondrial  enzyme) (chromosome 19)   Autosomal dominant; deletion on  the short arm of chromosome 5  (also called 5p minus syndrome)    Autosomal dominant:  mutation of either the merlin  (moesin-ezrin-radixin-like protein  or schwannomin) or the NF2 gene  (chromosome 22)    Autosomal recessive; mutation  CSTB gene (cystatin B, a cysteine  protease inhibitor) (chromosome  21)    Autosomal recessive; mutation  of the EMPZA gene (epilepsy,  progressive myoclonus type  2A or laforin) and EMP2B gene  (malin) (chromosome 6)   X-linked dominant; appears to  occur only in girls; defective  MeCP2 gene (methyl CpG binding  protein 2) (X-chromosome)    Autosomal dominant; mutation of  either the 7SC7 gene (hamartin)  (chromosome 9) or the 7SC2  gene (tuberin) (chromosome 16)    All types result in inability to  metabolize three amino acids; these  acids accumulate and are toxic at  high levels    Deletion of multiple genes responsible  for phenotype; evidence that deletion  of telomerase reverse transcriptase  gene contributes to phenotype    A large, complex protein; this protein  may act as a switch to regulate  cell growth; mutation may lessen  or inhibit the normal output of this  protein and allow irregular cell growth  that may lead to tumor development  A tumor-suppressor protein (merlin or  schwannomin)    Concentric amyloid (Lafora) bodies  found in neurons, liver, skin, bone,  and muscle; defects in protein  degradation and clearance    Protein involved in regulation of gene  expression; defects in this gene  allow other genes to be expressed at  inappropriate times in development   Caused by a deficiency of  hexosaminidase, an enzyme, which  results in accumulation of a material  that damages the brain    Little to no verbal language, mental retardation,  seizure disorder, sleep disorder, movement/  balance disorder    Develops normally until 6 months to 2 years of  age when progressive brain disease becomes  apparent; seizures, mental retardation, blindness,  and death    High-pitched cry; mental retardation, microcephaly,  low birth weight, failure to thrive; widely spaced  eyes (ocular hypertelorism), unusually small jaw  (micrognathia)   Mental retardation, progressive neurologic  disorder, compulsively bitten lips and fingers;  self-mutilating    Multiple tumors (schwannomas) on cranial and  spinal nerves, acoustic neuromas, hearing loss    Onset at age 6-15 years, severe incapacitating  stimulus-sensitive progressive myoclonus,  tonic-clonic epileptic seizures, and characteristic  abnormalities on electroencephalogram; also  may develop other neurologic symptoms. such as  ataxia, incoordination, dysarthria   Grand mal seizures and/or myoclonus at about  age 15; rapid and severe motor and coordination  impairments, rapid mental deterioration, often  with psychotic features; survival is short, less  than 10 years after onset   Progressive neurologic disorder; develops normally in  first year of life, then loss of mental capacity and  motor skills begins; loss of purposeful hand move-  ments; stereotypical hand wringing and flapping   Failure to thrive, blindness, seizures, progressive  paralysis; usually death by age 4    Develops in early childhood; seizures, mental  retardation, skin and eye lesions; multiple benign  tumors in brain and other vital organs   Environmental toxins (e.g., lead ingestion, methyl!  mercury ingestion from contaminated fish)    hypoxia or as unrelated structural alterations. These anoma-  lies may result in direct brain trauma that leads to infarction,  intraventricular hemorrhage, and subarachnoid hemorrhage.  Physical trauma to the central nervous system can occur during  the birthing process. Genetic, teratogenic, and early pregnancy  influences on the development of cerebral palsy are multifacto-  rial and not yet fully understood.*!”? The severity of the damage  depends on the gestational age at the time of the injury and the  type and degree of injury sustained. Magnesium sulfate in pre-  term newborns and head cooling during or after resuscitation at  birth may reduce brain damage and risk of CP.*>*4   CLINICAL MANIFESTATIONS. Although CP is by definition non-  progressive, its clinical manifestations change with growth and  maturation of the child. Associated problems are common and  may involve vision and hearing impairment, intellectual dis-  ability, seizures, swallowing problems, and more.*>*°   The syndromes associated with CP can be classified accord-  ing to the areas of the brain that are damaged and the part of the  body that is affected. Brain damage may affect the pyramidal  system, causing spasticity, or the extrapyramidal system, lead-  ing to dyskinetic, ataxic, or hypotonic CP. Pyramidal/spastic    cerebral palsy results from damage or defects in the brain’s  corticospinal pathways (upper motor neuron) in either one or  both hemispheres and accounts for approximately 70% to 80%  of cerebral palsy cases. It is associated with increased muscle  tone, prolonged primitive reflexes, exaggerated deep tendon  reflexes, clonus, rigidity of the extremities, scoliosis, and con-  tractures. Cognitive impairment occurs in about 30% of chil-  dren.°” If spasticity occurs throughout the body, the child has  spastic quadriparesis; if it occurs in primarily one half of the  body, the child has hemiparetic cerebral palsy. The latter type  can occur after a stroke in the middle cerebral artery territory  before or at the time of birth.   Extrapyramidal/nonspastic cerebral palsy is caused by dam-  age to cells in the basal ganglia, thalamus, or cerebellum and  includes two subtypes: dyskinetic and ataxic. Dyskinetic cerebral  palsy is associated with extreme difficulty in fine motor coordina-  tion and purposeful movements. Movements are jerky, uncon-  trolled, and abrupt, resulting from injury to the basal ganglia or  thalamus. This form of CP accounts for approximately 20% to  25% of cases. Ataxic cerebral palsy is associated with damage to  the cerebellum and manifests with gait disturbances and instabil-  ity. The infant with this form of CP may have hypotonia at birth,  but develops stiffness of the trunk muscles later in infancy. This  lack of flexibility exaggerates the infant’s inability to balance body  position without support. This form of CP accounts for approxi-  mately 5% of cases. A child may have symptoms of each of these  CP types, which leads to a mixed-variety disorder seen in approxi-  mately 13% of children with this disorder.   A few decades ago, a large percentage of children were iden-  tified as having CP for unknown reasons. Many had no history  of trauma or other cause for their CP. As imaging techniques  and other testing methods have improved, there is an increased  chance that the underlying cause of a child’s CP will be delin-  eated. A small percentage of these children may actually have  a treatable and slowly progressive condition; therefore, every  attempt to find an underlying cause for a child’s CP should  be made. One example of such an underlying cause is glucose  transporter deficiency, a condition where the concentration of  glucose in the cerebral spinal fluid is very low. Children with  this condition have ataxic movements that may be misidentified  as CP and also have intractable seizures. If this defect is identi-  fied, the child is treated with the ketogenic diet (see Epilepsy  section) with amelioration of some of the symptoms. Because  of examples like this, the American Academy of Neurology has  made specific recommendations regarding the evaluation of  a child with CP of an unknown cause as it may actually be a  slowly progressive encephalopathy.°*   EVALUATION AND TREATMENT. Although the brain injury is static,  the clinical picture of CP may change with growth and develop-  ment. The use of intrathecal baclofen pumps, botulinum toxin,  and selective dorsal rhizotomy for spasticity has led to improve-  ment in selected children with CP.°?*°   The management of children with CP varies with age, type  and severity of involvement, and associated disorders. Thus the  scope of care required by the child and family includes ongo-  ing medical, social, and educational intervention, and a family-  focused multidisciplinary team approach."!    INHERITED METABOLIC  DISORDERS OF THE CENTRAL  NERVOUS SYSTEM PRESENT-  ING AT DIFFERENT AGES    Pyridoxine dependency, galactosemia,  maple syrup urine disease and its variant,  phenylketonuria (PKU)   Tay-Sachs disease and its variants, infantile  Gaucher disease, infantile Niemann-Pick  disease, Krabbe disease (leukodystrophy),  Farber lipogranulomatosis, Pelizaeus-  Merzbacher disease and other sudanophilic  leukodystrophies, spongy degeneration,  Alexander disease, Alpers disease,   Late infancy and early isorders of amino acid metabolism,  childhood metachromatic leukodystrophy, late infantile   (Jansky-Bielschowsky disease, Batten disease,  Vogt-Spielmeyer disease, neuronal ceroid  lipofuscinosis), Cockayne syndrome   Progressive cerebellar ataxias of childhood and  adolescence, hepatolenticular degeneration  (Wilson disease), Hallervorden-Spatz disease,  Lesch-Nyhan syndrome and other uremic  states, familial calcification of vessels  in basal ganglia and cerebellum, familial  polymyoclonus, chronic familial leukodystrophy,  homocystinuria, Fabry disease    For more information regarding screening and parent education see  Medical Home Portal at www.medicalhomeportal.org/.    A large number of inherited metabolic disorders have been  identified. The advent of newborn metabolic screening for 28  metabolic conditions (in some states as many as 50) has led  to many of these children being identified before symptoms  develop. In these disorders, there is either a deficiency of an  essential product or an accumulation of a substrate with dam-  age induced either by overaccumulation or toxicity or by a com-  bination of both. Inborn errors of metabolism are present at  birth, although they may not manifest until childhood or even  adulthood, and most cause disturbances of the nervous sys-  tem. Restrictive diets can prevent symptoms from developing  for many children and those with these disorders can lead rela-  tively normal lives. The following website contains a list of the  newborn metabolic screening tests: www.marchofdimes.com/  professionals/bringinghome_screening.html. Table 20-5 lists  some of these inherited metabolic disorders. Defects in amino    acid and lipid metabolism are more common than rarely occur-  ring defects in carbohydrate metabolism.   Defects in Amino Acid Metabolism. Biochemical defects in  amino acid metabolism are examples of defects in inherited  metabolic disorders. They may be classified as (1) those in  which the transport of an amino acid is impaired; (2) those  involving an enzyme or cofactor deficiency; and (3) those  grouped around certain chemical components, such as sulfur-  containing amino acids.” Most of the disorders in the literature  described to date suggest that the absence of enzymatic activity  most often is caused by the genetically determined absence of  the enzyme protein. Diseases caused by an enzymatic deficiency  are associated with increased blood concentrations of the amino  acid whose degradation pathway is impaired and with the  appearance of the amino acid in the urine. With the exception  of phenylketonuria, the estimated incidence of each of these  defects is about 1 in 100,000 to 200,000 live births, although  this number may increase with newborn screening.   Phenylketonuria. Phenylketonuria (PKU) is an example of  an inborn error in the metabolism of amino acids. PKU is an  autosomal recessive inborn error of metabolism characterized  by mutations of the phenylalanine hydroxylase (PAH) gene.  PKU has a prevalence rate of about 1 per 15,000 live births in  the United States.*’ Because of its genetic component and dis-  tribution, this statistical prevalence varies widely on the basis of  geographic and ethnic differences.** Most natural food proteins  contain about 15% phenylalanine. The body uses tyrosine in the  biosynthesis of protein, melanin, thyroxine, and the catechol-  amines in the brain and adrenal medulla. Loss of PAH activity  results in phenylalanine hydroxylase deficiency and the inability  of the body to convert the essential amino acid phenylalanine  to tyrosine, leading to the accumulation of phenylalanine in the  serum. It is the accumulation of phenylalanine and associated  metabolites that causes damage to the central nervous system  (Figure 20-13). One of these phenyl acids, phenylpyruvic acid,  gives the urine a characteristic musty odor and is responsible  for the name given to the disorder. High blood levels of phe-  nylalanine prevent sufficient neutral amino acid entry into the  brain, which contributes to the neuropathologic process of  PKU. A baby with the genetic defect of PKU born to a mother  without PKU or to a mother with PKU who is well controlled  on a phenylalanine-restricted diet will not have any problems  because he or she is receiving nutrients from the mother. When  a baby is born with PKU and begins a regular diet high in phe-  nylalanine without treatment, buildup of phenylalanine occurs,  brain growth slows, and the child exhibits developmental delay  or intellectual disability, concomitant with jerking move-  ments, seizures, skin rashes, and attention problems. Because  of the lack of tyrosine and its relationship to the biosynthesis  of melanin, children with PKU have a characteristic phenotype  that includes blond hair, blue eyes, and fair skin. Children with  genetically darker complexions may be red haired or brunette.   Less severe variants of this disorder are caused by defects in  the phenylalanine hydroxylase system rather than the phenyl-  alanine hydroxylase enzyme itself. This related disorder, known  as hyperphenylalaninemia (HPA), occurs when plasma phe-  nylalanine levels rise above normal but do not rise as high as    in PKU.* Individuals with PKU also need to be screened for  response to BH4 (6-R-.-erythro-5,6,7,8-tetrahydrobiopterin),  which significantly decreases blood phenylalanine levels when  given as an oral supplement (sapropterin dihydrochloride).*°   When infants are treated appropriately, growth and devel-  opment are normal. Treatment for PKU involves restriction of  phenylalanine in the diet to maintain a nontoxic level and sup-  plementation with other essential amino acids. Treatment must  be continued for life and strict adherence to the diet is especially  important for pregnant women with PKU so that damage does  not occur prenatally to the fetus. The diet also must be supple-  mented with adequate sources of energy, protein, and nutrients  to allow for optimal growth and brain development. Supple-  mentation of tyrosine also may be required if plasma levels are  low. Enzyme replacement and gene and cell therapies are under  investigation.*”   Storage Diseases. Some metabolic disorders are caused by  abnormal accumulation of metabolites. These disorders are  generally not included in newborn screening. Lysosomal storage  diseases and Tay-Sachs disease will be discussed as examples of  storage diseases.   Lysosomal Storage Disease. Lipids are fat-like substances  that are important parts of the membranes found within and  between each cell and in the myelin sheath that coats and  protects the nerves. Lipids include oils, fatty acids, waxes,  steroids (such as cholesterol and estrogen), and other related  compounds. Although these compounds accumulate to some  extent in cells, excess amounts are broken down in lysosomes  (vesicles within the cell whose primary function is to degrade  the breakdown products of cellular metabolism as discussed    FIGURE 20-13 Metabolic Errors and Consequences in Phenylketonuria.  (Redrawn from Hockenberry MJ et al: Wong's nursing care of infants and children,  ed 9, St Louis, 2011, Mosby.)    in Chapter 1). An estimated 25 to 30 enzymes within lyso-  somes participate in the breakdown of excess compounds. A  genetic defect resulting in a missing or defective enzyme, such  as lysosomal hydrolase, causes an excessive accumulation of  the enzyme’s substrate, which alters cell function. The enzyme  defect may occur in the brain, liver, spleen, bone, or lung, thus  involving several organ systems. Prenatal diagnosis is available.  Enzyme replacement therapy and stem cell therapy have been  successful in some cases.*®   Tay-Sachs Disease. Tay-Sachs disease (GM2 gangliosido-  sis) is an example of a lysosomal storage disease. It is a fatal  autosomal recessive disorder (HexA gene on chromosome 15)  caused by deficiency of the lysosomal enzyme hexosaminidase  A (HexA), an enzyme that degrades GM2 gangliosides (fatty  acids) within nerve cell lysosomes. Consequently, there is accu-  mulation of gangliosides (gangliosidosis), which causes toxic-  ity to nerve cells.” French Canadians, Louisiana Cajuns, and  Ashkenazi Jews are all considered high-risk with a carrier rate  of 1 per 27.°° Prenatal screening is available.   In Tay-Sachs disease, GM2 ganglioside accumulates in neu-  rons throughout the body, although the pathologic progressive  changes prevail in the CNS. With time, neurons become dis-  torted and balloon, and microglial cells, which also are swollen  and filled with large granules, proliferate. Cystic degeneration  of the cerebral white matter and atrophy of the cerebellar hemi-  spheres often occur. The number of neurons is diminished.  Changes in the spinal cord, particularly in the motor cells of the  anterior horn of the cord, also are characteristic. Involvement  of this region of the spinal cord results in hypotonia, hypore-  flexia, and overall weakness.   Onset of symptoms usually occurs when the infant is 3 to  6 months old. A loss of milestones is associated with an exces-  sive startle response. Seizures, muscular rigidity, and blindness  become prominent after the first year of life, and head size may  increase. Death usually occurs by 2 to 5 years of age. No benefi-  cial therapy has been developed. Genetic counseling programs  are available, and some states require screening techniques for  couples and those at risk who may be carriers.*!   Intoxications of the Central Nervous System  Drug-induced encephalopathies always must be considered in  the child with unexplained neurologic changes. Such encepha-  lopathies may result from accidental ingestion, therapeutic  overdose, intentional overdose, or ingestion of environmental  toxins (the most commonly ingested poisons are listed in Box  20-2). Approximately 1.6 million children were exposed to poi-  sons and approximately 263 children died in the United States  in 2010 as a result of poisoning.»   Lead Poisoning. High blood levels of lead occur in lead  poisoning. If lead poisoning is not treated, lead encephalopathy  will result and cause serious and irreversible neurologic  damage*** (Figure 20-14). Those at greatest risk are children  2 to 3 years of age and those with pica or living in lead-  contaminated environments. Pica is the habitual, purposeful,  and compulsive ingestion of nonfood substances such as clay,  dirt, or paint chips. Lead intoxication also may occur from    long-term exposure to smelters, sniffing of gasoline, exposure  to lead-based paint, and ingestion of airborne lead.°°   An estimated 203,000 U.S. children have excessive amounts  of lead in their blood, which leads to varying amounts of intel-  lectual disability depending on level and length of exposure    Botulinum toxin  Alcohols  Ethyl, isopropyl, methy!  Pesticides  Organophosphates  Chlorinated hydrocarbons  Mushrooms  Venoms  Snake bite  Tick paralysis  Ethylene glycol    Data from Swaiman KF et al: Swaiman’s pediatric neurology: principles  and practice, vol 2, ed 5, St Louis, 2012, Mosby.    time.*° Young children are more likely to be exposed to lead-  containing materials than older children and also absorb lead  more easily than older children. Levels continue to be highest  among non-Hispanic black children, Mexican American, and  non-Hispanic white children, with the greatest risk being in the  non-Hispanic black population.°’ The American Academy of  Pediatrics has published recommendations for the treatment of  lead poisoning depending on blood lead level.°*    Meningitis is inflammation of the meninges and subarachnoid  space surrounding the brain and spinal cord, whereas the word  encephalitis reflects inflammation within the brain. In many  infections of the meninges, encephalitis also is present and the  term meningo-encephalitis is used. The origin of such inflam-  mation and acute encephalopathy can be caused by bacteria,  viruses, or other microorganisms. Aseptic meningitis has no  evidence of bacterial infection but may be associated with viral  infection, systemic disease, or drugs.   Bacterial Meningitis. Acute bacterial meningitis is one of  the most serious infections to which infants and children are  susceptible. In the United States approximately 4100 cases of  bacterial meningitis occurred each year between 2003 and 2007,    monocytogenes  Streptococcus pneumoniae, Neisseria  meningitidis, Haemophilus influenzae type b  Neisseria meningitidis, Streptococcus  pneumoniae    including 500 deaths.°? About half of these cases occurred in  children younger than 18 years of age. The microorganisms  accountable for this illness are summarized in Table 20-6.   The introduction of conjugate vaccines against Haemophilus  influenzae type B, Streptococcus pneumoniae, and Neisseria men-  ingitidis (meningococcus) has decreased the incidence of bacte-  rial meningitis. Vaccines for serogroup B N. meningitidis are  not yet available but clinical trials are in progress.°! Meningitis  is still prevalent in countries without access to the vaccine.*”  (Note that although many families are worried about giving  their infants vaccines, the change in incidence of many illnesses  has been drastically reduced with their introduction; bacterial  meningitis is just one example.)   Group B Streptococcus causes lethal meningitis and sepsis in  neonates and is transmitted to the child from the mother’s birth  canal. S. pneumoniae is the most common microorganism in  children 1 to 23 months of age. Staphylococcal or streptococcal  meningitis can occur in children of any age but shows a predi-  lection for children who have had neurosurgery, skull fracture,  or a complication of systemic bacterial infection. Infections  that originate in the middle ear, sinuses, or mastoid cells also  may lead to S. pneumoniae infection in children. Children who  have sickle cell disease or have undergone a splenectomy are  particularly at risk for infection.©? Escherichia coli and group B  streptococcus are the most common causes of meningitis in the  newborn period. The second most common microorganism  causing bacterial meningitis, particularly in children younger  than 4 years, is Neisseria meningitidis (meningococcus) and it  has the potential to occur in epidemics. Approximately 2% to  5% of healthy children are carriers of N. meningitidis. As the  incidence of N. meningitidis infection increases in adolescence  and with crowding, such as in dormitories and among military  personnel, it is recommended that all individuals 11 to 18 years  of age receive two immunizations against this pathogen.”   PATHOPHYSIOLOGY. The cause of bacterial meningitis is related  to the age of the child and to a number of factors that predispose  the child to bacterial infection or that alter the child’s response  to an invading microorganism. Staphylococcus aureus or Pseudo-  monas aeruginosa may develop in the child with cystic fibrosis or  severe burns. (See Chapter 10 for further discussion of bacterial  virulence and infection.) Any microorganism may be patho-  genic under the appropriate circumstances in a given individual.   Pathogens enter the nervous system by direct extension (i.e.,  paranasal sinuses or mastoid cells) or, more commonly, by hema-  togenous spread (see Figure 18-32). Infection may travel through    the blood to the meninges in children with infective endocarditis,  pneumonia, or thrombophlebitis, or to those who have under-  gone recent procedures or been severely burned. Many bacteria  are very successful at evading normal defenses (see Chapter 10).  Pathogens cross the blood-brain barrier, enter the cerebrospinal  fluid, and multiply. Bacterial toxins increase cerebrovascular per-  meability, causing alterations in blood flow and edema. Throm-  bosis and increased ICP can cause neurologic damage. As a result  of meningitis, thickened meninges and fibrous exudate in the sub-  arachnoid space at the base of the brain can obstruct CSF resorp-  tion, resulting in nonobstructing hydrocephalus. Untreated, this  can cause brainstem herniation and death.   CLINICAL MANIFESTATIONS. Acute bacterial meningitis often  is preceded by an upper respiratory tract or a gastrointestinal  tract infection. Inflammation leads to the general symptoms of  fever, headache, vomiting, and irritability and the CNS symp-  toms of photophobia, nuchal and spinal rigidity, decreased level  of consciousness, and seizures. Irritation of the meninges and  spinal roots causes pain and resistance to neck flexion (nuchal  rigidity), a positive Kernig sign (resistance to knee extension  in the supine position with the hips and knees flexed against  the body), and a positive Brudzinski sign (flexion of the knees  and hips when the neck is flexed forward rapidly). With severe  meningeal irritation the child may demonstrate opisthotonic  posturing (rigid arching of the back with the head extended).  Infants may have bulging fontanels. Meningococcal meningitis  can produce a characteristic petechial rash.   EVALUATION AND TREATMENT. A definitive diagnosis is made  by examination of CSF obtained from a lumbar puncture. The  principles of treatment are similar to those followed for adults  (see Chapter 18) and are based on the culture results in which  the causative microorganism is identified. Empirical antibiotic  therapy should be initiated and continued until CSF cultures  are negative™ or changed if the empirical therapy is not correct  for the bacteria cultured from the CSF. Bacterial lysis induced  by antibiotics can cause subarachnoid inflammation; the sever-  ity can be reduced with corticosteroid treatment.®° The factors  that influence outcomes are the age of the child (mortality is  highest in infants younger than 1 year), the infective microor-  ganisms (the lowest mortality is in meningococcal meningitis  and the highest in meningitis caused by gram-negative enteric  microorganisms), and the duration and extent of inflamma-  tion before treatment. Approximately 8% of children with H.  influenzae meningitis die; 35% of the survivors have serious and  permanent sensory or motor dysfunction caused by pressure  on the peripheral nerves during the early phases of the illness.  Approximately 5% of the children who survive meningitis have  hearing deficits; 10% to 15% have cerebral damage, hydroceph-  alus, motor deficits, or sensory impairments.°°°   Viral Meningitis. The hallmark of viral meningitis is a  mononuclear response in the CSF and the presence of normal  blood glucose level, although the findings with aseptic meningitis  are similar to those seen in bacterial meningitis in some cases.   The clinical manifestations are similar to those in bacterial  meningitis, although usually milder. Isolation of the specific  virus is difficult. An exception is when the virus responsible  is the herpes simplex virus, which can occur in infants after    exposure to the herpes virus type 2 in the birth canal, or spo-  radic cases caused by herpes virus type 1, which is the type that  causes cold sores. It is possible to test for the herpes virus and,  unlike most of the other viruses, there is a specific antiviral  medication.®* When a child has symptoms of bacterial or viral  meningoencephalitis, antibiotic and antiviral treatments are  administered until the cause is determined.   Human Immunodeficiency Virus Encephalopathy. Human  immunodeficiency virus type 1 (HIV-1) causes a syndrome  called HIV-1 encephalopathy (see Chapter 10 for details of HIV  infection which results in developmental delays and impaired  brain growth in children not directly related to opportunistic  infections in the brain).   PATHOPHYSIOLOGY. The CNS is a distinct reservoir for HIV-1  but the pathogenesis of HIV encephalopathy in children is not  clearly understood. HIV-1 invades the CNS early in infection,  primarily through infected monocytes/macrophages and CD4+  T lymphocytes. The presence of viral products and inflamma-  tory mediators and overstimulation of the N-methyl-p-aspar-  tate-type receptor system lead to neuronal injury and death,  particularly in the immature brain, and this is thought to cause  the HIV-1 encephalopathy.”   CLINICAL MANIFESTATIONS. The 1994 classification from the  Centers for Disease Control and Prevention (CDC) requires  one of the following progressing findings to be present for at  least 2 months,”? in the absence of a concurrent illness other  than HIV that could explain the findings:   1. Failure to attain or loss of developmental milestones, or  loss of intellectual ability, verified by standard develop-  mental scale or neuropsychologic tests   2. Impaired brain growth or acquired microcephaly dem-  onstrated by head circumference measurements or brain  atrophy established by CT or MRI, with serial imaging  required in children younger than 2 years   3. Acquired symmetric motor deficits manifested by affect-  ing a child 1 month of age or older   The onset of progressive encephalopathy may be a prog-  nostic indicator of a poor outcome and it may be difficult to  completely differentiate the effects of HIV infection on the CNS  from the effects of prenatal and perinatal exposure. In addition,  other insults may accompany HIV in a young child and affect  growth and development, such as drug exposure, prematurity,  and chronic illness.   EVALUATION AND TREATMENT. A definite diagnosis of HIV is  made by patient history, viral culture, and clinical manifesta-  tions. Monitoring CD8+ T lymphocytes and monocytes, in addi-  tion to CD4+ T lymphocytes, has been suggested for predicting  risk for progressive encephalopathy. Decreases in CD8+ T lym-  phocytes diminish defenses against viral infection and facilitate  infected monocytes to cross the blood-brain barrier. In general,  treatment is focused on preservation and maintenance of the  immune system, aggressive response to opportunistic infections,  and support and relief of symptomatic occurrences by adminis-  tration of highly active antiretroviral therapy (HAART). (HIV  treatment is discussed in Chapter 10.) Progressive HIV enceph-  alopathy is an infrequent and reversible complication of HIV  infection because the disease responds to HAART./)   Ischemic stroke—heart disease or cardiac disorders (most common), blood  disorders, clotting or coagulation disorders, sickle cell anemia, infec-  tions (chickenpox, meningitis, encephalitis, moyamoya disease), and  arterial dissection   formations (AVMs) and aneurysms; blood disorders, including thrombo-  cytopenia and leukemia; and malignancy, including intracranial tumors   internal carotid, middle cerebral, and basilar arteries; infarcts more often lim-   ited to deep regions of the cerebral hemispheres, mostly basal ganglion and    From Causes and outcome in childhood stroke. Available at www.  pediatricstroke.org/child_stroke.htm. Accessed April 4, 2013.    Perinatal arterial ischemic stroke is estimated to occur in 1 in  4000 live births and is a leading cause of perinatal brain injury,  cerebral palsy, and lifelong disability.”* Children with perinatal  stroke may not be diagnosed until later in infancy or childhood  when it becomes apparent that the child is not moving one side  of the body as much as the other. Early signs may consist of the  family noticing that one hand is preferred over the other at an  early age—typical “handedness” does not usually occur until 16  to 18 months of age—or one foot is dragging. An MRI is often  performed at this point and is most likely to show evidence of  a previous middle cerebral artery stroke. The clinical pattern  that usually results from this type of stroke is contralateral  hemiplegia with the arm more affected than the leg. Children  with hemiplegia caused by perinatal stroke (hemiplegic CP) are  prone to seizures although generally do well cognitively. Testing  for abnormalities in blood-clotting mechanisms, such as anti-  thrombin enzyme activity, protein C and protein S deficiencies,  or abnormal factor V Leiden, is often performed in children  with prenatal stroke. Although often normal, abnormalities in  these clotting mechanisms should be assessed because they may  make the child prone to further vascular events.    Childhood stroke occurs in about 1 to 13 per 100,000 live births  (Box 20-3).”4    PATHOPHYSIOLOGY. Ischemic stroke is rare in children and  may result from embolism, arteriopathy, or, rarely, sinovenous  thrombosis leading to a decreased flow of blood and oxygen to  areas of the brain. Children with arterial ischemic stroke do not  have the typical adult risk factors of atherosclerosis and hyper-  tension. Approximately 40% of children with ischemic stroke    have no identifiable underlying risk factors. Sickle cell disease,  cerebral arteriopathies, and cardiac anomalies are the most com-  mon disorders that lead to arterial ischemic stroke.”>”° Treat-  ment options for children with stroke are investigational.’””®    PATHOPHYSIOLOGY. Congenital cerebral arteriovenous malfor-  mations are the most common cause of intracranial bleeding  and hemorrhagic stroke in children.””? Hemorrhagic stroke may  result from vascular anomalies that lead to rupture, such as  aneurysm, or from congenital arteriovenous malformation; the  cause of hemorrhagic stroke is more likely to be found than the  cause of ischemic stroke. The rupture of a cerebral aneurysm is  rare in children younger than 19 years. Intraventricular hemor-  rhage associated with premature birth is related to immature  blood vessels and unstable blood pressure. There is a high risk  of developing posthemorrhagic hydrocephalus.*”*!   Moyamoya disease is a rare, chronic, progressive stenosis  of the anterior circulation, such as the internal carotid arteries  and middle cerebral arteries. Obstruction of arterial flow to the  brain occurs slowly, allowing time for new blood vessels to form  and increase collateral blood flow to ischemic areas. Moyamoya  is a Japanese term that means “puff of smoke,” which describes  the vascular appearance on cerebral angiogram. Moyamoya vas-  culopathy may be idiopathic or may be associated with certain  genetic or metabolic syndromes, or it can develop as a result  of cranial radiation therapy. Complications are developmental  delay/intellectual disability, and cerebral hemorrhage.** Treat-  ment is surgical bypass of the ischemic region.   CLINICAL MANIFESTATIONS. Symptoms of ischemic or hem-  orrhagic stroke may include degrees of hemiplegia (flaccid,  spastic), weakness, seizures, headache, high fever, nuchal rigid-  ity, hemianopia, sensory changes, facial palsy, and temporary  aphasia.   EVALUATION AND TREATMENT. Diagnosis of cerebrovascular dis-  ease is made through a series of tests, including imaging stud-  ies.°° History of evolving symptoms and medical history are of  vital importance in attaining an accurate diagnosis of stroke eti-  ology, although causative factors often cannot be determined.  Prophylactic medications may be prescribed in those children  who have suffered an ischemic stroke (e.g., from aspirin). Arte-  riovenous malformations that may leak and cause hemorrhagic  stroke vary in size, location, and symptoms and these factors  determine treatment. If a malformation is present, treatment  options include surgery, radiation therapy, and embolic occlu-  sion of the malformation™ (see Chapter 18).   Excellent collateral circulation in the child’s brain allows for  more rapid recovery of motor function, as compared to adults.  The developing brain, however, may suffer more global, long-  term effects leading to intellectual disability, behavior disor-  ders, and seizures.*°    Epilepsy is the occurrence of seizures. The incidence of epilepsy  varies greatly with age, geographic location, and study design.  The incidence is estimated to be 40 to 95 cases per 100,000,    with highest onset during the first 12 months of life. Incidence  then decreases with age. Approximately 181,000 persons in the  United States are newly diagnosed each year.°*7   PATHOPHYSIOLOGY. Seizures are caused by abnormal discharge  of electrical activity within the brain. When a sufficient num-  ber of neurons become overexcited, they discharge abnormally,  which sometimes results in clinical manifestations (seizures).  Dysregulation of inhibitory GABA, neurotransmission with  imbalance of excitatory and inhibitory mechanisms is specu-  lated to be a cause of early childhood seizures. Dysregulation  of other types of voltage- and ligand-gated ion channels (i.e.,  sodium, calcium, potassium, and chloride) is associated with  genetically determined epileptic syndromes.***’ If seizures  develop, the specific physical activity that occurs depends on  the origin of the electrical activity and its extent within the  brain. If a child has more than one unprovoked seizure, that  child is said to have epilepsy, although there are a few excep-  tions—one example being febrile seizures. Either seizures can  be symptoms of an underlying disorder (e.g., meningitis or a  brain tumor) or seizures may, themselves, be diseases; the latter  may have a genetic or a familial predisposition (for instance,  childhood absence epilepsy and juvenile myoclonic epilepsy)  (see Tables 17-16 and 17-17). Nearly half of childhood epilepsy  is of unknown etiology.”?”!   Seizures and seizure patterns may change as a child grows  and develops. The differences between the immature and  mature nervous systems may help explain the changing pat-  terns of clinical seizures with age. For example, febrile seizures  manifest in children 6 months to 3 years of age and juvenile  myoclonic epilepsy is first noted in adolescence. The immature  nervous system has a reduced capacity for sustaining well-orga-  nized seizures and, therefore, infants are prone to have seizures  that occur only in small parts of the body compared to gen-  eralized tonic-clonic seizures in older children. This is because  intracortical connections are poorly developed in children and  the sending of impulses throughout the cortex is limited. At  the cellular level, neurons are less capable of firing in repeti-  tive high-frequency bursts. The excitatory output of a seizure  focus is further diminished because the affected neurons do not  act synchronously. In addition, changing neurotransmitters,  immaturity of cells, and ongoing postnatal factors affect seizure  expression in children.   During the newborn period, asphyxia, intracranial hem-  orrhage, CNS infections, injury, electrolyte imbalances, and  inborn errors of metabolism may cause seizures, although often,  despite an extensive search for a cause, the etiology remains  unknown. Infants and children may have seizures based on  earlier brain damage (e.g., cerebral palsy) or may manifest spe-  cific epilepsy syndromes (childhood absence epilepsy, Lennox-  Gastaut syndrome). Adolescents may have seizures caused by  juvenile myoclonic epilepsy or because of other underlying  conditions. There is a peak new seizure occurrence in adoles-  cents with autism for unknown reasons.   CLINICAL MANIFESTATIONS. The clinical manifestations at  the time of the seizures vary depending on the primary cause  and the extent and involvement of abnormal electrical dis-  charges within the neuronal tissue. Because of the diversity and    complexity that seizure activity invariably displays, an inter-  national classification system was adopted. This classification  system groups seizures with similar clinical manifestations (see  Table 17-16). Its general purpose is to assist the clinician with  the type of evaluation needed, the identification of the most  appropriate treatment, and the evaluation of the individual’s  response to treatment.   The international classification system of epilepsy contains  three major groupings: (1) partial seizures, (2) generalized  seizures, and (3) unclassified epileptic seizures. Each major  grouping is then divided into subsets on the basis of clinical  manifestations and electroencephalogram (EEG) findings.   Partial seizures are characterized by seizure activity that  begins in and usually is limited to one part of either the left or the  right hemisphere. A simple partial seizure refers to seizure activ-  ity that occurs without loss of consciousness. A complex partial  seizure refers to seizure activity that occurs with impairment of  consciousness. The clinical activity displayed by the individual  is contingent on the particular part of the cortex from which the  seizure is generated. For example, partial seizures may result in  abnormal motor activity, such as twitching or loss of tone, or  sensory changes, such as tingling or numbness.   Both simple and complex partial seizures may evolve into  a generalized tonic-clonic, tonic, or clonic convulsion. Partial  seizures are more likely to be caused by an abnormality in a  specific part of the brain, and thus brain imaging is usually per-  formed in children whose seizures have started in a localized  manner, even if they generalize later. Possibilities include brain  tumors, small areas of localized brain damage, and other causes.   Generalized seizures are those in which the first clinical  manifestations indicate that the seizure activity starts in or  involves both cerebral hemispheres. Because both hemispheres  are involved, the clinical manifestations are almost always  bilateral. Consciousness may be impaired in this grouping of  seizures. The clinical manifestations may include convulsive  activity (tonic-tonic, tonic, or clonic activity) or nonconvulsive  activity (absence seizures). Generalized seizures are more likely  than partial seizures to have a genetic component; although the  genetics of some of the epilepsy syndromes have been identi-  fied, many appear to have a multifactorial genetic etiology.??*   Childhood absence epilepsy (also called petit mal seizures  or nonconvulsive epilepsy) is a type of generalized epilepsy. The  age of onset is 4 to 10 years. The genetic causes are unknown  and probably multifactorial; it also can be sporadic. Mutations  in inhibitory GABA, receptor subunit genes are associated with  absence seizures. The seizures are initiated at a cortical site and  spread to other cortical areas and to the thalamus. The EEG  shows a characteristic 3- to 4-Hz spike-wave discharge.”? The  characteristic absence seizure is of sudden onset and sudden  termination with impairment of consciousness and unrespon-  siveness usually lasting less than 10 seconds with no residual  deficits. There is interruption of ongoing voluntary activity  accompanied by staring, mild eyelid fluttering, or myoclonic  jerks. There is no aura. Seizures may be provoked by about 3  minutes of hyperventilation. Hundreds of seizures can occur  per day, disrupting school work and socialization. Antiepileptic  drugs provide beneficial treatment.”°””    Unclassified epileptic seizures are seizure disorders that do  not fit neatly into a classified grouping. These seizures char-  acteristically have a wide variety of abnormal clinical activity.  Examples of this activity include rhythmic eye movements,  chewing, and swimming movements. These activities are com-  monly seen in neonatal seizures.”*   In addition to the seizures classified by the international system,  there are several types of epileptic syndromes. These are sei-  zure disorders that display a group of signs and symptoms that  occur collectively and that characterize or indicate a particular  condition. Several syndromes associated with epilepsy occur  in infants and children. The four syndromes that occur most  often are febrile seizures, infantile spasms, Lennox-Gastaut syn-  drome, and juvenile myoclonic epilepsy.   Febrile seizures are defined as seizures associated with fever  in the absence of central nervous system infection. They are  divided into two types: simple febrile seizures and complex  febrile seizures. Simple febrile seizures occur in 2% to 5% of  children. They are benign and the most common childhood  seizure.   The pathogenesis of simple febrile seizures is unknown. A  familial incidence of simple febrile seizures indicates a genetic  predisposition to the problem. Factors that contribute to sus-  ceptibility include age, degree and rate of temperature eleva-  tion, and nature of the particular fever-inducing illness. Any  disorder producing a high fever may provoke benign febrile  seizures in susceptible children.   The following characteristic features distinguish simple  febrile seizures from complex seizures precipitated by fever:   1. Simple febrile seizures are rare before 9 months of age or   4. Most seizures occur during the first 24 hours of the illness.   Complex febrile seizures have characteristic features simi-  lar to those of simple febrile seizure except that (1) they have a  longer duration than do benign febrile seizures, usually longer  than 15 minutes; (2) they have focal characteristics; and (3) they  usually occur more than once in a 24-hour period. Complex  febrile seizures are considered a risk factor for the development  of epilepsy.”   Infantile spasms (also known as West syndrome) are a  severe form of epilepsy characterized by a variety of clinical  manifestations.!°° The infant may have episodes of sudden  flexion or extension movements involving the neck, trunk,  and extremities. Infantile spasms in some children are caused  by underlying brain abnormalities such as intrauterine stroke    or tuberous sclerosis, whereas others may be caused by muta-  tions in several genes.'°! Clinical manifestations of the resulting  spasms may range from subtle head nods to violent body con-  tractions, commonly referred to as jackknife seizures. Onset of  infantile spasms usually is between 4 and 8 months of age and  may be idiopathic or may occur in response to a CNS insult. !°  An EEG will display the classic hypsarrhythmic chaotic pattern  of epileptic discharges on a slow, disorganized background.  After infantile spasms begin, there is usually a typical clinical  course. The “spasms” usually occur in clusters and transpire  5 to 150 times per day. They are usually worse when the infant  is waking up or falling asleep. Once begun, the seizure activity  increases in intensity and severity over time. Invariably, a loss  of developmental milestones and disability is associated with  this syndrome. A short-term course of high-dose oral corti-  costeroids (usually prednisolone) is effective in many cases of  infantile spasms. !°°   Infantile spasms are present in about 30% of children with  tuberous sclerosis complex (TSC).'°! TSC develops from  mutations in hamartin (TSC1) or tuberin (TSC2) genes. Tubers  are cortical developmental malformations in the brain; they  also form in other organs. Epilepsy associated with TSC is often  difficult to treat. Vigabatrin, which may cause vision defects,  is the medication of choice for children with infantile spasms  attributable to tuberous sclerosis because it seems to be particu-  larly effective in these children.!°   Lennox-Gastaut syndrome is an epileptic syndrome char-  acterized by an onset of seizures early in childhood; it occurs  in males more often than females and begins between 1 and 8  years of age. This syndrome includes a variety of generalized  seizures—predominantly tonic-clonic, atonic (drop attacks),  akinetic, absence, and myoclonic activity and a specific pat-  tern on EEG (slow spike and wave). Seizures associated with  this syndrome are usually very difficult to treat; children may be  prescribed multiple medications and alternate therapies, such  as a ketogenic diet or a vagal nerve stimulator. Epilepsy surgery  may be necessary. Although children may be developmentally  on track when manifestations of this syndrome begin, develop-  ment is usually affected and the future manifestation of intel-  lectual disability is common.!°°   Juvenile myoclonic epilepsy is a primary, generalized epi-  lepsy that usually affects adolescents and young adults. Although  not fully understood, the genetics are in the process of being  elucidated. It is a relatively benign form of epilepsy involving  myoclonic jerks of the neck, shoulders, and arms as well as gen-  eralized tonic-clonic seizures. The seizures may occur singularly  or repetitively. This form of epilepsy is commonly associated  with a normal neurologic examination, normal intelligence,  and a family history of seizures. It is often underdiagnosed.'”  Children with this syndrome will usually need to take medica-  tions for life.   EVALUATION AND TREATMENT OF EPILEPSY. Diagnoses of epilepsy  and seizure classification are based on history, clinical presenta-  tion, physical and developmental examination, and the record  of milestone achievements. The first step in the evaluation is to  rule out other entities that may appear to be seizures; examples  include breath-holding spells and syncope. If the diagnosis of    seizure is confirmed, evaluation and testing include an EEG to  isolate the focus or origin and involvement of seizure activity  and an MRI brain scan to investigate the presence of a lesion  or abnormal tissue if the seizure semiology (the appearance of  the seizure to the observer) or the EEG shows a focal onset of  abnormal electrical activity. Depending on associated symp-  toms, a complete metabolic workup or genetic testing, or both,  may be performed to explore the possibility of deficiency or  malabsorption.!°°   Specific treatment for epilepsy is directed at the particular  clinical manifestations or syndrome of seizure activity and its  underlying causes. Treatment usually begins with the use of  anticonvulsant medications. Although seizures in most chil-  dren are controlled by one medication, the epileptic pattern and  clinical course may require more than one drug to control the  seizures.!° A ketogenic diet may be effective as a supplement  treatment for epilepsy that is difficult to control with drugs (see  Nutrition & Disease: Ketogenic Diet in Children with Epilepsy).   Surgery provides treatment for some forms of epilepsy that  cannot be controlled with drugs. As with medical interventions,  surgical therapy focuses on the particular clinical manifesta-  tions of seizure activity. Surgical interventions include resec-  tion of the epileptogenic zone of brain tissue (i.e., the temporal  lobe for partial seizures or partial or complete severing of the  corpus callosum for intractable generalized epilepsy). Children  with intractable epilepsy have shown some benefit from using a  vagal nerve stimulator.!!°    The goal of the ketogenic diet is to maintain a state of ketosis, which appears  to facilitate reduced seizure frequency and severity for difficult-to-control sei-  zures in children. The diet may be helpful to children who do not respond to  conventional therapy or have intolerable side effects. Seizure reduction can  occur within 5 to 14 days of initiating the diet and usually within 6 months.  Two basic approaches to the ketogenic diet are: (1) a traditional approach  with four parts fat to one part carbohydrate/protein in the diet, and (2) the  medium-chain triglyceride (MCT) approach, in which MCTs make up about  50% to 70% of the diet. Either diet may be unpalatable and difficult to follow,  particularly if the child has free access to food. Carbohydrates can be added  by 5-g increments after 3 to 6 months if there has been no seizure activity,  provided ketosis is maintained. Both dietary approaches include adequate  protein for growth. A medium-chain triglyceride diet, modified Atkins diet, and  low glycemic index treatment can also induce ketosis and does not restrict  protein, fluid, or calories. The mechanisms are not clearly understood, but  enhanced mitochondrial respiration, adenosine triphosphate (ATP) production,  and reduced reactive oxygen species formation may influence the dynamics  of excitatory and inhibitory neurotransmitter systems in the brain and may be  neuroprotective. Side effects can include acidosis, kidney stones, hypoglyce-  mia, gastrointestinal distress, dehydration, lethargy, and poor growth. Most  side effects are treatable.    Data from Groomes LB et al: J Child Neuro! 26(2):160-165, 2011;  Jozwiak S, Kossoff EH, Kotulska-JO6zwiak K: Neuro! Neurochir Pol  45(4):370-378, 2011; Kessler SK et al: Epilepsy Behav 22(1):17-22,  2011; Lee PR, Kossoff EH: Epilepsy Behav 21(2):115-121, 2011; Wang  HS, Lin KL: Biomed J 36(1):16-17, 2013.    For febrile seizures, the cause of the child’s fever should be  determined and meningitis should be considered in the differ-  ential diagnosis. Phenobarbital may be an effective medication  for preventing recurrence of simple febrile seizures in selected  children who have frequent, prolonged febrile seizures but it is  rarely used because it needs to be given daily to be effective.'!!   Status epilepticus is defined as the state of continuing or  recurring seizure activity in which the recovery from seizure  activity is incomplete. Seizure activity is unrelenting and usually  lasts for 30 minutes or more. Any one of the seizure activities  discussed can evolve into status epilepticus. Status epilepticus  is a medical emergency that requires immediate intervention.  Most emergency departments have a structured algorithm of  how to respond to a child in status epilepticus. !!*   The prognosis for epilepsy greatly depends on the type and  severity of the disorder; the age of onset; coexisting factors; and  the type and success of medical, surgical, and nutritional ther-  apy. Many children will become seizure free or have sustained  seizure remission after initiation of treatment.!°    Brain tumors are the most common solid tumor and the sec-  ond most common primary neoplasm in children, second only  to leukemia. Approximately 45% of primary brain tumors in  children are nonmalignant.'!* Overall, primary brain tumors  account for nearly 20% of all childhood cancers, with an annual    incidence of 3.82 per 100,000 for malignant tumors and 3.44  per 100,000 for nonmalignant tumors in the United States;  approximately 4300 new cases will be diagnosed in 2013.!°  Brain tumors remain the leading cause of death from disease in  children ages 1 to 15 years.'!°   Primary brain tumors arise from brain tissue and do not  metastasize outside the brain. The cause of brain tumors is  largely unknown.   PATHOPHYSIOLOGY. Most childhood brain tumors arise from  glial tissue, the supportive tissue of the brain. Tumors also may  originate in other tissue such as nerve cells, cranial nerves, the  pineal and pituitary glands, blood vessels, or neuroepithelium.  Brain tumors are classified by the tissue and location from  which they arise. Because a uniform pathologic nomenclature  has yet to be established, inconsistencies occur when statistical  data are compared.   Two thirds of all pediatric brain tumors are found in the pos-  terior fossa region of the brain. This area also may be referred  to as infratentorial because it is located below the tentorium.  The tentorium is the layer of dura mater that separates the  cerebellum from the hemispheres or cerebrum. Thus the area  above the tentorium is referred to as the supratentorial region.  Approximately one third of childhood brain tumors are located  in the supratentorial space, whereas in the adult population two  thirds of brain tumors are located in the supratentorial region  and only one third in the infratentorial region. The types and  characteristics of childhood brain tumors are summarized in  Table 20-7.    Arises from optic chiasm or  optic nerve (association with  neurofibromatosis type 1)  Slow-growing, low-grade astrocytoma    Often located in cerebellum,  extending into fourth ventricle and  spinal fluid pathway   In setting of visual impairment or progression  (increase in size), chemotherapy is usual initial  treatment   Radiation therapy for tumors that progress or recur in  spite of chemotherapy   Surgery for large tumors, or hydrocephalus, or other  complications; rarely for diagnosis   90-100% 5-year survival rate if  pilocytic type (most common); if  tumor recurs, it does so very slowly    20-80% 5-year survival rate  dependent on total resection  mor too great   Surgery possibly successful when complete resection  is performed (partial resection usually requires  further treatment)   Cystic and solid tumors that affect  vision, pituitary, and hypothalamic  functions    ¢ Located adjacent to the sella turcica (structure containing the pituitary gland), often    * Considered to have benign properties but is life threatening because of its location   ¢ Comprise 13% of childhood brain  tumors together with supratentorial  ependymomas    Supratentorial  e Ependymomas (6%) arise  from lining tissue of lateral  ventricle   ¢ Can invade fourth ventricle,  subarachnoid space, and  cerebrospinal fluid pathways    Brain tumors, by virtue of their location, have unique char-  acteristics that distinguish them from tumors found elsewhere  in the body. A number of brain tumors in children may be  considered histologically benign yet clinically malignant and  life threatening because of their location. For example, a tumor  located in the brainstem region may appear benign under the  microscope, but the clinical presentation threatens and all too  often overrides the vital functions of the brainstem.   Medulloblastoma, ependymoma, gliomas (astrocytoma, brain-  stem glioma, and optic nerve glioma), and craniopharyngioma  comprise approximately 75% to 80% of all pediatric brain  tumors.'!° The location of brain tumors in children is illus-  trated in Figure 20-15; specific characteristics, treatment strate-  gies, and prognoses are listed in Table 20-7.    CLINICAL MANIFESTATIONS. The location of the brain tumor,  cell type, and rate of growth dictate the presenting signs and  symptoms (discussed in greater detail with each particular  brain tumor type). The ability of the brain and intracranial cav-  ity to compensate for tumor growth is directly related to the  rate of its growth. This compensatory mechanism allows the  components of the intracranial space (blood, brain, and CSF)  to adapt temporarily to slow changes in increased intracranial  pressure. Therefore slow-growing tumors can grow to enor-  mous size before signs and symptoms are apparent. Conversely,  fast-growing tumors allow little time for compensation of the  space-occupying lesion, and clinical symptoms occur quickly.  Clinical symptoms may range from changes in personality to  paralysis, depending on the location of the tumor.   Signs and symptoms of brain tumors in children vary from  generalized and vague to those that are localized and related    specifically to the anatomic area. If the tumor is located in  the posterior fossa region, the fourth ventricle may become  blocked, which leads to hydrocephalus and signs of increased  ICP. Increased ICP also may occur because of the additional  mass volume within the fixed container of the skull vault. The  symptoms of increased ICP include headache, vomiting, leth-  argy, and irritability. If a young child complains of a headache,  a thorough investigation should take place because headache is  an uncommon complaint in young children. Headache caused  by increased ICP usually is worse in the morning and gradu-  ally improves during the day when the child is upright and  venous drainage is enhanced. Frequency of headache and other  symptoms worsens as the tumor grows. A headache related to  increased ICP generally occurs because of expansion of the lat-  eral ventricle and cerebral hemisphere, which causes a stretching  of the pain-sensitive dura mater. Irritability or possible apathy  and increased somnolence also may result from increased ICP.  Like headache, vomiting occurs more commonly in the morn-  ing. It frequently is not preceded by nausea and may become  projectile, differing from a gastrointestinal disturbance in that  the child may be ready to eat immediately after vomiting. Other  signs and symptoms that can accompany increased ICP include  increased head circumference with bulging fontanel in children  younger than 2 years, cranial nerve palsies, and papilledema.   Localized findings relate to the degree of disturbance in  physiologic functioning in the area where the tumor is located  (see Table 18-14). Infratentorial tumors exhibit localized signs  of impaired coordination and balance, including ataxia, gait  difficulties, truncal ataxia, and loss of balance. A medulloblas-  toma is an embryonal tumor and the most common childhood  malignant tumor. It occurs as a fast-growing, invasive tumor  that develops in the vermis of the cerebellum and may extend  into the fourth ventricle.'!” Angiogenesis is the hallmark of pro-  gressive medulloblastomas. The ependymoma develops in the  fourth ventricle and arises from the ependymal cells that line  the ventricular system. The histologic appearance of the epen-  dymoma varies, which makes the treatment course and prog-  nosis difficult to establish. They may contain cysts and areas of  calcification. Because both tumors are located in the posterior  fossa region along the midline, presenting signs and symptoms  are similar. In addition to those already described, they may  obstruct the fourth ventricle, resulting in hydrocephalus and  generalized increased ICP, headache, nausea and vomiting, and  nystagmus (involuntary eye movement).   In contrast, cerebellar astrocytomas are located on the sur-  face of the right or left cerebellar hemisphere. Most cerebellar  astrocytomas are low-grade, localized cystic tumors. They cause  unilateral symptoms (occurring on the same side of the tumor),  such as head tilt, limb ataxia, and nystagmus when the eyes are  turned toward the tumor.   Brainstem gliomas often cause a combination of cranial  nerve involvement, cerebellar signs of ataxia, and corticospinal  tract dysfunction. A common clinical pattern includes unilat-  eral paralysis of cranial nerves with contralateral paralysis of  the arm and leg, hyperreflexia, and extensor plantar responses.  Increased ICP generally does not occur. Children with diffuse  tumors usually die within 1 to 2 years.!!®    The area of the sella turcica, the structure containing the pitu-  itary gland, is the site of several childhood brain tumors, includ-  ing craniopharyngioma (the most common and is benign) and  pituitary adenoma (see Chapter 22). These tumors may origi-  nate from the pituitary gland or the hypothalamus. They are  usually slow growing and may be quite large by the time of diag-  nosis. Obstruction of the interventricular foramen can increase  ICP. Symptoms include headache, seizures, diabetes insipidus,  early onset of puberty, and growth delay. Other tumors located  in this region of the brain include optic gliomas. Tumors that  involve the optic tract may cause complete unilateral blindness  and hemianopia of the other eye. Optic atrophy is another com-  mon finding. Optic gliomas are common in children with neu-  rofibromatosis, a relatively common genetic condition.   Supratentorial tumors of the cerebral hemispheres in chil-  dren are not very common. Pilocytic astrocytomas are the  most common supratentorial tumors. These are localized  (grade I) slow-growing, cyst-filled tumors that are often com-  pletely removed surgically. Tumors located in the cortex may  cause focal cerebral dysfunction, weakness, hemiparesis, sei-  zures, and visual changes. Involvement of particular lobes may  result in more specific localized symptoms. For example, a  tumor located in the frontal lobe may cause changes in affect  and behavior, and a tumor in the occipital lobe may cause corti-  cal blindness or blindness in half of the visual field.   EVALUATION AND TREATMENT. A child with signs and symptoms  of a brain tumor requires a complete workup, including a neu-  rologic, developmental, and ophthalmic examination. CT with  contrast enhancement allows direct visualization of the tumor  mass. MRI provides advanced, dramatic examination of the  brain and neoplasms. Small low-grade tumors not seen on CT  may be detected by MRI. Although less commonly used, mag-  netic resonance angiography (MRA) is very helpful in assessing  the vascularity of the tumor and its relationship to major blood  vessels. Spine MRI examination may be used to evaluate tumor  dissemination along the spinal column. Lumbar puncture to  examine CSF for tumor cells also may be performed. Tumors  more likely to spread throughout the neuraxis include medul-  loblastomas and ependymomas.   The most useful treatment for brain tumors is surgical resec-  tion. Surgery to establish the diagnosis by biopsy or to excise  the tumor is part of the initial treatment for most brain tumors.  Some brain tumors may be cured with complete resection alone,  such as low-grade cerebellar astrocytomas. Contraindications  to such interventions are tumors in which surgical resection  and biopsy carry a high risk of mortality or serious morbidity  (brainstem gliomas). In these instances, diagnosis is made on  the basis of radiologic evidence and clinical manifestations.   Most brain tumors require additional radiation and chemo-  therapy. Although these treatments are essential for potential  eradication of the brain tumor, radiation to the child’s brain  is associated with significant morbidity, including acute- and  long-term sequelae. Prognosis varies according to the type and  location of the brain tumor (see Table 20-7). Historically, sur-  vival rates have been low; however, advances have been made  with the combination of surgery, radiation therapy, and che-  motherapy. Comprehensive care and management of these    children and their families are vital. Multidisciplinary teams  composed of neurosurgeons, neurologists, radiation thera-  pists, oncologists, nurses, social workers, physical therapists,  and other providers are necessary to provide the continuity and  consistency needed to care for these children.   Neuroblastoma is an embryonal aggressive tumor that origi-  nates outside the CNS in the developing sympathetic nervous  system (sympathetic ganglia and the adrenal medulla). The  primitive neural crest cells (also called sympathogonia) are plu-  ripotential (i.e., they develop into several cell types) and mature  into sympathetic ganglion cells, pheochromocytes (which are  found in the sympathetic nervous system), or neurofibrous tis-  sue. Thus tumors that develop from neural crest cells reflect the  varying degrees of differentiation of the cells. Ganglioneuro-  blastomas are tumors of an intermediate level of cellular differ-  entiation. The most differentiated tumor is a ganglioneuroma,  which is considered benign and does not metastasize.   Because neuroblastoma involves a defect of embryonal tissue,  it is most commonly diagnosed in infants and young children.  Although it accounts for 8% to 10% of pediatric malignancies,  neuroblastoma causes approximately 50% of all solid tumors in  children in the first year, and about 15% of cancer deaths in chil-  dren of all ages.'!? Although familial tendency has been noted in  individual cases, a nonfamilial or sporadic pattern is found in most  children with neuroblastoma. Familial cases of neuroblastoma are  considered to have an autosomal dominant pattern of inheritance  (mechanisms of inheritance are discussed in Chapter 4).   PATHOPHYSIOLOGY. Neuroblastoma is the most primitive, or  immature, form of the sympathetic nervous system tumors.  Areas of necrosis and calcification often are present in the  tumor. Neuroblastomas also are known to regress or mature  into benign lesions.!?°   The cause of neuroblastoma is elusive. The tumor has been  associated with a number of conditions, including neurofibro-  matosis and Hirschsprung disease, but most children with neu-  roblastoma have neither of these conditions.   CLINICAL MANIFESTATIONS. The most common location of neu-  roblastoma is in the retroperitoneal region (65% of cases), most  often the adrenal medulla. The tumor is evident as an abdomi-  nal mass and may cause anorexia, bowel and bladder altera-  tion, and sometimes spinal cord compression. The second most    common location of neuroblastoma is the mediastinum (15%  of cases), where the tumor may cause dyspnea or infection  related to airway obstruction. Less commonly, neuroblastoma  may arise from the cervical sympathetic ganglion (3% to 4% of  cases). Cervical neuroblastoma often causes Horner syndrome,  which consists of miosis (pupil contraction), ptosis (drooping  eyelid), enophthalmos (backward displacement of the eyeball),  and anhidrosis (sweat deficiency). Neuroblastoma can present  with a neurologic syndrome called opsoclonus-myoclonus syn-  drome (jerky movements of the limbs, ataxia, and chaotic eye  movements in all directions).!*!   A number of systemic signs and symptoms are characteris-  tic of neuroblastoma, including weight loss, irritability, fatigue,  and fever. Intractable diarrhea occurs in 7% to 9% of children  and is caused by tumor secretion of a hormone called vasoactive  intestinal polypeptide (VIP).   More than 90% of children with neuroblastoma have  increased amounts of catecholamines and associated metabo-  lites in their urine. High levels of urinary catecholamines and  serum ferritin are associated with a poor prognosis.   EVALUATION AND TREATMENT. Initial diagnostic studies are dic-  tated by the location of the primary tumor. Diagnosis begins  with a complete physical and neurologic examination. Imag-  ing studies provide further information. Laboratory analy-  ses include measurement of levels of urinary catecholamines;  plasma ferritin; serum neuron-specific enolase (NSE), an  enzyme produced by neuronal tissues; and gangliosides, lipid  molecules that may be shed from the surface of tumor cells.!77  The diagnosis of neuroblastoma is confirmed by surgical biopsy  and histopathologic results. Antenatal ultrasound may detect  the tumor in the antenatal period.   Treatment is based on the extent of the disease and prognos-  tic markers, such as age, MYCN copy numbers (a proto-onco-  gene), chromosome 11q status and DNA ploidy, and high serum  ferritin or NSE levels.!?> Low-risk disease is treated surgically.  Chemotherapy is used if there is recurrence. Intermediate-risk  tumors are treated with surgery and chemotherapy. High-risk  neuroblastomas are being treated with high-dose chemotherapy  and radiotherapy followed by transplantation of purged autol-  ogous bone marrow. Monoclonal antibody—based immuno-  therapy has been shown to be effective for high-risk tumors.!7*  Approximately 60% of children with high-risk disease will die  despite intensive therapy, although this percentage is improving  over time.   1. The central nervous system develops from the neural tube,  which is ectodermal in origin. The cranial end of the tube  forms the brain, and the spinal cord is formed from the  remainder of the tube.   2. The cranial and spinal ganglia (peripheral nervous system)  develop from the neural crest.   3. The nervous system develops in six stages, and disruption of  any of the stages can lead to malfunction of the nervous system.    4. The bones of the skull are joined by sutures; the wide, mem-  branous junctions of the sutures, known as fontanels, close by  20 months of age.   5. Myelin is a sheath that develops around axons to facilitate  speed of nerve impulse conduction. Progressive develop-  ment of reflexes corresponds to normal maturation of nerve  tissue and development of voluntary movement.   6. Neurologic functioning at birth is at the subcortical level  with reflex patterns mediated by the brainstem and spinal    cord. With maturation, neonatal reflexes disappear and vol-  untary motor functions develop.    is the fastest growing body part during infancy. Sutures close  by 5 to 8 years after birth.    Defects of neural tube closure include anencephaly (absence  of part of the brain and soft, bony part of skull), encepha-  locele (protrusion of brain and meninges through a skull  defect), and myelodysplasias: meningocele (cystlike defect  with protrusion of spinal fluid-filled meninges through a  vertebral defect), myelomeningocele (a defect like meningo-  cele only also containing the spinal cord), and spina bifida  (failure of the vertebrae to close with protrusion of neural  tube contents with intact skin).    one or more of the cranial sutures and prevents normal skull  expansion, causing compression of growing brain tissue.    caused by defects in neuronal cell migration and subsequent  abnormalities in connections between cells.    Static encephalopathies (i.e., cerebral palsy and epilepsy) are  nonprogressive disorders of the brain that can occur during  gestation, birth, or childhood and can be caused by trauma  or genetic factors.    that can be caused by prenatal cerebral hypoxia or perinatal  or postnatal trauma with symptoms of mental retardation,  seizure disorders, or developmental disabilities. CP can be  extrapyramidal/nonspastic or pyramidal/spastic.    metabolic defects in amino acid metabolism (phenylketon-  uria) and storage diseases.    Tay-Sachs disease (GM2 gangliosidosis). Both inherited dis-  orders and storage diseases result in abnormal behavior, sei-  zures, and deficient psychomotor development.    type B, S. pneumoniae, or N. meningitidis and may result  from respiratory tract or gastrointestinal tract infections  with symptoms of fever, headache, photophobia, seizure,  rigidity, and stupor.    Viral meningitis presents similar to bacterial meningitis, and  the specific virus is often unknown.   HIV-1 encephalopathy is a CNS infection that can occur in  infants and children.    Ischemic stroke is rare in children and may result from  embolism, arteriopathy, or, rarely, sinovenous thrombosis.    Epilepsy is the occurrence of seizures. Seizures are the abnor-  mal discharge of electrical activity within the brain. Seizure  disorders are associated with numerous nervous system dis-  orders and more often are a generalized rather than a partial  type of seizure.    spheres and include tonic-clonic, myoclonic, atonic, aki-  netic, and infantile spasms.    . Partial seizures suggest more localized brain dysfunction.  . Childhood absence epilepsy (petit mal seizures or noncon-    Brain tumors are the most common primary neoplasm in  children and the second most common type of childhood  cancer. The most common tumors include medulloblastoma,  ependymoma, gliomas (astrocytoma, brainstem glioma, and  optic nerve glioma), and craniopharyngioma.    . Tumors in children are most often located below the tento-    ized. The most common general symptom is increased ICP  (headache, irritability, vomiting, somnolence, and bulging of  fontanels).    include impaired coordination and balance. Cranial nerve  signs occur with tumors near the brainstem.    deep in the brain. Symptoms depend on the specific location  of the tumor.    nervous system and can be located anywhere there is sym-  pathetic nervous tissue. It is the most common type of solid  tumor occurring in the first year.    . Symptoms are related to tumor location and size of metastasis.   Brainstem glioma, 683  Cerebellar astrocytoma, 683  Cerebral palsy (CP), 670  Childhood absence epilepsy, 679  Complex febrile seizure, 679  Congenital hydrocephalus, 668  Cortical dysplasia, 668   Cranial meningocele, 664  Craniopharyngioma, 683  Craniosynostosis (craniostenosis), 666  Dandy-Walker malformation, 669  Dyskinetic cerebral palsy, 672  Encephalitis, 675    Medulloblastoma, 683  Meningitis, 675  Meningocele, 664  Microcephaly, 667  Moyamoya disease, 678  Myelodysplasia, 663  Myelomeningocele, 665  Neural crest, 660  Neural fold, 660  Neural groove, 660    National Center on Birth Defects and Developmental Disabilities: Folic  acid: reducing folic acid-preventable neural tube defects. Updated April 2,  2012. Available at www.cdc.gov/ncbddd/aboutus/birthdefects-folicacid.  html.    . De Marco P et al: Human neural tube defects: genetic causes and pre-    . Centers for Disease Control and Prevention: Spina bifida: data and    statistics in the United States. 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Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:  Case Study    Mechanisms of Hormonal Regulation, 689  Regulation of Hormone Release, 690  Hormone Transport, 691  Hormone Receptors, 691  Plasma Membrane Receptors and Signal Transduction, 692  Hormone Effects, 695    The endocrine system is composed of various glands located  throughout the body (Figure 21-1). These glands are capable  of synthesizing and releasing special chemical messengers called  hormones. The endocrine system has five general functions:  1. Differentiation of the reproductive and central nervous  systems in the developing fetus  2. Stimulation of sequential growth and development dur-  ing childhood and adolescence  3. Coordination of the male and female reproductive sys-  tems, which makes sexual reproduction possible  4. Maintenance of an optimal internal environment  throughout the life span  5. Initiation of corrective and adaptive responses when  emergency demands occur  Hormones convey specific regulatory information among  cells and organs and are integrated with the nervous system  to maintain communication and control. The mechanisms  of communication include autocrine (within cell), paracrine  (between local cells), and endocrine (between remote cells).    Structure and Function of the Endocrine Glands, 696  Hypothalamic-Pituitary Axis, 696  Thyroid and Parathyroid Glands, 700  Endocrine Pancreas, 703  Adrenal Glands, 706  Neuroendocrine Response to Stressors, 710  Tests of Endocrine Function, 710  AGING and the Endocrine System, 711    The endocrine glands respond to specific signals by synthesiz-  ing and releasing hormones into the circulation. Although a  wide variety of hormones function within the body, they share  certain general characteristics:   1. Hormones have specific rates and rhythms of secretion.  Three basic secretion patterns are: (1) circadian or diurnal  patterns, (2) pulsatile and cyclic patterns, and (3) patterns  that depend on levels of circulating substrates (e.g., cal-  cium, sodium, potassium, or the hormones themselves).   2. Hormones operate within feedback systems, either  positive or negative, to maintain an optimal internal  environment.   3. Hormones affect only cells with appropriate receptors  and then act on those cells to initiate specific cell func-  tions or activities.   4. Steroid hormones are either excreted directly by the  kidneys or metabolized (conjugated) by the liver, which    FIGURE 21-1 Principal Endocrine Glands. (From Patton KT, Thibodeau GA:  Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    inactivates them and renders the hormone more water  soluble for renal excretion. Peptide hormones are catabo-  lized by circulating enzymes and eliminated in the feces  or urine.   Hormones may be classified according to their structure,  gland of origin, effects, or chemical composition. (Table 21-1  categorizes hormones based on structure.) The secretion and  mechanisms of action of hormones represent an extremely  complex system of integrated responses. Although much has  been learned about these complex systems, many of the specific  mechanisms of action are not yet understood. The endocrine  and nervous systems work together to regulate responses to the  internal and external environments.    The release of hormones occurs either in response to an altera-  tion in the cellular environment or in the process of maintain-  ing a regulated level of certain hormones or certain substances.  Hormone release is regulated by one or more of the follow-  ing mechanisms: (1) chemical factors (such as blood glucose  or calcium levels); (2) endocrine factors (a hormone from one  endocrine gland controlling another endocrine gland); and (3)  neural control (such as stress-induced release of catecholamines  from the adrenal medulla).   Follicle-stimulating hormone  Luteinizing hormone  Thyroid-stimulating hormone  Adrenocorticotropic hormone  Antidiuretic hormone  Calcitonin   Thyroxine (an amine but lipid soluble) — Thyroxine (both thyroxine [T4] and  triiodothyronine [T3])    Feedback systems provide precise monitoring and control of  the cellular environment. The most common feedback system,  negative feedback, occurs because the changing chemical, neu-  ral, or endocrine response to a stimulus negates the initiating  change that triggered the release of the hormone. An example  of hormone negative feedback is shown in Figure 21-2, A. Thy-  roid-stimulating hormone (TSH) secretion from the anterior  pituitary is stimulated by thyrotropin-releasing hormone  (TRH) from the hypothalamus. Secretion of TSH stimulates the  synthesis and secretion of thyroid hormones. Increasing levels  of T, (thyroxine) and T; (triiodothyronine) then generate nega-  tive feedback on the pituitary and hypothalamus to inhibit TRH  and TSH synthesis.   Negative-feedback systems are important in maintaining  hormone concentrations within physiologic ranges. The lack of  negative-feedback inhibition on hormonal release often results  in pathologic conditions. As discussed in Chapter 22, various    FIGURE 21-2 Feedback Loops. A, Endocrine feedback loops involving the hypothalamus-pituitary gland and end organs;  in this example, the feedback loops for the thyroid gland (endocrine regulation). B, General model for control and negative  feedback to hypothalamic-pituitary target organ systems. Negative-feedback regulation is possible at three levels: target  organ (ultrashort feedback), anterior pituitary (short feedback), and hypothalamus (long feedback). TRH, Thyrotropin-releasing  hormone; TSH, thyroid-stimulating hormone; 7, triiodothyronine; Ty, tetraiodothyronine (thyroxine).    hormonal imbalances and related conditions are caused by  excessive hormone production, which is the result of failure to  “turn off? the system. These negative-feedback regulatory sys-  tems are diagrammed in Figure 21-2, B.   Once hormones are released into the circulatory system, they  are distributed throughout the body. Peptide or protein hor-  mones (pituitary, hypothalamic, and parathyroid hormones;  and insulin) are water soluble and circulate in free (unbound)  forms. Water-soluble hormones generally have a short half-life  because they are catabolized by circulating enzymes. For exam-  ple, insulin has a half-life of 3 to 5 minutes and is catabolized  by insulinases. Lipid-soluble hormones, such as cortisol and  adrenal androgens, are transported bound to a carrier or trans-  port protein (Table 21-2) and can remain in the blood for hours  to days. Only free hormones (those not bound to the carrier  protein) can signal a target cell. Because an equilibrium exists  between the concentrations of free hormones and hormones  bound to plasma proteins, a significant change in the concen-  tration of binding proteins can affect the concentration of free  hormones in the plasma (see Table 21-2). (Mechanisms of hor-  mone binding are discussed in Chapter 1.)   When a hormone is released into the circulatory system, it  is distributed throughout the body, but only those cells with  appropriate hormone receptors for that hormone are affected.  The target cell hormone receptors have two main functions: (1)  to recognize and bind with high affinity to their particular hor-  mones and (2) to initiate a signal to appropriate intracellular  effectors. See Chapter 1 for cell signaling pathways, particularly  Figures 1-19 and 1-20 on pp. 21-22.   The sensitivity of the target cell to a particular hormoneis related  to the total number of receptors per cell: the more receptors, the  more sensitive the cell. Low concentrations of hormone increase  the number of receptors per cell, called up-regulation (Figure  21-3, A). High concentrations of hormone decrease the number of  receptors, called down-regulation (Figure 21-3, B). Thus the cell  can adjust its sensitivity to the concentration of the signaling hor-  mone. The receptors on the plasma membrane are continuously  synthesized and degraded, so that changes in receptor concentra-  tion may occur within hours. Various physiochemical conditions  also can affect both the receptor number and the affinity of the  hormone for its receptor. Some of these physiochemical condi-  tions are the fluidity and structure of the plasma membrane, pH,  temperature, ion concentration, diet, and the presence of other    TABLE 21-2 BINDING PROTEINS, THEIR HORMONES, AND VARIABLES THAT AFFECT  THEIR CIRCULATING LEVELS    B Time  FIGURE 21-3 Regulation of Target Cell Sensitivity. A, Low hormone level  and up-regulation, or an increase in the number of receptors. B, High hormone level  and down-regulation, or a decrease in the number of receptors. (From Patton KT,  Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    chemicals (e.g., drugs). Finally, mutations in receptor structure  can affect target cell activation such that normal cellular responses  are increased or decreased. For example, mutations in thyroid  hormone receptors can lead to resistance to thyroid hormone and  can contribute to the development of tumors.!*   Hormone receptors may be located in or on the plaama mem-  brane or in the intracellular compartment of the target cell (Figure  21-4). Water-soluble hormones (see Table 21-1) have a high  molecular weight and cannot diffuse across the cell membrane.  They interact or bind with receptors in or on the cell membrane  and mediate short-acting responses.’ Lipid-soluble steroids,    Androgens  Hypothyroidism  Liver disease  Testosterone  Glucocorticoids  Liver disease  Liver disease  Malnutrition  Renal disease    vitamin D, retinoic acid, and thyroid hormones diffuse freely  across the plasma and nuclear membranes and bind with cytosolic  or nuclear receptors (see Figure 21-4). The hormone-receptor  complex binds to a specific region in the deoxyribonucleic acid  (DNA) and stimulates the expression of a specific gene. Some  lipid-soluble hormones (e.g., estrogen) also may bind with plasma  membrane receptors. By these mechanisms, lipid-soluble hor-  mones can mediate both long-acting and rapid-acting responses.*   A hormone is the first messenger, is secreted into the blood-  stream, and carries a message to a target cell. Signal transduction  is the process by which this message is communicated into a cell. In  general, signal transduction involves a series of steps that includes  receptor activation or binding of a hormone to its receptor, acti-  vation of a G protein (transducer) and membrane-associated  enzyme (effector enzyme), and production of a second messen-  ger (see Figure 1-22, p. 24, and Figure 21-5). The final event is  activation of an intracellular enzyme, such as protein kinase A or  C, which causes alterations in gene transcription and the result-  ing target cell response to the hormone.   Cell surface receptors are usually classified according to  how they initiate signal transduction: (1) G-protein—linked  receptors, (2) ion-channel receptors, and (3) enzyme-linked  receptors (including tyrosine kinase, serine kinase, and the  cytokine-receptor superfamily with intrinsic enzyme activ-  ity—such as the Janus family of tyrosine kinases [JAK] and  signal transducers and activators of transcription [STAT] mol-  ecules). With the exception of insulin, growth hormone, and  prolactin, most water-soluble hormones—such as adreno-  corticotropic hormone (ACTH), glucagon, norepinephrine,  and epinephrine—activate G-protein—linked receptors. Other  hormones, such as angiotensin II, activate G-protein—linked  and ion-channel receptors. Insulin activates a tyrosine kinase  receptor. Growth hormones, prolactin, and cytokines—such as  interleukins—activate the JAK/STAT receptors.    FIGURE 21-5 Examples of First- and Second-Messenger Signaling. A nonsteroid hormone (first messenger) binds to  a fixed receptor of the target cell (1). The hormone-receptor complex activates the G protein (2). The activated G protein (G)  reacts with guanosine triphosphate (G7P), which in turn activates the membrane-bound enzyme adenylyl cyclase (3). Adenyly!  cyclase catalyzes the conversion of adenosine triphosphate (ATP) to cyclic adenosine monophosphate (cAMP; second messen-  ger) (4). cAMP activates protein kinase (5). Protein kinases activate specific intracellular enzymes (6). These activated enzymes  then influence specific cellular reactions and metabolic pathways, thus producing the target cell’s response to the hormone  (7). (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby). ACTH, Adrenocorticotropic hormone.    Cyclic AMP Adrenocorticotropic hormone (ACTH)  Luteinizing hormone (LH)  Human chorionic gonadotropin (hCG)  Follicle-stimulating hormone (FSH)  Thyroid-stimulating hormone (TSH)  Antidiuretic hormone (ADH)  Thyrotropin-releasing hormone (TRH)  Parathyroid hormone (PTH)  Glucagon    AMP. Adenosine monophosphate; DAG, diacylglycerol; GMP  guanosine monophosphate; /P3, inositol triphosphate; JAK, Janus  family of tyrosine kinases; STAT, signal transducers and activators of  transcription.    Cyclic Adenosine Monophosphate (cAMP). Second-  messenger molecules are the initial link between the first signal  (hormone) and the inside of the cell (Table 21-3). For example,  binding of epinephrine to a f-adrenergic receptor subtype  activates (through a stimulatory G protein [G,]) the enzyme  adenylyl cyclase. Adenylyl cyclase catalyzes the conversion of  adenosine triphosphate (ATP) to the second messenger 3’,5’-  cAMP. Elevation of cAMP activates the enzyme cAMP-dependent  protein kinase A (PKA). PKA phosphorylates and activates  nuclear transcription factors (CAMP response element-binding  [CREB] proteins) that influence numerous cellular functions.°  For example, CREB proteins associated with the L-type channel  in cardiac muscle increase the influx of calcium into the cell,  which increases myocardial contractility. Alterations in CREB  activity have been implicated in many disease states including  diabetes and cancer.*’ The actions of cAMP are terminated  by the enzyme phosphodiesterase (PDE) II, which hydrolyzes  cAMP into inactive adenosine monophosphate (AMP).   Cyclic Guanosine Monophosphate (cGMP). Guanylyl cyclase  is an enzyme that converts guanosine triphosphate (GTP) to the  second-messenger 3’,5’-cGMP. cGMP activates cGMP-dependent  linase (protein kinase G), which in turn activates a number of  physiologic processes. The effects of various ligands, such as atrial  natriuretic hormone (vascular smooth muscle relaxation) and  nitric oxide (e.g., vascular smooth muscle relaxation and platelet    inhibition), are mediated by the second-messenger cGMP.  Drugs that target the actions of cGMP are being explored for the  treatment of vascular and pulmonary disorders.®   Calcium (Ca**). In addition to being an important ion that  participates in a multitude of cellular actions, Ca** is considered  an important second messenger. The binding of a hormone  (such as norepinephrine or angiotensin II) to a surface receptor  activates the enzyme phospholipase C through a G protein  inside the plasma membrane. This enzyme breaks down  membrane phospholipid phosphatidylinositol biphosphate  (PIP) into second-messengers inositol triphosphate (IP3) and  diacylglycerol (DAG) (see Figure 1-22, p. 24) IP; mobilizes  Ca** from intracellular stores (endoplasmic reticulum).  Increased intracellular calcium levels can lead to the formation  of the calcium-calmodulin complex, which mediates the  effects of calcium on intracellular activities that are crucial  for cell metabolism and growth. For example, calmodulin-  dependent protein kinases control intracellular contractile  components (myosin and actin, which cause contraction), alter  plasma membrane permeability to calcium, and regulate the  intracellular enzyme activity that promotes hormone secretion.   DAG, together with Ca**, activates protein kinase C (PKC).  Similar to other kinase enzymes, PKC activates (by phosphoryla-  tion) other proteins or enzymes. PKC initiates a variety of cellu-  lar responses that are linked to cell metabolism and growth. For  example, PKC activates glycogen synthase in liver cells to con-  vert glucose to glycogen. Calcium signaling systems are crucial to  healthy functioning of virtually every tissue system in the body  including heart, brain, bone, smooth muscle, and many others.’   Some hormones, such as insulin, growth hormone, and pro-  lactin, bind to surface receptors that directly activate tyrosine  kinases. These tyrosine kinases include the Janus family of tyrosine  kinases (JAK) and signal transducers and activators of transcrip-  tion (STAT). They regulate a wide range of intracellular processes  that contribute to cellular metabolism and growth, and are being  targeted in emerging treatments for diabetes.!° An example of  first- and second-messenger systems is presented in Figure 21-5.    Steroid (Lipid-Soluble) Hormone Receptors  The lipid-soluble hormones are steroid hormones and are syn-  thesized from cholesterol. They include androgens, estrogens,  progestins, glucocorticoids, mineralocorticoids, vitamin D, and  retinoid. Thyroid hormones are lipid soluble but are not syn-  thesized from cholesterol (see p. 701). Because these hormones  are relatively small, lipophilic, hydrophobic molecules, they  can cross the lipid plasma membrane by simple diffusion (see  Chapter 1). Some steroid hormones bind to receptor molecules  in the cytoplasm and then diffuse into the nucleus, whereas oth-  ers bind to receptors in the nucleus. The resulting hormone-  receptor complex binds to a specific site on the promoter region  of DNA. This binding activates ribonucleic acid (RNA) poly-  merase, which stimulates DNA transcription and increased syn-  thesis of specific proteins (increased gene expression) (Figure  21-6). Modulation of gene expression can take hours to days.  Steroid hormone receptors also may be found in the plasma  membrane and are associated with rapid responses (seconds or  minutes) that have nongenomic and genomic effects. Crosstalk    FIGURE 21-6 Steroid Hormone Mechanism. Lipid-soluble steroid hormone molecules detach from the carrier protein  (1) and pass through the plasma membrane (2). Hormone molecules then diffuse into the nucleus, where they bind to a  receptor to form a hormone-receptor complex (3). This complex then binds to a specific site on a DNA molecule (4), triggering  transcription of the genetic information encoded there (5). The resulting messenger ribonucleic acid (mRNA) molecule moves  to the cytosol, where it associates with a ribosome, initiating synthesis of a new protein (6). This new protein—usually an  enzyme or channel protein—produces specific effects on the target cell (7). The classic genomic action is typically slow (red  arrows}. Steroids also may exact rapid effects by binding to receptors on the plasma membrane (A) and activating an intercel-  lular second messenger (B). (Modified from Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    between gene transcription and nongenomic responses modu-  late each other, allowing cells to adapt rapidly to environmental  changes. Thyroid hormone, a nonsteroid lipid-soluble hor-  mone, also has been found to use a cell surface receptor for its  nongenomic actions. It first binds to an integrin receptor on the  plasma membrane, and then uses a specific transport mecha-  nism to gain access to its nuclear receptors where it can influ-  ence cell division and metabolic function."    The binding of hormones with their receptors stimulates three  general types of effects by:  1. Acting on pre-existing channel-forming proteins to alter  membrane channel permeability  2. Activating pre-existing proteins through a second-  messenger system  3. Activating genes to cause protein synthesis    Hormones have two general types of effects on target cells:  direct and permissive. Direct effects are the obvious changes  in cell function that specifically result from stimulation by  a particular hormone. Permissive effects are less obvious  hormone-induced changes that facilitate the maximal response  or functioning of a cell. For example, insulin has a direct effect  on skeletal muscle cells with insulin receptors, causing increased  glucose transport into these cells. Insulin also has a permissive  effect on mammary cells, facilitating the response of these cells  to the direct effects of prolactin.   Some hormones have biphasic pharmacologic effects that  are dependent on the concentration of the hormone. For exam-  ple, low or physiologic levels of antidiuretic hormone (ADH,  or arginine-vasopressin) stimulate renal tubular reabsorption  of sodium and water. However, at supraphysiologic levels (i.e.,  those that can be achieved by exogenous administration), ADH  acts as a vasoconstrictor.   The hypothalamic-pituitary axis (HPA) forms the structural  and functional basis for central integration of the neurologic  and endocrine systems, creating what is called the neuroendo-  crine system. The HPA produces a number of releasing/inhibi-  tory hormones and tropic hormones that affect a number of  diverse body functions (Figure 21-7). For example, the func-  tions of the thyroid gland, adrenal gland, and male and female  reproductive glands, as well as somatic growth and lactation,  are regulated by hormones originating from the HPA.   The hypothalamus is divided into several nuclei and nuclear  areas and is located at the base of the brain. The pituitary gland  is located at the sella turcica, a saddle-shaped depression on the  superior surface of the sphenoid bone (Figure 21-8). The com-  munication or anatomic connection (blood vessels and neural  tract) between the hypothalamus and anterior and posterior  pituitary is quite elaborate and well described. However, simply    described, the hypothalamus is connected to the anterior pitu-  itary by way of portal blood vessels (Figure 21-9), whereas the  hypothalamus is connected to the posterior pituitary by way of  a nerve tract referred to as the supraopticohypophysial tract (Fig-  ure 21-10). These connections are vital to the functioning of the  hypothalamus-pituitary system.!?   The special cells of the hypothalamus are like other neu-  rons in that they have similar electrical properties, organelles,  membranes, and synapses. Hypothalamic neurosecretory cells,  however, can synthesize and secrete the hypothalamic-releasing  hormones and synthesize the hormones of the posterior por-  tion of the pituitary gland. For example, antidiuretic hormone  (ADH) and oxytocin are synthesized in hypothalamic neurons  but are stored and secreted by the posterior pituitary. ADH and  oxytocin travel to the posterior pituitary by way of the hypothal-  amohypophysial nerve tract. Releasing/inhibitory hormones  also are synthesized in the hypothalamus and are secreted into  the portal blood vessels, through which they travel to the ante-  rior pituitary and control the release of tropic hormones. These  releasing/inhibitory hormones from the hypothalamus include  prolactin-inhibiting factor (PIF), thyrotropin-releasing hor-  mone (TRH), gonadotropin-releasing hormone (GnRH),    FIGURE 21-7 Pituitary Hormones and Their Target Organs. FSH, Follicle-stimulating hormone; LH, luteinizing  hormone. (Modified from Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    somatostatin, growth hormone-releasing factor (GRF),  corticotropin-releasing hormone (CRH), and substance P.  These hormones are summarized in Table 21-4.    The anterior pituitary (adenohypophysis) accounts for 75%  of the total weight of the pituitary gland. It is composed of  three regions: (1) the pars distalis, (2) the pars tuberalis, and  (3) the pars intermedia. The pars distalis is the major com-  ponent of the anterior pituitary and the source of the anterior  pituitary hormones. The pars tuberalis is a thin layer of cells  on the anterior and lateral portions of the pituitary stalk. The  pars intermedia lies between the two. In the adult the distinct  intermediate lobe disappears, and the individual cells are dis-  tributed diffusely throughout the pars distalis and pars nervosa  (neural lobe), which are part of the posterior pituitary.   The posterior pituitary (neurohypophysis) arises embryo-  logically from an outpouching of the floor of the third ventricle  within the brain. The posterior pituitary consists of three parts:  (1) the median eminence located at the base of the hypothala-  mus, (2) the pituitary stalk, and (3) the infundibular process,  also known as the pars nervosa or neural lobe. The median emi-  nence is composed largely of the nerve endings of axons that  arise primarily in the ventral hypothalamus. The median emi-  nence often is designated as part of the posterior pituitary but  contains at least 10 biologically active hypothalamic-releasing   FIGURE 21-8 Location and Structure of the Pituitary Gland (Hypophysis).  The pituitary gland is located within the sella turcica of the skull’s sphenoid bone  and is connected to the hypothalamus by a stalklike infundibulum. The infundibu-  lum passes through a gap in the portion of the dura mater that covers the pituitary  (the pituitary diaphragm). The inset shows that the pituitary is divided into an ante-  rior portion, the adenohypophysis, and a posterior portion, the neurohypophysis.  The adenohypophysis is further subdivided into the pars anterior and pars inter-  media. The pars intermedia is almost absent in the adult pituitary. (Modified from  Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    hormones, as well as the neurotransmitters dopamine, norepi-  nephrine, serotonin, acetylcholine, and histamine. The median  eminence therefore might be more appropriately considered  part of the hypothalamus. The pituitary stalk contains the  axons of neurons that originate in the supraoptic and paraven-  tricular nuclei of the hypothalamus. Axons originating in the  hypothalamus terminate in the pars nervosa, which secretes the  hormones of the posterior pituitary.   Because of the anatomic location and connection of the  pituitary gland to the brain, several neurotransmitters as well as  physical and emotional stressors influence the release of specific  hypothalamic releasing—inhibitory hormones and their respec-  tive tropic hormones. This allows for the integrated and coordi-  nated function of the hypothalamic-pituitary axis. Interestingly,  hypothalamic hormones also are synthesized outside the HPA.  For example, CRH is synthesized in cells of the immune system,  female and male reproductive organs, and the placenta. These  peripherally synthesized neuropeptides are thought to play a  role in the reproductive and immune responses to stress. !>)!4    FIGURE 21-9 Hypophyseal Portal System. Neurons in the hypothalamus  secrete releasing hormones into veins that carry the releasing hormones directly  to the vessels of the adenohypophysis, thus bypassing the normal circulatory  route. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013,  Mosby.)    FIGURE 21-10 Nerve Tracts from Hypothalamus to Posterior Lobe of  Pituitary Gland.   The posterior pituitary secretes two polypeptide hormones:  (1) ADH, also called arginine-vasopressin; and (2) oxytocin.  These peptide hormones are similar in structure, differing by  only two amino acids. They are synthesized, along with their  carrier proteins (the neurophysins), in the supraoptic and  paraventricular nuclei of the hypothalamus (see Figure 21-10).  Once synthesized, these hormones and their neurophysins are  packaged in secretory vesicles and are moved down the axons of  the pituitary stalk to the pars nervosa for storage. The posterior  pituitary thus can be seen as a storage and releasing site for hor-  mones synthesized in the hypothalamus.   The release of ADH and oxytocin is mediated by choliner-  gic and adrenergic neurotransmitters. The major stimulus to  both ADH and oxytocin release is glutamate, whereas the major  inhibitory input is through gamma-aminobutyric acid (GABA).  Before release into the circulatory system, ADH and oxytocin  are split from the neurophysins and are secreted in unbound  form.!°   Antidiuretic Hormone. The major homeostatic function of  the posterior pituitary is the control of plasma osmolality, as  regulated by ADH (see Chapter 3). At physiologic levels, ADH  acts on the vasopressin 2 (V2) receptors of the renal tubular cells  to increase their permeability (see Chapter 37). This increased  permeability leads to an increase in water reabsorption into the  blood and the production of more concentrated urine. These  effects may be inhibited by hypercalcemia, prostaglandin E, and    hypokalemia. At pathophysiologically high serum levels, ADH  acts on vasopressin 1 (V1) receptors and causes vasoconstriction.   The secretion of ADH is regulated primarily by the osmore-  ceptors of the hypothalamus, located near or in the supraoptic  nuclei. As plasma osmolality increases, these osmoreceptors are  stimulated, the rate of ADH secretion increases, more water is  reabsorbed from the kidney, and the plasma is diluted to its  set-point osmolality (approximately 280 mOsm/kg).'!° ADH  has no direct effect on electrolyte levels, but by increasing water  reabsorption, serum electrolyte concentrations may decrease  because of a dilutional effect.   ADH secretion also is increased by changes in intravascu-  lar volume, which are monitored by mechanoreceptors in the  left atrium and in the carotid and aortic arches. A volume loss  of 7% to 25% acts through these receptors to stimulate ADH  secretion. Stress, trauma, pain, exercise, nausea, nicotine, expo-  sure to heat, and drugs such as morphine also increase ADH  secretion. ADH secretion decreases with a decrease in plasma  osmolality; an increase in intravascular volume; hypertension;  an increase in estrogen, progesterone, and angiotensin II levels;  and alcohol ingestion.   As mentioned previously, ADH at high serum levels acts on  the V1 receptors and causes vasoconstriction and a resulting    TABLE 21-5 TROPIC HORMONES OF THE ANTERIOR PITUITARY AND THEIR FUNCTIONS   Synthesis of adrenal proteins contributing to maintenance  of the adrenal gland   Promotes secretion of melanin and lipotropin by anterior  pituitary; makes skin darker    Regulates metabolic processes related to growth and  adaptation to physical and emotional stressors, muscle  growth, increased protein synthesis, increased liver  glycogenolysis, increased fat mobilization   Induces formation of somatomedins, or insulin-like growth  factors (IGFs) that have actions similar to insulin    increase in arterial blood pressure. This baroreceptor-mediated  response is much less sensitive than the ADH response to  changes in osmolarity. Therefore, physiologic levels of ADH do  not significantly affect vessel tone. However, significant vaso-  constriction may be achieved pharmacologically. For example,  high doses of ADH (given as the drug vasopressin) may be  administered to achieve hemostasis during hemorrhage and to  raise blood pressure in shock states. !°   Oxytocin. Oxytocin is responsible for contraction of the  uterus and milk ejection in lactating women and may affect  sperm motility in men. In a woman, oxytocin is secreted in  response to suckling and mechanical distention of the female  reproductive tract. Stimulated by sucking, oxytocin binds to  its receptors on myoepithelial cells in the mammary tissues  and causes contraction of those cells. This results in increased  intramammary pressure and milk expression (“let down” reflex).  In response to distention of the uterus, oxytocin stimulates  contractions. Oxytocin functions near the end of labor to  enhance the effectiveness of contractions, promote delivery of  the placenta, and stimulate postpartum uterine contractions,  thereby preventing excessive bleeding. The function of this  hormone is discussed in more detail in Chapter 23.   Oxytocin has been implicated in behavior responses, espe-  cially in women. It has been suggested that oxytocin and its  receptor play a role in the brain’s responsiveness to stressful  stimuli, especially in the pregnant and postpartum states. Its  potential role in the treatment of maternal child neglect and a  variety of anxiety disorders is being explored.'7!®    The anterior pituitary is composed of two main cell types: (1)  the chromophobes, which appear to be nonsecretory; and (2)  the chromophils, which are considered the secretory cells of the  adenohypophysis. The chromophils are subdivided into seven  secretory cell types, each type secreting one or more specific  hormones (Table 21-5). In general, the regulation of the ante-  rior pituitary hormones is achieved by (1) feedback of hypotha-  lamic releasing—inhibitory hormones and factors, (2) feedback  from target gland hormones (i.e., cortisol, estrogen), and (3)  direct effects of neurotransmitters.   The major tropic hormones secreted by the anterior pitu-  itary include ACTH, melanocyte-stimulating hormone (MSH),  luteinizing hormone (LH), growth hormone (GH), prolactin,  follicle-stimulating hormone (FSH), and TSH. The actions of  these anterior pituitary tropic hormones are summarized in  Table 21-5. These major hormones can be grouped into three  categories: corticotropin-related hormones (ACTH and MSH),  glycoproteins (LH, FSH, and TSH), and somatomammotropins  (GH and prolactin). The corticotropin-related hormones are  all derived from the precursor pro-opiomelanocortin (POMC).  The role of ACTH is discussed later in this chapter. MSH pro-  motes the secretion of melanin, which makes the skin darker.  B-Lipotropin and f-endorphins are minor corticotropic hor-  mones also released from the anterior pituitary. B-Lipotropin  plays a role in fat catabolism and B-endorphins impact pain  perception, body temperature, and food and water intake. The  glycoprotein gonadotropins FSH and LH control reproductive    processes in men and women and are discussed in Chapter 23.  TSH and its effects on the thyroid gland are discussed later in  this chapter. Growth hormone and prolactin have diverse and  important effects on body tissues and are discussed next.   Growth Hormone (GH). GH secretion is controlled by  two hormones from the hypothalamus: growth hormone—  releasing hormone (GHRH), which increases GH secretion;  and somatostatin, which inhibits it. GH is released from the  pituitary in a pulsatile fashion, and overall secretion peaks  during adolescence. This hormone is essential to normal tissue  growth and maturation, and affects aging, sleep, nutritional  status, stress, and reproductive hormones. In the bone, GH  stimulates epiphyseal growth and increases osteoclast and  osteoblast activity, resulting in increased bone mass. GH also  increases amino acid transport in muscles. Other functions  of GH include lipolysis and enhancement of hepatic protein  synthesis.   Many of the anabolic functions of GH are mediated, at least  in part, by the insulin-like growth factors (IGFs), also known as  the somatomedins. There are two primary forms of IGF: IGF-1  and IGF-2, of which IGF-1 is the most biologically active. They  both circulate bound to a group of binding proteins (IGFBP).  IGF-1 binds to both insulin receptors, providing an insulin-like  effect on skeletal muscle, and with the IGF-1 receptor, which  mediates the anabolic effects of GH. IGF-2 causes a negative  effect on tissue growth, thus balancing the activity of the IGF-1.  Because of the anabolic effects of GH and IGF, they can be used  to treat growth disorders and increase muscle mass but their use  also has been linked to increased rates of cancer!” Interestingly,  deficiencies in the growth hormone receptor have been linked  to decreased risk of cancer and diabetes.”   Prolactin. Prolactin functions to induce milk production  during pregnancy and lactation. It also has effects on  reproduction and immune function. Its synthesis is stimulated  by vasoactive intestinal polypeptide, serotonin, and growth  factors. Its release is inhibited by dopamine. Hyperprolactinemia  is a complication of tumors of the pituitary gland and some  medications and is discussed in Chapter 22.    The pineal gland is located within the brain itself (see Figure  21-1) and is composed of photoreceptive cells that secrete  melatonin. It is innervated by noradrenergic sympathetic  nerve terminals controlled by pathways within the hypothala-  mus. Melatonin release is stimulated by exposure to dark and  inhibited by light exposure. It is synthesized from tryptophan,  which is first converted to serotonin and then to melatonin.  Melatonin regulates circadian rhythms and reproductive  systems, including the secretion of GnRH and the onset of  puberty. It also plays an important role in immune regulation  and is postulated to affect the aging process. Further effects of  melatonin include increasing nitric oxide release from blood  vessels, removing toxic oxygen free radicals, and decreasing  insulin secretion. Melatonin has been used therapeutically in  humans to help with sleep disturbances, jet lag, and psycho-  logic disorders. Its utility for numerous other disorders is being  explored.*!7    The thyroid gland, located in the neck just below the larynx,  produces hormones that control the rates of metabolic pro-  cesses throughout the body. The four parathyroid glands are  located near the posterior side of the thyroid and function to  control serum calcium levels.    The thyroid gland is composed of two lobes that lie on either  side of the trachea, inferior to the thyroid cartilage (Figure  21-11). The lobes are joined by a small band of tissue, the isth-  mus, which crosses the anterior surface of the trachea and lar-  ynx at the cricoid cartilage. The normal thyroid gland is not  visible on inspection, but it may be palpated on swallowing,  which causes upward displacement of the gland.   The thyroid gland is composed of follicles (Figure 21-12).  The follicles are composed of follicular cells that surround a vis-  cous substance called colloid. The follicular cells synthesize and  secrete some of the thyroid hormones. Neurons of the auto-  nomic nervous system terminate on blood vessels within the  thyroid gland and on the follicular cells themselves. Acetylcho-  line, catecholamines, and other peptides directly affect secre-  tory activity of the follicular cells and thyroid blood flow.   Regulation of Thyroid Hormone Secretion. Thyroid hormone  (TH) is regulated through a negative-feedback loop involving  the hypothalamus, the anterior pituitary, and the thyroid gland  (see Figure 21-2). Thyrotropin-releasing hormone (TRH),  which is synthesized and stored within the hypothalamus,  initiates this loop. TRH is released into the hypothalamic-  pituitary portal system and circulates to the anterior pituitary,  where it stimulates the release of TSH. TRH levels increase with  exposure to cold or stress and from decreased levels of Ty.   Thyroid-stimulating hormone (TSH) is a glycoprotein  hormone synthesized and stored within the anterior pituitary.  Once TSH is secreted by the anterior pituitary, it circulates to    FIGURE 21-11 Thyroid and Parathyroid Glands. Note the relationship of the  thyroid and parathyroid glands to each other, to the larynx (voice box), and to the  trachea. (From Thibodeau GA, Patton KT: Structure & function of the body, ed 14,  St Louis, 2012, Mosby.)    bind with TSH receptor sites located on the plasma membrane  of the thyroid follicular cells. The effects of TSH on the thy-  roid include: (1) an immediate increase in the release of stored  thyroid hormones, (2) an increase in iodide uptake and oxi-  dation, (3) an increase in thyroid hormone synthesis, and (4)  an increase in the synthesis and secretion of prostaglandins by  the thyroid. TSH is also important in stimulating the growth  and maintenance of the thyroid gland by stimulating thyro-  cyte hypertrophy and hyperplasia and decreasing apoptosis.”°  Thyroid gland hormones and their regulation and function are  summarized in Table 21-6.    Follicular epithelium  In the inactive follicle,  the follicular r  epithelium is simple  low cuboidal, or  squamous. During  their active secretory  phase, the cells  become columnar.    Thyroid hormones have a negative-feedback effect and  inhibit TRH and TSH, which decreases TH synthesis and secre-  tion. Thyroid hormone synthesis is also controlled by circulat-  ing enzymes called deiodinases that inactivate the precursor  molecule thyroxine.   Synthesis of Thyroid Hormone. Thyroid hormone synthesis  is summarized in the following steps:    AC cell can be  distinguished from  surrounding follicular  _ Cells by its pale  cytoplasm.    FIGURE 21-12 Thyroid Follicle Cells. (From Kierszenbaum AL, Tres L: Histology and cell biology: an introduction to    T, and T; levels are controlled by TSH  Released in response to metabolic demand  Influences on amount secreted:   Lowers serum calcium by opposing bone-resorbing effects of  PTH, prostaglandins, and calciferols by inhibiting osteoclastic  activity    From Monahan FD et al: Phipps’ medical-surgical nursing: health and illness perspectives, ed 8, St Louis, 2007, Mosby.  CNS, Central nervous system; GHIH, growth hormone-inhibiting hormone; G/, gastrointestinal; PTH, parathyroid hormone; RBC, red blood cell;  TSH, thyroid-stimulating hormone.    3. Iodide (the inorganic form of iodine) is actively trans-  ferred (pumped) from the blood into the colloid by  carrier proteins located in the outer membrane of the  follicular cells. This active transport system is called the  iodide trap and is very efficient at accumulating the trace  amounts of iodide from the blood.   4. Iodide is oxidized and quickly attaches to tyrosine within  the thyroglobulin molecule.   5. Coupling of iodinated tyrosine forms thyroid hor-  mones. Triiodothyronine (T3) is formed from coupling  of monoiodotyrosine (one iodine atom and tyrosine)  and diiodotyrosine (two iodine atoms and tyrosine). Tet-  raiodothyronine (T,), commonly known as thyroxine, is  formed from coupling of two diiodotyrosines.   6. Thyroid hormones are stored attached to thyroglobulin  within the colloid until it is released into the circulation.   The thyroid gland normally produces 90% T, and 10% T3.  Once released into the circulation, T; and T, are primarily  transported bound to one of three carrier proteins: thyroxine-  binding globulin, thyroxine-binding prealbumin (transthyre-  tin), or albumin. A small amount of thyroid hormone is also  carried by lipoproteins. In the body tissues, T, is converted  to T3. T; binds with three different receptors (TRal, TRB1,  and TRB2).   Thyroid hormones affect many body tissues. Similar to  some steroid hormones, thyroid hormones bind to intra-  cellular receptor complexes and then influence the genetic  expression of specific proteins. Thyroid hormones affect cell  metabolism by altering protein, fat, and glucose metabolism  and, as a result, heat production and oxygen consumption are  increased. Thus these hormones are essential for maintaining  healthy metabolic processes and normal growth and matura-  tion. Their use is being explored for the therapy of many meta-  bolic disorders.**?°   It is important to note that thyroid hormones exert a num-  ber of permissive effects on many organs, which are rather  modest at physiologic thyroid hormone levels. However, these  effects can become very pronounced when there are either high  or low levels of circulating thyroid hormones. For example,  in the heart, T; stimulates the synthesis of specific contractile  proteins (e.g., a-myosin heavy chain), sarcolemmal ion pumps  (Nat-K*-ATPase pump, Ca**-ATPase pump), and membrane  receptors ($-adrenergic receptors). Therefore, in hyperthyroid-  ism, which is associated with elevated levels of thyroid hor-  mones, cardiac effects include increased heart rate and cardiac  output, as well as the development of cardiomyopathy. Thyroid  hormones also affect the respiratory center, contributing to the  normal hypoxic and hypercapnic drives. In severe hypothyroid-  ism, ventilation can become very depressed. Thyroid hormone  also stimulates bone resorption, and hyperthyroidism is associ-  ated with osteopenia, hypercalcemia, and hypercalciuria. Thy-  roid hormone is essential for normal neurologic development  in the fetus and infant and affects neurologic functioning in  adults. Other manifestations of thyroid hormone alteration are  explained in Chapter 22. A newly described group of hormones  called thyronamines have effects that oppose those of thyroid  hormone (see What’s New? Thyronamines).”°    Thyronamines (TAMs) are a newly identified class of endogenous signaling  compounds. Their structure is nearly identical to that of thyroid hormone but  they have very different effects on tissues. Two TAMs, 3-iodothyronamine  (T1AM) and thyronamine (TAM), have been identified in humans. Among the  physiologic effects of TAMs found in experimental models are hypothermia,    decreased metabolic rate, decreased cardiac contractility, hyperglycemia,  and changes in adipose tissue metabolism. T1AM has been implicated in  heart failure and insulin resistance. TAMs may have future therapeutic uses  because they can induce hypothermia as a potential neuroprotective treat-  ment for stroke, and affect metabolism in many kinds of cells including cancer  cells.    Data from Galli E et al: J Clin Endocrinol Metab 97:E69-E74, 2012:  Piehl S et al: Endocr Rev 32(1):64-80, 2011; Roy G, Placzek E, Scanlan  T: J Biol Chem 287:1790-1800, 2012; Saba A et al: Endocrinology  151:5063-5073, 2010.    Also found in the tissue of the thyroid are parafollicular  cells, or C cells (see Figure 21-12). The C cells secrete various  polypeptides, including calcitonin. Calcitonin, also called thy-  rocalcitonin, acts to lower serum calcium levels by inhibition  of bone-resorbing osteoclasts. High levels of calcitonin are  required for these effects, and deficiencies of calcitonin do not  lead to hypocalcemia. (Bone resorption is described in Chapter  43.) Consequently, the metabolic consequences of calcitonin  deficiency or excess do not appear to be significant in humans  (see Table 21-6). However, calcitonin is used for treatment of  osteoporosis, osteoarthritis, Paget bone disease, hypercalcemia,  osteogenesis imperfecta, and metastatic cancer of the bone. The  precursor molecule to calcitonin, called procalcitonin, is a stress  hormone that is elevated in infectious and inflammatory dis-  orders and its measurement can aid in the diagnosis of these  serious diseases.?”7*   Two pairs of parathyroid glands normally are present, but the  number may range from two to six. They are small and located  behind the upper pole and lower pole of the thyroid gland (see  Figure 21-11). The parathyroid glands produce parathyroid  hormone (PTH), which works in concert with vitamin D to  increase serum calcium concentration (Figure 21-13).?? The  overall effect of PTH secretion is to increase serum calcium con-  centration and decrease serum phosphate level. Magnesium and  phosphate levels also affect PTH secretion. Hypomagnesemia in  persons with normal calcium levels acts as a mild stimulant to  PTH secretion, whereas in hypocalcemic individuals, hypomag-  nesemia decreases PTH secretion. Hyperphosphatemia leads  to hypocalcemia because of calcium phosphate precipitation  in soft tissue and bone. Alterations in serum phosphate levels  therefore may indirectly influence PTH secretion by affecting  serum calcium levels.   Once the parathyroid gland is stimulated, PTH is secreted.  On release, PTH enters the circulation in unbound form. The  hormone attaches to plasma membrane receptors in target tis-  sues, where the biologic effects of PTH are mediated primar-  ily by activation of the adenylyl cyclase system (see Chapter 1).    tDistal nephron reabsorption  of calcium and 4 proximal nephron  reabsorption of phosphate    FIGURE 21-13 Normal Calcium Metabolism Regulated by PTH and Vitamin D. /-CSF Macrophage-colony stimulat-  ing factor; PTH, parathyroid hormone; RANKL, receptor activator of NF-«® ligand.    To achieve regulation of serum calcium concentration, PTH  acts directly on bone and the kidneys. In bone, PTH has at least  two effects. In acute hypocalcemia, PTH secretion stimulates  osteoblasts to release receptor activator for nuclear factor—  kappa beta (NF-KB) ligand (RANKL) and macrophage-colony  stimulating factor (M-CSF), which results in osteoclast pro-  liferation, maturation, and release of acidic enzymes, such as  cathepsin.°° These enzymes mobilize calcium release from  bone, which increases the serum calcium level. Chronic stimu-  lation by PTH results in bone remodeling, a process in which  bone is broken down and re-formed. Chronic stimulation can  occur because of parathyroid tumors (primary hyperparathy-  roidism) or because of chronic hypocalcemia, such as that seen  in end-stage renal disease (secondary hyperparathyroidism).”°  This process can weaken the bone, leading to an increased risk  for fracture (e.g., renal osteodystrophy).*! Paradoxically, inter-  mittent therapeutic bursts of PTH can actually strengthen bone  and this treatment modality is used in individuals with osteo-  porotic fractures.*?*?   In the kidneys, PTH acts on its plaama membrane receptor  in the distal tubules of the nephron to increase reabsorption  of calcium. It acts on the proximal tubules to decrease reab-  sorption of phosphorus and bicarbonate. In renal cells, PTH  stimulates the activity of 1a-hydroxylase, which mediates a step  in the formation of the biologically active form of vitamin D  (1,25-dihydroxy-vitamin D,). The primary role of vitamin D;  is to serve as a cofactor with PTH to increase gastrointestinal  absorption of calcium. Vitamin D also increases PTH-mediated  osteoclast stimulation. Vitamin D deficiency is associated with  poor bone health and has been implicated in many other disor-  ders (see What’s New? Vitamin D).   Another hormone that plays an important role in calcium  and bone physiology is parathyroid hormone-related peptide  (PTHrP). This hormone is synthesized in many adult and fetal  tissues and affects tissues around it in a paracrine fashion. It has  similar biologic properties to PTH and utilizes the same recep-  tors; however, it also plays a role in placental calcium transport,  lactation, and tooth development in the fetus. It was discovered    Vitamin D is essential for bone health and is widely used for the prevention and  treatment of postmenopausal osteoporosis and renal osteodystrophy. More  recently, vitamin D deficiency has been associated with an increased risk for  infections, cancer, asthma, heart disease, dementia, diabetes, chronic pain  syndromes, and autoimmune disorders. Controversies continue as to whether  these associations indicate a direct cause and effect between low levels of    vitamin D and the pathophysiology of these diseases, and whether vitamin D  supplementation reduces risk or improves outcomes. However, many health  organizations recommend increased intake of vitamin D—containing foods  (seafood, vitamin D—fortified juices, and milk products), increased exposure  to sunlight, and supplementation with vitamin D. The Institute of Medicine  currently recommends 400 to 600 IUs of vitamin D per day for adults.    Data from De-Regil LM et al: Cochrane Database Syst Rev  2:CD008873, 2012; Fleet JC et al: Biochem J 441(1):61-76, 2012;  Holick MF et al: J Clin Endocrinol Metab 96(7):1911-1930, 2011; Hollis  BW: Curr Opin Clin Nutr Metab Care 14(6):598-604, 2011; Institute   of Medicine: Dietary reference intakes for calcium and vitamin D,  Washington, DC, 2010, National Academies Press; Karakas M et al:   J Clin Endocrinol Metab 98(1):272-280, 2013; Paul G et al: Am J Respir  Crit Care Med 185(2):124-132, 2012.    as the primary hormone involved in malignancy-related hyper-  calcemia (paraneoplastic disorders).°°    The pancreas is both an endocrine gland that produces hor-  mones and an exocrine gland that produces digestive enzymes.  (The exocrine pancreas is discussed in Chapter 40.) A major  disorder of the endocrine pancreas is diabetes mellitus.   The pancreas is located behind the stomach, between the  spleen and the duodenum. It houses the islets of Langerhans.  The islets of Langerhans have four types of hormone-secreting  cells: alpha cells, which secrete glucagon; beta cells, which  secrete insulin and amylin; delta cells, which secrete gastrin  and somatostatin; and F (or PP) cells, which secrete pancreatic  polypeptide that stimulates gastric secretion and antagonizes  cholecystokinin. These hormones regulate carbohydrate, fat,    FIGURE 21-14 The Pancreas. A, Pancreas dissected to show main and accessory ducts. The main duct may join the  common bile duct, as shown here, to enter the duodenum by a single opening at the major duodenal papilla, or the two ducts  may have separate openings. The accessory pancreatic duct is usually present and has a separate opening into the duodenum.  B, Exocrine glandular cells (around small pancreatic ducts) and endocrine glandular cells of the pancreatic islets (adjacent to  blood capillaries). Exocrine pancreatic cells secrete pancreatic juice, alpha endocrine cells secrete glucagon, and beta cells    secrete insulin. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    and protein metabolism. (The pancreas is illustrated in Figure  21-14.) Nerves from both the sympathetic and the parasympa-  thetic divisions of the autonomic nervous system innervate the  pancreatic islets.   The perfusion of the anterior lobe of the pancreas, where  alpha, beta, and delta cells are most numerous, comes from  branches of the superior mesenteric artery. The posterior lobe  is perfused by branches of the celiac artery. The pancreatic islets  receive 10% of the pancreatic blood flow but represent only 1%  of pancreatic mass. This is necessary for oxygenation and deliv-  ery of islet hormones to target cells.   The beta cells of the pancreas synthesize insulin from the pre-  cursor proinsulin. Proinsulin is formed from a larger and earlier  precursor molecule, preproinsulin. Proinsulin is composed of  an A peptide and a B peptide connected by a C peptide and two  disulfide bonds. C peptide is cleaved by proteolytic enzymes,  leaving the bonded A and B peptide chains that become insu-  lin. Insulin circulates freely in the plasma and is not bound to a    carrier. C peptide can be measured in the blood as an indirect  measure of serum insulin synthesis. Recent studies have shown  that C peptide has biologic activity and binds to cells through a  G-protein receptor, resulting in increased intracellular calcium  levels. Its role in diabetic complications is being explored.*4   Secretion of insulin is regulated by chemical, hormonal, and  neural control. Insulin secretion is promoted when blood levels  of glucose, amino acids (arginine and lysine), and gastrointes-  tinal hormones (glucagon, gastrin, cholecystokinin, secretin)  increase, and when the beta cells are stimulated parasympa-  thetically. Insulin secretion diminishes in response to low blood  levels of glucose (hypoglycemia), high levels of insulin (through  negative feedback to the beta cells), and sympathetic stimula-  tion of the alpha cells in the islets. Prostaglandin (PGE,) also  inhibits insulin secretion.   Insulin facilitates the rate of glucose uptake into many  cells within the body. At the target cell, insulin binds with an  enzyme-linked plasma membrane receptor that contains tyro-  sine kinase on the cytosolic surface. Insulin receptor bind-  ing sends a cascade of signals to activate glucose transporters    FIGURE 21-15 Insulin Action on Cells. Binding of insulin to its receptor causes autophosphorylation of the receptor,  which then itself acts as a tyrosine kinase that phosphorylates insulin receptor substrate 1. Numerous target enzymes, such  as protein kinase B and MAP kinase, are activated, and these enzymes have a multitude of effects on cell function. The glucose  transporter, GLUT4, is recruited to the plasma membrane, where it facilitates glucose entry into the cell. The transport of amino    suppressed, and cell growth is regulated by signal molecules that modulate gene expression. MAP Mitogen-activated protein.  (Redrawn from Levy MN, Koeppen BM, Stanton BA: Principles of physiology, ed 4, St Louis, 2006, Mosby.)    (GLUT) for entry of glucose into the cell.°° The primary GLUT  is called GLUTA4. It is stored in cellular vesicles until activated by  the insulin receptor and is then translocated to the cell surface  where it facilitates the diffusion of glucose into the cell. Trans-  location of GLUT4 to the cell surface is associated with a 10- to  21-fold increase in glucose diffusion into the cell, particularly  in skeletal and cardiac muscle, liver, and adipose cells (Figure  21-15). The sensitivity of the insulin receptor is a key compo-  nent in maintaining normal cellular function, and insulin resis-  tance has been implicated in numerous cardiovascular diseases,    including hypertension and diabetes. Adipocytes release a num-  ber of hormones that are altered in obesity and have an impor-  tant effect on insulin sensitivity.   Insulin is an anabolic hormone that promotes not only the  uptake of glucose but also the synthesis of proteins, carbohy-  drates, lipids, and nucleic acids. It functions mainly in the liver,  muscle, and adipose tissue. Table 21-7 summarizes the actions  of insulin. The net effect of insulin in these tissues is to stimu-  late protein and fat synthesis and decrease blood glucose level.  The brain, red blood cells, kidney, and lens of the eye do not    require insulin for glucose transport. Insulin also facilitates  the intracellular transport of potassium (K*), phosphate, and  magnesium. Insulin is metabolized in the liver and kidney by  enzymes that split disulfide bonds. Very little insulin is excreted  unchanged in the urine.    Glucagon  Glucagon is produced by the alpha cells of the pancreas and by  a number of cells lining the gastrointestinal tract. High glucose  levels cause glucagon release to be inhibited; low glucose levels  and sympathetic stimulation promote glucagon release. Amino  acids, such as alanine, glycine, and asparagine, also stimulate  glucagon secretion. A protein-rich meal has the same effect.  Glucagon acts primarily in the liver and increases blood glu-  cose level by stimulating glycogenolysis and gluconeogenesis;  thus glucagon acts as an antagonist to insulin. Glucagon also  stimulates lipolysis, which has a ketogenic effect caused by the  metabolism of free fatty acids in the liver. These effects have led  to the hypothesis that glucagon excess is as important as insulin  insufficiency in the pathogenesis of diabetes.*°   The incretin hormones are secreted from endocrine cells in  the gastrointestinal tract in the presence of carbohydrates,  proteins, and fats. The major incretin hormones are glucagon-  like peptide-1 (GLP-1) and glucose-dependent insulinotropic  polypeptide (GIP). They control postprandial glucose levels  by promoting glucose-dependent insulin secretion, inhibiting  glucagon synthesis, and delaying gastric emptying.*” Incretins  also enhance beta-cell mass and replenish intracellular stores of  insulin. Incretins are broken down by an enzyme called dipep-  tidyl peptidase 4 (DPP IV) and drugs that inhibit this enzyme  (called ‘gliptins’) increase incretin levels. The gliptins and other  drugs are incretin agonists used for the treatment of type 2  diabetes.***?   Amylin (islet amyloid polypeptide) is a peptide hormone co-  secreted with insulin by beta cells in response to nutrient stim-  uli. It regulates blood glucose level by delaying nutrient uptake  and suppressing glucagon secretion after meals. Amylin also has  a satiety effect. Through these mechanisms, amylin has an anti-  hyperglycemic effect. Aggregated amylin has cytotoxic proper-  ties and contributes to the loss of beta cells in type 2 diabetes  and in islet cell transplants.*°*! New drugs that serve as amy-  lomimetics are used for treatment of both type 1 and type 2  diabetes.‘”    Pancreatic somatostatin is produced by delta cells of the pan-  creas and is a hormone essential in carbohydrate, fat, and pro-  tein metabolism (i.e., homeostasis of ingested nutrients). It  differs from hypothalamic somatostatin, which inhibits release  of growth hormone and TSH. Pancreatic somatostatin is  involved in regulating alpha-cell and beta-cell function within  the islets by inhibiting secretion of insulin, glucagon, and pan-  creatic polypeptide.   Ghrelin levels increase before a meal and stimulate appetite,  then fall soon after a meal and promote a feeling of satiety.**  Ghrelin stimulates GH secretion and plays a role in obesity and  the regulation of insulin sensitivity.‘ Pancreatic polypeptide  is released by F cells in response to hypoglycemia and pro-  tein-rich meals. It stimulates Y receptors in numerous tissues,  including the gallbladder, exocrine pancreas, and parietal cells  in the gut. It promotes gastric secretion and antagonizes cho-  lecystokinin and is frequently increased in pancreatic tumors  and in diabetes.’° The function of pancreatic gastrin has not  been established; however, it likely plays a role in controlling  the secretion of glucagon.    The adrenal glands are paired pyramid-shaped organs located  behind the peritoneum and close to the upper pole of each kid-  ney. Each gland is surrounded by a capsule embedded in fat and  well supplied with blood from the phrenic and renal arteries  and the aorta. Venous return from the left adrenal gland is to  the renal vein and from the right is to the inferior vena cava.   Each adrenal gland consists of two separate portions: an  outer cortex and an inner medulla. These two portions have  different embryonic origins, different structures, and differ-  ent hormonal functions. In effect, each adrenal gland functions  like two separate glands, although there are interrelationships  between functions of each portion (Figure 21-16).    The adrenal cortex, or outer region of the gland, accounts for  80% of the weight of the adult gland. The cortex is histologically  subdivided into the following three zones:   1. The zona glomerulosa, the outer layer, constitutes about  15% of the cortex and primarily produces the mineralo-  corticoid aldosterone.   2. The zona fasciculata, the middle layer, constitutes 78%  of the cortex and secretes the glucocorticoids cortisol,  cortisone, and corticosterone.   3. The zona reticularis, the inner layer, constitutes 7% of  the cortex and secretes mineralocorticoids (aldosterone),  adrenal androgens and estrogens, and glucocorticoids.   The cells of the adrenal cortex are stimulated by the ante-   rior pituitary hormone ACTH. The adrenal cortex secretes sev-  eral steroid hormones, including the glucocorticoids (mainly  cortisol), the mineralocorticoids (mainly aldosterone), and  the adrenal androgens and estrogens. These hormones are all  synthesized from cholesterol. The best-known pathway of ste-  roidogenesis involves the conversion of cholesterol to pregnen-  olone, which is then converted to the major corticosteroids.*°   neurologic, anti-inflammatory, and  growth-suppressing  effects. They act through nuclear and nongenomic pathways  in the cell. The term glucocorticoid refers to those steroid  hormones that have direct effects on carbohydrate metabolism.  These hormones increase blood glucose concentration by  promoting gluconeogenesis in the liver and by decreasing  uptake of glucose into muscle cells, adipose cells, and lymphatic    FIGURE 21-16 Structure of the Adrenal Gland Showing Cell Layers (Zones) of the Cortex. Zona glomerulosa  secretes aldosterone. Zona fasciculata secretes abundant amounts of glucocorticoids, chiefly cortisol. Zona reticularis secretes  minute amounts of sex hormones and glucocorticoids. A portion of the medulla is visible at lower right in the photomicrograph  (x35) and at the bottom of the drawing. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 6, St Louis, 2007, Mosby.)    cells.4” In extrahepatic tissues, the glucocorticoids stimulate  protein catabolism and inhibit amino acid uptake and protein  synthesis. The ultimate effect on the body is protein breakdown  (catabolism).   The glucocorticoids act at several sites to influence immune  and inflammatory reactions (described in Chapters 7 and 11).*®  They affect innate immunity through several pathways,  including decreasing the activity of pattern receptors on  the surface of macrophages (see Chapter 7). Another major  immune suppressant effect is a glucocorticoid-mediated  decrease in the proliferation of T lymphocytes, primarily  T-helper lymphocytes.** There is a greater effect on T-helper  1 cytokine production (including antiviral interferons) than  there is T-helper 2 cytokine production and therefore greater  depression of cellular immunity than humoral immunity (see  Chapter 8). Glucocorticoids also decrease immune and inflam-  matory responses by decreasing natural killer cell activity and  suppressing the synthesis, secretion, and actions of chemical  mediators involved in inflammatory and immune responses.  Glucocorticoids suppress the inflammatory response by  blocking phospholipase A and the synthesis of prostaglandins,  thromboxanes, and leukotrienes; and by inhibiting inflamma-  tory gene expression.*® In addition, glucocorticoids stimulate  anti-inflammatory cytokines (e.g., interleukin-10 [IL-10] and  transforming growth factor-beta). Lysosomal membranes are  also stabilized, decreasing the release of proteolytic enzymes.  This suppression of innate and adaptive immunity by gluco-  corticoids means that infection and poor wound healing are    some of the most problematic complications of the use of  glucocorticoids in the treatment of disease. Similarly, psycho-  logic and physiologic stress increases glucocorticoid produc-  tion, which provides a pathway for the well-described decrease  in immunity seen in both acute and chronic stress conditions  (see Chapter 11).   Other effects of glucocorticoids include inhibition of bone  formation, inhibition of ADH secretion, and stimulation of  gastric acid secretion. Glucocorticoids appear to potentiate the  effects of catecholamines, including sensitizing the arterioles  to the vasoconstrictive effects of norepinephrine. Thyroid hor-  mone and growth hormone effects on adipose tissue also are  potentiated by glucocorticoids. A metabolite of cortisol may act  like a barbiturate and depress nerve cell function in the brain,  accounting for the noted effects on mood associated with ste-  roid level fluctuation in disease or stress.   Pathologically high levels of glucocorticoids increase the  number of circulating erythrocytes (leading to polycythemia),  increase the appetite, promote fat deposition in the face and  cervical areas, increase uric acid excretion, decrease serum cal-  cium levels (possibly by inhibiting gastrointestinal absorption  of calcium), suppress the secretion and synthesis of ACTH, and  interfere with the action of growth hormone so that somatic  growth is inhibited.”   The most potent of the naturally occurring glucocorticoids  is cortisol. It is the main secretory product of the adrenal cortex  and is necessary for the maintenance of life and for protection  from stress (see Chapter 11, particularly Figure 11-2). Cortisol    (especially cortisol)  FIGURE 21-17 Feedback Control of Glucocorticoid Synthesis and Secretion.    has a biologic half-life of approximately 90 minutes, with the  liver primarily responsible for its deactivation.   The secretion of cortisol is regulated primarily by the hypo-  thalamus and the anterior pituitary gland (Figure 21-17). In the  hypothalamus, CRH is produced in several nuclei and stored  in the median eminence. Once released, CRH travels through  the portal vessels to stimulate the production of ACTH from  POMG, £-lipotropin, y-lipotropin, endorphins, and enkepha-  lins by the anterior pituitary. ACTH is the main regulator of  cortisol secretion and adrenocortical growth.   Three factors appear to be primarily involved in regulat-  ing the secretion of ACTH: (1) high circulating levels of cor-  tisol and synthetic glucocorticoids suppress CRH and ACTH,  whereas low cortisol levels stimulate their secretion; (2) diurnal  rhythms affect ACTH and cortisol levels (in persons with regu-  lar sleep-wake patterns, ACTH peaks 3 to 5 hours after sleep  begins and declines throughout the day; and cortisol levels  follow a similar pattern, peaking just before awakening); and  (3) psychologic and physiologic (e.g., hypoxia, hypoglycemia,  hyperthermia, exercise) stress increases ACTH secretion, lead-  ing to increased cortisol levels.°°°! (Neurologic mechanisms  regulating sleep are discussed in Chapter 16.) A form of immu-  noreactive ACTH (ir ACTH) is produced by the cells of the  immune system and may account, in part, for integration of the  immune and endocrine systems.   Once ACTH is secreted, it binds to specific plasma mem-  brane receptors on the cells of the adrenal cortex and on other  extra-adrenal tissues. Because both adrenal and extra-adrenal  tissues have ACTH receptors, a number of effects result from  stimulation by ACTH (these effects are summarized in Box  21-1). In addition to increasing adrenocortical secretion of  cortisol, ACTH maintains the size and synthetic functions of  the adrenal cortex through activation of crucial enzymes and  storage of cholesterol for metabolism into steroid hormones.   Maintenance of enzymes active in converting pregnenolone to other steroids  Accumulation of cholesterol    Extra-adrenal effects of ACTH include stimulation of melano-  cytes and activation of tissue lipase.   Once ACTH stimulates the cells of the adrenal cortex, cor-  tisol synthesis and secretion immediately occur. In the healthy  person, the secretory patterns of ACTH and cortisol are nearly  identical. After secretion, most cortisol circulates in bound  form: 15% to 30% is bound to albumin, 55% to 75% is tightly  but reversibly bound to a plasma glycoprotein called transcortin,  and 10% to 15% is unbound. The levels of transcortin play a  role in the HPA feedback system controlling cortisol secretion.  Transcortin levels are significantly elevated by increased estro-  gen levels that occur with pregnancy and hormone therapy. The  unbound portion is free to diffuse into cells, but only those cells  with specific intracellular glucocorticoid receptors respond to  cortisol stimulation. ACTH is rapidly inactivated in the circula-  tion, and the liver and kidneys remove the deactivated hormone.   Mineralocorticoids: Aldosterone. Mineralocorticoid  steroids directly affect ion transport by epithelial cells,  causing sodium retention and potassium and hydrogen loss.    Nitric oxide from  macula densa  cAMP  Diuretics  Epinephrine  Norepinephrine  Early part of day  Erect posture    Increased effective  blood volume  to correct initial stimulus  to the system    Aldosterone is the most potent of the naturally occurring  mineralocorticoids and acts to conserve sodium by increasing  the activity of the sodium pump of the epithelial cells in the  nephron. (The sodium pump is described in Chapter 1.)   The initial stages of aldosterone synthesis occur in the zona  fasciculata and zona reticularis. The final conversion of corticos-  terone occurs in the zona glomerulosa. Aldosterone synthesis  and secretion are regulated primarily by the renin-angiotensin-  aldosterone system (described in Chapter 3 and Chapter 37;  see Figures 3-4 and 37-10), although other factors also may be  involved. The renin-angiotensin system is activated by sodium  and water depletion, increased potassium levels, and a dimin-  ished effective blood volume (Figure 21-18). Angiotensin I] is  the primary stimulant of aldosterone synthesis and secretion;  however, sodium and potassium levels also may directly affect  aldosterone secretion.   When sodium and potassium levels are within normal lim-  its, approximately 50 to 250 mg of aldosterone is secreted daily.  Of the secreted aldosterone, 50% to 75% binds to plasma pro-  teins. Aldosterone is degraded in the liver and is excreted by the  kidney.    Aldosterone maintains extracellular volume by acting on  distal nephron epithelial cells to increase sodium reabsorp-  tion and potassium and hydrogen excretion.” This renal  effect takes 90 minutes to 6 hours. Other effects of aldoste-  rone include enhancement of cardiac muscle contraction,  stimulation of ectopic ventricular activity through secondary  cardiac pacemakers in the ventricles, stiffening of blood ves-  sels with increased vascular resistance, and decreased fibrino-  lysis. Pathologically elevated levels of aldosterone have been  implicated in the myocardial changes associated with heart  failure.°°>*   Adrenal Estrogens and Androgens. The healthy adrenal  cortex secretes small amounts of estrogen and androgens.  ACTH appears to be the major regulator. The biologic effects  and metabolism of the adrenal sex steroids do not vary from  those produced by the gonads (see Chapter 23).   Some of the weak androgenic substances secreted by the cor-  tex (dehydroepiandrosterone [DHEA], androstenedione) are  converted by peripheral tissues to stronger androgens, such as  testosterone, thus accounting for some androgenic effects ini-  tiated by the adrenal cortex. Peripheral conversion of adrenal    androgens to estrogens is enhanced in aging or obese persons,  as well as in those with liver disease or hyperthyroidism.    The adrenal medulla, together with the sympathetic division of  the autonomic nervous system, is embryonically derived from  neural crest cells. The adrenal medulla functions as a sympathetic  ganglion without postganglionic processes. Chromaffin cells  (pheochromocytes) are the cells of the adrenal medulla. The  major products stored and secreted by the chromaffin cells are  the catecholamines epinephrine (adrenaline) and norepineph-  rine, which are synthesized from the amino acid phenylalanine  (Figure 21-19). Only 30% of circulating epinephrine comes from  the adrenal medulla; the other 70% is released from nerve termi-  nals. The medulla is only a minor source of norepinephrine.°°   Adrenal catecholamines are stored in secretory granules  within the chromaffin cells. Physiologic stress to the body (e.g.,  traumatic injury, hypoxia, hypoglycemia, and many others)  triggers release of adrenal catecholamines through acetylcholine  (from the preganglionic sympathetic fibers), which depolarizes  the chromaffin cells. Depolarization causes exocytosis of the  storage granules from the chromaffin cells with release of epi-  nephrine and norepinephrine into the bloodstream; therefore,  the catecholamines from the adrenal medulla are hormones and  not neurotransmitters.*° Secretion of adrenal catecholamines is  also increased by ACTH and the glucocorticoids.   Once released, the catecholamines remain in the plasma for  only seconds to minutes. The catecholamines exert their bio-  logic effects after binding to a plasma membrane receptor (a,  02, By, B2, B3) in target cells and activating the adenylyl cyclase  system (see Table 15-7). Catecholamines are rapidly removed  from the plasma by being taken up by neurons for storage in  new cytoplasmic granules, or they may be metabolically inacti-  vated and excreted in the urine.   Catecholamines have diverse effects on the entire body.  Their release and the body’s response have been characterized  as the “fight or flight” response (see Chapter 11).   In general, the metabolic effects of catecholamines pro-  mote hyperglycemia through a variety of mechanisms and  through interference with usual glucose regulatory feedback  mechanisms.    The endocrine system acts together with the nervous system to  respond to stressors. The integrated response to stressors also  includes the immune system. Hormones of the neuroendocrine  system affect components of the immune system, and media-  tors produced by immune components regulate the neuroen-  docrine response.   Perception that an event is stressful may be essential to  the emotional arousal and initiation of the stress response.  Some events, such as bacterial invasion, can activate the stress  response without emotional arousal. The hypothalamus  receives input from a variety of areas within the brain and ulti-  mately directs the neuroendocrine response to stress through  the actions of CRH, the locus ceruleus—norepinephrine auto-  nomic (sympathetic) nervous system, and the pituitary-adrenal    axis.°°°° In addition to the neuroendocrine components of the  stress response, the gamma motor neuron system is activated  to increase skeletal motor tone. Enhanced availability of vital  substrates occurs, and growth and reproduction are inhibited  to preserve energy for protective responses. Details of the stress  response are presented in Chapter 11.    Evaluation of the endocrine system is challenging because of: (1)  the complexity of the clinical presentation because of multiple  organ system involvement, (2) the nonspecific nature of com-  plaints frequently associated with endocrine dysfunction, and  (3) the inappropriate use of laboratory test interpretations.  Tests of the endocrine system involve several general types  of clinical evaluation. Measurement of hormone level is accom-  plished by radioimmunoassay, by enzyme-linked immunosor-  bent assay, and less commonly by bioassay. Radioimmunoassay  (RIA) is a technique for measuring the minute quantities of  hormones in the blood that uses antibodies and radiolabeled  hormones to determine the quantity of hormone in the plasma.  Enzyme-linked immunosorbent assay (ELISA) also is used to  determine circulating hormone levels. This method is similar to  that of RIA but is less expensive and easier to conduct. Instead  of radiolabeled hormones, an enzyme-labeled hormone is used.  A bioassay involves the use of graded doses of hormone in a    reference preparation and then comparison of the results with  an unknown sample. Bioassays are used more commonly in  investigative endocrinology than in clinical laboratories. If the  serum level is greater or less than the reference values, more  definitive tests are required to determine the source of the  problem.   Measurement of individual hormones does not always per-  mit differentiation between normal and abnormal values when  hormone levels are changing over time. For an accurate inter-  pretation, the broad normal range of some hormones requires  a knowledge of previous hormonal levels and timed sampling.  Stimulation and suppression tests that determine the response  to exogenous stimulants or inhibitors can help to decipher  some of these complexities.   Indirect assessment of hormonal function often includes mea-  surement of concentrations of serum glucose and electrolytes that  are affected by the endocrine process. Evaluation of hormonal  function also may include radiographic imaging of specific glands.    The precise relationship between aging and the endocrine  system is not clear. Perhaps most important, the question of  whether changes in endocrine function are a consequence or a  cause of aging has yet to be resolved. These relationships have  been difficult to identify, in part because of a number of age-  related variables that may coexist, such as acute and chronic  non-—endocrine disease; use of medications; alterations in diet,  body composition, and weight; and changes in sleep-wake  cycles. However, the endocrine system is so integral to health  that changes in endocrine function have been used as “bio-  markers” for unhealthy aging.    Investigation into the role of the endocrine glands and their  interactions in the aging process has generated much data,  although the evidence is contradictory. There are complex  changes within the HPA; and altered biologic activity of hor-  mones, altered circulating levels of hormones, altered secretory  response of the endocrine glands, altered metabolism of hor-  mones, and loss of circadian control of hormone secretion are  among the findings. Changes in secretion of hypothalamic reg-  ulatory factors and hormones or changes in hypothalamic feed-  back sensitivity may contribute to alterations in control of an  optimal internal environment.°’ The dynamic equilibrium of  the endocrine system also may be affected by altered secretion  of neurotransmitters within certain areas of the brain, affect-  ing hypothalamic and pituitary function. Such alterations may  include an excess or deficit in secretion of pituitary hormones  and loss of appropriate secretory pattern of those hormones.  Loss of endocrine steady states may be associated with or con-  tribute to aging.   The most studied changes in hormone function with aging  affect the levels of reproductive hormones and gonadotropins  (menopause and andropause) (discussed in Chapter 23). Two  of the most important endocrine changes associated with aging  affect the thyroid gland and the pancreas. Other important    hormone changes associated with aging include a decline in  serum levels of growth hormone and IGF-1, parathyroid hor-  mone, dehydroepiandrosterone, and ADH.   Thyroid Gland. Changes in thyroid structure and function  occur with aging.°® Structurally, some glandular atrophy and  fibrosis occur with nodularity and increasing inflammatory  infiltrates. These infiltrative changes may reflect age-related  autoimmune damage. Clinical signs of thyroid disease are  more difficult to detect in older adults. Overall, it is estimated  that there is some evidence of thyroid dysfunction in 5% to  10% of older adult women. The presence of thyroid nodules  increases after the age of 70 years. Changes relative to thyroid  hormone and its function are more difficult to assess and much  of the available data are contradictory. Most evidence, however,  supports the following age-related changes:   b. Plasma levels of T; decline, especially in men, but are  generally in the normal range.   Treatment for thyroid deficiency is also affected by aging.  The appropriate dose for thyroid hormone (TH) replacement  is often lower in older adults because the peripheral metabo-  lism of TH decreases with age. In addition, TH must be replaced  slowly in elderly individuals with coronary artery disease to pre-  vent angina and myocardial infarction.°®   Pancreas. It is estimated that 40% to 50% of individuals  older than age 65 have impaired glucose tolerance or diabetes.  With aging, the pancreatic cells are increasingly replaced with  fat tissue.°? Dysfunction of the pancreas with decreased insulin  secretion of beta cells and insulin receptors and increased  insulin resistance have all been documented and may be related  to changes in adipokine physiology.   These changes have significant implications for many target  organs, particularly the cardiovascular system, which is increas-  ingly at risk for both vascular (hypertension, atherosclerosis,  glomerulosclerosis) and cardiac (infarction, failure) disorders.  Exciting research is exploring the relationship between insulin  and activation of genes for the “sirtuins,” which are a group of  proteins that have been linked with the aging process.   Growth Hormone and Insulin-like Growth Factors. The  amounts of GH and IGF decline with aging, a process that has  been called the “somatopause.”™ This decline in anabolic stimuli  is linked to decreases in muscle size and function, decreased  amounts of fat and bone mass, and changes in reproductive and  cognitive function®’ (see What’s New? Growth Hormone [GH]  and Insulin-like Growth Factor [IGF] in Aging).   Parathyroid Glands. An age-related alteration in PTH  secretion has been proposed to explain alterations in calcium  homeostasis that have been noted in older adults.°° Calcium  intake, especially in women, tends to decrease with aging and  may contribute to osteoporosis (see Chapter 44). The average  daily intake of 450 to 500 mg/day causes a negative calcium    Aging is a multifactorial process that is influenced by genetic and environmen-  tal factors. The aging process is associated with many hormonal and metabolic  changes. The amounts of GH and IGF decline with aging, a process that has been  called the “somatopause.” Clinical findings related to somatotropic hormone  changes with aging include increased visceral fat, decreased lean body mass,    decreased bone density, and changes in reproductive and cognitive function. The  underlying mechanisms of aging and its relationship to GH and IGF are complex.  For example, not only do these hormones promote bone and muscle growth, but  also a recent study suggests that the brain IGF-1 receptor may be a significant  factor in determining overall life span and ability to respond to physiologic stress.  GH and IGF effects on inflammation and immunity also are important in the aging    process. Unfortunately, there remains much confusion and controversy over the  role of these hormones. Although most studies suggest that it is a deficiency of  these hormones that leads to an acceleration of the aging process, there are  several studies suggesting that lower lifetime levels of these hormones may  confer longevity by providing protection from cancer and other age-related dis-  eases. As these hormones are used to treat a wider range of disorders and for  different age groups, more information about their safety is emerging. Despite  the initial enthusiasm for the use of therapeutic doses of recombinant human  growth hormone (rhGH) as a way to slow the aging process, studies have not  been consistently positive and the risk for GH- and IGF-mediated oncogenesis  is being explored.    Data from Allen DB: J Clin Endocrinol Metab 96(10):3042-3047, 2011; Bartke A: Exp Geronto/ 46(2-3):108-111, 2011; Bartke A: Trends Endocrinol  Metab 22(11):437-442, 2011; Birzniece V, Nelson AE, Ho KK: Trends Endocrinol Metab 22(5):171-178, 2011; Di Somma C et al: Minerva Endocri-  nol 36(3):243-255, 2011; Holzenberger M: Nestle Nutr Workshop Ser Pediatr Program 68:237-245, 2011; Kokshoorn NE et al: Eur J Endocrinol  164(5):657-665, 2011; Rosenfeld RG et al: J Clin Endocrinol Metab 97(1):68-72, 2012.    balance greater than 40 mg/day and may be related to the  absolute bone loss of approximately 1.5% per year. Older  adults show decreased intestinal adaptation to variations in  calcium intake. Hyperparathyroidism may occur secondary to  calcium malabsorption and hypocalcemia with increased bone  remodeling that results in cortical bone thinning and porosity.  Elevated levels of parathyroid hormone have been linked with  an increase in mortality in older adults, many of whom also have  a mild, persistent hypercalciuria, which indicates a defective  renal mechanism for responding to decreased calcium intake.  Decreased circulating levels of vitamin D are common in older  adults, especially those in long-term care institutions. Vitamin  D deficiency has been linked to not only osteoporosis but also  cancer, autoimmune diseases, diabetes, cardiovascular disease,  and mental health disorders.   Adrenal Glands. The adrenal cortex loses some weight  and has more fibrous tissue after the age of 50 years. Age  does not appear to affect the feedback mechanisms involved  in maintaining glucocorticoid levels, but the decrease in the  metabolic clearance rate of the glucocorticoids is age related.   The metabolic clearance of cortisol decreases with an age-  related decline in liver and kidney function. Further, less cortisol  appears to be used by the body when aging is accompanied by  a loss of lean body mass. Decreased clearance and reduced use  of cortisol contribute to higher circulating cortisol levels, but  diurnal variation is maintained. Because feedback mechanisms    are intact, the higher cortisol levels cause a decrease in cortisol  secretion. Circadian patterns of ACTH and cortisol secretion  may change with aging.   Plasma levels of the adrenal androgens, as well as urinary  excretion of the metabolic end products, decrease gradually  but dramatically with age, to as much as 50% to 70% of the  young adult level. This change in adrenal function has been  called the “adrenopause” and is correlated with decreased  synthesis activity of dehydroepiandrosterone (DHEA).°”  This change appears to reflect a decline in the function of the  zona reticularis. In postmenopausal women, this decline in  adrenal androgen secretion is especially important because  nearly all sex steroids after menopause come from adrenal  and ovarian production of androgen precursors converted  to estrogens in the periphery. In older adult men, adrenal  androgen production accounts for more than half of circu-  lating testosterone levels.   Antidiuretic Hormone. Although hyponatremia is a  common finding in older adults, it appears related to changes  in renal function rather than to ADH-related mechanisms.  Morphologic studies have not shown significant age-related  degenerative changes in the neuroendocrine pathways that  regulate the synthesis and secretion of ADH. It appears that  ADH secretion is augmented when stimulated by changes in  osmotic concentration, whereas baroreceptor-mediated ADH  secretion is reduced.   1. The endocrine system has diverse functions, including  sexual differentiation, growth and development, continu-  ous maintenance of the body’s internal environment, and  adaptive responses to stress.   2. Hormones are chemical messengers synthesized by endo-  crine glands and released into the circulation; they work with  the nervous system to maintain communication and control.    3. Hormones have specific negative- and positive-feedback  mechanisms. Most hormone levels are regulated by nega-  tive feedback, in which tropic hormone secretion raises the  level of a specific hormone. The elevated level of the specific  hormone then causes negative feedback, decreasing secre-  tion of the tropic hormone.   4. Endocrine feedback is described in terms of short and long  feedback loops.    Water-soluble hormones circulate throughout the body in  unbound form, whereas lipid-soluble hormones (i.e., ste-  roid and thyroid hormones) circulate throughout the body  bound to carrier proteins.    cells with appropriate receptors and then act on those cells  to initiate specific cell functions or activities.    . Hormones have two general types of effects on cells: direct    effects, or obvious changes in cell function; and permis-  sive effects, or less obvious changes that facilitate cell  function.    . Receptors for hormones are proteins and may be located on    or in the plasma membrane or in the cytosol or nucleus of  the target cell. Receptors may be G protein linked, ion chan-  nels, or enzyme linked.    receptors on the cell’s plasma membrane. The signals ini-  tiated by hormone-receptor binding are then transmitted  into the cell by the action of second messengers.   Second messengers that have been identified include cAMP,  cGMP, and calcium, which associates with IP; and DAG to  produce physiologic effects.   For cells that have cAMP as their second messenger, a series  of interactions within the plasma membrane must activate  adenylyl cyclase.   Cells that have cGMP as their second messenger are acti-  vated by the enzyme guanylyl cyclase.   For cells that have calcium as their second messenger, an  increase in intracellular calcium concentration causes cal-  cium to bind with calmodulin, a regulatory protein. This  step then initiates other intracellular processes.  Lipid-soluble hormones (including steroid and thyroid  hormones) may have rapid effects by binding to a plasma  membrane or receptor or crossing the plasma membrane  through diffusion. These hormones then either bind to  cytoplasmic proteins or diffuse directly into the cell nucleus  and bind to nuclear receptors.   Hormones have direct effects (specific changes in cell func-  tion) or permissive effects (facilitate the effects of other  hormones).    The pituitary gland, consisting of anterior and poste-  rior portions, is connected to the central nervous system  through the hypothalamus.    prolactin secretion; TRH, which affects release of thyroid  hormones; CRH, which facilitates release of ACTH and  endorphins; and substance P, which inhibits ACTH release  and stimulates release of a variety of other hormones. ADH  and oxytocin are synthesized in the hypothalamus and  stored and secreted by the posterior pituitary.    The posterior pituitary stores and secretes ADH, also called  arginine-vasopressin, and oxytocin.   ADH controls serum osmolality, increases the permeability  of the renal tubules to water, and causes vasoconstriction  when administered pharmacologically in high doses. ADH  also may regulate some central nervous system functions.    women and may have a role in sperm motility in men. In  men and women, oxytocin has an antidiuretic effect similar  to that of ADH.    secretion of hypothalamic-releasing hormones or factors,  (b) negative feedback from hormones secreted by target  organs, and (c) mediating effects of neurotransmitters.    somatotropic hormones (GH and prolactin), and glycopro-  tein hormones (FSH, LH, and TSH).    tein metabolism in muscles, and lipolysis. Its effects are  mediated in part by IGFs.    secrete some of the thyroid hormones, and C cells, which  secrete calcitonin and somatostatin.   Regulation of TH levels is complex and involves the hypo-  thalamus (TRH), anterior pituitary (TSH), thyroid gland,  and numerous biochemical variables.   TH secretion is regulated by TRH through a negative-  feedback loop that involves the anterior pituitary and  hypothalamus.   TSH, which is synthesized and stored in the anterior pitu-  itary, stimulates secretion of TH by activating intracellular  processes, including uptake of iodine necessary for the syn-  thesis of TH.   Synthesis of TH depends on the glycoprotein thyroglobu-  lin, which contains a precursor of TH, tyrosine. Tyrosine  then combines with iodide to form precursor molecules of  the thyroid hormones T, and T3.   When released into the circulation, T; and T, are bound  by carrier proteins in the plasma that store these hormones  and provide a buffer for rapid changes in hormone levels.  Thyroid hormones alter protein synthesis and have a wide  range of metabolic effects on proteins, carbohydrates, lip-  ids, and vitamins. TH also affects heat production and car-  diac function.   Parafollicular cells or C cells secrete calcitonin and lower  serum calcium concentration by inhibiting bone-resorbing  osteoclasts.   The paired parathyroid glands normally are located behind  the upper and lower poles of the thyroid gland. These glands  secrete PTH, an important regulator of serum calcium and  phosphate levels.    PTH secretion is regulated by levels of ionized calcium in the  plasma and by cAMP within the cell. Some other substances—  hormones, neurotransmitters, and ions—affect PTH secre-  tion by inhibiting cAMP or by changing calcium levels.   In bone, PTH causes bone breakdown and resorption.  In the kidney PTH increases reabsorption of calcium,  decreases reabsorption of phosphorus and bicarbonate, and  stimulates synthesis of vitamin D.   Parathyroid hormone-related peptide (PTHrP) has prop-  erties similar to those of PTH and plays a role in placental  calcium transport, lactation, and fetal tooth development.  The endocrine pancreas contains the islets of Langerhans,  which secrete hormones responsible for much ofthe carbohy-  drate metabolism in the body.   The islets of Langerhans consist of alpha cells, beta cells,  delta cells, and F cells.   Beta cells synthesize insulin, a hormone that regulates  blood glucose concentrations and overall body metabolism of  fat, protein, carbohydrates, and amylin.   Alpha cells produce glucagon, which is secreted inversely to  blood glucose concentrations and stimulates glycogenoly-  sis, gluconeogenesis, and lipolysis.   Incretin hormones are produced by endocrine cells of the  gastrointestinal tract that promote glucose-dependent  insulin secretion, inhibit glucagon synthesis, and delay gas-  tric emptying.   Amylin promotes glucose-dependent insulin secretion,  inhibits glucagon synthesis, and delays gastric emptying,  producing an antihyperglycemic effect.   Delta cells secrete somatostatin, which inhibits glucagon,  insulin, and polypeptide secretion.   F cells secrete pancreatic polypeptide, which stimulates  Y receptors, promotes gastric secretion, and antagonizes  cholecystokinin.   The paired adrenal glands are situated on the kidneys. Each  gland consists of an adrenal medulla, which secretes cat-  echolamines, and an adrenal cortex, which secretes steroid  hormones.   The steroid hormones secreted by the adrenal cortex are all  synthesized from cholesterol. These hormones include glu-  cocorticoids, mineralocorticoids, and adrenal androgens  and estrogens.   Glucocorticoids directly affect carbohydrate metabolism  by increasing blood glucose concentration through gluco-  neogenesis in the liver and by decreasing use of glucose.  Glucocorticoids also inhibit immune and inflammatory  responses, inhibit bone formation and ADH secretion, and  stimulate gastric secretion.   Cortisol secretion is related to secretion of ACTH, which  is stimulated by CRH. ACTH binds with receptors of the  adrenal cortex, which activates intracellular mechanisms  (specifically cAMP) and leads to cortisol release.  Mineralocorticoids, especially aldosterone, are steroid hor-  mones that directly affect ion transport by epithelial cells,  causing sodium retention and potassium and hydrogen loss.    Aldosterone secretion is controlled by the renin-angiotensin-  aldosterone system and acts by binding to a site on the cell  nucleus and altering protein production within the cell. Its  principal site of action is the kidney, where it causes sodium  reabsorption and potassium and hydrogen excretion.  Androgens and estrogens secreted by the adrenal cortex act  in the same way as those secreted by the gonads.   The adrenal medulla secretes the catecholamines epineph-  rine and norepinephrine. Catecholamines are synthesized  from the amino acid phenylalanine. Their release is stimu-  lated by sympathetic nervous system stimulation, ACTH,  and glucocorticoids.   Catecholamines bind with various target cells and are taken  up by neurons or excreted in the urine. They cause a range  of metabolic effects that generally are characterized as the  “flight or fight” response.   The endocrine system acts together with the nervous and  immune systems to respond to stressors, providing an inte-  grated and protective response.   Several assay methods are used to measure levels of hor-  mones in the plasma. RIA compares the proportion of  radiolabeled and nonradiolabeled hormone against stan-  dard reference curves.   ELISA is a method similar to RIA, but uses a radiolabeled  enzyme rather than a radiolabeled hormone.   Bioassays use graded doses of hormone in a reference prep-  aration and then compare the results with an unknown  sample to determine the hormone level.    Endocrine changes that may be associated with aging  include altered biologic activity of hormones, altered cir-  culating levels of hormones, altered secretory responses of  endocrine glands, altered metabolism of hormones, loss of  circadian control of hormone release, and changes in secre-  tion of hypothalamic regulatory hormones.    grammed cell change, and chronic wear and tear may con-  tribute to endocrine gland dysfunction or alterations in the  responsiveness of target organs.    . Aging apparently causes atrophy of the thyroid gland and is    associated with infiltrative glandular changes. Secretion of  thyroid hormones may diminish with age.    which may be related to alterations in PTH secretion from  the parathyroid glands.    clearance of glucocorticoids and a decrease in levels of adre-  nal androgens. The effects of these changes, however, are  offset by feedback mechanisms that maintain glucocorti-  coid levels and by gonadal secretion of androgens.    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Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Mechanisms of Hormonal Alterations, 717  Alterations of the Hypothalamic-Pituitary System, 718  Diseases of the Posterior Pituitary, 718  Diseases of the Anterior Pituitary, 720  Alterations of Thyroid Function, 724  Hyperthyroidism, 725  Hypothyroidism, 728  Alterations of Parathyroid Function, 731  Hyperparathyroidism, 731  Hypoparathyroidism, 733    The function of the endocrine system involves complex inter-  relationships and interactions that maintain dynamic steady-  states, provide growth and reproductive capabilities, and allow  for adaptive changes in times of stress. Alterations in function  were thought only to be caused by either hypersecretion or  hyposecretion of the various hormones, leading to abnormal  hormone concentrations in the blood. Techniques for study-  ing the various components of the endocrine system have  improved, and evidence has shown that dysfunction may also  result from abnormal receptor function or from altered intra-  cellular response to the hormone-receptor complex.    Significantly elevated or depressed hormone levels may result  from a variety of causes (Table 22-1). Dysfunction of an endo-  crine gland may involve the gland’s failure to produce adequate    Dysfunction of the Endocrine Pancreas:  Diabetes Mellitus, 734  Types of Diabetes Mellitus, 735  Acute Complications of Diabetes Mellitus, 743  Chronic Complications of Diabetes Mellitus, 746  Alterations of Adrenal Function, 752  Disorders of the Adrenal Cortex, 752  Disorders of the Adrenal Medulla, 758    amounts of biologically free or active hormone forms. This fail-  ure may occur when the secretory cells are unable to produce or  obtain an adequate quantity of required hormone precursors or  when they are unable to convert the precursors to the active hor-  mone. A gland also may synthesize or release excessive amounts  of hormone. For example, feedback systems that recognize the  need for a particular hormone may fail to function properly  or may respond to inappropriate signals. Once hormones are  released into the circulation, they may be degraded at an altered  rate or they may be inactivated by antibodies before reaching  the target cell. Ectopic sources of hormones (hormones pro-  duced by nonendocrine tissues) may result also in abnormally  elevated hormone levels without benefit of the normal feedback  system for hormone control. In these cases the ectopic hormone  production is said to be autonomous.   Target cells may fail to respond to its hormone (hormone  insensitivity) (see Table 22-1). The general types of abnormal    target cell responses currently recognized are receptor-associated  disorders and intracellular disorders. Receptor-associated dis-  orders have been identified primarily in water-soluble hor-  mones, such as insulin. These types of disorders usually involve  one of the following: (1) a decrease in the number of receptors,  leading to decreased or defective hormone-receptor binding;  (2) impaired receptor function, resulting in insensitivity to the  hormone; (3) presence of antibodies against specific receptors  that either reduce available binding sites or mimic hormone  action; or (4) unusual expression of receptor function, as occurs  in some tumor cells.   Intracellular disorders may involve acquired defects in post-  receptor signaling cascades or inadequate synthesis of a second  messenger, such as cyclic adenosine monophosphate (cAMP),  needed to transduce the hormonal signal into intracellular  events. The target cell for water-soluble hormones may have a  faulty response to hormone-receptor binding and thus fail to  generate the required second messenger, or the cell also may  have an abnormal response to the second messenger if levels  of intracellular enzymes or proteins are altered. (Second mes-  sengers for various hormones are listed in Table 21-3.) Both  of these pathogenic mechanisms result in failure of the target  cell to express the usual hormonal effect. Pathogenic mecha-  nisms affecting target cell response for lipid-soluble hormones,  such as thyroid hormone or glucocorticoids, are recognized less  often than those affecting the water-soluble hormones. These  hormone-resistant states have been generally linked to muta-  tions in the nuclear receptor for the hormone. The number  of receptors may be decreased, or those receptors may have    an altered affinity or selectivity for hormones.! In other cases,  hormone responsiveness may be linked to alterations in nuclear  co-regulators, which are proteins (such as cAMP response  element-binding protein [CREB], see Chapter 21 p. 694) that  facilitate or inhibit the transcription of the target gene.” Altera-  tions in generation of new messenger ribonucleic acid (mRNA)  or absence of substrates for new protein synthesis also may  occur, resulting in altered target cell response.    Perhaps the most common cause of apparent hypothalamic  dysfunction is interruption of the pituitary stalk, which can be  caused by destructive lesions, rupture after head injury, surgical  transection, or tumor. The absence of hypothalamic releasing  or inhibiting hormones (Figure 22-1) causes a variety of mani-  festations that present clinically as pituitary disease. For exam-  ple, if there is an absence of gonadotropin-releasing hormone  (GnRH) from the hypothalamus, then there is a lack of stimula-  tion of gonadotropin follicle-stimulating hormone (FSH) and  luteinizing hormone (LH) from the pituitary; thus, menses  cease in women and spermatogenesis is impaired in men.    Diseases of the posterior pituitary usually cause abnormal  secretion of antidiuretic hormone (ADH, arginine vasopressin).  An excess amount of this hormone results in water retention  and a hypoosmolar state, whereas deficiency in the amount or  response to ADH results in serum hyperosmolarity. These com-  plex pathophysiologic states not only have significant clinical  effects on the modulation of body fluids and electrolytes, but  also affect cognitive and emotional responses to stress.    Syndrome of inappropriate antidiuretic hormone (SIADH)  secretion is characterized by high levels of ADH in the absence  of normal physiologic stimuli for its release. SIADH can com-  plicate malignancies, pulmonary disorders, central nervous  system disorders, surgical procedures, and the use of certain  medications.*? SIADH is associated with ectopic secretion of  ADH by several types of tumor cells. Tumors that have been  reported in association with SIADH include small cell carci-  noma of the lung, duodenum, stomach, and pancreas; can-  cers of the bladder, prostate, and endometrium; lymphomas;  and sarcomas. Pulmonary disorders associated with SIADH  include pneumonia (e.g., tuberculosis), asthma, cystic fibrosis,  and respiratory failure requiring mechanical ventilation. Cen-  tral nervous system disorders that may cause SIADH include  encephalitis, meningitis, intracranial hemorrhage, tumors,  and trauma. A nephrogenic form of SIADH has recently been  described. In these individuals, mutations in arginine vaso-  pressin (AVP) genes lead to chronic activation of tubular V2  receptor and resulting excessive free water reabsorption.’ Any  surgery can result in postoperative fluid volume shifts and tran-  sient SIADH for as long as 5 to 7 days after surgery. The precise    FIGURE 22-1 Loss of Hypothalamic Hormones. ACTH, Adrenocorticotropic hormone; CAH, corticotropin-releasing  hormone; FSH, follicle-stimulating hormone; GHAH, growth hormone-releasing hormone; GnAH, gonadotropin-releasing hor-  mone; LH, luteinizing hormone; 7AH, thyrotropin-releasing hormone; 7SH, thyroid-stimulating hormone.    mechanism is uncertain but is likely related to fluid and volume  changes following surgery, the amount and type of intrave-  nous fluids given, and the use of narcotic analgesics. Transient  SIADH is especially common after pituitary surgery because  stored ADH is released in an unregulated fashion. Medications  are an important cause of SIADH, especially in older adults.  These include antidepressants, antipsychotics, narcotics, gen-  eral anesthetics, chemotherapeutic agents, nonsteroidal anti-  inflammatory drugs, quinolone antibiotics, and synthetic ADH  analogs.’ These drugs serve either to simulate ADH release, to  enhance the physiologic effects of ADH, or to have a biologic  action similar to that of ADH.   PATHOPHYSIOLOGY. The pathophysiologic features of SIADH  are the result of enhanced renal water retention. Water reten-  tion results from the action of ADH on renal collecting ducts,  where it increases their permeability to water, thus increasing  water reabsorption by the kidneys. (Renal function is discussed  in Chapter 37.) This results in an expansion of extracellular  fluid volume that leads to dilutional hyponatremia (low serum  sodium concentration), hypoosmolarity, and urine that is inap-  propriately concentrated with respect to serum osmolarity.   CLINICAL MANIFESTATIONS. The symptoms of SIADH result  from hypotonic (dilutional) hyponatremia and are associated  with hypervolemia and weight gain. The severity and rapidity  of onset of the hyponatremia determine the extent of the symp-  toms. Thirst, impaired taste, anorexia, dyspnea on exertion,  fatigue, and dulled sensorium occur when the serum sodium  level decreases rapidly from 140 to 130 mEq/L. Peripheral edema  is usually absent. Severe gastrointestinal symptoms, including  vomiting and abdominal cramps, occur with a drop in sodium  concentration from 130 to 120 mEq/L. With a serum sodium  level below 115 mEq/L, confusion, lethargy, muscle twitching,  and seizures may occur. Even if hyponatremia develops slowly,  serum sodium levels below 110 to 115 mEq/L are likely to cause  severe and sometimes irreversible neurologic damage. Symp-  toms resolve with correction of hyponatremia.   EVALUATION AND TREATMENT. A diagnosis of SIADH requires  documentation of the following manifestations: (1) serum  hypoosmolality (<280 mOsm/kg) and hyponatremia (serum    sodium level <135 mEq/L); (2) urine hyperosmolarity (i.e., the  osmolality of the urine is always higher than the concurrent  serum osmolality); (3) urine sodium excretion that matches  sodium intake; (4) normal renal, adrenal, and thyroid function;  and (5) absence of conditions that can alter volume status (e.g.,  recent diuretic use, heart failure, hypervolemia from any cause,  or renal insufficiency).° Individuals with neurologic injury also  may develop hyponatremia caused by cerebral salt wasting syn-  drome. This can be differentiated from SIADH because cerebral  salt wasting is characterized by hypovolemia and weight loss. In  addition, urine sodium levels are elevated.°   The treatment of SIADH involves the correction of the  underlying causal problems; emergency correction of severe  hyponatremia by administration of hypertonic saline; and,  most importantly, fluid restriction to 800 to 1000 ml/day. Care-  ful monitoring is important. Resolution usually occurs within  3 days, with a 2- to 3-kg weight loss resulting from enhanced  free water clearance. If hyponatremia is corrected too rapidly,  a severe neurologic syndrome called central pontine myelinoly-  sis can ensue. No drug therapy is available to suppress ectopi-  cally produced ADH; however, demeclocycline, which causes  the renal tubules to develop resistance to ADH, may be used  to treat resistant or chronic SIADH. An ADH receptor agonist,  conivaptan, has been approved for the treatment of hospitalized  individuals with hyponatremia caused by ADH excess.° An oral  form of ADH receptor antagonists has been developed.’   Diabetes insipidus (DI) is an insufficiency of ADH, lead-  ing to polyuria (frequent urination) and polydipsia (frequent  drinking). There are three forms: neurogenic (hypothalamic),  nephrogenic (renal), and polydipsic (polydipsia-polyuria  syndrome).   Neurogenic DI is the form encountered most often in clini-  cal practice and is caused by insufficient amounts of ADH. It  occurs when any organic lesion of the hypothalamus, pituitary  stalk, or posterior pituitary interferes with ADH synthesis,  transport, or release.’ Causative lesions include primary or sec-  ondary brain tumors, aneurysms, thrombosis, infections, and    immunologic disorders. DI is a well-recognized complication of  closed-head trauma and of pituitary surgery in which DI can be  transient or permanent.* Neurogenic DI can be a complication  of pregnancy. In rare cases, it also can be caused by hereditary  disorders that affect ADH genes or result in structural changes  in the pituitary gland, such as septo-optic dysplasia (absence of  the septum pellucidum in the brain and underdevelopment of  the optic nerve).”   Nephrogenic DI is associated with an insensitivity of the  renal collecting tubules to ADH. The nephrogenic form of DI  can be genetic or acquired.° This form of DI is often idiopathic,  although several genetic abnormalities that affect the vasopres-  sin receptor have been noted. One of the best described is a  mutation in the gene that codes for aquaporin-2, which is one  of the four water transport channels in the renal tubule.’   Acquired nephrogenic DI is generally related to disorders  and drugs that damage the renal tubules or inhibit the genera-  tion of cAMP in the tubules. These disorders include pyelone-  phritis, amyloidosis, destructive uropathies, polycystic disease,  and intrinsic renal disease, all of which lead to irreversible DI.  Drugs that may induce a reversible form of nephrogenic DI  include lithium carbonate, colchicine, amphotericin B, loop  diuretics, general anesthetics such as methoxyflurane, and  demeclocycline.   Dipsogenic DI occurs when excessive fluid intake lowers the  plasma osmolarity to the point that it falls below the thresh-  old for ADH secretion.* This condition may be associated with  psychiatric disorders but also has been found in individuals  who have a low osmotic threshold for inducing thirst. Chronic  ingestion of extremely large quantities of fluid dilute the renal  medullary concentration gradient, which results in a partial  resistance to ADH. This condition resolves with effective man-  agement of water ingestion.   PATHOPHYSIOLOGY. Neurogenic, nephrogenic, and dipsogenic  DJ are all characterized by the inability of the kidney to increase  permeability to water. This causes excretion of large volumes of  dilute urine and an increase in plasma osmolality. In conscious  individuals, the thirst mechanism is stimulated and induces  polydipsia. For unknown reasons the person usually craves cold  drinks. The urine output is varied but can increase from the  normal output of 1 to 2 L/day to as much as 8 to 12 L/day. The  urine specific gravity is low, from 1.00 to 1.005, which is con-  sistent with the failure to reabsorb water. Dehydration develops  rapidly without ongoing fluid replacement. If the individual  with DI cannot maintain balance with the urinary loss of water,  serum hypernatremia and hyperosmolality occur. Other serum  electrolytes generally are not affected.   CLINICAL MANIFESTATIONS. The signs and symptoms of DI  include polyuria, nocturia, continuous thirst, and polydipsia.  Untreated individuals with long-standing DI may develop a  large bladder capacity and hydronephrosis (see Chapter 38).  Idiopathic neurogenic DI usually has an abrupt onset, and  many individuals can specifically recall the date of onset of their  symptoms. Those with posttraumatic or postneurosurgical DI  may develop a classic three-phase syndrome: (1) diuresis, (2)  antidiuresis, and (3) polyuria/polydipsia.* Nephrogenic DI usu-  ally has a more gradual onset.    EVALUATION AND TREATMENT. DI must be distinguished from  other polyuric states, including diabetes mellitus. The basic cri-  teria for the diagnosis of DI include polyuria, polydipsia, low  urine specific gravity (<1.010), low urine osmolality (<200  mOsm/kg), hypernatremia, high serum osmolality (300 mOsm  or more depending on adequate water intake), and continued  diuresis despite a serum sodium level of 145 mEq/L or greater.   The first step in the diagnosis of DI uses water deprivation  with measurement of serum osmolarity and plasma ADH levels.  Water restriction is a useful test because individuals without DI  respond with a rapid decrease in urine volume and an increase  in urine osmolality, whereas those with DI have no decrease  in urine volume or increase in urine osmolality. In individuals  with severe DI, water deprivation testing can be hazardous. If  the individual loses more than 3% of the pretest body weight,  circulatory collapse and shock can ensue. Neurogenic DI can be  differentiated from nephrogenic DI by measuring the response  to administered desmopressin. Neurogenic DI will respond  with an increased ability to concentrate the urine, whereas  nephrogenic DI will not respond.* The diagnosis of dipsogenic  DI can be extremely difficult, and differentiation from neph-  rogenic DI is based on plasma ADH levels. Copeptin, a stable  fragment of the ADH precursor molecule, is a reliable surrogate  measurement for ADH secretion and can be used for the diag-  nosis of dipsogenic DI.!°   Treatment for neurogenic DI is based on the extent of the  ADH deficiency and on individual variables such as age, endo-  crine and cardiovascular status, and lifestyle. Replacement  therapy for symptomatic neurogenic DI includes administra-  tion of the synthetic vasopressin analog desmopressin acetate  (DDAVP) given intranasally or orally."!   Treatment for nephrogenic DI requires treatment of any  reversible underlying disorders, discontinuation of etiologic  medications, and correction of associated electrolyte disorders.  Although the use of thiazide diuretics has been implicated as  a cause for DI, they improve salt and water absorption at the  proximal tubule and may be helpful in moderate DI.? New  treatments for genetic abnormalities involving the V2 receptor  are being evaluated.”    Disorders of the anterior pituitary may involve either hypo-  function or hyperfunction of the gland.   Hypopituitarism can be characterized by the absence of selective  pituitary hormones or the complete failure of all pituitary hor-  mone functions. Hypopituitarism results from either an inad-  equate supply of hypothalamic-releasing hormones, damage to  the pituitary stalk, or an inability of the gland to produce hor-  mones. The most common causes of hypopituitarism lie within  the pituitary gland itself. An important cause is pituitary infarc-  tion resulting from severe shock, pituitary apoplexy, aneurysms,  sickle cell disease, or pregnancy.!*!* Space-occupying lesions,  such as pituitary adenomas or aneurysms, also can compress the  gland. Head trauma is another important cause of panhypopitu-  itarism and may be transient or permanent.!>!° Other causes of    hypopituitarism include surgical removal or destruction of the  gland, infections (e.g., meningitis, syphilis, tuberculosis), sarcoid-  osis, autoimmune hypophysitis, or certain drugs (e.g., bexarotene,  carbamazepine).'* A rare form of hypopituitarism is character-  ized by combined hormonal deficiencies and is related to muta-  tions of the prophet of pituitary transcription factor (PROP-1)  gene involved in early embryonic pituitary development.!”!®   PATHOPHYSIOLOGY. The pituitary gland is highly vascular and  is therefore extremely vulnerable to ischemia and infarction.  It relies heavily on portal blood flow from the hypothalamus.  In traumatic brain injury, disruption of blood flow can cause  infarction with subsequent necrosis and fibrosis of pituitary tis-  sue.'* After tissue necrosis, edema with swelling of the gland  occurs. Expansion of the pituitary within the fixed compart-  ment of the sella turcica further impedes blood supply to the  pituitary. Over time the pituitary undergoes shrinkage, and  symptoms of hypopituitarism develop.   CLINICAL MANIFESTATIONS. The signs and symptoms of hypo-  function of the anterior pituitary are variable and depend on  which hormones are affected. In panhypopituitarism, all  hormones are deficient and the individual suffers from mul-  tiple complications including cortisol deficiency from lack of  adrenocorticotrophic hormone (ACTH), thyroid deficiency  from lack of thyroid-stimulating hormone (TSH), and loss of  secondary sex characteristics from lack of FSH and LH. Low  levels of growth hormone (GH) and insulin-like growth factor  1 (IGF-1) affect growth in children and can cause physiologic  and psychologic symptoms in adults. In addition, postpartum  women cannot lactate because of decreased or absent prolactin.   ACTH deficiency is a potentially life-threatening disorder  because cortisol is required for many aspects of cellular metabo-  lism. ACTH deficiency is usually encountered with generalized  pituitary hypofunction and rarely occurs as an isolated event.'?  Within 2 weeks of the complete absence of ACTH, symptoms  of cortisol insufficiency develop, including nausea, vomiting,  anorexia, fatigue, and weakness. Hypoglycemia is caused by  increased insulin sensitivity, decreased glycogen reserves, and  decreased gluconeogenesis associated with hypocortisolism. In  women, loss of body hair and decreased libido may be caused  by decreased adrenal androgen production. ACTH deficiency  also limits maximum aldosterone secretion, although the renin-  angiotensin system can stimulate some aldosterone secretion  with resultant hypotension and decreased urine output.   TSH deficiency also is rarely seen in isolation but most often  occurs in conjunction with other pituitary hormone deficien-  cies. The symptoms of decreased TSH levels may become appar-  ent in 4 to 8 weeks and may include cold intolerance, dryness of  skin, mild myxedema, lethargy, and decreased metabolic rate.  The symptoms are usually less severe than those associated with  primary hypothyroidism, in which lack of thyroxine is related  to disease in the thyroid gland (see p. 728).   The onset of FSH and LH deficiencies in women of repro-  ductive age is associated with amenorrhea and with atrophic  changes in the vagina, uterus, and breasts. In postpubertal  males, atrophy of the testes and decreased beard growth occur.  Men as well as women experience a decrease in body hair and  diminished libido.    FIGURE 22-2 Hypopituitary Dwarfism. A 4-year-old boy whose height is 25  inches. The girl is also 4 years old and has a normal height of 39 inches. Dwarf has  a normal face, as well as head, trunk, and limbs of approximately normal propor-  tions. (From Brashear HR, Raney RB: Shands’ handbook of orthopaedic surgery,  ed 10, St Louis, 1986, Mosby.)    GH deficiency occurs in children and adults. As described  previously, GH deficiency may result from any of the causes of  hypopituitarism. In children it may be genetic or it may be the  result of tumors such as craniopharyngiomas. Several genetic  defects have been identified in the GH axis that account for  impaired GH action. These include a recessive mutation in the  GHRH gene, resulting in a failure of GH secretion, and muta-  tions that cause GH insensitivity by affecting the GH receptor,  insulin-like growth factor 1 (IGF-1) biosynthesis, IGF-1 recep-  tors, or defects in GH signal transduction.?””! GH deficiency in  children is manifested by growth failure (Figure 22-2). Another  feature of GH deficiency in children is fasting hypoglycemia,  likely attributable to impaired substrate mobilization for gluco-  neogenesis and enhanced insulin sensitivity.   In both children and adults, acute GH and IGF-1 deficiency  has been implicated in significant metabolic perturbations seen  with critical illness.2*7 Symptoms of chronic adult GH defi-  ciency syndrome include increased body fat, decreased muscle  bulk and strength, reduced sweating, dry skin, and psychologic  problems, including depression, social withdrawal, fatigue, loss  of motivation, and a diminished feeling of well-being.‘ Several  studies also have documented increased mortality in adults who  are GH deficient. Osteoporosis and alterations in body compo-  sition (i.e., reduced lean body mass) are common concomitants  of adult GH deficiency. A decline in GH production is an inevi-  table consequence of aging.”°    EVALUATION AND TREATMENT. The diagnostic evaluation of  suspected pituitary disease is often challenging and must be  carefully interpreted together with the individual’s signs and  symptoms. Simultaneous measurements of the tropic hor-  mones from the pituitary and target endocrine glands are cru-  cial and, in some cases, dynamic testing of the various axes is  indicated.'* Radiographic assessment of the pituitary (mag-  netic resonance imaging [MRI] or computed tomography  [CT] scans) may demonstrate enlargement of the pituitary,  abnormal areas of enhancement suggestive of an adenoma,  deviation of the pituitary stalk, or evidence of a locally aggres-  sive tumor.   In general, treatment of hypopituitarism involves replac-  ing target gland hormone(s) that are deficient. In cases of  circulatory collapse, immediate therapy with glucocorticoids  and intravenous fluids is critical. Thyroid and cortisol replace-  ment therapy must be maintained. Gender-specific sex steroid  replacement therapy is also initiated to improve general well-  being and to prevent osteoporosis. Recombinant human GH  (rhGH) is used for treatment of GH deficiency in children and  results in both improved stature and metabolism. Treatment  of adult GH deficiency improves quality of life, metabolism,  body composition, and physical performance in some individu-  als.'*?° The use of GH to treat otherwise healthy aging is more  controversial.”    Pituitary adenomas are usually benign slow-growing tumors  that arise from cells of the anterior pituitary, most commonly  those that secrete GH and prolactin. They are very common in  the population with prevalence rates estimated to be around  17%. However, most are microadenomas found incidentally on  high-resolution MRI scanning and are hormonally silent and  do not pose significant hazards to the individual.*°?’ More sig-  nificant adenomas are associated with morbidity and mortality  attributable to alterations in hormone secretion or to invasion  or impingement of surrounding structures. The pathogenesis  of pituitary adenomas includes hypothalamic and intrapitu-  itary factors, including altered expression of pituitary cell cycle  genes, activation of pituitary selective oncoproteins, or loss of  pituitary suppressor factors.’® Several associated gene muta-  tions have been identified, including those associated with  multiple endocrine neoplasia (MEN) syndromes.”? Primary  pituitary carcinomas are rare, representing about 0.2% of all  pituitary tumors.   PATHOPHYSIOLOGY. Local expansion of pituitary adenomas  may cause both neurologic and secretory defects. Neurologi-  cally, the tumor may impinge on the optic chiasm if it extends  upward from the sella turcica. This causes a variety of visual  disturbances, depending on the area of the optic chiasm that  is compressed. If the tumor is locally aggressive, it may invade  the cavernous sinus and cause cavernous sinus thrombosis with  impairment of the function of the oculomotor, trigeminal,  trochlear, and abducens cranial nerves, evoking symptoms rela-  tive to their function. Extension also may involve the hypothal-  amus, disturbing hypothalamic control of wakefulness, thirst,  appetite, and temperature.    Hormonal effects of adenomas include hypersecretion from  the adenoma itself, and hyposecretion from surrounding pitu-  itary cells. The adenomatous tissue secretes the hormone of  the cell type from which it arose, without regard to physiologic  needs and without benefit of regulatory feedback mechanisms.   CLINICAL MANIFESTATIONS. The clinical manifestations of pitu-  itary adenomas are related to tumor growth and hormone  hypersecretion or hyposecretion. Effects from an increase in  tumor size include such nonspecific complaints as headache  and fatigue. Visual changes produced by pressure on the optic  chiasm include visual field impairments (occasionally begin-  ning in one eye and progressing to the other) and temporary  blindness. If the tumor infiltrates other cranial nerves, neuro-  logic function is affected.   Pituitary adenomas arise from hormone-producing cells  of the pituitary, and most often are associated with increased  secretion of GH and prolactin. Paradoxically, the pressure pro-  duced by a pituitary adenoma is also associated with decreased  function of neighboring anterior pituitary cells, which results  in hyposecretion of other anterior pituitary hormones. For  example, gonadotropic hyposecretion often results in men-  strual irregularity in women, decreased libido, and receding  secondary sex characteristics in men and women. If the tumor  exerts sufficient pressure, thyroid and adrenal hypofunction  may occur because of lack of TSH and ACTH, respectively.  These result in the respective symptoms of hypothyroidism and  hypocortisolism.   EVALUATION AND TREATMENT. Diagnosis of pituitary adenoma  involves physical and laboratory evaluations, including per-  tinent hormone assays and radiographic examination of the  skull (MRI [preferred] or contrast-enhanced CT). The goal of  treatment is to protect the individual from the effects of tumor  growth, to control hormone hypersecretion (if present), and to  replace deficient hormones while minimizing damage to appro-  priately secreting portions of the pituitary. Depending on the  tumor size and type, individuals may be treated with specific  medications to suppress tumor growth, transsphenoidal tumor  resection, or radiation therapy. Simple observation and close  follow-up is commonly employed for individuals who have no  evidence of hormonal hypersecretion and no suggestion of ana-  tomic aggressiveness.?””°    Acromegaly occurs in adults who are exposed to continuously  excessive levels of GH and concomitant elevation of IGF-1. In  children and adolescents whose epiphyseal plates have not yet  closed, the effect of increased GH levels on long bone growth is  termed giantism (Figure 22-3).   Approximately 15% of all pituitary tumors release exces-  sive GH. The most common cause of acromegaly is a primary  autonomous GH-secreting pituitary adenoma. Acromegaly  occurs more often in women than men and is diagnosed most  often in adults in their forties and fifties, although the disease is  usually present for years preceding the diagnosis.   Acromegaly is a slowly progressive disease that, if untreated,  is associated with a decreased life expectancy. The increased  number of deaths associated with acromegaly are caused by    FIGURE 22-3 Giantism. A pituitary giant and dwarf contrasted with normal-  size men. Excessive secretion of growth hormone by the anterior lobe of the pitu-  itary gland during the early years of life produces giants of this type, whereas  deficient secretion of this hormone produces well-formed dwarfs. (From Patton K,  Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    cardiac hypertrophy, hypertension, atherosclerosis, and type  2 diabetes mellitus that lead to coronary artery disease. Malig-  nancies, including colon, breast, and lung cancer, are also more  common in individuals with acromegaly.   PATHOPHYSIOLOGY. With a GH-secreting adenoma, the usual  GH baseline secretion pattern and sleep-related GH peaks  are lost, and an unpredictable secretory pattern ensues. With  only slight elevations of GH, IGF-1 levels increase, stimulating  growth. In children and adolescents whose epiphyseal plates  have not yet closed, the effect of increased GH levels causes  excessive skeletal growth, with some individuals becoming  8 or 9 feet tall. In the adult, epiphyseal closure has occurred  and increased amounts of GH and IGF-1 cause connective tis-  sue proliferation and increased cytoplasmic matrix, as well as  bony proliferation that results in the characteristic appearance  of acromegaly (Figures 22-4 and 22-5).   GH also has significant effects on glucose, lipid, and pro-  tein metabolism.*! Hyperglycemia results from GH’s inhibi-  tion of peripheral glucose uptake and increased hepatic glucose  production, followed by compensatory hyperinsulinism and,  finally, insulin resistance.°* Excessive levels of GH and IGF-1  also affect the cardiovascular system. Although the associated  pathophysiology is not clearly understood, hypertension and  left heart failure are seen in one third to one half of individuals  with acromegaly. Cardiomyopathy associated with progressive  and unrestrained myocardial growth is a significant factor.*>*4   GH also acts on the renal tubules to increase phosphate  reabsorption, leading to mild hyperphosphatemia. The ade-  noma increasingly becomes a space-occupying lesion and    FIGURE 22-4 Acromegaly in a female. Chronologic sequence of photographs  showing slow development of acromegaly. (From Belchetz P, Hammond P: Mosby's  color atlas and text of diabetes and endocrinology, Edinburgh, 2003, Mosby.)   FIGURE 22-5 Acromegaly in a male. Note large head, forward projection of  jaw, and protrusion of frontal bone. (Thibodeau GA, Patton K: The human body in  health & disease, ed 5, St Louis, 2010, Mosby.)    hypopituitarism may occur because of compression of sur-  rounding hormone-secreting cells.   CLINICAL MANIFESTATIONS. As a result of connective tissue pro-  liferation, individuals with acromegaly have enlarged tongues,  interstitial edema, increase in the size and function of sebaceous  and sweat glands (leading to increased body odor), and coarse  skin and body hair. The coarse skin condition becomes very  apparent when procedures such as inserting an intravenous  needle are performed; the skin is very thick and difficult to pen-  etrate. Bony proliferation results in large joint arthropathy with  swelling and decreased range of motion and periosteal vertebral    growth, which causes kyphosis. Enlargement of the facial bones  and the bones of the hands and feet result in protrusion of the  lower jaw and forehead and a need for increasingly larger sizes  of shoes, hats, rings, and gloves (see Figures 22-4 and 22-5).   Because IGF-1 stimulates cartilaginous growth, the increased  IGF-1 levels cause elongation of ribs at the bone-cartilage junc-  tion, leading to a barrel-chest appearance, and increased prolif-  eration of cartilage in the spine and joints. This in turn causes  backache, arthralgia, and arthritis. These are early manifesta-  tions of acromegaly. With continued bony and soft tissue over-  growth, entrapment of nerves may occur, leading to peripheral  nerve damage as manifested by weakness, muscular atrophy,  footdrop, and sensory changes in the hands.   Symptoms of diabetes, such as polyuria and polydipsia, may  occur. Acromegaly-associated hypertension is usually asymp-  tomatic until heart failure symptoms develop. Increased tumor  size results in central nervous system symptoms of headache,  seizure activity, visual disturbances, and papilledema. If com-  pression hypopituitarism occurs, gonadotropin secretion may  be affected, causing amenorrhea in women and sexual dysfunc-  tion in men. Approximately 20% of growth hormone-secreting  tumors also secrete prolactin, resulting in hypogonadism.   EVALUATION AND TREATMENT. Diagnosis of acromegaly is  accomplished by documenting elevated IGF-1 levels and GH  suppression during oral glucose tolerance testing. The goals  of treatment are to normalize GH and IGF-1 serum levels,  restoring normal pituitary function and relieving or prevent-  ing complications related to tumor expansion. The treatment  of choice for acromegaly is transsphenoidal surgery or endo-  nasal endoscopic surgery for removal of the GH-secreting ade-  noma.*° Treatment by radiation therapy may be effective when  rapid control of GH levels is not essential, when the individual  is not a good surgical candidate, or when hyperfunction per-  sists after subtotal resection. Octreotide, octreotide long-acting,  and lanreotide are somatostatin analogs that have been shown  to be effective in lowering elevated GH levels, reversing many  of the clinical manifestations of the disease, and causing tumor  shrinkage.*° Dopaminergic agonists, such as cabergoline, also  may be helpful, especially if the tumor also secretes prolactin.  Pegvisomant is an effective drug that induces tissue insensitivity  to GH by blocking the GH receptor.*”    Pituitary tumors that secrete prolactin are called prolactinomas  and are the most common of the hormonally active pituitary  tumors encountered in clinical medicine. These tumors  can be classified as microprolactinomas (<1 cm in size) or  macroprolactinomas (>1cminsize). Microprolactinomasare usu-  ally encapsulated and noninvasive, whereas macroprolactinomas  commonly expand into the optic chasm and invade local  structures.*® The physiologic actions of prolactin include breast  development during pregnancy, postpartum milk production,  and suppression of ovarian function in nursing women.   In addition to pituitary tumors, many conditions or medi-  cations can elevate prolactin level in the absence of pituitary  pathologic condition. For example, renal failure, hepatic cir-  rhosis, polycystic ovarian disease (see Chapter 24), breast    stimulation, or chest wall lesions can increase prolactin levels.  Because thyrotropin-releasing hormone (TRH) stimulates pro-  lactin secretion, in addition to enhancing TSH release, prolactin  level may be elevated in individuals with primary hypothyroid-  ism. Prolactin is under tonic inhibitory hypothalamic control  through the secretion of dopamine (prolactin inhibitor factor  [PIF]). Thus medications that block the effects of dopamine at  the pituitary can increase prolactin production and stimulate  proliferation of prolactin-secreting cells (lactotropes). These  include antipsychotics (risperidone, chlorpromazine), metoclo-  pramide, tricyclic antidepressants, methyldopa, and estrogens.  Any process that interferes with the delivery of dopamine from  the hypothalamus to the lactotropes (pituitary stalk tumor,  pituitary stalk transection, or compressive pituitary tumor) also  results in hyperprolactinemia.   PATHOPHYSIOLOGY. The hallmark of a prolactinoma is sus-  tained increases in serum prolactin concentration. Because the  adenoma becomes increasingly a space-occupying lesion, hypo-  pituitarism may occur because of compression of surrounding  hormone secreting cells. Central nervous system symptoms  may develop because of growth and pressure of the adenoma  within the sella turcica.   CLINICAL MANIFESTATIONS. Women with hyperprolactinemia  generally present with galactorrhea (nonpuerperal milk pro-  duction) and menstrual disturbances, including amenorrhea.  In susceptible women, hirsutism develops because of estrogen  deficiency. If not detected until after many years, this estrogen  deficiency also may result in osteoporosis. Men often develop  hypogonadism and erectile dysfunction but may not seek care  until symptoms related to the increasing size of the adenoma  (i.e., headache or visual impairment) develop.*?   EVALUATION AND TREATMENT. The diagnostic evaluation of  hyperprolactinemia starts with a careful history to exclude med-  ications that may cause elevations in prolactin level. A careful  search for a nonpituitary cause should be pursued if prolactin  concentration is less than 50 ng/ml. Symptoms of hypothyroid-  ism should be elicited, and screening with a serum TSH mea-  surement is indicated. Prolactin levels more than 200 ng/ml are  usually associated with a prolactinoma and are an indication for  MRI scanning of the pituitary.   Dopaminergic agonists (bromocriptine, cabergoline, and  pergolide) are the treatment of choice for prolactinomas,  and their use is often associated with both a rapid reduction  in the size of the tumor and a reversal of the gonadal effects  of hyperprolactinemia.*° Restoration of fertility in previously  anovulatory women is common. Although there is an associa-  tion between valvular heart disease and cabergoline used in the  treatment of parkinsonism, a similar association has not been  found when cabergoline is used to treat prolactinoma.*!“? In  individuals resistant or intolerant to these medications, trans-  sphenoidal surgery, endonasal endoscopic surgery, and radio-  therapy are options.°®    Disorders of thyroid function develop as a result of primary  dysfunction or disease of the thyroid gland or, secondarily, as a    Large amounts of circulating iodide can be associated with either hyperthyroid-  ism or hypothyroidism. lodinated contrast medium is commonly used for both  CT and radiographic imaging. A recent case controlled study of 178 and 213  incident hyperthyroid and hypothyroid cases, respectively, was matched to 655  and 779 euthyroid controls, respectively. The cases exposed to ICM did not have    preexisting hyperthyroidism or hypothyroidism. Large amounts of iodide inhibit  the oxidation of iodide within the thyroid follicle and decrease the release of  thyroid hormones into the bloodstream, an autoregulatory process (known as  the Wolff-Chaikoff effect), with return of normal thyroid function over weeks to  months. This mechanism may explain the incident hypothyroidism found in this  study. However, there was no incident hypothyroidism overall.    Normally, uptake of iodide and the subsequent synthesis and release of tri-  iodothyronine and thyroxine are tightly controlled. However, supraphysiologic  levels of iodide administered as ICM may overwhelm regulatory capacity and  precipitate hyperthyroidism. In this study there was a significant associa-  tion between ICM exposure and incident hyperthyroidism, and incident overt  hyperthyroidism.   Further research is needed to confirm the findings of this study, to establish  causality, and to provide guidance for clinical practice. However, individuals  unable to tolerate thyroid dysfunction (e.g., unstable cardiovascular disease)  should be monitored for thyroid disease after iodide exposure.    Data from Pearce EN: Arch Intern Med 172(2):159-161, 2012; Rhee CM et al: Arch Intern Med 172(2):153-159, 2012.    result of pituitary or hypothalamic alterations. Primary thyroid  disorders result in alterations of thyroid hormone (TH) lev-  els with secondary feedback effects on pituitary TSH levels. For  example, when there are primary elevations in TH level, TSH  level will secondarily decrease because of negative feedback.  When TH level is decreased because of a condition affecting the  thyroid gland, TSH level will be elevated. Thyroid disease also  can present with no or minimal symptoms but with abnormal  laboratory values. This is known as subclinical thyroid disease.  Central (secondary) thyroid disorders are related to disorders  of pituitary gland TSH production. When there is excessive  TSH production, TH level is elevated secondary to the primary  elevation of TSH level. The reverse is true with inadequate TSH  production. Exposure to iodinated contrast media has been  shown to be associated with development of both hyperthy-  roidism and hypothyroidism (see What’s New? Thyroid Disease  and Iodinated Contrast Media [ICM]).   PATHOPHYSIOLOGY. Thyrotoxicosis is a condition that results  from any cause of increased amounts of TH. Hyperthyroidism  is a form of thyrotoxicosis in which excess amounts of TH are  secreted from the thyroid gland. The terms thyrotoxicosis and  hyperthyroidism are often used interchangeably. The prevalence  of hyperthyroidism is estimated to be 0.7% to 2.1% in the United  States, of which 0.7% is subclinical and is more prevalent in  women and in iodine-deficient geographical areas.4* Common  diseases that cause primary hyperthyroidism include Graves  disease, toxic multinodular goiter, a solitary toxic adenoma  (Figure 22-6), and, very rarely, follicular thyroid carcinoma.  Central (secondary) hyperthyroidism is less common and is  caused by TSH-secreting pituitary adenomas. Thyrotoxicosis  not associated with hyperthyroidism includes subacute thy-  roiditis, ectopic thyroid tissue, and ingestion of excessive TH.  TSH progressively decreases in subclinical hyperthyroidism  and can be caused by thyroid hormone therapy or iatrogenic  exogenous disease. It is more prevalent in iodine-deficient pop-  ulations.** Identifying the cause is important because the treat-  ment and expected outcome vary accordingly. Each condition  is associated with specific pathophysiology and manifestations;    FIGURE 22-6 Causes of Hyperthyroidism. Hyperthyroidism may have sev-  eral causes, among them: 1, Graves disease; 2, toxic multinodular goiter; 3, fol-  licular adenoma; 4, thyroid medication. 7SH, Thyroid-stimulating hormone; 7S/,  thyroid-stimulating immunoglobulin. (From Damjanov |: Pathology for the health  professions, ed 4, St Louis, 2012, Saunders.)   CLINICAL MANIFESTATIONS. The clinical features of thyrotoxi-  cosis are attributable to the metabolic effects of increased cir-  culating levels of TH (Figure 22-7). This usually results in an  increased metabolic rate with heat intolerance and increased  tissue sensitivity to stimulation by the sympathetic division of  the autonomic nervous system. The major manifestations are  summarized in Table 22-2. Enlargement of the thyroid gland  (goiter) is common in hyperthyroid conditions caused by stim-  ulation of TSH receptors.   EVALUATION AND TREATMENT. The diagnosis of thyrotoxico-  sis is based on symptoms of TH excess and documentation of  increased circulating thyroid hormone levels. Elevated serum  thyroxine (T,) and triiodothyronine (T3) levels and decreased  serum TSH levels are diagnostic for primary hyperthyroidism.  By contrast, central (secondary) hyperthyroidism caused by    FIGURE 22-7 Clinical Manifestations of Hyperthyroidism and Hypothy-  roidism. (From Damjanov |: Pathology for the health professions, ed 4, St Louis,  2012, Saunders.)    TSH-secreting pituitary tumors is characterized by normal to  increased TSH levels in the face of elevated thyroid hormone  concentrations. Radioactive iodine is used to test for increased  uptake in primary hyperthyroidism (Figure 22-8).   Treatment is directed at controlling excessive TH produc-  tion, secretion, or action. The major types of therapy currently  used to achieve these goals include antithyroid drug therapy  (methimazole or propylthiouracil), radioactive iodine therapy,  and surgery. Guidelines for the treatment of hyperthyroidism  and thyrotoxicosis have been published.*? Treatment of sub-  clinical hyperthyroidism is based on levels of TSH and clinical  symptoms.“ A major complication of all forms of treatment for  hyperthyroidism is hypothyroidism.*°   Graves Disease. Graves disease is the underlying cause of  50% to 80% of cases of hyperthyroidism and has a prevalence  of approximately 0.5% in the U.S. population.*” It occurs more  commonly in women. Although the cause of Graves disease  is not known, genetic factors interacting with environmental  triggers play an important role in the pathogenesis of this  autoimmune thyroid disease. Graves disease results from  a form of type II hypersensitivity (see Chapter 9) in which  there is stimulation of the thyroid by autoantibodies directed  against the TSH receptor. These autoantibodies, called thyroid-  stimulating immunoglobulins (TSIs; also called thyroid-  stimulating antibodies [TSAbs] or thyroid receptor antibodies  [TRAbs]), override normal regulatory mechanisms. The TSI  stimulation of TSH receptors in the gland results in hyperplasia  of the gland (goiter) and increased synthesis of TH, especially  of triiodothyronine (T3). Increased levels of TH affect every  physiologic system and result in the classic signs and symptoms  of hyperthyroidism illustrated in Figure 22-8. TSH production  by the pituitary is inhibited through the usual negative feedback  loop.   TSIs also contribute to two major distinguishing clinical  manifestations of Graves disease: ophthalmopathy and pre-  tibial myxedema (Graves dermopathy). Graves ophthalmopa-  thy affects more than half of individuals with Graves disease.  There are two categories of ocular manifestations: (1) func-  tional abnormalities resulting from hyperactivity of the sym-  pathetic division of the autonomic nervous system (lag of the  globe on upward gaze or a lag of the upper lid on downward  gaze) and (2) infiltrative changes involving the orbital contents  with enlargement of the ocular muscles. The infiltrative changes  result from TSH receptor autoantibodies reacting with recep-  tors on orbital fibroblasts (Figure 22-9). Increased secretion of  hyaluronic acid, orbital fat accumulation, inflammation, and  edema of the orbital contents result in exophthalmos (protru-  sion of the eyeball). Periorbital edema and extraocular muscle  weakness lead to diplopia (double vision). The individual may  experience irritation, pain, lacrimation, photophobia, blurred  vision, decreased visual acuity, papilledema, visual field impair-  ment, exposure keratosis, and corneal ulceration.**   A small number of individuals with Graves disease and very  high levels of TSI experience pretibial myxedema (Graves  dermopathy), characterized by subcutaneous swelling on the  anterior portions of the legs and by indurated and erythema-  tous skin (Figure 22-10). Graves dermopathy is associated with  thyrotropin receptor antigens on fibroblasts and recruited T  lymphocytes that stimulate excess amounts of hyaluronic acid  production in the dermis and subcutis. The manifestations  occasionally appear on the hands giving the appearance of club-  bing of the fingers (thyroid acropachy).””   Therapy for Graves disease includes antithyroid drugs,  radioactive iodine (used with caution in Graves ophthalmopa-  thy because it may worsen the condition), or surgery. Unfortu-  nately, current treatment for Graves disease does not reverse the  infiltrative ophthalmopathy or the pretibial myxedema. Surgi-  cal orbital decompression and glucocorticoids can help many  individuals with progressive ophthalmopathy.*° Skin lesions    bruit over thyroid; increased cortisol degradation; hypercalcemia and  decreased PTH secretion; diminished sensitivity to exogenous insulin    libido; increased serum estradiol and estrone levels but lower than  normal levels of free estradiol and estrone    frequent stools; nausea, vomiting, anorexia, abdominal pain; increased  use of hepatic glycogen stores and of adipose and protein stores;  decrease in serum lipid levels (including triglycerides, phospholipids,  and cholesterol); changes in vitamin metabolism leading to decrease in  tissue stores of vitamins    soft, and straight; temporary hair loss; nails that grow away from nail   Ocular manifestations including elevated upper eyelid  decreased blinking and a staring quality; fine tremor  ocular changes associated with Graves disease    Hyperactivity of the thyroid gland; excess bone resorption  leading to hypercalcemia and a disruption of PTH-regulating  mechanisms; increased insulin degradation   Menstrual cycle alterations that may be related to hypothalamic  or pituitary disturbances; increase in sex hormone—binding  globulin   Increased catabolism leading to the body’s inability to meet  its metabolic needs; increased glucose absorption; increase  in cholesterol excretion in feces and cholesterol conversion  to bile salts; impaired conversion of B vitamins to their  coenzymes, causing increased need for water-soluble and  fat-soluble vitamins    left ventricular dilation and hypertrophy  Restlessness; short attention span; compulsive movement; fatigue;    Nervous Not clearly defined; alterations in cerebral metabolism resulting  from excess thyroid hormone    Thyroiditis Graves disease  -Postpartum Toxic multinodular goiter  -Painless Toxic adenoma  -de Quervain's (viral)    *Isotope scan aids in  differentiation of causes  FIGURE 22-8 Evaluation of Hyperthyroidism. Radioactive iodine is used in  the differential diagnosis of hyperthyroidism. TH, Thyroid hormone; TSH, thyroid-  stimulating hormone.    FIGURE 22-9 Thyrotoxicosis (Graves Disease). Note large and protruding  eyeballs in association with a large goiter. (From Stein HA, Slatt BU, Stein RM:  The ophthalamic assistant: fundamentals and clinical practice, ed 7, Philadelphia,    FIGURE 22-10 Pretibial Myxedema. Purple-brown edematous plaques on  shins of individual with Graves disease. Note orange peel appearance. (From Bolog-  nia JL, Jorizzo JL, Schaffer JV: Dermatology, ed 3, New York, 2013, Saunders.)    rarely require treatment, but if they are symptomatic they may  respond to topical glucocorticoids.°!   Hyperthyroidism Resulting from Nodular Thyroid Disease.  The thyroid gland normally enlarges in response to an increased  secretion of TSH that occurs in puberty, pregnancy, or iodine  deficiency, and from immunologic, viral, or genetic disorders.  The increased number of follicles is a compensatory mechanism  in response to increased TSH levels. When the condition  requiring increased TH resolves, TSH secretion normally  subsides and the thyroid gland returns to its original size.   Irreversible changes may occur in some follicular cells  and these cells function autonomously and produce exces-  sive amounts of TH. On the other hand, some follicular cells  may cease to function. The balance between the amount of TH  produced by hyperfunctioning nodules and that produced by  the remainder of the gland determines whether an individual  becomes euthyroid or hyperthyroid. Toxic multinodular  goiter occurs when there are several hyperfunctioning nodules  leading to hyperthyroidism. If only one nodule becomes hyper-  functioning it is termed solitary toxic adenoma. This condition  is more common in iodine-deficient regions. The classic clini-  cal manifestations of hyperthyroidism (see Figure 22-7) usually  develop slowly and exophthalmos and pretibial myxedema do  not occur. Nodules may be palpable on physical examination.  The incidence of malignancy in toxic multinodular goiter is  estimated to be as high as 9% and 10.5%, so most individu-  als should undergo a fine needle aspiration biopsy of suspicious  nodules before treatment.°? Treatment consists of a combina-  tion of radioactive iodine, surgery, or antithyroid drugs. Muta-  tions of the TSH receptor have been found in most solitary  toxic adenomas.°>4   Thyrotoxic Crisis (Thyroid Storm). Thyrotoxic crisis (thyroid  storm) is a rare but dangerous worsening of the thyrotoxic state,    in which death can occur within 48 hours without treatment.  The condition may develop spontaneously, but it occurs in  individuals who have undiagnosed or partially treated severe  hyperthyroidism and who are subjected to excessive stress from  other causes. These causes may include infection, pulmonary  or cardiovascular disorders, trauma, burns, seizures, surgery  (especially thyroid surgery), obstetric complications, emotional  distress, or dialysis. The symptoms of thyroid crisis are caused  by the increased action of thyroxine (T,) and triiodothyronine  (T3) exceeding metabolic demands.*°   The systemic symptoms of thyrotoxic crisis include hyper-  thermia; tachycardia, especially atrial tachydysrhythmias;  high-output heart failure; agitation or delirium; and nausea,  vomiting, or diarrhea, contributing to fluid volume deple-  tion. Treatment includes: (1) the use of drugs that block TH  synthesis (i.e., propylthiouracil or methimazole), (2) the use  of beta-blockers for control of cardiovascular symptoms, (3)  administration of corticosteroids or (4) iodine (e.g., saturated  solution of potassium iodide [SSKI]), and (5) supportive care.   Hypothyroidism is caused by a deficient production of TH by  the thyroid gland. Hypothyroidism is the most common dis-  order of thyroid function; it affects between 0.1% and 2% of  individuals in the United States and is more common in women  and the elderly. It may be primary or secondary. Primary  hypothyroidism is the most prevalent. Central (secondary)  hypothyroidism, which is much less common, includes condi-  tions that cause either pituitary or hypothalamic failure with  failure to stimulate normal thyroid function. Subclinical hypo-  thyroidism is mild thyroid failure and is estimated to occur in  4% to 8% of U.S. adults. It is defined as an elevation in TSH  level with normal levels of circulating TH.**   PATHOPHYSIOLOGY. In primary hypothyroidism the loss of  functional thyroid tissue leads to a decreased production of  TH. Causes in adults include autoimmune thyroiditis (Hashi-  moto disease), iatrogenic loss of thyroid tissue after surgical  or radioactive treatment for hyperthyroidism, head and neck  radiation therapy, medications, and endemic iodine deficiency.  Infants and children may present with hypothyroidism because  of congenital defects in the pituitary or thyroid glands.°° Most  states require newborn screening for hypothyroidism. Central  (secondary) hypothyroidism is caused by the pituitary’s failure  to synthesize adequate amounts of TSH or a lack of TRH. Pitu-  itary tumors that compress surrounding pituitary cells or the  consequences of their treatment are the most common causes  of secondary hypothyroidism. Other causes include traumatic  brain injury, subarachnoid hemorrhage, or pituitary infarction.  Hypothalamic dysfunction results in low levels of TRH, TSH,  and TH (Figure 22-11).   CLINICAL MANIFESTATIONS. Hypothyroidism generally affects  all body systems and occurs insidiously over months or years.  The extent of the symptoms is closely related to the degree of  TH deficiency (see Figure 22-7). The lowered levels of TH result  in decreased energy metabolism and decreased heat produc-  tion. The individual develops a low basal metabolic rate, cold  intolerance, lethargy, tiredness, and slightly lowered basal body    Low levels of TH Low levels of TSH | Low levels of  and high levels of and TH and high TRH, TSH  TSH and TRH levels of TRH and TH    FIGURE 22-11 Mechanisms of Primary and Central (Secondary)  Hypothyroidism. 7H, Thyroid hormone; TRH, Thyroid-releasing hormone;  TSH, Thyroid-stimulating hormone.    temperature and also may have diastolic hypertension. Many  organ systems are affected (Table 22-3). The decrease in the  level of TH leads to increases in TSH production and may cause  goiter.   The characteristic sign of severe or long-standing hypothy-  roidism is myxedema, which is histologically similar to the pre-  tibial myxedema deposits that often occur with Graves disease.  Myxedema is a result of an alteration in the composition of the  dermis and other tissues. The connective fibers are separated by  an increased amount of protein and mucopolysaccharides. This  protein-mucopolysaccharide complex binds water, producing  nonpitting, boggy edema, especially around the eyes, hands, and  feet and in the supraclavicular fossae. Myxedema is also respon-  sible for thickening of the tongue and the laryngeal and pharyn-  geal mucous membranes. This results in thick, slurred speech  and hoarseness, both of which are common in hypothyroidism.   Myxedema coma, a medical emergency, is a diminished  level of consciousness associated with severe hypothyroidism.  Precipitating events include infections and discontinuation of  thyroid supplements, overuse of narcotics or sedatives, or a  consequence of an acute illness in individuals who have hypo-  thyroidism. Older individuals with severe vascular disease and  with moderate or untreated hypothyroidism are particularly  at risk for developing myxedema coma. Signs and symptoms  include hypothermia without shivering, hypoventilation, hypo-  tension, hypoglycemia, lactic acidosis, and coma.°’ Symptoms  of hypothyroidism in older adults should not be attributed to  normal aging changes.   EVALUATION AND TREATMENT. The diagnosis of primary hypo-  thyroidism is made by documentation of the clinical symptoms  of hypothyroidism, and by measurement of increased levels of  TSH and decreased levels of TH (total T; and both total and free  T,). When hypothyroidism is caused by pituitary deficiencies,  serum TSH levels are decreased or are inappropriately normal  in the face of low levels of TH. Hormone replacement therapy  is the treatment of choice for hypothyroidism. Levothyroxine  (a synthetic hormone) is preferred over desiccated thyroid    (the crude extract from animal thyroid glands). Treatment of  myxedema coma with TH, combined with circulatory and ven-  tilatory support and management of hyponatremia and hypo-  thermia, is usually effective. Mortality can be as high as 25%.°°  Treatment of subclinical hypothyroidism is related to elevated  levels of TSH and clinical symptoms.** The goal of treatment  is maximal metabolic restoration consistent with the individu-  al’s overall well-being and normalization of TSH levels in pri-  mary hypothyroidism or normalization of TH levels in central  hypothyroidism.   Primary Hypothyroidism. Primary hypothyroidism has  several causes. Iodine deficiency (endemic goiter) is the most  common cause worldwide, but is relatively rare in the United  States because of the use of iodized table salt and fortified  foods. The most common cause of hypothyroidism in the  United States is autoimmune thyroiditis (Hashimoto disease,  chronic lymphocytic thyroiditis), which results in gradual  inflammatory destruction of thyroid tissue by infiltration  of lymphocytes and circulating thyroid autoantibodies  (antithyroid peroxidase and antithyroglobulin antibodies).  Autoreactive T lymphocytes, antibody activation of natural  killer cells (antibody-dependent cell-mediated cytotoxicity),  cytokines, and induction of apoptosis also are involved in the  tissue destruction seen in Hashimoto thyroiditis.°? Variants in  major histocompatibility complex (MHC) antigens have been  associated with autoimmune thyroiditis that are different from  those found in Graves disease. Hashimoto disease occurs in  genetically predisposed individuals and is associated with high  iodine intake, selenium deficiency, smoking, chronic hepatitis  C, and interferon-alpha (IFN-a).°° Epigenetic mechanisms are  probably involved.°! Goiter formation is commonly observed.   Spontaneous recovery of thyroid function is seen in three  conditions: subacute thyroiditis, painless thyroiditis, and  postpartum thyroiditis.°* Subacute thyroiditis (subacute  granulomatous thyroiditis, or de Quervain thyroiditis) is an  uncommon nonbacterial inflammation of the thyroid often  preceded by a viral infection. It is accompanied by fever, tender-  ness, and enlargement of the thyroid. The inflammatory pro-  cess initially results in elevated levels of TH caused by release  of stored thyroglobulin, and then is associated with transient  hypothyroidism before the gland recovers normal activity.  Symptoms may last 2 to 4 months and nonsteroidal anti-  inflammatory agents, corticosteroids, beta-blockers, and, pos-  sibly, TH supplementation may be required during the course  of the illness. Painless thyroiditis (silent or subacute lym-  phocytic thyroiditis) has a course similar to that of subacute  thyroiditis but is pathologically identical to Hashimoto disease.  Iatrogenic hypothyroidism results from radioiodine thyroid  ablation, thyroidectomy, and medications (lithium and amio-  darone). Postpartum thyroiditis generally occurs within 6 to  12 months of delivery, develops in up to 5.4% of all women, and  has a course similar to that of painless thyroiditis. Pathologic  specimens suggest it is related to Hashimoto disease. Spontane-  ous recovery is seen in most women affected with this form of  thyroiditis; however, persistent hypothyroidism does occur.°**    headaches, hearing loss, night blindness; slow, clumsy movements;  cerebellar ataxia; slow alpha-wave activity and loss of amplitude in  EEG; reduced cAMP response to epinephrine, glucagons, and PTH  stimulation; decreased appetite   Increased TSH production in primary hypothyroidism; enlarged pituitary  thyrotropes, increase in serum prolactin levels with galactorrhea;  decreased rate of cortisol turnover but with normal serum cortisol  levels    Decreased androgen secretion in men, increased estriol formation in  women; low total hormone values but with increased amounts of  unbound hormone; anovulation, decreased libido, menorrhagia, and a  high incidence of spontaneous abortion in women; erectile dysfunction,  decreased libido, and oligospermia in men   Decrease in red cell mass leading to normocytic, normochromic anemia;  macrocytic anemia associated with vitamin By. deficiency and  inadequate folate or iron absorption in the gastrointestinal tract    Reduction in stroke volume and heart rate causing lowered cardiac  output; increased peripheral vascular resistance to maintain systolic  blood pressure can cause hypertension; normal response to exercise  but with alterations in circulatory system at rest (prolonged circulation  time and decreased blood flow to tissues); cool skin and cold tolerance;  enlarged heart; decreased intensity of heart sounds and variety of ECG  changes (sinus bradycardia, prolonged PR interval, depressed P waves,  flattened or inverted T waves, and low-amplitude ORS complexes);  cardiac tamponade (although rare) (see Chapter 32)   Dyspnea; myxedematous changes in respiratory muscles leading to  hypoventilation and carbon dioxide retention, which contribute to  myxedema coma   Reduced renal blood flow and glomerular filtration rate leading to  decreased renal excretion of water; increase in total body water and  dilutional hyponatremia; reduced production of erythropoietin   Constipation, weight gain, and fluid retention; decreased absorption  of most nutrients; decreased protein metabolism leading to retarded  skeletal and soft tissue growth and slightly positive nitrogen balance;  edema; decreased glucose absorption and delayed glucose uptake;  elevated serum lipid values    Muscle aching and stiffness; slow movement and slow tendon jerk  reflexes; decreased bone formation and resorption, increased bone  density; aching and stiffness in joints   Dry, flaky skin; dry, brittle head and body hair; reduced growth of nails  and hair; slow wound healing    Decreased cerebral blood flow leading to cerebral hypoxia;  reduced intracellular processes caused by decreased B-  adrenergic activity that may be related to a decrease in the  number of B-adrenergic receptor sites    Impaired TH synthesis or defects in iodide trapping leading  to compensatory TSH production; chronic overstimulation  of thyrotropes of TRH and by TSH synthesis; stimulation of  lactotropes by TRH related to increased prolactin levels;  decreased deactivation of cortisol   Altered metabolism of estrogens and androgens; decreased  levels of sex hormone—binding globulin    Decreased basal metabolic rate and reduced oxygen  requirements; decreased production of erythropoietin;  possible relationship between TH and optimal hematologic  response to vitamin By.   Decreased metabolic demands and loss of regulatory and  rate-setting effects of TH; protein-mucopolysaccharide—rich  fluid in the pericardial sac associated with enlarged heart;  pericardial effusions associated with heart sounds and ECG  changes   Increases in peripheral vascular resistance and increased  blood volume can cause hypertension    Hemodynamic alterations associated with reduced blood  flow and filtration; increased total body water related to  decreased excretion and mucinous deposits in tissue   Reduced intake and reduced peristaltic activity that may  progress to fecal impaction; water absorption related to  prolonged transit time; fluid retention associated with  myxedematous changes; edema associated with high  concentrations of exchangeable albumin in the extravascular  space caused by increased capillary permeability to proteins;  depressed insulin degradation; depressed lipid synthesis and  degradation   Decreased rate of muscle contraction and relaxation  contributing to slow movement and reflexes    Reduced sweat and sebaceous gland secretion  Accumulation of hyaluronic acid, which binds water and    cAMP. Cyclic adenosine monophosphate; ECG, electrocardiogram; EEG, electroencephalogram; PTH, parathyroid hormone; TH, thyroid hormone;  TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone.    FIGURE 22-12 Adult Cretin. Note characteristic facial features, dwarfism (44  inches), absent axillary and scant pubic hair, poorly developed breasts, potbelly,  and small umbilical hernia. (From Schneeberg NG: Essentials of clinical endocrinol-  ogy, St Louis, 1970, Mosby.)    Congenital Hypothyroidism. Congenital hypothyroidism  (CH) is thyroid hormone deficiency present at birth. It occurs  as a result of absent thyroid tissue (thyroid agenesis) or with  hereditary defects in TH synthesis. Thyroid agenesis occurs  more often in female infants, with permanent abnormalities in  1 of every 3000 to 4000 live births.°° Because TH is essential for  embryonic growth, particularly of brain tissue, the infant will  be mentally retarded if there is no T, available during fetal life.   Clinical manifestations at birth are not the typical signs of  hypothyroidism and this is most likely caused by transplacental  passage of some maternal thyroid hormone in addition to some  residual neonatal thyroid function. Without treatment, symp-  toms may not be evident until after 4 months of age. Hypothy-  roidism is difficult to identify at birth, but high birth weight,  hypothermia, delay in passing meconium, and neonatal jaun-  dice are suggestive signs. Without treatment, symptoms include  difficulty eating, hoarse cry, and protruding tongue caused by  myxedema of oral tissues and vocal cords; hypotonic muscles  of the abdomen with constipation, abdominal protrusion, and  umbilical herniation; subnormal temperature; lethargy; exces-  sive sleeping; slow pulse rate; and cold, mottled skin. Skeletal  growth is stunted because of impaired protein synthesis, poor  absorption of nutrients, and lack of bone mineralization. The  individual will become dwarfed, with short limbs, if not treated  (cretinism) (Figure 22-12). Dentition is often delayed. Mental  retardation is a function of the severity of hypothyroidism and  the delay before initiation of treatment.    Cord blood can be screened in the first days of life for T, and  TSH levels. Neonatal screening has resulted in eradication of  mental retardation related to CH where screening is available.  Treatment is administration of Ty. The probability of normal  growth and intellectual function is high if treatment is started  within 2 weeks and before the child is 3 or 4 months old. The  earlier TH replacement is initiated, the better the child’s out-  come. Permanent congenital hypothyroidism will require treat-  ment for life.°°   Thyroid Carcinoma. Thyroid carcinoma is the most common  endocrine malignancy, accounting for 60,220 estimated new  cases and 1850 estimated cancer deaths in 2013 in the United  States, less than 4% of all neoplasms.°’ Exposure to ionizing  radiation, especially during childhood, is the most consistent  causal factor. Papillary and follicular thyroid carcinomas are the  most frequent, and medullary and anaplastic thyroid carcinomas  are less common. Most tumors are well differentiated.   Most individuals with thyroid carcinoma have normal T;  and T, levels and are therefore euthyroid. Thyroid cancer  typically is discovered as a small thyroid nodule or as a meta-  static tumor most commonly occurring in the regional lymph  nodes, lungs, brain, or bone. Changes in voice and swallow-  ing and difficulty in breathing are related to tumor growth  impinging on the trachea or esophagus. The diagnosis of thy-  roid carcinoma is generally made by fine-needle aspiration  of a thyroid nodule. Ultrasonographic characteristics may be  suggestive of malignancy, and staging requires appropriate  imaging.   Treatment for well-differentiated thyroid carcinoma remains  somewhat controversial mainly because of its protracted nature  and the relatively low mortality regardless of the method of  treatment. Treatment of well-differentiated tumors includes  surgical dissection (e.g., a near-total or total thyroidectomy),  postoperative radioactive iodine therapy to treat any micro-  scopic residual tumor, and suppression of TSH with levothy-  roxine to replace TH and suppress TSH on any tumor cells.°°  Anaplastic thyroid carcinoma carries a grave prognosis, and  palliation with surgical debulking, external beam radiotherapy,  and chemotherapy may be offered.”°    ALTERATIONS OF PARATHYROID FUNCTION  Hyperparathyroidism  Hyperparathyroidism is characterized by greater than normal  secretion of parathyroid hormone (PTH) and hypercalcemia.  Hyperparathyroidism is classified as primary, secondary, or  tertiary. Calcium levels are either low or normal in secondary  hyperparathyroidism. Normocalcemic hyperparathyroidism is  characterized by increased levels of intact PTH, normal total  and ionized serum calcium concentrations, and no underlying  etiology. Increased PTH screening for osteoporosis has led to  the development of this diagnosis. There may be tissue resis-  tance to PTH or the elevated level of PTH may represent an  early phase of primary hyperparathyroidism.’!  PATHOPHYSIOLOGY. Primary hyperparathyroidism is usually a  sporadic disease characterized by inappropriate excess secretion  of PTH by one or more of the parathyroid glands. PTH secretion    UNIT VI The Endocrine System  TABLE 22-4 MANIFESTATIONS OF PRIMARY HYPERPARATHYROIDISM  SYMPTOMS RESPONSIBLE DERANGEMENTS MECHANISMS    Renal colic, nephrolithiasis, recurrent urinary tract Hypercalciuria, hyperphosphaturia, proximal renal Calcium phosphate salts precipitate in alkaline    Renal disease, direct effect of calcium on arterial  smooth muscle, pheochromocytoma  Gout, pseudogout, periarticular classification    urine, renal pelvis, and collecting ducts; calcium  oxalate stones also formed   Osteoporosis now more commonly encountered,  but other disorders are more specific for  hyperparathyroidism   Characteristic myopathic changes in muscle  histology (neuropathy of type | and type II muscle  fibers)    Direct effect on renal tubule to decrease  responsiveness to antidiuretic hormone  Decreased peristalsis of gastrointestinal tract  Central stimulation of vomiting center  Plasma rennin activity elevated or normal    Data from Flint PW et al: Cummings otolaryngology: head & neck surgery, ed 5, St Louis, 2010, Mosby.    is increased and is not under the usual feedback control mech-  anisms. The calcium level in the blood increases because of  increased bone resorption and gastrointestinal absorption of  calcium, but fails to inhibit PTH secretion.   Primary hyperparathyroidism is one of the most common  endocrine disorders: 80% to 85% of cases are caused by para-  thyroid adenomas, another 10% to 15% result from parathyroid  hyperplasia, and approximately 1% are caused by parathyroid  carcinoma.’* Normal feedback mechanisms, such as elevated  serum levels of ionized calcium, fail to normally inhibit PTH  secretion by the parathyroid gland.   The cause of primary hyperparathyroidism is unknown;  however, recent data suggest that there are two mechanisms for  the development of this condition. The first is a monoclonal  proliferation of parathyroid cells with a higher threshold for  calcium feedback, and the second is generalized growth of para-  thyroid tissue. The former is most likely the cause of adeno-  mas, and the latter is probably the cause for hyperplasia. There  is also a familial form of the disease that includes a wide range  of inherited endocrine disorders including multiple endocrine  neoplasia syndromes (MEN-1 and MEN-2a).”° Hypercalcemia  and hypophosphatemia are the hallmarks of primary hyper-  parathyroidism. The effects of excessive PTH secretion and  primary hyperparathyroidism on various organ systems are  summarized in Table 22-4.   Secondary hyperparathyroidism is caused by an increase in  PTH secondary to a chronic disease state, such as chronic kid-  ney disease or intestinal malabsorption, which causes a decrease  in serum ionized calcium levels (hypocalcemia) or chronic vita-  min D deficiency. Hypercalcemia does not occur in secondary    hyperparathyroidism because the parathyroid tissue is not  autonomous and is only responding to a physiologic stimulus  of hypocalcemia.   The most common cause of secondary hyperparathyroidism  is chronic kidney disease (with failure of glomerular filtration),  which results in hyperphosphatemia, reduced levels of activated  vitamin D, and hypocalcemia, which stimulates PTH secretion.  Disturbances in calcium and vitamin D metabolism that arise  in chronic renal disease diminish activation of the parathyroid  calcium-sensing receptor leading to increases in PTH secretion.  Because vitamin D metabolism is impaired in kidney failure,  eucalcemia cannot be restored unless vitamin D supplements  are administered.” Other causes of secondary hyperpara-  thyroidism include chronic vitamin D or calcium deficiency;  decreased intestinal absorption of vitamin D or calcium; and  ingestion of drugs, such as phenytoin, phenobarbital, and laxa-  tives, which either accelerates the metabolism of vitamin D or  decreases intestinal absorption of calcium.   Tertiary hyperparathyroidism is excessive secretion of PTH  and hypercalcemia that occurs after long-standing secondary  hyperparathyroidism. The etiology is unknown but represents  autonomous secretion of PTH from persistent parathyroid  stimulation even after withdrawal of calcium and calcitriol  therapy. It develops in individuals with chronic secondary  hyperparathyroidism and after renal transplantation.   Two other conditions must be differentiated from primary  and secondary hyperparathyroidism. Pseudohypoparathyroid-  ism is an inherited condition that presents with increased PTH  levels, hypocalcemia, and hyperphosphatemia. These individu-  als are resistant to PTH and cannot produce cAMP in response    to PTH (a postreceptor defect in PTH action).’° Familial hypo-  calciuric hypercalcemia (FHH) is a benign autosomal domi-  nant condition that can mimic hyperparathyroidism and is  characterized by a high serum calcium level, low serum phos-  phate level, and low urine calcium excretion. It is caused by a  mutation in the calcium-sensing receptor in the parathyroid  gland. It can be differentiated from primary hyperparathyroid-  ism by measurement of 24-hour urine calcium excretion.’°   CLINICAL MANIFESTATIONS. Most individuals with primary  hyperparathyroidism are asymptomatic. Hypercalcemia and  hypophosphatemia commonly occur in primary hyperpara-  thyroidism. Hypercalcemia may be asymptomatic or affected  individuals may present with symptoms related to the mus-  cular, nervous, and gastrointestinal systems, including fatigue,  headache, depression, anorexia, and nausea and vomiting.  There also is an increased risk for cardiovascular disease includ-  ing hypertension.’’ Excessive osteoclastic and osteocytic activ-  ity resulting in bone resorption may cause pathologic fractures,  kyphosis of the dorsal spine, and compression fractures of the  vertebral bodies. (Bone resorption is discussed in Chapter 43.)   In primary hyperparathyroidism, hypercalcemia affects  proximal renal tubular function, causing hypercalciuria, met-  abolic acidosis, and production of abnormally alkaline urine.  PTH also enhances the renal excretion of phosphate, which  results in hypophosphatemia (low serum phosphate concentra-  tion) and hyperphosphaturia (increased urine phosphate level).  The combination of these three variables—hypercalciuria,  alkaline urine, and hyperphosphaturia—predisposes the indi-  vidual to the formation of calcium stones. Kidney stones are  often formed in the renal pelvis or in the renal collecting ducts  and may be associated with infections. Kidney stones and renal  infection may lead to impaired renal function.”* Hypercalce-  mia also impairs the concentrating ability of the renal tubule  by decreasing its response to ADH. Chronic hypercalcemia  of hyperparathyroidism is associated with mild insulin resis-  tance, necessitating increased insulin secretion to maintain  normal glucose levels. Hypercalcemia also affects the muscular,  nervous, and gastrointestinal systems. Elevated levels of PTH  increase the risk for cardiovascular disease.’”   Secondary hyperparathyroidism caused by renal disease  presents clinically not only with bone resorption but also  with the symptoms of hypocalcemia and hyperphosphatemia.  Hypocalcemia can cause many significant clinical problems (see  Chapter 3). Hyperphosphatemia can cause deleterious effects  on the cardiovascular system.*°   EVALUATION AND TREATMENT. The concurrent findings of  increased ionized calcium concentration in the face of elevated  intact PTH level (which documents an abnormal feedback  mechanism) are suggestive of primary hyperparathyroidism.  Sestamibi (a radioisotope) scanning, CT, or ultrasound is used  to localize adenomas before surgery.*! Definitive treatment of  severe primary hyperparathyroidism involves surgical removal  of the solitary adenoma or, in the case of hyperplasia, complete  removal of three and partial removal of the fourth hyperplastic  parathyroid glands. In those individuals who fail surgery, other  treatments such as bisphosphonates, corticosteroids, and cal-  cimimetics (e.g., cinacalcet) may be considered. Calcimimetics   If hypercalcemia is documented but PTH levels are low, the  differential diagnosis shifts to hypercalcemia of malignancy,  granulomatous diseases (sarcoidosis), excessive calcium inges-  tion, or to hypervitaminosis A or D. Treatment of these condi-  tions depends on the underlying cause.   If serum calcium level is low but PTH level is elevated, sec-  ondary hyperparathyroidism is likely. Evaluation for renal func-  tion frequently documents chronic renal disease. Treatment  for secondary hyperparathyroidism in chronic kidney disease  requires calcium replacement, dietary phosphate restriction  and phosphate binders, and vitamin D replacement. Treatment  also may include calcimimetics.**   Hypoparathyroidism (abnormally low PTH levels) most com-  monly is caused by damage to the parathyroid glands during  thyroid surgery and occurs because of the anatomic proximity  of the parathyroid glands to the thyroid. Hypoparathyroidism  also is associated with genetic syndromes, including familial  hypoparathyroidism and DiGeorge syndrome (velocardiofa-  cial syndrome) and an idiopathic or autoimmune form of the  disease.** Hypomagnesemia also can cause a decrease in PTH  secretion and function.®°   PATHOPHYSIOLOGY. A lack of circulating PTH causes depressed  serum calcium levels and increased serum phosphate levels.  In the absence of PTH, resorption of calcium from bone and  regulation of calcium reabsorption from the renal tubules are  impaired. The phosphaturic effects of PTH are lost, resulting in  hyperphosphatemia.   The effects ofhypomagnesemia on the peripheral metabolism  and clearance of PTH are not clearly understood. Once serum  magnesium levels return to normal, however, PTH secretion  returns to normal, as does the responsiveness of peripheral tis-  sues to PTH. Hypomagnesemia may be related to chronic alco-  holism, malnutrition, malabsorption, increased renal clearance  of magnesium caused by the use of aminoglycoside antibiotics  or certain chemotherapeutic agents, or prolonged magnesium-  deficient parenteral nutritional therapy.   CLINICAL MANIFESTATIONS. Symptoms associated with hypo-  parathyroidism are related to hypocalcemia. Hypocalcemia  causes a lowering of the threshold for nerve and muscle excita-  tion so that a nerve impulse may be initiated by a slight stimulus  anywhere along the length of a nerve or muscle fiber. This cre-  ates tetany manifested as muscle spasms, hyperreflexia, tonic-  clonic convulsions, laryngeal spasms, and, in severe cases, death  from asphyxiation. Chvostek and Trousseau signs may be used  to evaluate for neuromuscular irritability. Chvostek sign is elic-  ited by tapping the cheek, resulting in twitching of the upper  lip. Trousseau sign is elicited by sustained inflation of a sphyg-  momanometer placed on the upper arm to a level above the  systolic blood pressure with resultant painful carpal spasm.*°  Other symptoms of hypocalcemia are caused by mechanisms  that are not yet understood. These symptoms include dry skin,  loss of body and scalp hair, hypoplasia of developing teeth, hor-  izontal ridges on the nails, cataracts, basal ganglia calcifications    (which may be associated with a parkinsonian syndrome), and  bone deformities, including brachydactyly and bowing of the  long bones.   Phosphate retention caused by increased renal reabsorp-  tion of phosphate is associated also with hypoparathyroid-  ism. Hyperphosphatemia is associated with inhibition of the  renal enzyme necessary for the conversion of vitamin D to  its most active form. This enzyme, 25-hydroxy-vitamin D  la-hydroxylase, also is required by PTH. This tends to depress  serum calcium levels further by reducing gastrointestinal  absorption of calcium.   EVALUATION AND TREATMENT. A low serum calcium level and a  high phosphorous level in the absence of renal failure, intesti-  nal disorders, or nutritional deficiencies suggest hypoparathy-  roidism. Intact PTH levels are low in hypoparathyroidism, and  measurement of serum magnesium and urinary calcium excre-  tion can help in diagnosis.*°   The treatment of hypoparathyroidism is directed toward the  alleviation of hypocalcemia. In acute states this involves par-  enteral administration of calcium, which allows correction of  serum calcium deficit within minutes. Maintenance of serum  calcium level is achieved with pharmacologic doses of an active  form of vitamin D and oral calcium. PTH hormone replace-  ment therapy is being evaluated and results are encouraging.*°  Hypoplastic dentition, cataracts, bone deformities, and basal  ganglia calcifications do not respond to the correction of hypo-  calcemia; however, the other symptoms of hypocalcemia are  reversible.    As serum calcium levels return to normal, phosphaturia  usually is stimulated. This leads to a return to normal serum  phosphate levels. In some individuals, however, the absence of  the phosphaturic effect of PTH causes a persistent hyperphos-  phatemia. Significant elevations of phosphorous concentra-  tion should be treated with drugs that inhibit gastrointestinal  absorption of phosphate (phosphate binders).°°    Diabetes mellitus (DM) is a group of metabolic diseases char-  acterized by hyperglycemia resulting from defects in insulin  secretion, insulin action, or both. It affects 8.3% of the U.S.  population and 27% of Americans older than age 65.°” The  American Diabetes Association (ADA) classifies four categories  of diabetes mellitus®* (Table 22-5):   1. Type 1 (beta-cell destruction, usually leading to absolute  insulin deficiency)   2. Type 2 (ranging from predominantly insulin resistance  with relative insulin deficiency to predominantly an insu-  lin secretory defect with insulin resistance)   hemoglobin (HbA,,) levels, fasting plasma glucose (FPG) levels,  2-hour plasma glucose level during oral glucose tolerance test-  ing (OGTT) using a 75-g oral glucose load, or random glucose   Beta-cell destruction leading to absolute  insulin deficiency; immune-mediated  diabetes is most common form (=90%)   May range from predominantly insulin  resistant with relative insulin deficiency  to predominantly secretory defect with  insulin resistance    Genetic defects in insulin action  Diseases of the exocrine pancreas  Endocrinopathies   75% of individuals develop before 30 years of age; can occur up to the tenth decade   No defined etiologies; absolute requirement for insulin replacement therapy in affected individuals may be sporadic  Usually not insulin dependent but may be insulin requiring   Generally occurs in those older than 40 years, but the frequency is rapidly increasing in children  Strong genetic predisposition    Genetic abnormalities that decrease the ability of the beta cell to secrete insulin:   1. Maturity-onset diabetes of youth (MODY) includes 6 specific autosomal dominant mutations including genes for  hepatocyte nuclear factor-10. (HNF-1a; MODY 3), glucokinase (MODY 2), HNF-4a. (MODY 1), insulin-promoter  factor-1(IPF-1; MODY 4), HNF-16 (MODY 5), and NeuroD1 (MODY 6)   Mutations in the insulin receptor with hyperinsulinism or hyperglycemia or severe diabetes   Any process that diffusely injures the pancreas, including pancreatitis, neoplasia, and cystic fibrosis   Endocrine disorders including acromegaly, Cushing syndrome, glucagonoma, pheochromocytoma, hyperthyroidism,  somatostatinoma, and aldosteronoma   Commonly associated drugs include glucocorticoids and thiazide diuretics, although many others may be implicated    Gestational Diabetes Mellitus (GDM)  Any degree of glucose intolerance  with onset or first recognition during  pregnancy  risk of developing GDM    Reported with “stiff man syndrome” and individuals receiving interferon-c  Down, Klinefelter, Turner, and Wolfram syndromes    Insulin resistance combined with inadequate insulin secretion in relation to hyperglycemia  Women who are obese, older than 25 years of age, have a family history of diabetes, have a history of previous  GDM, or are of certain ethnic groups (Hispanic, Native American, Asian, or African American) are at increased    The metabolic stress of pregnancy may uncover a genetic tendency for type 2 diabetes mellitus    Data from Agency for Healthcare Research & Quality, U.S. Preventive Services Task Force (USPSTF): Screening for gestational diabetes mellitus  recommendation statement, May 2008. Available at www.ahrq.gov/clinic/uspstf08/gestdiab/gdrs.htm; American Diabetes Association (Committee   2. FPG =126 mg/dl (7.0 mmol/L); fasting is defined as no caloric intake for at  least 8 hr*   3. 2-hr plasma glucose =200 mg/dl (11.1 mmol/L) during an OGTT*   4. \In a patient with classic symptoms of hyperglycemia or hyperglycemic  crisis, a random plasma glucose =200 mg/dl (11.1 mmol/L)   2. 2-hr PG in the range of 75 to 199 mg/dl during an OGTT  3. HbA;, 5.7% to 6.4%   *In the absence of unequivocal hyperglycemia, criteria 1 through 3  should be confirmed by repeat testing.   DCCT, Diabetes Control and Complications Trial; FPG, fasting plasma  glucose; HbA,,, hemoglobin A,,; hr hour(s); OGTT, oral glucose toler-  ance test; PG, plasma glucose.    levels in an individual with symptoms (Box 22-1). Glycosylated  hemoglobin refers to the permanent attachment of glucose to  hemoglobin molecules and reflects the average plasma glucose  exposure over the life of a red blood cell (approximately 120  days).   The ADA classification “...categories at increased risk  for diabetes...”°* describes nondiabetic elevations of HbA,,,  FPG, or the 2-hour plasma glucose value during OGTT (see  Box 22-1). This classification includes impaired glucose tol-  erance (IGT), which results from diminished insulin secre-  tion, and impaired fasting glucose (IFG), which is caused by  enhanced hepatic glucose output. Individuals with IGT and  IFG are at increased risk of cardiovascular disease and pre-  mature death and carry a 3% to 7% yearly risk of developing  diabetes.**   Although type 2 diabetes affects a larger percentage of children  and adolescents each year, type 1 diabetes mellitus remains  the most common form of diabetes in those under age 12,  affecting 1 in 300 individuals in the United States. Diagnosis  is rare during the first 9 months of life and peaks at 12 years of  age. It is the result of a loss of beta cells in the pancreatic islets.  Table 22-6 summarizes the epidemiology of diabetes mellitus  (DM).   PATHOPHYSIOLOGY. Two distinct types of type 1 diabetes  have been identified: autoimmune and nonimmune. In auto-  immune-mediated diabetes mellitus, environmental-genetic  factors are thought to trigger cell-mediated destruction of pan-  creatic beta cells. Autoimmune type 1 diabetes is called type 1A.  Nonimmune type | diabetes is far less common than autoim-  mune. It occurs secondary to other diseases, such as pancreati-  tis, or to a more fulminant disorder termed idiopathic (type 1B)  diabetes. Type 1B diabetes occurs mostly in people of Asian or  African descent and affected individuals have varying degrees of  insulin deficiency.   Genetic Susceptibility. Between 10% and 13% of individuals  with newly diagnosed type 1 diabetes have a first-degree  relative (parent or sibling) with type 1 diabetes. There is a  50% concordance rate in twins.®’ The exact nature of genetic  susceptibility to type 1A diabetes is not clearly understood. The  strongest association is with major histocompatibility complex,  or MHC (histocompatibility leukocyte antigen [HLA] class II  alleles HLA-DQ and HLA-DR). Numerous other mutations  involving single genes both within and outside of the MHC  complex have been associated with an increased risk of type 1  DM.”   Environmental Factors. Environmental factors are thought  to have a significant contribution to the development of type  1 diabetes mellitus. Several types of viral infections have been  implicated with autoimmune damage to beta cells, especially  enteroviruses, although a cause-and-effect relationship has not  yet been proven?!*? (see What’s New? The Role of Viruses in  the Etiology of Type 1 Diabetes). Exposure to other infectious    One of the most common childhood diseases (5-10% of all  cases of diabetes mellitus)    Peak onset at age 11-13 yr (slightly earlier for girls than for  boys)   Rare in children younger than 1 yr and adults older than 30 yr    Accounts for most cases (~90-95%)  Prevalence rate for ages 45-64 yr is 10.5%, for ages 65-74 yr is 18.4%    Incidence in all age groups has doubled since 1980  Risk of developing diabetes increases after age 40 yr; in general,    incidence increases with age into the 70s; among Pima Indians,  incidence peaks between ages 40 and 50 yr, then falls    Similar in males and females overall, although black females have the  highest incidence and prevalence of all groups   Racial distribution Rates for whites 1.5-2 times higher than those for nonwhites —_ Risk is highest for blacks and Native Americans   Higher rates for those of Scandinavian descent than for those  of central or southern European descent   Obesity Generally normal or underweight Frequent contributing factor to precipitate type 2 diabetes among  those susceptible; a major factor in populations recently exposed to  westernized environment   Common theory Disease results from genetic susceptibility (polygenic) combined with  environmental determinants and other risk factors; inherited defects  in beta-cell mass and function combined with peripheral tissue insulin  resistance    Autoimmune: Genetic and environmental factors, resulting in  gradual process of autoimmune destruction in genetically  susceptible individuals   Islet cell autoantibodies (ICAs) and/or autoantibodies to  insulin, and autoantibodies to glutamic acid decarboxylase  (GADgs) and tyrosine phosphatases IA-2 and IA-28  are present in 85-90% of individuals when fasting;  hyperglycemia is initially detected   Insulin resistance at diagnosis is unusual, but insulin  resistance may occur as the individual ages and gains  weight    Insulin resistance Insulin resistance is generally caused by altered cellular metabolism    Typically increased at time of diagnosis, but progressively declines over  the course of the illness    The Role of Viruses in the Etiology of Type 1 Diabetes    The etiology of type 1 diabetes is believed to be the result of genetic and envi-  ronmental interactions. The role of viral infection in the etiology of type 1 diabe-  tes continues to be debated. The most recent studies focus on the association  between type 1 diabetes and enteroviruses, especially coxsackieviruses B (CV-    persistent infection. This is postulated to initiate both innate and adaptive  immune responses with consequent effects ranging from functional damage to  cell death. T-cytotoxic T cells play an important role in the autoimmune destruc-  tion of beta cells, and enteroviruses are potent stimulators of T-cytotoxic cell  activation. Another postulated mechanism by which enteroviral infection might  induce beta-cell autoimmunity is by infecting thymic epithelial cells, resulting in  an increase in autoreactive thymocytes. Further investigation into the relation-  ship between viral infection and type 1 diabetes may lead to prevention or treat-  ment through vaccination or immune modulation.    B). Enteroviruses have been implicated both epidemiologically and immunologi-  cally. In one recent study, type 1 diabetes incidence was found to have increased  after epidemics because of enteroviruses; in addition, enteroviral RNA can be  detected in the blood of more than half of individuals with type 1 diabetes at the  time of diagnosis. Enteroviruses can infect pancreatic beta cells and establish    Data from Coppieters KT, von Herrath MG: Clin Rev Allergy Immunol 41(2):169-178, 2011; Galleri L et al: Adv Exp Med Biol 771:252-271, 2012;  Grieco FA et al: Clin Exp Immunol 168(1):24—29, 2012; Hober D et al: Clin Exp Immuno! 168(1):47-51, 2012; Lind K, Huhn MH, Flodstrom-Tullberg  M: Clin Exp Immunol 168(1):30-38, 2012; Stene LC, Rewers M: Clin Exp Immunol! 168(1):12-23, 2012.    Autoantigens form on insulin-producing beta cells  and circulate in the bloodstream and lymphatics    Activation of macrophages Activation of autoantigen-  with release of IL-1 and TNF-o specific T cytotoxic (CD8) cells    FIGURE 22-13 Pathophysiology of Type 1 Diabetes Mellitus. GADgs, Glutamic acid decarboxylase; /FN-y, interferon-    microorganisms (such as Helicobacter pylori), exposure to  cow’s milk proteins, and a relative lack of vitamin D also have  been implicated.”*** Despite intensive research, the number of  identified possible environmental factors remains small.   Type 1 diabetes mellitus is a slowly progressive autoimmune  T cell-mediated disease that occurs in genetically susceptible  individuals (Figure 22-13 and see Chapter 9). The destruction  of beta cells progresses through the following stages:   1. Lymphocyte and macrophage infiltration of the islets result-  ing in inflammation (insulinitis) and islet beta-cell death.  Autoantigens are expressed on the surface of pancreatic  islet cells and circulate in the bloodstream and lymphatics  (see Figure 22-13). Circulating autoantigens are ingested  by antigen-presenting cells that activate CD4+ T helper  1 (Th1) lymphocytes.”° The activated T helper lympho-  cytes secrete interleukin-2 (IL-2) that activates beta-cell  autoantigen-specific T cytotoxic lymphocytes, causing  them to proliferate and attack islet cells through secretion  of toxic perforins and granzymes.”° T helper lymphocytes  also secrete interferon that activates macrophages and  stimulates the release of inflammatory cytokines (includ-  ing IL-1 and tumor necrosis factor [TNF]), which cause  further beta-cell destruction and apoptosis.”’   2. Production of autoantibodies against islet cells, insulin,  glutamic acid decarboxylase (GAD), and other cytoplas-  mic proteins. Activated T helper 2 (Th2) lymphocytes  produce IL-4, which stimulates B lymphocytes to pro-  liferate and produce antibodies (see Figure 22-13). Islet  cell autoantibodies (ICAs) precede evidence of beta-cell  deficiency and can be found in the serum years before  symptoms occur.”® Anti-glutamic acid decarboxylase  (antiGAD,;) antibodies (an enzyme in beta cells that is  involved in coordinating insulin release) are more per-  sistent, which makes them clinically useful in differ-  entiating the etiology of diabetes in a given individual.  Autoantibodies against insulin (insulin autoantibodies    [IAAs]) also have been noted. It is likely that [AAs may  form during the process of active islet cell and beta-cell  destruction.” Finally, another islet antigen against which  antibodies are produced in type 1 diabetes can now be  measured in the serum. It is called the zinc transporter 8  (Znt8) protein and is associated with variation in disease  progression, !0010!   An additional autommune mechanism being explored in  the pathogenesis of type 1 diabetes is a relative inactivity of T  regulatory cells. These T lymphocytes normally serve to inhibit  the immune response and maintain self tolerance.!°* Over time  these immune mechanisms lead to a decrease in beta-cell mass  and insulin production.   Hyperglycemia, Glucagon, and Hyperketonemia. Before  hyperglycemia occurs, 80% to 90% of the function of the  insulin-secreting beta cells in the islet of Langerhans must be  lost. Beta-cell abnormalities are present long before the acute  clinical onset of type 1 diabetes.   A disequilibrium of hormones produced by the islets of  Langerhans occurs in diabetes mellitus. Alpha-cell and beta-cell  functions are abnormal. Lack of insulin and amylin (produced  by beta cells) and a relative excess of glucagon (produced by  alpha cells) exist in type 1 diabetes. The ratio of insulin to glu-  cagon in the portal vein controls hepatic glucose and fat metab-  olism. The paracrine action of insulin and amylin normally  suppresses secretion of glucagon. Considerable data have doc-  umented that high levels of glucagon relative to insulin levels  contribute to the generation of hyperglycemia and hyperketo-  nemia. Thus, both alpha-cell and beta-cell functions are abnor-  mal and both a lack of insulin and amylin and a relative excess  of glucagon contribute to hyperglycemia in type 1 diabetes.  Relative hyperglucagonemia occurs in every form of diabetes  mellitus, leading some researchers to suggest that it is important  in propagating the metabolic abnormalities in diabetes, !0%"!°   CLINICAL MANIFESTATIONS. Historically, type 1 diabetes mellitus  has been thought to have an abrupt onset. It is now known,  however, that the natural history involves a long preclinical    TABLE 22-7 CLINICAL MANIFESTATIONS  AND RATIONALE FOR TYPE 1  DIABETES MELLITUS    Because of elevated blood glucose levels,  water is osmotically attracted from body  cells, resulting in intracellular dehydration  and hypothalamic stimulation of thirst   Hyperglycemia acts as an osmotic diuretic;  the amount of glucose filtered by the  glomeruli of the kidneys exceeds the  amount that can be reabsorbed by the renal  tubules; glycosuria results, accompanied by  large amounts of water lost in the urine   Depletion of cellular stores of carbohydrates,  fats, and protein results in cellular  starvation and a corresponding increase  in hunger   Weight loss occurs because of fluid loss  in osmotic diuresis and the loss of body  tissue as fat and proteins are used for  energy as a result of the effects of insulin  deficiency   Metabolic changes result in poor use of  food products, contributing to lethargy and  fatigue; sleep loss from severe nocturia  also contributes to fatigue    period with gradual destruction of beta cells, eventually leading  to insulin deficiency and hyperglycemia. Generally, this latent  period is longer in older individuals with type 1 diabetes and  often results in misclassification of those affected as having type  2 diabetes.   Type 1 diabetes mellitus affects the metabolism of fat, pro-  tein, and carbohydrates. Glucose accumulates in the blood  and appears in the urine as the renal threshold for glucose is  exceeded, producing an osmotic diuresis and symptoms of  polyuria and polydipsia. Wide fluctuations in blood glucose lev-  els occur. In addition, protein and fat breakdown occur because  of the lack of insulin, resulting in weight loss (Table 22-7).   Insulin normally stimulates lipogenesis and inhibits lipoly-  sis, thus preventing fat catabolism. With insulin deficiency,  lipolysis is enhanced and there is an increase in the amount of  nonesterified fatty acids delivered to the liver. The consequence  is increased glyconeogenesis contributing to hyperglycemia. In  the absence of insulin, the release of free fatty acids from adi-  pocytes increases production of ketone bodies (acetoacetate,  hydroxybutyrate, and acetone) by the mitochondria of the liver  at a rate that exceeds peripheral use. Accumulation of ketone  bodies causes a drop in pH and triggers the buffering sys-  tem associated with metabolic acidosis. Diabetic ketoacidosis  (DKA), caused by increased levels of circulating ketones in the  absence of the antilipolytic effect of insulin, may occur (p. 744).   EVALUATION AND TREATMENT. The criteria for diagnosis of  type 1 diabetes are the same as those for type 2 diabetes (see  Box 22-1). The diagnosis of diabetes is not difficult when the  symptoms of polydipsia, polyuria, polyphagia, weight loss, and    Many different kinds of immunologic approaches are being tested to prevent  the autoimmune destruction of beta cells in type 1 diabetes. These treat-  ments are aimed at preserving insulin synthesis early in the course of disease.  Some of these interventions create generalized immunosuppression, including  mycophenolate mofetil, monoclonal antibodies to B cells (rituximab), mono-  clonal antibodies to T cells (otelixizumab, teplizumab), interleukin-1 blockade,  and cyclosporine. Studies document their effectiveness in stabilizing beta-cell  function but, unfortunately, they also cause many side effects. More focused  immunologic therapies are “antigen specific,” which means they suppress  only the parts of the immune response that are attacking the beta cells. One  approach that has shown some promising (but mixed) results has been the use  of vaccines to induce T-regulatory cells that suppress the immune attack on  specific antigens. Vaccines that have been tested so far include insulin, glu-  tamic acid decarboxylase 65 (GAD-Alum), and heatshock proteins (DiaPep277).  Another ambitious new approach to preserving beta-cell function is through  the introduction of stem cells, which decrease autoimmune responses and  may engraft and become insulin-producing beta cells.    Data from Chen W, Xie A, Chan L: Trans! Res 161(4):217-229, 2013;  Godfrey KJ et al: Diabetic Med 29(1):14-23, 2012; Li CR, Baaten BJ,  Bradley LM: J Mol Cell Biol 4(1):38-47, 2012; Ludvigsson J et al:   N Engl J Med 366(5):433-442, 2012; Miller SA, St Onge E: Exp Opin  Biol Ther 11(11):1525-1532, 2011; Pozzilli P et al: Curr Pharm Design  17(29):3224-3228, 2011; Sherry N et al: Lancet 378:487-497, 2011;  Tooley JE, Waldron-Lynch F, Herold KC: Trends Mol Med 18(3):173-181,  2012; Zhao Y et al: BWC Med 10:3, 2012.    hyperglycemia are present in fasting and postprandial states.  C-peptide, a component of proinsulin released during insulin  production, can be measured in the serum as a surrogate for  insulin levels and is indicative of residual beta-cell mass and  function. Other important aspects of evaluation include assess-  ing for evidence of the chronic complications of type 1 diabetes,  including renal, nervous system, cardiac, peripheral vascular,  retinal, and bony tissue damage.   Nearly half of children aged 4 years and younger and nearly  one fourth of those between the ages of 5 and 15 with type 1  diabetes are first diagnosed when they present with the signs  and symptoms of DKA.!°° In DKA, acetone (a volatile form of  ketones) is exhaled by hyperventilation and gives the breath a  sweet or “fruity” odor. Occasionally, diabetic coma is the initial  symptom of the disease.   Many different kinds of approaches are being tested to pre-  vent the autoimmune destruction of beta cells that is charac-  teristic of type 1 diabetes. Avoidance of cow’s milk, utilization  of a gluten-free diet, and increased intake of omega-3 fatty  acids and vitamin D are all being explored.'°” Pharmacologic  prevention trials include immunosuppression with antirejec-  tion drugs (e.g., mycophenolate mofetil, rituximab, monoclo-  nal antibodies to CD3, and cyclosporine), immunomodulation  therapies, and oral or intranasal insulin'°* (see What’s New?  Immunomodulation in the Prevention and Treatment of Type  1 Diabetes).   Treatment regimens are designed to achieve optimal glu-  cose control (as measured by the HbA,, value) without causing  episodes of significant hypoglycemia. Successful management    Three of the following five traits:  Increased waist circumference (>40 inches in men; >35 inches in women)   Plasma high-density lipoprotein (HDL) cholesterol <40 mg/dl (men) or  <50 mg/dl (women)    requires individual planning according to type of disease, age,  and activity level. All individuals with type 1 diabetes require  some combination of insulin supplementation, meal planning,  exercise program, and self-monitoring of blood glucose level.  Several different types of insulin preparations are available, as  well as new technologies for more physiologic insulin delivery  systems, such as modern insulin pumps.! The use of pram-  lintide, a synthetic analog of amylin, can replace this hormone  in individuals with type 1 and type 2 diabetes.'!° Blood glucose  monitoring is an essential part of management and there are  numerous types of monitoring devices for both self and “real-  time” blood glucose monitoring.''! Individuals also should be  screened at least yearly for complications of diabetes. Finally,  islet cell and whole pancreas transplantation has been successful  in selected individuals.   Type 2 diabetes mellitus is much more common than type  1 and has been rising in incidence since 1940. In the United  States, type 2 diabetes affects 10.5% of those aged 45 to 64 years  and 18.4% of those aged 65 to 74 years, and has doubled in all  adult age groups in the past two decades.'!” Prevalence varies  by ethnic group and gender and is highest in African American  women with an overall prevalence of 34% in those aged 65 to  74. There also is a greatly increased prevalence of type 2 diabetes  in children, especially in Native American and obese children  (see Table 22-6).   An environmental-genetic interaction appears to be respon-  sible for type 2 diabetes.'!> The most well-recognized risk fac-  tors are age, obesity, hypertension, physical inactivity, and  family history. The metabolic syndrome is a constellation of  disorders (central obesity, dyslipidemia, prehypertension, and  an elevated fasting blood glucose level) that together confer a  high risk of developing type 2 diabetes and associated cardio-  vascular complications (Box 22-2). The metabolic syndrome  develops during childhood and is highly prevalent among over-  weight children and adolescents and affects approximately 55  million Americans. These individuals should be screened on a  regular basis for diabetes mellitus. Early recognition and treat-  ment, including vigorous lifestyle changes, are critical to reduc-  ing cardiovascular events and improving clinical outcomes.!!*  Polycystic ovary syndrome (PCOS) also is associated with insu-  lin resistance and risk of diabetes seven times the average risk  for women without PCOS.!!°    PATHOPHYSIOLOGY. Many organs contribute to the insulin resis-  tance and chronic hyperglycemia associated with type 2 diabetes  mellitus (Figure 22-14). Additionally, genes have been identi-  fied that are associated with type 2 diabetes, including those  that code for beta-cell mass, beta-cell function (ability to sense  blood glucose levels, insulin synthesis, and insulin secretion),  proinsulin and insulin molecular structure, insulin receptors,  hepatic synthesis of glucose, glucagon synthesis, and cellular  responsiveness to insulin stimulation. Genetic abnormalities  also are the result of epigenetic changes that occur in response  to environmental influences that span generations.'!®'!” The  combination of genetic, epigenetic, and environmental influ-  ences results in the basic pathophysiologic mechanisms of type  2 diabetes: insulin resistance and decreased insulin secretion by  beta cells (Figure 22-15). All of these mechanisms are essential  to the development of type 2 diabetes. Although many indi-  viduals with risk factors for type 2 diabetes (including obesity,  metabolic syndrome, and hypertension) are insulin resistant,  only those individuals who are genetically predisposed to beta-  cell dysfunction (and therefore a relative deficiency in insulin)  will develop type 2 diabetes.!'®   Insulin resistance is defined as a suboptimal response of  insulin-sensitive tissues (especially liver, muscle, and adipose  tissue) to insulin. Several mechanisms are involved in abnormal-  ities of the insulin signaling pathway and contribute to insulin  resistance. These include an abnormality of the insulin mole-  cule, high amounts of insulin antagonists, down-regulation of  the insulin receptor, decreased or abnormal activation of post-  receptor kinases, and alteration of glucose transporter (GLUT)  proteins. Obesity is present in 60% to 80% of those with type 2  diabetes and is a major contributor to insulin resistance through  several important mechanisms:   A nuclear receptor, called peroxisome proliferator—  activated receptor gamma (PPARy), is highly expressed  in adipose cells and is responsible for modulating changes  in adipokines in obese individuals, including increased  serum levels of leptin (leptin resistance) and resistin and  decreased levels of adiponectin. Changes in adipokines  have effects not only on tissues but also on hypothalamic  and pancreatic function.!'”!?° A group of insulin-sensi-  tizing drugs, called the thiazolidinediones that modulate  PPARy activity, have been used in the treatment of type 2  diabetes for many years.   2. Elevated levels of serum free fatty acids (FFAs) and intra-  cellular deposits of triglycerides and cholesterol are found  in obese individuals who have what has been termed  “metabolic overload” (high caloric and lipid intake).  FFAs bind to G-protein—coupled receptors, which modu-  late several responses. These changes interfere with intra-  cellular insulin signaling, decrease tissue responses to  insulin, cause alterations in insulin incretin and glucagon  secretion, and promote inflammation.!”!   3. Obesity causes release of inflammatory cytokines  (TNF-a, IL-6) from intra-abdominal adipocytes or  adipocyte-associated mononuclear cells and from acti-  vated macrophages in other tissues. These cytokines    LIVER Decreased stomach secretion KIDNEY a  Increased hepatic of gherlin Increased glucose reabsorption  APIPOSE TISSUE gluconeogenesis and gluconeogenesis MUSCLE    dependent glucose uptake sensitivity  Increased lipolysis Decreased glucose  Decreased adiponectin uptake  Increased leptin and resistin Increased lipid  Macrophage accumulation and accumulation  inflammation (TNF-a, IL-6)    FIGURE 22-14 Multiorgan Causes and Common Consequences of Chronic Hyperglycemia in Type 2 Diabetes  Mellitus. /L, Interleukin; PVD, Peripheral vascular disease; TNF, Tumor necrosis factor.    4 Activity of incretins =~ tDemand for insulin synthesis  Hypoinsulinemia i i i  Amylin yp Hyperinsulinemia  t Glucagon—-> Tissue effects and Tissue effects without  hyperglycemia hyperglycemia (insulin  (type 2 diabetes) resistance without diabetes)    induce insulin resistance through a postreceptor mecha-  nism and play an important role in the genesis of fatty  liver, atherosclerosis and dyslipidemia.!?*!*°   lar mitochondria have been documented, resulting  in reduced insulin-stimulated mitochondrial activity  and insulin resistance, especially in skeletal muscle and  hepatocytes, !?4!25   In most individuals with type 2 diabetes, compensatory  hyperinsulinemia prevents the clinical appearance of diabe-  tes for many years. Eventually, however, islet cell dysfunction  develops and leads to a relative deficiency of insulin activity.  Beta-cell dysfunction is caused, in part, by a decrease in beta-  cell mass. A progressive decrease in the weight and number of  beta cells occurs in type 2 diabetes, and several different mecha-  nisms have been implicated. Beta cells are extremely sensitive to  high levels of glucose and free fatty acids and, under these so-  called glucolipotoxic conditions, beta-cell endoplasmic reticu-  lum function is interrupted and beta cells undergo apoptotic  cell death.!?° Beta-cell dysfunction also is caused by inflamma-  tion and changes in adipokines. A variety of inflammatory cyto-  kines, including TNF-a, IL-1, and IL6, also have been shown  to be toxic to beta cells, and autoimmune beta-cell destruction  has been described in type 2 diabetes.!2” The adipokine leptin  decreases insulin synthesis in the beta cell. Thus many of the  obesity-related causes of insulin resistance (elevated free fatty  acid [FFA] hyperglycemia, adipokines, and inflammatory cyto-  kines) also promote programmed cell death in beta cells.   Glucagon is a hormone produced by the alpha cells of the  pancreas and acts primarily in the liver to increase blood glu-  cose level by stimulating glycogenolysis and gluconeogenesis.  Glucagon acts as an antagonist to insulin. In healthy individu-  als, high glucose levels cause glucagon release to be inhibited.  As in type 1 diabetes, pancreatic alpha cells in type 2 diabetes  are less responsive to glucose inhibition, resulting in increased  glucagon secretion. These abnormally high levels of glucagon  have long been known to play a role in the increased hepatic  production of glucose and resultant hyperglycemia seen in type  2 diabetes.10>128   Amylin (islet amyloid polypeptide) is another beta-cell hor-  mone that is decreased in both type 1 and type 2 diabetes. Amy-  lin increases satiety and suppresses glucagon release from the  alpha cells. It also contributes to islet cell destruction through  the deposition of abnormal (misfolded) amyloid polypeptide in  the pancreas.!?*'°° Pramlintide, a synthetic analog of amylin,  is used for treatment in both type 1 and type 2 diabetes.!041°!   The incretins, glucagon-like peptide-1 (GLP-1) and glu-  cose-dependent insulinotropic polypeptide (GIP), are a class  of peptides released from the gastrointestinal tract in response  to food intake. They increase the sensitivity of beta cells to cir-  culating glucose levels, thus improving insulin responsiveness  to meals. They are then inactivated by the enzyme dipeptidyl  peptidase IV (DPP-IV). These peptides are important in main-  taining glycemic control, and currently two GLP-1 agonists  and four DPP-IV inhibitors are approved for use in the United    The incretin hormone system is being explored as a possible therapeutic target  in diabetes. Incretin hormones are secreted by enteroendocrine cells of the  large and small intestines. The major component of this system, glucagon-like  peptide-1 (GLP-1), has many positive effects on glucose metabolism. GLP-1  augments glucose-dependent insulin secretion without causing hypoglycemia,  stimulates insulin gene expression, inhibits glucagon secretion, delays gastri  emptying, and induces a feeling of satiety through an effect on the cen  nervous system. GLP-1 also has been shown to induce new beta-cell differen-  tiation (neogenesis) from pancreatic ductal cells and to protect beta cells from  apoptosis (programmed cell death). There are two classes of incretin-related  therapies: GLP-1 receptor agonists (GLP-1 RAs) and dipeptidy! peptidase IV  (DPP-IV) inhibitors. Two incretin GLP-1 RAs (exenatide and liraglutide) are  approved for use in the United States and three are in development. They  lower postprandial plasma glucose level with little risk of hypoglycemia, assist  individuals with weight loss, and augment endogenous insulin secretion. A  recent study documented that nearly two thirds of persons treated with GLP-1  RAs alone achieved target HbA,, levels after 12 weeks of therapy. The avail-  able DPP-IV inhibitors (sitagliptin, saxagliptin, vildagliptin, and linagliptin) also  improve metabolic control but to a lesser degree than the GLP-1 RAs; however,  they have been shown to improve levels of serum lipids. Both classes are  well tolerated: GLP-1 RAs are associated with nausea and DPP-IV inhibitors  are associated with headaches and certain infections. Pancreatitis has been  reported in both but appears to be a rare complication.    Data from Blonde L, Montanya E: Diabetes Obes Metab 14(Suppl  2):20-32, 2012; Esposito K et al: Diabetes Obes Metab 14(3):228-233,  2012; Israili ZH: Am J Ther 18(2):117-152, 2011; Karagiannis T et al:  BMJ 344:e1369, 2012; Monami M et al: Adv Therapy 29(1):14—-25,  2012; Scheen AJ: Exp Opin Pharmacol! 13(1):81-99, 2012.   Ghrelin is a peptide produced in the stomach and pancre-  atic islets. Hyperinsulinemia and hyperleptinemia are asso-  ciated with decreased levels of ghrelin in type 2 diabetes.!*°  Decreased levels of circulating ghrelin have been associated  with alterations in insulin secretion, insulin resistance, and obe-  sity. Its use as a potential treatment for type 2 diabetes is being  investigated.!°419°   CLINICAL MANIFESTATIONS. Clinical manifestations of type 2  diabetes are nonspecific. The affected individual often is over-  weight, dyslipidemic, hyperinsulinemic, and hypertensive.  Classic symptoms of polyuria and polydipsia may present, but  more often individuals will complain of nonspecific symptoms  such as fatigue, pruritus, recurrent infections, visual changes, or  symptoms of neuropathy (paresthesias or weakness). In those  whose diabetes has progressed without treatment, symptoms  related to coronary artery, peripheral artery, and cerebrovascu-  lar disease may develop (Table 22-8).   EVALUATION AND TREATMENT. The diagnostic criteria for type 2  diabetes are the same as those for type 1 (see Box 22-1). Preven-  tion of type 2 diabetes hinges on diet and exercise to reduce  weight. Pharmacologic therapy may be considered for those at  highest risk for diabetes, especially if HbA, levels continue to  rise despite lifestyle modifications. Annual monitoring for dia-  betes is indicated in those with prediabetes. !°°    TABLE 22-8 CLINICAL MANIFESTATIONS  AND RATIONALE FOR TYPE 2  DIABETES MELLITUS    Growth of microorganisms is stimulated by  increased glucose levels; impaired blood  supply hinders healing    Recurrent infections  (e.g., boils and  carbuncles; skin  infections) and  prolonged wound  healing   Genital pruritus Hyperglycemia and glycosuria favor fungal  growth; candidal infections, resulting in  pruritus, are a common presenting symptom  in women   Blurred vision occurs as water balance in the  eye fluctuates because of elevated blood  glucose levels; diabetic retinopathy is  another cause of visual loss   Metabolic changes result in poor use of  food products, contributing to lethargy and  fatigue    The first step in management is to establish an appropri-  ate glycemic goal. Although treatment regimens that reduce  HbA,, to around 7% have been shown to reduce long-term  complications, intensive lowering of glucose concentration to  near-normal levels through the use of multiple agents is not  correlated with better outcomes and is associated with a greater  risk for hypoglycemic episodes and weight gain.'°°!°   Dietary measures, including restriction of the total caloric  intake, are of primary importance in both the prevention and  the treatment of type 2 diabetes.'*° As the obese individual loses  weight, the body’s resistance to insulin often diminishes. Non-  obese individuals with type 2 diabetes should consume calories  consistent with their ideal weight and pattern of activity. The  emphasis of medical nutrition therapy (MNT) in type 2 diabe-  tes mellitus should be focused on achieving glucose, lipid, and  blood pressure goals.!*!   Exercise is an important aspect of prevention and treatment  of type 2 diabetes.!*° Exercise reduces postprandial blood glu-  cose levels, diminishes insulin requirements, lowers triglyceride  and cholesterol levels, and increases the level of high-density  lipoprotein (HDL) cholesterol. In addition, exercise is a valu-  able adjunct to weight loss for the overweight individual. Hypo-  glycemia may result, however, when the exercising individual  receives sulfonylurea or insulin therapy.   In those individuals with morbid obesity unresponsive to  diet and exercise interventions, bariatric surgery may be indi-  cated. Studies suggest that gastric bypass surgery is associated  with marked improvements in glycemic control in those with  established diabetes!** (see What's New? Bariatric Surgery in  the Treatment of Diabetes).   For most individuals with type 2 diabetes, medications  are needed for optimal management. Although many older    The American Diabetes Association has endorsed bariatric surgery for the  treatment of type 2 diabetes in individuals with body mass indexes (BMIs)  >35 kg/m?. Gastric bypass surgery is now the procedure of choice, although  gastric banding procedures also have beneficial results. There is current pow-  erful evidence that bariatric surgery improves glycemic control in up to 80%  of individuals with type 2 diabetes, even before there is any significant weight  loss. The proposed mechanisms for these effects continue to be researched.  Current hypotheses relate to changes in neuroendocrine control involving the  hypothalamus, pancreas, liver, and gut. Hormones that have been implicated  include changes in the concentrations of ghrelin, leptin, and the incretins.  Long-term studies are now confirming the safety and efficacy of bariatric sur-  gery in achieving persistent glycemic control and reduced risk for diabetes-  associated cardiovascular complications. Further study is needed to determine  the mechanisms by which bariatric surgery has such profound effects on type  2 diabetes, and whether similar outcomes might be achieved with less-inva-  sive techniques.    Data from Dixon JB et al: Obes Rev 13(1):57-67, 2012; Ismail-Beigi  F: N Engl J Med 366(14):1319-1327, 2012; Li O et al: Diabetes  Obes Metab 14(3):262-270, 2012; McKenney RL, Short DK: Surg  Clin North Am 91(6):1139-1148, vii, 2011; Noria SF, Grantcharov T:  Can J Surg 56(1):47-57, 2013; Park CW, Torquati A: Surg Clin North  Am 91(6):1149-1161, vii, 2011; Sala PC et al: Obes Surg 22(1):  167-176, 2012.    individuals continue to use insulin injections, oral hypoglyce-  mic agents are the treatment of choice for most people.!*? There  are currently nine classes of oral agents available!’ (Table  22-9). Insulin therapy may be needed in the later stages of type  2 diabetes because of loss of beta-cell function; however, the  risks of treatment-related hypoglycemia must be considered.'*°    As described in Table 22-5 (p. 734), the American Diabetes  Association (ADA) classification of diabetes mellitus encom-  passes not only the most common forms of diabetes (type 1 and  type 2) but also “other specific types of diabetes mellitus” and  “gestational diabetes mellitus.” Other specific types of diabe-  tes include genetic defects in beta-cell function, genetic defects  in insulin action, diseases of the exocrine pancreas, endocri-  nopathies, drug- or chemical-induced beta-cell dysfunction,  infections, and other uncommon autoimmune and inherited  disorders that are associated with diabetes.   The most well described of these other specific types of dia-  betes is termed maturity-onset diabetes of youth (MODY).  MODY accounts for 1% to 2% of diabetes and should be con-  sidered in children who lack beta-cell antibodies. It also may  account for up to 5% of individuals diagnosed with gestational  diabetes.'44 MODY includes six specific autosomal dominant  mutations including genes for hepatocyte nuclear factor-  la (HNF-la; MODY 3), glucokinase (MODY 2), HNF-4a  (MODY 1), insulin promoter factor-1 (IPF-1; MODY 4), HNF-  18 (MODY 5), and NeuroD1 (MODY 6).'*° Interestingly, the  gene mutations found in MODY are not commonly found in  type 2 diabetes. The clinical diagnosis of MODY is based on the  following criteria: family history of diabetes with an autosomal    a-Glycosidase inhibitor  (miglitol and voglibose)  Biguanide  (metformin)  Meglitinides (glinides)  (repaglinide and nateglinide)  Sulfonylureas  (glyburide, glipizide, gliclazide, glimepiride)  Peroxisome proliferator-activated-receptor-gamma agonists  (thiazolidinediones, pioglitazone, and rosiglitazone)  Bile acid sequestrant  (colesevelam)  GLP-1 receptor agonists  (exenatide and liraglutide)  DPP-IV inhibitors  (sitagliptin, saxagliptin, vildagliptin, and linagliptin)  Amylin mimetics  (pramlintide)  SGLT2 inhibitor (sodium-glucose co-transporter 2)  n clinical trials: canagliflozin, dapagliflozin, empagliflozin    Decreases hepatic glucose production and increases insulin sensitivity and peripheral glucose  uptake  Stimulate insulin release from pancreatic beta cells    Stimulate insulin release from pancreatic beta cells  Increase insulin sensitivity, particularly in adipose tissue    Unknown; theories include decreased hepatic glucose production, increased insulin secretion,  and increased incretin release   Increase insulin secretion, decrease glucagon secretion, decrease rate of gastric emptying,  decrease appetite, weight loss   Increase insulin secretion, decrease glucagon secretion, decrease rate of gastric emptying,  decrease appetite   Decrease glucagon secretion, decrease rate of gastric emptying, and decrease appetite    Inhibits proximal tubular renal transport of glucose, decreasing glucose reabsorption and  increasing renal excretion of glucose independent of insulin    Data from Ismail-Beigi F: N Engl J Med 366(14):1319-1327, 2012; Misra M: J Pharm Pharmacol, published online August 9, 2012.    dominant mode of inheritance, insulin independence (nonke-  totic diabetes mellitus), and age at onset younger than 25 years.  Genetic testing confirms the diagnosis. It is important to iden-  tify those with MODY because many can be effectively treated  with an oral hypoglycemic agent (sulfonylureas) rather than  with injections of insulin.'4>!4°   Gestational diabetes mellitus (GDM) has long been defined  as any degree of glucose intolerance with onset or first recogni-  tion during pregnancy. However, the recent dramatic increase  in type 2 diabetes prevalence has led to the recommendation that  high-risk women found to have diabetes at their initial prenatal  visit receive a diagnosis of overt diabetes.** GDM complicates  approximately 7% of all pregnancies. The exact mechanism of  GDM is unknown, but insulin resistance and inadequate insu-  lin secretion are contributing factors. The American Diabetes  Association recommends that pregnant women with risk fac-  tors be screened for type 2 diabetes at their first prenatal visit.  Those without a history of DM also should be screened with an  oral glucose tolerance test at 24 to 28 weeks’ gestation. Women  with GDM should be monitored after delivery.!°° Often there  are no symptoms and careful glucose level control prenatally,  during pregnancy, and after delivery is essential to both the  short-term and the long-term health of mother and baby.'4”  There is an increased risk for type 2 diabetes and associated  complications later in life in women who develop gestational  diabetes. !“*   Hypoglycemia is a lowered plasma glucose level. In general,  hypoglycemia occurs when blood glucose levels are less than  35 mg/dl in newborns for the first 48 hours of life and less than 45  to 60 mg/dl in children and adults. Its causes may be exogenous    (medications, alcohol, or exercise), endogenous (tumors of the  pancreas or inherited disorders), or functional (hyperalimenta-  tion, spontaneous, or liver disease). Hypoglycemia in diabetes  is sometimes called insulin shock or insulin reaction. Individuals  with type 2 diabetes are at less risk for hypoglycemia than those  with type 1 diabetes because they retain relatively intact glu-  cose counterregulatory mechanisms. However, hypoglycemia  does occur in type 2 diabetes when treatment involves insulin  secretogogues (e.g., sulfonylureas) or exogenous insulin (Table  22-10).   Symptoms of hypoglycemia result either from activation of  the sympathetic nervous system (neurogenic adrenergic symp-  toms) or from an abrupt cessation of glucose delivery to the  brain (neuroglycopenic symptoms), or both.!47!>°   Neurogenic reactions occur when the decrease in blood glu-  cose level is rapid and present with tachycardia, palpitations,  diaphoresis, tremors, pallor, and arousal anxiety. Neuroglyco-  penia causes further symptoms including headache, dizziness,  irritability, fatigue, poor judgment, confusion, visual changes,  hunger, seizures, and coma. Hypoglycemia unawareness is  a phenomenon that occurs in individuals without appropri-  ate autonomic warning symptoms. Autonomic symptoms are  blunted, symptoms are reduced, and recovery from hypogly-  cemia may be delayed because of impaired glycogenolysis and  hampered delivery of gluconeogenic substrates to the liver.   The American Diabetes Association recommends that glu-  cose (15 to 20 g) be given to the conscious individual with  hypoglycemia. Doses of glucagon should be prescribed for  emergency use for all individuals at significant risk of severe  hypoglycemia, and caregivers should be instructed in their use.  Individuals with hypoglycemia unawareness or who have had  episodes of severe hypoglycemia should raise their glycemic  treatment targets to reduce risk of future episodes. '°°    Older adults or very young individuals with  type 2 diabetes, nondiabetic individuals with   Excessive insulin or sulfonylurea agent intake, lack of  sufficient food intake, excessive physical exercise,  abrupt decline in insulin needs (e.g., renal failure,  immediately postpartum), simultaneous use of insulin-  potentiating agents or beta-blocking agents that mask  symptoms   Neurogenic reaction: fatigue, irritability, headache,  loss of concentration, visual disturbances, dizziness,  hunger, confusion, transient sensory or motor defects,  convulsions, coma, death    Laboratory Analysis  Serum glucose <30 mg/dl in newborn (first 2-3 days)  and <55-60 mg/dl in adults    Stressful situation such as infection, accident,  trauma, emotional stress; omission of insulin;  medications that antagonize insulin    Malaise, dry mouth, headache, polyuria, polydipsia,  weight loss, nausea, vomiting, pruritus,  abdominal pain, lethargy, shortness of breath,  Kussmaul respirations, fruity or acetone odor to    Glucose levels >250 mg/dl, reduction in  bicarbonate concentration; increased anion gap;  increased plasma levels of B-hydroxybutyrate,    Polyuria, polydipsia, hypovolemia, dehydration  (parched lips, poor skin turgor), hypotension,  tachycardia, hypoperfusion, weight loss,  weakness, nausea, vomiting, abdominal pain,  hypothermia, stupor, coma, seizures    Glucose levels >600 mg/dl, lack of ketosis,  serum osmolarity >320 mOsm/L, elevated  blood urea nitrogen and creatinine   Ketoacidosis, a serious complication of diabetes mellitus, is a  common cause for hospital admissions. Diabetic ketoacidosis  (DKA) develops when there is an absolute or relative deficiency  of insulin and an increase in the levels of insulin counterregu-  latory hormones.'*! This is most common in individuals with  type 1 diabetes but can occur in those with type 2 diabetes as  well. In addition, a syndrome called ketosis-prone diabetes  (KPD) has been described and occurs most frequently in obese,  middle-aged men with a strong family history of type 2 diabe-  tes. These individuals do not fit the criteria for diagnosis of type  1 or type 2 diabetes but exhibit significantly impaired insulin  secretion spontaneously or in response to physiologic stress  such as infection.!°* The most common precipitating factor for  DKA is intercurrent illness, such as infection, trauma, surgery,  or myocardial infarction. Interruption of insulin administra-  tion also may result in DKA. Factors associated with increased  risk are younger or older age, diagnostic error, ethnic minority,  lack of health insurance in the United States, lower body mass  index, preceding infection, and delayed treatment.!°?    PATHOPHYSIOLOGY. In a state of relative insulin deficiency there  is an increase in the concentrations of insulin counterregulatory  hormones including catecholamines, cortisol, glucagon, and  GH. These counterregulatory hormones antagonize insulin by  increasing glucose production and decreasing tissue use of glu-  cose. Profound insulin deficiency results in decreased glucose  uptake, increased fat mobilization with release of fatty acids, and  accelerated gluconeogenesis and ketogenesis (Figure 22-16).!>!  Relatively increased glucagon levels also contribute to activa-  tion of the gluconeogenic (glucose-forming) and ketogenic  (ketone-forming) pathways in the liver. Because of the insulin  deficiency, hepatic overproduction of B-hydroxybutyrate and  acetoacetic acids causes increased ketone concentrations. Ordi-  narily ketones are used by tissues as an energy source to regen-  erate bicarbonate. This balances the loss of bicarbonate, which  occurs when the ketone is formed. Hyperketonemia (increased  blood ketone levels) may be a result of impairment in the use of  ketones by peripheral tissue, which permits strong organic acids  to circulate freely. Bicarbonate buffering then does not occur,  and the individual develops a metabolic acidosis.    CLINICAL MANIFESTATIONS. The signs and symptoms of DKA  are nonspecific. Polyuria and dehydration result from the  osmotic diuresis associated with hyperglycemia. In this case,  the plasma glucose level is higher than the individual’s renal  threshold, allowing significant amounts of glucose to be lost in  the urine. Deficits of sodium, phosphorus, and magnesium are  common. The most important electrolyte disturbance, how-  ever, is a marked deficiency in the level of total body potassium.  Although the serum potassium concentration may appear nor-  mal or elevated because of volume contraction and a shift of  potassium out of the cell and into the blood caused by metabolic  acidosis, the total body deficiency of potassium may reach 3 to  5 mEq/kg. Symptoms of diabetic ketoacidosis include Kussmaul  respirations (hyperventilation in an attempt to compensate for  the acidosis), postural dizziness, central nervous system depres-  sion, ketonuria, anorexia, nausea, abdominal pain, thirst, and  polyuria (see Table 22-10).   EVALUATION AND TREATMENT. The diagnosis of ketoacidosis  is suggested when individuals have symptoms of vomiting,  abdominal pain, dehydration, an acetone odor on the breath,  and change in sensorium. The American Diabetes Association  criteria for the diagnosis of DKA are: (1) a serum glucose level  >250 mg/dl, (2) a serum bicarbonate level <18 mg/dl, (3) a  serum pH <7.30, (4) the presence of an anion gap, and (5) the  presence of urine and serum ketones.!**   Treatment of DKA involves administration of insulin to  decrease glucose levels. Fluids are administered to replace lost  fluid volume. Electrolyte deficits become apparent as fluid  volume is replaced, and intravenous sodium, potassium, and  phosphorus are administered as needed. Fluids and electro-  lytes should be monitored closely.!°° After the administration  of insulin, the concentration of $-hydroxybutyrate promptly  begins to decrease, and after a slight increase, acetoacetate con-  centration also begins to decrease. A persistent ketonuria may    be observed for several days after treatment. Continuous moni-  toring of the individual is essential to ensure an uncomplicated  recovery from DKA. Health teaching emphasizes predisposing  factors and strategies for avoiding DKA.   Hyperosmolar hyperglycemic nonketotic syndrome  (HHNKS), or hyperglycemic hyperosmolar state (HHS), is a  life-threatening emergency most often precipitated by infec-  tions, medications, nonadherence to diabetes treatment, or  coexisting disease.!°! HHNKS is more commonly seen with  type 2 diabetes. It can also occur in individuals with pancreatic  destruction from other causes such as chronic pancreatitis.   PATHOPHYSIOLOGY. HHNKS differs from DKA in the degree  of insulin deficiency (which is more profound in DKA) and  the degree of fluid deficiency (which is more marked in  HHNKS) (see Figure 22-16). HHNKS is characterized by  a lack of ketosis. Because the amount of insulin required to  inhibit fat breakdown is less than that needed for effective glu-  cose transport, insulin levels are sufficient to prevent excessive  lipolysis but not to use glucose properly.!°! Glucose levels are  considerably higher in HHNKS than in DKA because of vol-  ume depletion.   CLINICAL MANIFESTATIONS. Glycosuria and polyuria in HHNKS  result from the extreme serum glucose level elevation. As much  as 19 g of glucose per hour may be lost in diuresis, which also  causes severe volume depletion, increased serum osmolarity,  intracellular dehydration, and loss of electrolytes including  potassium. Neurologic changes, such as stupor, correlate with  the degree of hyperosmolarity and are common in HHNKS;  thus, this syndrome is sometimes called hyperosmolar hypergly-  cemic coma.   EVALUATION AND TREATMENT. The diagnostic features of  HHNKS include a very high serum glucose concentration    (often more than 600 mg/dl), a near-normal serum bicar-  bonate level and pH, a serum osmolarity that is usually  greater than 320 mOsm/L, and either absent or low levels of  ketones in the urine and serum.'°! DKA and HHNKS show  considerable overlap in symptoms and treatment. Insu-  lin infusion should be combined with fluid repletion over  24 hours.!°° An important distinction, however, is that the  dehydration in HHNKS is far more severe than that in DKA.  Thus fluid replacement, with both crystalloids and colloids,  is more rapid. Potassium deficits may be extreme and require  several days of treatment. Phosphorus and sodium also may  be needed. HHNKS is a significant risk factor for infection,  sepsis, and venous thrombosis.!°'! Mortality also is high  in HHNKS, and is related to the age of the individual and  comorbid conditions including the severity of the precipi-  tating illness (see Table 22-10 for a comparison of the three  acute complications described thus far).   The Somogyi effect is a unique combination of hypoglycemia  followed by rebound hyperglycemia. The rise in blood glucose  concentration occurs because counterregulatory hormones  (epinephrine, GH, corticosteroids), which are stimulated by  hypoglycemia, cause gluconeogenesis. Excessive carbohydrate  intake may contribute to the rebound hyperglycemia. The clini-  cal occurrence of Somogyi effect is controversial.    The dawn phenomenon is an early morning rise in blood glu-  cose concentration with no hypoglycemia during the night. It is  related to nocturnal elevations of GH, which decrease metabo-  lism of glucose by muscle and fat. Increased clearance of plasma  insulin also may be involved. Altering the time and dose of  insulin administration manages the problem.    A number of serious complications are associated with any type  of DM, including microvascular (e.g., retinopathy, nephropa-  thy, and neuropathy) and macrovascular disease (e.g., coro-  nary artery disease, stroke, and peripheral vascular disease),  and infection. Most complications are associated with chronic  hyperglycemia (see Figure 22-14). Strict control of blood glu-  cose level significantly reduces some complications, particu-  larly microvascular events. Oxidative stress (overproduction  of reactive oxygen species) and activation of several complex  metabolic pathways have been associated with persistent hyper-  glycemia and the chronic complications of DM. They include  shunting of glucose into the polyol pathway, activation of pro-  tein kinase C isoforms, increased formation of advanced glyca-  tion end products (AGEs), increased expression of the receptor  for AGEs (RAGE), and increased activation of the hexosamine  pathway.'°’” It has been proposed that hyperglycemia induces  mitochondrial overproduction of oxygen free radicals and this  is a key pathologic mechanism for the activation of the meta-  bolic pathways associated with the chronic complications of  DM.!°*!5° Genetic and epigenetic factors contribute to the eti-  ology of diabetic complications.!'*!   Chronic hyperglycemia, insulin resistance, hyperinsulinemia,  and dyslipidemia contribute to the production of reactive  oxygen species (ROS) and the detrimental effects of oxidative  stress. Increased formation of AGEs, defects in the polyol path-  way, and uncoupling of nitric oxide synthase, xanthine oxidase,  and nicotinamide adenine dinucleotide phosphate (NADPH)  oxidase generate ROS, which damage large and small vessels  and contribute to atherogenesis and to micro- and macrovas-  cular disease. Direct cellular injury, as well as the formation of  gene products that cause endothelial cellular injury, contributes  to these late complications of diabetes mellitus.!°”   Tissues that do not require insulin for glucose transport, such as  the kidney, red blood cells (RBCs), blood vessels, eye lens, and  nerves, cannot down-regulate the cellular uptake of glucose.  Consequently, intracellular glucose is shunted into an alternate  metabolic pathway for glucose metabolism known as the polyol  pathway. Overactivation of the polyol pathway results in two  processes that may contribute to the complications of diabetes.  One is the excessive accumulation of sorbitol (a polyol-sugar  alcohol) through the action of the enzyme aldose reductase.  The accumulated sorbitol increases intracellular osmotic pres-  sure and attracts water in tissue. Swelling occurs along with  visual changes and predisposition to cataracts in the lens of the  eye. Sorbitol interferes with ion pumps in the nerves, damages  Schwann cells, and disrupts nerve conduction. RBCs become  swollen and stiff and interfere with perfusion. Second, activa-  tion of the polyol pathway reduces glutathione, an important  antioxidant, contributing to oxidative injury in cells and tissues,  particularly blood vessels. Aldose reductase inhibitors are being  evaluated for treatment of these complications. !°   Protein kinase C (PKC) is a family of intracellular signaling  proteins that can become inappropriately activated in dif-  ferent tissues by hyperglycemia. Intracellular hyperglycemia  increases the second-messenger diacylglycerol (DAG)-PKC  pathway, which in turn activates protein kinase C. Various  consequences have been observed, including insulin resistance,  extracellular matrix and cytokine production, vascular cell pro-  liferation, enhanced contractility, angiogenesis, and increased  permeability. These effects may contribute to the microvascular  complications of diabetes. Specific PKC inhibitors are under  investigation and have shown some promise in stabilizing or  preventing retinopathy, nephropathy, and neuropathy.'°°   Glycation is a normal non-enzymatic process that involves the  reversible attachment of glucose to proteins, lipids, and nucleic  acids without the action of enzymes. With recurrent or per-  sistent hyperglycemia, glucose becomes irreversibly bound to  collagen and other proteins in red blood cells (e.g., glycated  hemoglobin), blood vessel walls, interstitial tissue, and within  cells. The products of this binding are known as advanced gly-  cation end products (AGEs), and their receptor (RAGE). They    have a number of properties that may cause tissue injury or  pathologic conditions associated with diabetes!*+!®:   1. Cross-linking and trapping of proteins, including albu-  min, low-density lipoprotein (LDL), immunoglobulin,  and complement, with thickening of the basement mem-  brane or increased permeability in small blood vessels  and nerves   2. Binding to cell receptors, such as macrophages and glo-  merular mesangial cells, and inducing release of inflam-  matory cytokines and growth factors that stimulate  cellular proliferation in the glomeruli, smooth muscle of  blood vessels, and collagen synthesis with fibrosis   4. Inactivation of nitric oxide with loss of vasodilation and  diminished endothelial function   5. Procoagulant changes on endothelial cells with promo-  tion of platelet adhesion and reduced fibrinolysis   Chronic intracellular hyperglycemia causes shunting of excess  intracellular glucose into the hexosamine pathway and leads to  O-linked glycosylation (an enzymatic process) of several pro-  teins with alteration in signal transduction pathways and oxi-  dative stress. The O-linked attachment of N-acetylglucosamine  (O-GlcNAc) on serine and threonine residues of nuclear and  cytoplasmic proteins is associated with insulin resistance and  cardiovascular complications of diabetes mellitus.!°”    Microvascular Disease  Diabetic microvascular complications (disease in capillaries) are  a leading cause of blindness, end-stage renal failure, and various  neuropathies. Thickening of the capillary basement membrane,  endothelial cell hyperplasia, thrombosis, and pericyte degenera-  tion are characteristic of diabetic microangiopathy and emerge  over a period of 1 to 2 years. The thickening eventually results  in decreased tissue perfusion. Hyperglycemia is a prerequisite  for these microvascular changes and may be related to glyca-  tion of structural proteins, which results in the accumulation  of AGEs. The frequency and severity of the lesions appear to be  proportional to the duration of the disease and blood glucose  control. In the Diabetes Control and Complications Trial—  the Epidemiology of Diabetes Intervention and Complications  Study (DCCT-EDIC), the intensively treated cohort continued  to have significantly fewer complications (metabolic memory)  even though their HbA,, values were essentially equivalent to  those of the conventional therapy group.'®*!® Hypoxia and  ischemia accompany microangiopathy, particularly in the  retina, the kidney, and nerves. Many individuals with type 2  diabetes present with microvascular complications because of  the long duration of asymptomatic hyperglycemia that gener-  ally precedes diagnosis. This underscores the need for diabetes  screening.   Diabetic Retinopathy. The retina is the most metabolically  active structure per weight of tissue in the body. Thus the    retina is a vulnerable target for microvascular disease in  diabetes mellitus. Diabetic retinopathy is a leading cause  of blindness worldwide and in U.S. adults younger than age  60.!0 In comparison to type 1 diabetes, retinopathy seems  to develop more rapidly in individuals with type 2 diabetes  because of the likelihood of long-standing hyperglycemia  before diagnosis. Most individuals with diabetes will eventually  develop retinopathy and they also are more likely to develop  cataracts and glaucoma (see Chapter 16). Diabetic retinopathy  is associated with increased risk of life-threatening systemic  vascular complications, including stroke, coronary heart  disease, and heart failure.!’! The prevalence and severity of the  retinopathy are strongly related to the age of the individual, the  duration of diabetes, and the extent of glycemic control.   Diabetic retinopathy results from relative hypoxemia, dam-  age to retinal blood vessels and vasoconstriction, red blood cell  (RBC) and platelet aggregation, influence of vascular endothe-  lial growth factors and growth hormone, and angiogenesis. The  following three stages of retinopathy lead to loss of vision: stage  I: nonproliferative—characterized by thickening of the retinal  capillary basement membrane and an increase in retinal cap-  illary permeability, vein dilation, microaneurysm formation,  and superficial (flame-shaped) and deep (blot) hemorrhages;  stage II: preproliferative—progression of retinal ischemia with  areas of poor perfusion that culminate in infarcts; and stage II  proliferative—neovascularization (angiogenesis) and fibrous  tissue formation within the retina or optic disc (see Figures  22-17 and 22-18, and Table 22-11 for details). Traction of the  new vessels on the vitreous humor may cause retinal detach-  ment or hemorrhage into the vitreous humor. Maculopathy is  a progressive process that may accompany the increased retinal  capillary permeability, vessel occlusion, and ischemia. If for-  mation of exudates, edema, or ischemia occurs near the fovea,  serious loss of vision may result. Macular edema (fluid accu-  mulation and retinal thickening near the center of the macula)  is the leading cause of vision loss among persons with diabetes.  Blurring of vision also can be a consequence of hyperglycemia  and sorbitol accumulation in the lens. Dehydration of the lens,  aqueous humor, and vitreous humor also reduces visual acu-  ity.!”* Cataracts, optic neuropathy, and defects in eye muscle  function also are associated with the chronic complications of  hyperglycemia and diabetes mellitus.   Laser treatments are used to reduce the rate of vision loss  from diabetic macular edema and neovascularization. Vitrec-  tomy is a surgical procedure used to treat an intravitreal hem-  orrhage secondary to rupture of a neovascular capillary tuft.  Intravitreal delivery of steroids, antivascular endothelial growth  factor preparations, and renin-angiotensin system (RAS) inhib-  itors is being evaluated.!”°   Diabetic Nephropathy. Diabetes is the most common  cause of end-stage kidney disease in the Western world.  Without appropriate management, approximately 30% of  individuals with type 1 and 40% of those with type 2 diabetes  develop nephropathy.'”4 The early phases of nephropathy are  asymptomatic and begin to develop after 10 years with type 1  diabetes or after 5 to 8 years with type 2 diabetes. There are  some differences in renal lesions in type 1 and type 2 diabetes,    leakage Stage |  Macular edema Mild  (may occur at any stage) } nonproliferative  diabetic  retinopathy  Moderate visual loss (NPDR)  Epiretinal membranes  Moderate  1 NPDR  Moderate visual loss Vv  Stage Il  Severe  NPDR    FIGURE 22-17 Pathophysiology of Diabetic Retinopathy. VEGF Vascular endothelial growth factor. (From Mehlmed S  et al: Williams textbook of endocrinology, ed 12, Philadelphia, 2012, Saunders.)    with glomerular changes and earlier microalbuminuria in type  1 being most prominent; however, hyperglycemia is the major  initiating factor in both types.   The exact process responsible for destruction of the kidneys  in diabetes is unknown. Multiple mechanisms contribute to  nephropathy, including chronic hyperglycemia, systemic hyper-  tension, hyperperfusion, hyperfiltration, increased blood viscos-  ity, increased glomerular pressure, albuminuria, protein kinase  C, growth factors, advanced glycation end products, the polyol  pathway, inflammatory cytokines, oxidative stress, the renin-  angiotensin-aldosterone system, and hypercholesterolemia.!7>!78   The glomeruli are injured by protein denaturation, hypergly-  cemia with high renal blood flow (hyperfiltration), and intra-  glomerular hypertension exacerbated by systemic hypertension.    Renal glomerular changes can occur early in diabetes mellitus  and occasionally may precede the overt manifestations of the  disease (Figure 22-19). Progressive changes include glomerular  enlargement, glomerular basement membrane thickening with  proliferation of mesangial cells, and proliferation of the mesan-  gial matrix. This results in diffuse and nodular glomerulosclero-  sis (Kimmelstiel-Wilson nodule), loss of podocytes, resistance to  glomerular capillary blood flow, and decreased glomerular fil-  tration rates (GFRs). Alterations in glomerular membrane per-  meability occur with loss of negative charge and albuminuria.  Tubular and interstitial fibrosis contributes to loss of function.'””   Microalbuminuria is usually the first manifestation of kidney  dysfunction (30 to 300 mg/day). Continuous untreated pro-  teinuria generally heralds a life expectancy less than 10 years.    Microalbuminuria is an independent risk factor for cardiovas-  cular disease and progressive renal impairment.!*° The determi-  nants of proteinuria in diabetic nephropathy are not completely  understood.!*! Glycated albumin generates ROS and directly  damages glomerular membrane epithelial cells, vascular smooth  muscle, and mesangial cells. Glomerular endothelial dysfunc-  tion also promotes albuminuria.!*? As renal failure progresses,  extensive vascular and extravascular changes occur.    FIGURE 22-18 Proliferative Diabetic Retinopathy. Neovascularization is  present at the optic nerve (1) and along the vascular arcades (2). Retinal veins  are engorged (3), and a preretinal hemorrhage (4) is present inferior to the fovea.  This boat-shaped hemorrhage blocks the view of the retinal vessels. A more dif-  fuse hemorrhage (5) is present in an arcuate pattern just inferior to the preretinal  hemorrhage that represents a mild vitreous hemorrhage. A few small, hard exu-  dates are visible in the fovea (6). (From Palay D, Krachmer J: Ophthalmology, ed 2,  St Louis 2005, Mosby.)    Before the development of clinical proteinuria (more than  300 mg/day), no clinical signs or symptoms of progressive glo-  merulosclerosis are likely to be evident. Later, hypoproteinemia,  reduction in plasma oncotic pressure, fluid overload, anasarca  (generalized body edema), and hypertension may occur. In type  1 DM, about 24% of individuals have a decline in GFR with-  out albuminuria.'* As renal function continues to deteriorate,  individuals with type 1 diabetes may experience hypoglycemia,  which necessitates a decrease in insulin therapy. The hypogly-  cemia occurs because the kidney’s ability to metabolize insulin  is lost along with other renal functions. As the glomerular fil-  tration rate drops below 10 ml/minute, uremic signs such as  nausea, lethargy, acidosis, anemia, and uncontrolled hyperten-  sion occur (see Chapter 38 for a discussion of renal failure).  Impaired kidney function accelerates retinopathy and cardio-  vascular disease. Control of hypertension and hyperglycemia  delays the onset of end-stage kidney disease.   The development of more sensitive tests has permitted the  detection of small amounts of urinary albumin (ie., microal-  buminuria). Earlier intervention with tight glucose control and  angiotensin-converting enzyme (ACE) inhibitors or angioten-  sin II receptor blockers has reduced proteinuria and slowed the  progression of nephropathy. Aggressive treatment of hyperten-  sion is another therapeutic intervention definitively shown to  slow the progression of established renal disease.'**   Diabetic Neuropathies. Diabetic neuropathy is the most  common cause of neuropathy in the Western world and is  probably the most common complication of diabetes. Nerves  do not require insulin for glucose transport and are particularly  vulnerable to the pathologic effects of chronic hyperglycemia.  Peripheral neuropathy affects up to 50% of individuals with  diabetes. !*°   The underlying pathologic mechanism includes both meta-  bolic and vascular factors related to chronic hyperglycemia.  Inflammation, ischemia, oxidative stress, advanced glycation    Increased tortuosity, dilation with irregular constriction; frequency increases with increased severity of retinopathy  Mostly thin walled; 15-50 mcg in diameter; pathogenesis controversial   Caused by serum leakage through incompetent vessel walls; may resorb in several weeks    Infarcts of the nerve fiber layer caused by retinal ischemia  Tortuous shunts between patent and occluded retinal vessels    New vessels surrounded by connective tissue; five distinct groups representing different hazards to the eye  Often produced to reinforce neovascularization; may occur on optic disc and along vascular arcades  Traction occurring from the vitreous jelly; eventually causes small blood vessels to hemorrhage and retinal detachment    Microalbuminuria <—— Glomerular damage  Macroalbuminuria ¢ Loss of negative charge  ¢ Glomerulosclerosis  ¢ Thickening of basement  membrane  ¢ Mesangial expansion    end products and increased formation of polyols contribute  to demyelination, nerve degeneration, and delayed conduction  (Figure 22-20).'8° Both somatic and peripheral nerve cells show  diffuse or focal damage resulting in polyneuropathy. Sensory  deficits generally precede motor involvement. The extremities  are involved first in a “stocking and glove” pattern.   Diabetic neuropathy is a form of “dying back” neuropathy,  in which the distal portions of the neurons are initially and even-  tually more severely affected. The earliest morphologic change  is axonal degeneration that preferentially involves sensory nerve  fibers, particularly the smaller polymodal unmyelinated periph-  eral C fibers and the larger myelinated Ad fibers. Metabolic  activity of Schwann cells is disturbed, causing segmental loss of  myelin and a characteristic pattern of demyelination and remy-  elination observed in long-term diabetic neuropathy. The loca-  tion of the pathologic condition can include the spinal cord, the  posterior root ganglia, or the peripheral nerves. These changes  may occur alone or in combination. Nerve degeneration begins  in the periphery.   Distal symmetric polyneuropathy (sensory, autonomic,  and motor nerve involvement) is the most common neuropa-  thy with involvement of both large and small nerve fibers. Loss  of small nerve fiber function includes neuropathic pain and  loss of sensation, and carries high risk for development of foot  ulceration with subsequent gangrene and amputation. Large  nerve fiber involvement results in sensory loss of propriocep-  tion and vibration with ataxia, loss of coordination, and risk for    FIGURE 22-20 Multifactorial Pathogenesis of Diabetic Neuropathy. The  yellow boxes represent the consequences of chronic hyperglycemia in the develop-  ment of neuropathy. AGE, Advanced glycation end product; DAG, diacylglycerol;  ICF, intracellular fluid; PKC, protein kinase C.    falls and fractures. Motor involvement results in weakness and  muscle atrophy, particularly in the lower legs and feet.'*”   Involvement of the autonomic nervous system can occur  early. Multiple alterations can develop affecting gastrointes-  tinal enteric nerves (nausea, bloating, gastroparesis, diarrhea,  or constipation), bladder and sexual function (loss of bladder  sensation, urine retention, recurrent infection, erectile dysfunc-  tion), sweating, and body temperature regulation. Cardiovas-  cular autonomic neuropathy is a serious complication with  heart rate variability, changes in baroreceptor reflexes, postural  hypotension, dysrhythmias, exercise intolerance, painless myo-  cardial infarction, and sudden death.'®* Alterations in cogni-  tive function and increased risk for dementia may accompany  long-term complications in the brain, particularly in persons  with type 2 diabetes. The neurodegenerative mechanisms are  not clear.!®?   There are varying manifestations of diabetic neuropathies  involving both the somatic and the autonomic nerves (Table  22-12). Some of the neuropathic syndromes are progressive,  but many—such as painful peripheral neuropathy, mononeu-  ropathy (wristdrop, footdrop), diabetic amyotrophy, diabetic    Hyperesthesia, tingling and pain associated with hyperglycemia that resolves with glycemic control  Loss of large and small myelinated and unmyelinated nerve fibers  Longest nerves affected first with numbness, tingling, and pain (sharp, burning, aching) in toes and feet and then    ascending to hands (stocking and glove pattern); loss of vibration and proprioception (large nerve fiber); loss of  sensory light touch and temperature and pain (small nerve fiber)  Motor nerves affected later with weakness, depressed reflexes, and gait disturbances    Gastrointestinal: decreased esophageal motility, gastroparesis and delayed gastric emptying, diabetic constipation    Genitourinary tract: neurogenic bladder, urine retention, erectile dysfunction and retrograde ejaculation in men  Sudomotor: anhidrosis, gustatory sweating  Cranial nerve Ill: pain and ptosis and may spare the pupil    Compression and entrapment syndromes: carpel tunnel syndrome, radial nerve (wristdrop), peroneal nerve (footdrop),    Cranial neuropathies: cranial nerve Ill, pain and ptosis and may spare the pupil   Truncal mononeuropathy: abdominal or lower chest pain or hyperesthesia, abdominal muscle weakness   Asymmetric lower limb neuropathy (diabetic amyotrophy; diabetic polyradiculopathy): involvement of lower thoracic  and lumbar nerve roots (upper leg weakness, upper leg muscle atrophy, diminished knee and ankle tendon  reflexes); may have paresthesia, hyperesthesia, pain    neuropathic cachexia, and visceral manifestations associated  with autonomic neuropathy (e.g., diabetic diarrhea and ortho-  static hypotension)—may spontaneously improve. Charcot  neuroarthropathy (Charcot joint) is the progressive degenera-  tion and structural disorganization of a joint, particularly in the  feet of individuals affected by long-term diabetes. The patho-  genesis is not clear but may be related to loss of sensation or  neurally mediated vascular alterations with osteoclastic bone  resorption, or both.!”°    Macrovascular disease (lesions in large and medium sized  arteries) increases morbidity and mortality and increases risk  for accelerated atherosclerosis and myocardial infarction,  stroke, and peripheral vascular disease, particularly among  individuals with type 2 diabetes mellitus. Children with poorly  controlled diabetes have high risk for macrovascular disease  within one or two decades.'?! Unlike microangiopathy, ath-  erosclerotic disease is unrelated to the severity of diabetes and  is often present in those with insulin resistance and impaired  glucose tolerance.'’* The premature atherosclerosis of diabe-  tes has many contributing factors, including hyperinsulinemia  (insulin resistance), hyperglycemia, hypertriglyceridemia, low  levels of high-density lipoprotein (HDL), high levels of low-  density lipoprotein (LDL), lipoprotein oxidation, and platelet  abnormalities. Advanced glycosylated end products attach to  their receptor (RAGE) in the walls of blood vessels, promot-  ing oxidative stress, inflammation, and endothelial and vas-  cular smooth muscle dysfunction (Figure 22-21). The process  tends to be more severe and accelerated with the presence of  other risk factors, including hyperlipidemia, hypertension, and  smoking. !?°   Coronary Artery Disease. Coronary artery disease (CAD) is  the most common cause of morbidity and mortality (up to 75%)    in both men and women with diabetes mellitus. In general, the  prevalence of CAD increases with the duration but not the  severity of diabetes. Risk factors contributing to disease include  hyperglycemia and insulin resistance, high levels of LDLs and  triglycerides (lipotoxicity), low levels of HDLs, increased levels  of apolipoprotein B, platelet abnormalities, and endothelial cell  dysfunction.!”*   Myocardial infarction (death of heart muscle as a result of  coronary artery occlusion) is the cause of death in up to 75%  of those with diabetes. Individuals with diabetes mellitus have  a higher mortality during the acute phase of myocardial infarc-  tions than do nondiabetic individuals because they are often  asymptomatic as a result of sensory and autonomic neuropa-  thy. Atherosclerotic CAD is accelerated in diabetes because  of hyperglycemia-induced endothelial dysfunction, impaired  fibrinolysis, increased platelet aggregation, plaque instability,  dysfunctional arterial remodeling, and fibrotic and calcified  coronary arteries.!*° In addition, the incidence of cardiomyopa-  thy (heart failure or myocardial dysfunction in the absence of  CAD and hypertension) is higher in individuals with diabetes.  The reason is unclear but may be related to metabolic remodel-  ing of the myocardium with the presence of increased amounts  of collagen in the ventricular wall, which reduces the mechani-  cal compliance of the heart during filling, inflammation, and  changes in calcium management.!*°* Diastolic dysfunction is  the earliest symptom.!”° Guidelines have been developed to  reduce the risk and improve prevention, screening, and treat-  ment of cardiovascular and coronary artery disease in individu-  als with diabetes. !°°   Stroke. Stroke is twice as common in those with diabetes  (particularly type 2 diabetes) as in the nondiabetic population.  Ischemic stroke is more common than hemorrhagic stroke.  The survival rate for an individual with diabetes after a massive  stroke is typically shorter than that for a person without    FIGURE 22-21 Diabetes Mellitus and Atherosclerosis. Diabetes with its  associated hyperglycemia, relative hypoinsulinemia, oxidative stress, and proinflam-  matory state contributes to atherogenesis by causing arterial endothelial dysfunc-  tion (impaired vasodilation and adhesion of inflammatory cells), dyslipidemia, and  smooth muscle proliferation. LDL, Low-density lipoprotein; NO, nitric oxide; PKC,  protein kinase; RAGE, receptor for advanced glycation end product; 7G, triglyceride.  (Data from D'Souza A et al: Mo/ Cell Biochem 331[1-2]:89-116, 2009; Stratmann B,  Tschoepe D: Best Pract Res Clin Endocrinol Metab 23[3}:291—303, 2009.)    diabetes. Hypertension, hyperglycemia, hyperlipidemia, and  thrombosis are definite risk factors (see Chapters 17 and 32),  and aggressive management of blood pressure, hyperglycemia,  and lipidemia in individuals with diabetes has been shown to  reduce the incidence of stroke.!°   Peripheral Arterial Disease. There is an increased incidence  of peripheral arterial disease (PAD), neuropathy, gangrene, and  amputation in diabetic persons, particularly in individuals with  type 2 diabetes.!°°!°° The atherosclerotic process in diabetic  persons is more common, appears at a younger age, and  advances more rapidly than vascular changes in nondiabetic    persons.?”° The prevalence of PAD is nearly equal in males  and females with diabetes. Age, duration of diabetes, glycemic  control, genetics, and additional risk factors influence the  development of PAD.?°!   Atherosclerosis combined with peripheral neuropathy  causes the occlusions, ulcers, and gangrenous changes of the  lower extremities. They tend to occur in patchy areas of the  feet and toes.”°* Smaller vessels often have more occlusion than  larger vessels in the same individuals. Figure 22-22 illustrates  how foot lesions of diabetes can lead to amputation. More than  60% of nontraumatic amputations in the United States are per-  formed on individuals with diabetes. Referral to specialists can  reduce amputation rates by 45% to 85%.?°?   Increased morbidity and mortality from infectious agents  have been documented in those with diabetes.2°* The indi-  vidual with diabetes is at increased risk for infection for several  reasons?0?2;   1. The senses. Impaired vision caused by retinal changes and  impaired touch caused by sensory neuropathy lead to  loss of protection with injury. Repeated trauma increases  risk for infection in open wounds, soft tissue, or bones  (osteomyelitis).   2. Hypoxia. Once skin integrity is compromised, tissues’  susceptibility to infection increases as a result of vascu-  lar disease and hypoxia. In addition, the glycosylated  hemoglobin in the RBCs impedes the release of oxygen to  tissues.   3. Pathogens. Some pathogens proliferate rapidly because of  increased glucose in body fluids, which provides an excel-  lent source of energy.   4. Blood supply. Decreased blood supply results from vascu-  lar changes and autonomic dysfunction, which decreases  the supply of white blood cells to the affected area.   5. Suppressed immune response. Chronic hyperglyce-  mia impairs both the innate and the adaptive immune  responses, including abnormal vasoactive responses and  defective chemotaxis and phagocytosis. Clinical signs of  infection may be absent.   6. Delayed wound healing. Slower collagen synthesis and  decreased angiogenesis increase the opportunity for  infection.    Disorders of the adrenal cortex are related to either hyperfunc-  tion or hypofunction. Hyperfunction that causes increased lev-  els of circulating cortisol leads to Cushing disease, or Cushing  syndrome; hyperfunction that causes increased secretion of  adrenal androgens and estrogens leads to virilization or femini-  zation; and hyperfunction that causes increased levels of aldo-  sterone leads to hyperaldosteronism, which may be primary or    FIGURE 22-22 How Foot Lesions of Diabetes Can Lead to Amputation. (From Levin ME, O'Neal LW, Bowker JH: The   Cushing syndrome refers to the complex of clinical mani-  festations resulting from chronic exposure to excess cortisol.  Cushing disease is overproduction of pituitary ACTH by a  pituitary adenoma (can occur at any age). Ectopic secretion  of ACTH by an ectopic-secreting non—pituitary tumor (e.g.,  a small cell carcinoma of the lung; more common in older  adults) also can cause hypercortisolism. Rarely, ACTH-inde-  pendent hypercortisolism is caused by cortisol secretion from  a benign or malignant tumor of one or both adrenal glands  (more common in children). All are rare. A Cushing-like syn-  drome may develop as a result of the exogenous administra-  tion of glucocorticoids.?°*   PATHOPHYSIOLOGY. With ACTH-dependent hypercorti-  solism, the excess ACTH stimulates excess production of  cortisol and there is loss of feedback control of ACTH secre-  tion. Whatever the cause, two observations consistently apply  to individuals with Cushing syndrome: (1) they do not have  diurnal or circadian secretion patterns of ACTH and cortisol,    and (2) they do not increase ACTH and cortisol secretion in  response to a stressor.”°’ In individuals with ACTH-depen-  dent hypercortisolism, secretion of both cortisol and adrenal  androgens is increased, and corticotropin-releasing hormone  (CRH) secretion is inhibited. ACTH-independent secreting  tumors of the adrenal cortex, however, generally secrete only  cortisol. Elevated cortisol levels suppress CRH and ACTH  secretion from the hypothalamus and anterior pituitary,  respectively, which leads to low levels of ACTH. Low levels of  ACTH cause atrophy of the remaining normal portions of the  adrenal cortex, which over time will alter the cortisol-secret-  ing activity of normal cells. When the secretion of cortisol by  the tumor exceeds normal cortisol levels, symptoms of hyper-  cortisolism develop.   CLINICAL MANIFESTATIONS. Weight gain is the most common  feature and results from the accumulation of adipose tissue in  the trunk, facial, and cervical areas. These characteristic pat-  terns of fat deposition have been described as “truncal [cen-  tral] obesity,” “moon face,” and “buffalo hump” (Figures  22-23 and 22-24). Transient weight gain from sodium and  water retention may be present because of the mineralocor-  ticoid effects of cortisol, exhibited when cortisol is present in  high levels.    Glucose intolerance occurs because of cortisol-induced  insulin resistance and increased gluconeogenesis and glycogen  storage by the liver. Overt diabetes mellitus develops in approx-  imately 20% of individuals with hypercortisolism. Polyuria is a  manifestation of hyperglycemia and resultant glycosuria.   Protein wasting is caused by the catabolic effects of cortisol  on peripheral tissues. Muscle wasting leads to muscle weakness  and is especially obvious in the muscles of the extremities with  thinning of the limbs. In bone, loss of the protein matrix and  increases in bone resorption lead to osteoporosis and can result  in pathologic fractures, vertebral compression fractures, bone  and back pain, kyphosis, and reduced height. Hypercalciuria  may result in renal stones, which are experienced by approxi-  mately 20% of individuals with this disease. Loss of collagen  also leads to thin, weakened integumentary tissues through  which capillaries are more visible; the tissues are easily stretched  by adipose deposits. Together these changes account for the  characteristic purple striae most often observed in the truncal  area. Loss of collagenous support around small vessels makes  them susceptible to rupture, leading to easy bruising, even with  minor trauma. Thin, atrophied skin is also easily damaged,  leading to skin breaks and ulcerations. Bronze or brownish  hyperpigmentation of the skin, mucous membranes, and hair  occurs when there are very high levels of ACTH. This is caused  by increased levels of melanocyte-stimulating hormones result-  ing from excess conversion of pro-opiomelanocortin when  ACTH concentration is elevated.?!°    ae art Rall a Ps otha ba  FIGURE 22-24 Cushing Syndrome. A, Patient before onset of Cushing syn-  drome. B, Patient 4 months later. Moon facies is clearly demonstrated. (From Zitelli  BJ, McIntire SC, Nowalk Au: Zitell/ and Davis’ atlas of pediatric physical diagnosis,  ed 6, London, 2012, Saunders.)    With elevated cortisol levels, vascular sensitivity to catechol-  amines is increased significantly, leading to vasoconstriction  and hypertension. Metabolic syndrome with abdominal obesity,  hypertension, glucose intolerance, and dyslipidemias is a common  complication (see Box 22-2, p. 739). Individuals with Cushing  syndrome are at increased risk for cardiovascular complications  (CAD, heart failure, and stroke).?!! Chronically elevated cortisol  levels also cause suppression of the immune system, increased  susceptibility to infections, and poor wound healing.   Approximately 50% of individuals with Cushing syndrome  experience alterations in their mental status, caused by the  effects of cortisol on hippocampal neurons and the subsequent  implications on learning, memory, and other neurologic func-  tions when cortisol levels are elevated. These may range from  irritability and depression to severe psychiatric disturbances  such as schizophrenia.7!*   Females may experience symptoms of increased adrenal  androgen levels, increased hair growth (especially facial hair),  acne, and oligomenorrhea. Rarely do androgen levels become    high enough to cause changes of the voice, recession of the hair-  line, and clitoral hypertrophy unless an adrenal carcinoma is  involved. Infertility is more common among women.?!   EVALUATION AND TREATMENT. A variety of laboratory tests must  be used to diagnose hypercortisolism and to determine the  underlying disorder.*!* These include urinary free cortisol con-  centration higher than 50 mcg per 24 hours, abnormal dexa-  methasone suppressibility of either urinary or serum cortisol,  and simultaneous measurement of ACTH and cortisol levels.  Late evening salivary cortisol levels are used as a screening test  and to document alterations in the diurnal variation of cortisol  level. Routine laboratory examinations may reveal hyperglyce-  mia, glycosuria, hypokalemia, and metabolic alkalosis. Tumors  are diagnosed using imaging procedures. Guidelines are avail-  able for the diagnosis of Cushing syndrome.’!°   Treatment is specific for the cause of hypercorticoadrenalism  and includes medication, radiation, and surgery. Differentia-  tion among pituitary, ectopic, and adrenal causes is essential for  effective treatment. Without treatment, approximately 50% of  individuals with Cushing syndrome die within 5 years of onset  as a result of overwhelming infection, suicide, complications  from generalized arteriosclerosis, and hypertensive disease.”!°    Congenital adrenal hyperplasia is an autosomal recessive dis-  order that causes the deficiency of an enzyme that is critical in  cortisol biosynthesis. Because cortisol production is low, ACTH  concentration increases and causes adrenal hyperplasia, which  results in the overproduction of either mineralocorticoids or  androgens. The most common form is a 21-hydroxylase defi-  ciency that involves both mineralocorticoid and cortisol syn-  thesis. Affected female infants are virilized and infants of both  genders exhibit salt wasting.*!”    Hyperaldosteronism is characterized by excessive aldosterone  secretion by the adrenal cortex. There are both primary and sec-  ondary forms of hyperaldosteronism.   Primary hyperaldosteronism (Conn disease, primary aldo-  steronism) is caused by excessive secretion of aldosterone from  an abnormality of the adrenal cortex, usually a single benign  aldosterone-producing adrenal adenoma. Bilateral adrenal  nodular hyperplasia and adrenal carcinomas account for the  remainder of cases. The incidence is estimated to be between  1% and 2% of all hypertensive individuals and is the most com-  mon cause of secondary hypertension.”!®   Secondary hyperaldosteronism (secondary aldosteronism)  involves excessive aldosterone secretion from an extra-adrenal  stimulus, most often angiotensin II through a renin-dependent  mechanism. (Factors that affect renin and aldosterone secre-  tion are summarized in Table 22-13). This occurs in various  situations, including decreased circulating blood volume (e.g.,  in dehydration, shock, or hypoalbuminemia) and decreased  delivery of blood to the kidneys (e.g., renal artery stenosis,  heart failure, or hepatic cirrhosis). Here the activation of the  renin-angiotensin system and subsequent aldosterone secretion  may be seen as compensatory, although in some instances (e.g.,    FIGURE 22-25 Pathophysiology of Primary Hyperaldosteronism. (From  Bonow RO et al: Braunwald's heart disease: a textbook of cardiovascular medicine,  ed 9, Philadelphia, 2012, Saunders.)    congestive heart failure) the increased circulating volume fur-  ther worsens the condition. Other causes of secondary hyperal-  dosteronism include renin-secreting tumors of the kidney and  Bartter syndrome, an inherited renal tubular defect in tubular  reabsorption of sodium and resulting elevated aldosterone lev-  els and hypokalemia. Diuretic use is perhaps the most common  cause of secondary hyperaldosteronism. (Renal disorders are  discussed in Chapter 38.) Apparent mineralocorticoid excess  can be seen in individuals who consume excess licorice (glycyr-  rhizic acid) or chewing tobacco.   PATHOPHYSIOLOGY. In primary hyperaldosteronism, pathophys-  iologic alterations are caused by excessive aldosterone secre-  tion and the fluid and electrolyte imbalances that ensue (Figure  22-25). Hyperaldosteronism promotes (1) increased renal  sodium and water reabsorption with corresponding hypervol-  emia (see Chapter 3) and hypertension and (2) renal excretion  of potassium. The extracellular fluid volume overload and sup-  pression of normal feedback mechanisms of renin secretion are  characteristic of primary disorders.   Edema usually does not occur with primary aldosteronism.  Sodium loss and water loss are maintained by hypervolemia-  induced atrial natriuretic factor release, pressure natriuresis,  and aldosterone escape (spontaneous diuresis). The escape phe-  nomenon changes or resets the rate of sodium excretion in the    Increased aldosterone production and mineralocorticoid receptor (MR) activa-  tion are associated with genomic and nongenomic actions that contribute to  pancreatic fibrosis, impaired beta-cell function, and components of metabolic  syndrome, including insulin resistance, hypertriglyceridemia, low levels of  high-density lipoprotein, resistant hypertension, and obesity. Insulin resis-  tance may be related to increased levels of aldosterone and decreased insulin  responsiveness of GLUT4 in skeletal muscle and GLUT2 in the liver, as has  been found in animal studies, or be a result of direct effects on insulin signal-  ing and hepatic gluconeogenesis. Aldosterone increases oxidative stress and  the number of proinflammatory cytokines; combined with insulin resistance, it  contributes to reduced endothelial-mediated vasorelaxation, vascular injury,  and atherosclerosis, causing hypertension, cardiac disease, and renal disease.  High levels of aldosterone are associated with left ventricular hypertrophy,  cardiac fibrosis, and diastolic dysfunction, and promote both glomerular and  tubulointerstitial renal disease. MR antagonists have a significant role in the  management of complications associated with metabolic syndrome although  the side effects of gynecomastia and hypokalemia may limit their use.    Data from Briet M, Schiffrin EL: Curr Hypertens Rep 13(2):163-172,  2011; Briet M, Schiffrin EL: J Vasc Res 50(2):89-99, 2013; Ronconi V  et al: Curr Vasc Pharmacol 10(2):238-246, 2012; Tirosh A, Garg R,  Adler GK: Curr Hypertens Rep 12(4):252-257, 2010.    proximal tubules and prevents more severe sodium retention.  Although this mechanism provides protection from excessive  sodium reabsorption and edema, it can increase urinary losses  of potassium and cause hypokalemia (see Figure 22-24). Meta-  bolic syndrome (hypertension, obesity, dyslipidemia, insulin  resistance, and hyperglycemia) is associated with primary aldo-  steronism (see What’s New? Aldosteronism and Metabolic Syn-  drome). Activation of the aldosterone receptor induces insulin  resistance; promotes inflammation, endothelial dysfunction,  and cardiovascular remodeling; and affects adipose tissue dif-  ferentiation and function.?!???°   In secondary hyperaldosteronism the effect of increased extra-  cellular volume on renin secretion may vary. If renin secretion  is being stimulated by variables other than pressure-initiated  cellular changes at the juxtaglomerular apparatus (see Chapter  37), increased circulating blood volume may not decrease renin  secretion through feedback mechanisms. This physiologic pro-  cess is normal in pregnancy and related to increased levels of  plasma estrogen.   Potassium secretion also is promoted by aldosterone, so that  with excessive circulating levels of aldosterone, hypokalemia  occurs (see Chapter 3). In hyperaldosteronism, hypokalemic  alkalosis, myocardial conduction changes, and skeletal muscle  alterations may be seen, particularly with severe potassium  depletion (i.e., the renal tubules may become insensitive to  ADH, thus promoting excessive loss of free water). Rarely, this  may result in mild hypernatremia because water is not able to  follow the sodium that is reabsorbed.   CLINICAL MANIFESTATIONS. Hypertension, hypokalemia, renal  potassium wasting, and neuromuscular manifestations are the  hallmarks of hyperaldosteronism.’?! Hypertension is resis-  tant to treatment and may result from increased intravascular    volume or from a state of aldosterone-mediated vasoconstric-  tion, although the latter mechanism requires very high levels of  aldosterone. If hypertension is sustained, the long-term effects  of elevated arterial pressure become evident, which include the  development of left ventricular dilation and hypertrophy, vas-  cular disease, and renal disease. Because of the increased arte-  rial pressure, renin secretion is typically suppressed, although it  is elevated in secondary hyperaldosteronism, which provides a  means to clearly differentiate between these conditions.   Aldosterone-stimulated potassium loss can be variable.  Serum potassium levels below 3.0 mEq/L result in the typi-  cal manifestations of hypokalemia. Hypokalemic alkalosis is  caused by the movement of potassium from the intercellular  to extracellular space in exchange for hydrogen ions as well as  renal loss of hydrogen ions to facilitate sodium reabsorption  (see Chapter 3).   EVALUATION AND TREATMENT. Various clinical and laboratory  measurements are useful in the assessment of hyperaldosteron-  ism and include the following”:   is normal or elevated; serum potassium level is normal or  depressed, but urinary potassium level is elevated   Serum aldosterone and plasma renin activity both must be  measured under controlled situations and after careful dietary  regulation of sodium and potassium intake (see Table 22-13).   Imaging techniques, such as CT and nuclear magnetic reso-  nance (NMR), may be used to localize an aldosterone-secreting  adenoma. Sampling from both adrenal veins is also useful.   Treatment includes management of hypertension and hypo-  kalemia, as well as correction of any underlying causal abnor-  malities. If an aldosterone-secreting adenoma is present, it is  generally approached surgically. Medical management with  aldosterone receptor antagonists, such as spironolactone or  eplerenone (a drug without the side effects of spironolactone),  is a viable option in selected cases.”    Hypersecretion of adrenal androgens and estrogens may be  caused by adrenal tumors (either adenomas or carcinomas),  Cushing syndrome, or defects in steroid synthesis. The clini-  cal syndrome that results depends on the hormone secreted,  the gender of the individual, and the ages at which the hyper-  secretion was initiated. Hypersecretion of estrogens causes  feminization, the development of female sex characteristics.  Hypersecretion of androgens causes virilization, the develop-  ment of male sex characteristics (Figure 22-26).   The effects of an estrogen-secreting tumor are most evident  in men and result in gynecomastia (breast enlargement) (98% of  cases), testicular atrophy, and decreased libido. In female chil-  dren such tumors may lead to early development of secondary    FIGURE 22-26 Virilization. Virilization of a young girl by an androgen-  secreting tumor of the adrenal cortex. Masculine features include lack of breast  development, increased muscle bulk, and hirsutism. (From Thibodeau GA, Patton  KT: The human body in health & disease, ed 4, St Louis, 2010, Mosby.)    sex characteristics. An androgen-secreting tumor indicates  changes more easily observed in women, including hirsutism,  clitoral enlargement, deepening of the voice, amenorrhea, acne,  and breast atrophy. In children, virilizing tumors promote  precocious sexual development and bone aging. Treatment of  androgen-secreting tumors usually involves surgical excision.    Hypocortisolism (low levels of cortisol secretion) develops  because of either inadequate stimulation of the adrenal glands  by ACTH or a primary inability of the adrenals to produce and  secrete the adrenocortical hormones. In some syndromes, how-  ever, there is partial dysfunction of the adrenal cortex so that  only synthesis of cortisol and aldosterone or the adrenal andro-  gens is affected. Hypofunction of the adrenal cortex may affect  glucocorticoid or mineralocorticoid secretion or a combination  of both.   Addison Disease. Primary adrenal insufficiency is termed  Addison disease. Addison disease is relatively rare, occurring  most often in adults 30 to 60 years of age, although it may  appear at any time. Addison disease, caused by autoimmune  mechanisms, is more common in women.   The most common cause of Addison disease in the United  States is autoimmune destruction of the adrenal cortex and it    is more common in women. Other causes include infections  (tuberculosis, fungal infections, human immunodeficiency  virus [HIV]), infiltrative diseases (amyloidosis, metastatic car-  cinoma), or bilateral adrenal hemorrhage. Adrenoleukodystro-  phy and adrenomyeloneuropathy are two rare types of X-linked  adrenal deficiency that lead to symptoms of hypocortisolism  and progressive neurologic symptoms.   PATHOPHYSIOLOGY. Addison disease is characterized by inad-  equate corticosteroid and mineralocorticoid synthesis and  elevated serum ACTH levels. Before clinical manifestations of  hypocortisolism are evident, more than 90% of total adreno-  cortical tissue must be destroyed. Thus the adrenal glands are  smaller and may be misshapen.   Idiopathic Addison disease (organ-specific autoimmune  adrenalitis), which causes adrenal atrophy and hypofunction,  generally is recognized as an organ-specific autoimmune dis-  ease. (Autoimmunity is discussed in Chapter 9.) 21-Hydroxylase  autoantibodies and autoreactive T cells specific to adrenal cor-  tical cells are present in 50% to 70% of individuals with idio-  pathic Addison disease; this percentage increases in younger  persons and in those with other autoimmune diseases. Appar-  ently, a genetic defect in immune surveillance mechanisms  causes a deficiency of immune-suppressor cells. This deficiency  allows the proliferation of immunocytes directed against spe-  cific antigens within the adrenocortical cells. The adrenal glands  in idiopathic Addison disease are smaller than normal and may  be misshapen.?*?*4 Several genes have been identified.”°   Idiopathic Addison disease often is associated with other  autoimmune diseases and in such cases is known as autoim-  mune polyendocrine syndrome (APS). APSI (APS type I) is inher-  ited as autosomal recessive with childhood onset and includes  Addison disease, hypoparathyroidism, mucocutaneous candi-  diasis, and other less common symptoms. APSII (APS type II) is  more common and involves Addison disease, immune thyroid  disease, diabetes mellitus, celiac disease, and hypogonadism.*”°  (Mechanisms of inheritance are described in Chapter 4.)   CLINICAL MANIFESTATIONS. The symptoms of Addison disease  are primarily a result of hypocortisolism and hypoaldosteron-  ism. With mild to moderate hypocortisolism, symptoms usually  begin with weakness and easy fatigability. Skin changes, includ-  ing hyperpigmentation and vitiligo, may occur. As the condi-  tion progresses, anorexia, nausea, vomiting, and diarrhea may  develop. Of greatest concern is the development of hypotension  that can progress to complete vascular collapse and shock.   Decreased adrenal androgen secretion is usually not clini-  cally obvious in men because the adrenals are not a major  source of male androgens. Women may experience a loss of  some secondary sexual characteristics, such as pubic and axil-  lary hair, normally maintained by the adrenal androgens.”  Disturbances in mood and motivation are common. The symp-  toms of Addison disease are summarized in Table 22-14.   EVALUATION AND TREATMENT. Serum and urine levels of cortisol  are depressed with primary hypocortisolism and ACTH levels  are increased. Because of dehydration, blood urea nitrogen lev-  els may increase. Serum glucose concentration is low. Eosino-  phil and lymphocyte counts are often elevated. Hyperkalemia  is seen in Addison disease and may cause mild alkalosis (see    Weakness and easy fatigability  that worsen as the day  progresses, seen especially  after exposure to stressors    Not known, may be related to  hypoglycemia, hypotension,  decreased metabolism of proteins    Absence of cortisol leads to decreased  gluconeogenesis, decreased  glycogen storage by liver, decreased  metabolism of proteins, increased  insulin sensitivity   Combined effects of hypocortisolism,  hypoaldosteronism, extracellular  volume depletion, and some  precipitating stressor (e.g., infection,  vomiting, diarrhea); decreased  vasomotor tone caused by cortisol  deficiency    Chapter 3). The ACTH stimulation test may be used to evaluate  serum cortisol levels.   The treatment of Addison disease involves lifetime glucocor-  ticoid and mineralocorticoid replacement therapy, together with  dietary modifications and correction of any underlying disor-  ders. In the event of acute stressors, additional cortisol must be  administered to approximate the amount of cortisol that might  be expected to be secreted if normal adrenal function were pres-  ent (approximately 100 to 300 mg/day).’”* The individual’s diet  should include at least 150 mEq of sodium per day, with sodium  intake increased in the event of excessive sweating or diarrhea.   Secondary Hypocortisolism. Secondary hypocortisolism  commonly results from prolonged administration of  exogenous glucocorticoids, which suppress ACTH secretion.  This causes adrenal atrophy and results in inadequate  corticosteroidogenesis once the exogenous glucocorticoids  are withdrawn. Decreased ACTH secretion also can result  from pituitary infarction, pituitary tumors that compress  ACTH-secreting cells, or hypophysectomy. In all instances  of low ACTH levels, adrenal atrophy occurs and endogenous  adrenal steroidogenesis is depressed. Clinical manifestations  of secondary hypocortisolism are similar to those of Addison  disease, although hyperpigmentation usually does not occur.  The renin-angiotensin system usually is normal, so aldosterone  and potassium levels also tend to be normal.    FIGURE 22-27 Pheochromocytoma. Gross appearance of adrenal pheochro-  mocytoma. (From Rosai J: Rosai and Ackerman’s surgical pathology, ed 10, Phila-  delphia, 2011, Mosby.)   Adrenomedullary hyperfunction is caused by pheochromocy-  tomas (chromaffin cell tumors) of the adrenal medulla, which  secrete catecholamines (Figure 22-27). They are rare and less  than 10% of cases are malignant. Most pheochromocytomas  produce norepinephrine, although large tumors secrete epi-  nephrine and norepinephrine.   The true incidence of pheochromocytoma in the gen-  eral population is not known. About one tenth of 1% of the  adult hypertensive population has a pheochromocytoma. The  tumors are most common in people 40 to 60 years of age, with  men and women equally affected. Familial forms of the dis-  ease are associated with mutations in the RET proto-oncogene,  the von Hippel-Lindau (VHL) gene, and the neurofibroma-  tosis type 1 gene (NF1). Any of the succinate dehydrogenase  complex subunit genes can lead to pheochromocytoma (and  paragangliomas).’”°   PATHOPHYSIOLOGY. Pheochromocytomas cause excessive  production of norepinephrine, although large tumors secrete  epinephrine and norepinephrine because of autonomous func-  tioning of the tumor. Approximately 5% of people with pheo-  chromocytomas have no symptoms because the tumor appears  to be nonfunctioning; however, these tumors can release  catecholamines in response to stressors, such as abdominal  surgery.   CLINICAL MANIFESTATIONS. The clinical manifestations of a  pheochromocytoma are related to the chronic effects of cat-  echolamine secretion. Hypertension is the most common  sign and it may be sustained or paroxysmal. Other symptoms  include diaphoresis, tachycardia, palpitations, and severe head-  ache.”*? Hypertension is a result of increased peripheral vascular    resistance. Headaches appear because of sudden changes in cat-  echolamine levels in the blood, affecting cerebral blood flow.  Hypermetabolism and sweating are related to chronic acti-  vation of sympathetic receptors in adipocytes, hepatocytes,  and other tissues. Glucose intolerance may occur because of  catecholamine-induced inhibition of insulin release by the  pancreas. Complaints of warmth, heat intolerance, weight loss,  and constipation are common despite a normal or an increased  appetite.   An acute episode of hypertension related to hypersecretion  of catecholamines may follow specific events. Exercise, exces-  sive ingestion of tyrosine-containing foods (e.g., aged cheese,  red wine, beer, yogurt), ingestion of caffeine-containing foods,  external pressure on the tumor, and induction of anesthesia all  can increase secretion of catecholamines by the tumor.   These tumors tend to be extremely vascular and can rupture.  Such an event can cause massive and potentially fatal hemor-  rhage. Rupture of a pheochromocytoma is characterized by a  sudden, unexplained decrease in blood pressure; sudden, severe  abdominal pain; and a rigid abdomen.    EVALUATION AND TREATMENT. A diagnosis of pheochromo-  cytoma is made when increased catecholamine production is  demonstrated in the blood or urine. Individuals with this dis-  order can have total urine catecholamine levels greater than  250 mg/day. After elevation of urinary or plasma catecholamine  levels is documented, the site of the tumor is determined using  MRI. Because of the possibility of metastasis, whole-body scan-  ning may be done.   Management of catecholamine excess is essential to pre-  vent hypertensive emergencies and requires the use of a- and  B-adrenergic blockers. The usual treatment of pheochromocy-  toma is laparoscopic surgical excision of the tumor with adjunc-  tive radiopharmaceuticals or chemotherapy. Medical therapy  is continued to stabilize blood pressure before surgery. Drugs  used include a-adrenergic blocking agents and, possibly later,  p-adrenergic blocking agents. Open resection is completed for  large tumors or when metastasis is suspected. Malignant pheo-  chromocytoma is rarely curable and is usually managed by a  combination of surgical debulking of the tumor combined with  chemotherapy.?*!   1. Abnormalities in endocrine function may be caused by  hypersecretion or hyposecretion of hormones, causing  alterations in normal hormone levels.   2. Endocrine abnormalities also may be caused by alterations  in receptor function through a variety of mechanisms: (a)  a decrease in the number of receptors, (b) receptor insensi-  tivity to the hormone, (c) antibodies against specific recep-  tors, and (d) defects in second-messenger generation or  postreceptor defects.   3. Abnormally high levels of circulating hormones sometimes  are caused by hormone release from tissues outside the  endocrine system (ectopic foci) that may not respond to  normal feedback mechanisms, in which case they are said  to function autonomously.   1. Dysfunction in the release of hypothalamic hormones prob-  ably is related to interruption of the connection between the  hypothalamus and pituitary—namely, the pituitary stalk.   2. Disorders of the posterior pituitary include SIADH secretion  and DI. SIADH secretion is characterized by abnormally  high ADH secretion; DI is characterized by abnormally low  ADH secretion.   3. In SIADH, high ADH levels interfere with renal free water  clearance, leading to hyponatremia and hypoosmolality.  SIADH secretion is associated with certain forms of cancer,  apparently because of ectopic secretion of ADH by tumor  cells.   4. DI may be neurogenic, caused by insufficient amounts of  ADH, or nephrogenic, caused by an inadequate response  to ADH. Its principal clinical features are failure to con-  centrate urine with polyuria and polydipsia. Dipsogenic DI    occurs when excessive fluid intake lowers the plasma osmo-  larity to the point that it falls below the threshold for ADH  secretion.   5. Hypopituitarism is dysfunction of the anterior pituitary  that causes failure of hormonal functions. Symptoms may  be mild to severe.   6. Causes of hypopituitarism include pituitary infarction,  space-occupying lesions such as tumor or aneurysm, surgi-  cal removal, or infections. Symptoms are variable depend-  ing on which hormones are deficient (e.g., TSH, ACTH, or  GH).   7. Hyperpituitarism is caused by pituitary adenomas. These  are usually benign slow-growing tumors that arise from  cells of the anterior pituitary.   8. Expansion of a pituitary adenoma causes neurologic and  secretory effects. Pressure from the expanding tumor  causes hyposecretion of cells, dysfunction of the optic chi-  asm (leading to visual disturbances), and dysfunction of the  hypothalamus and some cranial nerves.   9. Hypersecretion of GH causes acromegaly in adults and  giantism in children. Pituitary adenoma is the most com-  mon cause of acromegaly.   10. Prolonged, abnormally high levels of GH lead to prolifera-  tion of body and connective tissues. Renal, thyroid, cardio-  vascular, and reproductive dysfunctions develop slowly,  together with a change in bony proportions and insulin  resistance.   11. GH deficiency in children results in growth failure and fast-  ing hypoglycemia. Adult GH deficiency results in fatigue,  osteoporosis, and increased mortality.   12. Pituitary prolactinomas, renal failure, and medications can  result in increased levels of prolactin and affect reproduc-  tive organs and function in both men and women.    Thyrotoxicosis is a general condition in which TH levels are ele-  vated and produce an exaggerated physiologic response in tis-  sues. The condition can be primary, secondary, or subclinical.    reproductive, gastrointestinal, integumentary, and ocular  manifestations. These are caused by increased circulating  levels of TH and by stimulation of the sympathetic division  of the autonomic nervous system.    ism, is caused by thyroid-stimulating immunoglobulins  that stimulate thyroid TSH receptors, resulting in thyroid  hyperplasia and increased synthesis of TH.    hyperthyroidism, diffuse thyroid enlargement, disorders of  the skin, and enlargement of extraocular muscles.    myxedema, a condition characterized by subcutaneous  swelling of the legs and, occasionally, the hands.    hyperactivity of the sympathetic division of the autonomic  nervous system and by immune-induced infiltration of  extraocular muscles, orbital fat accumulation, and edema  (exophthalmos).    when some hyperplastic, hyperfunctioning thyroid nodules  autonomously secrete TH, causing hyperthyroidism and  producing symptoms similar to those of Graves disease.    . Thyrotoxic crisis (thyroid storm) is a severe form of hyper-    thyroidism that often is associated with physiologic stress.  Without treatment, death occurs quickly.   Hypothyroidism is caused by deficient production of TH by  the thyroid gland. The condition may be primary, second-  ary, or subclinical.   Causes of primary hypothyroidism include iodine defi-  ciency, autoimmune thyroiditis, subacute or painless  thyroiditis, silent or subacute lymphocytic thyroiditis, iat-  rogenic hypothyroidism, and postpartum thyroiditis.  Autoimmune thyroiditis (Hashimoto disease) is associated  with lymphocyte infiltration, antibody activation of natural  killer cells, induction of apoptosis with gradual loss of thy-  roid function, and hypothyroidism.   Subacute thyroiditis, a form of hypothyroidism, is a self-  limited nonbacterial inflammation of the thyroid gland.  The inflammatory process damages follicular cells, causing  leakage of triiodothyronine (T;) and thyroxine (T,). Hyper-  thyroidism then is followed by transient hypothyroidism,  which is corrected by cellular repair and a return to normal  levels in the thyroid.   Secondary hypothyroidism is caused by hypothalamic-  pituitary dysfunction in which TRH and TSH are not pro-  duced in sufficient amounts.    Thyroid carcinoma is a relatively rare cancer. The most  consistent causal risk factor associated with thyroid car-  cinoma is exposure to ionizing radiation, especially in  childhood.   Hypothyroidism affects all body systems. Symptoms  depend on the degree of TH deficiency. Common mani-  festations include decreased energy metabolism and loss of  heat production.   Myxedema is the characteristic sign of hypothyroidism.  Myxedema is caused by alterations in connective tissue with  water-binding proteins. The excess water leads to thickened  mucous membranes and edema, particularly around the  eyes and in the hands and feet.   Myxedema coma is a severe form of hypothyroidism,  which may be life threatening without emergency medical  treatment.   Congenital hypothyroidism is TH deficiency at birth; it  occurs with thyroid agenesis and results in hypothyroid-  ism, growth failure, and mental retardation from absence  of thyroxine.   Papillary and follicular thyroid carcinomas are the most  common thyroid malignancies probably caused by  exposure to ionizing radiation, particularly during child-  hood. Thyroid nodules are present with normal thyroxine  levels.    Hyperparathyroidism may be primary, secondary, or ter-  tiary and is characterized by greater than normal secretion  of PTH.    thyroid adenoma with interruption of the normal mecha-  nisms that regulate calcium and PTH levels. Manifestations  include chronic hypercalcemia, increased bone resorption,  and hypercalciuria.    to hypocalcemia and often occurs with chronic renal failure  or chronic vitamin D deficiency.   and familial hypocalci-  uric hypercalcemia are inherited conditions. In pseudo-  hypoparathyroidism there is resistance to PTH action and  familial hypocalciuric hypercalcemia mimics hyperparathy-  roidism with failure of calcium sensing by the parathyroid  gland.    depressed serum calcium levels, increased serum phos-  phate levels, decreased bone resorption, and eventual  hypocalciuria.    Diabetes mellitus is a group of diseases characterized by  hyperglycemia resulting from defects in insulin secretion  or insulin action, or both. The two most common types of  diabetes mellitus are type 1 and type 2.    hemoglobin (HbA,,) levels, fasting plasma glucose (FPG)  levels, and 2-hour plasma glucose levels during oral glucose  tolerance testing (OGTT).    common) and a nonimmune type. The immune type (type  1A) is associated with genetic susceptibility, environmental  factors, and autoantibody, T-cell, and macrophage destruc-  tion of pancreatic beta cells with loss of insulin production  and a relative excess of glucagon. Antibodies also can be  formed against glutamic acid decarboxylase and insulin.  Nonimmune type diabetes (type 1B) occurs secondary to  other disease.    that is triggered by environmental factors. The most com-  pelling environmental risk factor is obesity. Insulin pro-  duction continues but the weight and number of beta cells  decrease.    linemia) cause reduced glucose uptake and metabolism  in type 2 diabetes. These mechanisms include alteration  in the production of adipokines by adipose tissue (i.e.,  leptin resistance), elevated levels of serum free fatty acids  and intracellular lipid deposits, release of inflammatory  cytokines from adipose tissue, reduced insulin-stimulated  mitochondrial activity, and obesity-associated insulin  resistance.    cagon secretion and hyperglycemia. Deposition of amyloid  in the pancreas contributes to beta-cell loss.    associated with autosomal dominant gene mutations and  gestational diabetes associated with onset of glucose intol-  erance during pregnancy.   Acute complications of diabetes mellitus include hypogly-  cemia, DKA, HHNKS, the Somogyi effect, and the dawn  phenomenon.   Hypoglycemia is a lowered blood glucose level that may  be related to exogenous (i.e., insulin shock or insulin reac-  tion), endogenous, or functional causes.   Symptoms of hypoglycemia are divided into adrenergic,  caused by activation of the sympathetic nervous system;  and neuroglycopenic, reflecting defective central ner-  vous system metabolism resulting from impaired energy  generation.    DKA develops when there is an absolute or relative defi-  ciency of insulin and an increase in the amounts of insulin  counterregulatory hormones of catecholamines, cortisol,  glucagon, and GH; increased lipolysis; and accelerated glu-  coneogenesis and ketogenesis. It is most common in type 1  diabetes, but also occurs in type 2.   HHNKS is pathophysiologically similar to DKA, although  levels of FFAs are lower in HHNKS and lack of ketosis indi-  cates that some level of insulin is present. The hyperosmolar  state can cause osmotic diuresis and profound dehydration,  causing coma.   The Somogyi effect is a combination of hypoglycemia with  rebound hyperglycemia caused by effects of counterregula-  tory hormones. It is most common in persons with type 1  diabetes mellitus and in children.   The dawn phenomenon is an early morning rise in glucose  levels caused by nocturnal elevations of GH concentration.  Chronic complications of diabetes mellitus are related to  chronic hyperglycemia and include microvascular disease  (e.g., retinopathy, nephropathy, and neuropathy), macro-  vascular disease (e.g., CAD, stroke, and peripheral vascular  disease), and infection. Metabolic changes contributing to  complications include oxidative stress, shunting of glucose  to the polyol pathway, activation of protein kinase C, for-  mation of AGEs, and accumulation of hexosamines.  Microvascular complications are associated with vascular  alterations in the endothelium and the basement mem-  brane as well as thrombosis.   Diabetic retinopathy is caused by several mechanisms  including microvascular changes and thrombosis that lead  to microvascular occlusion, retinal ischemia, increased  vascular permeability, microaneurysm formation, hemor-  rhages, and neovascularization with loss of vision.   Diabetic nephropathy is related to hyperglycemia, hyperper-  fusion, oxidative stress, and inflammation with glomerular  enlargement and glomerular basement membrane thicken-  ing, diffuse intercapillary glomerulosclerosis, expansion of  the mesangial matrix, and progressive renal failure.  Diabetic neuropathies may be caused by vascular and meta-  bolic mechanisms, or by a combination of both, with axo-  nal and Schwann cell degeneration and abnormalities in  sensory and motor nerve conduction velocity, and involve-  ment of the autonomic nervous system.   Macrovascular disease associated with diabetes mellitus is  associated with hyperglycemia, hyperlipidemia, inflamma-  tion, and altered endothelial function.   The incidence of coronary heart disease, peripheral vascular  disease, and stroke is greater in persons with diabetes than  in nondiabetic individuals.   CAD and stroke in diabetes are a consequence of acceler-  ated atherosclerosis, hypertension, and increased risk for  thrombus formation.   Peripheral vascular disease is a consequence of neuropathy  and occlusion of large and small arteries with an increased  risk of ischemia, necrosis, and amputation.    Individuals with diabetes are at risk for a variety of infec-  tions related to sensory impairment, vascular complica-  tions, impaired white blood cells and suppressed immunity,  rapid proliferation of pathogens, and delayed wound  healing.    Disorders of the adrenal cortex are related to hyperfunction  or hypofunction. No known disorders are associated with  hypofunction of the adrenal medulla, but medullary hyper-  function causes clinically defined syndromes.  Hypercortisolism is divided into ACTH-dependent (Cush-  ing disease or ectopic ACTH syndrome) and ACTH-  independent (adrenal adenoma or adenocarcinoma)  mechanisms.   Cushing disease is excessive anterior pituitary ACTH pro-  duction most commonly by an ACTH-secreting pituitary  microadenoma.   Cushing syndrome occurs whenever there is an excessive  level of cortisol regardless of cause. Exogenous forms result  from exogenous administration of glucocorticoids. Endog-  enous forms are either corticotropin dependent (most com-  mon and caused by an ACTH-secreting pituitary tumor) or  corticotropin independent (usually caused by an adrenal  cortical tumor).   Individuals with Cushing disease lose diurnal and circadian  patterns of ACTH and cortisol secretion, and they lack the  ability to increase secretion of these hormones in response  to a stressor. Individuals experience weight gain, glucose  intolerance, protein wasting, bone disease, hyperpigmenta-  tion, and immunosuppression.   Congenital adrenal hyperplasia is an autosomal recessive  disorder with inadequate synthesis of cortisol and increased  levels of ACTH that cause adrenal hyperplasia and overpro-  duction of mineralocorticoids or androgens.   Primary hyperaldosteronism is a disorder of excessive  aldosterone secretion usually caused by an adrenal cortical  adenoma or bilateral nodular hyperplasia. The condition is  characterized by hypertension, hypokalemia, renal potas-  sium wasting, and neuromuscular manifestations.    Secondary hyperaldosterone secretion is related to a vari-  ety of conditions associated with elevated renin release and  activation of angiotensin II. These include decreased circu-  lating blood volume, decreased renal blood supply, elevated  estrogen levels, Bartter syndrome, and renin-secreting  tumors.   Adrenal tumors, either adenomas or carcinomas, can  autonomously secrete androgens or estrogens.  Hypofunction of the adrenal cortex can affect glucocorti-  coid or mineralocorticoid secretion or both. Hypofunction  can be caused by a deficiency of ACTH or bya primary defi-  ciency in the gland itself.   Hypocortisolism (low levels of cortisol) is caused by inad-  equate adrenal stimulation by ACTH or by primary corti-  sol hyposecretion. Primary adrenal insufficiency is termed  Addison disease.   Addison disease is characterized by elevated ACTH lev-  els with inadequate corticosteroid synthesis and output.  Causes include idiopathic autoimmune disease, tuberculo-  sis of the adrenal gland, familial adrenal insufficiency, amy-  loidosis, metastatic destruction of the adrenal glands, and  adrenal hemorrhage.   Manifestations of Addison disease are related to hypocorti-  solism and hypoaldosteronism. Symptoms include weakness,  fatigability, hypoglycemia and related metabolic problems,  lowered response to stressors, vitiligo, hyperpigmentation,  and manifestations of hypovolemia and hyperkalemia.  Secondary hypercortisolism is characterized by low  to absent ACTH levels, leading to inadequate adrenal  stimulation, adrenal atrophy, and decreased corticoste-  roidogenesis. The most common cause is withdrawal of  exogenous administration of glucocorticoids. Manifesta-  tions are similar to those of Addison disease only without  hyperpigmentation.   Hyperfunction of the adrenal medulla is caused by a pheo-  chromocytoma, which is a_ catecholamine-producing  tumor. Symptoms of catecholamine excess are related to  their sympathetic nervous system effects and include hyper-  tension, palpitations, tachycardia, glucose intolerance,  excessive sweating, and constipation.   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Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Development of the Reproductive Systems, 768  Sexual Differentiation and Hormone  Production In Utero, 768  Puberty and Reproductive Maturation, 770  The Female Reproductive System, 771  External Genitalia, 771  Internal Genitalia, 772  Female Sex Hormones, 776  The Menstrual (Ovarian) Cycle, 778  Structure and Function of the Breast, 782  The Female Breast, 782  The Male Breast, 784    The male and female reproductive systems have several anatomic  and physiologic features in common. Most obvious is their major  function, reproduction, through which a 23-chromosome female  gamete, the ovum, and a 23-chromosome male gamete, the  spermatozoon (sperm cell), unite to form a 46-chromosome  zygote that is capable of developing into a new individual. The  male reproductive system produces sperm and delivers them to  the female reproductive tract. The female reproductive system  produces the ovum and, if it is fertilized, can nurture and pro-  tect it (at that point called the embryo and developing fetus)  and expel it at birth. These functions are determined not only by  anatomic structures but also by complex hormonal, neurologic,  and psychogenic factors.!    The Male Reproductive System, 784  External Genitalia, 784  Internal Genitalia, 787  Spermatogenesis, 789  Male Sex Hormones, 789    The structure and function of male and female reproductive  systems depend on steroid hormones called sex hormones and  their precursors. Hormonal effects on the reproductive systems  begin well before birth and continue for life.   Initially in embryonic development, the reproductive structures  of male and female embryos are homologous (the same) and  consist of one pair of primary sex organs, or gonads, and two  pairs of ducts, the mesonephric ducts (wolffian ducts) and the  paramesonephric ducts (miillerian ducts) (Figure 23-1). Both  pairs of ducts empty into an opening called the urogenital sinus.    FIGURE 23-1 Internal Genitalia Development. Embryonic and fetal development of the internal genitalia.    Between 6 and 7 weeks of gestation, the male embryo will  differentiate under the influence of testes-determining factor  (TDF), a protein expressed by a gene in the sex-determining  region on the Y chromosome (SRY). When the SRY gene is  expressed, male gonadal development prevails. TDF stimulates  the male gonads to develop into the two testes and by 8 weeks of  gestation testosterone secretion begins. By 9 months’ gestation,  the male gonads (testes) have descended into the scrotum. The  testes produce sperm after puberty.   Female gonadal development occurs in the absence of SRY  expression and with the expression of other genes.” The pres-  ence of estrogen and the absence of testosterone cause regression  of the wolffian system and, at 6 to 8 weeks’ gestation, the two  female gonads develop into ovaries, which will produce ova.  By the tenth week, the loss of wolffian ducts allows the miillerian  ducts to join and become the uterus, fallopian tubes, cervix, and  upper two thirds of the vagina. The fallopian tubes carry ova  from the ovaries to the uterus during a woman’s reproductive  years.    Like the internal reproductive structures, the external struct-  ures develop from homologous embryonic tissues. During the  first 7 to 8 weeks of gestation, both male and female embryos  develop an elevated structure called the genital tubercle (Figure  23-2). Testosterone is necessary for the genital tubercle to  differentiate into male genitalia; otherwise, female genitalia  develop, which may occur even in the absence of ovaries pos-  sibly because of the presence of placental estrogens.   Anterior pituitary gland development starts between the 4th  and 6th weeks of fetal life, and the vascular connection between  the hypothalamus and the pituitary is established by the 12th  week. Gonadotropin-releasing hormone (GnRH) is produced  in the hypothalamus by 10 weeks’ gestation and controls the  production of two gonadotropins by the anterior pituitary  gland, luteinizing hormone (LH) and follicle-stimulating hor-  mone (FSH). In the female fetus, high levels of FSH and LH  are excreted. FSH and LH stimulate the production of estrogen  and progesterone by the ovary. The production of FSH and LH  rises until about 28 weeks’ gestation, until the production of    estrogen and progesterone by the ovaries and placenta is high  enough to result in the decline of gonadotropin production!  Production of primitive female gametes (ova) occurs solely  during fetal life. From puberty to menopause, one female gam-  ete matures per menstrual cycle. Production of the male gam-  etes (sperm) begins at puberty; after that millions are produced  daily, usually for life.   By the end of pregnancy a sensitive negative-feedback sys-  tem, which includes the gonadostat (also known as the gonad-  otropin-releasing hormone pulse generator), is operative in  the human fetus. The gonadostat responds to high placental    estrogens by releasing low levels of GnRH. Soon after birth  steroid hormones levels drop because of withdrawal of maternal  placental hormones. Hypothalamic pulsatile GnRH is secreted  and gonadotropins LH and FSH are released and peak at 3 to  6 months for boys and 12 to 18 months for girls, and then fall  steadily. The gonadotropins will be suppressed until the onset  of puberty.    Puberty is the onset of sexual maturation and differs from  adolescence. Adolescence is the stage of human development    FIGURE 23-3 Hormonal Stimulation of the Gonads. The hypothalamic-  pituitary-gonadal axis.    between childhood and adulthood and includes social, psycho-  logic, and biologic changes. In girls, puberty begins at about  ages 8 to 9 years with thelarche (breast development). In boys,  it begins later—at about age 11 years. Genetics, environment,  ethnicity, general health, and nutrition can influence the timing  of puberty. Girls who are obese mature earlier, perhaps from  higher estrogen levels related to leptin and gonadotropin secre-  tion,’ and girls who have low body fat, reduced body weight,  and intense exercise may experience delayed maturation.*  Although leptin is not the trigger for puberty onset, it plays an  important permissive role.   Reproductive maturation involves the hypothalamic-  pituitary-gonadal (HPG) axis, the central nervous system,  and the endocrine system (Figure 23-3). A sequential series  of hormonal events promotes sexual maturation as puberty  approaches. About 1 year before puberty in girls, there is an  increase in frequency and amplitude of nocturnal pulses of  gonadotropin secretion, LH, and FSH and an increased response  in the pituitary to GnRH. This, in turn, stimulates gonadal mat-  uration (gonadarche) with estradiol secretion in girls and tes-  tosterone secretion in boys. Estradiol causes breast development  (thelarche), maturation of the reproductive organs (vagina,    uterus, ovaries), and fat deposit in hips in girls. Estrogen and  increased production of growth factors cause rapid skeletal  growth in both boys and girls. Testosterone causes growth of the  testes, scrotum, and penis. A positive feedback loop is created  with gonadotropins stimulating the gonads to produce more  sex hormones. The most important hormonal effects occur in  the gonads. In males the testes begin to produce mature sperm  that are capable of fertilizing an ovum. Male puberty is com-  plete with the first ejaculation that contains mature sperm. In  females, the ovaries begin to release mature ova. Female puberty  is complete with the first ovulatory menstrual period; however,  this can take up to 1 to 2 years after menarche. Adrenarche is  the increased production of adrenal androgens (dehydroepi-  androsterone and androstenedione, which is converted to tes-  tosterone and estrogen) prior to puberty, which occurs in both  sexes, and is exhibited by axillary and pubic hair growth and  body odor. Puberty is complete when an individual is capable  of reproduction.    The function of the reproductive system is to produce mature  ova and, when they are fertilized, protect and nourish them  through embryonic and fetal life and expel them at birth. In  females the most important internal reproductive organs in  females are the ovaries, fallopian tubes, uterus, and vagina. The  external genitalia protect body openings and play an important  role in sexual functioning.)>°    Figure 23-4 shows the external female genitalia, which are  known collectively as the vulva, or pudendum. The major  structures are as follows:   * Mons pubis (mons veneris). A fatty layer of tissue over the  pubic symphysis (joint of the pubic bones). During puberty  the mons pubis becomes covered with pubic hair, and seba-  ceous and sweat glands become more active. Estrogen causes  fat to be deposited under the skin, giving the mons pubis a  moundlike shape. This cushion of tissue protects the pubic  symphysis during sexual intercourse.   + Labia majora (singular, labium majus). Two folds of  skin that arise at the mons pubis and extend back to the  fourchette, forming a cleft. Like the mons pubis, the labia  majora undergo changes at puberty: the amount of fatty tis-  sue increases, pubic hair grows on the lateral surfaces, and  sebaceous glands on the hairless medial surfaces begin to  secrete lubricants. Because of an extensive network of nerve  endings, the labia majora are highly sensitive to tempera-  ture, touch, pressure, and pain and are homologous to the  male scrotum (see Figures 23-2 and 23-15). The principal  function of the labia majora is to protect the inner struc-  tures of the vulva.   + Labia minora (singular, labium minus). Two smaller, thin-  ner folds of skin lie within the labia majora. Anteriorly they  form the clitoral hood, or prepuce, and frenulum then split  to enclose the vestibule and converge near the anus, form-  ing the fourchette. The labia minora are hairless, pink, and    Mons pubis  (veneris)  Anterior  commissure  Glans of  clitoris  Prepuce of  clitoris Urethral or  urinary orifice  Frenulum  of clitoris  Vestibule  Labium  minus Labium  majus  Lesser vestibular or  Skene duct opening :  Vaginal  Greater vestibular or orifice  Bartholin duct opening  Hymen  Vestibule  Fossa  Fourchette navicularis  Posterior Anus  commissure    moist and are well supplied with nerves, blood vessels, and  sebaceous glands. These glands secrete a bactericidal fluid  that has a distinctive odor and lubricates and waterproofs the  vulvar skin. During sexual arousal the labia minora become  swollen with blood.   Clitoris. A richly innervated, erectile organ that lies anterior  between the labia minora. It is a small, cylindric structure  having a glans that is visible and a shaft that lies beneath  the skin (see Figure 23-4). The clitoris is homologous to the  male penis. Like the penis the clitoris is a major site of sexual  stimulation and orgasm. With sexual arousal erectile tissues  in the clitoris fill with blood, causing it to enlarge somewhat.  Similar to other vulvar glands, the clitoris secretes a fluid,  called smegma, which has a unique odor and may be eroti-  cally stimulating to the male.   Vestibule. An area protected by the labia minora and con-  tains the external opening of the vagina, called the introitus,  or vaginal orifice. A thin, perforated membrane called the  hymen may cover the introitus. The vestibule also contains  the opening of the urethra, or urinary meatus (orifice).  These structures are lubricated by two pairs of glands: Skene  glands and Bartholin glands. The ducts of Skene glands (also  called the lesser vestibular or paraurethral glands) open on  both sides of the urinary meatus. The ducts of Bartholin  glands (greater vestibular or vulvovaginal glands) open on  either side of the introitus. In response to sexual stimula-  tion, Bartholin glands secrete mucus that lubricates the inner  labial surfaces, as well as enhances the viability and motil-  ity of sperm. Skene glands help lubricate the urinary meatus  and the vestibule. Secretions from both sets of glands facili-  tate coitus. Also, in response to sexual excitement, the highly    vascular tissue just beneath the vestibule fills with blood and  becomes engorged.   * Perineum. An area with less hair, skin, and the subcuta-  neous tissue lying between the vaginal orifice and anus.  Unlike the rest of the vulva, this area has little subcutane-  ous fat so that the skin is close to the underlying muscles.  The perineum covers the muscular perineal body, a fibrous  structure that comprises elastic fiber, connective tissue, and  the common attachment of the bulbocavernosus, the exter-  nal anal sphincter, and the levator ani muscles (see Figure  23-4). The perineum varies in length from 2 to 5 cm or more  and stretches remarkably. The length of the perineum and  the elasticity of the perineal body influence tissue resistance  and injury during childbirth.   The vagina is an elastic fibromuscular canal, 9 to 10 cm long in  a reproductive-aged female, which extends up and back from  the introitus to the lower portion of the uterus. As Figure 23-5  shows, it lies between the urethra (and part of the bladder) and  the rectum. Mucosal secretions from the upper genital organs,  menstrual fluids, and products of conception leave the body  through the vagina, which also receives the penis during coitus.  During sexual excitement the vagina lengthens and widens and  the lower third becomes congested with blood.   1. Its lining is a mucous membrane of squamous epithelial  cells. (Types of epithelium are described and illustrated  in Chapter 1, Table 1-7.) This layer thickens and thins  in response to hormones, particularly estrogen. The    FIGURE 23-5 Internal Female Genitalia and Other Pelvic Organs. Midsagittal view. (Modified from Seidel HM et al:  Mosby's guide to physical examination, ed 7, St Louis, 2011, Mosby.)    squamous epithelial membrane is continuous with the  membrane that covers the lower part of the uterus. In  women of reproductive age, the mucosal layer is arranged  in transverse wrinkles, or folds, called rugae (singular,  ruga) that permit stretching during coitus and childbirth.   The upper part of the vagina surrounds the cervix, the lower  end of the uterus (see Figure 23-5). The recessed space around  the cervix is called the fornix of the vagina. The posterior for-  nix is “deeper” than the anterior fornix because of the angle at  which the cervix meets the vaginal canal. In most women this  angle is about 90 degrees. A pouch called the cul-de-sac sepa-  rates the posterior fornix and the rectum.   Its elasticity and relatively sparse nerve supply enhance the  vagina’s function as the birth canal. During sexual arousal the  vaginal wall becomes engorged with blood, like the labia minora  and clitoris. Engorgement pushes some fluid to the surface of  the mucosa, enhancing lubrication. The vaginal wall does not  contain mucus-secreting glands; rather, secretions drain into  the vagina from the endocervical glands or enter from the vesti-  bule, from the Bartholin and Skene glands.   Two factors help maintain the self-cleansing action of the  vagina and defend it from infection, particularly during the  reproductive years: (1) an acid-base balance that discour-  ages the proliferation of most pathogenic bacteria and (2) the    thickness of the vaginal epithelium. Before puberty, vaginal  pH is about 7 (neutral) and the vaginal epithelium is thin. At  puberty the pH becomes more acidic (4 to 5) and the squa-  mous epithelial lining thickens. These changes are maintained  until menopause (cessation of menstruation), at which time  the pH rises again to more alkaline levels and the epithelium  thins out. Therefore, protection from infection is greatest dur-  ing the years when a woman is most likely to be sexually active.  Between puberty and menopause, vulnerability to infection  varies somewhat with cyclic changes in pH and epithelial thick-  ness. Both defenses are greatest when estrogen levels are high  and the vagina contains a normal population of Lactobacillus  acidophilus, a harmless resident bacterium that helps maintain  pH at acidic levels. Any condition that causes vaginal pH to rise,  such as douching or use of vaginal sprays or deodorants, low  estrogen levels, or destruction of L. acidophilus by antibiotics,  lowers vaginal defenses against infection.    The uterus is a hollow pear-shaped organ whose lower end  opens into the vagina. The functions of the uterus are to anchor  and protect a fertilized ovum, provide an optimal environment  while it develops, and push the fetus out at birth. In addition, the  uterus plays an important role in sexual response and concep-  tion. During sexual excitement the opening of the uterus (the  cervix) dilates slightly. At the same time, the uterus increases in  size and moves upward and backward, creating a tenting effect  in the midvagina that results in the cervix “sitting” in a pool of    semen. During orgasm, rhythmic contractions facilitate move-  ment of sperm through the cervical os while also enhancing  physical pleasure.   At puberty the uterus attains its adult size and proportions  and descends from the abdomen to the lower pelvis, between  the bladder and the rectum (see Figure 23-5). The uterus of a  mature, nonpregnant female is approximately 7 to 9 cm long  and 6.5 cm wide, with muscular walls 3.5 cm thick. It is held  loosely in position by ligaments, peritoneal tissue folds, and    pressure of adjacent organs, especially the urinary bladder, sig-  moid colon, and rectum. In most women the uterus is ante-  verted; that is, it is tipped forward so that it rests on the urinary  bladder. However, it may be retroverted, or tipped backward.  Various degrees of flexion are normal (Figure 23-6).   Figure 23-7 shows a cross section of the uterus. The uterus  has two major parts: the body, or corpus, and the cervix. The  top of the corpus, above the insertion of the fallopian tubes, is  called the fundus. The diameter of the uterine cavity is widest at    FIGURE 23-7 Cross Section of Uterus, Fallopian Tube, and Ovary. (From Seidel HM et al: Mosby's guide to physical    the fundus and narrowest at the isthmus, which is the narrowed  part of the corpus just above the cervix. The cervix, or neck of  the uterus, extends from the isthmus to the vagina. The pas-  sageway between the cervix’s upper opening (the internal os)  and its lower opening (the external os) is called the endocervi-  cal canal. The entire uterus, like the upper vagina, is innervated  exclusively by motor and sensory fibers of the autonomic ner-  vous system.   The uterine wall is composed of three layers: the perime-  trium, the myometrium, and the endometrium (see Figure  23-7). The perimetrium (parietal peritoneum) is the outer  serous membrane that covers the uterus. The myometrium is  the thick muscular middle layer. The myometrium is thickest  at the fundus, apparently to facilitate birth. The endometrium,  or uterine lining, is composed of a functional layer (superficial  compact layer and spongy middle layer) and a basal layer. The  functional layer of the endometrium is responsive to sex hor-  mones. Between puberty and menopause this layer proliferates  and sloughs off monthly. The basal layer, which is attached  to the myometrium, regenerates the functional layer after it  sloughs (menstruation).   The endocervical canal does not have an endometrial layer.  Rather, it is lined with columnar epithelial cells (see Table 1-7).  The endocervical lining is continuous with that of the outer cer-  vix and vagina, but it is not made up of the same type of epithelial  cells. The point at which the columnar epithelium of the cervix  meets the squamous epithelium of the vagina is called the trans-  formation zone, or the squamous-columnar junction. The trans-  formation zone is especially susceptible to the oncogenic human  papillomavirus (HPV), especially HPV types 16 and 18, which  can lead to cervical dysplasia and, ultimately, cervical cancer (see  What’s New? Human Papillomavirus (HPV) Vaccine and Can-  cer Prevention in Women and Men); these are the cells sampled  during the Papanicolaou test (Pap test).’   The cervix acts as a mechanical barrier to infectious microor-  ganisms that may be present in the vagina. The external cervical  os is a very small opening that contains thick, sticky mucus (the    mucous plug) during the luteal phase of the menstrual cycle and  all of pregnancy. During ovulation the mucus changes under the  influence of estrogen and forms watery strands, or spinnbarkeit  mucus, to facilitate the transport of sperm into the uterus. In  addition, the downward flow of cervical secretions moves micro-  organisms away from the cervix and uterus. In women of repro-  ductive age, the pH of these secretions is inhospitable to most  bacteria. Furthermore, mucosal secretions contain enzymes  and antibodies (mostly immunoglobulin A) of the secretory  (humoral) immune system (see Chapter 8). These defenses do  not always prevent infection, even if they are intact. Besides infec-  tion, uterine pathophysiology includes displacement of the uterus  within the pelvis, benign growths (fibroids) of the uterine wall,  hyperplasia of the endometrium, endometriosis, and cancer.    The two fallopian tubes (oviducts, uterine tubes) enter the  uterus bilaterally just beneath the fundus (see Figure 23-7).  Their function is to conduct the ova from the spaces around  the ovaries to the uterus. From the uterus the fallopian tubes  curve up and over the two ovaries. Each tube is 8 to 12 cm long  and about 1 cm in diameter, except at its ovarian end, which  flares out like the bell of a trumpet. This widened end, called the  infundibulum, is fringed or fimbriated. The fimbriae (singu-  lar, fimbria) (fringes) move, creating a current that draws the  ovum into the infundibulum. Once the ovum has entered the  fallopian tube, cilia and peristalsis (muscle contractions) keep it  moving toward the uterus.   The ampulla, or distal third, of the fallopian tube is the usual  site of fertilization (see Figure 23-7). Sperm released into the  vagina travel upward through the endocervical canal and uter-  ine cavity and enter the fallopian tubes. If an ovum is present  in either tube, fertilization can occur. Whether or not the ovum  encounters sperm, it continues to travel through the fallopian  tube to the uterus. If fertilized, the ovum (then called a blasto-  cyst) implants itself in the endometrial layer of the uterine wall.  If not fertilized, the ovum breaks down within 12 to 24 hours.    Human Papillomavirus (HPV) Vaccine and Cancer Prevention in Women and Men    Two HPV vaccines are approved in the United States: the quadrivalent HPV  recombinant vaccine in males and females (HPV 6, 11, 16, and 18); and the biva-  lent HPV recombinant vaccine (HPV 16 and 18) in females. HPV types 16 and 18  are oncogenic and can cause cervical dysplasia, cervical cancer, anal cancer,  penile cancer, and cancer of the head and neck. Types 6 and 11 cause genital  warts. HPV is responsible for 99.7% of cervical cancer cases, 40% of penile    cancers, and an estimated 5% of all cancers worldwide. Symptoms of infection  are often silent, and approximately 50% of women are estimated to be infected,  usually during adolescence. Men who have sex with men are at high risk. The  incidence of genital warts and cancer is reduced in those receiving the vaccine.  The vaccine is administered by intramuscular injection and the recommended  schedule is a three-dose series with the second and third doses administered  2 and 6 months after the first dose. The recommended age for vaccination of    females is 11 to 12 years. The vaccine can be administered as young as age 9  years. Catch-up vaccination is recommended for females ages 13 to 26 years  who have not been previously vaccinated. The vaccine is not disease treatment,  and disease may develop related to non—vaccine-related HPV infection. Pap  smear screening for cervical cancer should be continued. Efforts are in progress  0 make the vaccine affordable in less-developed countries, with the hope of  eradicating cervical cancer.   Vaccination programs target women to prevent cervical cancer. The quadriva-  ent vaccine has been approved for males 9 to 26 years of age to prevent genital  warts. Rates of vaccination among men and low income minority women are  ow, and education and financing efforts need to be expanded for these groups.  Cost effectiveness of vaccinating men is controversial. There are no antiviral  therapies for this disease.    Data from Alexander KA, Giuliano AR: Am J Med 125(7):S1, 2012; Fontenot HB, Morelock N: Nurs Womens Health 16(1):57-65, 2012; Laz TH,  Rahman M, Berenson AB: Cancer 119(7):1386-1392, 2013; Low GM et al: Viral Immunol 25(3):174-186, 2012; Stanley MA: J Gen Virol 93(Pt 4):  681-691, 2012; Stupiansky NW, Alexander AB, Zimet GD: Curr Opin Infect Dis 25(1):86-91, 2012.    Disorders that affect the fallopian tubes (e.g., congenital mal-  formations, infection, and inflammation) can block the path  of sperm and ovum and cause infertility or ectopic (tubal)  pregnancy.    The ovaries, the female gonads, are the primary female repro-  ductive organs. Their two main functions are secretion of  female sex hormones and development and release of female  gametes, or Ova.   The almond-shaped ovaries are located on both sides of the  uterus and are suspended and supported by the mesovarian  portions of the broad ligament, ovarian ligaments, and suspen-  sory ligaments (see Figure 23-7). The ovaries are smaller than  their male homologs, the testes. In women of reproductive age,  each ovary is 3 to 5 cm long, 2.5 cm wide, and 2 cm thick and  weighs 4 to 8 g. Size and weight vary somewhat from phase to  phase of the menstrual cycle (see p. 778).   Figure 23-8, A shows a cross section of an ovary. The cen-  tral part, or medulla, is composed of connective tissue and  contains many small arteries, veins, and lymphatics that enter  at the hilum. Surrounding the medulla is the cortex. At birth  the cortex of each ovary contains approximately 2 million ova  within primordial (immature) ovarian follicles. Follicles grow  and undergo atresia continuously and irrevocably throughout  a woman’s life. By puberty the number ranges between 300,000  and 500,000 ova. Between puberty and menopause the ovar-  ian cortex always contains follicles and ova in various stages  of development, including the primary and secondary follicles  (see Figure 23-8, A). Once every menstrual cycle (about every  28 days), usually only one of the follicles reaches maturation  (see Figure 23-8, B and C) and discharges its ovum through the  ovary’s outer covering, the germinal epithelium. During the  reproductive years, 400 to 500 ovarian follicles mature com-  pletely and release an ovum (ovulation). The rest either fail to  develop at all or degenerate without maturing completely and  are known as atretic follicles! (see Figure 23-8).   After release of the mature ovum (ovulation), the follicle devel-  ops into another structure, the corpus luteum (see Figure 23-8).  The immediate fate of the corpus luteum depends on whether  the ejected ovum is fertilized. If fertilization occurs, the corpus  luteum enlarges and begins to secrete hormones that maintain  and support pregnancy. If fertilization does not occur, the cor-  pus luteum secretes these hormones for approximately 14 days  and then degenerates, which triggers the maturation of another  follicle. The ovarian cycle—the process of follicular matura-  tion, ovulation, corpus luteum development, and corpus luteum  degeneration—is continuous from puberty to menopause, except  during pregnancy or hormonal contraceptive use. At menopause  this process ceases and the ovaries atrophy to the point that they  cannot be felt during pelvic examination.   Sex hormones are secreted by cells within the ovarian cortex  including two types of cells in the ovarian follicle (theca cells  and granulosa cells) and cells of the corpus luteum (see Figure  23-8). These cells all contain receptors for the gonadotropins  (LH, FSH) or for the sex hormones, which are discussed in the  next section.    The sex hormones are all steroid hormones and are synthesized  from cholesterol (see Chapter 21). Male and female sex hor-  mones are present in all adults. However, the female body con-  tains low levels of testosterone and other androgens, and the  male body contains low levels of estrogen. Individual effects of  sex hormones depend on their amount and concentration in  the blood.   The dominant female sex hormones, estrogen and proges-  terone, are produced primarily by the ovaries. During fetal  development, infancy, and childhood, sex hormone produc-  tion is low. At puberty hormone production surges, triggering  sexual maturation and development of secondary sex character-  istics. From puberty to menopause, the sex hormones control  the menstrual cycle and are produced cyclically, that is, produc-  tion surges and diminishes monthly, creating the ovarian and  uterine changes associated with the menstrual cycle. These hor-  mones also are produced in higher levels during pregnancy by  the placenta, inhibiting ovulation. Androgens are produced in  small amounts by the ovaries and the adrenals and have impor-  tant functions in women.    Estrogen is a generic term for three similar hormones: estra-  diol, estrone, and estriol. Estradiol (E,) is the most potent and  plentiful of the three and is principally produced (95%) by the  ovaries (ovarian follicle and corpus luteum). Androgens are  converted to estrone in the ovary and peripheral adipose tissue.  Estriol is the peripheral metabolite of estrone and estradiol.   Estrogen has numerous biologic effects, many of which  involve interactions with other hormones, and is needed for  maturation of reproductive organs, development of second-  ary sex characteristics (differentiating male and female physi-  cal characteristics that are not directly related to reproduction),  closure of long bones after the pubertal growth spurt, regula-  tion of the menstrual cycle, and endometrial regeneration after  menstruation. Estrogen also has metabolic effects on the bones,  liver, blood vessels, brain and central nervous system, kidneys,  and skin. After menopause ovarian production of estradiol and  estrone is markedly diminished (see Menopause, p. 791). At  this time the majority of estrogen is derived from extraovarian  and extraglandular production of estrones.!   Like other steroid hormones, estrogens are derived from  cholesterol in a complex, enzyme-mediated series of reactions.  (Mechanisms of hormone synthesis and action are described in  Chapter 21.) The hypothalamus secretes GnRH in a pulsatile  manner that stimulates gonadotropin (LH and FSH) release  from the anterior pituitary. Gonadotropins trigger ovarian pro-  duction of estrogen. The primary function of LH is to stimu-  late theca cells of the ovarian follicle to produce androgens,  mainly androstenedione. (Androgens are discussed further  on p. 789 and in the section on male reproductive function.)  Some of these androgens are converted to estrogen by the theca  cells themselves, and others diffuse into the granulosa cells.  Within the granulosa layer, FSH induces conversion (aromati-  zation) of androgens to estrogens. Estrogens are then released  into the bloodstream. Estrogen and FSH together increase FSH    (Graffian follicle)  Primary Sanaa Theca externa  follicle Theca  Primordial interna  follicle - Oocyte  Granulosa  precursors  ; Atretic pellucida  Hilum follicle  Blood vessels 41 Day 12  Medulla  Corpus albicans  Day 28  Germinal  epithelium Ruptured follicle  hatare Ovulation  corpus luteum Day 14  A Ovulated oocyte    FIGURE 23-8 Cross Section of Ovary and Development of an Ovarian Follicle. A, Schematic representation (not to  scale) of the structure of the ovary, showing the various stages in the development of the follicle and its successor structure,  the corpus luteum. B, A developing oocyte surrounded by hormone-secreting follicular (granulosa) cells. €, A more mature  ovarian follicle has a fluid-filled cavity called the antrum. (A adapted from Berne RM, Levy MN, editors: Physiology, ed 5, St  Louis, 2003, Mosby. B and € from Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    receptors in the follicle, stimulating additional granulosa cells  until a dominant follicle is determined.   Disturbances of estrogen production can be caused by abnor-  malities that affect (1) secretion of GnRH by the hypothalamus,  (2) secretion of LH or FSH by the anterior pituitary, (3) hormonal  feedback mechanisms, or (4) structural integrity of the ovaries.  Estrogen’s role in the menstrual cycle is described on page 781.    Although androgens are primarily male sex hormones pro-  duced by the testes, small amounts are produced in the adre-  nal cortex in both men and women and in the ovaries. Some  androgens (dehydroepiandrosterone and its metabolite andro-  stenedione) are precursors of estrogens (estrone, estradiol). At  puberty, androgens contribute to the skeletal growth spurt and  cause growth of pubic and axillary hair. The androgens also    activate sebaceous glands, accounting for some cases of acne  during puberty, and play a role in libido.    Progesterone  Luteinizing hormone (LH) from the anterior pituitary stimu-  lates the corpus luteum to secrete progesterone, the second  major female sex hormone. LH surge occurs when there is a  peak level of estrogen, about 24 to 36 hours before ovulation. LH  promotes luteinization of the granulosa in the dominant follicle  and results in progesterone production and the development  of blood vessels and connective tissue. A rising level of proges-  terone can be detected from the preovulatory follicle as early as  day 10 of the menstrual cycle. Small amounts of progesterone  also are secreted steadily by the adrenal cortex. Before ovula-  tion the ovary and the adrenal glands each contribute approxi-  mately 50% of total progesterone production. Conversely, large  amounts are secreted from the ovary while the corpus luteum  is active for about 9 to 13 days after ovulation. Progesterone  secreted by the corpus luteum stimulates the thickened endo-  metrium to become more complex in preparation for implan-  tation of a blastocyst. If conception and implantation do occur,  the corpus luteum persists and secretes progesterone (and  estrogen) until the placenta is well established at approximately  8 to 10 weeks’ gestation. Together, estrogen and progesterone  control the menstrual cycle. The opposing and complementary  effects of progesterone and estrogen are listed in Table 23-1.  Progesterone is sometimes called the hormone of pregnancy.  Progesterone’s effects in pregnancy include: (1) maintaining  the thickened endometrium; (2) relaxing smooth muscle in  the myometrium, which prevents premature contractions and  helps the uterus expand; (3) thickening (hypertrophy) of the  myometrium, which prepares it for the muscular work of labor;  (4) promoting growth of lobules and alveoli in the breast in  preparation for lactation but prevents lactation until the fetus  is born; (5) preventing additional maturation of ova by way of  suppressing FSH and LH, thereby stopping the menstrual cycle;  (6) providing immune modulation allowing tolerance against  fetal antigens (the mother’s immune system does not attack the  fetus); and preventing preterm birth.*!°   Increase of blood flow; increase of contractile proteins and uterine  muscle and myometrial excitability and action potential; increase of    Activation of glands and blood vessels; accumulation of  glycogen and enzymes; decrease in number of estrogen  receptors    The Menstrual (Ovarian) Cycle  In addition to pregnancy the obvious manifestation of female  reproductive functioning is menstrual bleeding (the menses),  which starts with menarche (first menstruation) and ends with  menopause (cessation of menstrual flow for 1 year). In the United  States the average age of first menstruation is 12 years in black  females, 12.5 years in Hispanic females, and 12.6 years in white  females, with a range from 9 to 17 years.'! Menarche appears to  be related to body weight, especially percentage of body fat (ratio  of fat to lean tissue), which may trigger a change in the metabolic  rate and lead to hormonal changes associated with early men-  arche.!* There is an increased sensitivity to leptin (a regulatory  hormone of appetite and energy metabolism) during puberty  and, in theory, the adolescent consumes more calories to meet  caloric needs of the pubertal growth spurt.!° The percent of body  fat and leptin levels in girls continue to increase, whereas muscle  mass increases in boys.!4   At first, cycles are anovulatory and may vary in length from  10 to 60 days or more. As adolescence proceeds into adulthood,  regular patterns of menstruation and ovulation are established  at intervals ranging from 25 to 35 days. The length of the men-  strual cycle varies considerably among women. The commonly  accepted cycle average is 28 (27 to 30) days, with rhythmic  intervals of 21 to 35 days considered normal. Approximately  2 to 8 years before menopause, cycles begin to lengthen again.  Menstrual cyclicity and regular ovulation are dependent on  (1) the activity of the gonadostat (GnRH pulse generator);  (2) the initial pituitary secretion of the gonadotropin FSH; and  (3) estrogen (estradiol) positive feedback for the preovulatory  FSH and LH surge, oocyte maturation, and corpus luteum for-  mation and production of progesterone.!°   The menstrual (ovarian) cycle (Figure 23-9) consists of ovula-  tion, which occurs in two phases: the follicular/proliferative and  the luteal/secretory phase and each lasts about 14 days. Ovulation  occurs between the follicular and luteal phases. If implantation of  the blastocyst does not occur in the late luteal phase, menstruation  (menses) occurs, also known as the ischemic/menstrual phase.'°    FIGURE 23-9 The Menstrual Cycle. GnAh, Gonadotropin-replacing hormone. (Adapted from Lowdermilk DL et al:  Maternity and women’s health care, ed 10, St Louis, 2012, Mosby.)    Early follicular phase: estrogen levels low;  minute amount of progesterone secreted  Late follicular (preovulatory) phase: estrogen  levels high; progesterone increases with    During the follicular/proliferative phase GnRH and a  balance between activin and inhibin from the granulosa cells  contribute to the rise of FSH, which stimulates a number of fol-  licles. The pulsatile secretion of FSH from the anterior pituitary  gland rescues a dominant ovarian follicle from apoptosis by day  5 to 7 of the cycle. Together estrogen and FSH increase FSH  receptors in the granulosa cells of the primary follicle, mak-  ing them more sensitive to FSH. FSH and estrogen combine  to induce production of LH receptors on the granulosa cells,  thus promoting LH stimulation to combine with FSH stimula-  tion, causing a more rapid secretion of follicular estrogen. As  estrogen increases, FSH levels drop because of an increase in  inhibin-B secreted by the granulosa cells in the dominant fol-  licle. This drop in FSH decreases the growth of less-developed  follicles (see Figure 23-9). Estrogen causes cells of the endome-  trium to proliferate and stimulates production of LH. A surge  in both FSH and LH are required for final follicular growth and  ovulation.   Increase in stromal tissue in the late follicular phase is asso-  ciated with a rise in androgen levels. Androgen production  enhances the process of follicle atresia and may stimulate libido  at the point of ovulation.!   Ovulation marks the beginning of the luteal/secretory phase  of the menstrual cycle. The ovarian follicle begins its transfor-  mation into a corpus luteum (see Figure 23-8, A), hence the  name luteal phase. Pulsatile secretion of LH from the anterior  pituitary stimulates the corpus luteum to secrete progesterone,  which in turn initiates the secretory phase of endometrial devel-  opment. Glands and blood vessels in the endometrium branch  and curl throughout the functional layer, and the glands begin  to secrete a thin glycogen-containing fluid, the secretory phase.  If conception occurs, the nutrient-laden endometrium is ready  for implantation. Human chorionic gonadotropin (HCG) is  secreted 3 days after fertilization by the blastocytes and maintains  the corpus luteum once implantation occurs at about day 6 or 7.  HCG can be detected in maternal blood and urine 8 to 10 days    All fall sharply Corpus luteum begins to develop;  endometrium enters secretory phase  Corpus luteum fully developed; endometrium    All rise slightly Corpus luteum regresses; endometrium  breaks down; menstruation begins  More ovarian follicles begin to develop;    after ovulation. The production of estrogen and progesterone  continues until the placenta can adequately maintain hormonal  production. If conception and implantation do not occur, the  corpus luteum degenerates and ceases production of progester-  one and estrogen. Without progesterone or estrogen to maintain  it, the endometrium becomes ischemic (blood-starved) and dis-  integrates. Menstruation then occurs—the ischemic/menstrual  phase—marking the beginning of another cycle.   Ovarian cycles appear to have a minimum length of 24 to  26.5 days: the primary ovarian follicle requires 10 to 12.5 days  to develop, and the luteal phase appears relatively fixed at 14  days (+3 days). Menstrual blood flow usually lasts 3 to 7 days,  but it may last as long as 8 days or stop after 1 to 2 days and  still be considered within normal limits. Bleeding is consistently  scant to heavy and varies from 30 to 80 ml, with most blood  loss occurring during the first 3 days of menses. Menstrual dis-  charge consists of blood, mucus, and desquamated endometrial  tissue and does not clot under normal circumstances. It is usu-  ally dark and produces a characteristic musty odor on oxida-  tion. Environmental factors such as severe emotional stress,  illness, malnutrition, obesity, and seasonal variation may affect  the length of the menstrual cycle.!!7"!”   Hormonal control of the menstrual cycle depends on complex  interactions among the hypothalamus, the anterior pituitary,  and the ovaries (or hypothalamic-pituitary-ovarian [HPO]  axis)*? (Table 23-2). Hormonal control is dependent on nega-  tive and positive ovarian feedback mechanisms. GnRH controls  the gonadotropin production of FSH and LH, and the constant  and pulsatile release of GnRH is critical to the timing of the  menstrual cycle. GnRH is secreted by the hypothalamus into  the hypophyseal portal system and travels to the anterior pitu-  itary, where it stimulates the secretion of LH and FSH. FSH and  LH are released from the anterior pituitary in pulses that cor-  respond to the pulsatile secretion of GnRH.    During the early follicular phase, estrogen levels rise steadily  and, through negative feedback, suppress FSH and positively  increase the production of LH. During the late follicular phase,  the preovulatory rise in progesterone facilitates the positive  feedback of estrogen; estrogen levels begin to increase, stimu-  lating a surge of LH secretion from the anterior pituitary. The  midcycle surge of LH and FSH induces ovulation. A nonste-  roidal ovarian factor, gonadotropin surge-attenuating factor  (GnSAF), may antagonize the effect of estrogen on the pitu-  itary and regulate the surge of LH at midcycle.’! Rising estrogen  and progesterone levels during the luteal phase may inhibit the  anterior pituitary, and thus reduce LH and FSH secretion. Just  before the onset of menstruation, FSH and LH levels begin to  increase slightly, probably because of declining estrogen and  progesterone levels (see Figure 23-9).   A variety of growth factors and autocrine/paracrine peptides  influence hormonal control and follicular response.! During  the early follicular stage, FSH stimulates FSH and LH recep-  tors, insulin-like growth factor 1, and production of inhibin  and activin in the ovary. Activin from granulosa cells stimu-  lates the secretion of FSH and increases the pituitary response  to GnRH, and increases FSH-binding in the granulosa cells in  the dominant follicle. FSH stimulates inhibin secretion from  granulosa cells and it in turn suppresses FSH synthesis. Inhibin  B is primarily secreted in the follicular phase of the cycle but  sharply spikes when ovulation occurs. Inhibin A is secreted  in the luteal phase and further suppresses FSH. Inhibin also  restrains prolactin and growth hormone release, interferes with  GnRH receptors, and promotes breakdown of intracellular  gonadotropins. In summary, the balance between activin and  inhibin regulates FSH secretion, and follistatin inhibits activin  and boosts inhibin activity. Inhibin and activin also regulate  LH stimulation of androgen synthesis in theca cells.?*?> Figure  23-9 depicts fluctuating estrogen, progesterone, gonadotropin,  and inhibin levels. Research continues to advance understand-  ing of the function and structural complexity of these polypep-  tides and their interaction with GnRH, gonadotropins, and sex  hormones.”*    By stimulating follicles, gonadotropins initiate their growth and  maturation. The most important hormonal event is a rise in  FSH. The decline in the late luteal phase of estrogen, proges-  terone, and inhibin secretion allows FSH to rise; concurrently  there is a slight increase in LH levels (see Figure 23-9). FSH  stimulates granulosa cell growth and initiates estrogen produc-  tion in these cells in the next cycle. At this time a group of ovar-  ian follicles is recruited and begins to mature; the exact number  depends on the remaining pool of inactive follicles. As the  follicles mature, granulosa cells multiply, increasing estradiol  secretion. Within a few days of the cycle, one follicle becomes  dominant and the others atrophy. The mechanism for follicular  recruitment or dominance is unknown.*> The dominant fol-  licle begins to secrete progressively larger amounts of estrogen  (estradiol), which exerts an increase in GnRH receptor concen-  tration and an increase in pituitary sensitivity to GnRH, cre-  ating a positive-feedback effect causing an FSH and LH surge.    Ovulation generally occurs 1 to 2 hours before the final proges-  terone surge, or about 12 to 36 hours after the onset of the FSH  and LH surge. Progesterone, proteolytic enzymes, and prosta-  glandins (E and F series) trigger mechanisms controlling fol-  licular rupture and release of the ovum.! Possible mechanisms  include thinning, stretching, degradation, and digestion of the  follicular wall and contraction of smooth muscle cells of the fol-  licle. The role of prostaglandins is essential to ovulation, and  infertility patients should be advised to avoid the use of drugs  that inhibit prostaglandin synthesis.”°   The FSH and LH surge also transforms the granulosa cells  of the ovulatory follicle into the corpus luteum. The corpus  luteum secretes estrogen and progesterone in amounts that  depend in part on adequate development of the follicle before  ovulation. Progesterone acts centrally and locally within the  ovary to suppress new follicular growth during the early and  midluteal phases. If pregnancy does not occur, the corpus  luteum persists for 11 to 14 days, then regresses and eventually  disappears. An increase in pulse frequency of GnRH from alow  level of estrogen and progesterone reactivates hormonal control  of the menstrual cycle and FSH secretion increases.    Uterine phases of the menstrual cycle—proliferative, secretory,  and ischemic/menstrual phases—involve cyclic endometrial  changes controlled by estrogen and progesterone. Hormonal  effects are influenced by the presence of receptors and numer-  ous growth factors, peptides, and enzymes that act as inter-  mediaries between the sex steroids and the endometrium.”  During the midfollicular phase, increasing levels of estrogen  contribute to endometrial repair and proliferation, increas-  ing endometrial thickness. Once ovulation occurs and serum  progesterone levels increase, the endometrial tissue develops  secretory characteristics. If implantation of a fertilized ovum  does not take place, endometrial tissue begins to break down  approximately 11 days after ovulation. The period of break-  down is sometimes called the ischemic phase (see Figure 23-9).  Sloughing of tissue (menstrual bleeding) begins about 14 days  after ovulation.   Cervical mucus also undergoes cyclic changes. During the  proliferative phase the cervical mucus is thin and watery. Peak  estrogen levels occur just before ovulation and maximally stim-  ulate the cervical glands to produce mucus. Cervical mucus  becomes abundant and more elastic (spinnbarkeit). In the pres-  ence of estrogen, tiny channels develop in the mucus, which  allows sperm access to the interior of the uterus. Changes in  the consistency of cervical mucus can be used to identify fertile  intervals.    Vaginal endothelium also responds to cyclic hormonal changes.  Under the influence of estrogen, epithelial cells of the vagina  grow maximally during the follicular/proliferative phase. After  ovulation, layers of keratinized cells overgrow the basal epithe-  lium, a process known as cornification. Near the end of the  luteal phase, leukocytes invade vaginal epithelium, removing  the outer layers in a process termed decornification.    lactation Possible  extensions <  of mammary =  sist tissue  A ‘ B (posterior and medial)  FIGURE 23-10 Schematic Diagram of Breast. A, Lactating breast. B, Structures of the breast. (From Shah P: Breast. In  Standring S, editor: Grays anatomy, ed 39, London, 2005, Elsevier Churchill Livingstone.)  Body Temperature and endocrine factors, and contributes to the diversity of breast    Basal body temperature (BBT) undergoes characteristic bipha-  sic changes during menstrual cycles in which ovulation occurs.  During the follicular phase the BBT fluctuates around 37° C (98°  F). After the LH surge, the average temperature increases by 0.2°  to 0.5° C (0.4° to 1° F). At the end of the luteal phase, 1 to 3 days  before the onset of menstruation, BBT declines to follicular-  phase levels. The shift in temperature is related to ovulation, cor-  pus luteum formation, and increased serum progesterone levels.  Progesterone probably acts on the thermoregulatory center of  the hypothalamus to increase body temperature. Changes in  BBT are used to document ovulatory cycles but when used alone  are not the best method to predict the exact timing of ovulation.    The adult breast lies on the ventral surface of the thorax, within  the superficial fascia of the chest wall, extending vertically from  the second rib to the sixth or seventh intercostal space and later-  ally from the side of the sternum to the midaxillary line. Breast  tissue also may extend into the axilla; this tissue is known as the  tail of Spence.    The female breast is composed of 15 to 20 pyramid-shaped  lobes that are separated and supported by suspensory (Cooper)  ligaments (Figure 23-10). Each lobe contains 20 to 40 lobules  that are subdivided into glandular alveoli. The lobes and lob-  ules are surrounded and separated by muscle strands and fatty  connective tissue. The amount of fatty connective tissue varies  from individual to individual, depending on weight and genetic    size and shape and function of the mammary epithelium. Dur-  ing pregnancy the alveoli further develop, becoming composed  of secretory acini that synthesize milk (lactation) (see Figure  23-10). Given this function, it is only during a pregnancy/lac-  tation cycle and subsequent hormonal changes that the gland  remodels into a milk-secreting organ and reaches its ultimate  mature development stage.** The breast has the capacity to  regress to a resting state after cessation of lactation and then  undergo the same cycle of expansion and regression in sub-  sequent pregnancies, a process possibly maintained by stem  cells.2° This remarkable plasticity of the breast suggests tight  hormonal control and dramatic tissue-stromal restructuring.  Investigators are focusing on the anatomy as a tool to advance  knowledge on normal and aberrant breast development and to  understand the origin of breast cancer.°°°* After pregnancy,  the milk is continuously secreted into the alveolar lumen and  is stored there until the myoepithelial cells are stimulated by  oxytocin to contract, which triggers the let-down reflex.*’ The  alveoli empty into a network of lactiferous ducts. These ducts  reach the skin through 9 or 10 openings (pores) in the nipple.  The lobes and lobules are surrounded and separated by muscle  strands and fatty connective tissue.   An extensive capillary network surrounds the alveoli and  is supplied by perforating branches of the internal mammary,  the thoracoacromial, the internal and lateral thoracic, and  the intercostal arteries. Venous return follows arterial supply,  with relatively rapid emptying into the superior vena cava. The  breasts receive sensory innervation from branches of the second  through sixth intercostal nerves and the cervical plexus. This  accounts for the fact that breast pain may be referred to the    FIGURE 23-11 Lymphatic Drainage of the Female Breast. Arrows indicate the direction of lymphatic drainage.  (From Seidel HM et al: Mosby’s guide to physical examination, ed 7, St Louis, 2011, Mosby.)    chest, back, scapula, medial arm, and neck. Lymphatic drainage  of the breast occurs largely through axillary nodes with minor  drainage through the superficial mammary routes (Figure  23-11). There may be asymmetry between the breasts.*+°°   The nipple is a pigmented, cylindric structure that is  located within the central area of the areola. It measures 0.5  to 1.3 cm in diameter and is approximately 10 to 12 mm in  height when erect. On its surface lie multiple openings, one  from each lobe. The areola is the pigmented circular area in  the center of the breast surrounding the nipple. It may be 15  to 60 mm in diameter. A number of sebaceous glands, the  glands of Montgomery, are located within the areola and aid  in lubrication of the nipple during lactation. The nipple and  areola contain smooth muscles that receive motor innerva-  tion from the sympathetic nervous system. Breast-feeding,  sexual stimulation, and exposure to cold cause the nipple to  become erect.   Fetal and early postnatal breast tissue development occurs  independently from the sex hormones, but the fetal breast tis-  sue becomes progressively responsive to hormonal stimulation  at birth. The neonatal breasts are rudimentary, containing 10 to  12 branching ducts. During childhood, breast, nipple, and are-  ola growth is slow, keeping pace with other body tissues. (Male  breast development normally does not progress any further.) At  the onset of puberty in the female, estrogen secretion stimulates  mammary growth. Breast development, or thelarche, is usually  the first sign of puberty in the female. Full differentiation and  maturation of breast tissue occur over approximately 4 years  and are mediated by a variety of hormones, including estrogen,  progesterone, prolactin, growth hormone, thyroxine, insulin,  and cortisol. Estrogen promotes the increase in size of the breast    Ectopic breast development may occur in males and females with tissue in  the axilla, abdomen, labia in females, or back and buttocks (less common).  The breast tissue develops from the milk line, an embryonic mammary ridge  of ectoderm.   Accessory nipples (polythelia) or mammary glands (polymastia) are caused  by cellular migration along the milk line; polythelia occurs in approximately    1% of the population and is slightly more common in men.   Inverted nipples usually revert to normal during the first month; persistence  into adulthood may cause concerns with lactation.   Failed development of the nipple (athelia) or entire mammary gland (amas-  tia) is rare and may include a complete lack of development, unilateral fail-  ure, or extreme asymmetry. This is caused by complete involution of the  mammary ridge in the milk lines.   Symmetric or asymmetric hyperplasia occurs in approximately 1% to 4% of  all females.    Data from DeSilva NK, Merritt DF: Chapter 545, Breast concerns. In  Kliegman RM et al, editors: Nelson textbook of pediatrics, ed 19,   p 834, Philadelphia, 2011, Saunders; Greydanus DE, Matytsina L,  Gains M: Prim Care 33(2):455-502, 2006.    by the formation of a mass of tissue under the areola, increases  the size and pigmentation of the areola, and promotes develop-  ment of the lobular ducts. The breast cells of parous women  are different than those of women who never become pregnant.  During menopause the lobules of the parous breast regress to  prepregnancy composition and become identical to the nul-  liparous breast. Variations in breast development are listed in  Box 23-1.    During the reproductive years the breast undergoes cyclic  changes in response to changes in the levels of estrogen and  progesterone associated with the menstrual cycle. During the  follicular/proliferative phase of the menstrual cycle, high estra-  diol levels increase the vascularity of breast tissue and stimulate  proliferation of ductal and alveolar tissue. This effect is sus-  tained into the luteal/secretory phase of the cycle. During this  phase progesterone levels influence the growth of the alveoli  and increase and contribute to the breast changes induced by  estradiol. Specific effects of estrogen and progesterone include  dilation of the ducts and conversion of the alveolar cells into  secretory cells, as well as fluid secretion, mitotic activity, and  deoxyribonucleic acid (DNA) production of nonglandular  tissue and glandular epithelium.' Most women experience  some degree of premenstrual breast fullness, tenderness, and  increased nodularity. Breast volume may increase as much as  10 to 30 ml. Because the length of the menstrual cycle does not  allow for complete regression of new cell growth, breast growth  continues at a slow rate until approximately 35 years of age.  Because of the cyclic changes that occur in breast tissue, clinical  breast examination is recommended at the conclusion of or a  few days after menses, when hormonal effects are minimal and  breasts are at their smallest and least tender.   During pregnancy the breast reaches its maximum devel-  opment. With increased levels of estrogen the lobules further  differentiate. Progesterone stimulates development of cells  lining the alveoli to produce milk. Lactation (milk produc-  tion) occurs after childbirth in response to increased levels of  prolactin. Prolactin secretion, in turn, increases by continued  breast-feeding. Oxytocin, another hormone released during  and after delivery, controls milk ejection from alveolar cells.  Milk is continuously secreted into the alveolar lumen and is  stored there until the myoepithelial cells are stimulated by  suckling stimulation of oxytocin, which triggers the let-down  reflex.*> The alveoli empty into a network of lactiferous ducts.  These ducts reach the skin through 9 or 10 openings (pores)  in the nipple.   The function of the female breast is primarily to provide a  source of nourishment for the newborn. Physiologically, breast  milk is the most appropriate nourishment for newborns. Not  only does its composition change over time to meet the chang-  ing digestive capabilities and nutritional requirements of the  infant but it also contains immune cells, specific immunoglob-  ulins, especially immunoglobulin A (IgA), and nonspecific  antimicrobial factors, such as lysozymes and lactoferrin, that  protect the infant against infection, allergies, and asthma.  Evidence suggests breast-feeding decreases future incidence  in the infant of adult obesity, lowers atherosclerotic disease,  and lowers the incidence of types 1 and 2 diabetes.*° During  lactation high prolactin levels interfere with hypothalamic-  pituitary hormones that stimulate ovulation. Lactation usu-  ally suppresses the menstrual cycle (lactational amenorrhea)  and prevents ovulation for the first 6 months postpartum.*”  In many parts of the world breast-feeding is the major means  of contraception. Breasts are also a source of pleasurable sex-  ual sensation and in Western cultures have become a sexual  symbol.    Until puberty, development of the male breast is similar to that  of the female breast. In the absence of sufficiently high levels of  estrogen and progesterone, the male breast does not develop any  further. The normal male breast consists of a small underdevel-  oped nipple, some fatty and fibrous tissue, and a few ductlike  structures in the subareolar area. The male breast may appear  enlarged in obese men because of accumulation of fatty tissue.  Physiologic gynecomastia is a condition in which the breasts  temporarily enlarge as a result of hormonal fluctuations and is  common in newborns, adolescents, and older men. Of men 50  to 80 years of age, 30% to 60% may have palpable breast tis-  sue related to circulating or local production of estrogen from  elevated aromatase activity, particularly in adipose tissue.**?    In men the external genitalia perform the major functions of  reproduction, which are to produce sperm and deliver them  to the female reproductive tract. Sperm, are produced in the  male gonads, the testes, and delivered to the female vagina by  the penis. The internal male genitalia have a more accessory  function. They consist of conducting tubes and fluid-producing  glands, all of which aid in the transport of sperm from the testes  to the urethral opening of the penis. The male reproductive and  urinary structures are shown in Figure 23-12.   In men the testes (singular, testis) are the essential organs of  reproduction. Like the ovaries, the testes have two functions:  (1) production of gametes (in this case, sperm), and (2) pro-  duction of sex hormones (in this case, androgens and testoster-  one). The testes are suspended outside the pelvic cavity because  sperm production requires an environment that is 1° or 2° C  (1.6° to 3.6° F) cooler than body temperature.   During embryonic and fetal life, the testes develop within the  abdomen (see Figure 23-1). About 3 months before birth, the  testes start to descend toward the developing scrotum. About  1 month before birth they enter twin passageways called ingui-  nal canals. The inguinal canals are vaginal processes created by  outpouchings of the peritoneum (lining of the abdominal cav-  ity). The descent of a testis is shown in Figure 23-13. Each testis  moves down outside the peritoneum until it is suspended in the  scrotal sac by its supply lines: the ducts, blood vessels, lymphatic  vessels, and nerves of the spermatic cord. When descent is com-  plete, the abdominal end of each vaginal process closes up and  the inguinal canal disappears. If peritoneal closure at the site  of the inguinal canal is incomplete or weak, an inguinal hernia  may occur later in life. The scrotal end of each vaginal process  becomes the outer covering of the testis, the tunica vaginalis.   Figure 23-14 shows a sagittal section of a mature testis. The  adult testis is ovoid and varies considerably in length (3 to 6 cm),  width (2 to 3.5 cm), depth (3 to 4 cm), and weight (10 to 40 g).  The testis is almost entirely surrounded by an outer covering, the  tunica vaginalis, which separates the testis from the scrotal wall,  and an inner covering, the tunica albuginea. Inward extensions    FIGURE 23-12 Structure of the Male Reproductive Organs. (From Seidel HM et al: Mosby's guide to physical exami-    FIGURE 23-13 Descent of a Testis. The testes descend from the abdominal  cavity to the scrotum during the last 3 months of fetal development.    of the tunica albuginea form septa that separate the testis into  about 250 compartments, or lobules, each of which contains  several tortuously coiled ducts called seminiferous tubules. The  seminiferous tubules constitute the bulk (80%) of testicular vol-  ume and are the site of sperm production. (Sperm production,  termed spermatogenesis, is described on p. 789.) Tissue sur-  rounding these ducts contains blood and lymphatic vessels, fibro-  blastic support cells, macrophages, mast cells, and Leydig cells.  Leydig cells, which occur in clusters and account for about 1% to  5% of testicular volume, produce androgens, chiefly testosterone.   The two ends of each seminiferous tubule join and leave  the lobule through a short, straight section called the tubulus  rectus. Sperm travel from the seminiferous tubules into these  straight sections, which lead to the central portion of the testis,  the rete testis. From the rete testis, sperm move through the  efferent tubules, or vasa efferentia, to the epididymis, where  they mature.   The testes are innervated by adrenergic fibers, whose sole  function apparently is to regulate blood flow to the Leydig cells.  The testes receive arterial blood from the internal spermatic and  differential arteries. Arterial blood flows over the surface of the  testes before entering the parenchyma (functional tissues). Sur-  face flow cools the blood to temperatures that promote sper-  matogenesis, approximately 1° to 2° C (34° to 36° F) below body  core temperature.” Additionally, the testes are suspended out-  side the pelvic cavity to facilitate cooling.    Epididymis  The epididymis (plural, epididymides) is a comma-shaped  structure that curves over the posterior portion of each testis    (see Figure 23-14). It consists of a single highly packed and  markedly coiled (about 6 meters when uncoiled) duct mea-  suring 5 cm long, whose structural function is to conduct  sperm from the efferent tubules to the vas deferens. The duct  can become inflamed from infection by microorganisms that  ascend the urethra or from the prostate, causing epididymitis.  The epididymis has physiologic functions as well. When sperm  enter the head of the epididymis, they are not fully mature or  motile, nor are they capable of fertilizing an ovum. During  the 12 days (or more) sperm take to travel the length of the  epididymis, they receive nutrients and testosterone from the  epididymal epithelium, and some biochemical or physiologic  mechanism enhances their capacity for fertilization.*!   The tail of the epididymis is continuous with the vas defer-  ens (ductus deferens), a duct with muscular layers capable of  powerful peristalsis that transports sperm toward the urethra.  After traveling the length of the epididymis, sperm are stored in  the epididymal tail and vas deferens. The vas deferens enters the  pelvic cavity through the spermatic cord.   The testes, epididymides, and spermatic cord are enclosed and  protected by the scrotum. The scrotum is a skin-covered fibro-  muscular sac that is homologous to the female labia majora  (see Figure 23-2). The skin of the scrotum is thin and has  rugae (wrinkles or folds) that enable it to enlarge or relax away  from the body. At puberty the scrotal skin darkens, develops  active sebaceous glands, and becomes sparsely covered with    hair. Just under the skin lies a layer of connective tissue (fas-  cia) and smooth muscle, the tunica dartos (see Figure 23-14).  The tunica dartos also forms a septum that separates the two  testes. Exposure to cold temperatures causes the tunica dartos  to contract, pulling the testes close to the warm body. In warm  temperatures the tunica dartos relaxes, suspending the testes  away from body heat. These mechanisms promote optimal  temperatures for spermatogenesis. In addition, scrotal sensitiv-  ity to touch, pressure, temperature, and pain protects the testes  against potential harm. During sexual excitement the scrotal  skin and tunica thicken, the scrotum tightens and lifts, and the  spermatic cords shorten, partially elevating the testes toward  the body. As excitement plateaus, the engorged testes increase  50% in size, rotate anteriorly, and flatten against the body, sig-  naling impending ejaculation.    Penis  The penis has two main functions: delivery of sperm to the  female vagina and elimination of urine. (Urine formation and  excretion are the subjects of Chapter 37.) Embryonically, the  penis is homologous to the female clitoris (see Figure 23-2).  Figure 23-12 shows a sagittal section of the adult penis and  its anatomic relation to other urogenital structures. Externally  the penis consists of a shaft with a tip, the glans, which contains  the opening of the urethra. For protection, the skin of the glans  folds over the tip of the penis, forming the prepuce, or foreskin.  At birth, the foreskin is adhered to the glans. Penile erections,  which commonly occur, cause the adhesions to break so that    FIGURE 23-15 The Penis. A, Cross section of the penis. B, Cross section of the shaft of the penis showing three col-  umns of erectile, or cavernous, tissue. (A Netter illustration from www.netterimages.com. Copyright © Elsevier Inc. All rights  reserved. B from Vidic B, Suarez RF: Photographic atlas of the human body, St. Louis, 1984, Mosby.)    by age 3 years the foreskin becomes completely retractable. The  skin of the penis is continuous with that of the groin, scrotum,  and inner thighs. It is hairless, movable, and darker than sur-  rounding skin.   Internally the penis consists of the urethra and three com-  partments: two corpora cavernosa (singular, corpus caverno-  sum) and the corpus spongiosum (Figure 23-15). The three  compartments are separated by Buck fascia and, like the tes-  tes, are enclosed by a tunica albuginea. The urethra passes  through the corpus spongiosum and ends at a sagittal slit in  the glans. If the urethra is not completely surrounded by the  corpus spongiosum, the meatus may open on the ventral sur-  face of the penile shaft (hypospadias) or on the dorsal surface  (epispadias).   Penetration of the female vagina is made possible by the  erectile reflex, a process in which erectile tissues within the  corpora cavernosa and corpus spongiosum become engorged  with blood, generally 20 to 50 ml. The erectile tissues consist  of vascular spaces, or chambers, that are supplied with blood  by arterioles (small arteries). Most of the time the arterioles  are constricted through tonic noradrenaline release from  sympathetic nerves so that not much blood flows through  the erectile tissues. Sexual stimulation, however, causes the  arterioles to dilate through release of nitric oxide and fill with  blood.” Their rapid expansion fills the erectile tissues, causing  an erection. Erection apparently is maintained by compres-  sion or constriction of veins that drain the corpora cavernosa  and corpus spongiosum. When sexual stimulation ceases or  orgasm and ejaculation occur, these veins open up, blood  flows out of the arterioles, and the penis becomes flaccid (soft  and pendulous).   Erection is under the control of the autonomic nervous  system but can be stimulated or inhibited by central nervous  system input. Stimulation of mechanoreceptors of the penis,  particularly of the glans, causes parasympathetic nerves of the  autonomic nervous system to relax smooth muscle in the walls  of penile arterioles. At the same time, the effects of sympathetic  nerves, which normally cause arteriolar smooth muscle to con-  strict, are inhibited.   Erections begin in utero and continue throughout life, but  ejaculation does not occur until sperm production begins at    puberty. Growth of the penis and scrotal contents contin-  ues well past puberty, however, and may not be complete  until the late teens or early 20s. Penis size, when flaccid, var-  ies considerably; with an erection, differences in penis size  diminish. Sexual excitement causes the corpora cavernosa  to increase in length and width and become rigid; the penis  becomes erect. Stimulation of the glans, which is endowed  with copious sensitive nerve endings, provides maximum  erotic sensation. With sexual arousal, skin color deepens, the  glans doubles in size, and the urethral meatus dilates. Ejacu-  lation occurs with frequent, strong contractions of the vas  deferens, epididymis, seminal vesicles, prostate, urethra, and  penis. Erection and ejaculation can occur independently of  each other.**    Figure 23-13 shows the anatomy of the internal genitalia and  their relation to other pelvic organs. The internal genitalia  consist of ducts and glands. The ducts—the two vasa defer-  entia, the ejaculatory duct, and the urethra—conduct sperm  and glandular secretions from the testes to the urethral open-  ing of the penis. The glands—the prostate gland, two seminal  vesicles, and two Cowper (or bulbourethral) glands—secrete  fluids that serve as a vehicle for sperm transport and create an  alkaline, nutritious medium that promotes sperm motility and  survival. Together the sperm and the glandular fluids comprise  semen.   Sperm leave the epididymides and travel rapidly through the  internal ducts in a process called emission. Emission occurs just  seconds before ejaculation, at the moment when sexual arousal  peaks. Emission always leads to ejaculation.   Emission occurs as smooth muscle in the walls of the epi-  didymides and vasa deferentia begins to contract rhythmi-  cally, pushing sperm and epididymal secretions through the  vasa deferentia. Each vas deferens is a firm, elastic fibromus-  cular tube that begins at the tail of the epididymis, enters the  pelvic cavity within the spermatic cord, loops up and over  the bladder, and ends in the prostate gland (Figure 23-16;  see also Figure 23-12). Sperm are moved along by peristal-  tic contractions of smooth muscle in the walls of the vas  deferens.    Tunica vaginalis (parietal and visceral layer  Glans of penis enclosing cavity of tunica vaginalis)   B Cremaster muscle  FIGURE 23-16 Zones of the Prostate Gland and Seminal Vesicles. A, Zones of the prostate. The peripheral zone,  accounting for 70% of the prostate gland, is the site of origin of <70% of prostate cancers; the central zone, approximately  25% of the prostate gland, gives rise to only 1% to 5% of prostate cancers; and the transition zone, ~5% to 10% of the pros-  tate gland, gives rise to 20% of prostate cancers and is the site of origin of benign prostatic hyperplasia (BPH). B, Prostate  gland within the male reproductive system. (A copyright Baylor College of Medicine, Houston, TX. B from Drake et al: Grays    As sperm leave the ampulla (wide portion) of the vas deferens,  the seminal vesicles secrete a nutritive glucose-rich fluid into the  ejaculate (semen). The seminal vesicles are a pair of glands, each  about 4 to 6 cm long, that lie behind the urinary bladder and in  front of the rectum. The seminal vesicles provide fructose as a  source of energy for ejaculated sperm, and secrete prostaglandins  that promote smooth muscle contraction assisting with sperm  transport. The ducts of the seminal vesicles join the ampulla of  the vas deferens to become the ejaculatory duct, which contracts  rhythmically during emission and ejaculation. As can be seen in  Figures 23-12 and 23-16, the ejaculatory duct joins the urethra,  where both pass through the prostate gland. During emission  and ejaculation a sphincter (muscle surrounding a duct) closes,  preventing urine from entering the prostatic urethra.*    The prostate gland is about the size of a walnut, has three  zones, and surrounds the urethra (see Figure 23-16). It is  composed of glandular alveoli and ducts embedded in fibro-  muscular tissue. Prostate growth, development, and function  are regulated by androgens and the androgen receptor. With-  out them the prostate is at risk for hyperplastic and malignant  growth* (see Chapter 25). Nerves required for penile erec-  tion travel along the posterolateral surface of the prostate.  Included in prostate epithelial secretions are prostate-specific  antigen (PSA), cytokeratins, prostate-specific membrane anti-  gen (PSMA), and prostate-specific acid phosphatase. Prostate  secretions contribute to the ejaculate. While semen moves  through the prostatic portion of the urethra, the prostate  gland contracts rhythmically and secretes prostatic fluid into    the mixture. Prostatic fluid is a thin, milky substance with an  alkaline pH that helps sperm survive in the acid environment  of the female reproductive tract. In addition, clotting enzymes  and fibrinolysin in prostatic fluids help mobilize sperm after  ejaculation.   Cowper glands (bulbourethral glands), whose ducts  secrete mucus into the urethra near the base of the penis, are  the last pair of glands to add fluid to the ejaculate. Ejacula-  tion occurs as semen reaches the base of the penis and mus-  cles there begin the rhythmic contractions that push semen  out. Normally a man ejaculates between 2 and 6 ml of semen,  containing 75 million to 400 million sperm. About 98% of  the ejaculate consists of glandular fluids; 60% to 70% of vol-  ume comes from the seminal vesicles and 20% from the pros-  tate. Therefore, the ejaculate of a man who has undergone  vasectomy (a surgical procedure that prevents sperm from  entering the vas deferens) is not reduced by much: about 2%.  During vasectomy, the vas deferens are severed and then tied  in order to prevent sperm from entering the ejaculate; this  procedure is used for permanent male birth control.    Spermatogenesis begins at puberty and continues for life. In  this respect, spermatogenesis differs markedly from oogenesis  (production of primordial ova), which occurs during fetal life  only.   Spermatogenesis takes place within the seminiferous tubules  of the testes (see Figure 23-14). The basement membrane of each  seminiferous tubule is lined with diploid (46-chromosome)  germ cells called spermatogonia (singular, spermatogonium).  These cells undergo continuous mitotic division. (Mitotic divi-  sion, in which a cell divides into two identical cells, is described  in Chapter 1.) Some of the spermatogonia move away from  the basement membrane and mature, becoming primary  spermatocytes (Figure 23-17). The primary spermatocytes  undergo meiosis, a type of cell division that results in two hap-  loid (23-chromosome) cells called secondary spermatocytes.  (Meiosis is described and illustrated in Chapter 4.) The two sec-  ondary spermatocytes then undergo meiosis, resulting in four  spermatids. It is the spermatids that differentiate into sperma-  tozoa, or sperm, each of which contains 23 chromosomes (Fig-  ure 23-18).   The development of spermatids into sperm depends on the  presence of Sertoli cells (nondividing support cells) within  the seminiferous tubules. The spermatids attach themselves  to Sertoli cells, from which they receive the nutrients and the  hormonal signals (i.e., testosterone) they need to develop into  sperm.*° The process of spermatogenesis, from mitotic divi-  sion of a spermatogonium to maturation of the spermatids,  takes about 70 to 80 days. Mature sperm migrate from the  seminiferous tubules to the epididymis, where their capac-  ity for fertilization continues to develop. Although they are  completely mature by the time they are ejaculated, the sperm  do not become motile (capable of movement) until they are  activated by biochemicals in semen and in the female repro-  ductive tract.    The male sex hormones are androgens and testosterone is the  primary male sex hormone. Leydig cells of the testes and, to a  lesser degree, the adrenal glands produce testosterone and other  androgens. In men, sex hormone production is relatively con-  stant with some diurnal variation.   The androgens have a number of physiologic actions related  to growth and development of male tissues and organs. They are  responsible for fetal differentiation and development of the male  urogenital system and have some effects on the fetal brain. After  birth, the Leydig cells become quiescent until activated by the  gonadotropins during puberty. At puberty, androgens cause the  sex organs to grow and secondary sex characteristics to develop.   Testosterone affects nervous and skeletal tissues, bone  marrow, skin and hair, and sex organs. It has an anabolic  effect on skeletal muscle tissue, thereby contributing to the  difference in body weight and composition between men  and women. Testosterone also stimulates growth of the mus-  culature and cartilage of the larynx, causing a permanent  deepening of the voice. Testosterone directly stimulates the  bone marrow and indirectly stimulates renal erythropoietin  production to achieve increased hemoglobin and hemato-  crit levels. Because sebaceous gland activity is stimulated by  testosterone, acne may develop. In the presence of testoster-  one, hair becomes coarser in texture, and facial hair, axil-  lary hair, and pubic hair grow in male patterns. Later in life,  testosterone causes baldness in genetically susceptible indi-  viduals. Testosterone is required for spermatogenesis and  for secretion of fluid by the prostate gland, seminal vesicles,  and Cowper glands. Testosterone is also associated with an  increase in libido (sex drive). Other, less-understood, effects  of testosterone include alterations in fatty acid and choles-  terol metabolism.   The regulation of androgen production and spermatogen-  esis is achieved by a complex feedback system involving the  extrahypothalamic central nervous system, the hypothalamus,  the anterior pituitary, the testes, and the androgen-sensitive  end organs. These relationships, which are essentially the same  in women, are summarized in Figure 23-3. Extrahypothalamic  influences include such variables as physiologic and psychologic  stress, which may inhibit or augment hypothalamic activity. In  the hypothalamus, neurotransmitters regulate GnRH synthesis  and pulsatile release (about every 3 hours) into the hypophy-  seal portal veins. Norepinephrine stimulates GnRH secretion,  and serotonin and dopamine inhibit GnRH secretion. GnRH  is transported by portal flow to the median eminence of the  pituitary gland, where it binds to receptors and stimulates the  synthesis and secretion of gonadotropins, LH, and FSH. LH and  FSH, which are named for their effects in the female reproduc-  tive system, have important effects on the male system as well.  LH acts on the Leydig cells to regulate testosterone secretion.  FSH acts on the seminiferous tubule Sertoli cells to promote  spermatogenesis. FSH secretion is inhibited by inhibin secreted  by the Sertoli cells. Similar to their action in the female gonad,  inhibin functions as an autocrine/paracrine regulator in the  male gonad. Inhibin inhibits proliferation of spermatogonia by    FIGURE 23-17 Seminiferous Tubule. Section shows process of meiosis and sperm cell formation. (From Patton KT,  Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    FIGURE 23-18 Mature Sperm Cell (Spermatozoon). A, Anatomy of mature sperm cell. B, Human sperm with nuclear  material glowing with a fluorescent dye. (B from Lennart Nilsson.)    regulating pituitary FSH levels. In addition, inhibin facilitates  LH stimulation of androgen biosynthesis in Leydig cells.   Ninety-eight percent of testosterone, the major steroid  hormone produced by the testes, binds to either sex hormone-  —binding globulin (SHBG) (40%) or albumin (48%). The  remaining 2% remains unbound in the plasma and is free  to enter cells and wield its metabolic effects. Changes in the  amount of available SHBG affect the amount of testoster-  one within tissues. The testes secrete only 25% of circulating  estrogen (estradiol). The majority is produced by peripheral  conversion of testosterone and androstenedione. Estrogens  help regulate GnRH and LH secretion. Peripheral conversion  of testosterone by 5-alpha-reductase also produces dihy-  drotestosterone (DHT), another potent androgen. DHT  is necessary for external virilization during embryogenesis  and androgen activity beginning at puberty and continuing  throughout adulthood. Prolactin, a polypeptide synthesized  and secreted from the pituitary, helps maintain biosynthe-  sis of testosterone. However, elevated prolactin levels may  suppress biosynthesis.*”   In summary, hormones secreted at each level of the hypo-  thalamic-pituitary-testicular (HPT) axis control and coordi-  nate testicular function (Figure 23-19). This control is exerted  through positive and negative feedback signals by (1) sex ste-  roids that inhibit hypothalamic GnRH secretion and pituitary  LH responsiveness to GnRH; and (2) testicular inhibin that  inhibits pituitary FSH and, possibly, circulating estrogens (E}).  Any disruption along the HPT axis may lead to hypogonadism  or infertility.    Diagnostic tests of the male and female reproductive systems  are performed to determine the cause of infertility, to detect the  presence of cancerous lesions, or to identify the presence of sex-  ually transmitted infections. (Alterations of the female repro-  ductive system including carcinoma are discussed in Chapter  24. Alterations of the male reproductive system including car-  cinoma are discussed in Chapter 25. Sexually transmitted infec-  tions are discussed in Chapter 26.)   Tests of reproductive function are performed most com-  monly when infertility exists. Both partners are examined, and  several diagnostic evaluations may be completed. The types of  tests and their normal values are summarized in Tables 23-3  and 23-4, The man is evaluated for number, amount, structure,  and motility of sperm and obstruction along the reproductive  tract. Tests for women determine whether (1) the reproduc-  tive tract (cervix, uterus, fallopian tubes) is adequately patent  to allow for passage of ovum and sperm, (2) ovulation occurs  normally, (3) the endometrium is responding normally to  hormones, and (4) reproductive tissues are free of tumors or  infections. Hormonal assays evaluate the adequacy of pitu-  itary function and target organ response. The position and  size of organs or the presence of tumors can be detected by  direct observation procedures using a laparoscope or by radio-  graphic studies, such as plain films, computerized scans, or  tomography.*®    T ==> Sex accessory glands  FIGURE 23-19 Schematic Representation of Activity Along the  Hypothalamus-Pituitary-Testicular (HPT) Axis. £,, Estrogen; FSH, follicle-  stimulating hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing  hormone; 7, testosterone.    Natural menopause is a normal developmental event marking  the end of reproduction. It is universally experienced by midlife  women at the average age of 50.5 to 51.4 years in North America  with variability between 40 and 60 years.*”°° A number of fac-  tors are thought to influence the age of menopause, including  genetics, socioeconomic status, race, parity, oral contraceptive  use, and lifestyle, such as smoking or weight.*! It can occur 2  years sooner on average for smokers; thinner women also tend  to experience menopause at a slightly younger age. However, it  is genetically predetermined and has been documented by fam-  ily history. Menopause is the cessation of ovulation due to loss  of ovarian follicles resulting in reduced ovarian production of  estradiol, increased FSH and LH, and decreased inhibin (inhib-  its release of FSH). The primary changes of menopause are as  follows:°?  * Perimenopause: This is the transitional period between  reproductive and nonreproductive years, a transition lasting    Basic Assessment  Semen analysis (two samples at least 2  weeks apart)    Midluteal phase — one week before menses  Day 3 of cycle  Day 3 of cycle    Evaluates presence of ovulation from estrogenic effects at  ovulation; mucus also may be examined for pH, glucose, or  proteins or cultured for presence of infection    Tests ability of sperm to penetrate and maintain motility in  cervical mucus 2-4 hours after coitus approximately 1 day  before ovulation   Nonliving oocytes are surgically removed and bisected; sperm  added to the hemi-oocyte to test fertilizing capability    Provides superior quality resolution of the uterine, fallopian,  and ovarian structures; also can be used to study  folliculogenesis, ovulation, and luteogenesis to detect  abnormalities    Determines whether ovulation has occurred by obtaining  endometrial tissue on day 26 of 28-day menstrual cycle (or  postovulatory day 12)   Assessment of uterus and fallopian tubes for obstructions  using transuterine injection of contrast material and  radiography; performed 1-2 days after cessation of menses   Visualization of reproductive organs using a laparoscope  inserted within the pelvic cavity through the abdomen  to assess structure or determine presence of adhesions,  endometriosis, tumors, or infection   Visualization of uterine cavity using modified cystoscope  inserted through cervical os; best done during first 14 days  of cycle   Sperm MAR test (mixed antiglobulin reaction) =  <10% with adherent particles    Decrease in basal body temperature before  ovulation followed by a rise in temperature at  the time of ovulation   Fern pattern appears when cervical mucus dries on  a clean slide; mucus is clear, watery, and elastic  (spinnbarkeit 8-10 cm) with no inflammatory  cells   =10 motile sperm in each high-power field;  motility in one direction; previous sperm analysis  normal    Normal = >10 ng/dl, presumptive evidence of  ovulation; draw level between days 20-25  of 28-day cycle or 6-10 days postovulation   Normal = 300-1200 ng/dl; must be  interpreted with serum LH and FSH levels   serial blood draws  Serum FSH and LH  Resulting from diurnal and  pulsatile pattern, need  serial blood draws   High levels in males indicate primary  testicular disease; low levels in males  indicate hypogonadism caused by  hypothalamic-pituitary dysfunction    2 to 8 years.'°? Five to 10 years before menopause, approxi-  mately 90% of women note mild to extreme variability in fre-  quency and quality of menstrual flow. Changes in hormones  occur during this time including erratically higher estradiol  levels, decreased progesterone levels (in normal ovulatory,  short luteal phase, or anovulatory cycles), and a disturbed  ovarian-pituitary-hypothalamic feedback relationship with  higher LH levels. A decrease in the sensitivity of the target tis-  sue receptors and the development of perimenopausal symp-  toms commonly are experienced. Symptoms usually begin  with a lengthening of the menstrual cycle, which correlates  with anovulatory cycles. Unpredictable or irregular ovula-  tion uniformly precedes menopause.°? The perimenopause  experience varies among women and from cycle to cycle in  the same woman. Estradiol levels remain in the normal to  slightly elevated range until about 1 year before menopause.'  * Ovarian changes: Beginning in utero, the number of fol-  licles steadily decreases through activation, maturation,  and atresia. Starting in the late 30s, 10 to 15 years before  menstruation ceases, this process accelerates until the sup-  ply of follicles is depleted.°* This accelerated loss correlates  with increased FSH stimulation, delayed and attenuated LH  surges, and a decrease in inhibin. Increased FSH stimulation  seems to accelerate follicular loss, declining inhibin produc-  tion, slightly elevated estradiol levels, and decreasing anti-  miillerian hormone. Attenuated LH surges are associated  with impaired hypothalamic responses to estradiol posi-  tive feedback*> (Figure 23-20 and Box 23-2). The ovarian  response to high FSH recruits increasing numbers of folli-  cles; these follicles only partially develop, with a net effect of  irregular ovulation, lower progesterone levels, depleted fol-  licle reserve, and infertility. The ovaries begin to decrease in  size around age 30; this decrease accelerates after age 60.)°°  Of the 500,000 follicles present at the onset of puberty, the  number dwindles to approximately 1000 with menopause.  Table 23-5 summarizes endocrine events occurring during    MP Years  FIGURE 23-20 The Perimenopausal Hormone Transition. Mean circulating  hormone levels. FSH, Follicle-stimulating hormone; LH, luteinizing hormone.    BOX 23-2 CHANGES IN OVARIAN  FOLLICULOGENESIS DURING  THE PERIMENOPAUSE  LEADING TO ENDOGENOUS  OVERSTIMULATION    FP Follicular phase; FSH, follicle-stimulating hormone; LH, luteinizing  hormone; LP luteal phase.    E,, Estradiol; FP follicular phase; FSH, follicle-stimulating hormone; LP luteal phase.    the perimenopause. Table 23-6 provides a template to visu-  alize the complex physiology of the perimenopause and the  dynamic changes that occur during this time.   Uterine changes: Uterine changes occur primarily in the  endometrium. The increase in anovulatory cycles allows  for proliferative growth of the endometrium. The longer  exposure to estrogen alone results in greater thickness of  the endometrium, and 50% of perimenopausal women  will experience dysfunctional uterine bleeding that is  heavy and unpredictable. Increased endometrial bleeding  is correlated with a change from ovulatory to anovulatory  cycles and is associated with unopposed high estrogen  levels the week before menses. Estrogen causes endome-  trial tissue to thicken. However, without corresponding  stromal support from progesterone, estrogen production  leads to heavier periods, menorrhagia (heavy bleeding),  or metrorrhagia (midcycle bleeding)° (Table 23-7). In the  past this has put women at high risk for hysterectomy.  Newer treatment includes progesterone administration  or endometrial ablation by laser or electrocautery. New  methods of decreasing the function of the endometrial tis-  sue are being developed.   Systemic changes: Vasomotor flushes are characterized by a  rise in skin temperature, dilation of peripheral blood vessels,  increased blood flow in the hands, increased skin conduc-  tance, and a transient increase in heart rate followed by a  temperature drop and profuse perspiration over the area of  flush distribution. This usually occurs in the face and neck  and may radiate into the chest and other parts of the body.  Night sweats, dizziness, nausea, headaches, or palpitations    *Symptoms aggravated by anovulatory cycles; leads to dysfunctional  uterine bleeding (see Chapter 24).    may accompany the flush. These flushes can vary in fre-  quency, intensity, and duration and are experienced by up to  85% of perimenopausal to postmenopausal women from 1  to 15 years (mean 1 to 5 years). The physiology of vasomotor  flushes is poorly understood. One theory proposes that rapid  changes in estrogen may result in loss of negative feedback  over hypothalamic noradrenaline synthesis, the primary  neurotransmitter involved in thermoregulation.°° Estrogen  modulates adrenergic receptors. The decrease in estrogen in  menopause is thought to decrease the number of receptors  leading to increased noradrenaline levels and hot flushes.  Interestingly, emerging evidence shows that the intensity of  vasomotor flushes may be associated with increased risk for  cardiovascular disease.°’   Menopause: Menopause is defined by the point that marks  12 consecutive months of amenorrhea. This means that it  is determined retrospectively after a woman has not had a  menstrual period for 1 year. It is characterized by loss of  ovarian function, low estrodiol and progesterone levels, high  FSH and LH levels, and decreased follicular inhibin secre-  tion*”® (see Figure 23-20). Less androgens are produced but  sensitivity to them is increased because of the lost opposition  of estrogen.   Breast tissue changes: Glandular breast tissue becomes invo-  luted; fat deposits and connective tissue increase; and breasts  are reduced in size and firmness.   Urogenital tract changes: The ovaries shrink; the uterus atro-  phies; and the vagina shortens, narrows, and loses some elas-  ticity. Lubrication of the vagina diminishes and vaginal pH  increases, creating higher incidence of vaginitis. The cervix  atrophies, cervical os shrinks; vaginal epithelium atrophies;  labia majora and minora become less prominent; some pubic  hair is lost; urethral tone declines along with muscle tone  throughout the pelvic area; urinary frequency or urgency,  urinary tract infections, and incontinence are associated  with estrogen deficiency. Regular sexual activity and orgasm  may diminish some of these changes. Sexually active women  have less vaginal atrophy.   Skeletal changes: Postmenopausal bone mass is reduced, lead-  ing to increased brittleness and porosity and increases the  risk osteoporosis and fracture. Healthy bone is maintained  through a balance of breakdown and reformation. Estro-  gen promotes positive bone mass during the childbearing  years; however, once menopause occurs with the resultant  low estrogen levels, the balance tips toward reabsorption and  reduced bone mass.°?   Cardiac change: The risk of coronary heart disease (CHD)  increases significantly after menopause. Estrogen is  known to foster favorable lipid profiles and to have ben-  eficial effects on vessel endothelium through production  of nitric oxide. Once postmenopausal, blood pressure and  LDL levels rise, central adiposity and weight increases,  and HDL levels lower, together increasing the risk of  CHD,°®261   Other changes: Emotional stress with unpredictable mood  swings, weight gain, migraine headaches, and insomnia often  accompany the change in estrogen levels.°* Lower estrogen    levels decrease skin thickness and diminish skin elasticity,  thereby causing increased skin dryness and wrinkling.“    Men maintain reproductive capacity longer than women. There  is no known discrete event, comparable to menopause, that  characterizes aging of the male reproductive system, although  the term andropause is sometimes used to describe the changes  associated with male aging. Gradual changes do occur, and  aging in the male reproductive system is characterized by hypo-  gonadism, testosterone deficiency, erectile dysfunction, and  proliferative disorders of the prostate gland (see Chapter 25).  Aging changes are also influenced by chronic diseases and use  of medications.   Components of male sexual behavior include both sexual  drive and erectile and ejaculatory capacity. Libido, or sexual  drive, is a complex phenomenon that requires a baseline hor-  monal milieu but is influenced significantly by health status  and environmental, social, and psychologic factors. In men  older than 40 years, organic factors and chronic disease (e.g.,  vascular, endocrine, and neurologic disorders) are involved in  more than half of the cases of male sexual dysfunction. Aging  causes specific physical changes that may influence erectile and  ejaculatory capabilities. Alterations in sexual response include  the need for longer stimulation to achieve full erection; slower  and less forceful ejaculation, with less pelvic muscle involve-  ment; decreased vasocongestive response; and longer refractory  period (time during which erection and ejaculation are not pos-  sible), up to 24 hours in some men.   The testes undergo several age-related structural changes,  including decreased weight, atrophy, and softening. Degen-  erative changes in the seminiferous tubules may include  thickening of the basement membrane; increase in lumen  size; germ cell (spermatogonium) arrest and a decrease in  spermatogenic activity; and collapse of tubules, followed by  complete obstruction caused by sclerosis and fibrosis. Areas  of mild to severe degenerative change may be interspersed  with areas having intact tubules. These morphologic changes  may result from atherosclerosis (arterial clogging) in the tes-  ticular vascular bed.®° Alterations of the seminiferous tubules  do not appear to diminish sperm counts (20 million sperm  per milliliter of semen is estimated as the minimum concen-  tration for fertility),°” but they do reduce fertility because a  greater percentage of the sperm lack motility or have struc-  tural abnormalities.   Aging probably causes changes in the production of male  sex hormones, levels of SHBG, and responsiveness of target  tissues. Hormone synthesis by the testes and testicular respon-  siveness to the gonadotropins (FSH and LH) are diminished,  and pituitary secretion of these gonadotropins is elevated.°* The  reduced levels of testosterone may be related to alterations in  the Leydig cells, the testosterone producers of the testes. The  number of Leydig cells and their function decreases as age  increases, perhaps because of decreased arterial perfusion of the  testes and decreased responsiveness to LH. Even if testoster-  one levels are not decreased, older men may have less unbound  testosterone in their blood, decreasing the amount of unbound    hormone available to stimulate target tissues. Decreased testos-  terone levels have several effects, including functional deterio-  ration of the accessory sex organs (the prostate gland, seminal  vesicles, epididymis, and ductus deferens); loss of muscle mass,  strength, and endurance; increased visceral fat, osteopenia, and    cognitive decline; and, in many men, decrease in libido. This  last effect also may be caused by alterations in other variables  that affect libido.”” Modifiable risk factors for low testosterone  and symptoms of androgen deficiency include health status and    Differentiation of female and male genitalia begins around  weeks 7 to 8 of embryonic development, when the gonads  of genetically male embryos begin to secrete male sex hor-  mones, primarily testosterone. Until that time the primitive  reproductive organs of males and females are homologous  (the same).    tive systems are controlled by the hypothalamic-pituitary-  gonadal (HPG) axis, a set of complex neurologic and  hormonal interactions that accelerate at puberty and lead  to sexual maturation and reproductive capability.    secrete GnRH, which stimulates the anterior pituitary to  secrete gonadotropins—FSH and LH—that stimulate the  gonads (ovaries or testes) to secrete female or male sex  hormones. Paracrine hormones (inhibin, activin, and fol-  listatin) influence the positive and negative feedback loops  that occur along the HPG axis.    during fetal life. From puberty to menopause, one female  gamete matures per menstrual cycle. Production of the  male gametes (sperm) begins at puberty; after that, millions  are produced daily, usually for life. Females release a mature  ova at the time of puberty.    The function of the reproductive system is to produce  mature ova and, when fertilized, to protect and nourish them  through embryonic and fetal life, and expel them at birth.    majora, labia minora, clitoris, vestibule (urinary and vagi-  nal openings), Bartholin glands, and Skene glands.    . The vagina is a fibromuscular canal that receives the penis    during sexual intercourse and is the exit route for menstrual  fluids and products of conception. The vagina leads from  the introitus (its external opening) to the cervical portion  of the uterus.    . The uterus is the hollow, muscular organ in which a fer-    tilized ovum develops. The uterine walls have three layers:  the endometrium (lining), myometrium (muscular layer),  and perimetrium (outer covering, which is continuous  with the pelvic peritoneum). The endometrium proliferates  (thickens) and sloughs off in response to cyclic hormonal  changes. The cervix is the narrow, lower portion of the  uterus that opens into the vagina.    The two fallopian tubes extend from the uterus to the  ovaries. Their function is to conduct ova from the spaces  around the ovaries to the uterus. Fertilization normally  occurs in the distal third of the fallopian tubes.    . From puberty to menopause, the ovaries are the site of    (1) ovum maturation and release and (2) production of  female sex (estrogen and progesterone) and male (andro-  gens) hormones. Female sex hormones predominate and  are involved in sexual differentiation and development, the  menstrual cycle, pregnancy, and lactation. Androgens in  women contribute to prepubertal growth spurt, pubic and  axillary hair growth, and activation of sebaceous glands.    ovum) produce estrogen (primarily estradiol). The cor-  pus luteum, the structure that develops from the ruptured  ovarian follicle after ovulation or ovum release, produces  progesterone. Androgens are produced within the ovarian  follicle, adrenal glands, and adipose tissue.    . The average menstrual cycle lasts 27 to 30 days and consists    of three phases, which are named for ovarian and endome-  trial changes: the follicular/proliferative phase, the luteal/  secretory phase, and the ischemic/menstrual phase.  Ovarian events of the menstrual cycle are controlled by  gonadotropins. High FSH levels stimulate follicle and ovum  maturation (follicular phase), then a surge of LH causes  ovulation, which is followed by development of the corpus  luteum (luteal phase).   Ovarian hormones control the uterine (endometrial) events  of the menstrual cycle. During the follicular/proliferative  phase of the ovarian cycle, estrogen produced by the follicle  causes the endometrium to proliferate (proliferative phase)  and induces the LH surge and progesterone production  in the granulosa layer. During the luteal/secretory phase,  estrogen maintains the thickened endometrium, and pro-  gesterone causes it to develop blood vessels and secretory  glands (secretory phase). As the corpus luteum degener-  ates, production of both hormones drops sharply, and the  “starved” endometrium degenerates and sloughs off, caus-  ing menstruation, the ischemic/menstrual phase.   Cyclic changes in hormone levels also cause thinning and  thickening of the vaginal epithelium, thinning and thick-  ening of cervical secretions, and changes in basal body  temperature.    Until puberty the female and male breasts are similar, con-  sisting of a small underdeveloped nipple, some fatty and  fibrous tissue, and a few ductlike structures under the areola.    At puberty, however, a variety of hormones (estrogen, pro-  gesterone, prolactin, growth hormone, insulin, cortisol)  cause the female breast to develop into a system of glands  and ducts that is capable of producing and ejecting milk.    . The basic functional unit of the female breast is the lobe,    a system of ducts that branches from the nipple to milk-  producing units called lobules. The lobules contain alveolar  cells, which are convoluted spaces lined with epithelial cells  that secrete milk and subepithelial cells that contract, mov-  ing the milk into the system of ducts that leads to the nipple.    . Each breast contains 15 to 20 lobes, which are separated and    mone that is secreted by alveolar epithelial cells in larger  amounts after childbirth. Milk ejection is under the control  of oxytocin which causes contraction of myoepithelial cells.    . Prior to puberty the male breast development is similar to    female development. Lack of high levels of estrogen and pro-  gesterone prevents further development of the male breast.    The function of the male reproductive system is to pro-  duce male gametes (sperm) and deliver them to the female  reproductive tract.    tum, and penis. The internal genitalia are the vas deferens,  ejaculatory duct, prostatic and membranous sections of the  urethra, seminal vesicles, prostate gland, and Cowper glands.    within the scrotum. The testes have two functions: sper-  matogenesis (sperm production) and production of male  sex hormones (androgens, chiefly testosterone).    . The epididymis is a long coiled tube arranged in a comma-    shaped compartment that curves over the top and rear of  the testis. The epididymis receives sperm from the testis  and stores them while they develop further. Sperm travel  the length of the epididymis and then are ejaculated into the  vas deferens.    encloses the testes and epididymides, which are suspended  within the scrotum by the spermatic cord. The scrotum  keeps these organs at optimal temperatures for sperm sur-  vival (about 1° to 2° C lower than body temperature) by  contracting in cold environments and relaxing in warm  environments.    . The penis is a cylindric organ consisting of three longitudi-    nal compartments (two corpora cavernosa and one corpus  spongiosum) and the urethra. The urethra runs through  the corpus spongiosum. The corpora cavernosa and corpus  spongiosum consist of erectile tissue. Externally the penis  consists of a shaft and a tip, which is called the glans. The    glans contains sebaceous glands and the opening of the ure-  thra and is covered by a flap of skin (the foreskin).    . The penis has two functions: delivery of sperm to the female    vagina and elimination of urine. These two fluids are never  in the urethra at the same time.    . Sexual intercourse is made possible by the erectile reflex, in    which tactile or psychogenic stimulation of the parasympa-  thetic nerves causes arterioles in the corpora cavernosa and  corpus spongiosum to dilate and fill with blood, causing the  penis to enlarge and become firm.    . Emission, which occurs at the peak of sexual arousal, is the    movement of semen from the epididymides to the penis.  Ejaculation, which is a continuation of emission, is the pul-  satile ejection of semen from the penis. Both emission and  ejaculation involve rhythmic contractions of smooth mus-  cle within the internal glands and ducts.   The prostate gland is about the size of a walnut and sur-  rounds the urethra. Prostatic secretions are alkaline and  contribute to the ejaculate.   Cowper glands (bulbourethral glands) secrete mucus in the  urethra and add fluid to the ejaculate.   Spermatogenesis is a continuous process because spermato-  gonia, the primitive male gametes, undergo continuous  mitosis within the seminiferous tubules of the testes. Some  of the spermatogonia develop into primary spermatocytes,  which divide meiotically into secondary spermatocytes and  then spermatids. The spermatids develop into sperm with  the help of nutrients and hormonal signals from Sertoli cells.  Production of the male sex hormones is controlled (like  production of the female sex hormones) by the HPG axis  and by complex feedback mechanisms. The male hormones  are produced steadily, with diurnal variations.    Diagnostic tests are performed to evaluate fertility.  Evaluation of fertility includes reproductive hormone  assays and assessment of structural alteration or infections  and the determination of normal ovulation or adequate  sperm motility and count.    In women the transition from fertility to menopause  (perimenopause) starts about 2 to 8 years before the last  menstrual period and ends the following year. During this  transition period the ovaries produce erratic and high levels  of estrogen that contribute to such symptoms as hot flashes,  breast tenderness and nodularity, and migraine headaches.  Menstrual cycles shorten and then become irregular as  anovulation occurs. Menstruation ceases, and women  move into menopause.    In some men there are gradual changes with testosterone  deficiency, hypogonadism, proliferative disorders of the  prostate, and erectile dysfunction.    Rogol AD: Sex steroids, growth hormone, leptin and the pubertal growth   Mihm M, Gangooly S, Muttukrishna S$: The normal menstrual cycle in  women, Anim Reprod Sci 124(3-4):229-236, 2011.   Trealor AE et al: Variation of the human menstrual cycle through repro-  ductive life, Int J Fertil 12:77-126, 1970.    . Peacock A, Alvi NS, Mushtaq T: Period problems: disorders of menstrua-    tion in adolescents, Arch Dis Child 97(6):554—560, 2012.  Scheid JL, De Souza MJ: Menstrual irregularities and energy deficiency  in physically active women: the role of ghrelin, PYY and adipocytokines,    . Richards JS, Pangas SA: The ovary: basic biology and clinical implica-   Karligiotou E et al: FSH modulatory effect on human granulosa cells:   a gene-protein candidate for gonadotrophin surge-attenuating factor,  Reprod Biomed Online 23(4):440—448, 2011.   Makanji Y, Harrison CA, Robertson DM: Feedback regulation by inhib-  ins A and B of the pituitary secretion of follicle-stimulating hormone,    Sirotkin AV: Cytokines: signalling molecules controlling ovarian func-  tions, Int J Biochem Cell Biol 43(6):857—861, 2011.   Knight PG, Satchell L, Glister C: Intra-ovarian roles of activins and inhib-  ins, Mol Cell Endocrinol 359(1-2):53-65, 2012.    12.  REFERENCES Endocrinol 8:115, 2010.  1. 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Jung A, Schuppe HC: Influence of genital heat stress on semen quality in  humans, Andrologia 39(6):203—215, 2007.    . Andersson KE: Mechanisms of penile erection and basis for pharmaco-    . Giuliano F: Neurophysiology of erection and ejaculation, J Sex Med    . Ohi DA et al: Anejaculation and retrograde ejaculation, Urol Clin North    J Androl 32(3):210-217, 2011.  Walker WH: Molecular mechanisms of testosterone action in spermato-  genesis, Steroids 74(7):602—607, 2009.    in patients with macroprolactinomas after treatment with cabergoline,  Indian J Med Res 134:314—319, 2011.   Lenz GM et al: Comprehensive gynecology, ed 8, St Louis, 2013, Mosby.  Gold EB: The timing of the age at which natural menopause occurs,  Obstet Gynecol Clin North Am 38(3):425—440, 2011.    Palacios S et al: Age of menopause and impact of climacteric symptoms  by geographical region, Climacteric 13(5):419—428, 2010.   Voorhuis M et al: Human studies on genetics of the age at natural meno-  pause: a systematic review, Hum Reprod Update 16(4):364—377, 2010.  Hacker NF, Gambone JC, Hobel CJ, editors: Hacker and Moore’s essentials  of obstetrics and gynecology, ed 5, Phildelphia, 2010, Saunders.   Prior JC, Hitchcock CL: The endocrinology of perimenopause: need for a  paradigm shift, Front Biosci (Schol Ed) 3:474—486, 2011.   Broekmans FJ, Soules MR, Fauser BC: Ovarian aging: mechanisms and  clinical consequences, Endocr Rev 30(5):465—493, 2009.   Devoto L et al: Neuroendocrinology and ovarian aging, Gynecol Endocri-  nol 28(Suppl 1):14-17, 2012.   Vilar-Gonzalez S, Pérez-Rozos A, Cabanillas-Farpén R: Mechanism of  hot flashes, Clin Transl Oncol 13(3):143-147, 2011.   Thurston RC, Joffe H: Vasomotor symptoms and menopause: findings  from the Study of Women’s Health Across the Nation, Obstet Gynecol  Clin North Am 38(3):489-501, 2011.   Lobo RA: Chapter 14. Menopause and care of the mature woman:  endocrinology, consequences of estrogen deficiency, effects of hormone  replacement therapy, and treatment regimens. In Lenz GM et al: Compre-  hensive gynecology, ed 8, St Louis, 2013, Mosby.   Lo JC, Burnett-Bowie SA, Finkelstein JS: Bone and the perimenopause,  Obstet Gynecol Clin North Am 38(3):503-517, 2011.   Hutter R et al: Coronary artery disease in aging women: a menopause of  endothelial progenitor cells? Med Clin North Am 96(1):93-102, 2012.  Wellons M et al: Early menopause predicts future coronary heart disease  and stroke: the multi-ethnic study of atherosclerosis, Menopause, 2012,  Jun 11. [Epub ahead of print.].   Bromberger JT, Kravitz HM: Mood and menopause: findings from the  Study of Women’s Health Across the Nation (SWAN) over 10 years,  Obstet Gynecol Clin North Am 38(3):609-625, 2011.   MacGregor EA: Perimenopausal migraine in women with vasomotor  symptoms, Maturitas 71(1):79-82, 2012.   Emmerson E, Hardman MJ: The role of estrogen deficiency in skin age-  ing and wound healing, Biogerontology 13(1):3—20, 2012.   Pines A: Male menopause: is it a real clinical syndrome? Climacteric  14(1):15-17, 2011.   Hafez ESE, Hafez B, Hafez SD: An atlas of reproductive physiology in men,  London, 2003, Taylor & Francis Group.   Walsh TJ, Smith JF: Male infertility. In McAninch JW, Lue TF, editors:  Smith and Tanagho’s general urology, ed 18, Norwalk CT, 2012, McGraw-  Hill Lange.   Araujo AB, Wittert GA: Endocrinology of the aging male, Best Pract Res  Clin Endocrinol Metab 25(2):303—319, 2011.   Perheentupa A, Huhtaniemi I: Aging of the human ovary and testis,   Corona G et al: Update in testosterone therapy for men, J Sex Med  8(3):639-654, 2011.   Hall SA et al: Correlates of low testosterone and symptomatic andro-  gen deficiency in a population-based sample, J Clin Endocrinol Metab  93(10):3870-3877, 2008.    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Abnormalities of Reproductive Tract Development, 800  Alterations of Sexual Maturation, 802  Delayed Puberty, 802  Precocious Puberty, 803  Disorders of the Female Reproductive System, 804  Hormonal and Menstrual Alterations, 804  Infection and Inflammation, 813  Pelvic Organ Prolapse, 817    Alterations of the reproductive system span a wide range of  concerns, from delayed sexual development and suboptimal  sexual performance to structural and functional abnormalities.  Many common reproductive disorders carry potentially serious  physiologic or psychologic consequences. Sexual or reproduc-  tive dysfunction, such as impotence or infertility, can dramati-  cally affect self-concept, relationships, and overall quality of  life. Conversely, organic and psychosocial problems, such as  alcoholism, depression, situational stressors, chronic illness,  and medications, can affect ovulation and menstruation, sexual  performance, and fertility and may be risk factors for the devel-  opment of some types of reproductive tract cancers.' Breast  cancer is the second leading cause of cancer death in women.  Diagnosis and treatment of reproductive system disorders are  complicated because of the stigma and symbolism associated  with the reproductive organs and the emotion-laden beliefs and  behaviors related to reproductive health.* Treatment and diag-  nosis for related problems may be delayed because of embar-  rassment, guilt, fear, or denial.    Benign Growths and Proliferative Conditions, 820  Cancer, 825  Sexual Dysfunction, 834  Impaired Fertility, 835  Disorders of the Breast, 836  Galactorrhea, 836  Benign Breast Disease, 837  Cancer, 843    As discussed in Chapter 23, normal development of the female  reproductive tract requires absence of testosterone during  embryonic/fetal life. The resulting fusion of the two parame-  sonephric (miillerian) ducts produces the normal cervix and  the uterus with an internal cavity. The distal portions of the  paramesonephric ducts remain independent and form the  two fallopian/uterine tubes. Alterations in the normal process  include errors in cellular sensitivity to testosterone (andro-  gen insensitivity) or failures of cell line migration, resulting in  changes in structure of the reproductive organs.   Androgen insensitivity occurs in its most extreme form in  about 1 in 20,000 people? and it is discussed briefly in this chap-  ter because of the often-resulting female phenotype, despite a  male genotype. Children with complete androgen insensitiv-  ity may have testes palpable within the labia majora but are  often not diagnosed until puberty.* Breast development may be    FIGURE 24-1 Uterine Malformations. Congenital uterine abnormalities. A, The normal configuration of the uterus and  the ovaries. B, Double uterus with a double vagina and C, a single vagina. D, Bicornuate uterus. E, A uterus with a midline  septum. F, Unicornuate uterus. (From de Bruyn R: Pedjatric ultrasound, ed 2, London, 2010, Churchill Livingstone.)    normal, but pubic and axillary hair is often sparse and men-  arche does not occur because of the absence of a cervix, uterus,  and ovaries.‘ A short vagina that ends blindly also may be pres-  ent. Milder forms of androgen insensitivity (also a common  cause of male infertility)> are much more common and have  less dramatic phenotypic manifestations with many affected  having normal male genitalia. A genetic karyotype reveals a  male, genotype (XY).*   Other abnormalities of the uterus, cervix, and fallopian/  uterine tubes have multi-factorial origins, often the result  of an interaction between genetic predisposition and envi-  ronmental factors. Such interactions result in miillerian duct    abnormalities.” Some medications, chemicals, and toxins  have been implicated as a direct cause of uterine abnormali-  ties. For instance, diethylstilbestrol (DES) was prescribed from  1938 until 1971 as a drug to prevent miscarriages.° Although it  was not effective at preventing miscarriage, DES did affect cell  development and cause abnormal internal reproductive anat-  omy in exposed fetuses,° causing uterine malformations and a  predisposition to cancer.   Most uterine abnormalities stem from abnormal cell migra-  tion in the miillerian ducts during key moments in fetal develop-  ment (Figure 24-1). About 5% of the general female population  has some sort of uterine abnormality but the rate is much    higher in populations of women who have experienced infertil-  ity or miscarriage.’ Uterine abnormalities are rarely diagnosed  until the woman has trouble becoming pregnant or carrying a  baby to term because the uterus is capable of menstruation but  may have difficulty supporting a growing fetus.°   Uterine malformations are usually diagnosed by ultrasound  during pregnancy or with magnetic resonance imaging (MRI).  Their prognosis depends of the severity of the malformation  and the location and size of the placenta and fetus. Some abnor-  malities can be surgically corrected to improve the outcome of  subsequent pregnancies.” Abnormalities of the lower genital  tract also can result in women having two vaginas or a vaginal  septum (a thin membrane dividing the vaginal vault). For most  women this does not create functional problems but can be sur-  gically corrected if needed.    The process of sexual maturation, or puberty, is marked by the  development of secondary sexual characteristics, rapid growth,  and, ultimately, the ability to reproduce. A variety of congenital  and endocrine disorders can disrupt the timing of puberty, or  sexual maturation. These disorders may cause puberty to occur  too late (delayed puberty) or too early (precocious puberty).  Both types involve a disrupted onset of sex hormone produc-  tion by the gonads.   The age of puberty is multifactorial involving genetic and  environmental components. Girls of African descent and His-  panic/Latina girls begin puberty up to 1 year sooner than their  non-African and non-Latina counterparts.’ Obesity decreases  the age at onset of puberty by about 6 months. The normal range  for the onset of puberty is now 8 to 13 years of age. Although  there are conflicting and inconsistent reports, the age of puber-  tal onset appears to be decreasing for girls.* This earlier onset  appears primarily in breast development, not age of menarche.  On average breast development begins at age 10.4 for white  girls and 9.5 years for black girls. The average age for menarche  is 12.6 years for white girls and 12.1 for black girls. However,  5% of white girls and 15% of all girls will begin puberty before    age 8.° Both early puberty, known as precocious puberty, and  delayed puberty have implications for the child’s social interac-  tions and self-esteem.    About 3% of children in North America experience delayed  development of secondary sex characteristics.? One of the first  signs of puberty in girls is usually thelarche, or breast develop-  ment. Thelarche should begin by the time a girl is 13 years old.  Puberty is considered delayed if there are no clinical signs of  puberty by age 13 in girls (2 standard deviation [SDs] above  the mean age of pubertal onset). Clinical diagnosis also can be  made in the absence of menarche by age 15 or 16.   In 95% of cases, delayed puberty is a physiologic (consti-  tutional) delay in which hormonal levels are normal and the  hypothalamic-pituitary-gonadal (HPG) axis is intact, but mat-  uration is happening slowly. This physiologic delay tends to be  familial, is not as common in girls as it is in boys, and is fre-  quently diagnosed retrospectively once pubertal progression is  complete.'°   Many clinicians recommend intervention (i.e., exogenous  sex steroid administration) in physiologic cases of delayed  puberty to reduce the psychologic effects (e.g., self-esteem  issues, embarrassment) often associated with delayed puberty.  The other 5% of cases are caused by a disruption of the HPG  axis of various etiologies, including any chronic condition that  delays bone aging (i.e., celiac disease, anorexia, hypothyroid-  ism)!0!! (Table 24-1).   Human gonadal function is partially controlled by luteiniz-  ing hormone (LH) and follicle-stimulating hormone (FSH), the  release of which is regulated by the pulsatile secretion of hypo-  thalamic gonadotropin-releasing hormone (GnRH).'*!> The  G-protein—coupled receptor 54 (GPR54) has been identified as  the gatekeeper gene for activation of the GnRH axis. GPR54 is  required for the normal function of this axis, and data suggest  that the ligand kisspeptin-1 may act as a neurohormonal regu-  lator of the GnRH axis.!4   The mechanisms of childhood inhibition of GnRH release  and activation are poorly understood but appear to involve    Tumors or infiltrative diseases of  the central nervous system, GnRH  deficiency (isolated hypogonadotropic  hypogonadism, Kallmann syndrome),  combined pituitary-hormone deficiency,  chemotherapy, or radiation therapy    Systemic illness (inflammatory  bowel disease, celiac disease,  anorexia nervosa, or bulimia),  hypothyroidism, excessive exercise    From Palmert MR, Dunkel L: N Engl J Med 366(5):443-453, 2012.  GnRH, Gonadotropin-releasing hormone.    feedback inhibition by sex steroids and presumably other cen-  tral nervous system (CNS) pathways.'* Given the numerous  etiologies contributing to the occurrence of delayed puberty, a  thorough evaluation should be conducted that includes physi-  cal examination and medical and family history that specifically  targets known contributors to delayed puberty. Laboratory  workup may consist of x-ray studies for bone age, measure-  ment of thyroid function, serum levels of prolactin and adrenal  and gonadal steroids, radioimmunoassay of plasma gonado-  tropins, and screening for systemic disorders. Adolescents  with high gonadotropin levels require a karyotype to rule out  genetic causes, and those with low levels need skull imaging  (lateral skull film, computed tomography [CT], or MRI) to rule  out pituitary or other CNS infiltrate or tumor. Treatment of  delayed puberty depends on the cause; the goal of treatment  is the development of secondary sex characteristics and fertil-  ity, when possible. Insufficient sex hormone secretion can be  corrected by hormone replacement therapy, such as estrogen.  Idiopathic hypogonadotropic hypogonadism is treated with  synthetic GnRH or sex hormone administration, or both, and  may be lifelong.'!    Precocious puberty is a rare event, affecting about 1 in 10,000  girls and fewer than 1 in 50,000 boys. Precocious puberty has  been redefined as sexual maturation before age 6 in black girls  or age 7 in white girls, and before age 9 in boys.!° This reflects  a trend toward earlier puberty, primarily for breast develop-  ment in girls (see What’s New? Precocious Puberty). There have  been many postulated causes of precious puberty (Box 24-1),  including increased obesity, an increase in protein consump-  tion,!°!” and the growing prevalence of molecular compounds  known as endocrine disruptors in common household prod-  ucts.'® However, because precocious puberty can be a sign of  pathology, all cases of precocious puberty require thorough  evaluation.   Precocious puberty may be partial, complete, or mixed  types (Box 24-2) and can be further categorized into cen-  tral (GnRH dependent) and peripheral (GnRH independent)    Studies implicate obesity, leptin, ghrelin, and environmental endocrine disrup-  tor chemicals (EDCs) as possible contributors to precocious puberty in girls.  Obesity may affect the production and secretion of leptin and ghrelin, powerful    communicators of satiety, hunger, metabolic rate, and in timing of puberty.  EDCs may mimic, block, or alter the normal signaling systems involved in sex  hormone secretion, uptake, and use. EDCs include agrochemicals, widespread  industrial compounds, and persistent pollutants.    Data from Bluher S, Mantzoros CS: Curr Opin Endocrinol Diabetes  Obes 14(6):458-464, 2007; Buck Louis GM et al: Pediatrics 121 (Suppl  3):S192-S207, 2008; Caserta DL et al: Hum Reprod Update 14(1):  59-72, 2008; Euling SY et al: Pediatrics 121(Suppl 3):S167-S171,  2008; Kaplowitz PB: Pediatrics 121(Suppl 3):S208-S217, 2008; Rasier  G et al: Mol Cell Endocrino! 254-255:187-201, 2006; Tena-Sempere M:  Vitam Horm 77:285-300, 2008.   Central nervous system (CNS) disorders  Congenital anomalies (hydrocephalus)  Hypothalamic hamartoma  Postinflammatory/infectious condition  Trauma  Tumors (hypothalamic, pineal, other)    From Abreu AP et al: NEJM, 2013 [Epub ahead of print.]; Bhagavath B,  Layman LC: Semin Reprod Med 25(4):272-286, 2007; Burchett MLR  et al: Endocrine and metabolic diseases. In Burns CE et al, editors:  Pediatric primary care, St Louis, 2009, Saunders; Caserta DL et al:  Hum Reprod Update 14(1):59-72, 2008; Cesario SK, Hughes LA: J  Obstet Gynecol Neonatal Nurs 36(3):263-274, 2007; Jospe N: Disor-  ders of pubertal development. In Osborn LM et al, editors: Pediatrics,  Philadelphia, 2005, Mosby.   Premature development of appropriate characteristics for the child's sex  Hypothalamic-pituitary-ovarian axis working normally but prematurely   In about 10% of cases, lethal central nervous system tumor may be the cause   Premature thelarche (breast budding) seen in girls between 6 months and  2 years of age   Premature adrenarche (growth of axillary and pubic hair) tends to occur  between 5 and 8 years of age   Can progress to complete precocious puberty; may be caused by estrogen-  secreting neoplasms or may be a variant of normal pubertal development    Data from Burchett MLR et al: Endocrine and metabolic diseases. In  Burns CE et al, editors: Pediatric primary care, St Louis, 2009, Saun-  ders; Jospe N: Disorders of pubertal development. In Osborn LM et al,  editors: Pediatrics, Philadelphia, 2005, Mosby.    (see Box 24-1). Central precocious puberty is GnRH depen-  dent and occurs when the HPG axis is working normally but  prematurely. Besides the premature development of secondary  sex characteristics, precocity causes premature closure of the  epiphysis of long bones, which results in lifelong short stat-  ure.!° Central precocious puberty results from failure of central  inhibition of the GnRH pulse generator (the gonadostat). The  diagnosis of central precocious puberty is one of exclusion.!°  Because a CNS lesion may be missed, children with presumed  central precocious puberty require long-term surveillance.  Peripheral puberty is GnRH independent and develops when  sex hormones are produced by some mechanism other than  stimulation by the gonadotropins. Sex steroid—producing  tumors (ie., gonadal tumors), testotoxicosis, and exposure  to exogenous sex steroids (i.e., hormonal contraceptives and  environmental endocrine disruptors) are some of the causes  (see Box 24-1). Mutations in the imprinted gene MKRN3 was  recently reported as a cause of central precocious puberty.!*   Partial precocious puberty is the partial development of  appropriate secondary sex characteristics alone or in combina-  tion. A girl with incomplete precocious puberty might undergo  thelarche or pubarche and, rarely, premature menarche. Pre-  mature thelarche is seen in girls between 6 months and 2 years  of age. Premature pubarche tends to occur between ages 5 and  8 years. Premature pubarche is usually the consequence of  an early increase in the adrenal androgens that leads to early  growth of pubic hair and possibly a transient acceleration in  growth and bone maturation that has no significant effect on  timing of puberty or final height. Sparse hair growth on the  genitalia, in the absence of thelarche or menarche, does not  represent precocious puberty.   The diagnosis and cause of premature development are often  straightforward.® A thorough history and physical examination  are done to determine the velocity of the process and to rule  out life-threatening CNS, ovarian, or adrenal neoplasms. Fam-  ily occurrence helps exclude tumors. Children with precocious  puberty also have a tendency toward obesity.®   Treatment for all forms of precocious puberty includes  identifying and removing the underlying cause or administer-  ing appropriate hormones (see Boxes 24-1 and 24-2). Ifneeded,  precocious puberty can be reversed. Management goals include  diagnosing and treating intracranial disease; arresting matura-  tion until developmentally appropriate; maximizing eventual  adult height; reducing emotional problems. The most common  form, central precocious puberty, is usually treated with potent  GnRH agonist analogs, which induce reversible, selective sup-  pression of the HPG axis. Because many of these children are  obese and childhood obesity is predictive of morbidity in ado-  lescence and adulthood, it is important for clinicians to include  assessment and management of obesity as part of the treatment  for central precocious puberty.   Complete precocious puberty refers to the onset and  progression of all pubertal features (i.e., thelarche, pubarche,  and menarche). Mixed precocious puberty (virilization of a  girl or feminization of a boy) causes the child to develop some  secondary sex characteristics of the opposite sex. This condition  is usually evident at birth and is rare in older children (Box 24-3).    From Jospe N: Disorders of pubertal development. In Osborn LM et al,  editors: Pediatrics, Philadelphia, 2005, Mosby.    Primary Dysmenorrhea  Primary dysmenorrhea is painful menstruation associated with  the release of prostaglandins in ovulatory cycles, but not with  pelvic disease. Approximately 50% of all women experience  dysmenorrhea, 10% of whom are incapacitated for 1 to 3 days  because of pain severity. Primary dysmenorrhea usually begins  with the onset of ovulatory cycles, around age 15 or 16 years  with prevalence highest during adolescence.'? In contrast, sec-  ondary dysmenorrhea is related to pelvic pathology (i-e., ovar-  ian cysts, endometriosis) which manifests in later reproductive  years and may occur any time in the menstrual cycle.”°  PATHOPHYSIOLOGY. Primary dysmenorrhea is attributed to  excessive endometrial prostaglandin production.”°?! Women  with painful periods produce 10 times as much prostaglandin  F (PGF,a), a potent myometrial stimulant and vasoconstric-  tor, as asymptomatic women. Elevated levels of prostaglandins  (especially PGF, and PGE,a) cause uterine hypercontractility,  decreased blood flow to the uterus, and increased nerve hyper-  sensitivity, thus resulting in pain.?? Women with dysmenorrhea  may have up-regulated cyclo-oxygenase (COX) enzyme activ-  ity, which contributes to increased synthesis of prostaglandins.  Furthermore, leukotriene production is elevated further con-  tributing to increased levels of pain.” Prostaglandins are pri-  marily released during the first 48 hours of menstruation, when  symptoms are the most intense. Women who are anovulatory  because they use oral contraceptives rarely have primary dys-  menorrhea. Secondary dysmenorrhea results from disorders  such as endometriosis (the most common cause), endometri-  tis (infection), pelvic inflammatory disease, obstructive uterine  or vaginal anomalies, uterine fibroids, polyps, tumors, ovarian  cysts, pelvic congestion syndrome, or nonhormonal intrauter-  ine devices (IUDs).”°    CLINICAL MANIFESTATIONS. The chief symptom of dysmenor-  rhea is pelvic pain associated with the onset of menses. The  pain often radiates into the groin and may be accompanied by  backache, anorexia, vomiting, diarrhea, syncope, and headache.  The latter symptoms are caused by entry of prostaglandins and  prostaglandin metabolites into the systemic circulation. Usually  the discomfort associated with primary dysmenorrhea begins  shortly before the onset of menstruation and persists for the  first 1 to 3 days of menstrual flow.”   EVALUATION AND TREATMENT. Primary dysmenorrhea can be  differentiated from secondary dysmenorrhea by a thorough his-  tory and pelvic examination. Nonsteroidal anti-inflammatory  medication (NSAIDs, e.g., ibuprofen) is the treatment of choice  as these reduce COX enzyme activity, thus prostaglandin pro-  duction. NSAIDs work in the majority of women with primary  dysmenorrhea and are most effective if started at the first sign  of bleeding or cramping.”” In women who desire contraception,  dysmenorrhea may be relieved with hormonal contraceptives.”  Hormonal contraception stops ovulation and creates an atro-  phic endometrium, thereby decreasing prostaglandin synthesis  and myometrial contractility. Regular exercise and stress reduc-  tion are thought to prevent or reduce symptoms.” Other non-  pharmacologic approaches with some evidence of effectiveness  in pain relief include local application of heat; acupuncture;°  high-frequency transcutaneous electrical nerve stimulation  (TENS); supplements, such as thiamine and vitamin E; and  Chinese herbal treatment.”°    Amenorrhea means lack of menstruation, and the most com-  mon causes (aside from pregnancy) are caused by hypothalamic  dysfunction, polycystic ovarian syndrome, hyperprolactinemia,  and ovarian failure.27 Primary amenorrhea is the failure of  menarche and the absence of menstruation by age 13 years  without the development of secondary sex characteristics or by  age 15 regardless of the presence of secondary sex characteris-  tics (see p. 802 for discussion of delayed puberty).** Primary  amenorrhea differs from delayed puberty in that most cases of  delayed puberty require only reassurance, but when the diagno-  sis of primary amenorrhea is reached, a thorough evaluation is  needed. Secondary amenorrhea is the absence of menstruation  for a time equivalent to three or more cycles in women who  have previously menstruated. Pregnancy is the most common  condition to rule out prior to further evaluation.   PATHOPHYSIOLOGY. There are numerous classifications of the  etiologies of primary amenorrhea. One approach to under-  standing the pathophysiology is through compartmentalization.  Compartment IV disorders include CNS disorders, in particular  hypothalamic disorders. In some of the congenital syndromes  that cause primary amenorrhea, the hypothalamic-pituitary-  ovarian (HPO) axis is dysfunctional. The hypothalamus is  unable to synthesize GnRH, so the pituitary fails to secrete LH  and FSH. Therefore, the ovary does not receive the hormonal  signals required to stimulate estrogen production, and ovula-  tion and menstruation do not occur. Because the ovarian hor-  mones are absent, estrogen-dependent sex characteristics do  not develop.    Compartment ILI disorders are disorders of the anterior pitu-  itary, including tumors. Some anatomic defects of the CNS,  whether congenital or acquired, impinge on the hypothalamic-  pituitary unit so as to interfere with or interrupt the secretion of  GnRH or FSH and LH. Examples of such defects include hydro-  cephalus, craniopharyngiomas, and other space-occupying  lesions of the CNS. Again the target organ, the ovary, does not  receive the necessary signals, and ovulation and menstruation  do not occur. In some cases these lesions develop between the  onset and conclusion of puberty. Therefore, skeletal growth  may occur and secondary sex characteristics may develop, but  sexual maturation is interrupted before menarche.   Compartment II disorders involve the ovary and are often  linked with genetic abnormalities. These include gonadal dys-  genesis (Turner syndrome), androgen insensitivity syndrome  (AIS), formerly known as testicular feminizing syndrome or male  pseudohermaphroditism. Turner syndrome involves the lack of  two functional and complete X chromosomes in at least some  body tissues (45,X/46,XX; structural X or Y abnormalities;  mosaicism),”? which results in the ovaries lacking gametes and  ovarian failure. Without primitive gametes and follicles, fol-  licular development and estrogen secretion cannot occur. Lack  of estrogen accounts for failure of secondary sex characteristic  development and amenorrhea, although there are high levels of  circulating FSH and LH.??   In AIS, the individual is male genetically but female mor-  phologically. The individual does not develop male genitalia  because even though testosterone is produced in the fetus as  a result of the presence of the Y chromosome, the cells are  not sensitive to testosterone because androgen receptors are  absent in target cells forming the reproductive tract.*° In indi-  viduals with AIS, the gonads are found either in the abdomen  or in the inguinal canal, and they may produce both andro-  gens and estrogens. Because target tissues lack androgen  receptors but have estrogen receptors, most individuals with  AIS have female external genitalia and female secondary sex  characteristics. With the exception of a small vagina, internal  female genitalia are absent, accounting for amenorrhea and  infertility.°°   Compartment I disorders are anatomic defects of the outflow  tract associated with primary amenorrhea. They include con-  genital absence of the vagina and uterus and congenital uterine  hypoplasia (infantile uterus). Genetically normal females with-  out a uterus or vagina usually have normal ovarian function.  Therefore, skeletal growth occurs and secondary sex character-  istics develop in the proper sequence, but menstruation does  not occur because the uterus is too small or malformed to pro-  duce substantial endometrium.   CLINICAL MANIFESTATIONS. The major clinical manifestation  of primary amenorrhea is the absence of the first menstrual  period. The cause of the amenorrhea determines whether sec-  ondary sex characteristics and height are affected.   EVALUATION AND TREATMENT. Diagnosis of primary amenorrhea  is based on history and physical examination and whether sec-  ondary sexual characteristics are present or absent. Absence of  these sexual characteristics indicates that a girl or woman has  never been exposed to estrogen. If ovarian steroid hormone    levels are low, the individual has the appearance of an imma-  ture female. Physical examination may show structural or phys-  iologic alterations of the reproductive tract as outlined at the  beginning of the chapter. Laboratory studies may be required  to document karyotype, abnormal levels of gonadotropins, and  ovarian hormones. Diagnostic imaging is used to document  structural abnormalities (see Figure 24-1).   Treatment involves correction of any underlying disorders  and hormone replacement therapy to induce the development  of secondary sex characteristics as necessary (see p. 802 for a  discussion of delayed puberty). Although surgical alteration of  the genitalia may be undertaken to correct structural abnor-  malities, surgery should be delayed until the affected individual    Initial workup to include physical and pelvic  exam (to evaluate sexual maturation and  rule out outflow tract, absent uterus)    can make a truly informed decision. Hormonal manipulation  or embryo transplantation may make pregnancy possible for  women with primary amenorrhea who have a normal uterus.    A wide variety of disorders and physiologic conditions are asso-  ciated with secondary amenorrhea. Besides disease, secondary  amenorrhea can be triggered by dramatic weight loss, whether  the loss results from malnutrition or excessive exercise. Sec-  ondary amenorrhea is common during early adolescence and  the perimenopausal period, pregnancy, and lactation. The  most common causes (after pregnancy) are thyroid disorders  (e.g., hypothyroidism), hyperprolactinemia, HPO interruption    Serum prolactin Serum TSH  (nl = 0-21 ng/ml) (nl = 0.3 - 5/ml)  nl  High nl    FIGURE 24-2 Diagnosis of Amenorrhea. Pregnancy is the most common cause of amenorrhea. CNS, Central nervous  system; CT, computed tomography; DHEAS, dehydroepiandrosterone sulfate; FSH, follicle-stimulating hormone; hCG, human  chorionic gonadotropin; /HH, idiopathic hypogonadotropic hypogonadism; MAI, magnetic resonance imaging; n/, normal; PCOS,  polycystic ovary syndrome; TSH, thyroid-stimulating hormone. (Adapted from Schorge JO et al, editors: Williams gynecology,    secondary to excessive exercise, stress, weight loss, and polycys-  tic ovary syndrome (PCOS).   PATHOPHYSIOLOGY. The causes of secondary amenorrhea are  summarized in Figure 24-2. In women with normal ovarian  steroid hormone levels, secondary amenorrhea may be caused  by structural abnormalities (miillerian anomalies), Asherman  syndrome (removal of the endometrial decidua basalis), or  removal of the uterus. In women with elevated ovarian steroid  hormone levels, inhibited ovulation leads to amenorrhea. An  excess of ovarian hormones disrupts feedback relationships  within the HPO axis, preventing ovulation. Depressed ovarian  hormone levels, which are associated with a variety of clinical  disorders, also cause amenorrhea by preventing ovulation. Lack  of ovulation, termed anovulation, may result from increased  levels of prolactin, decreased levels of gonadotropins, irregular  secretion of gonadotropins, or abnormally low levels of CNS  neurotransmitters (i.e, dopamine and GnRH). Any of these  variables alters the feedback effects that the ovarian hormones  have on the hypothalamus and pituitary.   High levels of prolactin are physiologic during lactation  because it increases milk production and suppresses ovulation,  preventing closely spaced pregnancies. However, high levels of  prolactin not related to lactation are abnormal and will disrupt  the menstrual cycle. Hyperprolactinemia (overproduction of  prolactin by the pituitary) may have indirect effects that lead to  decreased secretion of GnRH by the hypothalamus. The result  is a reduction in FSH and LH secretion followed by anovula-  tion and secondary amenorrhea. Hyperprolactinemia should  be diagnosed through blood testing that specifically tests for  both normal-size and large molecular prolactin (macropro-  lactin). Hyperprolactinemia can have many causes including    Menopause  Congenital ovarian failure caused by:  Gonadal dysgenesis  Resistance to gonadotropins  Acquired ovarian failure caused by:  Autoimmune disease  Chemotherapy  Resistance to gonadotropins  Environmental toxins  Premature ovarian failure    medication side effects, hypothyroidism, excessive nipple stim-  ulation, and pituitary tumors*! (see pp. 724 and 837 for addi-  tional information).   CLINICAL MANIFESTATIONS. The major manifestation of second-  ary amenorrhea is the absence of menses after previous men-  strual periods. Infertility, vasomotor flushes, vaginal atrophy,  acne, osteopenia, and hirsutism (abnormal hairiness) also  may be present, depending on the underlying cause of the  amenorrhea.   EVALUATION AND TREATMENT. Pregnancy is the most common  cause of amenorrhea and must be ruled out prior to other eval-  uations. The menstrual cycle also may stop or become irregular  in response to stress, extreme exercise, large dietary changes,  eating disorders, or sleep abnormalities. A thorough history of  the womans life and stressors is important in assessing amenor-  rhea. Diagnosis of the organic cause of secondary amenorrhea  involves the identification of underlying hormonal or anatomic  alterations. A woman with secondary amenorrhea and nor-  mal secondary sex characteristics should have a complete his-  tory and physical examination. After ruling out pregnancy and  performing an in-depth history, initial laboratory evaluation  includes measurement of thyroid-stimulating hormone (TSH)  and prolactin levels (Figure 24-3). Elevated prolactin levels war-  rant further investigation, including a complete medication his-  tory, TSH, and brain CT or MRI if warranted.*! If these initial  tests are normal, further testing would include measurement of  gonadotropins (FSH), estrogen and testosterone, ultrasonogra-  phy of the outflow tract and ovaries or adrenal MRI, or both.   Treatment of amenorrhea depends on the cause and the  woman’s psychologic need for cycle stability. Treatments may  include replacing deficient hormones (e.g., estrogens, thyroid    FIGURE 24-3 Causes of Secondary Amenorrhea. Of note, hypothyroidism is a relatively common condition and should  be ruled out as the cause of hyperprolactinemia before more extensive evaluation (i.e., computed tomography or magnetic  resonance imaging) occurs. DHEAS, Dehydroepiandrosterone sulfate; PCOS, polycystic ovary syndrome.    Cycles shorter than 3 wk; may indicate disturbance  in endocrine control of ovulation   Cycles longer than 6-7 wk; may indicate  disturbance in endocrine control of ovulation   Intermenstrual bleeding or bleeding of light  character occurring irregularly between cycles;  may be a sign of organic disease   Prolonged flow associated with irregular and  intermittent spotting between bleeding episodes    hormone, glucocorticoids, gonadotropins) or correcting under-  lying pathology (e.g., tumor removal).°**°? A diagnosis of PCOS  might be treated with an insulin-sensitizing agent, such as met-  formin, as well as ovulation-inducing drugs if fertility is desired  (a discussion of PCOS is on p. 810).   Some treatments for amenorrhea prevent pregnancy,  whereas others may restore fertility; the choice of treatment  may be influenced by the woman’s childbearing plans. After  pathologies have been corrected and the menstrual cycle sta-  bilized, fertility may return. Occasionally, women with sec-  ondary amenorrhea may need additional ovulation-inducing  drugs to assist conception, whereas others are able to conceive  naturally.°°    Menstrual irregularity or abnormal bleeding patterns (Table  24-2) account for approximately 33% of all gynecologic visits.  Abnormal bleeding can be caused by a disruption in the HPG  axis, abnormalities of the uterus or endometrium, or bleed-  ing disorders. Anovulatory cycles (failure to ovulate) because  of various etiologies (age, stress, endocrinopathy) are the most  common cause of cycle irregularity. Other causes include uter-  ine tumors, polyps, ovarian cysts, complications of pregnancy,  and bleeding disorders (e.g., von Willebrand disease). Common  causes of abnormal uterine bleeding based on age group and  frequency are listed in Table 24-3. Pathophysiology and treat-  ment options vary and are based on etiology.**   Dysfunctional uterine bleeding (DUB) is heavy or irregu-  lar bleeding in the absence of organic disease, such as submu-  cous fibroids, endometrial polyps, blood dyscrasias, pregnancy,  infection, or systemic disease. The diagnosis of DUB is made  once these other causes have been excluded. DUB affects 15%  to 20% of all women at some time during their menstrual life  and accounts for 70% of all hysterectomies and almost all endo-  metrial ablation procedures.*? Perimenopausal women are by  far the most affected by DUB.   PATHOPHYSIOLOGY. The majority of abnormal uterine bleed-  ing, commonly known as dysfunctional bleeding, is due to  lack of ovulation.** Normal, regular periods are the result of a  complex interplay between the hypothalamus, the pituitary, the    TABLE 24-3 COMMON CAUSES OF  ABNORMAL (VAGINAL/  GENITAL) BLEEDING  IN DESCENDING ORDER  OF FREQUENCY    ovary, and the uterine endometrium (see Chapter 23). Disrup-  tions in this system can affect the amount and structure of the  uterine endometrium, causing it to shed irregularly or heavily.  Although DUB may occur at any time during the reproductive  years, 20% of cases occur in adolescents, and more than 50%  of cases occur in perimenopausal women ages 40 to 50 years  because women at the edges of the reproductive years are more  likely to ovulate irregularly. The formation of a follicle and its  rupture to release an ovum is an important component of the  menstrual cycle. As the follicle forms, it produces estrogen,  which causes proliferation of the endometrium. Following ovu-  lation, the remaining portions of the follicle, known as the cor-  pus luteum, release progesterone. The progesterone acts on the  proliferating endometrium to limit growth and cause changes  in the vasculature of the endometrium, which limits bleeding  during endometrial shedding.   If a follicle forms but never releases the ovum, the follicle  may continue to produce estrogen (estradiol [E,]) encouraging    endometrial proliferation beyond the normal 14-day time win-  dow. In addition, the lack of progesterone causes the thickened  endometrium to be unable to shed in a predictable fashion  without excessive blood loss. Women who fail to ovulate expe-  rience irregularities in their menstrual bleeding related to the  lack of progesterone and, in some cases, an excess of estrogen.   Many conditions are associated with irregular ovulation.  Women at the edges of their reproductive life span, both young  and old, are more likely to experience anovulatory cycles. In older  women this is a result of having fewer viable follicles for ovulation  (see Chapter 23 for a description of the many hormonal changes  associated with the time before and just after menopause). Other  conditions associated with chronic anovulation include PCOS,  in which follicles begin to form but never reach maturation and  rupture; obesity because adipose tissue excretes estrogen, which  can suppress the HPG axis; hyperthyroidism and hypothyroid-  ism; and estrogen-secreting ovarian neoplasms.   Without ovulation, menstrual flow may become irregular  (metrorrhagia) and excessive (menorrhagia) or both (menome-  trorrhagia), resulting from the large quantity of tissue available  for bleeding and the random breakdown of tissue that results  in exposure of vascular channels. In the absence of adequate  progesterone levels, usual endometrial control mechanisms are  missing, such as vasoconstrictive rhythmicity, tight coiling of  spiral vessels, and orderly collapse, and stasis does not occur.  Unopposed estrogen induces a progression of endometrial  responses beginning with proliferation, hyperplasia, and ade-  nomatous hyperplasia; over a course of many years, unopposed  estrogen may end with atypia and carcinoma.   Abnormal menstrual bleeding also can result from defects  of the corpus luteum, resulting in progesterone deficiencies or  from abnormalities of the uterus or cervix, such as endome-  trial polyps, uterine fibroids, or even uterine or cervical cancers.  (These conditions are covered in more detail later in the chap-  ter.) Coagulation defects also can cause heavy and abnormal  uterine bleeding and should be suspected in younger women  with a history of extensive bruising.   CLINICAL MANIFESTATIONS. Abnormal uterine bleeding is char-  acterized by unpredictable and variable bleeding. Especially  during perimenopause, abnormal bleeding also may involve  greatly increased menstrual flow and the passage of large clots,  leading to excessive blood loss. Excessive bleeding can lead  to iron deficiency anemia and associated symptoms (fatigue,  shortness of breath).   EVALUATION AND TREATMENT. The first step in assessing abnor-  mal bleeding is to determine the cause of bleeding. If an organic  cause can be found, the focus is on eliminating the pathology  or mitigating its effects. To determine the cause of the bleed-  ing, a complete and thorough history and physical examination  is needed. The woman’s age and risk factors for other abnor-  mal conditions are important in assessing the likely cause of the  bleeding. If no cause can be found, it is usually assumed that  the bleeding is caused by lack of regular ovulation because this is  the cause of the majority of abnormal bleeding. Irregular men-  strual bleeding because of anovulation is often referred to as  DUB. Treatment goals include preventing or controlling abnor-  mal bleeding, identifying underlying disease, and inducing    regular menstrual cycles. Treatment varies greatly by the age of  the woman and her desire for current and future fertility.   NSAIDs, such as ibuprofen and naproxen, are often first-  line treatments for excessive menstrual bleeding because they  reduce prostaglandin synthesis within the endometrial tissues,  which causes vasoconstriction and decreased menstrual blood  loss. NSAIDs can reduce menstrual bleeding significantly with  minimal side effects.*° For best effect they should be taken in the  few days preceding the beginning of the menstrual period and  be continued through the days of heaviest bleeding. NSAIDs are  not as effective in controlling menstrual blood loss as hormonal  therapies but they are readily available without a prescription.*°   Young women and those of childbearing age with abnormal  bleeding are often treated with hormonal therapies to override  the HPG axis and mimic normal menstrual bleeding or suppress  it entirely. Common treatments include oral contraceptive pills  that contain both estrogen and progesterone, long-term treat-  ment with medroxyprogesterone (Depo-Provera) (though the  U.S. Food and Drug Administration [FDA] black box warning  about potential bone loss has drastically curtailed the use of  this therapy), and the levonorgestrel intrauterine device (LNG-  IUD). The LNG-IUD has a dual indication from the FDA for  both birth control and suppression of abnormal menstrual  bleeding. The device releases a steady amount of progesterone  directly into the uterus to stabilize and suppress the uterine lin-  ing. In addition, the progesterone works to suppress the HPG  axis and prevent ovulation. There is no strong evidence to dif-  ferentiate whether estrogen and progesterone or progesterone  alone is superior in the treatment of abnormal uterine bleeding;  the woman should be allowed to select a treatment regimen that  is compatible with her life and needs.*”   Women whoare greater than 35 years old and smoke cigarettes  may not be candidates for oral contraceptive pills as the estrogen  increases their risk of cardiovascular incidents, such as myocar-  dial infarction. However, the LNG-IUD can still be used because  it contains only progesterone. The LNG-IUD is widely used as a  first step in controlling perimenopausal bleeding because it can  be inserted in a clinic office and is easily removed if the treat-  ment is ineffective. The LNG-IUD decreases blood loss by 86%  to 97% by decreasing endometrial proliferation and has similar  success rates as more invasive procedures.** Women who do  not wish to have future pregnancies also can opt for treatments  that permanently suppress their uterine lining. These treatments  include ablation, where the lining is burned to prevent future  proliferation of the endometrial cells, and complete removal of  the uterus in hysterectomy.°** If a woman is menopausal, and  has not had a menstrual period for greater than 1 year, all vagi-  nal bleeding should be investigated to rule out uterine and other  cancers. Appropriate initial evaluation includes ultrasound and  endometrial biopsy to rule out uterine cancer.*?   Women with coagulation disorders may have excessive men-  strual bleeding because they have a genetic predisposition to  bleeding or because they are taking anticoagulant medications  to overcome a genetic predisposition to excessive clotting.*°  To control their menstrual bleeding, these women can opt for  cycle suppression. Provision of birth control for these women  is important because pregnancy may be risk to their health.*!    Polycystic Ovary Syndrome  Polycystic ovary syndrome (PCOS) has at least two of the fol-  lowing conditions: oligo-ovulation or anovulation, elevated  levels of androgens, or clinical signs of hyperandrogenism and  polycystic ovaries. Polycystic ovaries do not have to be present  to diagnose PCOS, and conversely their presence alone does not  establish the diagnosis. PCOS remains one of the most com-  mon endocrine disturbances affecting women, especially young  women, and is a leading cause of infertility in the United States,  where prevalence rates are estimated at between 4% and 12%,  afflicting between 3.2 and 5.4 million young women.** PCOS  appears to be familial, and various features of the syndrome  may be differentially inherited.*°*+ Confusing the issue is the  frequency, expression, and timing of PCOS symptoms and diag-  nosis. From 22% to 30% of women have polycystic ovaries on  ultrasound, with 80% having one or more symptoms of the syn-  drome; 80% of women with normal ovaries also experience one  or more PCOS symptoms. Signs and symptoms of women with  PCOS may change over time, with metabolic syndrome becom-  ing more prominent with age. In addition, polycystic ovaries  may be associated with Cushing syndrome, acromegaly, prema-  ture ovarian failure, simple obesity, congenital adrenal hyper-  plasia, thyroid disease, androgen-producing adrenal tumors or  ovarian tumors (Figure 24-4), and syndromes with hyperpro-  lactinemia. Thus diagnosing PCOS can be difficult. In addition,  several diagnostic criteria are proposed by different agencies,  resulting in nonstandard application of the diagnosis.”   PATHOPHYSIOLOGY. Although the underlying cause of PCOS is  unknown, a genetic basis is suspected. Initial identification of  genes involved in steroid biosynthesis, androgen biosynthesis,  and insulin receptors within the ovary indicate genetic involve-  ment. No single factor fully accounts for the abnormalities of  PCOS.**4°48 A hyperandrogenic state is a cardinal feature in  the pathogenesis of PCOS. However, glucose intolerance/insu-  lin resistance (IR) and hyperinsulinemia often run parallel and  markedly aggravate the hyperandrogenic state, thus contribut-  ing to the severity of signs and symptoms of PCOS.***? Obe-  sity adds to and worsens IR. Although 50% of normal weight  women with PCOS have IR, all obese women with PCOS do.  Insulin stimulates androgen secretion by the ovarian stroma  and reduces serum sex hormone-binding globulin (SHBG)  directly and independently. The net effect is an increase in free  testosterone levels. Excessive androgens affect follicular growth,  and insulin affects follicular decline by suppressing apoptosis  and enabling follicles, which would normally disintegrate, to  survive? (Figure 24-5). Further, there appears to be a genetic  ovarian defect in PCOS, which makes the ovary either more  susceptible to or sensitive to insulin’s stimulation of androgen  production. Recent research suggests that decreased intraovar-  ian receptors for estrogen receptor-a or insulin-like growth  factor 1 (IGF-1), increased leptin levels, or direct IR within  selective ovarian cells (fibroblasts) may contribute to this phe-  nomenon.” Intrauterine and early childhood environments  may also contribute to the development of PCOS (see What’s  New? Early Programming for PCOS?).   Weight gain tends to aggravate symptoms, whereas weight  loss may ameliorate some of the endocrine and metabolic    FIGURE 24-4 Polycystic Ovary. A, Surgical view of polycystic ovaries. B,  Ultrasound of polycystic ovary. (A from Symonds EM, Macpherson MBA: Diagnosis  in color: obstetrics and gynecology, London, 1997, Mosby-Wolfe. B from King J:  J Midwifery Womens Health 51[6]:415—422, 2006. Reprinted with permission.)    FIGURE 24-5 Insulin Resistance and Hyperinsulinemia in Polycystic  Ovary Syndrome (PCOS). See text. FSH, Follicle-stimulating hormone; LH, lutein-  izing hormone; SHBG, sex hormone-binding globulin. (From Franks S, Berga SL:  Fertil Steril 97[1]:2-6, 2012.)    A fetal environment containing abnormal levels of pollutants, hormones, and  other factors yet undefined can induce epigenetic modifications of the DNA  and increased risk for adult disease. Female fetuses exposed to testosterone    at levels normally found with male fetuses appear programmed to develop  altered TGF-B signaling and increased risk of hyperinsulinemia and hyperan-  drogenism related to PCOS.    Kosova G, Urbanek M, Mol Cell Endocrinol 373(1-2):29-38, 2013;  Witchel SF et al: Endocrine 42(3):526-534, 2012; Xita N, Tsatsoulis A:  Ann NY Acad Sci 1205:148-155, 2010.    events and thus decrease symptoms. Women with PCOS tend  to have increased leptin levels (leptin levels are increased in thin  as well as overweight women with PCOS).°! Leptin influences  the hypothalamic pulsatility of GnRH and consequent interac-  tion along the entire HPO axis. Feedback from the polycystic  ovary is disturbed because of changes in ovarian steroid and  nonsteroidal (inhibins and related proteins) hormones.   In PCOS there is dysfunction in follicle development.°°  Inappropriate gonadotropin secretion triggers the beginning of  a vicious cycle that perpetuates anovulation. Typically, levels of  FSH are low or below normal and LH levels and LH bioactivity  are elevated. An increased frequency of GnRH pulses appears  to cause increased frequency of LH pulses.°**? Persistent LH  elevation causes an increase in androgens (dehydroepiandros-  terone sulfate [DHEAS] from the adrenal glands and testoster-  one, androstenedione, and DHEAS from the ovary). Androgens  are converted to estrogen in peripheral tissues, and increased  testosterone levels cause a significant reduction (approximately  50%) in SHBG, which in turn causes increased levels of free  estradiol. Elevated estrogen levels trigger a positive-feedback  response in LH and a negative-feedback response in FSH.    Because FSH levels are not totally depressed, new follicular  growth is continuously stimulated, but not to full maturation  and ovulation. The accumulation of follicular tissue in various  stages of development allows an increased and relatively con-  stant production of steroids in response to gonadotropin stim-  ulation. Thus PCOS is characterized by excessive production of  both androgen and estrogen.   Increased androgen secretion by the ovaries contributes to  premature follicular failure (atresia) and persistent anovula-  tion. In turn, persistent anovulation causes enlarged polycystic  ovaries characterized by a smooth, pearly white capsule. This  characteristic appearance is caused by an increase of surface area  and increased volume of up to 2.8 times, doubling of growing  and atretic follicles, thickening of the tunica (outermost area)  by 50%, increasing cortical stromal thickening by one third  and a fivefold increase in subcortical stroma, and escalating  hyperplasia. With advancing age, menstrual irregularities may  improve while metabolic syndrome and type 2 diabetes mel-  litus increases. Women with PCOS have a three times greater  incidence of uterine cancer in later life than normally cycling  women related to the anovulatory lack of progesterone in  PCOS. Without treatment for anovulation, women with PCOS  have a 9% lifetime risk for endometrial cancers related to the  effects of unopposed estrogen.**   CLINICAL MANIFESTATIONS. Clinical manifestations of PCOS  usually appear within 2 years of puberty but may appear after  a variable period of normal menstrual function and, possibly,  pregnancy. The symptoms are related to anovulation and hyper-  androgenism and include dysfunctional bleeding or amenorrhea,  hirsutism, acne, and infertility. Approximately 41% of women  with PCOS are obese.*° Box 24-4 contains a list of signs and  symptoms, summary of hormonal disturbances, and complica-  tions of PCOS. In addition, women with PCOS are more likely  to experience sleep apnea than unaffected women, which results  in impaired sleep and may reduce their overall quality of life.*°   Increased androgens (testosterone, androstenedione)  Increased DHEA (occurs in 50% of women)   Diabetes mellitus (30% of women with or without obesity develop type 2 diabe-  tes mellitus by age 30)    Other  Women with PCOS are at increased risk of gestational diabetes mellitus,  pregnancy-induced hypertension, preterm birth, and perinatal mortality    Adapted from Azziz R et al: Fertil Steril, October 22, 2008 [Epub ahead of print]; Boomsma CM et al: Semin Reprod Med 26(1):72-84, 2008;  Diamanti-Kandarakis E: Expert Rev Mol Med 10(2):e3, 2008; Simoni M et al: Hum Reprod Update 14(5):459-484, 2008.  DHEA, Dehydroepiandrosterone; LH, luteinizing hormone; PCOS, polycystic ovary syndrome; SHBG, sex hormone-binding globulin.    EVALUATION AND TREATMENT. Diagnosis of PCOS is based on  evidence of androgen excess, chronic anovulation, and inap-  propriate gonadotropin secretion. Tests for impaired glucose  tolerance are recommended. As stated, polycystic ovaries do not  have to be present and, conversely, their presence alone does  not establish the diagnosis. Goals of treatment include reversing  signs and symptoms of androgen excess, instituting cyclic men-  struation, restoring fertility, and ameliorating any associated  metabolic or endocrine, or both, disturbances.°>°° Tradition-  ally, treatment of PCOS focused on correcting anovulation and  the effects of hyperandrogenism with combined oral contracep-  tives (COCs), antiandrogens, and fertility agents. With a greater  understanding of the role that IR and hyperinsulinemia play in  this disease, insulin sensitizers, such as metformin,*°°’ may be  used to decrease insulin, prevent diabetes and heart disease (by  reducing microvascular events), and restore fertility if desired.  Progesterone therapy is recommended to oppose estrogen’s  effects on the endometrium and as a means to initiate monthly  withdrawal bleeding (at the expense of continued hirsutism).  For infertile women desiring pregnancy, clomiphene citrate,  an antiestrogen, can be used to facilitate ovulation, although  better effects are achieved (75% ovulation rates and 30% to  40% pregnancy rates) if therapy is combined with an insulin  sensitizer.>>°   Women who are primed with human chorionic gonadotro-  pin (hCG) before in vitro fertilization have greater success in  achieving and maintaining pregnancy (58% to 82%).°® Only a  small reduction of weight has shown a restoration of ovulation  and increased insulin sensitivity by 71% in obese women with  PCOS. Lifestyle changes are therefore encouraged, particularly  weight loss and exercise. Reduction of IR by loss of abdominal  fat appears crucial in restoring ovulation.°! However, lifestyle  changes alone have not been shown to reverse the hyperlipid-  emia and hyperinsulinemia of PCOS, and pharmacologic treat-  ment is often needed to prevent later health complications.  Management of PCOS is a near lifelong process because the  effects of the syndrome persist past childbearing years. Appro-  priate primary care is needed to control the systemic features of  PCOS so that it has minimal impact on a woman’s life.    Premenstrual syndrome (PMS) and premenstrual dysphoric  disorder (PMDD) are the cyclic recurrence (in the luteal phase  of the menstrual cycle) of distressing physical, psychologic, or  behavioral changes that impair interpersonal relationships or  interfere with usual activities.°? The prevalence of PMS and  PMDD is difficult to determine, in part because of the wide-  ranging nature of accepted symptoms. Symptoms of PMS and  PMDD begin after ovulation during the luteal phase and persist  up to 4 days into the menstrual cycle.   It has been estimated that 91% of women experience some  form of distress around their menstrual period but a much  smaller number, as low as 3.1%, meet the criteria for PMDD.  Sources vary but suggest that around 30% of women experience  enough distress to interrupt their daily life and routine.®°   The psychologic and physiologic changes of PMS/PMDD  occur in the luteal phase of ovulatory cycles and are linked with    BOX 24-5 AMERICAN COLLEGE OF  OBSTETRICIANS AND  GYNECOLOGISTS (ACOG)  CRITERIA: PMDD    A problem with premenstrual dysphoric disorder (PMDD) diagnosis is that  many women with clinically relevant premenstrual syndrome/premenstrual    dysphoric disorder (PMS/PMDD) symptoms do not meet the full criteria of the  Diagnostic and Statistical Manual of Mental Disorders-!V(DSM-IV). The ACOG  attempts to rectify this problem by using the following definitions: “Presence  of at least one psychological or physical symptom that causes significant  impairment and is confirmed by means of prospective ratings (i.e., 2 cycles of  a symptom diary).”    Data from American College of Obstetricians and Gynecologists:  ACOG Pract Bull 15, 2000; Yonkers KA et al: Lancet 371(9619):  1200-1210, 2008.    the complex hormonal changes of the menstrual cycle. There  are many theories on the cause(s) of the disorder, including that  the fall in estrogen following ovulation and the immediate rise  in progesterone interacts with hormones and neurotransmit-  ters to cause symptoms.°° However, the mechanisms involved  are not known and may involve an individual sensitivity to the  hormones more than hormonal levels. Furthermore, the neu-  rotransmitters serotonin, gamma-aminobutyric acid (GABA),  and noradrenaline may have mediating or moderating roles on  symptom manifestation. These neurotransmitters have demon-  strated interactions with estrogen and progesterone and all of  these are neuroactive with known mood and behavior effects,  including negative mood, irritability, aggression, and impulse  control.°° Sex steroids also interact with the renin-angiotensin-  aldosterone system (RAAS), which could explain some PMS/  PMDD signs and symptoms (e.g., water retention, bloating,  weight gain). A predisposition to PMS runs in families, perhaps  because of genetics or shared environment. Although research  is limited, evidence supports a relationship between the severity  and frequency of premenstrual symptoms and reports of low  general well-being, history of major affective disorder, and per-  sonality characteristics, such as perfectionism, increased stress,  poor nutrition, lack of exercise, low self-esteem, history of  sexual abuse, and family conflict.“ In turn, when premenstrual  symptoms are perceived as distressing, the quality of interper-  sonal relationships and self-image are negatively affected.   CLINICAL MANIFESTATIONS. The pattern of symptom frequency  and severity is more important than specific complaints. Nearly  300 physical, emotional, and behavioral symptoms have been  attributed to PMS/PMDD. Emotional symptoms, particularly  depression, anger, irritability, and fatigue, have been reported  as the most prominent and the most distressing, whereas physi-  cal symptoms seem to be the least prevalent and problematic.  Underlying physical or psychologic disease may be aggravated  premenstrually and must be diagnosed and treated indepen-  dently from PMS/PMDD.   EVALUATION AND TREATMENT. Diagnosis of PMS/PMDD is  based on prospective health history and symptoms. Diagnostic  criteria for PMDD are presented in Box 24-5. Because the cause  of PMS is not known and cannot be reduced to a single biologic    Women who are affected by premenstrual syndrome (PMS) often look for  ways to decrease their symptoms. Dietary interventions that can help are mul-  tiple: eating six small meals each day; increasing intake of complex carbohy-  drates, fiber, and water; and decreasing caffeine, alcohol, refined sugar, and  animal fat consumption. A low-fat vegetarian diet has been associated with  decreased symptoms, possibly because of an increase in serum sex hormone—  binding globulin concentration that lowers serum estrogen levels. It also may  be helpful to limit sodium intake, and some limited evidence suggests that  moderate doses (50 mg/day) of vitamin B, may reduce emotional symptoms  of depression, irritability, and tiredness. This finding needs to be confirmed.   Some researchers have suggested links between serotonin, endorphins, and  high sugar intake and PMS risk. One interesting craving is chocolate. Some  researchers suggest that a craving for chocolate is an unconscious desire for  a compound called phenylethylamine (PEA) in chocolate that stimulates the  release of the neurotransmitter dopamine, which regulates mood.   Mahan LK, Escott-Stump S: Krause’s food, nutrition, and diet therapy,  ed 10, Philadelphia, 2000, Saunders; Mura Kami K et al: Nutrition  24(6):554-561, 2008.    explanation, and because the occurrence and severity of PMS  are mediated by lifestyle and social and psychologic factors,  treatment for PMS is symptomatic. Nonpharmacologic thera-  pies, with or without medication, tend to be more effective in  controlling symptoms than medication alone (see Nutrition &  Disease: Premenstrual Syndrome). Initial treatment focuses on  validation of the premenstrual experience, education on PMS  and self-help techniques, and elimination of contributing fac-  tors or treatment of coexisting or underlying disorders.   After a trial of nonpharmacologic therapies or if criteria for  PMDD are met, medications may be beneficial. Two major  forms of treatment that have been well substantiated through  research include the use of hormonal cycle regulation and use  of selective serotonin reuptake inhibitor (SSRI) antidepressants.   If a woman does not desire immediate fertility, hormonal  cycle regulation may be beneficial in regulating her menstrual  cycle and decreasing the amount of circuiting steroidal hor-  mones. The oral contraceptive pill containing estrogen and pro-  gesterone has shown benefits in decreasing PMS/PMDD.”’ Pills  containing drospirenone have been shown to be particularly  helpful in decreasing bloating and other PMS/PMDD signs°®  but have an increased risk of blood clots when compared with  pills using another form of progestin.® Oral contraceptive pills  also can be used continuously for up to 3 months to decrease  the frequency of menstrual periods and PMS/PMDD.” SSRIs  have been well studied for use in prevention and treatment of  PMS/PMDD.” They relieve symptoms in about 60% to 90% of  women and may be given continually or only during the pre-  menstrual period but may have undesired side effects such as  sexual problems.   In severe cases, menses can be abolished using GnRH ago-  nists. However, if GnRH analogs are prescribed, continuous  estrogen replacement therapy should be used to avoid side  effects of “medical menopause.”7!    FIGURE 24-6 Salpingitis. A, Advanced pyosalpinx. Note the swollen fallopian  tubes. B, Bilateral, retort-shaped, swollen, sealed tubes and adhesions of ova-  ries are typical of salpingitis. (A from Seidel HM et al: Mosby guide to physical  examination, ed 7, St Louis, 2011, Mosby. B from Damjanov I, Linder J, editors:  Andersons pathology, ed 10, St Louis, 1996, Mosby.)    Infections of the genital tract may result from exogenous or  endogenous microorganisms. Exogenous pathogens are most  often sexually transmitted (see Chapter 26). Endogenous causes  of infection include microorganisms that are normally present  in the vagina, bowel, or vulva. Infection occurs if these micro-  organisms migrate to a new location or overproliferate or if the  immune system and other defense mechanisms are impaired.  A number of skin disorders can affect the vulva. They include  reactive dermatitis, contact dermatitis, psoriasis, and impetigo.  (See Chapter 46 for a discussion of skin disorders.) Many infec-  tious disorders that affect the vulva and vagina are sexually  transmitted; these disorders are described in Chapter 26.    Pelvic inflammatory disease (PID) is an acute inflammatory  process caused by infection. PID may involve any organ, or  combination of organs, of the upper genital tract—the uterus,  fallopian tubes, or ovaries—and, in its most severe form, the  entire peritoneal cavity. Inflammation of the fallopian tubes is  termed salpingitis (Figure 24-6); inflammation of the ovaries is    FIGURE 24-7 Ascension of Pelvic Inflammatory Disease (PID). Microorganisms from the lower genital tract ascend  into the endometrium, fallopian tubes, and peritoneum to cause endometritis-salpingitis-peritonitis (pelvic inflammatory  disease). The arrows indicate the “flow” of microorganisms from the lower genital tract to the upper genital tract. This is noted  as an ascending infection in the text. (Adapted from Brooks ML: Exploring medical language, ed 8, St Louis, 2012, Mosby.)    called oophoritis. Sexually transmitted microorganisms, such  as chlamydia and gonorrhea, that migrate from the vagina to  the uterus, fallopian tubes, and ovaries cause most cases of PID.  The ascension of these microorganisms into the upper genital  tract may be facilitated by disruptions in the normal vaginal  flora.’* Some cases of PID occur after invasive procedures, such  as IUD placement, when microorganisms are pushed up into  the upper genital tract.”°   Pelvic inflammatory disease is very common in the United  States and around the world and has both immediate and long-  term health implications for women. Infections of the upper  reproductive tract cause changes to the delicate cells of the fal-  lopian/uterine tubes, which can affect fertility and increase the  risk of ectopic pregnancy.”   PATHOPHYSIOLOGY. The development of upper genital tract  infections is mediated by the failure of a number of defense  mechanisms that usually are effective in preventing PID. Viru-  lence of the organism, size of the inoculum, and defense status of  the individual determine whether an infectious process results.  Gonorrhea and chlamydia are the main infectious causes of  PID.’>”° These microorganisms can infect the vagina and cervix  but do not ascend into the upper genital tract and cause PID  (Figure 24-7). However, when the normal vaginal microbial  flora is disrupted the pathogens can more easily ascend through  the cervix. Many anaerobic bacteria have been implicated in  increasing the risk of PID because they alter the pH of the vagi-  nal environment and may decrease the integrity of the mucus  blocking the cervical canal. Bacterial vaginosis (BV) is present in  up to 66% of women with PID and other anaerobes, such as Bac-  teroides, and Gardnerella vaginalis, Haemophilus influenzae, and  genital tract mycoplasmas (Mycoplasma hominis, Mycoplasma  genitalis and Ureaplasma urealyticum) are frequently isolated  from women with PID (see Chapter 26 for further discussion of  BV). Escherichia coli may contribute to pelvic infections in older  women. Therefore, although gonorrhea and chlamydia are the  main pathogens in PID, the disease is really polymicrobial in  origin and is treated with a broad spectrum of antibiotics to  ensure that all the causative agents are eliminated.’>”°    Once the infection is established within the uterus and fal-  lopian/uterine tubes, gonorrhea or chlamydia, or both, may  induce changes in the columnar epithelium that lines the upper  reproductive tract, causing permanent damage and facilitating  invasion by other microorganisms. The resultant inflammatory  response causes localized edema and occasionally necrosis of  the area. Gonorrhea gonococci attach to the fallopian tubes and  excrete a substance toxic to the tubal mucosa, causing further  inflammation and damage. Chlamydia enters the tubal cells and  replicates, bursting the cell membrane as it reproduces, caus-  ing permanent scarring. Gonorrhea and chlamydia can spread  to the abdominal cavity through the openings of the fallopian/  uterine tubes. Other mechanisms that may contribute to PID  include lymphatic drainage with parametrial spread of the  infection.   Luckily, the rate of mortality from PID in the United States  is fairly low. However, PID infection results in permanent  changes to the ciliated epithelium of the fallopian or uterine  tubes. A recent study found that one episode of mild, subclini-  cal PID resulted in a 40% decrease in later pregnancy rates, and  multiple episodes of PID further increase the risk of infertility.”  Scarring caused by PID greatly increases the risk of later ectopic  pregnancy by up to 10-fold.’” Scarring and adhesions also can  result in chronic pelvic pain”’ and, potentially, an increased risk  of later uterine cancer.”   CLINICAL MANIFESTATIONS. The clinical manifestations of  PID vary from sudden, severe abdominal pain with fever to  no symptoms at all. An asymptomatic cervicitis may be pres-  ent for some time before PID develops. Of women with sal-  pingitis, 67% to 75% may have a subclinical infection. The  first sign of the ascending infection may be the onset of low  bilateral abdominal pain, most often characterized as dull  and steady with a gradual onset. Symptoms are more likely  to develop during or immediately after menstruation. The  pain of PID may worsen with walking, intercourse, or other  activities involving movement. Other manifestations of PID  include dysuria (difficult or painful urination) and irregular  bleeding.    Additional Criteria That Increase Specificity of Diagnosis  Fever >38.3° C (101° F)    Definitive Criteria (Not Needed for Treatment)  Transvaginal ultrasound, magnetic resonance imaging, or  Doppler studies showing thickened and fluid-filled tubes  Laparoscopic visualization of PID-related abnormalities    Data from: Centers for Disease Control and Prevention: MMWR  59(RR-12), 2010; Yudin MH, Ross JDC: Pelvic Inflammatory disease. In  Zenilman JM, Shahmanesh M, editors: Sexually transmitted diseases,  pp 67-76, Sudbury, MA, 2012, Jones & Bartlett Learning.    EVALUATION AND TREATMENT. PID often has limited or vague  clinical symptoms, leading to undertreatment and long-term  health effects.” Because PID is a substantial health risk to a  woman, the Centers for Disease Control and Prevention (CDC)  encourage clinicians to consider PID as a likely diagnosis when  a sexually active woman has abdominal or pelvic tenderness  and one of the following: cervical motion tenderness, uterine  tenderness, or adnexal tenderness.”° Box 24-6 lists the diag-  nostic criteria for PID. No labs or studies are needed to begin  treatment, however, additional information can improve the  specificity of diagnosis.”> Abdominal pain in women can have  many causes, and it is important to rule out other diagnoses  (Figure 24-8); however, further studies to rule out other diag-  noses can be done while treating for PID.”°   Because of the significance of the complications of PID, rapid  treatment is recommended even before the causative pathogen  can be identified. Because treatment is empiric, it needs to be  effective against a broad range of pathogens, especially chla-  mydia, gonorrhea, and anaerobic bacteria.’° Treatment is usu-  ally outpatient unless the woman has symptoms of advanced  infection, cannot take oral medications, is pregnant, or other  pathologies cannot be excluded. The CDC-recommended  outpatient regimen is shown in Box 24-7.” Although alterna-  tive treatment regimens are available, the growing antibiotic    FIGURE 24-8 Diagnostic Algorithm for Pelvic Pain. LLOQ, Left lower quadrant; LUQ, left upper quadrant; ALO, right lower    Ceftriaxone: 250 mg IM ina single dose  Doxycycline: 100 mg orally twice a day for 14 days  WITH or WITHOUT    Data from Workowski KA, Berman S, Centers for Disease Control and  Prevention (CDC): MMWR Recom Rep 59(RR-12):1-110, 2010; Cen-  ters for Disease Control and Prevention (CDC): MMWR Morb Mortal  Wkly Rep 61(31):590-594, 2012.    resistance of gonorrhea limits antibiotic choices. The CDC  is closely monitoring gonorrhea’s antibiotic sensitivity and  updates treatment guidelines periodically to reflect new infor-  mation.”? The most up-to-date treatment guidelines can be  found on the CDC website.   Sexual partners of women with PID also should also receive  treatment, even if they are asymptomatic. Women receiv-  ing treatment should be reevaluated by their care provider in  3 days to ensure antibiotic treatment is effective.’”> Because  women with a history of PID are at increased risk for ectopic  pregnancy, they should seek care as soon as they know they are  pregnant because ectopic pregnancy is a major cause of mater-  nal mortality.”4   Vaginitis is irritation of the vagina that can be caused by a vari-  ety of microorganisms, irritants, pathologies, or a disruption of  the normal flora of the vagina. Vaginitis is characterized by an  increase in white blood cells on saline wet prep examination.  Vaginal irritation without white blood cells is known as vagi-  nosis.*° The major causes of vaginitis are overgrowth of nor-  mal flora, sexually transmitted diseases, and vaginal irritation  related to low estrogen levels during menopause (a condition  known as atropic vaginitis).°!   The irritation of vaginitis is related to an alteration in the vag-  inal environment, including changes in skin integrity, immune  reaction, and particularly vaginal pH. The pH of the vagina  depends on cervical secretions and the presence of normal flora  that help maintain an acidic environment. A neutral or alkaline  pH normally occurs before puberty, after menopause, and dur-  ing pregnancy. The acidic nature of vaginal secretions during  the reproductive years provides protection against a variety of  sexually transmitted pathogens (see Chapter 26). Changes in the  vaginal pH may predispose a woman to infection. Many sub-  stances and conditions can alter vaginal pH including douch-  ing; use of soaps, spermicides, feminine hygiene sprays, semen,  or deodorant menstrual pads or tampons; and conditions asso-  ciated with increased glycogen content of vaginal secretions,  such as pregnancy or diabetes. Antibiotics can destroy normal  vaginal flora, facilitating overgrowth of Candida albicans, caus-  ing a yeast vaginitis.   Normally vaginal discharge is a clear, milky, or cloudy secre-  tion with a slippery or clumpy texture. It is nonirritating, has  a mild smell, and may yellow after drying. Throughout the    menstrual cycle the amount and texture of a woman’s discharge  change in response to hormonal fluctuation. Vaginal secretions  increase at the time of ovulation, during pregnancy (because of  increased estrogen levels), and with sexual arousal; just before  menstruation, vaginal discharge becomes thick and sticky.  Unusual changes in the amount, color, or texture of vaginal  discharge may signal an infection, especially if the discharge is  copious, malodorous, or irritating. Irritation of the vaginal area  may be the result of many factors.   Diagnosis of the cause of vaginitis is based on history, physi-  cal examination, and examination of the discharge by wet  mount; treatment by physical symptoms alone is inadequate.*!  Treatment involves developing and maintaining an acidic envi-  ronment, relieving symptoms (usually pruritus), and adminis-  tering antimicrobial or antifungal medications to eradicate the  infectious organism. If the infection can be sexually transmit-  ted, a woman’s partner also will be treated. Research suggests  that probiotics, especially Lactobacillus crispatus, can encourage  normal vaginal flora and decrease the incidence of vaginitis in  women at risk for vaginitis.°**?   Cervicitis is a nonspecific term used to describe inflammation  of the cervix. The CDC defines cervicitis as having two diag-  nostic signs: a purulent or mucopurulent discharge from the  cervical os or endocervical bleeding, or both, induced by gently  introducing a cotton swab into the cervix.’ Cervicitis can have  infectious or noninfectious causes. Chemicals and substances  introduced into the vagina can cause cervicitis as well as disrup-  tions in the normal vaginal flora. However, there are conflict-  ing definitions of cervicitis used clinically and in research.*! Age  and risk factors are important in assessing a woman with cervi-  citis. Younger women are at risk for sexually transmitted infec-  tions (STIs) and should be tested for chlamydia, gonorrhea, and  trichomonas. Older women with cervicitis may have STIs but  are at risk for irritation from abnormal vaginal flora related to  low vaginal estrogen levels.   Mucopurulent cervicitis (MPC) usually is caused by one  or more sexually transmitted pathogens, such as Trichomonas,  gonorrhea, Chlamydia, Mycoplasma, or Ureaplasma. Infection  causes the cervix to become red and edematous. A mucopu-  rulent (mucus- and pus-containing) exudate drains from the  external cervical os, and the individual may report vague pel-  vic pain, bleeding, or dysuria. The cervix often becomes friable,  bleeding easily during sexual intercourse or with pelvic exami-  nations and Papanicolaou (Pap) smears. Because mucopuru-  lent cervicitis is a symptom of PID, women at risk for STIs,  especially those less than 26 years old, should receive treat-  ment for PID while awaiting results of microbial testing.” If  the woman is not at risk for STIs, a thorough evaluation often  reveals another cause for the inflammation.    Vulvodynia (also referred to as vulvitis, vestibulitis, or vulvoves-  tibulitis) is chronic pain and inflammation of the vulva or vesti-  bule, or both. In many cases it may represent several disorders  without an identifiable cause. Vulvodynia is fairly common,    FIGURE 24-9 Inflammation of Bartholin Gland. (Modified from Gershenson  DM et al: Operative gynecology, ed 2, Philadelphia, 2001, W.B. Saunders. In Fuller  JK: Surgical technology, ed 6, Philadelphia, 2013, Saunders.)    affecting approximately 8% of women at some point in life.®°  Whereas the inflammation of vulvodynia may be caused by  contact dermatitis (i.e., exposure to soaps, detergents, lotions,  sprays, shaving, menstrual pads/tampons, perfumed toilet paper,  tight-fitting clothes), the condition may be more complex and  represent abnormalities in multiple systems, including vestibu-  lar mucosa, pelvic floor musculature, and CNS pain regulatory  pathways.*° The condition may also represent an autoimmune  reaction, similar to fibromyalgia. Genetic and psychologic links  have also been proposed and studied.*° The mechanisms are  poorly understood; thus vulvodynia is difficult to evaluate and  treat. Vulvodynia can be classified as generalized or localized and  provoked and unprovoked.*° Assessment includes ruling out and  treating conditions that may contribute to or cause vulvar inflam-  mation (e.g., Candida, STI, seborrhea, psoriasis, lichen sclerosus,  and contact dermatitis) and testing for vulvodynia with a cotton-  tipped swab along the inner edge of the labia minora.   Women are advised to avoid potential irritants and to wear  loose, cotton clothing. Vulvodynia may increase susceptibility  to vaginal infection; likewise, it may be caused by vaginal infec-  tions (e.g., candidiasis, trichomoniasis) that spread to the labia,  where they cause inflammation and edema. Studies on treat-  ments are limited but suggest that women may benefit from  behavioral treatment, topical lidocaine (Xylocaine), topical  or systemic antidepressants, Botox injections into the affected  nerve, or vestibulectomy.®®*” Other skin diseases, such as tinea  cruris, psoriasis, lichen sclerosus, and inflammation of the apo-  crine (sweat) glands, can involve the vulva (see Chapter 46).    Bartholinitis, or Bartholin cyst, is an inflammation of one or  both of the ducts that lead from the introitus (vaginal opening)  to the Bartholin/greater vestibular glands (Figure 24-9). The  usual causes of bartholinitis are microorganisms that infect the  lower female reproductive tract, such as streptococci, staphylo-  cocci, and sexually transmitted pathogens.    Infection or trauma causes inflammatory changes that nar-  row the distal portion of the duct, leading to obstruction and  stasis of glandular secretions. The obstruction, or cyst, varies  from 1 to 8 cm in diameter and is located in the posterolateral  portion of the vulva. The cyst may be reddened and painful,  and pus may be visible at the opening of the duct. Any exudate  should be cultured and tested for gonorrhea and chlamydia.  The individual may have symptoms of the initiating infection,  fever, and malaise. Diagnosis of a Bartholin cyst is based on  the clinical manifestations and the identification of infectious  microorganisms.   Most Bartholin cysts are asymptomatic and require no treat-  ment. However, if they are uncomfortable or show signs of  infection, treatment is advised to prevent abscess formation.  Treatment is controversial but involves broad-spectrum anti-  biotics for suspected infection. Some clinicians also attempt to  drain the cyst using hot soaks, needle aspiration, insertion of  a catheter, or marsupialization of the infected gland. No one  treatment has proved to be superior in symptom relief and pre-  vention of recurrence.*®    The bladder, urethra, and rectum are supported by the endopel-  vic fascia and the perineal muscles, particularly the levator ani  group. This muscular and fascial tissue loses tone and strength  with aging and may fail to maintain the pelvic organs in the  proper position. The pelvic area contains many organs and has  the force of gravity and the abdominal contents pushing down  on it. If the pelvic fascia and musculature is not firm, the pelvic  organs to move to fill any space voids. With weak support, the  bladder and rectum tend to push into the vagina and vaginal  wall. The vagina is an opening in the pelvic musculature for  intercourse and childbirth. (Chapter 23 contains a discussion of  pelvic support structures.) However, as gravity acts on the pel-  vis, this opening becomes a weakness in the musculature sup-  port of the entire pelvic cavity and without proper support from  the vaginal muscles and fascia, the uterus and bulging vaginal  walls can begin to herniate through the vaginal opening.   Pelvic organ prolapse (POP) is the descent of one or more  of the following: the vaginal wall, the uterus, or the apex of the  vagina (after a hysterectomy).*? Up to 61% of women have some  version of POP on physical examination. However, most women  have no symptoms. As the degree of prolapse increases, women  feel more vaginal pressure. When prolapse becomes severe, the  function of the surrounding organs can be altered. For instance,  as the bladder is pulled posterior, incontinence and incomplete  voiding become more common. As the bowel bulges into the  vaginal space, defecation becomes more difficult. The severity  of POP and its symptoms increase with age, and half of women  older than age 50 have symptoms of POP. By 2050 it is estimated  that 43.8 million women will have symptoms of POP.”   POP is thought to be caused by direct trauma, such as child-  birth or pelvic surgery or damage to pelvic innervation, par-  ticularly the pudendal nerve. A strong familial tendency and  possibly a multifactorial genetic component place some women  at risk for the development of prolapse. Black and Asian women  have the lowest risk of POP, and Hispanic women appear to    From Hughes D: Pelvic organ prolapse. In Schorge JO et al, editors:  Williams gynecology, New York, 2008, McGraw-Hill.  *Most frequently cited factors.    Data from Hughes D: Pelvic organ prolapse. In Schorge JO et al, edi-  tors: Williams gynecology, pp 532-555, New York, 2008, McGraw-Hill;  Jelovsek JE et al: Lancet 369(9566):1027-1038, 2007.    have the highest risk.?! Risk factors in nulliparous women are  occupational activities that require heavy lifting or chronic  medical conditions, such as chronic lung disease or refractory  constipation. Some have neural abnormalities that interfere  with the innervation of the levator ani. A list of risk factors is  contained in Box 24-8.   The trend is to use terminology that describes physical  examination findings, thus avoiding assumptions about struc-  tural involvement (Box 24-9). The terms cystocele and rectocele  may be used when the structures involved (bladder, rectum)  have been definitively identified (ie., an anterior vaginal wall  prolapse may or may not be a cystocele involving the urinary  bladder) (see Figure 24-11, p. 819). Examining the woman in  multiple positions and straining maximally provides the best  information about the degree of pelvic organ relaxation.*?  Physical examination may be augmented with imaging by  ultrasound, or magnetic resonance. Several systems are used to  describe prolapse. One in widespread clinical use is based on  physical examination findings (see Box 24-9) and uses a grading  system to describe the extent of the prolapse (Box 24-10). Sub-  jective reports regarding the symptoms and effects of POP can    BOX 24-10 EVALUATION OF PELVIC  ORGAN PROLAPSE (BADEN-  WALKER HALFWAY SCORING  SYSTEM)   Note: Any type of prolapse (posterior, apical, anterior vaginal, uterine, etc.) can  be graded using this system.    FIGURE 24-10 Degrees of Uterine Prolapse. Grade 1 is minimal and rarely  requires correction; Grade 2 prolapse has moderate symptoms, and Grade 3 pro-  lapse is severe. The uterus is so low that the cervix protrudes from the vagina.  (From Phillips N: Berry & Kohn’s operating room technique, ed 12, Philadelphia,  2013, Mosby.)    be assessed through direct questioning or questionnaires such  as the Pelvic Floor Impact Questionnaire or the Pelvic Floor  Distress Inventory.   Uterine prolapse is decent of the cervix or entire uterus into  the vaginal canal (Figure 24-10). In severe cases the uterus falls  completely through the vagina and protrudes from the introitus.  Symptoms of other pelvic floor disorders also may be present.  Treatment depends on the severity of symptoms and the physi-  cal condition of the woman. A common first-line treatment is  a pessary, which is a removable mechanical device that holds  the uterus in position. The pelvic fascia may be strengthened  through Kegel exercises (repetitive isometric tightening and  relaxing of the pubococcygeal muscles) or by estrogen therapy  in menopausal women. Maintaining a healthy body mass index  (BMI), preventing constipation, and treating chronic cough  may help as well. Surgical repair with or without hysterectomy  is the treatment of last resort. Women should be active partici-  pants in the decision-making surrounding treatment because  they need to balance expectations for improvement with poten-  tial side effects.”    FIGURE 24-11 Cystocele and Rectocele. A, Grade 2: anterior vaginal wall prolapse. B, Grade 2: posterior wall prolapse.  C, Photo showing cystocele (C) and rectocele (A). (A and B from Seidel H et al: Mosby's guide to physical examination, ed 4, St  Louis, 1999, Mosby. € from Seidel HM et al: Mosby guide to physical examination, ed 7, St Louis, 2011, Mosby.)    Figure 24-11 shows vaginal prolapse caused by cystocele  and rectocele. Cystocele is descent of a portion of the posterior  bladder wall and trigone into the vaginal canal and usually is  caused by the trauma of childbirth. In severe cases the bladder  and anterior vaginal wall bulge outside the introitus. Usually  symptoms are insignificant in mild to moderate cases. Increased  bulging and descent of the anterior vaginal wall and urethra  can be aggravated by vigorous activity, prolonged standing,  sneezing, coughing, or straining and can be relieved by rest or  assumption of a recumbent or prone position. If the prolapse is  large, women may complain of vaginal pressure. Occasionally a  cystocele causes significant residual urine and an increased rate  of bladder infections.   Medical management can include vaginal pessary, Kegel  exercises (prophylactic use produces the best outcome), and  estrogen therapy for postmenopausal women. Surgical correc-  tion is used for severe anatomic injury unresponsive to medical  treatment (see What’s New? Vaginal Mesh).   A rectocele is the bulging of the rectum and posterior vaginal  wall into the vaginal canal. During childbirth women may sus-  tain damage that can lead to a rectocele, but symptoms usually  do not occur until several years after menopause.* Familial and  genetic predisposition and bowel habits contribute to rectocele  development. Lifelong chronic constipation and straining may    Because pelvic organ prolapse is often a result of weakened pelvic fascia and  musculature, a surgical mesh was developed to improve pelvic support. This  mesh was designed to be placed surgically along the area needing support.  The goal was to have the woman's tissues grow through the mesh and provide  consistent, long-term support. However, women who received the surgical  mesh had a high rate of complications, including infection and persistent post-  operative pain. In many cases the mesh eroded through the tissue, protruding  into the vagina and perforating other organs. In addition, the mesh may shrink  over time causing vaginal shortening, tightening, and pain.   Some large studies have shown a benefit from mesh use for some women.  However, once implanted, the mesh is difficult to remove if not effective,  resulting in long-term pain and the need for intensive surgeries and repairs.  The U.S. Food and Drug Administration has issued several warnings about  the mesh to caution women and practitioners and encourage fully informed  consent about the risks and benefits of mesh placement.    Data from U.S. Food and Drug Administration: FDA safety communica-  tion: UPDATE on serious complications associated with transvaginal  placement of surgical mesh for pelvic organ prolapse, 2010. Available  at http:/www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm  262435.htm. Accessed January 21, 2013; Maher C et al: Cochrane  Database Syst Rev (4):CD004014, 2010.    produce or aggravate a rectocele. Although most rectoceles are  asymptomatic, larger ones cause vaginal pressure, rectal fullness,  and incomplete bowel evacuation. If rectoceles are severe, defe-  cation is difficult and can be facilitated by applying manual pres-  sure to the posterior vaginal wall. Medical treatment focuses on  the management and prevention of constipation and, if needed,  the use of a pessary. Rectocele alone (without associated entero-  cele, uterine prolapse, and cystocele) seldom requires surgery.”   An enterocele is herniation of the rectouterine pouch  into the rectovaginal septum (between the rectum and poste-  rior vaginal wall). It can be congenital or acquired. Congeni-  tal enterocele rarely causes symptoms or progresses in size.  Enteroceles also can result from a muscular weakness caused  by previous surgery, especially surgeries through the vagina,  or pelvic relaxation disorders, such as uterine prolapse, cysto-  cele, and rectocele. Most large enteroceles are found in grossly  obese and older adults and can be complicated by rupture or  complete eversion of the vagina with trophic ulceration, edema,  and fibrosis. Treatment is surgical. Box 24-11 summarizes the  symptoms and treatments of POP.   Benign cysts of the ovary may occur at any time during the life  span, but are most common during the reproductive years and,  in particular, at the extremes of those years (Figure 24-12). An  increase in benign ovarian cysts occurs when hormonal imbal-  ances are more common, around puberty and menopause.”    However, ovarian masses can occur during fetal development  and throughout childhood as well.”   Benign ovarian cysts are quite common and are the fourth  leading diagnosis for gynecologic hospital admissions.?? Two  common causes of benign ovarian enlargement in ovulating  women are follicular cysts and corpus luteum cysts. These cysts  are called functional cysts because they are caused by variations  of normal physiologic events. Follicular and corpus luteum cysts  are usually unilateral. They are typically 5 to 6 cm in diameter but  can grow as large as 8 to 10 cm. Most women are asymptomatic.   Benign cysts of the ovary are produced when a follicle or  a number of follicles are stimulated but no dominant follicle  develops and completes the maturity process. Every month  about 120 follicles are stimulated, but in most cycles only one  succeeds in ovulating a mature ova. Normally, during the early  follicular phase of the menstrual cycle, follicles of the ovary  respond to hormonal signals from the pituitary gland. The pitu-  itary produces FSH to mature follicles in the ovary. As the fol-  licles enlarge, granulosa cells in the follicle multiply and secrete  estradiol (a form of estrogen). As a dominant follicle develops,  it secretes higher levels of estradiol, which stimulates the LH  surge that comes from the pituitary. A small cyst on the ovary  during the follicular phase is normal. The LH surge stimulates  the follicle to rupture, releasing the ova and transforming the  granulosa cells of the dominant follicle into the corpus luteum.  If the dominant follicle develops properly before ovulation, the  corpus luteum becomes vascularized and secretes progesterone.  Progesterone arrests development of other follicles in both ova-  ries in that cycle. LH, proteolytic enzymes, and prostaglandins  trigger follicular rupture and release of the ovum.   Follicular cysts can be caused by a transient condition in  which the dominant follicle fails to rupture or one or more of the  nondominant follicles fail to regress. This disturbance is not well  understood. It may be that the hypothalamus does not receive or  send a message strong enough to increase FSH levels needed to  develop or mature a dominant follicle. The hypothalamus moni-  tors blood levels of estradiol and progesterone; when FSH is low,  estradiol does not increase enough to stimulate LH. Evidence  indicates that when progesterone is not being produced, the  hypothalamus releases GnRH to increase the FSH level.’° FSH  continues to stimulate follicles to mature, and the granulosa cells  grow and, presumably, estradiol increases. This abnormal cycle  continues to stimulate follicular size and causes follicular cysts    to develop. Clinical symptoms of follicular cysts or even a single  cyst are bloating, swollen and tender breasts, and heavy or irreg-  ular menses. After several subsequent cycles in which hormone  levels once again follow a regular cycle and progesterone levels  are restored, cysts usually are absorbed or regress.   Follicular cysts can vary in size and symptoms from one  episode to the next and often can recur. Most are fluid filled;  the more solid an ovarian cyst, the greater the chance of malig-  nancy. Follicular cysts can be treated with oral contraceptives  because they block the HPG axis, effectively quieting the ovary.   A corpus luteum cyst is normally formed by the granulosa  cells left behind after ovulation. This cyst is highly vascular-  ized but limited in size and spontaneously regresses as part of  the normal menstrual cycle. However, an abnormal or hemor-  rhagic cyst may develop because of a hormonal imbalance in  low LH and progesterone levels causing an inadequate develop-  ment of the corpus luteum. In some cases, however, large cysts  can rupture, causing hemorrhage.°?   Corpus luteum cysts are less common than follicular cysts,  but luteal cysts typically cause more symptoms, particularly  if they rupture. Manifestations include dull pelvic pain and  amenorrhea or delayed menstruation, followed by irregular or  heavier than usual bleeding. Rupture occasionally occurs and  can cause massive bleeding with excruciating pain; immediate  surgery may be required. Corpus luteum cysts usually regress  spontaneously in nonpregnant women. A corpus luteum cyst is  a normal finding within the first trimester of pregnancy as the  corpus luteum produces progesterone to support the pregnancy  until the placenta is established.?’ Following the development  of a large, painful, or hemorrhagic cyst, oral contraceptives can  be used to suppress ovarian function and prevent future cysts.   Dermoid cysts are ovarian teratomas that contain elements  of all three germ layers; they are common ovarian neoplasms.  These growths may contain mature tissue including skin, hair,  sebaceous and sweat glands, muscle fibers, cartilage, and bone.  Dermoid cysts are usually asymptomatic and are found inciden-  tally on pelvic examination. However, cysts should be carefully  evaluated for removal because they have malignant potential.”*   Torsion of the ovary is a rare complication of ovarian cysts  or tumors or enlargement of the ovary and can occur in girls  or women. If a cyst is large enough it can cause the ovary to  twist on its ligaments, pinching off blood supply to the ovary  and causing extreme pain. Ovarian torsion is rare but is a  gynecologic emergency. Individuals present with acute, severe  unilateral abdominal or pelvic pain. Ovarian torsion is treated  surgically.”    An endometrial polyp is a benign mass of endometrial tissue,  covered by a surface epithelium, and contains a variable amount  of glands, stroma, and blood vessels. Endometrial polyps can  occur anywhere within the uterus. Polyps are morphologically  diverse and usually classified as hyperplastic, atrophic (or inac-  tive), or functional. In the last case, the surface epithelium may  be “out of phase” with other endometrial tissue. Hyperplastic  polyps are often pedunculated and may be mistaken for endo-  metrial hyperplasia or, if large, adenosarcoma (Figure 24-13).    FIGURE 24-13 Uterine Polyps Visible Through Hysteroscopy. (From  Cheng C et al: J Minim Invasive Gynecol 16[6]:739-742, 2009.)    Although polyps most often develop in women between ages  40 and 50, they can occur at all ages. These are often related to  estrogen stimulation. As many as 35% of women with abnor-  mal uterine bleeding are found to have polyps.!°°   Endometrial polyps are a common cause of intermenstrual  or excessive menstrual bleeding. Diagnosis is made by transvag-  inal sonography or hysteroscopy. Risk factors include obesity,  tamoxifen use, hypertension, and estrogenic states (i.e., anovu-  latory cycles and unopposed estrogen). Malignancy is rare (up  to 4.7% of polyps have evidence of malignancy) and polyps that  cause abnormal bleeding have twice the rate of malignancy of  asymptomatic polyps.!°! Coexistence of a separate endometrial  atypical hyperplasia or adenocarcinoma is common. Uterine  polyps have a high rate of spontaneous resolution but have  been associated with suboptimal fertility.!°* Polypectomy can  be performed through hysteroscopy for symptomatic women,  for those at risk for malignancy, or women who are struggling  to conceive.   Leiomyomas, commonly called myomas or uterine fibroids,  are benign smooth muscle tumors in the myometrium (Figure  24-14). Leiomyomas are the most common benign tumors  of the uterus, affecting as many as 70% to 80% of all women,  and most remain small, asymptomatic, and clinically insig-  nificant.!°° Prevalence increases in women ages 30 to 50 but  decreases with menopause. The incidence of leiomyomas in  black and Asian women is two to five times higher than that in  white women.!°° Complications related to leiomyomas are the  number one reason for gynecologic hospitalizations.”   The cause of uterine leiomyomas is unknown, although their  size appears to be related to estrogen, progesterone, growth  factors, angiogenesis, and apoptosis. There is a genetic com-  ponent to fibroids, and the leiomyomas exhibit chromosomal    FIGURE 24-14 Etiology of Uterine Leiomyomas. Leiomyomas are heterogeneous in their natural history and etiology.  Hereditary defects in FH, BHD, and TSC2 genes and somatic alterations affecting H/GZA genes contribute to the development  of leiomyomas, as do risk factors such as obesity, parity, and race. Tumor growth occurs by an increase in tumor cell number and  extracellular matrix production and is promoted by both endocrine and autocrine growth factors. (From Walker CL, Stewart EA:    changes within their tissues.!°° Leiomyomas are estrogen- and  progesterone-sensitive and are found to have increased num-  bers of estrogen receptors.'°* Uterine leiomyomas are not seen  before menarche, and those that develop during the reproduc-  tive years generally decrease in size after menopause. Occur-  rence is multifactorial but often linked with estrogen exposure.  Tumors in pregnant women may enlarge rapidly but often  decrease in size after the end of the pregnancy. Risk factors for  fibroids include nulliparity, obesity, PCOS, diabetes mellitus,  black race, and hypertension.'   PATHOPHYSIOLOGY. Most leiomyomas occur in multiples in  the fundus of the uterus, although they may occur singly and  throughout the uterus. Leiomyomas are classified as subserous,  submucous, or intramural according to their location within  the various layers of the uterine wall (Figure 24-15). Uterine  leiomyomas are usually firm and surrounded by a connective  tissue layer. Unlike cancer, leiomyomas are unable to cause  blood vessel proliferation to support their growth. Degenera-  tion and necrosis may occur when a large leiomyoma outgrows  its blood supply; the ensuing tissue necrosis causes pain.   CLINICAL MANIFESTATIONS. The major clinical manifestations  of leiomyomas are abnormal uterine bleeding, pain, and symp-  toms related to pressure on nearby structures. Fibroids also may  contribute to infertility and subfertility. The leiomyoma may  distort the uterine cavity and increase the endometrial surface  area. This increase may account for the increased menstrual  bleeding that is associated with leiomyomas. Pain is not an early  symptom but tends to occur with the devascularization of larger  leiomyomas. It is also associated with blood vessel compression  that limits blood supply to adjacent structures. Symptoms of    abdominal pressure are slow to develop, apparently because the  tumor is relatively slow growing, enabling adjacent structures  to adapt to pressure. Pressure on the bladder may contribute to  urinary frequency, urgency, and dysuria. Pressure on the ureter  may cause it to become distended “upstream” from the pres-  sure point; rectosigmoid pressure may lead to constipation. A  sensation of abdominal or genital heaviness may be felt with  larger tumors.   EVALUATION AND TREATMENT. Uterine leiomyomas are suspected  when the bimanual examination discloses uterine enlargement  and irregular, nontender nodularity of the uterus. Pelvic sonog-  raphy or MRI confirms diagnosis.'°* Treatment depends on the  symptoms, tumor size, age, reproductive status, overall health  of the individual, and the woman’s preference.!°> Most myomas  are asymptomatic and can be managed by observation only.  Medical treatment for symptomatic women not desiring preg-  nancy is aimed at shrinking the myoma, or reducing symptoms,  or both. Some leiomyomas shrink in response to oral contra-  ceptives, however, oral contraceptive pills (OCPs) may enhance  growth, so should be monitored carefully. An LNG-IUD may  be helpful for women who wish to reduce their bleeding and  decrease the size of the tumors, if their uterine cavity is not  completely blocked by large fibroids. GnRH agonists are usually  a temporary management for those close to menopause or as a  presurgical treatment. GnRH side effects related to decreased  estrogen, including hot flashes and osteoporosis, limit its use-  fulness. Various selective estrogen receptor modulators have  been studied in conjunction with GnRH agonists and appear  effective.!°° Progesterone receptor agonists, such as mifepris-  tone (RU486), also have shown some effectiveness in shrinking    FIGURE 24-15 Leiomyomas. A, Uterine section showing whorl-like appear-  ance and locations of leiomyomas, which are also called uterine fibroids. B,  Multiple leiomyomas in sagittal section. Typical, well-circumscribed, solid, light  gray nodules distort uterus. (B from Damjanov |, Linder J: Pathology: a color atlas,  St Louis, 2000, Mosby.)    leiomyomas. Surgical treatments are commonly used but may  be decreasing in frequency. Hysterectomy is commonly per-  formed for bleeding and pain related to fibroids. Myomec-  tomy, or removal of the fibroid from the muscle of the uterus,  may be less invasive than a full hysterectomy and remains the  standard of cure for women wishing to preserve their fertil-  ity. Newer less-invasive treatments that show promise include  uterine artery embolization, mifepristone, and MRI-guided  ultrasonography to coagulate areas of the fibroid, causing tis-  sue destruction and involution. The benefits and risks of each  therapy should be carefully explored with women who experi-  ence severe symptoms.!°°    Adenomyosis is the presence of islands of endometrial glands  surrounded by benign endometrial stroma within the uterine    myometrium. Endometrial cells migrate into the myometrial  layer because of an unknown mechanism. Estrogen and proges-  terone likely play a role and, perhaps, metaplasia of miillerian tis-  sue. Unlike endometriosis, this tissue does not respond to cyclic  hormone changes. It is more commonly found during the late  reproductive years; however, because adenomyosis is generally  diagnosed after hysterectomy, time of diagnosis may not cor-  respond with incidence. Adenomyosis has been found in up to  48% of hysterectomy specimens from otherwise normal women;  rates are higher for women taking tamoxifen.!* Parity also  increases the risk for adenomyosis. Adenomyosis may be asymp-  tomatic or may be associated with abnormal menstrual bleeding,  dysmenorrhea, uterine enlargement, and uterine tenderness dur-  ing menstruation. Secondary dysmenorrhea becomes increas-  ingly severe as disease progresses. On bimanual examination the  uterus is diffusely enlarged, globular, and most tender just before  or after menstruation. Diagnosis is confirmed with ultrasound  or MRI.!°° Treatment is symptomatic, similar to dysmenorrhea  (i.e., NSAIDs, combined oral contraceptives [COCs], and per-  haps LNG-IUDs). Surgical treatment includes resection of local-  ized areas of adenomyosis (though this is difficult) or, if severe,  hysterectomy. Uterine artery embolization and LNG-IUDs have  shown good initial results but need further testing.!07!%    Endometriosis is the presence of functioning endometrial tis-  sue or implants outside the uterus. Like normal endometrial  tissue, the ectopic (out of place) endometrium responds to the  hormonal fluctuations of the menstrual cycle.   The incidence of endometriosis is difficult to determine,  particularly in asymptomatic adolescent and fertile women. It  is estimated that 11% of reproductive-age women have endo-  metriosis, though for most it is mild.!°° In addition, as many as  50% of women evaluated for pelvic pain, infertility, or a pelvic  mass are diagnosed as having endometriosis. Moreover, the fre-  quency and severity of symptoms do not correlate well with the  extent or site of lesions.'°’ A large study has found that women  with endometriosis are at greater risk for cancers, especially  ovarian cancer.!!°   The cause of endometriosis is not known, but several the-  ories have been proposed. In 1927 Sampson!!! proposed that  endometriosis is caused by the implantation of endometrial  cells during retrograde menstruation, in which menstrual flu-  ids move through the fallopian tubes and into the pelvic cavity  (Figure 24-16). It is now known that retrograde menstruation  occurs in almost all women; however, not all women develop  endometriosis.   Another theory is that women with endometriosis have  impaired cellular and humoral immunity. Alterations in  cytokine and growth factor signaling have been identified.  Cytotoxic T-cell and natural killer (NK) cell activity has been  found to be depressed. At the same time, increased numbers  of macrophages appear to be stimulating endometrial cell pro-  liferation outside the uterus. An autoimmune response is also  suspected.'!* Such alterations may cause the body to tolerate  ectopic implantation of endometrial cells. Researchers also have  proposed that endometrial cells spread through the lymphatic    FIGURE 24-16 Endometriosis. The uterus is distended, and retrograde spill of  menstrual loss has led to the development of endometriosis (dark purple patches).  (From Symonds EM, Macpherson MBA: Color atlas of obstetrics and gynecology,  London, 1994, Mosby-Wolfe.)    or vascular systems or that multipotential cells in the epithe-  lial coverings of reproductive organs are somehow stimulated  to develop into endometrial and metaplastic cells. A genetic  predisposition to endometriosis has been documented. Some  genetic polymorphisms have been identified.   PATHOPHYSIOLOGY. Endometrial implants can occur through-  out the body but generally occur in the pelvic and abdominal  cavities. The most common sites of implantation are the ovaries,  uterine ligaments, rectovaginal septum, and pelvic peritoneum  (Figure 24-17). Other sites of implantation are the sigmoid  colon, small intestine, rectum, appendix, bladder, uterus, vulva,  vagina, cervix, lymph nodes, extremities, pleural cavity, lungs,  laparotomy scars, and hernial sacs.   Cyclic changes depend on the blood supply of the implants  and the presence of glandular and stromal cells. Given that  blood supply is sufficient, the ectopic endometrium prolifer-  ates, breaks down, and bleeds with the normal menstrual cycle.  The bleeding causes inflammation, triggering a cascade of cel-  lular inflammatory mediators, including cytokines, chemo-  kines, growth factors, and protective factors such as secretory  leukocyte protease inhibitor and superoxide dismutase.'!* The  inflammation may lead to fibrosis, scarring, adhesions, and  pain.   CLINICAL MANIFESTATIONS. The clinical manifestations of endo-  metriosis can mimic other disease processes (i.e., PID, irri-  table bowel syndrome, ovarian cysts). Symptoms are variable  in frequency and severity and include primarily infertility and  pain,!'? dysmenorrhea, dyschezia (pain on defecation), dyspa-  reunia (pain on intercourse), and, less commonly, constipation  and abnormal vaginal bleeding. If implants are located within  the pelvis they can cause an asymptomatic pelvic mass having  irregular, movable nodules and a fixed, retroverted uterus. Most  symptoms of endometriosis can be explained by the prolifera-  tion, breakdown, and bleeding of the ectopic endometrial tis-  sue with subsequent formation of adhesions. In most instances,  however, the degree of endometriosis is not related to the fre-  quency or severity of symptoms.!°’ Dysmenorrhea, for example,  does not appear to be related to the degree of endometriosis.    With involvement of the rectovaginal septum or the uterosacral  ligaments, dyspareunia develops. Dyschezia occurs with bleed-  ing of ectopic endometrium in the rectosigmoid musculature  and subsequent fibrosis.   Twenty-five percent to 40% of women with infertility have  endometriosis. The link between endometriosis and infertil-  ity is strong, yet the degree of disease and infertility is not as  closely associated. That is, women with untreated minimal to  mild disease may have high pregnancy rates or may experience  infertility.'!* The exact mechanism for infertility in women with  endometriosis is unknown. Infertility may result from mechan-  ical interference with ovulation or ovum transport through the  fallopian tube because of adhesions and the effects of inflamma-  tion and cytokine activity. However, the infertility also could be  a result of the underlying autoimmune disorder that caused the  endometriosis.''* There are conflicting reports regarding the  effect of endometriosis on sperm activity. An increased phago-  cytosis of spermatozoa by macrophages has been observed. The  uterine endometrium in women with endometriosis appears  to have an overactive response to estrogen and an underactive  response to progesterone, impairing the endometrial receptiv-  ity to blastocyst implantation, decreasing the chance of success-  ful pregnancy.!!°   EVALUATION AND TREATMENT. A presumptive diagnosis can  be made based on clinical manifestations but laparoscopy is  required for definitive diagnosis of endometriosis. A uniform  classification system that includes both extent and severity has  been developed (Table 24-4) but still does not correlate well  with a woman’s symptoms. Treatment is aimed at preventing  or decreasing progression and spread, alleviating pain, and  restoring fertility. Current therapies include suppression of  ovulation with noncyclic estrogen-progestin COCs, depome-  droxyprogesterone acetate (DMPA), danazol (which dimin-  ishes midcycle LH surge), GnRH agonists/analogs (to block  the menstrual cycle), gestrinone (a 19-nortestosterone deriva-  tive and antiprogestational steroid), mifepristone (RU486) (an    Data from Fertil Steril 67(5):817-821, 1997.  Classification system also documents the location of lesions and pres-  ence of adhesions.    antiprogestational and antiglucocorticoid agent that can inhibit  ovulation and disrupt endometrial integrity), and atrophy of  endometrium with progestins, including DMPA, oral proges-  tins, or an LNG-IUD.!!*!'4 A newer therapy is an injectable  GnRH antagonist, which produces immediate inhibition of  gonadotropin release but does not have substantially improved  success rates when compared with other therapies.!!° Conserva-  tive surgical treatment includes laparoscopic removal of endo-  metrial implants with conventional or laser techniques and  presacral neurectomy for severe dysmenorrhea. Effectiveness  may be increased when medical regimens are combined with  surgical techniques. All treatments have risks or side effects, and  recurrent symptoms develop in the majority of women within  a few years, even with surgical treatments. Women should be  fully informed about all options and carefully weigh the risk-to-  benefit ratio of nonreversible treatments.!'*    Malignant tumors of the female reproductive system are com-  mon. Cancers of the female reproductive tract can often grow  large before causing pain because the pelvis and abdomen are  poorly innervated and designed to accommodate a growing  fetus. Reproductive tract cancers are more likely to be diag-  nosed early if there are symptoms. Uterine cancer is the fourth  leading cancer diagnosis in women but is only the eighth lead-  ing cause of death in part because symptoms of vaginal bleeding  prompt women to seek treatment. Ovarian cancer, on the other  hand occurs less frequently, at 3% of total cancer diagnoses  in women, but is the fifth leading cause of death from cancer  related to its lack of symptoms and difficult detection.' Cervi-  cal cancer also has minimal symptoms until late in the process,  but is easy to detect early with Pap smears. Three percent of  cancers in women begin in the cervix but the death rate from  cervical cancer has plummeted since the advent of screening  techniques.!    Cancer of the cervix is the leading cancer-related death in most  of Africa, Central America, and South-Central Asia; however, it  has a lower prevalence in the United States.':'!° In the United  States, the rates of invasive cancer have steadily decreased (a  75% reduction since the 1960s) and mortality rates caused  by cervical cancer have declined (more than 45% since the  early 1970s) largely because of the increased prevalence and    frequency of cervical cancer screening with the Pap smear. In  2013, the American Cancer Society estimated 12,340 new cases  of cervical invasive cancer and 4030 cervical cancer deaths.!   PATHOGENESIS. It is established that cervical cancer is almost  exclusively caused by cervical human papillomavirus (HPV)  infection. Infection with “high-risk” (oncogenic) types of HPV  (predominantly 16 and 18) is a necessary precursor to develop-  ment of the precancerous cell changes, known as dysplasia, of  the cervix that leads to invasive cancer (also see Chapter 12).  Precancerous dysplasia, also called cervical intraepithelial car-  cinoma (CIN) and cervical carcinoma in situ (CIS), is a more  advanced form of the cell changes. Luckily, these cell changes  can be detected noninvasively through examination of the cer-  vical cells. The cells can be destroyed to prevent cancer develop-  ment if dysplasia can be detected early.   Fifty percent of adolescents and young women acquire HPV  (predominantly high-risk types) within 3 years of initiation of  sexual intercourse, and it is estimated that 8.8% of all women  ages 14 to 59 have persistent infection with high-risk HPV  strains!!” (also see Chapter 26). Young women are especially  vulnerable to HPV because of their cervical anatomy. There  are two main cell types of the cervix: squamous epithelium  cells and columnar epithelial cells. Squamous epithelial cells  in older women cover the portions of the cervix that protrude  into the vagina, and columnar epithelial cells line the inner por-  tions of the cervical canal. The line where the two cells types  meet, known as the transformation zone, is very vulnerable to  the oncogenic effects of HPV. The location of the transforma-  tion zone changes as girls and women age and in response to  estrogen and vaginal pH changes. In girls and young women a  large portion of their cervix is covered with columnar epithe-  lium, a condition known as squamous metaplasia.'!® As women  age, the transformation zone moves as the squamous epithe-  lium covers the surface of the cervix. Therefore, the younger a  woman is when she contacts HPV, the more sensitive cervical  cells are exposed. This is one reason vaccinations against HPV  are aimed at women prior to the initiation of sexual activity.'!*   Most HPV infections are cleared by the immune system; the  vast majority of infections do not cause cervical cancer. For this  reason, screening for cervical cancer prior to age 21 is not rec-  ommended. Previous efforts at early screening resulted in many  young women receiving treatments on their cervix. These treat-  ments destroyed or removed cervical cells and in many cases  altered the structural integrity of the cervix, resulting in an  increase in preterm births in women treated without substan-  tially decreasing the later rates of cervical cancer.!!”   It is unknown why some women are able to clear HPV infec-  tion and others cannot. Smoking has been shown to increase  the risks of persistent infection and later development of cer-  vical cancer.'*? In addition, certain gene polymorphisms on  the genes that control epidermal growth factor increase the  risk that HPV infection will lead to invasive cancer.'*! Any-  thing that affects the integrity of the immune system may affect  the later risk of cervical cancer including poor nutrition and  chronic stress.!*? HIV infection greatly increases the risk that  women infected with HPV will develop cervical cancer, and  women with HIV should be screened for cervical cancer more    where the columnar (grapelike) epithelium is replaced by metaplastic epithelium.  At its outer edge the metaplastic epithelium adjoins the squamous epithelium,  which extends into the vagina. (From Coppleson M, Pixley E, Reid B: Colposcopy:  a scientific approach to the cervix in health and disease, Springfield, IL, 1971,  Charles C Thomas.)    frequently than women without HIV.!”* In addition, infection  with Chlamydia trachomatis has been correlated with later risk  for cancer.!?° It is hoped that the widespread use of the HPV  vaccine in boys and girls will decrease rates of invasive cervical,  genital, and anal cancers over the next several decades.'**   Carcinoma in situ is most likely to develop in the squamous-  columnar junction—the transformation zone—where the  columnar epithelium of the cervical lining meets the squamous  epithelium of the outer cervix and vagina (Figure 24-18). In  this zone, columnar epithelium is constantly being replaced by  squamous epithelium in a process known as metaplasia. Meta-  plasia is thought to be affected by hormonal levels; change in  cervical epithelium is not understood as well as endometrial  tissue change in response to fluctuating hormones. Because  metaplastic cells are at increased risk of incorporating foreign  or abnormal genetic material, neoplastic changes are most com-  mon in the transformation zone.   Many chromosomes may contain genes that relate to HPV-  linked cervical cancer.'*° Like other cancers, cervical cancer  requires the accumulation of genetic alterations for carcino-  genesis to occur. However, the discrete tumor-suppressor gene  locations have yet to be identified.!?° Several chromosome  regions with recurrent loss of heterozygosity (LOH) have been  identified (also see Chapter 12). In addition, other genes may  influence a woman’s receptivity to HPV.'?! For instance, HPV    The problem with the use of the conventional Papanicolaou (Pap) smear in  screening for cervical cancer is the low sensitivity of the test, which ranges  between 44% and 77%. This means that a large number of cervical abnormali-  ties (23% to 56%) can be missed with a single test! Thus the success of Pap  smear screening in reducing cervical cancer in the United States lies in the  frequency of screenings and that cervical cancer is a slowly progressive condi-  tion. However, a high frequency of Pap smear screenings is often not feasible,  either economically, socially, culturally, or logistically, in many countries and  in some regions leads to much higher rates of invasive cervical cancer for  women in such populations or locales. Multiple, large, well-conducted studies  have demonstrated that human papillomavirus (HPV) testing is considerably  more sensitive (between 97% and 98%) than either conventional or liquid-  based Pap testing. HPV infection is known to be the required precursor to  cervical cancer. With sensitive HPV tests now widely available, requiring less  frequent screening (every 3 to 5 years), the future of cervical cancer screening  may rely on HPV screening, not on conventional cervical cytology testing.   In settings where there is not even adequate infrastructure for HPV testing,  several studies have shown that simple visualization with acetic acid (VIA) can  be used to diagnosis women with HPV infection and then immediately provide  onsite cryotherapy to reduce rates of later cervical cancer. Although not ideal,  this approach shows promise in low-resources settings, especially when the  baseline rate of HIV infection is high, because it allows women to be screened  and treated on the same visit.    Data from Hoppenot C, Stampler K, Dunton C: Obstet Gynecol! Surv  67(10):658-667, 2012.    may up-regulate the E6 oncoprotein in certain gene sequences,  causing a greater production of vascular epidermal growth fac-  tor, which allows the tumor to promote blood vessel growth  toward the proliferating cells, fueling growth.!7!)17°   CLINICAL MANIFESTATIONS. Cervical neoplasms are predomi-  nantly asymptomatic; therefore, regular Pap test or HPV screen-  ing is necessary for early detection (see Chapter 26 for screening  frequency guidelines). About 90% of cervical cancer cases can be  detected through early use of regular screening tests (see What’s  New? Cervical Cancer Screening in the Developing World). If  symptoms exist, they may include vaginal bleeding or abnormal  discharge. Bleeding is variable and may occur after intercourse  or between menstrual periods. Vaginal discharge is a less com-  mon presenting symptom and may be serosanguineous or yel-  lowish with a foul odor. Bleeding and discharge are subtle and  are likely to be disregarded by premenopausal women. Post-  menopausal women are more likely to seek medical attention if  these signs appear. Advanced disease may cause urinary or rectal  symptoms and pelvic or back pain along with anemia.   EVALUATION AND TREATMENT. Women should be screened for  cervical cancer and risk for future cervical cancer through Pap  smear and HPV testing.'?” HPV testing is now recommended  at the same time as the Pap smear because it is noninvasive and  identifies women at later risk for cellular abnormalities leading  to cancer. HPV is often detectable for more than a decade prior  to any noticed cellular changes.!*’   A Pap smear involves noninvasively taking a cell sample from  the surface of the cervix during a pelvic examination using a    Suggestive of but do not meet criteria for  LSIL (mild dysplasia)   Atypical squamous cells— Do not meet criteria for HSIL but do not  cannot exclude HSIL preclude HSIL (potentially CIN I/II;  (ASC-H) moderate to severe dysplasia)    CIN, Cervical intraepithelial neoplasia; C/S, carcinoma in situ; HS/L,  high-grade squamous intraepithelial lesion; LS/L, low-grade squamous  intraepithelial lesion.    speculum to allow for visualization of the cervix. Cervical cytol-  ogy is most accurate if cells are obtained from both the endo-  and ectocervix, which involves placing the collection device (a  small brush or broom) into the cervical os. These cells are then  sent to a laboratory for analysis. When dysplasia is detected,  further testing is indicated for diagnosis. Colposcopy involves  examining the cervix visually and taking needed biopsies. An  acetic acid (vinegar) solution is applied to the cervix, making  areas of HPV infection stand out in a white color, known as  aceto-white. The cervix is then viewed under magnification for  aceto-white areas, changes in the epithelium, and the presence  of abnormal vascular patterns.!*° Abnormal areas of the cer-  vix are biopsied. Because the vulnerable transformation zones  move into the cervical canal as a woman ages, the endocervix is  sampled using curettage for diagnosis (Table 24-5).   The progressive neoplastic changes of cervical cells are clas-  sified on a continuum from cervical intraepithelial neoplasia  (dysplasia), to cervical carcinoma in situ (full epithelial thick-  ness of the cervix is involved), to invasive carcinoma (see Tables  23-5 and 23-6). Various terms are used to describe the cellu-  lar changes in the cervix based on how the cells were obtained.  Screening for cervical cancer is done with a Pap smear, and  the cytology report describes Pap smear findings; these terms  are outlined on the left side of Table 23-5. If a Pap smear has  abnormal findings, a biopsy of the affected tissue is taken dur-  ing a colposcopy. The biopsy reveals the actual extent of the  lesion within the cervix. Terminology used in pathology reports  is listed on the right side of Table 23-5. Pathology reports that  involve cancer changes begin with the abbreviation CIN or CIS.   Cervical dysplasia is replacement of some epithelial cells  by atypical neoplastic cells, and is “staged” depending on the  depth of epithelial involvement (Figure 24-19). Risk of pro-  gression to invasive carcinoma rises steadily with the severity  of dysplasia; however, women with intact immune systems are  likely to resolve dysplasia on their own. More than half (57%) of  HIV-infected women with CIN 1, 42% of women with CIN 2,  and 32% of women with CIN 3 have a natural “regression”    of lesions. At least a third or more of all cervical intraepithe-  lial lesions persist without progression or regression. Women  with CIN 1 (low-grade squamous intraepithelial lesion [LSIL]  or mild dysplasia) have an 11% chance of progression to CIS  and a 1% chance of progression to cervical invasion. Women  with CIN 2 have a 22% chance of progression to CIS and a 5%  chance of invasive lesions. In cervical CIN 3 or HSIL (high-  grade squamous intraepithelial lesion), all or most of the cervi-  cal epithelium shows cellular features of carcinoma; however,  underlying tissue is not affected. At least 12% of women with  CIN 3 (CIS) progress to cervical invasion.   CIS is generally a precursor of invasive carcinoma of the  cervix. A number of factors, including tumor type, contribute  to the rate at which CIS becomes invasive. Because of the ease  of Pap smear screening, invasive cervical cancer is rare within  the United States, but much more common in the developing  world, where screening is not available. Invasive carcinoma of  the cervix consists of cancer invasion into adjacent tissues and  metastasis. Adjacent tissues most often involved are the ureters  and structures of the lateral pelvic wall, the vaginal stroma and  epithelium, and the lower uterine segment and myometrium.  The internal, external, and common iliac lymph nodes and the  obturator nodes are common sites of lymphatic involvement.  Invasive cervical cancer is most often discovered through Pap  smears, tentatively diagnosed with a biopsy during a colposcopy,  and then further diagnosed using surgery and lymphangiogra-  phy, CT scan, MRI, ultrasonography, or radioimmunodetec-  tion methods. The staging system for carcinoma of the cervix is  shown in Table 24-6.   Treatment depends on the degree of neoplastic change, the  size and location of the lesion, and the extent of metastatic  spread. For premalignant cellular changes and CIS, the goal is to  kill or remove abnormal cells; these procedures can be done in  a clinic with local anesthetic. Invasive carcinoma requires sur-  gery, including removal of the cervix and other affected tissues.   Common treatments can be classified as ablative, when the  cells are killed without being removed, or excisional in which  the abnormal cells are physically removed from the cervix.  Ablative therapies are appropriate for lower levels of cervical  dysplasia because the treatment does not produce a sample for  analysis. However, ablative therapies leave the cervix intact,  which may be beneficial for later childbearing. Ablative surger-  ies include cryotherapy and cold coagulation in which extreme  cold is applied to the surface of the cervix. Carbon dioxide laser  and electrocoagulation also are used to kill abnormal cells and  coagulate vessels supporting their growth. Excisional therapies  are appropriate if a more advanced lesion is suspected because  they produce tissue for analysis. Excisional therapies include  conization, in which a cone-shaped portion of the cervix is  removed, and the loop electrosurgical excision procedure  (LEEP), in which a small looped wire with electric current gen-  erates heat and burns off cancer cells. Heat, cold, or lasers are  used in excisional procedures to simultaneously excise the tis-  sue and obliterate abnormal blood vessels.   For invasive cervical carcinoma, treatment depends on the  stage of the tumor. Surgical intervention may include a hysterec-  tomy, pelvic lymphadenectomy, or pelvic exenteration (radical    FIGURE 24-19 Cervical Intraepithelial Neoplasia (CIN). A, Diagram of cervical endothelium showing progressive  degrees of CIN. B, Normal multiparous cervix. €, CIN stage 1. Note the white appearance of part of the anterior lip of the  cervix associated with neoplastic changes. D, CIN stage 2. Lesions reflected in distant capillaries. E, CIN stage 3. Lesion pre-  dominantly around the external os. (A from Herbst AL et al: Comprehensive gynecology, ed 2, St Louis, 1992, Mosby. B-E from    Symonds EM, Macpherson MBA: Color atlas of obstetrics and gynecology, London, 1994, Mosby-Wolfe.)    removal of contents of body cavity). Multidrug chemotherapy  regimens also have been used alone or in combination with radi-  ation.'*? Smokers tend to have a higher stage of disease at diag-  nosis, and their cancer is more resistant to radiation treatment.  With early detection and treatment, prognosis is excellent.  Overall, the 5-year survival rate is 95% for stage IA or lower  (e.g., early detection). A cure rate of 100% is possible for women    with dysplasia or CIS.' The prevention of HPV infection may  be the key to substantially reducing the risk of cervical cancer.  FDA-approved vaccines for two of the high-risk types of HPV  show excellent promise, and studies are underway to quantify  their benefit; however, it may take 10 to 20 years to see the full  effect of widespread vaccination due to the slow progression of  cervical cancer, !?4!°0    Cancer in situ, intraepithelial carcinoma; earliest stage  of cancer; cancer confined to its original site   Earliest form of stage |; there is very small amount of  cancer, which is visible only under a microscope   Area of invasion is <3 mm (about % inch) deep and <7  mm (about 4 inch) wide   Area of invasion is between 3 and 5 mm (about 14 inch)  deep, and <7 mm (about % inch) wide   Includes cancers that can be seen without a microscope;  also includes cancers seen only with a microscope  that have spread deeper than 5 mm (about ¥% inch)  into connective tissue of the cervix or are wider than  7mm   IB cancer that is no larger than 4 cm (about 1/4 inches)   Cancer has spread to the tissue next to the cervix, called   Cancer has spread to the lower part of the vagina or the   Cancer has spread to the lower third of the vagina but  not to the pelvic wall   Cancer extends to the pelvic wall, blocks urine flow to  the bladder, or both   Most advanced stage of cervical cancer; cancer has  spread to other parts of the body   Cancer has spread to the bladder or rectum, which are  organs close to the cervix   Cancer has spread to distant organs beyond the pelvic  area, such as the lungs    Reprinted from the American Cancer Society's Cancer Information  Database with permission.    Cancer of the vagina is the rarest of the female genital can-  cers and accounts for less than 2% of gynecologic cancers.!+!  Vaginal and cervical cancers are thought to have similar epide-  miology. Both start as intraepithelial lesions, occur in sexually  active women, and are associated with HPV infection. Prior  carcinoma of the cervix places a woman at higher risk for  developing vaginal cancer.'*” In utero exposure to nonsteroi-  dal estrogens is a risk factor. It has been estimated that 100,000  to 160,000 women were exposed in utero to such nonsteroi-  dal estrogens as DES, dienestrol, or hexestrol from 1960 to  1971.!°> Exposure to such hormones during the first 3 months    of gestation inhibits the normal replacement of columnar epi-  thelium by squamous epithelium in the vagina of the fetus.  The columnar epithelium, which is not normally found in the  vagina, may then undergo malignant transformation. Not all  women exposed to DES in utero develop neoplastic changes in  the vagina, however.!°?   Vaginal cancer is usually diagnosed in women in their 60s  and 70s but the cellular changes begin many years prior to  clinically visible signs of the disease.'?'! The most common type  of vaginal cancer is squamous cell carcinoma. About 90% of  tumors are squamous cell-type cancers; the remaining 10%  are adenocarcinomas, sarcomas (rare), and melanomas (rare).  Nonsquamous types of cancer are more common in younger  women. Vaginal sarcomas can develop in children younger  than 5 years and adenocarcinomas are the most common in  women less than 30 years old.!>!   Vaginal cancer is generally asymptomatic until fairly late  in the disease process. The major symptom of invasive cancer  is vaginal bleeding or bloody discharge. Other symptoms can  include vaginal discharge, vulvar pruritus, rectal or bladder  symptoms, pain, or leg edema.   Several mechanisms can be used to diagnose vaginal cancer  including Pap testing of abnormal vaginal skin, colposcopy, and  biopsy. Once a diagnosis of cancer is established, size and extent  of the lesion are determined using MRI, prior to surgery.!*! Like  cervical neoplasms, vaginal cancers are classified as intraepithe-  lial neoplasia (dysplasia), CIS, or invasive carcinoma and are  staged based on extension into local tissues and metastasis to  distant organs. Treatment depends on the type and extent of the  cancer and the overall health and expectations of the woman.!*!  Potential treatment modalities include removal of the affected  tissues (vagina, uterus, bladder, and rectum), excision of lymph  nodes, radiation, and chemotherapy. Many women with inva-  sive vaginal cancer develop recurrent pelvic cancer and need  intensive monitoring for recurrence. Recurrence and survival  rates vary greatly by the type and extent of cancer and the  aggressiveness of the treatment regimen.!*!    Cancer of the vulva is responsible for about 3% to 5% of all  gynecologic cancers; however, there has been a steady increase  in the incidence of vulvar cancers over the last 30 years. The  majority (90%) are squamous cell carcinomas, although mela-  noma (5%), Bartholin gland carcinoma (2%), sarcoma (2%),  and adenosquamous carcinoma (1%) may occur. A history of  HPV infection is a risk factor with 40% of lesions related to  infection with HPV subtype 16.'** Previous squamous dysplasia  of the vagina or cervix also is a major risk factor, as are smoking  and HIV infections.!°? Although it usually affects postmeno-  pausal women (median age of presentation is women in their  60s), vulvar cancer has been diagnosed in women between ages  30 and 90.!54!9° Usually women have a history of vulvar irrita-  tion and pruritus (70%); urinary symptoms and discharge are  less common. In addition, there may be a hard ulcerated area of  the vulva, large cauliflower lesions, or lesions similar to those  of chronic dermatitis. Biopsy confirms the diagnosis. Treat-  ment options include primarily ablative or excisional surgery,    FIGURE 24-20 Endometrial Cancer. Overview of the contribution of obesity  to endometrial cancer progression and preventive strategies. (From Schmandt RE  et al: Am J Obstet Gynecol 205[6]:518-525, 2011.)    and sometimes radiation with or without chemotherapy. Less  extensive removal of vulvar tissue is being studied to decrease  postsurgical morbidity and maintain function.'°° Progno-  sis depends on lesion size and location, histology, and lymph  involvement; risk of metastasis increases with tumor size. The  5-year survival rate depends on the extent of the lesion, the  treatment, and the overall health of the woman. Cancer caught  in the early stages has a greater than 90% 5-year survival rate  with progressively poorer prognosis with advancing stages.!°°    Endometrial carcinomas arise within the glandular epithe-  lium of the uterine lining. Estimates include 49,560 new cases  in 2013, with approximately 8190 deaths.! Most cases occur in  postmenopausal women (Figure 24-20), with peak incidence  occurring in the late 50s to early 60s.!°7 Women have a 3%  lifetime risk of developing uterine cancer. Although incidence  rates are higher in white than in black women, mortality rates  in black women are nearly twice as high. The primary risk factor  is prolonged exposure to estrogen without the presence of pro-  gesterone. Estrogen causes endometrial proliferation, whereas  progesterone changes the uterine lining to limit proliferation  and encourage normal shedding. Estrogen without the pres-  ence of progesterone is known as unopposed estrogen because its  proliferating effects are not restrained. Exposure to unopposed  estrogen includes estrogen-only hormone replacement ther-  apy, tamoxifen, early menarche, late menopause, never having  children, and a failure to ovulate (i.e., PCOS and anovulatory  cycles typical of the late reproductive years). Obesity also is a  known source of endogenous estrogen and is a risk factor for  endometrial cancer (see Figure 24-20).!** Other risk factors not  directly related to estrogen include diabetes, gallbladder disease,  and hypertension, though obesity may be a mediating factor for  these risks. A family history of colon, endometrial, or ovarian  cancer could signal hereditary nonpolyposis colorectal cancer  (HNPCC); women with this family history may wish to explore  genetic testing and more aggressive screening. !*?   Although estrogen and obesity increase the risk of endome-  trial cancer, several interventions have been shown to decrease  the risk of cancer. A review of modifiable risk factors and pre-  vention for endometrial hyperplasia and cancer indicates that    controlling obesity, hypertension, and diabetes may reduce an  individual’s risk of endometrial cancer.'4? Exposure to pro-  gesterone also decreases the risk of endometrial cancer both  immediately and long term. Large amounts of progesterone are  released during pregnancy. Smaller, but still effective, amounts  of progesterone are in OCPs and the progestin-containing IUD.  The use of birth control pills can decrease the risk of endome-  trial cancer by 80% even for more than a decade after use.'4!  The progestin-containing IUD is used to prevent endometrial  abnormalities in women who need to take tamoxifen as part of  breast cancer prevention. |“?   About 75% of endometrial cancers are adenocarcinomas.  Abnormal vaginal bleeding is the most common clinical mani-  festation of endometrial cancer. The bleeding is caused by dis-  ruption of the endometrial surface by neoplastic processes. Pain  and weight loss are symptoms of late disease.   Screening methods for early detection of endometrial cancer  are as effective as those for cervical cancer. Pap tests, which are  highly effective in detecting cervical dysplasia, are ineffective in  detecting early endometrial cancer. Transvaginal ultrasound  (TVUS) may be used to measure endometrial thickness and  screen postmenopausal and high-risk premenopausal women. If  the endometrium is abnormally thick (defined as >5 mm), then  further testing, such as endometrial biopsy, is warranted to rule  out cancer, especially in high-risk women.!** Endometrial biop-  sies can be performed in a normal clinic with minimal additional  equipment. The biopsy involves placement of a small thin tube  through the cervix to collect a specimen of the endometrium for  analysis.!*! Once cancer is confirmed by biopsy, a laparoscopy  and MRI may be performed to determine stage of disease.   Uterine cancers can be divided into two types by histology.  Type I tumors are by far the most common and result from  estrogen exposure leading to endometrial hyperplasia. Type  II cancers make up 10% of endometrial cancers but are more  likely to be invasive into the uterine muscle and metastasize  beyond their original location resulting in a much greater risk  for death.'“4 Treatment is based on the cancer type and the  extent of the disease. For women with simple hyperplasia, pro-  gestin therapy (orally or through LNG-IUD) may often suffice.  However, treatment for atypical hyperplasia or invasive disease  usually includes surgical intervention, such as curettage for  carcinoma in situ, total abdominal hysterectomy with bilateral  salpingo-oophorectomy, and lymphadenectomy.!*! Chemo-  therapy and radiation also may be used. The 1-year relative  survival rate for endometrial cancer is 92%; the 5-year relative  survival rate is 95% with early diagnosis and 16% if diagno-  sis occurred in the late stage. Survival rates for white women  exceed those for black women by 8% at every stage.!   Uterine sarcomas are rare neoplasms that arise from mes-  enchymal tissues of and near the uterus, including myometrial  smooth muscle, endometrial stroma, or adjacent connec-  tive tissues. Uterine sarcomas are rare, constituting up to 3%  of all genital tract cancers and 3% to 5% of all uterine malig-  nancies. The average age at diagnosis is the early 50s, though  some sarcomas can form in childhood. Uterine sarcomas can  be divided into endometrial stromal sarcoma, leiomyosarcoma,  and adenosarcoma based on the involved tissue types. The    FIGURE 24-21 Migration of epithelial cells from the fallopian/uterine tubes to the ovary. (Adapted from Kurman RJ,    very low occurrence and diversity of cellular composition of  these tumors explains the lack of epidemiologic and treatment  data.'*° Thus relatively few risk factors have been identified.  However, chronic excess estrogen exposure, tamoxifen, and  black race have been cited as risks. Symptoms include abnor-  mal uterine bleeding, awareness of a mass, and pelvic pressure  or pain. Vaginal discharge may be profuse and foul. Gastroin-  testinal and genitourinary complaints are common. Treatment  consists of total hysterectomy, which may include bilateral  salpingo-oophorectomy and selective lymphadenectomy fol-  lowed by radiation therapy or chemotherapy, or both. Molecu-  larly targeted therapies are also under investigation.'“° Five-year  survival rates range from 50% in early disease to 5% in advanced  disease. Like most cancers, stage and histopathology are the  most important determinant of prognosis. The survival rate at  5 years for stage I disease is 50%. Few women survive advanced-  stage disease.!*°   The incidence of ovarian cancer is estimated at 22,240 women  in the United States in 2013. In 2013 ovarian cancer accounted  for 3% of all cancers among women and caused more deaths  (14,030) than any other female reproductive cancer in part  because of the limited availability of early screening programs.  From 2005 to 2009, the incidence declined at a rate of 0.9% per  year.! Ovarian cancer in women older than 40 years is associ-  ated with conditions associated with increased ovulation over  the lifetime, such as early menarche, late menopause, nulli-  parity, and the use of fertility drugs (especially in women who  fail to carry a child after using fertility drugs).'4°!4° Race and  prior pelvic radiation also appear to increase risk.!*” Factors  that suppress ovulation decrease the risk of ovarian cancer and  include pregnancies, prolonged lactation, and the use of hor-  monal contraceptives that limit ovulation, including the birth  control pill.!47149    PATHOGENESIS. There is controversy about the pathogenesis  of ovarian cancer. The great majority (approximately 90%) of  ovarian cancers are sporadic and not associated with a known  pattern of inheritance.!°° Of the 5% to 10% that are familial, the  majority are associated with the breast cancer susceptibility gene  1 (BRCA1) and a smaller number with mutations of BRCA2 or  mismatched repair genes (HNPCC syndrome). Various path-  ways have been proposed. Women and families who are more  susceptible to cancer may have errors in the ability to repair  cellular DNA, related to abnormalities in RAD51D, which is an  enzyme crucial to DNA repair,'°! which allows aberrant cellular  proliferation that occurs with repetitive ovulatory tissue repair  in the ovary. In sporadic ovarian cancer, BRCAI and BRCA2  are rarely mutated. A newer theory proposes that many sponta-  neous, nonhereditary ovarian tumors arise from the migration  of cells from tissues of mesoderm origin to the surface of the  ovary.'°*!°5 Cells from a variety of intra-abdominal locations,  including endometrial tissue and epithelium of the fallopian/  uterine tubes, can attach to the ovary (Figure 24-21). The local  ovarian environment, including the ovarian stroma, may then  interact with the transplanted cells to enhance cellular growth  and encourage metastasis!** (Figure 24-22).   The two major types of ovarian cancer are epithelial ovar-  ian neoplasms and germ-cell neoplasms. Most ovarian malig-  nancies are epithelial ovarian neoplasms that usually develop  from the surface epithelium of the ovary or that which line cysts  immediately beneath the ovarian surface, or may be cells that  have migrated from the fallopian/uterine tubes.'*’ Most epithe-  lial cancers seem to arise from a single cell (i-e., clonal) because  of a loss of tumor-suppressor genes and activation of oncogenes  (see Chapter 12). Epithelial ovarian tumors may have cellular  similarities to other tissues within the abdomen, including the  lining of the fallopian/uterine tubes, or the endometrium, or  be undifferentiated. Tumors are often classified as type I (low  grade) and type II (high grade) based on their cellular type.    FIGURE 24-22 Ovarian Stroma. The ovarian stroma interacts with precancerous and cancerous cells within the ovary.    Pas >. <= ‘ ‘  FIGURE 24-23 Ovarian Tumors. Bilateral multicystic ovarian tumors. (From  Symonds EM, Macpherson MBA: Color atlas of obstetrics and gynecology, London,  1994, Mosby-Wolfe.)    Type I tumors grow more slowly but are more resistant to che-  motherapy. Type II tumors often grow rapidly and aggressively  but respond well to chemotherapy!**'°> (Figure 24-23). The  5-year survival rate is 92% if treated in stage I; however, only  15% of ovarian cancers are diagnosed this early. Five-year sur-  vival rates decline with stage of disease: women with regional  spread of the cancer have a 5-year survival rate of 72%, whereas  women with distant metastasis have only a 5-year survival rate  of 27%.!   Germ-cell tumors are derived from the primitive germ cells  (gametes) of the embryonic gonad and may be malignant or  benign. The benign cystic teratoma accounts for approximately    10% of all ovarian tumors. These tumors represent an error in  meiosis that results in the formation of ectoderm, endoderm,  and mesoderm cell lines. Hair, teeth, and skin can be visualized  within cystic teratomas. If the germ-cell tumor is malignant, it  tends to be highly aggressive and rapidly growing with a poor  prognosis. Cystic hygromas and other germ-cell tumors can  occur on the ovaries of girls and women. Germ-cell tumors in  children can be particularly aggressive.   CLINICAL MANIFESTATIONS. Ovarian cancer is commonly  asymptomatic until the tumors have grown very large. Given  the location of the ovaries, assessing abnormalities on routine  gynecologic examination poses difficulty, especially in obese  women. There is no sensitive and specific test for ovarian cancer  for screening low-risk women, and routine screening of women  without risk factors has not been shown to be beneficial and  may cause harm because more women have unnecessary surgi-  cal procedures.!°°   Common first symptoms of ovarian cancer are vague and  include persistent abdominal distention, loss of appetite due to  early satiety, and pelvic pain. Screening is warranted if women  have a new onset of these symptoms that persist for more than  12 days each month. However, many women fail to notice the  very first signs of ovarian cancer because they are vague and  fairly common in older women. The disease is most commonly  diagnosed after metastasis has occurred. Consequently, ovarian  cancer is often termed the silent killer. Symptoms of advanced  disease include pain and abdominal swelling from the pri-  mary ovarian mass or ascites and abdominal distention (Figure  24-24). Gastrointestinal manifestations may include dyspepsia,    FIGURE 24-24 Large Malignant Ovarian Tumor and Metastasis of Ovar-  ian Cancer. A, Tumor has caused massive abdominal distention. B, Pattern of  spread for epithelial cancer of the ovary. (A from Symonds EM, Macpherson MBA:  Color atlas of obstetrics and gynecology, London, 1994, Mosby-Wolfe.)    vomiting, and alterations in bowel habits caused by mechanical  obstruction. Abnormal vaginal bleeding may occur if the post-  menopausal endometrium is stimulated by a hormone-secret-  ing tumor. The tumor also may cause ulcerations through the  vaginal wall that result in bleeding. There also can be a feeling  of pressure in the pelvis and leg pain.   Tumor obstruction of vascular channels can cause venous  and, occasionally, arterial thrombosis. Alterations in coagu-  lability also occur, contributing to clot formation. Metastasis  often causes pleural effusion.   EVALUATION AND TREATMENT. Because ovarian cancer has no  early symptoms and there is no cost-effective screening tech-  niques for early detection, disease usually is advanced by the  time treatment is sought. Women with symptoms of disease,  as outlined earlier, should be assessed with minimally invasive  tests first. Screening commonly begins with a CA-125 blood  test looking for specific cancer markers and a transvaginal   No tumor on the external surface; capsule intact (90%  5-year survival with treatment)   Tumor present on the external surface, or capsule(s)  ruptured, or both   Tumor present on the external surface, or capsule(s)  ruptured, or both   Tumor either stage IA or stage IB, with ascites present  or with positive peritoneal washings   Tumor either stage IIA or stage IIB but with ascites  present or with positive peritoneal washings   Growth involving one or both ovaries with  intraperitoneal metastases outside the pelvis,  Or positive retroperitoneal nodes, or both; tumor  limited to the true pelvis with histologically proven  malignant extension to small bowel or omentum   Growth involving one or both ovaries with distant  metastases; if pleural effusion is present, there  must be positive cytology to allot a case to stage IV;  parenchymal liver metastases indicate stage IV    ultrasound.!°” Increased CA-125 levels are found in about 78%  to 80% of nonmucinous ovarian cancers; however, elevated  levels are produced in 29% of nongynecologic tumors and in a  variety of noncancerous conditions, for example, endometrio-  sis, PID, benign ovarian cysts, myomas, and pregnancy.   Women less than 40 years of age are more likely to have non-  epithelial cells tumors and should be assessed with the blood  tests to look for the CA-125 marker, alpha fetoprotein (AFP),  and B-human chorionic growth hormone to screen for tumors  of nonepithelial cell origin.'!°’ Some types of germ cells and,  rarely, adenocarcinoma may be associated with increased levels  of AFP, hCG, or CA-125.   If initial tests are suspicious for a cancerous mass, diagnosis  is confirmed by biopsy and extent of the disease is determined  by ultrasound, CT, MRI, or other imaging techniques. Women  undergoing surgery for ovarian cancer staging receive a thor-  ough assessment for metastasis. The International Federation  of Gynecologists and Obstetricians (FIGO) staging system is  described in Table 24-7. Other studies may be used to deter-  mine the extent of metastasis. These include an upper gastro-  intestinal series, barium enema, intravenous pyelogram (IVP),  mammography, and lymphography.    Intact genital sensations, decreased lubrication; difficulty with sexual activity/positioning because of muscle    spasticity, rigidity, and/or weakness; pain with positioning caused by contracture of knees and hips or because of    Difficulties in sexual positioning and sensitivity because of impaired motor strength, coordination or paralysis;    decreased sex drive with stroke on the dominant side of the brain    Diminished intensity of orgasm and gradual decline in ability to achieve orgasm; decreased lubrication and/or    Decreased arousal; increasingly rare and less intense orgasms; decreased lubrication  Painful sexual activity/positions because of swollen, painful joints, muscular atrophy and joint contracture; decreased    sex drive because of pain, fatigue, and/or medication; genital sensations remain intact    Similar to RA; decreased lubrication and vaginal lesions result in painful penetration  Most literature male oriented; problems related to medications  Diminished genital sensitivity; decreased lubrication; declining orgasmic ability; difficulty with sexual activity because    Reflex sexual response with injury above sacral area; disrupted response with lesion at or below sacrum; loss of    sensation, decreased lubrication; spasticity, incontinence, or pain with arousal; continued orgasmic sensations or  sensations diffused in general or to specific body parts, such as breast or lips    The initial approach to treatment is surgery, which is per-  formed to determine the stage of disease and to remove as much  of the tumor as possible. Future treatment is then customized  based on the clinical stage of the cancer, the woman’s desires,  and the cell type and sensitivity of the cancer cells. Ideally treat-  ment plans are developed and implemented by a multidisci-  plinary team from a variety of disciplines including surgeons,  pathologists, and oncologists.!°*   Radiation therapy and chemotherapy with an agent contain-  ing platinum are common treatments.!*? Even after initially  effective treatment, 55% to 75% of women relapse, and less  than 20% survive long term with stage III or IV disease. New  therapies under investigation include small-molecular-weight  inhibitors, monoclonal antibodies, epidermal growth factor  receptors, and gene therapy.!°    Sexual dysfunction is the lack of satisfaction with sexual  function resulting from pain or a deficiency in sexual desire,  arousal, or orgasm/climax.!°!)!©? Sexual function and dysfunc-  tion result from a complex interplay of the individual, culture,  and physiology.'®? Sexual problems are multifaceted and often  difficult to diagnose; adequate research is still needed. Sexual  dysfunction can have organic or psychogenic causes or, more  commonly, a combination of both.!® Studies show that at any  given time up to 45% of adult women have some form of sexual  dysfunction.!©   The sexual response cycle is complex, involving the brain/  mind, sympathetic and parasympathetic nervous systems, the  systemic and local vasculature, and local innervation. Any dis-  ruption in these systems can affect sexual response. Chronic  medical conditions can greatly affect both sexual desire and  sexual function (Table 24-8). Acute illness and infections also  can affect the woman’s desire and ability to engage in fulfill-  ing sexual activity. Vaginal infections are especially problematic    because they can lead to vaginal irritation and pain with fric-  tion. Medications also can disrupt the sexual response cycle.  Antihypertensives and antidepressants are commonly associ-  ated with sexual problems.'°!'® Surgeries on the genital area  can disrupt nerve pathways and hysterectomy may affect sexual  function because the uterus, cervix, and vagina are involved in  sexual response and orgasm. The mind is a large component  of sexual response, and any stressor that affects the woman  can affect her sexual response, including her feelings about her  sexuality and relationship and past sexual abuse.'® A thor-  ough history is needed to assess for sexual dysfunction, and  testing is appropriate to assess for organic dysfunction (Figure  24-25). The American College of Obstetricians and Gynecolo-  gists divide sexual dysfunction into four categories: disorders of  desire, arousal, orgasm, and sexual pain.'°!   Disorders of desire (hypoactive sexual desire, decreased  libido) is the most common sexual dysfunction in women.!°  The prevalence of hypoactive sexual desire increases with age  and may be a biologic manifestation of depression, alcohol or  other substance abuse, prolactin-secreting pituitary tumors, or  testosterone deficiency. B-Adrenergic blockers used for heart  disease also may inhibit sexual desire. Short-term treatment  with testosterone has been shown to improve sexual desire and  may be used to treat women who wish to improve their sexual  interest.!°!   Anorgasmia, or orgasmic dysfunction, is the inability of the  woman to reach or achieve orgasm. Dysfunction follows a con-  tinuum from difficulty in arousal to lack of orgasm. Any chronic  illness may affect arousal. Diabetes, alcoholism, neurologic dis-  turbances, hormonal deficiencies, and pelvic disorders, such as  infections, trauma, and surgical scarring, may block orgasm.  Narcotics, tranquilizers, antidepressants (especially SSRIs), and  antihypertensive medications also can inhibit orgasm.!°   Dyspareunia (painful intercourse) is common. Women  may experience pain during arousal, at the time of orgasm, at    FIGURE 24-25 Diagnostic and Treatment Algorithm for Sexual Dysfunction. The International Consultation in Sexual  Medicine (ICSM) stepwise diagnostic and treatment algorithm for sexual dysfunction in men and women. (From Hatzichristou    the initiation of intercourse, midway during intercourse, or  after intercourse. The pain may have a burning, sharp, searing,  or cramping quality and may be described as external, vagi-  nal, deep abdominal, or pelvic. A variety of psychosocial and  organic causes have been identified.   Inadequate lubrication may make penetration or intercourse  difficult or painful. Low estrogen levels, as are common with  menopause and lactation, can decrease vaginal lubrication.  Drugs with a drying effect, such as antihistamines, certain tran-  quilizers, and marijuana, can decrease lubrication. Infections  and skin problems of the vulva and vagina are a frequent cause  of acute onset dyspareunia. The use of products such as sper-  micides and fragrances on the sensitive vaginal mucosa may  increase the risk of irritation. Disorders of the vaginal opening,  such as scarring from female genital mutilation, episiotomy, or  an intact hymen, also can be problematic. Deep pelvic disorders  such as infection, tumors, and cervical or uterine abnormalities  can cause pain with intercourse.   Vaginismus is an involuntary muscle spasm in response to  attempted penetration. Vaginismus is often a response to previ-  ous painful penetration. Common causes include prior sexual  trauma or fear of sex; organic causes are less common and are  similar to those that cause dyspareunia, including vulvovestibu-  litis. Even after the underlying organic problem is detected and  successfully treated, vaginismus may persist.   Sexual dysfunction may develop as a coping mechanism.  Women with a history of sexual trauma—trape, incest, or moles-  tation—often have problems of desire, arousal, or orgasm or  experience pain with sexual activity. In extreme cases total sex-  ual aversion may develop.'® At other times sexual dysfunction    may be a symptom of marital or relationship problems. Because  sexual dysfunction has many causes, assessment and treatment  should be holistic and culturally sensitive.    Infertility affects approximately 15% of all couples and is  defined as the inability to conceive after 1 year of unprotected  intercourse with the same, opposite-sex partner. However,  many sources believe that medical intervention is indicated  for women who are older than 35 years old if they fail to con-  ceive after 6 months of unprotected intercourse.'“! The rate  of infertility may be increasing because of an increase in sexu-  ally transmitted disease and a delay in the start of childbearing  but the increase in incidence rates may also reflect the greater  utilization of medical services for infertility.'© Fertility can be  impaired by factors in the man or the woman or both partners.  The male is the sole cause of the infertility in 20% of cases, and  a co-contributor to infertility in 30% to 40% of cases.'°° The  majority of cases of infertility involve the female, caused in part  by the complexity of the female reproductive cycle and tract.  Ovulatory factors account for 40% of female infertility.*? Regu-  lar ovulation occurs as a result of a functioning hypothalamic/  pituitary axis. Ovulation can be disrupted by a wide variety of  factors, including imbalances in a diversity of hormones (TSH,  estrogen, progesterone, etc.), chronic conditions, and stress.  Age is a major factor in female fertility because the regularity  of ovulation and the quality of ova decrease with age (Figure  24-26). Abnormalities of the reproductive tract, including  tubal pathologies, cause another 40% of cases of infertility.°°  Endometriosis and adhesions and scarring from PID are major    FIGURE 24-26 Relationship of Fertility and Miscarriage with Maternal  Age. (From Heffner LJ: Advanced maternal age: how old is too old? N Eng! J Med  351(19):1927-1929, 2004.)    contributors to blockages within the female reproductive tract.  The remaining 20% of female infertility is caused by rare condi-  tions or unknown etiology.°°   Male infertility has a variety of causes, many of which can  be corrected. Hormonal disorders, such as thyroid disturbances  or low testosterone levels, can be diagnosed and corrected.!°’  Throughout the 82 days of their creation and maturation, the  sperm must be kept cooler than body temperature.** Eleva-  tions in temperature caused by illness, abnormal placement of  the testes, varicoceles near the testes, or exposure to high tem-  peratures in hot tubs or saunas may kill or disable sperm. Male  infertility is also linked to abnormalities of the seminal tract  and sexual dysfunction that disrupts ejaculation.'°? A number  of diagnostic procedures are required in the routine investiga-  tion of the infertile couple (see Table 23-3). In many instances  no cause may be identified.    Prior to the performance of even basic fertility tests, a complete  history should be obtained that includes coital (sex) timing and  frequency in relation to the menstrual cycle; an in-depth assess-  ment and charting of the menstrual cycle; a reproductive his-  tory, including all previous pregnancies from both partners and  their outcome; a medical history of systemic disease; current  medications; past surgeries; a sexual history including any pre-  vious STIs; and any exposure to toxins.!°* The history allows the  clinician to home in on the most useful tests. Testing starts with  the least invasive test or procedure and increases in invasiveness  and complexity as the duration of infertility increases. The types  of tests and their normal values are summarized in Table 22-4.  The most common test for male infertility is the basic semen  analysis, the man is evaluated for volume of semen and the con-  centration, morphology, and forward motility of sperm.!°%!®  More advanced semen analysis also examines the function of  the sperm including their ability to bind to and penetrate eggs.  In-depth analysis may also analyze the sperm’s DNA for num-  ber, fragmentation, and ability to merge with the egg’s DNA.!°    Tests for women determine whether: (1) ovulation occurs  normally, (2) the endometrium is responding normally to hor-  mones, (3) reproductive tissues are free of tumors or infections,  (4) the woman does not have any chronic conditions interfer-  ing with fertilization or implantation, and (5) the reproduc-  tive tract (cervix, uterus, fallopian tubes) is adequately patent  to allow for passage of ovum and sperm. Hormonal assays can  be useful to detecting underlying abnormalities. The position  and size of organs or the presence of tumors can be assessed  by pelvic examination, ultrasound, or hysterosalpingogram  that injects contrast dye into the reproductive tract to look for  normal anatomy and patency of the fallopian/uterine tubes.  Chromosomal analysis of the couple may reveal mutations or  translocations that result in very early embryo loss.**   Treatment of infertility aims at correcting underlying  pathologies or overriding the deficient system. Male infertility  can be overcome through injection of the male DNA directly  into the uterus or even the ovum. Anovulation in the female can  be overcome with ovulation-inducing drugs. Blockages within  the female reproductive tract can be bypassed with in vitro  fertilization.   There has been a proliferation in assisted reproductive tech-  nologies (ART) that enable women and couples to conceive  and bear children. ART results in more than 50,000 live births  per year in the United States, and the rate is rising.'!°’? However,  there are questions about the health and long-term safety of  infants conceived with assisted reproduction; for instance, con-  cerns about the high rate of twins and preterm birth in pregnan-  cies conceived with ART. In addition, children born through  ART have a higher rate of birth defects, even when other vari-  ables are controlled.'!”? The many theories about the cause of  this increase suggest that the birth defects may be the result of  epigenetic changes when the expression of the embryo’s DNA  is affected by the very early environment of the blastocysts.'7!  Research in this area and the field of epigenetics is ongoing.'7!    Galactorrhea (inappropriate lactation) is the persistent and  sometimes excessive secretion of a milky fluid from the breasts  of a woman who is not pregnant or nursing an infant. It can  occur in men, may involve one or both breasts, and is not asso-  ciated with breast cancer.   Incidence is difficult to estimate because of differences  among definitions of the condition, examination techniques,  and populations of women who have been studied. Prevalence  has been documented as 0.1% to 32% of all women.   PATHOPHYSIOLOGY. Galactorrhea is a manifestation of patho-  physiologic processes in the body, rather than a breast disor-  der. These processes are chiefly hormone imbalances caused  by hypothalamic/pituitary disturbances, pituitary tumors, or  neurologic damage. Exogenous causes include drugs, estrogen,  and manipulation of the nipples. When caused by hyperpro-  lactinemia it is manifested by the spontaneous appearance of  a milky secretion from multiple duct openings, usually from  both breasts. Galactorrhea caused by oral contraceptives (OCs)    Drug Causes  Amoxapine  Amphetamines  Anesthetic agents  Butyrophenones  Cimetidine  Estrogens  Hydroxyzine  Methyldopa  Metoclopramide  Narcotics    is more likely to occur with high-dose use; is characterized by  clear, serous, or milky discharge from multiple ducts; and is  noticeable during the drug-free interval between OC packets.  In premenopausal women, unilateral or bilateral spontaneous  multiple duct discharge that increases before menstruation  often is caused by fibrocystic change. Unilateral, spontaneous,  serous, or serosanguineous discharge from a single duct usu-  ally is caused by an intraductal papilloma; bloody discharge  suggests cancer; bilateral, sticky, multicolored discharge from  multiple ducts is often caused by duct ectasia; and purulent dis-  charge indicates a subareolar abscess. !7*   The most common cause of galactorrhea is nonpuerperal  hyperprolactinemia, or excessive amounts of prolactin (the  pituitary hormone that stimulates milk production) in the  blood not related to pregnancy or childbirth. Nonpuerperal  hyperprolactinemia can be caused by any factor that (1) stim-  ulates or overstimulates the prolactin-secreting units of the  pituitary gland; (2) interferes with production of prolactin-  inhibiting factor (PIF), a neurotransmitter (probably dopa-  mine) that inhibits prolactin secretion; or (3) interferes with  pituitary receptors for PIF. A variety of exogenous agents (such  as drugs) and disorders can trigger one of these three mecha-  nisms, thereby causing hyperprolactinemia (Box 24-12).   Hypothyroidism causes increased secretion of hypothalamic  TSH that stimulates prolactin release from the pituitary. Hypo-  thyroidism also is associated with reduced metabolic clearance  of prolactin, which prolongs its effects.   Many types of pituitary tumors cause hyperprolactinemia.  Prolactinomas cause hyperprolactinemia by secreting pro-  lactin, decreasing production of PIF, or putting pressure on  the pituitary stalk such that delivery of PIF to the anterior  pituitary is prevented. Growth hormone-secreting pituitary  tumors may cause galactorrhea through the intrinsic lactogenic    effect that growth hormone appears to have on mammary tis-  sue. Prolactin-secreting lung and kidney tumors also cause  hyperprolactinemia.   Chronic stress may cause hyperprolactinemia by inhibiting  PIF release. Cervical spinal injuries, head trauma, encephalitis,  meningitis, herpes zoster, or thoracotomy scars may stimulate  the afferent portion of the suckling reflex arc, which is carried in  the second to sixth thoracic nerves. The suckling reflex increases  prolactin secretion.   CLINICAL MANIFESTATIONS. A small amount of breast milk  expressed from the nipples of parous women usually is not a  concern, and normal breast milk color can be other than white.  Inappropriate lactation is manifested by the appearance of a  milky breast secretion in nonpregnant, nonlactating women  from one or both breasts. Most women with galactorrhea expe-  rience menstrual abnormality. Ifa pituitary process is involved,  the woman usually experiences hirsutism and infertility; if a  hypothalamic lesion is present, she may report such CNS symp-  toms as intractable headache, visual field disturbances, sleep  disturbances, and abnormal temperature, thirst, or appetite.   EVALUATION AND TREATMENT. Galactorrhea requires evaluation  when it (1) occurs in nulliparous women or in parous women  who have not been pregnant or have not breast-fed for 12  months, or (2) is associated with amenorrhea, headache, visual  field abnormalities, or other symptoms implying systemic ill-  ness. Evaluation includes a variety of diagnostic tests. When  amenorrhea accompanies galactorrhea, the assessment is the  same as for amenorrhea. Breast secretions are examined for  fat globules and neoplastic cells to verify their source. Serum  prolactin levels are measured. Because such variables as eating,  sleeping, stress, and breast examinations increase prolactin lev-  els, at least two positive results are needed for a diagnosis of  hyperprolactinemia. Prolactin levels greater than 25 to 30 ng/ml  (by radioimmunoassay) are elevated. Those in the range of 75  to 100 ng/ml are considered to be caused by a pituitary tumor  until proved otherwise. Serum thyroxine and TSH levels are  measured to rule out hypothyroidism, and LH and FSH levels  are obtained if the individual is amenorrheic. MRI may assist in  locating adenomas.   Treatment is specific to the underlying cause and occurs  after identification of the cause. Medical therapy is usual and  surgery or radiation therapy is rarely required.    Benign breast disease (BBD) is a spectrum of noncancerous  changes in the breast. Numerous benign alterations in ducts  and lobules occur in the breast, including irregular lumps, cysts,  sensitive nipples, and itching. The most common symptoms  reported by women are pain, palpable mass, or nipple discharge;  the majority of these prove to have a benign cause. After a diag-  nosis of BBD, however, major determinants of breast cancer risk  include degree of family history; histologic or biologic features, or  both; and previous biopsy.!”* This risk varies according to the his-  tologic category of BBD (moderate in women with proliferative  lesions without atypia [deviation from normal]) and substantial  in women with atypical (atypia) hyperplasia (AH)!”* (see p. 841).  Among premenopausal women, the risk appears to be greater for    those with atypical lobular hyperplasia (ALH) than with atypi-  cal ductal hyperplasia (ADH) (see p. 841). For postmenopausal  women, the risk of breast cancer was similar between those with  ALH or ADH.'”4 Family history is reported as an independent    BOX 24-13 CLASSIFICATION OF BREAST  BIOPSY TISSUE ACCORDING  TO RISK FOR BREAST CANCER   Adenosis (sclerosing or florid)  Apocrine metaplasia  Macrocysts or microcysts  Fibroadenoma  Fibrosis    Slightly Increased Risk (1.5 to 2 Times)  Moderate or florid hyperplasia  Papilloma    Moderately Increased Risk (4 to 5 Times)  Atypical hyperplasia (ductal or lobular)    risk factor for breast cancer. Women with atypia and a family  history had a breast cancer risk four times the expected risk.!7°  Risk was lower among those with atypia and no family history.   The College of American Pathologists has classified biopsy  tissue according to breast cancer risk. These classifications are  listed in Box 24-13. Benign epithelial lesions can be broadly  classified according to their risk of developing breast cancer as:  (1) nonproliferative breast lesions, (2) proliferative breast dis-  ease, and (3) atypical (atypia) hyperplasia. Table 24-9 includes  examples of benign breast tumors.    The term nonproliferative has been used to discriminate from  the proliferative changes commonly associated with increased  risk for development of breast cancer. Nonproliferative breast  lesions are generally not associated with an increase risk in  breast cancer.!”° Terms such as fibrocystic changes (FCCs) or  physiologic nodularity and cysts, fibrocystic disease, chronic  cystic mastitis, and mammary dysplasia refer to nonprolif-  erative lesions and are not clinically definitive because they  encompass a heterogeneous group of diagnoses.!”? Cysts  (fluid-filled sacs) are a specific type of lump that commonly  occurs in women in their 30s, 40s, and early 50s. Cysts feel  “squishy” when they occur close to the surface of the breast but  when deeply embedded they can feel hard (Figure 24-27). An    Puberty, early adulthood;  occurs earlier and more  frequently in young black  women    Ages 14-80 yr; average age  50 yr; increased in women  with fatty, voluminous  breasts; trauma    Slow-growing lesion composed of  variable proportions of epithelial and  connective tissue; thought to be under  influence of estrogen   Fibroepithelial tumor characterized by  marked proliferation of connective  tissue stroma and great size; initially  slow growing; 10%-25% may be  malignant    Subareolar tumor consists of epithelial  vegetation with central connective  tissue axis; found in lactiferous duct    Principal lactiferous ducts become  dilated and filled with cellular debris;  secondary inflammatory reaction;  possible rupture of ducts    Spheric, firm, usually well-  circumscribed multinodular  tumor with a diameter of  2-20 cm; trophic cutaneous  ulceration is a late  manifestation    friable, yellow or red, +5  mm, papillomatous growth  attached to duct wall by  short, thin stalk; rare nipple  retraction   Local excision of  benign or small  tumor; simple  mastectomy if  voluminous or  malignant tumor    estimated 50% to 80% of women normally experience some  of these changes. The prevalence of fibrocystic lesions is prob-  ably related to hormonal changes, which in turn are affected  by genetic background, age, parity, history of lactation, caf-  feine consumption, and use of exogenous hormones.!”° Based  on experimental animal studies, it is assumed that breast cysts  are the result of ovarian alterations, but the exact mechanism  is unknown. Calcifications, found in cysts and adenosis or an  increase in the number of acini per lobule, can form mammo-  graphically suspicious alterations.!’’” Cysts also can be associ-  ated with unilateral nipple discharge. A variety of substances  are secreted into cyst fluid, including polypeptide hormones  and male and female sex steroid hormones. Cysts often rup-  ture with release of secretory material into the adjacent tissue.  The resulting chronic inflammation and scarring fibrosis con-  tribute to the palpable firmness of the breast.'”” Fibrous tissue  increases progressively until menopause and regresses there-  after. Papillary apocrine (glandular) change, epithelial-related  calcifications, and mild hyperplasia of the usual type are all  considered nonproliferative breast lesions.!’”> Genetic aberra-  tions are more common in proliferative than in nonprolifera-  tive lesions.!””    These disorders are characterized by proliferation of ductal  epithelium and/or stroma without cellular signs of atypia or  deviation from normal. Criteria for the diagnosis of intraductal  proliferative lesions have been the subject of much research    FIGURE 24-27 Benign Breast Disease. A, Nonproliferative fibrocystic changes: The architecture of the terminal-duct   1. Usual ductal hyperplasia (UDH). In the normal breast,  only myoepithelial cells and a single layer of luminal cells  are present above the basement membrane.'”” UDH is  defined by the presence of more than two cell layers above  the basement membrane within the ductal space. Cyto-  logically they are benign cells, not monoclonal, and cells  can vary in size and shape.!’*!’* The additional or prolif-  erating epithelial cells fills and distends the ducts and lob-  ules by both luminal and myoepithelial cells. Moderate to  florid hyperplasia is more than four cell layers above the  basement membrane. Ductal hyperplasia is usually found  as an incidental finding on biopsy of mammographic  abnormalities.   2. Intraductal papillomas. Solitary papillomas are a  monotonous (sameness) array of papillary cells that grow  from the wall of a cyst into the lumen of the duct. Growth  occurs within a dilated duct often near or beside the  nipple causing benign nipple discharge (Figure 24-28).  These papillomas can harbor areas of atypia or ductal car-  cinoma in situ (DCIS) (see p. 841). Solitary intraductal  papillomas may present as a breast mass (mammogram),  a nodule (ultrasound) or image from MRI, or ductog-  raphy (galactogram).'’® Hyperplasia and metaplasia can  be present within the ducts. Atypical hyperplasia may be  present within or adjacent to papilloma, making the dis-  tinction from DCIS difficult (see p. 866). The presence of    lobular unit is distorted by the formation of microcysts, associated with interlobular fibrosis. B, Proliferative hyperplasia  without atypia: This is adenosis, a distinctive form of hyperplasia characterized by the proliferation of lobular acini, forming  crowded glandlike structures. For comparison, a normal lobule is on the left side. €, Proliferative hyperplasia without atypia:  There is moderate ductal hyperplasia, which is characterized by a duct that is partially distended by hyperplastic epithelium  within the lumen. D, Proliferative hyperplasia without atypia, which is florid ductal hyperplasia: The involved duct is greatly  expanded by a crowded, jumbled-appearing epithelial proliferation. E, Atypical ductal hyperplasia: These proliferations are  complex and partially formed secondary lumens and mild nuclear hyperchromasia in the epithelial cell population. The periph-  eral spaces are irregular and slitlike. F, Atypical lobular hyperplasia: Monomorphic, small, rounded loosely cohesive cells fill  the lumens of partially distended acini in this terminal-duct lobular unit (hematoxylin and eosin). (From Elmore JG, Gigerenzer  G: N Eng! J Med 353[3]:231, 2005.)    atypia (ductal or lobular) coexisting with a single papil-  loma (atypical papilloma) does not appreciably modify  the breast cancer risk attributable to just atypia.!”? A soli-  tary papilloma without atypia conveys a risk similar to  proliferative fibrocystic lesions. Although the breast can-  cer risk is small, multiple papillomas, called diffuse pap-  illomatosis, even without identified atypia, can increase  breast cancer risk. Diffuse papillomatosis is defined as a  minimum of five papillomas within a localized segment  of breast tissue.!7°   . Sclerosing adenosis. Sclerosing adenosis is a lobular  lesion with increased fibrous tissue and scattered glan-  dular cells.'7° Calcification is commonly present within  the lumens; however, the normal lobular arrangement is  maintained. It can present as a mass or suspicious finding  from mammogram but requires no treatment. Occasion-  ally, stromal fibrosis may mimic the appearance of inva-  sive carcinoma.!’”   . Radial scar. Radial scar (RS) refers to an irregular, radial  proliferation of ductlike small tubules entrapped in a  densely fibrotic stroma (Figure 24-29). The term scar  refers to the structural appearance only because these  lesions are not associated with scarring and fibrosis from  a prior injury, biopsy, or surgery. RS also has been called  radial sclerosing lesions and sclerosing papillary prolifera-  tion. RSs are usually discovered when a breast lesion or  radiologic abnormality is biopsied or removed. Occa-  sionally RSs are large enough to be detected by mam-  mography, which, however, cannot reliably differentiate  between these lesions and spiculated (spiky with pointed  features) carcinoma. Controversy exists about the need  for surgical excision when RSs are found. There is some  evidence that RSs may be premalignant lesions, and the  possibility of finding an unrecognized in situ or invasive    FIGURE 24-29 Radial Scar. Gross pathologic specimen of radial scar. (From  the Armed Forces Institute of Pathology.)    component suggests that they be surgically excised.!”* Yet  a retrospective study of 9556 women found that although  RSs mildly elevate the risk of invasive breast cancer, the  risk was largely attributed to the coexistent presence of  proliferative disease.'*° Invasive breast cancer risk was  further increased in women with AH.!*°!*! No additional  treatment is needed beyond excision and the risk of sub-  sequent breast cancer is small.!7°    solid tumors composed of both fibrous and glandular tis-  sue.!’® Fibroadenomas are now considered proliferative  lesions and the histologic features influence the risk of  breast cancer.!7*'*? If the fibroadenoma is complex with  adjacent proliferative disease or if there is a family his-  tory of breast cancer the risk of breast cancer is slightly  elevated. There is no increased risk of breast cancer in the  majority of women with a simple fibroadenoma. Multiple  fibroadenomas occur in the same breast or bilaterally in  about 20% of cases.'’* Fibroadenomas are found most  commonly in women between the ages of 15 and 35 years  but they can occur at any age, especially in older women  on hormone therapy.'®’ The etiology is unknown, but a  hormonal role is likely because they persist during the  reproductive years, increase in size during pregnancy or  with estrogen therapy, and usually regress after meno-  pause. Fibroadenomas usually present as a well-defined  mobile mass—smooth and hard like a marble—on  physical examination or a well-defined solid mass on    population of cells. Although some of the spaces are round and regular, the peripheral spaces are irregular and slitlike. These  features are highly atypical but fall short of a diagnosis of ductal carcinoma in situ (DCIS). B, Atypical lobular hyperplasia.  A population of monomorphic small, rounded, loosely cohesive cells partially fill a lobule. (From Kumar V: Robbins & Cotran    ultrasound. Not all biopsy-proven lesions require sur-  gical excision. If a fibroadenoma increases in size or is  symptomatic, surgical excision is mandated to know if  the lesion is malignant.!”°    Proliferative Breast Lesions with Atypia  Proliferative breast lesions with some abnormal structure or  atypia include atypical ductal hyperplasia (ADH), or abnor-  mal proliferating cells in breast ducts, and atypical lobular  hyperplasia (ALH), or abnormal proliferating cells in breast  lobules.'’”'78 ALH also can involve ducts.!”° Atypical hyper-  plasia (AH) is an increase in the number of cells with some  variation in cellular structure but lacks sufficient qualitative or  quantitative features of carcinoma. Studies continue to indicate  that women with AH have an increased risk (about fourfold) of  breast cancer compared with women who have nonproliferative  lesions.'’* AH is associated with an increased risk of both ipsi-  lateral (same side as lesion) and contralateral breast cancer indi-  cating some evidence of underlying breast abnormalities that  predispose to breast cancer.'’* Major determinants of breast  cancer risk include histologic/biologic findings, degree of fam-  ily history, and previous (age of) biopsy (see p. 843).!7* Recent  findings from the Nurses’ Health Study (NHS) found adoles-  cent alcohol consumption is associated with increased risk of  proliferative BBD.'** Among premenopausal women at the  time of their benign biopsy, the risk of breast cancer was sub-  stantially increased among women with AH (Odds ratio [OR],  7.3) than among women with ADH (OR, 2.72). The risks for  women who were postmenopausal at the time of benign biopsy  were similar for women with ALH and those with ADH.!4  Ductal hyperplasia is an increased number of uniform  epithelial cells within the lumen of the terminal ducts (Figure  24-30, A). Atypical ductal hyperplasia includes a continuum  of changes—cell structure and placement—ranging from    an increase in cellularity to features of DCIS (see p. 866). In  ADH, the cells fail to completely fill ductal spaces as compared  with DCIS.   Lobular hyperplasia refers to proliferation of small uniform  cells in the lumen of lobular units. The abnormal cells of ALH  and lobular carcinoma in situ (LCIS) share some of the cyto-  logic and structural features, but the cells in ALH do not distend  more than 50% of the acini within a lobule (see Figure 24-30,  B). ALH can extend into ducts, and this is associated with an  increased risk of invasive carcinomas.!’” Other benign condi-  tions are summarized in Table 24-10.   EVALUATION AND TREATMENT. Breast problems should be diag-  nosed from a multimodal approach that combines physical  examination, mammogram when applicable, sonogram, pos-  sibly MRI, and careful consideration of a biopsy. The principal  mammographic signs of breast carcinoma are densities and cal-  cifications. However, the dense breast tissue often seen in young  women can make interpretation extremely difficult. Newer  screening and diagnostic methods are being tested including  those without compression and ionizing radiation such as dif-  ferent technologies using MRI. Ultrasonography (ultrasound)  is used to differentiate a solid mass from a cystic (fluid-filled)  mass, which is generally benign.   Treatment consists largely of relieving symptoms. Risk  reduction for AH includes avoiding hormone therapy and oral  contraceptives, careful diet choices, and exercise. Certain selec-  tive estrogen modulators, such as tamoxifen and raloxifene, or  an aromatase inhibitor may be considered after a thorough dis-  cussion of risks and benefits.!”° Breast pain may be minimized  by wearing a brassiere that provides good support. Reduction of  caffeinated beverages, cola, root beer, and chocolate, which can  cause overstimulation of breast tissue for some women, may  reduce pain and nodularity. Given time the cysts may disappear  without treatment. Although still controversial and possibly    dose-dependent, isoflavone exposure has been associated witha — increasing omega-3 fatty acids may decrease associated pain  decreased risk of proliferative benign fibrocystic changes, non- caused by inflammation as well as the application of castor oil  proliferative changes, and breast cancer.!*°)!8° packs to the breasts. The use of anti-inflammatories also may   Iodine deficiency may increase fibrocystic breast change, decrease inflammation. Drugs used to treat severe breast pain  thus may be useful for relieving pain.'®” Although unknown, are listed in Table 24-11.    Increase in number of nipples or breasts results from persistent epidermal thickening along the milk line   Ductal system may extend into subcutaneous tissue of the chest wall and axillary region; this tissue can undergo lactational changes  and give rise to tumors   Is common and may be unilateral; can spontaneously correct during pregnancy; can be confused with retraction of nipple, which is  sometimes part of invasive cancer or inflammation   Juvenile hypertrophy may be caused by unusual tissue response to hormonal stimulus    Breast tissue can be replaced or augmented by skin and muscle flaps for synthetic prostheses; silicone implants, the most common,  are rubbery silicone filled with either silicone gel or saline; a common complication of implants is formation of a thick fibrous capsule  (i.e., chronic inflammatory responses) that can cause cosmetic deformity; the capsule can limit the spread of a ruptured implant but if    the capsule ruptures silicone gel can escape; long-term consequences of rupture are unknown    Inflammatory diseases of the breast are rare; acute mastitis is confined to the lactating period of nursing; the nipples can become dry,  cracked, and fissured, increasing risk of bacterial infection; infection may lead to abscess formation   Women or men present with a painful subareolar mass thought to be infectious; not associated with lactation; 90% of individuals  are smokers; vitamin A deficiency associated with smoking may alter the differentiation of the ductal epithelium; keratin is trapped  within the ductal system causing dilation and rupture; antibiotic therapy and surgery are usually indicated   Affects 50- and 60-year-olds, usually multiparous women, not associated with smoking; dilation of ducts with chronic granulomatous  inflammatory reaction; fibrosis may eventually lead to skin and nipple retraction, thus mistaken for cancer; may have white nipple secretions   Painless, palpable mass, skin thickening or retraction; mammographic density or calcification; may have hemorrhage; most women will  give a history of prior surgery or trauma; can be confused with breast carcinoma   Single or multiple hard, palpable masses; can be so hard that interferes with biopsy; lesion includes collagenized stroma surrounding  atrophic ducts and lobules; the breast membrane is frequently thickened; a prominent lymphocytic infiltrate surrounds epithelium and  blood vessels; most common in women with type 1 diabetes or autoimmune thyroid disease    Data from Lester SC: The breast. In Kumar V, Abbas AK, Fausto N, editors: Robbins & Cotran pathologic basis of disease, ed 7, Philadelphia, 2005,    Causes a decrease in cyclic pain and nodularity believed to reduce estrogen; also used for endometriosis; some side effects include  changes in menstrual cycle regularity, weight gain, acne, and flushing   Decreases cyclic pain, nodularity, and tenderness; decreases prolactin levels and may alter dopamine receptors; is also used to  suppress lactation after childbirth; can cause nausea, vomiting, hypotension, and dizziness   As an antiestrogen it can decrease cyclic pain; increase clot formation (phlebitis, emboli, strokes); cause hot flashes, amenorrhea,  weight gain, and increased risk of uterine cancers   Can decrease cyclic pain, nodularity, and tenderness; women with mastalgia believed to have low levels of breast linoleic acid;  reduces PGE2 prostaglandins and inflammation; too much oil, however, has been associated with increasing inflammation  (>1000 mg/day)    Can decrease cyclic pain and nodularity (see Nutrition & Disease: Premenstrual Syndrome, p. 813)  Decrease in cyclic pain and tenderness; not as effective for decreasing tenderness; antagonist to estrogen; can cause weight gain    May decrease estrogenic effects; however, related to endothelial vasospasms, weight gain, and increased risk of breast cancer    40-49 1 in 69  50-59 1 in 38  60-69 1 in 27  Ever* 1in8  Never in8    Data from Reis LAG et al: Cancer statistics review, 1975-2005,  Bethesda, MD, 2008, National Cancer Institute. Available at http://  seer.cancer.gov/csr/1975_2005. Based on November 2007 SEER data,  posted SEER website, 2008.   Note: These calculations are averages. An individual's risk may be  higher or lower depending on several factors (e.g., family history,  reproductive history, race/ethnicity, and others).   Breast cancer, the most common cancer in American women, is  the leading cause of death in women ages 40 to 44 years and the  second most common killer after lung cancer of women of all  ages. The incidence of breast cancer has risen steadily since the  1970s and started leveling off from 1998 to 1999; incidence for  all races combined is about 125 cases per 100,000 women per  year. It is estimated that 234,580 women and 2240 men will be  diagnosed with breast cancer, and 40,030 women and 410 men  will die from breast cancer in 2013.! Age and the chance of being  diagnosed with breast cancer are presented in Table 24-12. The  breast cancer death rate in the United States has been declining  from 1989 to 1990, peaking at a rate of 33 deaths per 100,000  women.!** The age-adjusted death rate from 2005 to 2009 in  the United States is 23 per 100,000 women per year. Breast can-  cer comprises clinically distinct subtypes. The National Cancer  Institute (NCI) reported subtypes by race including estrogen  receptor (ER), progesterone receptor (PR), HER2/neu, and  triple negative (ER negative, PR negative, and HER2 negative).  The luminal breast cancer subtype predominates across racial/  ethnic groups with lifetime risk lowest in Hispanic women and  highest in white women. Triple negative breast cancer is highest  in black women compared with Asians, followed by Hispanics  and whites.!*? Overall, black women have lower incidence of  breast cancer but a 41% higher mortality than white women.!”°  Black women in all age groups experience the highest mortality  rates for breast cancer although the reason for this disparity is  not clearly understood but includes diagnoses at later stages,  excess obesity, and triple negative breast cancer, which has a  more aggressive phenotype.!”? More than two thirds of breast  cancer cases occur in women older than 55 years. From 2005 to  2009, the median age for breast cancer diagnosis was 61 years  of age. The median age at death for breast cancer was 68 years  of age.!°! Because DCIS is almost exclusively detected by mam-  mography, the large increase in incidence of DCIS over the  past 20 years can be attributed to screening (see What’s New?  Screening Mammography: Why It Has Not Lived Up to Expec-  tations, Chapter 12, p. 393).    Risk factors and possible causes of breast cancer can be clas-  sified as reproductive, hormonal, environmental and lifestyle,  and familial (Table 24-13). However, two factors emerging as  important are postpartum involution of the mammary gland  and breast density, which are not as easily classified.    Reproductive Factors: Pregnancy  A clearer understanding of mammary gland structure (mor-  phology) and function from fetal development, to puberty,  pregnancy, and aging will help elucidate fundamental changes  to breast development and disease. A key element is “branching  morphogenesis,” in which the mammary gland produces and  delivers copious amounts of milk by forming a rootlike net-  work of branched ducts from a rudimentary epithelial bud.!?”  Branching morphogenesis begins in fetal development, pauses  after birth, starts again in response to estrogens at puberty, and  is modified by cyclic ovarian hormonal action. This systemic  hormonal action elicits local paracrine interactions between  the developing epithelial ducts and their adjacent mesen-  chyme (embryonic) or postnatal stroma. Then the local cellular  crosstalk directs the tissue remodeling, ultimately producing a  mature ductal tree.!°* The gland is unique because it undergoes  most of its branching during adolescence and not fetal develop-  ment. This allows experimental manipulation of the gland not  possible with any other organ.!?°   A woman’s age when her first child is born affects her risk  for developing breast cancer—the younger she is, the lower the  risk. Overall, lifetime risk of breast cancer is reduced in parous  women compared to nulliparous women, but pregnancy must  occur at a young age.'** A complete pregnancy before age 25  reduces the risk of breast cancer by about 36%, this protective  effect is weakened in multiparous women if their age at first  birth is greater than 30.!>!°° The protective factor is especially  observed in the years of peak incidence, the postmenopausal  years.!°? The risk reduction is limited to hormone receptor—  positive breast cancer.'? The influence of pregnancy on the  risk of breast cancer also depends on family history, lacta-  tion postpartum, and overall parity.!°° Paradoxically, women  of all ages have a transient increase in breast cancer risk with  a recent pregnancy and after each subsequent pregnancy.!°%!?8  Pregnancy-associated breast cancer (PABC) is defined as  breast cancers diagnosed up to 5 years after a completed preg-  nancy; however, risk may persist for a decade.!°°!%? Delayed  childbearing observed in the United States and all developing  countries is expected to show a rise in diagnosed breast can-  cers.!°° The transient increase in breast cancer risk for all parous  women includes events associated with pregnancy, including  pregnancy-related hormones, such as estrogen, progesterone,  and growth hormone, that promote or initiate cancer cells,  immune suppressive effects of pregnancy, and breast tissue  involution.!*° Breast gland involution after pregnancy and lac-  tation uses some of the same tissue remodeling pathways acti-  vated during wound healing (i.e., proinflammatory pathways).  The proinflammatory environment, although physiologically  normal, promotes tumor progression. One mechanism iden-  tified links fibrillar collagen deposition, noted during normal  involution, to high levels of COX-2 expression in tumor cells    Blacks have higher incidence up to age 40 yr;  whites have higher incidence after age 40  Breast cancer in first-degree relative before age 60 2-3  Premenopausal or bilateral breast cancer >4    *Normal lifetime risk in white non-Hispanic women: 1 in 8.  Relative risk is defined and discussed in Chapter 5.    *Data from Lester SC: The breast. In Kumar V, Abbas AK, Fausto N, editors: Robbins & Cotran pathologic basis of disease, ed 7, Philadelphia, 2005, Saunders.    5Currently debated.  DCIS, Ductal carcinoma in situ; LC/S, lobular carcinoma in situ.    and subsequent tumor cell metastasis.!° This alteration pro-  vides support to the tissue change in stroma for driving car-  cinogenesis.*"° The presence of macrophages in the involuting  mammary gland contributes to carcinogenesis.!°°°! Imma-  ture macrophages are capable of suppressing cytotoxic T-cell  function causing an immunosuppressive stroma conducive to  tumor cell promotion. Macrophage and T-cell abundance in  breast cancer represent prognostic indicators for tumor recur-  rence and overall survival.°* (Involution and pathophysiology  are discussed on p. 845.)   The main mechanisms for the protective effect of pregnancy  are controversial including: (1) induction of breast differentia-  tion with lasting protective phenotypic (morphologic) changes;  (2) altered cell fate with removal or modification of vulnerable  cells, possibly stem cells; (3) enhancement of the ability for DNA  repair or apoptosis, or both; (4) altered systemic hormonal  regulation and possible persistent changes in intracellular path-  ways regulating proliferation; (5) decreased proliferation in the  parous involuted gland; and (6) early-life hormonal and dietary  exposures.'”’ Longer duration of breast-feeding (at least 1 year)    is associated with a decreased risk of both hormone receptor—  positive and hormone receptor—negative breast cancer.?°° In  older first-time mothers, there is theoretically a greater chance  for precancerous breast lesions to continue to develop with  pregnancy or with events related to pregnancy, for example,  postpartum gland involution!” (see p. 845).   Amphiregulin (AREG) was found to be a major paracrine  mediator of ductal morphogenesis and plays an important  role in mammary stem cell self-renewal and differentiation.*™*  Recent studies show that AREG modulates WNT and NOTCH  signaling and functions in regulating the invasive phenotype.*”°  Investigators are focusing on the TP53 tumor-suppressor gene,  which has been demonstrated to be important in pregnancy-  related hormone-induced protection. The function of TP53  is required for hormone-mediated protection against the car-  cinogens dimethylbenz(a)anthracene (DMBA)-induced carci-  nogenesis in mice.!”? The functions of cadherins or adhesion  molecules and p53 (protein) are closely linked. A pivotal role  for p53 is the regulation of a balance between apoptosis and  cell proliferation.2°° Russo and colleagues*’’ have found that    the postpregnancy involuted mammary gland exhibits elevated  expression of genes involved in DNA repair and apoptosis.  Pregnancy may induce a protective mechanism at the post-  transcriptional level (epigenetically) that maintains the faithful-  ness of the transcriptional process.°*    Part of the uniqueness of the mammary gland is its profound  physiologic changes throughout the phases of a woman’s life:  puberty, pregnancy, lactation, postlactational involution, and  aging. The human breast is organized to 15 to 20 major lobes,  each with lobules containing milk-forming acini (see Figure  23-19). With aging, breast lobules regress or involute with a  decrease in the number and size of acini per lobule and replace-  ment of the intralobular stroma with the more dense collagen  of connective tissue.*”? Over time the glandular elements and  collagen are replaced with fatty tissue. This process is called  lobular involution whereby, over many years, the parenchymal  elements progressively atrophy and disappear. A first study of  its kind found lobular involution was associated with reduced  risk of breast cancer. Breast cancer risk decreased with increas-  ing extent of involution in both high- and low-risk subgroups  defined by family history of breast cancer, epithelial atypia,  reproductive history, and age. Based on histologic and epidemi-  ologic factors, these investigators propose that delayed involu-  tion (persistent glandular epithelium) is a major risk factor for  breast cancer.*°’ Widely appreciated is that as women age, their  risk of breast cancer increases. But the rate of increase of breast  cancer slows at about 50 years of age.*!° This slowing has been  attributed to a reduction in ovarian hormone production. Mila-  nese and colleagues””’ observed a definite increase in the process  of involution at about 50 years of age with complete involution  present in 5.8% of women ages 40 to 49 years and 21.6% of  women ages 50 to 59 years. Investigators propose that involu-  tion may contribute to this slowing in the rate of increase of  breast cancer among women older than 50 years. Importantly,  investigators found an inverse association between lobular  involution and parity.*” Other investigators have reported that  the more children a woman has, the more likely she is to have  persistent lobular tissue,?!! which Milanese and colleagues*””  found was associated with increased risk of breast cancer. How-  ever, multiparity also has been found to reduce risk of breast  cancer.”!?7!> This apparent contradiction may be explained by  studies documenting that full-term pregnancies after 35 years  of age are correlated with an increased risk of breast cancer.*!*  In the Milanese study, age of the mother at each child’s birth  was unknown.   Henson and colleagues’!° propose that late pregnancy with  its concomitant increase in the proliferation of the ductal-  alveolar epithelium is likely to interrupt the process of invo-  lution, which typically begins between 30 and 40 years of age.  The activated stromal environment in the process of involu-  tion is similar to that in invasive breast cancer. The long-term  protective effects of pregnancy with hormones released during  pregnancy affect remodeling of the stromal microenvironment  by causing apoptosis and involution. However, an increase in    3 Shas i Pas te DES  FIGURE 24-31 Extracellular Matrix (ECM) Is Different in Nulliparous,  Lactating, and Involuting Glands. Several ECM differences between nulliparous,  lactational, and involuting mammary glands are related to collagen-fiber organiza-  tion, cell motility and attachment, and cytokine regulation in a rodent model. Many  protumorigenic ECM proteins are mediators of breast cancer progression specific  to the involutional window, and systemic ibuprofen experimental treatment dur-  ing involution decreases its tumor promotional changes. (From O’Brien JH et al:  J Proteome Res 11:4894—4905, 2012.)    breast cancer risk following pregnancy may be caused by the  process of mammary gland involution, which returns the tissue  back to its prepregnant state and is co-opted by processes of  wound healing resulting in a proinflammatory environment  that although physiologically normal can promote carcinogen-  esis.7°! Postpartum involution uses the biologically coordinated  programs of epithelial cell death and stromal remodeling to  change the gland back to its original nonsecretory state before  the next pregnancy.!*4 In a mouse model, human breast cancer  cells exposed to the involuting mammary microenvironment  form large tumors with abundant fibrillar collagen, high COX-2  expression, and further evidence of an invasive phenotype.!”*  Additionally, macrophages, specifically M2-polarized macro-  phages, are necessary for the epithelial cell death during nor-  mal postpartum mammary gland involution.”!° Therefore, the  re-emerging stroma and activated immune cells seem key for  understanding the pathogenesis of pregnancy-associated breast  cancer. An important transcriptional regulator of genes, Stat3,  is associated with inflammation, wound healing, mammary  macrophages, and mast cells. Stat3 appears to have an impor-  tant role in modulating cell death and involution.”!” In postlac-  tational involution the mammary gland regresses and remodels  to its prepregnant state whereby fibroblasts secrete proteases  that degrade the extracellular matrix proteins. Consequently,  the increased release of bioactive matrix fragments can pro-  mote tumor growth, motility, and invasion.!’? The extracellular  matrix (ECM) is very different between nulliparous, lactating,  and involuting glands as shown in Figure 24-31 (see What’s  New? Breastfeeding and a New Emerging Target—NSAIDs for  the Prevention of Pregnancy-Associated Breast Cancer).   Interestingly, oophorectomy, which is associated with  a decrease in risk of breast cancer, leads to atrophy of breast  parenchyma in young women as is noted in older women. Thus  the risk reduction of oophorectomy may be caused by an accel-  erated involution.”!°    The link between breast cancer and hormones is based on six  factors that affect risk: (1) the protective effect of an early (i.e.,  in the 20s) first pregnancy; (2) the protective effect of removal of  the ovaries and pituitary gland; (3) the increased risk associated    Breastfeeding and a New Emerging Target —NSAIDs for the Prevention of Pregnancy-Associated    A longer duration of breast-feeding is correlated with a lower risk of breast  cancer.! In reports of large sample sizes, the risk-reducing effect was observed  for both pre-and postmenopausal women.'.? Longer duration of breast-feeding  reduced the risk of triple-negative cancers but not for luminal cancers.? The  longer the duration of breast-feeding per child was related to lowered risks  of breast cancer.*° Although it has not been adequately studied, one hypoth-  esis for why longer duration of breast-feeding is protective against breast  cancer is that a slow-paced weaning may decrease the stromal inflammatory  reaction during the breast involution. Pregnancy and postpartum involution  both affect a woman’s risk for breast cancer. The postpartum period is associ-  ated with a transient 5- to 10-year period of increased risk crossing over to a  protective effect.’ Recent pregnancy correlates with decreased survival for  breast cancer patients compared with nonpregnancy-associated breast can-  cer.'9 Postpartum breast cancers are known as type II pregnancy-associated  breast cancer (PABC). Mechanisms of postpartum mammary gland involution  in which the physiologic programs similar to those involved in wound healing  are activated to remodel the lactationally competent mammary gland back to a  nonsecretory state likely account for the poorer prognosis of PABC.'' Recently,  having breast-fed and the total duration of breast-feeding conferred a sub-  stantial reduction in breast cancer risk among BRCA7 but not BRCA2 mutation  carriers, of 32%.'2   Investigators using the lactogenic microenvironment to discover new therapies  that would promote breast differentiation (thus decrease the risk of cell trans-  formation) developed a lactogenic mouse model. These investigators showed  that the loss of a single gene, caveolin-3 (cav-3) expressed in myoepithelial    cells within the mammary gland, conferred protection against mammary tumor  formation.'? These results support the fact that the lactogenic microenviron-  ment is a critical factor in preventing mammary tumor onset, progression, and  metastases. 2   Investigators demonstrated that cyclo-oxygenase 2 (COX-2), an enzyme  involved in initiating inflammatory responses, is up-regulated in the mammary  gland during involution. COX-2 inhibition is considered an important target for  prevention and treatment of several cancers.'* NSAID treatment (ibuprofen) in  animal models of PABC decreases tumor-promotional attributes of postpartum  involution mammary extracellular matrix.'* Treatment inhibited tumor progres-  sion, in part, by suppressing COX-2—dependent collagen deposition. Investiga-  tors assessed drug effects on the process of mammary gland involution. They  demonstrated that COX-2 inhibition by NSAIDs can decrease COX-2 activity  in the gland without interruption of involution.'* NSAIDs suppress tenascin-  C, a glycoprotein, expressed in mesenchymal tissues during development  and re-expressed during carcinogenesis.'* Studies investigating promotion of  breast cancers that develop in the postpartum period have identified fibrillar  collagen as an ECM mediator of progression that can be targeted by ibupro-  fen treatment.'®'© Organization of collagen into radially aligned fibers, called  tumor-associated collagen, predicts survival in women with breast cancer.'’  M2-polarized macrophages are necessary for epithelial cell death during nor-  mal postpartum mammary gland involution.'® Macrophages and their monocytic  precursors can change their functional state (e.g., exhibit plasticity) in response  to cues from the microenvironment. For example, macrophages can be func-  tionally polarized into M1 (proinflammatory) and M2 (alternatively activated),    Mammary Epithelial Cells, Immune Modulation, Tumor Supportive. The switch from lactation (/eft) to involution  (right) promotes milk-producing epithelial cells to undergo apoptosis (dark blue cells) and then the cells extrude into the  alveolar lumen. Other milk-producing cells are activated to become phagocytic cells (/ight blue cells) and engulf the shed  apoptotic (dead) cells. Clearance by the immune system of apoptotic cells is thought to result in release of Th2 cytokines  and growth factors from the phagocytic mammary cells. This changed cytokine environment is anticipated to promote  alternative activation of macrophages (see text) and inhibition of a protective immune response or cytotoxic T lymphocyte  (CTL) cells, resulting in an immunosuppressive environment and promoting a tumor microenvironment (green cells). (From    Breastfeeding and a New Emerging Target—NSAIDs for the Prevention of Pregnancy-Associated Breast    called M2-polarized macrophages. ' Interleukin-4 (IL-4) and IL-13, cytokines of  the Th2 response, are the major inducers of the “alternative activation” of mac-  rophages that play an important role in the immune response to parasites, in  allergy, wound healing, and tissue remodeling." The figure on p. 846 represents  a recent model of phagocytic mammary epithelial cells and a protumorigenic  microenvironment.   NSAIDs potentially represent a promising treatment for type Il PABC without  interrupting postpartum remodeling. Elucidation on the mechanisms of lobular  involution is very important for understanding breast carcinogenesis and factors  that reduce breast cancer risk. Factors related to the risk of breast cancer are  diverse and not just limited to reproductive factors. However, with later age of  first full-term birth around the world, concern is for increasing the baseline risk  of breast cancers.    References  1. Collaborative Group on Hormonal Factors in Breast Cancer: Lancet  360(9328):187-195, 2002.  2. Ursin G et al: Br J Cancer 93(3):364—371, 2005.    with early menarche, late menopause, and nulliparity; (4)  the relationship between types of fat, free estrogen levels, and  oxidative changes in estrogen metabolism; (5) the hormone-  dependent development and differentiation of mammary gland  structures; and (6) the efficacy of antihormone therapies for  treatment and prevention of breast cancer. Throughout its exis-  tence, the mammary gland epithelium proceeds through critical  “exposure periods” of rapid growth or cycles of proliferation,  including neonatal growth, pubertal development, pregnancy,  lactation, and involution (after pregnancy and postmenopause;  see p. 845),201218   Our understanding of the role of systemic hormones as  powerful regulators of mammary gland development is shift-  ing. Evidence is pointing to the wide-ranging effects of systemic  hormones as possibly not due to their direct hormone action  but rather their induced actions from multiple secondary para-  crine effectors—thus the term hierarchical.!°? Unraveling is a  complex model of hormone, paracrine, and adhesion molecule-  signaling pathways affecting epithelial and stromal cell fate in  development and cancer (Figure 24-32). Despite differences  between the organized process of development and the less,  even chaotic, environment of invasive cancer, both processes  share many identical mechanisms and signaling pathways. Key  is tissue remodeling that applies to pubertal growth, imme-  diately after pregnancy and during involution (see previous  section).20!:219,220   The female reproductive hormones (estrogens, progester-  one, and prolactin) have a major role and effect on mammary  gland development and breast cancer (Figure 24-33).7!° A vast  majority of breast cancers are initially hormone dependent  (estrogen receptor positive [ER+] and/or progesterone recep-  tor positive [PR+]), with estrogens playing a crucial role in their  development.””! Estrogens control processes critical for cellular    . Gaudet MM et al: Breast Cancer Res Treat 130(2):587-597, 2011.   . Lambe M et al: NV Eng/ J Med 331(1):5—9, 1994.   . Lyons TR, Schedin PJ, Borges VF: J Mammary Gland Biol Neoplasia  14(2):87—98, 2009.   . O'Brien O et al: /nt J Dev Biol 55:745-755, 2011.   . Cassetta L, Cassol E, Poli G: Sci World J 11:2391—2402, 2011.    functions by regulating activities and expression of key signal-  ing molecules. These processes include regulation of recep-  tor activity, its interaction with other intracellular proteins,  and DNA.*’! Estrogens thus play prominent roles in cellular  proliferation, differentiation, and apoptosis.”*!?*> Estrogens  affect microtubules that are essential for establishing cell  shape and cell polarity, processes necessary for epithelial gland  organization.””!   Depending on the experimental model system used, proges-  terone in animal and in vitro studies show both an increase and  decrease in breast cancer risk?**?*° (see following discussion).  These data question the continuing view that PR is co-expressed  in every ER+ luminal cell, highlighting the potential for ER and  PR to individually contribute to the biology of normal breast  development, function, and role in breast carcinogenesis*”’  (Figure 24-34, and see p. 849). Additionally these data identify  a novel cell population that may be very important in under-  standing the cancer-causing effects of synthetic progestins in  hormone replacement therapy (HRT) (see p. 853).   Prolactin, produced by the pituitary gland, travels through  the blood and exerts multiple metabolic and reproductive  effects especially on the breast as the key regulator of lactation.  Prolactin is also produced in other tissues, including the breast  (known as extrapituitary prolactin).*7>?? Recently, investiga-  tors reported that autocrine prolactin is required for terminal  mammary epithelial differentiation during pregnancy and  production is regulated by the signaling pathway Pten-PI3K-  Akt.’? Although this finding is critical for normal breast devel-  opment, differentiation, and lactation it may also be important  in breast carcinogenesis because the PI3K-Akt signaling path-  way is commonly activated in human cancers. This suggests  the important possibility that autocrine prolactin may play a  role in breast cancer.    FIGURE 24-32 Figure of the Current Hypothesis of Mammary Gland During Development and Cancer. A tissue  model of interacting endocrine, paracrine, and adhesion signaling pathways that modulate epithelial and stromal cell behavior.  Some of the pathways depicted are not exclusive to one type of stromal cell. Dotted arrows indicate indirect interactions.  (From Lanigan F et al: Cell Mol Life Sci 64:3165, 2007.)    FIGURE 24-33 Factors Involved in Mammary Gland Development. Work of numerous laboratories led to the identifi-  cation of many genes important in mammary gland development that are summarized in the scheme. (Adapted from Brisken C,  O'Malley B: Cold Spring Harb Perspect Biol 2[12]:a003178. [Epub 2010 Aug 25.})    It is possible to consider four major hormonal hypotheses  for breast cancer: (1) ovarian androgen excess (testosterone,  for example), (2) estrogens and progesterone levels (ovarian  and hormonal replacement), (3) estrogens alone (ovarian and  hormone replacement), and, (4) local biosynthesis of estro-  gens in breast tissue. These hypotheses, however, may not be  mutually exclusive. HRT is discussed later in a separate section;  the present discussion is concerned with endogenous levels of  hormones.   The first hypothesis that breast cancer risk is increased  among women who have ovarian androgen excess also includes  chronic anovulation and reduction of luteal-phase (menstrual    cycle) progesterone production. Therefore, it is also called the  “ovarian hyperandrogenism/luteal inadequacy hypothesis.”  This hypothesis, proposed by Grattarola in the 1960s, was  based on the observation that women with breast cancer also  reveal hyperplasia of the endometrium—a common symptom  of ovarian, androgen excess chronic anovulation, and proges-  terone deficiency.”!? These findings have been confirmed and  extended’? in several studies including prospective studies.  From a pooled analysis of nine prospective studies of postmeno-  pausal women, all the androgens were positively (significantly)  associated with breast cancer risk.”*! The majority of data from  this pooled analysis were for testosterone. Similar findings were    FIGURE 24-34 Progesterone Progenitor Cells, a Working Model. The fate of progesterone receptor—positive (PR+)  progenitor cells is important to understand for normal breast development and breast carcinogenesis. When P levels peak  during the second phase of the menstrual cycle and during pregnancy, a subset of PR+ bipotent (more than one type of cell)  progenitor cells proliferate to expand the epithelial compartment providing a larger pool of cells susceptible to oncogenic  mutation. These cells can then differentiate into mature luminal cells that can respond to the proliferative and secretory sig-  nals of both estrogen (E) and progesterone (P). This process is increased by the E induction of PR expression in this cell subtype.    observed in the European Prospective Investigation into Cancer  and Nutrition (EPIC) cohort study.**” Four prospective studies  have reported a positive association for premenopausal women  between testosterone and risk of breast cancer.’*> A prospec-  tive Italian study showed a significant increase in breast can-  cer risk for premenopausal women who had elevated levels of  testosterone and lower levels of progesterone.*** In a recent  case-control study serum androgens were associated with both  ER+, PR+ and ER-, PR- cancers.**° A case-control study nested  with the New York University Women’s Health Study showed  premenopausal serum testosterone and free testosterone con-  centrations were positively associated with breast cancer risk.”°°  Unclear from studies is whether the association with testoster-  one is direct or indirect (i.e., enzyme conversion by tissue aro-  matase of testosterone to estradiol) (Figure 24-35). Overall, the  association between circulating testosterone in postmenopausal  women and subsequent risk of breast cancer is now well estab-  lished.?°” Indeed some investigators propose increased andro-  genic activity is the principal endocrine abnormality of women  with hormone-dependent breast cancer called the androgen-  excess theory.*** These investigators suggest that androgen  excess is the main growth stimulator of ER+ tumors through  testosterone conversion into estrogens through the aromatase  enzyme in stromal tissue (see the fourth hypothesis in the fol-  lowing text). Studies have demonstrated a correlation between  the androgen receptor (AR) and ER/PR pathways, a potential  role for AR in prognosis, carcinoma proliferative responses to  androgen in several AR expressing cell lines, and expression of  an androgen-dependent cascade of intracellular signaling in  AR expressing breast tumors. AR is reported to be expressed    in 50% to 100% of breast cancers; however, controversy exists  about the percentages because of study methods used.”°” A sub-  set of individuals with triple negative breast cancer (TNBC)  has been reported to express AR in carcinoma cells leading to  the treatment proposal of manipulation of androgen signaling  or AR targeted therapies. Further study is needed because of  the reported proliferative and antiproliferative effects of AR in  TNBC.?*? For those women with high testosterone/AR-negative  tumors, androgen excess does not stimulate tumor growth  directly through conversions to estrogens but can by increas-  ing the production of epidermal growth factor (EGF) and EGF  inhibitors may be indicated.”°*   The second hypothesis is increased breast cancer risk among  women with blood elevations of both estrogens and androgens.  These observations revealed increased proliferation rates of  breast epithelium during the luteal phase of the menstrual cycle  when the ovaries produce both estradiol and progesterone.  A recent reanalysis of 13 prospective studies showed that circu-  lating concentrations of sex hormones are associated with sev-  eral of the established or suspected risk factors for breast cancer.  The hormones were all positively correlated with each other,  implying they are all part of the same metabolic pathway.”“°  The strongest associations were with BMI and all the hormones  were higher in obese women with breast cancer than in women  with a low BMI. Analyses related to increasing age found large  decreases in circulating DHEAS and androstenedione, small  changes in estrogens and testosterone, and increases in SHBG  (consistent with other previous reports). The smaller decrease  in estrogen blood concentrations may be caused by increased  synthesis of estrogen in tissue by aromatization in older women    FIGURE 24-35 Local Biosynthesis of Estrogens. Three main enzyme complexes (ye//ow) involved in estrogen formation  in breast tissue, including aromatase, sulfatase, and 17B-estradiol hydroxysteroid dehydrogenase (17B-HSD). Thus despite low  levels of circulating estrogens in postmenopausal women with breast cancer, the tissue levels are several-fold higher than  those in plasma, suggesting tumor accumulation of these estrogens. Data suggest that most abundant is sulfatase in both  premenopausal and postmenopausal women with breast cancer. Numerous agents can block the aromatase action, explora-  tion of progesterone, and various progestins to inhibit sulfatase and 17B-HSD or stimulate sulfotransferase (i.e., breast cancer  cells cannot inactivate estrogens because they lack sulfotransferase) may provide new possibilities for treatment. LOH, Loss of  heterozygosity (see Chapter 12). (Adapted from Russo J, Russo |: Molecular basis of breast cancer: prevention and treatment,    or women with ovariectomy, or both.*“° Ovariectomy was asso-  ciated with androgen levels about 30% lower than from women  with natural menopause. Surprisingly, no significant differences  in those women with ovariectomy were found for total estra-  diol or estrone (researchers excluded women using exogenous  hormone therapies). Cigarette smoking and alcohol use were  associated with moderate increases in all the hormones. Age at  menarche, age at parity, age at first-term pregnancy, and fam-  ily history of breast cancer were not strongly related to any of  the hormones studies. From this study, type of hormone assay  used affected some of the results and assays that used a purifica-  tion step were more specific and sensitive.**° Overall, older data  are too few to draw any firm conclusions.”*» New data identify  mammary stem cells (MaSCs) as critical targets for ovarian  hormones, especially progesterone surges during the normal  reproductive cycle and pregnancy increasing the proliferation  of mammary stem cells.4!74? Progesterone-expanded MaSC  pools could accumulate mutations and acquire the properties of  tumor-initiating cells. From these studies the progestin in HRT  was proposed as a risk factor because of the presence of hidden  or occult preinvasive breast cancer in postmenopausal women  that contains ER-/PR-/CK5+ stem cells, which may be reac-  tivated by progestins and function as tumor-initiating cells.7*°    Overall, complex data indicate that progesterone as a prolif-  erative hormone is a risk factor for breast cancer (promotes  preneoplastic progression) and stimulates the normal breast  epithelium through a complex paracrine mechanism (Figure  24-36, A). Paradoxically, however, in the more advanced stage  of breast cancer, PR either independent of progesterone hor-  mone or in response to progesterone is proposed to impede  invasion and metastasis by maintaining epithelial cell differ-  entiation and inhibiting epithelial-mesenchymal transition  (EMT) a key developmental process often activated in cancer  invasion and metastasis (see Figure 24-36, B, and Pathogenesis  section). Dysregulation of the RANKL-RANK signaling path-  way is implicated in both the initiation and progression of pro-  gesterone-dependent mammary carcinomas, and inhibitors of  RANK or RANKL are suggested to have an effect on the devel-  opment of breast cancer.**°   The third hypothesis is often called the “estrogen-alone  hypothesis.” Substantial prospective data have accrued on cir-  culating estrogens and breast cancer risk in postmenopausal  women.”*!9744 From the EPIC study,”*? increasing blood lev-  els of estradiol also increased the risks for breast cancer (rela-  tive risks 1.4,1.2,1.8, 2). Updated analyses from two cohorts of  the pooled analysis of nine prospective studies provide strong    FIGURE 24-36 A Model of Progesterone Regulation of Mammary Cell Proliferation. A, Model for progesterone reg-  ulation of cell proliferation in the mammary epithelium mediated by the RANK-RANKL paracrine signaling pathway. This model  is based on work with the mouse mammary gland; RANKL is a direct target of PR induced by progesterone (P4) and is then  released to interact with the RANK receptor on either PR+ or PR— cells. In PR+ cells, RANKL activates the downstream IKK/  IkB/NFkB/cyclin D1 signaling pathway to stimulate proliferation. RANKL does not generate a sustained activation of the NFkB/  cyclin D1 proliferative pathway in PR+ cells because of the suppressive actions of TGF-B and/or other unknown mechanisms.    FIGURE 24-36, cont’d A Model of Progesterone Regulation of Mammary Cell Proliferation. B, Model for proges-  terone and PR action at stages of breast cancer progression. Progesterone is a risk factor for breast cancer and promotes pre-  neoplastic progression by stimulating cyclic proliferation of the mature breast epithelium and by activating mammary stem cell  pools or hidden tumor-initiating cells. Alterations in the progesterone/PR signaling axis, including a switch from a paracrine to  an autocrine regulation of proliferation, contribute to progression. In more advanced stage breast cancer PR, either indepen-  dent of P4 or in response to P4, suppresses tumor invasion and metastasis through maintaining epithelial cell phenotype and  impeding the epithelial-mesenchymal transition (EMT). 7GF Tumor growth factor. (Adapted from Obr AE, Edwards DP: Mol Cell    evidence that circulating hormones are an important marker of  increased risk in postmenopausal women and not a result of the  production of hormones by a tumor.**° Positive associations  with urinary estrogen levels also were similar from two prospec-  tive studies.“4°47 A recent large case-control study nested with  the EPIC prospective cohort study showed that serum levels of  total and bioavailable testosterone and estradiol are associated  with risks of ER+, PR+, joint ER+PR+, and surprisingly, with  ER-, PR-, and joint ER-PR- breast tumors. Estrogen binding  to the receptor ER-alpha increases tumor growth and in clinical  studies only individuals with ER+ tumors respond favorably to  antiestrogenic therapy. It is, therefore, paradoxical that in this  case-control study estrogens showed a direct association with  ER-, PR-, and joint ER-PR- breast cancer and only moderately  smaller (effect size) than seen for hormone receptor—positive  disease.?*°   EPIC and other studies, however, observed no clear relation-  ship between plasma estrogen levels and breast cancer risk in  premenopausal women.”°* Yet investigators had little ability to  evaluate hormonal levels with phases of the menstrual cycle. In  premenopausal women, the NHS I] found in the follicular phase  of the menstrual cycle, but not the luteal phase, that circulating  total and free estradiol was significantly associated with breast  cancer risk.*4* Experimental studies have also provided strong  and consistent evidence that estrogens can promote breast tumor  development and growth”? (see the Pathogenesis section).   Overall, the positive association between circulating estro-  gens in postmenopausal women and subsequent risk of breast  cancer is well established. The association appears strongest  for estrogen-positive tumors and is statistically robust across    groups of women at varying risk of breast cancer.’*’ Relatively  few studies on circulating sex steroids and breast cancer have  been conducted in premenopausal women, possibly because of  the difficulty to accurately assess hormones levels over the men-  strual cycle.   The fourth hypothesis suggests that Jocal (in situ; paracrine)  formation of estrogens in breast tumors may be more signifi-  cant than circulating estrogens in plasma for the growth and  survival of estrogen-dependent breast cancer in postmeno-  pausal women. The rationale is based on the following evidence:  (1) estradiol (E,) levels in breast tumors are equivalent to those  of premenopausal women, despite plasma E, levels being lower  after menopause; (2) E, concentrations in breast tumors of  postmenopausal women are at least 10 times higher than serum  levels; and (3) biosynthesis of estrogens in breast tumors occurs  through two different routes, the aromatase pathway and the  steroid sulfate (STS) pathway”?! (see Figure 24-35).   Estrogens in normal breast tissue in pre- and postmeno-  pausal women are comparable, reflecting other than ovarian  biosynthesis of estrogens that occurs in several peripheral tissues  including adipose, muscle, skin, bone, brain, aorta, and breast  tissues.?°°>! A series of enzymes are involved in in situ produc-  tion of estrogens in breast carcinoma tissues, but aromatase  (member of the cytochrome P-450 family) is a key enzyme of  estrogen production through conversion of adrenal androgens  in estrogen-dependent postmenopausal breast cancer.’>” Breast  tissue metabolism of estrogens through the aromatase-mediated  pathway is correlated with the risk of breast carcinogenesis.  Evidence suggests that the site of conversion of androgens to  estrogens in breast cancer is the stroma and not the malignant    FIGURE 24-37 Breast Cancer Cells and Stromal Fibroblasts Produce Estrogen. In the microenvironment of breast  carcinoma, breast cancer cells interact with different stromal cells through the secretion of growth factors and cytokines.  Fibroblasts adjacent to cancer cells produce estrogen through the expression of the enzyme aromatase, which is induced  by several factors including tumor necrosis factor alpha (TNF-a), interleukin 1 (IL-1), and cyclo-oxygenase 2 (COX-2). These  interactions lead to cancer cell proliferation, angiogenesis, and metastasis. (Adapted from Yamaguchi Y, Hayashi S: Endocr    epithelial cells.2°? Stromal fibroblasts adjacent to the tumor  express aromatase and actively induce local estrogen produc-  tion and signal crosstalk between estrogen and growth factors  affecting the progression of breast carcinomas (Figure 24-37).   Investigators also have reported aromatase in adipocytes and  carcinoma cells.2°° Stromal fibroblasts demonstrate multiple  functions in the genesis and progression of breast cancers and  carcinoma-associated fibroblast (CAFs) are potential therapeu-  tic targets for many other cancers.   Breast tissue also contains high sulfatase activity and produces  estrone through the hydrolysis of estrone sulfate’?! (see Figure  24-35). Thus quantitatively estrone sulfate may be the most  important circulating estrogen in women; it increases the res-  ervoir for the production of estrone and, ultimately, estradiol. It  was found that E,, itself, has antisulfatase action. This paradoxi-  cal effect of estradiol could be related to some studies that have  found estrogen replacement therapy (ERT) to have either no  effect or to decrease breast cancer mortality in postmenopausal  women?” (see p. 854). In summary, the blockage of estradiol  through both the aromatase and sulfatase pathways, as well as the  stimulation of sulfotransferase activity (i.e., sulfation is impor-  tant to estrogens because the addition of the charged sulfonate  group protects the hormones [estrogens] from binding to their  receptors and, consequently, inhibiting cell growth) can provide  new and potentially powerful applications in breast cancer.   Although experimental, clinical, and epidemiologic research  have implicated endogenous estrogens in the etiology of breast    and endometrial cancer and, possibly, ovarian cancer, the role  of individual patterns of estrogen metabolism is a new focus,  especially for epidemiology.*”? Estrogen metabolism from oxi-  dation of the parent estrogens, estrone, and estradiol occurs at  either the 2-, 4-, or 16-position of the carbon skeleton to yield  2-hydroxylated, 4-hydroxylated, or 16-hydroxylated estrogens,  respectively. The 4- and 16-a-hydroxylated pathways are poten-  tially tumor promoting; conversely, the 2-hydroxylated path-  way has been demonstrated to be less tumor promoting and,  possibly, inhibiting.*>* A recent prospective case-control study  found nearly all estrogens, estrogen metabolites, and metabolic  pathway groups were associated with an increased risk of breast  cancer especially unconjugated estradiol. These investigators  found more extensive 2-hydroxylation of estrogens is associated  with lower risk and less methylation of potentially genotoxic  4-hydroxylation pathway with a higher risk of breast cancer in  postmenopausal women.**° Thus potential imbalances in estro-  gen metabolites in breast tissue correlate with the development  of tumors and suggest possible biomarkers related to the risk of  developing breast cancer.   Hormone Replacement Therapy (HRT) and Breast Cancer  Risk: Estrogen Plus Progesterone and Estrogen Only (ERT). Most  epidemiologic studies have found an increase in breast cancer  risk related to HRT with combined estrogen and progestogens  (HRT)?°°?°7 (Table 24-14). Evidence comes from observational  studies and clinical trials and suggests an approximate 30% to  70% increase in breast cancer risk with HRT current use and    Breast (exposure during pregnancy),  vagina and cervix (exposure in  utero); limited evidence: testis  (exposure in utero), endometrium    breast cancer risk disappearing a few years after treatment  discontinuation.”°**° Additional support for HRT to increase  breast cancer risk was the reduction in risk reported by several  countries with discontinuation of HRT use.?°”°!   Evidence on the route of administration of HRT, oral ver-  sus transdermal (gel or patch), and the risk of breast cancer has  limited research. To date, epidemiologic data suggest the route  has no effect on the risk of breast cancer and hip fracture.”°  Results on route of HRT on risk of coronary heart disease and  colorectal cancer are inconsistent. Studies on the risks of dia-  betes and stroke are too few for clinical evidence. Additionally,  there is a suggestion, that needs research confirmation, that  oral route versus transdermal HRT may increase the risk of  thromboembolism.*™   HRT use has been associated with a greater breast cancer  risk than ERT. Intense debate is whether ERT is associated with  an increase in breast cancer risk compared with never use of  hormone therapy. Use of ERT was associated with a decreased  risk in the Women’s Health Initiative (WHI) randomized trial  even after cessation of treatment”***® but not in observational  studies.?°760.26%207 Prom the recent WHI report, women with  a prior hysterectomy who were followed for 10.7 years and  who used conjugated equine estrogen (CEE) for an average  of 3.5 years (median of 5.9 years) were not associated with an  increased or decreased risk of coronary heart disease (CHD),  deep vein thrombosis, stroke, hip fracture, colorectal can-  cer, or total mortality, and the previous finding of a decrease  in breast cancer risk persisted.*** According to investigators,  this decrease in risk is neither perplexing nor contradictory to  other findings in which estrogen increases risk because of the  underlying biology of breast cancer and estrogen. Laboratory  data support a protective effect of estrogen under the right envi-  ronment—that is, after a period of long-term natural (endog-  enous) estrogen deprivation. If this environment exists, then    exogenous estrogen will induce apoptosis or cell death of the  occult breast cancer cells.2*° The changing concepts in ERT  are related to acquired resistance to long-term antihormonal  therapy in breast cancer. This finding is the basis for the clini-  cal use of estrogen to treat advanced antihormone-resistant  breast cancer.”°”*°* One hypothesis is long-term antiestrogen  treatment or estrogen deprivation causes the development  and progression of antihormone resistance (e.g., from tamoxi-  fen).?°’ Under these environments laboratory data support a  mechanism of estrogen-induced apoptosis (estrogen E, sup-  pressed ER alpha signaling) and produced stress responses,  endoplasmic stress, and inflammatory stress responses, that led  to apoptosis.*° Other proposed causes of treatment resistance  include the changes in the stroma with carcinomas (mesenchy-  mal phenotype),’” p53 status,”! dysregulation of the estrogen  receptor,””* and low levels of nuclear Nu-Sta5a (signal trans-  ducer and activator of transcription-5a).’”> Nonetheless, care-  ful debate has continued about ERT and breast cancer. Issues  include: (1) a potential age effect (younger versus older women)  on the risk-to-benefit profile of hormone therapy (HT),  (2) overall duration and safety (short- and long-term) of HT  use, (3) differential effects of HT in slender or overweight/obese  women, and (4) estrogen decline or deprivation (menopause)  for a specified time (length unknown) then followed by ERT  replacement leads to apoptosis or cell killing of lingering breast  cancer cells. Thus because the use of ERT in the WHI in 80%  or greater (of study pills) was 3.5 years, longer use may still  increase breast cancer risk. Longer use in animal studies has  been linked with increasing cell proliferation, angiogenesis, and  inhibiting apoptosis.*”* Longer use of ERT that may increase  breast cancer risk was found in combined data of 16 studies and  another analysis of 52,705 women with breast cancer.7°?*° In  these studies and the Million Women Study, leaner women had  an even higher risk of breast cancer.?”> Women in the WHI do    not represent the typical woman who might be prescribed HT  for menopausal symptoms.’”° For example, 68% of the women  in the WHI were older than age 60 when enrolled in the study,  thus an older population than the average woman entering  menopause.   Insulin and Insulin-Like Growth Factors. IGFs regulate  cellular functions involving cell proliferation, migratory,  differentiation, and apoptosis. IGF-1 is a protein hormone with  a structure similar to insulin. The growth hormone-IGF-1 axis  can stimulate proliferation of both breast cancer and normal  breast epithelial cells.7”” A pooled analysis of 17 studies showed  a significant association of IGF-1 with breast cancer risk.*7®  Interestingly, no significant difference was found according to  menopausal status. Joint associations of IGF-1 and estradiol  together showed they were related to risk and those women  in the top thirds of estradiol and IGF-1 levels had the highest  risk. Estradiol increases IGF-1 activity in the breast.?”’ Insulin  and IGF-1 receptor family are now known to have a role in  macronutrient intake and cancer, diabetes and cancer, and  obesity and cancer.7*”   Light at night (LAT) can accelerate tumor growth (in vivo),  and one mechanism proposed is continuous activation of  IGF-1 receptor (IGF-1R) signaling.*®! A recent case-control  study of 1679 women exposed to LAT during sleep was signifi-  cantly associated with breast cancer risk.**! This study was the  first to identify bedroom light intensity and breast cancer risk.  Although inconclusive, shift-work and its disruptive effects on  circadian rhythms and sleep deprivation at night have been sug-  gested as a risk factor for breast cancer.?**   Prolactin and Growth Hormone. Grown hormone (GH)  injected in mice acts on mammary stroma.”** GH induces the  production of IGFs in the liver; IGF signaling is important for  breast development and is implicated in breast carcinogenesis.  Two studies, however, have reported a link with GH and  breast cancer risk.?**?*° In the largest prospective analysis of  circulating prolactin and breast cancer risk, those with the  highest levels had the highest risk.*°° (For more on prolactin  see p. 847.)   Human Chorionic Gonadotropin. hCG increases during the first  trimester and then rapidly declines to a steady state throughout  pregnancy. Data from rat studies indicate that hCG may be useful  in developing new therapies because it has antiproliferative and  anti-invasive effects.**” However, insufficient data exist on the  safety of hCG; its role in carcinogenesis is complex and much  research needs to be done.?**   Oral Contraceptives. The International Agency for Research  on Cancer (IARC) group confirmed that combined estrogen-  progestogen OCs increase the risk for breast, cervix, and liver  cancers.*°’ A recent meta-analysis of 66 studies showed current  use of oral contraceptives, nulliparity, and 30 years or older at  first birth were associated with a 1- to 1.5-fold increased risk  of breast cancer.**? Hormones are discussed further in the  Pathogenesis section.    Mammographic breast density (MBD) is the radiologic  appearance of the breast (largely stromal and epithelial tissues)    FIGURE 24-38 Breast Density Varies Among Women. The sensitivity of  mammography for detecting malignancy is significantly reduced if the breast con-  sists of a high proportion of fibroglandular (dense) breast tissue (A) compared to a  breast that is fatty (B). (From O'Malley FP, Pinder SE, Mulligan AM: Breast pathol-  ogy, ed 2, Philadelphia, 2011, Saunders.)    reflecting variations in breast tissue composition (Figure  24-38). Mammographic breast density appears white or dense  on a mammogram, is expressed as a percentage of the mam-  mogram (percent mammographic density), and is a strong and  consistent risk factor for breast cancer.?”?’! Percent mam-  mographic density (PMD) estimates the proportion of stro-  mal and epithelial tissues in relation to fat tissue in the breast.  Internationally, studies done in the United States, Canada, and  Europe all found that a significant increase in risk associated  with more extensive PMD; risk persisted for 8 to 10 years from  the date of the mammogram, and increased with increasing  PMD. Extensive PMD is associated with a markedly increased  risk of invasive breast cancer.**? Thus extensive breast density  is one of the strongest risk factors for developing breast can-  cer and second only to age and carrying a BRCAI or BRCA2  mutation.””** Lifestyle factors, including age, parity, BMI,  and exogenous hormone levels, explain about 20% to 30% of  the variation in PMD among women. The estimate of 61% to  67% of the variation could be caused by genetic factors; how-  ever, linkage and candidate gene association studies have not  reproducibly identified loci related to MBD.*°? A recent meta-  analysis of five genome-wide studies of PMD discovered an  association between common variants in ZNF365 and breast  cancer. DNA methylation or other epigenetic studies of breast  density are commencing.    The environmental causes of breast cancer possibly affect the  breast the most during critical phases or “windows” of devel-  opment including early differential stages—that is, undif-  ferentiated cells to alveolar buds and then lobules, puberty,  pregnancy and lactation, involution, and menopause. During  early phases, mitotic activity and cell division are greater than  later in life.    Radiation. Ionizing radiation is a known mutagen and  established carcinogen for breast cancer. To date, only  accidentally or medically induced radiation has been  demonstrated to exert a carcinogenic effect on the breast. The  Institute of Medicine (IOM) reports that the two most strongly  associated environmental factors are exposure to ionizing  radiation and combined postmenopausal HT.’** There are  many sources of ionizing radiation, including x-rays, CT  scans, fluoroscopy, and other medical radiologic procedures.  CT imaging is frequently used in the absence of evidence””>?”°  (see Chapter 13), and although only about 10% of diagnostic  radiologic procedures in large U.S. hospitals are CTs, they  contribute an estimated 65% of the effective radiation dose to  the public from all medical x-ray examinations.””’ The IOM  conclusion of a causal relationship between radiation exposure  in the same range as CT and cancer is consistent from a large  varied literature.””? The IOM makes it clear that avoidance  of medical imaging is an important and concrete step that  women [girls] can take to reduce their risk of breast cancer.?”°  Scientists and clinicians also have expressed concern about  the increasing number of CT scans performed, including on  children.??>7°8   The prevailing view has been that major predictors of risk  from radiation are a young age at exposure and the radiation  dose.*”’ Yet, recent data in cell models and epidemiologic  studies in older aged cells shows long-lasting and incomplete  DSB repair.2°°*>* These data show increased carcinogenic  risks of radiation exposure at older ages (see Chapters 2 and  13). Although protocols are continually updated, radiologic  exposure of the upper spine, heart, ribs, lungs, shoulders and  esophagus also can expose breast tissue to radiation. Breast tis-  sue may be exposed from abdominal CT scans.>°° X-rays and  fluoroscopy of infants may constitute whole-body irradiation.  The duration of increased risks from radiation is unknown, but  increased risk appears to have lasted at least 35 years in women  treated for mastitis, those treated with fluoroscopy, and atomic-  bomb survivors.   Cancer induction and exposure to low doses and low  energy x-rays are controversial and the topic of much debate  and research. Biologic understanding related to low doses of  radiation is presented in Chapters 2 and 13. There is continu-  ing debate and discussion of questionable radiation-induced  cancers caused by mammographic screening,*°**"* especially  among women with a positive family history of breast can-  cer.°?°°° Mammography is a low dose of low-energy x-rays  usually of two views done within an interval of a few minutes.  The computed average measure of the radiation absorbed by a  fixed mass of biologic tissue (dose equivalent) used to account  for the different biologic damage potential is about 2 mSv for  low-energy x-rays, although this value has been suggested to be  higher.°°7°8 The mean glandular dose can increase with breast  density,*°’ volume of breast tissue, lack of breast compression,*!°  breast augmentation prosthesis,*!! calling back individuals  for more views, and technical variations in the setup of digital  mammograms.*!? Radiosensitivity of individuals can vary and  become a modifying factor of the radiation response*!*~** (see  also Chapter 13).    Data from epidemiologic studies is challenging and con-  troversial because they may lack sufficient statistical power to  determine the health risks from low-dose radiation.*!” It is cur-  rently accepted that the benefits of screening mammography  outweigh the possible risk of radiation-induced breast cancer  in women 50 years and older. Still controversial and debated  is screening mammography for women 40 to 49 years old and  high-risk women especially those with genetic risk of breast  cancer (Table 24-15 and Box 24-14). Women with genetic risk  might be more susceptible to radiation-induced breast cancer  because suppressor genes are implicated in the response to  ionizing radiation.*!* Radiation-induced DNA double-strand  breaks (DSBs) are considered the most critical lesions and  their misrepair could lead to chromosomal instability.°!2*!°  Several studies have contributed to understanding the biologic  responses of low-dose radiation but have not duplicated the  protocols of mammographic screening (mGy doses, low-energy  x-rays, and repeated exposures) or with an appropriate cellular  model (ie., nontumoral and untransformed breast epithelial  cells) 307315-324   Investigators assessed in vitro mammographic radiation-  induced DNA damage in mammary epithelial cells from 30  women with low (LR) or high (HR) family risk of breast can-  cer. From this study low and repeated doses simulating a two-  view mammogram (2+2 mGy) created more damage than  2 mGy and, overall, more damage than 4 mGy.°!* The low  and repeated dose effect was exacerbated in high-risk women,  and these investigators even argue for avoidance of two view  mammography. According to the National Cancer Institute,  two-view examinations decrease the recall rate compared with  single-view examinations.”   Continuing investigation is whether DSB repair is equally  efficient after low and high doses. Using primary human fibro-  blasts in culture, investigators obtained the surprising finding  that DSBs induced by low radiation doses (a few milligray)  are repaired at a slower rate than DSBs produced by higher  doses.*°°°*?> Other investigators confirmed this finding and  showed that pretreating cells with 10 uL of H,O, generate single  strand breaks and base damage, and improve the ability of cells  to repair the DSBs induced by low radiation doses.°*° Overall,  these data suggest that the cellular response to DSBs is very dif-  ferent for low versus high radiation doses. Confirmation with  additional studies of DNA damage caused by mammographic  exposures needs more subjects and analysis of DNA damage  repair at more than 24 hours after mammography exposure.*!”   Women treated with chest radiation for a pediatric or  young adult cancer have a substantially increased risk of breast  cancer. Investigators from international studies have con-  cluded that diagnostic chest irradiation or radiation therapy  for benign or malignant diseases increases the risk of breast  cancer for cumulative doses as low as 130 mGy. The breast  cancer risk did not decrease when increasing the number of  radiologic treatment fractions for delivering the same total  dose but risk decreased greatly with increasing age of exposure  to ionizing radiation.*”’ International agencies are assessing  the utility of screening MRI and mammography in these high-  risk populations.    TABLE 24-15 BENEFITS AND HARMS OF SCREENING MAMMOGRAPHY:  SUMMARY OF THE EVIDENCE FOR THE UNITED STATES    Screening mammography in women ages 40 to 70 years decreases breast cancer mortality (see Magnitude of Effects below). The benefit is higher for older women,    Study design: Meta-analysis of individual data from four randomized controlled trials (RCTs) and three additional RCTs.  Internal validity: Validity of RCTs varies from poor to good; internal validity of meta-analysis is good.    Magnitude of effects on health outcomes: Relative breast cancer-specific mortality is decreased by 15% for follow-up analysis and 20% for evaluation analysis.  Absolute mortality benefit for women screened annually starting at age 40 is 4 per 10,000 women screened over 10.7 years. The comparable number for women  screened annually starting at age 50 years is approximately 50 per 10,000. Overall, the absolute benefit is approximately 1%, but depends on inherent breast    Treatment of insignificant cancers  (overdiagnosis, true positives)  can result in breast deformity,  lymphedema, thromboembolic  events, or chemotherapy-induced  toxicities    False sense of security, delay in Descriptive population  cancer diagnosis (false-negatives) based    Radiation-induced mutations can Descriptive population  cause breast cancer, especially based  if exposed before age 30 years;  latency is more than 10 years, and  the increased risk persists lifelong    Good Approximately 33% of Good  breast cancers detected by  screening mammograms  represent overdiagnosis    Estimated to occur in 50% of  women screened annually  for 10 years, 25% of whom  will have biopsies   6% to 46% of women with  invasive cancer will have  negative mammograms,  especially if young, with  dense breasts or with  mucinous, lobular, or fast-  growing cancers   Between 9.9 and 32 breast  cancers per 10,000 women  exposed to a cumulative  dose of 1 Sv; risk is higher  for younger women    Data from: National Cancer Institute: Summary of evidence. Available at www.cancer.gov/cancertopics/pdq/screening/breast/healthprofessional/  page 1update 03/30/2012; Nystrom L et al: Lancet 359(9310):909-919, 2002.    Currently an important topic is that radiation and other  treatments can transform cancer cells into treatment-resistant  breast cancer stem cells, even as the treatment kills half of all  cells.**° In some cases, cancer stem cells are generated by the  therapy, and scientists are studying the mechanisms of how this  occurs. DNA damage is a key factor for stem cell activation.  DNA accumulates errors from environmental factors, includ-  ing radiation, drugs (e.g., chemotherapy, hormones), chemi-  cals, viruses, bacteria, or DNA replication errors.*??>°°   The risk of secondary lung malignancy (SLM) is an impor-  tant concern for women treated with whole-breast radiation  therapy after breast-conserving surgery for early-stage breast  cancer.**! Investigators studied SLM risk associated with several  common methods of delivering whole-breast radiation therapy  (RT). Compared with supine whole-breast irradiation (WBI),    prone breast irradiation is associated with a significantly lower  predicted risk of secondary lung malignancy.*?!   Accelerated partial breast irradiation with brachytherapy  following lumpectomy versus traditional WBI has become a  standard treatment. Use of brachytherapy can shorten treat-  ment from 6 weeks to 5 days, theoretically with less risk for side  effects to the heart and lungs (comparison studies are minimal  and a randomized trial is ongoing). Concern is that brachyther-  apy increases the risk of acute skin and wound complications  and may lead to increased rates of mastectomies. Retrospective  data using Medicare claims data from older women indicate  that brachytherapy is more likely than WBI to lead to certain  complications, such as deep tissue and bone complications, and  lung injury is higher with WBI; more data are needed on the  severity of these complications.*°”    BOX 24-14 SUMMARY OF THE USPSTF  RECOMMENDATIONS ON  SCREENING FOR BREAST  CANCER    The USPSTF recommends against routine screening mammography in  women in their 40s who are not at increased risk for breast cancer. The  decision to start mammography before age 50 should be based on a wom-  an’s risk for breast cancer and personal preferences about the benefits and  harms.   The USPSTF recommends mammography every 2 years for women ages 50  to 74.   Current evidence Is not sufficient to assess the effectiveness of clinical  breast examination in addition to screening mammography.   Current evidence is not sufficient to assess the additional effectiveness of  digital mammography or breast magnetic resonance imaging instead of film  mammography for breast cancer screening.    Data from U.S. Preventive Services Task Force (USPSTF): Ann Intern  Med 716-726, 2009.    The first study of its kind using surveillance, epidemiology,  and end results (SEER) data examined trends from 1976 through  2008 of screening mammography on breast cancer incidence.*°*  These investigators conclude that despite substantial increases  in the number of cases of early-stage breast cancer detected,  screening mammography has only marginally reduced the rate  at which women present with advanced cancer. This imbalance  suggests substantial overdiagnosis involving more than 1 mil-  lion women in the last 30 years and, according to their estimate,  more than 70,000 women in 2008 (31% of all breast cancers  diagnosed in women 40 years and older) are overdiagnosed.  In addition, these investigators report that because the abso-  lute reduction in deaths (estimated at 20 deaths per 100,000  women) is larger than the number of cases of late-stage cancer  (8 cases per 100,000 women), the contribution of early detec-  tion to decreasing numbers of death must be small.*°? This  small reduction has been limited to regional (mostly node-  positive) disease, a stage that is often treated successfully with  an expected survival rate of 85% among women 40 years of age  and older.**+*° This study is important because overdiagnosis  leads to overtreatment whereby women are treated for abnor-  malities that would not have caused illness and the harms of the  treatment; surgery, radiation therapy, hormonal therapy for 5  years or more, chemotherapy, or a combination of the above  can lead to significant future health concerns.   The estimated fatal radiation-induced cancer risk for breast-  specific gamma imaging (BSGI), which involves a label-recom-  mended dose of 740 to 1100 MBq (20-30 mCi) of technetium  99m-sestamib1 is 20 to 30 times that of digital mammography in  women age 40 years, and a single positron emission mammog-  raphy (PEM) involving a labeled dose of 370 MBq (10 mCi)  of fluorine 18 fluorodeoxyglucose is 23 times higher than that  of digital mammography in women age 40 years.**° The new  3D tomosynthesis uses a series of 15 low-dose mammographic  images. This technology decreases the problem of overlapping  breast tissue that occurs with mammography. The radiation is    The understanding of radiation-induced breast cancer from mammographic  screening is not simple. The discussion is complex because of several issues:  (1) ongoing debate about the significance of epidemiologic studies lacking  sufficient statistical power to determine health risks from low-dose radiation;  (2) these epidemiologic studies have determined the estimated mathematical  extrapolations of low-dose health effects from high doses; (3) lacking are stud-  ies with exact protocols of mammographic procedures (mGy, low-energy x-rays,  repeated exposures) or appropriate cell models (nontumoral, untransformed  breast epithelial cells); (4) different reported mean glandular doses (MGDs) per  screening view with changes in equipment over time and MGD can increase  with breast density, volume (breast size), breast augmentation prosthesis, recall  of women for additional views, and the variations in setup of digital mammo-  graphs; (5) differences in individual susceptibility to radiation (i.e., modifying  factors such as genetic risk), and (6) carcinogenic effects at older ages.    Data from Colin C et al: /nt J Radiat Bio! 87(11):1103-1112, 2011;  Hernandez L et al: PLOS 8(5):e63052, 2013.    low dose and higher than regular mammography. No data are  available on long-term effects and whether it saves lives.   Since the late 1990s, experimental evidence has shown that  ionizing radiation can elicit secondary effects in nonirradiated  cells.°°” These secondary or nontargeted effects include radia-  tion-induced bystander effects (RIBEs) that are dependent on  intercellular communication between the irradiated cells and  the so-called innocent bystander cells. Included as a secondary  effect is radiation-induced genomic instability (RIGI) in which  the biologic effects include increased frequency of mutations  and chromosomal aberrations that occur in descendants of  irradiated cells. Several studies are ongoing and a comprehen-  sive understanding of the RIBE response is emerging but is now  incomplete. Box 24-15 includes a summary for understanding  radiation effects from screening mammography.   Diet. Prospective epidemiologic studies on diet and breast  cancer risk fail to show an association that is consistent, strong, and  statistically significant except for alcohol intake, being overweight,  and weight gain after menopause (see following discussion).*** Diet  has been postulated as important for breast cancer risk because of  the international correlations of consumption of specific dietary  factors (e.g., fats) and breast cancer incidence and mortality, and  because migrant studies show greater incidence of breast cancer  among descendants who relocated to another country compared  with those in the country of origin. International variations also  can occur because of differences in reproductive history, physical  activity, obesity, and other factors.   Dietary Fat. Dietary fat and breast cancer risk is the sub-  ject of much study, controversy, and debate. Potential biologic  mechanisms between fat intake and breast cancer risk include:  (1) that fat may stimulate endogenous steroid hormone produc-  tion (also affect weight gain, age of menarche), (2) fat interferes  with immune or inflammatory function, and (3) fat influences  gene expression. Evidence from large, prospective cohort stud-  ies has been mostly unsupportive, and clinical trials have not  supported a strong association with total fat intake.°°? Cohort    studies, however, suggest a modest positive association between  fat intake and the risk of breast cancer,*“° but so far more than  70 studies of dietary fat during midlife on risk of breast can-  cer show the relationship is likely to be small. After 8.1 years  of follow-up, the largest randomized controlled dietary trial  conducted in the United States showed no significant differ-  ence in the number of newly diagnosed breast cancer cases in  the women in the treatment group (intervention of a low-fat  diet) compared with the control group (usual fat intake).**!  The World Cancer Research Fund/American Institute for Can-  cer Research (WCRE/AICR) report indicated that although the  evidence is limited, there was an increase in breast cancer risk  among postmenopausal women consuming higher-fat diets.*“?  Concern also has been that any association with fat intake may  be because of total energy intake. Moreover, there is limited evi-  dence that modest reductions in fat intake (less than 20% of  caloric intake) reduce breast cancer risk.   A meta-analysis of 57 international and national studies indi-  cates that saturated fat intake is associated with an increased risk  for postmenopausal disease, polyunsaturated fats were associ-  ated with increased risk regardless of menopausal status, and  monounsaturated fats had no significant correlation with risk.***   Breast cancer risk may be determined earlier in life, before  the period of investigations, and adult dietary exposures may  have little influence on carcinogenesis. The hypothesis that  exposures that occur between menarche and first pregnancy are  especially important in determining subsequent risk of breast  cancer is supported by several lines of evidence. Animal stud-  ies demonstrate increased susceptibility to mammary carcino-  gens before first pregnancy compared with administration at a  later age,***>* and epidemiologic investigations of women who  survived the atomic bomb in Hiroshima and Nagasaki show  no increase in risk among women older than 35 at the time of  the bombing but increased breast cancer risk among women  younger than 20 years when exposed.*“° A recent and first pro-  spective study of 39,268 premenopausal women observed a  modest direct association between adolescent intake of fat and  breast cancer.**” This association persisted after adjusting for  adult fat intake. Additionally, from this same study, milk, dairy,  and total carbohydrate intake in adolescence, as well as the  quality of carbohydrate as assessed by glycemic load, glycemic  index, and dietary fiber, was not associated with breast cancer.  Frequent consumption of fat, especially saturated fat, during  adolescence was positively related to the incidence of hormone  receptor—negative breast tumors.   Red Meat. Another area of study is how consumption of red  meat could increase breast cancer risk. The hypotheses range  from available iron content, growth-promoting hormones used  in the cattle industry, and carcinogenic heterocyclic amines  released from cooking the fatty acid content. Case-control and  cohort studies have shown a modest association of red meat  intake with breast cancer incidence but no association in a pooled  analysis of prospective studies.*** Research has reported an  increased risk with red meat consumption.*“? °°! However, a 2010  meta-analysis supported the WCRE/AICR report that suggested  there was no conclusive evidence that red meat or processed  meat acts as an independent risk factor for breast cancer.*4?°?    Fiber. Fiber intake could affect breast cancer risk by several  mechanisms, including stimulation of the intestinal microflora  and reduction of the enterohepatic estrogen circulation that  could reduce overall body estrogen concentrations.*»*** Dietary  fiber has been shown to modify estrogen concentrations.* A  recent meta-analysis of prospective cohort studies showed that  every 10-g/day increment in dietary fiber was associated with a  significant reduction in breast cancer risk.*°° A meta-analysis of  prospective case-control studies also found an inverse associa-  tion between dietary fiber intake and breast cancer risk.°°” Simi-  lar in structure to estrogens, lignans are biphenolic compounds  in plant foods.*°* Primarily found in fiber-rich foods (seeds,  grains, vegetables, and fruits), lignans are the major source of  phytoestrogens in Western populations.°*°**** Plant lignans are  converted in the human gut by intestinal bacteria to the entero-  lignans, enterolactone, and enterodiol, which are bioactive  and are subsequently absorbed.°°* Enterolignans may protect  against cancer and several mechanisms have been proposed and  include: (1) they have weak estrogenic activity, therefore may  bind to estrogen receptors (thus preventing other more power-  ful estrogens from binding to ERs); (2) inhibit tumor growth;  (3) stimulate apoptosis; and (4) stimulate production of the  carrier SHBG (which presumably lowers circulating free estro-  gen).°°> Two meta-analyses found lignans to be associated with  a small risk reduction in postmenopausal breast cancer but not  premenopausal,*°?*°° and from a follow-up study those post-  menopausal women with higher enterolignan levels may have  better survival.°°*   Soy. Soy products are a hot topic because of their consump-  tion in Asian countries that have low rates of cancer. These iso-  flavone compounds, including daidzein and genistein, can bind  estrogen receptors but are far less potent than estradiol. Soy  may act like other antiestrogens, such as tamoxifen, by blocking  the action of endogenous estrogens to reduce breast cancer risk.  Thus, depending on the estradiol concentration and the tim-  ing of administration, soy exhibits weak estrogenic or antiestro-  genic activity. Isoflavones act through various mechanisms by  which they may be cancer protective including antiproliferative  effects, tyrosine kinase inhibition, induction of apoptosis, and  inhibition of angiogenesis. They modulate enzyme activities,  as well as signal transduction, and have antioxidant properties.  In 2011 the North American Menopause Society held a sym-  posium to review the latest evidence-based science on the role  of soy and found that soy foods generally appear to be breast  protective and recommended moderate lifelong soy consump-  tion.°°! Specific recommendations for breast cancer survivors  and soy or isoflavone consumption could not be reached,  because animals studies indicate potential for risk and stud-  ies in humans imply a null or protective effect.°°'~° A recent  large study of both American and Chinese women, however,  suggested that moderate intake of soy (210 mg isoflavones/day)  had a significant reduction in breast cancer recurrence as well as  a nonsignificant trend toward reduced all-cause mortality.°° In  addition, soy may optimize extrarenal 1,25(OH)2 cholecalcif-  erol or vitamin D; (a prodifferentiating vitamin D metabolite),  which could result in growth control and, conceivably, inhibi-  tion of tumor progression.°    There is limited evidence on the role of dietary patterns and  breast cancer risk modification. Some limited evidence sup-  ports the role of the Mediterranean diet.   Obesity. Obesity has been associated with a reduced risk of  premenopausal breast cancer. One mechanism suggested is the  direct relationship between irregular menstrual cycling, espe-  cially obesity and anovulatory cycling, which would result in a  decrease in estrogens and progesterone and thus decrease the  risk of breast cancer. It is possible that in obese women with  hyperinsulinemia the higher insulin levels increase the enzy-  matic conversion of testosterone to dihydrotestosterone, rather  than estradiol, lowering their estrogen levels.*°°   Obesity, however, is related to increased risk of breast cancer  in postmenopausal women. Despite strong links with endoge-  nous estrogen levels, body fat has been consistently but weakly  related to increased postmenopausal risk.*°° This observation  has been surprising because obese postmenopausal women  have endogenous estrogen levels (estrone and estradiol) nearly  double those of lean women.°**°” This weak association is pos-  sibly related to two factors. First, the premenopausal reduc-  tion in breast cancer risk related to being overweight possibly  persists, opposing the adverse effect of elevated estrogens after  menopause. Thus weight gain should be more strongly related  to postmenopausal breast cancer risk than attained weight. A  meta-analysis of 11 studies suggests that adult weight gain is  predictive of a twofold increase in the risk for ER+, as well as  ER+/PR+, breast tumors with a greater risk in postmenopausal  women.*°°   Premenopausal and postmenopausal weight gain also is  associated with higher estradiol and estrone levels and lower  SHBG as a transporter protein; low levels cause higher bioavail-  able estrogen.” This increase in estrogens, particularly estra-  diol, is from aromatization in the adipose tissue. Second, use  of exogenous hormones postmenopausally obscures the varia-  tion in endogenous estrogens caused by adiposity and elevates  breast cancer risk regardless of body weight.°° Excess body fat  and weight gain are stronger risk factors for women who do  not use hormone therapy. However, a prospective study found  weight gained at multiple time points throughout adulthood of  44 to 63 lbs was associated with a 56% higher risk of breast can-  cer, and weight gain of 88 to 108 lbs doubled the risk of breast  cancer among hormone users.*”” A recent animal study showed  obese animals deposited excess calories into the tumors them-  selves.*’! These tumors from obese animals had an increased  expression of progesterone receptors.*”!   Weight loss after menopause reduces circulating estrogens  and increases SHBG, making weight loss a potentially impor-  tant prevention strategy especially for those women not on  hormone therapy. Weight loss and postmenopausal cancer risk  have been examined in prospective studies. In one of the largest  studies, women who lost 22 lbs or more after menopause and  maintained this weight loss halved their risk for breast cancer.  This relationship was clearer in nonhormone users.*”*   The degree of obesity is an important indicator of risk as  reported in the largest study to date, a prospective analysis of  about 15,000 women with invasive breast cancer. Overweight  (55 to 66 lbs) was not associated with any excess risk compared    with normal weight. Similar associations were found for breast  cancer death and non-breast cancer death but not recurrence  of breast cancer. Women who were underweight and morbidly  obese before breast cancer diagnosis were at the greatest risk of  all-cause mortality. Morbidly obese women (BMI 2 88 lbs) were  also at increased risk of death from breast cancer.°”*   Alcohol. Data on alcohol and risk of breast cancer continue  to mount. From the analysis of the NHS, even low to moder-  ate alcohol intake may increase breast cancer risk, particularly  for postmenopausal women.*”* From this same study risk was  increased regardless of source of alcohol, wine, beer, or spir-  its.°”4 These investigators studied patterns of drinking and hab-  its earlier in adulthood, as well as binge drinking and both may  further increase risk. From the WHI an observational cohort  of 87,724 postmenopausal women and 2944 cases of breast  cancer over a 5-year follow-up, one drink daily was associated  with an 82% greater risk for hormone receptor—positive lobu-  lar breast cancer.*”° A follow-up analysis from other investi-  gators evaluated alcohol intake associated with ER+ disease  and a lower risk for triple-negative disease.*”° Recently, a com-  prehensive study of lifetime alcohol intake and risk of breast  cancer involved large numbers of Asian Americans.*”’ Regular  lifetime alcohol intake is a significant risk factor in U.S.-born  Asian Americans but not in non—U.S.-born Asian Americans.  Results by Asian ethnicity show that the prevalence of lifetime  alcohol intake is significantly higher in Japanese than in Chi-  nese and Filipino women and that lifetime alcohol intake is a  significant risk factor in Japanese Americans (U.S. born and  non-U.S. born) but not in Chinese- and Filipino-American  women.°”7   The exact mechanism of how alcohol increases breast cancer  risk is unknown. Suggested mechanisms include: (1) alcohol  may hinder the liver’s ability to rid the body of cancer-causing  agents; (2) alcohol stimulates liver enzyme activity and greater  sulfation of estrone, thus increasing the bioavailability of  estrone and possibly breast exposure to higher levels of estrone/  estradiol; (3) alcohol combined with hormone replacement  therapy may synergistically enhance the risk; (4) alcohol can  down-regulate the expression of BRCAI (i.e., the unmutated  tumor-suppressor gene) thus increasing estrogen receptor-a  responsiveness; (5) alcohol decreases folate levels causing  changes in methyl donors for DNA stability and some studies  show that folate intake may decrease this risk; and (6) alcohol  decreases melatonin levels at night, which might increase circu-  lating estrogen.   Iodine. Iodine deficiency is hypothesized as contributing to  the development of breast pathology and cancer.*”***° Iodine  plays a significant role in breast health.**°>*? Although research  is just beginning, some evidence reveals that iodine is an anti-  oxidant and antiproliferative agent contributing to the integrity  of normal mammary tissue. Seaweed, which is iodine-rich, is  an important dietary item in Asian communities and has been  associated with the low incidence of benign and breast cancer  disease in Japanese women.>** Other foods with iodine content  include iodized salt (1 teaspoon = 400 mcg iodine), bread with  iodate dough, haddock, shrimp, egg, cottage cheese, cheddar  cheese, and ground beef.    Environmental Chemicals. Evidence for linking chemicals to  the cause of breast cancer is difficult. It is challenging because  it is a life history of exposure that is important, not just a single  chemical but also complex mixtures of chemicals and their  interaction with endogenous hormones and with radiation. The  highest rates of breast cancer are found in superindustrialized  countries—North America and Europe—and the lowest rates  in central Africa and Asia. With industrial development, breast  cancer rates increase. An estimated 85,000 synthetic chemicals  are registered for use today in the United States, another 1000  or more are added each year, and toxicologic screening for these  chemicals is minimal—only about 7%.°°° EPA researchers are  going to change this serious challenge. They and their partners  are teaming up and tapping modern technologies such as  supercomputers and even robots to advance the scientific  hazard identification and risk assessment. Chemicals persist  in the environment, accumulate in adipose tissue, interact  with local adipose tissue physiology in an endocrine-paracrine  manner, and remain in breast tissue for decades. Some of  these chemicals are known human carcinogens and many have  been linked to mammary tumors in animals. Women who  emigrate to the United States from Asian countries experience  an enormous percent increase in risk within one generation. A  generation later their daughters’ risk approaches that of women  born in the United States. This change in risk suggests that in  utero exposures affect subsequent disease risk. However, it    is difficult to know whether these changes in risk come from  nutritional content, pollutants, cosmetics, food additives, or  other factors.   Xenoestrogens are synthetic chemicals that mimic the actions  of estrogens and are found in many pesticides, fuels, plastics,  detergents, and drugs. Because many factors correlated with  breast cancer (early menarche, delayed pregnancy and breast-  feeding, late menopause, etc.) are associated with lifetime expo-  sure to estrogens, investigators reasoned that environmental  chemicals affect estrogen metabolism and contribute to breast  cancer. The most significant chemicals may be polychlorinated  biphenyls (PCBs), pesticides, BPA (pervasive in polycarbonate  plastics), tobacco smoke (active and passive), dioxins (vehicle  exhaust, incineration, contaminated food supply), alkylphenols  (detergents and cleaning products), metals, phthalates (makes  plastics flexible, some cosmetics), parabens (antimicrobials),  food additives (recombinant bovine somatotropin [rBST] and  zeranol to enhance growth in cattle and sheep), HRT, and oth-  ers. Bisphenol A treatment of breast epithelial cells cultured  from premalignant biopsied tissue elicited a genetic expres-  sion profile associated with large, high-histologic-grade breast  tumors.**° Some chemicals are fat soluble and the estrogenic  effect would require that they either bind to the nuclear estro-  gen receptor and then cause cell division or gene transcrip-  tion or they activate reactive oxygen species through oxidative  catabolism of estrogens (see p. 853) (Table 24-16).    Studies have shown altered reproductive systems and breast tissue when exposed to BPA in utero!   Used in food packaging, medical products, appliances, cars, toys, credit cards, rainwear?   Has been found in the air near waste sites, landfills, and tobacco smoke   Has been linked to increased mortality from breast and liver cancer among manufacturing workers*?   Used in crops like corn and cotton from 1950s to 1970s   Banned by the EPA in 1975 except for termite control; completely banned in 1987   In vitro assays showed estrogenic activity and dieldrin found in 78% of women diagnosed with breast cancer®   High incidence of breast cancer in Massachusetts study found associations with higher income and regular use of  lawn services, termite treatments, and home pesticides’   Spray paints and paint removers may contain methylene chloride, documented breast cancer in lab animals?   Exposed daughters known to have higher rates of vaginal cancer, and in the mothers slight increased risk of  breast cancer?!   Daughters now known to have slight increased risk of breast cancer"!   In 2003 a Taiwanese study documented increased risk of breast cancer among electronic workers exposed to  chlorinated organic solvents!   A Danish study of women 22 to 55 years of age employed in industries (fabricated metal, lumber, furniture,   A 1995 study suggested increased risk with occupational exposure—validation in Finland, Sweden, and Italy'4~'   A Duke University study found it acts as hormone sensitizer in vivo and in vitro.'®.'° Compounds are found in   Found to be hormone sensitizing and prescribed for migraines and bipolar disorder'®:'9   Found in plastics, tobacco smoke, grilled meats and fish, combustion of wood chips and rubber. Exposure in    TABLE 24-16 SELECTED CHEMICALS AND RISK OF BREAST CANCER—cont’d  CHEMICAL COMMENTS    Dichlorodiphenyltrichloroethane (DDT) and PCB used in manufacture of electrical equipment”  polychlorinated biphenyls (PCBs) PCB and DDT are banned in the United States since 1970s but are still found in body fat, as well as breast milk24  DDT was used as pesticide for insects on farms and swamps  PCB deteriorates slowly in soil  PCB is difficult to study because it is a diverse class of compounds  A 1999 in vitro study showed PCBs proliferate in breast cancer cells”°  Conflicting results; several large studies failed to show relationship with PCBs  Polycystic aromatic hydrocarbons (PAHs, Found in soot and fumes from fuels  including tobacco) Increased DNA damage (DNA adducts) implicated from the Long Island Breast Cancer Study Project2®  Tobacco smoke also contains PAHs  Smokers who began smoking as adolescents have an increased risk of breast cancer?’~2°  In 2004 the California EPA concluded that environmental tobacco smoke (ETS) increases the risk of breast cancer,  and the association appears stronger for premenopausal women*?  Tobacco smoke also contains the carcinogens polonium-210, vinyl chloride, benzene, and 1-3 butadiene®"  Dioxin Products containing PVC, PCBs, or other chlorinated compounds release dioxin from incineration  Declared a known carcinogen by the EPA in 2000  lt may be the most prevalent of all toxic chemicals  Occurs in meat, poultry, dairy products, and human breast milk  A United Kingdom study linked dioxin to the development of mammary tumors in mice®?  A study in Seveso, Italy, connected dioxin with breast cancer?  Ethylene oxide Used to sterilize surgical instruments and in some cosmetics  Linked to breast cancer in women exposed to ethylene oxide in commercial sterilization facilities**   . Maxwell NI et al: Newton Breast Cancer Study, Newton, MA, 1999, Silent Spring Institute.   . National Toxicology Program (NTP): Chemicals associated with site-specific tumor induction in mammary glands, 2003. Available at http://ntp-server.niehs.nih.  gov/htdocs/sites/MAMM.html.   . Belli S et al: Scand J Work Environ Health 18(1):64-67, 1992.   . Walrath J et al: Am J Public Health 75(8):883-885, 1985.   . Weiderpass E et al: Am J Ind Med 36(1):48-53, 1999.   . Wennborg H et al: Am J Ind Med 35(4):382-389, 1999.   . Jansen MS et al: Proc Nat! Acad Sci U S A 101(18):7199-7204, 2004.   . National Toxicology Program (NTP), U.S. Department of Health and Human Services: Toxicology and carcinogenesis studies of 1,3-butadiene (CAS No 106-99-0)  in B6C3F1 mice (inhalation studies), NTP TR 434, NIH Pub No 93-3165, Research Triangle Park, NC, 1993, National Institutes of Health.   . Evans N: State of the evidence: what is the connection between the environment and breast cancer? ed 3, San Francisco, 2004, Breast Cancer Fund.   . Hatakeyama M, Matsumura F: J Biochem Molec Toxicol 13(6):296-302, 1999.   . Gammon MD et al: Cancer Epidemiol Biomark Prev 11(8):677—-685, 2002.   . Johnson KC, Hu J, Mao Y: Cancer Causes Control 11(3):211-221, 2000.   . California Environmental Protection Agency: Draft Report Part B, chap 7:147, 2004.   . Dorn J et al: Med Sci Sports Exercise 35(2):278-285, 2003.    FIGURE 24-39 Driver Mutations and Copy Number Changes in Breast Cancer. The left side identifies each of the  40 cancer genes in which a driver mutation or copy number change has been identified. From investigation of 100 tumors, the  number of mutations in each gene is shown (rows) as is the number of driver mutations in each breast cancer (columns). Point  mutations are red and copy number changes are blue. (From: Stephens PJ et al: Nature 486:400-404, 2012.)    Physical Activity. Physically active individuals have lower  rates of many cancers and improved cancer outcomes.**”3**  Activity also may reduce the invasiveness of breast cancer.°*?  Consistent evidence from 27 observational studies showed  physical activity is associated with all-cause, breast cancer—  specific, and colon cancer-specific mortality.°°’~°? A large  prospective study found walking for 1 hour per day and  additional weekly exercise seemed to be protective against  breast cancer regardless of menopausal status.*’! Mechanisms  for this protective effect are not known but include alterations  in endogenous free radical formation and oxidative damage,  effects on DNA repair capacity, changes in circulating insulin  and insulin-related pathways, inflammation, alteration in  carcinogen-metabolizing enzymes, increased intestinal transit  times (i.e., reduced exposures to carcinogens), weight loss,  changes in endogenous sex hormone, and possibly immunity  levels.    The causes of breast cancer have been difficult to define because  each woman has a different genetic profile called genetic het-  erogeneity.°°* Genetic heterogeneity is common among indi-  viduals but also at the level of the tumor itself, involving both  genetic and epigenetic processes. These facts are sobering and  make the understanding of the genetic driving force behind  tumor initiation, progression, and metastasis very complicated.  Driver mutations are causally implicated in tumor develop-  ment. Investigators examined the genomes of 100 tumors for  somatic mutations and found they varied markedly between  individual tumors.*”? Several new driver mutations were iden-  tified, including AKT2, ARIDIB, CASP8, CDKN1B, MAP3K1,  MAP3K13, NCOR1, SMARCD1, and TBX3 (Figure 24-39).   A history of breast cancer in first-degree relatives (mother  or sister) increases a woman’s risk two to three times. Risk    increases even more if two first-degree relatives are involved,  especially if the disease occurred before menopause and was  bilateral. In some families, breast cancer occurs at an earlier age  and the frequency of bilateral tumors is greater. A small total  proportion of breast cancers (incidence 5% to 10%, although  the prevalence is significant) are the result of highly penetrant  dominant genes (ie., hereditary breast cancers). The most  important of the dominant genes are the breast cancer suscep-  tibility genes (BRCAI, BRCA2). BRCA1 is located on chromo-  some 17 and BRCAZ2 is located on chromosome 13. BRCAI and  BRCA2 (unmutated; normal) are tumor-suppressor genes. Box  24-16 summarizes key points about BRCAI and BRCA2.°”°  PATHOGENESIS. Most breast cancers arise from the ductal epi-  thelium (Figure 24-40). Tumors of the infiltrating ductal type  do not become large, but they metastasize early. Some types  of breast carcinomas are summarized in Table 24-17.This type  accounts for the majority of breast cancers. Breast cancer is a  heterogeneous—not a single—disease with diverse molecular,  biologic, phenotypic, and pathologic, changes.°°? Complex is  that breast cancer also is heterogeneous within the same tumor  (also see above). Despite heroic efforts, this diversity has greatly  challenged the understanding of breast cancer evolution and  the development of therapeutic strategies. Gene expression pro-  filing studies have identified at least four major subtypes clas-  sified as luminal A, luminal B, HER2+, and basal-like.°” Yet  with mounting evidence it appears there are “subtypes within  subtypes,” and evidence is emerging suggesting that the biology  of specific breast cancer subtypes reflects contributions from  the tissue microenvironment.°*” In fact, in their updated article  “Hallmarks of Cancer,” Hanahan and Weinberg state, “In addi-  tion to cancer cells, tumors exhibit another dimension of com-  plexity: they contain a repertoire of recruited, ostensibly normal  cells that contribute to the acquisition of hallmark traits by  creating the ‘tumor microenvironment.”*?” P- 6 Historically,  many models of breast carcinogenesis have been suggested    A deleterious mutation in BRCA7 or BRCA2 increases a woman’s risk of devel-  oping breast cancer or ovarian cancer, or both.   Harmful BRCA7 mutations may increase a woman's risk of developing cervi-  cal, uterine, pancreatic, and colon cancer.   en with harmful BRCA7 mutations have an increased risk of breast cancer  and possibly of pancreatic, testicular, and early-onset prostate cancer.   ale breast cancer, however, and pancreatic and prostate cancer appear to  be more strongly associated with harmful BRCA2 mutations   Harmful mutations in BRCA7 or BRCA2 are highest in families with a history of  both breast and ovarian cancer, family members with tumors that develop from  different sites in the body, or an Ashkenazi (Central European descent) Jewish  background. However, not every woman in these families carries a harmful  BRCA1 or BRCA2 mutation. Additionally, not every woman who has a harmful  BRCA1 or BRCA2 mutation will develop breast or ovarian cancer, or both.   A woman with a mutated BRCA7 or BRCA2 is about five times more likely to  develop breast cancer than a woman without the mutation.   Women with a harmful BRCA7 or BRCA2 have a probability of being diag-  nosed with ovarian cancer (150 to 400 out of 1000) compared with women  without the mutation (14 out of 1000).    The estimates of cancer risks are based on large families with multiple  affected family members and may not accurately reflect other genetic and  environmental risk factors.   Options for those that have a positive test for a harmful BRCA7 or BRCAZ  mutation include surveillance to find cancers early, prophylactic surgery (i.e.,  bilateral salpingo-oophorectomy), risk factor avoidance (e.g., avoid hormone  replacement therapy [HRT], breast-feed), and chemoprevention.   BRCA1 and BRCA2 function is a common pathway of genome protection.  They work at different stages in the DNA damage response (DDR) and in DNA  repair.   BRCA functions in both cell cycle check point activation and DNA repair,  whereas BRCA2 is a mediator of the DNA repair mechanism—homologous  recombination.   Both BRCA71 and BRCA2 work together to protect the genome from double-  strand DNA damage during DNA replication.   The prevalence and penetrance of both BRCA7 and BRCA2 vary with race; so  far evidence indicates highest in whites compared to Asians and blacks.    Data from: National Cancer Institute: BRCA7 and BRCA2: cancer risk & genetic testing. Available at www.cancer.gov/cancertopics/factsheet/Risk/    including: (1) the multihits sequential acquisition model, (2)  sporadic clonal evolution model, (3) telomere crisis, and (4)  imprinted stem cell or cancer stem cell model.°”* In an effort to  understand breast cancer biology three interrelated themes also  have emerged and include: (1) gene addiction, (2) phenotypic  plasticity, and (3) cancer stem cells.°”?   Cancer gene addiction includes oncogene addiction, whereby  these genes play key roles in human breast cancer, and nonon-  cogene addiction, whereby these genes may not initiate cancer  but play major roles in cancer development and progression°””  (see p. 863). Phenotypic plasticity is exemplified by a distinctive  phenotype called epithelial to mesenchymal transition (EMT)  (see Chapter 12).4°° EMT is intimately involved in the genera-  tion of tissues and organs during embryogenesis, is essential for  driving plasticity during development, and is an unintentional  process during cancer progression. The EMT-associated repro-  gramming is involved not only in migration of cancer cells but  also suppression of apoptosis and senescence, recapitulation  during wound healing, weakening of cell-cycle progression, and  resistance to radiotherapy and chemotherapy.*°! Much research  is ongoing to define cancer stem cells in breast carcinogenesis  including their origin and renewability properties. Numerous  factors govern invasiveness and metastasis and include hetero-  geneity of cell subsets within the primary tumor, the interac-  tion of tumor cells with the microenvironment, cell signaling  factors, and the receptivity of metastatic colonization sites (the  soil). EMT generates multiple epithelial cell subsets with differ-  ent states of stemness relative to more differentiated cells.*°? In  an effort to include all of these themes, it is striking that the same  pathways and interactions observed in the normal mammary  gland during development are exploited by tumors during their  progression to metastatic disease (Figure 24-41).   The normal breast and breast tumors share molecular, cel-  lular, systemic, and microenvironment components that are    necessary for tumor progression.*”° The microenvironment is  now recognized as a critical player in tumor progression and  therapeutic responses.*°> Components of the microenviron-  ment, including myoepithelial and endothelial cells, macro-  phages, and many ECM molecules, play a critical role in normal  duct morphogenesis, and are increasingly recognized as major  regulators of carcinogenesis*”” (see Figure 24-41).   Front and center for breast carcinogenesis is that cancer is  a heterogeneous disease based on tumor anatomy, location,  grade, lymph node metastasis, expression of growth factor  receptors, and—emerging—several biomarkers assessed in  the clinic.°°° Some breast tumors may be heterogeneous from  their initial preinvasive stages,*’* but tumors are continuously  evolving. Emerging is the understanding that the tumor micro-  environment plays a major role in driving tumor heterogene-  ity.°° Multiple microenvironment-related genes have been  identified and include FGF, TGF-B, MMP, and collagen fam-  ily members. Additionally, genetic signatures of genes involved  in wound healing are thought to originate from fibroblasts of  the tumor microenvironment. ECM-related gene expression  modules are associated with tumor intrinsic subtypes and with  clinical outcomes.**° Gene expression prognostic signatures of  motility and proliferation-related genes as well as stromal cells  “reactive” phenotype during cancer progression show some  commonality with normal branching morphogenesis and invo-  lution. Table 24-18 shows a comparison of similarities and dif-  ferences between normal mammary gland branching and breast  cancer invasion.*”°   The majority of studies evaluating gene expression stro-  mal-derived signatures have focused on intratumoral stromal  expression rather than the microenvironment surrounding  normal breast or extratumoral expression.*°* Intratumoral  stromal responses include: (1) elevated expression of immune  mediators from stromal tissue,*°° (2) a signature of fibroblast    The nipple contains connective  tissue and smooth muscle cells  forming a circular sphincter.  Sympathetic nerve fibers are  found among smooth muscle    Duct system of an inactive f  gland. The lactiferous duct ;  ends into a small saccular i  evagination. .    A lobule consists of a !  lactiferous duct and several  alveolar acini. The lactiferous  duct opens into a lactiferous |  sinus.   Each tubuloalveolar  secretory unit consists of  cuboidal or low columnar  epithelial cells, myoepithelial  cells, and a basal lamina.    Paget carcinoma extends from the lactiferous ducts in the  nipple into the adjacent skin of the nipple and areola.  Cancerous cells—called Paget cellsinvade the epidermis.    Intraductal carcinoma consist of cancerous cells  proliferating within lactiferous ducts. The tumoral proliferation  sites usually have a necrotic center ("comedone-like’).    Breast tumors arise in the ductal  epithelium (90%), or within the lobular  alveolar-ductal epithelium (10%).    M : Bes f Intraductal carcinoma originates in the terminal ductules of the lactiferous  Hcus-comalning ces duct and the alveolar acini. Mucus-containing cells are observed.    FIGURE 24-40 Normal Breast and Breast Cancer. A, Normal breast. B, Breast cancer. (From Kierszenbaum AL: Histol-  ogy and cell biology: an introduction to pathology, ed 2, Philadelphia, 2007, Mosby.)    Well-delineated cystic masses in multiple areas; hemorrhage often present; majority appear in 40- to 60-year age  group; often involves skin   Often accompanied with evidence of inflammation; well-circumscribed tumors within the duct; well-differentiated  tumor cells; rarely ulcerates the skin    Fibrous, firm, glistening, gray-tan mass with chalky streaks, mixture of patterns; may cause discharge from the  nipple; represents about 79% of all breast cancer   Usually large (>3 cm in diameter), circumscribed, and encapsulated; glistening appearance, varies in color; two  types: pure and mixed; pure tumor is surrounded by mucin; infrequent; found in the lateral half of the breast;  tends to occur in women after age 70 years   Encapsulated and grows to be very large (7-8 cm in diameter); commonly surrounded by lymphocytic inflammatory  infiltrate; occurs after age 50 years   Well differentiated with orderly tubules in center (stroma) of mass; can be associated with noninfiltrating ductal  carcinoma; occurs in women about 50 years of age; nodal metastasis infrequent; occurrence rare   Very rare; well-circumscribed, painless mass arising from the nipple and areola    Found in individuals with fibrocystic disease; localized to upper breast quadrants; risk of 15%-35% becoming    invasive; occurs frequently in mid-40s; infiltrating variety occurs in early 50s    Infiltrates from duct; firm mass with chalky streaks  Eczema of the nipple that extends to the areola; cancer usually found underneath the nipple; poorly circumscribed;    large Paget cells arise from the duct and directly invade nipple; history of scaly, red rash spreading from the  nipple; lesion palpable beneath the nipple, often bilateral; occurs in middle age    Not a histologic type; fairly diffuse within the breast tissue, diffuse edema of the overlying skin; extremely    Usually large (>17 cm in diameter); mostly localized but can rupture through the skin; rarely metastasizes to lymph  nodes; history of painless nodule present for years before it forms a large mass; ulceration and bleeding of skin  often present; occurs in wide age range (ages 13-77 years)   Well circumscribed, firm, and usually does not involve the skin or nipple; well differentiated to extremely  undifferentiated; arises from connective tissue; extremely rare (e.g., liposarcoma, angiosarcoma)    Data from Beahrs OH, Hutter RV, Kennedy BJ, editors: Breast manual for staging of cancer, ed 45, Philadelphia, 1992, Lippincott.    response,*°° (3) fibromatosis and macrophage-associated sig-  nature,“°’ and (4) stromal responses activated early possibly  before invasion.*°* Growing evidence suggests that extratumoral  microenvironment—called field effects—also may play a role in  tumor progression.*°* Normal homeostatic or developmental  pathways and molecular processes, such as wound healing and  TGF-f in the presence of initiated tumor cells, become tumor  promoting.*°** The study of field effects has only just began  in human cancer outcomes. Investigators demonstrated that  wound responses may be divided into two types: active and inac-  tive. Active cancer-adjacent tissue reveals characteristics of active  EMT or cellular dedifferentiation (regression of specialized cel-  lular features or simpler, more embryonic) and was associated  with poor survival. Inactive extratumoral tissue has evidence  of more differentiated tissue with higher expression of cellular  adhesion genes and lower expression levels of EMT-related tran-  scription factors.*°* Complicated and important are future stud-  ies to determine intra- and extratumoral changes to understand    their dependence and independence on tumor characteristics. It  seems clear that cancer heterogeneity and clinical outcome reflect  signaling from a heterogeneous microenvironmental recurring  theme that hopefully promises greater therapeutic outcomes.    Ductal carcinoma in situ (DCIS) is a complex, heterogeneous  group of proliferations limited to breast ducts and lobules with-  out invasion of the basement membrane. About 84% of all in  situ disease is DCIS; the remainder is mostly LCIS disease.*!°  DCIS occurs predominantly in women but can occur in men.  Since 1980, the widespread adoption of screening mammog-  raphy has led to an epidemic of diagnoses of DCIS.*!! DCIS  accounts for about 20% to 27% of newly diagnosed cases of  breast cancer in the United States, and about 17% to 34% of  mammographically detected cases.*!!+!* SEER data from 1983  to 2003 depict a 500% increase in DCIS among women age  50 years and older and a decline of DCIS in 2003.4! Among    FIGURE 24-41 A Model of Breast Carcinogenesis: Dynamic Microenvironments Regulate Both Normal Breast  Development and Breast Carcinogenesis. Anatomic changes during mammary gland development, called branching mor-  phogenesis, require extensive dialogue between epithelial and stromal cells and their underlying extracellular matrix (ECM).  These events are central and amplified during carcinogenesis and are often required for tumor progression. Loss of the myoepi-  thelial cell layer and basement membrane is key for invasive progression. Potential crosstalk between cell-cell and cell—matrix  interactions are abnormally regulated by autocrine and paracrine signaling networks of proteolytic enzymes and chemokines,  and cytokines continue to attract leukocytes, modulate tumor remodeling, and increase tumor cell invasion eventually leading  to metastasis. Tumors steal or “hack” the normal developmental program to manifest carcinogenesis. (From Boudreau A, van't    Requires heterotypic, paracrine interactions between epithelial cell proliferation and directional migration    Stromal cells secrete growth factors guiding epithelial cell proliferation and directional migration  Proliferative epithelial cells secrete growth factors to enrich their adjacent stroma    Conserved growth factors and receptors used, albeit at different amplitudes of signaling   Epithelial cell apoptosis yields a lumen  Deposition of basement membrane  Differentiation into polarized, bilayered ducts    Data from Boudreau A, van’t Veer LJ, Bissell M: Cell Adh Migr 6(3):236-248, 2012.    women younger than 50 years, there has been a 290% increase  in DCIS since 1983 and the incidence is still increasing.*!' The  American Cancer Society estimates about 64,640 new cases of  carcinoma in situ in 2013.*' The type of DCIS across all age  groups not associated with subsequent DCIS or invasive can-  cer (i.e., noncomedo type) has mostly increased, and subse-  quent DCIS or invasive cancer has been constant or decreased.  Importantly and despite 20 years of detecting DCIS by mam-  mography, a decline in invasive cancer in the United States was  not observed until the large decline in postmenopausal hor-  mone therapy. Population data report screening rates of DCIS    to be similar among white, black, and Asian/Pacific Islanders.*!°  The majority of DCIS presents as linear or multiple clusters of  calcifications on a mammogram.   Although risk factors for DCIS and invasive breast can-  cer are similar and therefore suggest a common etiology for  both diseases, some characteristics are more strongly associ-  ated with invasive cancer. The risk factors that increase the  risk of both DCIS and invasive cancers include family history  of a first-degree relative, nulliparity or late age of first birth,  history of biopsy, late age at menopause, long-term use of  postmenopausal HRT, and increased BMI in postmenopausal    women not taking hormone therapy.*!? A strong risk fac-  tor for invasive breast cancer and for DCIS is high mammo-  graphic breast density.*!**!° Conflicting studies for DCIS have  been on smoking, lactation, early menarche, increased alco-  hol consumption, and oral contraceptive use. The prevalence  of mutation carriers BRCA1 and BRCA2 is similar among  women diagnosed with DCIS to that of women with invasive  breast cancer.*!°   Recently it was shown that about 5900 genes are expressed  in the epithelium during the transition from normal to DCIS  and that only three epithelial genes had differential expression  from DCIS to invasive carcinoma, suggesting the importance of  the stroma in cancer progression.°”° Allinen and coworkers*!”  performed the first systematic profiling of the various stromal  cell types. They demonstrated gene expression alterations in all  cell types within the tumor microenvironment accompanying  progression from normal breast tissue to DCIS to invasive duc-  tal carcinoma (IDC) provided evidence that these cell types all  participate in tumorigenesis.*”°   Changes in the tumor microenvironment are observed  early at the DCIS stage or even earlier.*°° With the secretion  of chemokines causing accumulation of leukocytes and many  other cells, stromal and epithelial cells participate in recipro-  cal and paracrine acting signaling loops (Figure 24-42). These  communicating signaling links appear to stabilize the increased  localization of macrophages, myofibroblasts, and fibroblasts at  the DCIS stage, which ultimately remodel the ECM and pro-  mote tumor proliferation.°*° Depending on location, genetics,  and other changes, the altered microenvironment may stiffen,  increase blood vessel density, increase breast density, and result  in calcifications. Although DCIS may remain stable and never  progress (or may regress), for invasive DCIS the cells within  the DCIS breach the myoepithelial layer and the basement  membrane defining the moment when an invasive carcinoma  is formed.°*° Importantly, the layer of myoepithelial cells is  thought to be natural “tumor suppressors” and critical to main-  taining tissue polarity (cell directional orientation) (see Figure  1-11), a role that is lost in invasive breast carcinomas. Inves-  tigators and clinicians are intensely studying this key step, or  breach, in terms of cellular alterations because of tumor biology  or iatrogenic stimuli, or both.   The natural history of DCIS is actually elusive and reflects  the diversity of the condition. Preinvasive lesions do not invari-  ably progress to invasive malignancy. DCIS is detected more  often in younger women than in older women.   Although there is no universally accepted histopathologic  classification, historically most pathologists divided DCIS into  five subtypes (papillary, micropapillary, cribriform, solid, and  comedo) and often compare the first four types, noncomedo,  with comedo. In a single biopsy, however, several types may be  mixed and some noncomedo types may express characteristics  of the comedo type. Although the term comedo type is widely  used it does not specify a grade or an architecture, so newer  categories most often use nuclear grade (high, intermediate, or  low) and record the architectural pattern separately.*!* When it  comes to the architecture of DCIS, however, the literature is full  of contradictory information.    Lobular carcinoma in situ (LCIS) originates from the terminal  duct—lobular unit (see Figure 24-40, B). Unlike DCIS, LCIS has  a uniform appearance in which the cells occur in noncohesive  (discohesive) clusters, primarily in lobules. Today, however,  there is limited knowledge of the biology of LCIS.*!? Atypical  lobular hyperplasia (ALH) and LCIS represent a spectrum of  breast disease called lobular neoplasia (LN). Research suggests  that some lobular and ductal carcinomas are closely related.*”°  LCIS is not associated with calcifications or a stromal involve-  ment that would form a density (lump). Thus it is usually an  incidental finding from biopsy for something else. LCIS is fairly  uncommon (up to 3.8% of all specimens).*7! LCIS is bilateral in  20% to 40% of women, and the majority (80% to 90%) occur  before menopause. Although the cells of LCIS and invasive  lobular carcinoma are identical,!’” whether LCIS is a true neo-  plasm or a marker of breast cancer risk remains controversial.  Evidence to support LCIS as a precursor lesion of invasive carci-  noma comes from molecular genetic data highlighting chromo-  somal alterations and that LOH on chromosome 16q is present  in an invasive carcinoma.*”*”? Invasive carcinoma develops in  25% to 35% of women with LCIS, and the contralateral (oppo-  site) breast also is at risk.47? Chemoprevention is recommended  for atypia types, including LCIS, to reduce breast cancer risk.***    Dominating the cancer field is the idea that epithelial function  depends on the entire tissue, including the stroma or micro-  environment. The specific location where a tumor develops  in the breast can have a major influence on its breast cancer  outcome.’ Variations in tumor development depend on the  architecture and the microenvironment of the tumor in vivo  and plays an important role in phenotypic outcome of genetic  mutations.*?° Importantly, people can harbor potentially  malignant tumors that remain dormant for many years.*”? The  microenvironment surrounding a tumor may normally sup-  press tumor development by providing tumor-suppressive sig-  nals, and the loss of tissue homeostasis causes the development  of an aberrant microenvironment and over time becomes a  potent tumor promoter.°?°0?*?7-#?? The stromal response (the  “soil”) is often associated with invasive breast cancer. Emerging  are two views regarding the tissue stromal response to breast  carcinogenesis—is the stromal response unique to the tumor or  is the stromal response a host response, an individual’s innate  healing response to disrupted tissue? Embedded in these views  is the stromal response, sometimes called an aberrant “wound”  with an inflammatory stromal (reactive stroma) compo-  nent**” (see Chapter 12). This “wound response” is exempli-  fied by expression of a set of genes associated with healing.  Evidence of the link between wound healing and carcinogenesis  is based on the fact that these two distinct pathologies share a  common “footprint” or “signature,” a common molecular gene  expression signature.”?! Gene expression signatures derived  from tumor stroma have been linked to clinical outcomes.’  The genetic expression profile from a wound-healing model of  fibroblasts actually predicted metastasis and death in several  epithelial cancers. The “activated fibroblast gene signature” also    FIGURE 24-42 Signaling Interactions in the Tumor Microenvironment During Malignant Progression. A, Numer-  ous cell types constitute the tumor microenvironment and are orchestrated and maintained by reciprocal interactions. B, The  reciprocal interactions between the breast main tissue or parenchyma and the surrounding stroma are important for cancer  progression and growth. Certain organ sites of “fertile soil” or “metastasis niches” facilitate metastatic seeding and coloniza-  tion. Cancer stem cells are involved in some or all stages of tumor development and progression. (Adapted from Hanahan D,  Weinberg R: Cel/ 144:646-674, 2011.) CSC, Cancer stem cells.    was shown to be an independent marker for local recurrence of  breast cancer.4°0?!   Early alterations in the stroma that occur with wound heal-  ing and inflammation include activation of (1) mesenchymal  cells (embryonic) fibroblasts; (2) endothelial cells; and (3)  immune cells, including macrophages. Evidence of this type  of activation is noted adjacent to tumors and is pathologically  known as desmoplastic stroma.   To help answer the question as to whether the stromal  response is unique to the tumor (tumor-provoked) or a host  reaction (patient-dependent) to tissue alteration, investigators  studied the variability in stromal responses in clinically distinct  tumors from the same patient (paired primary tumors). They  did studies of the stromal response to biopsy site changes and  carcinoma to identify the differences and similarities.7”” These  studies indicate that the desmoid-type fibromatosis (DTF)  fibroblast response (clonal fibroblastic proliferations arise in  deep soft tissue characterized by infiltrative growth and local  recurrence) is present in individuals with paired breast pri-  mary tumors. Stroma taken from normal breast and biopsy  site changes showed that the response to biopsy site changes is  similar to the response to carcinoma and concluded that the  DTF fibroblast response is a generalized response to tissue  disruption and injury that appears to be specific to individual  patients.’’? From the larger study cohort, the macrophage-asso-  ciated pattern of gene overexpression called the CSF1 response  showed no significant similarity or concordance in separate  tumors within a given patient. The DTF fibroblast signature  showed more concordance across normal, cancer, and biopsy  site samples from within a patient than across a random group  of patients’ normal, cancer, and biopsy site samples but the  CSF1 macrophage response did not. In summary from these  studies is that the DTF fibroblast response is host-specific and  the CSF1 response may be tumor-provoked.’”” Studies of this  nature are challenging and are continuing to better understand  the characteristics of the stromal response in breast carcinogen-  esis. Emerging evidence suggests that the development of this  wound-reactive pattern and change in tumor tissue architec-  ture creates an EMT (see p. 864 and Chapter 12).4°    Invasive breast carcinoma is a malignant invasive epithelial  lesion derived from the terminal duct lobular unit (Figure 24-40,  B, p. 865). It can arise from anywhere in the breast parenchyma  or accessory breast tissue, but it appears to be more common  in the upper outer quadrant. The exact molecular events lead-  ing to invasion are complex and not completely understood.  Because myoepithelial cells form a semi-continuous protec-  tive sheet separating the human breast epithelium and the sur-  rounding stroma, it has been a major focus of understanding  invasive carcinogenesis (Figure 24-43).   Two theories are proposed for the mechanism of tumor  epithelial cells’ progression from the in situ to invasive car-  cinogenesis stages.°* The first theory of invasion is the result  of proteolytic enzymes and their degradation capacities by  myoepithelial cells and surrounding tumor cells. The second  theory is that tumor invasion is a multistep process, involving    dynamic interactions between damaged myoepithelial cells,  and the immunoreactive cells initiate the release of base-  ment membrane-degrading enzymes causing tumor progres-  sion.**? Several lines of evidence suggest that myoepithelial  cells block proliferation of breast carcinoma cells by inducing  growth arrest and apoptosis. They also secrete many effector  and inhibitor molecules that interfere or suppress the invasive  behavior of tumor cells and block angiogenesis and basement  membrane degradation.**? Patterns of local dissemination are  strongly constrained by the local ECM microenvironment and  critically, if the basement membrane remains intact, cancer  cells remain indolent. Studies have shown that even micro-  scopic breaks in the myoepithelium are correlated with a  poor prognosis.****°> The critical difference in clinical prog-  nosis between in situ and invasive or metastatic cancer results  importantly and predominantly from the presence or absence  of the surrounding basement membrane (BM).*°° The BM  physically segregates all normal or preinvasive tumor epithe-  lia from lymphatic ducts and blood vessels and from vascu-  lar structures within the stroma.**° The BM continuous sheet,  commonly called the tumor capsule, consists of mainly type  IV collagen, laminins, and other molecules*** In human breast,  prostate, and major salivary glands, the capsule is further rein-  forced by the single layer of myoepithelial cells in the breast  and salivary glands and “basal cells” in the prostate.**° The  basal or myoepithelial cell layer lies between the epithelial cells  and the BM. In the gastrointestinal tract, the normal mucosa  and in situ cancer are further separated from the submucosa by  the muscularis mucosa, a dense band composed of two layers  of smooth muscle cells.*°” Because of these structural relation-  ships, the disruption of the tumor capsule and its associated  physical barriers is an absolute prerequisite for tumor cell inva-  sion or metastasis.**° Importantly, myoepithelial cells modu-  late the expression of matrix metalloproteinases (MMPs) in  the tumor, as well as in the surrounding cells, and assist in the  prevention of tumor invasion, which is possibly mediated by  these proteolytic enzymes.*®   A long-standing theory is that progression from in situ to  invasive or metastatic cancer is caused by proteolytic enzymes  produced by tumor cells that increase linearly with tumor pro-  gression, reaching their highest level at the in situ cancer stage.  It has been hypothesized that these proteolytic enzymes cause  degradation or disruption of the tumor capsule and allow the  in situ cancer cells to migrate into the adjacent stroma or to  disseminate to distant organs. This theoretic model of tumor  invasion and metastasis is consistent with results obtained from  tissue culture and animal model studies; however, it is debated  because it appears inconsistent with a number of other well-  established observations.**° Therefore, other models exist for  understanding tumor invasion and metastases and prominently  include the role of the ECM, immune cells, and stem cells (Box  24-17). The intrinsic impact of focal myoepithelial cell degener-  ation, aberrant lymphocyte infiltration, and capsule disruptions  is likely to be associated with tumor progression and invasion.  Advanced breast cancer is associated with complete loss of the  myoepithelial cell layer and basement membrane, invasion of  epithelial cells, and angiogenesis (Figure 24-44).    FIGURE 24-43 The Role of Myoepithelial Cells in Invasive Breast Cancer. A, Cross section of a normal mammary  gland. B, Schematic of the anatomic relationship between mammary gland duct cells, basement membrane (BM), and stroma.  C, With degradation of the normal “tumor suppressing” basement membrane tumor cells invade the stroma; (1) myoepithelial  cells are damaged by various factors and release their inner contents (for example, diffusible molecules and chemoattrac-  tants); (2) immunoreactive cells (IRCs) are drawn to the luminal space by these chemoattractants; (3) IRCs become activated  after contact with chemoattractants and secrete various proteolytic enzymes; (4) these enzymes then degrade the basement  membrane resulting in gaps; and (5) tumor cells enter the stromal region through these gaps. (Data and adapted figures from  Pandey PR, Saidou J, Watabe K: Front Biosci 15:226—236, 2011.) GF Growth factor.   Proteolytic enzymes cause degradation or disruption of the tumor capsule and  allow the in situ cancer cells to migrate into the adjacent stroma or to dissemi-  nate to distant organs.   Infiltration of immune cells into tumor tissues and direct physical contact  between tumor cells and infiltrated immune cells are associated with physical  destructions of the tumor cells, reduction of the tumor burden, and improved  clinical prognosis.   Macrophages are recruited to the invasive tumor front by expression of tumor-  derived chemotactic factors and in response to the disruption of the basement  membrane. At this invasive site macrophages increase tumor cell migration and  invasion through their secretion of chemotactic and chemokinetic factors includ-  ing epidermal growth factor (EGF). Macrophages promote angiogenesis by the  synthesis of angiogenic factors including vascular endothelial growth factor  (VEGF), and they remodel the extracellular matrix and in particular, regulate col-  lagen fibrillogenesis.   |L-4-expressing CD4+ T lymphocytes indirectly promote invasion and subsequent  metastasis of breast cancer by directly regulating the phenotype and effector  function of tumor-associated macrophages that in turn enhance metastasis  through activation of epidermal growth factor receptor signaling in breast cancer  epithelial cells. The same concept and similar pathways have been extended to  lymphocytes and their subtypes.   Macrophages ingest tumor cells leading to the fusion of genetic materials from  the two cell types, resulting in the creation of a hybrid phenotype. This pheno-  type is associated with chemotactic migration in vitro toward fibronectin and  shows high frequencies of metastasis when implanted in mice.   Recruitment of Treg cells to the tumor supports disease progression through a  dual mechanism: (1) the decrease of antitumor immunity, and (2) through the  establishment of a proangiogenic reprogramming of the tumor microenvironment.    Monocyte-Mediated Protection Against Natural Killer (NK)  Cell Lysis of Cancer Stem Cells  Alterations in NK cell effector function could ultimately aid in driving differen-  tiation of a population of surviving healthy as well as transformed stem cells.  Because the majority of NK cells have lost cytotoxic activity in those with cancer,  they may eventually contribute rather than ha/t the progression of cancer by  allowing the growth and expansion of the pool of cancer stem cells.   This hypothesis provides a general mechanism how immune cells may behave  in inflammatory microenvironment for the ultimate goal of tissue regeneration  and the resolution of inflammation.   Focal basal or myoepithelial cell degeneration, aberrant lymphocyte infiltration,  and capsule disruptions may be correlated events that contribute to tumor pro-  gression and invasion. Research findings suggest that tumor invasion or metas-  tasis is triggered by focal capsule degeneration—induced lymphocyte infiltration  that causes physical disruptions within the capsule, which selectively favors  proliferation and dissemination of overlying tumor stem cells.   An extension of the above hypothesis is that aberrant tumor-infiltrating lympho-  cytes can trigger tumor metastasis through three correlated pathways: (1) the  physical movement of infiltrated lymphocytes into the budding tumor cell nest  can disrupt intercellular junctions and surface adhesion molecules, causing dis-  sociation of some cells from the tumor core; (2) lymphocytes can conjoin with  dissociated tumor cells through cell membrane fusion to form tumor-lymphocyte  chimeras (TLCs; fusion); and (3) the ability to migrate and to cross intercellular  barriers enables lymphocytes to physically drag tumor cells to remote sites and  to intravasate into blood vessels or lymph ducts.    FIGURE 24-44 Breast Cancer Progression with Stromal Cells. The normal breast duct is composed of a layer of epi-  thelial cells and a layer of myoepithelial cells, which is separated from the stroma by a basement membrane (BM). Examples of  stromal cells include fibroblasts, bone marrow-derived cells (BMDCs), endothelial cells (important for angiogenesis), and other  cells. Ductal carcinoma in situ (DCIS) is associated with luminal epithelial cell proliferation, and recruitment and expansion of  stromal cells. In invasive ductal carcinoma, the myoepithelial cell layer is degraded with the underlying basement membrane  and cancerous cells invade the surrounding microenvironment. Advanced breast cancer is associated with complete loss of  myoepithelial cell layer and basement membrane, invasion of epithelial cells, proliferation of stromal cells, and angiogenesis.  (From Khamis ZI, Sahab ZJ, Sang OX: Int J Breast Cancer 2012:574025, 2012.)    FIGURE 24-45 Retraction of Nipple Caused by Carcinoma. (From del  Regato JA, Spjut HJ, Cox JD: Ackerman and de! Regato'’s cancer: diagnosis, treat-  ment, and prognosis, ed 6, St Louis, 1985, Mosby.)    CLINICAL MANIFESTATIONS. The first sign of breast cancer is usu-  ally a painless lump. Lumps caused by breast tumors do not  have any classic characteristics. Other presenting signs include  palpable nodes in the axilla, retraction of tissue (dimpling)  (Figure 24-45), or bone pain caused by metastasis to the ver-  tebrae. Table 24-19 summarizes the clinical manifestations of  breast cancers. Manifestations vary according to the type of  tumor and stage of disease.   EVALUATION AND TREATMENT. Clinical breast examination,  mammography, ultrasound, thermography, MRI, biopsy or  minimally invasive biopsy, hormone receptor assays, and gene  expression profiling are used in evaluating breast alterations  and cancer.   Treatment is based on the extent or stage of the cancer. The  extent of the tumor at the primary site, the presence and extent  of lymph node metastasis, and the presence of distant metasta-  ses are all evaluated to determine the stage of disease. Treatment  includes surgery, radiation, chemotherapy, hormone therapy,  and biologic therapy.    Obstruction of venous return by a fast-growing tumor; obstruction dilates superficial  veins    Dimpling of the skin Can occur with invasion of the dermal lymphatics because of retraction of Cooper   Pitting of the skin (similar to the surface of an orange [peau d’orange})  Reddened skin, local tenderness, and warmth  Skin retraction   Spontaneous and intermittent discharge caused by tumor obstruction  Shortening of the mammary ducts   Obstruction of the subcutaneous lymphatics, resulting in the accumulation of fluid  Inflammation    Data from Griffiths MJ, Murray KH, Russo PC: Oncology nursing: pathophysiology, assessment, and intervention, New York, 1984, Macmillan.   1. Sexual maturation, or puberty, should begin in girls  between ages 8 and 13 years. Delayed puberty is the onset  of sexual maturation after these ages; precocious puberty is  onset before these ages. The average age of puberty has been  occurring earlier than in previous generations.   2. Alterations of sexual maturation can be idiopathic or caused  by a disease or congenital anomaly. In most cases of delayed  puberty, the hypothalamic pituitary gonadal (HPG) axis  is intact but the surge of activity that stimulates puberty is  delayed. Precocious puberty, more common in girls, also  can be caused by mistiming of the stimulatory surge in a  child whose HPG system is otherwise normal. Obesity is  associated with younger pubertal age.    3. Precocious puberty can be complete (sex appropriate),  mixed (not sex appropriate), or partial (development of  one secondary sex characteristic only). Causes of delayed or  incomplete puberty can be divided into categories based on  gonadotropic secretion: hypergonadotropism (increased  levels of FSH and LH), and hypogonadotropism (decreased  LH and FSH levels).    Disorders of the Female Reproductive System  1. The female reproductive system can be altered by hormonal  imbalances, infectious microorganisms, inflammation,  structural abnormalities, and benign or malignant prolif-  erative conditions.    Menstrual disorders usually involve some disruption of the  HPG axis and subsequent alteration of hormone produc-  tion, reception by target organs, or feedback mechanisms.    ated with pelvic disease. It often results from excessive syn-  thesis of prostaglandins (or sensitivity to prostaglandins),  which cause the myometrium to contract and constrict  blood vessels, resulting in ischemic pain.    and menstrual function by 14 years of age without the  development of secondary sex characteristics or by age 16  years if these changes have occurred.   Secondary amenorrhea is the absence of menstruation for  a time equivalent to more than three cycles or 6 months  in women who have previously menstruated. Secondary  amenorrhea is usually associated with anovulation.  Amenorrhea is divided into compartments that reflect  the underlying disorder: compartment I, disorders of the  outflow tract or uterine target organ; compartment II, dis-  orders of the ovary; compartment III, disorders of the ante-  rior pituitary; and compartment IV, disorders of the CNS  or hypothalamic factors.    to diagnose because several factors are involved. It is a syn-  drome in which at least two of the following are present:  oligo-ovulation or anovulation, elevated levels of andro-  gens, or clinical signs of hyperandrogenism and polycystic  ovaries. Prolonged anovulation leads to infertility, men-  strual bleeding disorders, hirsutism, acne, endometrial  hyperplasia, cardiovascular disease, and diabetes mellitus in  women with hyperinsulinemia.    behavioral changes distressing enough to disrupt normal  activities or interpersonal relationships. More than 200  emotional, physical, and behavioral symptoms have been  attributed to PMS. Emotional symptoms, particularly  depression, anger, irritability, and fatigue, are reported as  the most distressing; physical symptoms tend to be less  problematic. Treatment is symptomatic and includes self-  help techniques, lifestyle changes, counseling, and selective  serotonin reuptake inhibitors (SSRIs).   Infection and inflammation of the female genitalia can  result from microorganisms from the environment or over-  proliferation of microorganisms that normally populate the  genital tract.   Pelvic inflammatory disease (PID) is an acute ascending  polymicrobial infection of the upper genital tract and is  sexually transmitted.   Vaginitis, or vaginal infection, is usually caused by sexually  transmitted pathogens or C. albicans, which causes can-  didiasis. Development is related to the overall health of a  woman and local defense mechanisms, particularly vaginal  pH. Variables such as antibiotics, douching, soaps, feminine    hygiene sprays, and pregnancy alter vaginal pH or the bac-  tericidal nature of secretions and predispose a woman to  infection.   Cervicitis, which is inflammation of the cervix, can be acute  (mucopurulent cervicitis) or chronic.   Vulvovestibulitis is an inflammation of the skin of the vulva.  It can be caused by chemical and mechanical irritants, aller-  gens, skin disorders, nerve problems, or vaginal infections,  such as candidiasis.   Bartholinitis, also called Bartholin cyst, is an inflammation  of the ducts that lead from the Bartholin glands to the sur-  face of the vulva. Inflammation blocks the glands, prevent-  ing the outflow of glandular secretions, and is caused by  trauma or infection.   Pelvic organ prolapse—uterine prolapse, cystocele, recto-  cele, and urethrocele—is caused by loss of support provided  by the pelvic muscles and fascia. Age and pelvic trauma are  associated. Women with a familial or genetic predisposition  have a higher risk.   Benign growths and proliferative conditions of the female  reproductive tract tend to affect the ovaries (benign ovarian  cysts) or uterine tissues (endometrial polyps, leiomyomas,  and endometriosis).   Benign ovarian cysts develop from mature ovarian fol-  licles that do not release their ova (follicular cysts) or  from a corpus luteum that persists abnormally instead of  degenerating (corpus luteum cyst). Cysts usually regress  spontaneously.   Endometrial polyps are overgrowths of endometrial tissue  and often cause abnormal bleeding.   Leiomyomas, also called uterine fibroids, are tumors arising  from the muscle layer of the uterus, the myometrium. Inci-  dence increases in women between ages 30 and 50; most  myomas remain small and asymptomatic. Adenomyosis is  the presence of endometrial glands and stroma within the  uterine myometrium.   Endometriosis is the presence of functional endometrial  tissue (i.e., tissue that responds to hormonal stimulation)  at sites outside the uterus. Endometriosis causes an inflam-  matory reaction at the site of implantation and is a cause of  infertility.   Most cancers of the female genitalia involve the uterus (par-  ticularly the cervix) and the ovaries. Cancer of the vagina is  rare.   Infection with high-risk HPV, a sexually transmitted infec-  tion, is a necessary precursor to developing CIN and cervical  cancer. Smoking, immunosuppression, and poor nutrition  are cofactors. HPV vaccination can substantially reduce the  risk of cervical cancer.   Cervical cancer arises from the cervical epithelium. The  progressively serious neoplastic alterations are: (1) cervi-  cal intraepithelial neoplasia (cervical dysplasia), (2) cervical  carcinoma in situ, and (3) invasive cervical carcinoma.  Risk factors for vaginal cancer are in utero diethylstilbestrol  (DES) exposure and prior or concurrent cervical cancer.    Like cervical cancers, vaginal cancers arise from the epi-  thelium and are identified as intraepithelial neoplasia (dys-  plasia), carcinoma in situ, or invasive carcinoma. Most are  secondary in nature.   The major risk for vulvar cancer is a history of HPV infec-  tion or squamous dysplasia of the vagina or cervix. Symp-  toms include chronic vulvar irritation, pruritus, bloody  discharge, and a hard, ulcerated area of the vulva or large  cauliflower-like lesions. Peak incidence is in postmeno-  pausal women, but younger women can be affected.  Endometrial cancer is the most common cancer of the  pelvic region. Risk factors for endometrial cancer include  unopposed estrogen exposure, obesity, infertility, failure to  ovulate, early menarche or late menopause, and tamoxifen.  Oral contraceptive use protects against endometrial and  ovarian cancers. Peak incidence occurs at 58 to 60 years of  age, approximately 10 years later than peak incidence of  precursor lesions.   Risk factors for ovarian cancer include an increased num-  ber of total lifetime ovulations including early menarche,  late menopause, nulliparity, use of fertility drugs. BRCA1,  BRCA2, and HNPCC gene abnormalities also are linked  with ovarian cancer. Ovarian cancer causes more deaths  than any other genital cancer in women.   Awareness of sexual dysfunction is relatively new. Chronic  illness, medications, infection, sexual trauma, and a variety  of psychosocial concerns have been implicated as causes.  Infertility, or the inability to conceive after 1 year of unpro-  tected intercourse, affects approximately 15% of all couples.  Women’s fertility decreases with age, and older women may  opt for intervention sooner than younger women. Fertil-  ity can be impaired by factors in the male, female, or both  partners. Treatment depends on the cause of the infertility;  ovulation disorders and tubal blockages are the most com-  mon pathologies.    Most disorders of the breast are disorders of the mammary  gland, that is, the female breast.   Galactorrhea, or inappropriate lactation, is the persistent  secretion of a milky substance by one or both breasts in  nonpregnant, nonlactating women. It can occur in men. Its  most common cause is nonpuerperal hyperprolactinemia,  a rise in serum prolactin levels that is not associated with  pregnancy and childbirth. Hyperprolactinemia can be  caused by medications, pituitary tumors, hypothyroidism,  chronic stress, or persistent and repeated suckling.    the breast. Benign breast disease is a spectrum of noncancer-  ous changes in the breast. Benign lesions are broadly classi-  fied as (1) nonproliferating breast lesions, (2) proliferative  breast disease, and (3) atypical (atypia) hyperplasia.    Fibrocystic changes or physiologic nodularity and cysts  are not clinically definitive because they include a hetero-  geneous group of disorders and refer to nonproliferative  lesions. Symptoms affect women ages 30 to 50 and include  cyclic bilateral breast tenderness and transient breast lumps.    by proliferation of ductal epithelium and/or stroma. Crite-  ria for the diagnosis of intraductal proliferative lesions have  been the subject of much research and controversy and  include the following structurally diverse lesions: (1) usual  ductal hyperplasia, (2) intraductal papillomas, (3) scleros-  ing adenosis, and (4) simple fibroadenoma.    ALH. ADH is an increased number of cells mostly within  the lumen of the terminal ducts. It includes a continuum of  changes—cell structure and placement—ranging from an  increase in cellularity to features of DCIS. The cells in ALH  do not distend more than 50% of the acini within a lobule.    . Breast cancer is the most common form of cancer in Amer-    ican women and second only to lung cancer as the most  frequent cause of cancer death. Most breast cancer occurs  in women older than 50 years. The major risk factors for  breast cancer are classified as reproductive, such as nul-  liparity; familial, such as inherited gene syndromes; and  environmental and lifestyle, such as hormonal factors and  radiation exposure. Important factors not easily classified  are involution of the mammary gland and breast density.    then may metastasize to the lymphatics, opposite breast,  abdominal cavity, lungs, bones, kidneys, liver, adrenal  glands, ovaries, and pituitary glands.   Breast cancer is a heterogeneous disease with diverse  molecular, biologic, phenotypic, and pathologic changes.  Breast cancer also is heterogeneous within the same tumor.  With mounting evidence it appears there are “subtypes  within subtypes” and that the biology of specific breast  cancer subtypes reflect contributions from the tissue  microenvironment.   Several models of pathogenesis exist for breast cancer. Evi-  dence suggests multiple genetic and epigenetic pathways of  complex crosstalking networks that progress toward malig-  nancy. Components of the microenvironment, includ-  ing myoepithelial and endothelial cells, macrophages, and  many ECM molecules, play a critical role in normal duct  morphogenesis and increasingly recognized as major regu-  lators of carcinogenesis.   DCIS refers to a complex heterogeneous group of lesions  limited to ducts and lobules without invasion to the base-  ment membrane. Preinvasive lesions do not invariably  progress to invasive malignancy. LCIS originates from the  duct-lobular unit, and the biology of LCIS is limited.  Dominating the cancer field is the idea that epithelial func-  tion depends on the entire tissue including the stroma or  microenvironment. Breast cancer and other types of cancer  are getting known as tissue-based diseases with a possible    abnormal aberrant wound healing and inflammatory stro-  mal (reactive stroma) component. Early alterations in the  stroma that occur with wound healing and inflammation  include activation of (1) mesenchymal cells (embryonic)  fibroblasts; (2) endothelial cells; and (3) immune cells,  including macrophages   Epithelial-mesenchymal transition (EMT) is the distinctive  phenotype created from the change in tumor tissue archi-  tecture (remodeled tissue).   The exact molecular events leading to invasion are com-  plex and not completely understood. Because myo-  epithelial cells form a semi-continuous protective sheet  separating the human breast epithelium and the surround-  ing stroma, it has been a major focus of understanding    invasive carcinogenesis. The critical difference in clini-  cal prognosis between in situ and invasive or metastatic  cancer results importantly and predominantly from the  presence or absence of the surrounding basement mem-  brane (BM).    a small, painless lump in the breast. Other manifestations  include palpable lymph nodes in the axilla, dimpling of the  skin, nipple and skin retraction, nipple discharge, ulcer-  ations, reddened skin, and bone pain associated with bony  metastases.    . Treatment is based on the extent or stage of the cancer and   Polycystic ovary syndrome (PCOS), 810  Precocious puberty, 803  Pregnancy-associated breast cancer (PABC), 843  Premenstrual dysphoric disorder (PMDD), 812  Premenstrual syndrome (PMS), 812  Primary amenorrhea, 805    7. 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Boghaert E et al: Host epithelial geometry regulates breast cancer cell  invasiveness, PNAS 109(48):19632—19637, 2012.   Soto AM, Sonnenschein C: The tissue organization field theory of  cancer: a testable replacement for the somatic mutation theory, Bioessays  33(5):332-340, 2011.   Kenny PA, Bissell MJ: Tumor reversion: correction of malignant behav-  ior by microenvironment cues, Int J Cancer 107(5):688-695, 2003.  Sieweke MH et al: Mediation of wound-related Rous sarcoma virus  tumorigenesis by TGF-beta, Science 248(4963):1656—1660, 1990.    Weaver VM et al: Reversion of the malignant phenotype of human  breast cells in three dimensional culture and in vivo by integrin blocking  antibodies, J Cell Biol 137(1):231—245, 1997.   Chang HY et al: Robustness, scalability, and integration of a wound-  response gene expression signature in predicting breast cancer survival,  Proc Natl Acad Sci U § A 102(10):3738-3743, 2004.   Nuyten DS et al: Predicting a local recurrence after breast-conserving  therapy by gene expression profiling, Breast Cancer Res 8(5):R62, 2006.  Pandey PR, Saidou J, Watabe K: Role of the myoepithelial cells in breast  tumor progression, Front Biosci 15:226—236, 2011.   Adriance MC et al: Myoepithelial cells: good fences make good neigh-  bors, Breast Cancer Res 7(5):190-197, 2005.   Man YG, Sang QX: The significance of focal myoepithelial cell layer  disruptions in human breast tumor invasion: a paradigm shift from the  “protease-centered” hypothesis, Exp Cell Res 310:103—118, 2004.  Nguyen-Ngoc KV et al: ECM microenvironment regulates collective  migration and local dissemination in normal and malignant mammary  epithelium, PNAS 109(39):15543-15544, 2012.   Man YG et al: Tumor-infiltrating immune cells promoting tumor inva-  sion and metastasis: existing theories, J Cancer 4(1):84—95, 2013.  Noffsinger A et al: Gastrointestinal diseases, Washington, DC, 2007,  American Registry of Pathology and Armed Forces Institute of Pathol-  ogy, pp 1-13.   Jones JL et al: Primary breast myoepithelial cells exert an invasion  suppressor effect on breast cancer cells via paracrine down-regulation  of MMP expression in fibroblasts and tumour cells, J Pathol  201(4):562-572, 2003.    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Alterations of Sexual Maturation, 885  Delayed Puberty, 886  Precocious Puberty, 886  Disorders of the Male Reproductive System, 888  Disorders of the Urethra, 888  Disorders of the Penis, 888  Disorders of the Scrotum, Testis, and  Epididymis, 891    Alterations of the reproductive system span a wide range of  concerns, from delayed sexual development and suboptimal  sexual performance to structural and functional abnormalities.  Many common male reproductive disorders carry potentially  serious physiologic or psychologic consequences. Sexual or  reproductive dysfunction, such as impotence or infertility, can  dramatically affect self-concept, relationships, and overall qual-  ity of life. Conversely, organic and psychosocial problems, such  as alcoholism, depression, situational stressors, chronic illness,  and medications, can affect sexual performance and fertility  and may be risk factors for the development of some types of  reproductive tract cancers. Prostate cancer is the second leading  cause of cancer death in men and is the most frequently diag-  nosed cancer in men aside from skin cancer. Incidence rates for  prostate cancer changed substantially between the mid-1980s  and mid-1990s and have since fluctuated widely from year to  year, in large part reflecting changes in prostate cancer screen-  ing with the prostate specific antigen (PSA) blood test. Since  2004, incidence rates have act actually decreased by 2.7% per   Impairment of Sperm Production and Quality, 912  Disorders of the Male Breast, 913    year among men 65 years of age and older and have remained  stable among men younger than 65 years.' Diagnosis and treat-  ment of male reproductive system disorders are, like female  reproductive system disorders, complicated because of the  stigma and symbolism associated with the reproductive organs  and the emotion-laden beliefs and behaviors related to repro-  ductive health. Treatment and diagnosis for related problems  may be delayed because of embarrassment, guilt, fear, or denial.    The process of sexual maturation, or puberty, is marked by the  development of secondary sexual characteristics, rapid growth,  and, ultimately, the ability to reproduce. A variety of congeni-  tal and endocrine disorders can disrupt the timing of puberty, or  sexual maturation. These disorders may cause puberty to occur too  late (delayed puberty) or too early (precocious puberty). Both  types involve a disrupted onset of sex hormone production by the  gonads, although there is little change in the age of puberty for boys.   About 3% of children in North America experience delayed  development of secondary sex characteristics.* Normally, boys  tend to mature later than girls, around 14 to 14.5 years of age.  In boys the first sign is enlargement of the testes and thinning  of the scrotal skin. Puberty is considered delayed if there are no  clinical signs of puberty by age 14 in boys (2 standard deviations  [SDs] above the mean age of pubertal onset). Boys especially  tend to be embarrassed by sexual immaturity;? therefore, early  diagnosis and treatment are recommended, as well as reassur-  ance for boys as well as girls.   In 95% of cases delayed puberty is a physiologic delay, that  is, hormonal levels are normal and the hypothalamic-pituitary-  gonadal (HPG) axis is intact, but maturation is happening  slowly.* This constitutional delay tends to be familial and is  much more common in boys than in girls. Physiologic delay is  difficult to distinguish from isolated gonadotropin deficiency  and is usually diagnosed retrospectively once pubertal progres-  sion is complete.   Delayed puberty also may be related to consequences of  any chronic condition that delays bone aging (i.e., lung dis-  ease, renal failure, cystic fibrosis) (Box 25-1).? Many clinicians  recommend intervention (i.e., exogenous sex steroid adminis-  tration) in physiologic cases of delayed puberty to reduce the  psychologic effects (e.g., self-esteem issues, embarrassment)  often associated with delayed puberty.’   The other 5% of cases are caused bya disruption of the HPG  axis of various etiologies (see Box 25-1).° Human gonadal  function is partially controlled by luteinizing hormone  (LH) and follicle-stimulating hormone (FSH), the release of  which is regulated by the pulsatile secretion of hypothalamic  gonadotropin-releasing hormone (GnRH).*° Most recently,  the G-protein—coupled receptor 54 (GPR54) has been identi-  fied as the gatekeeper gene for activation of the GnRH axis  based on loss of function studies in mice and humans. GPR54  is required for the normal function of this axis, and data sug-  gest that the ligand kisspeptin-1 may act as a neurohormonal  regulator of the GnRH axis.° The mechanisms of childhood  inhibition of GnRH release and activation are poorly under-  stood but appear to involve feedback inhibition by sex ste-  roids and presumably other central nervous system (CNS)  pathways.’ Given the myriad etiologies contributing to the  occurrence of delayed puberty, a thorough evaluation should  be conducted that includes physical examination and medical  and family history. Such evaluation should specifically target  known contributors to delayed puberty.* Laboratory workup  generally consists of x-ray studies for bone age, measurement  of thyroid function, serum levels of prolactin and adrenal  and gonadal steroids, radioimmunoassay of plasma gonad-  otropins, and screening for systemic disorders. Adolescents  with high gonadotropin levels require a karyotype, to rule out  genetic causes, and those with low levels need skull imaging  (lateral skull film, computed tomography [CT], or magnetic  resonance imaging [MRI]) to rule out pituitary or other CNS  infiltrate or tumor.” Although several genes involved in the  HPG maturation cascade have been characterized from famil-  ial or sporadic cases of primitive isolated hypogonadotropic    Chronic or Systemic Conditions  Chronic renal disease  Cystic fibrosis  Diabetes mellitus  Excessive exercise  Hematologic diseases  Hypothyroidism  Irritable bowel diseases  Poor nutrition (eating disorders, GI diseases, poverty)  Gonadal dysgenesis  e Turner syndrome (genetic karyotype 45, XO)  Bilateral gonadal failure  Autoimmune  Congenital anorchia  Postsurgical, postirradiation, postchemotherapy  Traumatic or infectious    Hypogonadotropic Hypogonadism (Deficient FSH/LH)  e Central nervous system defects (GnRH deficiency)  Craniopharyngioma  GPR54 mutations  Hemochromatosis  Hypopituitarism  Kallmann syndrome, Bardet-Bied! syndrome, Prader-Willi syndrome  Marijuana use  Pituitary adenoma/tumor  Prolactinomas    Data from Burchett MLR, Hanna CE, Steiner RD: Endocrine and meta-  bolic diseases. In Burns CE, Brady MA, Dunn AM, editors: Pediatric  primary care, ed 4, St Louis 2009, Saunders; Jospe N: Disorders of  pubertal development. In Osborn LM et al, editors: Pediatrics, Phila-  delphia, 2005, Mosby; Karagiannis A, Harsoulis F: Eur J Endocrinol  152(4):501-513, 2005.   FSH, Follicle-stimulating hormone; Gi, gastrointestinal; GnRH, gonado-  tropin-releasing hormone; LH, luteinizing hormone.    hypogonadism, many genes regulating puberty onset remain  undetermined. Treatment of delayed puberty depends on the  cause; the goal of treatment is the development of secondary  sex characteristics and fertility, when possible. Insufficient  sex hormone secretion can be corrected by hormone replace-  ment therapy, such as testosterone for boys.® Idiopathic  hypogonadotropic hypogonadism is treated with synthetic  GnRH or sex hormone administration, or both, and may be  lifelong.?*°   Precocious puberty is a rare event in boys, affecting less than  1 in 50,000. Precocious puberty in boys has been redefined as  sexual maturation before age 9.° One study has noted observed  mean ages of beginning male genital and pubic hair growth  and early testicular volumes tending toward younger ages  than earlier studies have suggested, although this seems to be  dependent on race and ethnicity.'° For instance, black boys are  showing significantly earlier mean ages for stages 2 to 4 genital   Premature development of appropriate characteristics for the child's sex  Hypothalamic-pituitary-ovarian axis working normally but prematurely   In about 10% of cases, lethal central nervous system tumor may be the cause    Partial Precocious Puberty  Partial development of appropriate secondary sex characteristics  Premature thelarche (breast budding) seen in girls between 6 months and 2   Premature adrenarche (growth of axillary and pubic hair) tends to occur  between 5 and 8 years of age   Can progress to complete precocious puberty; may be caused by estrogen-  secreting neoplasms or may be a variant of normal pubertal development   Causes the child to develop some secondary sex characteristics of the  opposite sex    Data from Burchett MLR et al: Endocrine and metabolic diseases. In  Burns CE et al, editors: Pediatric primary care, St Louis, 2009, Saun-  ders; Jospe N: Disorders of pubertal development. In Osborn LM et al,  editors: Pediatrics, Philadelphia, 2005, Mosby.    development and stages 2 to 4 pubic hair than white and His-  panic boys. All cases of precocious puberty require thorough  evaluation.   Precocious puberty may be partial, complete, or mixed  (heterosexual) types (Box 25-2) and can be further catego-  rized into central (GnRH-dependent) and peripheral (GnRH-  independent) (Box 25-3). Central precocious puberty is  GnRH-dependent and occurs when the HPG axis is working  normally but prematurely. Besides the premature development  of secondary sex characteristics, precocity causes premature  closure of the epiphysis of long bones, which results in shorter  stature. Central precocious puberty results from failure of cen-  tral inhibition of the GnRH pulse generator (the gonadostat).  The diagnosis of central precocious puberty is one of exclusion.  Because a CNS lesion may be missed, children with presumed  central precocious puberty require long-term surveillance.  Peripheral puberty is GnRH-independent and develops when  sex hormones are produced by some mechanism other than  stimulation by the gonadotropins. Sex steroid—producing  tumors (i.e., gonadal tumors), testotoxicosis, and exposure  to exogenous sex steroids (i.e., hormonal contraceptives and  environmental endocrine disruptors) are some of the causes  (see Box 25-3).   Complete precocious puberty refers to the onset and pro-  gression of all pubertal features. Partial precocious puberty is  the partial development of appropriate secondary sex charac-  teristics alone or in combination. Premature pubarche tends to  occur between ages 5 and 8 years. Premature pubarche is usually  the consequence of an early increase in the adrenal androgens  that leads to early growth of pubic hair and possibly a transient  acceleration in growth and bone maturation that has no signifi-  cant effect on timing of puberty or final height.    Central (Gonadotropin-Releasing Hormone [GnRH]  Dependent)  \diopathic  Central nervous system (CNS) disorders  Congenital anomalies (hydrocephalus)  Hypothalamic hamartoma  Postinflammatory/infectious condition  Trauma  Tumors (hypothalamic, pineal, other)  Hypothyroidism (severe)    From Bhagavath B, Layman LC: Semin Reprod Med 25(4):272-286,  2007; Burchett MLR et al: Endocrine and metabolic diseases. In Burns  CE et al, editors: Pediatric primary care, St Louis, 2009, Saunders;  Caserta DL et al: Hum Reprod Update 14(1):59-72, 2008; Cesario SK,  Hughes LA: J Obstet Gynecol Neonatal Nurs 36(3):263-274, 2007;  Jospe N: Disorders of pubertal development. In Osborn LM et al,  editors: Pediatrics, Philadelphia, 2005, Mosby.    The diagnosis and cause of premature development are often  obvious. A thorough history and physical examination are done  to determine the velocity of the process and to rule out life-  threatening CNS or adrenal neoplasms. Family occurrence  helps exclude tumors. Children with precocious puberty also  have a tendency toward obesity.”"!   Treatment for all forms of precocious puberty includes iden-  tifying and removing the underlying cause (see Boxes 25-2 and  25-3) or administering appropriate hormones. In many cases  precocious puberty can be reversed. Management goals include  diagnosing and treating intracranial disease; arresting matura-  tion until early teen years; maximizing eventual adult height;  reducing emotional problems; and providing contraception, if  necessary. The most common form, central precocious puberty,  is usually treated with potent GnRH agonist analogs, which  induce reversible, selective suppression of the HPG axis. Treat-  ment does not seem to affect body composition or increase obe-  sity in children with central precocious puberty. Because many  of these children are obese and childhood obesity is predictive  of morbidity in adolescence and adulthood, it is important for  clinicians to include assessment and management of obesity as  part of the treatment for central precocious puberty.   Mixed precocious puberty (e.g., feminization of a boy)  causes the child to develop some secondary sex characteristics  of the opposite sex. This condition is usually evident at birth  and is rare in older children (Box 25-4).    From Jospe N: Disorders of pubertal development. In Osborn LM et al,  editors: Pediatrics, Philadelphia, 2005, Mosby.   Urethritis and urethral strictures are common disorders of the  male urethra. Urethral carcinoma occurs in men older than  60 years, but it is an extremely rare form of cancer.    Urethritis is an inflammatory process of the urethra without  concurrent bladder infection that is usually, but not always,  caused by a sexually transmitted microorganism. Biologic  agents associated with infectious urethritis in males include  Neisseria gonorrhoeae and Chlamydia trachomatis, Ueaplasma  urealyticum, and other, less common, mycobacteria; para-  sites (e.g., Trichomonas vaginalis); and viruses (herpes simplex  virus [HSV]).!*!> Infectious urethritis caused by N. gonor-  rhoeae often is called gonococcal urethritis (GU); infection  caused by other microorganisms is called nongonococcal ure-  thritis (NGU)."* (Sexually transmitted urethritis is described in  Chapter 26.) Nonsexual origins of urethritis include inflamma-  tion or infection as a result of urologic procedures, insertion  of foreign bodies into the urethra, anatomic abnormalities, or  trauma.   Noninfectious urethritis is rare and is associated with the  ingestion of wood alcohol, ethyl alcohol, or turpentine. It is  seen also with Reiter syndrome, which involves a number of  mucocutaneous lesions.   Symptoms of urethritis include urethral tingling, itching,  or burning sensation on urination (dysuria), frequency, and  urgency. The individual may note a purulent or clear mucus-  like discharge from the urethra. Nucleic acid detection ampli-  fication tests allow easy detection of N. gonorrhoeae and C.  trachomatis in first-void urine.'* Treatment consists of appro-  priate antibiotic therapy for infectious urethritis and avoidance  of future chemical or mechanical irritation.    A urethral stricture is a fibrotic narrowing of the urethra caused  by scarring. The scars may be congenital but are more likely to  result from trauma or untreated or severe urethral infections,  most often from long-term use of indwelling urinary catheters.  It can present at any age and has a wide range of etiologic fac-  tors, including infection, trauma, and instrumentation. Large  catheters and instruments cause internal trauma and ischemia,  whereas external trauma, such as pelvic fracture, can partially  or completely sever the urethra and cause severe and complex  strictures.'> In addition, a report has concluded that stricture  may occur decades after initial hypospadias surgery.'° Ure-  thral carcinoma is a less common cause of urethral stricture.  Prostatitis and infection secondary to urinary stasis are com-  mon complications. Severe and prolonged obstruction can  result in hydronephrosis and renal failure. In addition, chronic,  severe strictures may lead to urethral fistulas and periurethral  abscesses.!>!7   The clinical manifestations of urethral stricture are caused  by bladder outlet obstruction. The primary symptom is dimin-  ished force and caliber of the urinary stream; other symptoms  include urinary frequency and hesitancy, mild dysuria, double  urine stream or spraying, and postvoiding dribbling. Symp-  toms of acute urinary retention may occur in the presence of  infection or urinary obstruction. Induration at the stricture site  may be palpable. Tender, enlarged masses along the urethra  usually indicate periurethral abscesses. Urethral stricture often  manifests itself as lower urinary tract symptoms or urinary tract  infections with significant impairment in the quality of life.   Urethral stricture is diagnosed on the basis of history, physi-  cal examination, urinary flow rates, voiding cystourethrogram,  and urethroscopy; biopsy confirms carcinoma. Treatment is  usually surgical and may involve urethral dilation, urethrot-  omy, or a variety of open surgical techniques. The choice of sur-  gical intervention depends on the age of the individual and the  severity of the problem. Strictures may recur up to | year after  treatment. Follow-up is necessary during this time; urinary flow  measurements and urethrogram help determine extent of resid-  ual obstruction.   Phimosis and paraphimosis are disorders in which the fore-  skin (prepuce) is “too tight” to be moved easily over the glans  penis. Phimosis is a condition in which the foreskin cannot  be retracted back over the glans, whereas paraphimosis is the  opposite: the foreskin is retracted and cannot be moved forward  (reduced) to cover the glans (Figure 25-1). Both conditions can  cause penile pathologic conditions.   The inability to retract the foreskin is normal in infancy and  is caused by congenital adhesions. During the first 3 years of  life these adhesions separate naturally with penile erections and  are not an indication for circumcision. Although most cases  occur in uncircumcised males, stenosis and resultant phimo-  sis can occur in males with excessive skin remaining after cir-  cumcision.!’ Phimosis can occur at any age and is caused most  commonly by poor hygiene and chronic infection. Chronic    FIGURE 25-1 Phimosis and Paraphimosis. A, Phimosis: the foreskin has a narrow opening that is not large enough to  permit retraction over the glans. B, Lesions on the prepuce secondary to infection cause swelling, and retraction of foreskin  may be impossible. C, Paraphimosis: the foreskin is retracted over the glans but cannot be reduced to its normal position.  Here it has formed a constricting band around the penis. D, Ulcer on the retracted prepuce with edema. (A, € from Monahan  FD, et al: Phipps’ medical-surgical nursing, ed 8, St Louis, 2007, Mosby; B from Taylor PK: Diagnostic picture tests in sexually  transmitted diseases, London, 1995, Mosby-Wolfe; D from Morse SA, Holmes KK, Ballard RC: Atlas of sexually transmitted    balanoposthitis (inflammation of the glans and prepuce) pre-  disposes older diabetic men to phimosis. It rarely occurs with  normal foreskin.   Edema, erythema, and tenderness of the prepuce and puru-  lent discharge are usually the reasons for seeking treatment;  inability to retract the foreskin is a less common complaint.  Circumcision, if needed, is performed after infection has been  eradicated. Complications of phimosis include inflammation of  the glans (balanitis) or prepuce (posthitis) and paraphimosis.  There is a higher incidence of penile carcinoma in uncircum-  cised males, which is associated with morbidity and mortal-  ity, but chronic infection, most likely with HPV, is usually the  underlying factor in such cases. Approximately 40% of invasive  penile carcinomas are attributable to HPV.!7!®   Paraphimosis, in which the foreskin is retracted, can con-  strict the penis, causing edema of the glans. If edema is such  that the foreskin cannot be reduced manually, surgery must  be performed to prevent necrosis of the glans caused by con-  stricted blood vessels. Severe paraphimosis is a surgical emer-  gency and phimosis may require immediate release if there is  urinary obstruction.   Peyronie disease (bent nail syndrome) is a fibrotic condition  of the tunica albuginea of the penis resulting in varying degrees  of curvature and sexual dysfunction!’ (Figure 25-2). Peyronie  disease develops slowly and is characterized by tough, fibrous  thickening of the fascia in the erectile tissue of the corpora cav-  ernosa. A dense fibrous plaque is usually palpable on the dor-  sum of the penile shaft. The problem usually affects middle-age  men and is associated with painful erection, painful intercourse  (for both partners), and poor erection distal to the involved  area. In some cases, impotence or unsatisfactory penetration  occurs. There is no pain when the penis is flaccid.   Although the exact cause is unknown, a local vasculitis-like  inflammatory reaction occurs and decreased tissue oxygenation  results in fibrosis and calcification. Peyronie disease is associ-  ated with Dupuytren contracture (a flexion deformity of the  fingers or toes caused by shortening or fibrosis of the palmar  or plantar fascia), diabetes, tendency to develop keloids, and in  rare cases, use of beta-blocker medications.   There is no definitive treatment for Peyronie disease. Spon-  taneous remissions occur in as many as 50% of cases. Treatment    FIGURE 25-2 Peyronie Disease. (From Taylor PK: Diagnostic picture tests in  sexually transmitted diseases, London, 1995, Mosby-Wolfe.)    with pharmacologic therapies include colchicine, aminobenzo-  ate potassium (Potaba), L-carnitine, and liposomal superox-  ide dismutase. Men suffering with Peyronie disease who have  significant penile deformity precluding successful coitus can  be appraised for surgical correction. Surgery is considered the  gold standard and includes plication, incision and grafting, or  penile-prosthesis-related procedures.!7"   Priapism is an uncommon condition of prolonged penile  erection. It is usually painful and is not associated with sexual  arousal (Figure 25-3). Priapism is idiopathic in 60% of cases;  the remaining 40% of cases are associated with spinal cord  trauma, sickle cell disease, leukemia, pelvic tumors or infec-  tions, or penile trauma. Priapism also has been associated with  cocaine use.”°?! Intracavernous injection therapy for impo-  tence seems to be the most common cause. Prolonged sexual  stimulation often is associated with initial development of the  idiopathic type.!’ The two corpora cavernosa within the erect  penis are filled with blood and are tender to palpation; neither  the corpus spongiosum nor the glans is engorged. The vascular  congestion is thought to be associated with venous obstruction.  If the erection remains over a period of days, edema and fibrosis  develop, leading to erectile dysfunction (impotence).   Priapism is a urologic emergency. Treatment within hours  is effective and prevents impotence. Conservative approaches  include iced saline enemas, ketamine administration, and spinal  anesthesia. Needle aspiration of blood from the corpus through  the dorsal glans is often effective and is followed by catheteriza-  tion and pressure dressings to maintain decompression. More  aggressive surgical treatments include the creation of vascular  shunts to maintain blood flow. Erectile dysfunction results in  up to 50% of prolonged cases.   Balanitis is an inflammation of the glans penis (Figure 25-4)  and usually occurs in conjunction with posthitis, an inflam-  mation of the prepuce. It is associated with poor hygiene and    FIGURE 25-3 Priapism. (From Lloyd-Davies RW, Gow JG, Davies DR: Co/or  atlas of urology, ed 2, London, 1994, Mosby-Wolfe.)    FIGURE 25-4 Balanitis. Itchy, red rash on glans of penis secondary to Can-  dida albicans. (From Taylor PK: Diagnostic picture tests in sexually transmitted  diseases, London, 1995, Mosby-Wolfe.)    phimosis. The accumulation under the foreskin of glandular  secretions (smegma), sloughed epithelial cells, and Mycobacte-  rium smegmatis can irritate the glans directly or lead to infec-  tion. Skin disorders (e.g., psoriasis, lichen planus, eczema) and  candidiasis must be differentiated from inflammation resulting  from poor hygienic practices. Balanitis is seen most commonly  in men with poorly controlled diabetes mellitus and candidia-  sis. Antimicrobials are used to treat infection. Circumcision can  prevent recurrences and can be considered after the inflamma-  tion has subsided.    In the United States, carcinoma of the penis is rare and affects  about 1 in 100,000 men. Approximately 1570 cases and 310  deaths were estimated in the year 2012.! Although rare in North  America and Europe, where it accounts for about 0.2% of  cancers and 0.1% of cancer deaths in men, penile cancer may  account for up to 10% of cancers in African and South Ameri-  can men.   In the United States, about four out of five cases of the dis-  ease are diagnosed in men older than age 55 years.’* Major risk  factors include infection with HPV (mainly serotypes 16 and    FIGURE 25-5 Squamous Cell Carcinoma Involving the Glans Penis. (From  Callen JP et al: Color atlas of dermatology, Philadelphia, 1993, Saunders.)    18), smoking, and psoriasis treated with a combination involv-  ing the drug psoralen and ultraviolet (UV) light. Men circum-  cised at birth have less than half the chance of getting penile  cancer than those who were not. Penile cancer is more com-  mon in men with phimosis and those with acquired immuno-  deficiency syndrome (AIDS).”* About two thirds of men with  penile cancer are diagnosed at more than 65 years of age.!   Before the development of penile cancer, signs of prema-  lignant cancer or epidermal cancer in situ are present.’ These  include thick white plaque (leukoplakia) that typically involves  the meatus; red, inflamed areas of Paget disease; red, velvety,  ulcerative lesions of erythroplasia of Queyrat that usually involve  the glans; large, invasive, scaly growths of Buschke-Léwenstein  tumor; red plaque with encrustations of Bowen disease; and in  situ carcinoma that generally affects the penile shaft. Men with  leukoplakia or erythroplasia of Queyrat may have concurrent  invasive penile carcinoma.’*‘ Pain and bleeding are late signs  of penile cancer. Condylomata (genital warts) caused by HPV  may be involved in the development of precancerous lesions  (see Chapter 26 for a discussion of HPV). At times the penis  might be the site of metastatic spread of solid tumors from the  bladder, prostate, rectum, or kidney. Early squamous cell car-  cinoma and premalignant epidermal lesions are easily treated  but are often ignored. Delays in seeking treatment are attrib-  uted to denial, embarrassment, failure to detect lesions under a  phimotic foreskin, fear, guilt, and ignorance.   Penile cancer is mostly squamous cell carcinoma, which usu-  ally begins as a small, fat, ulcerative or papillary lesion on the  glans or foreskin that grows to involve the entire penile shaft  (Figure 25-5). Extensive lesions are associated with metas-  tases and a poor prognosis.*> These lesions are not as painful  as the amount of tissue involvement would seem to indicate.  The regional femoral and iliac nodes are common metastatic  sites. Rarely the urethra and bladder are involved. Weight loss,  fatigue, and malaise accompany chronic suppurative lesions.  Untreated, progressive disease causes death within 2 years.   The specific diagnosis is made by biopsy after examination  to document the location, size, and fixation of the lesion. After  a positive biopsy the extent of cancer spread is determined by  imaging tests such as ultrasound, CT, or MRI. Fine-needle    aspiration of lymph tissue confirms absence or presence of  regional adenopathy.”* About 30% of penile cancers spread to  lymph nodes before diagnosis. Distant metastases occur in less  than 10% of cases and may involve lung, liver, bone, or brain.”*  The following stages are used for penile cancer: stage 0 (carci-  noma in situ), stage I, stage II, stage III, and stage IV.”   Penile carcinoma is primarily managed with surgery. Newer,  innovative surgical techniques can preserve as much penile  tissue as possible without compromising cancer control. For  invasive penile carcinoma, complete excision leaving adequate  tumor-free margins is the goal. A simple circumcision may be  sufficient for localized lesions of the prepuce. If the primary site  is the glans and distal shaft, removal of the penis may be nec-  essary. Although conventional radical surgery continues to be  an effective approach, the emasculating nature of the treatment  has serious psychologic and sexual consequences. Recent stud-  ies have challenged the conventional belief that a 2-cm margin  was required for adequate cancer control.?> Newer innovative  surgical techniques can preserve as much penile tissue and  functional integrity as possible without compromising cancer  control. Inguinal lymph nodes also are removed if metastasis  to these structures is known or suspected. Palliative treatment  with radiation or chemotherapy may be used when the disease  is inoperable and bulky inguinal metastases have occurred.  Options for individuals with carcinoma in situ include local  excision, radiation, laser surgery, cryosurgery, chemosurgery,  or chemotherapy with topical (5%) 5-fluorouracil (5-FU). Dif-  ferentiation, tumor stage, and age influence prognosis.”>° The  5-year survival rate for stage I disease is greater than 80%; aver-  age 5-year survival rate for all stages is 50%.    Disorders of the Scrotum, Testis, and Epididymis  Disorders of the Scrotum   Men may seek treatment for painful or painless scrotal masses.  Masses may be serious (cancer or torsion) or benign (hydro-  cele or cyst) and may require immediate surgical intervention  or allow for careful observation.”’ Varicocele, hydrocele, and  spermatocele are common intrascrotal disorders.***° A varico-  cele is an abnormal dilation of a vein within the spermatic cord  and is classically described as a “bag of worms” (Figure 25-6).  Most (95%) occur on the left side and may be painful or tender.  Varicocele occurs in 10% of males and is seen most often after  puberty. Sudden development of a varicocele in an older man  is a late sign of renal tumor.*! Unilateral right-sided varicoceles  are rare and result from compression or obstruction of the infe-  rior vena cava by a tumor or thrombus. Color Doppler ultraso-  nography is used to confirm the diagnosis.?’   The cause of varicocele is incompetent or congenitally  absent valves in the spermatic veins. The valves that normally  prevent backflow are absent or do not close adequately, permit-  ting blood to pool in the veins rather than flow into the venous  system. Varicocele decreases blood flow through the testis.  This interferes with spermatogenesis and is a cause of infertil-  ity.?>°? If infertility is a problem, treatment consists of ligation  of the spermatic vein or occlusion of the vein by percutaneous  methods, such as balloon catheter and sclerosing fluids.*? If  varicocele is mild and fertility is not an issue, a scrotal support    FIGURE 25-6 Varicocele. A, Dilation of veins within the spermatic cord. B, Varicocele on physical examination. (A from    Seidel H et al: Mosby's guide to physical examination, ed 7, St Louis, 2011, Mosby. B from Swartz MH: Textbook of physical   A hydrocele is a collection of fluid within the tunica vagi-  nalis*®*° (Figure 25-7). It is the most common cause of scro-  tal swelling. Hydroceles occur in 6% of male newborns and  are congenital malformations (patent processus vaginalis) that  often resolve spontaneously in the first year of life. Surgical liga-  tion is recommended if hydrocele persists after age 1 year.°°  Hydroceles in adults may be caused by an imbalance between  the secreting and absorptive capacities of scrotal tissues. Hydro-  celes range in size from slightly larger than the testes to the size  of a grapefruit or larger and may be flaccid or tense. Compres-  sion of testicular blood supply may lead to atrophy.   The exact mechanism of idiopathic hydrocele is unknown.  Secondary hydrocele may result from trauma or infection of the  testis or epididymis or from a testicular tumor. Rapid accumu-  lation of fluid occurs after local injury, radiotherapy, or infec-  tion (epididymitis or orchitis), or it may accompany testicular  neoplasm. Chronic hydroceles are more common and occur in  men older than 40 because of an imbalance between fluid secre-  tion and reabsorption in the tunica vaginalis. A painless, extra-  testicular mass that easily transilluminates is found on physical  examination. Ultrasonography of a large hydrocele, which may  conceal a testicular tumor, is recommended. Treatment is usu-  ally not required unless a large, bulky hydrocele causes consider-  able physical discomfort or undesirable cosmetic appearance.”®  Treatment for uncomplicated hydrocele is aspiration of the  fluid and injection of a sclerosing agent into the scrotal sac.***°  The goal of treatment is to remove the hydrocele and prevent  recurrence by sclerosing or excising the tunica vaginalis.   Spermatoceles (epididymal cysts) are benign cystic collec-  tions of fluid of the epididymis located between the head of  the epididymis and the testis. Efferent ducts of the epididymis  have potential for cystic dilation to form a spermatocele **”°    (Figure 25-8). Spermatoceles are filled with milky fluid that  contains sperm. Spermatocele is differentiated from a hydrocele  in that aspiration of the hydrocele recovers a clear, yellow fluid,  and unlike a hydrocele, a spermatocele does not cover the entire  anterior surface of the testis.   Spermatoceles manifest as discrete, firm, freely mobile  masses distinct from the testis that may be transilluminated.  Epididymal cysts do not require treatment.°’ A spermatic cord  tumor may feel like a tense spermatocele but does not contain  fluid and will not transilluminate.?”? Spermatoceles that cause  pain or discomfort are excised. Usually, however, spermatoceles  are asymptomatic or produce mild discomfort that is relieved  by scrotal support.*° Neither hydroceles nor spermatoceles are  associated with infertility.   Cryptorchidism is a condition of testicular maldescent,  whereas an ectopic testis has strayed from the normal pathway  of descent. Ectopy may be caused by an abnormal connection  at the distal end of the gubernaculum testis that leads the gonad  to an abnormal position, usually at the superficial inguinal site.  In cryptorchidism the descent of one or both testes is arrested,  with unilateral arrest occurring more often than bilateral  arrest.*> The testes may remain in the abdomen, or testicular  descent may be arrested in the inguinal canal or the puboscro-  tal junction. Cryptorchidism is a common congenital anomaly,  with an incidence of approximately 3% in full-term infants.  However, this rate increases significantly with low birth weight  infants; for instance, the rate of cryptorchidism at 3 months has  been found to be 7.7% for infants with birth weights less than  2000 g, 2.5% for birth weights of 2000 to 2500 g, and 1.41% for  birth weights of 2500 g or more.°?° The incidence of cryptor-  chidism in adults is 0.7% to 0.8%.** Cryptorchidism is com-  monly associated with vasal or epididymal abnormalities. These    FIGURE 25-7 Depiction of a Hydrocele. A, Accumulation of clear fluid  between the visceral (inner) and parietal (outer) layers of the tunica vaginalis.  B, The appearance of a hydrocele on ultrasound examination. (B from Adam A,  et al: Grainger & Allisons diagnostic radiology, ed 6, London, 2008, Churchill  Livingstone.)    congenital anomalies affect about one third to two thirds of new-  borns with cryptorchidism. Other structural anomalies include  posterior urethral valves (less than 5%), upper tract abnormali-  ties (less than 5%), and hypospadias. The presence of hypo-  spadias as well as cryptorchidism raises the suspicion of mixed  gonadal dysgenesis (intersex infant). It has been hypothesized  that cryptorchidism may result from an absence or abnormality  of the gubernaculum, a cordlike structure that extends from the  lower pole of the testis to the scrotum; a congenital gonadal or  dysgenetic defect that makes the testes insensitive to gonado-  tropins (a likely explanation for unilateral cryptorchidism); or  lack of maternal gonadotropins (a likely explanation for bilat-  eral cryptorchidism of prematurity).°* Mechanical possibilities  include a short spermatic cord, fibrous bands or adhesions in    Bey  FIGURE 25-8 Spermatocele. Retention cyst of the head of the epididymis or  of an aberrant tubule or tubules of the rete testis. The spermatocele lies outside  the tunica vaginalis; therefore, on palpation it can be readily distinguished and  separated from the testis. (From Lloyd-Davies RW, Gow JG, Davies DR: Color atlas  of urology, ed 2, London, 1994, Mosby-Wolfe.)    the normal path of the testes, or a narrowed inguinal canal.  Chromosomal studies do not support a genetic component.  Physiologic cryptorchidism, also called retractile or migratory  testis, is an involuntary retraction of the testes out of the scro-  tum that occurs with excitement, physical activity, or exposure  to cold and is caused by the small mass of prepubertal testis  and the strength of the cremaster muscle. This is a common  phenomenon that is self-limiting (descent occurs at puberty).  Physical examination discloses the absence of one or both  testes in the scrotum and an atrophic scrotum on the affected  side. If the undescended testis is in a vulnerable position, for  example, over the pubic bone, an individual may complain of  severe pain secondary to trauma. The adult male with bilateral  cryptorchidism may be infertile. Ultrasonography, CT, or MRI  can be used to locate an intra-abdominal or nonpalpable testis.  Testicular cancer is also a well-established complication of  cryptorchidism. In men with a history of unilateral cryptor-  chidism, neoplasms also develop more commonly in the con-  tralateral testis. This finding suggests cryptorchidism affects the  testes and is a process more significant than simply the position  of the testis in childhood.*° The risk of testicular cancer is 35 to  50 times greater for men with cryptorchidism or a history of  cryptorchidism than for the general male population. Because  definite histologic change (decreased Leydig cells, loss of germ  cells, and peritubular fibrosis) occurs in the cryptorchid testis by  1 year of age, surgical correction is recommended earlier.*” Treat-  ment often begins with administration of GnRH or human cho-  rionic gonadotropin (hCG), hormones that may initiate descent,  making surgery unnecessary. GnRH is given as a nasal spray in  Europe and may enhance germ-cell counts even when the testis  does not descend.*” If hormonal therapy is not successful, the  testis is located and moved surgically (orchiopexy) in young  children or removed (orchiectomy) in adults and children older  than 10 years.*’ The testis that is properly placed in the scrotum  provides adequate hormonal function and gives the scrotum a  normal appearance. A successful operation does not ensure fer-  tility if the testis is congenitally defective. Approximately 20%  of males with unilateral undescended testis remain infertile even    FIGURE 25-9 Torsion of the Testes. A, Left testicular torsion in an adolescent with acute scrotum; the testis is necrotic.  B, Late phase torsion in an adolescent with severe testicular pain 1 month previously. Note the absence of inflammation and  high position of testis in scrotum. C, The testes appear dark red and partially necrotic owing to hemorrhagic infarction. (A and  B from Kliegman RM et al: Ne/son’s textbook of pediatrics, ed 19, Philadelphia, 2011, Saunders. € from Damjanov |, Linder J,    though orchiopexy is performed by age 1 year; most individu-  als with treated or untreated bilateral testicular maldescent have  poor fertility. In addition, placement of the cryptorchid testis  into the scrotal sac does not decrease the potential for malig-  nancy; it does facilitate examination and tumor detection.    Torsion of the testis is rotation of a testis, which twists blood  vessels in the spermatic cord. It causes an acute scrotum, which  is testicular pain and swelling (Figure 25-9). Differentiation  between testicular torsion and two other common causes of  an acute scrotum is based on physical examination and his-  tory’? (Table 25-1). This event is most common among neo-  nates and pubertal adolescents, but it can occur in males at any  age.” Onset may be spontaneous or follow physical exertion or  trauma. Torsion twists the arteries and veins in the spermatic  cord, reducing or stopping circulation to the testis. Vascular  engorgement and ischemia develop, causing scrotal swelling and  pain. These manifestations are not relieved by scrotal elevation  (Prehn sign), rest, or scrotal support. On physical examination,  men have a tender high-riding testis, a thickened spermatic  cord, and an absent cremasteric reflex. Unlike epididymitis, the  epididymis cannot be differentiated from the testis.*° Diagnos-  tic testing includes urinalysis (to rule out infection) and color  Doppler ultrasonography.” Torsion of the testis is a surgical    emergency. If the torsion cannot be reduced manually, surgery  must be performed within 6 hours after the onset of symp-  toms to preserve normal testicular function. Surgery includes  untwisting the spermatic cord and anchoring both testes in cor-  rect position within the scrotum to prevent recurrences. With  successful manual detorsion, surgical fixation should be done  within a few days.    Orchitis is an acute infection of the testes (Figure 25-10) and is  uncommon except as a complication of systemic infection or as  an extension of an associated epididymitis*® (see p. 897). Infec-  tious microorganisms may reach the testes through the blood  or the lymphatics or, most commonly, by ascent through the  urethra, vas deferens, and epididymis. Most cases of orchitis are  actually cases of epididymo-orchitis. Occasionally, in middle-  age men, a nonspecific, apparently noninfectious, inflamma-  tory process (called granulomatous orchitis) occurs. It seems  to be an autoimmune disease that triggers a granulomatous  response to spermatozoa.   Mumps is the most common infectious cause of orchitis and  usually affects postpubertal males. The onset is sudden, occur-  ring 3 to 4 days after the onset of parotitis. Signs and symptoms  include high fever, reaching 40° C (104° F), marked prostration,  bilateral or unilateral erythema, edema and tenderness of the    FIGURE 25-10 Orchitis. Inflammation of the testicle with enlargement  or swelling. (From Seidel H et al: Mosbys guide to physical examination, ed 7,  St Louis, 2011, Mosby.)    scrotum, and leukocytosis. An acute hydrocele may develop.  Urinary signs and symptoms, which accompany epididymi-  tis, are absent. Atrophy with irreversible damage to spermato-  genesis may result in 30% of affected testes. Bilateral orchitis  does not affect androgenic function but may cause permanent  sterility.   Treatment is supportive and includes bed rest, scrotal sup-  port, elevation of the scrotum, hot or cold compresses, and anal-  gesic agents for relief of pain. If an acute hydrocele develops, it  is aspirated. Testicular abscess usually requires orchiectomy  (removal of the testis). Appropriate antimicrobial drugs should  be used for bacterial orchitis, and corticosteroids are indicated  in proved cases of nonspecific granulomatous orchitis.    Testicular cancer is a highly treatable, usually curable, can-  cer that most often develops in young and middle-aged men.  For men with seminoma (all stages combined), the cure rate  exceeds 90%. For those with low-stage seminoma or non-  seminoma, the cure rate approaches 100%.°? Overall, testicu-  lar cancers are rare, yet they are the most common form of  cancer in young men between ages 15 and 35. Approximately  8590 cases and 360 deaths were estimated for 2012.' In the  United States, the lifetime probability of developing testicular  cancer is 0.2% for white men, an incidence that is four times  higher than for blacks. Testicular tumors are slightly more  common on the right side than on the left, a pattern that par-  allels the occurrence of cryptorchidism; about 1% to 2% of  primary testicular cancers are bilateral (Figure 25-11), and  50% of these tumors arise from treated or untreated crypt-  orchid testes.   PATHOGENESIS. Ninety percent of testicular cancers are  germ-cell tumors arising from the male gametes. Germ-cell  tumors constitute 90% of testicular cancers and can be broadly    classified into two types: seminomas and nonseminomas.  Seminomas are the most common, are the least aggressive,  and make up about 30% to 35% of testicular cancers. Non-  seminomas include embryonal carcinomas, teratomas, and  choriocarcinomas, the most aggressive but rare (less than 1%)  form of testicular cancer. Testicular cancers can include a mix  of types.“ In addition, testicular tumors can arise from spe-  cialized cells of the gonadal stroma. These tumors, which are  named for their cellular origins, are Leydig cell, Sertoli cell,  granulosa cell, and theca cell tumors and constitute less than  10% of all testicular cancers."!   The cause of testicular neoplasms is unknown. A genetic pre-  disposition is suggested by the fact that the incidence is higher  among brothers, identical twins, and other close male rela-  tives. Genetic predisposition is supported further by statistics  showing that the disease is relatively rare among black Africans,  black Americans, Asians, and native New Zealanders. Familial  testicular germ cell tumors may be associated with transgen-  erational inheritance of epigenetic events.” Risk factors include  history of cryptorchidism, abnormal testicular development,  human immunodeficiency virus (HIV) and AIDS, Klinefelter  syndrome, and history of testicular cancer.*”   CLINICAL MANIFESTATIONS. Painless testicular enlargement  commonly is the first sign of testicular cancer. Enlargement is  usually gradual and may be accompanied by a sensation of tes-  ticular heaviness or dull ache in the lower abdomen.*” Occa-  sionally, acute pain occurs because of rapid growth, resulting  in hemorrhage and necrosis. Ten percent of affected men have  epididymitis, 10% have hydroceles,*° and 5% have gynecomas-  tia or hydrocele. Incidence of gynecomastia increases consid-  erably (30% to 45%) in men with Sertoli or Leydig tumors.  Approximately 10% of individuals already have symptoms  related to metastases at the time of initial diagnosis, which cor-  relates with the typical delay of 3 to 6 months from initial rec-  ognition to definitive treatment. Lumbar pain may be present    TABLE 25-2 TESTICULAR TUMORS OF GERM CELL ORIGIN  CELL TYPES OCCURRENCE METASTATIC PATTERN    A. Seminoma (germinoma 30%-35% of all testicular tumors Rarely to retroperitoneal lymph  nodes    Excellent; tumor usually remains localized and  is responsive to radiation; cure rate stages |  and Il >95%; stages Ill and IV >80%   a. Embryonal carcinoma 20%-25% of all testicular tumors;  most common testicular tumor in  infants and children    Good; complete remission rate stages | and II  >95%; stages Ill and IV >70%-80%    . Mixed tumors  a. Teratocarcinoma  . Other 10%-15% of all testicular tumors  i. Teratocarcinoma with  seminoma  ii. Embryonal cancer with  seminoma  ill. Teratoma with seminoma  iv. Any combination with  choriocarcinoma  . Non—germ cell tumors (Leydig  cell, Sertoli cell, granulosa cell,  and thecal cell tumors)    Variable; prognosis becomes that of the most  malignant element  Variable; prognosis becomes that of the most    Data from American Cancer Society. In Cancer response system document #10029, New York, 1995, The Society; Cancer Net: Cancer facts: ques-  tions and answers about testicular cancer, National Cancer Institute, 2000. Available at www.cancernet.nci.nih.gov.    and usually is caused by retroperitoneal node metastasis. Signs  of metastasis to the lungs include cough, dyspnea, and bloody  sputum (hemoptysis). Supraclavicular node involvement may  cause difficulty swallowing (dysphagia) and neck swelling.  Alterations in vision or mental status, papilledema, and seizures  may be experienced with metastasis to the CNS. Approximately  10% of affected individuals are asymptomatic; the tumor may  be detected by the man’s sexual partner or incidentally follow-  ing trauma.   EVALUATION AND TREATMENT. An incorrect diagnosis at the ini-  tial examination occurs in as many as 25% of men with testicu-  lar cancer. Epididymitis and epididymo-orchitis are the most  common misdiagnoses; others include hydrocele and sper-  matocele. Evaluation begins with careful physical examination,  including palpation of the scrotal contents with the individual  in the erect and supine positions. The abdomen and lymph  nodes are palpated to rule out metastases. Signs of testicular  cancer include abnormal consistency, induration, nodularity,  or irregularity of the testis. A firm, nontender testicular mass or  diffuse enlargement is found in the majority of cases. Primary  testicular cancer can be assessed rapidly and accurately by scro-  tal ultrasonography. Tumor markers are higher than normal  in the presence of a tumor and may help detect a tumor that is  too small to be palpated during physical examination or seen    on imaging.°? Tumor type is identified after inguinal biopsy  or orchiectomy. Scrotal incisions may cause dissemination of  the tumor and increase the risk of local recurrence and there-  fore are avoided. Chest x-ray, lymphangiogram, intravenous  pyelogram (IVP), abdominal ultrasound, and CT are used in  clinical staging of disease. Treatment is based on type of tumor,  stage of disease, general health, and age. Besides surgery, treat-  ment involves radiation and chemotherapy singly or in com-  bination. A number of factors influence the prognosis (Table  25-2). They include histology of the tumor, stage of the disease,  and selection of appropriate treatment. Serum markers, such  as alpha fetoprotein (AFP), B-hCG, and lactate dehydrogenase,  are useful for detecting metastases and assessing responses to  therapy. With appropriate treatment survival rates from tes-  ticular cancer are excellent, although some have persistent par-  esthesias, Raynaud phenomenon, or infertility. According to  the National Cancer Institute, the overall 5-year survival rate  from testicular cancer was 95.3% between 1999 and 2005. If  the cancer was confined to the testis at the time of diagnosis,  the survival rate was 99.2% and dropped only slightly to 95.9%  with regional extension. For those with distant metastases, the  survival rate was 71%.°>*9 Orchiectomy does not affect sexual  function, but infertility can result from chemotherapy or sur-  gical removal of affected abdominal lymph nodes if nerves    FIGURE 25-12 Epididymitis Secondary to Gonorrhea or Nongonococcal  Urethritis. This infection spread to the testes, and rupture through the scrotal wall  is threatened. (From Taylor PK: Diagnostic picture tests in sexually transmitted dis-  eases, London, 1995, Mosby-Wolfe.)   Epididymitis, or inflammation of the epididymis, generally  occurs in sexually active young males (younger than 35 years)  and is rare before puberty (Figure 25-12). In young men the  usual cause is a sexually transmitted microorganism, such as  N. gonorrhoeae or C. trachomatis. Men who practice unpro-  tected anal intercourse may acquire sexually transmitted  epididymitis because of Escherichia coli, Haemophilus influ-  enzae, tuberculosis (especially in regions where incidence of  pulmonary tuberculosis is high), Cryptococcus, or Brucella.*°  In men older than 35 years, enterobacteriaceae (intestinal  bacteria) and Pseudomonas aeruginosa associated with uri-  nary tract infections and prostatitis also may cause epididy-  mitis. Besides an infectious etiology, epididymitis may result  from a chemical inflammation caused by the reflux of sterile  urine into the ejaculatory ducts.** It is associated with ure-  thral strictures, congenital posterior valves, and excessive  physical straining in which increased abdominal pressure is  transmitted to the bladder. Chemical epididymitis is usually  self-limiting and does not require evaluation or intervention  unless it persists.   PATHOGENESIS. The pathogenic microorganism usually  reaches the epididymis by ascending the vasa deferentia from  an already infected urethra or bladder. The presence of bacte-  ria initiates the inflammatory response, causing symptoms of  bacterial epididymitis. Epididymitis caused by heavy lifting or  straining results from reflux of urine from the bladder into the  vas deferens and epididymis. Urine is extremely irritating to  the epididymis and initiates an inflammatory response called  chemical epididymitis.   CLINICAL MANIFESTATIONS. Pain is the main symptom of epi-  didymitis. Scrotal or inguinal pain is caused by inflammation of  the epididymis and surrounding tissues. The pain is usually    acute and severe. Flank pain may occur if, as the urethra passes  over the spermatic cord, edematous swelling of the cord  obstructs the urethra. The individual may have pyuria and bac-  teriuria and a history of urinary symptoms, including urethral  discharge. The scrotum on the involved side is red and edema-  tous as a result of inflammatory changes. The tail of the epididy-  mis near the lower pole of the testes usually swells first; then  swelling ascends to the head of the epididymis. The spermatic  cord also may be swollen and tender.   Complications of epididymitis include abscess formation,  infarction of the testis, recurrent infection, and infertility.  Infarction probably is caused by thrombosis (obstruction by  blood clots) of the prostatic vessels secondary to severe inflam-  mation. Recurrent epididymitis may result from inadequate  initial treatment or failure to identify or treat predisposing fac-  tors. Chronic epididymitis can cause scarring of the epididymal  endothelium. Once scarring has occurred, treatment with anti-  biotics is ineffective because adequate antibiotic levels cannot  be achieved within the epididymis.*°   EVALUATION AND TREATMENT. A history of recent urinary tract  infection or urethral discharge suggests the diagnosis of epi-  didymitis. The relief of pain when the inflamed testis and epi-  didymis are elevated (Prehn sign) is also diagnostic. Definitive  diagnosis is based on culture or Gram stain of a urethral swab.  Epididymal aspiration may be necessary to obtain a specimen,  especially if the individual has been taking antibiotics and has  sterile urine.   Treatment includes antibiotic therapy for the infection itself  (see Chapter 26). Analgesics, ice, and scrotal elevation can  provide symptomatic relief. If the individual does not steadily  improve, he should be reevaluated for possible complications,  such as abscess formation, sepsis, or continued infection.*° Bed  rest and scrotal elevation are recommended until the scrotum  is no longer tender. Scrotal elevation facilitates maximal lym-  phatic and venous drainage. Abscess formation is rare with  antibiotic therapy. If an abscess occurs and persists, it is drained  surgically and an orchiectomy may be indicated. Complete res-  olution of swelling and pain may take several weeks to months.  The individual’s sexual partner should be treated with antibi-  otics if the causative microorganism is a sexually transmitted  pathogen.   Benign prostatic hyperplasia (BPH), also called benign pros-  tatic hypertrophy, is the enlargement of the prostate gland  (Figure 25-13). Because the major prostatic changes are caused  by hyperplasia, not hypertrophy, benign prostatic hyperplasia  is the preferred term. This condition becomes problematic as  prostatic tissue compresses the urethra, where it passes through  the prostate, resulting in frequency of lower urinary tract symp-  toms. The prevalence among U.S. men 60 years and older is  about 50% and among men 70 years or older 90%.** BPH is  common and involves a complex pathophysiology with several  endocrine and local factors and remodeled microenvironment.  Its relationship to aging is well documented. At birth the pros-  tate is pea sized, and growth of the gland is gradual until puberty.    FIGURE 25-13 Prostate Zones, Benign Prostatic Hyperplasia (BPH), and Prostate Cancer Locations. BPH occurs  in the peripheral zone of the prostate gland that can enlarge (not shown). BPH nodules and atrophy are associated with inflam-  mation in the transition zone. Most cancer lesions occur in the peripheral zone. Carcinoma can involve the central zone but  rarely occurs in isolation, suggesting that prostatic intraepithelial neoplasia (PIN) lesions do not easily progress to carcinoma  in this region. (Adapted from De Marzo AM et al: Nat Rev Cancer 7:256-269, 2007.)    A period of rapid development continues until the third decade  of life, when the prostate reaches adult size. Around 40 to 45  years of age, benign hyperplasia begins and continues slowly  until death. Although dihydrotestosterone (DHT) is neces-  sary for normal prostatic development, its role in BPH remains  unclear. Among all androgen-metabolizing enzymes within  the human prostate, 5a-reductase is the most powerful. This  reductase corresponds to an age-dependent DHT level. There-  fore, although 5a-reductase and DHT decrease with age in the  epithelium, they remain relatively constant in the stroma of the  prostate gland.   PATHOGENESIS. Current causative theories of BPH focus on  levels and ratios of endocrine factors such as androgens, estro-  gens, gonadotropins, and prolactin and changes in the balance  between autocrine/paracrine growth-stimulatory and growth-  inhibitory factors. These factors include insulin-like growth  factors (IGFs), epidermal growth factor, nerve growth factor,  fibroblast factors, IGF binding proteins, and transforming  growth factor-beta (TGF-B).*°   Aging and circulating androgens are associated with BPH  and enlargement. These factors are predisposed as disrupting  the balance of growth factor signaling pathways and stromal/    epithelial interactions creating a growth-promoting and tissue  remodeling microenvironment. However, BPH is a multifac-  torial disease, and not all men respond well to available treat-  ments, suggesting factors other than androgens are involved.  Testosterone, the primary circulating androgen in men, also  can be metabolized through CYP19/aromatase into the potent  estrogen, estradiol-17B. The prostate is an estrogen target tis-  sue and estrogens directly and indirectly affect growth and dif-  ferentiation of prostate. The precise role of endogenous and  exogenous estrogens in directly affecting prostate growth and  differentiation in the context of BPH is an understudied area.  Estrogens and selective estrogen receptor modulators have been  shown to promote or inhibit prostate proliferation, signifying  potential roles in BPH.*° Taken together these interactions lead  to an increase in prostate volume. The remodeled stroma pro-  motes local inflammation with altered cytokine, reactive oxy-  gen/nitrogen species, and chemoattractants.‘” The resultant  increased oxygen demands of proliferating cells causes a local  hypoxia that induces angiogenesis and changes to fibroblasts.  Functional and phenotypic changes (transdifferentiation) of  fibroblasts to the myofibroblasts is a hallmark of the remodeled  microenviroment.*®    BPH begins in the periurethral glands, which are the inner  glands or layers of the prostate. The prostate enlarges as nod-  ules form and grow (nodular hyperplasia) and glandular cells  enlarge (hypertrophy). The development of BPH occurs over a  prolonged period, and changes within the urinary tract are slow  and insidious.   CLINICAL MANIFESTATIONS. As nodular hyperplasia and cellular  hypertrophy progress, tissues that surround the prostatic urethra  usually compress it but not always cause bladder outflow obstruc-  tion. These symptoms are sometimes called the spectrum of lower  urinary tract symptoms (LUTS). Symptoms include the urge to  urinate often, some delay in starting urination, and decreased  force of the urinary stream. As the obstruction progresses, often  over several years, the bladder cannot empty all the urine and the  increasing volume leads to long-term urine retention. The volume  of urine retained may be great enough to produce uncontrolled  “overflow incontinence” with any increase in intra-abdominal  pressure. At this stage the force of the urinary stream is signifi-  cantly reduced, and much more time is required to initiate and  complete voiding. Hematuria, bladder or kidney infection, blad-  der calculi, acute urinary retention hydroureter, hydronephrosis,  and renal insufficiency are common complications.”   Some men initially have signs of uremia and renal failure.  On digital rectal examination the hyperplastic prostate is a soft  or firm enlargement with smooth mucosal surface and no dis-  cernible distinction between lobes; asymmetry is common. The  palpated prostate does not always reflect the degree of BPH  because a substantial portion of the enlargement is intravesicu-  lar.°° Thirty percent of men with mild to moderate symptoms  improve with watchful waiting.   EVALUATION AND TREATMENT. Diagnosis is made from a medical  history, physical exam, and laboratory tests including urinalysis.  Careful review of symptoms is necessary. Digital rectal exami-  nation (DRE) and PSA are conducted to determine hyperplasia.  PSA alone, however, cannot determine whether symptoms are  caused by BPH because PSA is elevated in both BPH and pros-  tate cancer. Annual DREs are used to screen men older than  40 years of age for BPH, sooner in high-risk men.*! If marked  enlargement, moderate to severe symptoms, or complications  are present, transrectal ultrasound (TRUS) is used to determine  bladder and prostate volume and residual urine. Urinalysis,  serum creatinine and blood urea nitrogen, uroflowmetry, post-  void residual (PVR) urine, pressure-flow study, cystometry,  and cystourethroscopy are used to determine kidney and blad-  der function.’” BPH has been treated successfully with drugs.  o.,-Adrenergic blockers (prazosin and tamsulosin) are used to  relax the smooth muscle of the bladder and prostate. Antian-  drogen agents, such as finasteride (Proscar), selectively block  androgens at the prostate cellular level and cause the prostate  gland to shrink.*! By shrinking the prostate, these drugs have  been shown to improve BPH-related symptoms and reduce the  risk of future urinary retention and BPH-related surgery. o,-  Adrenergic blockers do not affect PSA and have no effect on  prostate cancer risk. However, antiandrogen agents lower PSA  by 50% after 6 months of therapy.°!   Newer minimally invasive procedures include intersti-  tial laser therapy, transurethral radiofrequency procedure    BOX 25-5 NATIONAL INSTITUTES OF  HEALTH CLASSIFICATION OF  THE PROSTATITIS SYNDROMES    This system, developed for clinical research purposes, can be simplified for  use in primary care practice.   Category |, or acute bacterial prostatitis (ABP), is an acute infection of the  prostate and is manifested by systemic signs of infection and a positive urine  culture.   Category Il, or chronic bacterial prostatitis (CBP), is a chronic bacterial infec-  tion, in which bacteria are recovered in significant numbers from a purulent  prostatic fluid. These bacteria are thought to be the most common cause of  recurrent urinary tract infection in men.   Category Ill, or chronic pelvic pain syndrome (CPPS), is diagnosed when no  pathogenic bacteria can be localized to the prostate (culture of expressed pros-  tatic fluid or postprostatic massage urine specimen) and is further divided into  Illa and Illb. Category Illa refers to inflammatory CPPS in which a significant  number of white blood cells (WBCs) are localized to the prostate, whereas,  category IIIb is noninflammatory.   Category IV refers to asymptomatic inflammatory prostatitis, in which bac-  teria or WBCs are localized to the prostate, but individuals are asymptomatic.    (TUNA), cooled Thermo Therapy and prostate artery emboli-  zation. When necessary, the hyperplastic tissue may be removed  surgically to prevent the serious consequences of urethral  obstruction. A permanent indwelling catheter is inserted if the  individual cannot tolerate surgery.   Prostatitis is an inflammation of the prostate. Some degree  of prostatic inflammation is present in 4% to 36% of the male  population, increasing to 50% in older men. Inflammation is  usually limited to a few of the gland’s excretory ducts.   Prostatitis syndromes have been classified by the National  Institutes of Health as: (1) acute bacterial prostatitis (ABP), (2)  chronic bacterial prostatitis (CBP), (3) chronic pelvic pain syn-  drome (CPPS), and (4) asymptomatic inflammatory prostatitis  (Box 25-5). ABP and CBP are caused mostly by gram-negative  enterobacteriaceae and enterococci species, which originate in  the gastrointestinal flora. The most common microorganism is  E. coli, which is identified in the majority of infections.°* Kleb-  siella species, P. aeruginosa, and Serratia species are common  gram-negative cultured microorganisms. Nonbacterial prosta-  titis (CP/CPPS) syndromes are caused by a cascade of inflam-  matory, immunologic, neuroendocrine, and neuropathic  mechanisms in which the initiating cause is unknown.   Bacterial Prostatitis. Acute bacterial prostatitis (ABP,  category I) is an ascending infection of the urinary tract that  tends to occur in men between the ages of 30 and 50 years but  also is associated with BPH in older men. Infection stimulates  an inflammatory response in which the prostate becomes  enlarged, tender, firm, or boggy. The onset of prostatitis may  be acute and unrelated to previous illnesses or it may follow  catheterization or cystoscopy.   Clinical manifestations of acute bacterial prostatitis are those  of urinary tract infection or pyelonephritis. Sudden onset of  malaise, low back and perineal pain, high fever (up to 40° C  [104° F]) and chills is common, as are dysuria, inability to empty    the bladder, nocturia, and urinary retention. The individual  also may have symptoms of lower urinary tract obstruction,  such as slow, small, “narrowed” urinary stream, which may be  a medical emergency. Acute inflammatory prostatic edema can  compress the urethra, causing urinary obstruction. Systemic  signs of infection include sudden onset of a high fever, fatigue,  arthralgia, and myalgia. Prostatic pain may occur, especially  when the individual is in an upright position, because the pelvic  floor muscles tighten with standing and the prostate gland is  compressed. Some individuals experience low back pain, pain-  ful ejaculation, and rectal or perineal pain. Palpation discloses  an enlarged, extremely tender and swollen prostate that is firm,  indurated, and warm to the touch.   Because ABP is usually associated with a bladder infection  caused by the same microorganism, urine cultures disclose its  identity. Prostatic massage may express enough secretions from  the urethra for direct bacterial examination, but massage may  be painful and increases the risk that the infection will ascend  to adjacent structures or enter the bloodstream and cause  septicemia.   To resolve the infection and control its spread, individuals  may require antibiotics. In severe cases, the individual is hos-  pitalized and treated with intravenous antibiotics, followed by  oral antibiotics. Analgesics, antipyretics, bed rest, and adequate  hydration also are therapeutic. Complications include urinary  retention that resolves with antibiotic therapy; prostatic abscess  that may rupture into the urethra, rectum, or perineum; epidid-  ymitis; bacteremia; and septic shock. Urinary retention requir-  ing drainage is best managed with a suprapubic catheter. Foley  catheterization is contraindicated during acute infection.   Chronic bacterial prostatitis (CBP, category II) is charac-  terized by recurrent urinary tract symptoms and persistence of  pathogenic bacteria (usually gram negative) in urine or pros-  tatic fluid. This form of prostatitis is the most common recur-  rent urinary tract infection in men. Symptoms may be similar to  those of an acute bladder infection, such as frequency, urgency,  dysuria, perineal discomfort, low back pain, myalgia, arthral-  gia, and sexual dysfunction. The prostate may only be slightly  enlarged or boggy but it may be fibrotic because repeated infec-  tions can cause it to be firm and irregular in shape.   When the initial urine sample is bacteria-free, prostatic  massage is used to express secretions. Subsequently, the first  10 ml of voided urine is collected and examined microscopi-  cally. Prostatic secretions showing more than 10 white blood  cells (WBCs) per high-power field and macrophages containing  fat are indicative of bacterial infection; diagnosis is confirmed  by culture. A pelvic x-ray or TRUS may show prostatic calculi.   Treatment of chronic bacterial prostatitis is difficult because  it is often caused by prostatic calculi. Calculi are silent and are  found in up to 50% of men with prostatitis, and infected cal-  culi can serve as a source of bacterial persistence and relaps-  ing urinary tract infection.’ Calculi harbor pathogens within  the stone, and consequently pathogens cannot be eradicated  from the urinary tract. Permanent cure is achieved by surgical  intervention.   Chronic Prostatitis/Chronic Pelvic Pain Syndrome. Chronic  prostatitis/chronic pelvic pain syndrome (CPPS, category III)    is diagnosed when no pathogenic bacteria can be localized to  the prostate and is further divided into categories Ia and IIIb  (see Box 25-5). Category IIa refers to inflammatory chronic  pelvic pain syndrome where WBCs are elevated and localized  to the prostate. Symptoms tend to be milder but are persistent  and annoying. Presumably, noninfectious prostatitis or pain  is caused by reflux of sterile urine into the ejaculatory ducts  because of high-pressure voiding.*’ Reflux may be triggered by  spasms of the external or internal sphincters. Category IIIb is  noninflammatory; in category IV, individuals are asymptomatic  but have an increase in bacteria and WBCs localized to the  prostate. Microorganisms suspected of causing CP/CPPS  include E. coli, Enterobacter, P. aeruginosa, and Helicobacter  pylori, a new suspect.>*   Men with nonbacterial prostatitis may complain of pain or  a dull ache that is continuous or spasmodic in the suprapubic,  infrapubic, scrotal, penile, or inguinal area. Other symptoms  are pain on ejaculation and urinary symptoms, such as fre-  quency of urination. The prostate gland generally feels normal  on palpation.   Nonbacterial prostatitis is a diagnosis by exclusion. Digital  examination of the prostate, bacterial cultures of the urogeni-  tal tract, microscopic examination of expressed prostatic fluid,  urethroscopy, and urodynamic studies are used to verify the  diagnosis of nonbacterial prostatitis.   There is no generally accepted treatment for nonbacterial  prostatitis. Hot sitz baths, bed rest, alpha-blockers, anticholin-  ergics, and anti-inflammatory drugs can relieve symptoms.    Prostate cancer is the most commonly diagnosed nonskin can-  cer in men in the United States, with a lifetime risk for diagno-  sis currently estimated at 15.9%.°° The incidence varies greatly  worldwide (Figure 25-14), but it is still considered to be the  second most frequently diagnosed cancer and the sixth leading  cause of death worldwide. Importantly, incidence rates vary by  more than 25-fold worldwide, and the highest rates recorded  mostly in developed countries include Oceania, Europe, and  North America, largely because of the wide use or overuse of  PSA testing.°° Screening with PSA can amplify the incidence of  prostate cancer by allowing detection of prostate lesions that  although meeting the pathologic criteria for malignancy, may  have low potential (e.g., latent, indolent, preclinical) for growth  and metastasis. In countries with higher use of PSA testing, such  as United States, Canada, Australia, and the Nordic countries,  trends in incidence rates follow similar patterns.*°   Different from Western countries, incidence and mortal-  ity rates are rising in several Asian (including Japan) and cen-  tral and Eastern European countries.*° Death rates have been  decreasing in several countries including Australia, Canada,  the United Kingdom, the United States, Italy, and Norway, in  part from improved treatment. Males of African descent in the  Caribbean have the highest mortality rates from prostate cancer  in the world.°° Most cases of prostate cancer have a good prog-  nosis even without treatment but some cases are aggressive;  the lifetime risk for dying of prostate cancer is 2.8%. Prostate  cancer is rare before age 50 years and very few men die from it    Southern Europe 36  Central America La) 31  Middle Africa =] 25  Western Africa (== 19  Central & Eastern Europe  17  Eastern Africa =] 14  Western Asia  11  South-Eastern Asia  7  Northern Africa (J 6  South-Central Asia [7] 4  Eastern Asia [2] 4    FIGURE 25-14 Selected World Population Age-Standardized (to the World Population) Incidence Rates of  Prostate Cancer. (Modified from Jemal A et al: Biomark Prev 19:1893, 2010.)    before 60 years of age. Indeed, more than 75% of all prostate  cancer is diagnosed in men older than 65.°° With aging, most of  the androgen-metabolizing enzymes undergo significant altera-  tion and older age, race (black), and family history remain the  well-established risk factors.°°   Dietary Factors. Although evidence exists for a dietary role in  prostate cancer, the epidemiologic evidence is inconsistent. The  problem has been confounded by lack of biomarkers for certain  nutrients, difficulties in measuring and quantifying diet, and a  limitation of clinical trials to study diet over time. Important are  the effects of diet on signaling pathways, hormones, oxidative  stress, and reactive oxygen species (ROS). The nutrients in  the epidemiology of prostate cancer that have received the  most attention include carotenoids, fat, vitamin E, vitamin  D/calcium, and selenium. Less studied are isoflavones, curcumin,  lycopene, zinc, green tea, omega 3 polyunsaturated fats, and  sulforaphane (see Nutrition & Disease: Summary of Diet for  Prostate Cancer). Associations between obesity and prostate  cancer are not clear, with some research inconsistencies, but  obesity seems to be negatively associated with more indolent  prostate cancer and positively associated with more aggressive  disease and a worse outcome.*’ In process is a randomized  clinical trial of diet and early-stage prostate cancer, Men’s  Eating and Living Study (MEAL). The hypothesis for MEAL  is that a change in diet of higher intake of animal products to  vegetables and fruits will slow the progression of the indolent  to the aggressive form of prostate cancer.°’ As adipose tissue  is increasingly being regarded as hormonally active tissue, high  body fat and obesity need in-depth exploration to understand  the associated risk of prostate problems. Adipose tissue is  now known to affect circulating levels of several bioactive  messengers and therefore could affect the risk of developing  prostate problems in addition to several other well-recognized    health problems.°* High-energy intake (consumption of excess  calories) indicates that this may indeed increase insulin levels  and IGF-1, a powerful carcinogenic agent”? (see Pathogenesis,  p. 904). More robust, high-quality research trials are needed to  guide understanding of the complex relationship between diet  and prostate cancer.   Hormones. Prostate cancer develops in an androgen-  dependent epithelium and is usually androgen sensitive.  Androgens are synthesized not only in the testis, accounting for  50% to 60% of the total testosterone in the prostate, but also  in the prostate gland itself. In a process called intraprostatic  conversion, the hormone dehydroepiandrosterone (DHEA)  produced by the adrenal glands®°! is converted to testosterone  and then into DHT in the prostate (Figure 25-15). Additionally,  prostate cancer cells have been reported to make androgens  from cholesterol (i.e. de novo).°* However, these overall  relative contributions from intratumoral sources remain  to be determined. Population studies have not, however,  provided clear and convincing patterns involving associations  between circulating hormone concentrations (e.g., not tissue  concentrations) and prostate cancer risk.°>°* Thus there is  universal agreement that androgens are important for prostatic  growth, development, and maintenance of tissue balance but  their role in cancer is controversial.°° Evidence for involvement  of 5a-reductase activity, which is critical in androgen activity  in the prostate, is contradictory and inconsistent®* (see  Figure 25-15). A prevention study has provided some of the  strongest hormonal data with the drug finasteride, which  inhibits 5a-reductase. The 7-year intervention study reduced  prostate cancer risk in healthy men by about 25%.°° Important,  however, was that more high-grade tumors were found in  those men who developed prostate cancer while on the drug.  In men younger than 50 years, circulating levels of androgens    e Epidemiologic studies have found total fat intake, animal and saturated fat, red through cellular antioxidants, leading to increased apoptosis and sensitizing    meat, and dairy products are associated with an increase in prostate cancer risk.  Obesity is linked to advanced and aggressive prostate cancer.   High body mass index (BMI) is associated with more aggressive disease and  a worse outcome.   Calorie-dense or excessive carbohydrate intake and obesity, independent of  dietary fat intake, may increase the risk of developing prostate cancer.  Dietary fat may increase androgens, increase oxidative stress, and increases  reactive oxygen species (ROS).   High levels of linoleic acid (e.g., found in corn oil; safflower) tend to act as  a proinflammatory eicosanoid, which is implicated in promotion of cell prolif-  eration and angiogenesis as well as inhibition of apoptosis.   The Western diet has increased omega-6/omega-3 ratios and therefore is  proinflammatory.   Cooking meat at high temperatures produces heterocyclic amines and aro-  matic hydrocarbons that are carcinogenic.   Carcinogenic nitrosamines are formed after consumption of processed meat  hat contains nitrites and from heme iron present in large quantities of red meat.  Vitamin E has been long considered a candidate for prostate cancer preven-  ion from in vitro and in vivo animal studies. Vitamin E belongs to the family  of tocopherols and tocotrienols that exist as a, B, ‘y, and 5 isoforms. Among  hese, 5-tocopherol is the major dietary isoform, whereas supplements con-  ain a-tocopherol. Vitamin E is a fat-soluble vitamin obtained from vegetable  oils, nuts, and egg yolk. It is a potent intracellular antioxidant known to inhibit  peroxidation and DNA damage. The Alpha-Tocopherol, Beta-Carotene Cancer  Prevention (ATBC) study showed supplementation with vitamin E could reduce  he incidence of prostate cancer among men who smoked. In vitro studies dem-  onstrate that y- and 6-tocopherol induces cell cycle arrest in human prostate  cancer cells (i.¢., induces apoptosis) and inhibits the androgen receptor. Mouse  studies show vitamin E can inhibit the growth-promoting effects of a high-fat  diet; however, vitamin E in combination with selenium does not reduce the inci-  dence of prostate cancer in lady mice models. In the prospective large clinical  trial SELECT, the study found no apparent benefit of administering vitamin E.  Selenium is a trace mineral and exists in food as selenomethionine and sele-  nocysteine. It is essential for the functioning of many antioxidant enzymes  and proteins in the body. Humans receive selenium in their diet through plant  (dependent on soil concentrations) and animal products. Several large pro-  spective studies reported 50% to 65% reductions in prostate cancer risk with  high levels versus low levels of selenium as measured in toenails and plasma.  The Nutritional Prevention of Cancer (NPC) trial reported a 50% reduction  in risk of developing prostate cancer. No potential benefit was found in the  SELECT trial, whereas a small insignificant increase was noted for type 2 dia-  betes. From these two trials two different forms of selenium were used—the  NPC trial used selenized yeast and the SELECT trial used selenomethionine.  A meta-analysis of 12 studies with 13,254 subjects and 5007 cases of pros-  tate cancer showed that the risk of prostate cancer decreased with increas-  ing plasma/serum selenium up to 170 ng/ml. Selenium has several modes of  action depending on its form. Selenomethionine inhibits cell proliferation and  induces cell cycle arrest of human prostate cells (i.e., apoptosis) and inhibits  angiogenesis mediated in part by the androgen receptor. This also is true  of methylselenic acid. Sodium selenite’s anticancer effects are mediated    cells to radiation-induced killing. Selenium and its derivatives can activate  both intrinsic and extrinsic pathways of apoptosis. Selenium intervention may  depend on individual genotype.   Vitamin D may play an important role in prostate cancer prevention.   Zinc may be important for prostate cancer; however, data are lacking.   Soy contains isoflavones purported to have anticancer properties including  inhibition of cell proliferation and angiogenesis and reduction in prostate spe-  cific antigen (PSA) and androgen receptor levels.   Tomatoes or tomato products ingested daily seem to reduce prostate cancer  risk. In vitro studies show lycopene inhibits DNA strand breaks. Unresolved i  whether lycopene itself or a metabolic product is responsible for its biologi  effect. In clinical studies tomato paste, which is high in lycopene, reduce  plasma PSA levels in those men with benign prostatic hyperplasia. Lycopen  administration is associated with cell cycle arrest (apoptosis) and grow  factor signaling. In 2007 the U.S. Food and Drug Administration (FDA) evalu-  ated 13 available studies and found the relationship between lycopene and  reduced risk of prostate cancer inadequate. A Cochrane review found that  given only three randomized controlled trials were included in the analysis  and a high risk of bias in two, there is insufficient evidence to support or refute  lycopene for the prevention of prostate cancer.   Vegetables including broccoli, cabbage, cauliflower, Brussels sprouts, Chi-  nese cabbage, and turnips (all crucifers) may be protective (several epide-  miologic studies) against prostate cancer. In particular, a diet high in broccoli  reduced cancer risk. By contrast, four studies revealed no cancer preventive  effects. Cruciforms have anticancer properties mediated by the phytochemi-  cals phenethyl isothiocyanate, sulforaphane, and indole-3-carbinol. Sul-  foraphane is a naturally occurring isothiocyanate that was first isolated in  broccoli. It protects against carcinogen-induced cancer in many rodents. Mice  given 240 mg of broccoli sprouts per day showed a significant reduction in  growth of prostate cancer cells. Sulforaphane treatment lowered androgen  receptor protein and gene expression.   Green tea contains polyphenols, including epigallocatechin gallate (EGCG).  Green tea consumption has been associated with a reduced incidence of  several cancers including prostate cancer. Green tea consumed within a bal-  anced controlled diet in humans improved overall antioxidant potential. The  anticancer effect potential of green tea from in vitro and experimental stud-  ies shows these compounds bind directly to carcinogens and induce phase  ll enzymes that inhibit heterocyclic amines. EGCG administration decreased  NF-« activity. Green tea was shown to inhibit IGF-1 and increase IGFBP3,  leading to inhibition of prostate cancer development and progression. Yet, in  two small randomized studies in individuals with high-grade prostatic neopla-  sia, it showed no effects. In a population prospective large study (n= 27,293)  green tea did not protect against prostate cancer and black tea showed a  positive association with prostate cancer.  Curcumin has anticarcinogenic potential with well-characterized anti-inflam-  matory, antiangiogenic, and antioxidant properties. Recent studies report  curcumin modulates the Wingless signaling pathway (Wnt) that supports its  antiproliferative potential.  Overall, multiple signaling pathways are involved in prostate cancer develop-  ment and progression, many of which are affected by dietary and lifestyle  factors.    Data from: Astorg P: Cancer Causes Control 15:367-386, 2004; Beier R et al: EWBO J 19(21):5813-5823, 2000; Dagnelie PC et al: BU Int  93(8):1139-1150, 2004; Demark-Wahnefried W, Moyad MA: Curr Opin Urol 17:168-174, 2007:737-743, 2001; Freedland SJ, Aronson WJ: Urology  65:433-439, 2005; Giovannucci E et al: Int J Cancer 121:1571-1578, 2007; Greenwald P: J Nutr 134(12 suppl):3507S-3512S, 2004; Hill P et al:  Cancer Res 39:5101-5105, 1979; Hurst R et al: Am J Clin Nutr 96(1):111-122, 2012; Khan N, Mukhtar H: Biochem Pharmacol, 2012 [Epub ahead  of print]; Kim DJ et al: Cancer Causes Control 11:65-77, 2000; Kobayashi N et al: Clin Cancer Res 12(15):4660-4670, 2006; Kolonel LN: Epidemiol  Rev 23:72-81, 2001; Llic D, Forbes KM, Hassed C: Cochrane Database Syst Rev (11):CD008007, 2011; Lloyd JC et al: J Uro! 183:1619-1624, 2010;  Matsumara K et al: Anticancer Res 28:709-714, 2008; Montague JA et al: Caner Causes Control 23(10):1635-1641, 2012; Ngo TH et al: Cancer  Causes Control 13:929-935, 2002; Ngo TH et al: Clin Cancer Res 9:2734-2743, 2003; Ni J, Yeh S: Vitam Horm 76:493-518, 2007; Rodriguez C et al:  Cancer Epidemiol Biomarkers Prev 16:63-69, 2007; Sinha R et al: Am J Epidemiol 170:1165-1177, 2009; Teiten M et al: Int J Oncol 38:603-611,  2011; Yang CS, Suh N, Kong AN: Cancer Prev Res (Phil) 5(5):701-705, 2012.    FIGURE 25-15 Sources of Androgens and Aromatase and Estrogen Signaling in the Prostate. A, Body sources o  androgens in the prostate gland. Hypothalamic GnRH causes the release of LH from the anterior pituitary gland. LH stimulates  the testes to produce testosterone, which then accumulates in the blood. Pituitary ACTH release stimulates the adrena  glands, which secrete the androgen precursor DHEA into the blood. DHEA is converted into testosterone and then into DHT  in the prostate. B, Aromatase and estrogen signaling in the prostate. In normal and benign tissue, aromatase is expressed  within the stroma and regulated by promoter Pll. Estrogen then exerts its effects in an autocrine fashion through the stroma  ER-o. receptor and also in a paracrine fashion through both ER-o. and ER-f receptors. With prostate cancer, aromatase is now  expressed within the tumor cells and in stromal cells, and regulated by aromatase promoters 1.3, 1.4, and Pll. Thus estrogen  exerts its effects in an autocrine way through stromal and epithelial ER-o. and ER-6. Consequently, the increased levels o  estrogen and abnormal ER-o signaling promote inflammation, which increases aromatase expression and the developmen  of a positive feedback cycle. Inflammation drives aromatase expression, thus increasing estrogen, which in turn promotes  further inflammation. ACTH, Adrenocorticotropic hormone; DHEA, dehydroepiandrosterone; DHT, dihydrotestosterone; GnRH,  gonadotropin-releasing hormone; LH, luteinizing hormone. (A adapted from Labrie F: Nat Rev Uro/ 8:73-80, 2011; B from Ellem  SJ, Risbridger GP: J Steroid Biochem Mol Biol 118[4-5):246-251, 2010.)    and estrogens appear to be higher in men of African descent  than in European-American men.   Despite the well-documented importance of androgens, their  pathophysiologic process in prostate diseases is incomplete.°°  Androgens also are metabolized to estrogens (see Figures 25-17  and 24-35) through the action of the enzyme aromatase, and a  growing body of evidence implicates estrogens in the etiology  of prostate disease (see Pathogenesis section). Importantly, the  aberrant expression of aromatase has been implicated in other  tissues, such as the breast and endometrium.°°   Only a few associations with prostate cancer risk have been  observed consistently (in at least three studies), and their asso-  ciations are weak: (1) slightly higher circulating testosterone  and estrogen levels and lower DHEA (sulfate) levels in high-risk  black men as compared with lower-risk European-American  men; and (2) a cytosine-adenine-guanine (CAG) repeat-length  polymorphism in the androgen-receptor gene associated with  increased risk and increased receptor activity (androgen recep-  tor). Moreover, in a more recent collaborative analysis of exist-  ing worldwide epidemiologic data (18 prospective studies),  the Endogenous Hormones and Prostate Cancer Collaborative  Group found no associations between the risk of prostate can-  cer and serum concentrations of testosterone, calculated free  testosterone, dihydrotestosterone, dehydroepiandrosterone  sulfate, androstenedione, androstanediol glucuronide, estra-  diol, or calculated free estradiol.°”   As the results of the above-mentioned Endogenous Hor-  mones and Prostate Cancer Collaborative Group suggest,  investigations directed at understanding the hormonal basis of  prostate carcinogenesis have numerous problems. The com-  plexities of interacting hormones and separating out the effects  of a single hormone are profound. In addition, only single blood  samples are generally available, tisswe hormone samples impor-  tant for paracrine signaling are not consistently measured,  and within-subject variations over time and differences in cir-  cadian rhythms cannot be adequately measured. The results  of several animal studies do support elevation of bioavailable  and bioactive androgens in the circulation and in target tissue  as an important risk factor. Animal studies also indicate that  increased biologic activity of the androgen receptor may be  associated with prostate cancer. See the Pathogenesis section  for a more thorough discussion of the role of hormones in the  pathogenesis of prostate cancer.   Vasectomy. Vasectomy has been identified as a possible  risk factor for prostate cancer in case-controlled and cohort  studies.°°'7° Three mechanisms by which vasectomy could  increase risk are (1) elevation of circulating androgens; (2)  immunologic mechanisms involving antisperm antibodies; and  (3) reduction of seminal fluid levels of 5a-dihydrotestosterone,  the active metabolite of testosterone in the prostate, in  vasectomized men. These results suggest an elevation of  circulating free testosterone following vasectomy. However,  with these combined mechanisms it is unlikely that vasectomy  plays a causal role.’!   Chronic Inflammation. Data from the Medical Therapy of  Prostatic Symptoms (MTOPS) study suggest the risk of BPH  progression and acute urinary retention is greater in men    with prostatic inflammation.”’* In certain mouse models  prostatic hyperplasia is associated with inflammation.’ The  results of a 5-year longitudinal study of the influence of chronic  inflammation and prostate cancer have been reported.”° The  study included 144 men, 33 of whom presented with chronic  inflammation in their initial biopsy. Biopsies revealed prostatic  hyperplasia and proliferative inflammatory atrophy in those  with chronic inflammation. Upon repeat biopsy, 29 new  cancers were diagnosed, representing a new cancer incidence  of 20%.”° In contrast, of the 33 men initially showing no  inflammation, 2 (6%) were found to have adenocarcinoma.  Certain metabolic comorbidities, including obesity, diabetes,  sleep apnea, and erectile dysfunction may be linked to both  BPH and inflammation.”° The causes of chronic inflammation  are unknown (possible causes are shown in Figure 25-16). Thus  chronic inflammation may be an important risk factor for  prostatic adenocarcinoma.   Genetic and Epigenetic Factors. Other possible causes  are genetic predisposition (familial and hereditary forms).  Genetic studies suggest that strong familial predisposition  may be responsible for 5% to 10% of prostate cancers.!  Compared with men with no family history, those with one  first-degree relative with prostate cancer have twice the risk  and those with two first-degree relatives have five times the  risk.’” Germline mutations in the breast cancer predisposition  gene 2 (BRCA2) are the genetic events known to date that  confer the highest risk of prostate cancer (8.6-fold in men $65  years). Although the role of BRCA2 and BRCAI in prostate  tumorigenesis remains unrevealed, deleterious mutations in  both genes have been associated with more aggressive disease  and poor clinical outcomes.’* Men with BRCA2 germline  mutations have a 20-fold increase in risk for prostate cancer.  Using previously estimated population carrier frequencies,  investigators have recently found that deleterious BRCA1  mutations confer a relative risk of prostate cancer of  approximately 3.75-fold, translating to an 8.6% cumulative  risk by age 65.7 A common type of somatic mutation that  gives rise to chromosomal rearrangements is the ETS gene.  The most common epigenetic alteration in prostate cancer is  hypermethylation of the glutathione S-transferase (GST-P1)  gene. This gene is located on chromosome 11 and is part of  the pathway that helps protect against carcinogen damage.  More than 30 independent peer reviewed studies have  reported a consistently high sensitivity and specificity of GST-  P1 hypermethylation in prostatectomy or biopsy tissue.®° A  number of other epigenetic modifications found on tumor  suppressor genes include PTEN, RB, p16/INK4a, MLH1,  MSH21, and APC.*!:®2 There is no clear evidence of a causal  link between BPH and prostate cancer even though they may  often occur together. Variations in several other genes related  to inflammatory pathways might affect the probability of  developing prostate cancer.*?   PATHOGENESIS. More than 95% of prostatic neoplasms are  adenocarcinomas** and most occur in the periphery of the  prostate. Prostatic adenocarcinoma is a heterogeneous group of  tumors with a diverse spectrum of molecular and pathologic  characteristics and therefore clinical behaviors and challenges.*°    FIGURE 25-16 Possible Causes of Prostate Inflammation. A, Infection, including viruses, bacteria, fungi, and para-  sites. B, Hormones, for example, estrogen at key times during development. C, Physical trauma, any type of blunt physical    The biologic aggressiveness of the neoplasm appears to be  related to the degree of differentiation rather than the size of  the tumor (Box 25-6).   Hormonal. Just as the testicles are the male equivalent of  the female ovaries, the prostate is the male equivalent of the  female uterus; in both situations they originate from the same  embryonic cells. This may be important in understanding the  role of the associated hormones testosterone (T), DHT, and  estrogens in prostate carcinogenesis. Testicular testosterone  synthesis and serum testosterone levels fall as men age,  remaining unchanged or increasing with age; however,  the levels of estradiol do not decline.*°*” The relationship  between hormones and the pathophysiology of prostate  carcinogenesis is incomplete and controversial. The main  issues and controversies include: (1) sources of androgen  production outside of the testes, or extratesticular sources  (e.g., from adrenal DHEA and from prostate cholesterol [de  novo], itself); (2) the role of prostatic androgen receptor  (AR); (3) the role of estrogens, aromatase enzyme, and the    BOX 25-6 DETERMINING THE GRADE OF  PROSTATE CANCER WITH THE  GLEASON SCORE    Grade 1: The cancer cells closely resemble normal cells. They are small,  uniformly shaped, evenly spaced, and well differentiated (i.e., they remain  separate from one another).   Grade 2: The cancer cells are still well differentiated, but they are arranged  more loosely and are irregular in shape and size. Some of the cancer cells have  invaded the neighboring prostate tissue.   Grade 3: This is the most common grade. The cells are less well differenti-  ated (some have fused into clumps) and are more variable in shape.   Grade 4: The cells are poorly differentiated and highly irregular in shape.  Invasion of the neighboring prostate tissue has progressed further.   Grade 5: The cells are undifferentiated. They have merged into large masses  that no longer resemble normal prostate cells. Invasion of the surrounding  tissue is extensive.    estrogen receptors (ERs) ER-a and ER-f; and (4) the role of  the surrounding microenvironment or stroma.   Testicular testosterone provides the main source of andro-  gens in the prostate (see Figure 25-15) and is the major cir-  culating androgen, whereas DHT predominates in prostate  tissue and binds to the AR with greater affinity than does T.**  The adrenal cortex contributes the far less potent DHEA that  promotes synthesis of androgens in the prostate. In the target  tissues and, to a lesser extent, in the testes themselves, tes-  tosterone is converted to DHT by the enzyme 5a-reductase  (Figure 25-17). Thus DHT is the most potent intraprostatic  androgen. About half of circulating testosterone is bound  to sex hormone-binding globulin (SHBG), about half binds  to albumin, and about 1% to 2% exists in a free state. Free  testosterone, including testosterone disassociated from albu-  min and possibly SHBG, enters the prostate cell, where it is  converted to DHT.** DHT is a paracrine hormone because  it affects the local environment or stroma. Several intrapros-  tatic enzymes encoded by genes, HSD3A and HDS3B, are  activated by DHT and are important components of intra-  prostatic androgen regulation. The conjugated byproduct,  3a-androstenediol glucuronide (AAG), a terminal metabolite  of DHT, can be measured in the circulation and used as an  indicator of DHT levels.   Accumulating evidence shows that estrogens participate  in the pathogenesis and development of BPH and prostate  cancer by activating estrogen receptor-a. In contrast, estro-  gen receptor-f is involved in the differentiation and matura-  tion of prostatic epithelial cells, and thus possesses antitumor  effects in prostate cancer.®’ The effect of estrogen is deter-  mined by the two receptors ER-a and ER-B. ER-a leads to  abnormal proliferation, inflammation, and the development  of premalignant lesions. In contrast, ER-§ leads to antipro-  liferative, anti-inflammatory, and potentially anticarcinogenic  effects that act in concert or balance the actions of ER-a and  androgens.*’ Increased expression of ER-a has been found  to be associated with prostate cancer progression, metasta-  sis, and the so-called castration-resistant (medical treatment  that suppresses androgens) phenotype.” A specific oncogene  is regulated by ERs, and those hormones that stimulate the  ER-a receptor-like (i.e., agonists) endogenous estrogens can  stimulate oncogene expression.”!   Normally a small amount of estrogen is produced per day—  estrone and estradiol—by the aromatization of androstenedi-  one and testosterone, respectively. This reaction is catalyzed by  the enzyme system aromatase. A small quantity of estradiol is  released by the testes (see Figure 25-17); the rest of the estrogens    in males are produced by adipose tissue, liver, skin, brain, and  other nonendocrine tissue. Thus testosterone is a precursor of  the two hormones, DHT and estradiol.   Studies show aromatase is expressed in stromal tissue in the  benign human prostate gland.”* Thus it appears that both nor-  mal prostate and benign prostate have the capacity to locally  metabolize androgens to estrogens through aromatase. Investi-  gators have demonstrated altered aromatase expression in pros-  tate cancer®”"* (see Figure 25-15, B).   Chronic exposure to arsenic, as well as estrogen, is a known  risk factor for prostate cancer. Though the evidence suggests that  exposure to arsenic or estrogens can disrupt normal DNA meth-  ylation patterns and histone modifications, the mechanisms by  which these chemicals induce epigenetic changes are not fully  understood. Moreover, the epigenetic effects of coexposure to  these two chemicals are little known. Investigators have revealed  that exposure to arsenic, estrogen, and their combination alters  the expression of epigenetic regulatory genes and changes global  DNA methylation and histone modification patterns.”°   Most of the androgen-metabolizing enzymes undergo a  significant age-dependent alteration. In epithelium, both the  5a-reductase activity and the DHT level decrease with age,  whereas in stroma (prostate), not only the 5a-reductase activity  but also the stromal DHT level is rather constant over the life-  time. In contrast to the relatively unaltered DHT level over time,  the estrogen concentration follows an age-dependent increase.  Thus the age-dependent decrease of the DHT accumulation in  epithelium and the concomitant increase of the estrogen accu-  mulation in stroma lead to a tremendous increase with age of the  estrogen/androgen ratio in the human prostate. In animal studies  chronic exposure to testosterone plus estradiol is strongly carci-  nogenic, whereas testosterone alone is weakly carcinogenic.™ In  mice studies elevated testosterone level in the absence of estro-  gen leads to the development of hypertrophy and hyperplasia but  not malignancy. High estrogen and low testosterone levels have  been shown to lead to inflammation with aging and the emer-  gence of precancerous lesions.*” The mechanism is not clearly  understood and may involve estrogen-generated oxidative stress  and DNA toxicity, and it requires androgen-mediated and estro-  gen receptor—mediated processes, such as changes in sex steroid  metabolism and receptor status.°! In addition, there are changes  in the balance between autocrine/paracrine growth-stimulatory  and growth-inhibitory factors, such as the IGFs.°* When exog-  enous estradiol is added to testosterone treatment of rats, prostate  cancer incidence is markedly increased, and even a short course of  estrogen treatment results in a high incidence of prostate cancer.*   Androgen Receptor Signaling. The androgenic hormone  responses in the normal prostate and prostate cancer are mediated  by AR signaling. Exactly how AR drives the growth of prostate  cancer cells is not fully known. Several mechanisms have been  suggested,”? and specific pathways of signaling are important  because they can provide novel therapeutic targets. A study using  animal models found that loss of androgen receptor function  prevented prostatic carcinogenesis, malignant transformation,  and metastasis. Tissue-specific evaluation of androgen hormone  action demonstrated that epithelial androgen receptor was not  necessary for prostate cancer progression, whereas stromal    FIGURE 25-18 Cellular and Molecular Model of Early Prostate Neoplasia Progression. A, This stage includes infil-  tration of lymphocytes, macrophages, and neutrophils caused by repeated infections, dietary factors, urine reflux, injury, onset  of autoimmunity (which triggers inflammation), and wound healing. B, Epigenetic alterations mediate telomere shortening.  C, Genetic instability and accumulation of genetic alterations. D, Continued proliferation of genetically unstable cells leading    androgen receptor was essential for prostate cancer progression,  malignant transformation, and metastasis.”°   Prostate Epithelial Neoplasia. A precursor lesion, prostatic  epithelial neoplasia (PIN), has been described. PIN may be  more concentrated in prostates containing cancer and is  noted in proximity to cancer.*! However, the final fate of PIN  is unknown, including the possibilities of latency, invasion,  and even regression. The current working model of prostate  carcinogenesis suggests that repeated cycles of injury and cell  death occur to the prostate epithelium as a result of damage  (i.e., from oxidative stress) from inflammatory responses.”  The direct injury is hypothesized as a response to infections;  autoimmune disease; circulating carcinogens or toxins, or both,  from the diet; or urine that has refluxed into the prostate (see  Figure 25-16). The resultant manifestation of this injury is focal  atrophy or prostatic intraepithelial atrophy (PIA). Biologic  responses cause an increase in proliferation and a massive  increase in epithelial cells that possess a phenotype intermediate  between basal cells and mature luminal cells (Figure 25-18).?” In  a small subset of cells, some may contain “stem cell” or tumor-  initiating properties and telomere shortening (see Chapter 12). A  subset of PIN cells may activate telomerase enzyme, causing the  cells to become immortal.”* Molecular, genetic, and epigenetic  changes can increase genetic instability that might progress to  high-grade PIN and early prostate cancer formation. This model  of prostate carcinogenesis needs much more research.   Stromal Environment. The prostate gland is composed of  secretory luminal epithelium, basal epithelium, neuroendocrine  cells, and various cell types comprising supportive tissue  or stroma. Stroma, or tissue microenvironment, produces  autocrine/paracrine factors, as well as structural supporting  molecules that help regulate normal cell behavior and organ  homeostasis.” Fibroblasts are the most important cells during  the reconstructive phase of wound healing (see Chapter 7). The  collagen and connective tissue proteins produced by fibroblasts  are deposited in wounded areas after fibroblasts have entered  the lesion. Thus their presence is a signature of alterations in the  stroma. Reactive tumor stroma is associated with an increased  number of fibroblasts, increased capillary density, and collagen    and fibrin deposition. These findings suggest that alteration in  the prostate microenvironment, mediated by changes associated  with aging or senescence, or both, promote epithelial responses  that contribute to diseases. In animal studies, investigators have  noted that the microenvironment has an increased number of  cells that promote inflammation and a collapsed appearance  of the smooth muscle cells within adjacent glandular stroma.”  Fibroblast spreading has been proposed as indicative of decreased  mechanical tension because ofa lack of direct association of the  fibroblasts with aged fragmented collagen fibrils.!°'°! These  alterations in mechanical tension and cell shape are suggested as  determinants in altering gene expression and cellular function.  These alterations in aged prostate stroma for mice and men  include significant enhancement for inflammation pathways  (e.g., NF-«B, collagens).!°°!°! Inflammation can induce cell  stress, and stressed mesenchymal cells can secrete inflammatory  mediators (chemoattractants); however, it remains to be  determined whether inflammatory infiltrates are a cause of  or response to the alterations of aged stroma.!°? Evidence  supports that inflammation has a role in the pathogenesis of  prostate cancer.’”!°° Investigators have found that disruption  of fibroblast growth factor signaling pathways leads to strongly  activated and atypical stroma that preceded the development of  mice PIN (mPIN).   Epithelial-mesenchymal transition (EMT) was first described  in embryonic development, and is observed in a number of  solid tumors! (also see Chapter 12). Cells that undergo EMT  become more migratory and invasive and gain access to vascular  vessels.'°° Numerous studies have shown that these transition  states (EMT and mesenchymal-epithelial transition [MET]) are  a consequence of tumor-stromal interactions. 1010   Investigators studying prostate cancer cells in vitro cor-  related EMT with increased growth, migration, and invasion.  These investigators demonstrated that the microenvironment  is a critical site for the transition of human prostate cancer cells  from epithelial to mesenchymal structure, resulting in increased  metastatic potential for bone and adrenal gland.'°”   Prostate cancer is known to be diverse and composed of mul-  tiple genetically distinct cancer cell clones. Studies, however,    indicate that most metastatic cancers arise from a single precur-  sor cancer cell.!°* Various research models have been proposed  to understand EMT (MET) and invasion and metastases. !°°   In summary, the following multifactorial general hypothesis  of prostate carcinogenesis emerges from all of these observa-  tions: (1) androgens act as strong tumor promoters through  androgen receptor—-mediated mechanisms to enhance the car-  cinogenic activity of strong endogenous DNA toxic carcino-  gens, including reactive estrogen metabolites and estrogen, and  prostate-generated reactive oxygen species; (2) alterations in  autocrine/paracrine growth-stimulating and growth-inhibiting  factors between the prostate tumor cells and microenviron-  ment influence cancer pathogenesis; and (3) possibly unknown    FIGURE 25-19 Carcinoma of the Prostate. A, Schematic of carcinoma of  the prostate. B, Carcinoma of the prostate extending into the rectum and urinary  bladder. (B from Damjanov I, Linder J, editors: Pathology: a color atlas, St Louis,  2000, Mosby.)    environmental-lifestyle carcinogens may contribute to prostate  cancer. All of these factors are modulated by diet and genetic  determinants, such as hereditary susceptibility genes and poly-  morphic genes, which encode receptors and enzymes involved  in the metabolism and action of steroid hormones.   The most common sites of distant metastasis are the lymph  nodes, bones, lungs, liver, and adrenals. The pelvis, lumbar  spine, femur, thoracic spine, and ribs are the most common  sites of bone metastasis. Local extension is usually posterior,  although late in the disease the tumor may invade the rectum  or encroach on the prostatic urethra and cause bladder outlet  obstruction (Figure 25-19). The spread of cancer through blood  vessels is illustrated in Figure 25-20.   CLINICAL MANIFESTATIONS. Prostatic cancer often causes no  symptoms until it is far advanced. The first manifestations of  disease are those of bladder outlet obstruction: slow urinary  stream, hesitancy, incomplete emptying, frequency, nocturia,  and dysuria. Unlike the symptoms of obstruction caused by  BPH, the symptoms of obstruction caused by prostatic cancer  are progressive and do not remit. Local extension of prostatic  cancer can obstruct the upper urinary tract ureters as well. If  rectal obstruction occurs, a man may experience a large bowel  obstruction or difficulty in defecation. Symptoms of late dis-  ease include bone pain at sites of bone metastasis, edema of the  lower extremities, enlargement of lymph nodes, liver enlarge-  ment, pathologic bone fractures, and mental confusion associ-  ated with brain metastases.   EVALUATION AND TREATMENT. Screening for prostatic cancer  includes DRE, PSA blood tests, and TRUS. The most signifi-  cant test used in the diagnosis and management of prostate  cancer is prostate-specific antigen (PSA). DRE may detect  early prostatic carcinomas but is has low sensitivity and  specificity.*! Cancer diagnosis is confirmed through tissue  biopsy and microscopic examination of tissue. Lymphog-  raphy, bone scans, MRI, and CT scans also may be used to  determine metastasis to lymph, bone, or other adjacent tissue.  Important for treatment is to accurately measure the size of  the index (longest) tumor and its percentage Gleason grade of  differentiation. !!°    FIGURE 25-20 Distribution of Hematogenous Metastases in Prostate  Cancer. Study of 556 individuals with metastatic prostate cancer. (Adapted from  Budendorf L et al: Hum Patho! 31:578, 2000.)    PSA screening for prostate cancer has led to considerable con-  troversy. A review of the evidence for the U.S. Preventive Services  Task Force regarding screening for prostate cancer concluded that  PSA-based screening results in small or no reduction in prostate  cancer-specific mortality and is associated with harms related to  subsequent evaluation and treatments, some of which may be  unnecessary (See What’s New? Summary of the American Col-  lege of Physicians (ACP) Guidance Statement on Screening for  Prostate Cancer).'!! Convincing evidence demonstrates that the  PSA test unfortunately often produces false-positive results. Men  who have a false-positive test are more likely to have additional  testing, including one or more biopsies. Over a 10-year span,  approximately 15% to 20% of men will have a PSA test result that  triggers a biopsy, depending on the PSA threshold and testing  interval used.*° In addition, because PSA is organ specific and not  cancer specific, it can increase and overlap with BPH, prostatitis,  infarct, manipulation from instrumentation, and ejaculation.*!  The annual rate by which PSA rises is known as PSA velocity or  doubling time (generally described as PSA kinetics). Its calcula-  tion has been judged to be far from straightforward. More than  20 different methods for calculation have been proposed, and  many of these give divergent results. Evidence clearly shows that  PSA kinetics are critical for understanding prognosis in advanced  or relapsed prostate cancer. However, PSA kinetics have ques-  tionable value for men with an untreated prostate; neither PSA  velocity nor doubling time has an established role in diagnosing  prostate cancer or providing a prognosis for men before treat-  ment.'!? In fact, investigators recently evaluated guidelines on the  use of PSA velocity in prostate cancer detection and found that  change in PSA levels over time is such a poor predictor of pros-  tate cancer (in a previously untreated prostate) that it is highly  likely many unnecessary biopsies have been performed.'!? It is  thus somewhat doubtful at this juncture that PSA velocity adds  any additional predictive accuracy to PSA alone or positive digi-  tal rectal examination, or both, for purposes of prostate cancer  screening.   Older age is the strongest risk factor for the development of  prostate cancer. However, neither screening nor treatment tri-  als show benefit in men older than 70 years. Across age ranges,  black men and men with a family history of prostate cancer  have an increased risk of developing and dying of prostate  cancer. Black men are approximately twice as likely to die of  prostate cancer than other men in the United States and the  reason for this disparity in unknown. Black men represent a  very small minority of participants in randomized clinical tri-  als of screening and, thus, no firm conclusions can be made  about the balance of benefits and harms of PSA-based screen-  ing in this population. As such, it is a questionable practice  to selectively recommend PSA-based screening for black men  in the absence of data that support a more favorable balance  of risks and benefits.°° The ability to predict cancer rises sig-  nificantly when TRUS is added to the annual DRE and PSA  testing. Researchers are studying microRNAs as potential new  biomarkers for prostate cancer.   Prostate cancer is now detected in greater numbers at lower  stages of disease and is amenable to multiple forms of effica-  cious treatment. However, there is a lack of conclusive data    demonstrating a definitive mortality benefit from this earlier  diagnosis and treatment of prostate cancer. This is likely because  of the treatment of a large proportion of indolent cancers that  would have had little adverse effect on health or life span if left  alone (Box 25-7).   Because of this “overtreatment” phenomenon, active sur-  veillance with delayed intervention is gaining traction as a viable  management approach in contemporary practice. The ability  to distinguish clinically insignificant cancers from those with  a high risk of progression or lethality, or both, is critical to the  appropriate selection of surveillance protocols versus immedi-  ate intervention'!* (Box 25-8). The most important observation  for pathologists to make to facilitate cure of any individual of  prostate cancer is that of accurately measuring the size of the  index (longest) tumor and Gleason score (degree of differentia-  tion) (see Box 25-6).!15   Treatment of prostatic cancer depends on the stage of the  neoplasm (see Box 25-6); the anticipated effects of treatment;  and the age, general health, and life expectancy of the individual.  Options include no treatment; surgical treatments such as total  prostatectomy, transurethral resection of the prostate (TURP),  or cryotherapy; nonsurgical treatments such as radiation therapy,  hormone therapy, or chemotherapy; watchful waiting; and any  combination of these.*° In addition, new approaches are using  immunotherapy. Palliative treatment is aimed at relieving uri-  nary, bladder outlet, or colon obstruction; spinal cord com-  pression; and pain. Prognosis and survival rates have improved  steadily since the early 1960s. According to the most recent  data, 10- and 15-year relative survival rates are 98% and 91%,  respectively.!   Treatment for prostate cancer may lead to loss of urinary  control, which may or may not return to normal after several  weeks or months. Stress incontinence can occur after surgery,  and mild urge incontinence can occur after radiation therapy.  Prostate cancer and its treatment can affect sexual function-  ing. Sensation of orgasm is not usually affected, but smaller  amounts of ejaculate will be produced or men may experience a  “dry” ejaculate because of retrograde ejaculation.    In essence, it has become necessary to rethink screening for both prostate  and breast cancer because since screening was introduced, the incidence of  both prostate and breast cancer increased and never returned to prescreen-  ing levels, and the absolute number of advanced prostate and breast cancers    diagnosed during this period has not decreased as predicted. Furthermore,  whereas colon and cervical cancer screening detects precancerous treatable  conditions, prostate and breast cancer screening detects so-called early can-  cers that may not be destined to grow or become lethal. Thus it is possible  that prostate and breast cancer screening may be increasing the burden of  low-risk cancers without any significant reduction of burden associated with  aggressive lesions, thereby not resulting in the anticipated reduction in breast  and prostate cancer mortality.    Data from Esserman L, Shieh Y, Thompson |: J Am Med Assoc  302(15):1685-1920, 2009.    WHAT'S NEW?  Summary of the American College of Physicians (ACP) Guidance Statement on Screening for Prostate Cancer   Indications for discussing e Men between the age of 50 and 69 years of age   screening e Earlier age in men who are at increased risk for prostate cancer (African American race and first-degree relative   (father or brother diagnosed with prostate cancer, especially before age 65 years)   Frequency of screening e No clear evidence guides the periodically or frequency of screening  e No clear evidence that PSA screening more frequently than every 4 years produces any additional benefit  e PSA levels of 2.5 pg/L or greater may warrant yearly evaluation   Harms of screening e False alarms related to number of high false-positive results associated with DRE and especially PSA  e High false-negative rates  e OQverdiagnosis (detection of cancer that is not destined to cause future morbidity and mortality)  e OQvertreatment and associated harms, including bleeding, pain, and hospitalization   Positive screening results may lead to further testing, such as biopsies, which not only can be painful but also can lead to   complications, such as infections  Recommendations Guidance statement 1: ACP recommends that clinicians inform men between the age of 50 and 60 years about the limited poten-   tial benefits and substantial harms of screening for prostate cancer. ACP recommends that clinicians base the decision to screen  for prostate cancer using the prostate-specific antigen test on the risk for prostate cancer, a discussion of the benefits and harms  of screening, the man’s general health and life expectancy, and preferences. ACP recommends that clinicians should not screen  for prostate cancer using the prostate-specific antigen test in men who do not express a clear preference for screening.   Guidance statement 2: ACP recommends that clinicians should not screen for prostate cancer using the prostate-specific antigen test   in average-risk men under the age of 50 years, over the age of 69 years, or men with a life expectancy of less than 10 to 15 years.   Talking points with patients PSA screening can detect prostate cancer, but for most men, the chances of harm from screening with the PSA test outweigh the  chances of benefit.   A small number of prostate cancer cases are serious and can cause death; however, the vast majority of prostate cancer is slow-   Most men who choose not to have PSA testing will not be diagnosed with prostate cancer and will die of something else.   Men who choose PSA testing are much more likely than those who decline PSA testing to be diagnosed with prostate cancer.   The PSA test often does not distinguish between cancer cases that are serious and those cases that are not serious; however,   men with markedly elevated PSA levels (>101g/L) may have a reduced chance of dying from prostate cancer by having surgical   The small potential benefit of prostate cancer screening corresponds to preventing, at most, 1 death caused by prostate cancer   e Problems interpreting test results: the PSA test result may be high because of an enlarged prostate but not because of cancer,  or it may be low even though cancer is present.  e lf a prostate biopsy is needed, it, too, is not free from risk—the biopsy involves multiple needles being inserted into the pros-  ate under local anesthesia, and there is a risk for infection or significant bleeding as well as risk for hospitalization (1.4%).   If cancer is diagnosed, it will often be treated with surgery or radiation, which are associated with risks; there is a small risk  or death with surgery, loss of sexual function (approximately 37% higher risk), and loss of control of urination (approximately  11% higher risk) compared with no surgery; these risks may vary depending on the man’s and surgeon's characteristics and  reatment method.  The PSA test is not “just a blood test;” it is a test that can open the door to more testing and treatment that a man may not ac-  ually want and that may actually harm him; a man’s chances of being harmed are much greater than his chances of benefitting  rom the PSA test; thus, each man should have the opportunity to decide for himself whether to have the PSA screening test.  Studies are ongoing, so clinicians expect to learn more about the benefits and harms of screening, and recommendations may  change over time; men also are welcome to change their minds at any time by asking for screening that they have previously  declined or discontinue screening that they have previously requested.    DRE, digital rectal examination; PSA, prostate-specific antigen  Data from Oaseem A et al: Ann Intern Med 158(1):761, 2013.    Screening may benefit a small number of men but will result in harm to many others. A person choosing to be screened should believe that the possibility of benefit  is more important than the risk for harm. The U.S. Preventive Services Task Force assessment of the balance of benefits and harms in a screened population is that    What are the benefits and harms of screening 1000 men ages 55 to 69 years’ with a prostate specific antigen (PSA) test every 1 to 4 years for   Possible benefit of screening:  Reduced 10-year risk for dying of prostate cancer:   Do not die of prostate cancer because of screening  Harms of screening:  At least one false-positive screening PSA test result:    Most positive test results lead to biopsy. Of men having biopsy, up to 33% will have moderate or major bothersome symptoms,    including pain, fever, bleeding, infection, and temporary urinary difficulties; 1% will be hospitalized    Although a diagnosis of prostate cancer may not be considered a harm, currently 90% of diagnosed men are treated and thus    are at risk for the harms of treatment. A large majority of the men who are being treated would do well without treatment.  A substantial percentage of these men would have remained asymptomatic for life.    Complications of treatment (among persons who are screened):  Develop serious cardiovascular events because of treatment    Develop erectile dysfunction because of treatment  Develop urinary incontinence because of treatment  Die because of treatment    2 in 1000  1 in 1000  29 in 1000  18 in 1000  <1 in 1000    Data from Moyer VA, U.S. Preventive Services Task Force: Ann Intern Med 157(2):120-134, 2012. Also see Esserman L, Shieh Y, Thompson |:  J Am Med Assoc 302(15):1685-1920, 2009 for further reading on this matter. A brief summary of the thinking of Esserman and colleagues is    provided in the prostate cancer evaluation and treatment section (p. 908).    Calculations of the estimated benefits and harms rely on assumption and are, by nature, somewhat imprecise. Estimates should be considered in  the full context of clinical decision making and used to stimulate shared decision making.    'The best evidence of possible benefit of PSA screening is in men ages 55 to 69 years.  2The rate of complications depends on the proportion of men having treatment and the method of treatment. The above reflects a distribution of    60% surgical treatment, 30% radiation treatment, and 10% observation. Other harms of radiation, such as bowel damage, are not shown.    In men the normal sexual response involves three processes:  erection, emission, and ejaculation. Sexual dysfunction is the  impairment of any or all of these processes. Impairment can  be caused by a number of physiologic and psychologic factors.   Until the late 1970s, most cases of male sexual dysfunction  were thought to be psychogenic. Studies of this problem indicate  that in men older than 40 years, organic factors are involved in  more than 50% of cases. The causes of organic sexual dysfunc-  tion include: (1) vascular, endocrine, and neurologic disorders;  (2) chronic disease, including renal failure and diabetes mel-  litus; (3) penile diseases and penile trauma; and (4) iatrogenic  factors, such as surgery and pharmacologic therapies. Most of  these disorders cause erectile dysfunction.   PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS. Vascular dis-  orders can prevent erection. Some arterial diseases diminish or  interrupt circulation to the penis. This prevents engorgement  of erectile tissues in the corpora cavernosa and corpus spon-  giosum. Rarely, excessive venous drainage of the corpora caver-  nosa prevents erection.   Endocrine disorders that reduce testosterone production  affect sexual function and libido. The reduction may be caused    by inadequate secretion of the gonadotropins caused by pitu-  itary dysfunction or hyperprolactinemia. Feminizing tumors  and estrogen therapy reduce relative levels of testosterone. Tes-  ticular atrophy from any cause also decreases testosterone levels  and contributes to sexual dysfunction.   Neurologic disorders can interfere with the important sym-  pathetic, parasympathetic, and CNS mechanisms required for  erection, emission, and ejaculation. They include spinal cord  injury or tumor, multiple sclerosis, and disorders that cause  peripheral neuropathies, such as diabetes mellitus and chronic  renal failure. Spinal cord injuries or tumors can alter one or more  components of the sexual response, depending on the location  of the lesion. For example, in most men with upper motor neu-  ron lesions, reflexogenic erection is possible but emission and  ejaculation (ie., orgasm) are not possible. Lesions affecting the  lower motor neurons usually prevent erection. In approximately  40% of such cases, emission and ejaculation are prevented.   Many chronic diseases are associated with sexual dysfunc-  tion. In some conditions the sexual dysfunction has a spe-  cific physiologic cause. Diabetes mellitus, for example, causes  peripheral vascular and neurologic pathology that can lead to  erectile dysfunction. Impotence occurs in about 50% of men    undergoing dialysis due to decreased testosterone levels, auto-  nomic neuropathy, accelerated vascular disease, multiple medi-  cations, worsening of primary disease, and psychologic stress.  Potency may be restored by successful renal transplantation,  except in bilateral transplantation if arterial flow is diminished  or interrupted. Cirrhosis of the liver, scleroderma, chronic  debilitation, and cachexia also are known to cause impotence.  Emotional and psychologic response to chronic illness, such as  anxiety, depression, and loss of self-esteem, can affect sexual  functioning. In other chronic conditions, sexual dysfunction is  associated with low energy levels and loss of libido. The patho-  physiologic mechanisms responsible for such changes are not  known.   Priapism causes fibrosis of trabeculae (erectile tissues) within  the corpora cavernosa, making erection difficult. The penile  curvature caused by Peyronie disease does not make erection  impossible but may make it extremely painful and intercourse  impossible. Penile trauma can damage the erectile tissue, disrupt  the posterior urethra, and disrupt the pudendal arteries or nerves.   Iatrogenic factors, including drugs and surgery, have a sig-  nificant effect on erectile function. The following surgical  procedures carry the risk of erectile dysfunction: radical pel-  vic surgery; radical prostatectomy; transurethral, suprapubic,  or simple retropubic prostatectomy; and aortoiliac surgery.  Erectile dysfunction is caused by the severing of small nerve  branches that are essential for erection. Aortoiliac surgery, ret-  roperitoneal lymphadenectomy, and sympathectomy cause the  loss of ejaculation capacity in some individuals.   A few pharmacologic agents enhance the sexual response,  but most have the opposite effect. Men who are taking anti-  hypertensives, antidepressants, antihistamines, antispasmodics,  sedatives or tranquilizers, barbiturates, diuretics, sex hormone  preparations, narcotics, or psychoactive drugs may experience  some degree of sexual dysfunction. Drug-induced sexual dys-  function consists of decreased desire, decreased erectile ability,  or decreased ejaculatory ability. Ethyl alcohol may induce alco-  holic neuropathy or increased estrogens because of hepatic dys-  function; marijuana depresses testosterone levels; and cigarette  smoking contributes to vasoconstriction and venous leakage. A  number of pharmacologic agents also diminish the quality or  quantity of sperm. A few may cause priapism. Drugs can assist  in maintaining an erection.   EVALUATION AND TREATMENT. Evaluation of sexual dysfunction  includes a physical examination, with particular attention to  the genitalia, prostate, and nervous system, and basic labora-  tory tests to identify the presence of endocrinopathies or other  underlying disorders that can cause the dysfunction. If no phys-  iologic cause is found and the condition does not improve with  psychotherapy, the man is referred for further investigation of  organic causes. Psychologic evaluation is indicated for younger  men with a sudden onset of sexual dysfunction or men of any  age who are able to achieve but not maintain an erection.   Sophisticated diagnostic techniques can be used to assess  penile blood flow, erectile tissue anatomy, nervous system func-  tion, and occurrence of erection or emission during sleep (noc-  turnal emission). Penile blood flow is measured by Doppler  techniques and penile arteriography. Corpus cavernosography,    in which contrast material is injected into the corpora caver-  nosa, provides anatomic information about the erectile tissue of  the penis. Neuropathic causes of sexual dysfunction are evalu-  ated by measuring the speed of the bulbocavernosus reflex. Noc-  turnal penile tumescence monitoring measures the frequency  of nocturnal erections. Depending on the equipment used, this  information may be correlated to rapid eye movement (REM)  or non-REM sleep.   Treatments for organic sexual dysfunction include medical  and surgical interventions. Nonsurgical interventions include  correction of underlying disorders, particularly drug-induced  dysfunction and endocrinopathy-related (e.g., reduced tes-  tosterone associated with chronic renal failure) dysfunction.  Vasodilators and cessation of smoking can benefit individuals  with vasculogenic erectile dysfunction. Surgical interventions  include penile implants, penile revascularization, and correction  of other anatomic defects contributing to sexual dysfunction.    Spermatogenesis requires adequate secretion of FSH and LH by  the pituitary; sufficient secretion of testosterone by the Leydig  cells; sufficient function of the Sertoli cells, including secretion  of androgen-binding protein, growth factors, inhibin B, and a  number of other important (but poorly understood) peptides;  and adequate spermatogonia.*~!'° The Leydig cells are located  in the testicular interstitium between the tubules, and the Ser-  toli cells and spermatogonia are located within the seminiferous  tubules. The Sertoli cells extend from the basement mem-  brane to the lumen, display tight junctions between adjacent  cells, and form the blood-testis barrier. Inadequate secretion  of gonadotropins may be caused by hypothyroidism, hyper-  adrenocortisolism, hyperprolactinemia, or hypogonadotropic  hypogonadism. In these situations gonadotropin levels are low  because of feedback inhibition or idiopathic hyposecretion. In  the absence of adequate gonadotropin levels, the Leydig cells are  not stimulated to secrete testosterone and sperm maturation  is not promoted in the Sertoli cells. Spermatogenesis depends  not only on appropriate stimulation by the gonadotropins but  also an appropriate response by the testes. Defects in testicu-  lar response to the gonadotropins result in decreased secretion  of testosterone and inhibin B and, as a result of normal feed-  back mechanisms, high levels of circulating gonadotropins. In  the absence of adequate testosterone levels, spermatogenesis  is impaired. Newer research demonstrates the significance of  inhibin B as an important marker of the competence of Sertoli  cells and spermatogenesis. Inhibin B is strongly correlated with  severity of spermatogenic effects. A positive correlation exists  between serum inhibin B levels and sperm concentration and  testicular volume, and lower levels have been associated with  azoospermia, testicular disorders, and infertility.'1°   Impaired spermatogenesis also can be caused by genetic dis-  orders (such as Klinefelter syndrome), myotonic dystrophy, or  testicular trauma. Other conditions associated with impaired  spermatogenesis include systemic illness, such as renal fail-  ure, hepatic disease, or sickle cell disease; exposure to gonado-  toxins, such as chemotherapy or radiation; varicocele; and  cryptorchidism.    Fertility is adversely affected if spermatogenesis is normal but  the sperm are chromosomally or morphologically abnormal or  are produced in insufficient quantities. Chromosomal abnormal-  ities are caused by genetic factors and by external variables, such  as exposure to radiation or toxic substances. Ongoing research  using small ribonucleic acids (RNAs) is elucidating the molecu-  lar mechanisms regulating spermatogenesis.'!’ A sperm count of  20 million sperm per milliliter of semen has been suggested as  the minimum concentration required for fertility. Average fertile  men have 50 to 100 million sperm per milliliter.*?   Sperm motility is another important variable affecting fer-  tility. Motility appears to be affected by the sperm’s chemical  environment, that is, the characteristics of semen. Prostatic  dysfunction, excessive semen viscosity, presence of drugs or  toxins in the semen, and presence of antisperm antibodies are  associated with impaired sperm motility. Approximately 3% to  7% of infertile males have antisperm antibodies in their semen.  Antisperm antibodies may develop as a result of epididymitis or  other inflammation of the genitourinary tract, testicular injury  or torsion, a previous vasectomy or biopsy, and cryptorchi-  dism. Antisperm antibodies may be (1) cytotoxic antibodies,  which attack sperm and reduce their number in the semen; or  (2) sperm-immobilizing antibodies, which impair sperm motil-  ity and reduce their ability to traverse the endocervical canal.  Intrinsic, biologic factors leading to the production of anti-  sperm antibodies seem to play a greater role than extrinsic fac-  tors. The exact mechanism remains unclear.°?   A male factor contributes to the cause of up to 50% of cases  of infertility. As understanding of the male factor in infertil-  ity increases, evaluation becomes more complex and essential  to appropriate treatment (Box 25-9). Treatment for impaired  spermatogenesis involves correction of any underlying disor-  ders and avoidance of radiation or toxins. Androgens, human  gonadotropins, and antiestrogens (e.g., clomiphene citrate,  tamoxifen citrate) may enhance spermatogenesis. Semen  can be modified to improve sperm motility. If conception is  desired, the semen is obtained by masturbation (or mechanical  device),*” after which it can be diluted, concentrated, or washed  to remove antisperm antibodies. These alterations are followed  by artificial insemination.    Thorough history and physical, including imaging for varicocele  Two semen analyses and quantification of serum FSH, LH, testosterone levels,  and prolactin if indicated   Gynecomastia is the overdevelopment of breast tissue in a  male. Gynecomastia accounts for approximately 85% of all  masses that develop in the male breast and affects 32% to 40%  of the male population. If only one breast is involved, it is typi-  cally the left. Incidence is greatest among adolescents and men  older than 50 years.   Gynecomastia results from hormonal alterations, which  may be idiopathic or caused by systemic disorders, drugs, or  neoplasms. It usually involves an imbalance of the estrogen/  testosterone ratio, which can be altered in one of two ways.  First, estrogen levels may be excessively high, although tes-  tosterone levels are normal, as in drug-induced and tumor-  induced cases of hyperestrogenism. Second, testosterone levels  may be extremely low although estrogen levels are normal, as  is the case in hypergonadism. Gynecomastia also can be caused  by alterations in breast-tissue responsiveness to hormonal  stimulation. Breast tissue may have increased responsiveness  to estrogen or decreased responsiveness to androgen. Altera-  tions of responsiveness may cause many cases of idiopathic  gynecomastia.   Besides puberty and aging, estrogen-testosterone imbalances  are associated with hypogonadism, Kinefelter syndrome, and  testicular neoplasms. Hormone-induced gynecomastia is usually  bilateral. Pubertal gynecomastia is a self-limiting phenomenon  that usually disappears within 4 to 6 months. Senescent gyneco-  mastia usually regresses spontaneously within 6 to 12 months.   Systemic disorders associated with gynecomastia include  obesity, cirrhosis of the liver, infectious hepatitis, chronic renal  failure, chronic obstructive lung disease, hyperthyroidism,  tuberculosis, and chronic malnutrition. It may be that these dis-  orders ultimately alter the estrogen/testosterone ratio, initiating  gynecomastia.   Gynecomastia is often seen in men receiving estrogen ther-  apy, either in preparation for a sex-change operation or for  prostatic carcinoma. Other drugs that can cause gynecomastia  include digitalis, cimetidine, spironolactone, reserpine, thia-  zide, isoniazid, ergotamine, tricyclic antidepressants, amphet-  amines, vincristine, and busulfan. Gynecomastia is usually  unilateral in these instances.   Malignancies of the testes, adrenals, or liver can cause gyne-  comastia if they alter the estrogen/testosterone ratio. Pituitary  adenomas and lung cancer also are associated with gynecomastia.   PATHOPHYSIOLOGY. The breast enlargement consists of hyper-  plastic stroma and ductal tissue. Hyperplasia results in a firm, pal-  pable mass, at least 2 cm in diameter located beneath the areola.   EVALUATION AND TREATMENT. The diagnosis of gynecomastia is  based on physical examination. Identification and treatment of  the cause are likely to be followed by resolution of the gyne-  comastia. The man should be taught to perform breast self-  examination and is examined at 6- and 12-month intervals if  the gynecomastia persists. All unilateral breast enlargement in  men warrants an evaluation for malignancy; workup includes  fine-needle aspiration, cytology, mammography, ultrasound,  and biopsy.    Male breast cancer (MBC) accounts for 1% of all male cancers  and less than 1% of all breast cancers. Global incidence rates  were generally less than 1 per 100,000 man-years in contrast to  much higher rates in females (see Chapter 24). The highest inci-  dence rate for MBC is in Israel with 1.24 per 100,000, and the  lowest incidence rates for males (0.16) and females (18.0) were  observed in Thailand.'!® It occurs most commonly after age 60,  with the peak incidence between 60 and 69 years (men tend to  be diagnosed at an older age than women). It has, however, been  reported in males as young as 6 years and in adolescents. Kline-  felter syndrome is the strongest risk factor for developing male  breast carcinoma. Other risk factors include germline mutation  in BRCAI1 or BRCA2, but familial cases usually have BRCA2  rather than BRCA1 mutations.'!?"'?! Obesity increases the risk of  MBC. Testicular disorders, including cryptorchidism, mumps,  orchitis, and orchiectomy are related to risk.'** The relationship  between these factors and risk of disease is not clearly defined.  Recent data on most frequent molecular subtypes of male  breast cancer appear to be different than female breast cancers  with Luminal A and Luminal B the most common subtypes    and basal-like, unclassifiable triple-negative, and HER2-  driven male breast cancer subtypes are rare.!*°"!*> The major-  ity of MBCs express estrogen and progesterone receptors.!*°  The malignant male breast lesion is usually a unilateral solid  mass located near the nipple. Because the nipple is commonly  involved, crusting and nipple discharge are typical clinical  manifestations. Other findings include skin retraction, ulcer-  ation of the skin over the tumor, and axillary node involve-  ment. Patterns of metastasis are similar to those in females.   The diagnosis of cancer is confirmed by biopsy. Because  of delays in seeking treatment, male breast cancer tends to be  advanced at the time of diagnosis and therefore tends to have  a poor prognosis. Treatment protocols are similar to those  for female breast cancer, but endocrine therapy is used more  often for males because a higher percentage of male tumors  are hormone dependent. The mainstay of treatment is modi-  fied mastectomy with axillary node dissection to assess stage  and prognosis. Because 90% of tumors are hormonal receptor  positive, tamoxifen is standard adjuvant therapy. For metastatic  disease, hormonal therapy is the main treatment but chemo-  therapy also can provide palliation.!!°   1. Sexual maturation, or puberty, should begin in boys  between 9 and 14 years of age. Delayed puberty is the onset  of sexual maturation after these ages; precocious puberty is  onset before these ages.   2. Alterations of sexual maturation can be idiopathic or caused  by a disease or congenital anomaly. In most cases of delayed  puberty, the hypothalamic-pituitary-gonadal (HPG) axis  is intact but the surge of activity that stimulates puberty  is delayed. This situation is common in boys. Precocious  puberty also can be caused by mistiming of the stimulatory  surge in a child whose HPG system is otherwise normal.   3. Precocious puberty can be complete (sex appropriate),  mixed (not sex appropriate), or partial (development of  one secondary sex characteristic only). Causes of delayed or  incomplete puberty can be divided into categories based on  gonadotropic secretion: hypergonadotropism (increased  levels of FSH and LH), and hypogonadotropism (decreased  LH and FSH levels).   1. Disorders of the urethra include urethritis (inflammation of  the urethra) and urethral strictures (narrowing or obstruc-  tion of the urethral lumen caused by scarring).   2. Although noninfectious urethritis can occur, most cases  of urethritis result from sexually transmitted pathogens.  Symptoms of urethritis include dysuria, frequency, urgency,  urethral tingling or itching, and clear or purulent discharge.  Treatment consists of appropriate antibiotic therapy and  avoidance of future chemical or mechanical irritation.   3. Acquired or congenital scarring that causes urethral stric-  ture can be caused by trauma or by severe or untreated    urethral infection. The primary symptom is diminished  force and caliber of the urinary stream; other symptoms  include urinary frequency and hesitancy, mild dysuria,  double urine stream or spraying, and postvoiding drib-  bling. Treatment is usually surgical.   4, Phimosis and paraphimosis are penile disorders involving  the foreskin (prepuce). In phimosis the foreskin cannot be  retracted over the glans. In paraphimosis the foreskin is  retracted and cannot be returned to its normal anatomic  position over the glans. Phimosis is caused by poor hygiene  and chronic infection and can lead to paraphimosis. Para-  phimosis can constrict the penile blood vessels, preventing  circulation to the glans.   5. Peyronie disease consists of fibrosis, affecting the corpora  cavernosa, which causes penile curvature during erection.  Fibrosis prevents engorgement on the affected side, causing  a lateral curvature that can prevent intercourse.   6. Priapism, a prolonged painful erection not stimulated by  sexual arousal, is a urologic emergency. The corpora caver-  nosa (but not the corpus spongiosum) fills with blood that  does not drain out, probably because of venous obstruc-  tion. Priapism is associated with spinal cord trauma, sickle  cell disease, leukemia, and pelvic tumors. It can also be idio-  pathic and can occur with cocaine use.   7. Balanitis is an inflammation of the glans penis and usually  occurs in conjunction with posthitis. It is associated with  phimosis, inadequate cleansing under the foreskin, skin  disorders, and infections.   8. Cancer of the penis is rare; major risk factors include HPV,  smoking, and consequences of treatment for psoriasis.  Penile carcinoma in situ tends to involve the glans; invasive  carcinoma of the penis involves the shaft as well.    A varicocele is an abnormal dilation of the veins within  the spermatic cord caused by either congenital absence of  valves in the internal spermatic vein or acquired valvular  incompetence.   A hydrocele is a collection of fluid between the testicular  and scrotal layers of the tunica vaginalis. Hydroceles can be  idiopathic or caused by trauma or infection of the testes.  A spermatocele is a cyst located between the testis and epi-  didymis that is filled with fluid and sperm.   Cryptorchidism is a congenital condition in which one or  both testes fail to descend into the scrotum. Uncorrected  cryptorchidism is associated with infertility and a signifi-  cantly increased risk of testicular cancer.   Testicular torsion is the rotation of a testis, which twists  blood vessels in the spermatic cord. This interrupts blood  supply to the testis, resulting in edema and, if not corrected  within 4 to 6 hours, necrosis and atrophy of testicular tissues.  Orchitis is an acute infection of the testes. Pathogenic organ-  isms may reach the testes through the blood or the lym-  phatics; most commonly, they reach the testes by ascending  through the vas deferens and epididymis. Complications  of orchitis include hydrocele and atrophy. Granulomatous  orchitis, an autoimmune disease, is a nonspecific, noninfec-  tious, inflammatory process that occurs in middle-aged men.  Testicular cancer is the most common malignancy in males  ages 15 to 35 years. Although its cause is unknown, high  androgen levels, genetic predisposition, and a history of crypt-  orchidism, trauma, or infection may contribute to tumori-  genesis. Most testicular neoplasms are germ-cell tumors.  Epididymitis, an inflammation of the epididymis, is usu-  ally caused by a sexually transmitted pathogen that ascends  through the vasa deferentia from an already infected ure-  thra or bladder.   BPH is enlargement of the prostate gland. This condition  becomes symptomatic as the enlarging prostate compresses  the urethra, causing symptoms of bladder outlet syndrome  and urine retention.   Prostatitis is inflammation of the prostate. Prostate syn-  dromes have been classified by the National Institutes of  Health as: (a) acute bacterial prostatitis (ABP), (b) chronic  bacterial prostatitis (CBP), (c) chronic pelvic pain syndrome  (CPPS), and (d) asymptomatic inflammatory prostatitis.    Prostate cancer is the most common cancer in American  men, and the incidence varies greatly worldwide. Pos-  sible causes include genetic predisposition, environmental  and dietary factors, inflammation, and alterations in lev-  els of hormones (testosterone, dihydrotestosterone, and  estradiol) and growth factors. Incidence is greatest among  northwestern European and North American men (partic-  ularly blacks) older than 65 years of age.   Most cancers of the prostate are adenocarcinomas that  develop at the periphery of the gland.   Sexual dysfunction in males can be caused by any physi-  cal or psychologic factor that impairs erection, emission, or  ejaculation.   Spermatogenesis (sperm production by the testes) can be  impaired by disruptions of the HPG axis that reduce testos-  terone secretion and by testicular trauma or atrophy from  any cause. Sperm production is also impaired by neoplastic  disease, cryptorchidism, or any factor that causes testicular  temperature to rise.   Sperm quality is impaired by chromosomal abnormalities  resulting from genetic factors, irradiation, or toxins. Sperm  motility can be impaired by unfavorable constituents or  characteristics of semen.    Gynecomastia is the overdevelopment (hyperplasia) of  breast tissue in a male resulting from hormonal alterations,  which may be idiopathic or caused by systemic disorders,  drugs, or neoplasms. It usually involves an imbalance of the  estrogen/testosterone ratio.    The incidence is greatest among adolescents and men older  than 50 years.    tions that cause estrogen to dominate. These alterations can  result from systemic disorders, drugs, neoplasms, or idio-  pathic causes.    . Breast cancer is relatively uncommon in males, but it has a    poor prognosis because men tend to delay seeking treatment  until the disease is advanced. The incidence is greatest in  men in their 60s.   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Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Sexually Transmitted Urogenital Infections, 919  Bacterial Infections, 919  Chlamydial Infections, 929  Viral Infections, 932  Parasitic Infections, 937    Throughout recorded history, infectious diseases have threat-  ened humans. Even into the twentieth century, epidem-  ics of diphtheria, typhoid, tuberculosis, cholera, and other  catastrophic infections have decimated entire communities  almost overnight (see Chapter 10). Despite medical advances,  improved living standards, and better nutrition, epidemics still  arise as major public health problems, and some pose lethal  threats to individuals and communities. Some of these epidem-  ics are caused by sexually transmitted infections (STIs). At this  time, many people consider the number of individuals with  acquired immunodeficiency syndrome (AIDS), human immu-  nodeficiency virus (HIV), and human papillomavirus (HPV)  infections to be at epidemic levels.   Sexually contracted infections affect more than 19 million  Americans per year (see What’s New? Sexually Transmitted  Infection [STI] Statistical Summary from 2010 CDC Report),  and half of those are younger than 25 years! and account for  about one third of the reproductive mortality in the United  States. They have been called the “hidden epidemic” by the  Centers for Disease Control and Prevention (CDC)? because of  their stigma and overall lack of knowledge of the prevalence and  consequences of sexually transmitted infections. Complications    Sexually Transmitted Infections of Other  Body Systems, 940  Hepatitis B Virus, 940  Acquired Immunodeficiency Syndrome, 941    of STIs include pelvic inflammatory disease, infertility, ectopic  pregnancy, chronic pelvic pain, neonatal morbidity and mor-  tality, and genital cancers. Long-term sequelae of untreated or  undertreated STIs can affect a person’s physical, emotional, and  financial well-being.   In the past an infection transmitted through sexual  intercourse was called a venereal disease. Because of its lim-  ited scope, the term venereal disease has been replaced with  sexually transmitted infection (STI). STIs are contracted by  intimate, as well as sexual, contact and include systemic infec-  tions, such as tuberculosis and hepatitis, that can be spread  to a sexual partner. The etiology of an STI may be bacterial,  viral, protozoal, parasitic, or fungal (Table 26-1). Although  the majority of STIs can be treated, viral STIs cannot be  cured, only treated naturally or pharmacologically. Many  infected individuals do not seek treatment because symptoms  are absent, minor, or transient or because health services are  inaccessible, unaffordable, or culturally insensitive. High-risk  sexual behaviors (e.g., multiple partners) and poor health  habits (e.g., failure to use a condom in nonmonogamous or  new relationships, drug use) increase an individual’s risk of  exposure or the severity of infection if exposed. Perhaps partly    Each year in the United States:  19 million individuals contract a sexually transmitted infection; half of  those infected are younger than 25 years  17 billion dollars are spent on STls, not including long-term healthcare  costs  Only half of people who need STI screening receive needed services  Chlamydia cases:  e 1.3 million cases were reported and treated but an estimated 2.6 million  additional cases remain untreated  Gonorrhea cases increased in 2010 and have become resistant to many previ-  ous treatments and may soon become resistant to remaining antibiotics  Syphilis cases have decreased for the first time in a decade:  e There was a 134% increase in the syphilis rate among young black men  e The syphilis rate is highest among men who have sex with men  Viral STls affect more than 70 million people in the United States:  e 20 million currently infected with human papillomavirus; more than half  of all sexually active people will get HPV in their lifetime  e 50 million with genital herpes  e 1 million with HIV    Data from Centers for Disease Control and Prevention: Sexually trans-  mitted disease surveillance, 2010, Atlanta, 2011, U.S. Department of  Health and Human Services. Available at www.cdc.gov/std/stats.    because of risk-taking behavior (unprotected intercourse or  selection of high-risk partners), adolescents have the greatest  risk for STI exposure and infection. In addition, adolescent  women may have a physiologically increased susceptibility to  infection because of cervical immaturity. Rates of gonorrhea,  chlamydia, vaginitis, cervical condyloma, genital warts, and  pelvic inflammatory disease (PID) are highest in adolescents  and young women and decline exponentially with increasing  age (Figure 26-1). The health consequences of STIs are both  immediate and long-term. Women and infants bear the great-  est health burden from STIs.   STIs are stereotyped as occurring only among urban poor  and minority populations. Because the CDC does not require  that all STIs be reported, private physicians may not report  them. Thus reported STIs often are provided by public health  clinics, giving the impression that a greater number of the  urban poor and minority populations are infected with STIs. In  fact, STIs are prevalent in all socioeconomic and racial/ethnic  groups.   Gonorrhea is caused by gonococci (singular, gonococcus),  which are microorganisms of the species Neisseria gonorrhoeae.  Neisser first identified gonococci in stained smears of vaginal,  urethral, and conjunctival exudate in 1879. Until 1994 gonor-  rhea was the most commonly reported communicable infec-  tion in the United States. After reaching a record low in 2009,   Gardnerella vaginalis interaction  with anaerobes (Bacteroides and  Mobiluncus spp.) and genital  mycoplasmas    the rates for gonorrhea increased 2% between 2009 and 2010.  Although the number of reported cases in 2010 was 309,341,”  the actual number of cases is estimated to be twice as high.   Infection rates are highest in the southern region of the  United States.2 Other demographic and lifestyle risk factors  may include transient or urban residence, early onset of sexual  activity, multiple serial or consecutive sex partners, drug use,  prostitution, and previous gonorrheal or concurrent STI.? The  risk of developing gonorrhea from intercourse with an infected  male partner is 50% to 80% for women, and with an infected  female partner, it is 20% to 30% for men. The risk increases  threefold to fourfold for men after four exposures to an infected  partner. Men who have sex with infected men have a greater  risk of contracting gonorrhea if they are the receptive partner in  oral or anal intercourse.”    20%  8% |  Hepatitis B HIV* Syphilis HSV-2  Total: 19,000 41,400 55,400 776,000    Bars are for illustration only; not to scale, due to wide range in numbers of infections    FIGURE 26-1 Incidence and Prevalence of Sexually Transmitted Infections. (From Centers for Disease Control and  Prevention: CDC fact sheet: incidence, prevalence, and cost of sexually-transmitted infections in the United States, 2013.  Available at www.cdc.gov/std/stats/STI-Estimates-Fact-Sheet-Feb-2013.pdf. Accessed February 24, 2013, using data from    Transmission of gonococcal infection generally requires  contact of epithelial (mucosal) surfaces, such as occurs dur-  ing sexual, oral, or anal intercourse. A pregnant woman also  can transmit gonorrhea to her fetus. The infection passes from  mother to child predominantly through infected cervical and  vaginal secretions. Fomites (contaminated objects) are rarely  involved in the transmission of N. gonorrhoeae, primarily  because the gonococcus requires a rich medium (e.g., body flu-  ids) and an environment high in carbon dioxide (5% to 10%)  for growth.   Treatment for gonorrhea is becoming more difficult because  of rapidly developing resistance to available antibiotics. The  CDC states that it is reasonable to expect that gonorrhea may  become resistant to all known antibiotics in the near future.°   PATHOPHYSIOLOGY. Humans are the only natural hosts for  N. gonorrhoeae, which is an aerobic, non-spore-forming, oxidase-  positive gram-negative coccal (round) microorganism that  usually appears in pairs (diplococci), with the adjacent sides  slightly flattened. Hairlike filaments, called pili, appear to help  the microorganisms attach themselves to host cells: the epi-  thelial cells of mucous membranes (Figure 26-2). Columnar,  transitional, and stratified squamous epithelial cells are infected  most often. First the microorganisms become attached to the  plasma membranes (cell walls) of these cells, and then they    FIGURE 26-2 Gonococci. Scanning electron microscopy showing gonococci  attaching to the nonciliated cells of human fallopian tube mucosa. (From Morse  SA et al, editors: Atlas of sexually transmitted diseases and AIDS, ed 3, London,  2003, Mosby.)    invade the cells and begin to damage the mucosa. Generally a  quick leukocytic (inflammatory) response and exudation at the  site of infection occur.   In women the endocervical canal (inner portion of the cer-  vix) is the usual site of initial gonococcal infection, although  urethral colonization and infection of glands (paraurethral  [Skene glands] and greater vestibular [Bartholin glands]) near  the urethra and vagina also are common. Several factors can  facilitate ascent of gonococci into the uterus and the fallopian  tubes, where they cause PID. Among these factors are: (1) disin-  tegration of the cervical mucous plug and an increase in vaginal  pH to greater than 4.5 during menstruation, (2) uterine contrac-  tion that may cause retrograde menstruation into the fallopian/  uterine tubes, and (3) various microbes that possess virulent  potentiating factors for chlamydia or gonococcal PID. Bacte-  ria (N. gonorrhoeae, Chlamydia trachomatis) also may adhere  to sperm and be transported to the fallopian/uterine tubes. In  the fallopian/uterine tubes, progressive mucosal and submuco-  sal invasion and sloughing of normal, ciliated tubal epithelium  are accompanied by a marked inflammatory response, causing  the tubes to fill with exudate (see Chapter 25 for more on PID).  In men the gonococci typically infect the urethra or rectum.  Untreated urethral infection can cause epididymitis in men,  and, if untreated, urethral stricture, fistula, and sterility. Con-  current oropharyngeal and anorectal infection can be found in  infected men and women.’ Virulence is determined by varia-  tions in the bacterial properties and host response.   CLINICAL MANIFESTATIONS. The clinical manifestations of  gonorrhea can be categorized as local or systemic and uncom-  plicated or complicated. Uncomplicated local infections are  seen as urethral infections in men and urogenital infections in  women. The majority of infected men will have sudden onset  of painful urination or purulent penile discharge, or both,  within a week of infection.’ These severe symptoms encourage  most men in developed countries to seek treatment.2* How-  ever, some men have little discharge or urethral itching (i.e.,  pruritus) only, and 5% to 10% never have signs or symptoms.  Most cases of untreated gonococcal urethritis resolve sponta-  neously after several weeks, and more than 95% of individuals  are asymptomatic by 6 months after infection (although they  may still be infectious). Some men develop urethritis even after  being appropriately treated. If untreated, gonorrhea can cause  penile abscesses, fistulae, and strictures.*   In women, the incubation period varies, but those who  develop symptoms usually manifest within 10 days of expo-  sure or within 1 to 2 days after the next menstrual period. More  than half of gonorrhea infections in women are initially asymp-  tomatic. Symptoms often do not appear until the infection  has spread to the upper reproductive tract (uterus, fallopian/  uterine tubes, and ovaries). Symptoms can include dysuria,  increased vaginal discharge, abnormal menses (increased flow  or dysmenorrhea), dyspareunia, lower abdominal/pelvic pain,  and fever. Physical examination may disclose cervical friability  and erythema (redness) and mucopurulent discharge from the  cervical os (Figure 26-3). There may be a discharge from the  paraurethral (Skene) or greater vestibular (Bartholin) glands if  these sites are involved.    FIGURE 26-3 Gonococcal Cervicitis. The cervix is involved in 85% to 90%  of cases in women, but the resultant discharge is profuse enough to be recognized  in only 10%. (From Centers for Disease Control and Prevention: S7D clinical slides  (website). Available at www.cdc.gov/std/training/clinicalslides/slides-dl.htm.  Accessed March 5, 2013.)    Anal and rectal gonococcal infection is found in 30% to 50%  of women diagnosed with urogenital gonorrhea. In women,  anorectal infection is usually asymptomatic and not necessar-  ily related to anal intercourse. Symptomatic anorectal gonor-  rhea occurs more commonly in men who have sex with men.?  Symptoms of anorectal gonorrhea range from mild anal pruri-  tus (itching), mucopurulent rectal discharge, and slight rectal  bleeding to severe rectal pain, tenesmus (painful and ineffec-  tual straining at stool), and constipation. Physical examination  findings include anal erythema and discharge and evidence  of mucosal damage to the anus and rectum, such as friability,  edema, and purulent exudate.   Gonococcal pharyngitis occurs after oral sexual contact with  an infected partner. Symptomatic pharyngitis is indistinguish-  able from any other bacterial pharyngitis and can include fever,  lymphadenopathy, and tonsillitis. Approximately 60% of these  infections are asymptomatic.   Other sites of uncomplicated local infections include the  eye, leading to conjunctivitis; however, this is rare in adults.  Primary cutaneous infection also has been reported and is usu-  ally manifested as a localized ulcer of the genitalia, perineum,  proximal lower extremities, or fingers. It is important to deter-  mine whether such infections are the result of N. gonorrhoeae or  secondary colonization by a preexisting lesion.   Complicated gonococcal infections include prostatitis, epi-  didymitis, lymphangitis, and urethral stricture in men and  salpingitis, PID, and bartholinitis in women. Chronic salpin-  gitis or perididymitis can cause scarring and adhesions that  lead to sterility in men and women. Approximately 10%? of  women with untreated cervical gonorrhea develop salpingitis  or PID. Importantly, salpingitis has the potential for long-term  sequelae, especially infertility and ectopic pregnancy.   The onset of symptoms for women may be rapid and usu-  ally occurs during menses. Women may experience chills,  fever, nausea, vomiting, and lower abdominal/pelvic pain that  worsen with movement, such as walking, coughing, sneezing,  or intercourse. Abdominal palpation often discloses bilateral  lower quadrant tenderness and rebound tenderness resulting  from peritoneal irritation caused by tubal exudate. Marked    tenderness of the internal genitalia is often noted during pel-  vic examination. Enlargement or masses may be palpable in the  upper genital tract. Tubal infertility is found in 12% of women  after one episode of PID. If a woman has three or more episodes  of PID, she has a 50% risk of tubal infertility.” Disseminated  gonococcal infection (DGI) is a rare systemic complication  caused by the spread of infection through the bloodstream.  Symptoms of this life-threatening condition include a general-  ized rash and severe joint pain. Proliferation of N. gonorrhoeae  to the liver causes a condition known as perihepatitis or Fitz-  Hugh-—Curtis syndrome. C. trachomatis also has been identi-  fied as a causative agent of this condition. Inflammation of the  capsule of the liver produces sudden and intense right upper  quadrant pain.° This complication usually develops after acute  salpingitis in women and is very rare in men.   If a mother has untreated gonorrhea at the time of birth, she  can transmit the infection to her child, regardless of whether  the baby is delivered vaginally or by cesarean section. Most  states require all infants to receive prophylactic ophthalmic  antibiotics to prevent gonococcal eye infection (ophthalmia  neonatorum) (Figure 26-4) and risk for associated blindness.  Newborns born to infected mothers also may develop gonor-  rheal rhinitis, anorectal infection, or an abscess at the site of  electrode placement for fetal monitoring. Onset of symptoms  generally occurs 1 to 12 days after birth, with a mean of 4 to 6  days. Affected newborns usually are born to mothers who have  suffered from prolonged ruptured membranes. In these cases,  immediate treatment with a topical antibiotic is not effective  because the infection is already established. Established infec-  tion causes bilateral corneal ulceration, with a profuse yellow  or gray purulent exudate, and is followed by necrosis, scarring,  and permanent blindness.   EVALUATION AND TREATMENT. Clinical signs and symptoms are  not sufficient for the differential diagnosis of gonococcal infec-  tions. Microscopic evaluation of Gram-stained slides of clinical  specimens is deemed positive for N. gonorrhoeae if gram-negative  diplococci with typical “kidney bean” morphology are seen inside  polymorphonuclear leukocytes. Such a finding is considered  adequate for the diagnosis of gonococcal urethritis in a sympto-  matic man. For women, the Gram-stain technique is less accurate  and reliable and is replaced with a single sample of endocervi-  cal secretions. Most clinic settings now use nucleic acid hybrid-  ization tests because these samples do not require an anaerobic  incubation, are highly sensitive, and can be easily transported to a  laboratory for testing. Because of the large percentage of infected  women without symptoms, routine screening for at-risk women  (i.e., those younger than age 25 or with a new sexual partner) is  recommended. Samples can be obtained from the urine or the  vagina, endocervix, urethra, rectum, or oropharynx. Although  nucleic acid hybridization is acceptable for screening, the CDC  prefers direct culture for testing because this will provide infor-  mation about antibiotic susceptibility and help provide a cure.’   N. gonorrhoeae has developed resistance to many antibiotics  and has the potential to become resistant to all current treat-  ment drugs.’ Several types of drug-resistant strains have been  identified, including penicillinase-producing N. gonorrhoeae  (PPNG), which is resistant to penicillin; tetracycline-resistant   FIGURE 26-4 Gonococcal Ophthalmia Neonatorum. Examiner would be  gloved. (From McMillan A, Scott GR: Sexually transmitted infections, ed 2, London,  2000, Churchill Livingstone.)    N. gonorrhoeae (TRNG), which is resistant to tetracycline; chro-  mosomal control of mechanisms of resistance of N. gonorrhoeae  (CMRNG), which is resistant to penicillin and tetracycline;  and increasingly a fluoroquinolone-resistant N. gonorrhoeae  (QRNG).”® Until 2007 fluoroquinolones were the first-line  treatment recommended by the CDC. In 2010 more than 27%  of CDC-monitored samples were resistant to one or more anti-  biotics.? The only class of drugs still recommended for treat-  ment of gonorrhea are the cephalosporins; however, there is  increasing resistance to this type of medication in the United  States, Canada, and around the world. There is currently only  one CDC recommended drug, ceftriaxone, to treat gonorrhea  although less-effective alternatives are available.’ To prevent  further drug resistance, the CDC recommends a multidrug  treatment for gonorrhea that also is effective against chlamydia.*   The CDC is closely observing the drug resistance of gonor-  rhea through monitoring of samples obtained at sexually trans-  mitted disease (STD) clinics around the country.’ Treatment for  gonorrhea is influenced by three factors: (1) the spread of infec-  tion caused by drug-resistant strains, (2) the high frequency  of chlamydia infection accompanying gonorrhea, and (3) the  recognition of the serious complications of chlamydia and gon-  orrhea infections. CDC treatment guidelines are updated regu-  larly, and the most recent edition should be used. Current CDC  treatment guidelines for uncomplicated gonorrheal infections  are listed in Box 26-1; complicated infections require intrave-  nous antibiotic therapy and possibly hospitalization.   Sexual partners also are assessed and treated according to  these protocols, and sexual contact is avoided until treatment  is completed. Condoms are strongly recommended to prevent  future infection.    Syphilis  Syphilis, a disease with local and systemic manifestations, has  been well-known throughout history. Many famous figures    Ceftriaxone, 125 mg IM ina single dose  e AND to prevent drug resistance and treat potential infection with chlamydia:  Azithromycin, 1 g PO in a single dose  or  Doxycycline, 100 mg PO bid x 7 days    Data from Centers for Disease Control and Prevention: MMWR Morb  Mortal Wkly Rep 61(31):590-594, 2012.  bid, Twice per day; /M, intramuscularly; PO, orally.    from the ancient world and from the royal families of Europe  were thought or known to have had syphilis.’ In the early half  of the 1900s, an estimated 1 in 4 to 1 in 20 Americans were  infected.’ With the advent of antibiotics and intensive public  health efforts during and after World War II, the prevalence  of syphilis declined sharply. Rates of syphilis declined in the  1990s and reached a record low in 2000 (2.2 cases per 100,000).  However, between 2000 and 2009, the syphilis rate in the  United States increased. In 2010, the rate of syphilis infection  was 7.9 cases per 100,000 population for men and 1.1 cases  per 100,000 for women.’ The rate of primary and secondary  syphilis has risen dramatically among men. Data suggest this  increase is driven by increased transmission of syphilis among  men who have sex with men (MSM), and accounts for 67%  of these cases. The rate of primary and secondary syphilis is  now nearly six times greater in men than women, whereas  rates were almost equivalent a decade ago. Syphilis remains  a problem in certain geographic regions, particularly in the  South. Syphilis facilitates the transmission of human immu-  nodeficiency virus (HIV) infection and seems to contribute  to HIV transmission in those parts of the United States where  rates of both infections are high. From 2003 to 2009, the rates  have increased for all groups; in 2010 the reported rate among  non-Hispanic whites was 2.1 per 100,000, among Hispanics  the rate was 4.6 per 100,000, among Asian/Pacific Islanders  the rate was 1.3 per 100,000, among Native American/Alaskan  Natives the rate was 2.5 per 100,000, and among blacks the  rate was 16.8 per 100,000.   While rates in men have increased dramatically, rates in  women have decreased slightly from a recent high in 2008.  There also has been a slight decline in the rate of congenital  syphilis, currently reported as 8.7 cases of congenital syphilis  per 100,000 live births.’ During pregnancy, untreated early  syphilis results in perinatal death in as many as 40% of cases and  may lead to fetal infection in more than 70% of cases because  the spirochete that causes syphilis can cross the placental mem-  brane to infect the fetus.'°   Race, ethnicity, and gender alone do not alter STI risk but  rather act as risk markers that correlate with other more funda-  mental determinants of health status, such as poverty, access to  quality care, and health-seeking behavior. Higher infection rates  have been associated with urban areas, with the exchange of sex  for drugs, and with prison populations.*'! A growing concern    Stage I, primary syphilis—local invasion: 7reponema pallidum multiplies  in epithelium, producing granulomatous tissue reaction (chancre); lymph-  containing microorganisms drain into adjacent lymph nodes and stimulate  immune responses    spread to all major organ systems; immune system suppresses infection  and symptoms regress spontaneously   Stage III, latent syphilis—silent infection: transmission of infection pos-  sible even though there are no clinical signs of infection   Stage IV, tertiary syphilis—noninfectious disease: significant morbidity and  mortality occur; destructive skin, bone, and soft tissue lesions, or gummas,  result from severe hypersensitivity; cardiovascular complications (aneu-  rysms, heart valve insufficiency, heart failure) and neurosyphilis develop    is the incidence of co-infection with HIV among MSM. Since a  syphilitic chancre is an open wound, it greatly increases the risk  of acquiring other STIs such as HIV.   PATHOPHYSIOLOGY. Treponema pallidum, the cause of syphilis,  is an anaerobic bacterium that cannot be cultured in vitro. The  treponema (individual microorganism) resembles a corkscrew,  with regular, tight spirals and a rotary motion; it can infect any  organ or tissue. Because the bacterium is present in exudate  from moist mucosal or cutaneous lesions, the spirochete is usu-  ally transmitted to others during the first few years of infection.  Transmission generally occurs through minor abrasions during  sexual intercourse but can occur extragenitally as well. Approx-  imately 30% to 50% of partners who have sexual intercourse  with an individual in early stage syphilis develop the disease.’  Although condoms can decrease the likelihood of infection,  syphilis can be easily transmitted by contact with areas not cov-  ered by the condom.   Syphilis becomes a systemic disease shortly after infection  and can be transmitted from a pregnant woman to her fetus as  early as the ninth week of gestation. The risk of transmission  to the fetus gradually declines with each subsequent pregnancy;  therefore, a mother who has given birth to several children with  severe congenital syphilis may later have a healthy child.'* The  course of untreated syphilis consists of four stages: primary,  secondary, latent, and tertiary (Box 26-2).   Primary syphilis begins at the site of bacterial invasion  (Figure 26-5), where T. pallidum multiplies in the epithelium  and produces a granulomatous tissue reaction called a chan-  cre. Some microorganisms drain with lymph into adjacent  lymph nodes. Within the nodes and at the site of the chan-  cre, the cell-mediated and humoral immune responses are  stimulated.   Secondary syphilis is systemic. During this stage, blood-  borne bacteria spread to all major organ systems. The secondary  stage is followed by a period during which the immune system  is able to suppress the infection. Even without treatment, spon-  taneous resolution of the skin lesions occurs and the individual  enters the latent stage of infection.   Latent syphilis may be subdivided into early and late stages;  however, no specific criteria delineate one from the other.!!    * ov “7 f sti  FIGURE 26-5 Primary Syphilis. A, Penile chancre. B, Vulval chancres; the  labia and perineum show induration and edema of chancres. (A from McMillan  A, Scott GR: Sexually transmitted infections, ed 2, London, 2000, Churchill Living-  stone; B courtesy Barbara Romanowski, MD, from Morse SA et al, editors: Atlas of    Medical history and serologic studies show that syphilis is pres-  ent, but the individual has no clinical manifestations. Transmis-  sion is possible during the late and early latent stages.   Tertiary syphilis is the most severe stage, involving signifi-  cant morbidity and mortality. The pathogenesis of syphilitic  manifestations at this stage remains unclear. The destructive  skin, bone, and soft tissue lesions (called gummas) of tertiary  syphilis probably are caused by a severe hypersensitivity reac-  tion to the microorganism. Within the cardiovascular system,  infection with T. pallidum may cause aneurysms, heart valve  insufficiencies, and heart failure. Within the central nervous  system (CNS), the presence of T. pallidum in cerebrospinal  fluid may cause the manifestations of neurosyphilis, which can  occur within any stage of syphilis infection.'!   Congenital syphilis is estimated to cause a half million fetal  and neonatal deaths every year worldwide.!” The risk of acquir-  ing congenital syphilis (CS) is estimated at up to 80% in pri-  mary syphilis and declines with advancing stages of the disease.  Intrauterine infection causes fetal or perinatal death in 40% of    FIGURE 26-6 Secondary Syphilis. Secondary syphilis to the palms and plan-  tar surfaces. (From Morse S et al, editors: Atlas of sexually transmitted diseases  and AIDS, ed 4, London, 2013, Saunders.)   Primary Stage. In adults, the incubation period of syphilis  ranges from 12 days to 12 weeks after exposure and averages 3  weeks. A sore, or hard chancre, develops at the site of treponemal  entry. Typically the chancre is an eroded, painless, firm, and  indurated (hard) ulcer that may be a few millimeters to 2 cm in  diameter. Firm, enlarged, and nontender regional lymph nodes  accompany chancres. Figure 26-5 shows typical chancres of  the penis and vulva. Syphilitic chancres are not always typical,  however, and syphilis should be considered in the presence of  any open lesion. Secondary infection can cause chancres to  become necrotic and painful, and lesions on the fingers may be  dry, scaly, and papular or moist and vegetative. If left untreated,  the chancre of primary syphilis heals in 2 to 8 weeks and then  spontaneously disappears, usually without leaving a scar.   Secondary Stage. Clinical manifestations of secondary  syphilis usually develop 6 weeks after the first appearance of  the chancre but may overlap with those of the primary stage.  Typically this stage presents with variable systemic symptoms,  including low-grade fever, malaise, sore throat, hoarseness,  anorexia, generalized adenopathy, headache, joint pain, and  skin or mucous membrane lesions or rashes. Cutaneous (skin)  rashes are generally papulosquamous (raised and scaly), but any  variation or combination of macular (flat), papular (raised),  and pustular (pus-filled) lesions may be seen. Often lesions are  widespread and bilateral and appear on the palms and soles  (Figure 26-6). Some lesions become hypertrophied, flat, moist,  and wartlike or vegetative (e.g., cauliflower-like). These lesions,  called condylomata lata, are highly contagious and develop on  the perineum, vulva, and groin of women (Figure 26-7) and  around the inner thigh and the anal area in men and women.  Besides skin sores, oral mucous membrane lesions (known as  mucous patches), lymphadenopathy, pruritus, and alopecia  are common. Some individuals develop anemia, leukocytosis,  increased sedimentation rate, hepatitis, transitory proteinuria,    FIGURE 26-7 Condylomata Lata. Broad-based, moist, darkfield-positive con-  dylomata lata of the perineum. (From McMillan A, Scott GR: Sexually transmitted  infections, ed 2, London, 2000, Churchill Livingstone.)    arthritis, electrocardiographic abnormalities, and central  nervous system (CNS) symptoms. Regardless of whether  treatment is given, the cutaneous lesions generally heal in 2 to  10 weeks, but relapses may occur for several years.'!   Latent and Tertiary Stages. The asymptomatic, latent stage  of syphilis may be as short as 1 year or as long as a lifetime. After  the latent stage, tertiary syphilis may present with gummas,  cardiovascular lesions, and neurosyphilis. These manifestations  of tertiary syphilis are quite rare because antibiotics can cure  syphilis.   Congenital Syphilis. Congenital syphilis (CS) is  characterized by vasculitis, necrosis, fibrosis, and distribution  of T. pallidum throughout the tissues; it is divided into early and  late stages. Signs and symptoms of early CS manifest in the first  2 years of life, and clinical manifestations of the late stage often  occur near puberty. Affected newborns often are premature and  have growth abnormalities, hepatosplenomegaly, bone marrow  depression, destructive bone and skin lesions (see Figure 26-6),  retinal inflammation, glaucoma, blood dyscrasia, nephrotic  syndrome, and varying degrees of CNS involvement.’ Late  manifestations of classic congenital syphilis are rare and are  similar to those of tertiary syphilis in the adult.   EVALUATION AND TREATMENT. Because T. pallidum cannot be  cultured in vitro, early definitive diagnosis of primary or sec-  ondary syphilis depends on darkfield microscopy of a specimen  taken from an infected site. If the initial result is negative, the  darkfield examination is repeated on 2 successive days. In addi-  tion to darkfield microscopy, serologic testing is useful in diag-  nosis. An algorithmic approach to the diagnosis of genital ulcers  is presented in Figure 26-8.   Two categories of serologic testing exist: nontreponemal  antigen tests and treponemal antibody tests.” Nontrepone-  mal antigen tests, which demonstrate the presence of reagin (a  group of antibodies present in syphilis) in serum, provide indi-  rect evidence of infection. Examples of nontreponemal analysis  are the Venereal Disease Research Laboratory (VDRL) antigen    and the rapid plasma reagin (RPR) tests (Box 26-3). These tests  yield a positive result (presence of reagin) in more than 50%  of individuals with primary syphilis and in 100% of individu-  als in the secondary phase of disease. Because the VDRL and  RPR tests have high rates of false positives, a treponemal test is  performed if the screening test is positive. Treponemal tests are  serologic-specific tests that are used to assess antibody response  to T. pallidum and include the fluorescent treponemal antibody  absorption (FTA-ABS) test and the passive particle agglutina-  tion (TP-PA) assay.”   Numerous dermatologic disorders can mimic the skin  lesions of secondary syphilis, making differential diagnosis dif-  ficult. Again, laboratory confirmation is important; darkfield  microscopy of scrapings from condylomata lata or other skin  lesions is diagnostic for the disease. Serologic blood tests are  almost always strongly positive in this stage.   During the latent stage, individuals continue to have sero-  logic evidence of untreated disease, but confirmation through  darkfield microscopy is difficult. Examination of cerebrospinal  fluid may confirm that the treponemata are present.   Preferred treatment for all stages of syphilis is parenteral  injection of benzathine penicillin G. If the individual has mani-  fested signs of the disease for less than 1 year, a single intra-  muscular dose is appropriate. If signs have been present for  more than 1 year, the treatment is three weekly injections. This  therapy is also appropriate for pregnant women.’ There is no  evidence to date that T. pallidum has developed resistance to  penicillin. In fact, it is highly sensitive; but because of the slow  replication time, serum levels must be maintained for 7 to  14 days. Nonpregnant women who are allergic to penicillin  may receive oral doxycycline, 100 mg twice daily for 14 days.  Pregnant women with a penicillin allergy should be desensitized  and then treated with benzathine penicillin G as recommended  by the CDC because tetracycline will cause permanent, lifelong  discoloration of the forming teeth of the fetus.’ Repeated assess-  ment of VDRL or RPR titers is used to determine effectiveness  of treatment. Titers should decrease fourfold if treatment has  been successful. Sexual partners also are examined and treated,  and the use of condoms is recommended until effective treat-  ment is verified.   Newborns of mothers with documented syphilis need care-  ful evaluation after birth. Definitive diagnosis of congenital  syphilis is made by microscopic identification of T. pallidum in  material from skin lesions, nasal discharge, or placental tissue.  Nontreponemal tests are performed on the infant’s blood and  compared with maternal levels.’ In all cases of maternal syphi-  lis, the goal is to treat the mother to prevent congenital syphilis  through early maternal treatment with penicillin. If the infant  requires treatment, penicillin is the drug of choice. Such infants  are then given serologic tests for syphilis every 2 to 3 months  until the test becomes nonreactive or the titer has decreased  fourfold.’    Chancroid, or soft chancre, is an acute infectious disease that  was first differentiated from syphilis in 1852. It is caused by  Haemophilus ducreyi, a gram-negative bacillus. The incidence of    History and exam suggest herpes?  1. History of vesicles  2. History of recurrences    5 Reconsider all diagnoses, including LGV,  Chancroid chancroid, scabies, fixed drug eruption,  trauma, pyoderma. If ulcer(s) chronic, consider  biopsy for donovanosis malignancy. Consider  trial of antimicrobial therapy. Repeat serologic  tests for syphilis. If lesion(s) resolve and then  recur, reassess for herpes.    FIGURE 26-8 Genital Ulceration. Algorithm outlining an approach to the diagnosis of an individual who presents with a  genital ulceration. FTA-ABS, Fluorescent treponemal antibody absorption; HSV, herpes simplex virus; LGV lymphogranuloma  venereum; MHA-7P microhemagglutination assay—/reponema pallidum; RPR, rapid plasma reagin; VDAL, Venereal Disease  Research Laboratory. (Redrawn from Pitot P, Plummer FA. In Holmes KK et al, editors: Sexually transmitted diseases, ed 2,  New York, 1990, McGraw-Hill.)    Reasons for False-Positive, Nontreponemal Reactions  (VDRL, RPR)  Transient Reactions (<6 Months)  Technical error (low titer)  Mycoplasma pneumonia  Enterovirus infections  Infectious mononucleosis  Pregnancy    FTA-ABS, Fluorescent treponemal antibody absorption; APR, rapid  plasma reagin; VDAL, Venereal Disease Research Laboratory.    chancroid is decreasing worldwide. The incidence in the United  States is low; 24 cases were reported to the CDC in 2010.’ Spo-  radic outbreaks occur throughout the world and tend to be  associated with conditions such as poverty, prostitution, and  illicit drug use, in which individuals continue to engage in inter-  course in spite of the presence of a painful lesion.’  PATHOPHYSIOLOGY. H. ducreyi is a gram-negative bacillus with  rounded ends. Under a microscope it is commonly observed    in small chains or clusters along mucous strands. Transmission  can occur through sexual contact and autoinoculation. There  is no evidence of maternal-fetal transfer before or after deliv-  ery. Chancroid lesions usually are found throughout the genital  region, most commonly on the internal surface of the foreskin  or at its point of attachment to the penis (the frenulum) in men  and on the labia, clitoris, or fourchette in women. Initially the  papule enlarges; it then erodes into a soft, circumscribed ulcer  containing a superficial exudate. Beneath the ulcer is a lesion  characterized by edema, endothelial proliferation, and a base of  granulation tissue that is full of lymphocytes and plasma cells.  Adjacent lymph nodes are acutely inflamed and full of poly-  morphonuclear leukocytes and necrotic cells.'°   CLINICAL MANIFESTATIONS. Chancroid has an incubation period  of 3 to 10 days.'* Generally, women are asymptomatic, but  depending on the site of infection, can present with less obvi-  ous symptoms (dysuria, dyspareunia, vaginal discharge, pain  on defecation, or rectal bleeding). Constitutional symptoms  are unusual. At the site of inoculation, an initial vesicopustule  lesion forms and erodes into a soft ulcer with a necrotic base,  surrounding erythema, and a ragged, serpiginous (spreading)  border (Figure 26-9). Unilateral, painful, local lymphadenopa-  thy presents in about half of infected individuals—primarily  men. (Women tend to have multiple lesions.) Inguinal buboes  (unilocular abscess of the inguinal lymph nodes) develop 7 to  10 days after the initial chancre and fill with exudate. In 25% to  60% of cases, the buboes spontaneously rupture out onto the  skin, spreading the infection through autoinoculation.   Ulcers on the prepuce may lead to phimosis or paraphimo-  sis. Other complications of chancroid include balanitis, second-  ary infections, necrosis, and fistula formation. Recalcitrant,  serpiginous lesions may take months or years to heal.   EVALUATION AND TREATMENT. Chancroid is easily confused with  other types of genital ulcers, particularly those of syphilis, genital  herpes, and granuloma inguinale (see Figure 26-9). Unlike the  syphilitic ulcer, chancroidal ulcer is painful, tender, and nonin-  durated. Microscopic analysis of a Gram-stained smear from the  chancroid helps to identify the microorganism. Definitive diag-  nosis depends on recovery of H. ducreyi from cultured specimens;  however, the culture medium is not widely available.’ Because  10% of infected individuals are coinfected with syphilis or her-  pes simplex virus (HSV), testing includes serologic examination  for syphilis and viral culture for HSV. In addition, HIV testing is  recommended: chancroid is a cofactor for transmission of HIV.   Resistance to recommended antibiotics has emerged in iso-  lated instances worldwide. Recent treatment recommendations  include a single intramuscular injection of ceftriaxone (250 mg)  or a single dose of oral azithromycin (1 g). Effective oral  multiple-dose regimens include ciprofloxacin, 500 mg orally  twice daily for 3 days; or erythromycin, 500 mg three times  daily for 7 days. Persons infected with HIV have higher rates  of treatment failure with single-dose therapy and may require a  longer treatment regimen. As a palliative measure, buboes can  be aspirated through adjacent, healthy skin. In approximately  5% of cases, relapses at the site of original ulcer have occurred.’  Simultaneous treatment of sexual partners and use of condoms  are recommended to prevent reinfection.    FIGURE 26-9 Chancroid. A, Ulcers on the penile shaft. B, Multiple vulvar lesions. C, Differences in clinical appearance  among chancroid, syphilis, and genital herpes. (From Morse SA et al, editors: Atlas of sexually transmitted diseases and AIDS,    Granuloma inguinale (donovanosis) is a chronic, progressively  destructive bacterial infection caused by Calymmatobacterium  granulomatis, recently reclassified as Klebsiella granulomatis.'*  Although sexually transmissible, granuloma inguinale is only  mildly contagious and repeated exposure is necessary to cause  disease. Often, individuals are coinfected with syphilis.!°   Granuloma inguinale very rarely occurs in the United States.’  Yet it is more prevalent in some tropical and subtropical parts  of the world (India, New Guinea, Africa, central Australia, and  to a lesser extent the Caribbean and Brazil). Infection is usu-  ally acquired through sexual intercourse with an individual who  has active disease or asymptomatic rectal infection. As with all  genital ulcerative diseases, granuloma inguinale plays a role in  HIV transmission.”   PATHOPHYSIOLOGY. C. granulomatis is a gram-negative, non-  sporing, nonmotile, encapsulated rod that is not easily isolated  in the laboratory. After exposure the bacteria survive and mul-  tiply within vacuoles of large histiocytic cells or polymorpho-  nuclear leukocytes. The bacteria reproduce within these cells    until a vacuole may contain 20 to 30 microorganisms. These  bacteria-filled vacuoles were identified by Donovan in 1905 and  are termed Donovan bodies. The presence of Donovan bodies  in tissue smears of material from the lesions is considered the  gold standard for diagnosis of lymphogranuloma inguinale, but  this test is difficult even in well-equipped labs.!>!°   The initial lesion is an indurated subcutaneous nodule that  is often preceded and accompanied by itching. The primary  sites for development of the lesions are the distal penis in  men and the introitus in women. Single lesions often coalesce  with nearby lesions or form new lesions by autoinoculation of  nearby skin surfaces. Progression from the initial nodule to a  large, granuloma-heaped ulcer occurs slowly. Secondary infec-  tion may occur, increasing tissue damage and residual scarring.  The disease may spread to the bones, joints, and liver.   CLINICAL MANIFESTATIONS. The incubation period of granu-  loma inguinale is 8 to 80 days. The initial lesion is an indurated,  sharply defined, painless, subcutaneous nodule that is often  preceded and accompanied by itching. Nodules bleed easily  and contain abundant red, beefy-looking granulation tissue.    Progression to a large granuloma-heaped ulcer occurs slowly;  single lesions coalesce or form new lesions by autoinoculation of  nearby skin surfaces. Secondary infection may occur, increasing  tissue damage and residual scarring. Although systemic symp-  toms are rare, the disease may spread to the bones, joints, and  liver. In some cases, infection spreads to the inguinal area and  produces pseudobuboes. In these instances, the affected lymph  nodes are not directly affected, but the surrounding area may be  infected and abscessed.   EVALUATION AND TREATMENT. Although the clinical manifesta-  tions of this disease are important for diagnosis, confirmation  in the developed world involves microscopic examination in  which Donovan bodies are found in a smear or biopsy speci-  men. No FDA-cleared polymerase chain reaction (PCR) tests  for the detection of K. granulomatis DNA exist.'°   Many antibiotics have been used successfully against  K. granulomatis. Because other STIs frequently coexist, individ-  uals should be tested for chlamydia, gonorrhea, syphilis, hepa-  titis B, and HIV. Because of the persistent nature of the disease,  duration of therapy tends to be relatively long. With effective  antibiotic treatment, lesions begin to heal in 7 days, but treat-  ment is continued for at least 3 weeks and until all lesions are  completely healed. Oral therapy includes doxycycline, 100 mg  twice a day; azithromycin, 1 g once a week for 3 weeks and until  lesions are healed; ciprofloxacin, 750 mg twice a day for at least  3 weeks; erythromycin base, 500 mg four times a day for at least  3 weeks; or trimethoprim-sulfamethoxazole, 160 mg/800 mg,  double-strength tablet twice a day for at least 3 weeks.’ Relapses  can occur 6 to 18 months later despite effective initial therapy,  so prolonged follow-up is necessary, as is treatment of sexual  partners.   Bacterial vaginosis (BV)—previously called nonspecific vagi-  nitis; nonspecific vaginosis; or Haemophilus, Corynebacterium,  or Gardnerella vaginitis—is a sexually associated condition, but  is not necessarily considered an STI. The condition is associ-  ated with sexual contact including genital touching and digi-  tal penetration, oral sex, and penile penetration. Although BV  occurs mostly in sexually active women of reproductive age, it  can affect women, especially menopausal women, who are not  sexually active. BV is diagnosed by the presence of characteristic  symptoms and clinical findings. Prevalence rates vary from 17%  among women in family planning clinics to 37% among some  groups of pregnant women. ! Fifty percent of women with signs  of BV are asymptomatic.   PATHOPHYSIOLOGY. The exact etiology of BV is unknown but  is thought to be a dysbiosis of normal vaginal flora that is asso-  ciated with sexual contact. Gardnerella vaginalis and various  anaerobes, including Mycoplasma hominis, Bacteroides, and  Mobiluncus, interact and proliferate when lactobacilli (the nor-  mal predominant vaginal flora) are decreased or absent. Bac-  teria adhere to vaginal epithelium, and massive overgrowth  occurs and causes a noninflammatory response. Catabolic  enzymes degrade proteins into amines. In turn, amines elevate  the vaginal pH and produce the characteristic fishy odor associ-  ated with BV. BV has been implicated in PID, chorioamnionitis,    preterm labor, and postpartum endometritis. In addition, BV  increases a woman’s risk of contracting other STIs, such as HIV.   CLINICAL MANIFESTATIONS. BV is characterized by a thin, gray,  homogeneous, and malodorous discharge that adheres to the  vaginal walls but is often copious enough to drain into the  vulva. Occasionally the discharge is bubbly or frothy. Usu-  ally the vaginal pH is 5 to 5.5, and women often complain of  a strong, foul, fishy vaginal odor, particularly after intercourse  and during menses. Odor is caused by contact with alkaline  secretions, including semen and menstrual discharge. Male and  female partners of infected women may harbor the microor-  ganisms responsible for BV but have no signs or symptoms.   EVALUATION AND TREATMENT. Diagnosis of BV can be made  on the basis of three of four of the following criteria, known  as Amsel’s criteria: (1) presence of adherent gray vaginal dis-  charge, (2) vaginal pH greater than 4.5, (3) positive amine odor  in the presence of an alkali such as potassium hydroxide, and  (4) presence of clue cells on wet mount.!’ Clue cells are con-  sidered pathognomonic for BV. The saline wet mount also may  show absence of lactobacilli and few or no leukocytes. Clue cells  are vaginal epithelial cells that are covered with bacteria and  look as if pepper has been sprinkled on them. A Gram stain  is considered the “gold standard” for diagnosis but is difficult  to perform quickly in a clinic laboratory.'® Cultures for BV are  not recommended; however, high-risk individuals should be  screened for gonorrhea and chlamydia.   The most commonly used treatment for BV is a course of  oral metronidazole (Flagyl), 500 mg twice daily for 7 days, or  0.75% vaginal gel once daily for 5 days.’ Alternative regimens  include tinidazole 2 g once daily for 2 days or 1 g orally for  5 days. Oral clindamycin, 300 mg twice daily for 7 days; or 2%  vaginal cream, once daily for 7 days, is another choice for treat-  ment.’ Clindamycin vaginal suppositories are a 3-day treat-  ment regimen in nonpregnant women. Clindamycin cream  is oil based, and for up to 72 hours after completing therapy,  it may weaken latex condoms and diaphragms. BV treatment  in women infected with HIV is the same as that in individu-  als who are HIV-negative. In pregnancy, treatment decisions  are more complex because even though the presence of BV  is associated with preterm labor, the risk of preterm labor is  actually increased with treatment. The CDC recommends that  practitioners consider delaying treatment until 36 weeks and  provide women with informed consent about the risk of pre-  term birth with treatment.’ Treatment of sexual partners is not  recommended.”!”   Chlamydia is the common name for infections caused by  Chlamydia trachomatis (CT). C. trachomatis is responsible for  a variety of syndromes, including acute urethral syndrome,  nongonococcal urethritis (NGU), mucopurulent cervicitis,  and PID. Chlamydia, the most common reportable STI in the  United States, affects about 3 million individuals annually and  is a leading cause of preventable infertility and ectopic preg-  nancy.” In 2010, more than 1.3 million cases of chlamydial  infections were reported, which was an increase of 5% from    2 years earlier.” Rates of chlamydia are increasing in all age  groups, areas of the country, and racial/ethnic groups. This  increase probably reflects the continued expansion of screen-  ing efforts and increased use of more sensitive diagnostic tests  as well as an actual increase in incidence.* The majority of  reported cases of chlamydia are in people less than 26 years  old but the incidence in older adults is increasing.**° Up to  90% of women with CT infection are asymptomatic, which  can delay diagnosis and increase the risk of long-term health  sequelae.*   Risk groups for chlamydia include age younger than 26 (with  highest rates in people younger than 20 years old), recent new  sexual partner, and drug use or other risky behaviors.* The  incidence of CT infection in pregnancy has been estimated at  between 2% and 21%.? Like gonorrhea, Chlamydia infection  can be transmitted from mother to infant during birth and can  cause eye infections and pneumonia in affected newborns.’   PATHOPHYSIOLOGY. C. trachomatis is an obligate, gram-negative  intracellular bacterium that lacks the ability to reproduce inde-  pendently. Like viruses, Chlamydia can reproduce only within  host cells. It is differentiated from other bacteria by its unique  two-part growth cycle. The first part consists of an elemen-  tary body that is small, resilient, metabolically inert, and able  to survive extracellularly. Once this elementary body attaches  itself to a receptor host cell, it is able to enter by endocytosis.  Once inside the cell, the second part of the cycle begins and the  microorganism becomes a metabolically active parasite, repro-  ducing within the cell until the cell is destroyed and ruptures,  disseminating up to 1000 new elementary bodies. Rarely does  this cause a secondary infection. Infection with C. trachomatis  produces a mononuclear inflammatory reaction rather than a  polymorphonuclear inflammatory reaction. The mononuclear  inflammatory reaction produces permanent scarring of tissues.”   Chlamydia microorganisms are always pathogens; they are  not part of the normal flora of the urogenital tract, despite  the fact that infection is often asymptomatic. Numerous sero-  types, or strains, of C. trachomatis have been identified. Some  cause urogenital infection; some, ocular trachoma; and others,  lymphogranuloma venereum, which is discussed in the next  section.   The strains of C. trachomatis that cause urogenital infec-  tion apparently require squamous-columnar and columnar-  epithelial cells as hosts. C. trachomatis infects and disrupts  epithelial tissues but does not seem to invade or destroy deeper  tissues or organs.7!   In newborns, several sites may be inoculated with Chla-  mydia during passage through the infected maternal cervix.  These include the eye, nasopharynx, rectum, and vagina. The  infant also may aspirate infected secretions with its first breaths,  resulting in chlamydial pneumonitis and substantial newborn  morbidity.   CLINICAL MANIFESTATIONS. Asymptomatic chlamydial infec-  tion in adults is common. Urogenital infections caused by  Chlamydia closely parallel those caused by gonorrhea. Both  microorganisms infect superficial genital tract tissues, such  as mucosa of the urethra and cervix, and both can invade the  epididymides, fallopian/uterine tubes, and (rarely) the hepatic    TABLE 26-2 SIMILARITY OF CLINICAL  SYNDROMES CAUSED BY  NEISSERIA GONORRHOEAE  AND CHLAMYDIA  TRACHOMATIS    Women  Urethra  Bartholin gland  Cervix  Fallopian tube  Conjunctiva  Liver capsule  Systemic    Data from Stamm WE, Holmes KK: Chlamydia trachomatis infections  in the adult. In Holmes KK et al, editors: Sexually transmitted diseases,  ed 2, New York, 1990, McGraw-Hill.    capsule. Table 26-2 lists the pathophysiologic similarities of  chlamydial and gonococcal infections.   Chlamydial infection accounts for 50% to 60% of cases of  nongonococcal urethritis in men. Clinically, urethritis caused  by gonorrhea and chlamydia cannot be differentiated: both have  a 7- to 21-day incubation period and cause dysuria. Although  urethral discharge in men may be similar in the two infections,  chlamydial discharge tends to be more clear and gonococcal  discharge more purulent. Men might note a clear, mucous dis-  charge or mild burning with urination. Chlamydial urethritis  is generally milder than gonorrheal urethritis and more likely  to be asymptomatic. Gram-stained smears of the urethral dis-  charge show numerous polymorphonuclear leukocytes, which  indicate ongoing inflammation.   Chlamydial epididymitis can accompany chlamydial ure-  thritis in men and is characterized by fever and a unilaterally  painful, swollen scrotum. Chlamydial infection also causes  proctitis (rectal inflammation) in people who have recep-  tive anal intercourse. Chlamydial proctitis is generally mild,  although it may, like gonorrheal proctitis, cause rectal bleed-  ing, mucous discharge, and diarrhea. Reiter syndrome (urethri-  tis, conjunctivitis, arthritis, and characteristic mucocutaneous  lesions) is also associated with untreated chlamydial infections  of the urogenital tract.   Chlamydia infection is the leading cause of tubal infertility  in women. Risk factors for infertility include numbers of chla-  mydial infections and duration and severity of infection. Even    FIGURE 26-10 Chlamydial Cervicitis. Beefy red mucosa of columnar epithe-  lium of cervix. (Courtesy Paul Weisner. From Morse SA et al, editors: Atlas of sexu-  ally transmitted diseases and AIDS, ed 4, London, 2013, Saunders.)    FIGURE 26-11 Chlamydial Ophthalmia. (From McMillan A, Scott GR: Sexu-  ally transmitted infections, ed 2, London, 2000, Churchill Livingstone.)    women with asymptomatic salpingitis have a risk of subsequent  infertility. This may reflect an antigen-antibody response rather  than inflammatory damage.”   In sexually active women, C. trachomatis can cause acute ure-  thral syndrome (dysuria, urinary frequency, and presence of  sterile pus in the urine). C. trachomatis also causes asymptomatic  urethral infection in women. Chlamydial infection of Bartholin/  greater vestibular glands can cause purulent discharge and for-  mation of a Bartholin cyst. Women with chlamydial cervicitis  may be asymptomatic or may have a yellow mucopurulent dis-  charge from the cervical os and a hypertrophic, edematous, and  friable area of cervical ectopy. The woman also may report inter-  menstrual or postcoital spotting. Although ectopy alone does not  indicate a pathologic condition, an erythematous, raw, and fri-  able cervix is suggestive of chlamydial cervicitis (Figure 26-10).   The most common clinical manifestations of chlamydial  infections in the newborn are conjunctivitis and pneumonia.  Prophylactic treatment with antibiotic eye ointment at birth  does not provide complete protection against neonatal con-  junctivitis and does not protect against neonatal pneumonia.  Chlamydial conjunctivitis begins between 5 and 14 days after  delivery, when the infant’s eyes begin to water. This discharge  may become purulent, and both eyes may become red and  swollen (Figure 26-11).    Scarring of the conjunctivae may result, but this infection  does not cause blindness, as does the ophthalmia neonatorum  caused by N. gonorrhoeae. The pneumonia is mild or severe and  may accompany the conjunctivitis. Infants with chlamydial  pneumonia develop staccato coughing spells, nasal congestion,  dyspnea, and minimal fever at 3 to 11 weeks of age. Affected  infants may have persistently abnormal pulmonary function  tests into childhood.’   EVALUATION AND TREATMENT. Methods for diagnosing chlamyd-  ial infections include tissue culture, direct chlamydial enzyme  immunoassay, fluorescein-labeled monoclonal antibody tests,  and nucleic acid amplification testing (NAAT). Currently, tests  using chlamydia-specific nucleic acid sequences are the most  sensitive and cost-effective tests available.” Concurrent testing  for gonorrhea can be done using the same swab. NAAT can be  performed on samples taken from the vagina, endocervix, ure-  thra, or urine specimens. The ease of use means that screening  can be performed without a clinician if needed.’   C. trachomatis is susceptible to inexpensive, readily acces-  sible antibiotics. Treatment includes antibiotic therapy for  infected individuals and all sexual contacts; abstinence or use of  condoms during treatment and for 7 days after treatment is rec-  ommended. Azithromycin is given 1 g orally, as a single dose, or  a 7-day course of oral doxycycline, 100 mg twice daily. Single-  dose azithromycin is preferred if adherence to a multiple-dose,  multiple-day regimen may not be feasible for the individual.  Alternative regimens include a 7-day course of oral erythromy-  cin, 500 mg four times a day; or erythromycin E, 800 mg four  times daily for 7 days. Ofloxacin, 300 mg twice daily; and levo-  floxacin, 500 mg once daily for 7 days, are also effective alterna-  tives.” Azithromycin is the drug of choice in pregnancy. Because  of the asymptomatic nature of Chlamydia and the potential  sequelae of untreated infection, the CDC recommends routine  annual screening for chlamydia for all sexually active women  who are less than 26 years old. In addition, the CDC recom-  mends that all women, regardless of age, be screened if they  have a new sexual partner or their partner is not monogamous.”  Pregnant women should be routinely screened for Chlamydia at  least once during pregnancy.’    C. trachomatis (invasive serovars of strains L1, L2, or L3) can  cause a chronic STI known as lymphogranuloma venereum  (LGV), which may be confused with syphilis, herpes, or chan-  croid. LGV was previously rare in the developed world but now  is increasingly found in men who have sex with men and may  spread to other populations. The infection is acquired during  sexual intercourse or through contact with contaminated exu-  date from active lesions.’   PATHOPHYSIOLOGY. The strain of C. trachomatis that causes  LGV probably penetrates skin and mucous membranes through  tiny abrasions. LGV spreads to genital and rectal lymphatic tis-  sue, where it causes marked inflammation, necrosis, buboes,  abscesses of inguinal lymph nodes, and infection of surround-  ing tissues. Healing occurs by fibrosis after several weeks or  months and results in scarring, damaging the lymph nodes and  disrupting their function. LGV can cause permanent lymphatic    disruption and genital disfigurement. Affected nodes become  chronically swollen, hardened, and enlarged. C. trachomatis  also spreads systematically through the bloodstream and can  enter the CNS.?°   CLINICAL MANIFESTATIONS. The primary lesion of LGV appears  after an incubation period of 5 to 21 days. The lesion is most  commonly a herpetiform (multivesicular) ulcer, but it can  assume various forms. The ulcer generally is asymptomatic and  inconspicuous and heals rapidly, leaving no scar. In men, the  lesion is found most commonly on the penis or scrotum; in  women, it is found on the vaginal wall, cervix, or labia. Other  signs of primary LGV include a large, tender lymphatic nodule  or bubo, urethritis, and cervicitis.   The secondary stage of untreated LGV in men is charac-  terized by inflammation and swelling of the lymph nodes. At  first the inguinal bubo is a firm, somewhat painful mass. As  the bubo gradually enlarges, it becomes very painful, thereby  restricting mobility, and is deep blue in color. This color change  signals impending rupture of the bubo through the skin. Thick  yellow pus may drain from the site for weeks or months. Heal-  ing is slow and results in scar formation. Systemic manifesta-  tions of secondary LGV include meningitis, pneumonitis, and  other major infections. In some cases the bubo does not rupture  but rather involutes and becomes firm. Bubo formation is most  common in men and may result in a distinctive inguinal swell-  ing, known as the “groove sign.”!’ In women the path of pelvic  lymph drainage is different and the inguinal lymph nodes are  involved in less than one third of cases.   Anorectal LGV may be caused by direct inoculation during  anal intercourse, or it may be a chronic or late manifestation of  lymphatic spread from the inguinal area. Most individuals with  anorectal LGV have had receptive anal intercourse with males.  Clinical symptoms include multiple ulcerations of the rectal  mucosa, chronic inflammation, mucopurulent rectal discharge,  and rectovaginal fistulae in women. Individuals may have fever,  rectal pain, and tenesmus. Rectal strictures, perirectal abscesses,  and anal fissures may develop and are the cause of most of the  severe morbidity associated with LGV.   EVALUATION AND TREATMENT. Clinical manifestations and labo-  ratory tests are used to diagnose LGV. Tests include the LGV  complement-fixation test, isolation of the microorganism in  tissue culture, and monoclonal antibody tests. The diagnosis  usually is made serologically and by excluding other causes of  genital ulcers or inguinal lymphadenopathy. LGV is treated  with oral doxycycline, 100 mg twice daily for 21 days. A 21-day  course of erythromycin is also effective. Sexual partners also  should be treated regardless of symptoms.’    Nongonococcal urethritis (NGU), also known as nonspecific  urethritis, is a nonreportable STI. This terminology is slightly  antiquated since it was originally developed to describe all  forms of urethritis not associated with gonorrhea. At the time  this term was first used, it was difficult to test for many micro-  organisms. However, with current lab tests clinicians are better  able to diagnosis the exact cause of urethritis when test results  are available. This diagnosis remains in use in part because it    is clinically useful until definitive test results can be obtained.  In student health centers and STI clinics, more than 50% of  individuals with urethritis have NGU. Approximately 2 million  men are affected each year. NGU may be complicated by epi-  didymitis in men younger than 35 years or in men who have  proctitis or Reiter syndrome, or both.   PATHOPHYSIOLOGY. Nongonococcal urethritis is a syndrome  caused by a variety of microbes, including C. trachomatis and  Ureaplasma urealyticum. Chlamydial infections are discussed  earlier in this chapter (see p. 929).   C. trachomatis is the most common cause of NGU (15% to  55%). Trichomonas vaginalis and herpes simplex virus (HSV)  sometimes cause NGU. However, Mycoplasma genitalium is  implicated in as many as one third of the cases of NGU. Enteric  bacteria also may cause NGU, especially if the man has had  insertive anal intercourse.’   CLINICAL MANIFESTATIONS. Clinically, NGU infection caused  by CT cannot be differentiated from NGU caused by another  microbe. In both cases, men present after a 7- to 21-day incu-  bation period with complaints of dysuria and mild to moder-  ate white or clear urethral discharge. Discharge may be absent,  and urethral itching may be the only symptom. Asymptomatic  infection is common.   EVALUATION AND TREATMENT. NGU is a diagnosis of exclusion.  Urethral exudate is Gram-stained, and an endourethral swab  or a urine NAAT test may be taken for testing or culture. Urine  sediment also may be examined. All individuals who have ure-  thritis should be evaluated for the presence of gonococcal and  chlamydial infection. A treatment of a single 1-g oral dose of  azithromycin should be initiated as soon as possible after diag-  nosis. Doxycycline, 100 mg orally twice a day for 7 days, is also  effective. Single-dose regimens have the advantage of improved  compliance and of directly observed therapy.’ These regimens  have the advantage of providing coverage for a wide array of  potential causes of urethritis, including Trichomonas and  enteric bacteria. However, if improvement does not occur, the  man should be evaluated again to rule out other pathologies.’    Viral Infections  Genital Herpes  Genital herpes, which causes blisters (cold sores), is the most  common infectious cause of genital ulcerations in the United  States. In fact, genital infection with HSV is an epidemic in the  United States. Herpes simplex virus is not a reportable disease  so national statistics are not available. However, HSV infections  are estimated to affect 1 million new individuals each year.  Recurrent infections are mostly asymptomatic (50% to 70%)  and affect an estimated 50 million Americans annually.’ Eighty  percent of infected individuals do not know they have herpes.?  Genital herpes can be caused by either of the two serotypes  of HSV: HSV-1 or HSV-2. Although infections caused by the  serotypes are clinically indistinguishable, serologic studies show  that more than 80% of initial and 98% of recurrent genital HSV  infections are caused by HSV-2.   The seroprevalence of HSV-2 is estimated to range from  16% to 20% of the total adult population to 50% for subgroups,  for example, individuals treated at STI clinics and black women.    Genital herpes can be caused by either the HSV-1 or the HSV-2  subtype but HSV-2 has more virulent and frequent outbreaks.’   Herpes simplex virus infection is transmitted through geni-  tal skin or mucosal contact with a person who is shedding  the virus. Persons without symptoms probably transmit most  infections. Transmission rates are not well identified. However,  women are more susceptible than men to contracting herpes  related to prolonged semen contact with the vaginal or rectal  mucosa. It is estimated that a woman has an 80% to 90% risk  of developing genital herpes after being exposed to an infected  man. In 1992 Mertz and colleagues** studied monogamous het-  erosexual couples in which one partner had HSV-2 infection.  The noninfected partner seroconverted in 10% of couples over  a 1-year period. As many as 70% of such infections seem to be  acquired during periods of asymptomatic shedding. Uninfected  female partners were at greater risk than men, especially if they  were seronegative for HSV-1 antibodies as well. Both HSV-1  and HSV-2 can be transmitted through genital-genital contact  or orogenital contact. The likelihood of nonsexual transmis-  sion of genital herpes, through aerosolized secretions of other  fomites, is unlikely.!   Condoms do not fully protect against HSV infection because  there is still contact between genital skin not covered by the  latex. Female condoms offer a bit more protection from HSV  since they cover and protect the vulva but they do not eliminate  the risk of transmission.*° HSV infection greatly increases the  risk of HIV acquisition. People with HSV are four times more  likely to contract HIV if exposed, potentially because of small  skin splits that occur as a result of HSV infection.’ Prevention  of the spread of HIV and HSV through safer sex practices is  essential for infected people.   Neonatal infections can begin in utero or, more commonly,  during the intrapartum or postpartum period. The risk of  transmission of HSV to the neonate varies from <3% among  women with recurrence of known herpes at term who acquired  HSV during the pregnancy to up to 30% to 60% in women who  are exposed and acquire HSV near term.”° Perinatal transmis-  sion can cause extensive morbidity and mortality.   Intrauterine transmission is rare but can occur through  transplacental or ascending infection and can cause fetal mal-  formations.’’ Eighty-five percent of infections are transmitted  intrapartally. Infants are at greatest risk if the mother has a pri-  mary infection acquired near the time of delivery rather than a  recurrent infection or an infection acquired during the first half  of pregnancy. Ruptured membranes have a role in the develop-  ment of HSV. Rupture of membranes for more than 4 hours  increases the risk of the fetus for contracting HSV. Internal fetal  monitoring devices also increase the risk of vertical transmis-  sion because they break the skin.’* Infants also may be exposed  after birth through mouth-to-mouth kissing by family mem-  bers; there have been several cases of infants exposed during  ritual circumcision involving direct orogenital suction.””   PATHOPHYSIOLOGY. After initial exposure and entry of the virus  at mucocutaneous sites or abraded skin, the virus undergoes  replication locally in the dermis and epidermis. This leads to  cell destruction, transudation, and vesicle formation. The virus  spreads to contiguous cells and eventually into sensory nerves.    Eventually the virus is transported intra-axonally to the dorsal  root, where it remains in a latent stage until it becomes reac-  tivated. During the latent period the genome for the virus is  maintained in the host cell nucleus without causing the death  of the cell. After oral infection the latent virus resides in the tri-  geminal ganglion; after genital infection it resides in the dorsal  sacral nerve roots.   Latent infections can become reactivated, often during times  of physical or emotional stress, and cause a recurrent infection  with similar manifestations. Reactivation of the HSV-2 infec-  tion is twice as common as HSV-1 infections, and the likelihood  of HSV-2 recurrent infections is 8 to 10 times. Reactivation of  HSV is not well understood but may be attributable to physical,  hormonal, and immunologic stimuli. Other triggering events  may be menstruation, stress, and sun exposure.*” During reacti-  vation the viral genomes are transported through the peripheral  sensory nerves back to the dermal surface.   CLINICAL MANIFESTATIONS. Three distinct syndromes associ-  ated with HSV infection are first-episode primary genital infec-  tion, first-episode nonprimary HSV, and recurrent infections.  The manifestations of each one depend on the individual’s  immune state. First-episode primary genital infection occurs  when an individual has no antibodies to HSV-1 or HSV-2. Up  to 60% of primary infections with HSV-2 and one third of pri-  mary infections with HSV-1 are asymptomatic.°! If symptoms  occur, the individual may have small (1 to 2 mm), multiple,  vesicular lesions at the site of infection, usually on the labia  minora, fourchette, penis, or mouth (Figure 26-12). They also  may appear on the cervix, buttocks, and thighs and are often  painful and pruritic. These lesions usually last about 10 to  20 days. The lesions of HSV-1 and HSV-2 are indistinguishable  to the naked eye. These wet lesions actively shed virus for about  10 to 14 days, after which they heal by reepithelialization. Small  lesions may coalesce into larger ulcers and become secondarily  infected.   Systemic manifestations often accompany primary HSV  infection, and an individual may experience fever, malaise,  myalgias, lymphadenopathy, and urinary retention. Pharyngi-  tis, aseptic meningitis, and hepatitis also may accompany pri-  mary HSV infection. Figure 26-13 illustrates the clinical course  of primary genital HSV.   First-episode non-primary HSV occurs in individuals who  have preexisting antibodies. In some individuals the primary  infection may not have had any clinical manifestations, but the  HSV virus has become latent in the nerve root and can reac-  tivate later in life. Compared with primary infection, the first  episode of nonprimary HSV is often milder with fewer lesions  that are less painful and heal faster. Fewer systemic manifesta-  tions occur and viral shedding is of shorter duration.   Recurrent infections produce mild local symptoms. The  number of lesions is greatly reduced, and the lesions are less  painful. Lesions are often unilateral, with crusting within 4 to  5 days. Recovery and healing are usually complete within 10  days. Asymptomatic viral shedding can occur with both HSV-1  and HSV-2, but is more common with HSV-2.’   Individuals affected with HSV-2 are more likely to experi-  ence recurrent infections. Recurrent infections occur an average    FIGURE 26-12 Herpes Lesions. A, Herpetic vesicles on the penis. B, Herpetic  ulceration of the vulva. (From McMillan A, Scott GR: Sexually transmitted infec-  tions, ed 2, London, 2000, Churchill Livingstone.)    of five to eight times per year but may be as frequent as every  month for many years. Individuals may experience prodromal  symptoms (e.g., pruritus, tingling, dysesthesias) a few hours to  2 days before the eruption of lesions. Women may experience  a vaginal discharge and dysuria, and 44% of men have dysuria.  Symptomatic HSV infection of the newborn may occur any  time in the first month of life. Manifestations range from a local  infection of the eyes, skin, or mucous membranes to a severe  disseminated infection with CNS involvement. About 70% of  affected infants present with skin lesions. CNS involvement  includes seizures and is associated with a mortality of more than  50% and extensive neurologic sequelae in survivors. Eighty-five  percent of untreated infants with disseminated disease will die.”  EVALUATION AND TREATMENT. Genital HSV infection is sug-  gested if typical genital lesions are present. Diagnosis can be    FIGURE 26-13 Clinical Course of Primary Genital Herpes. (From Corey L:  Genital herpes. In Holmes KK et al, editors: Sexually transmitted diseases, ed 2,  New York, 1990, McGraw-Hill.)    made after viral culture, but these cultures have a low sensitiv-  ity especially when lesions are healing. The CDC recommends  serologic testing for diagnosis and to determine the virus sub-  type because the prognosis and the risk of transmission differ.°   There is no cure for HSV, only symptom management and  viral suppression treatments. Oral acyclovir, valacyclovir, pen-  ciclovir, and famciclovir are used for primary and periodic out-  breaks and to prevent recurrences. Acyclovir has a better safety  profile for pregnant and nursing women, but there is ongoing  research supporting the safety of valacyclovir as well.’° Intrave-  nous acyclovir is reserved for pregnant or severely immunocom-  promised individuals.*? Suppressive treatment is recommended  for individuals with more than six recurrences per year and  pregnant women at term with a history of herpes. Suppres-  sive treatment also may reduce asymptomatic viral shedding,  decreasing transmission to sexual partners and vaginally-born  infants. Although condoms offer some protection, individuals  with HSV should refrain from all genital contact when prodro-  mal or symptomatic and understand that an undetermined risk  of transmission exists even during asymptomatic periods.    Human Papillomavirus Infection  Human papillomavirus (HPV) infection is the most common  symptomatic viral STI in the United States. Although more  than 5.5 million cases are diagnosed yearly, prevalence is con-  sidered underestimated because HPV infection is often subclin-  ical. More sensitive measures of HPV indicate that 50% of all  sexually active people are infected with the virus at some point  in their lives.°   More than 120 different types of HPV have been identified.  More than 40 serotypes are unique to the stratified squamous  epitheliums of the genital area. These are divided into serotypes  that have a high risk of causing cervical cancer and low-risk sero-  types, which are associated with benign genital lesions or warts:  condylomata acuminata of the vulva, vagina, penis, and perianal  areas. High-risk types 16 and 18 are the most common, causing  up to 70% of anogenital cancers.’ Serotypes 6 and 11 are asso-  ciated with 90% of genital warts. Low-risk subtypes can coex-  ist with the high-risk types, but do not cause cancer. Although  rare, these types also may cause oral lesions. It is now known  that infection with persistent, high-risk serotypes of HPV is    necessary for the development of cervical or anal cancer (see  also Chapters 10 and 24). Fortunately, most cases of HPV are  transient and resolve on their own within 2 years.’ Persistence  of the virus, immune response, and the presence of cofactors,  including smoking and hormonal contraceptive exposure, may  play a role in the development of cervical dysplasia and cancer  following HPV exposure.** HPV infection is closely associated  with multiple sexual partners and early onset of sexual activity  and is most common in teens and young adults, 16 to 25 years  of age.   Genital warts are very contagious, with transmission rates  among individuals estimated to be between 38% and 95%. Such  a wide range is attributable to the subclinical nature of some  infections and various influencing factors that include number  of exposures, HPV type, location of lesions, and cellular immu-  nity response. Infants and children also have been identified as  being infected with HPV. Infants can be infected in utero and  by passage through an infected birth canal. HPV infection in  children has been traced to child sexual abuse; however, reports  vary in making this connection.**°°   A vaccine against HPV serotypes 6, 11, 16, and 18 is available  and has shown to be effective in prevention of HPV acquisition.  Approved for use in males and females age 11 to 26 years, the  three-dose vaccine offers protection from the most dangerous  HPV strains to young adults.°°°” Prevention of HPV acquisi-  tion in young adults is important because they are more likely  than older adults to contract STIs and the cervixes of younger  women are more vulnerable to HPV. Although there has been  widespread resistance to the vaccine, public health officials are  hopeful that vaccination in boys and girls before they become  sexually active will decrease the burden of HPV infection in the  future (see What’s New? HPV Vaccine).   The immune system is prepared to eliminate the virus  through immune response when previously vaccinated. When  an individual has not been vaccinated, he or she may or may not  be able to clear this viral infection. Although most HPV sub-  types are not associated with abnormal cellular growth, high-  risk HPV subtypes cause cellular changes that can lead to cell  proliferation, causing warts or cancer.   PATHOPHYSIOLOGY. HPV is a nonenveloped, circular, double-  stranded DNA virus, one of the papovaviruses, that belongs to  the Papovaviridae family.** Transmission of the virus is believed  to occur through sexual contact; however, the exact transmis-  sibility of the virus into the cell is unknown. The initial infec-  tion follows trauma to the epithelium that allows the virus to  reach and infect the basal cells of the epithelium, which appear  to be supportive of viral propagation. Such minor trauma may  occur during sexual intercourse. Epithelial cells that are infected  with HPV undergo transformation, proliferate, and may form  a warty growth. HPV manifestations may appear in about 2 to  3 months or may not be noticed for years.   CLINICAL MANIFESTATIONS. Condylomata acuminata are soft,  skin-colored, whitish pink to reddish brown discrete growths.  They may occur singly or in clusters and may be broad based  or pedunculated and feathery or smooth (Figure 26-14). Some-  times the warts enlarge to form cauliflower-like masses on the  male frenulum, glans, foreskin, urinary meatus, shaft, scrotum,   Gardasil is available in the United States to vaccinate against four types of   e Recommended for females and males as early as age 9 or 10 years and  up to age 26 years  Given in a series of three injections over 6 months; administration of  all three doses recommended; efficacy not established if series not  completed  Highly effective in preventing high-risk HPV types associated with  cervical cancer; proven safe and effective by the Centers for Disease  Control and Prevention (CDC), ongoing safety monitoring  Not recommended for pregnant women because safety is not yet  established  Women still need cervical cancer screening at regular intervals because  the vaccine will not protect against all HPV types  The vaccine costs approximately $125 per shot, or $375 total, and  is covered by most insurance plans, Medicaid, and the Vaccines for  Children (VFC) program if individuals meet eligibility requirements,  including age and financial need    For more information, visit the Centers for Disease Control and  Prevention’s STD website at www.cdc.gov/std. Data from Centers  for Disease Control and Prevention: HPV vaccine information, 2012,  Atlanta, 2012, U.S. Department of Health and Human Services. Avail-  able at www.cdc.gov/std/Hpv/STDFact-HPV-vaccine.htm.    \ S ea # : SS  FIGURE 26-14 Condylomata Acuminata—Penile. Asymptomatic, flesh-  colored papules are present on the shaft of the penis. (From Morse SA et al, editors:    Atlas of sexually transmitted diseases and AIDS, ed 4, London, 2013, Saunders.)    or anus and on the female labia, clitoris, perineum, vagina, or  anus (Figure 26-15). Although the lesions are usually not pain-  ful, they may cause dyspareunia (painful intercourse) and may  be friable and bleed easily. Some individuals complain of pruri-  tus. Cervical lesions are generally flattened and may not be seen  easily without colposcopy.” Urethral condylomata may occur  in men, are always preceded by skin lesions, and can become    FIGURE 26-15 Condylomata Acuminata—Vulva and Perineum. The clini-  cal diagnosis was giant condylomata of Buschke and Lowenstein. Such large and  confluent lesions should be carefully examined and multiple biopsies obtained to  rule out underlying malignancy. (From Morse SA et al, editors: Atlas of sexually  transmitted diseases and AIDS, ed 4, London, 2013, Saunders.)   Laryngeal papillomas can occur in infants whose mothers  had genital warts at the time of delivery. Clinical manifestations  of laryngeal warts include stridor, hoarseness, abnormal cry,  cough, and respiratory distress.*°   EVALUATION AND TREATMENT. Generally, diagnosis of condylo-  mata acuminata is made on the basis of clinical manifestations.  Verrucose, fleshy pink lesions caused by HPV must be differen-  tiated from condylomata lata (the whitish gray, flat lesions) of  secondary syphilis. Because HPV infection often accompanies  other STIs, gonorrhea culture, chlamydia culture, serologic test  for syphilis, and wet mount for other vaginal microorganisms  also should be performed.   Treatments for external genital warts are considered cosmetic—  not curative—and include patient-applied therapies (podofilox,  imiquimod, and sinecathechins) and provider-administered ther-  apies (cryotherapy, podophyllin resin, trichloroacetic acid [TCA],  bichloroacetic acid [BCA], and surgery). Vaginal, urethral, or anal  warts are treated in the clinic using TCA, BCA, cryotherapy, or  surgical excision. Success of treatment depends on response of the  immune system. Warts resolve in approximately one third of indi-  viduals and another one third of patients experience a decrease in  wart size.*! Surgical excision is the treatment for laryngeal warts  in infants.   HPV infection, especially with high-risk strains, is a risk fac-  tor for the development of cancer. Before the development of  adequate tests for screening for cervical cancer, it was a leading    cause of death among older women. This is caused in part by  the poor innervation of the upper pelvis, allowing cancerous  masses to grow large before causing symptoms. The develop-  ment of the Papanicolaou or “Pap” smear helped reduce deaths  from cervical cancer by 70% since the 1950s.** Ideally, infec-  tions and cellular changes can be detected early so preventive  measures and early treatment can begin.   The appropriate interval for screening for HPV and genital  cancers has been controversial. Following the development of  the Pap smear, women were advised to have yearly Pap tests  to detect cancer. Over time, however, it became apparent that  while younger women often had abnormal Pap tests, they were  often able to clear HPV infection and resolve cellular changes  without any treatment. Recent systematic reviews of the research  support that treatment of women less than 20 years of age pro-  vides little to no benefit in reducing later rates of cervical cancer  but results in pain, anxiety, and increased health care costs. In  addition, the procedures used on the cervix to treat abnormal  cells may increase the risk of the woman giving birth preterm.*°  Therefore, in 2012 the United States Preventive Services Health  Task Force, the American College of Obstetricians and Gynecol-  ogists, and many other national cancer agencies recommended  that Pap smear and HPV testing begin only after 21 years of age.   Women ages 21 to 29 should receive Pap testing alone every  3 years. Women 30 to 66 years of age may receive Pap testing  with HPV screening every 5 years** (preferred) or Pap testing  alone every 3 years.’ After 65 years of age, Pap testing and HPV  screening are no longer recommended since the risk of malig-  nancy is lw. Women who have had a hysterectomy with removal  of the uterine cervix for a noncancerous condition do not need  Pap smears or HPV testing for the rest of their life. Although the  HPV vaccine does reduce the risk for cervical cancer, it does not  change the frequency or need for Pap and HPV testing.   If the results of a Pap test are abnormal, the woman’s cer-  vix will be further evaluated using colposcopy, which involves  applying acetic acid (vinegar) and using magnification to exam-  ine the cervix for changes indicative of cancer or precancerous  lesions. HPV-infected cells will appear white when exposed to  acetic acid. In some developing countries with limited labora-  tory facilities, this test alone is used to screen for cervical cancer  (see What’s New? Cervical Cancer Screening in the Develop-  ing World, Chapter 24, p. 826). Following visual investigation  of the cervix during colposcopy, the clinician can take biopsies  of suspicious areas for further investigation. Treatment of pre-  cancerous and cancerous lesions varies and involves removal or  destruction of the affected cells through excision or ablation so  they cannot continue to divide.   Although infection with high-risk HPV strains is a risk fac-  tor for development of anogenital cancers, as well as cervical  cancer, there is no consensus on screening for rectal and anal  cancers. Anyone who engages in receptive anal intercourse is  at risk for rectal acquisition of HPV and subsequent develop-  ment of anal cancers. Women are about twice as likely as men  to develop anal cancer, but men who have sex with men also are  at risk.*° Hopefully the need for treatment of HPV-related geni-  tal conditions will decrease as more children and young adults  receive the HPV vaccine before becoming sexually active.    We } : 2 Pe  FIGURE 26-16 Molluscum Contagiosum. Flesh-colored papules of mol-  luscum may be distinguished by their umbilicated centers. The papules contain  a white cheesy substance that may be stained for the presence of viral inclusion  bodies. (From Morse SA et al, editors: Atlas of sexually transmitted diseases and  AIDS, ed 4, London, 2013, Saunders.)   Molluscum contagiosum is a benign viral infection of the skin  in children and adults. Primarily the face, hands, lower abdo-  men, and genitalia are affected; papules found on other parts of  the skin or widely distributed are not uncommon. Molluscum  contagiosum also is a symptom of immunosuppression in HIV-  positive individuals.*”   Molluscum contagiosum occurs throughout the world and  has been a common childhood disease in the developing world.  It is much less common in the United States, where the inci-  dence is highest among young adults. The childhood disease is  transmitted by skin-to-skin contact and fomites (e.g., towels,  wet surfaces and equipment) and affects the face, trunk, and  limbs. Adult disease is more commonly sexually transmitted  and affects the lower abdomen, genitalia, and perianal area.*”  Molluscum contagiosum in adults is most common in men 20  to 29 years of age and in those with multiple sexual partners.  The molluscum contagiosum virus is taken into epithelial cells  by phagocytosis and replicates within the cytoplasm, where it  produces superficial cytoplasmic inclusions (molluscum bod-  ies) and cellular hyperplasia. After an incubation period of  2 to 7 weeks, white or flesh-colored, round or oval dome-shaped  papules appear. The lesions are relatively small (2 to 5 mm) but  occasionally may coalesce to form larger lesions up to 15 mm.  The surface has a characteristic central umbilication, from which  a thick, creamy core material can be expressed (Figure 26-16).  Generally the lesions are not painful or pruritic unless second-  arily infected. The papules usually resolve in 6 to 12 months but  may last several years and spread by autoinoculation.*”   The appearance of the lesions is generally all that is needed to  make the diagnosis, although direct microscopic examination  of stained material from the core of the papule discloses mollus-  cum bodies within the swollen and rounded epithelial cells. The    lesions often heal spontaneously after several months but are  contagious until completely healed. Other effective means of  removing the lesions include curettage or application of liquid  nitrogen (cryotherapy), silver nitrate, or topical creams; how-  ever, these treatments may cause scarring. Individuals tend to  have lifetime immunity once lesions are healed.   Originally discovered in 1836, T. vaginalis was at first thought  to be a harmless commensal microorganism. T. vaginalis is now  known to be a common cause of sexually transmitted lower  genital tract infection and urethritis.   Because trichomoniasis (infection by T. vaginalis) is not  a reportable disease, its prevalence can only be estimated.  The latest estimates suggest that as many as 3 million cases of  trichomoniasis occur each year in the United States,!* and that  T. vaginalis accounts for one of four cases of infectious vagini-  tis. Although sexual transmission is clearly the most common  means of disease spread, transmission through fomites is theo-  retically possible. To cause infection, the warm, moist fomite  would have to introduce an inoculum of about 10,000 microor-  ganisms directly into the vagina.**   PATHOPHYSIOLOGY. 7. vaginalis is an anaerobic, unicellular,  flagellated, parasitic protozoan that adheres to and damages  squamous epithelial cells. Because this protozoan selectively  affects squamous epithelia, vaginal and urethral tissue is often  infected, as are periurethral (Skene) and greater vestibular (Bar-  tholin) glands. The endocervical canal is not affected because it  is lined with columnar epithelium. In men, the urethra is the  most common site of infection, although the protozoa, called  trichomonads, also can infect the epididymis and (rarely) the  prostate.   Trichomoniasis is most common in men and women of  reproductive age, and it is primarily an infection of the vagina.  T. vaginalis can induce a marked inflammatory response in the  vagina, causing a copious discharge that contains large num-  bers of polymorphonuclear neutrophils. Trichomonads adhere  to but do not invade the squamous epithelial cells.   CLINICAL MANIFESTATIONS. Manifestations of vaginal tricho-  moniasis range from none to severe, with some women report-  ing an increase in distressing symptoms immediately after  menses. Vaginal discharge and internal pruritus are the most  common complaints. Dyspareunia and dysuria are also fairly  common. Secretions are usually copious, frothy, malodorous,  and yellow-green to gray-green. The vaginal walls may appear  erythematous and sore. Small, punctate red marks, sometimes  called strawberry spots, are sometimes visible on the vaginal  walls and cervix. Vaginal pH is usually more than 4.5.? Most  men with trichomoniasis are asymptomatic but may have scant  intermittent discharge, slight pruritus, and mild dysuria.’   EVALUATION AND TREATMENT. History and symptoms are inad-  equate for diagnosis of trichomoniasis. Microscopic or labo-  ratory confirmation of the presence of the trichomonads in  vaginal secretions or urine provides a definitive diagnosis. In a  fresh wet mount preparation that has been warmed slightly, the  epithelial cells have relatively clean and sharp edges, the ratio    of polymorphonuclear leukocytes to epithelial cells exceeds 1:1,  and the trichomonads are visible. The ovoid microorganism  is slightly larger than a polymorphonuclear leukocyte and has  one rounded, flagellated end and one slightly pointed, flagel-  lated end. The flagella give the trichomonads their characteristic  twisting motility. Fresh secretions have a pH higher than 4.5  and a positive amine odor when mixed with 10% KOH (posi-  tive “whiff test”). In an acidic environment, such as urine, the  trichomonads assume a “balled-up” or spherical shape and  become less motile.   There are a variety of clinical tests for trichomoniasis,  including microscopic examination of vaginal discharge and  pH testing, as well as laboratory tests, such as an immunochro-  matographic dipstick (e.g., OSOM Trichomonas Rapid Test)  and a nucleic acid probe (e.g., Affirm VPIII).? Many tests have  a high false-negative rate that can delay adequate treatment of  infected individuals.   The treatment of choice for trichomoniasis is a single 2-gram  dose of metronidazole (Flagyl) or tinidazole. The single-dose  therapy is effective, has fewer side effects than multiple-dose  therapy, and eliminates the need for individual compliance  with longer regimens. Sexual partners, even if asymptomatic,  also should be treated for trichomoniasis. The 2-gram single  dose of metronidazole can be used to treat pregnant women.  However, lactating women should suspend breast-feeding for  12 to 24 hours after single-dose therapy.’    Scabies is a common parasitic infection that can be spread by  skin-to-skin and sexual contact. Discovered by Bonomo in  1687, it is considered to be the first human disease with a known  cause.”   Scabies has a worldwide distribution, but actual preva-  lence is unknown.!4 Outbreaks are common in childcare cen-  ters, nursing homes, and prisons and are often spread to the  larger community through familial contact. Transmission of  scabies requires prolonged close skin-to-skin contact, which  occurs within families or between sexual partners. Mites also  can be transferred through infested bedding, clothes, and other  fomites. Nonsexual transmission is common in residential  institutions and hospitals, especially when crusted scabies, a  highly contagious variant of scabies, is present.>”   PATHOPHYSIOLOGY. Only 5 to 10 mites are needed to estab-  lish infection in a previously uninfected individual. The adult  female itch mite, Sarcoptes scabiei, is 0.3 to 0.4 mm long and  has a life span of about 30 days. Once deposited on human  skin, it burrows through the horny layer of the stratum gran-  ulosum. Within hours of burrowing, the female begins lay-  ing two or three large eggs per day, each of which progresses  through larval and nymphal stages to become an adult itch  mite in about 10 days. The most common places for scabies  to burrow are on the hands (between the fingers) and on the  flexor surfaces of the wrists and the extensor surfaces of the  elbows. The groin is a common location for sexually transmit-  ted scabies. Lesions may occur on the penile shaft, glans, scro-  tum, and buttocks.°!»? Figure 26-17 shows the typical sites of  scabies burrows.    FIGURE 26-17 Distribution of Skin Lesions of Sarcoptes scabiei \nfesta-  tion. Unshaded areas are rarely affected in healthy adults. (From Morse SA et al,  editors: Atlas of sexually transmitted diseases and AIDS, ed 3, London, 2003,  Mosby.)    FIGURE 26-18 Scabies Burrow. An S-shaped burrow with a tiny vesicle at  one end. (From Marks JG, Miller JJ: Lookingbill and Marks’ principles of dermatol-  ogy, ed 4, St Louis, 2006, Saunders.)    CLINICAL MANIFESTATIONS. The classic symptom of scabies is  intense pruritus, which may increase at night. Pruritus is a result  of a reaction to the presence of the S. scabiei mite. This reac-  tion may take weeks to develop with initial infection, but only  24 hours if the person has been previously infected. The typical  burrow of the S. scabiei is a short, linear, curved, or S-shaped  line (Figure 26-18). There may be small, erythematous, excori-  ated larval papules near the burrows. Secondary infections are  common and are caused by scratching. In some individuals a    hypersensitivity reaction occurs a month or more after the infes-  tation and causes multiple, reddish brown, pruritic nodules on  the covered portions of the body—most commonly, the upper  thighs, buttocks, male genitalia, and axillary regions. These nod-  ules may persist for more than 1 year despite treatment with a  scabicide. Even after successful treatment, some individuals will  continue to experience pruritus for several weeks.°!   EVALUATION AND TREATMENT. Although the diagnosis of scabies is  often made clinically, microscopic identification of the mite or its  eggs, larvae, or feces is recommended because the symptoms of  scabies can imitate those of many other dermatologic conditions.  Superficial scrapings from a recently developed unexcoriated  papule or burrow can be observed easily under the microscope;  the addition of KOH allows easier visualization of the mite.   Preferred treatment is topical application of 5% permethrin  massaged into the skin and left for 8 to 14 hours, or ivermectin  1% dosed at 200 mcg/kg orally and repeated again in 2 weeks.  Lindane (1%) lotion or cream also is effective if applied thinly  to all areas of the body below the neck and washed thoroughly  at 8 hours.’ Close household and sexual contacts should be  treated even if they are not yet symptomatic. Permethrin has  been used safely in infants as young as 2 months and is the treat-  ment of choice for children. Pregnant women should be treated  with permethrin only if infestation with scabies can be docu-  mented. For population-based outbreaks, such as those in resi-  dential institutions, the CDC recommends treating the entire  population; ivermectin has advantages in these settings because  it is easy to administer and is not dependent on thorough topi-  cal treatment and bathing.’ To prevent reinfestation, clothing  and bed linens should be machine washed and dried at high  temperatures, or kept away from body contact for 72 hours.’    Phthirus pubis, the crab louse, is one of three species of lice that  infest humans. P. pubis is commonly transmitted sexually and  causes pediculosis pubis, or “crabs.” Adolescents and young  children are most commonly infected.   P. pubis is transmitted primarily by intimate sexual contact  or contact with infected bed linens or clothing. It is highly con-  tagious; there is a 95% chance of contracting the disease dur-  ing a single sexual encounter. Fomites are another common  method of infection because crabs can live away from the body  for several days. The transfer of lice from pubic hair is prob-  ably mechanical, assisted by scratching, fingernails, towels, and  other similar means rather than by self-propulsion. Pubic lice  usually infect the perineal and axillary hair and occasionally the  hair of the trunk, beard, scalp, and eyelashes.   PATHOPHYSIOLOGY. The crab louse has a 25- to 30-day life cycle  from egg to egg that consists of five stages: an egg (or nit) stage,  three nymphal stages, and an adult stage, all of which occur in  the host. The nits of crab lice are found “glued” to hairs; they  are oval, 0.8 by 0.3 mm, and whitish, and they hatch in 5 to  10 days (Figure 26-19). In the adult stage, pubic lice are gray-  ish, are approximately 1 mm in length, and have a segmented  body and claws particularly designed for clinging to pubic hairs.  Because lice depend on blood for nutrition, they bite into the  skin to obtain food.    Va leh :  FIGURE 26-19 Pubic Louse and Crab Louse. A, Pubic louse (Phthirus pubis)  encircling a pubic hair; the clawlike legs produce a firm grip. B, Crab louse bites  (P pubis). (From Morse SA et al, editors: At/as of sexually transmitted diseases and  AIDS, ed 4, London, 2013, Saunders.)    CLINICAL MANIFESTATIONS. Symptoms range from mild pruri-  tus to severe, intolerable itching, depending on the individual’s  sensitivity to louse bites. Allergic sensitization occurs in about  5 days, when itching, erythema, and inflammation may worsen.  Excessive scratching may lead to secondary infection.   EVALUATION AND TREATMENT. The individual usually presents  with a history of localized itching in the infected area. Because  the lice and nits are visible to the naked eye, a thorough clinical  examination permits definitive diagnosis. Pediculosis pubis is  treated with 1% permethrin cream rinse or 1% lindane lotion,  cream, or shampoo or with over-the-counter pyrethrin or  piperonyl butoxide. Infection of the eyelashes should be treated  with occlusive ophthalmic ointment for 10 days.? For nonoc-  cular infections, the pediculicide is applied to infested and adja-  cent hairy areas and removed after a specified length of time  by thorough washing. Remaining nits can be removed with a  fine-toothed comb. Permethrin is recommended for young  children and pregnant women and has less potential toxicity    with inappropriate use. On the other hand, lindane is the least  expensive and nontoxic if used correctly. Lindane should not  be used after a bath, or by persons with extensive dermatitis, by  pregnant or lactating women, or by children less than 2 years of  age.’ Sexual contacts from the past month should be treated  regardless of symptoms, and any other intimate household con-  tacts also should be examined and treated if needed. Clothing  and bed linens should be machine washed and dried at high  temperatures or kept away from body contact for 72 hours.  Treatment can be repeated in 7 days to eradicate any newly  hatched lice.   Resistance to treatment is increasing and is widespread. If  initial treatment fails, malathion 0.5% lotion is a second-line  treatment but has an unpleasant odor and must be kept on the  body for 8 to 12 hours.’    There are a variety of infectious diseases, including some enteric  bacterial and systemic viral diseases, in which the main mode of  transmission is not through sexual contact. Some, however, are  transmitted through sexual contact, more so among men who  have sex with men. Although the major mode of transmission  may be by ingestion (i.e., gastrointestinal system through hand-  to-mouth or water or food consumption), respiratory exposure  (i.e., hand to nose or eye, or inhalation), or direct contact with  blood or body fluids (i.e., sharing of needles among drug users,  blood transfusions, vertical transmission from mother to baby,  health worker exposures), infection can be transmitted through  intimate sexual contact as well. Among the most serious of these  infections is acquired immunodeficiency syndrome (AIDS)  caused by the human immunodeficiency virus (HIV) and hepa-  titis (all types). Worldwide, the main mode of transmission of  HIV and hepatitis B is through sexual intercourse (primarily het-  erosexual), but nonsexual exposure to infected blood and body  fluids contributes significantly to infection rates for both. The  epidemiology, modes of transmission, pathophysiology, clini-  cal manifestations, and evaluation and treatment of AIDS and  hepatitis are discussed in detail in Chapters 10 and 41. Less seri-  ous, but often debilitating, are gastrointestinal infections, such as  shigellosis and giardiasis, and systemic diseases, such as Epstein-  Barr virus and cytomegalovirus infections. Table 26-3 provides  a list of several gastrointestinal and systemic infections that are  known to be transmitted by intimate sexual contact, but in which  the mode of transmission is primarily through other routes.   Hepatitis is a liver infection that can be caused by six types of  viruses: hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepa-  titis E, and hepatitis G. Each virus causes a syndrome of acute,  icteric (jaundice-producing) liver inflammation. Of the three  types, the hepatitis B virus (HBV) is known to be sexually trans-  mitted. (Hepatitis A, like most other predominantly enteric  infections, may be considered an STI because of anal-oral trans-  mission.) Although hepatitis C virus (HCV) is not recognized  as an STI, the CDC has listed sexual exposure, particularly for    INFECTIONS WITH KNOWN  SEXUAL TRANSMISSIBILITY:  MAIN MODE OF TRANSMIS-  SION BY OTHER MEANS    Contact with infected feces  Hand-to-mouth  Primarily an animal pathogen  Hand-to-mouth  Contaminated drinking water  Hand-to-mouth  Contaminated drinking water  Hand-to-mouth  Hepatitis A: contact with infected  feces; hand-to-mouth  Hepatitis C: blood-borne pathogen;  direct exposure to contaminated  blood; sexual transmission very  uncommon    Reported Cases of Acute Hepatitis C by  Selected Risk Factors, United States,  1982-2001*   FIGURE 26-20 Risk for Hepatitis C Exposure. Comparison of injecting drug  use (b/ue), transfusions (purple), health-related work (green), and sexual exposure  (red). Note the rise in sexually transmitted incidences. (From Centers for Disease  Control and Prevention: Hepatitis C: What clinicians and other health professionals  need to know, 2000. Available at www.cdc.giv/ncid/diseases/hepatitis/c_training/  edu/intro).    individuals with multiple partners, as a potential HCV risk fac-  tor (Figure 26-20). Data indicate sexual transmission may occur  in approximately 1% of HCV cases; however, the virus is inef-  ficiently spread through this manner.™* Additional information  about hepatitis is found in Chapter 41.   The prevalence of HBV infection varies dramatically  worldwide. Widespread screening of pregnant women and    vaccination of all infants since 1991 has decreased the rate of  infection in the United States by more than 80% and is expected  to have lasting effects into future decades.°° In the United  States, approximately 5% to 20% of the general population  has evidence of HBV infection, and more than 1.4 million are  chronically infected.* Seropositivity generally increases with  age. Serologic tests of STI clinic patients show evidence of past  infection in 28% of individuals ages 25 years and older and 7%  in those younger than 25 years.°’ Those at risk for HBV infec-  tion in the United States are infants born to hepatitis-infected  mothers, healthcare workers, individuals who have sexual con-  tact with HBV-infected persons, and immigrants from areas of  high HBV prevalence. However, larger portions of the popula-  tion are at risk in developing countries. For example, 60% to  80% of the population in Southeast Asia and Africa may harbor  serologic evidence of past or current infection.   Transmission of HBV can occur through needle puncture,  blood transfusion, cuts or abrasions in the skin, and absorption  by mucosal surfaces. Direct contact with infected body fluids,  such as tears, cerebrospinal fluid, synovial fluid, gastric juices,  pleural fluid, semen, and urine, may pass the infection. The  hepatitis B virus can survive dry and outside the body for up  to 1 week, making it easily infectious on fomites, such as medi-  cal equipment. Only very high temperatures or bleach can kill  the hepatitis virus.’ Perinatal transmission of HBV is relatively  common. Neonates whose mothers are infectious have a 90%  chance of becoming chronically infected with HBV during labor  or delivery if they do not receive treatment.°° Infants of infected  mothers should receive HBV vaccine and immunoglobulin  against hepatitis within 12 hours of birth to reduce risk. The  vaccine and immunoglobulin combination successfully pre-  vents chronic carrier status 85% of the time.°? Although HBV  is in many maternal body fluids, it is not found in breast milk  and breast-feeding is still encouraged for mothers with HBV.°°   Hepatitis delta agent is a defective virus that is similar to  HBV antigen but cannot cause hepatitis B by itself, requiring  the presence of HBV to cause hepatitis. Hepatitis delta infection  is rare in the United States, but cases have been documented  in intravenous drug users and their sexual contacts and in    recipients of contaminated blood. It is most commonly found  in men who have sex with men, persons requiring kidney dialy-  sis, and healthcare workers.   PATHOPHYSIOLOGY. After exposure, HBV passes through the  bloodstream to the liver, where it infects liver cells and multi-  plies. The infection is usually self-limiting, with most patients  mounting an effective immune response. Approximately 6% to  10% of infected adults cannot eradicate the virus and become  chronic carriers of HBV. There is an inverse relationship  between age and chronic carrier status, with younger individu-  als at greater risk for infection.’   CLINICAL MANIFESTATIONS. Most HBV infections are clinically  asymptomatic and result in permanent immunity. Symptoms  of hepatitis usually develop only after an HBV antigen has been  circulating in the blood for 3 to 6 weeks. Approximately 15%  to 20% of individuals develop a prodromal syndrome charac-  terized by an erythematous rash, urticaria, polyarthralgias, and  arthritis. Symptoms of infection also may include lassitude,  anorexia, nausea, vomiting, headache, fever, dark urine, jaun-  dice, and moderate liver enlargement with tenderness. Long-  term sequelae include chronic persistent and chronic active  hepatitis, cirrhosis, hepatocellular carcinoma, hepatic failure,  and death. In neonates who contract HBV, the disease may be  manifested in many ways from mild illness to a severe infection  with liver damage.   EVALUATION AND TREATMENT. HBV infection is clinically indis-  tinguishable from other types of hepatitis. Diagnosis can be  made only through serologic testing. No specific therapy exists  for HBV infection in adults. Treatment consists of supportive  care and relief of symptoms. Since 1991, the CDC has promoted  an aggressive vaccination campaign and recommends vaccina-  tion for all infants, children, and adolescents and a diversity of  high-risk adults. The three-injection vaccine series is begun at  birth for all infants.   Epidemiology, modes of transmission, pathophysiology, clini-  cal manifestations, and evaluation and treatment of AIDS are  discussed in detail in Chapter 10.   1. Gonorrhea is a sexually transmitted communicable disease  that can be local or systemic. Complications include PID,  sterility, and disseminated infection.   2. Gonorrhea passed to the fetus from the mother typically  manifests as an eye infection and develops 1 to 12 days after  birth. Usually ophthalmic antibiotic prophylaxis is not suf-  ficient to prevent infection.   3. Gonorrhea is rapidly becoming resistant to available antibi-  otics. Multidrug therapy is now recommended to decrease  drug resistance.   4. Syphilis is an STI that becomes systemic shortly after infec-  tion. The four stages of the disease are: (a) primary syphilis    with a chancre at the site of infection; (b) secondary syphilis  with systemic spread to all body systems; (c) latent syphilis  with minimal symptoms or the development of skin lesions;  and (d) tertiary syphilis, the most severe stage, with destruc-  tion of bone, skin, and soft and neurologic tissues.   5. Congenital syphilis contributes to prematurity of the new-  born with bone marrow depression, CNS involvement,  renal failure, and intrauterine growth retardation.   6. Syphilis is diagnosed by darkfield microscopy and serologic  testing and is treated with injectable penicillin. Sexual part-  ners also are treated.   7. With chancroid infection, women are generally asympto-  matic and men may develop inflamed, painful genital ulcers    and inguinal buboes. Incubation period is 1 to 14 days.  Single-dose therapy with injectable ceftriaxone or oral  azithromycin for both partners is recommended. Persons  with HIV may require a longer treatment regimen.    States. The bacteria are gram negative and survive within  macrophages. Localized nodules coalesce to form granulo-  mas and ulcers on the penis in men and labia in women.  Antibiotics provide effective treatment. Although rare and  mildly infectious, granuloma inguinale is a chronic, pro-  gressively destructive bacterial infection.    caused by an overgrowth of anaerobic bacteria that pro-  duce aromatic amines and raise the pH of the vagina, pro-  moting further bacterial growth (without an inflammatory  response) and a fishy odor. “Clue cells” are found on the  wet mount. Metronidazole (Flagyl) provides effective treat-  ment. BV has been associated with PID, chorioamnionitis,  preterm labor, and postpartum endometritis. Treatment of  male sexual partners is not recommended.   Chlamydia is the most common bacterial STI in the United  States and a leading preventable cause of infertility and  ectopic pregnancy. The causative organism, C. trachoma-  tis, localizes to epithelial tissue and can spread throughout  the urogenital tract or pass from infected mother to the  eyes and respiratory tract of newborn infants during birth.  C. trachomatis is susceptible to inexpensive, readily acces-  sible antibiotics. Single-dose azithromycin is the drug of  choice. Antibiotic therapy for infected individuals and all  sexual contacts is recommended. Because of the asymp-  tomatic nature of chlamydia and the potential sequelae of  untreated infection, extensive and widespread screening is  recommended by the CDC.   Lymphogranuloma venereum is a chronic STI uncommon  in the United States. The lesion begins as a skin infection  and spreads to the lymph tissue, causing inflammation,  necrosis, buboes, and abscesses of the inguinal lymph  nodes. Primary lesions appear on the penis and scrotum in  men and on the cervix, vaginal wall, and labia in women.  Secondary lesions involve inflammation and swelling of  the lymph nodes with formation of large blue buboes that  rupture and form draining ulcerative lesions. A 21-day  or longer course of oral doxycycline or erythromycin is  needed for treatment. Treatment of sexual partners is  recommended.   Genital herpes is the most common genital ulceration in  the United States and is caused by either HSV-1 or HSV-2.  Lesions initially appear as groups of vesicles that progress  to ulceration with pain, lymphadenopathy, and fever. Her-  pes simplex virus passes from mother to fetus; thus, women  with active lesions should give birth by cesarean section to  avoid vertical transmission. Acyclovir reduces symptoms  but does not cure the disease.   Herpes simplex virus (HSV) infection is lifelong and can  result in an initial outbreak and subsequent outbreaks.    Individuals are contagious during outbreaks and episodes  of asymptomatic viral shedding. Recurrent infections are  most often attributable to HSV-2 and are generally milder  and of shorter duration.   Human papillomavirus (HPV) is associated with the  development of cervical dysplasia and cancer as well as  condylomata acuminata. The high-risk strains of HPV  (HR-HPV) that are precursors to the development of cer-  vical cancer do not cause genital warts. Testing is available  to detect HR-HPV and a vaccine is now available for HPV  types 16 and 18, which have the highest risk for cervical  cancer.   Condylomata acuminata (genital warts) are sexually trans-  mitted and highly contagious. The velvety cauliflower-like  lesions occur in the genital and anal areas, vagina, and cer-  vix and are painless. They can be transmitted to the infant  at birth.   Molluscum contagiosum is a benign viral infection of the  skin. It is transmitted by skin-to-skin contact in children  and adults. In adults, it tends to occur on the genitalia and  to be transmitted by sexual contact.   Trichomoniasis (T. vaginalis) causes vaginitis in women,  and urethritis in men. Both partners usually are infected.  Women usually have a copious, malodorous, gray-green  discharge with pruritus. Men usually are asymptomatic.  Metronidazole is the treatment for both partners.   Scabies is a common parasitic infection that can be spread  by skin-to-skin contact and sexual contact. The scabies mite  burrows through the skin, depositing two or three large eggs  per day. Intense pruritus, especially at night, is the most  pronounced clinical manifestation. Treatment consists of  topical application of a pediculicide.   Pediculosis pubis (crabs) is commonly transmitted sexually  and is caused by the crab louse, P. pubis. The lice bite into  the skin for nutrition. Symptoms include mild and severe  pruritus. Topical application of prescription or over-the-  counter pediculicides is effective treatment.    Systemic diseases known to be sexually transmitted include  AIDS (see Chapter 9), cytomegalovirus infection, and  Epstein-Barr virus.    ture, blood transfusion, cuts in the skin, and contact with  infected body fluids.    chronic liver disease and hepatocellular cancer. Immunization  against hepatitis B is the most effective means of preventing  transmission. Universal vaccination of infants and children is  recommended, as well as vaccination of high-risk adults.    . The risk of perinatal transmission of HBV is high for infants   Chlamydia, 929  Condylomata acuminata, 935  Condylomata lata, 924  Congenital syphilis (CS), 925  Disseminated gonococcal infection (DGI), 922  Donovan body, 928    National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Preven-  tion: Annual report 2008, Atlanta, 2008, U.S. Department of Health and  Human Services. Available at www.cdc.gov/std/stats.   Centers for Disease Control and Prevention: Sexually transmitted disease  surveillance, 2010, Atlanta, 2011, U.S. Department of Health and Human  Services. Available at www.cdc.gov/std/stats.   Centers for Disease Control and Prevention: Update to CDC’s sexually  transmitted diseases treatment guidelines, 2012: oral cephalosporins no  longer recommended treatment for gonococcal infections, MMWR Morb  Mortal Wkly Rep 61(31):590-594, 2012.   Zenilman JM: Gonorrhea and chlamydia. In Zenilman JM, Shahmanesh  M, editors: Sexually transmitted diseases, Sudbury, MA, 2012, Jones &  Bartlett Learning, pp 31-42.   Yudin MH, Ross JDC: Pelvic inflammatory disease. In Zenilman JM,  Shahmanesh M, editors: Sexually transmitted diseases, Sudbury, MA,  2012, Jones & Bartlett Learning, pp 67—76.   Krieger JN: Sexually transmitted diseases in men. In Tanagho EA, McAninch  JW, editors: Smith’s general urology, ed 17, New York, 2007, McGraw-Hill.  Zenilman JM: Gonorrhea: clinical and public health issues, Hosp Pract  28(2a):29, 1993.   Workowski KA, Berman S: Centers for Disease Control and Preven-  tion: Sexually transmitted diseases treatment guidelines, 2010, MMWR  Recomm Rep 59(RR-12):1-110, 2010.   World Health Organization (WHO): The global elimination of congenital  syphilis: rationale and strategy for action, Geneva, 2007, Author.   Fenton KA, French P: Infectious syphilis. In Zenilman JM, Shahmanesh  M, editors: Sexually transmitted infections, Sudbury, MA, 2012, Jones &  Bartlett Learning.   World Health Organization: Division of Reproductive Health and  Research: Investment case for eliminating mother-to-child transmission of  syphilis: promoting better maternal and child health and stronger health  systems, Geneva, 2012, Author.   M, editors: Sexually transmitted infections, Sudbury, MA, 2012, Jones &  Bartlett Learning.   Wooldridge WE: Syphilis: a new visit from an old enemy, Postgrad Med  89(1):193-196, 199-202, 1991.   Para MF, Baird IM: Genital ulcer syndromes. In Spagna VA, Prior RB,  editors: Sexually transmitted diseases: a clinical syndrome approach,   Committee on Infectious Disease: Red Book 2000, Elk Grove Village, IL,  2000, American Academy of Pediatrics.   Hart G: Donovanosis. In Holmes KK et al: Sexually transmitted diseases,  ed 4, New York, 2008, McGraw-Hill.   Centers for Disease Control and Prevention: Sexually transmitted disease  surveillance, 2007Atlanta, GA, December 2008, U.S. Department of  Health and Human Services. Available at www.cdc.gov/std/stats.  Richens J: The diagnosis of treatment of donovanosis (granuloma ingui-  nale), Genitourin Med 67(6):441—452, 1991.   Centers for Disease Control and Prevention (CDC): NCHHSTP atlas  (online interactive database), 2012. Available at http://gis.cdc.gov/GRASP/  NCHHSTPAtlas/main.html. Accessed August 31, 2012.    Hepatitis B virus (HBV), 940  Hepatitis delta agent, 941  Human papillomavirus (HPV), 934    Pediculosis pubis, 939  Perihepatitis, 922  Primary syphilis, 923  Pseudobuboes, 929  Scabies, 938    Amsel R et al: Nonspecific vaginitis. Diagnostic criteria and microbial and  epidemiologic associations, Am J Med 74(1):14-22, 1983.   Kellogg ND et al: Comparison of nucleic acid amplification tests and cul-  ture techniques in the detection of Neisseria gonorrhoeae and Chlamydia  trachomatis in victims of suspected child sexual abuse, J Pediatr Adolesc  Gynecol 17(5):331-339, 2004.   Schachter J, Barnes R: Infections caused by Chlamydia trachomatis. In  Morse SA, Moreland AA, Holmes KK, editors: Atlas of sexually transmit-  ted diseases and AIDS, ed 2, London, 1996, Mosby-Wolfe.   Mertz GJ et al: Risk factors for the sexual transmission of genital herpes,  Ann Intern Med 116(3):197, 1992.   Cates W, Harwood B: Vaginal barriers and spermicides. In Hatcher RA  et al: Contraceptive technology, Atlanta, 2011, Ardent, pp 391-408.  American Academy of Obstetricians & Gynecologists: Management of  herpes in pregnancy, Obstet Gynecol 109(6):1489-1498, 2007.   Knezevic A et al: Disseminated neonatal herpes caused by herpes simplex  virus types 1 and 2, Emerg Infect Dis 13(2):302-304, 2007.   Chambers HF: Infectious diseases: bacterial and chlamydial. In McTier-  ney LM, McPhee SJ, Papadakis MA, editors: Current medical diagnosis  and treatment, ed 35, Norwalk, CT, 1996, Appleton & Lange.   pes simplex virus infection following Jewish ritual circumcisions that  included direct orogenital suction—New York City, 2000-2011, MMWR  Morb Mortal Wkly Rep 61(22):405—409, 2012.   Hillier SL et al: Association between bacterial vaginosis and preterm  delivery of a low-birth-weight infant, N Engl J Med 333(26):1737-1742,  1995.   Perine PI, Osoba AO: Lymphogranuloma venereum. In Holmes KK et al:  Sexually transmitted diseases, ed 2, New York, 1990, McGraw-Hill.  Landenberg AG et al: A prospective study of new infections with herpes  simplex virus type 1 and type 2. Chiron HSV Vaccine Study Group,   Stephenson J: Genital herpes vaccine shows limited promise, JAMA  284(15):1913-1914, 2000.   Centers for Disease Control and Prevention: Sexually transmitted disease  surveillance 2007 supplement, syphilis surveillance report, Atlanta, GA, 2009,  U.S. Department of Health and Human Services, Centers for Disease  Control and Prevention, March 2009. Available at www.cdc.gov/std/stats.  Rose FB, Camp CJ: Genital herpes: how to relieve patients’ physical and  psychological symptoms, Postgrad Med 84(3):81—86, 1988.   Giuliano AR et al: Efficacy of quadrivalent HPV vaccine against HPV  infection and disease in males, N Engl J Med 364(5):401-411, 2011.  Mufioz N et al: Safety, immunogenicity, and efficacy of quadrivalent  human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in  women aged 24-45 years: a randomised, double-blind trial, Lancet  373(9679):1949-1957, 2009.   Wright TC et al: Interim guidance for the use of human papillomavirus  DNA testing as an adjunct to cervical cytology for screening, Obstet Gyne-  col 103(2):304—309, 2004.   Derksen DJ: Children with condylomata acuminata, J Fam Pract  34(4):419-423, 1992.   Alary M et al: Strategy for screening pregnant women for chlamydial  infection in a low-prevalence area, Obstet Gynecol 82(3):399, 1993.  Brandt AM: No magic bullet: a social history of venereal disease in the  United States since 1880, expanded edition, New York, 1987, Oxford  University Press.   M, editors: Sexually transmitted infections, Sudbury, MA, 2012, Jones &  Bartlett Learning.   Vesco KK et al: Screening for cervical cancer: a systematic evidence review  for the U.S. Preventive Services Task Force [Internet], Rockville, MD, 2011,  Agency for Healthcare Research & Quality.   U.S. Preventive Services Task Force: Screening for cervical cancer: clinical  summary of U.S. Preventive Task Force recommendation, March 2012.  Available at www.uspreventiveservicestaskforce.org/uspstfl 1/cervcancer/  cervcancersum.htm. Accessed January 10, 2013.   Saslow D et al: American Cancer Society, American Society for Colpos-  copy and Cervical Pathology, and American Society for Clinical Pathol-  ogy screening guidelines for the prevention and early detection of cervical  cancer, Am J Clin Pathol 137(4):516—542, 2012.   Centers for Disease Control and Prevention: Human papillomavirus—  associated cancers—United States, 2004-2008, MMWR Morb Mortal  Wkly Rep 61(15):258-261, 2012.   Centers for Disease Control and Prevention, National Center for Emerg-  ing and Zoonotic Infectious Diseases, and Division of High-Consequence  Pathogens and Pathology: Clinical information: molluscum contagiosum,  2011. Available at www.cdc.gov/ncidod/dvrd/molluscum/clinical_  overview.htm. Accessed September 12, 2012.   Harper DM et al: Efficacy of a bivalent L1 virus-like particle vaccine in  prevention of infection with human papillomavirus types 16 and 18 in  young women: a randomised controlled trial, Lancet 364(9447):  1757-1765, 2004.   In Spagna VA, Prior RB, editors: Sexually transmitted diseases: a clinical  syndrome approach, New York, 1985, Marcel Dekker.   Bouvresse S, Chosidow O: Scabies in healthcare settings, Curr Opin Infect  Dis 23(2):111-118, 2010.   Chosidow O: Clinical practice. Scabies, N Engl J Med 354(16):1718-1727,  2006.   Rein MR, Holmes KK: Nonspecific vaginitis, vulvovaginal candidiasis,  and trichomoniasis: clinical features, diagnosis, and management. In  Remington J, Schwartz MN, editors: Current clinical topics in infectious  diseases, New York, 1983, McGraw-Hill.   Berger TG: Skin diseases of the external genitalia. In Tanagho EA,  McAninch JW, editors: Smith’s general urology, Norwalk, CT, 1995,  Appleton & Lange.   Emmert DH, Kirchner JT: Sexually transmitted diseases in women:  gonorrhea and syphilis, Postgrad Med 107(2):181-184, 189-190, 193-197,  2000.   Mast EE et al: A comprehensive immunization strategy to eliminate  transmission of hepatitis B virus infection in the United States: recom-  mendations of the Advisory Committee on Immunization Practices  (ACIP) part 1: immunization of infants, children, and adolescents,  MMWR Recomm Rep 54(RR-16):1—31, 2005.   Shi Z et al: Breastfeeding of newborns by mothers carrying hepatitis B  virus: a meta-analysis and systematic review, Arch Pediatr Adoles Med  165(9):837-846, 2011.    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Components of the Hematologic System, 945  Composition of the Blood, 945  Lymphoid Organs, 951   Development of Blood Cells, 954  Hematopoiesis, 954  Development of Erythrocytes, 959  Development of Leukocytes, 964  Development of Platelets, 965   Mechanisms of Hemostasis, 965  Function of Blood Vessels, 965  Function of Platelets, 967    All the body’s tissues and organs require oxygen and nutrients  to survive. These essential needs are provided by the blood that  flows through miles of vessels throughout the human body. The  red blood cells provide the oxygen and remove carbon dioxide,  and the fluid portion of the blood carries the nutrients and ions  for proper acid-base balance. The blood also cleans discarded  waste from the tissues; transports hormones; conveys cells (white  blood cells), platelets, and other ingredients that are necessary  for protecting the entire body from injury and infection and  initiating healing; and provides thermal regulation to maintain  organs and tissues within an acceptable range of temperatures.   Blood consists of various cells that circulate in the cardiovas-  cular system suspended in a solution of protein and inorganic  materials (plasma), which is approximately 92% water and 8%    Function of Clotting Factors, 969  Control of Hemostatic Mechanisms, 970  Lysis of Blood Clots, 971   Tests of Bone Marrow Function, 973  Blood Tests, 975  PEDIATRICS and the Hematologic System, 975  AGING and the Hematologic System, 975    dissolved substances (solutes) (Figure 27-1). The blood volume  amounts to about 6 quarts (5.5 L) in adults. The continuous  movement of blood guarantees that critical components are  available to all parts of the body to carry out their chief func-  tions: (1) delivery of substances needed for cellular metabolism  in the tissues, (2) removal of the wastes of cellular metabolism,  (3) defense against invading microorganisms and injury, and  (4) maintenance of acid-base balance.    In adults, plasma accounts for 50% to 55% of blood volume.  Plasma is a complex aqueous liquid containing a variety of  organic and inorganic elements (Table 27-1). The concentra-  tion of these elements varies depending on diet, metabolic  demand, hormones, and vitamins. Plasma differs from serum  in that serum is plasma that has been allowed to clot in the lab-  oratory in order to remove fibrinogen and other clotting factors  that may interfere with some diagnostic tests.    FIGURE 27-1 Composition of Whole Blood. Approximate values for the components of blood in a normal adult. (From  Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    The plasma contains a large number of proteins (plasma  proteins) that constitute about 7% of the total plasma weight.  These vary in structure and function and can be classified into  two major groups, albumin and globulins. Most plasma pro-  teins are produced by the liver. The major exception is antibod-  ies (immunoglobulins), which are produced by plasma cells in  the lymph nodes and other lymphoid tissues (see Chapter 8).   Albumin (about 60% of total plasma protein at a concen-  tration of about 4 g/dl) serves as a carrier molecule for normal  components of blood as well as drugs that have low solubility  in water (e.g., free fatty acids, lipid-soluble hormones, thyroid  hormones, bile salts). Its most essential role is regulation of  the passage of water and solutes through the capillaries. Albu-  min molecules are large and do not diffuse freely through the  vascular endothelium, and thus they maintain the critical col-  loidal osmotic pressure (or oncotic pressure) that regulates  the passage of water and solutes into the surrounding tissues  (see Chapters 1 and 3). Water and solute particles tend to dif-  fuse out of the arterial portions of the capillaries because the  blood pressure is greater in arterial than in venous blood ves-  sels (see Chapter 3). Water and solutes move from tissue cells  into the venous portions of the capillaries where the pressures  are reversed, oncotic pressure being greater than intravascu-  lar pressure or hydrostatic pressure. In the case of decreased  production (e.g., cirrhosis, other diffuse liver diseases, protein    malnutrition) or excessive loss of albumin (e.g., certain kidney  diseases, extensive burns), the reduced oncotic pressure leads  to excessive movement of fluid and solutes into the tissue and  decreased blood volume.   The remaining plasma proteins, or globulins, are often clas-  sified by their properties in an electric field (serum electropho-  resis). Under the normal conditions used to perform serum  electrophoresis, albumin is the most rapidly moving protein.  The globulins are classified by their movement relative to albu-  min: alpha (a) globulins (those moving most closely to albu-  min), beta (8) globulins, and gamma (y) globulins (those with  the least movement). Depending on the electrophoretic proce-  dure the alpha and beta globulins may be subdivided into sub-  regions (@;-, Q-, B,-, or B-globulins). Fibrinogen is a major  plasma protein (about 4% of total plasma protein) that would  move between the beta and gamma regions but is removed  during the formation of serum. The gamma-globulin region  consists primarily of immunoglobulin G (IgG) (see Chapter 8).   Plasma proteins can also be classified into groups by func-  tion: clotting, defense, transport, or regulation. The clotting  factors promote coagulation and stop bleeding from damaged  blood vessels. Fibrinogen is the most plentiful of the clotting fac-  tors and is the precursor of the fibrin clot. Proteins involved in  defense, or protection, against infection include antibodies and  complement proteins (see Chapters 7 and 8). Transport proteins    Water 93% of plasma weight  Electrolytes Total <1% of plasma weight  Nat 142 mEq/L (142 mM)  Kt 4 mEq/L (4 mM)  Ca2+ 5 mEq/L (2.5 mM)  Mg?+ 3 mEq/L (1.5 mM)  Cl 103 mEq/L (103 mM)  HCO; 27 mEq/L (27 mM)  Phosphate (mostly) 2 mEq/L (1 mM)  Sulfate 1 mEq/L (0.5 mM)  Proteins 7.3 g/dl (2.5 mM)  Albumin 45 g/dl  Globulins 2.5 g/dl  Fibrinogen 0.3 g/dl  Transferrin 250 mg/dl  Ferritin 15-300 meg/L  Gases  CO, content 22-32 mmol/L plasma  0, Pao, 80 torr or greater (arterial);  Pvo, 30-40 torr (venous)  No 0.9 ml/dl  Nutrients  Glucose and other carbohydrates  Total amino acids  Total lipids  Cholesterol   150-250 mg/dl (4-7 mM)  Individual vitamins 0.0001-2.5 mg/dl  Individual trace elements 0.001-0.3 mg/dl  Iron 50-150 mcg/dl   Waste products  Urea (blood urea nitrogen [BUN)])  Creatinine (from creatine)  Uric acid (from nucleic acids)  Bilirubin (from heme)    Provide colloid osmotic pressure of plasma; act as buffers;  bind other plasma constituents (lipids, hormones, vitamins,  minerals, etc.); clotting factors; enzymes; enzyme precursors;  antibodies (immunoglobulins); hormones; transporters    Byproduct of oxygenation, most CO, content is from HCO3 and  acts as a buffer  Oxygenation    Byproduct of protein catabolism  Provide nutrition and substances for tissue repair   End product from energy metabolism  End product from protein metabolism  End product of red blood cell destruction  Functions specific to target tissue    Data from Vander AJ, Sherman JH, Luciano DS: Human physiology: the mechanisms of body function, ed 8, New York, 2001, McGraw-Hill.    specifically bind and carry a variety of inorganic and organic mol-  ecules, including iron (transferrin), copper (ceruloplasmin), ste-  roid hormones, and vitamins (e.g., retinol-binding protein). The  plasma lipids, triglycerides, phospholipids, cholesterol, and fatty  acids are carried through the blood as complexes with plasma  proteins; they are known as lipoproteins (see Chapters 1 and  32). Regulatory proteins include a variety of enzymatic inhibi-  tors (e.g., ,-antitrypsin) that protect the tissues from damage,  precursor molecules (e.g., kininogen) that are converted into  active biologic molecules when needed, and protein hormones  (e.g., cytokines) that communicate between cells.   Plasma also contains several charged inorganic ions (electro-  lytes) that regulate cell function, osmotic pressure, and blood  pH. (Electrolytes are described in Chapters 1 and 3.)    The cellular elements of the blood are broadly classified as  red blood cells (RBCs) (i.e., erythrocytes), white blood cells    (WBCs) (i.e., leukocytes), and platelets (thrombocytes). The  components of the blood are listed in Table 27-2.   Erythrocytes. In 1628 Robert Burton described blood as a  “hot, temperate red humor whose office is to nourish the whole  body, to give it strength and color being dispersed by the veins  through every part of it.”' A few years later, with the invention  of the microscope, researchers learned that erythrocytes give  blood its red color.   Erythrocytes (red blood cells [RBCs]) are the most abun-  dant cells of the blood, occupying approximately 48% of the  blood volume in men and about 42% in women. Erythro-  cytes are primarily responsible for tissue oxygenation. The  erythrocyte contains hemoglobin, which carries the gases, and  electrolytes, which regulate diffusion through a cell’s plasma  membrane. The mature erythrocyte lacks a nucleus and cyto-  plasmic organelles (e.g., mitochondria), so it cannot synthe-  size protein or carry out oxidative reactions. Because it cannot  undergo mitotic division, the erythrocyte has a limited life span    granulocyte with granules  stainable by eosin dyes  Segmented polymorphonuclear  granulocyte with granules  stainable by neutral staining  Lobate nuclear granulocyte with  granules stainable by basic dyes    FIGURE 27-2 Blood Cells. Leukocytes are spherical and have irregular sur-  faces with numerous extending pili (appear as yellow). Erythrocytes are flattened  spheres with a depressed center. Activated platelets are green. (Copyright Dennis  Kunkel Microscopy, Inc.)    (approximately 100 to 120 days), ages, and is removed from the  circulation to be replaced by new erythrocytes.   The erythrocyte’s size and shape are ideally suited to its func-  tion as a gas carrier. An RBC is a small disk with two unique prop-  erties: (1) a biconcave shape and (2) the capacity to be reversibly  deformed (Figure 27-2 and Figure 27-6). The flattened, biconcave  shape provides a surface area/volume ratio that is optimal for gas  diffusion into and out of the cell and for deformity.” During its life  span, the erythrocyte, which is 6 to 8 um in diameter, repeatedly   Phagocytosis, particularly during early 4 days  phase of inflammation, bacterial  killing   Similar to mast cell, secretes  inflammatory mediators (e.g.,  histamine, chemotactic factors for  eosinophils and neutrophils), involved  with allergic reactions    circulates through sinusoids of the spleen and capillaries that are  only 2 um in diameter. Reversible deformity enables the eryth-  rocyte to assume a more compact torpedo-like shape, squeeze  through the microcirculation, and return to normal.   Leukocytes. Leukocytes (white blood cells [WBCs])  defend the body against microorganisms that cause infection  and remove debris, including dead or injured cells of all kinds  (see Figure 27-2). The leukocytes act primarily in the tissues  but are transported in the circulation. The average adult has  approximately 5000 to 10,000 leukocytes/mm? of blood.   Leukocytes are classified according to structure as either  granulocytes or agranulocytes and according to function as  either phagocytes or immunocytes. The granulocytes, which  include neutrophils, basophils, and eosinophils, are all phago-  cytes. (Phagocytic action is described in Chapter 7.) Of the  agranulocytes, the monocytes and macrophages are phagocytes,  whereas the lymphocytes are immunocytes (cells that create  immunity; see Chapter 8).   Granulocytes. Granulocytes have many membrane-bound  granules in their cytoplasm. These granules contain enzymes  capable of killing microorganisms and catabolizing debris  ingested during phagocytosis. The granules also contain pow-  erful biochemical mediators with inflammatory and immune  functions. These mediators, along with the digestive enzymes, are  released from granulocytes in response to specific stimuli. The  biochemical mediators have vascular and intercellular effects and  the enzymes participate in the breakdown of debris from sites of  infection or injury. Granulocytes are capable of amoeboid move-  ment, by which they migrate through vessel walls (diapedesis)  and then to sites where their action is needed (see Chapter 7).    D, Lymphocyte. E, Monocyte. (From Erlandsen S, Magney J: Color atlas of histology, St Louis, 1992, Mosby.)    The neutrophil (polymorphonuclear neutrophil [PMN])  is the most numerous and best understood of the granulocytes  (Figure 27-3, A). Neutrophils constitute about 55% of the total  leukocyte count in adults. The cytoplasm of neutrophils con-  tains small lysosomal granules and a central nucleus with two  to five distinct lobes. Immature neutrophils are called bands  or stabs. Mature neutrophils are called segmented neutrophils  because of the characteristic appearance of their nucleus. Neu-  trophils reach a fully mature state in the bone marrow, and these  mature neutrophils are called the marrow neutrophil reserve.  Normally it takes about 14 days for neutrophils to develop from  early precursors, but this process is accelerated by infection and  treatment with colony-stimulating factors.   Neutrophils are the chief phagocytes of early inflamma-  tion. Soon after bacterial invasion or tissue injury, neutrophils  migrate out of the capillaries and into the inflamed site, where  they ingest and destroy microorganisms and debris and then die  in 1 or 2 days. The dissolution of dead neutrophils releases diges-  tive enzymes from their cytoplasmic granules. These enzymes  dissolve cellular debris and prepare the site for healing. (This  final function, called débridement, is described in Chapter 7).   Eosinophils have large, coarse granules and constitute  only 1% to 4% of the normal leukocyte count in adults (see  Figure 27-3, B). Like neutrophils, eosinophils are capable of  amoeboid movement and phagocytosis. Using a spectrum  of pattern-recognition receptors, eosinophils ingest antigen-  antibody complexes and viruses and are induced by mast cell  chemotactic factors to attack parasites.’ Eosinophil secondary  granules contain toxic chemicals (e.g., major basic protein,  eosinophil cationic protein, eosinophil peroxidase, eosinophil-  derived neurotoxin) that are highly destructive to parasites and  viruses. The eosinophil granules contain a variety of enzymes  (e.g., histaminase) that help to control inflammatory processes.  (Their function in inflammation and defense against parasites    is described in Chapters 7 and 8.) Eosinophils also release leu-  kotrienes, prostaglandins, platelet-activating factor (PAF), and  a variety of cytokines (e.g., interleukin-1 [IL-1], IL-6, tumor  necrosis factor-alpha [TNF-a], granulocyte-macrophage col-  ony-stimulating factor [GM-CSF]) and chemokines (e.g., IL-8)  that augment the inflammatory response.* Type I hypersensi-  tivity allergic reactions and asthma are characterized by high  numbers of circulating eosinophils, which may be involved in a  dual role of regulation of inflammation and may contribute to  the destructive inflammatory processes observed in the lungs of  persons with asthma (see Chapter 9).   Basophils, which comprise less than 1% (0.01% to 0.3%)  of the leukocytes, contain cytoplasmic granules that have an  abundant mixture of biochemical mediators, including hista-  mine, chemotactic factors, proteolytic enzymes (e.g., elastase,  lysophospholipase), and an anticoagulant (heparin) (see Fig-  ure 27-3, C). Stimulation of basophils also induces synthesis  of vasoactive lipid molecules (e.g., leukotrienes) and cytokines.  Basophils produce IL-6 which induces IL-10 by Thl cells  and induction of Th2 cells that favor B-cell differentiation.°  Basophils also are a particularly rich source of the cytokine IL-4,  which preferentially guides B-cell differentiation toward plasma  cells that secrete IgE (see Chapter 8).   The numbers of basophils are often increased at sites of aller-  gic inflammatory reactions and parasitic infection, particularly  exoparasites (e.g., ticks). IgE receptors on the basophil would  induce degranulation at sites of IgE-mediated hypersensitivity  reactions and contribute to the local inflammatory response.   Mast cells are highly similar to basophils, but are generated  from a different set of precursor cells in the bone marrow, from  which they migrate in an immature form into tissues.° They  reside in vascularized connective tissues just beneath body epi-  thelial surfaces, including the submucosal tissues of the gastro-  intestinal and respiratory tracts and the dermal layer that lies    just below the surface of the skin. Mast cells play a central role  in inflammation, and their activation and degranulation affect a  great number of cells, including those involved in inflammation  (e.g., vascular endothelial cells, smooth muscle cells, circulating  platelets and leukocytes, nerves) and healing (e.g., fibroblasts),  as well as glandular cells and cells of the immune system. Their  activation contributes greatly to increased permeability of  blood vessels and smooth muscle contraction (see Figure 7-11).   The agranulocytes—monocytes, macrophages, and lym-  phocytes—differ from the granulocytes in that they contain  relatively fewer granules in their cytoplasm. The lymphocytes  do not contain any enzyme-filled digestive vacuoles, and the  digestive vacuoles of the monocytes and macrophages are larger  and fewer than those of the granulocytes.   Lymphocytes constitute approximately 36% of the total leu-  kocyte count and are the primary cells of the immune response  (see Figure 27-3, D, and Chapter 8). Most lymphocytes tran-  siently circulate in the blood and eventually reside in second-  ary lymphoid tissues as mature T cells, B cells, or plasma cells.  The life span of the lymphocyte can be days, months, or years,  depending on its type and subtype. (Lymphocyte function and  dysfunction are described in detail in Unit II.)   Natural killer (NK) cells, which resemble large granular  lymphocytes, kill some types of tumor cells (in vitro) and some  virus-infected cells without being induced by previous exposure  to these antigens (see Chapters 7 and 8). Hence they are named  natural killer cells to differentiate them from T-cytotoxic cells,  which are induced by antigen. NK cells also have the capacity to  activate T cells and phagocytes and produce a variety of cyto-  kines that can regulate immune responses. The predominant  form of NK cells develops in the bone marrow and circulates in  the blood, where it accounts for 5% to 10% of the circulating  lymphoid pool, and is found mainly in the peripheral blood and  spleen. NK cells develop independent of a thymus, although  some NK precursors are found in the thymus and may develop  into NKT cells that have markers of NK and T cells.   The monocytes and macrophages make up the mononuclear  phagocyte system (MPS), formerly called the reticuloendothelial  system (RES).’ Monocytes and macrophages are active phagocytes  that participate in the immune and inflammatory responses. They  also ingest dead or defective host cells, particularly blood cells.   Monocytes are the largest normal blood cell and have a  horseshoe-shaped nucleus (see Figure 27-3, E). They are formed  and released by the bone marrow into the bloodstream. Mono-  cytes migrate into a variety of tissues and fully mature into tis-  sue macrophages and myeloid dendritic cells (Table 27-3).  Other monocytes may mature into macrophages in the circula-  tion and migrate out of the vessels in response to infection or  inflammation. Macrophages are generally larger and are more  active as phagocytes than monocytes. Dendritic cells frequently  extend projections (dendrites) into the tissue and take on a  “neuron-like” appearance. The origin and turnover of many of  the tissue macrophages are not precisely known. It seems clear  that once monocytes leave the circulation, they do not return.  They can survive many months or even years.   The normal role of macrophages is to remove old and dam-  aged cells and large-molecular substances from the blood.    Bone marrow  Bone marrow  Bone marrow  Bone marrow and peripheral blood    Modified from Kumar V et al: Robbins & Cotran pathologic basis of  disease, ed 7, Philadelphia, 2005, Saunders.   tDevelopment of blood cells from stem cells in the marrow is de-  scribed on this page and illustrated in Figure 27-10.    Cellular targets of macrophage phagocytosis include circulat-  ing senescent or damaged erythrocytes and platelets (removed  primarily in spleen), dead neutrophils (in the circulation and at  sites of inflammation), and cells undergoing apoptosis. Non-  cellular targets include antigen-antibody complexes, cellular  debris, products of coagulation, and macromolecules (such as  lipids and carbohydrates synthesized by the body as the result of  faulty metabolism, as in storage diseases). Macrophages remove  and kill contaminating microorganisms in the blood (mostly in  the liver and spleen) and at sites of infection. Macrophages and,  particularly, dendritic cells are the major “antigen-processing”  and “antigen-presenting” cells that initiate immune responses  (see Chapter 8). Macrophages initiate wound healing and tissue  remodeling and if activated by cytokines from T cells secrete a  large array of biologically active chemicals that if uncontrolled  result in chronic inflammation and tissue injury (see Chap-  ter 7). Osteoclasts are multinucleated macrophage-like cells  specialized for the function of lacunar bone resorptions and  remodeling in addition to phagocytosis.®   Platelets. Platelets (thrombocytes) are not true cells but  irregularly-shaped cytoplasmic fragments that are essential  for blood coagulation and control of bleeding.’ They are  formed by fragmentation of very large (40 to 100 um in  diameter) cells known as megakaryocytes (Figure 27-4).  They lack a nucleus and deoxyribonucleic acid (DNA),  and are incapable of mitotic division. They do, however,  contain cytoplasmic granules (ie., dense granules, alpha  granules) capable of releasing biochemical mediators when  stimulated by injury to a blood vessel. The contents of the  dense granules are generally proinflammatory (e.g., adenosine   FIGURE 27-4 Megakaryocyte and Platelets. Note the large number of plate-  lets (purple) surrounding the large megakaryocytes in the center. (From Miale JB:  Laboratory medicine: hematology, ed 6, St Louis, 1982, Mosby.)    diphosphate [ADP], adenosine triphosphate [ATP], calcium,  serotonin, and histamine).'° The alpha granules contain  a mixture of coagulation factors, growth and angiogenic  factors (e.g., platelet-derived growth factor [PDGF], vascular  endothelial growth factor [VEGF], and basic fibroblast growth  factor), and angiogenesis inhibitors (e.g., platelet factor 4,  thrombospondin, and inhibitors of metalloproteinases).  Depending upon the particular stimulus, platelets may  selectively release promoters or inhibitors of angiogenesis."  Activation also stimulates synthesis of arachidonic acid  pathway products (e.g., thromboxane A,) (see Chapter 7).   There are approximately 140,000 to 340,000 platelets/mm?  of circulating blood. An additional one third of the body’s  available platelets are in a reserve pool in the spleen. A platelet  circulates for approximately 10 days, ages, and is removed by  macrophages of the MPS, mostly in the spleen.   The lymphoid system is closely integrated with the circula-  tory system. The lymphoid organs, some of which are merely  aggregations of lymphoid tissue, are classified as primary or  secondary. The primary lymphoid organs are the thymus and  the bone marrow. The secondary lymphoid organs consist  of the spleen, lymph nodes, tonsils, and Peyer patches of the  small intestine (see Figure 8-3). All of the lymphoid organs  link the hematologic and immune systems in that they are sites  of residence, proliferation, differentiation, or function of lym-  phocytes and mononuclear phagocytes (monocytes and mac-  rophages).'* (The liver, which also has hematologic functions,  is primarily a digestive organ and is described in Chapter 40.)    The spleen is the largest of the secondary lymphoid organs.  It is a site of fetal hematopoiesis; its mononuclear phagocytes    filter and cleanse the blood; its lymphocytes mount an immune  response to blood-borne microorganisms; and it serves as a  blood reservoir (see Chapter 29).   The spleen is a concave, encapsulated organ that weighs  approximately 150 g and is about the size of a fist. It is located  in the left upper abdominal cavity, curved around a portion of  the stomach (see Figure 8-3). Strands of connective tissue (tra-  beculae) extend from the capsule, dividing the spleen into com-  partments (Figure 27-5). The compartments contain masses of  lymphoid tissue called splenic pulp. The spleen is interlaced with  many blood vessels, some of which are capable of distending  to store blood. Blood that circulates through the spleen comes  from the splenic artery, which branches from the descending  aorta and reenters the circulatory system through the splenic  vein and into the portal vein.   The portion of arterial blood that enters the spleen first encoun-  ters the white splenic pulp, which consists of masses of lymphoid  tissue containing macrophages and lymphocytes, primarily T  lymphocytes in proximity to the arterioles (see Figure 27-5, B and  D). Cellular clumps (lymphoid follicles) are formed in the white  pulp around the splenic arterioles. The lymphoid follicles consist  primarily of B lymphocytes. These are the chief sites of immune  function within the spleen. Here blood-borne antigens encounter  lymphocytes, initiating the immune response and the conversion  of lymphoid follicles into germinal centers (see Chapter 8).!°   Some of the blood that enters the terminal capillaries con-  tinues through the microcirculation and enters highly disten-  sible storage areas called venous sinuses in the red pulp of the  spleen. The venous sinuses are capable of storing more than 300  ml of blood. Passive dilation of the venous sinuses enables the  spleen to increase its storage capacity as needed by the body.  Sudden reductions in blood pressure cause the sympathetic  nervous system to stimulate constriction of the sinuses, result-  ing in expulsion of as much as 200 ml of blood into the venous  circulation, which helps restore blood volume and increases the  hematocrit by as much as 4%.   The endothelial lining of the venous sinuses is discontinuous  (having gaps between endothelial cells) and therefore extremely  permeable so that blood cells are allowed to exit the circulation  (Figure 27-6). The red pulp contains a system of loosely inter-  connected resident macrophages that provide the principal site  of splenic filtration. Because of the slow circulation in the sinuses,  the macrophages easily phagocytose old, damaged, or dead  blood cells of all kinds (but chiefly erythrocytes), microorgan-  isms, macromolecules, and particles of debris. Hemoglobin from  phagocytosed erythrocytes is catabolized, and heme (iron) is  stored in the cytoplasm of the macrophages or released back into  the blood (see Figure 27-17). The macrophages also can remove  particulate inclusions containing denatured hemoglobin (Heinz  bodies) from erythrocytes without harming the cells themselves.  Blood that filters through the red pulp also finds its way into the  venous sinuses and hence into the portal circulation.   The spleen is not absolutely necessary for life or for adequate  hematologic function. However, splenic absence from any  cause (atrophy, traumatic injury, or removal because of disease)  has several secondary effects on the body. For example, leuko-  cytosis (high levels of circulating leukocytes) often occurs after    FIGURE 27-5 Spleen Architecture. A, Spleen section stained with hematoxylin and eosin shows areas of densely  packed cells, referred to as the white pulp (WP), separated by areas with more dispersed cell populations, referred to as the  red pulp (AP). B, Spleen section that has been stained with fluorescently labeled antibodies specific for B cells (orange) and  T cells (green) shows the distinct localization of B cells and T cells within the white pulp. €, Staining for macrophages (orange)    shows the density of macrophages and phagocytic cells in the red pulp and marginal    zone. D, The spleen is enclosed in a capsule with the interior pulp divided into compartments by strands of connective tissue.  The splenic pulp contains regions that are rich in lymphocytes (white pulp) and those containing erythrocytes (red pulp). The  central arteries are frequently surrounded by a periarterial lymphoid sheath, primarily containing T cells, B cells, and macro-    The secondary lymphoid follicles contain B cells that are proliferating in response to    antigen. (A, B, and C from Mandell G, Bennett J, Dolin R: Mandell, Douglas, and Bennett's principles and practice of infectious  diseases, ed 7, Philadelphia, 2010, Churchill Livingstone; D from Hoffman R et al: Hematology: basic principles and practice,    splenectomy, suggesting that the spleen exerts some control  over the rate of proliferation of leukocyte stem cells in the bone  marrow or their release into the bloodstream. Circulating lev-  els of iron may also decrease, reflecting the spleen’s role in the  iron cycle. The immune response to encapsulated bacteria (e.g.,  Streptococcus pneumoniae [pneumococcus], Neisseria menin-  gitidis [meningococcus], Haemophilus influenzae), which is pri-  marily an IgM response, may be severely diminished, resulting  in increased susceptibility to disseminated infections. Loss of  the spleen results in an increase in morphologically defective  blood cells in the circulation, confirming the spleen’s role in  removing old or damaged cells.   Structurally, lymph nodes are part of the lymphatic system.  Lymphatic vessels collect interstitial fluid from the tissues and  transport it, as lymph, through vessels of increasing size to the  thoracic duct, which drains into the superior vena cava return-  ing the lymph to the circulation. Lymph nodes are distributed  throughout the body and provide filtration of the lymph dur-  ing its journey through the lymphatics. Each lymph node is  enclosed in a fibrous capsule, branches of which (trabeculae)  extend inward to partition the node into several compartments  (Figure 27-7). Reticular fibers of connective tissue divide the  compartments into a meshwork throughout the lymph node.    FIGURE 27-6 Splenic Sinus. Transmission electron micrograph and schematic of erythrocytes in the process of squeezing  from the red pulp cords into the sinus lumen. Note the degree of deformability required for red cells to pass through the wall  of the sinus. (From Damjanov |, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby. Schematic from Kumar  V, Fausto N, Abbas A: Robbins & Cotran pathologic basis of disease, ed 7, St Louis, 2005, Saunders.)    FIGURE 27-7 Lymph Node Architecture. Drawing in lower center: Lymph enters via the afferent lymphatics and exits via  the efferent lymphatics. T cells enter the lymph nodes via the high endothelial venules and exit via the medulla to the efferent  lymphatics. B, B-cell follicles; /, medullary cords; 7, T-cell zone. Other structures are labeled. Stained microscopic images: All  images are linked to the drawing of the lymph node. DC, Dendritic cell. (All scale bars 50 jum.) (From Lindquist RL et al: Nat  Immunol 5:1243—-1250, 2004, by permission from Macmillan Publishers Ltd.)    The node consists of outer (cortex) and inner (paracortex) cor-  tical areas and an inner medulla. Lymph enters through multiple  small afferent lymphatic vessels into the subcapsular sinus, just  beneath the capsule; drains into the cortical sinuses to the med-  ullary sinuses, from which the lymph is collected; and leaves the  node by way of the efferent lymphatic vessel. Blood flows into  the lymph nodes through the lymphatic artery, which ends in  groups of postcapillary venules disturbed throughout the outer  cortex. The blood is drained through the lymphatic vein.  Functionally, lymph nodes are part of the hematologic and  immune systems and are the primary site for the first encounter  between antigen and lymphocytes. Lymphocytes enter the lymph  node from the blood through the postcapillary venules by means  of diapedesis across the endothelial lining. B lymphocytes tend to  migrate preferentially to nodes in the cortex and medulla, whereas  T lymphocytes predominantly migrate to the paracortex (see Fig-  ure 27-7). Macrophages reside in the lymph node; help filter the  lymph of debris, foreign substances, and microorganisms; and  provide antigen-processing functions. The dendritic cells encoun-  ter and process antigens and microorganisms in other tissues, enter  the lymph node through the afferent lymph vessels, and migrate  throughout the nodes. The reticular network provides adhesive  surfaces for trapping large numbers of phagocytes and lympho-  cytes and facilitating their organization into follicles or primary  nodules. The presence of antigen, either removed from the lymph  by macrophages or presented on the surface of dendritic cells,  results in the production of secondary nodules containing germi-  nal centers. In the germinal centers lymphocytes, particularly B  cells, respond to antigenic stimulation by undergoing proliferation  and further differentiation, including class-switch, into memory    cells and plasma cells (see Chapter 8). Plasma cells migrate to the  medullary cords. The B-lymphocyte proliferation in response to a  great deal of antigen (e.g., during infection) may result in lymph  node enlargement and tenderness (reactive lymph node).    The typical human requires about 100 billion new blood cells  per day. Blood cell production, termed hematopoiesis, is con-  stantly ongoing, occurring in the liver and spleen of the fetus and  only in bone marrow (medullary hematopoiesis) after birth (see  Chapter 30). This process involves the biochemical stimulation  of populations of relatively undifferentiated cells to undergo  mitotic division (i.e., proliferation) and maturation (i.e., differ-  entiation) into mature hematologic cells (Table 27-4). Although  proliferation and differentiation are usually sequential, certain  blood cells proliferate and differentiate simultaneously. Eryth-  rocytes and granulocytes generally differentiate fully before  entering the blood, but monocytes and lymphocytes continue  to mature in the blood and in secondary lymphatic organs.   Hematopoiesis continues throughout life, increasing in  response to a need to replenish destroyed circulating cells (e.g.,  during hemorrhage, hemolytic anemia [peripheral destruc-  tion of erythrocytes], consumptive thrombocytopenia) or in  response to infection. In general, long-term stimuli, such as  chronic diseases, cause a greater increase in hematopoiesis than  acute conditions, such as hemorrhage.   Various abnormalities in medullary hematopoiesis have  been identified and are discussed in Chapter 28. Extramedullary    M-CSF  GM-CSF Macrophage, T cell, endothelial cell, fibroblast, mast cell  G-CSF Macrophage, fibroblast, endothelial cell    IL-4 Th cell  IL-5 Th cell, mast cell  IL-7 Stromal cell, intestinal epithelium    IL-11 Stromal cell  IL-15 Monocyte/macrophage  Erythropoietin Peritubular kidney cell and Kupffer cell   Common myeloid progenitor to progenitors for megakaryocyte,  erythroid, granulocyte, and monocyte series   Common lymphoid progenitor to progenitor B cell, pro NK cell, and  progenitor T cell   Progenitor T cell to T cell and progenitor B cell to B cell   All cells in megakaryocyte lineage from common myeloid progenitor  to platelet   Common myeloid progenitor to progenitors for megakaryocyte,  erythroid, granulocyte, and monocyte series    G-CSF, Granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; /L, interleukin; M-CSF macrophage    hematopoiesis—blood cell production in tissues other than  bone marrow—of apparently normal blood cells has been  reported in the spleen, liver, and, less frequently, lymph nodes,  adrenal glands, cartilage, adipose tissue, intrathoracic areas, and  kidneys. In adults, however, extramedullary hematopoiesis is  usually a sign of disease, occurring in pernicious anemia, sickle  cell anemia, thalassemia, hemolytic disease of the newborn  (erythroblastosis fetalis), hereditary spherocytosis, and certain  leukemias.    Bone marrow is confined to the cavities of bone and is the pri-  mary site of residence of hematopoietic stem cells (Figure 27-8).  Adults have two kinds of bone marrow: red, or active (hema-  topoietic), marrow (also called myeloid tissue) and yellow, or  inactive, marrow. The large quantity of fat in inactive marrow  gives its characteristic yellow color. Not all bones contain active  marrow. In adults, active marrow is found primarily in the  flat bones of the pelvis (34%), vertebrae (28%), cranium and    A megakaryocyte lies against the  outside of a venous sinusoid and  discharges proplatelets into the lumen  through an epithelial cell gap.    mandible (13%), sternum and ribs (10%), and in the extreme  proximal portions of the humerus and femur (4% to 8%). Inac-  tive marrow predominates in cavities of other bones. (Bones are  discussed further in Chapter 43.)   Hematopoietic marrow is vascularized by the primary arteries  of the bones, which terminate in a capillary network forming large  venous sinuses. Hematopoietic marrow and fat fill the spaces sur-  rounding the network of venous sinuses. Newly produced blood  cells traverse narrow openings between endothelial cells in the  venous sinus walls and thus enter the circulation. Normally,  immature cells have not developed the appropriate surface recep-  tors to interact with the endothelium and enter the circulation.   The hematologic compartment of the bone marrow con-  sists of a variety of cellular microenvironments, called niches,  that control differentiation of hematopoietic progenitor cells!  (Figure 27-9). The cellular composition of niches includes  osteoclasts, osteoblasts, sinusoidal endothelial cells, fibroblasts,  megakaryocytes, macrophages, and nerve cells.!° Osteoblasts are  derived from fibroblasts and are responsible for construction of   interconnected cells lining the blood vessels.  A basal lamina separates endothelial cells    Developing granulocytes are found  adjacent to venous sinusoids. Mature  granulocytes leave the bone marrow by  diapedesis.    Branching stromal cells form a cellular  network under the endothelial lining and  extend into the hematopoietic tissue.  Stromal cells produce hematopoietic  short-range regulatory molecules induced  by colony-stimulating factors.    A macrophage, found near an erythroid  progeny, will engulf nuclei extruded from  orthochromatic erythroblasts before their  conversion to reticulocytes.    FIGURE 27-8 Bone Marrow: Structure and Vascularization. (From Kierszenbaum A, Tres L: Histology and cell biology:  an introduction to pathology, ed 3, Philadelphia, 2012, Mosby. Scanning electron micrograph from Kessel RG, Kardon RH: Jis-    FIGURE 27-9 Bone Marrow Stem Cell Niches. Stem cell niches are microenvironments where stem cells undergo    hematopoiesis into all forms of blood cells. Stem cell niches retain and maintain adult resting hematopoietic stem cells (HSCs)  and are activated after cell injury to promote cell renewal or differentiation to form new tissues. The fate of individual HSCs  is determined by interactions (intercellular adherence, cytokines, chemokines) with specialized cells within the niches. Within  osteoblastic niches the HSC interacts primarily with the osteoblasts and specialized mesenchynal stem cells (MSCs) that  include nestin-expressing (Nestin+) MSCs and CXCL12-abundant reticular (CAR) cells. Within the vascular niches, the HSC  interacts with vascular endothelial cells, Nestin+t MSC, and a more abundant population of CAR cells.    bone. Osteoclasts are multinucleate cells of monocytic origin that  remodel bone by resorption. Both cells can produce cytokines  that affect proliferation of hematopoietic cells. Recent studies  have identified macrophage and megakaryocyte populations in  bone marrow niches. The area is innervated through the sympa-  thetic nervous system. At least two populations of stem cells are  found in bone marrow niches. Mesenchymal stem cells (MSCs)  are stromal cells that can differentiate into a variety of cells,  including osteoblasts, adipocytes, and chondrocytes (produce  cartilage). Hematopoietic stem cells (HSCs) are progenitors of  all hematologic cells. Both populations of stem cells also undergo  self-renewal in the bone marrow so that additional MSCs and  HSCs are produced to replace those undergoing differentiation.   Two distinct types of niches have been identified: the osteo-  blastic (also called endosteal) niche and the vascular niche. The  osteoblastic niche is centralized around osteoblasts, which line  the surface of bone, whereas the vascular niche is organized  around sinusoidal endothelial cells. In both niches, HSCs are  affected by direct cell-to-cell signaling and by soluble mediators  produced by cells within each niche. Each niche also contains  two specialized cells derived from MSCs: CXCL12-abundant  reticular (CAR) cells and nestin-expressing cells.'°   CAR cells resemble reticular cells with long cellular processes.  CAR cells closely interact with HSCs and provide important  intercellular signaling through several HSC regulatory molecules,  including CXCL12, SCF, VCAM-1, and ANG1. Chemokine  ligand 12 (CXCL12) is a chemokine that reacts with the C-X-C  chemokine receptor type 4 (CXCR4) on HSCs. The cytokine stem    cell factor (SCF; also known as steel factor), which is expressed  as a cell surface transmembrane protein or a soluble protein,  reacts with the HSC KIT receptor (named stem cell growth fac-  tor receptor, proto-oncogene c-Kit, or CD117). Vascular cell  adhesion molecule 1 (VCAM-1) mediates intercellular adhesion  through its receptor integrin 0461 (also called very late antigen  4, or VLA4). The secreted protein angiopoietin 1 (ANG1) reacts  with a tyrosine kinase receptor. Nestin-expressing cells express  large amounts of the intermediate filament protein nestin and,  particularly, SCF and VCAM-1. Although both MSC-derived  cells are present in the osteoblastic niche and vascular niche, the  CAR cell is the predominant cell in the vascular niche.'”   Each bone marrow niche affects HSCs differently. In the osteo-  blastic niche, HSCs are in direct contact with osteoblasts, CAR  cells, and nestin-expressing cells. The effect is retention of HSCs  in the bone marrow in a quiescent (dormant) state.!* HSCs that  traffic to the vascular niche directly contact endothelial cells, as  well as nestin-expressing cells and larger numbers of perivascular  CAR cells. The cumulative signaling events induce HSC activa-  tion, proceeding to increased cellular division and hematopoietic  differentiation. Other cells in the bone marrow, including macro-  phages and adipocytes, contribute to regulation of hematopoiesis.   Within the bone marrow niches, each type of blood cell origi-  nates from common hematopoietic stem cells that proliferate  and differentiate under control of a variety of cytokines and  growth factors (Figure 27-10 and see Table 27-4). During this   rid SCF, IL-3, IL-11 SCF, IL-7 4  Common Common  myeloid lymphoid  progenitor progenitor    Eosinophil Granulocyte/ Megakaryocyte Erythroid ProBcell ProNkKcell ProT cell  progenitor monocyte progenitor progenitor progenitor |  IL-3, GM-CSF GM-CSF GM-CSF TPO | EPO, IL-3 | IL-7 IL-15 IL-2  IL-7  Monocyte Granulocyte B cell  progenitor progenitor |  SECONDARY THYMUS  LYMPHOID  M-CSF G-CSF ORGANS  IL-4, IL-2 IL-2,  antigen antigen  Eosinophilo- Monoblast Myeloblast Megakary- Proerythro-  blast | oblast blast  ,  Neutrophil Platelets Erythrocyte Plasma cell NK cell T cell  Eosinophil Monocyte/ ’ '  macrophage    FIGURE 27-10 Differentiation of Hematopoietic Cells. Curved arrows indicate proliferation and expansion of prehe-  matopoietic stem cell populations. EPO, Erythropoietin; G-CSF granulocyte colony-stimulating factor; GM-CSF granulocyte-  macrophage colony-stimulating factor; /L, interleukin; M-CSF macrophage colony-stimulating factor; NK, natural killer; SCF  stem cell factor; TPO, thrombopoietin.    FIGURE 27-11 Hematopoiesis. Hematopoiesis from the stem cell pool; activity occurs mainly in the bone marrow and  in the peripheral blood. (Modified from Harmening DM, editor: Clinical hematology and fundamentals of hemostasis, ed 3,    process some hematopoietic stem cells undergo alternative  paths of differentiation into more differentiated stem cells that  are committed to a particular line of blood cells.   Hematopoietic stem cells represent just one stage in a pro-  cess of progressive cellular differentiation. All humans originate  from a single cell (the fertilized egg) that has the capacity to  proliferate and eventually differentiate into the huge diversity of  cells of the human body. After fertilization, the egg divides over  a 5-day period to form a hollow ball (blastocyst) that implants  on the uterus. Until about 3 days after fertilization, each cell  (blastomere) is undifferentiated and retains the capacity to dif-  ferentiate into any cell type. In the 5-day blastocyst, the outer  layer cells have undergone differentiation and commitment to  become the placenta. Cells of the inner cell mass (embryonic  stem cells), however, continue to have unlimited differentia-  tion potential (currently referred to as being pluripotent) and  can grow into different kinds of tissue—blood, nerves, heart,  bone, and so forth. After implantation, cells of the inner cell  mass begin differentiation into other cell types. Differentiation  is a multistep process and results in intermediate groups of stem  cells (multipotent stem cells) with more limited, but still impres-  sive, abilities to differentiate into many different types of cells  (see Figure 27-10).!°   Hematopoietic stem cells have partially differentiated.” They  have the capacity to differentiate easily into any of the hemato-  logic cell populations but are very difficult to differentiate into  other cell types, like nerve or muscle cells. The challenge of get-  ting any partially committed multipotent stem cells to differ-  entiate reliably involves coaxing them with identical chemical  signals that the body uses naturally for differentiation. This is a  daunting task with potentially astonishing clinical implications.    For example, bone marrow might become the reservoir from  which stem cells are harvested and then stimulated to produce  nerve cells to help with the treatments of spinal cord injuries.   As with all stem cells, the hematopoietic stem cells are self-  renewing (they have the ability to proliferate without further  differentiation) so that a relatively constant population of stem  cells is available. Some hematopoietic stem cells will continue  differentiation into hematopoietic progenitor cells. Progenitor  cells retain proliferative capacity but are committed to possi-  ble further differentiation into particular types of hematologic  cells: lymphoid (lymphocytes, NK cells), granulocyte-monocyte  (granulocytes, monocytes, macrophages), and megakaryocyte-  erythroid (platelets, erythrocytes) progenitor cells (see Figure  27-10).   In addition to intercellular signaling events between HSCs  and cells in the osteoblastic and vascular niches, several cyto-  kines participate in hematopoiesis, particularly colony-stimu-  lating factors (CSFs or hematopoietic growth factors), which  stimulate the proliferation of progenitor cells and their progeny  and initiate the maturation events necessary to produce fully  mature cells (see Figure 27-10).*! Multiple cell types in the  hematopoietic organs, including endothelial cells, fibroblasts,  and lymphocytes, produce the necessary CSFs.   Hematopoiesis in the bone marrow occurs in two separate  pools: the stem cell pool and the bone marrow pool (Figure  27-11). The stem cell pool is the product of self-renewal that  maintains the number of pluripotent stem cells and partially  committed progenitor cells. The bone marrow pool contains  cells that are proliferating and maturing in preparation for  release into the circulation and mature cells that are stored for  later release into the peripheral blood. The peripheral blood    also contains two pools of cells: those in the circulation and  those stored around the walls of the blood vessels (often called  the marginating storage pool). The marginating storage pool  primarily consists of neutrophils that adhere to the endothe-  lium in vessels where the blood flow is relatively slow. These  cells can rapidly move into tissues and mucous membranes  when needed in an inflammatory response.   Under certain conditions of rapid depletion of the circulat-  ing pool, the circulating hematologic cells need to be rapidly  replenished. Medullary hematopoiesis can be accelerated by  any or all of three mechanisms: (1) conversion of yellow bone  marrow, which does not produce blood cells, to hematopoietic  red marrow by the actions of erythropoietin (a hormone that  stimulates erythrocyte production); (2) faster differentiation of  progenitor cells; and (3) faster proliferation of stem cells into  progenitor cells (see Table 27-4).   Neutrophils are normally present in the blood in the range of  4000 to 6000 cells/uL, and in response to a bacterial infection,  numbers usually increase to 10,000 to 20,000 cells/yL. Sus-  ceptibility to infection develops when levels drop below 1000  cells/uL, such as during congenital neutropenia or as a conse-  quence of cytotoxic therapy for cancer. Similarly normal levels  of other hematologic cells may be suppressed (e.g., congenital  or acquired immune deficiencies and anemia; see Chapters 9  and 28).   The numbers of circulating hematologic cells are under the  control of CSFs (see Table 27-4). Administration of CSFs can  raise white cell numbers to extremely high levels in healthy  individuals. These excessive levels of white blood cells may  result in production of toxic products and tissue damage.  Therapy with CSFs has been tested in individuals with subnor-  mal levels of circulating blood cells, such as acquired immu-  nodeficiency syndrome (AIDS), aplastic anemia, or congenital  neutropenia or as a consequence of cytotoxic therapy lym-  phoma or leukemia (Figure 27-12). The results of CSF use in  individuals with cancer have been disappointing. An analysis  of 19 trials in which CSFs were administered postchemother-  apy to those with acute myelogenous leukemia detected no  effect on overall survival or infections.’* Results of using CSF  prophylactically to avoid neutropenia in individuals undergo-  ing chemotherapy for metastatic solid tumors have been con-  troversial.*> An analysis of randomized trials of prophylactic  use of granulocyte-macrophage CSF (GM-CSF) and granulo-  cyte CSF (G-CSF) in individuals undergoing chemotherapy  for metastatic breast cancer indicated a significant effect on  prevention of febrile neutropenia and a decrease of general  mortality and need for hospital care.** However, no effect was  observed on the incidence of severe neutropenia, infections,  or infection-related mortality. CSF therapy can stimulate  increases in circulating granulocyte-monocyte populations,  but the degree of response depends on the available numbers  of stem and progenitor cells that have survived chemotherapy  or the effects of disease. CSF treatment has corrected some  cases of congenital neutropenia and resulted in reconstitu-  tion of hematopoiesis after bone marrow transplantation.”    FIGURE 27-12 Colony-Stimulating Factor (CSF) Effects. Morphologic  effects of growth factor. Marrow aspirate from a patient receiving granulocyte  colony-stimulating factor (G-CSF) showing an early neutrophil response. There  is a marked shift toward immaturity in the neutrophils with the majority at the  promyelocyte and early myelocyte stages of maturation (Wright-Giemsa stain).  (From Damjanov |, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996,  Mosby.)    CSF treatment can result in shorter periods of intensive nurs-  ing and hospitalization. Recombinant CSFs (e.g., granulocyte  colony-stimulating factor [G-CSF], GM-CSF, erythropoietin)  are being mass-produced for therapeutic use.   For almost 100 years it was believed that erythrocytes developed  from lymphocytes that were transformed in the spleen. It was  not until the 1850s that the bone marrow was identified as the  site of erythropoiesis, or development of red blood cells.   In the confines of the bone marrow erythroid progenitor cells  proliferate and differentiate into large, nucleated proerythro-  blasts, which are committed into producing cells of the ery-  throid series (Figure 27-13). Erythroid development from the  proerythroblast onward is contained in a compartment referred  to as the erythron.*° The proerythroblast, which has ribosomes  and can produce protein, differentiates through several inter-  mediate forms of erythroblast while synthesizing hemoglobin  and progressively eliminating most intracellular structures,  including the nucleus. Thus the maturing erythroblast becomes  more compact and progressively assumes the shape and char-  acteristics of an erythrocyte. Hemoglobin is readily apparent  and increases in quantity as nuclear size shrinks throughout  the basophilic and polychromatophilic stages. The orthochro-  matic erythroblast (normoblast) is the smallest of the nucleated  erythrocyte precursors.   The last immature form of erythroblast is the reticulo-  cyte, which is anucleate and contains a meshlike (reticular)  network of ribosomal ribonucleic acid (rRNA) that is visible  microscopically after staining with certain dyes. The reticulo-  cyte contains polyribosomes (for globin synthesis) and mito-  chondria (for oxidative metabolism and heme synthesis). The    FIGURE 27-13 Erythrocyte Differentiation. Erythrocyte differentiation from large nucleated progenitor cells to small  nonnucleated erythrocytes.    FIGURE 27-14 Role of Erythropoietin in Regulation of Erythropoiesis. (1) Decreased arterial oxygen levels result in  (2) decreased tissue oxygen (hypoxia) that (3) stimulates the kidney to increase (4) production of erythropoietin. Erythropoietin  is carried to the bone marrow (5) and binds to erythropoietin receptors on proerythroblasts, resulting in increased red cell  production and maturation and expansion of the erythron (6). The increased release of red cells into the circulation frequently  corrects the hypoxia in the tissues (7). (8) Perception of normal oxygen levels by the kidney causes (9) diminished production  of erythropoietin (negative feedback) and return to normal levels of erythrocyte production. EPO, Erythropoietin; O,, oxygen in    reticulocyte matures into an erythrocyte within 24 to 48 hours.  During this period, mitochondria and ribosomes disappear  and the cell becomes smaller and more disk-like. With these  final changes, the erythrocyte loses its capacity for hemoglo-  bin synthesis and oxidative metabolism. Reticulocytes remain  in the marrow approximately 1 day and are released into the  venous sinuses. They continue to mature in the bloodstream  and may travel to the spleen for several days of additional  maturation. The normal reticulocyte count is 1% of the total  red blood cell count. Approximately 1% of the body’s circu-  lating erythrocyte mass normally is generated every 24 hours.  Therefore, the reticulocyte count is a useful clinical index of  erythropoietic activity and indicates whether new red cells are  being produced.    In healthy individuals, the total volume of circulating erythro-  cytes remains surprisingly constant. Most steps of erythropoiesis    are primarily under the control of a feedback loop involving the  glycoprotein erythropoietin (see Table 27-4). In conditions of  tissue hypoxia, erythropoietin is secreted by the liver and, pri-  marily, by the peritubular cells of the kidney (Figure 27-14).?  Rising levels of circulating erythropoietin cause a compensatory  increase in proliferation and differentiation of proerythroblasts  in the bone marrow. The density of cellular erythropoietin  receptor decreases progressively during erythroid maturation  to almost undetectable levels on reticulocytes. The normal  steady-state rate of production of approximately 2.5 million  erythrocytes per second can increase to 17 million per second  during anemia or under conditions of low oxygen concentra-  tion, such as high-altitude environments or pulmonary disease.  Thus the body responds to reduced oxygenation of blood in two  ways: (1) stimulation of chemoreceptors of the carotid body  and aortic arch that signal the brain to increase respiration, and  (2) stimulation of receptors on the kidney peritubular cells to  increase erythropoietin synthesis and release.    FIGURE 27-15 Molecular Structure of Hemoglobin. Molecule is a spherical  tetramer weighing approximately 64,500 daltons. It contains a pair of «-polypeptide  and a pair of §-polypeptide chains and several heme groups.    One of the most significant advances in the study of hema-  topoietic growth factors has been the development of eryth-  ropoietin for use in individuals with chronic renal failure. In  1986 large amounts of recombinant human erythropoietin  (r-HuEPO) became widely available for clinical research. Eryth-  ropoietin is administered intravenously or subcutaneously for  the treatment of anemia caused by decreased production of  erythropoietin. An immediate effect of increased endogenous  or exogenous erythropoietin is an increase in the blood retic-  ulocyte count, followed by increasing levels of erythrocytes.  The most significant side effect associated with r-HuEPO is  increased blood pressure.   Hemoglobin (Hb), the oxygen-carrying protein of the  erythrocyte, constitutes approximately 90% of the cell’s dry  weight. Hemoglobin-packed blood cells take up oxygen in  the lungs and exchange it for carbon dioxide in the tissues.  A single erythrocyte can contain as many as 300 hemoglo-  bin molecules. Hemoglobin increases the oxygen-carrying  capacity of blood by 100-fold. Each hemoglobin molecule is  composed of two pairs of polypeptide chains (the globins)  and four colorful complexes of iron plus protoporphyrin  (the hemes) (Figure 27-15).?* Hemoglobin is responsible for  blood’s ruby-red color.   Several variants of hemoglobin exist, but they differ only  slightly in primary structure based on the use of different poly-  peptide chains; alpha, beta, gamma, delta, epsilon, or zeta (a,  6, y, 6, €, or C) (Table 27-5). Each polypeptide chain contains  approximately 150 amino acids and is arranged in the knot-  ted-sausage configuration shown in Figure 27-15. The chains  assemble to form a tetrahedron containing two pairs of identi-  cal chains. Hemoglobin A, the most common type in adults,  is composed of two a- and two (-polypeptide chains (a2{,).  A normal variant, fetal hemoglobin (hemoglobin F), is a com-  plex of two a- and two y-polypeptide chains (a2y) that binds   2% of adult Hb; increased in beta-  thalassemia (see Chapter 30)   Major fetal Hb from the third  through ninth month of  gestation; promotes oxygen  transfer across platelets;  increased in beta-thalassemia    oxygen with a much greater affinity than that found in adult  hemoglobin.   Heme is a large, flat, iron-protoporphyrin disk that is syn-  thesized in the mitochondria and can carry one molecule of  oxygen (O,). Thus an individual hemoglobin molecule with its  four hemes can carry four oxygen molecules. If all four oxygen-  binding sites are occupied by oxygen, the molecule is said to be  saturated. Through a series of complex biochemical reactions,  protoporphyrin, a complex four-ringed molecule, is produced  and bound with ferrous iron. It is crucial that the iron be cor-  rectly charged; reduced ferrous iron (Fe?*) can bind oxygen in  the lungs and release it in the tissues, where oxygen concentra-  tion is less, whereas ferric iron (Fe**) cannot. Binding of oxygen  to ferrous iron (oxyhemoglobin) temporally oxidizes Fe?* to  Fe**, but after the release of oxygen the body reduces the iron  to Fe*t (deoxyhemoglobin [reduced hemoglobin]) and reac-  tivates the hemoglobin’s capacity to bind oxygen. Without  reactivation by methemoglobin reductase, the Fe*+-containing  hemoglobin (methemoglobin) cannot bind oxygen.   Several other molecules can competitively bind to deoxy-  hemoglobin. Carbon monoxide (CO) directly competes with  oxygen for binding to ferrous ion with an affinity that is about  200-fold greater than that of oxygen. Thus even a small amount  of CO can dramatically decrease the ability of hemoglobin to  bind and transport oxygen. Hemoglobin also binds carbon  dioxide (CO,), but at a binding site separate from where oxy-  gen binds. In the lungs, CO, is released, allowing hemoglobin  to bind oxygen.   Erythrocytes may play a role in the maintenance of vascu-  lar relaxation. Nitric oxide (NO) produced by blood vessels is  a major mediator of relaxation and dilation of the vessel walls.  In the lungs, hemoglobin can concurrently bind oxygen to  the ferrous ion and NO to cysteine residues in the globins. As    Synthesis of hemoglobin  Cobalamin (vitamin B,»)  folate metabolism  Folate (folic acid)  Vitamin Bg (pyridoxine)  Vitamin B, (riboflavin)  Vitamin C (ascorbic acid)    Iron metabolism; acts as a reducing agent to maintain iron in its    None, but needed for respiration in mature erythrocytes  Heme synthesis ; protection against oxidative damage in   Hemolytic anemia with increased cell membrane fragility;  shortens life span of erythrocytes in individuals with  cystic fibrosis    Data from Ames BN, Atamna H, Killilea DW: Mineral and vitamin deficiencies can accelerate the mitochondrial decay of aging, Mol Aspects of  Med 26(4-5), 367-378, 2005; Strine-Martin EA, Lotspeich-Steininger CA, Koepke JA: Clinical hematology: principles, procedures, correlations, ed 2,    *Although pantothenic acid is important for optimal synthesis of heme, experimentally induced deficiency failed to produce anemia or other hema-    hemoglobin transfers its oxygen to tissue, it may also shed small  amounts of nitric oxide, contributing to dilation of the blood  vessels and helping the oxygen gain access to tissues.    Normal development of erythrocytes and synthesis of hemo-  globin depends on an optimal biochemical milieu and adequate  supplies of the necessary building blocks, including protein,  vitamins, and minerals (Table 27-6). If these components are  lacking for a prolonged time, erythrocyte production slows and  anemia (insufficient numbers of functional erythrocytes) may  result (see Chapter 28).   Erythropoiesis cannot proceed in the absence of vitamins,  especially Bj, folate (folic acid), Bg, riboflavin, pantothenic  acid, niacin, ascorbic acid, and vitamin E. Dietary vitamin B,,  is a large molecule that requires a protein secreted by pari-  etal cells into the stomach (intrinsic factor [IF]) for trans-  port across the ileum. Once absorbed, vitamin B,, is stored  in the liver and used as needed in erythropoiesis. Defects in IF  production lead to decreased B,, absorption and pernicious  anemia.   Folate is the second most important vitamin for erythro-  cyte production and maturation. Folate is necessary for DNA  synthesis, being a component of three of the four DNA bases  (thymine, adenine, and guanine), and RNA synthesis. Folate  absorption occurs principally in the upper small intestine and is  stored in the liver. Folate deficiency is more common than vita-  min Bj, deficiency and occurs more rapidly. Folate stores can  be depleted within a few months, whereas vitamin B,, depletion  can take years. Folate supplements are prescribed for pregnant  women because pregnancy increases the demand for folate and  may cause anemia.    After about 100 to 120 days in the circulation, old erythrocytes  are removed by tissue macrophages, primarily in the spleen.  Although mature erythrocytes lack nuclei, mitochondria, and  endoplasmic reticulum, they do have cytoplasmic enzymes  capable of glycolysis (anaerobic glucose metabolism) and pro-  duction of small quantities of ATP, which provides the energy  needed to maintain cell function and membrane pliability.  Metabolic processes diminish as the erythrocyte ages, so less  ATP is available to maintain plasma membrane function. Dis-  ruption of the anchorage between the cytoskeleton and the  plasma membrane results in the senescent red cell becoming  increasingly fragile and losing its reversible deformability, and  thus becoming susceptible to rupture while passing through  narrowed regions of the microcirculation.   Additionally, the plasma membrane of senescent red cells  undergoes phospholipid rearrangement (movement of the  phospholipid phosphatidylserine from the cytoplasmic surface  of the membrane to the external surface) that is recognized by  receptors for phosphatidylserine on macrophages (primarily in  the spleen) that selectively remove and sequester the red cells.”’  If the spleen is dysfunctional or absent, macrophages in the liver  (Kupffer cells) take over.   The erythrocytes are digested by proteolytic and lipolytic  enzymes in the phagolysosomes (digestive vacuoles) of the  macrophage. The heme and globin of methemoglobin dissoci-  ate easily, and the globin is broken down into its component  amino acids. The iron in hemoglobin is oxidized, forming Fe**  (methemoglobin), and recycled (see following section).   Porphyrin is reduced to bilirubin, which is transported to  the liver, conjugated, and finally excreted in the bile as gluc-  uronide (Figure 27-16). Approximately 6 g of hemoglobin is    catabolized daily, producing 200 mg of bilirubin. Bacteria in the  intestinal lumen transform conjugated bilirubin into urobilino-  gen. Although a small portion is reabsorbed for further metabo-  lism by the liver or excreted by the kidney into the urine, most  urobilinogen is excreted in feces. Conditions causing acceler-  ated erythrocyte destruction increase the load of bilirubin for  hepatic clearance, leading to increased serum levels of unconju-  gated bilirubin and increased urinary excretion of urobilinogen.  Gallstones (cholelithiasis) can result from a chronically elevated  rate of bilirubin excretion.    Approximately 67% of total body iron is bound to heme in  erythrocytes (hemoglobin) and muscle cells (myoglobin), and  approximately 30% is stored in mononuclear phagocytes (i.e.,  macrophages) and hepatic parenchymal cells as either ferritin  or hemosiderin. The remaining 3% (less than 1 mg) is lost daily  in urine, sweat, bile, sloughing of epithelial cells from the skin  and intestinal mucosa, and minor bleeding. Approximately  25 mg of iron is required daily for erythropoiesis; only 1 to 2  mg of iron is dietary and the remainder is obtained from iron  recycling of erythrocytes.   Iron is continually recycled.*” The methemoglobin released  from the breakdown of senescent or damaged erythrocytes (see  preceding section) is dissociated by the enzyme heme oxygen-  ase, and the iron is released into the bloodstream, where it is free  to bind again to transferrin or be stored in the macrophage’s  cytoplasm as ferritin or hemosiderin (Figure 27-17). A minute  amount of iron is stored in muscle cells by the heme-containing  protein myoglobin. Unavailable stores of iron are present in  cytochromes, catalases, and peroxidase enzymes.    The protein ferritin is the major intracellular iron storage  protein. Apoferritin, which is ferritin without attached iron,  can store thousands of atoms of iron. Several apoferritin com-  plexes combine to form the micelle ferritin. Large aggregates of  micelles (if a large amount of iron is present) produce numer-  ous ferritin micelles, known as hemosiderin. Hemosiderin is  visible as an iron-based pigment under a light microscope as cell  inclusions. The iron within deposits of hemosiderin is poorly  available to supply iron when needed. The most common cause  of hemosiderin deposition is simple bruising. Hemosiderin in  small amounts within iron-rich tissues (i.e., spleen, liver, bone  marrow) is considered normal. Large aggregates or its pres-  ence in tissue such as the lungs or subcutaneous tissue suggest a  pathologic condition.   Iron from either dietary sources, release of iron stores, or  erythrocyte catabolism is transported in the blood bound to  apotransferrin, thus becoming transferrin; under normal con-  ditions, only one third of the iron-binding sites on transferrin  molecules are occupied.*! Apotransferrin is a glycoprotein syn-  thesized primarily by hepatocytes in the liver but also produced in  small quantities by tissue macrophages, submaxillary and mam-  mary glands, and ovaries or testes. Iron for hemoglobin produc-  tion is carried by transferrin to the bone marrow, where it binds  to transferrin receptors on erythroblasts. Transferrin receptors  are on the plasma membrane of all nucleated cells, although at  particularly high levels on erythroid precursors and rapidly pro-  liferating cells (e.g., lymphocytes), and are thought to be the only  route of cellular entry for transferrin-attached iron. Transferrin  is recycled (transferrin cycle) in the following manner:    FIGURE 27-17 Iron Cycle. lron (Fe) released from gastrointestinal epithelial cells circulates in the bloodstream associ-  ated with its plasma carrier, transferrin. It is delivered to erythroblasts in bone marrow, where most of it is incorporated into  hemoglobin. Mature erythrocytes circulate for approximately 100 to 120 days, after which they become senescent and are  removed by the mononuclear phagocyte system (IMPS). Tissue macrophages (mostly in spleen) break down ingested erythro-  cytes and return iron to the bloodstream directly or after storing it as a ferritin or hemosiderin.   The iron is transported to the erythroblast’s mitochondria  (the site of hemoglobin production), where the enzyme heme  synthetase inserts ferrous iron into protoporphyrin to form  heme. Heme then is bound to globin to form hemoglobin. Iron  not used in erythropoiesis is stored temporarily as ferritin or  hemosiderin and later excreted.   The body’s iron homeostasis is primarily controlled by the  hormone hepcidin.** Hepcidin is synthesized in the liver and  released as a 25 amino acid peptide, most of which is bound in  the plasma with high affinity to a,-macroglobulin and relatively  lower affinity to albumin. Hepatocellular hepcidin production  is regulated physiologically by the body’s dietary absorption of  iron, rate of erythropoiesis, and level of oxygen saturation.**  Hepatocytes sense levels of circulating iron by means of recep-  tors for transferrin, the major transporter of iron in the plasma.  Excess iron is stored in hepatocytes and macrophages. Hepato-  cytes sense these levels by means of receptors for bone morpho-  genetic protein (BMP), most likely BMP-6, which is a growth  factor produced to a large extent by bone marrow sinusoid  endothelial cells. Hepcidin production also can be induced by  inflammation by means of IL-6.   Hepcidin regulates iron levels through its binding capacity  to ferroportin, which is a transmembrane iron exporter found    in the plasma membrane of cells that transport or store iron,  including macrophages, hepatocytes, and enterocytes. The  body’s total iron balance is maintained through controlled  absorption rather than excretion.*‘ Dietary iron (primarily as  Fe?*) is transported directly across the membranes of epithelial  cells (enterocytes) in the duodenum and proximal jejunum.*°  (Transport mechanisms are described in Chapter 1.) Hepcidin  induces internalization and degradation of ferroportin, thus  leading to increased intracellular iron stores, decreased dietary  iron absorption, and decreased levels of circulating iron.*°  Decreased production of hepcidin leads to release of stored iron  and increased dietary absorption. Thus, if the body’s iron stores  are low or the demand for erythropoiesis increases, dietary  iron is transported rapidly through the epithelial cell and into  the plasma. If body stores are high and erythropoiesis is not  increased, iron transport is stopped, although iron can cross  the epithelial cells’ plasma membrane passively and be stored  as ferritin.    Leukocytes consist of lymphocytes, granulocytes, and mono-  cytes. Most of the leukocytes arise from stem cells in the  bone marrow (their pathways of differentiation are shown in  Figure 27-10). Hematopoietic stem cells differentiate into two  populations of progenitor cells: common lymphoid progeni-  tors and common myeloid progenitors. Lymphoid progeni-  tors that remain in the bone marrow undergo differentiation  into the B-cell lineage, after which they are released into the    circulation and undergo further maturation in the periph-  eral lymphoid organs (described in Chapter 8 [see Figure  8-3]). The common myeloid progenitors further differenti-  ate into progenitors for basophils, mast cells, eosinophils,  and megakaryocytes, and granulocyte/monocyte progenitors.  The granulocyte/monocyte progenitors further differenti-  ate into monocyte progenitors and granulocyte progenitors,  which develop into monocytes/macrophages and neutro-  phils, respectively. Development from hematopoietic stem  cells to common granulocyte-monocyte progenitors primarily  is under the control of stem cell factor, IL-3, and GM-CSF,  whereas further differentiation into granulocytic and mono-  cytic progenitors is controlled by G-CSF and M-CSF, respec-  tively (see Table 27-4).   Monocytic progenitors undergo development into mono-  cytes within 24 hours and are released into the circulation.  Monocytes mature into various forms of macrophages, a pro-  cess that is usually completed within 1 or 2 days after their  release (see Tables 27-3 and 27-4).*”   Progenitor cells for granulocytes normally fully mature  in the bone marrow into neutrophils, eosinophils, and baso-  phils. The ultimate phenotype is determined by relative local  bone marrow concentrations of early- and late-acting cyto-  kines, including GM-CSF, G-CSF, IL-3, IL-5, stem cell factor,  and others (see Table 27-4). Granulocytes are released into the  blood within 14 days of development. The bone marrow selec-  tively retains immature granulocytes as a reserve pool that can  be rapidly mobilized in response to the body’s needs.   Most leukocytes exist in the body from days to years, depend-  ing on type. Maintenance of optimal levels of granulocytes and  monocytes in the blood depends on the availability of pluripo-  tent stem cells in the marrow, induction of these into commit-  ted stem cells, timely release of new cells from the marrow, and  mobilization of the granulocyte reserve pool. Leukocyte pro-  duction increases in response to infection, to the presence of  steroids, and to reduction or depletion of reserves in the mar-  row. It is also associated with strenuous exercise, convulsive  seizures, heat, intense radiation, paroxysmal tachycardias, pain,  nausea and vomiting, and anxiety.    Platelets (thrombocytes) are derived from stem cells and  progenitor cells that differentiate into megakaryocytes.*®  During thrombopoiesis, the megakaryocyte progenitor is  programmed to undergo an endomitotic cell cycle (endomi-  tosis) during which DNA replication occurs, but anaphase  and cytokinesis are blocked (see Chapter 1). Thus the mega-  karyocyte nucleus enlarges and becomes extremely polyploidy  (up to 100-fold or more of the normal amount of DNA) with-  out cellular division. Concurrently, the numbers of cytoplas-  mic organelles (e.g., internal membranes, granules) increase,  and the cell develops cell surface proplatelet elongations into  the sinusoidal blood vessels.*” These branches progressively  fragment into platelets. A single large (30 to 100 pm) mega-  karyocyte may produce thousands of smaller platelets (2 to  3 um).*° Like erythrocytes, platelets released from the bone  marrow lack nuclei.    About two thirds of platelets enter the circulation; the  remainder reside in the splenic pool. Platelets circulate in the  bloodstream for about 8 to 10 days before losing their abil-  ity to carry out thrombogenic activity. Senescent platelets are  sequestered and destroyed in the spleen by mononuclear cell  phagocytosis.   An adequate level of committed platelet precursors (mega-  karyoblasts) in the bone marrow and differentiation into circu-  lating platelets are controlled by specific interactions between  megakaryocyte progenitors and stromal cells in the bone mar-  row as well as thrombopoietin (TPO, a hormonal growth fac-  tor primarily produced by the liver) and various cytokines and  colony-stimulating factors and interleukins (see Table 27-4).  Platelets express high-affinity receptors for TPO, and when cir-  culating platelet levels are normal, TPO is adsorbed onto the  platelet surface and prevented from accessing the bone mar-  row and initiating further platelet production.*! TPO stimu-  lates committed cells at further stages of differentiation to  differentiate faster so that rates of megakaryocyte development,  endomitosis, and platelet release are increased. During inflam-  mation IL-6 induces increased production of TPO, which  increases production of newly formed platelets, which are more  thrombogenic.    Hemostasis is defined as arrest of bleeding (Figure 27-18). As  a result of hemostasis, damaged blood vessels maintain a rel-  atively steady-state of blood volume, pressure, and flow. The  importance of hemostasis clearly varies with vessel size. Dam-  age to large vessels cannot easily be controlled by hemostasis  but requires vascular contraction and dramatically decreased  blood flow into the damaged vessels.   Three equally important components of hemostasis are  the vasculature (endothelial cells and subendothelial matrix),  platelets, and blood proteins (clotting factors). The following  describes the general sequence of events in hemostasis: (1) vas-  cular injury leads to a transient arteriolar vasoconstriction to  limit blood flow to the affected site; (2) damage to the endothe-  lial cell lining of the vessel exposes prothrombogenic subendo-  thelial connective tissue matrix, leading to platelet adherence  and activation and formation of a hemostatic plug to prevent  further bleeding (primary hemostasis); (3) tissue factor, pro-  duced by the endothelium, collaborates with secreted platelet  factors and activated platelets to activate the clotting (coagula-  tion) system to form fibrin clots and further prevent bleeding  (secondary hemostasis); and (4) the fibrin/platelet clot con-  tracts to form a more permanent plug, and regulatory pathways  are activated (fibrinolysis) to limit the size of the plug and begin  the healing process.    The vessel walls consist of a layer of endothelial cells that adhere  to an underlying matrix of connective tissue. The matrix con-  tains a variety of proteins, including collagen, fibronectin, and  laminins. Endothelial cells adhere to the matrix and to each  other through receptors (e.g., vascular endothelial cell-specific    FIGURE 27-18 Hemostasis. Endothelium controls hemostasis by preventing platelet activation (1-3) and preventing  activation of the clotting system (4-6). (1) Prostacyclin production: |njury activates inflammation (COX-17, arachidonic acid).  Enzymes convert arachidonic acid into prostacylin |, (PG/,) in endothelial cells. PGl, eventually increases intracellular cyclic  adenosine monophosphate (cAMP); cAMP inhibits platelet aggregation and induces vasodilation. Nitric oxide (NO) forma-  tion is induced by NO synthases (NOS) and NO causes increased cyclic guanosine monophosphate (cGMP). (2) Nitric oxide  system: Endothelial cell NOS produces nitric oxide, which controls platelet activation through cGMP-mediated signaling.  (3) ADPase: Endothelial cells express a surface bound ADPase (CD39) that converts circulating ADP and ATP to AMP. (4)  Antithrombin Ill-heparan sulfate system: Antithrombin III (A7-///) inhibits thrombin slowly when heparan sulfate (HS) is  absent. When HS is present, it quickly activates thrombin because it binds to a specific site on AT-III that causes an instant  conformational change in AT-III, allowing it to quickly activate thrombin. (5) Tissue factor inhibitor (TFI) system: Expression  of TFI on the endothelial cells and secreted into the circulation complexes with factor IXa to form a competitive inhibitor  of the tissue factor/factor Vila complex (7F/Vila) and prevent further activation of factor X to Xa. (6) Protein C/protein S  pathway (thrombomodulin): Thrombin in the circulation binds to thrombomodulin on the endothelial cell, creating a complex  that can bind and activate protein C to activated protein C (APC) that complexes in the blood or on the surface of active  platelets with protein S. This complex degrades circulating clotting factors Va and Villa to inactive forms (iVa, iVilla) to    cadherin [VE-cadherin], platelet-endothelial cell adhesion mol-  ecule 1 [PECAM-1], integrins [especially 0261 and a581]) that  are expressed only on the intercellular and basal surfaces.   Under normal conditions the endothelium actively regu-  lates blood flow and prevents spontaneous activation of plate-  lets and the clotting system (see Figure 27-18). Endothelial  cells produce nitric oxide (NO) from L-arginine and synthe-  size prostacyclin (PGI,) from arachidonic acid. Both NO, via  cGMP, and PGI, are vasodilators that work in concert with  endothelin (a vasoconstrictor) to maintain blood flow and  pressure.** NO and PGI, also inhibit platelet adhesion and  aggregation. Synergism between PGI, and NO is significant.  PGI, production varies a great deal in response to stimuli,  whereas NO is released continually to regulate vascular tone.  NO has other biologic functions including cell signaling, free  radical production, and possibly others. Endothelium also  produces adenosine diphosphatase, which degrades ADP (a  potent activator of platelets).    The endothelial cell surface contains antithrombotic mol-  ecules, such as glycosaminoglycans (e.g., heparan sulfate),  thrombomodulin, and plasminogen activators. These limit  platelet activation and fibrin deposition. Although thrombo-  modulin and plasminogen activators help control hemostasis  in normal vessels, their effects are magnified during vascular  damage and clot formation; therefore, further information is  provided on these molecules in the following section on control  of hemostatic mechanisms.   As a result of damage to the vessels, the endothelial cell bar-  rier is frequently compromised, the remaining endothelial cells  are activated by products of tissue damage, and the underly-  ing matrix is exposed. Endothelial cells contain intracellular  structures (Weibel-Palade bodies) that contain von Willebrand  factor (vWF) that is released during damage. The matrix, in  addition to collagen and other connective tissue, contains VWF  and can bind additional vWF released by the endothelium.”  The matrix itself and vWF are potent activators of platelets.    t Activation. A, After endothelial denudation, platelets and leukocytes adhere to the sub-    endothelium in a monolayer fashion. B, Higher-power view showing leukocytes and platelets adherent to the subendo-  thelium. €, High magnification of a thrombus showing a mixture of red cells and platelets incorporated into the fibrin  meshwork. D, An electron micrograph showing entrapped RBCs in a fibrin clot. (A and B from Libby P et al: Braunwald’s  heart disease: a textbook of cardiovascular medicine, ed 8, Philadelphia, 2007, Saunders, as reproduced from Faggiotto  A, Ross R: Arteriosclerosis 341-356, 1984; € from Damjanov I, Linder J, editors: Anderson's pathology, ed 10, St Louis,    Platelets normally circulate freely, suspended in plasma, in  an unactivated state. The role of platelets is to (1) contribute  to regulation of blood flow into a damaged site by induction  of vasoconstriction (vasospasm), (2) initiate platelet-plate-  let interactions resulting in formation of a platelet plug to  stop further bleeding, (3) activate the coagulation (or clot-  ting) cascade to stabilize the platelet plug, and (4) initiate  repair processes including clot retraction and clot dissolu-  tion (fibrinolysis). The normal platelet count ranges from  140,000 to 340,000/mm+>. If platelet counts drop below  100,000/mm? an individual is usually considered thrombo-  cytopenic (abnormally low numbers of platelets) and may  experience prolongation of normal clotting but is usually not  at risk for spontaneous major bleeding episodes unless the  platelet count falls below 20,000/mm*. If platelet numbers  are elevated (thrombocytosis) the risk for spontaneous blood  clots (thrombosis), stroke, or heart attack is increased.   The state of platelet activation is primarily under the con-  trol of endothelial cells lining the vessels. Damage to the vessel  initiates a process of platelet activation: (1) increased platelet  adhesion to the damaged vascular wall; (2) activation leading to  secretion of chemicals from platelet granules, which stimulate  changes in platelet shape and biochemistry; and (3) aggrega-  tion as platelet—vascular wall and platelet-platelet adherence  increases.“ This process leads to activation of the clotting    system and development of an immobilizing meshwork of  platelets and fibrin (Figure 27-19).    Normally, platelets are generally observed “rolling” along the mar-  gins of vessels. At sites of vessel injury, however, platelets become  adherent to the site of endothelial damage, where the subendo-  thelial matrix is exposed and endothelial cells have released VWF  and decreased their antithrombotic activities (Figure 27-20).  Platelet adhesion is mostly mediated by the binding of platelet  surface receptor glycoprotein-Ib (GPIb) (in a complex with clot-  ting factors IX and V) to von Willebrand factor (VWF).*° The  vWF protein is found in the subendothelial matrix and is released  by endothelial cells and platelets. Deficiencies in GPIb (Bernard-  Soulier syndrome) or vWF (von Willebrand disease) lead to  highly defective hemostasis and congenital bleeding disorders.*°  Platelet adhesion narrows the diameter of the blood vessel, result-  ing in increasing shear forces that could strip platelets off the ves-  sel surface. However, those same forces induce conformational  changes in the vWF molecule that result in increased affinity with  GPIb, thus stabilizing the adherent platelet.*”   Platelet adhesion is also facilitated by other interactions  between platelet receptors and exposed molecules of the sub-  endothelial matrix. For instance, adhesion is increased through  binding of the platelet collagen receptors GPVI and integrin  0.261 to exposed collagen in the matrix.    ¢ Adhesion is initiated by loss of endothelial cells  (or rupture or erosion of atherosclerotic plaque),  which exposes adhesive glycoproteins such as  collagen and von Willebrand factor (vWF) in  the subendothelium. vWF and, perhaps, other  adhesive glycoproteins in the plasma deposit  on the damaged area. Platelets adhere to the  subendothelium through receptors that bind to  the adhesive glycoproteins (GPlb, GPla/lla,  GPllb/Iila).    ¢ After platelets adhere they undergo an activation  process that leads to a conformational change in  GPllb/IIla receptors, resulting in their ability to  bind adhesive proteins, including fibrinogen and  von Willebrand factor.   * Stabilization of the platelet plug (blood clot)  occurs by activation of coagulation factors,  thrombin, and fibrin    * Clot retraction, using large number of platelets,  joins the edges of the injured vessel.    As a result of interactions with the endothelium or the suben-  dothelial matrix, as well as exposure to inflammatory media-  tors produced by the endothelium and other cells, the platelets  are activated. Activation results in reorganization of the platelet  cytoskeleton, leading to dynamic changes in platelet shape from  smooth spheres to those with spiny projections and degranula-  tion (also called the platelet-release reaction) and resulting in  the release of various potent biochemicals (Figure 27-21).**    Platelets contain three types of granules: lysosomes, dense  bodies, and alpha granules.*? The contents of the dense bod-  ies and alpha granules are particularly important in hemostasis.  The dense bodies contain ADP, serotonin, and calcium. ADP  recruits and activates other platelets through specific receptors.  During activation the platelet plasma membrane undergoes  several important changes, including becoming ruffled and  sticky, undergoing cellular spreading to make tight contacts  between neighboring platelets that cause the platelet plug to    FIGURE 27-21 Micrograph of an Active and Moderately Active Platelet.  (Copyright Dennis Kunkel Microscopy, Inc.)    seal the injured endothelium, and externalizing the phospho-  lipid phosphatidylserine, which provides a matrix for activation  of clotting factors (see Figure 27-20). Serotonin is a vasoactive  amine that functions like histamine and increases vasodilation  and vascular permeability. Calcium is necessary for many of the  adhesive interactions as well as intracellular signaling mecha-  nisms that control platelet activation.   Alpha granules contain a large number of clotting factors  (e.g., fibrinogen, factor V), growth factors (e.g., PDGF), and  heparin-binding proteins (e.g., platelet factor 4). Many of these  mediators either promote or inhibit platelet activity and the  eventual process of clot formation. PDGF stimulates smooth  muscle cells and promotes tissue repair. Heparin-binding pro-  teins enhance clot formation at the site of injury.   Platelets also initiate production of the prostaglandin deriv-  ative thromboxane A, (TXA,), which counters the effects of  PGI, that is produced by endothelial cells (see Figure 27-20).  TXA, promotes the degranulation of platelets, increases expres-  sion of platelet fibrinogen receptors, and stimulates platelet  aggregation. The balance between TXA, and PGI, affects plate-  let aggregation, which is favored by TXA, excess and inhib-  ited by PGI, excess. An isoform of cyclooxygenase (COX-1)  converts arachidonic acid to TXA, in platelets. Aspirin at low  doses specifically and irreversibly inactivates COX-1, decreas-  ing production of TXA, and decreasing platelet activation.°° A  few days of low doses of aspirin lead to more than 95% inhibi-  tion of TXAy.   Other stimuli of platelet activation include epinephrine,  thrombin, and collagen. Thrombin and collagen are particu-  larly strong stimuli. Thrombin cleaves the extracellular domain  of G-protein—coupled protease-activated receptors (PARs),  thereby initiating transmembrane signaling.   Platelet aggregation is stimulated primarily by TXA, and  ADP, which induce functional fibrinogen receptors on the  platelet. The GPIIb/IIIa complex (also called integrin alIbp3)  undergoes a conformational change during activation to  become a calcium-dependent receptor for fibrinogen (see  Figure 27-20). It is a member of the integrin receptor family  and binds other matrix proteins (e.g., fibronectin, fibrinogen,    thrombospondin). Defects in expression of the GPIIb/IHa  complex (Glanzmann thrombasthenia) result in a failure  to aggregate and diminished clotting times.°! Although the  GPIIb/IIIa complex is the most abundant aggregation receptor  on the platelet, receptors for vWF (GPIb) and collagen (GPVI)  also contribute to the process. Interplatelet aggregation and  clot retraction that form the primary hemostatic plug are facili-  tated by fibrinogen bridges between receptors on the platelets.  The GPIb-Hla—fibrinogen pathway is essential for the forma-  tion of a thrombus and as such is an important therapeutic  target for blockage by antiplatelet drugs. In addition, fibrin  strands within the clot shorten and become denser and stron-  ger, helping the clot to approximate the edges of the injured  vessel wall and sealing the site of injury. Contraction of myo-  sin and actin filaments in the platelet cytoskeleton mediates  platelet contraction and fusion of the platelet mass into a sec-  ondary hemostatic plug. Contraction expels serum from the  fibrin meshwork, resulting in greater packing and increased  strength. This process usually begins within a few minutes  after a clot has formed, and most of the serum is expelled  within 20 to 60 minutes.*?   If blood vessel injury is minor, primary hemostasis is  achieved by formation of the platelet plug within 3 to 5 min-  utes of injury. Platelet plugs seal the many minute ruptures that  occur daily in the microcirculation, particularly in capillaries.  With too few platelets, numerous small hemorrhagic areas  called purpuras develop under the skin and throughout the  tissues (see Chapter 29). If primary hemostasis is inadequate  to prevent further bleeding, the process proceeds through sec-  ondary hemostasis to create a larger complex of more tightly  interactive platelets within a matrix created by activation of the  clotting system.   A blood clot is a meshwork of protein strands that stabilizes the  platelet plug and traps other cells, such as erythrocytes, phago-  cytes, and microorganisms. The strands are made of fibrin,  which is produced by the clotting (coagulation) system. The  clotting system was described in Chapter 7 and consists of a  family of proteins that circulate in the blood in inactive forms  (proenzymes). Initiation of the system results in sequential  enzymatic activation (cascade) of multiple members of the sys-  tem until a fibrin clot is created (Table 27-7).   The clotting system is usually presented as two pathways  of initiation (intrinsic and extrinsic pathways) that join in a  common pathway (Figure 27-22). The intrinsic pathway is  activated when Hageman factor (factor XII) in plasma contacts  negatively charged subendothelial substances exposed by vas-  cular injury. Activated factor XII (XIa) is an active enzyme  with factor XI as a substrate. The extrinsic pathway is activated  when tissue factor (TF) (also called tissue thromboplastin)  reacts with a high affinity with circulating activated factor VII  (TEF/VHa); approximately 1% of circulating factor VII has been  spontaneously activated to VII.°° TF is a transmembrane pro-  tein that exists in an inactive form on the endothelial mem-  brane, but is activated into an active enzyme with factors IX  and X as substrates.**   Vila forms a complex with  tissue factor and activates  factors IX and X    Activated platelets are important participants in clotting.  The phosphatidylserine-rich surface produced during activa-  tion provides a matrix on which several important complexes  of clotting factors are formed. These include the intrinsic path-  way’s tenase complex (factor X and activated factors VIII and  IX) that activates factor X and the prothrombinase complex  (prothrombin and activated factors X and V) that activates  prothrombin into thrombin (see Figure 27-22). Thrombin  then converts fibrinogen into fibrin, which polymerizes into  a fibrin clot. Thrombin has broad reactivity in the inflamma-  tory response. In addition to producing fibrin, thrombin is an  activator of other coagulation proteins (e.g., factors V, VII, XI,  XD, platelets (e.g., aggregation, degranulation), endothelial  cells (e.g., up-regulation of adhesion molecules for leukocytes,  increased NO, PGI,, PDGF), and monocytes (e.g., cytokine  secretion, increased receptors for endothelial cells).   The extrinsic pathway is clearly predominant; individuals with  deficiencies in intrinsic pathway components (i.e., factor XI, factor  XII) do not have prolonged bleeding.°° As with the complement  cascade, the clotting system is complex with a large number of  alternative activators and inhibitors, and the relative importance  of particular factors may differ between in vivo hemostasis and  in vitro testing of clotting or may depend on the particular mech-  anism by which the pathway is activated.°’ Also there is interac-  tion between components of the intrinsic and extrinsic pathways  so that an activated member of one pathway may activate a mem-  ber of the other pathway (e.g., factor VIIa of the extrinsic pathway  can directly activate factor IX of the intrinsic pathway).    Another similarity with the complement system is that  some complexes may have biologic activities outside the pre-  dominantly described pathway. For instance, in vitro studies  have showed that the TF/VIIa complex activates protease-  activated receptors (PARs); thus TF may contribute to other  biologic processes by facilitating signaling in vascular cells  (Figure 27-23). Abnormal TF expression in the vessel wall  and/or low circulating cells initiates life-threatening throm-  bosis in various diseases. TF also contributes to inflamma-  tion, tumor angiogenesis and metastasis, and cell migration  (Figure 27-24).    The endothelium is the major site of hemostasis. Despite the  continual presence of clotting factors and platelets in the cir-  culation, blood normally remains fluid. Thus the major regula-  tory factors that control hemostasis reside where the greatest  probability of clotting would occur: on the endothelial cell  surface (see Figure 27-18). The primary anticoagulant mecha-  nisms include thrombin inhibitors (e.g., antithrombin IID), tis-  sue factor inhibitors (e.g., tissue factor pathway inhibitor), and  mechanisms for degrading activated clotting factors (e.g., pro-  tein C).°° Antithrombotic mechanisms are listed in Table 27-8.   Antithrombin III (AT-II) is a circulating plasma serine  protease inhibitor produced by the liver. Specifically, it inhib-  its thrombin and several activated clotting factors (e.g., VIIa,  IXa, Xa, XIa, XIa). Clinically administered heparin or heparan  sulfate (on the surface of endothelial cells) binds to AT-HI and  induces a conformational change that greatly enhances its activ-  ity. Under normal conditions the presence of endothelial cell  heparan sulfate and available AT-II in the circulation coop-  erate to protect the vessels from the effects of spontaneously  activated thrombin (see Figure 27-18).   Acquired AT-III deficiencies can result from infection with  bacteria that produce AT-III inhibitors, sepsis, liver disease,  and nephrotic syndrome and lead to venous thrombosis and  pulmonary embolism.   Tissue factor pathway inhibitor (TFPI) is produced by  endothelial cells and platelets and complexes to, and reversibly  inhibits, factor Xa.°? The resultant TFPI/Xa complex inhibits  TE/VIla, which mediates feedback inhibition of tissue factor as  well as factor VIIa (see Figure 27-18). Although the majority of  TFPI remains associated with endothelial or platelet surfaces,  about 20% circulates in plasma with lipoproteins. Hepa-  rin increases plasma levels of TFPI, which may contribute to  heparin’s antithrombotic effects.   Thrombomodulin is a membrane thrombin-binding pro-  tein on the surface of endothelial cells. Protein C in the cir-  culation binds to thrombomodulin in a thrombin-dependent  manner and is converted to activated protein C (see Figure  27-18). Activated protein C, in association with a cofactor  (protein S), degrades factors Va and VIIla. Deficiencies of AT-  IL, protein C, or protein S are important causes of hypercoagu-  lation (increased clotting).°! Expression of thrombomodulin  and the endothelial cell protein C receptor is down-regulated  by cytokines and other products of inflammation (e.g., IL-la,  tumor necrosis factor-alpha [TNF-a], endotoxin). Decreased    FIGURE 27-22 The Clotting System. The clotting system is frequently presented with two routes of initiation: the intrin-  sic and extrinsic pathways. The intrinsic pathway is initiated by activation of factor XII to Xlla by negatively charged molecules  or surfaces or by the action of kallikrein, a member of the kinin system. Factor Xlla induces enzymatic activation of factor XI  to Xla, which activates IX to Xa. A complex of factors IXa/VIlla/X and calcium aggregate on the surface of activated platelets  that have externalized the plasma membrane phospholipid phosphatidylserine (PS). The IXa/VIlla complex is an active enzyme  (“tenase") that can activate factor X to Xa. The extrinsic pathway is the primary physiologic route of activation and is activated  by exposure of tissue factor (7F) on endothelial cells or in the circulation. TF activates factor VII in the blood to factor Vila. The  TF/Vlla complex associates with circulating factors IX and X and calcium on the PS-rich surface of activated platelets. The TF/  Vila/IX complex is a tenase that produces Xa. The Vila/TF complex also can activate factor IX to IXa and facilitate the formation  of the Villa/IXa tenase. Factor Xa associates with activated factor V (Va) and prothrombin (P7) in a PS and calcium-dependent  complex that is a “prothrombinase,” which converts PT to thrombin (7). Thrombin is an active enzyme that converts fibrinogen  (Fib) to fibrin. Thrombin also activates factor XIII to XIlla, which cross-links fibrin into a matrix that seals clots. Thrombin ampli-  fies the clotting process by activating factor VIII to Villa and facilitating formation of the Villa/IXa tenase and by activating  factor V to Va to create further prothrombinase complexes.    expression prevents protein C activation, thereby enhancing clot Lysis of Blood Clots   formation. Activated protein C inhibits the adhesion of neutro- Concurrent with activation of coagulation is the activation  phils to the endothelium, but during inflammation the neutro- of pathways that limit the size of the clot and remove the  phil enzyme elastase enzymatically removes thrombomodulin __ clot after bleeding has ceased and repair has begun. The pri-  from the endothelial cell surface.°? mary mechanism for lysis (breakdown) of blood clots is the    fibrinolytic system (plasminogen-plasmin system) that pro-  duces plasmin. Plasmin (also called fibrinase or fibrinolysin) is  a serine protease that degrades fibrin polymers in clots.°?   The inactive precursor of plasmin is plasminogen, which  is produced in the liver (Figure 27-25). Plasminogen activa-  tion may occur by several means, although the most physi-  ologically important is by the action of tissue plasminogen  activator (t-PA). Endothelial cells at a site of vascular injury  express t-PA, which is also a serine protease that reaches maxi-  mal enzymatic activity after binding to fibrin and proteolyti-  cally activates plasminogen to plasmin. Another activator of  plasminogen is urokinase-like plasminogen activator (u-PA).  The u-PA is a serine protease that can bind to a specific cellular    Fibrous _Lipid-rich  cap core  FIGURE 27-23 Tissue Factor (TF) in Thrombus Formation after Rupture of  an Atherosclerotic Plaque. In atherosclerosis TF is expressed by macrophage-  derived foam cells and within atherosclerotic plaque. High levels of TF exposed  on rupture trigger thrombosis and myocardial infarction. In addition, blood-borne  TF may contribute to thrombus propagation. TF is also expressed by adventitial  cells (blue). EC, Endothelial cells; SMC, smooth muscle cells. (Modified from  Mackman N: Arterioscler Thromb Vasc Biol 24[6]:1015-1022, 2004.)    u-PA receptor (u-PAR), causing activation of plasminogen and  resulting in plasmin generation. This urokinase is the major  activator of fibrinolysis in the extravascular or tissue compart-  ment, whereas t-PA is largely involved in intravascular fibrino-  lysis. Several cancers appear to use membrane-bound u-PA to  digest intercellular matrix and greatly facilitate tumor invasion  and metastasis. Both t-PA and u-PA have been used clinically  to treat diseases associated with a blood clot (e.g., pulmonary  embolism, myocardial infarction, stroke).   As with most components of inflammation, plasmin inter-  acts greatly with other factors. In addition to activation by t-PA  and u-PA, plasminogen is activated to plasmin by thrombin,  fibrin, factor XIIa, factor XIa, and kallikrein. Plasmin is pro-  teolytic to several substrates, including activation of collage-  nases, complement components Cl and C3, and factor XII,  and cleaves fibronectin, fibrin, thrombospondin, laminin, and  vWF. Plasmin activity is usually controlled directly by the serine  protease inhibitor @,-antiplasmin or by inhibiting plasminogen  activation by specific plasminogen activator inhibitors (PAIs).   Congenital defects in the fibrinolytic system are very rare  and variable in effects. Congenital plasminogen deficiency is  associated with venous thrombosis if the plasminogen level is  decreased by more than 50%. Apparent defects in plasmino-  gen may result from dysfunctional plasminogen or an absence  of fibrinogen. Congenital deficiencies of plasminogen activator  or abnormal increases in plasminogen activator inhibitor also  may increase the chance for spontaneous thrombosis. Alter-  native routes of fibrin degradation may mitigate the sever-  ity of symptoms in these deficiencies. Other enzymes released  during inflammation (e.g., leukocyte elastase, cathepsin G,  metalloproteinases [MMPs]) are fibrinolytic.   Cross-linked fibrin is deposited in tissues around wounds,  inflammatory sites, and tumors. Fibrin removal is an    FIGURE 27-24 Factor Vila Signaling Through Tissue Factor (TF) Expressed on the Surface of Cells Mediates  Changes in Disease-Related Cellular Activities. EC, Endothelial cell; MC, monocyte/macrophage; SMC, smooth muscle  cell. (Modified from Rao LV, Pendurthi UR: Arterioscler Thromb Vasc Biol 25[1]:47—56, 2005.)    important biologic process, for intravascular and extravas-  cular spaces, with various controlling mechanisms that can  lead to abnormalities of fibrin accumulation and throm-  botic events and can be a structural barrier to tumor invasion  (see Chapter 13).   Products of fibrinolysis include fibrin degradation products  (FDPs) (see Figure 27-25). A major FDP is p-dimer. p-dimer  is two pv domains from adjacent fibrin monomers that are  cross-linked by factor XII]a and released as a result of enzy-  matic cleavage by plasmin. Measurement of levels of circulating  p-dimer has been used for diagnosis of deep venous thrombosis  (DVT) or pulmonary embolism (PE). Despite extensive litera-  ture, the diagnostic role of p-dimer is unclear because of the  use of multiple p-dimer assays with different sensitivities and  variabilities.©°   The bone marrow is the soft spongy tissue found within bones,  especially the sternum, pelvis, and femur. Several abnormal  conditions in the numbers or morphology of circulating blood  cells or suspected infection of the marrow may justify further  investigation of the bone marrow.   Usually bone marrow is aspirated from the sternum or pel-  vis using a needle. In children a bone marrow aspirate can be  obtained from the vertebrae or the femur. The aspirate is exam-  ined microscopically and may be cultured if infection (e.g.,  fungi, mycobacteria, brucellosis, typhoid fever) is suspected.  Microscopic evaluation may also include flow cytometry, chro-  mosome analysis, or polymerase chain reaction (PCR) related  to the presence of atypical cells, the presence of atypical num-  bers of normal cells, and the absence of particular cell types.  A normal bone marrow aspirate contains stromal cells (fibro-  blasts, macrophages, osteoblasts, adipocytes), stem cells (hema-  topoietic, mesenchymal, and endothelial), and immature and  mature forms of blood cells (erythrocytes, leukocytes, platelets)  (Figure 27-26). The differential cell count of a bone marrow  aspirate involves examining approximately 400 nucleated cells    FIGURE 27-25 The Fibrinolytic System. Fibrinolysis is initiated by the bind-  ing of plasminogen to fibrin. Although tissue plasminogen activator (t-PA) initiates  intravascular fibrinolysis, urokinase plasminogen activator (u-PA) is the major acti-  vator of fibrinolysis in tissue (extravascular). Inhibitors (indicated by red lines) of  fibrinolysis include a -antiplasmin (o2-AP) that inhibits plasmin and plasminogen  activator inhibitor 1 (PA/-7)that inhibits t-PA. Plasmin digests the fibrin into smaller  soluble pieces (fibrin degradation products). u-PAR, Urokinase-like plasminogen  activator receptor.    under oil-immersion magnification and counting populations  of cells differentiated based on morphology. The relative num-  ber of each type of stem cell is expressed as a fraction of 400  (Table 27-9).   Bone marrow iron stores, primarily in macrophages, can  be examined using special stains (e.g., Prussian blue) for iron-  containing granules. A direct measure of iron stores also can be  obtained only from liver biopsy specimens, although bone mar-  row is preferred as a safer procedure and because the bone mar-  row is the immediate source of iron destined for erythrocyte  production.   Bone marrow aspiration is an important diagnostic test for  severe central defects in hematopoiesis (e.g., aplastic anemia,  metabolic anemias arising from insufficient iron or inadequate  erythropoietin, thrombocytopenia, neutropenia; see Chapters  28 and 29). Examination of the bone marrow is also useful to  diagnose B-lymphocyte immune deficiencies (see Chapter 9),  nonmalignant myeloproliferative disorders (e.g., polycythemia  vera), and lymphoid/monocytic malignancies (e.g., leukemias,  myelomas, lymphomas; see Chapters 29 and 30). This test can  also be used to monitor the effects of chemotherapy on malig-  nancies that have invaded the bone marrow (see Figure 27-26).  A marrow aspirate that is richly cellular implies normal or  increased hematopoiesis but does not indicate whether marrow  activity is effective.   Results from bone marrow aspiration are sometimes limited  because this technique disturbs the architecture of the marrow  and only provides an analysis of the general cellularity (num-  bers of constituent cells) of the marrow. On occasion, analysis  of an aspirate may only suggest the presence of a malignancy or  a central defect in hematopoiesis without being clearly confir-  matory, or the sample may be inadequate for diagnosis of bone  marrow fibrosis. In these cases the need for a bone marrow  biopsy may be indicated.    FIGURE 27-26 Bone marrow samples. Images A through D contain bone marrow aspirates; images E through I contain  bone marrow biospy specimens. A, Normal bone marrow aspirate stained by the May-Grlinwald/Giemsa technique. B, A normal  megakaryocyte with budding platelets at the plasma membrane (Wright stain). C, Osteoclasts containing multiple nuclei that are  separated by cytoplasm. These cells may be confused with megakaryocytes. D, Metastatic adenocarcinoma of the breast. E, Nor-  mal bone marrow biospy with paratrabecular space with immature myeloid cells (two-headed arrow) and circled erythron (site of  erythrocyte production). F, A normal erythroid island in which several erythroid precursor clusters. G, Essential thrombocytopenia  with normal cellularity, but increased numbers of large megakaryocytes. H, Bone marrow biopsies representing conditions of  normal cellularity (left), hypocellularity (middle) as would be seen in conditions of bone marrow depletion such as aplastic anemia,  and hypercellularity (right) as seen in malignant conditions. I, Advanced chronic idiopathic myelofibrosis marked by extensive  replacement of the normal marrow stroma by fibrous tissue (stained pink; hematoxylin-eosin stain). (Sources for photographs: A, C  from Hoffbrand V et al: Color atlas of clinical hematology, ed 4, Philadelphia, Mosby, 2013; B from Rodak BF et al: Hematology, ed 4,  Philadelphia, Saunders, 2012; D, F, G, H from Jaffe E: Hematology, Philadelphia, Saunders, 2010; E from Young: Clinical hematol-  ogy, ed 1, Mosby, 2005; I from Cleveland Clinic: Current clinical medicine, ed 2, Philadelphia, Saunders, 2010.)    DEVELOPING CELLS IN MARROW BIRTH 1 MONTH-1 YEAR 1-4 YEARS 4-12 YEARS ADULT  Erythrocytic series 14 19 Z\ 20    Note: Values are percentages of cell types counted during examination of a marrow specimen containing approximately 400 nucleated cells.    During a biopsy, a special needle is used to obtain a “core”  or cylindrical sample of bone and marrow in which the  three-dimensional structure of the marrow is preserved. The  biopsy specimens provide the most reliable and complete  information about marrow cellularity (see Figure 27-26).  Obtaining a bone marrow biopsy is, however, usually more  painful and expensive than aspiration. Therefore, biopsy is  not performed unless insufficient information is obtained  from aspiration.    Blood tests provide information about the absolute and rela-  tive numbers of blood cells in a specimen of blood, as well as  various structural and functional characteristics of the cells, and  usually provide the initial justification for performing a bone  marrow aspiration. Deviations from the normal differential  distribution and the presence of abnormal or immature cells  can reflect disease, physiologic states (e.g., pregnancy, infancy,  old age), injury, or dysfunction in almost any part of the body.  Blood tests that reflect chiefly hematologic disorders are listed  in Table 27-10.    Blood cell counts tend to rise above adult levels at birth and  then decline gradually throughout childhood. Table 27-11 lists  normal ranges during infancy and childhood. The immediate  rise in values is the result of accelerated hematopoiesis during  fetal life, increased numbers of cells that result from the trauma  of birth, and cutting of the umbilical cord.   Average blood volume in the full-term neonate is 85 ml/  kg of body weight. The premature infant has a slightly larger  blood volume of 90 ml/kg of body weight, with the mean  increasing to 150 mg/kg during the first few days after birth. In  both full-term and premature infants, blood volume decreases  during the first few months. Thereafter the average blood vol-  ume is 75 to 77 ml/kg, which is similar to that of older children  and adults.   The hypoxic intrauterine environment stimulates eryth-  ropoietin production in the fetus and accelerates fetal eryth-  ropoiesis, producing polycythemia (excessive proliferation of  erythrocyte precursors) of the newborn. After birth the oxygen  from the lungs saturates arterial blood, and more oxygen is  delivered to the tissues. In response to the change from a pla-  cental to a pulmonary oxygen supply during the first few days of  life, levels of erythropoietin and the rate of blood cell formation  decrease.   The very active rate of fetal erythropoiesis results in a large  number of immature erythrocytes (reticulocytes) in the periph-  eral blood of full-term neonates. After birth the number of  reticulocytes decreases about 50% every 12 hours so that it is  rare to find an elevated reticulocyte count after the first week of  life. During this period of rapid growth, the rate of erythrocyte  destruction is greater than that in later childhood and adult-  hood. In full-term infants, normal erythrocyte life span is 60  to 80 days; in premature infants, it may be as short as 20 to 30    days; and in children and adolescents, it is the same as that in  adults—120 days.   The postnatal decrease in hemoglobin and hematocrit val-  ues is more marked in premature infants than in the full-term  infant. In the preschool and school-age child, hemoglobin,  hematocrit, and red blood cell counts gradually rise. Metabolic  processes within the erythrocytes of neonates differ significantly  from those of erythrocytes in the normal adult. Among other  differences, the relatively young population of erythrocytes in  the newborn consumes greater quantities of glucose than do  erythrocytes in adults.   Children have quantitative and qualitative differences in  clotting factors that result in decreased risk for thrombotic  diseases and complications.°° Levels of some clotting-related  proteins are reduced in newborns (e.g., antithrombin III). Sev-  eral clotting factors are initially produced in fetal forms (e.g.,  fibrinogen, antithrombin II/) that are less active in thrombosis  than adult forms.   At birth, the lymphocyte count is high and continues to rise  during the first year of life, and then steadily declines until lower  adult values are reached. The lymphocytes of children also tend  to have more cytoplasm and less compact nuclear chromatin  than do the lymphocytes of adults. A possible explanation is  that children tend to have more frequent viral infections, some  of which are subclinical, and are receiving vaccinations, both of  which are associated with atypical lymphocytes.   The neutrophil count, like the lymphocyte count, is high at  birth and rises during the first days of life. After 2 weeks the  neutrophil count falls to within or below the normal adult  range. By approximately 4 years of age, the neutrophil count  is the same as that of an adult. The eosinophil count is high in  the first year of life and higher in children than in teenagers or  adults. Monocyte counts also are high in the first year of life but  then decrease to adult levels. Platelet counts in full-term neo-  nates are comparable with platelet counts in adults and remain  so throughout infancy and childhood.    Blood composition changes little with age. Erythrocyte life span  in older adults is normal, although erythrocytes are replenished  more slowly after bleeding, probably because of iron depletion.  Total serum iron, total iron-binding capacity, and intestinal  iron absorption are all decreased in older adults. Iron deficiency  is often responsible for the low hemoglobin levels noted in older  adults. The plasma membranes of erythrocytes become increas-  ingly fragile, presumably because of physical trauma inflicted  during circulation.   Lymphocyte function decreases with age (see Chapters  8 and 9), causing changes in cellular immunity with some  decline in T-cell function. The humoral immune system is less  able to respond to antigenic challenge. No changes in plate-  let numbers or structure have been observed in elderly per-  sons, yet platelet adhesiveness probably increases. Although  fibrinogen levels and levels of factors V, VIL, and IX tend to be  increased in older adults, evidence concerning hypercoagula-  bility is inconclusive.   Differential white cell count (absolute  number of a type of leukocyte/l of  blood)   Concentration of hemoglobin in each erythrocyte  (percentage of erythrocyte occupied by hemoglobin)   Percentage of a given volume of blood that is occupied  by erythrocytes   Number of reticulocytes/uL of blood (also expressed as  percentage of reticulocytes in total red cell count)   Amount of iron in serum plus amount of transferrin  available in serum (mcg/dl)    Concentration of protoporphyrin in erythrocytes (mcg/  dl); an indicator of iron-deficient erythropoiesis  Antibody binding to erythrocytes    Detection of antibodies to erythrocyte antigens (other  than the ABO antigens)    Anemias, hemolytic disease caused by ABO or Rh  incompatibility, Hodgkin disease, polycythemia vera,  thalassemia major   Sickle cell disease, sickle cell trait, hemoglobin C disease,  hemoglobin C trait, thalassemias   Acute hemorrhage, hemochromatosis, hemosiderosis,  sideroblastic anemia, iron deficiency anemia, iron  overload, thalassemias    Hemolytic disease of the newborn, autoimmune hemolytic  anemia, drug-induced hemolytic anemia, transfusion reaction  Same as for DAT   Infectious lymphocytosis, infectious mononucleosis,  hematopoietic disorders, anemias, leukemia,  lymphosarcoma, Hodgkin disease, primary immune  deficiency   Hodgkin disease, infectious mononucleosis, monocytic  leukemia, non-Hodgkin lymphoma, polycythemia vera,  primary immune deficiency    Circulating anticoagulants  (immunoglobulin G [IgG] or M [IgM]  antibodies that inhibit coagulation)    Duration of bleeding following a standardized  superficial puncture wound of the skin, integrity of  the platelet plug, measured in minutes following  puncture    Platelet number and function, fibrinogen quantity and  use, measured in hours required for expression of  serum from a clot incubated in a test tube    Overall ability of blood to clot, as measured in minutes  in a test tube    Presence of antibodies that neutralize clotting  factors and inhibit coagulation, as indicated by  prolonged clotting time, prothrombin time, or partial  thromboplastin time   Effectiveness of clotting factors (except factors VII  and VIII), effectiveness of intrinsic pathway of  coagulation cascade, as measured by a test tube (in  seconds)    Effectiveness of activity of prothrombin, fibrinogen,  and factors V, VII, and X; effectiveness of vitamin  K—dependent coagulation factors of the extrinsic and  common pathways of the coagulation cascade as  measured in a test tube (in seconds)    Quantity and activity of fibrinogen as measured in a  test tube (in seconds)    Fibrinogenic activity as measured by levels of fibrin-  fibrinogen degradation products (in mcg/ml of blood)    Anemias, multiple myeloma, myelofibrosis, polycythemia  vera, leukemia, disseminated intravascular coagulation  (DIC), hemolytic disease of the newborn, idiopathic  thrombocytopenic purpura, transfusion reaction,  lymphoproliferative disorders   Leukemia, anemias, DIC, fibrinolytic activity, purpuras,  hemorrhagic disease of the newborn, infectious  mononucleosis, multiple myeloma, clotting factor  deficiencies, thrombasthenia, thrombocytopenia, von  Willebrand disease   Acute leukemia, aplastic anemia, factor XIII deficiency,  increased fibrinolytic activity, Hodgkin disease,  hyperfibrinogenemia or hypofibrinogenemia, idiopathic  thrombocytopenic purpura, multiple myeloma, polycythemia  vera, secondary thrombocytopenia, thrombasthenia   Anemia, macroglobulinemia, Bernard-Soulier syndrome,  multiple myeloma, myeloid metaplasia, plasma cell  dyscrasias, thrombasthenia, thrombocytopathy, von  Willebrand disease   Afibrinogenemia, Bernard-Soulier syndrome, thrombasthenia,  hemorrhagic thrombocythemia, myeloid metaplasia,  plasma cell dyscrasias, platelet release defects,  polycythemia vera, preleukemia, sideroblastic anemia, von  Willebrand disease, Waldenstrém macroglobulinemia,  hypercoagulability   Afibrinogenemia, clotting factor deficiencies, excessive  fibrinolysis, hemorrhagic disease of the newborn,  hypofibrinogenemia, hypoprothrombinemia, leukemia   Afibrinogenemia, presence of fibrin-fibrinogen degradation  products, macroglobulinemia, multiple myeloma, DIC,  plasma cell dyscrasias    Presence of circulating anticoagulants, DIC, clotting factor  deficiencies, excessive fibrinolysis, hemorrhagic disease  of the newborn, hypofibrinogenemia and afibrinogenemia,  prothrombin deficiency, von Willebrand disease, acute  hemorrhage   Hypofibrinogenemia, dysfibrinogenemia, and afibrinogenemia;  presence of circulating anticoagulants; DIC; deficiency  of factors V, VII, or X; presence of fibrin degradation  products, increased fibrinolytic activity, hemolytic jaundice,  hemorrhagic disease of the newborn; acute leukemia,  polycythemia vera, prothrombin deficiency, multiple myeloma   Hypofibrinogenemia, dysfibrinogenemia, and  afibrinogenemia; presence of circulating anticoagulants;  hemorrhagic disease of the newborn, polycythemia  vera; increase in fibrin-fibrinogen degradation products;  increased fibrinolytic activity   Acute leukemia, congenital hypofibrinogenemia or  afibrinogenemia, DIC, increased fibrinolytic activity, severe  hemorrhage   Transfusion reactions, DIC, internal hemorrhage in the  newborn, deep vein thrombosis, pulmonary embolism    Data from Byrne CJ et al: Laboratory tests: implications for nursing care, Menlo Park, CA, 1986, Addison-Wesley; Bick RL et al: Hematology:  clinical and laboratory practice, St Louis, 1993, Mosby.  *Note: See Figure 27-22 and Table 27-7 for information about clotting factors and their sequence of activation in the coagulation cascade.    HEMOGLOBIN HEMATOCRIT RETICULOCYTES LEUKOCYTES NEUTROPHILS LYMPHOCYTES EOSINOPHILS MONOCYTES PLATELETS  AGE (g/dl): MEAN : MEAN : MEAN (WBC/mm?):MEAN : MEAN : MEAN : MEAN :MEAN __(103/mm3)   3 mo 12.0 36 1.0 12,000 30 63 140-340  6 mo-6 yr 12.0 37 1.0 10,000 45 48 140-340  7-12 yr 13.0 38 1.0 8,000 59 38 140-340  Adult 13.0 40 1.0 8,000 59 35 140-340  Female 14 4] 0.8-4.1 7,400 = 140-340  Male 16 47 0.8-2.5 7,400 140-340    Blood consists of cells suspended in a solution of about 90%  water and 10% solutes. In adults the total blood volume is  approximately 5.5 L.    . Plasma, the liquid portion of the blood, contains two major    . Erythrocytes are the most abundant cells of the blood, occu-    pying approximately 48% of the blood volume in men and  approximately 42% in women. Erythrocytes are responsible  for tissue oxygenation.    stitute approximately 5000 to 10,000 cells/mm? of blood.  Leukocytes defend the body against infection and remove  dead or injured host cells.    mately 55% of the leukocytes) and is the primary granulo-  cyte that defends against infections.    . Lymphocytes are the primary cells of the immune response.  . Platelets are not cells—they are disk-shaped cytoplasmic    fragments. Platelets are essential for blood coagulation and  control of bleeding.   The lymphoid organs are classified as primary (thymus and  bone marrow) or secondary (spleen, lymph nodes, tonsils,  and Peyer patches of the small intestine).   The lymphoid organs are sites of residence, proliferation,  differentiation, and function of lymphocytes and mono-  nuclear phagocytes.   The spleen is the largest of the secondary lymphoid organs  and functions as the site of hematopoiesis in the fetus, filters  and cleanses the blood, and is a reservoir for lymphocytes  and other blood cells.   The lymph nodes are the site of development or activ-  ity of large numbers of lymphocytes, monocytes, and  macrophages.   The MPS is composed of macrophages in tissue and lym-  phoid organs.   The MPS is the main line of defense against bacteria in  the bloodstream and cleanses the blood by removing old,  injured, or dead blood cells; antigen-antibody complexes;  and macromolecules.    Hematopoiesis, or blood cell production, occurs in the liver  and spleen of the fetus and in the bone marrow after birth.  Hematopoiesis involves two stages: (a) proliferation, and  (b) maturation.   Hematopoiesis continues throughout life to replace blood  cells that grow old and die, are killed by disease, or are lost  through bleeding.    Bone marrow consists of red (hematopoietic) marrow  (blood vessels, mononuclear phagocytes, stem cells, blood  cells in various stages of differentiation, stromal cells) and  yellow marrow (fatty tissue).    cells; mesenchymal stem cells develop into fibroblasts,  osteoclasts, and adipocytes; and hematopoietic stem cells  develop into blood cells.    ronments (niches) in the bone marrow (an osteoblastic niche  and a vascular niche) in which hematopoietic stem cells are  signaled to undergo differentiation through the effects of  multiple cytokines and chemokines and through direct con-  tact with osteoblasts (osteoblastic niche) or vascular endothe-  lial cells (vascular niche), as well as several other specialized  cells, including CAR cells and nestin-expressing cells.    stimulating factors) are necessary for the adequate produc-  tion of myeloid, erythroid, lymphoid, and megakaryocytic  lineages.    erythropoietin. Erythropoietin is secreted by the kidneys  in response to tissue hypoxia and causes a compensatory  increase in erythrocyte production if the oxygen content  of the blood decreases because of anemia, high altitude, or  pulmonary disease.    cyte, enables the blood to transport 100 times more oxygen  than could be transported dissolved in plasma alone.   The iron cycle reutilizes iron released from old or dam-  aged erythrocytes. Iron binds to transferrin in the blood, is  transported to macrophages of the MPS, and is stored in the  cytoplasm as ferritin.   Iron homeostasis is controlled by hepcidin, a small hormone  produced by hepatocytes, which regulates ferroportin, the  principal transporter of iron from stores in hepatocytes and  macrophages and from intestinal cells that take up dietary  iron.   Granulocytes and monocytes in the blood develop from  common myeloid progenitor cells in the bone marrow  under the direction of several growth factors, including  stem cell factor, IL-3, and GM-CSF.   Platelets develop from megakaryocytes by a process called  endomitosis, which is controlled by thrombopoietin. Dur-  ing endomitosis the megakaryocytes undergo mitosis but  not cell division and the cytoplasm and plasma membrane  fragment into platelets.    Hemostasis, or arrest of bleeding in damaged vessels,  involves: (a) vasoconstriction, (b) damage to the endothe-  lium and exposure of connective tissue resulting in forma-  tion of a platelet plug, (c) activation of the clotting cascade,  (d) formation of a blood clot, and (e) activation of fibrino-  lysis for clot retraction and clot dissolution.    . Platelet activation involves three linked processes: (a) adhe-  sion, (b) activation, and (c) aggregation.   . A blood clot is a meshwork of protein strands that stabilizes  the platelet plug. The strands are made of fibrin. Fibrin is  the end product of the coagulation cascade.   . The coagulation cascade is composed of intrinsic and  extrinsic pathways, with the extrinsic pathway being domi-  nant. The intrinsic pathway is initiated by TF that forms a  complex with the TF/VIla complex.   . The endothelium prevents the formation of sponta-  neous clots in normal vessels by several anticoagulant  mechanisms, including by production of NO and PGI,  thrombin inhibitors (antithrombin III), and tissue factor  inhibitors (tissue factor pathway inhibitors) and by deg-  radation of activated clotting factors (thrombomodulin—  protein C).   . Fibrinolysis (breakdown of blood clots) is the function  of the plasminogen-plasmin system. Plasmin is a degrad-  ing enzyme of fibrin clots. It is produced from plas-  minogen by activation of plasminogen activators (t-PA,  u-PA), thrombin, fibrin, factor XIla, factor XIa, and  kallikrein.   . Products of fibrinolysis include fibrin degradation prod-  ucts, such as p-dimer.    Blood cell counts rise above adult levels at birth and then  gradually decline throughout childhood.    . The average blood volume of an infant is 75 to 77 ml/kg,    . In response to the change from a placental to a pulmonary    oxygen supply during the first few days of life, levels of  erythropoietin and the rate of blood cell formation decrease.    . The normal erythrocyte life span is 60 to 80 days in full-    term infants, 20 to 30 days in premature infants, and  120 days in children, adolescents, and adults.    . The lymphocyte count is high at birth, rises further during    the first year of life, and steadily declines until lower adult  volumes are reached.    . 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Bates SM: D-dimer assays in diagnosis and management of thrombotic    . _Ignjatovic V, Mertyn E, Monagle P: The coagulation system in children:    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Anemia, 982  Classification, 982  Macrocytic-Normochromic Anemias, 987  Microcytic-Hypochromic Anemias, 989  Normocytic-Normochromic Anemias, 993    Alterations of erythrocyte function involve either insufficient  or excessive numbers of erythrocytes in the circulation or nor-  mal numbers of cells with abnormal components. Anemias are  conditions in which there are too few erythrocytes or an insuf-  ficient volume of erythrocytes in the blood. Polycythemias are  conditions in which erythrocyte numbers or volume is exces-  sive. Each of these conditions has many causes and is a patho-  physiologic manifestation of a variety of disease states.    Strictly speaking, anemia is a reduction in the total number of  erythrocytes in the circulating blood or a decrease in the qual-  ity or quantity of hemoglobin. Anemias commonly result from  (1) impaired erythrocyte production, (2) blood loss (acute or  chronic), (3) increased erythrocyte destruction, or (4) a combi-  nation of these three factors.    Anemias are classified by their causes (e.g., anemia of  chronic disease) or by changes that affect the size, shape, or    Myeloproliferative Red Blood Cell Disorders, 1002  Polycythemia Vera, 1003  Iron Overload, 1004    hemoglobin content of the erythrocyte (Box 28-1). The most  common classification is based on changes that affect the  erythrocyte’s size or hemoglobin content (Table 28-1). The  terminology reflects these characteristics; terms that end in  “-cytic” refer to cell size, whereas “-chromic” refers to hemo-  globin content (Table 28-2). Additional descriptors of eryth-  rocytes associated with some anemias include anisocytosis  (assuming various sizes) or poikilocytosis (assuming various  shapes) (Figure 28-1).   CLINICAL MANIFESTATIONS. The fundamental physiologic  manifestation of anemia is a reduced oxygen-carrying capac-  ity of the blood resulting in tissue hypoxia. Symptoms of  anemia vary, depending on the body’s ability to compensate  for reduced oxygen-carrying capacity (Figure 28-2). Ane-  mia that is mild and develops gradually is usually easier to  compensate and may cause problems for the individual only  during physical exertion. As the reduction in red blood cells  (RBCs) continues, symptoms become more pronounced  and alterations of specific organs and compensatory effects  become more apparent. Compensation generally involves  the cardiovascular, respiratory, and hematologic systems.    Pernicious anemia (decreased By, folate)  Stem cell dysfunction  Aplastic anemia  Myeloproliferative leukemia  Bone marrow infiltration  Carcinoma  Lymphoma  Pure red cell aplasia    Pernicious anemia: lack of vitamin B;2 (cobalamin)  for erythropoiesis; abnormal deoxyribonucleic acid  (DNA) and ribonucleic acid (RNA) synthesis in the  erythroblast; premature cell death   Folate deficiency anemia: lack of folate for  erythropoiesis; premature cell death   Iron deficiency anemia: lack of iron for hemoglobin  production; insufficient hemoglobin    Sideroblastic anemia: dysfunctional iron uptake by  erythroblasts and defective porphyrin and heme  synthesis   Thalassemia: impaired synthesis of a- or B-chain  of hemoglobin A; phagocytosis of abnormal  erythroblasts in the marrow    Hemolytic anemia: premature destruction (lysis) of  mature erythrocytes in the circulation   Sickle cell anemia: abnormal hemoglobin synthesis,  abnormal cell shape with susceptibility to damage,  lysis, and phagocytosis    Congenital or acquired deficiency of intrinsic  factor (IF); genetic disorder of DNA synthesis    Chronic blood loss; dietary iron deficiency;  disruption of iron metabolism or iron cycle (see  Chapter 27)   Congenital dysfunction of iron metabolism in  erythroblasts; acquired dysfunction of iron  metabolism as a result of drugs or toxins  Congenital genetic defect of globin synthesis   Acute or chronic hemorrhage that stimulates  increased erythropoiesis, which eventually  depletes body iron    FIGURE 28-1 Appearance of Red Blood Cells in Various Disorders. A, Normal blood smear. B, Microcytic-hypochromic  anemia (iron deficiency). C, Macrocytic anemia (pernicious anemia). D, Macrocytic anemia in pregnancy. E, Hereditary  elliptocytosis. F, Myelofibrosis (teardrop). G, Hemolytic anemia associated with prosthetic heart valve. H, Microangiopathic  anemia. I, Stomatocytes. J, Spherocytes (hereditary spherocytosis). K, Sideroblastic anemia; note the double population of  red blood cells. L, Sickle cell anemia. M, Target cells (after splenectomy). N, Basophil stippling in case of unexplained anemia.  0, Howell-Jolly bodies (after splenectomy). (From Wintrobe MM et al: Clinical hematology, ed 8, Philadelphia, 1981, Lea &  Febiger.)    (Hematologic findings associated with various anemias are  listed in Table 28-3 and progression and manifestations of  anemias are shown in Figure 28-2.)   A reduction in the number of blood cells in the blood causes  a reduction in the consistency and volume of blood. Compen-  sation for a reduced blood volume causes interstitial fluid to  move into the intravascular space, expanding plasma volume.  This movement maintains adequate blood volume, but the  viscosity (thickness) of the blood decreases. The diluted blood  flows faster and more turbulently than normal blood, caus-  ing a hyperdynamic circulatory state. This hyperdynamic state  creates cardiovascular changes—increased stroke volume and  heart rate. These changes may lead to cardiac dilation and heart  valve insufficiency if the underlying anemic condition is not  corrected.   Hypoxemia, reduced oxygen levels in the blood, further  contributes to cardiovascular dysfunction by causing dilation  of arterioles, capillaries, and venules, thus leading to decreased  vascular resistance and increased flow. Increased peripheral  blood flow and venous return further contribute to an increase    in heart rate and stroke volume in a continuing effort to meet  normal oxygen demand and prevent cardiopulmonary con-  gestion. These compensatory mechanisms may lead to heart  failure.   Tissue hypoxia creates additional demands and compen-  satory actions on the pulmonary and hematologic systems.  The rate and depth of breathing increase in an attempt to  increase the availability of oxygen. These demands are  accompanied by an increase in the release of oxygen from  hemoglobin. (Mechanisms of oxygen transport and release  by hemoglobin are described in Chapter 27.) All of these  compensatory mechanisms may cause individuals to experi-  ence shortness of breath (dyspnea); a rapid, pounding heart-  beat (palpitations); dizziness; and fatigue. In mild, chronic  conditions, these symptoms might be present only when  demand for oxygen is increased (e.g., during physical exer-  tion), but in severe conditions they may be experienced at  rest.   Manifestations of anemia may be observed in other parts  of the body. The skin, mucous membranes, lips, nail beds, and    conjunctivae become pale as a result of reduced hemoglobin  concentration. If anemia is caused by RBC destruction (hemo-  lysis), the skin may become yellowish because of accumulation  of the products of hemolysis. Tissue hypoxia of the skin results  in impaired healing and loss of elasticity, as well as thinning  and early graying of the hair. Nervous system manifestations  can occur if the anemia is caused by a vitamin B,, deficiency.  Myelin degeneration may occur, causing a loss of nerve fibers  in the spinal cord and producing paresthesias (numbness), gait  disturbances, extreme weakness, spasticity, and reflex abnor-  malities. Decreased oxygen supply to the gastrointestinal (GI)  tract often produces abdominal pain, nausea, vomiting, and  anorexia. A low-grade fever of less than 38.5° C (less than about  101° F) occurs in some anemic individuals and may result from  the release of leukocyte pyrogens from ischemic tissues.   When the anemia is severe or acute in onset (e.g., hemor-  rhage), the initial compensatory mechanism is peripheral  blood vessel constriction, diverting blood flow to vital organs.  Decreased blood flow detected by the kidneys activates the renal  renin-angiotensin response, causing salt and water retention  in an attempt to increase blood volume. These situations are  emergencies and require immediate intervention to correct the  underlying problem that caused the acute loss of blood; there-  fore, long-term compensatory mechanisms do not develop.   Therapeutic interventions for slowly developing anemic  conditions require treatment of the underlying disorder and  palliation of associated symptoms. Therapies include transfu-  sions, dietary correction, and administration of supplemental  vitamins or iron.    The macrocytic (megaloblastic) anemias are characterized by  unusually large stem cells (megaloblasts) in the marrow that  mature into erythrocytes that are unusually large in size (mac-  rocytes), thickness, and volume.' The hemoglobin content is  normal (normochromic). These anemias are the result of defec-  tive erythrocyte DNA synthesis, commonly caused by deficien-  cies of vitamin B,, (cobalamin) or folate (folic acid), coenzymes  that are required for nuclear maturation and DNA synthesis.  These defective erythrocytes die prematurely, which decreases  their numbers in the circulation, causing anemia.   Premature death of damaged erythrocytes, eryptosis, is a  common mechanism of cellular loss in individuals with ane-  mias secondary to deficiencies of iron, infections (e.g., malaria,  mycoplasma), chronic diseases (e.g., diabetes, renal disease),  genetic diseases (e.g., beta-thalassemia, glucose-6-phosphate  dehydrogenase [G6PD] deficiency, sickle-cell trait), and  myelodysplastic syndrome.*? The process is similar to the  removal of old or senescent erythrocytes (see Chapter 27),  but is triggered by erythrocyte damage before the cell’s nor-  mal life span. Damaged erythrocytes undergo cell shrinkage,  membrane changes (blebbing), and rearrangement of plasma  membrane phospholipid distribution with efflux of phospha-  tidylserine (PS). Macrophages have receptors that recognize  surface PS and remove the damaged erythrocytes from the cir-  culation. The erythrocyte’s life span may be decreased by as  much as 50%.°    Defective DNA synthesis in megaloblastic anemias causes red  cell growth and development to proceed at unequal rates. DNA  synthesis and cell division are blocked or delayed. However,  ribonucleic acid (RNA) replication and protein (hemoglobin)  synthesis proceed normally. Asynchronous development leads  to an overproduction of hemoglobin during prolonged cellular  division, creating a larger-than-normal erythrocyte with a dis-  proportionately small nucleus. With each cell division, the dis-  proportion between RNA and DNA becomes more apparent.   Immature precursors of the megaloblastic erythrocytes have  a greater chance of dying during maturation than do normo-  blastic precursors. Additionally, there is an increase in the  amounts of lactic dehydrogenase, reflecting cellular destruc-  tion, and indirect bilirubin, from the breakdown of heme. Both  of these substances may be measured in the blood, providing  biochemical evidence of ineffective erythropoiesis.   Defective DNA synthesis also may result in significant  enlargement of neutrophil precursors creating giant metamy-  elocytes with a tendency to have more nuclear lobes than nor-  mal. Other cells throughout the body also may demonstrate  enlargement and nuclear abnormalities. Cells lining epithelium  and those with high turnover rates are most affected.    Pernicious anemia (PA), the most common type of mega-  loblastic anemia, is caused by vitamin B,) deficiency, which  is often associated with the end stage of type A chronic atro-  phic (congenital or autoimmune) gastritis (see Figure 28-1, C;  Figure 28-3).* Pernicious means highly injurious or destructive  and reflects the fact that this condition was once fatal. It most  commonly affects individuals older than the age of 30 (60 being  the median age of diagnosis) who are of Northern European  descent, primarily those of Scandinavian, English, and Irish  descent, and PA is less common in individuals of Greek or    FIGURE 28-3 Bone Marrow Aspirate from Individual with Pernicious  Anemia. Bone marrow aspirate smear from an individual with megaloblastic red  blood cell precursors and giant metamyelocytes. The chromatin in the red blood  cell nuclei is more dispersed than that in normal red blood cell precursors at com-  parable stages of maturation; the giant metamyelocytes have dispersed nuclear  chromatin in contrast to a normal metamyelocyte, which has condensed chromatin  (Wright-Giemsa stain). (From Damjanov I, Linder J, editors: Anderson's pathology,  ed 10, St Louis, 1996, Mosby.)    Italian origin, Recently, PA has also been reported in blacks and  Hispanics. Females are more prone to develop PA, with black  females having an earlier onset.   PATHOPHYSIOLOGY. The principal disorder in PA is an absence  of intrinsic factor (IF), a transporter required for absorption  of dietary vitamin B,,, which is essential for nuclear matura-  tion and DNA synthesis in erythrocytes. IF is secreted by gastric  parietal cells and complexes with dietary vitamin B,, in the small  intestine. The B,,-IF complex binds to cell surface receptors in  the ileum and is transported across the intestinal mucosa.   Deficiency in IF secretion may be congenital or, more often,  an autoimmune process directed against gastric parietal cells.  Congenital IF deficiency is a genetic disorder that demonstrates  an autosomal recessive inheritance pattern.° The autoimmune  form of the disease also has a genetic component, as do most  autoimmune diseases (see Chapter 9). Family clusters have been  identified; 20% to 30% of individuals related to persons with  PA also have PA. These relatives, particularly first-degree female  relatives, also demonstrate a higher frequency of the presence  of gastric autoantibodies. PA is also frequently a component of  autoimmune polyendocrinopathy, which is a cluster of autoim-  mune diseases of endocrine organs (e.g., chronic autoimmune  thyroiditis [Hashimoto thyroiditis], type 1 diabetes mellitus,  Addison disease, primary hypoparathyroidism, Graves disease,  and myasthenia gravis) that frequently present as comorbidi-  ties. Autoimmune thyroiditis and type 1 diabetes mellitus, in  particular, are associated with PA.   Most cases of PA result from an autoimmune gastritis  (type A chronic gastritis) in which gastric atrophy results from  destruction of parietal and zymogenic cells. Individuals with  PA commonly have autoantibodies against the gastric Ht-K*  ATPase, which is the major protein constituent of parietal cell  membranes. Early in the disease process the gastric submucosa  becomes infiltrated with inflammatory cells, including CD4  lymphocytes, eventually extending into the lamina propria  and causing degeneration of the parietal and zymogenic cells.  The parietal and zymogenic cells are destroyed and replaced by  mucous-containing cells (intestinal metaplasia). Gastric muco-  sal atrophy, in which gastric parietal cells are destroyed, results  in a deficiency of all secretions of the stomach—hydrochloric  acid, pepsin, and IF. A direct correlation exists between the  severity of the gastric lesion and the degree of malabsorption  of vitamin B,,.° Additionally, autoantibodies against IF prevent  the formation of the B,,-IF complex. Thus, PA is secondary to  autoimmune destruction of parietal cells, thus diminishing the  production of IF, and the presence of autoantibodies that neu-  tralize the capacity of remaining IF to transport vitamin B)).   Initiation of the autoimmune process may be secondary to a  past infection with Helicobacter pylori.’ Although active infec-  tion with H. pylori is rare in individuals with PA, more than  half of these individuals possess circulating antibodies against  this microorganism, suggesting a history of infection. The cur-  rent opinion is that in genetically prone individuals, antigens  expressed by H. pylori mimic the parietal cell H*-K* ATPase,  resulting in production of an antibody that binds and dam-  ages the parietal cell (see Chapter 9 for a discussion of antigenic  mimicry and autoimmune disease).    Environmental conditions also may contribute to chronic  gastritis. These include excessive alcohol or hot tea ingestion  and smoking. Complete or partial removal of the stomach (gas-  trectomy) causes IF deficiency. Drugs known as proton pump  inhibitors (PPIs) are used to decrease gastric acidity, but also  may decrease cobalamin absorption, although it is not thought  that they actually cause PA. Although PA is a benign disorder,  individuals with type A chronic gastritis also are at risk for  developing gastric adenocarcinoma and gastric carcinoid type  I. The incidence of carcinoma in these individuals is 2% to 3%.   CLINICAL MANIFESTATIONS. PA develops slowly (possibly over  20 to 30 years); 60 years of age is the median age at time of  diagnosis. Because of the slow onset of symptoms, PA is usu-  ally severe by the time treatment is sought. Early symptoms  are often ignored because they are nonspecific and vague and  include infections, mood swings, and gastrointestinal, cardiac,  or kidney ailments. When the hemoglobin level has decreased  significantly (7 to 8 g/dl), the individual experiences the clas-  sic symptoms of anemia—weakness, fatigue, paresthesias of the  feet and fingers, difficulty in walking, loss of appetite, abdom-  inal pains, weight loss, and a sore tongue that is smooth and  beefy red secondary to atrophic glossitis. The skin may become  “lemon yellow” (sallow) as a result of a combination of pallor  and icterus. Hepatomegaly, indicating right-sided heart failure,  may be present in the elderly along with splenomegaly, which  is nonpalpable.   Neurologic manifestations result from nerve demyelination  that may produce neuronal death. The posterior and lateral  columns of the spinal cord also may be affected, causing a loss  of position and vibration sense, ataxia, and spasticity. These  complications pose a serious threat because they are not revers-  ible, even with appropriate treatment. The cerebrum also may  be involved with manifestations of affective disorders, most  commonly of the depressive types. An increased prevalence of  serum vitamin Bj deficiency has been reported among indi-  viduals with Alzheimer disease.   EVALUATION AND TREATMENT. Diagnosis of PA is based on a  variety of tests (see Table 28-3), which include blood tests, bone  marrow aspiration, serologic studies, gastric biopsy, and clini-  cal manifestations. A good test for PA was the Schilling test (no  longer offered in most laboratories), which indirectly evaluated  vitamin B,, absorption by administering radioactive B,, and  measuring excretion in the urine. Low urinary excretion was  significant for PA.   Serologic studies, however, have replaced the Schilling test  for diagnosing PA. Measuring methylmalonic acid and homo-  cysteine levels, which are elevated early in PA, is more sensi-  tive. The presence of circulating antibodies against parietal cells  and intrinsic factor is also useful in diagnosis.® Gastric biopsy  reveals total achlorhydria (absence of hydrochloric acid), which  is diagnostic for PA because it occurs only in the presence of this  gastric lesion.   Replacement of vitamin B,, (cobalamin) is the treatment of  choice. Initial injections of vitamin B,, are administered weekly  until the deficiency is corrected, followed by monthly injec-  tions for the remainder of the individual’s life. The effectiveness  of cobalamin replacement therapy is determined by a rising    reticulocyte count. Within 5 to 6 weeks, blood counts return  to normal. PA cannot be cured so maintenance therapy is life-  long. Conventional wisdom and practice assumed that oral  preparations were ineffective because there was no IF to facili-  tate absorption of vitamin B,,. However, recent experience has  shown that higher doses of orally administered vitamin B,, will  be absorbed across the small bowel and is beneficial.   Untreated PA is fatal, usually because of heart failure. Death  occurs after a course of remissions and exacerbations lasting  from 1 to 3 years. Since 1926, when replacement therapy began,  mortality has been reduced significantly. Today, death from PA  is rare, and any relapses that occur are usually the result of non-  compliance with therapy.    Folate (folic acid) is an essential vitamin for RNA and DNA  synthesis within the maturing erythrocyte. Folates are coen-  zymes required for the synthesis of thymine and purines  (adenine and guanine) and the conversion of homocysteine  to methionine. Deficient production of thymine, in particular,  affects cells undergoing rapid division (e.g., bone marrow cells  undergoing erythropoiesis). Humans are totally dependent on  dietary intake to meet the daily requirement of 50 to 200 mcg/  day. Increased amounts are required for pregnant and lactat-  ing females. Absorption of folate occurs primarily in the upper  small intestine and does not depend on the presence of any  other facilitating factor, such as IF. After absorption, folate cir-  culates through the liver, where it is stored. Folate deficiency  is more common than B) deficiency, particularly in alcoholics  and individuals with chronic malnourishment. Alcohol inter-  feres with folate metabolism in the liver, causing a profound  depletion of folate stores. Fad diets and diets low in vegetables  also may cause folate deficiency because of the absence of plant  sources of folate. It is estimated that at least 10% of North  Americans have a folate deficiency, although the incidence has  been on the decrease in the United States since the fortification  of foods with folate and the increased use of folate supplements.   PATHOPHYSIOLOGY. Impaired DNA synthesis secondary to  a folate deficiency results in megaloblastic cells with clumped  nuclear chromatin. Anemia may result from apoptosis of  erythroblasts in the late stages of erythropoiesis. In addition  to anemia, folate deficiency in pregnant women is associated  with neural tube defects of the fetus. Folate is necessary for the  reduction of circulating levels of homocysteine, a risk factor  for the development of atherosclerosis (see Chapter 32); thus  a folate deficiency increases the risk for developing coronary  artery disease. A deficiency of folate also is implicated in the  development of cancers, specifically colorectal cancers.   CLINICAL MANIFESTATIONS. Clinical manifestations are simi-  lar to the cachectic, malnourished appearance of individuals  with PA. Specific symptoms include severe cheilosis (scales  and fissures of the lips and corners of the mouth), stomatitis  (inflammation of the mouth), and painful ulcerations of the  buccal mucosa and tongue, characteristic of burning mouth  syndrome. Burning mouth syndrome may be secondary to a  large number of disorders (e.g., extremely dry mouth, infec-  tion, autoimmune disease, nutritional deficiencies, and other    conditions). The mechanisms underlying folate deficiency as  a cause remain unknown. Gastrointestinal symptoms may be  present and include dysphagia (difficulty swallowing), flatu-  lence, and watery diarrhea, as well as histologic and roentgeno-  graphic changes of the GI tract suggestive of sprue (a chronic  malabsorption syndrome). Undiagnosed inflammatory bowel  disease (e.g., Crohn disease, ulcerative colitis) may be the  underlying cause of folate malabsorption in some individuals,  and folate deficiency may suppress proliferation of the intesti-  nal mucosa, leading to exacerbation of gastrointestinal damage.  Neurologic manifestations, such as those that occur in PA, are  generally not seen in folate deficiency anemia. Any neurologic  symptoms are usually caused by a thiamine deficiency, which  often accompanies folate deficiency.   EVALUATION AND TREATMENT. Evaluation of folate deficiency is  based on measurement of serum folate levels and symptoms.  Treatment requires daily oral administration of folate prepa-  rations until adequate blood levels are obtained and clinical  symptoms are reduced or eliminated. One milligram per day is  sufficient for most individuals, although persons with alcohol-  ism may require 5 mg. Prophylactic dosages of 0.1 to 0.4 mg/  day are sometimes given during pregnancy. Parenteral adminis-  tration of folic acid (citrovorum factor or leucovorin) generally  is not used except in situations in which an individual has been  using drugs that inhibit dihydrofolate reductase. After adminis-  tration of folate, the manifestations of anemia disappear within  1 to 2 weeks.   After the folate deficiency has been corrected, long-term  treatment with folate is not necessary if the appropriate dietary  adjustments are made to maintain adequate intake. An intake of  folate (400 mcg/day) is recommended as a measure to prevent  heart disease.    The microcytic-hypochromic anemias are characterized by  abnormally small erythrocytes that contain abnormally reduced  amounts of hemoglobin (see Figure 28-1, B). Hypochromia  occurs even in cells of normal size.   Microcytic-hypochromic anemia can result from (1) disor-  ders of iron metabolism, (2) disorders of porphyrin and heme  synthesis, or (3) disorders of globin synthesis. Specific disorders  include iron deficiency anemia, sideroblastic anemia, and thal-  assemia (thalassemia is discussed in Chapter 30).    Iron deficiency anemia (IDA) is the most common type of  anemia worldwide, occurring in both developing and devel-  oped countries and affecting as many as one fifth of the world  population. Certain populations are at high risk for devel-  oping hypoferremia and IDA and include individuals living  in poverty, women of childbearing age, and children. Iron  deficiency in children is associated with numerous adverse  health-related manifestations, especially cognitive impair-  ment, which may be irreversible. Teens with a history of iron  deficiency as infants are likely to score lower on cognitive  and motor tests, even if the iron deficiency was identified and  treated in infancy.    Children in developing countries often are affected by  chronic parasite infestations that result in intestinal blood and  iron loss that outpaces dietary intake.? Treatment of helminth  infections results in an improvement in the anemia as well as in  appetite and growth. Iron deficiency also occurs in individuals  with lead poisoning. Treatment of the iron deficiency is associ-  ated with a decrease in lead levels.   Females have a higher incidence of hypoferremia (13.9%)  than do males (8.3%), as well as IDA— 4% to 6% in females and  4% in males. The incidence peaks in females during their repro-  ductive years and decreases after menopause. Those at highest  risk are black females living in urban poverty.'° Males have a  higher incidence during childhood and adolescence, a decrease  occurring during young adulthood, and an upswing during  late adulthood. In the United States, 720,000 children (9%)  ages 1 to 2 years are estimated to be iron deficient, of whom  240,000 (3%) are anemic, which may be a result of increased  iron requirements with growth. An increased prevalence of iron  deficiency has been observed in overweight children.   PATHOPHYSIOLOGY. IDA can arise from one of two different  etiologies or a combination of both—inadequate dietary intake  or excessive blood loss. In both instances there is no intrinsic  dysfunction in iron metabolism; however, both deplete iron  stores and reduce hemoglobin synthesis. A second category is a  metabolic or functional iron deficiency in which various meta-  bolic disorders lead to either insufficient iron delivery to bone  marrow or impaired iron use within the marrow. Paradoxically,  iron stores may be sufficient but delivery is inadequate to main-  tain heme synthesis, thus producing a functional or relative  iron deficiency.   The most common cause of IDA in developed countries  is pregnancy and chronic blood loss.!' Blood loss of 2 to 4 ml/  day (1 to 2 mg of iron) is sufficient to cause iron deficiency and  may result from erosive esophagitis, gastric and duodenal ulcers,  colon adenomas, or cancers. H. pylori infections also have been  found to cause IDA of unknown origin, although H. pylori  impairs iron uptake. In females, menorrhagia (excessive bleeding  during menstruation) is a common cause of primary IDA. Other  causes of IDA for both genders are (1) use of medications that  cause gastrointestinal bleeding (such as aspirin or nonsteroidal  anti-inflammatory drugs [NSAIDs]); (2) surgical procedures that  decrease stomach acidity, intestinal transit time, and absorption  (e.g., gastric bypass); (3) insufficient dietary intake of iron; and  (4) eating disorders, such as pica, which is the craving and eating  of nonnutritional substances, such as dirt, chalk, and paper.   Iron in the form of hemoglobin is in constant demand by the  body. Iron is recyclable; therefore, the body maintains a balance  between iron that is contained in hemoglobin and iron that is  in storage and available for future hemoglobin synthesis (see  Chapter 27). Blood loss disrupts this balance by creating a need  for more iron, thus depleting the iron stores more rapidly to  replace the iron lost from bleeding.   Iron also contributes to immune function by regulat-  ing immune effector mechanisms (i.e., cytokine activities  [interferon-gamma (IFN-y)], nitric oxide formation, and T-cell  proliferation). Acquired hypoferremia may be part of the body’s  response to infection. Anemia can be part of the nonspecific    acute phase response to any type of inflammation of sufficient  degree. Many pathogens require iron for survival; thus hypo-  ferremia would hamper their growth. However, the precise  benefits or detriments of iron deficiency and immunity are still  controversial.   IDA occurs when the demand for iron exceeds the supply  and develops slowly through three overlapping stages. In stage  I, the body’s iron stores are depleted. Erythropoiesis proceeds  normally, with the hemoglobin content of erythrocytes remain-  ing normal. In stage II, iron transportation to bone marrow  is diminished, resulting in iron-deficient erythropoiesis. Stage  III begins when the small hemoglobin-deficient cells enter the  circulation to replace the normal aged erythrocytes that have  been removed from the circulation. The manifestations of IDA  appear in stage III when there is depletion of iron stores and  diminished hemoglobin production.   CLINICAL MANIFESTATIONS. Symptoms of IDA begin gradu-  ally, and individuals usually do not seek medical attention  until hemoglobin levels have decreased to about 7 to 8 g/dl.  Early symptoms are nonspecific and include fatigue, weakness,  shortness of breath, and pale earlobes, palms, and conjunctivae  (Figure 28-4, A).   As the condition progresses and becomes more severe, struc-  tural and functional changes occur in epithelial tissue (see Fig-  ure 28-4). The fingernails become brittle, thin, coarsely ridged,  and “spoon-shaped” or concave (koilonychia) as a result of  impaired capillary circulation (Figure 28-4, B). IDA also is  associated with unexplained burning mouth syndrome, as was    FIGURE 28-4 Manifestations of lron Deficiency Anemia. A, Pallor and iron  deficiency. Pallor of the skin, mucous membranes, and palmar creases in an indi-  vidual with a hemoglobin level of 9 g/dl. Palmar creases become as pale as the  surrounding skin when the hemoglobin level approaches 7 g/dl. B, Koilonychia. The  nails are concave, ridged, and brittle. C, Glossitis. Tongue of individual with iron  deficiency anemia has bald, fissured appearance caused by loss of papillae and  flattening. (From Hoffbrand AV, Pettit JE, Vyas P: Color atlas of clinical hematology,  ed 4, London, 2009, Mosby; B courtesy Dr. S.M. Knowles.)    discussed for folate deficiency. Tongue papillae atrophy and  cause soreness along with redness and burning (glossitis) (Fig-  ure 28-4, C). The degree of pain experienced is directly associ-  ated with the amount of iron deficiency, and these changes can  be reversed within 1 to 2 weeks of iron replacement therapy.  Individuals also experience dryness and soreness in the epithe-  lium at the corners of the mouth, known as angular stomati-  tis. Difficulty in swallowing is associated with an esophageal  “web,” a thin, concentric, smooth extension of normal esopha-  geal tissue consisting of mucosa and submucosa at the juncture  between the hypopharynx and esophagus. The duration of iron  deficiency required for web formation is uncertain. Dysphagia  also is exacerbated by hyposalivation. The pathophysiology  associated with these epithelial lesions is not well understood,  but the lesions have the potential to become cancerous.   Nonheme iron is a component of many enzymes in the body  (e.g., cytochromes, myoglobin, catalases, peroxidases), particu-  larly those involved in the metabolism of amine neurotransmit-  ters, reduction of nucleotides, and biosynthesis of methionine.  Abnormalities and deficiencies of iron-dependent enzymes may  account for many of the clinical manifestations of IDA. Indi-  viduals with IDA also exhibit gastritis, neuromuscular changes,  irritability, headache, numbness, tingling, and vasomotor dis-  turbances. Gait disturbances are rare. The pathogenesis of neu-  rologic symptoms is unknown but may be caused by hypoxia  in already compromised cerebral vessels. In the elderly, mental  confusion, memory loss, and disorientation are often associated  with anemia and may be wrongly perceived as “normal” events  related to aging.   EVALUATION AND TREATMENT. Initial evaluation is based on  clinical symptoms and decreased levels of hemoglobin and  hematocrit. Additional measurements, however, are needed  to determine the cause of the anemia (see Table 28-3). Iron  stores may be measured directly by bone marrow biopsy and  iron staining or indirectly by laboratory tests for serum ferritin,  transferrin saturation, or total iron-binding capacity. Serum  ferritin is a widely accepted and available measurement of iron  status that has been used for the past 25 years; 1 mcg/L serum  ferritin corresponds to 8 to 10 mg or 120 mcg of storage iron/  kg body weight. A limitation on interpretation of serum fer-  ritin levels is that values may be elevated independently of iron  status during acute or chronic inflammation, malignancy, liver  disease, or alcoholism. A sensitive indicator of heme synthesis  is the amount of free erythrocyte protoporphyrin (FEP) within  erythrocytes. A test that determines the concentration of sol-  uble fragment transferrin receptor differentiates primary IDA  from IDA that is associated with chronic disease.   An indicator of iron levels is the level of serum transferrin  receptor (sTfR). Transferrin receptors are membrane glycopro-  teins that bind circulating transferrin for transport into cells.  Soluble forms of the receptor are found in serum. The ratio of  serum levels of transferrin receptor to ferritin (R/F) estimates  body iron stores and differentiates primary IDA from anemia  secondary to chronic disease. A major drawback, however, is  the lack of proper standardization for the sTfR assay.   The first step in treatment of IDA is to identify and eliminate  sources of blood loss.'* With ongoing bleeding, any replacement    therapy is likely to be ineffective. Iron replacement therapy is  required and very effective. Initial doses are 150 to 200 mg/day.  Hematocrit levels should improve within 1 to 2 months of ther-  apy; however, the serum ferritin level is a more precise mea-  surement of improvement and total body stores of iron. Once  the serum ferritin level reaches 50 mcg/L, adequate replacement  of iron has occurred. A rapid decrease in fatigue, lethargy, and  other associated symptoms is generally seen within the first  month of therapy. Replacement therapy usually continues for  6 to 12 months after the bleeding has stopped but may continue  for as long as 24 months. Menstruating females may need daily  oral iron replacement therapy (325 mg/day) until menopause.   Parenteral iron replacement is used in instances of uncon-  trolled blood loss, intolerance to oral iron, intestinal malab-  sorption, or poor adherence to oral therapy. Iron dextran has  been the only parenteral agent available in the United States.  Intramuscular injection is the recommended method; however,  intravenous (IV) administration is generally preferred because  of the ability to administer larger doses. A significant concern  in the use of IV dextran is the potential for severe anaphylactic  reaction. Delayed allergic reactions are also major concerns.   Newer medications that have recently been approved for  parenteral therapy in treating IDA are sodium ferric gluco-  nate complex in sucrose (Ferrlecit) and iron sucrose injection  (Venofer). Iron dextran is recommended as the first choice in  spite of its higher rate of adverse reactions. For individuals who  are intolerant of iron dextran, the two newer agents are safe and  effective alternatives. Drawbacks to their use include higher cost  and the need for multiple infusions.    Sideroblastic anemias (SAs) are a heterogeneous group of dis-  orders characterized by anemia of varying severity caused by a  defect in mitochondrial heme synthesis.!> SA is characterized  by the presence of ringed sideroblasts within the bone marrow.  Ringed sideroblasts are erythroblasts that contain iron-laden  mitochondria arranged in a perinuclear collar around one third  or more of the nucleus (see Figure 28-1, K).!* Individuals with  SA also have increased levels of iron in their tissue. The blood  contains hypochromic erythrocytes, either microcytic or mac-  rocytic depending on the form of the disease.   PATHOPHYSIOLOGY. SAs have multiple etiologies but all share  the commonality of altered heme synthesis in the erythroid cells  in bone marrow. Mitochondrial aminolevulinic acid (ALA)  synthase uses glycine to convert succinyl CoA into ALA.'° ALA  undergoes further enzymatic modification in the cytoplasm to  the porphyrin structure, becoming coproporphyrinogen III,  which reenters the mitochondria. Within the mitochondria  the molecule is progressively converted to protophorphyrin IX,  which has ferrous iron (Fe**) inserted by the enzyme ferroche-  latase. Disruptions to this pathway lead to the accumulation of  iron in the mitochondria and the characteristic sideroblasts.   SAs are either acquired or hereditary. Acquired sideroblastic  anemia, which is the most common, occurs as a primary disor-  der with no known cause (idiopathic) or is associated with other  myeloproliferative or myeloplastic disorders. Another form  is described as reversible SAs; these are secondary to various    conditions such as alcoholism, drug reactions, copper deficiency,  and hypothermia. Reversible sideroblastic anemia, associated  with alcoholism, results from nutritional deficiencies of folate.  Alcohol impairs heme synthesis by reducing the activity of spe-  cific enzymes along the biosynthetic pathway and also by direct  effects of alcohol or acetaldehyde, or both, on the heme biosyn-  thetic steps or mitochondrial metabolism. Some specific drugs  also cause reversible SA and include antituberculous agents (iso-  niazid [INH], pyrazinamide, cycloserine, and chlorampheni-  col) that interfere with B,, metabolism or directly injure the  mitochondria. Copper deficiency also causes reversible SA by  interfering with conversion of ferric iron to ferrous iron. This  is extremely rare and is associated with gastrectomy and pro-  longed parenteral nutrition without copper supplements. Hypo-  thermia causes decreased heme synthesis and incorporation into  hemoglobin.   Hereditary sideroblastic anemia is rare and occurs almost  exclusively in males, suggesting a predominant recessive X-linked  transmission. Hereditary SA (X-linked sideroblastic anemia  [XLSA]) has been linked to missense mutations in the erythroid-  specific ALAS-E gene Xp11.21.'° More than 25 missense muta-  tions have been identified. ALAS is the first and rate-limiting  enzyme in the heme biosynthesis pathway, and mutations lead  to reduced synthesis of protoporphyrin IX and the characteristic  accumulation of iron in the erythrocyte. An occasional autoso-  mal recessive transmission affecting females occurs with mito-  chondrial mutations and deficiencies of ferrochelatase. Other  genetic, chromosomal, or enzyme dysfunctions also have been  associated with hereditary SA. The anemia of hereditary SA is  usually present in infancy or childhood, but may remain unde-  tected until midlife. In some instances, other symptoms (e.g.,  diabetes or cardiac failure resulting from tissue iron overload)  may be the first manifestation of SA. Differentiation of SA from  idiopathic hemochromatosis needs to be confirmed because  both are characterized by tissue iron deposition.   The leading known cause of primary ASA, myelodysplas-  tic syndrome (MDS), is a group of disorders of hematopoietic  stem cells, with all three stem cell lines demonstrating dysplas-  tic characteristics.!” Initially, all ASAs associated with myelo-  dysplastic syndrome were considered to be one and the same  and identified as refractory anemia with ringed sideroblasts.  This classification proved unsatisfactory because different out-  comes were observed in individuals who had the same appar-  ent disease. Further investigations discovered morphologic and  chromosomal characteristics that predicted different clinical  courses. Two subsets of myelodysplastic ringed sideroblasts  were identified based on the cell lines that were affected. In one  subset, dysplastic features were limited to the erythroid line and  it was classified as pure SA. Individuals with pure SA require  transfusions, which may produce iron overload.!* With ade-  quate chelation therapy, they are able to survive and thrive for  many years. A significant outcome of this condition is the rare  occurrence of conversion to leukemia.   The second subset of MDS was characterized by abnormali-  ties of multiple cell lineages. In addition to SA, major alterations  of neutrophil and platelet were observed. Infections, frequently  fatal, are common secondary to neutropenia and neutrophil    dysfunction. Bleeding from thrombocytopenia and platelet dys-  function also is prevalent. Of those who survive, 40% develop  acute (myeloblastic) leukemia.   CLINICAL MANIFESTATIONS. The anemias of SA are generally  moderate to severe, with hemoglobin levels varying from 4 to  10 g/dl. In addition to the cardiovascular and respiratory mani-  festations common to all anemias, individuals with SA may show  signs of iron overload (hemochromatosis). Mild to moderate  enlargement of the spleen (splenomegaly) and liver (hepato-  megaly) occurs; however, liver function remains normal or only  slightly impaired. Occasionally abnormal skin pigmentation  (bronze-tinted) is seen. Neurologic and epithelial alterations  commonly associated with other anemias are absent. Hemosid-  erosis of cardiac tissue resulting in heart rhythm disturbances  and congestive heart failure are major life-threatening compli-  cations related to cardiac iron overload. These manifestations  are fortunately rare and occur late in the progression of the dis-  ease. Young children and infants who are severely affected may  demonstrate growth and developmental impairment.   EVALUATION AND TREATMENT. Initially, SA may be mistaken for  deficiency of stem cells in the marrow (hypoplastic anemia) or  iron deficiency anemia (laboratory findings are listed in Table  28-3). Bone marrow examination establishes the diagnosis. The  marrow is packed with erythrocyte stem cells, and mononuclear  phagocytes in the marrow are loaded with iron in the form of  hemosiderin. The presence of sideroblasts confirms the diag-  nosis of SA. Platelet and leukocyte values are generally normal;  however, they may be reduced if splenomegaly is evident.   The severity of the anemia is quite variable and qualitative  alterations of the erythrocytes (e.g., decreased mean corpuscu-  lar volume [MCV] and increased erythrocyte volume distribu-  tion width) may be evident even when anemia is not present.  Dimorphism, in which normocytic and normochromic cells  are seen concomitantly with microcytic-hypochromic cells,  may be present and is seen more commonly in individuals with  mild anemia, in female carriers, or in those receiving treatment  with pyridoxine. Anisocytosis and poikilocytosis also are seen  on examination of the blood smear.   Initial treatment of SA is directed toward identification of a  causative agent (i.e., drugs or toxins).!? Treatment is support-  ive, with transfusions being the primary intervention. Follow-  ing removal of the agent, oral pyridoxine (100 mg/day) may be  administered on a trial basis. Acquired SA related to alcohol  abuse and pyridoxine antagonists often demonstrates a com-  plete response to pyridoxine. SA caused by other etiologies does  not demonstrate the same improvement.   Individuals with hereditary SA are initially treated with  pyridoxine therapy (50 to 200 mg/day), which is effective in  approximately one third of individuals. An optimal response  is reticulocytosis with blood hemoglobin levels and low free  erythrocyte protoporphyrin levels also returning to normal  within 1 to 2 months. Morphologic abnormalities of cells  (microcytosis), however, do not disappear, even in the presence  of normal ALA synthase activity and hemoglobin. Hemoglobin  levels also may increase in response to therapy but stabilize at  less than normal levels. When a response to pyridoxine therapy  is observed, lifelong maintenance therapy at a lowered dosage is    instituted. Discontinuing therapy initiates a relapse. Individu-  als not responding to pyridoxine require blood transfusions to  relieve symptoms and permit growth and development.   Evidence of iron overload requires iron depletion therapy to  prevent or minimize organ damage. Phlebotomy, or removal  of blood from the circulation, is generally well tolerated and  preferable for individuals who have a mild to moderate ane-  mia without other complications (e.g., heart disease). Once  all the stored iron is removed, maintenance phlebotomies are  performed on a continuing basis. Individuals who have severe  anemia and/or depend on transfusions become extremely over-  loaded with iron. When this occurs, therapy with deferoxamine  (an iron chelating agent) is necessary to eliminate excess iron.   Individuals with acquired SA infrequently respond to pyri-  doxine. Fortunately, these individuals are rarely incapacitated  by SA. In the absence of abnormalities of other blood cells  and without iron overload, progression takes place over years.  Transfusion and chelation therapy is the same as for hereditary  SA when indicated.   Recent advances in treatment for SAs include prolonged  administration of erythropoietin and stem cell transplant.  Treatment with recombinant human erythropoietin improves  anemia in 30% of those with myelodysplastic syndrome.”° Indi-  viduals with the subset of MDS identified as refractory anemia  have the overall best response rate. Congenital SA has been  treated successfully with stem cell transplants; however, this  treatment is in the early stages of use, and long-term efficacy  has not yet been established. Death from SA is rare and often  secondary to complications, such as infection, bone marrow  failure, liver failure, or cardiac failure or arrhythmias, or both.    Normocytic-normochromic anemias (NNAs) are character-  ized by erythrocytes that are relatively normal in size and hemo-  globin content but insufficient in number. These anemias have  no common etiology, pathologic mechanisms, or morpho-  logic characteristics. They are less frequent than macrocytic-  normochromic and microcytic-hypochromic anemias. NNAs  include five distinct groups: aplastic (damage to bone marrow  erythropoiesis); posthemorrhagic (acute blood loss); acquired  hemolytic (immune destruction of erythrocytes); hereditary  hemolytic, such as sickle cell (destruction by eryptosis); and  anemia of chronic inflammation (multiple causes). (Sickle cell  anemia is discussed in Chapter 30.)    Aplastic anemia (AA) is a critical condition characterized by  pancytopenia, a reduction or absence of all three blood cell  types, resulting from failure or suppression of bone marrow to  produce adequate amounts of blood cells (Figure 28-5). The  rate or decline in the quantity of blood cells is related to their  respective life span; thus erythrocytes (life span about 120 days)  are last to demonstrate a reduction in numbers.   The incidence of AA is relatively rare (annual rate of 2 to  5 new cases per million per year). The incidence in devel-  oping countries is somewhat higher and may be related to  greater exposure to certain chemicals known to cause AA. The    topoietic cells account for approximately 40% of marrow’s cellularity. B, There is  a marked reduction in hematopoietic cells with expansion of fat cells. (From Dam-  janov I, Linder J: Pathology: a color atlas, St Louis, 2000, Mosby.)    incidence is bimodal, with one peak occurring between 15 and  25 years of age and a second peak occurring in individuals older  than age 60. AA is equally distributed between genders.   AAs are the most common type, with idiopathic AA (primary  acquired) accounting for approximately 75% of all confirmed  cases and being an autoimmune disease. Secondary AA, which  accounts for approximately 15% of cases, is caused by a vari-  ety of known chemical agents and ionizing radiation. Chemical  agents include benzene, arsenic, and multiple drugs, including  chloramphenicol and alkylating and antimetabolite chemother-  apeutic drugs (6-mercaptopurine, vincristine, and busulfan).’!  Other drugs known to cause AA are identified in Table 28-4.  The development of AA with use of these agents is generally  dose related, and the effect can be controlled with diminished  dosages. In other instances, AA might develop after the use of  small amounts of these drugs (idiosyncratic), with the anemia  following a severe, rapid, irreversible progression. Liver disease  (seronegative hepatitis) is also recognized as a cause of AA.   AA is constitutional or familial in origin or is associated with  one or more somatic abnormalities in approximately 5% to  10% of affected individuals. A subset of these is found to have  defective telomerase RNA resulting in shortened telomeres.  This abnormality also is found in some individuals with idio-  pathic AA.    X, Rare number of reported cases; XXXX, substantial number of reported cases; XX, XXX, intermediate number of reported cases; X*, “pure red  cell" aplasia; X?, uncertain.    Total body irradiation also causes AA and in certain instances  may be used therapeutically for this effect. Infections are also  known to cause AA, with viruses being the most common agent.  These include infections with the human immunodeficiency  virus (HIV), Epstein-Barr virus, and hepatitis (non-A, non-B,  non-C, and non-G forms of the virus). Persistent parvovirus  B19 infection also has been identified as producing bone mar-  row failure resulting in AA. Parvovirus B19 has been identified  as the cause of aplastic crisis in children who have sickle cell  hemoglobinopathies and hereditary spherocytosis.   Another condition associated with AA is pure red cell apla-  sia (PRCA), in which only the erythrocytes are affected. PRCA  is a rare disorder and has been associated with autoimmune,  viral, and neoplastic (leukemias) disorders; infiltrative disor-  ders of the bone marrow (myelofibrosis); renal failure; hepa-  titis; mononucleosis; and systemic lupus erythematosus. It also  is a well-recognized but infrequent complication of allogeneic  bone marrow transplantation, particularly when there is donor-  recipient ABO mismatch. A thymoma often is found in asso-  ciation with PRCA and is also present in Diamond-Blackfan  syndrome, a congenital disorder.   A very small percentage of AA cases are linked to genetic  alterations. Fanconi anemia is a rare genetic anemia character-  ized by pancytopenia resulting from defects in DNA repair.”  This anemia develops early in life and is accompanied by mul-  tiple congenital anomalies.   PATHOPHYSIOLOGY. The characteristic lesion of AA is a hypo-  cellular bone marrow that has been replaced with fat. Most  cases of idiopathic AA result from an autoimmune disease  directed against hematopoietic stem cells.7> As with most auto-  immune diseases, a genetic predisposition is apparent and has  been attributed to polymorphisms in human leukocyte antigens  (HLAs) and inhibitory cytokines (e.g., tumor necrosis factor-  alpha [TNF-a], transforming growth factor-beta [TGF-f], and  interferon-gamma [IFN-y]).74 The evidence supporting an  autoimmune process includes the response of AA to immu-  nosuppressive therapy including depletion of T cells by anti-  thymocyte antibodies. Cytotoxic T cells (Tc cells) appear to be  the main culprits, although the causative antigen has yet to be  identified. Th1 cytokines (involved in the differentiation of Tc  cells), such as IFN-y and TNF-a, as well as cellular contact with  Tc cells through FasL, induce apoptosis of CD34+ target cells,  which includes most of the hematopoietic progenitors.   CLINICAL MANIFESTATIONS. The onset of symptoms is insidi-  ous and related to the rapidity with which the bone marrow  is destroyed and replaced. Approximately 50% of AA cases  progress rapidly, with a high risk of death from overwhelming  infection or bleeding. In some cases the rate of decline is slow  and the individual may adapt progressively to a new level of  hematologic function. This condition is referred to as hypoplas-  tic anemia rather than aplastic anemia.   Initial symptoms depend on which cell line is affected. Rap-  idly progressing disease is usually associated with hypoxemia,  pallor (occasionally with a brownish pigmentation of the skin),  and weakness along with fever and dyspnea with rapidly devel-  oping signs of hemorrhaging if platelets are affected (e.g., unex-  plained bruising, nosebleeds, bleeding gums, bleeding in the    GI tract, prolonged bleeding at sites of minor injury). A slower  onset over weeks or months is characterized by progressive  weakness and fatigue with developing signs of hemorrhaging.  Major hemorrhage may occur from any organ; however, it is  generally observed in the late stages and is often secondary to  other events. Menorrhagia and purpura also may be evident;  however, purpura is not necessarily a classic indication of AA  and may not be representative of the degree of thrombocyto-  penia. In both rapid and slow onset AA, diminished leukocyte  production may result in a progressive frequency and prolonga-  tion of infections.   Late manifestations of the condition include ulcerations of  the mouth and pharynx or a low-grade cellulitis in the neck.  Splenomegaly is extremely rare, and if present, other conditions  that may imitate AA should be ruled out. Neurologic changes  are only evident when hemorrhages have occurred within  the system; however, some individuals have complained of  paresthesias.   EVALUATION AND TREATMENT. Diagnosis is made by blood tests  and bone marrow biopsy. AA is suspected if levels of circulat-  ing erythrocytes, leukocytes, and platelets are diminished: a  granulocyte count less than 500/pL, a platelet count less than  20,000/uL, and an absolute reticulocyte count less than or equal  to 40 x 10°/L. The diagnosis is confirmed by a bone marrow  biopsy. The bone marrow usually has reduced cellularity (i.e.,  less than 25% normal cellularity). The morphology of the few  remaining hematopoietic cells is usually normal. Occasionally  the erythrocytes are macrocytic, with anisocytosis and poikilo-  cytosis, and may appear immature.   Marrow biopsied from individuals with typical AA contains  yellowish white material consisting mainly of fat, fibrous tis-  sue, and lymphocytes. Pancytopenia is usually characterized by  decreased stem cell and progenitor cell populations to approxi-  mately 1% or less of normal.   Up until 20 years ago, treatment involved determining the  cause, removal of exposure to the potential causative agent,  transfusion, and prevention and treatment of infection and  hemorrhage. Stimulation of blood cell production also was  used, and in some instances splenectomy was recommended.  The prognosis with these forms of treatment was extremely  poor. In acute cases, 25% of individuals succumbed within  4 months, and approximately 70% died within 5 years; only  about 10% experienced complete recovery. Newer forms of  treatment, such as bone marrow transplant (BMT), immuno-  suppression, and identification of high-risk individuals, have  decreased mortality significantly.”°   Bone marrow and, most recently, peripheral blood stem cell  transplantation from a histocompatible sibling often cures the  underlying bone marrow failure.”° Survival rates of 75% to 80%  have been reported, and death rates within the first 100 days have  decreased. Before transplantation the recipient usually received  radiation or chemotherapy to deplete the bone marrow of  disease-causing lymphocytes. Thus an unsuccessful transplanta-  tion may leave the recipient with a depleted immune system and  an increased vulnerability to infection. Graft-versus-host (GVH)  disease remains a risk and is a major contributor to premature  death.’’ Children demonstrate higher survival than adults.    For those individuals unable to undergo bone marrow  transplantation or who lack a suitable sibling donor, immuno-  suppression remains the treatment of choice. Antithymocyte  globulin (ATG) specifically suppresses lymphocytes, including  those autoreactive lymphocytes destroying the bone marrow  cells. Drugs like cyclosporine, which is often used in combina-  tion with ATG, broadly suppress the activity of immune cells.  Response rates, that is, increased blood cell counts, of 40% to  50% may occur in individuals who receive ATG. The addition  of cyclosporine has increased the response and survival rates to  as much as 70% to 80%, with a 5-year survival rate between 80%  and 90%. Cyclosporine as a single therapeutic agent is not as  effective. Corticosteroids are often used concurrently with ATG  and cyclosporine. Cyclophosphamide also has been used as an  immunosuppressive agent and has produced the same effects  as ATG; however, its use has been discontinued because of its  toxicity. The addition of recombinant hematopoietic growth  factors, such as granulocyte-macrophage colony-stimulating  factor (GM-CSF), IL-6, and epoetin, to immunosuppressive  therapy has produced significant additional benefit in both chil-  dren and adults.   Immunosuppressive therapy is not without risk. Individu-  als receiving immunosuppressive therapy are at risk of expe-  riencing treatment failure or late clonal/malignant conditions,  or both. Late clonal/malignant conditions include paroxysmal  nocturnal hemoglobinuria (PNH), MDS, acute leukemia, or  solid tumor. Although quite rare (less than 3%), administration  of ATG may cause an anaphylactic reaction in some individuals.    Posthemorrhagic anemia is a normocytic-normochromic  anemia caused by acute blood loss. Initial manifestations of  this event depend on the severity of blood loss. If blood loss is  severe, the significant manifestations are related to loss of blood  volume rather than loss of hemoglobin.   A normal, healthy young adult can tolerate a blood loss of  500 to 1000 ml (10% to 20% of volume) without experiencing  any symptoms. Additional losses up to 1500 ml do not cause  obvious symptoms if the individual is recumbent—symptoms  appear only when assuming an upright position. When blood  loss exceeds 1500 ml, symptoms are apparent even in a recum-  bent position (Table 28-5).   Volume loss reduces mean systemic filling pressure, result-  ing in decreased venous return. The initial manifestations  (increased sympathetic nerve activation and a reduction in  blood pressure, cardiac output, and central venous pressure)  are caused by cardiovascular adaptations to blood volume  depletion. If blood loss exceeds 2000 ml, severe shock, lactic  acidosis, and death occur. (Shock is discussed in Chapter 48.)   If the acute blood loss is not severe (does not cause the pre-  ceding manifestations), complete recovery is possible. Within  24 hours of blood loss, lost plasma is replaced by mobilizing  water and electrolytes from tissues and interstitial spaces into  the vascular system. The hemodilution that results lowers the  hematocrit value; concurrently, there is often a rapid elevation  of circulating neutrophils and platelets. Neutrophils can rise to  levels between 10,000 and 30,000/uL within a few hours as a    TABLE 28-5 CLINICAL MANIFESTATIONS  OF ACUTE BLOOD LOSS OF  INCREASING SEVERITY   When person is at rest, it is difficult, if not  impossible, to detect volume loss; tachycardia is  common with exercise and a slight drop in blood  pressure with postural change   Neck veins are flat in supine position; exercise  tachycardia and postural hypotension are usually  present; resting supine blood pressure and pulse  can still be normal   Central venous pressure, cardiac output, and arterial  blood pressure are below normal even at rest and  supine position; person commonly has air hunger;  a rapid, thready pulse; and cold, clammy skin    Adapted from Hillman RS: Acute blood loss anemia. In Beutler E et al,  editors: Williams hematology, ed 5, New York, 1995, McGraw-Hill.  *Data based on a 70-kg person with a total blood volume of 5000 ml.  TBV, Total blood volume.    result of a shift of marginated leukocytes into the circulation  and a release of leukocytes from the bone marrow. The platelet  count can rise to levels of about 1 million/uL. In severe blood  loss, more immature cells—metamyelocytes, myelocytes, and  nucleated red blood cells—may enter the circulation. Reduc-  tion in tissue oxygenation stimulates production of erythropoi-  etin and increasing production of erythrocytes (reticulocytes)  in the bone marrow. Iron recovery from destroyed erythrocytes  may occur if the acute blood loss is internal; however, if blood  is lost externally, iron stores may be depleted and erythropoi-  esis may be impeded. Hemorrhage that is chronic (occult [i.e.,  bleeding ulcer or neoplasm]) produces adaptations that are less  prominent, but the individual may experience an IDA when  iron reserves become depleted.   Initial treatment for acute blood loss is restoration of blood  volume by intravenous administration of saline, dextran, albu-  min, or plasma. Large volume losses may require transfusion of  fresh whole blood.   Successful therapy is first indicated by a return of erythro-  cytes to their normal size and shape. As the bone marrow begins  to produce more erythrocytes, an increase in the number of  reticulocytes (10% to 15% after 7 days) is seen. Changes in the  appearance of erythrocytes (polychromatophilia and macrocy-  tosis) associated with reticulocytosis may give the impression  that an underlying hemolytic process is occurring. A normal  erythrocyte count is usually noted in 4 to 6 weeks, but hemo-  globin restoration may take 6 to 8 weeks.    The predominant event in hemolytic anemias is premature  accelerated destruction of erythrocytes, either episodically or    Transfusion reaction  Hemolytic disease of the newborn (see Chapter 30)  Autoimmune hemolytic anemia (see text)    Presence of prosthetic heart valves  Structural abnormalities of the heart  Hemolytic uremic syndrome  Disseminated intravascular coagulation  Hemodialysis    Antibody-mediated: intravascular hemolysis by activation  of complement system; extravascular hemolysis by  phagocytosis of antibody-coated erythrocytes in spleen  (see Chapter 9)    Diminished cellular production of substances required for  erythrocyte life and function    continuously. The consequences of the anemia are elevated  levels of erythropoietin to induce accelerated production of  erythrocytes and an increase in the products of hemoglobin  catabolism.   Hemolytic anemias may be either congenital or acquired.  Congenital hemolytic anemias result from intrinsic defects in  erythrocytes, including the red cell membrane (e.g., heredi-  tary spherocytosis, paroxysmal nocturnal hemoglobinuria),  enzymatic pathways (e.g., glucose-6-phosphate dehydrogenase  deficiency), and hemoglobin synthesis (e.g., the thalassemia  syndromes, sickle cell anemia). (Glucose-6-phosphate dehy-  drogenase deficiency, thalassemia, and sickle cell disease are dis-  cussed in Chapter 30.) Acquired hemolytic anemias are usually  immunologic (immune hemolytic anemias), such as erythrocyte  destruction caused by autoantibodies against erythrocyte anti-  gens (e.g., autoimmune hemolytic anemia), isohemagglutinins    (e.g., mismatched erythrocyte transfusions), or allergic reac-  tions against drug antigens adsorbed onto the erythrocyte sur-  face (drug-induced hemolytic anemia). (Isohemagglutinins,  erythrocyte antigens, autoantibodies, and allergic reactions are  discussed in Chapter 9.) Acquired hemolytic anemia may also  be secondary to erythrocyte damage caused by cardiac valve  prostheses or by increased shear stresses in narrowed small  vessels (e.g., during disseminated intravascular coagulation).  Causes of acquired and hereditary hemolytic anemias are listed  in Table 28-6.   PATHOPHYSIOLOGY. Hemolytic anemias can be classified by a  variety of parameters, although no system is entirely satisfac-  tory. Dividing these anemias into inherited or acquired is the  preferred and most useful method. Pathophysiologic mecha-  nisms also can be discussed in the context of where hemolysis  occurs. Hemolysis occurs within blood vessels (intravascular)    or lymphoid tissues (extravascular) that filter blood—that is,  spleen and liver. Intravascular hemolysis is the least common  and typically caused by physical destruction of erythrocytes  in the circulation, frequently by antibody and complement.  Extravascular hemolysis results from removal of damaged or  opsonized erythrocytes by cells of the mononuclear phagocyte  system (MPS). Erythrocytes continuously circulate through the  spleen, passing through the thin-walled splenic cords into the  splenic sinusoids, a spongelike labyrinth of macrophages with  long dendritic processes. Normally, erythrocytes are able to alter  their shape to allow passage through openings in the splenic  cords. Macrophages will phagocytose erythrocytes with struc-  ture alterations of the membrane surface or that have become  more rigid and are incapable of maneuvering through this net-  work. In some cases, IgG antibodies or complement compo-  nent C3b can coat erythrocytes without causing hemolysis, but  can function as opsonins that are recognized by macrophages.   Paroxysmal nocturnal hemoglobinuria may be congenital  or acquired secondarily to acquired aplastic anemia. The dis-  ease results from a mutation in the X-linked gene for phos-  phatidylinositol glycan—class A (PIG-A), which results in a  defect in expression of glycosylphosphatidylinositol (GPI) in  hematologic stem cells.2° GPI is a lipid anchor that is neces-  sary for attachment of a large number of proteins to the plasma  membrane. Several GPI-anchored proteins on erythrocytes  are complement regulatory proteins, including CD55 (decay-  accelerating factor) and CD59 (membrane attack complex  [MAC] inhibitory protein). Normally low levels of comple-  ment are activated on cell surfaces through the alternative  pathway (see Chapter 7). Erythrocytes are protected from  complement-mediated damage by CD55, which accelerates the  degradation of any C3 convertase that forms on the cell sur-  face, and by CD59, which prevents C9 aggregation and pore  formation by the membrane attack complex. Thus erythrocytes  deficient in CD55 and CD59 undergo complement-mediated  intravascular lysis and release of hemoglobin.” In addition to  anemia and hemoglobinuria, affected individuals also present  with severe fatigue, abdominal pain, and thrombosis.*” The  cause of death is usually thrombosis of the abdominal or cere-  bral veins.?'! Thrombosis most likely results from a depletion  of vascular nitric oxide (NO) by free hemoglobin, which has  a high affinity for NO. The result is dysregulation of normal  hemostasis and increased platelet vascular adherence and clot  formation (see Chapter 27).   Autoimmune hemolytic anemias (AITHAs) are acquired dis-  orders caused by autoantibodies against antigens normally on  the surface of erythrocytes.°* Three types of AIHAs have been  described: (1) warm reactive antibody type, (2) cold agglutinin  type, and (3) cold hemolysin type (paroxysmal cold hemoglo-  binuria). This classification is based on the optimal temperature  at which the antibody binds to erythrocytes and the mechanism  of erythrocyte destruction.   Warm autoimmune hemolytic anemia is uncommon (inci-  dence of about 1 per 80,000 population annually), although  it is the most common form of AIHA (80% to 90% of cases),  and generally occurs in individuals older than the age of 40.°°  Approximately half of the cases are secondary to other diseases,    especially lymphomas but also chronic lymphocytic leukemia,  other neoplastic disorders, or systemic lupus erythemato-  sus (SLE). The anemia is caused by IgG that binds optimally  to erythrocytes at normal body temperature (37° C, 98.6° F).  Most cases are related to antibody against Rh-related antigens  other than the D epitope (Rh antigens are discussed in Chapter  9). The spectrum of antibody specificities includes antibodies  against the e, E, or c antigens of the Rh complex. Other cases  are caused by IgG antibodies against erythrocyte antigens out-  side the Rh complex and include antibodies against wr, En’,  the Kell blood group, and many others. The warm reactive IgG  antibodies usually do not activate complement because of the  rather sparse distribution of antigens on the erythrocyte sur-  face. (Activation of complement by antibody is discussed in  Chapters 7, 8, and 9.) Erythrocyte destruction is caused by  extravascular processes. The IgG-coated erythrocytes bind to  the Fc receptors on monocytes and splenic macrophages and  are removed by phagocytosis.   Cold agglutinin autoimmune hemolytic anemia is medi-  ated by immunoglobulin M (IgM) antibodies and occurs  less often than warm antibody hemolysis, affecting mostly  middle-aged and older adults. Cold antibodies optimally bind  to erythrocytes at colder temperatures (lower than 31° C  [87.8° F]) with maximal binding capacity at 4° C (39.2° F). Cold  agglutinin autoantibodies may appear acutely during recovery  of certain infectious disorders, particularly infectious mononu-  cleosis, mycoplasma pneumonia, and disseminated tuberculo-  sis.°* With these conditions, the individuals are usually younger  than those with primary disease; the anemia may be severe  but may be self-limiting. Chronic cold agglutinin AIHAs also  can occur in association with lymphoid neoplasm and other  unknown or idiopathic conditions.*°   The IgM autoantibody is usually monoclonal and directed  against erythrocyte carbohydrate antigens of the I system  (i.e, i, 1) or the P system (i.e., Pr).*° In the colder areas of the body,  particularly during cold weather (e.g., fingers, toes, nose, ears,  exposed skin), the IgM autoantibodies bind to circulating eryth-  rocytes. The IgM is rapidly released when the blood recirculates  and warms. IgM is an extremely efficient activator of comple-  ment, resulting in the stable deposition of C3b on the cell surface.  If an adequate amount of complement is deposited, the eryth-  rocytes become vulnerable to recognition and rapid phagocyto-  sis by mononuclear phagocytes in the liver and spleen (also see  Chapter 9). The severity of hemolysis is variable and may result  in a progressive chronic anemia. If the level of antibody is high  or has particularly strong binding, hemagglutination may occur  in the capillaries of exposed sites, such as fingers, toes, and ears,  when temperatures are below 30° C (86° F). Obstruction of blood  flow caused by erythrocyte agglutination may lead to a bluish  discoloration of the skin (acrocyanosis) that resolves as the skin  is warmed. Prolonged exposure to the cold may lead to gangrene.   Cold hemolysin autoimmune hemolytic anemia (parox-  ysmal cold hemoglobinuria) is a disorder in which exposure  to cold initiates acute and severe intravascular hemolysis that,  unlike cold agglutinin anemia, results in hemoglobulinuria.  The chronic form of this anemia is extremely rare, but an acute  form of paroxysmal cold hemoglobinuria is frequently observed    (30% to 40% of cases) in AIHA of childhood. The acute form  occurs primarily in children younger than the age of 10 years  and is usually preceded by an upper respiratory tract infection  or flulike symptoms. Infections with measles, mumps, Myco-  plasma (pneumonia), and Varicella have also been linked to an  onset of paroxysmal cold hemoglobinuria. The anemia may be  rapidly progressing and severe and associated with fever, red-  dish brown urine, hemoglobinuria, jaundice, abdominal pains,  and pallor, with about 25% of individuals presenting with hepa-  tomegaly and splenomegaly.   Paroxysmal cold hemoglobinuria is generally caused by  IgG autoantibodies against the P blood group antigen. Anti-  body binding occurs in the colder portions of the body. As  the erythrocyte recirculates, enzymes of the complement cas-  cade are activated, and cells are destroyed in the vasculature by  complement-mediated lysis. The involved antibody, also called  Donath-Landsteiner antibody, was first recognized in individu-  als with anemia secondary to chronic syphilis infection. A trans-  fusion reaction is an example of alloimmune hemolytic anemia  (also see Chapter 9). Transfused blood that is mismatched for  ABO antigens is destroyed by preexisting isohemagglutinins in  the recipient. Isohemagglutinins, which are generally IgM anti-  bodies, activate complement, resulting in a rapid intravascular  hemolysis. The individual may immediately experience fever,  chills, dyspnea, and hypotension and may progress to shock. In  some cases the hemolytic reaction may be delayed and develop  3 to 10 days after transfusion. The delayed reaction is caused  by a low titer of preexisting antibodies to minor erythrocyte  antigens.    Drug-induced hemolytic anemia is a form of immune  hemolytic anemia usually resulting from an allergic reaction  against foreign antigens (e.g., antibiotics)*” (also see Chapter  9). Usually the drug is low molecular weight, functions as a  hapten, and binds to proteins on the surface of erythrocytes.  This is sometimes called the hapten model and is based on ane-  mia caused by penicillin, cephalosporins (more than 90% of  cases), and, very recently, hydrocortisone (Figure 28-6, A).°*  IgG antibody against the drug or against the unique antigen  formed by the interface of the drug and erythrocyte protein is  formed and binds to the erythrocyte at normal body tempera-  ture. Hemolysis is usually extravascular because the opsonized  erythrocytes are removed by phagocytes in the spleen and liver,  although complement-dependent intravascular hemolysis may  occur in some individuals. This form of drug-induced anemia  usually follows a large intravenous infusion of an antibiotic  and occurs | to 2 weeks after the initiation of therapy. Cessa-  tion of administration of the drug results in rapid resolution  of the anemia.   The erythrocyte plasma membrane contains receptors of  components of the complement system, such as C3b, and  can bind circulating immune complexes that have activated  the complement cascade (see Chapter 9 for a discussion of  immune complexes). This forms the basis for the immune  complex model of drug-induced hemolytic anemia and was  first described for anemia resulting from administration of  the drug quinidine (Figure 28-6, B). The drug or a metabo-  lite of the drug, both of which are haptens, initially binds to  plasma proteins and becomes immunogenic (see Chapter 8).    FIGURE 28-6 Models of Drug-Induced Hemolytic Anemia. See discussion in text. /gG, Immunoglobulin G; RBC,    The circulating drug/protein complex reacts with the resul-  tant antibody (usually IgM, although IgG complexes have also  been described) and activates the complement system, result-  ing in the deposition of C3b into the complex. Binding of the  immune complexes to the erythrocyte surface results in fur-  ther complement activation and intravascular hemolysis. This  mechanism also may explain some of the anemia observed in  other immune complex conditions, such as SLE.   In at least one instance, administration of the drug  a-methyldopa induces an immune response against normal  erythrocyte antigens and thus initiates a true AIHA (autoim-  mune model) (Figure 28-6, C). The autoantibody is usually  against Rh blood group antigens. It is estimated that 20% of  individuals taking a-methyldopa develop detectable antibodies,  but only 1% actually develop clinically significant anemia. The  mechanism by which a-methyldopa induces autoantibodies  against the erythrocytes is unknown.   CLINICAL MANIFESTATIONS. The presence and severity of signs  and symptoms of hemolytic anemia depend on the degree of  anemia and hemolysis and the success of compensatory eryth-  ropoiesis. Adaptation to red cell destruction is facilitated by  increased red cell production. Bone marrow is capable of  increasing red cell production up to eight times its normal rate.  Accelerated erythrocyte production that is incapable of keeping  up with destruction develops into a true hemolytic anemia.   The severity of anemia varies widely from individual to indi-  vidual, even in individuals who have the same illness. Severe  disease is commonly diagnosed shortly after birth or within  the first year of life. Mild to moderate anemia is more com-  mon because the shortened erythrocyte survival time is offset  by increased erythropoiesis. Some individuals have no symp-  toms of anemia, and the underlying hemolytic process remains  undetected unless some other complications develop during the  course of the disease.   Jaundice (icterus) is present when heme destruction exceeds  the liver’s ability to conjugate and excrete bilirubin. Jaundice is  first noticed in the neonatal period. Children and adults with  congenital hemolytic anemia may not have icterus, or it may  be mild enough that it remains unnoticed. In some individu-  als, faint scleral icterus may be the only indication of hemolytic  disease.   Acute conditions that disrupt the delicate equilibrium of  accelerated erythropoiesis and erythrocyte destruction may  precipitate a crisis. The most common type of crisis is aplastic  and results from failure of bone marrow erythrocyte produc-  tion. The most common cause of aplastic crisis is human par-  vovirus B19 infection.   Commonly, individuals with congenital hemolytic disorders  demonstrate splenomegaly, which is often only mild in nature.  In some cases the spleen may become quite enlarged and may  cause discovery of the underlying hemolytic disorder. Another  underlying condition that may be the cause of inadvertently  determining the presence of the anemic disorder is the develop-  ment of gallstones.   Children who have hemolytic anemia often demon-  strate skeletal abnormalities caused by expansion of ery-  throid bone marrow during the active phase of growth and    development. These alterations are more pronounced in the  bony structures of the face and skull and may result in patho-  logic fractures (see Chapter 30). Cardiovascular and respiratory  manifestations vary with the degree of anemia. In spite of the  disorder being characterized as hemolytic in nature, throm-  boembolism may occur. Pulmonary embolism is a common  finding during autopsies of individuals with immune hemolytic  anemia.   EVALUATION AND TREATMENT. Diagnosis is based on clini-  cal manifestations, bone marrow studies, and blood tests (see  Table 28-3). Abnormally increased numbers of erythrocyte  stem cells are found in the marrow, a finding termed erythroid  hyperplasia. Accelerated erythropoiesis causes large numbers of  fragile and immature erythrocytes (stem cells and reticulocytes)  to be released prematurely into the circulation. These cells are  observed in blood smears. If the bone marrow is able to consis-  tently maintain adequate compensation, the hemoglobin may  remain stable. The mean corpuscular volume, however, may  be decreased in the presence of reticulocytes. A blood smear is  helpful in determining the presence of spherocytes or schisto-  cytes, as well as examining white blood cells and platelets for  coexisting hematologic or malignant conditions.   Acquired hemolytic anemias are treated by removing the  cause or treating the underlying disorder. Corticosteroids are  used for initial treatment. Approximately 75% of individuals  initially respond to treatment with corticosteroids, but many of  these relapse within a year. The most commonly used second-  line treatments are splenectomy and administration of rituximab.  Splenectomy is performed if the spleen is the major site of hemo-  lysis and splenomegaly is significant. Analysis of multiple studies  confirms that some response (complete or partial) is achieved in  between 59% and 100% of individuals.*’ Although some individ-  uals relapse after splenectomy, most achieve long-term remission.   The therapeutic use of monoclonal antibody has proven ben-  eficial in individuals who relapse or are resistant to the effects of  corticosteroids. Rituximab is a monoclonal antibody directed  against the CD20 antigen and specifically depletes or suppresses  B cells throughout the body. CD20 is expressed on most cells in  the B-cell lineage, except hematopoietic stem cells and plasma  cells. Rituximab is used to treat a variety of leukemias and lym-  phomas and autoimmune diseases (e.g., rheumatoid arthritis,  idiopathic thrombocytopenia, multiple sclerosis, type 1 diabe-  tes mellitus, systemic lupus erythematosus). It is used success-  fully in several types of immune hemolytic anemias, although,  as with most other therapies, individuals vary in the degree  of response, potential to relapse, the optimal dose and timing  for an optimal response, and complications.*° Eculizumab is a  monoclonal antibody against complement protein C5, which  blocks the enzymatic activation of C5 to C5a and C5b, and  thus may be useful to treat paroxysmal nocturnal hemoglo-  binuria. Treatment with eculizumab prevents the formation  of the membrane attack complex and complement-mediated  cell lysis (see Chapter 7). In multiple trials, use of eculizumab  resulted in reduced hemolysis, the need for transfusion, and  the risk for thrombosis, as well as diminished other symptoms,  including fatigue and abdominal pains.*! Blockage of C5 activa-  tion mimics individuals who have congenital deficiencies in C5    (see Chapter 9). Lack of C5 increases the risk for disseminated  infections with Neisseria sp., particularly Neisseria meningitidis;  thus immunization with the meningococcal vaccine is recom-  mended before treatment with eculizumab.*”   Acute fulminating hemolytic anemia (hemolytic crisis) is  treated with fluid and electrolyte replacement to prevent shock  and renal damage, which may be caused by erythrocyte debris  clogging the kidney tubules. Transfusions of blood products  sometimes are given. Folate also is used in treating chronic  hemolytic disease to prevent megaloblastic crisis because long-  term erythrocyte turnover increases folate requirements.    Anemia of chronic disease (ACD) is a mild to moderate ane-  mia resulting from decreased erythropoiesis in individuals with  conditions of chronic systemic disease or inflammation (e.g.,  infections, cancer, and chronic inflammatory or autoimmune  diseases). These conditions include acquired immunodeficiency  disease (AIDS), malaria (particularly that caused by Plasmo-  dium falciparum), rheumatoid arthritis, systemic lupus erythe-  matosus (SLE), acute and chronic hepatitis, and chronic renal  failure (a condition in which almost all affected individuals are  anemic).*? This form of anemia also is commonly noted in the  presence of congestive heart failure (CHF). The anemia devel-  ops after 1 to 2 months of disease activity. The initial severity is  related to that of the underlying disorder but, although persis-  tent, it usually does not progress. Individuals may be asymp-  tomatic, or the anemia may be a coincidental clinical finding.   ACD is one of the most common conditions encountered  in medicine and is probably only secondary to IDA in overall  incidence. In individuals older than age 65, anemia is present in  10% of those who live in the community and more than 50%  of those who reside in nursing homes, two thirds of which is  ACD or unexplained anemia. The elderly may be predisposed  to ACD related to age-associated hematopoietic restriction  and generally have increased concentrations of inflammatory  cytokines, which play a significant role in the development  of ACD. The elderly who present with characteristics of ACD  without an underlying malignancy or inflammatory condi-  tion are described as having primary defective iron-utilization  syndrome.   PATHOPHYSIOLOGY. ACD results from a combination of (1)  decreased erythrocyte life span, (2) suppressed production of  erythropoietin, (3) ineffective bone marrow erythroid progeni-  tor response to erythropoietin, and (4) altered iron metabo-  lism and iron sequestration in macrophages.“ During chronic  inflammation a large variety of cytokines are released by lym-  phocytes, macrophages, and the affected tissue.*° These include  TNF-a, IFN-y, interleukin-16 (IL-16), IL-3, and IL-6 (also see  Chapters 7 and 8).*°   Impaired iron metabolism is partially the result of iron  sequestration.*” IL-6 in particular affects hepatocytes and  increases the release of the peptide hepcidin, which regulates  the activity of ferroportin. Ferroportin is the primary trans-  porter for the export of iron from macrophages to the plasma,  and increased levels of hepcidin result in decreased ferroportin  activity and suppression of iron release (Figure 28-7).    Erythrocyte destruction is the result of eryptosis (described  earlier in this chapter). Most of the diseases responsible for  ACD damage erythrocytes, resulting in increased efflux of  plasma membrane phosphatidylserine and susceptibility to  removal by macrophages. Normal iron transport by transferrin  also may be decreased as a result of competitive iron binding by  inflammation-related increases in the levels of circulating lac-  toferrin and apoferritin. Lactoferrin is a member of the trans-  ferrin family of nonheme iron-binding glycoproteins, and  under normal conditions is present in the blood in only small  amounts. During inflammation neutrophils release lactofer-  rin to bind iron and reduce its availability for bacteria. How-  ever, the affinity of iron for lactoferrin is 260 times greater than  that for transferrin. Lactoferrin-bound iron is removed by the  mononuclear-phagocyte system and converted into ferritin, the  storage form of iron. Apoferritin also has a higher affinity for  iron and affects available iron in a similar manner.   The erythropoietic defect in ACD is failure to increase eryth-  ropoiesis in response to decreased numbers of erythrocytes. In  part, decreased erythropoiesis results from diminished produc-  tion of erythropoietin by the kidneys. The kidney is frequently  affected by chronic inflammatory processes caused by circulat-  ing immune complexes and other factors that deposit in the  kidney and activate secondary inflammatory mechanisms. In  addition, the failure in erythropoiesis may reflect decreased  responsiveness of erythroid progenitors to erythropoietin.  Decreased availability of iron would diminish the rate of eryth-  ropoiesis. Proliferation of erythroid cells is also inhibited by  proinflammatory cytokines, especially TNF-a, IFN-y, and  IL-16. TNF-a also directly induces apoptosis of erythroid pro-  genitors, thus diminishing the number of responsive cells. In  individuals who had anemia secondary to rheumatoid arthritis,  the bone marrow contained elevated levels of IL-3, which cor-  related with diminished expression of integrins on the surface  of cells of the erythroid series.*® Loss of integrins may prevent  adequate interaction with stromal cells and matrix proteins and  inhibit erythropoiesis.   Anemia associated with chronic renal failure may result from  a variety of simultaneous mechanisms. Damage to the kidney  affects the secretion of erythropoietin, a necessary hormone for  production of erythrocytes in the bone marrow, thus resulting  in diminished bone marrow erythropoiesis.*? Uremic toxins  (e.g., uric acid, sulfates, phosphates) that increase in the blood  secondarily to renal failure may suppress bone marrow func-  tion and damage erythrocytes, which undergo eryptosis. Plate-  let function also may be defective in these individuals, which  results in chronic bleeding and loss of erythrocytes.   Anemia may arise from the direct action of bacterial tox-  ins. For example, Clostridium perfringens (gas gangrene and a  cause of food poisoning) produces an alpha-toxin. This toxin  has enzymatic activity (phospholipase C, sphingomyelinase)  that disrupts the membrane of cells. If the cells are erythrocytes,  hemolysis will result.   CLINICAL MANIFESTATIONS. The anemia of ACD is usually in the  mild to moderate range, with few additional complications. If  hemoglobin levels drop significantly, clinical manifestations of  IDA appear.    TrFe = transferrin bound to iron  LFFe = lactoferrin bound to iron  MPS = mononuclear phagocyte system    FIGURE 28-7 Pathophysiology of Anemia of Chronic Disease. Normal iron metabolism is indicated by the narrow  arrows. Abnormal mechanisms that are instrumental in the development of anemia of chronic inflammation are indicated by    EVALUATION AND TREATMENT. Morphologically, ACD is initially  normocytic-normochromic, but as the condition persists it  becomes hypochromic and microcytic. ACD is characterized by  abnormal iron metabolism with low levels of circulating iron  (less than 60 mcg/dl) and reduced levels of transferrin. The most  significant finding of ACD is a very high total body iron stor-  age, although inadequate iron is released from the bone marrow  for erythropoiesis. Very often the first indication of ACD is a  failure to respond to conventional iron replacement therapy.  Levels of erythropoietin are generally lower than expected for  the degree of anemia. The affected individuals also frequently  present with low or normal total iron-binding capacity (TIBC),  normal or high serum ferritin levels, and low concentrations  of soluble transferrin receptor (blood test findings are listed  in Table 28-3). Occasionally it may be difficult to differentiate  ACD from IDA; however, measurement of sTfR may be useful.  Levels of sTfR do not respond to iron supplementation in ACD  but do so in IDA.   Use of erythropoietin in treatment of ACD associated with  arthritis, malignancies, and AIDS has met with limited success.    Individuals with severe anemia secondary to chronic kidney dis-  ease can be treated successfully with erythropoietin and treat-  ments to increase iron stores.4> However, the optimal degree  of restoration of hemoglobin levels (a measure of anemia) has  not been determined; achievement of normal levels increases  the risk of hypertension, stroke, and death.°° Transfusion of  critically ill individuals may worsen the outcome and increase  morbidity and mortality.*! The principal treatment is allevia-  tion of the underlying disorder. Individuals who have ACD but  demonstrate no evidence of inflammatory or infectious condi-  tions are screened for the presence of malignancies.    Hematologic dysfunction results from an overproduction of  cells as well as a deficiency. One or more hematopoietic lines may  be overproduced in the marrow in response to exogenous (e.g.,  exposure to radiation, drugs) or endogenous (e.g., physiologic  compensatory responses, immune disorders) signals. Excessive    red blood cell production is classified as polycythemia. Poly-  cythemia exists in two forms: relative and absolute. Relative  polycythemia results from hemoconcentration of the blood  associated with dehydration that may be caused by decreased  water intake, diarrhea, excessive vomiting, or increased use of  diuretics. Its development is usually of minor consequence and  resolves with fluid administration or treatment of the underly-  ing condition.   Absolute polycythemia consists of two forms: primary or  secondary. Secondary polycythemia, the more common type, is  a physiologic response resulting from increased erythropoietin  secretion in response to chronic hypoxia. This hypoxia is noted  in individuals who live at higher altitudes (i.e., above 10,000  feet), smokers with increased levels of carbon monoxide (CO),  and individuals with chronic obstructive pulmonary disease or  congestive heart failure, or both. Abnormal types of hemoglo-  bin (e.g., Hbgan piego OF Hbchesapeake)» Which have a greater affin-  ity for oxygen, also can cause secondary polycythemia, as does  secretion of erythropoietin by certain tumors (e.g., renal cell  carcinoma, hepatoma, and cerebral hemiangioblastoma).   Polycythemia vera (PV) (also known as primary polycythemia)  is one of several disorders collectively known as chronic myelo-  proliferative disorders (CMPDs).°* Others in this group include  essential thrombocytosis, chronic idiopathic myelofibrosis,  chronic myeloid leukemia, chronic neutrophilic leukemia, and  chronic eosinophilic leukemia. All result from abnormal regu-  lation of the multipotent hematopoietic stem cells. The major  characteristics shared by these disorders are: (1) involvement of  a multipotent hematopoietic progenitor cell; (2) overproduc-  tion of one or more of the formed elements of the blood in the  absence of a defined stimulus; (3) dominance of a transformed  progenitor cell over the nontransformed progenitor cells; (4)  marrow hypercellularity or fibrosis; (5) cytogenetic abnormali-  ties; (6) predisposition to thrombus formation and hemor-  rhage; and (7) spontaneous transformation to acute leukemia.  Determining a precise distinction between the CMPDs is dif-  ficult if not impossible because of overlapping clinical features  and a lack of specific molecular markers. As a result, diagnosis  is quite challenging.   PV is quite rare with an estimated incidence of 2.3 per  100,000 individuals; peak incidence is between the ages of 60  and 80 years, with a median incidence of 55 to 60. However, PV  has been observed in individuals younger than the age of 40.  Males are twice as likely as females to develop PV. PV is more  common in whites, particularly those of Eastern European Jew-  ish ancestry, than in blacks. PV is rarely found in children or  in multiple members of a single family; however, an autosomal  dominant form exists that is characterized by increased produc-  tion of erythropoietin.   PATHOPHYSIOLOGY. Polycythemia vera (PV) is a chronic neo-  plastic, nonmalignant condition characterized by overproduc-  tion of red blood cells (frequently with increased levels of white  blood cells [leukocytosis] and platelets [thrombocytosis]) and  splenomegaly. Erythrocytosis is the essential component of  PV. Clonal proliferation of erythroid progenitors occurs in the    bone marrow independent of erythropoietin, although the cells  express a normal erythropoietin receptor. However, more than  95% of individuals with PV possess an acquired mutation in  Janus kinase 2 (JAK2).°° JAK2 increases the activity of the eryth-  ropoietin receptor and is self-regulatory so that JAK2 activity  diminishes over time. The mutation associated with PV negates  the self-regulatory activity of JAK2 so that the erythropoietin  receptor is constitutively active regardless of the level of eryth-  ropoietin.*’ These red blood cell precursors also demonstrate  sensitivity to other growth factors, such as interleukin-3 (IL-3),  granulocyte-macrophage colony-stimulating factor (GM-CSF),  or insulin-like growth factor   CLINICAL MANIFESTATIONS. Almost every individual initially  presents with an enlarged spleen, frequently with abdominal  pain and discomfort. As the disease progresses many of the  symptoms are related to the increased blood cellularity and  viscosity. Increased viscosity, as well as thrombocythemia and  increased platelet dysfunction, leads to a hypercoagulable state  with formation of venous and arterial thrombosis and ves-  sel occlusion.°? Thrombi with occlusion of major and minor  blood vessels lead to tissue and/or organ injury (ischemia) and  death (infarction). Extreme thrombocythemia (greater than  1,500,000/mm? of blood) increases the risk for excessive bleed-  ing, rather than thrombosis.   Increased blood viscosity results in a variety of circulatory  alterations in PV, such as plethora (ruddy, red color of the face,  hands, feet, ears, and mucous membranes) and engorgement of  the retinal and cerebral veins. Individuals also may experience  headache, drowsiness, delirium, mania, psychotic depression,  chorea, and visual disturbances. Death from cerebral thrombo-  sis is increased approximately fivefold in individuals with PV.   Cardiac workload and output remain essentially unchanged;  however, increased blood volume may lead to elevated blood  pressure. Coronary blood flow may be affected, precipitating  angina, although cardiovascular infarctions are relatively rare.  Other evidence of cardiovascular involvement is the develop-  ment of Raynaud phenomenon and thromboangiitis obliterans.   Additionally, gastrointestinal gastric and duodenal throm-  bosis may occur with resultant hemorrhaging. The development  of mesenteric thrombosis requires immediate medical interven-  tion. Splenomegaly and hepatomegaly result from pooling of  blood in these organs; consequently, individuals may develop  portal hypertension. The respiratory system is generally not  affected by PV, unless thrombosis and embolization occur.   A unique feature of PV, one helpful in diagnosis, is the devel-  opment of intense, painful itching that is intensified by heat  or exposure to water (aquagenic pruritus), particularly warm  water when bathing or showering. The intensity of the itching  is related to the concentration of mast cells in the skin and is  generally not responsive to antihistamines or topical lotions.   EVALUATION AND TREATMENT. PV is frequently suspected on the  basis of clinical features, such as a thrombotic event, spleno-  megaly, or aquagenic pruritus. Diagnosis of PV is made from  blood and laboratory findings (Box 28-2). An absolute increase  in the number of red blood cells and in total blood volume con-  firms the diagnosis. Hematocrit levels may range from 18 to  24 g/dl and red blood cell counts may range from 7 x 10!? to    Major Criteria (A)  Increased total red blood cell (RBC) volume (RBC mass):  >25% above normal predicted value  M 236 ml/kg (Hb >18.5 g/dl)  F >32 ml/kg (Hb >16.5 g/dl)  0, saturation =>92%  Splenectomy  Clonal genetic abnormality other than Philadelphia chromosome or ber/abl  fusion gene in marrow™  Endogenous erythroid formation in vitro*   Panmyelosis (myeloid metaplasia with abnormal immature blood cells in  spleen and/or liver) with prominent erythroid/megakaryocytic hyperplasia  on marrow biopsy*    *World Health Organization (WHO) Criteria for Diagnosis: Elevated red  cell mass (RCM) and any other major criteria or elevated RCM and any  two minor criteria.   LAP Leukocyte alkaline phosphatase; UB;2BC, unbound B,,-binding  capacity; W/BC, white blood cell.    7 x 10!3/mm/?. Erythrocytes appear normal but anisocytosis may  be present. A bone marrow examination may be done but is not  very valuable unless performed in association with cytogene-  tic and molecular studies for relevant mutations in JAK2.°° The  presence of a JAK2 mutation confirms the diagnosis.°” Typi-  cally the marrow is hypercellular but not in such a manner as to  differentiate it from other myeloproliferative disorders. Addi-  tional observations on abnormal megakaryocyte morphologies,  formation of clusters of abnormal cells, and increased fibrosis  add more specificity and usefulness to bone marrow analysis.  Elevated serum levels of erythropoietin are not helpful because  most individuals with PV have normal or low levels.   Treatment of PV is challenging and directed toward mini-  mizing the risk of thrombosis and preventing progression to  myelofibrosis and acute leukemia. In low-risk individuals (e.g.,  those younger than age 60 or with no history of thrombosis  and without risk factors for cardiovascular disease), the rec-  ommended therapy is phlebotomy (300 to 500 ml at a time to  reduce erythrocytosis and blood volume) and low-dose aspi-  rin. Initial phlebotomies are done two or three times a week  until the hematocrit drops sufficiently, and repeated every 3 to  4 months to maintain a safe hematocrit (less than 45%). Aspi-  rin is used for its antithrombotic (decrease in thromboxane)  properties.   Hydroxyurea, an antimetabolite that blocks DNA synthesis  and reduces vascular cellularity, is the drug of choice for myelo-  suppression. Unlike other similar drugs, hydroxyurea reduces  the risk of thrombotic complications, but does not increase the    risk for developing leukemia.** Radioactive phosphorus (*P)  has been used to suppress erythropoiesis. Its effects may last up  to 18 months. Side effects of **P treatment include suppression  of hematopoiesis resulting in anemia, leukopenia, or thrombo-  cytopenia. Acute leukemia also is a side effect, although most  often it occurs after 7 or more years of treatment, making this  therapy more useful in the elderly.   Interferon-alpha (IFN-a) has been used when other forms  of treatment have failed. Interferon inhibits the growth of the  abnormal progenitors and inhibits the actions of cytokines that  may lead to the development of myelofibrosis. Therapy with IFN-  a is complicated by its proinflammatory activities; thus fever,  flulike symptoms, and more severe complications are common.  IFN-c is not consistently effective in high-risk adult cases, but  is considered in individuals who are intolerant to hydroxyurea,  younger individuals, and individuals who are pregnant.   Treatment with inhibitors of the JAK2 pathway has resulted  in reduction of many associated disease symptoms (e.g., throm-  bosis) and a significant improvement in the quality of life.°®  However, the optimal target defining successful treatment  (hematocrit) and the effects on life span have not yet been deter-  mined. Recent studies comparing the effects of phlebotomy or  hydroxyurea, or both, concluded that a goal of maintaining a  hematocrit of less than 45% was preferable to the goal of 45% to  50%.°? The lower target goal resulted in a significantly lower rate  of death from cardiovascular causes or major thrombotic events.   Survival for 10 to 15 years is common. However, without  proper treatment, 50% of individuals with PV die within  18 months of the onset of initial symptoms. The primary cause of  death is thrombosis, which is more prevalent in elderly individu-  als and those with prior vascular complications. Death because of  hemorrhage is rare but more common in individuals with high  platelet counts and those taking antiplatelet drugs. Conversion  to acute myeloid leukemia (AML) occurs spontaneously in 10%  of individuals within 15 years, increasing to 50% within 20 years.  This leukemia is generally refractory to conventional treatment.  Conversion to AML is most likely related to treatment with cyto-  toxic myelosuppressive agents, such as chlorambucil.°’ Those  individuals treated only with IFN or hydroxyurea had the same  incidence of conversion as those who received no treatment.  Although PV is a chronic disorder, appropriate therapy results  in remissions and prevention of significant morbidity.    Iron overload can be primary, as in hereditary hemochroma-  tosis, or secondary. The secondary causes of iron overload  include anemias with inefficient erythropoiesis (e.g., sideroblas-  tic anemia, aplastic anemia), dietary iron overload, or condi-  tions that require repeated blood transfusions or iron dextran  injections.   Hereditary hemochromatosis (HH) is a common inherited,  autosomal recessive disorder of iron metabolism and is charac-  terized by increased gastrointestinal iron absorption with sub-  sequent tissue iron deposition. Excess iron is deposited in the  liver, pancreas, heart, joints, and endocrine glands, causing tis-  sue damage that can lead to diseases such as cirrhosis, diabetes,  heart failure, arthropathies, and impotence.”    HH is caused by two genetic base-pair alterations, C282Y  and H63D. These are mutations in the HFE gene on chromo-  some 6. Homozygosity of C282Y is the most common geno-  type and accounts for 82% to 90% of HH cases. The remaining  cases appear to be caused by environmental factors or other  genotypes. HFE mutations are common in the United States  with 1 in 10 white individuals heterozygous for the HFE C282Y  mutation and 4.4 in 1000 homozygous for the C282Y mutation.  C282Y homozygosity is much lower among Hispanics (0.27 in  1000), Asian Americans (<0.001 per 1000), Pacific Islanders  (0.12 per 1000), and blacks (0.14 per 1000).   PATHOPHYSIOLOGY. Studies in mice have confirmed that the  HFE gene is responsible for HH. HFE protein, found in the  crypt cells of the duodenum, facilitates transferrin receptor—  dependent iron uptake into crypt cells. Mutant HFE protein  loses its functional ability and causes a relative iron deficiency  in duodenal crypt cells. The deficiency results in an increase in  the expression of an iron transport protein, divalent metal ion  transporter 1 (DMT-1), which is responsible for dietary iron  absorption in the villus cells of the small intestine. This inap-  propriate intestinal iron absorption leads to iron overload and,  eventually, end-organ damage that can result in cirrhosis, diabe-  tes mellitus, hypothyroidism, cardiomyopathies, and arthritis.   Although the natural history of HH is not well understood,  there appears to be a long latent period with individual varia-  tion in biochemical expression modified by environmental fac-  tors, such as blood loss from menstruation or donation, alcohol  intake, and diet. Cirrhosis is a late-stage development of HH that  can shorten life expectancy. Cirrhosis also is a risk factor for hepa-  tocellular carcinoma that occurs between 40 and 60 years old. Cir-  rhosis prevention is a major goal of HH screening and treatment.    CLINICAL MANIFESTATIONS. Clinical manifestations of HH  include symptoms such as fatigue, malaise, abdominal pain,  arthralgias, and impotence, and clinical findings of hepatomeg-  aly, abnormal levels of liver enzymes, bronzed skin, diabetes,  and cardiomegaly. Many individuals are diagnosed as a result  of serum iron studies as part of a health screening panel. Most  (>75%) are asymptomatic and have a low frequency (<25%) of  cirrhosis, diabetes, or skin pigmentation.   EVALUATION AND TREATMENT. Laboratory findings in individu-  als with HH show elevations in serum iron levels, transferrin  saturation, and ferritin levels. Documentation of iron over-  load relies on quantitative phlebotomy with calculation of the  amount of iron removed, or liver biopsy with determination  of quantitative hepatic iron. With the advent of genetic testing,  individuals who are C282Y homozygous or compound hetero-  zygous, less than 40 years old, and have normal liver functions,  no further workup is necessary.   Treatment of HH is simple and consists of phlebotomy of  550 ml of whole blood, which is equivalent to 200 to 250 mg  of iron. Frequency of phlebotomy depends on ferritin levels  and should continue until the ferritin level is between 20 and  50 ng/ml. Initially, phlebotomy may be needed weekly but once  therapeutic ferritin levels are reached, phlebotomy may only  be needed every 2 to 3 months. Blood banks now accept blood  donations from persons with documented HH. Iron chelating  agents are sometimes used in addition to phlebotomy, but this  is not the mainstay of treatment. Individuals with HH should  be instructed to refrain from taking iron and vitamin C supple-  ments and consuming raw shellfish; in addition, alcohol should  be used in moderation. Family screening is recommended and  necessary for all first-degree relatives of a person with HH.   1. Anemia is defined as a reduction in the number or volume  of circulating erythrocytes or a decrease in hemoglobin  level. Polycythemias are excessive levels of erythrocytes or  volume.   2. Anemias can be classified according to (a) erythrocyte size  or concentration of hemoglobin or (b) their cause.   3. Clinical manifestations of anemia may be demonstrated  in all organs and tissues (tissue hypoxia) throughout the  body. Decreased oxygen delivery to tissues causes fatigue,  dyspnea, syncope, angina, compensatory tachycardia, and  organ dysfunction.   4. Macrocytic-normochromic, or megaloblastic-normochromic,  anemias are characterized by larger than normal erythrocytes  with normal levels of hemoglobin. They most commonly are  caused by deficiency of vitamin B, (PA) or folate.   5. PA results from inadequate vitamin B,7 absorption because  of autoantibodies against the B, transporter IF. Folate  deficiency anemia is caused by inadequate dietary intake of  folate. Both anemias respond to replacement therapy.   6. Microcytic-hypochromic anemias are characterized by  abnormally small erythrocytes with insufficient hemo-  globin content. This disorder results from disorders of    (a) iron metabolism (IDA), (b) porphyrin and heme syn-  thesis (SAs), or (c) globin synthesis (thalassemia).   7. IDA is the most common type of anemia worldwide. It usually  develops slowly, with gradual insidious onset of symptoms.  Fatigue, weakness, dyspnea, alteration of various epithelial  tissues, and vague neuromuscular complaints result.   8. IDA is usually a result of blood loss or poor nutritional  intake. Individuals at highest risk for developing IDA  include older adults, women, infants, and those living in  poverty. Anemia is also recognized as part of the nonspe-  cific acute phase response to any type of inflammation.  Once the source of blood loss is identified and corrected,  oral iron replacement therapy can be initiated.   9. SA results from defects in mitochondrial metabolism lead-  ing to ineffective iron uptake and dysfunctional heme syn-  thesis. The characteristic cell in the bone marrow, a ringed  sideroblast, is an erythroblast containing iron granules  arranged around the nucleus. SAs may be hereditary or  acquired, and treatment varies depending on the cause.   10. Normocytic-normochromic anemias are characterized by  insufficient numbers of normal erythrocytes. Included in  this category are aplastic, posthemorrhagic, and hemolytic  anemias and ACD.    AA is a critical condition characterized by a reduction or  absence of all three blood cell types (pancytopenia). Unless  the cause is determined, bone marrow aplasia results in death.  Acute blood loss from hemorrhage results in posthemor-  rhagic anemia with the severity depending on the amount of  hemorrhage. Restoration of blood volume by plasma expand-  ers or transfusions may diminish subjective symptoms of  anemia. Hemoglobin restoration may take 6 to 8 weeks.  Hemolytic anemia is a result of excessive destruction of  erythrocytes and may be acquired or hereditary. Of the  acquired forms, autoimmune reaction (immunohemolytic)  and drug-induced hemolysis are the most common.   AIHAs include (a) warm reactive antibody type, (b) cold  agglutinin type, and (c) cold hemolysin type (paroxysmal  cold hemoglobinuria).   ACD results from decreased erythropoiesis secondary to  chronic diseases. The anemia is mild to moderate and one  of the most common conditions encountered in medicine.    erythrocyte life span, (b) reduced production of erythro-  poietin, (c) ineffective bone marrow response to eryth-  ropoietin, and (d) iron sequestration in macrophages. In  particular, the proinflammataory cytokine IL-6 increases  hepatocyte release of hepcidin, which suppresses ferropor-  tin transport of iron out of macrophages.    Myeloproliferative Erythrocyte Disorders (Polycythemia)  1. Polycythemia vera is a myeloproliferative disorder char-    acterized by excessive proliferation of erythrocyte precursors  in the bone marrow. Signs and symptoms result directly from  increased blood volume and viscosity and a predisposition to  thrombosis.   Therapeutic phlebotomy to remove excessive blood volume  andthe use ofhydroxyurea have been helpfulin decreasing the  excessive erythrocyte population.    Cold agglutinin autoimmune hemolytic anemia, 998  Cold hemolysin autoimmune hemolytic anemia  (paroxysmal cold hemoglobinuria), 998    Mufioz M, Garcia-Erce JA, Remacha AF: Disorders of iron metabolism.  Part II: iron deficiency and iron overload, J Clin Pathol 64(4):287-296,  2011.   Lang E, Qadri SM, Lang F: Killing me softly—suicidal erythrocyte death,  Int J Biochem Cell Biol 44(8):1236—-1243, 2012.   Handelman GJ, Levin NW: Red cell survival: relevance and mechanism  involved, J Renal Nutr 20(5S):S84—S88, 2010.   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Davies JK, Guinan EC: An update on the management of severe idio-  pathic aplastic anaemia in children, Br J Haematol 136(4):549-564, 2007.  Brodsky RA: Narrative review: paroxysmal nocturnal hemoglobinuria:  the physiology of complement-related hemolytic anemia, Ann Intern Med  148(8):587-595, 2008.   Risitano AM: Paroxysmal nocturnal hemoglobinuria and the comple-  ment system: recent insights and novel anticomplement strategies, Adv  Exp Med Biol 735:155—172, 2013.   Ziakas PD, Poulou LS, Pomont A: Thrombosis in paroxysmal noctur-  nal hemoglobinuria at a glance: a clinical review, Curr Vasc Pharmacol  6(4):347-353, 2008.   Brodsky R: Advances in the diagnosis and therapy of paroxysmal noctur-  nal hemoglobinuria, Blood Rev 22(2):65-74, 2008.   Valent P, Lechner K: Diagnosis and treatment of autoimmune haemolytic  anaemias in adults: a clinical review, Wien Klin Wochenschr 120(5-6),  2008.   Packman CH: Hemolytic anemia due to warm autoantibodies, Blood Rev  22(1):17-31, 2008.   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Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Alterations of Leukocyte Function, 1008  Quantitative Alterations of Leukocytes, 1009  Infectious Mononucleosis, 1011  Leukemias, 1013   Alterations of Lymphoid Function, 1023  Lymphadenopathy, 1023  Malignant Lymphomas, 1023  Plasma Cell Malignancies, 1030    There are many disorders involving leukocytes, ranging from  deficiencies in the quality and quantity of leukocytes (leu-  kopenia) to increased numbers of leukocytes (leukocytosis)  in response to infections or proliferative disorders, such as  leukemia. Many hematologic disorders are malignancies,  and many nonhematologic malignancies act like malignan-  cies and can metastasize to bone marrow, affecting leukocyte  production. Because of the complexity of hematologic disor-  ders a large portion of this chapter is devoted to malignant  disease.   The primary role of clotting (hemostasis) is to stop bleed-  ing through an interaction among the vascular endothelium,  platelets, and the clotting system. Many disease states are  associated with clinically significant aberrations in any of  these three necessary components of clotting. This chapter  discusses various components of clotting and their control  systems.    Alterations of Splenic Function, 1036  Alterations of Platelets and Coagulation, 1037  Disorders of Platelets, 1037  Disorders of Coagulation, 1042    Leukocyte function is affected if too many or too few white cells  are present in the blood or if the cells that are present are struc-  turally or functionally defective. Quantitative leukocyte disor-  ders, such as infections and leukemias, result from decreased  production in the bone marrow or accelerated destruction of  cells in the circulation. Other quantitative alterations, however,  occur in response to infections.   Qualitative leukocyte disorders consist of disruptions of  leukocyte function. Phagocytic cells (granulocytes, monocytes,  macrophages) may lose their phagocytic capacity to function.  Lymphocytes may lose their capacity to respond to antigens.  (Qualitative disruptions of inflammatory and immune pro-  cesses caused by leukocyte disorders are described in Chapter  9.) Other leukocyte alterations include infectious mononucleo-  sis and cancers of the blood—leukemia and multiple myeloma.    Leukocytosis is a leukocyte count that is higher than normal;  conversely, leukopenia is a count that is lower than normal.  Leukocytosis or leukopenia may affect all cell types or only a  specific type of leukocyte and may result from a variety of phys-  iologic conditions and alterations.   Leukocytosis occurs as a normal protective response to physi-  ologic stressors, such as infection, strenuous exercise, emotional  changes, temperature changes, anesthesia, surgery, pregnancy,  and some drugs, hormones, and toxins. It is also caused by  pathologic conditions, such as malignancies and hematologic  disorders. Leukopenia is never normal and is defined as an  absolute blood cell count less than 4000 cells/mm*. Leukopenia  is associated with a decrease in neutrophils, which increases risk  for infection. The absolute neutrophil count (ANC) is calcu-  lated by multiplying the white blood cell count by the percent of  band and segmented neutrophils. The ANC is classified as mild  (1000 to 1500 cells/mm*), moderate (500 to 1000 cells/mm‘’),  or severe (<500 cells/mm). When the ANC is less than 500/  mm’, the possibility for life-threatening infections is high. Leu-  kopenia can be caused by radiation, anaphylactic shock, auto-  immune disease (e.g., systemic lupus erythematosus), immune  deficiencies (see Chapter 9), and exposure to certain drugs and  chemotherapeutic agents.   Increased numbers of circulating granulocytes (neutrophils,  eosinophils, basophils) and monocytes are primarily a response  to infection. Increased numbers also occur as a result of  myeloproliferative disorders (i.e., polycythemia vera, chronic  myelogenous leukemia, chronic neutrophilic leukemia, chronic  eosinophilic leukemia) that increase stem cell proliferation in  bone marrow.   Decreased numbers occur when infectious processes exhaust  the supply of circulating granulocytes and monocytes by draw-  ing them out of the circulation and into infected tissues faster  than they can be replaced. Decreases also can be caused by dis-  orders that suppress marrow function.   Granulocytosis—an increase in the number of granulocytes  (neutrophils, eosinophils, basophils )—begins with the release  of stored leukocytes from the venous sinuses of the marrow.  Neutrophilia is another term that may be used to describe  granulocytosis because neutrophils are the most numerous of  the granulocytes (Table 29-1). Neutrophilia occurs in the early  stages of infection or inflammation and is established when  the absolute neutrophil count exceeds 7500/uL. Stored neu-  trophils are approximately 20 to 40 times greater in number  than circulating neutrophils. On rare occasions when the neu-  trophil count increases greatly—more than 100,000/pL (usu-  ally seen only in those with myelocytic leukemia)—the blood  viscosity may increase greatly so that thrombosis or occlusion  of blood vessels occurs. Release and depletion of stored neu-  trophils from the venous sinuses stimulate granulopoiesis to  replenish neutrophil reserves. Specific conditions associated  with neutrophilia are identified in Table 29-1.   When the demand for circulating mature neutrophils  exceeds the supply, the marrow begins to release immature    neutrophils (and other leukocytes) into the blood. Premature  release of the immature white cells is responsible for the phe-  nomenon known as a shift-to-the-left or leukemoid reaction.  This refers to the microscopic detection of disproportionate  numbers of immature leukocytes in peripheral blood smears.  Many diagrams present cellular differentiation and maturation  progressing from left to right within the drawing, instead of ver-  tically as shown in Figure 27-10. When immature leukocytes  are released prematurely they cause a shift in the distribution  of cells in the blood toward the left side, or immaturity side, of  the diagram. This phenomenon is also seen in the blood smear  of individuals with leukemia as well, hence the term leukemoid  reaction. As infection or inflammation diminishes and as gran-  ulopoiesis replenishes circulating granulocytes, a shift back to  normal occurs.   Neutropenia is a condition associated with a reduction in  the number of circulating neutrophils. Clinically, neutropenia  exists when the neutrophil count is less than 2000/uL.! The  absolute neutrophil count reflects not only the degree of neu-  tropenia but also the risk for infection (see preceding discus-  sion of leukocytosis). A reduction in the number of neutrophils  can occur in severe, prolonged infections when production of  granulocytes cannot keep up with demand.   Other causes of neutropenia, in the absence of infection, may  be (1) decreased neutrophil production or ineffective granu-  lopoiesis, (2) reduced neutrophil survival, and (3) abnormal  neutrophil distribution and sequestration. Neutropenia also is  categorized as primary or secondary; primary disorders are fur-  ther identified as congenital or acquired.   Congenital defects in neutrophil production include cyclic  neutropenia and neutropenia with congenital immunodefi-  ciency diseases, as well as multiple syndromes (e.g., Kostmann,  Shwachman-Diamond, Diamond-Blackfan, Griscelli, Chédiak-  Higashi, and Barth syndromes). Primary acquired neutropenia  is associated with multiple conditions, for example, hypoplastic  anemia or aplastic anemia, leukemia (acute myelogenous leu-  kemia [AML]/chronic lymphocytic leukemia [CLL]), lympho-  mas (Hodgkin, non-Hodgkin), and myelodysplastic syndrome  (MDS). The megaloblastic anemias (vitamin B,, and folate  deficiency) as well as starvation and anorexia nervosa cause  neutropenia because of an inadequate supply of vitamins and  nutrients for protein production.   Reduced neutrophil survival and abnormal distribution  and sequestration are usually secondary to other disorders.  Neutropenia occurs in a variety of immunologic disorders,  particularly systemic lupus erythematosus, rheumatoid arthri-  tis, Felty and Sjégren syndromes, splenomegaly, and drug-  related causes.   Severe neutropenia, granulocytopenia (less than 500/uL),  or agranulocytosis (complete absence of granulocytes in the  blood) is usually secondary to arrested hematopoiesis in the  bone marrow or massive cell destruction in the circulation.   Chemotherapeutic agents used to treat hematologic and  other malignancies cause generalized bone marrow suppression.  Several other drugs and large doses of ionizing radiation cause  agranulocytosis, which occurs rarely but carries a high mortal-  ity (10% to 50%). Clinical manifestations of agranulocytosis    include recurrent and persistent life-threatening infection (par- Eosinophilia is an absolute increase (more than 450/pL) in  ticularly of the respiratory system) leading to septicemia, gen- __ the total numbers of circulating eosinophils. Allergic disorders  eral malaise, fever, tachycardia, and ulcers in the mouth and _ (type I hypersensitivity) associated with asthma, hay fever, and  colon. If untreated, sepsis caused by agranulocytosis results in _ drug reactions, as well as parasitic infections (particularly with  death within 3 to 6 days. metazoal parasites) are often cited as causes. Hypersensitivity    TABLE 29-1 OTHER CONDITIONS ASSOCIATED WITH NEUTROPHILS, EOSINOPHILS,  BASOPHILS, MONOCYTES, AND LYMPHOCYTES    Neutrophil  Neutrophilia (granulocytosis) Inflammation or tissue necrosis Surgery, burns, MI, pneumonitis, rheumatic fever, rheumatoid arthritis  Infection Bacterial: gram-positive (staphylococci, streptococci, pneumococci), gram-negative  (Escherichia coli, Pseudomonas species)  Physiologic Exercise, extreme heat or cold, third-trimester pregnancy, emotional distress  Hematologic Acute hemorrhage, hemolysis, myeloproliferative disorder, chronic granulocytic leukemia  Drugs or chemicals Epinephrine, steroids, heparin, histamine, endotoxin  Metabolic Diabetes (acidosis), eclampsia, gout, thyroid storm  Neoplasm Liver, Gl tract, bone marrow  Neutropenia Decreased marrow production Radiation, chemotherapy, leukemia, aplastic anemia, abnormal granulopoiesis  Increased destruction Splenomegaly, hemodialysis, autoimmune disease  Infection Gram-negative (typhoid), viral (influenza, hepatitis B, measles, mumps, rubella), severe  infections, protozoal infections (malaria)    Eosinophil  Eosinophilia Allergy Asthma, hay fever, drug sensitivity  Infection Parasites (trichinosis, hookworm), chronic (fungal, leprosy, TB)  Malignancy CML, lung, stomach, ovary, Hodgkin disease  Dermatosis Pemphigus, exfoliative dermatitis (drug-induced)  Drugs Digitalis, heparin, streptomycin, tryptophan (eosinophilia-myalgia syndrome), penicillins,  propranolol  Eosinopenia Stress response Trauma, shock, burns, surgery, mental distress  Drugs Steroids (Cushing syndrome)   Basophilia Inflammation Infection (measles, chickenpox), hypersensitivity reaction (immediate)  Hematologic Myeloproliferative disorders (CML, polycythemia vera, Hodgkin lymphoma, hemolytic anemia)  Endocrine Myxedema, antithyroid therapy   Monocytosis Infection Bacterial (subacute bacterial endocarditis, TB), recovery phase of infection  Hematologic Myeloproliferative disorders, Hodgkin disease, agranulocytosis  Physiologic Normal newborn    Lymphocyte  Lymphocytosis Physiologic 4 months to 4 years  Acute infection Infectious mononucleosis, CMV infection, pertussis, hepatitis, mycoplasma pneumonia,  typhoid  Chronic infection Congenital syphilis, tertiary syphilis  Endocrine Thyrotoxicosis, adrenal insufficiency  Malignancy ALL, CLL, lymphosarcoma cell leukemia  Lymphocytopenia Immunodeficiency syndrome AIDS, agammaglobulinemia  Lymphocyte destruction Steroids (Cushing syndrome), radiation, chemotherapy, Hodgkin lymphoma, CHF, renal  failure, TB, SLE, aplastic anemia    AIDS, Acquired immunodeficiency syndrome; ALL, acute lymphocytic leukemia; CHF, congestive (left) heart failure; CLL, chronic lymphocytic  leukemia; CML, chronic myelogenous leukemia; CMV, cytomegalovirus; G/, gastrointestinal; M/, myocardial infarction, SLE, systemic lupus  erythematosus; 7B, tuberculosis.    reactions and the normal defense against parasites trigger  the release of eosinophil chemotactic factor of anaphylaxis  (ECF-A) from mast cells, attracting eosinophils to the area.  (These processes are described and illustrated in Chapters 8  and 9.) Tissues with abundant mast cells, such as the respi-  ratory and gastrointestinal tracts, are particularly common  sites for eosinophil invasion. Mast cells also release interleu-  kin-5 (IL-5), which stimulates the bone marrow to produce  and release more eosinophils into the blood. Eosinophilia  may also be associated with dermatologic disorders, such as  atopic dermatitis, eczema, and pemphigus. Various types of  eosinophilic scleroderma-like diseases also have been reported  to occur in association with hemato-oncogenic disorders (i.e.,  eosinophilic cellulitis [Wells syndrome] and eosinophilic  fasciitis [Shulman syndrome]). Increased numbers of eosin-  ophils have been observed in individuals with eosinophilia-  myalgia syndrome (EMS), which is associated with ingestion  of the supplement L-tryptophan. EMS may develop in indi-  viduals with fibromyalgia syndrome as an allergic reaction to  L-tryptophan.”   Eosinopenia, a decrease in circulating numbers of eosino-  phils, generally is caused by migration of eosinophils into  inflammatory sites. It also may be seen in Cushing syndrome  and as a result of stress caused by surgery, shock, trauma, burns,  or mental distress. Other conditions causing eosinopenia are  detailed in Table 29-1.   Basophilia, an increase in circulating numbers of baso-  phils, is rare and generally is a response to inflammation and  immediate hypersensitivity reactions. Basophils contain hista-  mine that is released during an allergic reaction. An increase  in the levels of basophils is seen also in myeloproliferative dis-  orders, such as chronic myeloid leukemia and myeloid meta-  plasia. Other conditions associated with basophilia are listed  in Table 29-1.   Basopenia (also known as basophilic leukopenia), a decrease  in circulating numbers of basophils, is seen in hyperthyroidism,  acute infection, and long-term therapy with steroids. A decrease  in the number of basophils may be seen during ovulation and  pregnancy. Other conditions associated with basopenia are  listed in Table 29-1.   Monocytosis is an increase (generally greater than 800/pL)  in numbers of circulating monocytes. The condition is often  transient and not related to a dysfunction of monocyte pro-  duction. When present, it most commonly occurs with neu-  tropenia associated with bacterial infections, particularly in the  late stages or recovery stage, when monocytes are needed to  phagocytize surviving microorganisms and debris. Monocyto-  sis often is seen in chronic infections, usually with intracellular  bacteria, such as tuberculosis (TB), brucellosis, listeriosis, and  subacute bacterial endocarditis (SBE). Peripheral monocyto-  sis has been found to correlate with the extent of myocardial  damage following myocardial infarction. Increased numbers of  monocytes also may indicate marrow recovery from agranu-  locytosis. Other conditions associated with monocytosis are  identified in Table 29-1.   Monocytopenia, a decrease in numbers of circulating  monocytes, is rare, and not much is known about this condition    because of the small numbers of monocytes generally present in  the blood. Monocytopenia, however, has been identified with  hairy cell leukemia and prednisone therapy.   Quantitative alteration of lymphocytes occurs when lympho-  cytes are activated by antigenic stimuli, usually microorgan-  isms (see Chapter 8). Lymphocytosis is rare in acute bacterial  infections and occurs most commonly in acute viral infec-  tions, particularly those caused by the Epstein-Barr virus  (EBV), a causative agent in infectious mononucleosis. Other  specific disorders associated with lymphocytosis are listed in  Table 29-1.   Lymphocytopenia may be attributable to (1) abnormalities of  lymphocyte production associated with neoplasias and immune  deficiencies, and (2) destruction by drugs, viruses, or radiation. It  also can occur in individuals for no apparent reason. Other con-  ditions associated with lymphocytopenia are identified in Table  29-1. The lymphocytopenia associated with heart failure and  other acute illnesses may be caused by elevated levels of cortisol.  Lymphocytopenia is a major problem in acquired immunodefi-  ciency syndrome (AIDS) in which the human immunodeficiency  virus (HIV) is cytopathic for T helper lymphocytes. (For a more  detailed discussion of AIDS, see Chapter 10.)    Infectious mononucleosis (IM) is an acute, self-limiting, neo-  plastic lymphoproliferative clinical syndrome characterized  by acute viral infection of B lymphocytes (B cells). The most  common etiologic agent is EBV, a ubiquitous, lymphotrophic,  gamma-group herpesvirus that was first recognized as the caus-  ative agent in IM in the late 1960s. EBV accounts for approx-  imately 85% of all IM cases. Other etiologic agents that may  cause symptoms resembling IM are viruses (cytomegalovirus  [CMV], adenovirus, HIV, hepatitis A, influenza A and B, and  rubella), as well as the bacteria Toxoplasma gondti, Corynebac-  terium diphtheriae, and Coxiella burnetii. IM caused by CMV is  generally noted in older individuals, with fever and malaise the  major complaints; the major manifestations of EBV-induced  IM are the classic triad of symptoms of pharyngitis, lymphade-  nopathy, and fever.   Approximately 50% to 85% of children are infected with  EBV by age 4, and more than 90% of adults have indications  of subclinical EBV infections. These early infections are usu-  ally asymptomatic and provide immunity to EBV; thus early  EBV infections rarely develop into IM. IM may arise when  the initial infection occurs during adolescence or later, but  still only results in IM in 35% to 50% of these individuals.  Symptomatic IM usually affects young adults between ages  15 and 35 years, with the peak incidences occurring between  15 and 24 years; males have a later peak (18 to 24 years)  than females. The overall incidence rate for this age group  is 6 to 8 cases per 1000 persons per year. Children from low  socioeconomic environments are particularly susceptible to  infections with EBV. IM is uncommon in individuals older  than age 40, but if it does occur, it is more commonly caused  by CMV.    Transmission of EBV is usually by saliva through personal  contact (e.g., kissing, hence the term “kissing disease”). The  virus also may be present in other mucosal secretions of the gen-  ital, rectal, and respiratory tract, as well as blood. No evidence  of aerosol transmission through sneezing or coughing has been  documented. The disease begins with widespread infection of  B lymphocytes, all of which possess receptors for EBV. The  virus initially infects the oropharynx, nasopharynx, and sali-  vary epithelial cells with later spread to the lymphoid tissue and  B cells. Infection of B cells permits the virus to enter the blood-  stream, which spreads the infection systemically.   PATHOPHYSIOLOGY. In the immunocompetent individual,  unaffected B cells produce antibodies (IgG, IgM, IgA) against  the virus. Concomitantly, there is a massive activation and  proliferation of cytotoxic T cells (CD8) directed against EBV-  infected cells; CD8 lymphocytes can account for greater than  50% of the total circulating lymphocytes. The immune response  against EBV-infected cells (cellular infiltration, production of  cytokines) is largely responsible for the cellular proliferation in  the lymphoid tissues (lymph nodes, spleen, tonsils, occasionally  liver). Sore throat and fever, two of the earliest manifestations,  are caused by inflammation at the site of viral entry and initial  infection (the mouth and throat).   CLINICAL MANIFESTATIONS. The incubation period of IM is  approximately 30 to 50 days (4 to 8 weeks) followed by a 3- to  5-day prodrome of fever, malaise, and arthralgias that are often  attributed to viral infection, although some individuals remain  asymptomatic. These symptoms may vary in severity for the  next 7 to 20 days. At the time of diagnosis the individual usu-  ally has the classic triad of symptoms: fever, pharyngitis, and  lymphadenopathy of the cervical lymph nodes. The pharyn-  gitis is usually diffuse and often accompanied by a whitish or  grayish green, thick exudate. It also is quite painful and is the  symptom that most often causes the individual to seek treat-  ment. IM is usually self-limiting, and recovery occurs in a few  weeks. Fatigue may last for 1 to 2 months after resolution of the  infection.   Although severe clinical complications are rare, as the con-  dition progresses generalized lymph node enlargement may    develop and enlargement of the spleen and liver also may occur.  Splenomegaly is clinically evident 50% of the time and is dem-  onstrated radiologically 100% of the time. Difficulty in detect-  ing splenomegaly with physical examination contributes to the  underestimation of actual enlargement. Splenic rupture is rare  (only 0.1% to 0.5% of all cases) and can occur spontaneously  as a result of mild trauma, occurring primarily in men younger  than 25 years of age and between days 4 and 21 after the onset of  symptoms. It is the most common cause of death related to IM.  Other causes of fatalities are hepatic failure, extensive bacterial  infection, or viral myocarditis.   Other organ systems are rarely involved, but such involve-  ment may result in additional symptoms, such as meningitis,  encephalitis, Guillain-Barré syndrome, Bell palsy, optic neuri-  tis, mental impairment, transverse myelitis, cerebellar ataxia,  and demyelinating diseases. Ocular manifestations may include  eyelid and periorbital edema, dry eyes, keratitis, uveitis, con-  junctivitis, retinitis, oculoglandular syndrome, choroiditis,  papillitis, and ophthalmoplegia. In children, Reye syndrome  also has been associated with EBV infection.   Pulmonary involvement is rare, but when present may include  hilar and mediastinal lymphadenopathy, interstitial pneumoni-  tis, and pleural effusion. Pneumonia and respiratory failure have  been documented; however, they are more likely to develop in  immunocompromised individuals. Approximately 3% to 10%  of adults older than 40 years of age have never been infected  with EBV and are susceptible to IM later in life. In these indi-  viduals the classic symptoms are not generally present, making  diagnosis more difficult. If an older individual has an elevated  temperature that cannot be explained and persists for more than  2 weeks, EBV infection should be suspected, particularly in the  presence of abnormal liver function tests with hepatomegaly and  jaundice. Other neurologic manifestations that may be present  include peripheral neuropathy and Guillain-Barré syndrome.   EVALUATION AND TREATMENT. The blood of affected individu-  als contains an increased number of atypical lymphocytes  (Figure 29-1). Diagnosis of IM is commonly based on Hoa-  gland’s criteria of at least 50% lymphocytes and at least 10%  atypical lymphocytes in the blood in the presence of fever,    FIGURE 29-1 Peripheral Blood Smear in Infectious Mononucleosis. Low power (A) shows moderately high white  blood cell count and high number of reactive, or “atypical,” lymphocytes. Higher power (B-G) illustrates the spectrum of lym-  phoid morphology, including small resting lymphocyte (B) for comparison, large granular lymphocyte (C), atypical forms (D-F),  also referred to as “reactive” lymphs, and circulating plasma cell (G). (From Hoffman R et al: Hematology: basic principles and    pharyngitis, and adenopathy confirmed by a positive sero-  logic test. Serologic tests are used to determine a heterophile  antibody response.° Heterophile antibodies are a heteroge-  neous group of immunoglobulin M (IgM) antibodies that are  agglutinins against nonhuman red blood cells (e.g., sheep,  horse) and are detected by qualitative (Monospot) or quanti-  tative methods (heterophile antibody test).   The Monospot test is limited because other infections (e.g.,  CMV, adenovirus) and toxoplasmosis also produce hetero-  philic antibodies. Thus 5% to 15% of Monospot tests yield  false-positive results. Levels of heterophilic antibodies in the  blood increase as the condition progresses, although some  individuals and children younger than age 4 years do not  produce them. These individuals give a false-negative result.  Specificity for diagnosis of EBV infection may be increased  with viral-specific serologic tests that identify EBV-specific  antibodies (e.g., IgG or IgM against the viral capsid antigen  [VCA], or IgG against the EBV nuclear antigen [EBNA]).  These tests are more expensive and labor intensive; therefore  they are reserved for instances in which the Monospot test is  not appropriate.   Because IM is usually self-limiting, medical intervention is  rarely required. Treatment of IM is supportive and includes rest  and alleviation of symptoms with analgesics and antipyretics.  Ibuprofen, not aspirin, is used with children and adolescents  because of the reported incidence of Reye syndrome associated  with EBV infection. Pharyngitis of streptococcal origin, which  occurs in 20% to 30% of cases, is treated with penicillin or  erythromycin. Ampicillin is contraindicated because it causes a  rash in most individuals with IM.   Bed rest and avoidance of strenuous activity should be  included in the therapy. Steroids may be used, but only in  the presence of severe complications (e.g., impending airway  obstruction) or other organ system involvement (e.g., nervous  system manifestations, thrombocytopenic purpura, myocar-  ditis, pericarditis). Acyclovir has been used with immunosup-  pressed individuals; however, clinical improvement has been  minimal and therefore it is not recommended for standard  treatment.   In the rare event of splenic rupture, the treatment has been  removal of the spleen and continues to be the choice in hemo-  dynamically unstable individuals. However, new research is  suggesting that it may be better to repair the spleen to avoid  overwhelming post-splenectomy infection (OPSI). Children  are at greater risk of OPSI than adults. Post-splenectomy vacci-  nations for Streptococcus pneumoniae, Haemophilus influenzae,  and Meningococcus are essential because these microorganisms  are responsible for 92% of fatal infections. Treatment may also  be necessary for airway obstruction from massive edema of the  Waldeyer ring or for autoimmune hemolytic anemia, which  occurs in approximately 3% to 5% of cases.   Fatal IM also is expressed with the inherited X-linked lym-  phoproliferative (XLP) syndrome (Duncan disease). Duncan  disease is a rare disorder characterized by severe dysregula-  tion of the immune system, often in response to EBV. The  underlying cause leading to death is the absence of a functional  SAP protein that allows for the unregulated proliferation of    cytotoxic T cells and the concomitant production and release  of cytokines.    Leukemia is a clonal malignant disorder of leukocytes in the  blood and blood-forming organs. The common feature of all  forms of leukemia is an uncontrolled proliferation of malig-  nant leukocytes, causing an overcrowding of bone marrow and  decreased production and function of normal hematopoietic  cells. The first description of a “leukemic” individual was writ-  ten by Velpeau in 1827.* Virchow, a pathologist, coined the  term white blood (Weissus blut) and later originated the term  leukemia. Since Virchow’s initial discovery, the overall clas-  sification of leukemia has become increasingly complex and  undergone several permutations.   The current classification of leukemia is based on (1) the  predominant cell of origin (either myeloid or lymphoid) and  (2) the rate of progression, which usually reflects the degree at  which cell differentiation was arrested when the cell became  malignant (acute or chronic) (Figure 29-2). Acute leukemia is  characterized by undifferentiated or immature cells, usually a  blast cell, and the onset of disease is abrupt and rapid with a  short survival time. In chronic leukemia the predominant cell  is more differentiated but does not function normally, with a  relatively slow progression. There are four types of leukemia:  acute lymphocytic (ALL), acute myelogenous (AML), chronic  lymphocytic (CLL), and chronic myelogenous (CML). In 1976  the French-American-British Cooperative Group developed  more extensive criteria for the classification of acute leukemias.  This system is based on characteristics that may provide sig-  nificant therapeutic prognostic information, such as structure,  number of cells, genetics, identification of surface markers, and  histochemical staining. Since this time, the World Health Orga-  nization has developed a classification that incorporates more  recent research on the genetics and clinical features of AML that  have prognostic and therapeutic relevance.°   Leukemia occurs with varying frequencies at different ages  and is more common in adults than children (Figure 29-3).  It is estimated that more than 44,600 cases of leukemia were  newly diagnosed in 2011, with males having a slightly higher  incidence than females (Table 29-2).° In all types of leukemia  males have a higher incidence rate (56%) as do Americans of  European descent. White children have higher rates of leukemia  than children of other racial groups. ALL is the least common  type overall, but is the most common in children (approxi-  mately 66% of ALL cases are diagnosed before the age of 20).  Leukemia accounts for about 34% of all childhood cancers, and  ALL accounts for almost 78% of all new cases of leukemia in  children. CLL and AML are the most common types in adults.  CML is found mostly in adults.   Over the past two decades the rates of induced remission  and survival in most forms of leukemia have increased. Current  survival rates range from 24% for AML to 81% for CLL, and as  high as 91% for children and adolescents younger than 15 years  of age with ALL.”   This progress is the result of more effective chemotherapeu-  tic agents, improved blood product and antimicrobial support,    stem cell  Common myeloid Common lymphoid  progenitor progenitor  AML AML AML AML AML Precursor B-cell ALL Precursor T-cell  Acute Acute Acute Acute Acute lymphoma lymphoma  basophilic eosinophilic myelomonocytic megakaryocytic erythroid I l  leukemia leukemia leukemia leukemia leukemia ALL ALL  | | | |  Basophil Eosinophil Granulocyte/ Megakaryocyte Erythroid Fal scnisot SF aaphal Becta  . : : : B-cell Nk-cell T-cell  progenitor progenitor Monocyte progenitor progenitor  progenitor ! ! F ! A  Burkitt lymphoma Blastic Lymphoblastic  I NK-cell lymphoma  B-cell CLL lymphoma  I  AML AML =  Aoute eure Hodgkin lymphoma  myeloblastic monocytic  leukemi leukemi  eu enue leu amis Secondary Mature  Granulocyte Monocyte lymphoid organs Feel  progenitor — progenitor  I I Mantle cell lymphoma Peripheral  Chronic myelogenous leukemia F T-cell  Follicular lymphoma lymphoma  Diffuse B-cell lymphoma  Basophil Eosinophil Platelet Erythrocyte |  ie Mu Nk-cell  Neutrophil Monocyte —  Effector  Plasma cell T-cell  FIGURE 29-2 Origins of Leukemias and Lymphomas. Differentiation pathways of blood-forming cells and reported  sites from which specific leukemias and lymphomas originate. Tumors of similar types are given the same background coloring.  ALL, Acute lymphocytic leukemia; AML, acute myelogenous leukemia; CLL, chronic lymphocytic leukemia; VK, natural killer.  35 and specialized nursing care. Chemotherapy and bone marrow  30 transplants have significantly increased the survival time for  S —ALL individuals with acute leukemia.  = 25 PATHOPHYSIOLOGY. All leukemias have certain pathophysi-  =) —AML ;  = ologic features in common. Although the exact cause of leu-  o —CLL kemia is unknown, several risk factors and related genetic  8 15 —CML aberrations are associated with the onset of malignancy. There  5 is a statistically significant tendency for leukemia to reappear  3 ~ in families. There is also an increased incidence of leukemia in  = 5 association with other hereditary abnormalities such as Down  syndrome, Fanconi aplastic anemia, Bloom syndrome, tri-  0 ; ear  KT OTOTSTSTSP RPSL Ss somy 13, Patau syndrome, and some immune deficiencies (ie.,  Veo re E EPP FT PPT TTT Pw ataxia-telangiectasia, Wiskott-Aldrich syndrome, and congeni-  OCMNONMNONMNONWMONODNMNOMNM SO  THrHNNYNMYMNTTONOOOKRKR O   FIGURE 29-3 Age-Related Incidence at Diagnosis of Leukemias. The  incidences of acute myelogenous leukemia (AML), chronic lymphocytic leukemia  (CLL), and chronic myelogenous leukemia (CML) are relatively stable until middle  age and then increase dramatically. The incidence of acute lymphocytic leuke-  mia (ALL) peaks in childhood, and then diminishes until middle age when the  incidence begins rising slowly with age. (Data obtained from Howlader N et al,  editors: SEER cancer statistics review, 1975-2009 [vintage 2009 populations],  Bethesda, MD, 2012, National Cancer Institute. Available at http://seer.cancer.  gov/csr/1975_2009_pops09/.)   Genetic translocations (mitotic errors) are observed in  leukemic cells. The most common genetic abnormality is the  reciprocal translocation between chromosomes 9 and 22 t(9;22)  (q34;q11), the Philadelphia chromosome.*   The Philadelphia chromosome was first observed in per-  sons with CML, and is present in 95% of those with CML,  3% of individuals with AML, and 25% to 30% of adults with  ALL and 2% to 10% of children with ALL.’ This transloca-  tion results in the novel fusion of the BCR1 gene region from   Acute lymphocytic  eukemia  Chronic lymphocytic  eukemia  Acute myelogenous  eukemia  Chronic myelogenous  eukemia    *Based on SEER Stat Fact Sheet, posted to the SEER website, NCI, 2013.    chromosome 22 and the proto-oncogene ABL1 from chromo-  some 9 (Figure 29-4). The BCR-ABL1 joining results in the  expression of a unique fused oncoprotein, BCR-ABL1.° The  ABL] protein is a tyrosine kinase in the signaling pathway that  promotes cell proliferation. The BCR-ABLI variant possesses  greater tyrosine kinase activity and has proven to be essential  for transformation into leukemic cells. BCR-ABL1 appears to  excessively activate intracellular pathways, leading to increased  proliferation, decreased sensitivity to apoptosis, and prema-  ture release of immature cells into the circulation. In most  leukemias and lymphomas a single major genetic abnormality,  such as the t(9;22) translocation, does not lead to an aggressive  malignancy. The initial event is usually followed by a series of  secondary genetic changes.!° Thus the original tumor becomes  genetically unstable and diverse.   Risk factors for the onset of leukemia include environmen-  tal factors as well as other diseases. Increased risk in adults has  been linked to exposure to cigarette smoke, benzene, and ion-  izing radiation. Large doses of ionizing radiation particularly  result in an increased incidence of myelogenous leukemia.  There is growing concern about the effect of low-dose radia-  tion on subsequent risk of leukemia.'! Infections with HIV or  hepatitis C virus increase the risk for leukemia, and it is now  widely accepted that some types of leukemia are caused by  infection with the human T-cell leukemia/lymphoma virus  type 1 (HTLV-1). Drugs that cause bone marrow depression  (e.g., chloramphenicol, phenylbutazone, and certain alkylat-  ing agents, such as cytoxan) also can predispose an individual  to leukemia. AML is the most frequently reported second-  ary cancer after high doses of chemotherapy for Hodgkin  lymphoma, non-Hodgkin lymphoma, multiple myeloma,    ovarian cancer, and breast cancer. Acute leukemia also may  develop secondary to certain acquired disorders, including  CML, CLL, polycythemia vera, myelofibrosis, Hodgkin lym-  phoma, multiple myeloma, ovarian cancer, and sideroblastic  anemia.   Leukemias are considered clonal disorders in that a single  progenitor cell undergoes malignant transformation. The leu-  kemia blasts literally “crowd out” the marrow and cause cel-  lular proliferation of the other cell lines to cease. Normal  granulocytic-monocytic, lymphocytic, erythrocytic, and mega-  karyocytic progenitor cells cease to function, resulting in pan-  cytopenia (a reduction in all cellular components of the blood).  An interesting observation is that leukemic cells apparently  divide more slowly and take longer to synthesize deoxyribonu-  cleic acid (DNA) than other blood precursors. Leukemic cells  accumulate relentlessly in the bone marrow causing overcrowd-  ing of the marrow, and they compete with cellular proliferation  and function of normal hematopoietic cells. Thus leukemia has  been termed an accumulation disorder, as well as a proliferation  disorder. In the majority of cases, leukemic cells are ejected into  the blood, where they accumulate. These cells also may infiltrate  and accumulate in the liver, spleen, lymph nodes, and other  organs throughout the body. The presentation of large numbers  of leukemic cells in the blood may be one of the most dramatic  indicators of leukemia; however, leukemia is still a primary dis-  ruption of the bone marrow.   Acute leukemias consist of two types: acute lymphocytic leu-  kemia (ALL) and acute myelogenous leukemia (AML). Acute  leukemias are seen in both genders and in all ages, with the    FIGURE 29-4 Philadelphia Chromosome. The Philadelphia chromosome is  an example of a reciprocal chromosomal translocation that results in an abnormal  gene product responsible for a clinical disorder. A, An exchange occurs between  the long arm of chromosome 9 (black chromosome) and the long arm of chromo-  some 22 (blue chromosome); t(9;22)(q34;q11). B, Mechanism of action of imatinib.  By occupying the ATP-binding pocket of the ABL kinase domain, imatinib prevents  substrate phosphorylation and downstream activation of signals, thus inhibiting  the leukemogenic effects of BCR-ABL on cells in chronic myelogenous leukemia.  ADP, Adenosine diphosphate; A7P, adenosine triphosphate; P, phosphate group.  (A, Top portion from Rakel R, Bope E: Conn’s current therapy 2008, Philadelphia,  2008, Saunders. Lower portion from Yanoff M, Duker J: Ophthalmology, ed 3, Edin-  burgh, 2009, Mosby. B from Goldman L, Schafer Al: Goldman’ Cecil medicine,  ed 24, Philadelphia, 2012, Saunders.)    incidence increasing dramatically in individuals older than 50  years. Mortality for all acute leukemias in the United States is  about 7 per 100,000. In children younger than 15 years, leu-  kemia accounts for one third of all deaths from cancer. North  American and Scandinavian countries have the highest mortal-  ity; Eastern European countries, Asia (except Japan), and Cen-  tral America have the lowest mortality. Japan’s higher mortality  is the result of the atomic bombs dropped in World War II.  Blacks have consistently shown a lower mortality than whites.  More than 6070 new cases of ALL and 14,590 cases of AML are    estimated in 2013, with more than 1430 deaths attributed to  ALL and 10,370 to AML.®!2:!9   PATHOPHYSIOLOGY. ALL is a progressive neoplasm defined  by the presence of greater than 30% lymphoblasts in the bone  marrow or blood. Most cases of ALL occur in children (80% of  ALL), and it is the most common leukemia in children, most  often occurring in the first decade. The median age of diagnosis  of ALL is age 13. Although adults with ALL account for only  20% of all cases, their mortality is significantly higher (see Table  29-2). The 5-year survival rate for individuals 20 to 59 years  old is about 30% to 40%, about 15% to 16% for persons older  than 60 years, and 5% for persons older than 70 years. The sur-  vival rate in children is about 78%. The significant difference  between the incidence of ALL in adults and children is thought  to be determined by differences in the biology of the disease.  Children with the highest survival rate (82% to 83%) have no  radiographic manifestations, whereas children with five or more  skeletal lesions have a survival rate of about 72% to 73%.'4   Immunotyping of leukemic blast cells allows for the identifi-  cation of subtypes of ALL. Approximately 75% of ALL cases in  children originate from transformed precursor B cells, whereas  adult ALL is a mixture of cancers of precursor B-cell or precur-  sor T-cell origin (Table 29-3). A small percentage of ALL cases  have neither B- nor T-cell origination and are called null cell.  Precursor B-cell ALL can be subdivided into different pheno-  types, depending on their progression through the B-cell mat-  uration process before becoming malignant.'>!° The general  phenotype of precursor B-cell ALL expresses CD19, human  leukocyte antigen DR (HLA-DR), and other B-cell—associated  antigens in the cytoplasm. The most immature form (pro-B-  cell ALL) occurs in about 5% of precursor B-cell ALL and is  characterized by lack of expression of CD10. CD10 (common  acute lymphocytic leukemia antigen [CALLA]) is a cell sur-  face metalloprotease. Lack of CD10 is frequently associated  with translocation of the myeloid/lymphoid leukemia (MLL)  gene and a poor prognosis. The common precursor B-cell  ALL comprises approximately 80% of precursor B-cell ALL  cases; these express surface CD10, but have not yet undergone  rearrangement of the immunoglobulin genes. The remaining  individuals have a more mature form of precursor B-cell ALL  (pre—B-cell ALL) in which the cells express immunoglobulin  molecules in the cytoplasm. Less common variations include  cells that are intermediate between the common precursor and  pre—B-cell phenotypes and express immunoglobulin heavy  chain, but no light chain, and cells that are more mature than  the pre—B-cell ALL and express surface immunoglobulin and  do not stain for the enzyme terminal deoxynucleotidyl trans-  ferase (TdT).   The T-cell lineage ALL (precursor T-cell ALL) is distin-  guished by T-cell—associated markers.!°!° Cytoplasmic CD3 is  the most common T-cell lineage specific marker, but CD7, CD2,  and CD5 are frequently used. In addition to lymphoid markers,  T-cell receptor (TCR) gene rearrangements are the most com-  mon genetic alteration in T-cell ALL. No specific cytogenetic  abnormality, however, has been linked to the subtype of T-cell  ALL. ALL blast cells also can express myeloid markers in 15% to  50% of adults and 5% to 35% of children.    Precursor B-cell ALL is strongly associated with aneuploidy  of various types, ranging from hypodiploid to hyperdiploid with  more than 50 chromosomes.”!>!° Individuals with hyperdiploid  ALL usually have a better prognosis than those with fewer than  46 chromosomes. Individuals with precursor T-cell ALL generally  have fewer cytogenetic abnormalities, and the majority of cases  involve deletions. Genetic translocations between the MYC locus  on chromosome 8 and one of the loci for the immunoglobulin  (Ig) heavy- or light-chain genes (14q32, 2p12, and 22q11) are  characteristic (also see Chapters 8 and 12). Several other transloca-  tions are commonly observed in ALL, including the Philadelphia  chromosome and translocations involving the ETV6 (formerly  TEL) and MLL genes (Figure 29-5).? Philadelphia chromosome—  positive ALL carries the worst prognosis of all types of ALL and is  found in 25% to 30% of adult ALL cases but less than 5% of child-  hood ALL cases. A translocation between chromosomes 12 and 21  (t[12;21]) results in fusion of the ETV6 oncogene from chromo-  some 12 with the AML] (acute myeloid leukemia 1) gene on chro-  mosome 21 to produce a fusion protein, ETV6-AML1. AMLI is a  transcription factor for several genes important in hematopoiesis  (e.g., IL-3, granulocyte-macrophage colony-stimulating factor  [GM-CSF], CSF1 receptor).? The t(12;21) translocation occurs  in 25% to 30% of childhood pre—B-cell ALL cases but in only  2% of adult ALL cases. This translocation significantly affects the  prognosis of childhood ALL; children younger than 10 years with  pre—B-cell ALL and the ETV6-AMLI translocation have a 5-year  cure rate of 90%, compared with 60% to 65% in those without  the translocation.   Translocations of the MLL gene on chromosome 11 occur  in about 10% of individuals with ALL and in 70% of infants  with AML or ALL.’ Infants and adults with this translocation  develop a very aggressive form of leukemia with a very poor  prognosis and frequent treatment failure, although children  with this abnormality have better outcomes. The most com-  mon translocations involving MLL are t(4;11) and t(11;19). The  t(4;11) translocation results in a fusion of MLL with the AFFI  (ALL1 fused gene from chromosome 4) gene, and the t(11;19)  translocation fuses MLL with the MLLT1 (formerly ENL) gene.   Specific causes of ALL are unknown, but multiple factors  may contribute to its development.!>!° Risk factors for child-  hood ALL include prenatal exposure to x-rays and postnatal  exposure to high-dose radiation. Viral infections with HTLV-1  can cause a rare form of ALL and Epstein-Barr virus is linked to  a form of ALL.!”   Individuals with Down syndrome have an increased risk for  developing ALL and AML. Increased risk for ALL is also seen  in individuals with other genetic conditions, including neuro-  fibromatosis, Shwachman syndrome, Bloom syndrome, and  ataxia-telangiectasia (see Chapter 9). A unique characteristic of  ALL, unlike other forms, is that ALL develops at different rates  in different geographic locations, although the reason for this is  unclear. Individuals in developed countries and in higher socio-  economic categories have an increased incidence of ALL. Preven-  tion is almost impossible because there are no known causes.   AML is the most common adult leukemia; the mean age  of diagnosis is 67 years of age. Approximately 60% to 70% of  adults with AML can expect to attain complete remission status    following appropriate induction therapy. Remission rates in  adult AML are inversely related to age; remission rates for  those younger than 60 years are more than 65%. AML!* results  from an abnormal proliferation of myeloid precursor cells, a  decreased rate of apoptosis, and an arrest in cellular differen-  tiation.!’ Therefore, the bone marrow and peripheral blood  are characterized by leukocytosis and a predominance of blast  cells. As the number of immature blasts increases, they replace  normal myelocytic cells, megakaryocytes, and erythrocytes.  This displacement eventually leads to complications of bleed-  ing, anemia, and infection. AML increases with age, peaking in  the sixth decade of life. Certain risk factors have been identi-  fied as possible causes, including exposure to radiation, ben-  zene, and chemotherapy. Hereditary conditions, such as Down  syndrome, Fanconi aplastic anemia, Bloom syndrome, ataxia-  telangiectasia, trisomy 13 (Patau syndrome), Wiskott-Aldrich  syndrome, and congenital X-linked agammaglobulinemia, are  known to be associated with a higher risk for AML (see Table  29-2). AML subtypes are classified based on the stage of devel-  opment the myeloblasts have reached at the time of diagnosis.  These subtypes are included in Box 29-1.   More than 150 structural chromosomal abnormalities and  several duplications or deletions within genes have been identi-  fied in AML.’ The most common abnormalities are balanced  translocations or inversions that disrupt genes critical to hema-  topoiesis of myeloid cells. The most common translocation is  between chromosomes 8 and 21 in which the RUNXIT1 (for-  merly ETO) (encodes a transcription factor) gene on chro-  mosome 8 is fused with the AML1 gene on chromosome 21,  resulting in an AML1-RUNXITI1 fusion gene and a fusion gene  product, AMLI-RUNXIT1. Production of AML1-RUNXIT1  disrupts the normal hematopoiesis process for myeloid cells  and directly leads to the AML malignant phenotype.   Many kinds of mutations have been found in AML; how-  ever, a mutation in the receptor tyrosine kinase FLT3 occurs  in about one third of persons affected by AML. FLT3 con-  veys a proliferation signal normally expressed early in the  development of bone marrow stem cells, but mutated FLT3  remains active and promotes blast cell proliferation. Several  FLT3 inhibitors are in various stages of clinical development.  Another mutation in receptor tyrosine kinases is KIT, which  also provides a proliferative and/or survival signal to progeni-  tor cells. Together these mutations result in proliferation but  not differentiation.   CLINICAL MANIFESTATIONS. The clinical manifestations of all  the varieties of acute leukemia are generally similar. (Mecha-  nisms associated with common manifestations are summarized  in Table 29-4.) Signs and symptoms related to bone marrow  depression include fatigue caused by anemia, bleeding resulting  from thrombocytopenia (reduced numbers of circulating plate-  lets), and fever caused by infection. Sites of infection include  the oral cavity, throat, respiratory tract, lower colon, urinary  tract, and skin. Common organisms include the gram-negative  bacilli Escherichia coli, Pseudomonas aeruginosa, and Klebsiella  pneumoniae. Fever is an early sign, often accompanied by chills.  Bleeding can occur in skin, gums, mucous membranes, and gas-  trointestinal and genitourinary tracts. Visible signs of bleeding    LINEAGE TDT HLA-DR CD34 CD19 CD22 CD79A CD10 CYp  Precursor B-cell ALL   Pre-B ALL + + = i i = & a  Transitional precursor B-cell ALL + + = + rn = = x  Mature B-cell ALL - + - + + = =  T-lineage ALL    From Fader! S et al: Cancer 98:1337-1354, 2003.  *Usually no surface light chain (L) expression.  ALL, Acute lymphoblastic leukemia; cALL, common acute lymphoblastic leukemia; cy, cytoplasmic; TdT, terminal deoxynucleotidyl! transferase.    TAL1 TAL2  LMO1 LMO2  LyL1 OLIG2 4% BCR-ABL1  TLX1 MYC  TLX3 LCK t(19;22)    1%  TCF3-HLF Low hypodiploid I Tel  t(17;19)  Mature B cell    t(1;19)  FIGURE 29-5 Frequency of the Major Chromosomal Translocations in (A) Pediatric and (B) Adult Acute Lympho-  cytic Leukemia (ALL). The genes affected by chromosomal translocation are shown. TCR translocations in T-ALL can activate  a number of different proto-oncogenes as shown in the insert, including TAL7, LMO1/2, TLX1, TLX3, and MYC. (From Hoffman  R et al: Hematology: basic principles and practice, ed 6, Philadelphia, 2013, Churchill Livingstone.)    CGx/i SLGH/L CYCD3 CD7 CD1A  — aye  + +  + + -  - + -  + + -  - + -    Acute myeloblastic leukemia, minimally differentiated (AML-MO)  Acute myeloblastic leukemia without maturation (AML-M1)  Acute myeloblastic leukemia with maturation (AML-M2)  Acute promyelocytic leukemia (AML-M3)   Acute monocytic leukemia, differentiated (AML-M5B)  Erythroleukemia (AIML-M6)  Acute megakaryoblastic leukemia (AML-M7)    From Damjanov I, Linder J: Pathology: a color atlas, St Louis, 2000,  Mosby.    include petechiae and ecchymosis, as well as discoloration of  the skin, gingival bleeding, hematuria, and midcycle or heavy  menstrual bleeding.   Anorexia can occur in all varieties of acute leukemia and is  associated with weight loss, diminished sensitivity to sour and  sweet tastes, muscle atrophy, and difficulty in swallowing. Liver,  spleen, and lymph node enlargement is more common in ALL  than in AML (Figure 29-6). Splenomegaly and hepatomegaly  usually occur together. The leukemic individual often experi-  ences abdominal pain and tenderness and breast tenderness.  Pain in the bones and joints is thought to result from leukemia  infiltration with secondary stretching of the periosteum.   Central nervous system (CNS) involvement is common and  may be caused by either leukemic infiltration or cerebral bleed-  ing. Headache, vomiting, papilledema, facial palsy, blurred  vision, auditory disturbances, and meningeal irritation can  occur if leukemic cells infiltrate the cerebral or spinal meninges.  CNS involvement at the time of diagnosis is rare, and less than  5% of children and less than 10% of adults are affected. With-  out CNS prophylaxis, approximately one third of individuals  will develop CNS complications. Interventions associated with  CNS prophylaxis include cranial irradiation, chemotherapy,    and high doses of systemic chemotherapy. Specific treatment  modalities or combinations of treatment vary and are deter-  mined by age and risk status.   EVALUATION AND TREATMENT. Leukemia is often confused with  other conditions, making early detection difficult. Persistent  symptoms need intensive medical investigation. The diagno-  sis is made through examination of blood cells and bone mar-  row. A stained peripheral blood smear will exhibit low red  blood cell and platelet counts along with the presence of leu-  kemic blast cells (Figure 29-7). Examination of bone marrow  demonstrates hypercellularity with 60% to 100% blast cells, an  occasional normal myeloid, erythroid precursors, and few to no  megakaryocytes.   Chemotherapy, used in varying combinations, is the treat-  ment of choice for leukemia.'*'! Supportive measures include  blood transfusions, antibiotics, antifungals, and antivirals. Allo-  purinol is used for preventing production of uric acid (which  is elevated from cellular death because of treatment). Stem cell  transplantation is now considered standard therapy for selected  individuals with leukemia.   Bone marrow transplantation as a treatment has been  increasing during the past two decades for both ALL and  AML. Studies examining arsenic trioxide with all-trans-  retinoic acid in combination with chemotherapy found that  80 of 85 subjects achieved remission. all-trans-Retinoic acid  is made in the body from vitamin A and helps cells to grow  and develop. In the leukemic individual, retinoic acid drives  cells to develop into functional cells to alleviate the disease.  It is a chemotherapeutic agent used to treat some forms of  leukemia. In one study in which this chemical was utilized,  although there were five deaths, the 5-year event-free survival  rate was 89%, a remarkable improvement over historically  bleak survival rates.”°   The 5-year survival rate for those with leukemia is 38%,  largely because of poor survival rates of individuals with certain  types of leukemia (e.g., acute myelogenous). Since the 1970s,  5-year survival rates for those with ALL have increased from  38% to 65% for adults and from 53% to 85% for children.  Factors influencing increased survival rate include the use of  combined and multimodality treatment methods, improved  supportive services such as blood banking and nutritional    Key is the relative proportion of  erythroblasts to total count  (decreased in anemia)    or immune deficiency secondary to  chemotherapy, corticosteroids, and the  disease process    Weight loss Decreased 24-hr urinary  creatinine excretion;  hypoalbuminemia therapy,  in taste   Normal excretion of uric acid  is 300-500 mg/day; the  leukemic individual can  excrete 50 times more    In acute leukemia, anemia is usually  present from the beginning, often the first  symptom noticed, and severe; mild form  without symptoms is common in CML and  CLL; hemorrhage common in acute forms,  occasional in CML, but rare in CLL   Major sites of infection: oral cavity, throat,  lower colon, urinary tract, lungs, and  skin; prevention of infection focuses on  restoration of host defenses, decreasing  invasive procedures, and reducing  colonization of organisms   Severe weight loss may be related to  excess production of TNF-c    Hyperuricemia is present in both acute  leukemia and CML; increasing urine pH or  decreasing acid production with the drug    CLL, Chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; TNF tumor necrosis factor.    support, and the implementation of antimicrobial treatment.  The presence of the Philadelphia chromosome (observed in  about 5% of children with ALL, in 30% of adults with ALL, and  occasionally in AML) is a poor prognostic indicator.   Myelosuppression is both a consequence of leukemia and  its treatment. Hematologic support with blood products and  granulocyte colony-stimulating factor (G-CSF) or granulocyte-  macrophage colony-stimulating factor (GM-CSF) has effec-  tively shortened the time of neutropenia and improved survival  by reducing the risk for infection. A trial of individuals with  CML demonstrated improved disease-free survival in the group  receiving GM-CSF (23 months vs. 11 months; 2-year disease-  free survival 48% vs. 21%).?! The administration of colony-  stimulating factors (CSFs) can increase white cell numbers and  afford protection from infections.    The two main types of chronic leukemia are (1) chronic myelog-  enous leukemia (CML) and (2) chronic lymphocytic leuke-  mia (CLL) (see Table 29-2). Several forms of CML can occur,  depending on the lineage of the malignant cells (e.g., chronic  neutrophilic leukemia [CNL], chronic eosinophilic leukemia  [CEL]). Unlike cells in acute leukemia, chronic leukemic cells  are well differentiated and can be readily identified. Individu-  als with chronic leukemia have a longer life expectancy, usually  extending several years from the time of diagnosis.    The chronic leukemias account for the majority of cases  in adults, comprising approximately 30% of leukemias in the  Western world. It is estimated that in 2012 more than 15,680  cases of CLL and 5920 cases of CML were newly diagnosed  in the United States.?*?>75* The incidences of CLL and CML  increase significantly in individuals older than 40 years, with  prevalence in the sixth through eighth decades. CML is a group  of diseases called myeloproliferative disorders, which also include  polycythemia vera, primary thrombocytosis, and idiopathic  myelofibrosis (invasion of bone marrow by fibrous tissue).   PATHOPHYSIOLOGY. CLL involves malignant transformation  and progressive accumulation of monoclonal B lymphocytes;  rarely (less than 5%) are CLL malignancies of T-cell origin. The  characteristic immunophenotype is expression of CD5, CD19,  and CD23 molecules and low amounts of surface membrane  Ig and CD20 molecules.** CD5 is a signal transduction mol-  ecule linked to the B-cell receptor (BCR); CD19 is a low-affinity  antigen receptor expressed on maturing B cells, but is lost in  plasma cells; and CD23 is a low-affinity receptor for the Fc por-  tion of IgE. CLL is derived from a transformation of a partially  mature B cell that has not yet encountered antigen. The gene  for the variable region of the antibody heavy chain (IGHV) is  frequently mutated (30% to 40% of persons). (See Chapter 8  concerning immunoglobulin heavy-chain structure.) Individu-  als with a mutated IGHV tend to have a more benign condi-  tion with a more slowly developing and less malignant disease.    FIGURE 29-6 Lymphadenopathy. Individual with lymphocyte leukemia with  extreme but symmetric lymphadenopathy. (Courtesy Dr. A.R. Kagan, Los Angeles.  From Del Regato JA, Spjut HJ, Cox JD: Ackerman and Del Regato’s cancer, ed 2,  St Louis, 1985, Mosby.)    Significant numbers of this mutation are associated with a  median survival in excess of 20 to 25 years, whereas the absence  of mutations is associated with a poorer survival rate (median  survival 8 to 10 years).?°   The etiology of CLL is unknown. A familial tendency sug-  gests a genetic linkage; first-degree relatives have a three times  greater risk of developing the disease. It is rare in individuals  younger than 45 years of age, and when diagnosed, 95% of  individuals are older than age 50. Genetic anomalies occur in  approximately 90% of cases, frequently as deletions, although  none has been linked to the etiology of CLL.   CLL cells that accumulate in the marrow do not interfere  with normal blood cell production to the extent found in  acute leukemias. This is a significant feature explaining the  reduced severity in the beginning stage of disease. Accumu-  lation of malignant B cells is the result of cell cycle arrest in  the G)/G, phase. CLL cells tend to express increased levels of  anti-apoptotic proteins (e.g., BCL2) and suppress pro-apop-  totic proteins (e.g., BAX), which reduces their sensitivity to  apoptosis. Because the major pathophysiologic deficit in CLL  is the failure of B cells to mature into plasma cells that synthe-  size immunoglobulin, this often results in hypogammaglobu-  linemia (60% of clients).   CML is a member of the family of myeloproliferative dis-  orders that also includes polycythemia vera (see Chapter 28),  essential thrombocythemia, chronic idiopathic myelofibrosis    (invasion of bone marrow by fibrous tissue), chronic neutro-  philic leukemia, and chronic eosinophilic leukemia. CML is  clonal and thought to arise from a hematopoietic stem cell. The  cells observed in CML are heterogeneous in differentiation,  depending on the stage of the disease.*° During the chronic  phase the predominant cell is a long-lasting hematopoietic stem  cell. A leukemic granulocyte-monocyte progenitor cell is seen.  The Philadelphia chromosome is present in more than 95% of  CML, and the presence of the BCR-ABLI protein is responsible  for initiation of CML. In advanced disease, the accumulation  of additional mutations leads to the more aggressive leukemic  phenotype.   CLINICAL MANIFESTATIONS. Chronic leukemia advances slowly  and insidiously. Approximately 70% of individuals with CLL  are asymptomatic at the time of diagnosis. When symptoms  do appear, the most common finding is lymphadenopathy.  The most significant effect of CLL is suppression of humoral  immunity and increased infection with encapsulated bacteria.  Frequently the level of neutrophils is depressed, which adds to  the risk of infection. Invasion of most organ cells is uncommon  but infiltration does occur in lymph nodes, liver, spleen, and  salivary glands. CNS involvement is rare. Approximately 10%  of individuals develop a more aggressive malignancy, usually  a diffuse large B-cell lymphoma. In these individuals, extreme  fatigue, weight loss, night sweats, low-grade fever, elevated lev-  els of the enzyme lactic dehydrogenase, hypercalcemia, anemia,  and thrombocytopenia are common.   Individuals with CML may progress through three phases  of the disease: a chronic phase lasting 2 to 5 years during which  symptoms may not be apparent; an accelerated phase of 6 to 18  months during which the primary symptoms develop; and a ter-  minal blast phase (“blast crisis”) with a survival of only 3 to 6  months. The accelerated phase is characterized by excessive pro-  liferation and accumulation of malignant cells. Splenomegaly is  the most common finding, which may be prominent and painful,  but lymphadenopathy generally is not present. Liver enlargement  also occurs, but liver function is rarely altered. Hyperuricemia  is common and produces gouty arthritis. Infections, fever, and  weight loss also are frequent. The terminal blast phase is char-  acterized by rapid and progressive leukocytosis with an increase  in the number of basophils. In the later stages of the terminal  phase, which then resembles AML, blast cells or promyelocytes  predominate, and the individual experiences a blast crisis.   The acute effects of CML resemble those of acute leukemia  but with more prominent and painful splenomegaly. Liver  function rarely is altered despite enlargement, and lymphade-  nopathy generally is found only in the acute phase of the dis-  ease. Hyperuricemia invariably is present and produces gouty  arthritis. Infections, fever, and weight loss are common findings  in clients with CML.   EVALUATION AND TREATMENT. Diagnosis of chronic leukemia  depends on laboratory analyses of peripheral blood and bone  marrow samples. Diagnosis of CLL is based on detection of a  monoclonal B-cell lymphocytosis in the blood. The cells must  have the immunophenotype characteristic of CLL (CD5+,  CD19+, CD20 [weak], CD23+), at levels in excess of 5000  cells/uL, over a sustained period of time (usually 4 weeks). Bone    marrow may contain more than 30% lymphocytes and be nor-  mocellular or hypercellular.   Treatment is frequently based on prognostic indicators and  ranges from observation with treatment of infection, hemor-  rhage, or immune complications to a variety of drug therapies.    Because this disease typically occurs in older adults and the rate  of progression is slow, it is often simply observed until the dis-  ease progresses. Meta-analysis of randomized trials shows no  survival advantage for immediate vs. delayed treatment for  those individuals with early stage disease.”’    . A, Typical uniform  lymphoblasts with intermediate-sized nuclei, fine but “smudgy” chromatin, absence of nucleoli, and scant cytoplasm. B,  Lymphoblasts with more cytologic variation, including variability in size, number of nucleoli, and amount of cytoplasm. C,  Histologic features of ALL in bone core biopsy. Acute myeloid leukemia (AML) (D-G). D, Acute myeloblastic leukemia with  minimal or no maturation. The cells are myeloblasts with dispersed chromatin and variable amounts of agranular cytoplasm.  Some display medium-sized, poorly defined nucleoli. E, Acute monoblastic leukemia; characteristic monoblasts with round  nuclei and delicate chromatin and prominent nucleoli. Cytoplasm is abundant. F, Acute monocytic leukemia with most of the  cells in this field being promonocytes. Monoblasts and an abnormal monocyte also are present. G, Marrow biopsy of acute  megakaryoblastic leukemia containing large and small blasts and atypical megakaryocytes. Chronic lymphocytic leukemia  (CLL) (H-K). H, Peripheral blood smear typically shows lymphocytosis. Cytologic features of CLL cells differ. I, Classic cells  have a small nucleus with a “soccer ball” chromatin pattern. J, Some cases have increased large cells, or prolymphocytes,  with more open chromatin and prominent “punched-out” nucleoli (prolymphocyte, right side). K, The bone marrow can show  nodular infiltrates of CLL cells. Chronic myelogenous leukemia (CML) (L-N). L, Peripheral smear shows marked leukocytosis  attributable to a granulocytic proliferation of all stages with particularly increased myelocytes and absolute basophilia. M,  Bone core biopsy illustrates markedly hypercellular marrow attributable to granulocytic proliferation and increased small  hypolobated megakaryocytes. N, Bone marrow aspirate shows granulocytic proliferation and small, “dwarf” megakaryocyte.  (A-C, H-N from Hoffman R et al: Hematology: basic principles and practice, ed 6, Philadelphia, 2013, Churchill Livingstone.  D-G from Abeloff M et al: Abeloff's clinical oncology, ed 4, Philadelphia, 2008, Churchill Livingstone.)    Typically, individuals with CLL survive 10 years or more.  However, those with certain risk markers have a more aggres-  sive form of the disease that shortens survival to less than 3  years. Markers of high risk include anemia, thrombocytopenia,  and the absence of mutations in the IGHV gene. Mutations in  IGHV correlate very closely with levels of intracellular ZAP-70,  detection of which may be substituted for tests of IGHV muta-  tion. ZAP-70 is a tyrosine kinase that is linked to the T-cell  receptor (see Chapter 8). ZAP-70 negativity is associated with  improved mean survival.” It is not normally detected in CLL  cells with mutated IGHV, but is easily detectable by immuno-  histologic analysis in cells with an unmutated IGHV.   Chlorambucil, administered with or without corticosteroids,  on a daily or intermittent schedule is the most common treat-  ment for individuals with the most aggressive disease. Relief of  symptoms is often achieved, but there is no substantial effect on  survival. Combination therapy (CHOP) that includes cyclophos-  phamide, hydroxydaunomycin (Adriamycin), vincristine (Onco-  vin), and prednisone has an improved response rate but still does  not demonstrate improved survival. Fludarabine, a purine analog,  has a higher response rate and disease-free intervals, although sur-  vival is not affected. Rituximab, a murine anti-CD20 monoclonal  antibody, has shown limited promise in CLL (20% response rate).  Ofatumumab is a human anti-CD20 monoclonal antibody that  has shown overall response rates of 50% in persons with CLL.   Present treatment modalities for CML do not cure the dis-  ease, prevent blastic transformation, or prolong the average  survival time. Standard treatment consists of combined chemo-  therapy, biologic response modifiers, and allogeneic stem cell  transplant. Although transplantation is potentially curative, its  use is limited by donor availability and high toxicity in older  adults, thus limiting use to those older than 65 years. Alloge-  neic bone marrow transplantation has increased survival time  significantly (20% to 30%) when used after high-dose radiation  and chemotherapy and with concurrent treatment with inter-  feron. Traditional chemotherapy agents used are hydroxyurea  and busulfan. The development and introduction of the tyro-  sine kinase inhibitor imatinib mesylate (Gleevec) as a treatment  modality have changed current management of CML. Imatinib  mesylate is highly specific for CML and suppression of BCR-  ABL kinase activity, and it produces a complete cytogenetic  response in more than 80% of newly diagnosed persons. Sup-  pression of hematologic symptoms occurs in 97% of treated  individuals, and the use of imatinib mesylate has become the  standard of care for CML. A small percentage of clients develop  additional mutations in BCR-ABL that confer resistance to  imatinib mesylate.” Several new tyrosine kinase inhibitors are  under investigation as treatments for CML.   Lymphadenopathy is characterized by enlarged lymph nodes.  Lymph node enlargement is caused by an increase in size and  number of its germinal centers caused by proliferation of lym-  phocytes and monocytes or invasion by malignant cells. Nor-  mally, lymph nodes are not palpable or are barely palpable.    Enlarged lymph nodes are characterized by being palpable and  often also may be tender or painful to touch, although not in all  situations (see Figure 29-6).   Localized lymphadenopathy usually indicates drainage of an  area associated with an inflammatory process or infection (reac-  tive lymph nodes). Generalized lymphadenopathy is generally  a result of malignant or nonmalignant disease, particularly in  adults. Palpable nodes, however, do not always indicate seri-  ous disease and may indicate only a reaction to minor trauma  or infection of a specific structure. The location and size of the  enlarged nodes are important factors in diagnosing the cause  of the lymphadenopathy, as are the individual’s age, gender,  and geographic location. Generalized lymphadenopathy occurs  with non-Hodgkin lymphomas, chronic lymphocytic leuke-  mia, histiocytosis, and disorders that produce lymphocytosis.  In general, lymphadenopathy results from one of four types of  conditions: (1) neoplastic disease, (2) immunologic or inflam-  matory conditions, (3) endocrine disorders, or (4) lipid stor-  age diseases. Diseases of unknown cause, including reactions to  drugs, also may lead to generalized lymphadenopathy.   Lymphomas consist of a diverse group of neoplasms that  develop from the proliferation of malignant lymphocytes in the  lymphoid system. The classification of lymphomas was pub-  lished by the World Health Organization (WHO) and is derived  from the Revised European-American Lymphoma (REAL)  classification. This classification is based on the cell type from  which the lymphoma probably originated (Box 29-2).°° The  groups include Hodgkin lymphoma and two that were previ-  ously classified as non-Hodgkin lymphoma (B-cell neoplasms,  T-cell, and natural killer [NK] cell neoplasms). With the new  classification, multiple myeloma, which was previously classi-  fied independently, is included as a B-cell lymphoma.   Incidence rates of lymphoma differ with respect to age,  gender, geographic location, and socioeconomic class. The  estimated number of new cases of lymphoma for 2013 is  more than 79,030 individuals (see Table 29-2). It is estimated  that more than 20,200 individuals will have died from lym-  phoma in 2013. Since the early 1970s, the incidence of non-  Hodgkin lymphoma has nearly doubled. The exact reason for  this increase remains a mystery; however, a modest portion  of the increase had been attributed to lymphomas develop-  ing in association with immune deficiencies, including AIDS  and organ transplants. Conversely, the incidence of Hodgkin  lymphoma has declined over the same time period, especially  among older adults.   In general, lymphomas are the result of genetic mutations  or viral infection. Malignant transformation produces a cell  with uncontrolled and excessive growth that accumulates in the  lymph nodes and other sites, producing tumor masses. Lym-  phomas usually start in the lymph nodes or lymphoid tissues of  the stomach or intestines.    Hodgkin Lymphoma  Hodgkin lymphoma (HL) is a malignant lymphoma first char-  acterized by Thomas Hodgkin in 1832. It is estimated that more   Precursor B-Cell Neoplasms  Precursor B-lymphoblastic leukemia/lymphoma  Precursor B-cell acute lymphoblastic leukemia    Mature (Peripheral) B-Cell Neoplasms  B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma  B-cell prolymphocytic leukemia  Lymphoplasmacytoid lymphoma  Splenic marginal zone B-cell lymphoma (with/without villous lymphocytes)  Hairy cell leukemia  Plasma cell myeloma/plasmacytoma  Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid  tissue (MAL type)  Nodal marginal zone B-cell lymphoma (with/without monocytoid B cells)  Follicular lymphoma  Mantle-cell lymphoma  Diffuse large B-cell lymphoma  Mediastinal large B-cell lymphoma  Primary effusion lymphoma  Burkitt lymphoma/Burkitt cell leukemia    T-Cell and NK-Cell Neoplasms  Precursor T-Cell Neoplasms  Precursor T-lymphoblastic lymphoma/leukemia  Precursor T-cell acute lymphoblastic leukemia    Mature (Peripheral) T-Cell Neoplasms  T-cell prolymphocytic leukemia  T-cell granular lymphocytic leukemia  Aggressive NK-cell leukemia  Adult T-cell lymphoma/leukemia (HTLV-1 positive)  Extranodal NK/T-cell lymphoma, nasal type  Enteropathy-type T-cell lymphoma  Hepatosplenic gamma-delta T-cell lymphoma  Subcutaneous panniculitis-like T-cell lymphoma  Mycosis fungoides/Sézary syndrome  Anaplastic large-cell lymphoma, T/null cell, primary cutaneous type  Peripheral T-cell lymphoma, not otherwise characterized  Angioimmunoblastic T-cell lymphoma  Anaplastic large-cell lymphoma, T/null cell, primary systemic type    Hodgkin Lymphoma (Hodgkin Disease)  Nodular lymphocyte predominant Hodgkin lymphoma  Classic Hodgkin lymphoma    From National Institutes of Health, National Cancer Institute: Surveillance Epidemiology and End Results (SEER) program, available at: http://training.    than 9290 individuals will be newly diagnosed with HL in 2013  (see Table 29-2). The incidence of HL is approximately 26.6 per  100,000 men and 18.9 per 100,000 women.*! The median age of  diagnosis is 64. Incidence rates for HL have declined, especially  among older adults. The decrease in incidence in older adults  is attributed to improved diagnostic accuracy. The incidence is  greater in whites than blacks. Denmark, the Netherlands, and  the United States have the highest incidence of HL, and Japan  and Australia have the lowest incidence. HL peaks at two differ-  ent ages: early in life in the second and third decades and later  in life during the sixth and seventh decades.   PATHOPHYSIOLOGY. HL is characterized by its progression from  one group of lymph nodes to another, the development of sys-  temic symptoms, and the presence of Reed-Sternberg (RS) cells  (Figure 29-8). Itis widely accepted that the RS cell represents the  malignant transformed lymphocyte. The RS cells are often large  and binucleate, with occasional mononuclear variants. RS cells  are the hallmark of HL. RS cells are necessary for the diagnosis  of HL; however, they are not specific to HL. In rare instances,  cells resembling them can be found in benign illnesses, as well as  in other forms of cancer, including non-Hodgkin lymphomas  and solid tissue cancers and in infectious mononucleosis.   The triggering mechanism for the malignant transformation  of cells remains unknown. Classic HL appears to be derived  from a B cell in the germinal center that has not undergone suc-  cessful immunoglobulin gene rearrangement (see Chapter 8)  and would normally be induced to undergo apoptosis. Survival    4 :  FIGURE 29-8 Reed-Sternberg Cell. A large multinucleated or multilobed  cell (center of photograph) with inclusion body—like nucleoli surrounded by a halo  of clear nucleoplasm. (From Damjanov |, Linder J, editors: Anderson's pathology,  ed 10, St Louis, 1996, Mosby.)    of this cell may be linked to infection with EBV. Laboratory  and epidemiologic studies have linked HL with EBV infections  and EBV DNA. RNA and proteins are frequently observed in  HL cells. The RS cells secrete and release cytokines (e.g., IL-10,  transforming growth factor-beta [TGF-f]) that result in the  accumulation of inflammatory cells that produces the local and   Found in all ages but most common in adults  ncidence in males exceeds that in females  Uncommon subtype    and persons in nonindustrialized countries  ncidence in males exceeds that in females    systemic effects. HL is subcategorized into two main types: clas-  sic Hodgkin and nodular lymphocyte-predominant Hodgkin.  Classic HL is subclassified into four types (Table 29-5) based  on the morphology of RS cells, and the characteristics of the  inflammatory cell infiltrate in the tumor. Lymphocyte-predom-  inant disease presents with earlier-stage disease, longer survival,  and fewer treatment failures than classic HL.** However, despite  a more favorable prognosis, lymphocyte-predominant HL has  a tendency to histologically transform into diffuse large B-cell  lymphoma by 10 years in approximately 10% of people.°?   The molecular events causing malignant transformation  remain controversial; although RS cells are apparently from  B-cell lineage, they express very few B-cell markers and express  markers normally not found on B cells. For instance, RS cells  do not express immunoglobulin, but do express CD15 (a car-  bohydrate adhesion molecule found on neutrophils), TARC  (a Th2-cell specific chemokine), and T-cell—associated anti-  gens (e.g., -chain of the T-cell receptor).*° The precise genetic  defects leading to development of HL are unknown, although  several have been suggested. These generally include defects in  immunoglobulin variable region gene rearrangement or defects  in other B-cell-specific differentiation genes.   CLINICAL MANIFESTATIONS. Many of the characteristic clinical  features (Box 29-3) of HL can be explained by the complex  action of cytokines and other growth factors that are secreted  by the malignant cells. These substances induce infiltra-  tion and proliferation of inflammatory cells, resulting in an  enlarged, painless lymph node in the neck (often the first  sign of HL) (Figure 29-9). The discovery of an asymptom-  atic mediastinal mass on routine chest x-ray is not uncom-  mon and is often an initial sign of HL. The cervical, axillary,  inguinal, and retroperitoneal lymph nodes are commonly  affected in HL (Figure 29-10). Local symptoms caused by  pressure and obstruction of the lymph nodes are the result of  the lymphadenopathy.   About one third of individuals will have some degree of sys-  temic symptoms.* Intermittent fever, without other symptoms    ost common subtype in developing countries  Found in all ages but most common in adolescents and  young adults (median age of onset is about 28 years)    Large tumor nodules with RS cells surrounded by collagen and  fibrous bands    RS cells with mixed inflammatory cell (lymphocytes, monocytes/  macrophages, eosinophils, plasma cells) infiltrates   Usually widespread disease: abdominal lymphadenopathy;  spleen, liver, and bone marrow involvement, without peripheral  lymphadenopathy    FIGURE 29-9 Hodgkin Lymphoma and Enlarged Cervical Lymph Node.  Typical enlarged cervical lymph node in the neck of a man with Hodgkin lymphoma.  The scar of previous biopsy incision is well healed. (From Hoffbrand AV, Pettit  JE, Vyas P: Color atlas of clinical hematology, ed 4, Philadelphia, 2009, Mosby  Elsevier.)    FIGURE 29-10 Common and Uncommon Involved Lymph Node Sites for  Hodgkin Lymphoma.    of infection, drenching night sweats, itchy skin (pruritus), and  fatigue are relatively common. These constitutional symptoms  accompanied by weight loss are associated with a poor prog-  nosis. The Cotswold staging classification system used for HL  is able to establish a correlation between the anatomic extent  of the disease and prognosis (Table 29-6). This classification  system is based on the individual’s medical history, examina-  tion (presence of symptoms and palpable lymph nodes), and  other radiologic and hematologic results. Prognostic indicators  include clinical stage, histologic type, tumor cell concentration  and tumor burden, constitutional symptoms, and age.   Although HL rarely arises in the lung, mediastinal and hilar  node adenopathy can cause secondary involvement of the  trachea, bronchi, pleura, or lungs. Retroperitoneal nodes can  involve vertebral bodies and nerves, causing displacement of  ureters. Spinal cord involvement is more common in the dor-  sal and lumbar regions than in the cervical region. Although  uncommon, skin manifestations include psoriasis and eczema-  toid lesions, causing itching and scratching.   As a result of direct invasion from mediastinal lymph nodes,  pericardial involvement can cause pericardial friction rub,  pericardial effusion, and engorgement of the neck veins. The  gastrointestinal (GI) tract and urinary tract rarely are involved.  Anemia often is found in individuals with HL, accompanied  by a low serum iron level and decreased iron-binding capacity.  Other laboratory findings include elevated sedimentation rate,  leukocytosis, and eosinophilia. Leukopenia occurs in advanced  states of HL.    Involvement of a single lymph node region or single  extranodal organ or site  Involvement of two or more lymph node regions on the  same side of the diaphragm or a single extranodal  organ or site and its regional lymph nodes  Involvement of lymph node regions or structures on both  sides of the diaphragm  Disseminated involvement of one or more  extralymphatic organs or an isolated extralymphatic  organ with distant nodal involvement  Modifying characteristics for all four stages:  A: No B symptoms  B: Unexplained fever of >38° C (100.4° F), drenching  night sweats, unexplained loss of >10% of body  weight in the 6 months preceding diagnosis  E: Large mediastinal mass with direct extension into  extranodal sites    Splenic involvement of HL depends on histopathologic  type (see Table 29-5). The spleen is involved in 60% of cases of  mixed cellularity and lymphocytic depletion types. With lym-  phocyte predominance and nodular sclerosis types, only 34%  of cases reveal splenic involvement.   EVALUATION AND TREATMENT. Because of the variability in  symptoms, early definitive detection may be difficult. Asymp-  tomatic lymphadenopathy can progress undetected for several  years. Careful evaluation, including chest x-rays, lymphangiog-  raphy, and biopsy, should be carried out for individuals with  fever of unknown origin and peripheral lymphadenopathy.**  A lymph node biopsy with scattered RS cells and a cellular  infiltrate is highly indicative of HL. The effectiveness of treat-  ment is related to the age of the individual and the extent of  the disease. Approximately 75% of individuals diagnosed with  HL are cured, largely because of successful combined treatment  with radiation therapy and chemotherapy (Figure 29-11). Over  the past 50 years, the death rate has fallen more rapidly for HL  than for any other malignancy. More recent treatments include  high-dose chemotherapy with bone marrow or stem cell trans-  plantation. Monoclonal antibodies also are being developed  and nonmyeloablative allogeneic stem cell transplant has been  found to help certain individuals even though this treatment is  still under development.   The 5-year survival rate varies depending on the stage that is  identified at diagnosis.** The 5-year survival rate for stages I and  IL is 90% to 95%, 80% to 85% for stage II, and 75% for stage  IV. Those with stage I or II disease are candidates for chemo-  therapy, radiation therapy, or a combination of these treatment  modalities. Individuals with stage II or IV disease, bulky dis-  ease (more than 10-cm mass or mediastinal disease with a trans-  verse diameter exceeding 33% of the transthoracic diameter),  or presence of B symptoms require combined chemotherapy  with or without additional radiation treatment. Other factors, if    FIGURE 29-11 Cervical Hodgkin Lymphoma (Extreme Case). A, Young boy with extensive cervical Hodgkin lym-  phoma. B, Appearance several years later and after treatment, when axillary manifestations developed. C, Appearance 23  years after initial treatment with radiation. (From del Regato JA, Spjut HJ, Cox JD: Ackerman and del Regato’s cancer, ed 2,    present, have an influence on survival. Poorer survival is related  to a high white blood cell count (greater than 15,000/uL) or low  hemoglobin (Hb) level (less than 10.5 g/dl); low lymphocyte  count (less than 600/pL); and male gender. Cure for HL can be  achieved in 75% of cases with current therapies.   The previously used generic classification of non-Hodgkin lym-  phoma (NHL) has been reclassified in the WHO/REAL scheme  into B-cell neoplasms, which include a variety of lymphomas  including myelomas that originate from B cells at various stages  of differentiation, and T-cell and NK-cell neoplasms, which  include lymphomas that originate from either T or NK cells.  These cancers are differentiated from HL by lack of RS cells and  other cellular changes not characteristic of HL.   More than 69,740 cases of NHL and 19,020 deaths are pre-  dicted for 2013 (see Table 29-2).*° The median age of diagnosis  is 67 years of age. The incidence of NHL has increased from 8  persons per 100,000 in 1973 to 19.6 per 100,000 in 2009. Lym-  phomas from HIV and EBV have accounted for some of the  increase but an actual cause has yet to be determined. Con-  versely, the mortality rate has risen at a slower rate. It is thought  that newer treatment modalities are improving survival rates.   PATHOPHYSIOLOGY. NHL is best described as a progressive  clonal expansion of B cells, T cells, or NK cells. The genetic  lesions affecting proto-oncogenes or tumor-suppressor genes  result in cell immortalization and the resultant increase in  malignant cells. Oncogenes may be activated by chromosomal  translocations or the tumor-suppressor loci may be inactivated  by deletion or mutation of chromosomes. Oncogenic viruses  also may alter the genome of certain subtypes. The various sub-  types of NHL may be identified by specific diagnostic markers  related to various cytogenic lesions.   Lymphomas most likely originate from mutations in cellular  genes (many of which are environmentally induced) in a single  cell that lead to loss of control of proliferation and other aspects  of cell growth. The most common type of chromosomal altera-  tion in NHL is translocation, which disrupts the genes encoded    at the breakpoints. Risk factors include family history, expo-  sure to a variety of mutagenic chemicals, irradiation, infection  with certain cancer-related viruses (e.g., EBV, human herpes-  virus-8, HIV, HTLV-1, hepatitis C), and immune suppression  related to organ transplantation. Gastric infection with Helico-  bacter pylori increases the risk for gastric lymphomas. NHL is a  disease of middle age, usually found in individuals more than  50 years old.   B cells account for 80% to 90% of NHLs, with T cells and NK  cells accounting for the remaining percentage. A very small per-  cent originates from macrophages. NHL tumors are categorized  by the level of differentiation, cell of origin, and rate of cellular  proliferation. Tumor aggressiveness of many B-cell NHLs may  be predicted by the pattern of cell growth and size. Tumors with  a characteristic nodular pattern, vaguely resembling lymphoid  follicular structures, are generally less aggressive than lympho-  mas with a diffuse pattern of proliferation. Small lymphocyte  lymphomas are less aggressive than large cell lymphomas,  which are generally intermediate to high grade in aggressive-  ness. However, small cells are characteristic of some subtypes of  high-grade lymphomas.   CLINICAL MANIFESTATIONS. Clinical manifestations of NHL usu-  ally begin as localized or generalized lymphadenopathy, similar  to HL. The cervical, axillary, inguinal, and femoral chains are  the most commonly affected sites. Generally, the swelling is  painless and the nodes have enlarged and transformed over a  period of months or years. Other sites of involvement are the  nasopharynx, gastrointestinal (GI) tract, bone, thyroid, tes-  tes, and soft tissue. Some individuals have retroperitoneal and  abdominal masses with symptoms of abdominal fullness, back  pain, ascites (fluid in the peritoneal cavity), and leg swelling.   Lymphomas are classified as low, intermediate, or high grade.  A low-grade lymphoma, which also may be termed indolent,  has a slow progression. Individuals with low-grade lymphoma  commonly present with a painless, peripheral adenopathy.  Spontaneous regression of these nodes may occur, mimicking  the presence of an infection. Night sweats with an elevated tem-  perature (more than 38° C [100.4° F]) and weight loss, as well    Nodal Multiple Localized to single axial group  involvement peripheral of nodes (i.e., cervical,  nodes mediastinal, para-aortic)  Mesenteric nodes = Mesenteric nodes and Waldeyer  and Waldeyer ring rarely involved  ring commonly  involved  Noncontiguous Orderly spread by contiguity  Uncommon Common  Common Rare    as extranodular involvement, are not commonly present in the  early stages but are common in advanced or end stages of the  disease. Cytopenia, reflective of bone marrow involvement, is  often observed. Hepatomegaly is common; however, spleno-  megaly is present in approximately 40% of individuals. Fatigue  and weakness are more prevalent with advanced stages.   Immediate and high-grade lymphomas, which are more  aggressive, have a more varied clinical presentation. A high-  grade lymphoma also may be termed aggressive. Adenopathy  is common with more than one third of individuals having  extranodal involvement. Common sites are the GI tract, skin,  bone marrow, sinuses, genitourinary (GU) tract, thyroid, and  CNS. Night sweats, with an increased temperature (more than  38° C [100.4° F]), as well as weight loss (more than 10% from  baseline within 6 months) are present in approximately 30% to  40% of individuals. Some individuals have retroperitoneal and  abdominal masses with symptoms of abdominal fullness, back  pain, ascites (fluid in the peritoneal cavity), and leg swelling.  Hepatomegaly and splenomegaly are often present. Differences  in clinical features are noted in Table 29-7.   EVALUATION AND TREATMENT. Biopsy is considered the primary  means for diagnosis of NHL. Staging of NHL is necessary to  identify treatment and make a prognosis. In addition to biopsy,  computed tomography (CT) scans of the neck, chest, abdomen,  and pelvis, as well as bilateral bone marrow aspirate examina-  tion, are performed. Data from all three procedures are nec-  essary for appropriate staging. A common finding in NHL is  noncontiguous lymph node involvement, which is not com-  mon in HL. The Ann Arbor staging system is most commonly  used to stage NHL (Table 29-8).   Treatment for NHL is quite diverse and depends on type (B  or T cell), tumor stage, histologic status (low, intermediate, or  high grade), symptoms, age, and any comorbidities. Depend-  ing on the type (B or T cell) of the tumor, the stage of the dis-  ease, and the aggressiveness of the tumor, treatment is usually    Diffuse involvement of one or more  extralymphatic organs with or without  associated lymph node involvement    Subclassifications  E Involvement of adjacent extralymphatic site  S Involvement of spleen  A Asymptomatic  B Fever, night sweats, weight loss    initiated at the time of diagnosis. However, because treatment  is not curative for some low-grade indolent lymphomas that  are widely disseminated, observation without treatment may be  the most appropriate choice. These indolent tumors are often  not symptomatic for the individual and this approach improves  quality of life. In some cases the disease may be so slow growing  that treatment is not needed for an extended period of time.   Success of treatment is dependent on several parameters,  including the type of lymphoma, stage of disease, cell type,  involvement of organs outside the lymph nodes, age of the per-  son, and the severity of the body’s reaction to the disease (e.g.,  fever, night sweats, weight loss).°*°° Treatment with chemo-  therapy alone may be adequate in many cases, although radia-  tion therapy is frequently included. Low-dose chemotherapy  has been followed by autologous stem cell transplantation in  some NHLs or for recurrent disease. Treatment of B-cell lym-  phomas with rituximab has proven effective. Rituximab is a  commercial monoclonal antibody against antigen CD20, which  is expressed on the surface of all B cells, including those that  are malignant. Administration of rituximab depletes most B  cells and allows the replenishment of normal B cells from the  lymphoid stem cell pool. It has also proven useful in a variety  of autoimmune diseases, including immune thrombocytopenia  purpura, autoimmune anemias, systemic lupus erythematosus,  and rheumatoid arthritis.   Radioimmunotherapy, a newer treatment approach, com-  bines radiation therapy with monoclonal antibody therapy and  is used to improve rates of complete remission both in indo-  lent forms of lymphoma (follicular and marginal zone) and in  aggressive forms, including large B-cell and mantle cell lym-  phoma. Studies suggest improved complete remission rates  and longer disease-free survival in persons with these types of  lymphomas.   Individuals with NHL can survive for extended periods.*+°°  A partial remission may be achieved in some cases in which  evidence of the disease remains but it does not progress. Sur-  vival with nodular lymphoma ranges up to 15 years, but those  with diffuse disease generally do not survive as long. Overall,    FIGURE 29-12 Burkitt Lymphoma. Burkitt lymphoma involving the jaw in  a young African boy. (Courtesy |. Magrath, MD, Bethesda, MD. From Zitelli BJ,  Melntire SC, Nowalk Au: Zitelli and Davis’ atlas of pediatric physical diagnosis,  ed 6, Philadelphia, 2012, Saunders.)    the survival rates of NHL are less than those for Hodgkin lym-  phoma. For NHL, the survival rates are 1 year, 77%; 5 years,  59%; and 10 years, 42%. Many investigators believe that more  aggressive treatment increases the cure rate. High-grade NHL is  seen with increasing frequency in persons with AIDS and has an  extremely poor prognosis.   Burkitt lymphoma is a B-cell tumor with unique clinical and  epidemiologic features that accounts for 30% of childhood lym-  phomas worldwide. It is a highly aggressive B-cell non-Hodgkin  lymphoma that is the fastest growing human tumor. It occurs in  children from east-central Africa and New Guinea and is char-  acterized by a rapidly growing tumor primarily in the jaw and  facial bones (Figure 29-12). In the United States, Burkitt lym-  phoma is rare, usually involves the abdomen, and is character-  ized by extensive bone marrow invasion and replacement. EBV,  found in nasopharyngeal secretions, is associated with Burkitt  lymphoma in African children.   PATHOPHYSIOLOGY. EBV is associated with almost all cases  (more than 90%) of Burkitt lymphoma. It is suspected that  suppression of the immune system by other illnesses (e.g., HIV  infection, chronic malaria) increases the individual’s suscepti-  bility to EBV. B cells are particularly sensitive because of spe-  cific surface receptors for EBV. As a result, the B cell undergoes  chromosomal translocations that result in overexpression of  the C-MYC proto-oncogene and loss of control of cell growth  (Figure 29-13). The most common translocation (75% of indi-  viduals) is between chromosomes 8 (containing the C-MYC  gene) and 14 (containing the immunoglobulin heavy-chain  genes). Other translocations have been reported between chro-  mosome 8 and chromosomes 2 or 22, which contain genes for  immunoglobulin light chains.    FIGURE 29-13 Burkitt Lymphoma Cells. A, A case of Burkitt lymphoma  illustrated at low power showing the “starry sky” appearance. This is due to the  dense proliferating cells producing the dark sky, and the scattered lighter-staining  tingible body macrophages (stars) phagocytizing dying cells. B, Higher magnifica-  tion illustrating the syncytia of intermediate-sized cells with coarse chromatin and  multiple nucleoli. Note the tingible body macrophage with abundant light cyto-  plasm and ingested debris (center bottom). C, Burkitt cells as seen on a Wright-  stained bone marrow aspirate in a person with Burkitt leukemia. Notice deep blue  cytoplasm with numerous vacuoles. D, Fluorescence in situ hybridization (FISH)  with probes to MYC and /GH illustrate the IGH/MYC fusion. E, The 8, 14 chromo-  somal translocation and associated oncogenes in Burkitt lymphoma. (A-D cour-  tesy Dr. Y. Zhang, University of Chicago. From Hoffman R et al: Hematology: basic  principles and practice, ed 6, Philadelphia, 2013, Churchill Livingstone. E from  Kumar V et al: Robbins & Cotran pathologic basis of disease, ed 8, Philadelphia,  2010, Saunders.)    CLINICAL MANIFESTATIONS. In non-African Burkitt lymphoma  the most common presentation is abdominal swelling. More  advanced disease may involve other organs—eye, ovaries, kid-  neys, glandular tissue (breast, thyroid, tonsil)—and presents  with type B symptoms (night sweats, fever, weight loss).    EVALUATION AND TREATMENT. The distribution of tumors and  biopsies of enlarged lymph nodes or the bone marrow con-  taining malignant B cells are usually indicative of Burkitt lym-  phoma. It is one of the most aggressive and quickly growing  malignancies. However, the African variety in children has been  successfully treated with radiotherapy and cyclophosphamide  (60% survival overall; 90% survival with limited disease). The  American type is more resistant to treatment. Adjuvant mono-  clonal antibody therapy with rituximab appears to be a promis-  ing agent for improving outcomes with minimal toxic effects.°”   Lymphoblastic lymphoma (LL) is a relatively rare variant of  NHL (2% to 4%) but accounts for almost one third of cases of  NHL in children and adolescents, with a male predominance.  It is estimated that there will be more than 6000 new cases and  more than 1400 deaths in 2012. The vast majority of LL (more  than 85%) is of T-cell origin, and the remainder arises from B  cells. LL is similar to acute lymphoblastic leukemia and may be  considered a variant of that disease.   PATHOPHYSIOLOGY. The disease arises from a clone of relatively  immature T cells that becomes malignant in the thymus. As  with most lymphoid tumors, LL is frequently associated with  translocations, primarily of the chromosomes that encode for  the T-cell receptor (chromosomes 7 and 14). These aberrations  result in increased expression of a variety of transcription fac-  tors and loss of growth control.   CLINICAL MANIFESTATIONS. The first sign of LL is usually a pain-  less lymphadenopathy in the neck. Peripheral lymph nodes in  the chest become involved in about 70% of individuals, mostly  above the diaphragm. LL is a very aggressive tumor that pres-  ents as stage IV in most people. T-cell LL is associated with a  unique mediastinal mass (up to 75%) because of the apparent  origin of the tumor in the thymus.   The mass results in chest pain and may cause compression of  bronchi or the superior vena cava. The tumor may infiltrate the  bone marrow in about half of those affected, and suppression  of bone marrow hematopoiesis leads to increased susceptibility  to infections. Other organs, including the liver, kidney, spleen,  and brain, may also be affected. Many individuals express type  B symptoms: fever, night sweats, and significant weight loss.   EVALUATION AND TREATMENT. The most common therapeutic  approach is combined chemotherapy with multiple drugs. In  early disease, the response rate is high with increased survival;  the 5-year survival in children is 80% to 90%, and 45% to 55%  in adults. Although LL is easily treated, there is a high relapse  rate: 40% to 60% of adults.   Certain other clinical conditions mimic the malignant lym-  phomas. These conditions include tuberculosis (TB), syphilis,  systemic lupus erythematosus, lung cancer, and bone cancer.  An important distinction between lymphomas and other con-  ditions is that lymphomas usually involve localized lymphade-  nopathy. Infectious precursors of malignant lymphomas are  characterized by more generalized lymphadenopathy with sys-  temic signs and symptoms.   The plasma cell is the end-stage cell of the humoral immune  response (see Chapter 8). Immunocompetent B cells pre-  sented with antigen and stimulated with cytokines from T  helper cells will undergo proliferation and differentiation  into antibody-producing plasma cells. Antigen-reactive B  cells have undergone rearrangement of immunoglobulin  heavy-chain variable region genes (V, D, J) and express sur-  face IgM or IgD, or both. After stimulation with antigen, the  B cells may not undergo any further genetic rearrangement  and develop into plasma cells that secrete IgM or selectively  rearrange the immunoglobulin heavy-chain genes to irrevers-  ibly switch to secreting IgG, IgA, or IgE. During this process  some cells may undergo malignant transformation, leading  to one of several types of plasma cell malignancies (Figure  29-14). The most common and most aggressive plasma cell  tumor is multiple myeloma. Other diseases in this classifica-  tion include precursors to malignant myeloma (smoldering  myeloma, monoclonal gammopathy of undetermined sig-  nificance [MGUS]}), solitary plasmacytoma of the bone, and  Waldenstrém macroglobulinemia.** A common characteris-  tic of these tumors is secretion of complete or partial immu-  noglobulin molecules.   Multiple myeloma (MM) is a clonal plasma cell cancer  characterized by the slow proliferation of malignant cells as  tumor cell masses in the bone marrow that usually results in  destruction of the bone. Most MMs secrete large amounts of  monoclonal proteins that resemble intact immunoglobulins.  The reported incidence of myeloma has doubled in the past  two decades, possibly as a result of more sensitive testing  used for diagnosis. The annual incidence rate in the United  States is 5.6 per 100,000, with more than 21,700 new cases  and more than 10,700 deaths estimated for 2012.°° Multiple  myeloma occurs in all races, but the incidence in blacks is  about twice that of whites. It rarely occurs before the age  of 40 years—peak age of incidence is about 70 years. It is  slightly more common in men than in women. Neoplastic  cells of multiple myeloma reside in the bone marrow and  are usually not found in the peripheral blood. Occasionally  it may spread to other tissues, especially in very advanced  disease.   PATHOPHYSIOLOGY. Many myelomas are aneuploidy, with  chromosomal numbers ranging from 44 chromosomes to  near tetraploid. Chromosomal translocations (breakpoints)  are responsible for development of myeloma in most indi-  viduals. The primary translocation involves the immuno-  globulin heavy chain on chromosome 14 that relocates to  sites containing genes that cell cycle (cyclins) on chromo-  somes 11(q13), 12(p13), and 6(p21); oncogenes on chromo-  somes 16(q23), 8(q24), and 20; and fibroblast growth factor  receptor on chromosome 4(p16).’ A progression of further  secondary genetic alterations causes development to an  aggressive MM (Figure 29-15). The molecular pathogenesis  of multiple myeloma also involves proto-oncogene muta-  tions and, more rarely, inactivation of tumor-suppressor    genes. The precise timing and reason for the genetic altera-  tion and accumulation are unknown, but probably occur  initially late in B-cell development after exposure to antigen.  Investigators are studying various epigenetic alterations in  multiple myeloma, for example, miRNAs and global changes  in chromatin.*°    Malignant plasma cells arise from one clone of B cells that  produce abnormally large amounts of one class of immu-  noglobulin (usually IgG, occasionally IgA, and rarely IgD  or IgE). The malignant transformation may begin early in  B-cell development, possibly before encountering antigen in  the secondary lymphoid organs. The myeloma cells return    FIGURE 29-14 Distribution of Monoclonal Gammopathy Types. A, Distribution of serum monoclonal proteins in 1485  patients seen at the Mayo Clinic during 2008. B, Diagnoses in 1612 cases of monoclonal gammopathy seen at the Mayo  Clinic during 2008. /g, Immunoglobulin; MGUS, monoclonal gammopathy of undetermined significance; PC, plasmacytoma;  SMM, smoldering multiple myeloma; WM, Waldenstrom macroglobulinemia. (From Goldman L, Schafer Al: Goldman's Cecil  medicine, ed 24, Philadelphia, 2012, Saunders.)    FIGURE 29-15 Myeloma Cell Proliferation and Disease Progression. Development of the malignant myeloma results  from multiple genetic changes, initially a translocation involving the immunoglobulin heavy-chain genes on chromosome 14 or  a deletion in chromosome 13. The intermediate phenotype is frequently genetically unstable, leading to further mutations that  result in a myeloma. Interactions between myeloma cells and extracellular matrix proteins further increase adhesion molecule  expression, anti-apoptotic pathways, angiogenesis, bone resorption, and cytokine secretion. /L-6, Interleukin-6; KRAS, V-Ki-ras  Z Kirsten rat sarcoma viral oncogene homolog; MGUS, monoclonal gammopathy of undetermined significance; MIP-1o., mac-  rophage inflammatory protein-1a; NRAS, neuroblastoma RAS viral (v-ras) oncogene homolog; OPG, osteoprotegerin; RANKL,  receptor activator of nuclear factor-«B ligand; VEGF vascular endothelial growth factor. (From Abeloff M et al: Abeloffs clinical  oncology, ed 4, Philadelphia, 2008, Churchill Livingstone.)    either to the bone marrow or to other soft tissue sites. Their  return is aided by cell adhesion molecules that help them  target favorable sites that promote continued expansion and  maturation.   Myeloma cells in the bone marrow directly secrete hepato-  cyte growth factor and parathyroid hormone-related peptide  and adhere to stromal cells, inducing their production of sev-  eral cytokines (e.g., IL-6, IL-1, TNF-a, TNF-f, IL-11, macro-  phage inflammatory protein). (Lymphocytes and cytokines are  described in Chapter 8.) These factors, particularly IL-6, act  as an osteoclast-activating factor and stimulate osteoclasts to  reabsorb bone. This process results in bone lesions and hyper-  calcemia (high calcium levels in the blood) resulting from  release of calcium from the breakdown of bone.   The antibody produced by the transformed plasma cell is  usually defective, containing truncations, deletions, and other  abnormalities, and is frequently referred to as a paraprotein  (abnormal protein in the blood). Because of the large number  of malignant plasma cells, the abnormal antibody, called the M  protein, becomes the most prominent protein in the blood in  80% of myeloma clients (Figure 29-16). Suppression of normal  plasma cells by the myeloma results in diminished or absent  normal antibodies. The excessive amount of M protein also  may contribute to many of the clinical manifestations of the  disease. The myeloma may produce free immunoglobulin light  chain (Bence Jones protein) that is present in the blood and  urine in approximately 80% of clients and contributes to dam-  age of renal tubular cells.   CLINICAL MANIFESTATIONS. The common presentation of MM  is characterized by elevated levels of calcium in the blood  (hypercalcemia) (13% of persons), renal failure (19%), ane-  mia (72% of persons), and bone lesions (80% of persons).*!  The hypercalcemia and bone lesions result from infiltra-  tion of the bone by malignant plasma cells and stimulation  of osteoclasts to reabsorb bone. This process results in the  release of calcium (hypercalcemia) and the development of  “lytic lesions” (round, “punched-out” regions of bone) (Fig-  ure 29-17). Destruction of bone tissue causes pain, the most  common presenting symptom, and pathologic fractures. The  pain may be felt in a single bone of the entire skeleton, and the  bones most commonly involved, in decreasing order of fre-  quency, are the vertebrae, ribs, skull, pelvis, femur, clavicle,  and scapula. Spinal cord compression, because of the weak-  ened vertebrae, occurs in about 10% of individuals. The pain  is initially aching, intermittent, and aggravated by weight-  bearing. As the disease progresses, pain becomes severe and  prolonged. It is common for the individual with myeloma  to be treated for a slipped disk or arthritis before the correct  diagnosis of myeloma is established. The individual may com-  plain of weakness, fatigue, weight loss, and anorexia in addi-  tion to pain.   Proteinuria is observed in 90% of individuals. Renal failure  may be either acute or chronic and is usually secondary to the  hypercalcemia. Bence Jones protein may lead to damage of the  proximal tubules. Anemia is usually normocytic and normo-  chromic and results from inhibited erythropoiesis caused by  tumor cell infiltration of the bone marrow.    The high concentration of paraprotein in the blood may  lead to hyperviscosity syndrome. The increased viscosity inter-  feres with blood circulation to various sites (brain, kidneys,  extremities). Hyperviscosity syndrome is observed in up to  20% of individuals with MM. Additional neurologic symp-  toms (e.g., confusion, headaches, blurred vision) may occur  secondary to hypercalcemia or hyperviscosity.   Suppression of the humoral (antibody-mediated) immune  response results in repeated infections, primarily pneumonias  and pyelonephritis. The most commonly involved organisms  are encapsulated bacteria that are particularly sensitive to the  effects of antibody: pneumonia caused by Streptococcus pneu-  moniae, Staphylococcus aureus, or Klebsiella pneumoniae or  pyelonephritis caused by Escherichia coli or other gram-negative  organisms. Cell-mediated (T-cell) function is relatively normal.  Overwhelming infection is the leading cause of death from MM.   MM is a progressive disorder and is often preceded by a con-  dition known as monoclonal gammopathy of undetermined  significance (MGUS). MGUS is diagnosed by the presence of an  M protein in the blood or urine without additional evidence of  MM.*! MGUS is present in approximately 1% of the general pop-  ulation and in 3% of individuals older than 70 years. Although  MGUS is considered nonpathologic and requires no treatment,  about 2% of individuals with MGUS progress to malignant plasma  cell disorders. Progression of MM following MGUS advances to  asymptomatic MM and finally symptomatic MM. Asymptomatic  MM also may be referred to as smoldering myeloma and indo-  lent myeloma.*! Smoldering myeloma is usually characterized by  the presence of an M protein and clonal bone marrow plasma  cells, but with no indication of end-organ damage.   Most cases of symptomatic plasma cell tumors are multiple  myeloma (about 94%). The remaining 6% is divided equally  between solitary plasmacytomas and extramedullary plasmacy-  tomas.°* Solitary plasmacytoma is characterized by a solitary  tumor of malignant plasma cells that may result in a single  lytic bone lesion or may be in the tissues (extramedullary plas-  macytoma).*! Extramedullary plasmacytoma can be found in  a variety of soft tissues, but commonly in those of the upper  respiratory tract (e.g., tonsils, nasopharynx, sinuses). Addition-  ally, MM is staged to help determine prognosis and appropriate  treatment (Table 29-9).   EVALUATION AND TREATMENT. Diagnosis of MM is made by  symptoms, radiographic and laboratory studies, and a bone  marrow biopsy. Quantitative measurements of immuno-  globulins (IgG, IgM, IgA) are usually performed. Typically,  one class of immunoglobulin (the M protein produced by the  myeloma cell) is greatly increased, whereas the others are sup-  pressed. Serum electrophoretic analysis reveals increased lev-  els of M protein. Because the M protein is monoclonal, each  molecule has the same electric change and migrates at about  the same site on electrophoresis, resulting in a highly concen-  trated protein (M spike). Bence Jones protein is observed in  the urine or serum by immunoelectrophoresis or in the serum  using enzyme-linked immunosorbent assay (ELISA). Usually  individuals with Bence Jones protein also have M protein in  their blood. However, variants of MM include individuals in  which free light chain only is produced and a rare variant that    FIGURE 29-16 M Protein. Serum protein electrophoresis (PEL) is used to screen for M proteins in multiple myeloma. A,  In normal serum the proteins separate into several regions between albumin (A/b) and a broad band in the gamma (y) region,  where most antibodies (gamma globulins) are found. Immunofixation (/FE) can identify the locations of IgG (G), IgA (A), IgM  (M), and kappa (K) and lambda (L) light chains. B, Serum from an individual with multiple myeloma contains a sharp M protein  (M spike). The M protein is monoclonal and contains only one heavy chain and one light chain. In this instance the IFE identi-  fies the M protein as an IgG containing a lambda light chain. €, Serum and urine protein electrophoretic patterns in a client  with multiple myeloma. Serum demonstrates an M protein (immunoglobulin) in the gamma region, and the urine has a large  amount of the smaller-sized light chains with only a small amount of the intact immunoglobulin. (A and B from Abeloff M  et al: Abeloff's clinical oncology, ed 4, Philadelphia, 2008, Churchill Livingstone. € from McPherson R, Pincus M: Henry’ clini-  cal diagnosis and management by laboratory methods, ed 22, Edinburgh, 2012, Saunders.)    FIGURE 29-17 Osteolytic Lesions in Individuals with Multiple Myeloma. A, Lesions in the skull on radiograph in a  client with myeloma. B, Roentgenogram of femur showing extensive bone destruction caused by tumor. Note absence of reac-  tive bone formation. (A from Abeloff M et al: Abe/offs clinical oncology, ed 4, Philadelphia, 2008, Churchill Livingstone. B from  Kissane JM, editor: Anderson's pathology, ed 9, St Louis, 1990, Mosby.)   *There are two categories for stage II: serum B-microglobulin <3.5 mg/L  but serum albumin <3.5 g/dl; or serum B2-microglobulin 3.5 to <5.5 mg/L  irrespective of the serum albumin level.    produces only free heavy chain, and approximately 1% are  nonsecretory so that neither an M protein nor Bence Jones pro-  tein is produced. The amount of M protein in the blood may be  used as a measure of the extent of the disease or as a measure  of response to therapy. The serum level of another protein, free  B2-microglobulin, is a useful indicator of prognosis or effec-  tiveness of therapy.   A bone marrow biopsy is performed to confirm the pres-  ence of myeloma cells in the marrow (Figure 29-18). Radio-  graphic studies include x-ray, CT scans, and magnetic  resonance imaging (MRI) to document the presence of bone  lesions and areas of destruction. Diagnosis is based on findings  and the degree of involvement. The individual must have all  three major criteria (Box 29-4); however, new more sensitive  and specific criteria have been proposed but not yet accepted  into practice.*?   Combinations of chemotherapy, radiation therapy, and  plasmapheresis (exchange), and marrow transplantation have  been the standards of treatment.** Conventional combina-  tions of chemotherapeutic agents have included melphalan and    prednisone (MP); MP with vincristine, carmustine, and cyclo-  phosphamide; vincristine, doxorubicin, and dexamethasone;  and thalidomide and dexamethasone. The drug thalidomide  disrupts the stromal marrow—MM cell interaction by modulat-  ing cell surface adhesion molecules and inhibiting angiogenesis.  In addition, it increases apoptosis and G, growth arrest (i.e., the  cell cycle gap 1; see Chapter 1) of MM cells.   Dose intensification improves the outcomes in younger cli-  ents; however, long-term remissions are obtained in a minor-  ity of clients. Thus intensive research measuring the effect of  novel new therapies is the objective of ongoing trials. Gene  expression profiling (GEP) helps improve the treatment of  MM because it identifies prognostic subgroups and defines the  molecular pathways associated with these subgroups. Newer  agents (e.g., bortezomib, lenalidomide) have broadened the  therapeutic regimens for end-stage myeloma. Lenalidomide is  related to thalidomide; however, it increases treatment efficacy  while avoiding the adverse effects associated with thalidomide.  In combination with dexamethasone, lenalidomide is now an  approved second-line treatment for MM.   High-dose chemotherapy followed by blood-forming stem  cell transplantation (SCT) has become standard treatment for  younger individuals (up to 70 years old in some trials).°**? Sur-  vival is increased with SCT compared with chemotherapy alone.  SCT uses the client’s own blood-forming stem cells (autolo-  gous) or a donor’s cells (allogeneic). Survival may be prolonged  by performing a second autologous transplant, called tandem  transplant, within 6 to 12 months from the first transplant.   Radiation with high-energy x-rays is used more for a local-  ized effect rather than systemic. It is most often used to treat  areas of the bone that have been damaged and are not respond-  ing to chemotherapy. In addition, it may be used to treat sites  where tumor has led to collapse of vertebrae and spinal cord  compression.    FIGURE 29-18 Myeloma Cells. The typical myeloma type has fairly mature-appearing plasma cells with eccentric nuclei  on bone marrow aspirate (A) and biopsy (B). €, Osteosclerotic myeloma in which the left side of the photograph shows bone  sclerosis and the marrow cavity replaced by myeloma. (From Hoffman R et al: Hematology: basic principles and practice, ed 6,   More than 30% plasma cells in bone marrow sample  Monoclonal antibody in blood/urine    Additional interventions are used to prevent and treat compli-  cations arising from progression of the disease. Drugs that inhibit  bone resorption—bisphosphonates—reduce the incidence of  skeletal damage, which also reduces hypercalcemia and decreases  bone pain. Hydration and diuretics may be used to maintain a  high urine output, and antibiotics to treat recurring infections.   The prognosis for persons with MM remains poor. The  median survival for all states of MM is 3 years. Individuals with  multiple bone lesions, if untreated, rarely survive more than 6  to 12 months. Individuals with inactive (indolent) myeloma,  however, can survive for many years. With chemotherapy and  aggressive management of complications, median survival may  increase to 24 to 30 months, with a 10-year survival rate of 3%.   Waldenstrém macroglobulinemia (WM), also called lympho-  plasmacytic lymphoma, is a rare type of slow-growing plasma  cell tumor that secretes a monoclonal IgM molecule. Approxi-  mately 1500 new cases are diagnosed yearly in the United  States; the median age of diagnosis is 63 years of age.‘* WM  shares a great deal of similarity with multiple myeloma regard-  ing its plasma cell origin, diagnosis, and treatment. However,  the overproduction of the macromolecule IgM leads to certain  unique clinical characteristics.   PATHOPHYSIOLOGY. WM arises from plasma cells that have  undergone genetic rearrangement of the variable region genes  (V, D, J), but have not undergone class-switch. Therefore, the  principal secretory product of the tumor is IgM. Although no  definitive genetic defect has been identified, WM may originate  from aberrant B-cell maturation and class-switch.    Most of the pathology is associated with the production of  large amounts of IgM, a high-molecular-weight protein (about  900,000 daltons). Excessive production leads to thickening of  the blood and abnormally high blood viscosity (hyperviscos-  ity syndrome). The increased viscosity interferes with circu-  lation to various sites (e.g., eyes, brain, kidneys, extremities).  IgM paraprotein may also result in cryoglobulins (proteins that  precipitate from the blood at lower than body temperature).  Hyperviscosity syndrome is observed in up to 20% of individu-  als with WM.   CLINICAL MANIFESTATIONS. Many clients with WM are asymp-  tomatic. The most common symptoms include weakness and  fatigue, bleeding (from gums and nose), weight loss, and bruis-  ing. Bleeding may result secondary to formation of complexes  among the macroglobulin, clotting factors, and platelets that  diminish hemostatic capacity. If hyperviscosity syndrome  occurs, the individual may develop neurologic problems (e.g.,  blurred vision, loss of vision, headaches, dizziness, vertigo). The  macromolecules may also precipitate in colder regions of the  body (cryoglobulins) leading to Raynaud phenomenon.   Although the malignant plasma cells invade the bone mar-  row, erosion of the bone is not commonly observed; less than  5% of individuals have lytic bone lesions. The tumor often dis-  seminates to other organs, including the spleen, lymph nodes,  and liver. Anemia occurs in about 10% of individuals, secondary  to tumor infiltration of the bone marrow. Peripheral hemolysis  can also result from production of cold agglutinins.   EVALUATION AND TREATMENT. Diagnosis is made on the basis of  high levels of monoclonal IgM in the blood and the identifica-  tion of malignant cells in bone marrow aspirates. Other hema-  tologic abnormalities may be observed, especially anemia (80%  of clients with symptomatic WM) but also thrombocytopenia  and leukopenia. Bence Jones protein may be observed in almost  half of individuals with WM.   Treatment is similar to that described for multiple  myeloma.’ First-line therapy includes combined chemo-  therapy with nucleoside analogs, alkylating agents, and mono-  clonal antibody (e.g., rituximab). Bone marrow stem cell  transplantation has also proven effective in some individu-  als. The current recommendations include treatment with a  combination of dexamethasone, rituximab, and cyclophos-  phamide, with the use of other drugs (e.g., doxorubicin, vin-  cristine, and nucleoside analogs) in individuals with very high  levels of M protein.    The spleen has been an organ of mystery and perplexity in the  study of medicine. Its relationship to other organs and disease  processes, particularly the immune and hematologic systems,  was not identified until the eighteenth century. The complexi-  ties of splenic function are not totally understood, and its mys-  teries are still being explored. The spleen is a useful organ, but  its functions overlap those of other organs so that one is capable  of living a normal, healthy life without the spleen. The relation-  ship between asplenia and a higher risk for infection was not  recognized until the early 1950s.   In the past, splenomegaly (enlargement of the spleen) was  associated with various disease states. It is now recognized that  splenomegaly is not necessarily pathologic; an enlarged spleen  may be present in certain individuals without any evidence of  disease. Splenomegaly may be, however, one of the first physi-  cal signs of underlying conditions, and its presence should not  be ignored. In conditions in which splenomegaly is present, the  normal functions of the spleen may become overactive, produc-  ing a condition known as hypersplenism.   Current criteria indicating the presence of hypersplenism  include: (1) cytopenias (anemia, leukopenia, thrombocytope-  nia, or combinations of these); (2) cellular bone marrow; (3)  splenomegaly; and (4) improvement after splenectomy. Some  individuals may seek treatment for problems even though they  have not met all these clinical criteria; therefore, the relevance  and significance of hypersplenism are still uncertain. Primary  hypersplenism is recognized when no etiologic factor has been  identified; secondary hypersplenism occurs in the presence of  another condition.   PATHOPHYSIOLOGY. Splenomegaly without a specific etiol-  ogy is seen in 7% to 15% of individuals who are being evalu-  ated for primary splenomegaly and is generally a diagnosis  of exclusion. Specific conditions causing secondary spleno-  megaly and resulting hypersplenism are many and are related  to all other categories of disease that affect individuals. Sec-  ondary splenomegaly may be classified according to the  underlying cause. Specific conditions related to these various  classifications of splenomegaly are detailed in Box 29-5. Dif-  ferent pathologic processes that produce splenomegaly are  described briefly.   Acute inflammatory or infectious processes cause spleno-  megaly because of an increased demand for defensive activities.  Acutely enlarged spleens secondary to infection may become so  filled with erythrocytes that their natural rubbery resilience is  lost and they become fragile and vulnerable to blunt trauma.  Splenic rupture is a complication associated with infectious  mononucleosis; rupture occurs mostly in males between the  fourth and twenty-first day of acute illness.   Congestive splenomegaly is accompanied by ascites, portal  hypertension, and esophageal varices and is most commonly  seen in those with hepatic cirrhosis. Splenic hyperplasia devel-  ops in disorders that increase splenic workload and is associ-  ated most commonly with various types of anemia (hemolytic)  and chronic myeloproliferative disorders (i.e., polycythemia  vera).   Acute: viral (hepatitis, infectious mononucleosis, cytomegalovirus), bacterial  (Salmonella, gram negative), parasitic (typhoid)   Subacute or chronic: bacterial (subacute bacterial endocarditis, tuberculosis),  parasitic (malaria), fungal (histoplasmosis), Felty syndrome, systemic lupus  erythematosus, rheumatoid arthritis, thrombocytopenia    Cirrhosis, heart failure, portal vein obstruction (portal hypertension), splenic  vein obstruction   Malignant: polycythemia vera, chronic or acute leukemias, Hodgkin lymphoma,  metastatic solid tumors   Cysts: true cysts (lymphangiomas, hemangiomas, epithelial, endothelial); false  cysts (hemorrhagic, serous, inflammatory)    Infiltrative splenomegaly is caused by engorgement by the  macrophages with indigestible materials associated with vari-  ous “storage diseases.” Tumors and cysts cause actual growth  of the spleen. Metastatic tumors in the spleen are rare and may  result from primary tumors of the skin, lung, breast, and cervix.   CLINICAL MANIFESTATIONS. Overactivity of the spleen results  in hematologic alterations that affect all blood components.  Sequestering of red blood cells, granulocytes, and platelets  results in a reduction of all circulating blood cells. The spleen  may sequester up to 50% of the red blood cell population,  thereby upsetting the normal physiologic concentration of  red blood cells in the circulation. The rate of splenic pooling is  directly related to spleen size and the degree of increased blood  flow through it. Sequestering exposes the red blood cells to  splenic conditions that accelerate destruction, further contrib-  uting to the decreased red blood cell concentration. Anemia is  the result of these combined activities. Anemia may be further  potentiated by an increase in blood volume, which produces a  dilutional effect on the already reduced concentration of red  blood cells. The dilutional effect, as well as the removal and  destruction of red blood cells, depends primarily on the degree  of splenomegaly.   White blood cells and platelets also are affected by seques-  tering, although not to the same degree as the red blood cell.  Again, the size of the spleen is the determining factor in the  number of cells sequestered.   EVALUATION AND TREATMENT. Treatment for hypersplenism is  splenectomy; however, it is not always the treatment of choice.  A splenectomy should be performed when its removal is con-  sidered necessary to alleviate the destructive effects on red blood  cells. Clinical indicators should determine the need for splenec-  tomy, not necessarily the specific condition. Splenectomy for  splenic rupture no longer is considered mandatory in light of    the possibility of overwhelming sepsis after removal. Repair and  preservation of the ruptured spleen are now considered before  the decision to remove the spleen. Splenectomy also may be  performed as treatment for hairy cell leukemia, Felty syndrome,  agnogenic myeloid metaplasia, thalassemia major, Gaucher dis-  ease, hemodialysis, splenomegaly, splenic venous thrombosis,  and thrombotic thrombocytopenic purpura (TTP).   Individuals are able to lead normal lives after splenectomy,  but hematologic abnormalities often exist after removal of the  spleen. The red blood cells become thinner, broader, and wrin-  kled as a result of increases in surface area and membrane lipids.  The white blood cell count increases dramatically 1 week after  removal and then stabilizes to approximately 40% greater than  normal. Platelet numbers also rise immediately after surgery  and then equilibrate to above-normal levels for the duration of  the individual’s life. Increased platelet levels have been impli-  cated in ischemic heart disease in males because of increased  thrombocytosis and hypercoagulability.   A major postoperative complication following splenectomy  is overwhelming post-splenectomy infection (OPSI). Unless  treated in time, OPSI may rapidly progress to septic shock and  possibly disseminated intravascular coagulation (DIC). Initial  statistics indicate a death rate of 50% to 70%, with most deaths  occurring within the first 48 hours after hospitalization. Prompt  medical attention can reduce the death rate to 10%.    Hemostasis is dependent on adequate numbers of platelets  and levels of coagulation factors. Diminished or excessive  levels may lead to defective hemostasis or spontaneous and  unnecessary activation of clotting. (Hemostasis is described in  Chapter 27.) Diminished hemostasis results in either internal  or external hemorrhage. Diffuse hemorrhage into skin tissues  that is visible through the skin causes a red-purple discolor-  ation identified as a purpura. Purpuric disorders occur when  there are not enough normal platelets to plug damaged vessels  or prevent leakage from the many minute tears that occur daily  in normal capillaries. Disorders of the clotting system tend to  result in more serious internal bleeding than platelet defects  and usually are caused by a deficiency of one or several clot-  ting factors. Disorders that result in spontaneous clotting can  result from genetic disorders of clotting system components or  from acquired diseases that activate clotting. These disorders  are known collectively as thromboembolic disease.    Quantitative or qualitative abnormalities of platelets can inter-  rupt normal blood coagulation and prevent hemostasis.*° The  quantitative abnormalities are thrombocytopenia, a decrease in  the number of circulating platelets, and thrombocythemia, an  increase in the number of platelets. Qualitative disorders affect  the structure or function of individual platelets and can coex-  ist with the quantitative disorders. Qualitative disorders usually  prevent platelet adherence and aggregation, preventing forma-  tion of a platelet plug.   Thrombocytopenia is defined as a platelet count less than  150,000 platelets/uL of blood, although most healthcare pro-  viders do not consider the decrease of significance unless the  count falls to less than 100,000 platelets/uL of blood.*” Hemor-  rhage resulting from minor trauma does not usually occur until  the count falls below 50,000/pL. Spontaneous bleeding without  apparent trauma can occur with counts between 10,000 and  15,000/uL, resulting in petechiae, ecchymoses, larger purpuric  spots, or frank bleeding from mucous membranes. Severe spon-  taneous bleeding may result if the count is less than 10,000/pL  and can be fatal if it occurs in the gastrointestinal tract, respira-  tory system, or CNS.   Before the diagnosis of thrombocytopenia is made, pseu-  dothrombocytopenia must be ruled out. This phenomenon  occurs in approximately 1 in 1000 to 1 in 10,000 laboratory  samples and is an in vitro artifact that may occur when a blood  sample is analyzed by an automated cell counter. Platelets in  the sample may become nonspecifically agglutinated by immu-  noglobulins in the presence of ethylenediaminetetraacetic acid  (EDTA), a preservative in banked blood. The agglutinated  platelets are not counted, thus giving an apparent, but false,  thrombocytopenia. Thrombocytopenia also may be falsely  diagnosed because of a dilutional effect observed after massive  transfusion of platelet-poor packed cells to treat a hemorrhage.  This occurs when more than 10 units of blood have been trans-  fused within a 24-hour period. The hemorrhage that necessi-  tated the transfusion also accelerates the loss of platelets, which  further contributes to the pseudothrombocytopenic state.  Splenic sequestering of platelets secondary to hypersplenism  (congestive) induces an apparent thrombocytopenia, as does  hypothermia (less than 25° C [77° F]), which is reversed when  temperatures return to normal, suggesting an increased platelet  sequestration in response to chilling.   PATHOPHYSIOLOGY. Thrombocytopenia results from decreased  platelet production, increased consumption, or both. The  condition also may be congenital or acquired and primary or  secondary to other acquired or congenital conditions. Throm-  bocytopenia secondary to congenital conditions occurs in a  large number of different diseases, although each is relatively  rare. These include thrombocytopenia with absence of radius  (TAR) syndrome, Wiskott-Aldrich syndrome (see Chapter  9), various forms of MYH9 gene mutation (e.g., May-Hegglin  syndrome), X-linked thrombocytopenia, and many other  examples.   Acquired thrombocytopenia is more common and may  occur as a result of decreased platelet production secondary  to viral infections (e.g., EBV, rubella, CMV, HIV), drugs (e.g.,  thiazides, estrogens, quinine-containing medications, chemo-  therapeutic agents, ethanol), nutritional deficiencies (vitamin  B,. or folic acid in particular), chronic renal failure, bone  marrow hypoplasia (e.g., aplastic anemia), radiation therapy,  or bone marrow infiltration by cancer. Most common forms  of thrombocytopenia are the result of increased platelet con-  sumption. Examples include heparin-induced thrombocyto-  penia, idiopathic (immune) thrombocytopenic purpura, and  thrombotic thrombocytopenic purpura.    Heparin-Induced Thrombocytopenia. Heparin is a common  cause of drug-induced thrombocytopenia. Approximately 4%  of individuals treated with unfractionated heparin develop  heparin-induced thrombocytopenia (HIT). The incidence  is lower (about 0.1%) with the use of low-molecular-weight  heparin. HIT is an immune-mediated, adverse drug reaction  caused by IgG antibodies against the heparin—platelet factor 4  complex leading to platelet activation through platelet FcyIa  receptors (Figure 29-19).4° The release of additional platelet  factor 4 from activated platelets and activation of thrombin lead  to increased platelet consumption and a decrease in platelet  counts beginning 5 to 10 days after administration of heparin.   CLINICAL MANIFESTATIONS. The hallmark of HIT is thrombocy-  topenia. A decrease of approximately 50% in the platelet count  is seen in more than 95% of individuals. However, 30% or more  of those with thrombocytopenia are also at risk for venous or  arterial thrombosis.** Venous thrombosis is most common and  results in deep venous thrombosis and pulmonary emboli. Arte-  rial thromboses affect the large arteries of the lower extremi-  ties, causing acute limb ischemia. Arterial thrombosis also may  lead to cerebrovascular accidents and myocardial infarctions.  Other major arteries (renal, mesenteric, upper limb) also may  be affected. Bleeding is uncommon in HIT, even with low plate-  let counts.   EVALUATION AND TREATMENT. Diagnosis is primarily based on  clinical observations.*® The individual presents with dropping  platelet counts after 5 days or longer of heparin treatment.  On average, platelet counts may reach 60,000/mm+>. Because    most individuals develop this condition after surgery, and the  onset of symptoms, including thrombosis, may be delayed  until after release from the hospital, other possible causes of  thrombocytopenia (e.g., infection, other drug reactions) must  be considered.   Tests are available to measure antibodies against heparin—  platelet factor 4.*° The test sensitivity is extremely high (more  than 90%), but the specificity is less because of false-positive  reactions (e.g., persons receiving dialysis). HIT antibody titers  may be measured, but the titers must be evaluated in the con-  text of the clinical presentation. If HIT is not recognized and  treated, intravascular aggregation of platelets causes rapid  development of arterial and venous thrombosis. Although rare,  heparin antibodies have caused anaphylactic shock.   Treatment is the withdrawal of heparin and use of alterna-  tive anticoagulants. A switch to low-molecular-weight hepa-  rin is not indicated, and warfarin should not be used until  the symptoms of HIT have resolved because of an increased  risk of initiating skin necrosis. The thrombocytopenia should  progressively resolve. The chance of spontaneous blood clots  can be diminished using thrombin inhibitors (e.g., lepirudin,  argatroban).**   Immune Thrombocytopenic Purpura. The most common  cause of thrombocytopenia secondary to increased platelet  destruction is immune thrombocytopenic purpura (ITP). The  incidence of ITP is estimated to be 5.8 to 6.6 per 100,000 in  the general population. ITP was formerly known as idiopathic  thrombocytopenic purpura; however, it is widely recognized    FIGURE 29-19 Pathogenesis of Heparin-Induced Thrombocytopenia (HIT). (1) Activated platelets release proco-  agulant proteins from c-granules, including platelet factor 4 (PF4). Administered heparin binds PF4 (2), which undergoes a  conformational change and expresses a new antigen (neoepitope). Individuals with HIT produce an immunoglobulin G (IgG)  antibody that specifically reacts (3) with multiple identical neoepitopes on the heparin-PF4 complex. The reaction forms  heparin-PF4-IgG immune complexes. Platelets express FcyRlla receptors (Fey receptor) that react (4) with the Fe portion of  IgG in immune complexes. Cross-linking of Fc receptors (5) results in FeyRlla-dependent platelet activation. The activated  platelets mediate a series of events that lead to further activation of the coagulation cascade, resulting in thrombin genera-  tion. Further release of PF4 from newly activated platelets leads to a cycle of continuing platelet activation and (6) formation  of a primary clot. The reaction can be enhanced by the release of platelet-derived microparticles that are rich in surface  phosphatidylserine and increase activation of coagulation, and by the binding of heparin-PF4 complexes and HIT-IgG to the    now as an immune process, hence the change from idiopathic  to immune.*” ITP may be acute or chronic. The acute form is  frequently observed in children and typically lasts 1 to 2 months  with a complete remission. In some instances it may last for  up to 6 months, and some children (7% to 28%) may progress  to the chronic condition. Acute ITP is usually secondary to  infections (particularly viral) or other conditions that lead to  large amounts of antigen in the blood, such as drug allergies  or systemic lupus erythematosus (SLE) (see Chapter 9). Under  these conditions the antigen usually forms immune complexes  with circulating antibody, and it is thought that the immune  complexes bind to Fc receptors on platelets, leading to their  destruction in the spleen. The acute form of ITP usually resolves  as the source of antigen is removed (e.g., the viral infection  resolves).   Chronic ITP is associated with autoantibodies against plate-  let-specific antigens. This form is more commonly observed in  adults, with highest prevalence in women between 20 and 40  years old, although it can develop at most any age. The chronic  form tends to get progressively worse.   The autoantibodies are generally of the IgG class, although  IgA and IgM antibodies also have been identified. They react  against one or more of several platelet glycoproteins (e.g.,  GPIIb-II]a, GPIb-IX, GPlIa-IIa) (see Chapter 27).°! The anti-  body-coated platelets are removed from the circulation by  mononuclear phagocytes in the spleen through the Fc receptor.   CLINICAL MANIFESTATIONS. Initial manifestations are usually  minor bleeding problems (development of petechiae and pur-  pura) over the course of several days that progress to major  hemorrhage from mucosal sites (epistaxis, hematuria, menor-  rhagia, bleeding gums). Rarely will an individual present with  intracranial bleeding or internal bleeding at other sites.   During pregnancy, an individual with ITP may have a new-  born that is also thrombocytopenic. In most individuals the  antiplatelet antibody is an IgG that readily crosses the placenta  (see Chapters 8 and 9). If the fetal platelets express the same  antigen as the mother, the maternal antibody will coat the  platelets, potentially resulting in thrombocytopenia in utero.  A variant of neonatal thrombocytopenia (neonatal alloim-  mune thrombocytopenia) occurs when the mother does not  have ITP, but makes IgG antibodies against an antigen inher-  ited from the father and found on fetal platelets but not on  maternal platelets.°* Alloimmune neonatal thrombocytopenia  occurs in 1 of 2000 pregnancies. The most common antibody  in this condition is against the human platelet antigen-a (HPA-  a) antigen on the GPIIIa protein. Neonatal thrombocytopenia,  either secondary to maternal autoimmune thrombocytopenia  or as alloimmune thrombocytopenia, may occur to various  degrees. The most severe form results in fetal platelet counts  below 20,000/mm? with a high associated risk of intracranial  hemorrhage.   EVALUATION AND TREATMENT. Diagnosis of ITP is based on a  history of bleeding and associated symptoms, such as weight  loss, fever, and headache. Physical examination includes nota-  tions on the types of bleeding, location, and severity. Evidence  of infections (bacterial, HIV, and other viral), medication  history, family history, and evidence of thrombosis are also    assessed. Other diagnostic tests include complete blood count  (CBC) and peripheral blood smear. Unlike some other forms  of thrombocytopenia, splenectomy is rarely observed. Test-  ing for antiplatelet antibodies is usually not helpful. Although  most cases of ITP are associated with elevated levels of IgG on  platelets, other forms of thrombocytopenia also have a high  incidence of platelet-associated antibodies; thus the specificity  is low (50% to 65%).°° In addition, some cases of ITP will not  present with elevated platelet-associated antibodies; the sensi-  tivity is 75% to 94%, so that a negative test does not completely  rule out ITP.   The acute form of ITP usually resolves without major clini-  cal consequences. As with most autoimmune diseases, the  course of the chronic form is variable, with multiple remissions  and exacerbations. For many individuals the platelet count  may remain adequate enough to avoid clinically serious bleed-  ing. However, the presence of spontaneous bleeding suggests  more severe disease and requires immediate attention. Treat-  ment is initiated when platelet counts are less than 30,000/uL  or less than 50,000/uL with evidence of bleeding from mucous  membranes or when the individual is at high risk to develop  bleeding.   Treatment is palliative, not curative, focusing on prevention  of platelet destruction. Initial therapy for ITP is infusion of glu-  cocorticoids (e.g., prednisone), which suppresses the produc-  tion of antiplatelet antibodies and prevents sequestering and  further destruction of platelets. If platelet counts do not increase  appropriately, other medications, such as prednisone, may be  tried. Treatment with intravenous immunoglobulin (IVIG) is  used to prevent major bleeding. The response rate is 80%, but  the effects are transient, lasting only days or a few weeks. Anti-  (Rh,)D (RhoGAM), which is a preparation of antibody against  the D antigen of the Rh blood group, has been used with limited  success to treat individuals who are Rh-positive.   Newer treatments include romiplostim (trade name Nplate)  and eltrombopag (trade name Promacta in the United States,  Revolade in the European Union). Both drugs are thrombo-  poiesis—stimulating Fc-peptide fusion proteins (peptibody).  Romiplostim is administered subcutaneously and eltrom-  bopag is taken orally. These drugs increase platelet counts and  decrease bleeding. Romiplostim is often used as a second-line  treatment after IVIG or in individuals who experience relapse  post-splenectomy.   If all other therapies are ineffective, splenectomy is consid-  ered to remove the primary site of platelet destruction.°* The  response rate (resolution of the thrombocytopenia) is 60% to  70%; however, the procedure is not without risk. Approxi-  mately 10% to 20% of individuals who undergo splenectomy  suffer a relapse and require further treatment. It is thought  that other reticuloendothelial organs, particularly the liver, can  become major sites for platelet destruction. If splenectomy is  unsuccessful and life-threatening thrombocytopenia persists,  more aggressive immunosuppressive medications (e.g., azathi-  oprine, cyclophosphamide) may be used. Because of potential  major complications, these medications are reserved for indi-  viduals who are severely thrombocytopenic and refractive to  other therapies.    Thrombotic Thrombocytopenic Purpura. Thrombotic  thrombocytopenic purpura (TTP) is characterized by  thrombotic microangiopathy in which platelets aggregate  and cause occlusion of arterioles and capillaries within the  microcirculation.°° Aggregation may lead to increased platelet  consumption and organ ischemia. TTP is relatively uncommon,  occurring in about 5 per 1 million individuals per year. The  incidence is increasing, which appears to be an actual increase  in the number of affected individuals rather than a result of  improved recognition. There are two forms of TTP: familial  or acquired idiopathic. The familial form is the more rare and  is usually chronic, relapsing, and seen in children. The child  experiences predictable recurring episodes at approximately  3-week intervals and is responsive to treatment. Acquired TTP  is more common, as well as more acute and severe. It occurs  mostly in females in their thirties and is rarely observed in  infants or older adults.   Platelet aggregation and microthrombi formation are found  throughout the entire vascular system, causing damage to mul-  tiple organs. Organs most susceptible to damage are the kidney,  brain, and heart. Other organs often affected are the pancreas,  spleen, and adrenal glands. The thrombi are primarily composed  of platelets with minimal fibrin and red cells, differentiating them  from thrombi secondary to intravascular coagulation. Most  cases of TTP are related to a dysfunction of the plasma metal-  loprotease ADAMTS13. This enzyme is responsible for digest-  ing large precursor molecules of von Willebrand factor (vWF)  produced by endothelial cells into smaller molecules. Defects in  ADAMTS13 result in expression of large-molecular-weight VWF  on the endothelial cell surface and the formation of large aggre-  gates of platelets. The aggregates may break off and form occlu-  sions in smaller vessels. Most individuals with TTP (about 80%)  have less than 5% of normal plasma ADAMTS13 levels. TTP  also is commonly associated with an IgG autoantibody against  ADAMTS13 that is able to neutralize the enzyme’s activity and  accelerate its clearance from the plasma.   CLINICAL MANIFESTATIONS. The rare familial chronic relapsing  TTP observed in children is usually recognized and successfully  treated. The acquired acute idiopathic TTP is much more com-  mon and more severe.°° Early diagnosis and treatment is impor-  tant because the disease may be fatal within 90 days of onset.  TTP is clinically related to and must be distinguished from other  thrombotic microangiopathic conditions, including hemolytic  uremic syndrome, malignant hypertension, preeclampsia, or the  pregnancy-induced HELLP (hemolysis, elevated liver enzymes,  low platelet count) syndrome. Hemolytic uremic syndrome  (HUS) shares many of the clinical characteristics of TTP; how-  ever, HUS often follows a hemorrhagic, diarrheal illness.   EVALUATION AND TREATMENT. Acute idiopathic TTP is charac-  terized by a “pathognomonic pentad” of symptoms. However,  only 20% to 30% of people present with the classic pentad.  These include extreme thrombocytopenia (less than 20,000  platelets/uL), intravascular hemolytic anemia, ischemic signs  and symptoms most often involving the CNS (about 65%  present with memory disturbances, behavioral irregulari-  ties, headaches, or coma), kidney failure (affecting about 65%  of individuals), and fever (present in about 33%).*° It is not    mandatory that all five be present to begin treatment. A routine  blood smear usually reveals fragmented red cells (schizocytes)  produced by shear forces when red cells are in contact with the  fibrin mesh in clots that form in the vessels. As a result of tis-  sue injury, serum levels of lactate dehydrogenase (LDH) may  be very high, and low-density lipoprotein (LDL) levels may be  elevated. Tests for antibody on red cells are negative, excluding  immune hemolytic anemia.   Untreated acute TTP has a death rate of 90%, which can  be reduced to 10% to 20% with prompt treatment. Plasma  exchange with fresh frozen plasma replenishes functional  ADAMTS13 and is the treatment of choice, achieving a response  rate of 70% to 85%. Additionally, steroids (glucocorticoids)  are administered. In the absence of major organ damage, this  approach may lead to complete recovery with no long-term  complications. The anti-CD20 monocolonal antibody ritux-  imab has shown some activity in people who are refractory to  plasma exchange.”° Relapses do occur at a rate of 13% to 36%,  and recurrences have been reported, some as long as 9 years  after the initial treatment. Individuals who do not respond to  conventional treatment may be candidates for splenectomy;  however, postoperative hemorrhage remains a dangerous com-  plication. Immunosuppressive (azathioprine) therapy has been  successful in some individuals.   Thrombocythemia (also called thrombocytosis) is defined as  a platelet count greater than 400,000/pL of blood.°”? Thrombo-  cythemia may be primary or secondary (reactive) and is usually  asymptomatic until the count exceeds 1 million/mm* of blood.  Then intravascular clot formation (thrombosis), hemorrhage,  or other abnormalities can occur.   PATHOPHYSIOLOGY. Secondary thrombocythemia may occur  after splenectomy because platelets that normally would be  stored in the spleen remain in circulating blood. The increase  in the number of platelets may be gradual, with thrombocythe-  mia not occurring for up to 3 weeks after splenectomy. Reactive  thrombocythemia may occur during some inflammatory condi-  tions, such as rheumatoid arthritis and cancers. In these condi-  tions, excessive production of some cytokines (e.g., IL-6, IL-11)  may induce increased production of thrombopoietin in the liver,  resulting in increased megakaryocyte proliferation. Reactive  thrombocythemia may also occur during a variety of physiologic  conditions, such as after exercise. Because of the relatively self-  resolving nature of secondary thrombocythemia, the remaining  discussion will focus on the more severe primary form.   Essential (primary) thrombocythemia (ET) is a chronic  myeloproliferative disorder characterized by excessive plate-  let production resulting from a defect in bone marrow mega-  karyocyte progenitor cells.°* The overall incidence of ET is 0.8  per 100,000 in the United Kingdom, 2.53 in the United States,  and 0.59 in Denmark. It is more common in middle-age indi-  viduals, with the majority of cases occurring between ages 50  and 60 years. There is no known gender preference. There also  is a rare hereditary type of ET called familial essential throm-  bocythemia (FET) that is inherited in an autosomal dominant  pattern.    The thrombocythemia is secondary to increased plasma  thrombopoietin levels resulting from defects in the throm-  bopoietin receptor. The defective receptor cannot adequately  bind and remove thrombopoietin from the blood, thus circu-  lating levels remain high. Along with increased platelet levels,  there may be a concomitant increase in red blood cells (RBCs),  indicating a myeloproliferative disorder; however, the increase  in red cells is not to the extent seen in polycythemia vera (see  Chapter 28). The bone marrow of affected individuals with ET  is characterized by hyperplasia of megakaryocytes. The platelets  of affected individuals appear to have a normal survival time,  compatible with a defect in production rather than an increase  in platelet life span.   RBCs in ET tend to aggregate and contribute to the block-  age of flow in the microvasculature and altered interactions  between platelets and the vascular endothelium.*? Increased  adherence of erythrocytes to the endothelium appears to result  from a mutation in an erythrocyte Janus kinase 2 (JAK2) that is  responsible for phosphorylation of the erythrocyte receptor for  endothelial laminin.©°°! The frequency of JAK2 mutations in  ET is about 30%. Increased platelet aggregation arises from sev-  eral mutations that result in altered platelet membrane glyco-  proteins, particularly resulting in increased expression of GPIV,  and increased secretion of thromboxane.   CLINICAL MANIFESTATIONS. Clinical manifestations vary sig-  nificantly among individuals. Those with ET are at risk for  large-vessel arterial or venous thrombosis, although the most  common complication is microvasculature thrombosis leading  to ischemia in the fingers, toes, or cerebrovascular regions.’ The  primary presenting symptoms of microvasculature thrombosis  are erythromyalgia, headache, and paresthesias. Erythromyalgia  is characterized by unilateral or bilateral warm, congested, red  hands and feet with painful burning sensations, particularly in  the forefoot sole and one or more toes. The lower extremities  are affected more often, and only one side may be involved. The  pain is initiated by standing, exercise, or warmth and relieved by  elevation and cooling. In extreme situations, acrocyanosis and  gangrene may result.   Arterial thrombosis is more common than venous thrombo-  sis and may involve the coronary and renal arteries. The carotid,  mesenteric, and subclavian arteries also may be affected. Myo-  cardial ischemia and infarction have occurred without clear evi-  dence of coronary artery disease. Deep venous thrombosis of the  lower extremities and pulmonary embolism are the major sites  for venous involvement. Intra-abdominal venous thrombosis of  the portal and hepatic veins also is common. People older than  60 years of age or those with prior history of thrombotic events  have as much as a 25% chance of developing a cerebral, cardiac,  or peripheral arterial thrombus. Conversion to acute leukemia  is found in less than 10%.   Microvascular thrombosis in the CNS is usually associated  with headache and dizziness, with paresthesias, transient isch-  emic attacks, strokes, visual disturbances, and seizures also  being reported. Major thrombotic events, not directly related  to the platelet count, occur in about 20% to 30% of individu-  als with ET. Prior history of thrombotic events, advanced  age, and duration of thrombocytosis are predictors of future    thrombotic complications. Individuals older than age 60 are at  greatest risk.   Although thrombosis is the most common symptom, hem-  orrhage can also occur. Sites for bleeding include the gastro-  intestinal (GI) tract, skin, mucous membranes, urinary tract,  gums, tooth sockets (after extraction), joints, eyes, and brain.  GI bleeding may be mistaken for a duodenal ulcer. Hemor-  rhage is not severe, and generally occurs in the presence of  very high platelet counts, and occasionally requires transfu-  sion. Important is recognition that bleeding and clotting may  exist simultaneously and individuals will not necessarily be  “bleeders” or “clotters.”   EVALUATION AND TREATMENT. Initial diagnosis is not difficult; as  many as two thirds of affected individuals are diagnosed from  a routine complete blood count (CBC). Secondary thrombo-  cytosis may present as a moderate rise in the platelet count  that resolves with treatment or resolution of the underlying  condition. The World Health Organization (WHO) criteria  for the diagnosis of ET require the following four conditions  be met: (1) sustained platelet count of at least 450,000/uL; (2)  bone marrow biopsy showing proliferation of enlarged mature  megakaryocytes and no increase of granulocyte or erythocyte  precursors; (3) failure to meet the criteria of polycythemia vera,  myelofibrosis, CML, or other myelodysplastic syndrome; and  (4) the presence of JAK2 617F or another clonal marker or evi-  dence of reactive thrombocytosis.°   After diagnosis, these individuals may recall events related to  thrombosis or hemorrhage. Manifestations of ET may be mis-  taken for CML; therefore, differentiation of the two is impor-  tant because treatment varies significantly. Identification of the  Philadelphia chromosome is recommended in all cases of ET.   Treatment of ET is directed toward preventing thrombosis  or hemorrhage.” The importance of reducing the platelet count  remains a significant treatment issue. Historically, treatment of  ET relied on the use of alkylating agents (busulfan) or radio-  phosphorus (*?P) to suppress platelet production. Hydroxy-  urea, a nonalkylating myelosuppressive agent, has been the drug  of choice to suppress platelet production: however, long-term  use may cause progression to other myelodysplastic disorders,  particularly AML or myelofibrosis.°! Conversion to myelofi-  brosis occurs approximately 8% of the time and conversion to  AML occurs approximately 3.5% of the time when treated with  hydroxyurea as a single cytotoxic agent, but increases to 14%  when more than one cytotoxic agent is used.   Interferon (IFN) also may be used and has a response rate of  80%. IFN may not be effective for everyone because it has many  side effects and 20% of individuals may be intolerant. Anagrelide  is now considered to be the drug of choice. Anagrelide specifi-  cally interferes with platelet maturation rather than production,  thus not affecting erythropoiesis or leukopoiesis.   Aspirin also is used in the treatment of ET; however, its  action is not to reduce the platelet count but to prevent adher-  ence of platelets to each other and prevent thrombus forma-  tion. Early studies with aspirin found hemorrhage to be a major  contraindication for its use; however, in lower doses (80 to 160  mg/daily) it effectively alleviates erythromyalgia and transient  neurologic manifestations.    Prognosis and survival of individuals with ET have been  somewhat difficult to establish. ET is not necessarily considered  life threatening, but in those older than age 60 and who have a  history of previous incidences of thrombosis, complications are  more common and have a higher risk of mortality.    Qualitative alterations in platelet function occur with an  increased bleeding time in the presence of a normal platelet  count. Associated clinical manifestations include spontaneous  petechiae and purpura, as well as bleeding from the GI tract,  genitourinary tract, pulmonary mucosa, and gums. Congenital  alterations in platelet function (thrombocytopathies) are quite  rare and may be categorized into several types of disorders: (1)  platelet—vessel wall adhesion, (2) platelet-platelet interactions,  (3) platelet granules and secretion, (4) arachidonic acid path-  ways, and (5) membrane phospholipid regulation (coagulation  protein—platelet interactions).   Disorders of platelet-vascular wall adhesion result from  aberrations of the platelet membrane glycoprotein GPIb-IX-V  complex (Bernard-Soulier syndrome) or the collagen receptor  GPVI, or deficiencies of VWF. The GPIb protein is the most  commonly mutated in individuals with Bernard-Soulier syn-  drome. Lack of these proteins prevents platelets from adher-  ing to collagen, resulting in impaired hemostasis and clinical  hemorrhage.   Disorders of platelet-platelet interactions result in failure  of platelets to aggregate in response to adenosine diphos-  phate (ADP), collagen, epinephrine, or thrombin because of  a deficiency in the glycoprotein (alIb§3) that acts as a recep-  tor for fibrinogen, vWF, and fibronectin (Glanzmann throm-  basthenia). Lack of this protein results in a failure to build  “fibrinogen bridges” between platelets (see Figure 27-20).  Defects also can occur in platelet receptors for platelet acti-  vators. These include mutations in the receptors for throm-  boxane or ADP.   Disorders of platelet granules and secretion and arachidonic  pathways are characterized by initial normal platelet aggregation  with collagen or ADP; however, there is failure of subsequent  processes, specifically secretion of prostaglandins and release of  granules. Defective «-granule numbers or release (gray platelet  syndrome) results from mutations in several aspects of granule  function, including biosynthesis or loading of proteins normally  found in these granules. Defects in dense granules include Her-  mansky-Pudlak syndrome, Chédiak-Higashi syndrome, and  delta-storage pool disease. These usually result from mutations  in proteins involved in formation of dense granules or their  movement to the plasma membrane. Defects in the thrombox-  ane pathway prevent the release of this mediator.   Externalization of plasma membrane phosphatidylserine  (PS) is necessary for effective platelet function. In Scott syn-  drome, the enzyme responsible for PS efflux is defective; thus  platelets are unable to support the activation of factor X and  prothrombin. The reverse of Scott syndrome is Stormorken  syndrome, in which platelets constitutively externalize PS.   Acquired disorders of platelet function are more common  than the congenital disorders and may be categorized into three    principal causes: (1) drug effects, (2) systemic inflammatory  conditions, and (3) hematologic conditions.   Multiple drugs are known to affect platelet function in sev-  eral ways: inhibition of platelet membrane receptors, inhibition  of prostaglandin pathways, and inhibition of phosphodiesterase  activity. Aspirin is the most commonly used drug that affects  platelets and the only drug specifically used for its platelet effects.  It irreversibly inhibits cyclooxygenase function for several days  after administration. Nonsteroidal anti-inflammatory drugs  also affect cyclooxygenase, although in a reversible fashion.   Systemic disorders that affect platelet function are chronic  renal disease, liver disease, cardiopulmonary bypass surgery,  severe deficiencies of iron or folate, and the presence of anti-  platelet antibodies associated with autoimmune disorders.  Hematologic disorders that cause platelet dysfunction are  chronic myeloproliferative disorders, multiple myeloma, leu-  kemias, myelodysplastic syndromes, and dysproteinemias.    Disorders of coagulation usually are caused by defects or defi-  ciencies of one or more of the clotting factors. (Normal function  of the clotting factors is described in Chapter 27.) Qualitative or  quantitative abnormalities of clotting factors interfere with or  prevent the enzymatic reactions that transform circulating clot-  ting proteins into a stable fibrin clot (see Figure 27-22).   Some clotting factor defects are inherited and usually involve  a single factor, such as hemophilias and von Willebrand disease,  caused by deficiencies of specific clotting factors (see Chapter  30). Other coagulation defects are acquired and tend to result  from deficient synthesis of clotting factors by the liver. Causes  include liver disease and dietary deficiency of vitamin K.   Other coagulation disorders are attributed to pathologic  conditions that trigger coagulation inappropriately. For exam-  ple, any cardiovascular abnormality that alters normal blood  flow by acceleration, deceleration, or obstruction can result in  spontaneous coagulation within the vessels. Coagulation is also  stimulated by the presence of tissue factor, which is released  by damaged or dead tissues. Vasculitis, or inflammation of  the blood vessels, as well as vessel damage, activates platelets,  which in turn activates the coagulation cascade. In extensive or  prolonged vasculitis, blood clot formation can suppress mech-  anisms that normally control clot formation and breakdown,  leading to clogging of the vessels. In each of these acquired con-  ditions, normal hemostatic function proves detrimental to the  body by consuming coagulation factors excessively or by over-  whelming the normal control of clot formation and breakdown  (fibrinolysis).   Impaired hemostasis, or the inability to promote coagulation  and the development ofa stable fibrin clot, is commonly associ-  ated with liver disorders, either from the lack of vitamin K or  from specific diseases of the liver.   Vitamin K Deficiency. Vitamin K, a fat-soluble vitamin,  is necessary for synthesis and regulation of prothrombin,  procoagulant factors (VII, IX, X), and anticoagulant  regulators (proteins C and S) within the liver.°° The primary    dietary source of vitamin K is green, leafy vegetables. Vitamin  K also is synthesized by intestinal flora, but its contribution  to the overall supply of vitamin K is uncertain. The most  common cause of vitamin K deficiency is the use of parenteral  nutrition in combination with broad-spectrum antibiotics  that destroy normal gut flora. Rarely is a deficiency caused by  lack of dietary intake; however, bulimia can suppress vitamin  K-dependent activity. Clinical manifestations of vitamin K  deficiency are caused by a reduction of vitamin K—dependent  proteins. The severity of manifestations is related to the degree  of deficiency and ranges from laboratory abnormalities to  significant hemorrhage.   Parenteral administration of vitamin K is the treatment  of choice and usually results in correction of the deficiency.  Improvement of clotting tests is usually noted within 8 to 12  hours. Fresh frozen plasma may be administered but usually is  reserved for individuals with life-threatening hemorrhages or  who require emergency surgery.   Liver Disease. Individuals who have liver disease (e.g.,  acute or chronic hepatocellular diseases, cirrhosis, vitamin  K deficiency) or have undergone major liver surgery present  with a broad range of hemostasis derangements that may be  characterized by defects in the clotting or fibrinolytic systems or  platelet function.®° The hepatic parenchymal cells produce most  of the factors involved in hemostasis. Thus damage to the liver  frequently results in diminished production of factors involved  in clotting, usually in proportion to the degree of hepatic  parenchymal cell damage. For instance, factor VII is most  sensitive to liver damage because of its rapid turnover. Factor IX  levels are less affected and do not decline until liver destruction  is well advanced. The liver is also a major site for production  of plasminogen and Q)-antiplasmin of the fibrinolytic  system, as well as thrombopoietin and the metalloprotease  ADAMTS13. Diminished levels of thrombopoietin may lead  to thrombocytopenia from decreased platelet production.  Decreased production of ADAMTS13 results in increased  levels of large precursor molecules of vWF, which leads to the  formation of large aggregates of platelets.   In conditions of severe liver disease (e.g., cirrhosis) circu-  lating levels of most clotting factors are significantly depressed.  Concurrently, production of clotting system regulators  (e.g., antithrombin, protein C, protein S) and of fibrinogen  is diminished. The fibrinolytic system is commonly active  because of decreased levels of plasmin inhibitor and unaf-  fected levels of fibrinolytic activators (e.g., tissue plasmino-  gen activator [tPA], urokinase-like plasminogen activator  [uPA]). The affected individuals also are thrombocytopenic  because of diminished thrombopoietin and ADAMTS13, as  well as increased platelet sequestration in the spleen, which is  frequently enlarged in cirrhosis and is associated with portal  hypertension. Thus the individuals with cirrhosis may appear  to have a condition similar to disseminated intravascular  coagulation (DIC) (see next section).   Treatment of hemostatic alterations in liver disease must be  comprehensive to cover all aspects related to platelet, clotting,  and fibrinolytic dysfunctions. Fresh frozen plasma administra-  tion is the treatment of choice, but not all individuals tolerate    the volume needed to adequately replace all deficient factors.  Alternative modalities include the addition of exchange trans-  fusions and platelet concentration to plasma administration.    Consumptive thrombohemorrhagic disorders are a heteroge-  neous group of conditions that demonstrate the entire range of  hemorrhagic and thrombotic pathologic conditions. Symptoms  range from subtle to devastating and generally are considered  to be intermediary disease processes that complicate many pri-  mary disease states. These disorders also are characterized by  confusion and controversy regarding diagnosis, treatment, and  management. No single definition can cover all possible varie-  ties of these disorders; however, DIC is the most common term  used in the clinical setting to describe a pathologic condition  associated with hemorrhage and thrombosis.   Disseminated Intravascular Coagulation. Disseminated  intravascular coagulation (DIC) is an acquired clinical  syndrome characterized by widespread activation of  coagulation, resulting in the formation of fibrin clots in  medium and small vessels throughout the body. Disseminated  clotting may lead to blockage of blood flow to organs, resulting  in multiple organ failure. The magnitude of clotting may result  in consumption of platelets and clotting factors, leading to  severe bleeding. The Subcommittee on DIC of the International  Society on Thrombosis and Hemostasis defined DIC as  “an acquired syndrome characterized by the intravascular  activation of coagulation with loss of localization arising from  different causes. It can originate from and cause damage to  the microvasculature, which if sufficiently severe, can produce  organ dysfunction.”°7»°*   The clinical course of DIC largely is determined by the  intensity of the stimulus, host response, and comorbidities  and ranges from an acute, severe, life-threatening process that  is characterized by massive hemorrhage and thrombosis to a  chronic low-grade condition. The chronic condition is charac-  terized by subacute hemorrhage and diffuse microcirculatory  thrombosis. DIC may be localized to one specific organ or gen-  eralized, involving multiple organs.   Because of the complexity and wide variations in mani-  festations of DIC, diagnosis has been confusing and difficult.  Minimally acceptable diagnostic criteria have been established  and include a systemic thrombohemorrhagic disorder with  laboratory evidence of (1) clotting activation, (2) fibrinolytic  activation, (3) coagulation inhibitor consumption, and (4) bio-  chemical evidence of end-organ damage or failure.   DIC is secondary to a wide variety of well-defined clinical  conditions, specifically those capable of activating the clotting  cascade (Box 29-6). These include: (1) arterial hypotension, fre-  quently accompanying shock; (2) hypoxemia; (3) acidemia; and  (4) stasis of capillary blood flow.   Sepsis is the most common condition associated with DIC.  Gram-negative microorganisms, as well as some gram-positive  microorganisms, fungi, protozoa (malaria), and viruses (influ-  enza, herpes), are capable of precipitating DIC by causing dam-  age to the vascular endothelium. Gram-negative endotoxins are  the primary cause of endothelial damage; DIC may occur in up    BOX 29-6 MAJOR ETIOLOGIES IDENTIFIED  AS ANTECEDENTS TO THE  INITIATION AND DEVELOPMENT  OF DISSEMINATED INTRAVAS-  CULAR COAGULATION (DIC)    Malignancy: acute leukemias, metastatic solid malignancies  Infections: bacterial (gram-negative endotoxin, gram-positive mucopolysac-  charides), viral (hepatitis, varicella, cytomegalovirus), fungal, parasitic   Intravascular hemolysis: transfusion reactions, drug-induced hemolysis  Medical devices: aortic balloon, prosthetic devices   Hypoxia and low blood flow states: arterial hypotension secondary to shock,  cardiopulmonary arrest    Data from Bick RL et al: Hematology: clinical and laboratory practice,  St Louis, 1993, Mosby.    to 50% of individuals with gram-negative sepsis. DIC occurs in  approximately 10% to 20% of individuals with metastatic can-  cer or acute leukemia. Direct tissue damage (e.g., ischemia and  necrosis, surgical manipulation, crushing injury) also results in  release of tissue factor (TF) by the endothelium. Severe trauma,  especially to the brain, can induce DIC. DIC occurs in about  two thirds of individuals with a systemic inflammatory response  to trauma. Some complications of pregnancy also are associated  with DIC; incidences range from 50% for women with placental  abruptions to less than 10% for women with severe preeclamp-  sia. Other causes of DIC have been identified, most notably  blood transfusion. Transfused blood dilutes the clotting fac-  tors, as well as circulating naturally occurring antithrombins. In  hemolytic transfusion reactions, the endothelium is damaged  by complement-mediated reactions.   PATHOPHYSIOLOGY. The coagulation system is designed to  function at local areas of vascular damage, resulting in cessa-  tion of bleeding and activation of repair to the vessels. DIC  results from abnormally widespread and ongoing activation of  clotting (Figure 29-20). A variety of conditions are associated  with DIC (see Box 29-6), primarily by activating the extrinsic  clotting cascade. The common pathway for DIC appears to be  excessive and widespread exposure of TF. This may occur by  several mechanisms. Widespread damage to the vascular endo-  thelium results in exposure of subendothelial TF. Several types  of cells, either after stimulation by cytokines or constitutively,  express TF on their surfaces. Endothelial cells and mono-  cytes do not normally express surface TF unless stimulated by  inflammatory cytokines (particularly IL-6 and TNF-a). Many  tumors express surface TF or produce cytokines that stimulate  TF expression by endothelium or monocytes, or both.”° These  cytokines are abundantly produced during many of the con-  ditions listed in Box 29-6. Endotoxin, in particular, triggers  the release of multiple cytokines that play a significant role in  the development and maintenance of DIC. Proinflammatory  cytokines (TNF-a, interleukins [IL-1, IL-6, IL-8], and platelet  activating factor [PAF]) are responsible for the clinical signs  and symptoms associated with sepsis. They also contribute to    the development of DIC by activating endothelial cells, caus-  ing release of TF and vWF, increasing plasminogen activator  inhibitor-1 (PAI-1) synthesis and tissue factor activity, and  decreasing thrombomodulin expression, thereby promoting  development of thrombi. TF also may be released directly into  the bloodstream from circulating white blood cells (monocyte/  endotoxin interaction).   TF binds clotting factor VII, which leads to conversion of  prothrombin to thrombin and formation of fibrin clots (see  Figure 27-22). This pathway appears to be the primary route  by which DIC is initiated; inhibition of TF or factor VIIa com-  pletely prevents the generation of thrombi by gram-negative  bacterial endotoxin in animal models of DIC.   Not only is the clotting system extensively activated in DIC,  but also the predominant natural anticoagulants (tissue fac-  tor inhibitor, antithrombin III [AT III], protein C) are greatly  diminished (see Figure 27-18). During DIC the activation of  clotting is prolonged by the increased rate of consumption  because of persistent thrombin production, as well as decreased  synthesis, of these inhibitors and protein S and by cytokine-  mediated decreased expression of thrombomodulin on the  endothelial cell surface. Hepatic dysfunction in sepsis results in  decreased antithrombin synthesis and extravascular leakage of  this protease inhibitor because of capillary leakage. Addition-  ally, antithrombin is degraded by elastase released by activated  neutrophils, and clotting is initiated concurrently with loss  of regulation of the extent of thrombosis; thus the amount  of thrombin produced during DIC exceeds the ability of the  body’s naturally occurring anticoagulants to regulate it.   The rate of fibrinolysis is also diminished in DIC. The pri-  mary component of fibrinolysis is plasmin, which exists in  the circulation as an inactive precursor, plasminogen (see Fig-  ure 27-25). Plasminogen is activated to plasmin that digests  fibrin clots, thus controlling the extent of fibrin deposition  in the vessels. During DIC the activity of plasmin is dimin-  ished by increased production of its natural inhibitor, PAI-1.  Although some fibrinolytic activity remains, the level is inad-  equate to control the systemic deposition of fibrin. The slow  breakdown of fibrin by plasmin produces fibrin degradation  products (FDPs) that are released into the blood. These are  potent anticoagulants that are normally removed from blood  by fibronectin and macrophages. FDPs, along with thrombin,  induce further cytokine release from monocytes, contributing  to endothelial damage and TF release. During DIC the presence  of fibrin degradation products is prolonged, probably because  of diminished production of fibronectin. Fibronectin is a glyco-  protein with adhesive properties that mediate removal of par-  ticulate matter (e.g., fibrin clumps). Low levels of fibronectin  suggest a poor prognosis.   Although thrombosis is generalized and widespread, individ-  uals with DIC are paradoxically at risk for hemorrhage. Hem-  orrhage is secondary to the abnormally high consumption of  clotting factors and platelets, as well as the anticoagulant prop-  erties of FDPs, which interfere with polymerization of fibrin  monomers. Both thrombin and FDPs have a high affinity for  platelets and cause platelet activation and aggregation—an event  that occurs early in the development of DIC—which facilitates    FIGURE 29-20 Pathophysiology of Disseminated Intravascular Coagulation (DIC). DIC is initiated by a variety of  factors (endothelial injury, tissue injury, inflammation, and others), most of which either directly or indirectly result in release of  large amounts of tissue factor. Many cytokines create a procoagulant environment by concurrently (1) suppressing normal con-  trol of homeostasis and (2) inducing tissue factor release by endothelium or monocytes. Tissue factor initiates the coagulation  cascade (3) leading to the activation of thrombin, production of fibrin, and polymerization into a fibrin clot. Fibrinolysis normally  digests clots (4) through the activity of plasmin, resulting in the production of various fibrin degradation products. However, dur-  ing DIC, factors, such as TNF-a, induce (5) inhibitors of plasmin generation, thus leading to diminished fibrinolysis. Fibrin split  products possess several biologic activities that affect DIC, including (6) the induction of further cytokine release by monocytes.  Enzymatically active products of the coagulation cascade, including thrombin, activate (7) other inflammatory systems, including  platelets and the kinin and complement systems. Activation of platelets and monocytes continues the procoagulant cycle (indi-  cated by circular arrows) by inducing additional tissue factor and cytokines. Mediators produced from the kinin and complement  system (8) affect vascular endothelium, leading to increased vascular permeability that contributes to hypotension and potential  shock. The uncontrolled consumption of platelets and clotting factors (9) compromises the normal hemostatic mechanisms,  resulting in potential systemic hemorrhages. Excess activation of the coagulation cascade and platelets, with decreased fibri-  nolysis, leads to systemic microvascular thrombosis (10) and blockage of the vessels with progressive ischemia. Uncontrolled  DIC will eventually lead to multiple end-organ failure. For further details of these mechanisms see Chapters 7 and 27. AT ll,  Antithrombin Ill; /L-6, interleukin-6; PA/, plasminogen activator inhibitor; 7, thrombin; 7F tissue factor; 7F/, tissue factor inhibitor;  TM/PC, thrombomodulin/protein C complex; 7NVF-c, tumor necrosis factor-alpha. The inset is an example of DIC resulting from  staphylococcal septicemia. Note the characteristic skin hemorrhage ranging from small purpuric lesions to larger ecchymoses.    microcirculatory coagulation and obstruction in the initial phase.  However, platelet consumption exceeds production, resulting in  a thrombocytopenia that increases bleeding (Box 29-7).  Activation of clotting also leads to activation of other inflam-  matory pathways, including the kallikrein-kinin and comple-  ment systems (see Chapter 7). Factor XIa, generated in DIC,    converts prekallikrein to kallikrein, ultimately resulting in con-  version to circulating kinins. Activation of these systems con-  tributes to increased vascular permeability, hypotension, and  shock. Activated complement components also induce platelet  destruction, further contributing initially to the thrombosis and  later to the thrombocytopenia.    BOX 29-7 CLINICAL MANIFESTATIONS  ASSOCIATED WITH DISSEMI-  NATED INTRAVASCULAR  COAGULATION (DIC)   Oozing from puncture sites, incisions, mucous membranes  Acrocyanosis (irregularly shaped cyanotic patches)  Gangrene    Central Nervous System  Subarachnoid hemorrhage  Altered state of consciousness (slight confusion to convulsions and coma)    Modified from Bailes BK: AORN J 55(2):517-529, 1992.  ARDS, Acute respiratory distress syndrome.    The deposition of fibrin clots in the circulation interferes  with blood flow, causing widespread organ hypoperfusion.   This condition may lead to ischemia, infarction, and necro-  sis, further potentiating and complicating the existing DIC  process by causing further release of TF and eventually organ  failure.   In addition to initiation of clotting by TF, DIC may be pre-  cipitated by direct proteolytic activation of factor X. This has  been described as “thrombin mimicry” and is the result of acti-  vated factor X directly converting fibrinogen to fibrin. The pro-  teases that activate factor X may come from snake venom, some  tumor cells, or the pancreas and liver, where they are released  during episodes of pancreatitis and various stages of liver dis-  ease. Direct proteolytic activity appears to be independent of  any type of damage to the endothelium or tissue.   Vascular obstruction results from circulatory deposition of  thrombin and clot formation that impedes blood flow, caus-  ing widespread organ hypoperfusion that can lead to tissue  ischemia, infarction, and necrosis. The resulting tissue damage  further potentiates and complicates the existing DIC process.  Because organ perfusion is drastically impaired, manifestations  of multisystem organ dysfunction and failure ultimately result.  Multisystem organ dysfunction and failure are discussed in  Chapter 48. Whatever initiates the process of DIC, the cycle of    thrombosis and hemorrhage persists until the underlying cause  of the DIC is removed or appropriate therapeutic interventions  are used.   CLINICAL MANIFESTATIONS. Clinical signs and symptoms of  DIC present a wide spectrum of possibilities, depending on  the underlying disease process that initiates DIC and whether  the DIC is acute or chronic (see Box 29-7). Most symptoms  are the result of either hemorrhage or thrombosis. Acute DIC  presents with rapid development of hemorrhaging, such as oo0z-  ing from venipuncture sites, arterial lines, and surgical wounds,  or development of ecchymotic lesions (purpura, petechiae) and  hematomas. Other sites of bleeding include the eyes (sclera and  conjunctiva), the nose (epistaxis), and the gums. Most individ-  uals with DIC demonstrate bleeding at three or more unrelated  sites, and any combination may be observed. Shock of variable  intensity, out of proportion to the amount of apparent blood  loss, also may be observed. Hemorrhaging into closed compart-  ments of the body also can occur and may precede the develop-  ment of shock.   DIC has been conceptualized as a systemic hemorrhagic dis-  order because bleeding, sometimes very extensive, is usually the  initial observation. Symptoms of thrombosis are not always as  evident, even though it is often the first pathologic alteration to  occur and ultimately determines the degree of morbidity and  risk for death. A large amount of microvascular and macrovas-  cular occlusion may occur that is not clinically obvious. Sev-  eral organ systems are susceptible to microvascular thrombosis  that affects their function; these include the cardiovascular,  pulmonary, central nervous, renal, and hepatic systems. Quick  and accurate clinical diagnosis is critical to preventing further  progression of DIC that may lead to multisystem organ dys-  function or failure. Indicators of multisystem failure include  changes in level of consciousness, behavior, and mentation;  confusion; seizure activity; oliguria; hematuria; hypoxia; hypo-  tension; hemoptysis; chest pain; and tachycardia. Symmetric  cyanosis of the fingers and toes (“blue finger/toe syndrome”)  and, in some instances, of the nose and breasts may be present.  Symmetric parts are often affected and are indicative of micro-  vascular thrombosis. This may progress to infarction and gan-  grene, requiring amputation. Jaundice also may be present and  is believed to result from red blood cell destruction rather than  hepatic dysfunction.   Individuals with chronic or low-grade DIC do not present  with overt manifestations of hemorrhaging and thrombosis but  instead have subacute bleeding and diffuse thrombosis and are  described as having a compensated DIC, or non-overt DIC.  The major characteristic of this state is an increased turnover  and decreased survival time of the components of hemostasis:  platelets and clotting factors. On occasion diffuse or localized  thrombosis develops, but this is infrequent.   EVALUATION AND TREATMENT. No single laboratory test can be  used to effectively diagnosis DIC. Diagnosis is based primar-  ily on clinical symptoms and confirmed by a combination of  laboratory tests. The individual must present with a clinical  condition that is known to be associated with DIC. The most  commonly used combination of laboratory tests usually con-  firms thrombocytopenia or a rapidly decreasing platelet count    Group | Tests (Indicators of Procoagulant Activation)  evated prothrombin fragment 1+2    Group IV Tests (Indicators of End-Organ Damage/Failure)  1. Elevated lactic dehydrogenase (LDH)    Data from Bick RL: Semin Thromb Hemost 24(1):3, 1998.  *Satisfactory criteria for laboratory diagnosis of DIC require one abnor-  mality in each of groups | through III and at least two abnormalities in  group IV.    on repeated testing, prolongation of clotting times, the presence  of fibrin degradation products, and decreased levels of coagula-  tion inhibitors. The relationships among these criteria are sum-  marized in Box 29-8. Platelet counts less than 100,000/mm? or a  progressive decrease in platelet counts is very sensitive for DIC,  although not greatly specific. These changes usually indicate  consumption of platelets.   The standard coagulation tests (e.g., prothrombin time  [PT], activated partial thromboplastin time [aPTT]) also have  a high degree of sensitivity, but they are not highly specific for  DIC. As a result of consumption of circulating clotting fac-  tors, these tests are usually abnormal, ranging from shortened  to prolonged times. However, conditions other than DIC may  prolong clotting times. Assays of specific clotting factors do not  contribute meaningful diagnostic information.   Detection of various fibrin degradation products is more  specific for DIC; of these tests the detection of p-dimers is the  most widely used, reliable, and specific test.”1 A p-dimer is a  molecule produced by plasmin degradation of cross-linked  fibrin in clots. p-dimers in the blood can be quantified using  enzyme-linked immunosorbent assay (ELISA) tests that include  commercially available and highly specific monoclonal anti-  body against the p-dimer. Agglutination tests for other fibrin    degradation products are available. Levels of fibrin degradation  products, in general, are elevated in the plasma in 95% to 100%  of cases; however, they are less specific and only document the  presence of plasmin and its action of fibrin, whereas detection  of p-dimers measures a specific DIC-related product.   ELISAs for markers of thrombin activity are sometimes  used. Normal conversion of prothrombin to thrombin pro-  duces an inactive prothrombin fragment 1.2 (PF1+2).’! This  fragment is released from the prothrombin molecule, gen-  erating an intermediate factor, prethrombin 2. Once gener-  ated, prethrombin 2 can be split to produce thrombin that  can then proteolyze fibrinogen, liberating fibrinopeptide A  (FPA), or can combine with its major antagonist, antithrom-  bin, and form a stable inactive enzyme-inhibitor complex, the  thrombin-antithrombin (TAT) complex. Assays of these fac-  tors (PF1+2, FPA, TAT) are now generally available to quan-  tify their blood levels, providing evidence of excessive factor Xa  (PF1+2) and thrombin (FPA) generation.   Levels of coagulation inhibitors (e.g., AT III, protein C) can  be measured by assays that rely on function or by ELISAs that  quantify the amount of the specific inhibitor. AT III levels can  provide key information for diagnosing and monitoring ther-  apy of DIC. Initial levels of functional AT III are low in DIC  because thrombin is irreversibly complexed with activated clot-  ting factors and AT II.   Treatment of DIC is directed toward (1) eliminating the  underlying pathology, (2) controlling ongoing thrombosis, and  (3) maintaining organ function. Elimination of the underlying  pathology is the initial intervention in the treatment phase in  order to eliminate the trigger for activation of clotting. Once  the stimulus is gone, production of coagulation factors in the  liver leads to restoration of normal plasma levels within 24 to  48 hours.   Control of thrombosis is more difficult to attain. Heparin has  been used for this; however, its use is controversial because its  mechanism of action is binding to and activating AT III, which  is deficient in many types of DIC. Currently heparin is indicated  only in certain situations related to DIC. For instance, heparin  seems to be effective in DIC caused by a retained dead fetus or  associated with acute promyelocytic leukemia. Organ function  is compromised by microthrombi, and there is a risk of losing  an extremity because of vascular occlusion; thus heparin is also  indicated in these conditions. Heparin’s usefulness, however,  for DIC that is precipitated by septic shock has not been estab-  lished and so is contraindicated in that instance; heparin is also  contraindicated when there is evidence of postoperative bleed-  ing, peptic ulcer, or CNS bleeding.   Replacement therapy (interventions based on restoring the  balance of coagulation factors, deficient coagulation factors,  platelets, and other coagulation elements) is gaining recogni-  tion as an effective treatment modality. Components used in  replacement therapy include platelets, fresh frozen plasma,  and cryoprecipitate. Platelets are given for thrombocytope-  nia, plasma provides volume and replaces clotting factors, and  cryoprecipitate replaces fibrinogen. Their use is not without  controversy, however, because of the possible risk of adding  components that will increase the rate of thrombosis. Clinical    FIGURE 29-21 Thrombus. Thrombus arising in valve pocket at upper end of  superficial femoral vein. Postmortem clot on the right is shown for comparison.  (From McLachlin J, Paterson JC: Surg Gynecol Obstet 93:1, 1951.)    judgment is the key factor in determining whether replacement  is to be used as a treatment modality.   Several clinical trials are evaluating replacement of antico-  agulants (i.e., AT HI, protein C). Replacement of AT III appears  to be effective in DIC caused by sepsis. Low levels of AT II  correlate with sepsis-initiated DIC, which makes a case for its  use. AT III is an a -globulin that inactivates thrombin, factor  Xa, factor [Xa, and other activated components of the clotting  system. Heparin augments AT III, but the increased benefit of a  combination of heparin with AT III replacement has not been  established. Antifibrinolytic drugs also are used in treatment  but are limited to instances of life-threatening bleeding that  have not been controlled by blood component replacement  therapy.   Maintenance of organ function is achieved by fluid replace-  ment to sustain adequate circulating blood volume and to  maintain optimal tissue and organ perfusion. Fluids may be  required to restore blood pressure, cardiac output, and urine  output to normal parameters.    Certain conditions within the blood vessels predispose an  individual to develop clots spontaneously.” A stationary clot  attached to the vessel wall is called a thrombus (Figure 29-21).  A thrombus is composed of fibrin and blood cells and can  develop in either the arterial or the venous system. Arterial  thrombi form under conditions of high blood flow and are  composed mostly of platelet aggregates held together by fibrin  strands. Venous thrombi form in conditions of low flow and  are composed mostly of red cells with larger amounts of fibrin  and few platelets.   A thrombus may eventually grow large enough to reduce  or obstruct blood flow to tissues or organs, such as the heart,    brain, or lungs, depriving them of essential nutrients critical  to survival. A thrombus also has the potential of detaching  from the vessel wall and circulating within the bloodstream  (referred to as an embolus). The embolus may become lodged  in smaller blood vessels, blocking blood flow into the local  tissue or organ and leading to ischemia. Whether episodes of  thromboembolism are life threatening depends on the site of  vessel occlusion.   Therapy consists of removal or lysis of the clot and support-  ive measures. Anticoagulant therapy is effective in treating or  preventing venous thrombosis; it is not as useful in treating or  preventing arterial thrombosis. Parenteral heparin is the major  anticoagulant used to treat thromboembolism. Oral coumarin  drugs also are widely used, particularly for individuals not hos-  pitalized. More aggressive therapy may be indicated for such  conditions as pulmonary embolism, coronary thrombosis, or  thrombophlebitis. Streptokinase and urokinase activate the  fibrinolytic system and are administered to accelerate the lysis  of known thrombi. Thrombolytic therapy has limited uses and  is prescribed with a high degree of caution because it can cause  hemorrhagic complications.   The risk for developing spontaneous thrombi is related to  several factors, referred to as the Virchow triad: (1) injury to  the blood vessel endothelium, (2) abnormalities of blood flow,  and (3) hypercoagulability of the blood.   Vascular endothelial injury can result from atherosclerosis  (plaque deposits on arterial walls). Atherosclerosis initiates  platelet adhesion and aggregation, promoting the development  of atherosclerotic plaques that enlarge, causing further damage  and occlusion. Other causes of vessel endothelial injury may be  related to hemodynamic alterations associated with hyperten-  sion and turbulent blood flow. Injury also is caused by radia-  tion injury, exogenous chemical agents (toxins from cigarette  smoke), endogenous agents (cholesterol), bacterial toxins or  endotoxins, or immunologic mechanisms. Whatever the pre-  cipitating cause of endothelial injury, it is a potent thrombo-  genic agent.   Sites of turbulent blood flow in the arteries and stasis of  blood flow in the veins are at risk for thrombus formation. In  areas of turbulence, platelets and endothelial cells may be acti-  vated, leading to thrombosis. In sites of stasis, platelets may  remain in contact with the endothelium for prolonged times,  and clotting factors that would normally be diluted with fresh-  flowing blood are not diluted and may become activated. The  most common clinical conditions that predispose to venous  stasis and subsequent thromboembolic phenomena are major  surgery (e.g., orthopedic surgery), acute myocardial infarction,  congestive heart failure, limb paralysis, spinal injury, malig-  nancy, advanced age, the postpartum period, and bed rest lon-  ger than 1 week. Turbulence and stasis occur with ulcerated  atherosclerotic plaques (myocardial infarction), hyperviscosity  (polycythemia), and conditions with deformed red cells (sickle  cell anemia).   Hypercoagulability, or thrombophilia, is the condition in  which an individual is at risk for thrombosis. Hypercoagulabil-  ity is differentiated according to whether it results from primary  (hereditary) or secondary (acquired) causes. Primary causes    BOX 29-9 CLINICAL CONDITIONS  ASSOCIATED WITH HIGH  RISK FOR THROMBOSIS OR  THROMBOEMBOLISM   Left ventricular failure Congestive heart failure  Oral contraceptives Nephrotic syndrome  Estrogens Obesity   High lipoprotein A Varicose veins  Polycythemia Postphlebotic syndrome  Hyperviscosity syndrome Oral contraceptives  Leukostasis syndrome Estrogens  Thrombocythemia Thrombocythemia    include defects in proteins involved in hemostasis. Secondary  causes include a variety of clinical disorders or conditions (Box  29-9). It is unclear why the incidence of thrombosis formation  in hypercoagulable states associated with various disease states  and conditions is not more than anticipated.   Hereditary Thrombophilias. A \arge number of inherited  conditions have been identified that increase the risk of  developing thrombosis (Box 29-10).”> Most are autosomal  dominant; thus individuals who are homozygous for the  mutation are at greatest risk for thrombosis. These include  mutations in coagulation proteins, fibrinolytic proteins, platelet  receptors, and other factors. The particular mutations that have  been most strongly linked as risk factors for venous thrombosis  or for arterial thrombosis leading to coronary artery disease  or stroke include those that affect fibrinogen, prothrombin  (G20210A variant), factor V (factor V Leiden) of the coagulation  system, PAI-1 of the fibrinolytic system, the platelet receptor  GPIHa, and methylenetetrahydrofolate reductase (MTHFR), as  well as mutations that result in excessive levels of homocysteine  (hyperhomocysteinemia). Other inherited thrombophilias are  risk factors primarily for venous thrombosis.”*7° These include  deficiencies in protein C, protein S, and AT III.”°   Factor V Leiden results from a single nucleotide mutation  of guanine to adenine at nucleotide 1691 (G1691A). Activated  factor V (Va) is usually inactivated by protein C, but this  single mutation results in a change in amino acid 506 from  arginine to glutamine. The change alters the site where pro-  tein C would cleave factor Va and confers partial resistance,  resulting in prolonged high levels of Va and prolongation of  clot formation.”” Although this mutation increases the risk  for thrombosis, most individuals with factor V Leiden do not  have clinically relevant thrombotic events. It is the most com-  mon hereditary thrombophilia and is found in about 30% of  individuals presenting with deep venous thrombosis (DVT)    Inherited Disorders (Primary)  Activated protein C resistance  Factor V Leiden mutation  Factor V Cambridge mutation  Factor V Hong Kong  Factor V HR2 mutation  Prothrombin 20210A mutation  Factor XII deficiency (Hageman trait)  Dysfibrinogenemia  Hyperhomocysteinemia  Platelet defects  Wien-Penzing defect  Sticky platelet syndrome    Acquired Disorders (Secondary)  Antiphospholipid antibodies  Anticardiolipin antibodies  Lupus anticoagulant  Subgroup phospholipid antibodies  Myeloproliferative syndromes  Trousseau syndrome    or pulmonary embolism. It is primarily observed in individ-  uals of European ancestry and in about 5% of whites in the  United States and Europe.   The second most common inherited thrombophilia is a  mutation in the prothrombin gene, resulting in a replacement  of guanine at nucleotide 20210 with an adenine (G20210A vari-  ant).’4 This mutation is observed in about 2% to 5% of indi-  viduals of European ancestry, but is found in 5% to 10% of  individuals presenting with venous thrombosis. The G20210A  variant leads to overproduction of prothrombin and prolonga-  tion of clot formation.   MTHER mutation leads to alterations in the metabolism of  the amino acid homocysteine into methionine and abnormally  elevated levels of that amino acid in the blood (hyperhomocys-  teinemia).”° Acquired hyperhomocysteinemia may result from  deficiencies in vitamins Bg or Bj», endocrine diseases (e.g., dia-  betes mellitus, hypothyroidism), pernicious anemia, inflamma-  tory bowel disease, renal failure, and therapy with some drugs.  Individuals with homocysteine levels above the 95th percentile  are 2.5 times more likely to experience an episode of DVT.   More than 100 different known mutations lead to defects of  proteins C, protein S, and AT III and increase the risk of venous  thrombosis. Mutations may lead to either quantitative (low lev-  els of protein) or qualitative (production of defective protein)  changes.    FIGURE 29-22 Arterial Thrombosis Associated with Antiphospholipid  Antibodies. A 12-year-old girl with systemic lupus erythematosus and antiphos-  pholipid antibodies with painful cutaneous vasculitis of the right foot. Arterial  thrombosis documented by angiography resulted in cyanosis of the large toe.  Symptoms resolved with treatment with heparin and corticosteroids. (From  Kliegman R et al: Ne/son textbook of pediatrics, ed 18, Philadelphia, 2007,  Saunders.)    Tests to diagnose inherited thrombophilias include pro-  thrombin time, partial thromboplastin time, and levels of pro-  tein C, protein S, and AT III. More elaborate tests to detect    precise mutations in factor V, prothrombin, or MTHFR may  be indicated.   Acquired Hypercoagulability. Deficiencies in proteins  S and C and AT III may be acquired and contribute to a  hypercoagulable state.’” Conditions associated with an acquired  protein deficiency include DIC, liver disease, infection, DVT,  acute respiratory distress syndrome, l-asparaginase therapy,  HUS, and TTP. The postoperative state also predisposes an  individual to protein C or S deficiency; however, its role in  contributing to DVT remains unclear.   Acquired hypercoagulable states include the antiphos-  pholipid syndrome (APS), an autoimmune syndrome  characterized by autoantibodies against plasma membrane  phospholipids and phospholipid-binding proteins. As with  most autoimmune diseases, the predominantly affected indi-  vidual is female and of reproductive age. Those with APS are  at risk for arterial and venous thrombosis and a variety of  obstetric complications, including pregnancy loss and pre-  eclampsia or eclampsia (Figure 29-22).”° In severe cases the  person may die from recurrent major thrombus formation.°°  The pathophysiology is related to autoantibodies directly  reacting with platelets or endothelial cells (increasing the  risk for thrombosis) or the placental surface (resulting in  damage to the placenta). The predominant diagnostic tests  measure prolongation of laboratory blood coagulation tests  related to an antibody inhibitor (lupus anticoagulant) and  specific ELISAs for antibodies against phospholipids (e.g.,  anticardiolipin antibody) or proteins that bind to phospho-  lipids (e.g., B-glycoprotein I).°!*? Highly effective ther-  apy (ie., unfractionated or low-molecular-weight heparin  with low-dose aspirin) is available to prevent the obstetric  complications.**   1. Quantitative alterations of leukocytes (too many or too  few) can be caused by bone marrow dysfunction or prema-  ture destruction of cells in the circulation. Many quantita-  tive changes in leukocytes occur in response to invasion by  microorganisms.   2. Leukocytosis is a condition in which the leukocyte count is  higher than normal and is usually a response to stress and  invasion of microorganisms.   3. Leukopenia is a condition in which the leukocyte count is  lower than normal and is caused by pathologic conditions  such as malignancies and hematologic disorders.   4. Granulocytosis (particularly as a result of an increase in  neutrophils) occurs in response to infection. The marrow  releases immature cells, causing a shift-to-the-left, when  responding to an infection that has created a demand for  neutrophils that exceeds the supply in the circulation.   5. Eosinophilia results most commonly from parasitic  invasion and ingestion or inhalation of toxic foreign  particles.   6. Basophilia is seen in hypersensitivity reactions because of  the high content of histamine and subsequent release.    7. Monocytosis occurs during the late or recuperative phase of  infection when macrophages (mature monocytes) phago-  cytose surviving microorganisms and debris.   8. Granulocytopenia, a significant decrease in the number  of neutrophils, can be a life-threatening condition if sep-  sis occurs; it is often caused by chemotherapeutic agents,  severe infection, and radiation.   9. Infectious mononucleosis is an acute infection of B lympho-  cytes most commonly associated with EBV, a type of herpes-  virus. Transmission of EBV is by personal contact, commonly  through saliva, thus its nickname, the kissing disease.   10. Two of the earliest manifestations of mononucleosis are  sore throat and fever caused by inflammation at the pri-  mary site of viral entry.   11. Most cases of EBV mononucleosis include fever lasting 7  to 10 days, sore throat, and enlargement and tenderness of  the cervical lymph nodes. It is self-limiting, and treatment  consists of rest and relief of symptoms.   12. The common pathologic feature of all forms of leukemia is  an uncontrolled proliferation of leukocytes and overcrowd-  ing of the bone marrow, causing a decreased production  and function of the other blood cell lines.    All leukemias are classified by the cell type involved, lym-  phocytic or myelogenous, and are differentiated by onset,  acute or chronic. Thus there are four major types of leuke-  mia: ALL, CLL, AML, and CML.   Although the exact cause of leukemia is unknown, it is con-  sidered a clonal disorder. A higher incidence of acute leu-  kemias and CLL is reported in certain families, suggesting a  possible genetic predisposition.   The most common genetic abnormality in adult ALL is the  Philadelphia chromosome.   In approximately one third of clients with AML, there is a  mutation in the receptor tyrosine kinase FLT3.   In leukemia, blasts (precursor cells) “crowd out” the marrow  and cause cellular proliferation of the other cell lines to cease.  The major clinical manifestations of leukemia include  fatigue caused by anemia, bleeding caused by thrombo-  cytopenia, fever secondary to infection, anorexia, and  weight loss.   Chemotherapy is the treatment of choice for leukemia.  Acute leukemias are associated with an increasing survival  rate of 80% to 90%, with long-term survival of 30% to 40%.  Chronic leukemias are associated with a longer life expec-  tancy than are acute leukemias.   Chronic leukemias progress differently than acute leukemias,  advancing slowly and without warning. The presence of the  Philadelphia chromosome is a diagnostic marker for CML.    The number of lymphocytes is decreased (lymphocytope-  nia) in most acute infections and in some immunodefi-  ciency syndromes.    (thymus, bone marrow) or secondary lymphoid tissue  (lymph nodes, spleen, tonsils, intestinal lymphoid tis-  sue). The two major types of malignant lymphomas are  Hodgkin lymphoma (HL) and non-Hodgkin lymphoma  (NHL).    associated with HL. The RS cell is derived from a malignant  B cell that usually becomes binucleate.    . A virus might be involved in the pathogenesis of HL.    the neck, is an initial sign of HL. Local symptoms are pro-  duced by lymphadenopathy, usually caused by pressure or  obstruction.    therapy. A cure is possible regardless of the stage of HL;  however, individuals treated with chemotherapy who  relapse in less than 2 years have a poor prognosis.    The cause of lymph node enlargement and cancerous  transformation in NHL is unknown. Immunosuppressed  persons have a higher incidence of NHL, suggesting an  immune mechanism.    . Generally, with NHL, the swelling of lymph nodes is pain-    less, and the nodes enlarge and transform over months or  years.   Individuals with NHL can survive for long periods. Treat-  ment is chemotherapy.   Burkitt lymphoma involves the jaw and facial bones and  occurs in children from east-central Africa and New  Guinea.   Multiple myeloma (MM) is a neoplasm of B cells (imma-  ture plasma cells) and mature plasma cells. It is character-  ized by multiple malignant tumors of plasma cells scattered  throughout the skeletal system and occasionally in soft  tissue.   Myeloma cells usually secrete monoclonal protein (M pro-  tein) that is an abnormal antibody molecule. The myeloma  cell may also secrete free antibody light chain that is excreted  in the urine (Bence Jones protein).   The exact cause of MM is unknown, but genetic factors  and chronic stimulation of the mononuclear phagocyte  system by bacteria, viral agents, and chemicals have been  suggested.   The major clinical manifestations for MM include recur-  rent infections caused by suppression of the humoral  immune response and renal disease as a result of Bence  Jones proteinuria.   Chemotherapy is the treatment of choice for MM. Treat-  ment with tandem transplant or thalidomide, or both, is  showing promise as an effective therapeutic agent in pro-  ducing long-term remissions.   Waldenstr6m macroglobulinemia is a rare type of slow-  growing plasma cell tumor that secretes a monoclonal IgM  molecule.    Splenomegaly (enlargement of the spleen) may be consid-  ered normal in certain individuals, but its presence should  not be ignored.    tious processes, (b) congestive disorders, (c) infiltrative pro-  cesses, and (d) tumors or cysts.    spleen). Hypersplenism results in blood cell sequestration,  causing destruction of red blood cells and the development  of anemia.    Thrombocytopenia is characterized by a platelet count  less than 100,000 platelets/uL of blood; a count less than  50,000/uL increases the potential for hemorrhage associ-  ated with minor trauma.    Thrombocytopenia exists in primary or secondary forms  and is commonly associated with autoimmune diseases  and viral infections; bacterial sepsis with DIC also results in  thrombocytopenia.   Heparin-induced thrombocytopenia develops in approx-  imately 4% of individuals receiving unfractionated  heparin.   Immune thrombocytopenic purpura (ITP) is a major cause  of platelet destruction, often affecting females, and results  in hemorrhaging that ranges from petechiae to bleeding  from mucosal sites.   Thrombotic thrombycytopenic purpura (TTP) causes  platelet aggregation leading to microcirculatory occlusion.  Thrombocythemia is characterized by a platelet count more  than 400,000 platelets/uL of blood and is symptomatic  when the count exceeds 1 million/wL, which increases the  risk for intravascular clotting (thrombosis).  Thrombocythemia is caused by accelerated platelet produc-  tion in the bone marrow.   Qualitative alterations in normal platelet adherence or  aggregation prevent platelet plug formation and may result  in prolonged bleeding times.   Prolonged bleeding can result from alterations in platelet  function, including adhesion between platelets and the ves-  sel wall, platelet-platelet adhesion, platelet granule secre-  tion, arachidonic acid pathway activity, and membrane  phospholipid regulation.   Disorders of coagulation are usually caused by defects or  deficiencies of clotting factors.   Coagulation is impaired when there is a deficiency of vita-  min K because of insufficient production of prothrombin    and synthesis of clotting factors II, VII, IX, and X, often  associated with liver diseases.   DIC is a complex syndrome that results from a variety of  clinical conditions that release tissue factor, causing an  increase in fibrin and thrombin activity in the blood and  producing augmented clot formation and accelerated fibri-  nolysis. Sepsis is often associated with DIC.   DIC is characterized by a cycle of intravascular clotting  followed by active bleeding caused by the initial con-  sumption of coagulation factors and platelets and diffuse  fibrinolysis.   Diagnosis of DIC is based on dysfunctional coagulation  activity. Treatment is complex, nonstandardized, and  focused on removing the primary cause, restoring hemo-  stasis, and preventing further organ damage.  Thromboembolic disease results from a fixed (thrombus)  or moving (embolus) clot that blocks flow within a vessel,  denying nutrients to tissues distal to the occlusion; death  can result when clots obstruct blood flow to the heart,  brain, or lungs.   Hypercoagulability is the result of deficient anticoagulation  proteins. Secondary causes are conditions that promote  venous stasis.   The term Virchow triad refers to three factors that can cause  thrombus formation: (a) vessel wall injury, (b) blood flow  abnormalities, and (c) altered blood constituents leading to  hypercoagulability.   Autoantibodies against phospholipids result in a state  of acquired hypercoagulability, an increased risk for venous  or arterial thrombosis, and a higher incidence of pregnancy  complications.   Chronic lymphocytic leukemia (CLL), 1020  Chronic myelogenous leukemia (CML), 1020  Chronic relapsing TTP, 1040   Qualitative leukocyte disorder, 1008  Quantitative leukocyte disorder, 1008  Reed-Sternberg (RS) cell, 1024  Shift-to-the-left, 1009   T-cell neoplasm, 1027  Thrombocythemia, 1040  Thrombocytopenia, 1037  Thrombocytosis, 1040  Thromboembolic disease, 1037  Thrombophilia, 1048    Dubos F, Delebarre M, Martinot A: Predicting the risk of severe infection  in children with chemotherapy-induced febrile neutropenia, Curr Opin  Hematol 19(1):39—43, 2012.   Schwartz MJ et al: Evidence for an altered tryptophan metabolism in  fibromyalgia, Neurobiol Dis 11(3):434—442, 2002.   Hanna B: Re: the diagnosis of infectious mononucleosis, Clin Otolaryngol  37(1):80-81, 2012.   Gunz FW: The dreaded leukemias and the lymphomas: their nature and  their prospects. In Wintrobe MM, editor: Blood, pure and eloquent: a story  of discovery, of people, and of ideas, New York, 1980, McGraw-Hill.  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Selleng K, Selleng S, Greinacher A: Heparin-induced thrombocytopenia  in intensive care patients, Semin Thromb Hemost 34(5):425—438, 2008.  Warkentin TE, Sheppard J-AI: Testing for heparin-induced thrombocy-  topenia antibodies, Transfus Med Rev 20(4):259-272, 2006.   Lakshmanan S, Cuker A: Contemporary management of primary  immune thrombocytopenia (ITP) in adults, J Thromb Haemost, August 3,  2012. [Epub ahead of print.].    Curtis BR: Genotyping for human platelet alloantigen polymorphisms:  applications in the diagnosis of alloimmune platelet disorders, Semin  Thromb Hemost 34(6):539—548, 2008.   Kuhne T, Imback P: Management of children and adolescents with pri-  mary immune thrombocytopenia: controversies and solutions, Vox Sang,  July 17, 2012. [Epub ahead of print.].   Bennett CM, de Jong JLO, Neufeld EJ: Targeted ITP strategies: do they  elucidate the biology of ITP and related disorders? Pediatr Blood Cancer  47(Suppl 5):706-709, 2006.   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Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Fetal and Neonatal Hematopoiesis, 1055  Postnatal Changes in the Blood, 1056  Erythrocytes, 1057  Leukocytes and Platelets, 1057  Disorders of Erythrocytes, 1058  Acquired Disorders, 1058  Inherited Disorders, 1062    This chapter briefly explains fetal and neonatal hematopoiesis  and postnatal changes in blood as a foundation for understand-  ing the pathophysiology of specific blood disorders in child-  hood. Among the diseases that affect erythrocytes are acquired  disorders, such as iron deficiency anemia, hemolytic disease of  the newborn, and anemia of infectious disease; and inherited  disorders, such as glucose-6-phosphate dehydrogenase (G6PD)  deficiency, hereditary spherocytosis, sickle cell disease, and the  thalassemias. Disorders of coagulation and platelets include  inherited hemorrhagic diseases, such as the hemophilias,  and antibody-mediated hemorrhagic diseases, which include  idiopathic thrombocytopenic purpura, autoimmune neona-  tal thrombocytopenias, and autoimmune vascular purpuras.  Finally, leukocyte disorders, such as leukemia and the lympho-  mas (non-Hodgkin lymphoma as well as Hodgkin disease), are  discussed.    Disorders of Coagulation and Platelets, 1070  Inherited Hemorrhagic Disease, 1070  Antibody-Mediated Hemorrhagic Disease, 1073    As the developing embryo becomes too large for oxygenation  of tissues by simple diffusion, the production of erythrocytes  begins within the vessels of the yolk sac. Shortly after 2 weeks  of gestation, circulating erythrocytes play a major role in deliv-  ering oxygen to the tissues. At approximately the eighth week  of gestation, the site of erythrocyte production shifts from the  vessels to the liver sinusoids, and the production of leukocytes  and platelets begins in the liver and spleen. Erythropoiesis in  the liver and, to a lesser extent, in the spleen and lymph nodes,  reaches a peak at approximately 4 months. Hepatic blood for-  mation declines steadily thereafter but does not disappear  entirely during the remainder of gestation. By the fifth month  of gestation, hematopoiesis begins to occur in the bone marrow  and increases rapidly until hematopoietic (red) marrow fills the    entire bone marrow space. By the time of delivery, the marrow  is the only significant site of hematopoiesis.   In neonates and young infants, hematopoietic marrow  progressively fills the bony cavities of the entire axial skeleton  (skull, vertebrae, ribs, sternum), the long bones of the limbs,  and many intramembranous bones. (These structures are  described in Chapter 45.) Fatty (yellow) marrow gradually  replaces hematopoietic marrow in some bones. During child-  hood, hematopoietic tissue retreats centrally to the vertebrae,  ribs, sternum, pelvis, scapulae, skull, and proximal ends of the  femur and humerus.   In diseases characterized by hemolysis, erythrocyte produc-  tion can increase as much as eight times the normal because  erythropoietin causes hematopoietic marrow to increase in vol-  ume. Initially, hematopoietic marrow expands from the ends of  the long bones toward the middle of the shafts, replacing fatty  marrow. Next, blood cell production begins to occur outside  the marrow cavities, especially in the liver and spleen. Extra-  medullary hematopoiesis is more likely to occur in children  than in adults because the bony cavities of children already are  filled with red marrow (Figure 30-1). This is why hemolytic    FIGURE 30-1 Sites of Hematopoiesis in Health and Illness. With normal  maturation, red marrow is partly replaced by yellow marrow in the shafts of the  long bones. In adults, red marrow is largely restricted to the proximal ends of the  femur and humerus. In response to hemolysis, red marrow replaces yellow marrow  in the long bones. In infants, whose long bones already are filled with red marrow,  additional hematopoiesis takes place in the liver and spleen. In children and adults,  red marrow can replace yellow marrow in response to hemolysis, necessitating  less hematopoiesis in the liver and spleen.    disease causes especially pronounced enlargement of the spleen  and liver in children.   The erythrocytes undergo striking changes during gestation,  particularly during the first two trimesters, at which time they  nearly double in numbers and in hemoglobin content. A pro-  portionate increase in hematocrit also occurs. By the end of ges-  tation the erythrocyte count has more than tripled but the size  of each erythrocyte has decreased.   A biochemically distinct type of hemoglobin is synthesized  during fetal life. The three embryonic hemoglobins (Gower 1,  Gower 2, and Portland) and the fetal hemoglobin (HbF) are  composed of two a- and two y-chains of polypeptides, whereas  the adult hemoglobins (HbA and HbA.) are composed of two  a-chains and two f-chains. (The structure of an adult hemoglo-  bin molecule is illustrated in Figure 27-15, and types of hemo-  globin are defined in Table 27-5.) Some unknown regulatory  mechanism promotes y-chain synthesis and inhibits B- and  6-chain synthesis in utero. This results in production of embry-  onic or fetal hemoglobin. After birth, y-chain synthesis is inhib-  ited, whereas B- and 6-chain synthesis is facilitated, resulting in  production of adult hemoglobins.   Fetal hemoglobin has greater affinity for oxygen than  does adult hemoglobin because it interacts less readily with  an enzyme (2,3-diphosphoglycerate [DPG]) that inhibits  hemoglobin-oxygen binding. The decreased inhibitory effects  of 2,3-DPG enable fetal blood to transport oxygen despite  the relative lack of oxygen in the uterine environment. The  increased affinity for oxygen enables Hb F to bind with mater-  nal oxygen in the placental circulation.   During the first trimester nearly all of the hemoglobin in the  fetus is embryonic, but some Hb A can be detected. Therefore,  it is possible to identify as early as 16 to 20 weeks of gestation  some disorders of adult hemoglobin, such as sickle cell anemia  and thalassemia major. In the 6-month fetus, Hb F constitutes  90% of the total. This percentage then begins to decline. At  birth, neonatal hemoglobin consists of 70% Hb F, 29% Hb A,  and 1% Hb A>. Between 6 and 12 months of age, normal adult  hemoglobin percentages are established (see Chapter 27).    Blood cell counts tend to rise above adult levels at birth and  then decline gradually throughout childhood. Table 30-1 lists  normal ranges during infancy and childhood. The immediate  rise in values is the result of accelerated hematopoiesis during  fetal life, increased numbers of cells that result from the trauma  of birth, and cutting of the umbilical cord. These events sur-  rounding the birth also are accompanied by the presence of  large numbers of immature erythrocytes and leukocytes (par-  ticularly granulocytes) in peripheral blood (see Chapter 27). As  the infant develops over the first 2 to 3 months of life, the num-  bers of these immature blood cells decrease.   Average blood volume in the full-term neonate is 85 ml/kg  of body weight. The premature infant has a slightly larger blood  volume of 90 ml/kg of body weight, with the mean increasing to  150 mg/kg during the first few days after birth. In full-term and  premature infants, blood volume decreases during the first few    From Behrman R et al, editors: Nelson textbook of pediatrics, ed 17th, Philadelphia, 2004, Saunders.    months. Thereafter the average blood volume is 75 to 77 ml/kg,  which is similar to that of older children and adults.   The hypoxic intrauterine environment stimulates erythropoie-  tin production in the fetus. This accelerates fetal erythropoiesis,  producing polycythemia (excessive proliferation of erythrocyte  precursors) of the newborn. After birth the oxygen from the  lungs saturates arterial blood, and the amount of oxygen deliv-  ered to the tissues increases. In response to the change from  a placental to a pulmonary oxygen supply during the first few  days of life, levels of erythropoietin and the rate of blood cell  formation decrease. The very active rate of fetal erythropoiesis is  reflected by the large numbers of immature erythrocytes (retic-  ulocytes) in the peripheral blood of full-term neonates. After  birth the number of reticulocytes decreases about 50% every  12 hours, so it is rare to find an elevated reticulocyte count after  the first week of life. A decrease in extramedullary hematopoi-  esis also occurs at this time. In the peripheral blood the erythro-  cyte count drops for 6 to 8 weeks after birth. During this period  of rapid growth the rate of erythrocyte destruction is greater  than that in later childhood and adulthood. In full-term infants,  normal erythrocyte life span is 60 to 80 days; in premature  infants it may be as short as 20 to 30 days; and in children and  adolescents, it is the same as that in adults—120 days. (Mecha-  nisms of hemolysis are described in Chapter 27.)   In the premature infant the postnatal fall in hemoglobin and  hematocrit values is more marked than in the full-term infant.  In the preschool and school-age child, there is a gradual rise in  hemoglobin, hematocrit, and red blood cell (RBC) count. Val-  ues in males and females first begin to diverge in adolescence. In  the female the gradual hemoglobin increase continues into early  puberty, at which time it stabilizes. In the male the hemoglobin  increase keeps pace with growth and maturation and eventually  surpasses that of the female. This higher value of hemoglobin in  the mature male is related to androgen secretion.    Metabolic processes within the erythrocytes of neonates dif-  fer significantly from those of erythrocytes in the normal adult.  The relatively young population of erythrocytes in the newborn  consumes greater quantities of glucose than do erythrocytes in  adults. Several enzymes that regulate glucose consumption are  increased in the erythrocytes of neonates, with a subsequent  increase in the rate of glycolysis.   The lymphocytes of children tend to have more cytoplasm and  less compact nuclear chromatin than do the lymphocytes of  adults. The significance of these differences is unknown. One  possible explanation is that children tend to have more frequent  viral infections, which are associated with atypical lymphocytes.  Even minor infections, in which the child fails to exhibit clinical  manifestations of illness, or administration of immunizations  may result in lymphocyte changes.!   The lymphocyte count is high at birth and continues to rise  in some healthy infants during the first year of life. Then a steady  decline occurs throughout childhood and adolescence until lower  adult values are reached. It is unknown whether these develop-  mental variations are physiologic or are a pathologic response to  frequent viral infections and immunizations in children.   At birth the neutrophil count is very high and rises further  during the early days of life.? After 2 weeks neutrophil counts  fall to within or below normal adult ranges. By approximately  4 years of age the neutrophil count is the same as that of an  adult. White children have slightly higher counts than black  children.’   Eosinophil count is high in the first year of life and is higher  in children than in teenagers or adults.* Monocyte counts are  high in the first year of life and then decrease to adult levels. No  relationship between age and basophil count has been found.  Platelet counts in full-term neonates are comparable to plate-  let counts in adults and remain so throughout infancy and  childhood.°    Decreased stem cell population in marrow (congenital or acquired pure red cell aplasia)  Decreased erythropoiesis despite normal stem cell population in marrow (infection, inflammation, cancer, chronic    renal disease, congenital dyserythropoiesis)  Deficiency of a factor or nutrient needed for erythropoiesis  Cobalamin (vitamin B,,), folate  lron    Alloimmune disease (maternal-fetal Rh, ABO, or minor blood group incompatibility)  Autoimmune disease (idiopathic autoimmune hemolytic anemia, symptomatic systemic lupus erythematosus,   Blood vessel disorders (cavernous hemangioma, large vessel thrombus, renal artery stenosis, severe coarctation of | Hemolytic anemia  the aorta) (see Chapter 33)    Anemia is the most common blood disorder in children. Like  anemia in adults, the anemias of childhood are caused by inef-  fective erythropoiesis or premature destruction of erythrocytes.  The most common cause of insufficient erythropoiesis is iron  deficiency, which may result from insufficient dietary intake  or chronic loss of iron caused by bleeding. The hemolytic ane-  mias of childhood may be divided into two large categories. The  first category consists of disorders that result from premature  destruction caused by intrinsic abnormalities of the erythro-  cytes, and the second category consists of disorders that result  from damaging extraerythrocytic factors. The hemolytic ane-  mias are inherited, congenital, or both.   The most dramatic form of acquired congenital hemo-  lytic anemia is hemolytic disease of the newborn (HDN), also  termed erythroblastosis fetalis. HDN is an alloimmune disor-  der in which maternal blood and fetal blood are antigenically  incompatible, causing the mother’s immune system to produce  antibodies against fetal erythrocytes. Fetal erythrocytes that have  been bound to maternal antibodies are recognized as foreign or  defective by the fetal mononuclear phagocyte system and are  removed from the circulation by phagocytosis, usually in the fetal  spleen. (For a complete discussion of HDN, see p. 1059.) Other  acquired hemolytic anemias—some of which begin in utero—  include those caused by infections or the presence of toxins.   The inherited forms of hemolytic anemia result from intrin-  sic defects of the child’s erythrocytes, any of which can lead to    nherited defects of plasma membrane structure (spherocytosis, elliptocytosis, stomatocytosis) or cellular size or    ntrinsic and inherited enzymatic defects (deficiencies of glucose-6-phosphate dehydrogenase [G6PD], pyruvate emolytic anemia    erythrocyte destruction by the mononuclear phagocyte system.  Structural defects include abnormal red blood cell size and  abnormalities of plasma membrane structure (spherocytosis).  Intracellular defects include enzyme deficiencies, the most com-  mon of which is G6PD deficiency, and defects of hemoglobin  synthesis, which manifest as sickle cell disease or thalassemia,  depending on which component of hemoglobin is defective.  These and other causes of childhood anemia, some more com-  mon than others, are listed in Table 30-2.    Acquired Disorders  lron Deficiency Anemia  Iron deficiency anemia is the most common blood disorder of  infancy and childhood, with the highest incidence occurring  between 6 months and 2 years of age. Incidence is not related  to gender or race, but socioeconomic factors are important  because they affect nutrition, for example, the risk of iron defi-  ciency anemia in children of single, homeless women.° How-  ever, greater use of iron-fortified products has decreased the  prevalence of anemia in low-income infants.’ Iron deficiency  anemia is a common disorder in children because of their  extremely high need for iron for normal growth to occur.  Between 4 years of age and the onset of puberty, dietary iron  deficiency is uncommon. During adolescence, however, it is  relatively common, especially in menstruating females. Rapid  growth, together with the average adolescent’s dietary hab-  its, causes iron depletion. (Mechanisms of iron depletion are  described in Chapter 27.)    PATHOPHYSIOLOGY. Although inadequate intake of iron is the  most common cause of iron deficiency anemia during the first  few years of life and during adolescence, blood loss is the most  common cause in childhood. Chronic iron deficiency anemia  from occult (hidden) blood loss may be caused by a gastroin-  testinal lesion, parasitic infestation, or hemorrhagic disease.  Infants and young children who develop severe iron deficiency  anemia have chronic intestinal blood loss induced by exposure  to a heat-labile protein in cow’s milk. Such exposure causes  an inflammatory gastrointestinal reaction that damages the  mucosa and results in diffuse microhemorrhage.   The amount of iron available for hemoglobin synthesis in  the infant depends on maternal iron stores present at birth,  rate of growth, the amount of dietary iron absorbed, and physi-  ologic or pathologic loss of iron. During the period of inactive  erythropoiesis immediately after birth, iron from erythrocytes  that die at the end of their normal life span is stored, as hemo-  siderin, in bone marrow and liver tissue. This creates an iron  reserve that can be used in lieu of dietary intake. The greatest  stores are present 4 to 8 weeks after birth. Until erythropoie-  sis resumes, these iron stores are mobilized. In the premature  infant, resumption of erythropoiesis depletes iron stores within  6 to 12 weeks; in the full-term infant, depletion takes longer—  about 16 to 20 weeks. Once iron stores have been used, the  infant depends on dietary iron.   The amount of dietary iron available for erythropoiesis  depends on which foods are consumed. Iron-fortified cere-  als, green and yellow vegetables, fruits, and milk are common  in the average 6-month-old infant’s diet and provide iron in  the amount of 0.9 to 1.5 mg/kg/day, amounts that satisfy the  normal average daily requirement. Iron-fortified formulas are  available commercially, and although the amount of iron in  breast milk is low, it is easily absorbed.   CLINICAL MANIFESTATIONS. The symptoms of mild anemia—  lethargy and listlessness—usually are not present or incon-  sequential in infants and young children, who are unable to  describe these symptoms. Therefore, parents usually do not  notice any change in the child’s behavior or appearance until  moderate anemia has developed. General irritability, decreased  activity tolerance, weakness, and lack of interest in play are  nonspecific indications of anemia. In mild to moderate iron  deficiency anemia (hemoglobin of 6 to 10 g/dl), compensatory  mechanisms of tissue oxygenation, such as increased amounts of  2,3-DPG within erythrocytes and a shift of the oxyhemoglobin  dissociation curve, may be so effective that few clinical manifes-  tations are apparent. When the hemoglobin falls below 5 g/dl,  however, pallor, tachycardia, and systolic murmurs often occur.   Splenomegaly is evident in 10% to 15% of children with iron  deficiency anemia, and if the condition is long-standing, the  sutures of the skull may be widened. Chronic anemia also may  result in decreased physical growth and developmental delays.  Some children exhibit pica, a behavior in which nonfood sub-  stances are eaten. Weight is not necessarily an indicator of iron  deficiency anemia because children may be obese, underweight,  or of normal weight.   Iron deficiency anemia may affect neurologic and intellec-  tual function. Decreased iron in the blood may affect attention    span, alertness, and learning ability, even when anemia is not  severe.   EVALUATION AND TREATMENT. The most definitive test for dif-  ferentiating iron deficiency from other microcytic anemias  is the absence of iron stores in the bone marrow. However,  measurement of serum ferritin iron concentration, transfer-  rin saturation, iron-binding capacity, and serum transferrin  receptors often is an adequate diagnostic tool and often pre-  vents proceeding to actual bone marrow evaluation. Evaluation  and treatment of iron deficiency anemia in children are similar  to evaluation and treatment in adults (see Chapter 27). Oral  administration of simple ferrous salts usually is satisfactory, and  additional vitamin C helps promote absorption.® Administra-  tion of supplementary trace metals or other vitamins is not nec-  essary. Iron in a liquid form should be administered through a  straw because it can stain teeth. If malabsorption is the cause of  the anemia (or if oral administration has not been successful),  iron dextran is given intravenously. Iron therapy is continued  for at least 2 months after erythrocyte indexes have returned to  normal in order to replenish iron stores.’   Dietary modification is required to prevent recurrences of  iron deficiency anemia. Intake of iron-rich foods is increased,  and the intake of cow’s milk may be restricted, with the exact  amount depending on the child’s age (from 16 to 32 ounces).  Limiting milk intake makes the child hungrier for other iron-  rich foods and prevents gastrointestinal blood loss in children  whose anemia is aggravated or caused by inflammatory reac-  tions to proteins in cow’s milk.    HDN can occur only if antigens on fetal erythrocytes differ from  antigens on maternal erythrocytes. The antigenic properties of  erythrocytes are determined genetically: they may be type A, B,  or O and may or may not include Rh antigen D. Erythrocytes  that express Rh antigen D are Rh-positive; those that do not are  Rh-negative. The frequency of Rh negativity is higher in whites  (15%) than in blacks (5%), and is rare in Asians. Maternal-fetal  incompatibility exists if mother and fetus differ in ABO blood  type or if the fetus is Rh-positive and the mother is Rh-negative.  (The antigenic properties of erythrocytes are described in  Chapter 9.)   ABO incompatibility occurs in about 20% to 25% of all preg-  nancies, but only 1 in 10 cases of ABO incompatibility results in  HDN. Rh incompatibility occurs in less than 10% of pregnan-  cies and rarely causes HDN in the first incompatible fetus. Even  after five or more pregnancies, only 5% of women have babies  with hemolytic disease. Usually erythrocytes from the first  incompatible fetus cause the mother’s immune system to pro-  duce antibodies that affect the fetuses of subsequent incompati-  ble pregnancies. Only one in three cases of HDN is caused by Rh  incompatibility; most cases are caused by ABO incompatibility.   PATHOPHYSIOLOGY. If the mother and fetus have antigenically  incompatible erythrocytes, HDN will result if the mother’s  blood contains preformed antibodies against fetal erythrocytes  or produces them on exposure to fetal erythrocytes, if suffi-  cient amounts of antibody (usually immunoglobulin G [IgG])  cross the placenta and enter fetal blood, and if IgG binds with    sufficient numbers of fetal erythrocytes to cause widespread  antibody-mediated hemolysis or splenic removal. (Antibody-  mediated red blood cell destruction is discussed in Chapter 9.)   IgM antibodies are formed against the ABO antigen that a  person does not express, the A antigen if the mother is blood  type O or B, or the B antigen if the mother is type O or A. These  antibodies are produced early in life against gastrointestinal  bacteria that make antigens similar to A and B. IgM antibodies  do not cross the placenta or cause HDN. Occasionally a mother  with blood type O may have also produced IgG against the A or  B antigen. If the fetus is blood group A or B, the ABO incom-  patibility can cause HDN in the first pregnancy. HDN is usually  not severe because A and B antigens are expressed on most cells,  including the placenta, and much of the IgG against A or B is  absorbed before encountering fetal blood cells.   Anti-Rh antibodies, on the other hand, are formed only in  response to the presence of incompatible (Rh-positive) eryth-  rocytes in the blood of an Rh-negative mother. Sources of expo-  sure include fetal blood that is mixed with the mother’s blood at  the time of delivery or transfused blood.   The first Rh-incompatible pregnancy usually presents no  difficulties because very few fetal erythrocytes cross the pla-  cental barrier during gestation. However, when the placenta  detaches at birth, large numbers of fetal erythrocytes usually  enter the mother’s bloodstream. If the mother is Rh-negative  and the fetus is Rh-positive, the mother produces anti-Rh anti-  bodies. The capacity of the mother’s immune system to pro-  duce anti-Rh antibodies depends on many factors, including  her genetic capacity to make antibodies against the Rh antigen  D, the amount of fetal-to-maternal bleeding, and the occur-  rence of any bleeding earlier in the pregnancy. Anti-Rh anti-  bodies persist in the bloodstream for a very long time, and if the  next offspring is Rh-positive, the mother’s anti-Rh antibodies  can enter the fetus’s bloodstream and destroy the erythrocytes.  Antibodies against Rh antigen D are of the IgG class and easily  cross the placenta.   IgG-coated fetal erythrocytes are destroyed through extra-  vascular hemolysis, primarily by mononuclear phagocytes in  the spleen. As hemolysis progresses, the fetus becomes anemic.  Erythropoiesis accelerates, particularly in the liver and spleen,  and immature nucleated cells (erythroblasts) are released into  the bloodstream, hence the name erythroblastosis fetalis (Figure  30-2). The degree of anemia depends on the length of time the  antibody has been in the fetal circulation, antibody concentra-  tion, and the ability of the fetus to compensate for increased  hemolysis. Unconjugated (indirect) bilirubin, which is formed  during breakdown of hemoglobin, is transported across the  placental barrier into the maternal circulation and is excreted  by the mother. Hyperbilirubinemia occurs in the neonate after  birth because excretion of lipid-soluble unconjugated bilirubin  through the placenta no longer is possible.   The pathophysiologic effects of HDN are more severe in Rh  incompatibility than in ABO incompatibility. ABO incompat-  ibility may resolve after birth without life-threatening compli-  cations. Maternal-fetal incompatibility in which a mother with  type O blood has a child with type A or B blood usually is so  mild that it does not require treatment.    FIGURE 30-2 Rh Incompatibility in Hemolytic Disease of the Newborn.  This micrograph shows immature red blood cells not normally found in blood. Large  purple cells are erythroblasts; nucleated red blood cells are normoblasts. Normal  red blood cells also are shown (x 500). (Copyright Ed Reschke.)    Rh incompatibility is more likely than ABO incompatibility  to cause severe or even life-threatening anemia, death in utero,  or damage to the central nervous system (CNS). Severe anemia  alone can cause death as a result of cardiovascular complications  (see Chapter 28). Extensive hemolysis also results in increased  levels of unconjugated bilirubin in the circulation. If bilirubin  levels exceed the liver’s ability to conjugate and excrete bilirubin,  some of it is deposited in the brain, causing cellular damage and  eventually death, if exchange transfusions are not administered.   Fetuses that do not survive anemia in utero usually are still-  born, exhibiting gross edema throughout the entire body, a  condition called hydrops fetalis. Death can occur as early as 17  weeks of gestation and results in spontaneous abortion.   CLINICAL MANIFESTATIONS. Neonates with mild HDN may  appear healthy or slightly pale, with slight enlargement of the  liver and spleen. Pronounced pallor, splenomegaly, and hepato-  megaly indicate severe anemia, which predisposes the neonate  to cardiovascular failure and shock. Life-threatening Rh incom-  patibility is rare today, largely because of maternal testing and  the routine use of Rh immune globulin.   Because maternal antibodies remain in the neonatal circu-  lation after birth, erythrocyte destruction can continue. This  causes hyperbilirubinemia and icterus neonatorum (neonatal  jaundice) that occurs shortly after birth. Without replacement  transfusions, in which the child receives Rh-negative erythro-  cytes, the bilirubin is deposited in the brain, causing a condition  termed kernicterus. Kernicterus produces cerebral damage and  usually causes death (icterus gravis neonatorum). Infants who  do not die may have significant developmental delay, cerebral  palsy, or high-frequency deafness.   EVALUATION AND TREATMENT. Routine evaluation for HDN  includes the Coombs test. The indirect Coombs test measures  antibody in the mother’s circulation and indicates whether the  fetus is at risk for HDN. The direct Coombs test measures anti-  body already bound to the surfaces of fetal erythrocytes and is  used primarily to confirm the diagnosis of antibody-mediated  HDN. Determining prior history of fetal hemolytic disease,  as well as diagnostic tests, may help predict the severity of the    FIGURE 30-3 Hemolytic Disease of the Newborn (HDN). A, Before or during delivery, Rh-positive erythrocytes from the  fetus enter the blood of an Rh-negative woman through a tear in the placenta. B, The mother is sensitized to the Rh antigen  and produces Rh antibodies. Because this usually happens after delivery, there is no effect on the fetus in the first pregnancy.  C, During a subsequent pregnancy with an Rh-positive fetus, Rh-positive erythrocytes cross the placenta, enter the maternal  circulation, and (D) stimulate the mother to produce antibodies against the Rh antigen. The Rh antibodies from the mother  cross the placenta, using agglutination and hemolysis of fetal erythrocytes, and HDN develops. (Modified from Seeley RR,  Stephens TD, Tate P: Anatomy and physiology, ed 3, St Louis, 1995, Mosby.)    disorder. Diagnostic measures include maternal antibody titers,  fetal blood sampling, amniotic fluid spectrophotometry, and  ultrasound fetal assessment. !°   The key to treatment of HDN resulting from Rh incompatibil-  ity lies in prevention (immunoprophylaxis). Rh immune globu-  lin (RhoGAM), a preparation of antibody against Rh antigen D  administered within 72 hours of exposure to Rh-positive erythro-  cytes, ensures that the mother will not produce antibody against  the D antigen, and the next Rh-positive baby will be protected  (Figure 30-3). The injected antibodies remain in the mother’s  bloodstream long enough to prevent her immune system from  producing its own anti-Rh antibodies but not long enough to affect  subsequent offspring. The mother must be given Rh immune  globulin injections after the birth of each Rh-positive baby and  after a miscarriage. The mother must be especially careful not to  receive a transfusion containing Rh-positive blood, because this  would stimulate production of anti-Rh antibodies. In many hos-  pitals Rh immune globulin is given prophylactically at 28 weeks to  all pregnant Rh-negative women with Rh-positive partners. Vari-  ous international recommendations suggest that antenatal anti-D    prophylaxis should be administered to unsensitized Rh(D)-nega-  tive women as a complement to postpartum prophylaxis.!!   If antigenic incompatibility of the mother’s erythrocytes  is not discovered in time to administer Rh immune globulin  and a child is born with HDN, treatment consists of exchange  transfusions in which the neonate’s blood is replaced with new  Rh-positive blood that is not contaminated with anti-Rh anti-  bodies. This treatment is instituted during the first 24 hours of  extrauterine life to prevent kernicterus. Phototherapy also is  used to reduce the toxic effects of unconjugated bilirubin.   Jaundice and indirect hyperbilirubinemia are reduced when  the infant is exposed to high-intensity light in the visible spec-  trum from 420 to 470 nm. Bilirubin in the skin absorbs light  energy, which, by photoisomerization, converts the toxic  unconjugated bilirubin into conjugated isomers that are  excreted in the bile. Phototherapy also causes autosensitization  that results in oxidation reactions. Breakdown products from  the oxidation reactions are excreted by the liver and kidney  without need for conjugation. The therapeutic effect of pho-  totherapy depends on the light energy emitted in the effective    wavelengths, the distance between the infant and the light  source, and the amount of skin exposed; the rate of hemoly-  sis and the infant’s ability to excrete bilirubin also are factors  in determining the effectiveness of phototherapy in lowering  serum bilirubin levels.    Infections of the newborn, often initially acquired by the  mother and transmitted to the fetus, may result in a hemolytic  anemia with clinical manifestations similar to those of HDN.  Congenital syphilis, toxoplasmosis, cytomegalic inclusion dis-  ease, rubella, coxsackievirus B infection, herpesvirus infection,  and bacterial sepsis can cause hemolytic anemia in the neonate.   The exact mechanism of anemia caused by congenital infec-  tions is unclear. In some instances it is related to direct injury of  erythrocyte membranes or erythrocyte precursors by the infec-  tious microorganism. In other instances it results from trau-  matic destruction of erythrocytes during their passage through  inflamed capillaries.    Anemia is a common occurrence in critically ill children (see  Chapter 49). The causes are numerous and include decreased  erythropoietin activity, poor iron use by the body, and blood  loss from diverse conditions and consequences of treatment. A  topic of discussion is anemia has been shown to worsen patient  outcomes presumably because of decreased oxygen delivery.  Controversial is whether transfusion of blood products, par-  ticularly packed RBCs, improve outcomes because of problems  related to blood storage. New research is ongoing and needed  to understand these problems, the development of new blood  transfusion strategies, and blood substitutes.'!*    A number of inherited and intrinsic erythrocyte defects are  known to cause increased hemolysis (see Table 30-2). These  defects may be associated with enzymatic abnormalities that  disrupt metabolic processes and prevent normal biochemical  balance within the cell, with alterations of hemoglobin struc-  ture or synthesis, or with plasma membrane defects accompa-  nied by changes in erythrocyte size or shape.    Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an  inherited, X-linked recessive disorder, most fully expressed in  homozygous males, although partial expression and a carrier  state are possible in heterozygous females. (X-linked inheri-  tance is discussed in Chapter 4.) The deficiency is present in  10% of blacks and tends to occur in Sephardic Jews, Greeks,  Iranians, Chinese, Filipinos, and Indonesians, with a frequency  ranging from 5% to 40%.   PATHOPHYSIOLOGY. G6PD is an enzyme that normally enables  erythrocytes to maintain metabolic processes despite injury,  such as the presence of certain drugs (sulfonamides, antimalar-  ial agents, salicylates, or naphthaquinolones); ingestion of fava  beans (a dietary staple in some Mediterranean areas); hypox-  emia; infection; fever; or acidosis. Therefore, G6PD deficiency is    usually asymptomatic unless one of these events occurs. Eryth-  rocyte damage in affected children begins after intense or pro-  longed exposure to one of these substances or conditions, and  it will cease when they are removed. In black males the G6PD  defect becomes more pronounced as the erythrocyte ages and in  other populations the defect is profound even in young erythro-  cytes. By ingesting a substance with oxidant properties, such as  a salicylate (aspirin), a pregnant woman may cause an episode  of hemolysis in a fetus with G6PD deficiency.   In the absence of G6PD, oxidative stressors damage hemo-  globin and the plasma membranes of erythrocytes and possibly  interfere with the activities of other enzymes within the cell.  Hemoglobin is oxidized progressively to methemoglobin, sulf-  methemoglobin, and denatured globin-glutathione complexes.  Eventually, exposure to oxidating substances results in the pre-  cipitation of insoluble hemoglobin inclusions, called Heinz bod-  ies, within the cell. Plasma damage and the presence of Heinz  bodies cause hemolysis, primarily in the spleen.   CLINICAL MANIFESTATIONS. In Asian and Mediterranean infants,  G6PD deficiency is likely to be associated with icterus neonato-  rum. The most common clinical manifestation of G6PD defi-  ciency is acute hemolytic anemia, usually after infections or the  ingestion of certain oxidative drugs. The fava bean produces a  severe hemolytic reaction in infants with G6PD deficiency.   Hemolytic episodes are characterized by pallor, icterus, dark  urine, back pain, and, in severe cases, shock, cardiovascular col-  lapse, and death. Between hemolytic episodes, the child does  not have anemia and erythrocyte survival is normal.   EVALUATION AND TREATMENT. Reduced G6PD activity in eryth-  rocytes is required for diagnosis. Immediately after a hemo-  lytic episode, reticulocytes and young erythrocytes are evident.  Because young erythrocytes have significantly higher enzyme  activity than do older cells, laboratory evaluation should be  performed shortly after a crisis so that a low level of enzyme  activity can be demonstrated. G6PD activity that is within the  low normal range in the presence of a high reticulocyte count  suggests G6PD deficiency. G6PD deficiency also can be detected  by electrophoretic analysis.   Prevention of hemolysis is the most important therapeutic  measure. Males from high-risk groups (Greeks, southern Ital-  ians, Sephardic Jews, Filipinos, Chinese, Africans, Thais) should  be tested for the defect before being given drugs known to be  oxidative. When hemolysis occurs supportive treatment may  include blood transfusions and oral iron therapy. Spontaneous  recovery generally follows treatment.    Hereditary spherocytosis (HS), also known as congenital  hemolytic anemia or congenital acholuric jaundice, is the most  common of the hemolytic disorders in which there is no hemo-  globin abnormality.   PATHOPHYSIOLOGY. Transmitted as an autosomal dominant  trait, HS represents approximately new mutations in about  25% of cases. The defect is believed to be caused by an unde-  fined abnormality in the erythrocyte membrane. Affected cells  are overly permeable to sodium and acquire a particular char-  acteristic structure (Figure 30-4). An increased concentration of    FIGURE 30-4 The Microspherocyte. A, Blood smear from individual with  hereditary spherocytosis (Wright stain). B, Scanning electron micrograph. (A from  Hoffbrand AV, Pettit JE, Vyas P: Color atlas of clinical hematology, ed 4, Phila-  delphia, 2009, Mosby. B courtesy Dr. M. Bessis. In Miale JB, editor: Laboratory  medicine: hematology, ed 6, St Louis, 1982, Mosby.)    intracellular sodium is believed to lead to increased use of ade-  nosine triphosphate (ATP) to drive the so-called cation pump.  Early aging or destruction of erythrocytes is believed to result  from metabolic overwork and loss of erythrocyte membrane.   The spleen is intimately involved in the hemolytic process.  The spherocyte is relatively rigid and passes with difficulty  through the small openings between the splenic cords and  sinuses. Circulation of blood to the spleen creates repeated  circulation through a metabolic environment that results in  sequestration and destruction of spherocytes.   CLINICAL MANIFESTATIONS. The presenting signs of HS are ane-  mia, jaundice, and splenomegaly. Anemia may be mild or absent  in some cases depending on physiologic compensation. If this  is the case the reticulocyte count will be elevated. Splenomegaly  is usually mild. HS can present at any age, from the neonatal  period until older adulthood. More severe types of HS present  during the newborn period when the infant develops signs of  hemolytic anemia and hyperbilirubinemia.'* These children  therefore may have life-threatening anemia with clinical symp-  toms ranging from difficulty feeding, circumoral pallor, tachy-  cardia, nasal flaring, diaphoresis, and lethargy. They also are at  increased risk for gallstones because of the presence of extra bile  pigment. Infection (specifically parvovirus),'* fever, and stress    stimulate the spleen to destroy more red blood cells than usual,  leading to a worsening anemia in an already baseline anemic  child.   EVALUATION AND TREATMENT. It is important to ascertain fam-  ily history of spherocytosis. Laboratory findings include sphe-  rocytes in the peripheral blood smear, elevated reticulocyte  count (with or without anemia), indirect hyperbilirubinemia,  and a positive osmotic fragility test. An osmotic fragility test  is performed by placing red blood cells in a saline solution for  24 hours. Spherocytes do not tolerate saline solutions, thus  causing them to burst more readily than normal red blood cells.  Treatment of HS is based on disease severity. Although some  children with HS will have severe anemia, blood transfusions  are rarely required. Treatment before the age of 5 years consists  of daily folic acid supplementation to increase production of  healthy red blood cells. In the past, splenectomy was the first  line of treatment. Currently, however, splenectomy is only rec-  ommended for those children more than 5 years of age with  severe disease or those who develop symptomatic gallstones.  Partial splenectomy, in which only a portion of the spleen is  removed, is being performed on children with HS in an attempt  to decrease the risk of postsplenectomy complications.'*   Sickle cell disease (SCD) is a group of disorders character-  ized by the presence of an abnormal form of hemoglobin—  hemoglobin S (HbS)—within the erythrocytes. Hb S is formed  by a genetic mutation in which one amino acid (valine) replaces  another (glutamic acid) (Figure 30-5, A). Hb S, also known as  sickle hemoglobin, reacts to deoxygenation and dehydration  by solidifying and stretching the erythrocyte into an elongated  sickle shape. This change causes a variety of pathologic conse-  quences, including hemolytic anemia.   SCD is an inherited autosomal recessive disorder that is  expressed as sickle cell anemia, sickle cell—-thalassemia disease,  or sickle cell-Hb C disease, depending on mode of inheritance  (Table 30-3). (See Chapter 4 for a discussion of genetic inheri-  tance of disease.) Sickle cell anemia, a homozygous form, is the  most severe. Sickle cell-thalassemia disease and sickle cell-Hb  C disease are heterozygous forms in which the child simultane-  ously inherits another type of abnormal hemoglobin from one  parent. Sickle cell trait, in which the child inherits Hb S from  one parent and normal hemoglobin (Hb A) from the other, is  a heterozygous carrier state that rarely has clinical manifesta-  tions. All forms of SCD are lifelong conditions. Bone marrow or  stem cell transplants can cure sickle cell anemia. However, they  are currently not an option for most children because it is often  difficult to find well-matched stem cell donors.   SCD tends to occur in people with origins in equatorial  countries, particularly central Africa, the Near East, the Medi-  terranean, and parts of India. In the United States, about 1 out  of 500 black children and 1:36,000 Hispanic-American born  have sickle cell anemia. Most infants with SCD born in the  United States are now identified by routine neonatal screen-  ing. Sickle cell trait occurs among about 1:12 blacks and 1:100  Hispanic-Americans. It is estimated that 2.5 million Americans  are heterozygous carriers for the sickle cell trait.'° The sickle cell   | tension decreases. 2 | Preferential adhesion of  sickled cells to endothelial cell  surfaces increases with peripheral  resistance and causes narrowing  of the vascular lumen.    Sickle cell anemia is determined by the substitution of normal  hemoglobin (Hb A) by hemoglobin S (Hb S) caused by a point  mutation (replacement of the nucleotide triplet CTC coding   glutamic acid at the mRNA level [GAG] by the CAC triplet [GUG]  coding for valine) that modifies the physicochemical properties of the  B-globin chain of hemoglobin. All hemoglobin is abnormal in  homozygous individuals for the mutant gene, and red blood cells    GJ Hemolysis caused by  precipitation of Hb and dissociation of  the red blood cell plasma membrane  from the subjacent cytoskeleton.    show a sickling deformity and hemolytic anemia in the presence or  absence of normal oxygen tension. Heterozygous individuals contain a  mixture of Hb A and Hb S, and sickling and anemia are observed  when the tension of oxygen decreases.   Irreversibly sickled red blood cells are trapped within the splenic  sinusoids and are destroyed by adjacent macrophages. Hemolysis may  also occur in the macrophage-sheathed capillaries of the red pulp.    FIGURE 30-5 Sickle Cell Hemoglobin. A, Sickle cell hemoglobin is produced by a recessive allele of the gene encoding  the B-chain of the protein hemoglobin. It represents a single amino acid change—from glutamic acid to valine at the sixth  position on the chain. In this model of a hemoglobin molecule, the position of the mutation can be seen near the end of the    a red blood cell containing the abnormal hemoglobin. (A from Raven PH, Johnson GB: Biology, ed 3, St Louis, 1992, Mosby.  B copyright Dennis Kunkel Microscopy, Inc. € from Miale JB: Laboratory medicine: hematology, ed 6, St Louis, 1982, Mosby.)   Hb S  Hb S Hb C or D (both abnormal Hb)    *See Chapter 27 for a description of normal fetal and adult hemoglobins.    FIGURE 30-6 Normal and Sickle-Shaped Blood Cells. Scanning electron  micrograph of normal and sickle-shaped red blood cells. The irregularly shaped  cells are the sickle cells; the circular cells are the normal blood cells. (From Raven  PH, Johnson GB: Biology, ed 3, St Louis, 1992, Mosby.)    trait may provide protection against lethal forms of malaria, a  genetic advantage to carriers who reside in endemic regions for  malaria (Mediterranean and African zones) but no advantage to  carriers living in the United States.   PATHOPHYSIOLOGY. Deoxygenation is probably the most  important variable in determining the occurrence of sickling.  The degree of deoxygenation required to produce sickling var-  ies with the percentage of Hb S in the cells. Sickle trait cells will  sickle at oxygen tensions of about 15 mmHg, whereas those  from an individual with SCD will begin to sickle at about 40  mmHg. Hb S that is not bound with oxygen forms aggregates  of semisolid gel that become stacked within the erythrocyte,  stretching it into an elongated crescent (see Figure 30-5, C;  Figure 30-6). Sickled erythrocytes are stiff and cannot change  shape as easily as normal cells when they pass through the  microcirculation. (The reversible deformability of erythrocytes  is described in Chapter 27.) As a result, sickled erythrocytes tend  to plug the blood vessels, causing vascular occlusion, pain, and  organ infarction. Sickled cells undergo hemolysis in the spleen  or become sequestered there, causing blood pooling and infarc-  tion of splenic vessels. The anemia that follows triggers erythro-  poiesis in the marrow and, in extreme cases, in the liver.'°   Most sickled erythrocytes regain a normal shape after reox-  ygenation and rehydration. Irreversible sickling is not caused    Defective or insufficient a.- or B-chains of Sic  Hb A (alpha- or beta-thalassemia)    Hb is mostly Hb S, with the remainder fetal hemoglobin (Hb F)    e cell: thalassemia disease (heterozygous inheritance of  Hb S and alpha- or beta-thalassemia)   Sickle cell: Hb C (or D) disease (heterozygous inheritance of  Hb S and either Hb C or Hb D)   Sickle cell trait, the carrier state (heterozygous inheritance of  Hb S and normal Hb)    by irreversible hemoglobin changes but rather by irreversible  plasma membrane damage caused by sickling. The precise  nature of the permanent membrane injury is not known, but it  is known that while in the sickled state, the plasma membrane  loses some of its capacity for active transport, permitting an  influx of calcium ions. (Membrane transport and the effects of  calcium influx are described in Chapters 1 and 2.) In people  with sickle cell anemia, in which the erythrocytes contain a high  percentage of Hb S (75% to 95%), up to 30% of the erythro-  cytes can become irreversibly sickled. Occasionally, irreversible  sickling occurs in SCD but not in children with sickle cell trait.   Sickling is an occasional, intermittent phenomenon that can  be triggered or sustained by one or more of the following stress-  ors: decreased oxygen tension (Po ) of the blood (i.e., hypox-  emia), increased hydrogen ion concentration in the blood  (decreased pH), increased plasma osmolality, decreased plasma  volume, and low temperature (Figure 30-7).   The same decrease in Po, will cause the most sickling in per-  sons with sickle cell anemia (high concentrations of Hb S), the    second most in children with sickle cell thalassemia, the third  most in those with sickle cell-Hb C disease, and the least or  none in those with sickle cell trait. The duration of the Po,  decrease also is important, because sickling tends to occur only  after the inciting stimulus has been present for some time.   The level of Po, in the microcirculation also affects sickling  because hemoglobin releases the oxygen it is carrying to tissues.  The Po, normally is lower in the microcirculation. The added  reduction in Po, caused by persistent hypoxemia—induced  by stressors—eventually results in sickling in the microcircu-  lation of all cells that contain Hb S in that site (not through-  out the body). Sickling within the microcirculation decreases  blood flow as sickled cells clog the vessels. Reduced blood flow  causes hypoxemia to worsen and perpetuates sickling. Finally,  decreased blood pH reduces hemoglobin’s affinity for oxygen.  As less oxygen is taken up by hemoglobin in the lungs, Po,  drops, promoting additional sickling.   Polymerization of sickle hemoglobin is central to the disor-  der. Polymerization stiffens the sickled erythrocyte, changing  it from a flexible, beneficial cell to an inflexible one that starves  and damages tissues.   Increased osmolality of the plasma (increased concentration  of solutes; see Chapters 1 and 3) draws water out of the eryth-  rocytes. This promotes sickling by raising the relative Hb S con-  tent in erythrocytes. Decreased plasma volume, which occurs in  states of dehydration, causes the blood to become viscous (thick  and sticky). Increased viscosity of the blood is the final com-  mon pathway leading to many pathologic effects. Viscous blood  flows slowly and promotes vascular obstruction by increasing  opportunities for sickling while decreasing opportunities for  reoxygenation in the lungs. This is an example of positive feed-  back in a vicious cycle of events. Low temperatures precipitate  sickle crisis, presumably because of vasoconstriction. !”   Once sickling begins, it tends to continue until Po, returns to  normal; then it ceases spontaneously. The extent, severity, and  clinical manifestations of sickling depend to a great extent on  the percentage of hemoglobin that is Hb S. That is why homozy-  gous inheritance of Hb S produces the severest form of SCD—  sickle cell anemia. Heterozygous inheritance of SCD results in  less sickling because the individual’s erythrocytes contain other  forms of abnormal hemoglobin that although defective, do not  contribute to sickling to any great degree. Heterozygous inheri-  tance (sickle cell trait), in which abnormal hemoglobin is inher-  ited from one parent and normal hemoglobin from the other,  rarely results in sickling because normal Hb F and Hb A do not  contribute to sickling at all. Anemia persists because Hb F does  not live 120 days.   CLINICAL MANIFESTATIONS. Clinical manifestations of SCD may  first be seen at 6 to 12 months of age as fetal hemoglobin is  replaced by Hb S. Two characteristics of SCD determine pre-  sentation: the first is its nature to be a chronic disease with acute  exacerbations; the second is that it is a condition affecting RBCs  that supply oxygen to all cells of the body. Therefore, SCD can  affect any part of the body. When sickling occurs, the general  manifestations of hemolytic anemia—pallor, fatigue, jaundice,  and irritability—sometimes are accompanied by acute manifes-  tations called crises. Extensive sickling can precipitate four types    of crises: (1) vaso-occlusive (or thrombotic) crisis, (2) aplastic  crisis, (3) sequestration crisis, or rarely (4) hyperhemolytic cri-  sis. Sites of specific dysfunction are shown in Figure 30-8.   Vaso-occlusive crisis (thrombotic crisis) begins with  sickling in the microcirculation. As blood flow is obstructed  by tangled masses of rigid, sickled cells, vasospasm occurs  and a “log jam” effect brings all blood flow through the ves-  sel to a halt. Unless the process is reversed, thrombosis and  infarction (death caused by lack of oxygen) of local tissue  follow. Vaso-occlusive crisis is extremely painful and may  last for days or even weeks, with an average duration of 4  to 6 days. The frequency of this type of crisis is variable and  unpredictable.   Vaso-occlusive crises may develop spontaneously or be pre-  cipitated by infection, exposure to cold, dehydration, low Po,  acidosis (low pH), or localized hypoxemia. Symmetric, pain-  ful swelling of the hands and feet (hand-foot syndrome) caused  by infarction in the small vessels of the extremities often is the  initial manifestation of SCD in infancy. In older children and  adults the large joints and surrounding tissue become painful  and swollen. Priapism (persistent erection of the penis) may  occur if penile veins become obstructed. Severe abdominal  pains often are caused by infarction in abdominal structures.  Strokes resulting from cerebral occlusion may leave the child  with paralysis (usually hemiplegia) or other CNS deficits.   Aplastic crisis, a transient cessation in red blood cell pro-  duction resulting in acute anemia, occurs as a result of a viral  infection, almost always infection with parvovirus B19, which  is the virus responsible for the common childhood infection  known as fifth disease. The virus causes temporary shutdown of  RBC production in the bone marrow. However, hemolysis, the  destruction of RBCs, continues. The outcome is a severe drop in  hemoglobin with an extremely low reticulocyte count.   In sequestration crisis large amounts of blood become  pooled in the liver and spleen. This type of crisis is seen only in  young children. Because the spleen can hold as much as one fifth  of the blood supply at one time, mortality rates up to 50% have  been reported, with death caused by cardiovascular collapse. If  blood volume and pressure are maintained by hydration and  blood transfusion, much of the sequestered blood eventually  returns to circulation. Removal of the spleen is the treatment  for recurrent sequestration crises and may be performed after  the child reaches 5 years of age.'®   Hyperhemolytic crisis, an accelerated rate of RBC destruc-  tion, is unusual but may occur in association with certain  drugs or infections. It is characterized by anemia, jaundice, and  reticulocytosis. The concomitant presence of G6PD deficiency  (see p.1062) contributes to hyperhemolytic episodes, especially  when combined with infections.   Acute chest syndrome is the presence of a new pulmonary  infiltrate (not atelectasis), involving at least one complete lung  segment and chest pain, a temperature of more than 38.5° C  (101.3° F) increased respiratory rate (tachypnea), wheezing, or  cough. Sickled RBCs attach to the endothelium of the injured,  underventilated, and inflamed lung and, as they fail to be reox-  ygenated, will eventually undergo additional inflammation  and lung infarction. The prognosis is poor, and infarction is a    Bones and joints  Hand-foot syndrome  (painful swelling of  hands and feet)    leading cause of morbidity. Acute chest syndrome is the cause of  death in approximately 25% of all deaths in people with SCD.'”   Infection is the most common cause of death resulting from  SCD. Sepsis and meningitis develop in as many as 10% of chil-  dren with sickle cell anemia during the first 5 years of life, with a  mortality rate of 25%. Survival time is unpredictable, and many  young adults die in their 20s.   Glomerular disease, characterized by damage to the glom-  eruli allowing protein and often red blood cells to leak into the  urine, is caused by sickling of red blood cells in the kidneys.    Extensive damage to the glomeruli results in nephropathy that  may progress to renal failure. The earliest manifestation of SCD  in the kidney is hyposthenuria, or the inability of the tubules of  the kidneys to concentrate urine. Very low urine specific gravity  occurs and in young children this often results in bed-wetting.  Proteinuria also is an early manifestation of sickle nephropathy.   Cholecystitis, inflammation of the gallbladder that occurs  when a gallstone blocks the cystic duct, can be caused by hemo-  lysis resulting in an increase of bilirubin, which in turn causes  the formation of gallstones in the gallbladder. The presence of    gallstones can cause right upper quadrant pain, nausea, vomit-  ing, and an elevated white blood cell count and alkaline phos-  phatase. Cholecystectomy may be required.   Sickle cell-Hb C disease is usually milder than sickle cell ane-  mia. The peripheral blood smear reveals many target cells result-  ing from the presence of Hb C. The main clinical problems are  related to vaso-occlusive crises and are believed to result from  higher hematocrit values and viscosity. In older children, sickle  cell retinopathy, renal necrosis, and aseptic necrosis of the fem-  oral heads occur along with obstructive crises.   Sickle cell-thalassemia has the mildest clinical manifesta-  tions of all the SCDs. Even though most of the child’s hemo-  globin is Hb S (60% to 90%), normal hemoglobins (Hb A and  Hb F) also are present. The normal hemoglobins, particularly  Hb F, inhibit sickling. In addition, the erythrocytes tend to be  small (microcytic) and to contain relatively little hemoglobin  (hypochromic). Their small size makes them less likely than  normal-size cells to clog the microcirculation, even when in a  sickled state.   The sickle cell trait does not affect life expectancy or interfere  with daily activities. However, on rare occasions, severe hypoxia  caused by shock, vigorous exercising at high elevations, flying  at high altitudes in unpressurized aircraft, or undergoing anes-  thesia is associated with vaso-occlusive episodes in individuals  with sickle cell trait. These cells form an ivy shape instead of a  sickle shape.   EVALUATION AND TREATMENT. The parents’ hematologic his-  tory and clinical manifestations may suggest that a child has  SCD, but hematologic tests are necessary for diagnosis. If the  sickle solubility test confirms the presence of Hb S in peripheral  blood, hemoglobin electrophoresis provides information about  the amount of Hb S in erythrocytes. Prenatal diagnosis can be  made by chorionic villus sampling as early as 8 to 10 weeks of  gestation or amniotic fluid analysis at 15 weeks of gestation.  Newborn screening for SCD should be performed according to  state law.   Treatment advances since the late 1980s have significantly  decreased morbidity and mortality in children with SCD.  Aggressive management of fever, early diagnosis of acute chest  syndrome (hypoxia, anemia, progressive multilobar pneumo-  nia, fat emboli), red blood cell transfusions, and proper pain  management can improve quality of life and prognosis for these  children. Treatment of SCD consists of supportive care aimed  at preventing consequences of anemia and avoiding crises.  Crises can be prevented by avoiding fever, infection, acidosis,  dehydration, constricting clothes, and exposure to cold. Imme-  diate correction of acidosis and dehydration with appropriate  intravenous fluids is imperative. In addition to routine child-  hood immunizations, children with SCD should receive an  annual influenza vaccine and also pneumococcal and meningo-  coccal vaccine series to prevent infection (Box 30-1). Infections  require aggressive antibiotic therapy. Oxygen is not needed  unless the child becomes hypoxic. Pain associated with SCD is  very complex, requiring accurate assessment and multimodal  management.”?   Protocols to implement individual-controlled analgesia in  the emergency department shorten the time of initiation of    A systematic review was conducted to determine the efficacy of pneumococ-  cal vaccines in preventing morbidity and mortality in patients with sickle cell  disease. Two authors searched the Cochrane Cystic Fibrosis and Genetic Dis-  orders Group Trials Register and critically reviewed and determined the quality    of randomized and quasi-experimental trials that compared a polysaccharide  or conjugate pneumococcal vaccine to a different regimen or no vaccine. Nine  trials including 547 participants were included. Overall results suggest that  the vaccine is able to induce an immune response in these patients. Clinical  outcomes of effectiveness still need to be determined, but the vaccine is safe  to use in children.    Data from Davies EG et al: Cochrane Database Syst Rev 2012(2), 2012.    BOX 30-2 DIFFERENT TYPES OF  SPLENECTOMY IN CHILDREN  WITH CONGENITAL HEMOLYTIC  ANEMIAS    The purpose of this study was to evaluate the effectiveness of partial or total  splenectomy on hematologic function and adverse events in children with    sickle cell disease, hereditary spherocytosis, and thalassemias. The methodol-  ogy of 93 studies was assessed on the basis of the Agency for Healthcare  Research and Quality criteria. No hematologic advantage was determined  between the types of splenectomy; however, adverse events were minimized  with the use of laparoscopy. Results determined there is a need for additional  randomized controlled trials, but both partial and total splenectomy appears  to be effective.    narcotic therapy and are preferred by individuals.”! Hydroxy-  urea increases Hb F synthesis in individuals with sickle cell ane-  mia and increases hemoglobin and mean corpuscular volume  while decreasing reticulocytes and bilirubin. It is safe and well  tolerated and has been used successfully in children for more  than 10 years.’? To avoid increased acidosis, acetaminophen is  preferable to salicylates for antipyretic therapy. Blood transfu-  sion, including hypertransfusion therapy (e.g., packed RBCs to  raise the hematocrit to a level of 35% for a period of time), can  be effective but must be weighed against the risks of hemosid-  erosis and iron and splenic overload. Oral maintenance ther-  apy with folic acid is needed to meet the increased demands of  chronic hemolytic anemia. Laparoscopic splenectomy has been  demonstrated to be safe and effective in children with recurrent  sequestration crises and is associated with minimal complica-  tions, zero mortality, and a short hospital stay. Partial splenec-  tomy has been recently evaluated and appears to be successful  in children (Box 30-2). The most definitive approach to the  treatment of SCD requires a permanent alteration in the hemo-  globin phenotype. This can be accomplished through stem cell  transplantation, although well-matched donors are difficult to  identify.   Genetic counseling and psychologic support are important  for the child and family. Recently, a genetic technique called pre-  implantation genetic diagnosis has been performed on parents    FIGURE 30-9 Prepregnancy sickle cell test. (This technique has potential for other inherited diseases.) 1, Fertilization  produces several embryos. 2, The embryos are tested for the presence of the gene. 3, The embryo(s) without the gene are  implanted. 4, Amniocentesis confirms whether the fetus (or fetuses) has the sickle cell gene. 5, Woman has a normal child.    to diagnose whether their offspring will carry the gene for SCD.  Figure 30-9 summarizes this prepregnancy sickle cell test. Genetic  counseling enables people with SCD or trait to make informed  decisions about transmitting this genetic disorder to their off-  spring because there is a 25% chance with each pregnancy that  a child born to two parents with sickle cell trait will have SCD.    The alpha- and beta-thalassemias are inherited autosomal  recessive disorders that cause an impaired rate of synthesis of  one of the two chains—a or B—of Hb A. The disorder was  named thalassemia, which is derived from the Greek word for  sea, because it was defined initially in people with origins near  the Mediterranean Sea. Beta-thalassemia, in which synthesis of  the B-globin chain is slowed or defective, is prevalent among  Greeks, Italians, and some Arabs and Sephardic Jews. Alpha-  thalassemia, in which the a-chain is affected, is most common  among Chinese, Vietnamese, Cambodians, and Laotians. Both  alpha- and beta-thalassemia are common among blacks.   Alpha- and beta-thalassemia is characterized as major or  minor, depending on how many of the genes that control  a- or §-chain synthesis are defective and whether the defects  are inherited homozygously (thalassemia major) or hetero-  zygously (thalassemia minor). Pathophysiologic effects range  from mild microcytosis to death in utero, depending on the  number of defective genes and mode of inheritance. Anemia  associated with thalassemia is microcytic-hypochromic hemo-  lytic anemia.   PATHOPHYSIOLOGY. Normally two genes control f-chain syn-  thesis and four genes control a-chain synthesis. The number of  genetic defects in the controlling genes determines the severity  of the disorder. As in SCD the hemoglobin abnormality usually  consists of the substitution of a single amino acid for another  amino acid. Other molecular abnormalities that cause thalas-  semia are two amino acid substitutions, amino acid deletions or  fusions, and synthesis of elongated chains.    The fundamental defect in beta-thalassemia is the uncoupling  of a- and 6-chain synthesis. }-Chain production is depressed—  moderately in the heterozygous form, beta-thalassemia minor,  and severely in the homozygous form, beta-thalassemia major  (also called Cooley anemia). Depression of B-chain synthesis  results in erythrocytes having a reduced amount of hemoglo-  bin and accumulations of free a-chains. The free a-chains are  unstable and easily precipitate in the cell. Most erythroblasts  that contain precipitates are destroyed by mononuclear phago-  cytes in the marrow, resulting in ineffective erythropoiesis and  anemia. Some of the precipitate-carrying cells do mature and  enter the bloodstream, but they are destroyed prematurely in  the spleen, resulting in mild hemolytic anemia.   1. Alpha trait (the carrier state), in which a single a-chain—   four alpha-forming genes are defective; death is inevi-  table because a-chains are absent and oxygen cannot be  released to the tissues   Beta-thalassemia occurs more commonly than does alpha-  thalassemia. Occasionally synthesis of y- or 6-polypeptide  chains is defective, resulting in gamma- or delta-thalassemia.  (Hemoglobin chains are described in Chapter 27.)   CLINICAL MANIFESTATIONS. Beta-thalassemia minor causes  mild to moderate microcytic-hypochromic hemolytic anemia,  mild splenomegaly, bronze coloring of the skin, and hyperpla-  sia of the bone marrow. The degree of reticulocytosis depends  on the severity of the anemia, resulting in skeletal changes.  Hemolysis of immature (and therefore fragile) erythrocytes  may cause a slight elevation in serum iron and indirect bili-  rubin levels. Persons with beta-thalassemia minor usually are  asymptomatic.   Congenital deficiency  Congenital deficiency is hemophilia A (classic hemophilia)  Congenital deficiency is hemophilia B   Congenital deficiency  Congenital deficiency, sometimes referred to as hemophilia C  Congenital deficiency is not associated with clinical symptoms  Congenital deficiency    Persons with beta-thalassemia major may become quite  ill. Anemia is severe and results in a significant cardiovascular  burden, with high-output congestive heart failure. In the past,  death resulted from cardiac failure. Today, blood transfusions  can increase life span by one to two decades, and death usually is  caused by hemochromatosis (from transfusions). (Hemosidero-  sis and hematochromatosis are described in Chapters 27 and 28.)  Liver enlargement occurs as a result of progressive hemosidero-  sis, whereas enlargement of the spleen is caused by extramedul-  lary hematopoiesis and increased destruction of red blood cells.  Spinal impairment that starts in infancy retards linear growth  and subsequent upper and lower limb-length discrepancy. Bone  marrow hyperplasia causes a characteristic deformity of the  facial bones, as the nasal bridge, mandible, and maxilla widen.  Osteopenia or osteochondrosis, or both, may develop.   People who inherit the mildest form of alpha-thalassemia,  the alpha trait, usually are symptom free, having, at most, mild  microcytosis. Alpha-thalassemia minor has clinical manifesta-  tions that are virtually identical to those of beta-thalassemia  minor: mild microcytic-hypochromic reticulocytosis, bone  marrow hyperplasia, increased serum iron concentrations, and  moderate splenomegaly.   Signs and symptoms of alpha-thalassemia are similar to  those of beta-thalassemia major but milder. Moderate micro-  cytic-hypochromic anemia, enlargement of the liver and spleen,  and bone marrow hyperplasia are evident.   Alpha-thalassemia major causes hydrops fetalis and fulmi-  nant intrauterine congestive heart failure. In addition to edema  and massive ascites, the fetus has a grossly enlarged heart and  liver. Diagnosis usually is made postmortem. Prenatal screen-  ing for this disorder can be performed by use of chorionic villus  sampling. These cells can be analyzed, and a deoxyribonucleic  acid (DNA) genetic map can be constructed and evaluated for  the characteristic abnormalities associated with hydrops fetalis.   Alpha-thalassemia major and beta-thalassemia major are  life threatening. Children with thalassemia major generally are  weak, fail to thrive, show poor development, and experience  cardiovascular compromise with high-output failure caused by  anemia. Untreated, they will die by 5 to 6 years of age.   EVALUATION AND TREATMENT. Diagnosis of thalassemia is based  on familial disease history, clinical manifestations, and blood  tests. Peripheral blood smears show microcytosis and hemo-  globin electrophoresis demonstrates diminished amounts of    a- or B-chains. Analysis of fetal DNA from withdrawn amniotic  fluid is used as a screening test to detect hydrops fetalis (alpha-  thalassemia major). Newborn screening for thalassemia should  be done according to state law.   “Silent” carriers or those who have thalassemia minor gener-  ally have few if any symptoms and require no specific treatment.  Therapies to support and prolong life are necessary, however,  for thalassemia major. Prenatal diagnosis and genetic counsel-  ing may be the most important therapeutic measures offered.   1. Blood transfusions, which can return hemoglobin and  hematocrit levels to normal thus alleviating the anemia-  induced cardiac failure; iron overload and hemochroma-  tosis are complications of transfusion therapy   2. Iron chelation therapy in combination with hypertrans-  fusion (transfusion to a hematocrit of 35 ml/dl)   3. Splenectomy, which can reduce the need for transfusions  by eliminating the site of hemolysis, thus prolonging  erythrocyte survival   4. Bone marrow, cord blood, and stem cell transplantation  is currently the only cure for thalassemia   Awareness of a serious bleeding disorder in males was docu-  mented nearly 2000 years ago in the Babylonian Talmud, which  exempted from the rite of circumcision those boys having male  relatives prone to excessive bleeding. In 1803 the first descrip-  tion of this disorder appeared in the medical literature, where  it was noted to be X linked and associated with joint bleeding  and crippling.   Table 30-4 lists the coagulation factors. Until 1952 the term  hemophilia was reserved for deficiency of factor VII (antihemo-  philic factor). Since then two additional coagulation proteins,  factor IX (plasma thromboplastin component [PTC]) and fac-  tor XI (plasma thromboplastin antecedent [PTA]), have been  identified and their deficiency associated with similar clinical  manifestations. Congenital deficiencies of these three plasma  clotting factors—VIH, IX, XI—account for 90% to 95% of the  hemorrhagic bleeding disorders collectively called hemophilia.    Types of Hemophilia. Hemophilia A (classic hemophilia) is  caused by factor VIII deficiency and occurs in 1 in 5000 male  births. It is the most common of the hemophilias—80%  to 85% of those with hemophilia have hemophilia A. It is  inherited as an X-linked recessive disorder that affects men and  is transmitted by women.   Hemophilia B (Christmas disease), caused by factor IX  deficiency, also is transmitted as an X-linked recessive trait and  is clinically indistinguishable from factor VIII deficiency. It  occurs in 1:25,000 male births.** Hemophilia A and hemophilia  B occur with varying degrees of clinical severity, depending on  concentrations of clotting factor VIII or IX in the blood. Severe  hemophilia (concentration of clotting factors less than 1% of  normal) is associated with spontaneous bleeding. In moderate  hemophilia (1% to 5% of normal), bleeding usually occurs only  after trauma; in the mild form (5% to 35% of normal), bleed-  ing occurs only after severe trauma or surgery. The severity of  hemophilia is similar in all affected members of a family.   Hemophilia C (factor XI deficiency) occurs as an autosomal  recessive disease and occurs equally in men and women. Bleed-  ing usually is less severe than in hemophilia A or B.   von Willebrand disease results from an inherited autoso-  mal dominant trait with variable clinical manifestations and  hematologic findings. The factor VIII deficiency differs from  that of hemophilia A in mode of inheritance and response to  treatment. In hemophilia A the deficiency is inherited as an  X-linked recessive trait, whereas in von Willebrand disease, it is  inherited as an autosomal dominant trait. The most important  difference, however, is in responses to the infusion of plasma.  In von Willebrand disease, infusion of plasma causes factor VIII  activity to increase for several days because infusion of factor  VIII temporarily induces endogenous synthesis of factor VIII.   PATHOPHYSIOLOGY. Two types of defects dominate the heredi-  tary defects of hemophilia to date: gene deletions and point  mutations. Both types of genetic defects are associated with  severe hemophilia A, in which no factor VIII circulates in the  blood. Many different gene deletion mutations are associated  with factor VIII and factor IX disease. The molecular defect that  leads to the deletional mutation is identical among members of  a given family.**   Point mutations, in which a single base in the DNA is  mutated to another base, represent a second type of mutation  that causes hemophilia. When a point mutation gives rise to  a de novo stop codon (nonsense mutation), translation of the  protein ceases and a shortened version of the protein is syn-  thesized. Usually the protein is destroyed intracellularly and  never reaches the plasma. This type of defect is associated with  severe hemophilia, that is, with coagulant activity levels below  1%, Point mutations in which one amino acid is substituted for  another can cause phenotypes of varying severity. The muta-  tion of an important amino acid can destroy protein function,  activation, or folding; inhibit intracellular processing; or cause  protein clearance.”° Unlike deletional mutations, point muta-  tions at the same site have been recorded in different families  with hemophilia.   Table 30-4 summarizes the types of coagulation disorders.  Not all the disorders are discussed in this chapter because some    are extremely rare (congenital dysfibrinogenemias) and others  have no clinical significance (e.g., Hageman factor deficiency, a  condition in which profound laboratory deficiency of factor XII  is associated with absolutely no clinical defects).   CLINICAL MANIFESTATIONS. Children with severe hemophilia  start to bleed at different ages. Although there is no transfer of  maternal clotting factor to the fetus, many boys with hemophilia  are circumcised without excessive bleeding. Normal hemostasis  is achieved in these infants because clotting is activated through  the extrinsic coagulation cascade, which does not involve fac-  tors VII, IX, or XI.   During the first year of life spontaneous bleeding often is  minimal, but hematoma formation may result from immuni-  zations and from firm holding (e.g., under the arms). Many  children are diagnosed around the time they become mobile  (i.e., crawling, pulling to stand) and become easily injured (i.e.,  increased bruising, swelling, redness at joints, mouth bleeding).  By 3 to 4 years of age, 90% of children with hemophilia have  had episodes of persistent bleeding from relatively minor trau-  matic lacerations (e.g., to the lip or tongue). This usually is the  first clinical manifestation of hemophilia. Hemorrhage into the  elbows, knees, and ankles causes pain, limited joint mobility,  and predisposes the child to degenerative joint changes. Spon-  taneous hematuria and epistaxis are troublesome but minor  complications.   Recurrent bleeding—spontaneous and after minor trauma—  is a lifelong problem. Many affected individuals experience  cycles of spontaneous bleeding episodes. Mechanisms that  cause this phenomenon are unknown. Intracranial hemorrhage  and bleeding into the neck or abdomen are rare but constitute  life-threatening emergencies.   EVALUATION AND TREATMENT. Although laboratory tests are of  primary value in the diagnosis of hemorrhagic disorders, the  history and physical assessment also should be given careful  consideration. The three phases of coagulation are assessed  individually by simple, reliable tests. In any hemorrhagic con-  dition, the adequacy of phase III should be determined first.  Unless adequate fibrinogen is present, the blood is incapable of  coagulation; thus other laboratory tests that require formation  of a visible clot will be invalid. Phase III can be evaluated by the  thrombin time, the time required for plasma to clot after the  addition of bovine thrombin. Fibrinogen can be measured by  chemical or immunologic methods.   Phase II is assessed by the prothrombin time (PT), the time  required for plasma to clot after the addition of thromboplas-  tin and calcium. If phase III is intact, a prolonged prothrom-  bin time indicates a deficiency involving factors I, V, VII, or X,  alone or in combination. Specific assays for each of the factors  are available.   Phase I, the most complex part of coagulation, is evaluated  by several tests. The activated partial thromboplastin time  (aPTT) is the time required for clotting of plasma that has been  activated by incubation with kaolin when calcium and plate-  lets (or partial thromboplastin) are added. aPTT assesses the  adequacy of factors XII, XI, IX, and VII. The prothrombin con-  sumption time is a standard prothrombin test of serum instead  of plasma. Because prothrombin is used up during coagulation,    the serum normally contains little prothrombin and the serum  prothrombin time is prolonged. Deficiencies of the phase I fac-  tors are associated with poor use of prothrombin. If the serum  and plasma prothrombin times are similar, deficiency of a  phase I factor is likely. The thromboplastin generation test is  the most sensitive of all phase I tests. The test can precisely iden-  tify deficiencies of factors VIII and IX. If the aPTT, prothrom-  bin consumption, or thromboplastin generation test results are  abnormal, the way in which they can be corrected identifies the  specific deficiency.   The treatment of hemophilia has changed markedly since  the early 1920s. Plasma first was used in the 1920s, and by the  1940s it was used routinely to treat persons with hemophilia.  The disadvantages of fresh frozen plasma (FFP), which is low  in factor VIII per volume of plasma, led to the development  of cryoprecipitate. In 1964 cryoprecipitate (quick-frozen pre-  cipitate), which is rich in factor VIII per volume, was used to  treat individuals with hemophilia. Although cryoprecipitate  advanced the treatment of hemophilia A, it had several disad-  vantages. The most notable complication was the possibility  of transmission of viral diseases, including hepatitis B and C  and human immunodeficiency virus (HIV). Factor VII con-  centrates were first introduced in 1965. In addition to the pre-  dictable factor VII content, other advantages of the early factor  VII concentrates included greater purity than cryoprecipitate  and less contamination with other plasma proteins. The devel-  opment of recombinant factor VIII resulted in new factor VII  products that minimize the risk of transmission of viral infec-  tion (e.g., HIV and hepatitis) and are potentially less expensive  than plasma-derived factor VIII.   Recombinant antihemolytic factor plasma/albumin-free  method (rAHF-PFM, Advate) is a product used for the pre-  vention and control of bleeding episodes in individuals with  hemophilia A, and in the perioperative management of those  with hemophilia A. By excluding proteins or raw materials  derived from human or animal sources in the final product, the  risk of transmission of potentially infectious agents is removed.”°   Primary prophylaxis consists of regular infusions of factor  VII or IX with the goal of preventing joint bleeding. It is usu-  ally given to children with severe hemophilia. A 5-year, multi-  center trial found prophylaxis initiated in children between 6  and 30 months of age to be effective in the prevention of joint  bleeding, structural joint damage, and frequency of bleeding in  boys with factor VIII deficiency.’”    Congenital Hypercoagulability and Thrombosis  Hereditary bleeding disorders, such as hemophilia, have been  recognized and treated for centuries; however, the counterpart  of these disorders, thrombophilia, has not been recognized  until very recently. The inherited thrombophilic conditions  generally are caused by defects in the clotting factors that  inhibit clot formation; thus the balance between bleeding and  clotting is directed toward the clotting aspects of hemostasis.  Defects in specific proteins (C and S) and antithrombin (AT),  as well as resistance to activated protein C (APC) and hyper-  homocystinemia, are the major recognized causes of inherited  thrombophilia.    Both proteins C and S are inhibitors of coagulation and  depend on vitamin K for synthesis in the hepatocytes of the  liver. Decreased levels of either of these proteins interfere with  the normal homeostatic balance of procoagulant and anticoag-  ulant activity at the endothelial level. Protein C and S deficiency  states predispose affected individuals to thrombosis, especially  venous thrombosis of the lower extremities.   Inheritance of protein C deficiency is autosomal dominant.  Heterozygotes have protein C levels 50% to 60% of normal and  may develop superficial thrombophlebitis, deep venous throm-  bosis, or pulmonary embolism in their late teens and early 20s.  The majority of these thrombotic events (75%) occur sponta-  neously, whereas only 25% are the result of predisposing con-  ditions.** Homozygotes have less than 1% of normal levels of  protein C and tend to develop thrombosis of the cutaneous ves-  sels with large areas of skin necrosis. It is rare for individuals  with protein C deficiency to develop arterial thrombosis.   Protein C deficiency exists in two forms: types I and II. Type  I, the more common form, involves a reduction in both bio-  logic and immunologic activity of protein C. Type I is caused  by deletion of the entire gene. In type I, the less common form,  there is a normal level of protein C antigen but decreased func-  tional levels of activity.   Neonatal purpura fulminans is a fatal syndrome found  in neonates who are homozygous or double heterozygous for  types I and II protein deficiency. Ecchymosis becomes appar-  ent on the first day of life and develops around the head,  trunk, and extremities and often is accompanied by cere-  bral thrombosis and infarction. The ecchymotic areas often  coalesce, and ulceration and necrosis develop. Treatment  includes administration of FFP and heparinization, although  the infant rarely survives.   Heparin is the treatment for acute episodes of thrombosis  caused by protein C deficiency. Long-term therapy is required  and consists of either oral warfarin sodium (Coumadin) or  subcutaneous heparin. Supplemental protein C concentrates  (human) are also available and have been approved for use in  children.”   Protein S deficiency is similar to protein C deficiency, and  the inheritance pattern (autosomal dominant) is also similar.  Heterozygotes demonstrate a strong tendency for deep venous  thrombosis, with the first incidence often occurring before age  25 years. Other manifestations include superficial thrombo-  phlebitis and pulmonary emboli. There are predisposing condi-  tions for thrombi development in some cases, with evidence of  spontaneous thrombi development in most cases.   Protein S deficiency exists in two forms: type I and type II.  Type I is identified as a quantitative deficiency and manifests as  low levels of protein S antigen and activity, and type IJ is identi-  fied as a qualitative deficiency with low levels of free protein S  and normal levels of free and total protein S antigen.”   Homozygotes demonstrate severe manifestations of the con-  dition and may develop a form of purpura fulminans in the  neonatal period. It also is possible that the homozygous state  may lead to uterine death. Treatment with heparin, warfarin  (Coumadin), and protein C concentrate is similar to that of  protein C deficiency.    Antithrombin III (AT IID) deficiency is inherited as an auto-  somal dominant condition—the heterozygous state is the most  common. AT III also exists in two forms, type I and type II, with  type I being a quantitative deficiency of the AT III antigen. Type  II is characterized as a dysfunctional form: normal levels of AT  III are present but with reduced activity.   Individuals with AT III deficiency are at risk for early devel-  opment of venous thrombosis and pulmonary embolism. These  events often occur in the middle to late teens, and can occur as  early as 10 years of age. The deep veins of the lower extremi-  ties are usually involved, most commonly the iliofemoral  vein. Other sites include the mesenteric veins, vena cava, renal  veins, and retinal veins. Cerebral thromboses also have been  described, and arterial thrombotic events are rare. In some cases  thrombosis is precipitated by surgery, trauma, pregnancy, oral  contraceptives, and infection.   The treatment of choice for AT HI deficiency is heparin.  Antiplatelet agents (e.g., aspirin, dipyridamole) may be used, as  well as AT III concentrates.    The antibody-mediated hemorrhagic diseases are a group of  disorders caused by the immune response. Antibody-mediated  destruction of platelets or antibody-mediated inflammatory  reactions to allergens damage blood vessels and cause seepage  into tissues. The thrombocytopenic purpuras may be intrinsic  or idiopathic, or they may be transient phenomena transmitted  from mother to fetus. The inflammatory, or “allergic,” purpu-  ras occur in response to allergens in the blood. All these disor-  ders first appear during infancy or childhood.   Acute idiopathic thrombocytopenic purpura (ITP) (autoim-  mune or primary thrombocytopenic purpura) is the most  common of the thrombocytopenic purpuras of childhood. It is a  disorder of platelet consumption in which antiplatelet antibod-  ies bind to the plasma membranes of platelets, causing platelet  sequestration and destruction by mononuclear phagocytes in  the spleen and other lymphoid tissues at a rate that exceeds the  ability of the bone marrow to produce them.   PATHOPHYSIOLOGY. Platelets have several tissue-specific anti-  gens on their plasma markers that may be targets for anti-  platelet antibody. In approximately 70% of cases of ITP, there  is an antecedent viral disease (e.g., cytomegalovirus [CMV],  Epstein-Barr virus [EBV], HIV, parvovirus, or viral respira-  tory infection), suggesting that viral sensitization has occurred.  The interval between infection and onset of purpura is 1 to 4  weeks. A comparison with purpura seen in adults has identified  an immune mechanism as the basis for ITP. High levels of IgG  have been found bound to platelets and may represent immune  complexes on the platelet surface.*”   CLINICAL MANIFESTATIONS. One to 4 weeks after a viral infection,  bruising and a generalized petechial rash often occur with acute  onset. Asymmetric bleeding is typical and is found most often  on the legs and trunk. Hemorrhagic bullae of the gums, lips, and  other mucous membranes may be prominent. Epistaxis (nose-  bleed) may be severe and difficult to control. Except for the signs    of bleeding, the child appears well. The acute phase of the disease  associated with spontaneous hemorrhages lasts 1 to 2 weeks, but  thrombocytopenia often persists. Intracranial hemorrhage is the  most serious complication of ITP, although the incidence is less  than 1%. In some cases the onset is more gradual and clinical man-  ifestations consist of moderate bruising and scattered petechiae.   EVALUATION AND TREATMENT. Laboratory examination reveals  a reduced platelet count, and the few platelets observed on a  peripheral blood smear are large in size, reflecting increased  bone marrow production. Bone marrow aspiration reveals  megakaryocytes in normal or increased numbers and normal  erythrocytes and granulocytes. The use of bleeding time for  diagnosis is not recommended because the results are often  confounded by a child who is crying or moving, the depth and  direction of the cut, and the device used.   Even without treatment the prognosis for children with ITP  is excellent—75% recover completely within 3 months. After  the initial acute phase spontaneous clinical manifestations sub-  side. By 6 months after onset, 80% to 90% of affected children  have regained normal platelet counts.””   Because of the short life span of platelets (10 days), fresh blood  or platelet transfusions are only a transient benefit; however, their  use is indicated when life-threatening hemorrhage occurs. Corti-  costeroid therapy reduces the severity and shortens the duration  of the initial phase by suppressing the immune attack on platelets.  Recent evidence indicates that the use of high-dose methylpred-  nisolone increases bone resorption and may cause osteonecrosis  in children with ITP.’* Intravenous IgG has been demonstrated  to increase the platelet count in some children with ITP, but it is  quite costly. Anti-D, is a gamma globulin fraction containing a  high proportion of antibodies to the Rh,(D) antigen of the RBCs.  Intravenous anti-D is a safe and effective treatment for Rh-pos-  itive, nonsplenectomized individuals with ITP. It is an effective  treatment for Rh-positive nonsplenectomized children with ITP,  although it is associated with side effects including chills, fever,  headache, and a decrease in hemoglobin levels. Administration  of steroids and antipyretics prior to the anti-D treatment may  prevent side effects. Rituximab, a chimeric monoclonal antibody  against the protein CD20, has been tested in children with ITP  and demonstrated an overall response rate of 69% (see What’s  New? Clinical Trials of TPO Receptor Agonists for Treatment  of Idiopathic Thrombocytopenic Purpura [ITP]). Only mild  and self-limited side effects were observed in 18%, and no major  infections or long-term toxicities were reported.*!    Clinical Trials of Thrombopoietin (TPO)  Receptor Agonists for Treatment of Idiopathic  Thrombocytopenic Purpura (ITP)    Rituximab, a chimeric monoclonal antibody against the protein CD20, has been  tested in children with ITP. Long-term follow-up at 39.5 months of 49 children  with ITP who were treated with rituximab demonstrated an overall response    rate of 69%: 21 children had platelet counts of greater than 50,000/mmé at 20  months’ post-treatment. Only mild and self-limited side effects were observed  in 18%, and no major infections or long-term toxicities were reported.    Data from Parodi E et al: Br J Haematol! 144(14):552-558, 2009.    Parents should be instructed to discourage activities that  might cause trauma that could result in bleeding (e.g., con-  tact sports, skateboarding, skiing, bicycle riding). Splenectomy  should be reserved for chronic cases that fail to respond to non-  surgical intervention.    Autoimmune Neonatal Thrombocytopenias  Antibody-mediated thrombocytopenic purpura occurs in neo-  nates in either autoimmune or alloimmune form. Both forms  are characterized by the immunologic destruction of platelets  by antibodies (IgG) against tissue-specific antigens expressed by  the platelets (i.e., platelet-specific antigens).   Autoimmune neonatal thrombocytopenia was first noted  in the early 1950s, when it was observed that mothers with ITP  often delivered infants who were transiently thrombocytopenic.  Neonatal thrombocytopenia was observed in approximately  50% of infants at risk and lasted an average of 1 month. As plate-  let counts returned to normal, a concomitant drop in the level of  maternal antiplatelet antibody on the child’s platelets occurred.  The antibody is directed against antigens common to maternal  and neonatal platelets. The prognosis generally is favorable and  the frequency of intracranial hemorrhage is rare (1% to 3% of  cases). Medical management of affected infants is to prevent the  severe thrombocytopenia that can cause significant morbidity  by administering intravenous immunoglobulins.   Neonatal alloimmune thrombocytopenic purpura (NATP)  is less common, estimated to occur in 1 to 2 per 1000 live births.  NATP is caused by maternal immunization against fetal pater-  nally derived platelet-specific antigens (similar to rhesus [Rh]  disease). The mother has a normal platelet count, while the  fetus can be severely thrombocytopenic.   The diagnosis of NATP is confirmed by detection in the  maternal serum of antibody that reacts with platelets from  the infant and father but not with platelets from the mother.  In approximately 75% to 85% of cases, NATP recurs in sub-  sequent pregnancies. Purpura usually develops in the affected  infant shortly after delivery, and intracranial, renal, and gastro-  intestinal hemorrhages are possible. The mortality rate from  intracranial hemorrhage has been estimated at 10% to 15%.  Management of the newborn with NATP includes an immedi-  ate cranial ultrasound because of the significant risk of intra-  cranial hemorrhage. Severely thrombocytopenic newborns  (<10,000/uL) or newborns with intracranial or visceral hemor-  rhages should receive a matched platelet transfusion (maternal  or homozygous human platelet antigen 1b [HPA-1b] donor)  as soon as possible. If maternal platelets are used, they must be  processed to remove platelet alloantibodies. Newborn throm-  bocytopenia is difficult to predict because newborn platelet  counts do not correlate with maternal platelet counts or anti-  platelet antibody titers.*?   Most of the life-threatening clinical manifestations of tran-  sient neonatal thrombocytopenia and NATP can be avoided  through cesarean delivery. If the mother has antiplatelet dis-  ease, however, surgery can result in hemorrhage and serious  maternal morbidity. Maternal morbidity resulting from NATP  during pregnancy is low (less than 5%): the principal maternal  risk is bleeding from surgical incisions during cesarean deliv-  ery. The incidence of transient thrombocytopenia in infants    born to mothers with NATP is about 50%. If all deliveries were  cesarean, half the mothers would undergo cesarean delivery  unnecessarily. Conversely, if all deliveries were vaginal, half  the infants—those with thrombocytopenia—would be at risk  for intracranial bleeding. Therefore, in the absence of any clear  benefit to the neonate (given the low rate of intracranial hem-  orrhage in infants born to mothers with ITP), cesarean delivery  should be reserved for the usual obstetric indications.   Autoimmune vascular purpura (allergic purpura) is caused by  antibody-mediated injury of blood vessel walls, typically arte-  rioles and capillaries. The inflammatory reaction is to foreign  proteins or chemicals in the blood (microorganisms, drugs, or  other chemicals).   Autoimmune vascular purpura usually is seen in young chil-  dren, with the incidence decreasing in adolescents and adults  and occurring only rarely in older adults. The average age at  onset is 5 years, with a slightly higher proportion of males  affected. Purpura occurs as vessel integrity is disrupted by  inflammatory processes, causing effusion of serosanguineous  exudate to perivascular tissues.   Clinical manifestations include headache, anorexia, fever,  abdominal pain, constipation, arthralgias and urticaria, and  erythema that are located symmetrically on the proximal por-  tions of the extremities, particularly on the legs and buttocks,  and may be accompanied by itching or paresthesias. Abdomi-  nal pain results from hemorrhage into the bowel, which may  lead to colic, nausea, and vomiting. These symptoms may pre-  cede the appearance of skin lesions. The pain usually is midab-  dominal but may radiate to other parts of the abdomen. Joint  pain and tenderness may be present, but hemarthrosis does not  occur. Periarticular swelling and edema of the hands and feet  are common and may precede the onset of abdominal pain and  purpura. Subacute glomerulonephritis occurs in some cases but  usually is reversible.   The characteristic skin lesions (purpura and cutaneous man-  ifestations of allergy), accompanied by a history of joint and  abdominal pain, are suspicious for diagnosis. Laboratory test  results often reveal no major abnormalities. Attacks may last  several weeks and may recur at odd intervals and with chang-  ing manifestations with each episode. Treatment, if necessary,  consists of symptom management.    Leukemia, the most common malignancy of childhood, repre-  sents approximately 40% of all childhood cancers. Childhood  lymphoma is the third most common malignant neoplasm of  children in the United States, representing approximately 11%  of all childhood cancers. (See Chapter 29 for a discussion of leu-  kemia in adults.)    Of the varieties of childhood leukemia, 75% to 80% of leuke-  mias in children are acute lymphocytic leukemia (ALL) or acute  undifferentiated leukemia (AUL). The remaining 20% to 25%  are acute nonlymphocytic leukemias (ANLLs) (which include    myeloblastic, promyelocytic, monocytic, and myelomono-  blastic leukemias) and the very rare red blood cell leukemia,  erythroleukemia. Because the vast majority of ANLLs involve  the myeloblastic cell, many experts refer to the disease as acute  myelogenous leukemia (AML). Leukemia accounts for 25% of  cases of cancer in black children and 34% of cases of cancer  in white children. Approximately 4100 new cases are diagnosed  each year in the United States.**   The peak incidence for childhood ALL is between 2 and 6  years of age. ALL affects more white and Hispanic than black  children and more males than females. Male predominance is  greater in T-cell disease. Incidence of ALL is higher in Western  and industrialized nations.°°    A number of different classifications are used for the leuke-  mias. First, acute leukemia is differentiated from chronic leu-  kemia. Second, the cell line determines whether lymphoid cells  or myeloid cells are involved. In acute leukemia this difference  separates ALL from AML and vice versa. Within each of these  categories, further subdivisions have been developed. (See  Chapter 29 for a discussion of leukemias in adults.)   Cytogenic studies of leukemic cells are performed routinely  at most major treatment centers during the diagnostic process.  Abnormal morphologic characteristics, as well as abnormalities  in the number of copies of chromosomes, are found in leukemic  cells. Hyperdiploidy (increased number of chromosome cop-  ies) is associated with a good prognosis. Common transloca-  tions associated with ALL are TEL-AML1, BCR-ABL, and MLL.  TEL-AMLI is the most common abnormality (in 20% to 30%  of cases) and occurs when the TEL gene on chromosome 12p13  fuses with the AML gene on chromosome 21q22. TEL-AML1 is  associated with a favorable outcome. MLL arrangement, t(4;11),  is located on chromosome 11q23. This translocation, the most  common within this subtype, is found in infant ALL and is asso-  ciated with a poor prognosis despite intensive therapy. Phila-  delphia chromosome-positive (Ph+) leukemia expresses the  BCR-ABL protein and is characterized by the presence of t(9;22)  (q34;q11) translocation. Ph+ leukemia can be ALL or chronic  myelocytic leukemia (CML), depending where the breakpoint  on chromosome 22 occurs. In CML, the translocation can be  detected in multiple cell lines. Ph+ ALL occurs in 2% to 3% of  cases and responds poorly to conventional chemotherapy. In  CML, 99% of cases are characterized by the presence of t(9;22).**   Classification of childhood leukemia has become a complex  but essential process to determine treatment. Previous classi-  fication by the French-American-British Cooperative Group  (FAB) was based primarily on the morphologic and biochemi-  cal system. A classification scheme developed by the World  Health Organization (WHO) is based on a more comprehen-  sive system that uses morphology, immunophenotyping, and  cytogenic and clinical features. The three major classifications  of childhood leukemia are ALL (75% to 80%), AML (15% to  20%), and CML (less than 5%).   Flow cytometric immunophenotyping has made distinguish-  ing between lymphoblastic and nonlymphoblastic leukemia  much easier than in the past, when the degree of immaturity of  the cell sometimes made such distinction difficult.    Immunologic classification has been used on identification  of various surface markers. Five categories of ALL have been  identified on the basis of their presumed origin from thymic  cells (T cells) and bursa-equivalent cells (B cells) of normal  lymphocytes:   T lymphocytes and found more commonly in older boys  whose diagnosis includes mediastinal masses, high white  blood cell counts, and hepatosplenomegaly (20% of ALL)   2. B-cell ALL—characterized by the presence of abnormal B  lymphoblasts and associated with a poor prognosis (5%  of ALL)   3. Pre—B-cell ALL—characterized by the presence of pre-B  lymphoblasts (20% of ALL)   4. Unclassified ALL—also known as null cell (meaning nei-  ther T nor B lymphoblasts), and now classified as early  B-cell lineage (15% of ALL)   5. Common ALL—characterized by the presence of a spe-  cific antigen known as common ALL antigen, or common  acute lymphocytic leukemia antigen (CALLA), recently  designated cellular differentiation 10 or CD10, in which  the actual cell usually is considered to be of the B lineage  (39% of ALL)   PATHOGENESIS. The exact cause of childhood leukemia is  unclear. Investigations have focused on genetic susceptibility,  environmental factors, and viral infections (see Chapter 14).  Extraordinary doses of radiation and certain cancer therapies  are possible causes (Facts, Spring 2013; Leukemia & Lymphoma  Society, White Plains, NY. Accessed June 2013). Repeated expo-  sure to benzene may cause AML. The relationship between  childhood cancer and radon*° and electromagnetic fields has  been the focus of many epidemiologic studies, yet no conclusive  evidence has been observed. In 2007 a task group of scientific  experts convened by WHO reported that it could not confirm  the existence of any health consequences from exposure to low-  level magnetic fields.°°   Although not determined to be genetically transmitted, a  child who has a sibling with leukemia has a risk for the devel-  opment of leukemia that is two to four times greater than for  children with healthy siblings. The occurrence of leukemia in  monozygous twins is estimated as being as high as 25%. In 2006,  the Office of the U.S. Surgeon General suggested evidence of a  causal relationship between childhood leukemia, lymphoma,  and brain tumors and prenatal or postnatal environmental  tobacco smoke exposure; the results have suggested an associa-  tion between parental exposure to pesticides before or during  pregnancy.*’ A later study suggested that the risk of leukemia  and lymphoma increased when the mother was exposed to pes-  ticides in the prenatal period, and the risk of brain tumors was  correlated with paternal exposure (occupational or household  use) either before or after birth.**   Inherited diseases that predispose a child to leukemia (ALL  and AML) include Down syndrome, Fanconi anemia, Bloom  syndrome, Diamond-Blackfan anemia, Klinefelter syndrome,  Shwachman-Diamond syndrome, and _ataxia-telangiectasia.  Leukemia also has been associated with known genetic diseases,  such as congenital agammaglobulinemia. AML in children  sometimes is associated with loss or deletion of chromosome 7.    (see Figure 29-5). AML can develop from preexisting myelo-  proliferative disorders that also are preleukemia syndromes  (i.e., myelodysplastic syndrome).   Childhood exposure to ionizing radiation, drugs, or viruses  has been associated with the risk of developing cancer. Retro-  spective research has shown a significant correlation between  radiation-induced malignancies from radiotherapy (as cancer  treatment) or from radiation exposure from diagnostic imag-  ing. The relationship between childhood cancer and electro-  magnetic fields, small appliances, radon, and other sources has  been the focus of many epidemiologic studies; however, no  conclusive evidence has been observed.*?   Although chemicals such as benzene have been associated  with the development of AML in adults, no evidence suggests  a similar chemical or drug association in childhood leukemia.  Leukemia (primarily AML) has been reported as a secondary  malignancy (development of a second cancer after the first)  in children treated for Hodgkin disease and Wilms tumor,  although such cases are rare. In most cases the children received  chemotherapy (alkylating agents or dactinomycin) and radia-  tion therapy for the primary cancer, perhaps accounting for the  subsequent development of another cancer.   Leukemic “clusters” that represent a greater number of leu-  kemia cases occurring in a particular geographic location have  raised speculation about environmental factors or infectious  patterns of transmission. Careful follow-up, however, has failed  to document the abnormal clustering.”   The strongest association between viruses and the devel-  opment of cancer in children has been EBV and Burkitt lym-  phoma, and nasopharyngeal carcinoma and Hodgkin disease.  Children with acquired immunodeficiency syndrome (AIDS)  have an increased risk of developing non-Hodgkin lymphoma  and Kaposi sarcoma. However, with the use of highly active  antiretroviral therapy in the developed world, the incidence of  AIDS-related malignancies has declined dramatically. Retrovi-  ruses have not been linked with childhood leukemia.   CLINICAL MANIFESTATIONS. Few variations appear in the pre-  senting symptoms of the various cell types of acute leuke-  mias. The onset may be abrupt or insidious, but the most  common symptoms reflect the consequence of bone marrow  failure, which results in decreased red blood cells and plate-  lets and changes in white blood cells. Pallor, fatigue, petechiae,  purpura, bleeding, and fever generally are present. Approxi-  mately 45% of children have a hemoglobin level less than 7 g/  dl; in contrast to adults, children seem to demonstrate fewer  symptoms. If acute blood loss occurs, however, characteristic  symptoms of tachycardia, air hunger, restlessness, and thirst  may be present. Epistaxis, excessive bruising, and hematuria  often occur in children with severe thrombocytopenia. Three  quarters of children with ALL have platelet counts less than  100,000/mm* at diagnosis, and 28% have platelet counts less  than 20,000/mm‘°. Half of all children newly diagnosed with  AML have platelet counts less than 50,000/mm/°. Disseminated  intravascular coagulation occurs more commonly with AML,  particularly with promyelocytic leukemia. The granules in the  leukemic promyelocytes may then indicate thromboplastin  activity.    Fever usually is present as a result of two causes: (1) infec-  tion associated with the decrease in functional neutrophils and  (2) hypermetabolism associated with the ongoing rapid growth  and destruction of leukemic cells. In most children with ALL,  the total white blood count is less than 10,000/mm*, and with  AML most have white cell counts less than 50,000/mm>. In a  few children, however, the peripheral white blood count can go  well above 100,000/mm?. White blood cell counts greater than  200,000/mm? can cause leukostasis, an intravascular clumping  of cells that result in infarction and hemorrhage, usually in the  brain and lung. The three most important favorable prognos-  tic factors are age at diagnosis (2 to 10 years), initial leukocyte  count (<50,000/mm+), and initial response to treatment.   Renal failure as a result of hyperuremia (high uric acid lev-  els) can be associated with ALL, particularly at diagnosis. Cell  breakdown results as a natural process in the presence of a  high white blood cell count or as a result of cellular breakdown  caused by chemotherapy. Uric acid levels rise as an end prod-  uct of purine metabolism from cellular destruction. Because the  major excretory pathway is through the kidney, urates can pre-  cipitate in renal tubules or ureters and can lead to oliguria and  acute renal failure. Renal failure is preventable if uric acid levels  are monitored and treatment is aimed at optimal hydration,  alkalinization of urine to assist with the excretion of soluble  urates, and blockage of further uric acid formation by adminis-  tration of the drug allopurinol.   Extramedullary invasion with leukemic cells can occur  in nearly all body tissue. Most children with ALL have some  extramedullary involvement at diagnosis. Leukemic invasion of  tissue other than bone marrow is believed to represent meta-  static infiltration. Hepatosplenomegaly and lymphadenopathy,  resulting from extramedullary hematopoiesis, occur in nearly  half of children with ALL, but they are less common in children  with AML.   The CNS is a common site of infiltration of extramedullary  leukemias, although less than 10% of children with ALL have  CNS involvement at diagnosis. CNS infiltration manifests later  in the course of the disease. Because successful chemotherapy  prolongs the time of remission, the incidence of CNS involve-  ment has increased. The most common symptoms of CNS  involvement relate to increased intracranial pressure, causing  early morning headaches, nausea, vomiting, irritability, and  lethargy. Prophylactic CNS treatment therefore is necessary  because systemic treatment with chemotherapy does not cross  the blood-brain barrier.   Gonadal involvement, with testicular and ovarian infil-  tration, has been demonstrated in postmortem examination  in 57% and 35% of children, respectively. Clinical detection  of gonadal involvement is much less frequent. The inci-  dence of testicular involvement, like CNS involvement, has  increased with lengthened duration of remission. Prophy-  lactic treatment has not been successful and currently is not  recommended.   Leukemic infiltration into bones and joints is common in  children. Reports of bone or joint pain actually lead to the  diagnosis of leukemia in some children. In most children bone  pain is characterized as migratory, vague, and without areas of    i Z  FIGURE 30-10 Monoblasts from Acute Monoblastic Leukemia. Mono-  blasts in a marrow smear from an individual with acute monoblastic leukemia  (M5A). The monoblasts are larger than myeloblasts and usually have abundant  cytoplasm, often with delicate scattered azurophilic granules (an element that  stains well with blue aniline dyes). (From Damjanov |, Linder J, editors: Anderson's  pathology, ed 10, St Louis, 1996, Mosby.)    Oo 2 ay a oO co  FIGURE 30-11 Leukocytosis and Basophilia in Chronic Myeloid Leuke-  mia. Blood smear from a child with chronic myeloid leukemia (blasts) showing  marked leukocytosis and basophilia. Karyotype analysis identified a Philadelphia  chromosome (Wright-Giemsa stain). (From Damjanov |, Linder J, editors: Ander-  sons pathology, ed 10, St Louis, 1996, Mosby.)    swelling or inflammation. If joint pain is the primary symptom  and some swelling is associated with the pain, however, misdi-  agnoses of rheumatoid arthritis may occur.   Other organs reported to be sites of leukemic invasion  include the kidneys, heart, lungs, thymus, eyes, skin, and gastro-  intestinal tract. Of these, the kidneys, lungs, and gastrointestinal  tract are the most frequently reported sites. Skin involvement is  more common in AML than in ALL.   EVALUATION AND TREATMENT. A bone marrow aspiration and  biopsy are required to establish the diagnosis. The blast cell is  the hallmark of acute leukemia (Figure 30-10). The blast cell  is a relatively undifferentiated cell characterized by diffusely  distributed nuclear chromatin, with one or more nucleoli and  basophilic cytoplasm (Figure 30-11).    Age  <2 yr or >10 yr  2-7 yr  Gender*  Male  Female  Initial white blood cell count*  >50,000/mm:  <10,000/mm3  Race  Black  White  Immunology*  T- or B-cell ALL  Early pre—B-cell or common  acute lymphocytic leukemia  antigen (CALLA)  Leukemic involvement  Mediastinal mass  Central nervous system  involvement at diagnosis  Splenic enlargement    *The four most reliable prognostic factors. Initial prognostic factors  become less effective predictors with increasing length of remission.  Age and gender are not significant after 15 months of continuous  remission, and white blood cell count is not significant after 24 months  of continuous remission.    Healthy children have less than 5% blast cells in the bone  marrow and none in the peripheral blood. The bone marrow is  categorized on the basis of blast percentage. Normal bone mar-  row is called M1 marrow; M2 and M3 represent an increased  percentage of blasts in the sample. This categorization system  should not be confused with the similar terminology used to  denote subtypes of AML. In ALL the bone marrow often is  replaced by 80% to 100% blast cells, with a reduction in nor-  mally developing red blood cells and granulocytes. The marrow,  which is considered hypercellular, is composed of a homoge-  neous population of cells. Occasionally, however, the marrow  appears hypocellular, making the diagnosis difficult to differen-  tiate from aplastic anemia. When this occurs, the result of the  bone marrow biopsy is necessary to confirm the diagnosis.   Combination chemotherapy, with or without radiation ther-  apy to localized sites, such as the CNS, is the treatment of choice  for acute leukemia. In ALL, identification of various risk groups  has led to the development of different intensities of drug pro-  tocols. Thus treatment is tailored specifically for a particular risk  group. (Table 30-5 outlines the various prognostic factors for  ALL that are considered in determining the degree of risk.).   Most ALL treatment programs have four distinct phases: (1)  induction of remission, (2) preventive therapy for the CNS, (3)  intensification (also called consolidation), and (4) maintenance.  In remission induction, the goal is no clinical evidence of disease    and a normal bone marrow biopsy result, which is achieved in  95% of children with ALL. Children with persistent leukemia  at the end of 1 month of induction therapy have a dismal prog-  nosis. Prophylactic CNS treatment historically included both  chemotherapy and radiation, but therapy, although effective  in preventing CNS leukemia, adversely affects neurologic and  intellectual function. A marked incidence of learning disabili-  ties has been identified in children previously treated to prevent  CNS disease.*! CNS radiation is no longer given and intrathecal  regimens are less toxic. Once remission is achieved, an inten-  sification phase of treatment begins. This treatment is neces-  sary because leukemic cells will continue to be present despite  successful remission. Thus the goal of the intensification phase  is to further decrease and eliminate the remaining leukemic  cells. Intensification therapy often overlaps prophylactic CNS  treatment. The final phase of initial treatment is called main-  tenance therapy. The goal of this phase is to maintain disease  control. The optimal duration of maintenance therapy is not  well defined, but it usually continues for 2.5 to 3 years. Dur-  ing maintenance therapy intermittent “pulses” of new drugs  are usually given. Periods of intensified therapy are believed to  minimize development of drug-resistant leukemic cells.   An estimated 1310 cancer deaths are expected to occur  among children ages 0 to 14 in 2013, about one third from  leukemia. However, death rates from childhood cancer have  decreased by 66% since 1969 so impressive strides have been  made in the treatment of these children.*’ Today, with prompt  and appropriate treatment, 80% of children with ALL are  cured. Those children with the more favorable early pre—B-cell  or CALLA-positive ALL have a survival rate of 90%.*7   Prognostic factors in AML are not as well defined as they are  for ALL because of the small number of affected children and  their overall poor prognosis. The goal of treatment for AML is  similar to that of ALL except that much more aggressive che-  motherapy is administered. With intensive chemotherapy, sig-  nificant bone marrow suppression is necessary but predisposes  children to infection, bleeding, and anemia. The use of colony-  stimulating factor (CSF), which stimulates the rapid proliferation  of specific blood cell lines, is an advance that shortens this period  of bone marrow aplasia (CSFs are discussed in Chapter 27).  Although initial remission is achieved relatively easily in all cases  of ALL, successful and lasting remission can be achieved in only  70% to 80% of children with AML.°! If remission is achieved,  further treatment, called continuation therapy, is required. The  specific intensity, timing, and length of continuation therapy  are controversial. The use of either a stem cell or bone marrow  transplantation (BMT) is an important treatment consideration  in AML. Because long-term remission and cure of AML are diffi-  cult to achieve with chemotherapy alone, transplant often is rec-  ommended after the first remission is achieved. Transplant is the  treatment of choice after relapse of AML. The long-term survival  rate for children with AML, whether treated with chemotherapy  or chemotherapy and BMT, is approximately 50%.°?    Lymphomas  Non-Hodgkin lymphoma (NHL) and Hodgkin disease make up  approximately 15% of all childhood cancer. Approximately 800    cases of childhood lymphoma are diagnosed in the United States  annually.°’ Either group of diseases is rare before age 5 years, and  the relative incidence increases throughout childhood. NHL is  1.5 times more common than Hodgkin disease in children. Boys  are more likely to be diagnosed with a malignant lymphoma than  are girls. There is an increased incidence of lymphoma in children  with congenital immunodeficiency syndromes such as Wiskott-  Aldrich syndrome, severe combined immunodeficiency (SCID),  X-linked lymphoproliferative disease, and ataxia-telangiectasia.  Increased incidence of NHL also is associated with immunosup-  pression after solid organ and stem cell transplants, particularly  T-cell—depleted stem cell transplantation. The strongest associa-  tion between viruses and the development of cancer in children  has been the EBV, Burkitt lymphoma, and Hodgkin disease.  Children with AIDS have an increased risk of developing NHL.  However, with the use of highly active antiretroviral therapy in  the developed world, the incidence of AIDS-related malignan-  cies has declined dramatically.**   The classification of non-Hodgkin lymphoma (NHL) has been  confusing because of the heterogeneity of this group of dis-  eases. Generally most classification systems divide NHL into  two categories—nodular or diffuse—on the basis of cellular  pattern. Whereas half of all adults with NHL have a nodular  form of the disease, children rarely demonstrate this pattern.  Nodular disease represents a less aggressive form of lymphoma.  Almost without exception, childhood NHL becomes evident  as a diffuse disease and can be further subdivided into three  groups: (1) large cell (histiocytic), (2) lymphoblastic, and (3)  small noncleaved cell (Burkitt or non-Burkitt lymphoma).  Large-cell NHL often involves chromosomal translocations.  Disease sites commonly involve extranodal sites, such as brain,  lung, bone, and skin. Lymphoblastic NHL also shows chromo-  somal translocations, particularly chromosomes 7 and 14. Dis-  ease sites commonly include the mediastinum and peripheral  lymph nodes. Small noncleaved cell NHL involves chromosome  translocations of 8 and 14. It is believed that this translocation  triggers the c-myc oncogene. Children with small noncleaved  cell NHL commonly have intra-abdominal disease at diagnosis.   An area of intensive study concerns the apparent biologic  similarities of NHL and ALL in children. These two diseases are  cytologically identical, and the histologic distinction between  them is indicated by the degree of infiltration in the blood and  bone marrow. The more bone marrow involvement and the less  nodal and organ infiltration present, the more likely the disease  is to be classified as ALL. Childhood NHL also is much more  like ALL in its clinical manifestations and much less like Hodg-  kin disease or adult NHL.   As in ALL, immunophenotyping is an important part of the  classification of childhood NHL. Almost 45% of the disease in  children originates from T cells; an equal number originates  from B cells. The remaining group, which represents 10% of  childhood NHLs, is classified as non-T, non-B.   PATHOGENESIS. The origin of NHL in childhood is still elu-  sive. Although defective host immunity is implicated in most  children in whom NHL develops, an immune deficit cannot be    identified. Viral etiology is suggested, but the role in develop-  ment of human lymphoma is still unclear. The strongest corre-  lation exists between EBV and African Burkitt lymphoma. This  form of NHL is associated with a breakpoint on chromosome  8 that is located near the c-myc oncogene."* The relationship  between EBV infection and Burkitt lymphoma outside Africa  is weak, however, even though the tumor is histopathologi-  cally and clinically indistinguishable. Chronic immunostimula-  tion also has been suggested as a factor in the development of  lymphomas because these diseases are seen more often when  chronic persistent antigenic stimulation occurs from infection,  such as malaria or intestinal parasites. Genetic susceptibility  also may play a role in the process of malignant transformation.   CLINICAL MANIFESTATIONS. In children, NHL has been found to  arise from any lymphoid tissue. Signs and symptoms therefore are  specific for the site involved. Some children have such widespread  involvement that no original site can be determined. Because  childhood NHL is a rapidly progressive disease, symptoms gen-  erally are present only a few weeks before diagnosis is made. Rap-  idly enlarging lymphoid tissue and painless lymphadenopathy  are common in about one third of children with abdominal sites  of involvement, usually representing a gastrointestinal origin for  the disease. Symptoms often include abdominal pain and vomit-  ing, but a palpable mass is not always present. Most children with  abdominal symptoms have diffuse, small noncleaved cell NHL  (Burkitt or non-Burkitt) of B-cell origin. If the tumor recurs, it  appears again in the abdomen before distant spread.   The other common site of childhood NHL is the chest  region. An anterior mediastinal mass, with or without pleural  effusion, often is present. If the mass is large enough, respira-  tory compromise, tracheal compression, and superior vena cava  syndrome may arise, which constitute a medical emergency.  Children with anterior mediastinal involvement often are male  adolescents and usually have diffuse lymphoblastic lymphoma  of T-cell origin. This form of diffuse lymphoblastic lymphoma  often evolves into extensive bone marrow involvement and  is considered to be an overt leukemic phase (Figure 30-12);  therefore, it is referred to as leukemic transformation. CNS  involvement and testicular infiltration often then occur. CNS  involvement occurs in about 30% of individuals with NHL,  usually causing multiple deep-seated lesions within the brain  parenchyma. In children with AIDS, NHL is the most common  mass lesion found in the brain.   Bone marrow involvement is less common than other pri-  mary sites, whereas CNS involvement is common. Relatively  few children (10% to 20%) with NHL have lymphoid tissue  involvement of the head and neck (Waldeyer ring, nasopharynx,  sinuses). Signs and symptoms include tonsillitis, sinusitis, and  a painless nasopharyngeal mass. In African Burkitt lymphoma,  involvement of facial bones, particularly the jaw, is common,  although this occurs infrequently in non-African cases.   EVALUATION AND TREATMENT. Diagnosis is made by biopsy of  disease sites, usually the involved lymph nodes. Other sites of  biopsy include the tonsils, bone marrow, spleen, liver, bowel,  or skin. Advances in understanding the disease and progress in  treatment strategies have meant that most children with NHL  are cured of the disease. The primary therapeutic modality for    Beas ye  30-12 Bone Marrow Aspirate from a Child with T-Cell Lymphoma  in a Lymph Node Biopsy. There is marked histiocytic hyperplasia. Two of the  histiocytes contain phagocytosed red cells. The histiocytic hyperplasia regressed  with disease remission and recurred with relapse of the lymphoma (Wright-Giemsa  stain). (From Damjanov I, Linder J, editors: Anderson’ pathology, ed 10, St Louis,  1996, Mosby.)    childhood NHL is chemotherapy, regardless of stage or site(s)  of the disease. The tumor responds to many different agents.  Many children with NHL receive intrathecal agents (metho-  trexate [Mexate] or cytarabine [cytosine arabinoside], or both)  for CNS prophylaxis. Radiation is not routinely used to treat  childhood NHL, with the exception of emergent situations  when airway, intestinal, or spinal obstruction requires immedi-  ate reduction in tumor size. Cranial radiation therapy (RT) may  be used for children with T-cell lymphoblastic lymphoma.   Children with advanced small noncleaved cell lymphoma of  the abdomen have the poorest prognosis. Although remission  occurs in more than 90% of these children, most experience  subsequent relapses. Even in the presence of advanced lym-  phoblastic lymphoma, however, 70% to 80% of children can  be cured. Children with localized disease in more easily treated  sites are likely to be cured with prompt and appropriate treat-  ment. Overall, children with localized diseases have a 90% sur-  vival rate and those with advanced disease have a 70% to 80%  survival rate.*?    Hodgkin Lymphoma  Hodgkin lymphoma accounts for 6% of all childhood cancers  with a significant male-to-female dominance of 4:1 in young  children. There is an increased incidence in children with  immunologic disorders, whether caused by genetics, infection,  or iatrogenic agents. EBV has been associated with Hodgkin  lymphoma. Approximately 15% to 25% of adolescents and  young adults have EBV-positive Hodgkin lymphoma.*° Clus-  tering of cases within families may suggest a genetic predisposi-  tion to the disease or common exposure to a causative agent.*°  Hodgkin lymphoma accounts for 6% of all childhood can-  cers. It occurs infrequently in children younger than 2 years,  and few cases are observed before age 5 years. A gradual rise in  incidence occurs through age 11 years, with a marked increase  through adolescence that continues into the 30s.    Individuals typically have painless supraclavicular or  cervical adenopathy. These nodes are firm and rubbery and  may be sensitive to palpation if they have grown rapidly. At  least two thirds of individuals have mediastinal involvement  that may cause symptoms ranging from a nonproductive  cough to tracheal or bronchial compression leading to air-  way obstruction. Systemic symptoms may include fatigue,  anorexia, weight loss, fever, drenching night sweats, and  pruritus.    The Ann Arbor staging system considers extent and location  of disease, as well as substage classifications that consider sys-  temic symptoms (presence of fever of 38° C [100.4° F] for 3  consecutive days, drenching night sweats, or unexplained loss  of 10% or more of body weight in the 6 months preceding diag-  nosis), extranodal, or bulky disease. Combination chemother-  apy used in conjunction with involved field low-dose radiation  has been shown to be an effective treatment, with long-term  cure rates reported from 90% to 95%.*°   1. After 2 weeks of gestation, circulating erythrocytes play a  major role in delivering oxygen to the tissues.   2. Erythropoiesis in the liver and, to a lesser extent, in the  spleen and lymph nodes reaches a peak at about 4 months.   3. By the fifth month of gestation, hematopoiesis begins to  occur in the bone marrow, and by the time of delivery it is  the only significant site of hematopoiesis.   4. A biochemically distinct type of hemoglobin is synthesized  during fetal life, including Gower 1, Gower 2, and Portland.   1. Blood cell counts tend to rise above adult levels at birth and  then decline gradually throughout childhood.   2. The immediate rise in blood cell counts is the result of  increased hematopoiesis during fetal life, trauma of birth,  and cutting of the umbilical cord.   3. The active rate of fetal erythropoiesis is observed in the large  numbers of reticulocytes in the peripheral blood of the full-  term neonate.   4, Erythrocyte values are age dependent, and values in males  and females are apparent in adolescence.   5. The lymphocyte count is high at birth, and continues to rise  in some healthy infants during the first year of life.   6. Platelet counts in full-term neonates are comparable to  platelet counts in children and adults.   1. Iron deficiency anemia is the most common blood disor-  der of infancy and childhood; the highest incidence occurs  between 6 months and 2 years of age.   2. Hemolytic disease of the newborn (HDN) results from  incompatibility between the maternal and the fetal blood,  which may involve differences in Rh factors or blood type  (ABO). Maternal antibodies enter the fetal circulation and  cause hemolysis of fetal erythrocytes. Because the immature  liver is unable to conjugate and excrete the excess bilirubin  that results from the hemolysis, icterus neonatorum, or ker-  nicterus or both can develop.   3. Kernicterus, which may result from other causes as well,  results in increased breakdown of red blood cells or decreased  liver output of enzymes.   4. Infections of the newborn, often acquired by the mother and  transmitted to the infant, may result in hemolytic anemia.    5. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is  an inherited enzyme deficiency in erythrocytes that results in  a disruption of a common pathway of glycolysis, shortening  erythrocyte life span.   6. Hereditary spherocytosis is the most common of the hered-  itary hemolytic states in which there is no abnormality of  hemoglobin. The basic defect is an undefined abnormality  of the proteins or spectrins of the erythrocyte membrane in  which affected cells are unduly permeable to sodium and  acquire a characteristic structure.   7. Sickle cell disease (SCD) is a genetically determined defect of  hemoglobin synthesis, inherited by an autosomal recessive  transmission; it causes a change in the shape of a red blood  cell that results in decreased oxygen or hydration. This dis-  ease is most common among Africans, blacks, and those of  Mediterranean descent.   8. The thalassemias are a heterogeneous group of hereditary  hypochromic anemias of varying severity. Basic genetic  defects include abnormalities of messenger ribonucleic acid  (mRNA) processing or deletion of genetic materials, result-  ing in a decrease in the chains for hemoglobin.   1. Hemophilia is a condition characterized by impairment of  the coagulation of blood and subsequent tendency to bleed.  The classic disease is hereditary and limited to males, being  transmitted through the female to the second generation.  Many similar conditions attributable to the absence of vari-  ous clotting factors are recognized.   2. von Willebrand disease is a dominantly inherited disease  characterized by a vascular abnormality that produces a  prolongation of bleeding time and by decreased levels of  clotting factor VIII. The platelets in von Willebrand disease  have decreased adhesiveness because the plasma factor is  absent.   3. Disorders of congenital hypercoagulability and thrombosis  include protein C deficiency, protein S deficiency, neonatal  purpura fulminans, and antithrombin II deficiency.   4. The acquired antibody-mediated hemorrhagic diseases  include idiopathic thrombocytopenic purpura (ITP), auto-  immune neonatal thrombocytopenia, and autoimmune vas-  cular purpura.   5. ITP, the most common of the childhood thrombocytope-  nic purpuras, is a disorder of platelet consumption in which    Acute lymphoblastic leukemia is a potentially curable dis-  The lymphomas of childhood are non-Hodgkin lymphoma  The origin of non-Hodgkin lymphoma is unknown. Fac-  tors that have been implicated include defective host immu-  nity, a viral agent, chronic immunostimulation, and genetic    The risk of Hodgkin lymphoma is associated in part  with infectious diseases, immune deficits, and genetic   platelets. This results in platelet sequestration and destruc- ease, with more than 80% of cases cured.   tion by mononuclear phagocytes at a rate that exceeds the 4.   ability of the bone marrow to produce them. and Hodgkin lymphoma.  6. Autoimmune neonatal thrombocytopenia is an antibody- 5:   Leukemia and Lymphoma 7;  1. The types of childhood leukemia include, in order of their   rate of incidence, ALL, AML, and CML. susceptibility.  2. Although the cause of childhood leukemia is not known, itis 8.    probably the result of multiple interactions between heredi-  tary or genetic predisposition and environmental influences.    Hodgkin lymphoma is a readily curable disease with long-  term cure rates of 90% to 95%.    1. Nagaoka H: Immunization and infection change the number of  recombination activating gene (Rag) expressing B cells in the 10.  periphery by altering immature lymphocyte production, J Exp Med   Idiopathic thrombocytopenic purpura (ITP) (auto-  immune or primary thrombocytopenic purpura),  1073   Prothrombin consumption time, 1071  Prothrombin time (PT), 1071  Sequestration crisis, 1066   Thromboplastin generation test, 1072  Vaso-occlusive crisis (thrombotic crisis), 1066  von Willebrand disease, 1071    nutrition and development in children under 12 years of age, Cochrane  Database Syst Rev (12):CD009085, 2011.   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Laurier D et al: Epidemiological studies of leukaemia in children and  young adults around nuclear facilities: a critical review, Radiat Prot  Dosimetry 132:182-190, 2008.   National Cancer Institute: Late effects of the central nervous system, 2012.  Available at www.cancer.gov/cancertopics/pdq/treatment/lateeffects/Heal  thProfessional/page4. Accessed January 28, 2013.   Alvarnez JC et al: Acute lymphoblastic leukemia, J Natl Comp Canc Netw  10(7):858-914, 2012.   Pajand O et al: Detection of Epstein-Barr virus DNA in plasma and  lymph node biopsy samples in pediatric and adult patients with Hodgkin  lymphoma, Pediatr Hematol Oncol 28(1):10-15, 2011.   Gross TG, Perkins SL: Malignant non-Hodgkin lymphomas in children.  In Pizzo PA, Poplack DG, editors: Principles and practice of pediatric oncol-  ogy, ed 6, Philadelphia, 2012, Lippincott Williams & Wilkins, pp 722-747.  Metzger M et al: Hodgkin lymphoma. In Pizzo PA, Poplack DG, editors:  Principles and practice of pediatric oncology, ed 6, Philadelphia, 2012,  Lippincott Williams & Wilkins, pp 695-721.    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:  Case Study    Circulatory System, 1083  The Heart, 1085  Structures That Direct Circulation Through the Heart, 1085  Structures That Support Cardiac Metabolism: The  Coronary Vessels, 1090  Structures That Control Heart Action, 1092  Factors Affecting Cardiac Output, 1101  Systemic Circulation, 1106  Structure of Blood Vessels, 1106  Factors Affecting Blood Flow, 1109    The functions of the circulatory system include delivery of  oxygen, nutrients, hormones, cells of the immune system, and  other substances to body tissues and removal of the waste prod-  ucts of cellular metabolism. Delivery and removal are achieved  by a complex array of tubing—the blood and lymphatic ves-  sels—connected to a pump—the heart. The heart continuously  pumps blood through the blood vessels in collaboration with  other systems, particularly the nervous and endocrine systems,  which are intrinsic regulators of the heart and blood vessels.  Immune system cells, nutrients, and oxygen are supplied by the  immune, digestive, and respiratory systems; gaseous wastes of  cellular metabolism are blown off by the lungs; and other wastes  are removed by the kidneys and digestive tract.   A critical component of the circulatory system is the vascu-  lar endothelium, which is considered by some to be a separate    Regulation of Blood Pressure (Arterial Pressure), 1114  Regulation of Coronary Circulation, 1117   Tests of Cardiovascular Function, 1119  Cardiac and Coronary Artery Evaluation, 1119  Systemic Vascular Evaluation, 1122  AGING and the Cardiovascular System, 1123    organ. It is a multifunctional tissue whose health is essential to  normal vascular and hemostatic physiology and whose dysfunc-  tion is an important factor in the pathogenesis of vascular and  other diseases.'    The heart is comprised of two conjoined pumps that power the  movement of blood through two separate circulatory systems,  one to the lungs and one to all other parts of the body. Struc-  tures on the right side of the heart, or right heart, pump blood  through the lungs. (This system, termed the pulmonary circu-  lation, is described in Chapter 34.) The left side of the heart,  or left heart, sends blood throughout the systemic circulation,  which supplies all of the body except the lungs (Figure 31-1).    FIGURE 31-1 Diagram Showing Serially Connected Pulmonary and Systemic Circulatory Systems and How to  Trace the Flow of Blood. A, Right heart chambers propel unoxygenated blood through the pulmonary circulation, and the  left heart propels oxygenated blood through the systemic circulation. B, The direction of blood flow begins at the left ventricle  of the heart; flows to the arteries, arterioles, capillaries of each body organ, venules, veins, right atrium, right ventricle, pul-  monary artery, lung capillaries, pulmonary veins, and left atrium; and then returns to the left ventricle. LA, Left atrium, LV left  ventricle; RA, right atrium; RV, right ventricle; SL, semilunar. (A from Patton KT, Thibodeau GA: Anatomy & physiology, ed 8,  St Louis, 2013, Mosby. B from Thibodeau GA, Patton KT: The human body in health & disease, ed 6, St Louis, 2014, Mosby.)    These two systems are serially connected so that the output of  one pump becomes the input of the other.   Arteries carry blood from the heart to all parts of the body,  where they branch into arterioles and even smaller vessels until  they become a fine meshwork of capillaries. Capillaries allow  the closest contact and exchange between the blood and the  interstitial space, or interstitium—the environment in which  the cells live. Veins then carry blood from capillaries back to  the heart. Some of the plasma or liquid component of the blood  passes through the walls of the capillaries into the interstitial  space. This fluid, called lymph, is returned to the cardiovascu-  lar system by vessels of the lymphatic system. The lymphatic  system is also a critical component of the immune system as  described in Chapter 8.    The adult heart weighs between 200 and 350 g and is about the  size of a fist. It lies obliquely (diagonally) in the mediastinum,  the area above the diaphragm and between the lungs. Wom-  en’s hearts are typically about 0.40% of their total body weight  whereas men’s hearts are about 0.45% of total body weight.”   1. Structural support of heart tissues and circulation of pul-  monary and systemic blood through the heart. This cate-  gory includes the heart wall and fibrous skeleton, which  enclose and support the heart and divide it into four  chambers; the valves that direct flow through the cham-  bers; and the great vessels that conduct blood to and from  the heart.   2. Maintenance of heart cells. This category comprises vessels  of the coronary circulation—the arteries and veins that  serve the metabolic needs of all the heart cells—and the  lymphatic vessels of the heart.   3. Stimulation and control of heart action. Among these  structures are the nerves and specialized muscle cells that  direct the rhythmic contraction and relaxation of the  heart muscles, propelling blood throughout the pulmo-  nary and systemic circulatory systems.   The heart wall has three layers—the epicardium, myocardium,  and endocardium—and is enclosed in a double-walled mem-  branous sac, the pericardium (Figure 31-2). The pericardial  sac has several functions. It (1) prevents displacement of the  heart during gravitational acceleration or deceleration, (2) acts  as a physical barrier that protects the heart against infection and  inflammation from the lungs and pleural space, and (3) con-  tains pain receptors and mechanoreceptors that can elicit reflex  changes in blood pressure and heart rate. The outer layer of the  pericardium, the parietal pericardium, is composed of a sur-  face layer of mesothelium over a thin layer of connective tissue.  The visceral pericardium, or epicardium, is the inner layer of  the pericardium. At one point the visceral pericardium folds  back and becomes continuous with the parietal pericardium,    FIGURE 31-2 Wall of the Heart. The cutout section of the heart wall shows  the outer fibrous pericardium and the parietal and visceral layers of the serous  pericardium (with the pericardial space between them). Note that a layer of fatty  connective tissue is located between the visceral layer of the serous pericardium  (epicardium) and the myocardium. Note also that the endocardium covers beamlike  projections of myocardial muscle tissue, called trabeculae carneae. (From Patton KT,  Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    allowing the large vessels to enter and leave the heart without  breaching the pericardial layers.   The visceral and parietal pericardia are separated by a fluid-  containing space called the pericardial cavity. The pericardial  fluid (about 20 ml), which is secreted by cells of the mesothe-  lium, lubricates the membranes that line the pericardial cavity,  enabling them to slide over one another with a minimum of  friction as the heart beats. The amount and character of the  pericardial fluid are altered by inflammation of the pericardium  (see Chapter 32).   The outer layer of the heart, the epicardium, provides a  smooth surface that allows the heart to contract and relax within  the pericardium with a minimal amount of friction. The thick-  est layer of the heart wall, the myocardium, is composed of car-  diac muscle and is anchored to the heart’s fibrous skeleton. The  thickness of the myocardium varies tremendously from one  heart chamber to another. Thickness is related to the amount  of resistance the muscle must overcome to pump blood from  the different chambers. The internal lining of the myocardium    is composed of connective tissue and a layer of squamous cells  called the endocardium (see Figure 31-2). The endocardial lin-  ing of the heart is continuous with the endothelium that lines all  the arteries, veins, and capillaries of the body, creating a contin-  uous, closed circulatory system (see What’s New? The Potential  for Using Epicardial Cells in Myocardial Repair).    The heart has four chambers: the right atrium, left atrium,  right ventricle, and left ventricle. These chambers form two  pumps in series: the right heart, which is a low-pressure sys-  tem pumping blood through the lungs; and the left heart, which  is a high-pressure system pumping blood through the rest of  the body. (Blood flow through these chambers is illustrated in  Figure 31-3.) The atria are smaller than the ventricles and have    With cardiovascular disease, including myocardial infarction as one of the  leading causes of death and disability, there is great interest in regenera-  tive therapies for the heart muscle. Bone marrow transplants have been tried  in an attempt to grow new myocardium but the results are unimpressive.  Because studies of heart development in the embryo have shown that both  the epicardium and the myocardium develop from a common progenitor, called    epicardium-derived cells (EPDCs), there is now great interest in identifying  these precursor cells and using them to repair ischemic or dying myocardial  tissue. One advantage of using these cells that apparently can be isolated  from an adult's heart is that in addition to forming new heart muscle they also  will release the appropriate cytokines and growth factors for muscle regenera-  tion and the growth of nourishing blood vessels.    Data from Gittenberger-de Groot AC et al: Differentiation 84(1):41-53,  2012; Limana F, Capogrossi MC, Germani A: Pharmacol Ther 129(1):82-96,  2011.    FIGURE 31-3 Structures That Direct Blood Flow Through the Heart.  Arrows indicate path of blood flow through chambers, valves, and major vessels.    thinner walls. The walls of the right and left atria are about 1 to  2 mm thick. The ventricles have a thicker myocardial layer and  make up much of the bulk of the heart. The wall of the right  ventricle is about 4 to 5 mm thick, and that of the left ventricle,  the most muscular chamber, is about 12 to 15 mm.” The ven-  tricles are formed by a continuum of muscle fibers that origi-  nate from the fibrous skeleton at the base of the heart (chiefly  around the aortic orifice).   The wall thickness of each cardiac chamber depends on the  amount of pressure or resistance it must overcome to eject blood.  The two atria have the thinnest walls because they are low-pressure  chambers that serve as storage units and conduits for blood that is  emptied into the ventricles. Normally, there is little resistance to  flow from the atria to the ventricles. The ventricles, on the other  hand, must propel blood all the way through the pulmonary or  systemic circulation. The ventricular myocardium must be strong  enough to pump against pressures in the pulmonary or systemic  vessels. The mean pulmonary capillary pressure, the force the  right ventricle must overcome, is only 15 mmHg whereas the  mean arterial pressure, the force the left ventricle must overcome,  is about 92 mmHg. Because the pressure is markedly higher in the  systemic circulation, the left ventricle’s myocardial wall is several  times thicker than that of the right ventricle.   The right ventricle is shaped like a crescent, or triangle,  enabling it to function like a bellows and efficiently eject large  volumes of blood through the pulmonary semilunar valve  into the low-pressure pulmonary system. The left ventricle is  larger and bullet shaped, helping it to eject blood through the  larger aortic semilunar valve into the high-pressure systemic  circulation.   The ventricles are structurally more complex than the atria.  Each ventricle contains muscle fibers that divide it roughly into an  inflow tract, which receives blood from the atrium, and an out-  flow tract, which sends blood to the circulation (see Figure 31-3).   Normally blood does not flow between the chambers of the  right side of the heart and the chambers of the left side of the  heart except in the fetus before delivery. The adult right and left  sides of the heart are separated by intact septal membranes. The  atria are separated by the interatrial septum and the ventricles  by the interventricular septum. There is an opening between the  right and left atria before birth called the foramen ovale; how-  ever, this opening closes shortly after birth in most individuals  (see Chapter 33). The interventricular septum is an extension of  the fibrous skeleton of the heart. Indentations of the endocar-  dium form valves that separate the atria from the ventricles and  the ventricles from the aorta and pulmonary arteries.    Four rings of dense fibrous connective tissue provide a firm  anchorage for the attachments of the atrial and ventricular  musculature, as well as the valvular tissue. The fibrous rings are  adjacent and form a central, fibrous supporting structure col-  lectively termed the annuli fibrosi cordis.    One-way blood flow through the heart is ensured by the four  heart valves as well as the pressure gradients that they maintain.    CHAPTER 31 Structure and Function of the Cardiovascular and Lymphatic Systems    During ventricular relaxation the two atrioventricular valves  open and blood flows from the relatively higher pressure in  the atria to the lower pressure in the relaxed ventricles. With  increasing ventricular pressure these valves close and prevent  backflow into the atria as the ventricles contract. The semilunar  valves of the heart open when intraventricular pressure exceeds  aortic and pulmonary pressures and blood flows out of the  ventricles and into the systemic and pulmonary circulations,    respectively. After ventricular contraction and ejection, intra-  ventricular pressure falls and the pulmonic and aortic semi-  lunar valves close when the pressure in the vessels is greater  than the pressure in the ventricles, thus preventing backflow  into the right and left ventricles, respectively (Figure 31-4; also  see Figure 31-3).   The atrioventricular (AV) (tricuspid and mitral) valve open-  ings are composed of flaps of tissue called leaflets or cusps that    FIGURE 31-4 Chambers and Valves of the Heart. Chambers and valves of the heart. A, During atrial contraction car-  diac muscle in the atrial wall contracts, forcing blood through the atrioventricular (AV) valves and into the ventricles. Bottom  illustration shows superior view of all four valves, with semilunar (SL) valves closed and AV valves open. B, During ventricular  contraction that follows, the AV valves close and the blood is forced out of the ventricles through the SL valves and into the  arteries. Bottom illustration shows superior view of SL valves open and AV valves closed. (From Patton KT, Thibodeau GA:    are attached at the upper end to one of the rings in the fibrous  skeleton of the heart and at the lower end to papillary muscles  by the chordae tendineae (see Figure 31-3). The papillary mus-  cles are extensions of the myocardium that help hold the cusps  together and downward at the onset of ventricular contraction,  thus preventing their backward expulsion, or prolapse, into the  atria (see p. 1087 for a description of pressure changes and val-  vular function).   The right AV valve is called the tricuspid valve because it  has three cusps. The tricuspid opening (orifice) has the largest  diameter of all the heart valves. The left AV valve is a bicus-  pid (two cusps) valve called the mitral valve. The mitral valve  resembles a cone-shaped funnel that extends into the cusps,  which are connected by a fibrous tissue called the commissure.  The anterior cusp of the mitral valve is continuous with sup-  porting tissues of the aortic semilunar valve cusps and the left  coronary valve cusps. (The coronary circulation is described on  p. 1090.) Thus damage to this continuous tissue can alter func-  tion of the aortic as well as the mitral valves.   The tricuspid and mitral valves function as a unit because  the atrium, fibrous rings, valvular tissue, chordae tendineae,  papillary muscles, and ventricular walls are all connected.  Collectively, these six structures are known as the mitral and  tricuspid complex. Damage to any one of the complex’s six  components can alter function significantly.   Blood leaves the right ventricle through the pulmonic semi-  lunar valve, and it leaves the left ventricle through the aortic  semilunar valve (see Figures 31-3 and 31-4). The pulmonic and  aortic semilunar valves have three cup-shaped cusps that arise  from the fibrous skeleton. The pulmonic cusps are slightly thin-  ner than the aortic cusps. The lower edges of each cusp are sus-  pended from the root of the pulmonary artery or aorta, with the  upper valve edges freely projecting into the vessel lumen. When  the ventricles contract, the cusps behave like one-way swinging  doors. The force of the blood propels the cusps outward against  the vessel wall. When the ventricles relax, blood fills the cusps  and causes their free edges to meet in the middle of the vessel,  closing the valve and preventing any backflow.   Blood moves in and out of the heart through several large vessels  (see Figure 31-3). The right heart receives venous deoxygenated  blood from the systemic circulation through the superior vena  cava and the inferior vena cava, which enter the right atrium.  Blood leaves the right ventricle and enters the pulmonary cir-  culation through the pulmonary artery. The pulmonary artery  divides into right and left pulmonary arteries to transport  unoxygenated blood from the right heart to the right and left  lungs. The pulmonary arteries branch further into the pulmo-  nary capillary bed, where oxygen enters the blood and carbon  dioxide leaves it as each gas moves from its higher to lower con-  centration gradient.   Four pulmonary veins, two from the right lung and two  from the left lung, carry oxygenated blood from the lungs to the  left side of the heart. The oxygenated blood moves through the  left atrium and ventricle and out into the aorta, which delivers  it to systemic vessels that supply the body.   The pumping action of the heart consists of contraction and  relaxation of the heart muscle or myocardium. Each ventricu-  lar contraction and the relaxation that follows it constitute one  cardiac cycle. (Blood flow through the heart during a single  cardiac cycle is illustrated in Figure 31-4.) During the period  of relaxation, termed diastole, blood fills the ventricles. The  contraction that follows, termed systole, propels the blood out  of the ventricles and into the pulmonary and systemic circu-  lations. Contraction of the left ventricle occurs slightly earlier  than contraction of the right ventricle.   During ventricular systole, blood from the veins of the  systemic circulation enters the thin-walled right atrium from  the superior and inferior venae cavae (see Figures 31-3 and  31-4). Venous blood from the coronary circulation enters the  right atrium through the coronary sinus. The right atrium  fills, which, along with the falling right ventricular pressures,  allows the right AV (tricuspid) valve to open and fill the right  ventricle during ventricular diastole (occasionally called atrial  systole). The same sequence of events occurs a split second  earlier in the left heart. The four pulmonary veins, two from  the right lung and two from the left lung, carry blood from  the pulmonary circulation to the left atrium. As the left atrium  fills and left ventricular pressure falls, the mitral valve opens  and blood flows into the left ventricle. Left atrial contraction,  termed “atrial kick,” provides significant increases in the vol-  ume of blood entering the left ventricle at the end of diastole.  Filling of the right and left ventricles occurs during one period  of diastole.   Five phases of the cardiac cycle can be identified (Figures  31-5 and 31-6):   Phase 1: Ventricular diastole or atrial systole begins with  opening of the mitral and tricuspid valves and then ven-  tricular filling from the atria occurs. The ventricles fill  rapidly in early diastole and again in late diastole when  the atria contract.   Phase 2: Ventricular systole begins with “isovolumetric  contraction,” so-called because ventricular volume is  constant since both the AV and the semilunar valves are  closed. The first detectable rise in ventricular pressure  occurs during isovolumetric contraction. This contrac-  tion pushes the AV valves shut. Their cusps bulge slightly  into the atria but are prevented from opening back into  the atria by their anchors, the chordae tendineae (see  Figure 31-3).   Phase 3: When ventricular pressure reaches and then slightly  exceeds that of the pulmonary artery and aorta, the semi-  lunar valves open and ventricular ejection occurs. Intra-  ventricular pressure and ventricular volume decrease  rapidly.   Phase 4: With ventricular relaxation and decreased ventricu-  lar pressure, the aortic valve closes and “isovolumetric  relaxation” occurs. Again, both the AV and the semilunar  valves are closed during this phase.   Phase 5: When left ventricular pressure falls below atrial  pressure, the mitral and tricuspid valves open and passive  ventricular filling occurs.    Time (sec)  FIGURE 31-5 Composite Chart of Heart Function. This chart is a composite of  several diagrams of heart function (blood pressure, blood flow, volume, heart sounds,  venous pulse, and electrocardiogram [ECG)), all adjusted to the same time scale.    FIGURE 31-6 Phases of the Cardiac Cycle. 1, Atrial systole. 2, Isovolumetric  ventricular contraction. Ventricular volume remains constant as pressure increases  rapidly. 3, Ejection. 4, lsovolumetric ventricular relaxation. Both sets of valves are  closed, and the ventricles are relaxing. 5, Passive ventricular filling. The atrioven-  tricular (AV) valves are forced open, and the blood rushes into the relaxing ventricles.  (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    As blood is pushed through the inflow and outflow tracts of  the ventricles, it flows around the crista supraventricularis—  the muscle that separates the inflow from the outflow tracts—  and is mixed by passing through the strands of the trabeculae  carneae.    Normal intracardiac pressures are shown in Table 31-1 and  Figure 31-7. Atrial pressure (see venous pulse in Figure 31-5)  curves are composed of the a wave, which is generated by  atrial contraction, and the v wave, which is an early diastolic  peak caused by filling of the atrium from the peripheral veins.  A smaller pressure increase, the c wave, occurs after the a  wave in early systole and may represent bulging of the mitral  valve into the left atrium during early systole. Two aspects of  falling atrial pressure have also been named. The x descent  follows the a wave and is produced by the descent of the tri-  cuspid valve ring and by the ejection of blood from both ven-  tricles. The y descent that follows the v wave reflects the rapid    flow of blood from the great veins and right atrium into the  right ventricle. Left ventricular pressures are illustrated by a  peak systolic pressure and an end-diastolic pressure, which  is the ventricular pressure immediately before the onset of  systole. The minimal left ventricular pressure occurs in early  diastole.   To supply oxygen and other nutrients to the myocardium,  heart structures are nourished by vessels of the systemic circu-  lation, the coronary circulation. The coronary arteries receive  blood through openings in the aorta, called the coronary ostia.  The cardiac veins empty into the right atrium through another  ostium, the opening of a large vein called the coronary sinus  (Figure 31-8).    Systole range  (15-28 mmHg;  mean = 24 mmHg)  End-diastolic range  (0-8 mmHg;    The major coronary arteries are the right coronary artery  (RCA) and the left coronary artery (LCA) (see Figure 31-8).  These arteries traverse the epicardium and branch several  times. The right coronary artery has greater flow than the left in  70% of individuals, the left greater than the right in 10%, and  equal flow in each is found in 20% of individuals.* The pattern  of branching through the visceral pericardium differs among  individuals. The branches of the coronary arteries enter the  myocardium and endocardium and branch further to become  arterioles and then capillaries. The coronary arteries are smaller  in women than in men, a fact that is attributed to differences in  heart weight.   The left coronary artery arises from a single ostium (open-  ing) behind the left cusp of the aortic semilunar valve. This  artery ranges from a few millimeters to a few centimeters in  length. It passes between the left atrial appendage and the pul-  monary artery and generally divides into two branches—the  left anterior descending artery and the circumflex artery. Other  branches of the left main coronary artery are distributed diago-  nally across the free wall of the left ventricle.   The left anterior descending (LAD) artery delivers blood to  portions of the left and right ventricles and much of the inter-  ventricular septum. The left anterior descending artery initially  travels in a groove between the left and right ventricles down  the anterior surface of the interventricular septum toward the  apex of the heart.   The circumflex artery travels in a groove called the coro-  nary sulcus, which separates the left atrium from the left ven-  tricle, to the left border of the heart. It supplies blood to the left  atrium and the lateral wall of the left ventricle. The circumflex    Systole range  (96-140 mmHg)  Diastole range  (60-90 mmHg)  *mean = 120 mmHg    Systole range  (90-140 mmHg;  mean = 130 mmHg)  End-diastolic range  (4-12 mmHg;    FIGURE 31-7 Normal Intracardiac Pressures. Ao, Aorta; LA, left atrium; LV, left ventricle; PA, pulmonary artery;    CHAPTER 31 Structure and Function of the Cardiovascular and Lymphatic Systems    artery often branches to the posterior surfaces of the left atrium  and left ventricle (see Figure 31-8).   The right coronary artery originates from an ostium behind  the right aortic cusp, travels behind the pulmonary artery, and  extends around the right heart to the heart’s posterior surface,  where it branches to the right atrium and ventricle. The three  major branches of the right coronary artery include the conus,  which supplies blood to the upper right ventricle; the right  marginal branch, which traverses the right ventricle to the apex;  and the posterior descending branch, which lies in the posterior  interventricular sulcus and supplies smaller branches to both  ventricles.    The collateral arteries are connections, or anastomoses,  between branches of the same coronary artery or connections of  branches of the right coronary artery with branches of the left.  They are particularly common within the interventricular and  interatrial septa, at the apex of the heart, over the anterior sur-  face of the right ventricle, and around the sinus node. The epi-  cardium contains more collateral vessels than the endocardium.   The functional importance of the collateral circulation is  that it protects the heart from ischemia. The collateral circula-  tion is responsible for supplying blood and oxygen to the myo-  cardium that has been deprived of oxygen following narrowing    FIGURE 31-8 Coronary Circulation. A, Arteries. B, Veins. Both A and B are anterior views of the heart. Vessels near the  anterior surface are more darkly colored than vessels of the posterior surface seen through the heart. C, View of the anterior  (sternocostal) surface. (A and B modified from Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.  C from Seeley RR, Stephens TD, Tate P: Anatomy & physiology, ed 3, St Louis, 1995, Mosby.)    of a major coronary artery (coronary artery disease). Gradual  coronary occlusion results in the growth of coronary collater-  als. New collateral vessels are formed through two processes:  arteriogenesis (new artery growth branching from pre-existing  arteries) and angiogenesis (growth of new capillaries within a  tissue).* A key stimulus to collateral growth is the shear stress  caused by increased blood flow velocity that occurs close to sites  of stenosis (narrowing) or occlusion. Shear stress activates the  endothelium of the pre-existing arterioles and stimulates the  production of growth factors and cytokines, including mono-  cyte chemoattractant protein-1 (MCP-1) and vascular endo-  thelial growth factor (VEGF).° Current research is focused on  identifying whether some of these factors that stimulate col-  lateral growth might prove to be useful treatments for persons  with myocardial ischemia, although to date none have been  demonstrated to be effective.°    The heart has an extensive capillary network, with approxi-  mately 3300 capillaries per square millimeter (ca/mm*) or  about one capillary per muscle cell (muscle fiber). Blood travels  from the arteries to the arterioles and then into the capillaries,  where exchange of oxygen and other nutrients takes place.   Alterations of the cardiac muscles dramatically affect blood  flow in the capillaries. For example, in ventricular hypertrophy  (enlargement of the ventricular myocardium), the capillary net-  work does not expand along with muscle fiber size. Therefore,  the same number of capillaries must now perfuse a larger area.  This results in decreased exchange of oxygen and nutrients. At  rest, the heart extracts 70% to 80% of the oxygen delivered to it  and coronary blood flow is directly correlated with myocardial  oxygen consumption.°    After passing through the extensive capillary network, blood  from the coronary arteries drains into the cardiac veins, which  travel alongside the arteries. Most of the venous drainage of  the heart occurs through veins in the visceral pericardium. The  veins then feed into the great cardiac vein (see Figure 31-8) and  coronary sinus on the posterior surface of the heart, between  the atria and ventricles, in the coronary sulcus. Venous coro-  nary blood empties into the right atrium from the coronary  sinus. Blood from the left ventricular walls generally is drained  through the coronary sinus and its tributaries, which together  form the largest system of coronary veins. The anterior interven-  tricular vein flows beside the LAD artery and then turns to join  the circumflex artery and becomes the great cardiac vein that  primarily drains the anterior surface of the heart. The posterior  vein of the left ventricle, the largest on the posterior surface of  the heart, branches from the coronary sinus and accompanies  the circumflex artery and then joins the great cardiac vein.  The myocardium has an extensive system of lymphatic capil-  laries and collecting vessels within the layers of the myocardium  and also in the valves. With cardiac contraction the lymphatic  vessels drain fluid to the paratracheal lymph nodes in the ante-  rior mediastinum and then continue to join the mediastinal  lymphatic vessels. Impairment of cardiac lymphatic function    has been hypothesized to impact cardiac conduction, protec-  tion from infection, and the development of myocardial fibrosis  and atherosclerosis.”    Our lives depend on the continuous repetition of the cardiac  cycle (systole and diastole) that occurs because of the transmis-  sion of electrical impulses, termed cardiac action potentials,  through the myocardium. (Action potentials are described in  Chapters 1 and 3.) As an electrical impulse passes from cell to  cell (fiber to fiber) in the myocardium, it stimulates an intracel-  lular process that results in fiber shortening—that is, muscular  contraction or systole. Between action potentials, the fibers relax  and return to their resting length, causing diastole. The muscle  fibers of the myocardium are electrically coupled so that action  potentials pass from cell to cell very rapidly and efficiently. The  myocardial structures that allow the action potentials to move  so rapidly through the heart are the gap junctions in the interca-  lated disks. In the intercalated disks, the channel-forming pro-  teins, called connexins, form pores in the gap junctions.® As a  result of these structures plus the heart’s conduction system, an  action potential generated in one part of the myocardium passes  very quickly throughout the heart, causing rapid, organized,  sequential contraction of the atria and then the ventricles.   The myocardium differs from skeletal muscle tissue in that  it contains its own pacemakers and conduction system—  specialized cells that enable it to generate and transmit action  potentials without input from the nervous system (Figure 31-9).  The pacemaker cells are concentrated at two sites in the myocar-  dium called nodes, the sinoatrial (SA) node and the atrioventricu-  lar (AV) node. Although the heart is innervated by the autonomic  nervous system (sympathetic and parasympathetic fibers), neural  impulses are not needed to maintain the cardiac cycle. Thus the  heart will beat in the absence of any nervous connection, one of  the many factors that allow heart transplantation to be successful.  The cardiac cycle is stimulated by the nodes of specialized cells  and then adjusted to the physical needs of the body by the auto-  nomic fibers. The sympathetic and parasympathetic nerves affect  the speed of the cardiac cycle (heart rate, or beats per minute),  the force of contraction, and the diameter of the coronary vessels  (Figure 31-10). The sympathetic nervous system increases heart  rate and conduction through the nodes, the parasympathetic ner-  vous system slows heart rate and prolongs intranodal conduction  time, and both systems cause coronary vasodilation.’   Heart action is also influenced by substances delivered to  the myocardium in coronary blood. Nutrients and oxygen are  needed for cellular survival and normal function, and hor-  mones and biochemicals, including medications, can affect the  strength and duration of myocardial contraction and the degree  and duration of myocardial relaxation. Normal or appropri-  ate function depends on the availability of these substances,  which is why coronary artery disease can seriously disrupt heart  function.    Normally electrical impulses arise in the sinoatrial (SA) node  (SA node, sinus node), the usual pacemaker of the heart. The SA    CHAPTER 31 Structure and Function of the Cardiovascular and Lymphatic Systems    Atrioventricular Interatrial bundle  (AV) node au gm Sinoatrial (SA) node _ 2nd fibers  (pacemaker)  Internodal  bundle :  Right atrium and fibers Left atrium  (RA) (LA)    my au Lateral ventricular  wall Lateral Septum Septum Lateral  wall wall  Right ventricle (RV) Left ventricle (LV)  A B    FIGURE 31-9 Conduction System of the Heart. Specialized cardiac muscle cells (bo/dface type) in the wall of the heart  rapidly initiate or conduct an electrical impulse throughout the myocardium. Both the sketch of the conduction system (A) and  the flowchart (B) show the origin and path of conduction. The signal is initiated by the SA node (pacemaker) and spreads to the  rest of the right atrial myocardium directly, to the left atrial myocardium by way of a bundle of interatrial conducting fibers, and  to the AV node by way of three internodal bundles. The AV node then initiates a signal that is conducted through the ventricular  myocardium by way of the AV bundle (of His) and subendocardial branches (Purkinje fibers). (From Patton KT, Thibodeau GA:  Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    ; J : node is located at the junction of the right atrium and superior  vena cava, just above the tricuspid valve (see Figure 31-9). The  SA node sits only about 1 mm beneath the visceral pericardium,   artery, which passes through the center of the node. The SA  node is heavily innervated by both sympathetic and parasympa-  thetic nerve fibers. Impulse formation is thought to occur in two  cell types found in the node—spindle- and spider-shaped cells.’   In the resting adult the SA node generates about 60 to 100  action potentials per minute depending on age and physical  condition. Each action potential travels rapidly from cell to cell  Receptor and through special pathways in the atrial myocardium, causing  , afferents both atria to contract, beginning systole. The action potential  is transmitted from the atrial to the ventricular myocardium  through fibers of the conduction system, traveling first to the  atrioventricular (AV) node, then to the bundle of His (atrio-  ventricular bundle, common bundle), and finally through the  bundle branches of the interventricular septum to Purkinje  fibers in the heart wall (see Figure 31-9).   The AV node is well situated for mediating conduction  between the atria and ventricles. It is located in the right atrial  wall above the tricuspid valve and anterior to the ostium of the  coronary sinus. There is variability in the size and length of the  AV node fibers. Generally the AV node is thicker and shorter  in size than the SA node. Behind the AV node are numerous  autonomic parasympathetic ganglia. (The nervous systems are  described in Chapter 15.)    Blood vessels Heart  FIGURE 31-10 Autonomic Innervation of Cardiovascular System. +, Acti-  vation; -, inhibition; Symp, sympathetic.    Conducting fibers from the AV node converge to form  the bundle of His. The bundle of His, which is triangular  shaped, lies within the posterior border of the interventricu-  lar septum. The two lower ends of the triangle give rise to  the right and left bundle branches. The right bundle branch  (RBB) is thin and travels without much branching to the right  ventricular apex. Because of its thinness and relative lack of  branches, the RBB is susceptible to interruption by damage to  the endocardium.   The left bundle branch (LBB) arises perpendicularly from  the bundle of His and, in some hearts, divides into two branches,  or fascicles. The left anterior bundle branch (LABB) passes the  left anterior papillary muscle and the base of the left ventricle  and crosses the aortic outflow tract. Damage to the aortic valve  or the left ventricle can interrupt this branch. The left poste-  rior bundle branch (LPBB) travels posteriorly, crossing the left  ventricular inflow tract to the base of the left posterior papil-  lary muscle. This branch spreads diffusely through the posterior  inferior left ventricular wall. Blood flow through this portion  of the left ventricle is relatively nonturbulent, so the LPBB is  somewhat protected from injury caused by wear and tear. The  Purkinje fibers are the terminal branches of the right and left  bundle branches. They extend from the ventricular apexes  to the fibrous rings and penetrate the heart wall to the outer  myocardium.   Cardiac Excitation. From the SA node the impulse that  begins systole spreads throughout the right atrium at a  conduction velocity of about 35 cm/sec.’ Because impulses  from the SA node arrive at the AV node very quickly,  investigators have proposed that these nodes are connected by  internodal pathways, called the anterior, middle, and posterior  internodal pathways. However, the existence of these pathways  is controversial; not all experts agree that they exist.’   The action potential is delayed in the region of the AV node,  possibly because of electrophysiologic differences in the cells  that comprise the AV region. Conduction velocity within the  node is about 10 cm/sec, markedly slower than conduction  through the atria.” The delay between atrial and ventricular  excitation permits an additional boost to ventricular filling by  atrial contraction (atrial kick). From the AV node the impulse  travels from the AV bundle and through the bundle branches to  the Purkinje fibers. Conduction velocities in the AV and Pur-  kinje fibers are the most rapid in the heart.   Ventricular activation occurs sequentially in three phases:  (1) septal activation, (2) apical activation, and (3) basal (upper)  and posterior activation. The first areas of the ventricles to be  excited are portions of the interventricular septum. The sep-  tum is activated from both the RBB and the LBB, although  the impulse travels from left to right. The extensive network  of Purkinje fibers promotes the rapid spread of the impulse to  the ventricular apexes. Activation traverses the heart wall from  the inside outward (from the endocardium to the epicardium;  see Figure 31-2). The basal and posterior portions of the ven-  tricles are the last to be activated. Deactivation, which begins in  diastole, occurs in the opposite direction, spreading from the  outside inward (epicardium to endocardium). All areas of the  ventricle recover at about the same time.    From Bonow RO et al, editors: Braunwald’s heart disease: a textbook  of cardiovascular medicine, ed 9, Philadelphia, 2012, Elsevier Saunders.  M, Moles; mM, millimoles per kilogram.    Propagation of Cardiac Action Potentials. Electrical  activation of the muscle cells, termed depolarization, is caused  by the movement ofions, including sodium, potassium, calcium,  and chloride, across cardiac cell membranes. Deactivation,  called repolarization, occurs the same way. (Movement of  ions across cell membranes is described in Chapter 1; electrical  activation of muscle cells is described in Chapter 43.)   Movement of ions into and out of the cell creates an elec-  trical (voltage) difference across the cell membrane called the  membrane potential. The resting membrane potential of myo-  cardial cells is between —80 and —90 millivolts (mV), whereas  the SA node is between —50 and —60 mV and the AV node is  between —60 and —70 mV.’ During depolarization the inside of  the cell becomes less negatively charged. In cardiac cells the dif-  ference between resting membrane potential (in millivolts) and  the decreased negative charge caused by depolarization is the  cardiac action potential. Table 31-2 summarizes the intracel-  lular and extracellular ionic concentrations of cardiac muscle.  The various phases of the cardiac action potential are related  to changes in the permeability of the cell membrane to sodium,  potassium, chloride, and calcium. Threshold is the point at  which the cell membrane’s selective permeability to these ions  is temporarily disrupted, leading to depolarization. If the rest-  ing membrane potential becomes more negative as a result of  a decrease in extracellular potassium concentration (hypokale-  mia), it is termed hyperpolarization.   Normal myocardial cell depolarization and repolarization  occur in five phases numbered 0 through 4 (Figure 31-11).  Phase 0 consists of depolarization. This phase lasts 1 to 2 mil-  liseconds (ms) and represents rapid sodium entry into the cell.  Phase 1 is early repolarization, in which calcium slowly enters  the cell. Phase 2, also called the plateau, is a continuation of  repolarization, with slow entry of calcium and sodium into the  cell. Potassium is moved out of the cell during phase 3, with  a return to resting membrane potential in phase 4.’ The time  between action potentials corresponds to diastole.   The phases of depolarization and repolarization occur some-  what differently in the SA and AV node cells, a difference that  enables these cells to generate cardiac action potentials inde-  pendently. The cells of the Purkinje fibers, atria, and ventricles  begin with a negative resting membrane potential and proceed  to a rapid upstroke, or depolarization (phase 0), a rapid early    C -100  FIGURE 31-11 Cardiac Action Potentials. A, Ventricle. B, Sinoatrial (SA)  node. €, Atrium. Sweep velocity in B is half that in A or C. (Modified from Koep-  pen BM, Stanton BA: Berne and Levy physiology, ed 6, Philadelphia, 2010, Mosby.)    repolarization (phase 1), a plateau (phase 2), and a rapid later  repolarization (phase 3) (see Figure 31-11, A and C). The fast  inward current of phase 0 is mediated by sodium ions flowing  through “fast channels” in the cell membrane and causes the  rapid upstroke of the action potential in Purkinje fibers, atria,  and ventricles. In contrast, the cells of the SA and AV nodes  begin with a less negative resting membrane potential, proceed  to a slow upstroke (phase 0), and usually lack a plateau (phase 2)  (see Figure 31-11, B). The slow inward current, mediated by cal-  cium through transient and long-lasting channels and sodium  ions flowing through “slow channels” of the cell membrane, is  responsible for the action potential of the SA node and the AV  node. Hence, drugs that block calcium have profound effects on  the slow inward current and can alter heart rate. Slow channel-  blocking drugs, such as verapamil, are used to treat a variety of  cardiovascular disorders.   A refractory period, during which no new cardiac action  potential can be initiated by a stimulus, follows depolarization.  This effective or absolute refractory period corresponds to the  time needed for the reopening of channels that permit sodium  and calcium influx (phase 0 through half of phase 3). A relative  refractory period occurs near the end of repolarization, follow-  ing the effective refractory period. During this time the mem-  brane can be depolarized again but only by a greater than normal    stimulus. Abnormal refractory periods as a result of disease can  cause abnormal heart rhythms, or dysrhythmias, including ven-  tricular fibrillation and cardiac arrest (see Chapter 32).   Normal Electrocardiogram. The genesis of the normal  electrocardiogram is from electrical activity recorded by skin  electrodes, that is, the sum of all cardiac action potentials  (Figure 31-12). The P wave represents atrial depolarization.  The PR interval is a measure of time from the onset of atrial  activation to the onset of ventricular activation; it normally  ranges from 0.12 to 0.20 second. The PR interval represents  the time necessary to travel from the sinus node through the  atrium, AV node, and His-Purkinje system to activate ventric-  ular myocardial cells. The QRS complex represents the sum of  all ventricular muscle cell depolarizations. The configuration  and amplitude of the QRS complex vary considerably among  individuals. The duration is normally between 0.06 and 0.10  second. During the ST interval the entire ventricular myocar-  dium is depolarized. The QT interval is sometimes called the  “electrical systole” of the ventricles. It lasts about 0.4 second,  but it varies inversely with the heart rate.   Automaticity. Automaticity, or the property of generat-  ing spontaneous depolarization to threshold, enables the SA  and AV nodes to generate cardiac action potentials without  any stimulus. Cells capable of spontaneous depolarization are  called automatic cells. The automatic cells of the cardiac con-  duction system can stimulate the heart to beat even when the  heart is removed from the body. Spontaneous depolarization  is possible in automatic cells because the membrane poten-  tial does not “rest” during phase 4. Instead, it slowly creeps  toward threshold during the diastolic phase of the cardiac  cycle. Because threshold is approached during diastole, phase 4  in automatic cells is called diastolic depolarization. The elec-  trical impulse normally begins in the SA node because its cells  depolarize more rapidly than other automatic cells. The ionic  basis for this diastolic depolarization is the regular rhythmic  oscillation of calcium with the automatic cells, a phenomenon  known as the “calcium clock.”?   Rhythmicity. Rhythmicity is the regular generation of an  action potential by the heart’s conduction system. The SA node  sets the pace because normally it has the fastest rate of depo-  larization, which is why it is called the natural pacemaker of the  heart. The SA node depolarizes spontaneously 60 to 100 times  per minute. Ifthe SA node is damaged, the AV node will become  the heart’s pacemaker at a rate of about 40 to 60 spontaneous  depolarizations per minute. Purkinje fibers also are capable of  spontaneous depolarization but at a rate of only 30 to 40 beats/  minute; therefore they only function as pacemakers when the  SA and AV nodes are diseased or there is interruption to move-  ment of electrical current through the heart.    Although the heart’s nodes and conduction system gener-  ate cardiac action potentials independently, the autonomic  nervous system influences the rate of impulse generation (fir-  ing), depolarization, and repolarization of the myocardium  and the strength of atrial and ventricular contraction. Auto-  nomic neural transmission produces changes in the heart and    FIGURE 31-12 Electrocardiogram (ECG) and Cardiac Electrical Activity. A, Normal ECG. Depolarization and repo-  larization. B, ECG intervals among P, ORS, and T waves. C, Schematic representation of ECG and its relationship to cardiac  electrical activity. AV Atrioventricular; LA, left atrium; LBB, left bundle branch; LV, left ventricle; AA, right atrium; ABB, right  bundle branch; AY right ventricle. (A and B from Thibodeau GA, Patton KT: Anatomy & physiology, ed 5, St Louis, 2003, Mosby.  C from Thibodeau GA: Anatomy & physiology, St Louis, 1987, Mosby.)    circulatory system faster than metabolic or humoral agents  (see Figure 31-10). Speed is important, for example, in stim-  ulating the heart to increase its pumping action during times  of stress and fear, the so-called fight-or-flight response, or with  increased physical activity. Although increased delivery of oxy-  gen, glucose, hormones, and other blood-borne factors sustains  increased cardiac activity, the rapid initiation of increased activ-  ity depends on the sympathetic and parasympathetic fibers of  the autonomic nervous system. (The autonomic nervous sys-  tem is described and illustrated in Chapter 15.)   Sympathetic and Parasympathetic Nerves. Sympathetic and  parasympathetic nerve fibers innervate all parts of the atria and  ventricles and the SA and AV nodes. In general, sympathetic  stimulation increases electrical conductivity and the strength of  myocardial contraction, and vagal parasympathetic nerve activity  does the opposite, slowing the conduction of action potentials  through the heart and reducing the strength of contraction.    Efferent sympathetic fibers originate in the thoracic spinal  cord and branch into the superior middle and inferior car-  diac nerves. They join at the cardiac plexus, a neural junction  located at the root of the aorta in front of the trachea. Sym-  pathetic nervous activity enhances myocardial performance.  Catecholamines speed heart rate, shorten the conduction time  through the AV node, and increase the rhythmicity of the AV  pacemaker fibers. Neurally released norepinephrine or circulat-  ing catecholamines interact with B-adrenergic receptors on the  cardiac cell membranes. The overall effect is an increased influx  of Cat* during the action potential plateau that increases the  contractile strength of the heart.   The efferent parasympathetic fibers originate in the medulla  oblongata and travel by way of the vagus nerves to join the sym-  pathetic nerves in the cardiac plexus. Parasympathetic (vagal)  activity causes the release of acetylcholine. Receptors for these  neurotransmitters are found in the myocardium and coronary    vessels of the heart. Acetylcholine decreases heart rate, slows  conduction through the AV nodes, and reduces myocardial  contraction strength.’   Adrenergic Receptor Function. Sympathetic neural stimulation  of the myocardium and coronary vessels depends on the  presence of G-protein—coupled adrenergic receptors, which bind  specifically with neurotransmitters of the sympathetic nervous  system. (Receptor physiology is discussed in Chapter 1.) The  effects of sympathetic stimulation depend on whether (1) the a-  or B-adrenergic receptors are most plentiful on cells of the effector  tissue, (2) the neurotransmitter is norepinephrine or epinephrine,  and (3) the extent to which the individual variations in receptor  structure caused by single nucleotide polymorphisms (SNPs)  influence receptor responsiveness.1°1!   There are five types of adrenergic receptors: B,, B2, B3, 1,  and © (see Table 15-7). Each of the a-adrenergic receptors also  has three subtypes, so some sources indicate that there are nine  types of adrenergic receptors.!!!* Overall, cardiovascular struc-  tures have more f than a receptors; therefore, effects mediated  by the B receptors predominate. Norepinephrine is released by  postsynaptic sympathetic nerve endings in the heart while epi-  nephrine is mainly released by the adrenal medulla and reaches  the heart through the bloodstream.   The §,; receptors are found mostly in the heart, specifically  the conduction system (AV and SA nodes, Purkinje fibers) and  the atrial and ventricular myocardium. The B, receptors are  found in the heart and also on vascular smooth muscle. Stimu-  lation of both the §, and B, receptors results in an increase in  heart rate (chronotropy) and force of myocardial contraction  (inotropy).!° In addition, stimulation of the B receptors results  in vasodilation because of the location of the receptors on vas-  cular smooth muscle. Overall 6; and 6, stimulation enables the  heart to pump more blood and £, stimulation also increases  coronary blood flow, and $3 receptors are also found in the  myocardium and coronary vessels. In the heart, stimulation  of these receptors opposes the effects of B,- and §,-receptor  stimulation and decreases myocardial contractility (negative  inotropic effect).!° Thus B; receptors may provide a “safety  mechanism” to prevent overstimulation of the heart by the  sympathetic nervous system.   Norepinephrine binding with a, receptors, all of which  are postsynaptic in the systemic and coronary arteries, causes  smooth muscle contraction and thus vasoconstriction. One of  the three subtypes of a, receptors, d2,, is located on the sympa-  thetic ganglia and nerve terminals. The effect of norepinephrine  on these receptors is to inhibit release of more norepinephrine,  which promotes vasodilation, thus providing another safety  mechanism to prevent excess blood pressure elevation.! Dys-  function of a- and B-adrenergic receptors can occur in many  conditions (e.g., diabetes, hypertension) and has been impli-  cated in the pathogenesis of many cardiac diseases, including  heart failure, myocardial ischemia, and dysrhythmias.'°!!)!°   The cells of cardiac muscle (the myocardium) and of skeletal mus-  cle are nearly identical in structure, function, and microscopic  appearance. (The properties of skeletal muscle are described in    detail in Chapter 43.) Both types of muscle tissue are composed  of long, narrow cells, called fibers, that contain basically the same  structures: bundles of longitudinally arranged myofibrils; a sin-  gle nucleus (cardiac muscle) or many nuclei (skeletal muscle);  mitochondria; an internal membrane system (the sarcoplasmic  reticulum); cytoplasm (sarcoplasm); and a plasma membrane  (the sarcolemma), which encloses the cell. Cardiac and skeletal  muscle cells also have an “external” membrane system made up  of transverse tubules (T tubules) formed by invaginations of the  sarcolemma. The sarcoplasmic reticulum forms a network of  channels that surround the muscle fiber.   The microscopic appearance of cardiac and skeletal muscle is  somewhat similar as well (see Chapter 1, Table 1-8). Because the  myofibrils in both types of fibers consist of alternating light and  dark bands of protein, the fibers appear striped, or striated. The  dark and light bands of the myofibrils comprise longitudinal  repeating units called sarcomeres. The length of the sarcomeres,  normally between 1.6 and 2.2 mm, is important because it deter-  mines the limits of myocardial stretch at the end of diastole and  subsequently the force of contraction during systole.   Cardiac muscle differs from skeletal muscle in several  respects that reflect heart function. Cardiac cells are arranged  in branching networks throughout the myocardium, whereas  skeletal muscle cells tend to be arranged in parallel throughout  the length of the muscle. Cardiac fibers have only one nucleus,  whereas skeletal muscle cells have many nuclei. Other differ-  ences enable cardiac fibers to (1) transmit action potentials  quickly from cell to cell, (2) maintain high levels of energy syn-  thesis, and (3) gain access to more ions, particularly sodium and  potassium, in the extracellular environment.   Rapid transmission of electrical impulses from cardiac fiber  to cardiac fiber is possible because the network of fibers is con-  nected at specialized intercellular junctions called intercalated  disks. Intercalated disks are thickened portions of the sarco-  lemma that enable electrical impulses to spread quickly in a  continuous cell-to-cell (syncytial) fashion. The intercalated  disks contain three junctions: desmosomes, or macula adher-  ens; the fascia adherens, which mechanically attach one cell to  another; and gap junctions, also known as tight junctions or the  nexus, which allow the electrical impulse to spread from cell  to cell (see Chapter 1). Changes in the function of these junc-  tional elements have been associated with an increased risk of  dysrhythmias.?   Unlike skeletal muscle, the heart cannot rest and is in con-  stant need of energy that is supplied by molecules such as  adenosine triphosphate (ATP). Therefore, the cytoplasm sur-  rounding the bundles of myofibrils in each cardiac muscle cell  contains a larger number of mitochondria (25% of the cellu-  lar volume) than that found in skeletal muscle cells. The large  numbers of mitochondria provide the necessary respiratory  enzymes for aerobic metabolism and supply quantities of ATP  sufficient for the constant action of the myocardium.   The third major difference between cardiac and skeletal  muscle cells involves the T tubule system. Cardiac fibers con-  tain more T tubules than skeletal muscle fibers. This increased  proximity to the T tubules gives each myofibril in the myo-  cardium faster access to molecules it needs for the continuous    FIGURE 31-13 Sliding-Filament Model. A, During contraction, myosin cross-bridges pull the thin filaments toward the  center of each sarcomere, thus shortening the myofibril and the entire muscle fiber. B, Color-enhanced transmission electron  micrographs (TEMs) showing the shortening of a sarcomere caused by the sliding of filaments during muscle contraction.  (A from Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby. B courtesy H.E. Huxley, Brandeis    transmission of action potentials, a process that involves  transport of sodium and potassium through the walls of the  T tubules. (The mechanisms by which sodium and potassium  transport causes transmission of cardiac action potentials are  described in Chapters 1 and 43.) Because the T tubule system  is continuous with the extracellular space and the interstitial  fluid, it facilitates the rapid transmission of electrical impulses  from the surface of the sarcolemma to the myofibrils inside the  fiber. This activates all the myofibrils of one fiber simultane-  ously. The sarcoplasmic reticulum is located around the myo-  fibrils. When an action potential is transmitted through the  T tubules, it induces the sarcoplasmic reticulum to release its  stored calcium, which activates the contractile proteins, actin  and myosin, within the sarcomere at the same time. T tubule  loss, disruption, and dysregulation are associated with heart  failure and atrial fibrillation.'4   Actin, Myosin, Troponin-Tropomyosin Complex, and Titin.  Within each myocardial sarcomere the thick filaments of  myosin constitute the central dark band called the anisotropic,  or A, bands (Figure 31-13). The myosin molecule resembles a  golf club with two large bulbous heads protruding from one end  of a straight shaft (Figure 31-14). The bilobed heads contain an  actin-binding site and a site of ATPase activity. A thick filament  called myosin microfilament is composed of about 200 myosin   FIGURE 31-14 Structure of Myosin. A, Each myosin molecule is a coil of two  chains wrapped around each other. At the end of each chain is a globular region,  much like a golf club, called the head. B, Myosin molecules usually are combined  into filaments, which are stalks of myosin from which the heads protrude at regular  intervals.    molecules bundled together with outward-facing molecule heads  called cross-bridges because with activation of contraction they  will form force-generating bridges with exposed actin molecules  (see Figure 31-14, B).The actin molecules are part of the thin  filaments (Figure 31-15). The light bands are called isotropic, or  I, bands (see Figure 31-13). The thin filaments of actin appear  light and extend from the Z line, a dense fibrous line that crosses  the center of each I band. A sarcomere is the area from one dark  Z line to an adjacent Z line with a length that varies from 1.6 to  2.2 mm. In the center of a sarcomere is the H zone, a somewhat  less dense region. A thin, dark M line travels the center of the H  zone. A single tropomyosin molecule (a relaxing protein) lies  alongside seven actin molecules. Troponin, another relaxing  protein, associates with the tropomyosin molecule, forming  the troponin-tropomyosin complex (see Figure 31-15). The  troponin complex itself has three components. Troponin T aids  in binding of the troponin complex to actin and tropomyosin;  troponin I inhibits the ATPase of actomyosin; and troponin  C contains binding sites for the calcium ions involved in  contraction. Troponin and tropomyosin are referred to as  relaxing proteins because when they cover the myosin-binding  sites on the actin, the cross-bridges release and the myocardium  relaxes. Also within the sarcomere is a giant elastic protein called  titin (or connectin), which acts as a spring and is one of the  factors responsible for myocardial stiffness and thus impacts  diastolic filling of the myocardium.   Myocardial Metabolism. Cardiac muscle, like other muscle  tissue, depends on the constant production of ATP for energy.  ATP is produced within the mitochondria mainly from glucose,  fatty acids, and lactate. If the myocardium is inadequately  perfused because of coronary artery disease, anaerobic  metabolism must be used as a source of energy (see Chapter 1).  The energy produced by metabolic processes is used for muscle  contraction and relaxation, electrical excitation, membrane  transport, and synthesis of large molecules. Normally, the  amount of ATP produced supplies sufficient energy to pump  blood systemically.   Cardiac work often is expressed in terms of myocardial oxy-  gen consumption (MV O,). Because oxidative metabolism is  the main process of cardiac energy generation, the rate of oxy-  gen consumption correlates closely with total cardiac energy  requirements. MVO), is determined by three major factors:  (1) the amount of wall stress during systole, which can be esti-  mated by measuring the systolic blood pressure; (2) the dura-  tion of systolic wall tension, which is measured indirectly by the  heart rate; and (3) the contractile state of the myocardium, for  which no clinical measurement exists.   The oxygen supply to the myocardium is delivered exclu-  sively by the coronary arteries. From 70% to 75% of the oxy-  gen from the coronary arteries is used immediately by cardiac  muscle, leaving little oxygen in reserve. Therefore, increased  energy needs can be met only by increasing coronary blood  flow. Myocardial oxygen consumption can increase several-fold  with exercise and decrease moderately under conditions such  as hypotension and hypothermia. As myocardial metabolism  and consumption of oxygen increases, the concentration of  local vasoactive metabolic factors increases. Some of these, such    as adenosine, nitric oxide, and prostaglandins, dilate coronary  arterioles, thus increasing coronary blood flow.'°    Myocardial contractility is a change in developed tension at a  given resting fiber length. In functional terms, contractility is  the ability of the heart muscle to shorten. On a molecular basis,  thin filaments of actin slide over thick filaments of myosin,  called the cross-bridge cycle of muscle contraction.'” It is the  cycling of cross-bridges that is the molecular basis for myocar-  dial force generation and thus ultimately the heart’s ability to  pump blood through the circulation. Anatomically, contraction  occurs when the sarcomere shortens, causing adjacent Z lines to  move closer together (Figure 31-16). The width of the A band,  which contains the thick myosin filaments, is unchanged while  the I band becomes narrower as the overlap between the thick  and thin filaments increases. The degree of shortening of the  muscle fibers depends on how much the thin filaments over-  lap the thick filaments. Maximal contraction occurs when the  sarcomere length is 2.2 mm. At 2.2 mm the number of cross-  bridge attachments between actin and myosin is maximal.   Cross-Bridge Cycling. The globular head-end of the myosin  contains a binding site for actin and a separate enzymatic site  that catalyzes the breakdown of ATP to adenosine diphosphate  (ADP) and inorganic phosphate (P;) (see Figure 31-16). This  reaction releases the chemical energy stored in ATP. Magnesium  is required for the binding of ATP to the myosin site. The  splitting of ATP occurs on the myosin molecule before it  attaches to actin, but the ADP and inorganic phosphate released  remain bound to the active site on myosin. The chemical energy  released is transferred to myosin (m), producing a high-energy  form of myosin (M):    The binding of this high-energy myosin-actin form to a  cross-bridge releases the energy stored in myosin (e.g., ADP  and P;), producing the force necessary for movement of the  cross-bridge. With the attachment of actin to myosin at the  cross-bridge, the myosin head molecule undergoes a position  change, exerting traction on the rest of the myosin bridge,  causing the thin filaments to slide past the thick filaments (see  Figure 31-16). During contraction each cross-bridge under-  goes several cycles of attachment, movement, and dissociation  from the thin filaments.!”   Calcium and Excitation-Contraction Coupling. Excitation-  contraction coupling is the process by which an action potential  in the plasma membrane of the muscle fiber triggers the cycle  of events leading to cross-bridge activity and contraction.  Activation of this cycle depends on the availability of calcium.   Calcium is stored in the tubule system and the sarcoplas-  mic reticulum. It enters the myocardial cell from the interstitial  fluid after electrical excitation, which increases the membrane  permeability to calcium. Two types of calcium channels (L-type  and T-type) are identified in cardiac tissues. The L-type, or  long-lasting, channels are the predominant type of calcium  channels and are the channels blocked by calcium channel-  blocking drugs (verapamil, nifedipine, diltiazem). The major    FIGURE 31-15 Myofilaments and Mechanisms of Muscle Contraction. A, Thin and thick myofilaments. In resting  muscle, calcium ions are stored in the sarcoplasmic reticulum. When an action potential reaches the muscle cell, the T tubules  carry the action potential deep into the sarcoplasm. The action potential causes the sarcoplasmic reticulum to release the  store of calcium ions. B, In resting muscle the myosin-binding sites are covered by troponin and tropomyosin. The calcium ions  released into the sarcoplasm as a result of the action potential bind to the troponin. This binding causes the tropomyosin and  troponin to move out of the way of the myosin-binding sites, leaving the myosin heads free to bind to the actin microfilament.  C, ATP is used as an energy molecule to the myosin cross-bridge. (Adapted from Raven PH, Johnson GB: Understanding biol-  ogy, ed 3, Dubuque, IA, 1995, Brown.)    FIGURE 31-16 Cross-Bridge Theory of Muscle Contraction. A, Each myosin cross-bridge in the thick filament moves  into a resting position after an adenosine triphosphate (ATP) molecule binds and transfers its energy. B, Calcium ions released  from the sarcoplasmic reticulum bind to troponin in the thin filament, allowing tropomyosin to shift from its position blocking  the active sites of actin molecules. C, Each myosin cross-bridge then binds to an active site on a thin filament, displacing  the remnants of ATP hydrolysis—adenosine diphosphate (ADP) and inorganic phosphate (P;). D, The release of stored energy  from step A provides the force needed for each cross-bridge to move back to its original position, pulling actin along with it.  Each cross-bridge will remain bound to actin until another ATP molecule binds to it and pulls it back into its resting position  (A). (Adapted from Thibodeau GA, Patton KT: Anatomy & physiology, ed 4, St Louis, 1999, Mosby.)    effect of these medications is to decrease the strength of cardiac  contraction. The T-type, or transient, channels are much less  abundant in the heart and are not blocked by currently available  calcium channel-blocking drugs. Calcium that enters the cell  from the interstitial fluid triggers release of calcium from the  storage sites. The storage sites most important for contraction  are from the sarcoplasmic reticulum. Calcium from these sites  diffuses toward the myofibrils, where it binds with troponin.   The calcium-troponin complex facilitates the contraction  process. In the resting state, troponin I is bound to actin and  the configuration of the tropomyosin molecule is such that it  covers the sites where the myosin heads bind to actin, thus pre-  venting interaction between actin and myosin. Calcium bind-  ing to troponin inhibits troponin C (which enhances troponin  I-actin binding) and results in tropomyosin moving troponin I,  which uncovers the binding sites on the myosin heads. Myosin  and actin can then form cross-bridges, and ATP can be dephos-  phorylated to ADP. Sliding of the thick and thin filaments can  then occur, and the myocardium contracts.    Relaxation is just as vital to optimal cardiac function as con-  traction, and calcium, troponin, and tropomyosin also facili-  tate relaxation. After contraction, free calcium ions are actively  pumped out of the cell back into the interstitial fluid or taken  up again by the sarcoplasmic reticulum and stored. As the con-  centration of calcium within the sarcomere subsequently falls,  troponin releases its bound calcium. The tropomyosin complex  blocks the active sites on the actin molecule, preventing cross-  bridges with the myosin heads. Each tropomyosin molecule is  held in this blocking position by a molecule of troponin. Tropo-  nin is bound to both tropomyosin and actin (see Figure 31-15).    Cardiac output is the volume of blood flowing through either  the systemic or the pulmonary circuit and is expressed in liters  per minute. Cardiac output is calculated by multiplying heart  rate in beats per minute by stroke volume in liters per beat.    Normal adult cardiac output at rest is about 5 L/min. The ven-  tricles do not eject all of the blood they contain with each heart-  beat and the amount ejected is called the ejection fraction. The  ejection fraction is calculated by dividing the stroke volume by  the end-diastolic volume. The end-diastolic volume (EDV) of  the normal ventricle is about 70 to 80 ml/m? and the normal  ejection fraction of the resting heart is 55% or higher. Ejection  fraction is a valuable clinical indicator of ventricular function. '®  Four factors affect cardiac output directly: preload, afterload,  myocardial contractility, and heart rate (Figure 31-17). Preload  (pressure generated at the end of diastole) and afterload (resis-  tance to ejection during systole) depend on the heart as well as  the vascular system. Contractility and heart rate are characteris-  tics of the cardiac tissue per se and are influenced by neural and  humoral mechanisms. To understand the role of these factors  in cardiac performance, it is first necessary to understand two  physical laws that explain the mechanisms of heart action: the  Frank-Starling law of the heart and Laplace’s law.    Cardiac muscle, like other muscle, increases its strength of con-  traction when it is stretched. This relationship was described in  1914 by a British physiologist, Ernest Starling, and was based  on the earlier work of a German physiologist, Otto Frank. The  Frank-Starling law of the heart, or the length-tension rela-  tionship of cardiac muscle, relates resting sarcomere length,  expressed as the volume of blood in the heart at the end of dias-  tole (end-diastolic volume), to tension generation, described  as development of left ventricular pressure. Thus the volume  of blood in the heart at the end of diastole (the length of its  muscle fibers) is directly related to the force of contraction dur-  ing the next systole. Although the change in pressure is related  to the volume of the ventricle and, consequently, to the length  of the ventricular muscle fibers, preload (i.e., filling pressure) is  commonly used as an index of ventricular volume. The length-  tension mechanism is the main mechanism by which the nor-  mal right and left ventricles maintain equal minute outputs  even though their stroke outputs may vary considerably during    a oe ee ry  Preload |~—~| Afterload |~—~ | Contractility Central nervous  ry ry ry system  Autonomic  End- nervous system  diastolic  End- re volume Neural  systolic |-— gulls reflexes  clare pressure  Sympathetic Atrial  stimulation receptors  Aortic  ioe | vahulc: — Hormones  function Myocardial  oxygen supply  FIGURE 31-17 Factors Affecting Cardiac Performance. Cardiac output, which is the amount of blood (in liters) ejected  by the heart per minute, depends on heart rate (beats per minute) and stroke volume (milliliters of blood ejected during ven-    Cardiac output or stroke  volume or stroke work or  systolic muscle tension   FIGURE 31-18 Frank-Starling Law of the Heart. Relationship between  length and tension in the heart. End-diastolic volume determines end-diastolic  length of ventricular muscle fibers and is proportional to tension generated during  systole, as well as to cardiac output, stroke volume, and stroke work. A change in  myocardial contractility causes the heart to perform on a different length-tension  curve. A, Increased contractility; B, normal contractility; C, heart failure or decreased  contractility. (See text.)    normal respiration. For example, changes in volume occur  when an individual assumes a reclining position after being in  a standing position; the volume of blood returning to the heart  temporarily increases. The right ventricle stretches to accom-  modate this increase in volume and thereby increases its force  of contraction. A larger stroke volume (1.e., the amount of blood  ejected per beat) is pumped to the lungs, generating higher  pressures. Pulmonary vascular pressure increases, causing a rise  in the left ventricular filling pressure or preload. Left ventricular  volume and pressure increase. The left ventricle pumps a larger  stroke volume, and arterial vascular pressure rises.   The mechanical function of the heart is characterized by a  number of length-tension curves (Figure 31-18). Factors that  increase contractility (i.e., positive inotropic), such as sympa-  thetic nerve stimulation, cause the heart to operate on a higher    length-tension curve (curve A in Figure 31-18). A higher ten-  sion or increase in ventricular stroke volume is generated with-  out a necessary change in left ventricular end-diastolic volume  or fiber length. Heart failure (curve C in Figure 31-18) is char-  acterized by a lower length-tension curve (see Chapter 32). The  Frank-Starling law of the heart may not apply to dilated or fail-  ing hearts because their fibers are already stretched beyond their  optimal length. The failing heart responds to increased filling  or stretch with a progressive decline in the force of contraction.  Thus at the same left ventricular end-diastolic volume as curves  A and B (see Figure 31-18), the force of contraction of stroke  volume is decreased.   The cross-bridge arrangement with the sarcomere partially  accounts for the length-tension mechanism of cardiac muscle.  According to the Frank-Starling law, the longer the initial rest-  ing length of the cardiac muscle fiber (optimal length is between  2.2 and 2.4 mm), the greater the strength of contraction. At  2.2 mm an optimal number of active cross-bridges exist between  actin and myosin. However, if the fibers are stretched beyond  2.2 to 2.4 mm, the force of contraction decreases because actin  and myosin become partially disengaged, disrupting many  of the cross-bridges. Excessive stretching, to about 3.65 mm,  causes actin and myosin to become completely disengaged so  that tension (force of contraction) drops to zero. The relation-  ship between stretch and contraction can be compared with that  of a rubber band. Up to a certain point, the more the rubber  band is stretched the farther it will fly when one end is released;  beyond that point, however, the rubber band will break but, of  course, the myocardium does not actually break!    Laplace’s law states that wall tension is related directly to the  product of intraventricular pressure and internal radius and    inversely related to the wall thickness as shown in the Laplace  equation:    where T = wall tension, p = intraventricular pressure, r = internal  radius of the sphere, and um = wall thickness. In other words,  the amount of tension generated in the ventricular wall (or  any chamber or vessel) to produce a given intraventricular  pressure depends on the size (radius and wall thickness) of the  ventricle.   Laplace’s law is useful for understanding aneurysm forma-  tion, distensibility in blood vessels, and the effects of ventricu-  lar dilation on myocardial contraction. Dilation is an important  factor in heart failure (see Chapter 32). With a dilated ventricle,  myocardial fibers in the wall must develop greater tension to  produce a given pressure within the ventricle. The disadvantage  of dilation is that the increased force, or tension, in the myocar-  dial fibers required to develop a given pressure inside a dilated  ventricle decreases the rate of fiber shortening, thereby decreas-  ing the ability of the ventricle to eject blood.    Left ventricular preload is the pressure generated in the left  ventricle at the end of diastole, or left ventricular end-diastolic  pressure (LVEDP). It is determined by the left ventricular end-  diastolic volume (LVEDV), which stretches the cardiac muscle  fibers and in turn develops tension, or force, for contraction  according to the Frank-Starling law. Preload is determined by  two primary factors: (1) the amount of venous return to the  ventricle, and (2) the blood left in the ventricle after systole or  end-systolic volume (see Figure 31-17). End-systolic volume is  dependent on the strength of ventricular contraction and the  resistance to ventricular emptying. Within a physiologic range  of muscle stretching (2.2 to 2.4 mm), increased preload increases  cardiac output. When preload exceeds the physiologic range,  further muscle stretching causes a decline in cardiac output (see  Frank-Starling law, p. 1101). In monitoring preload the clini-  cian measures indexes of left ventricular end-diastolic pressure.  Pressure changes are important because increased left ventricu-  lar filling pressures “back up” into the pulmonary circulation,  where they force plasma out through vessel walls, causing fluid  to accumulate in lung tissues that can cause pulmonary edema  (see Chapter 35). Treatment goals in heart failure management  are to maintain an end-diastolic volume and pressure that will  maintain or increase cardiac output.    Ventricular afterload is the resistance to ejection of blood  from the ventricle. Aortic systolic pressure is a good index of  afterload for the left ventricle. Low aortic pressures (decreased  afterload) enable the heart to contract more rapidly, whereas  high aortic pressures (increased afterload) slow contraction and  cause higher workloads against which the heart must function  to eject blood. Pressure in the ventricle must exceed aortic pres-  sure before blood can be pumped out during systole. Increased  aortic pressure is usually the result of increased peripheral vas-  cular resistance (PVR), also called total peripheral resistance    (TPR). In individuals with hypertension, increased PVR means  that afterload is chronically elevated, resulting in increased ven-  tricular workload and hypertrophy of the myocardium. The  situation is similar for the right ventricle except the pressures  are much lower and the afterload for the right ventricle is pul-  monary arterial pressure.    Stroke volume, or the volume of blood ejected during systole,  depends on the force of contraction, which is a function of  myocardial contractility, the degree of myocardial fiber short-  ening. In healthy persons, three major factors determine the  force of contraction: (1) changes in the stretching of the ven-  tricular myocardium caused by variations in ventricular vol-  ume (preload), (2) alterations in nervous system input to the  ventricles, and (3) adequacy of myocardial oxygen supply (see  Figure 31-17). As discussed previously, increased blood flow  from the veins into the heart distends the ventricle by increas-  ing preload, which, within the physiologic range, increases the  stroke volume and, subsequently, cardiac output.   Chemicals affecting contractility are called inotropic agents.  The most important positive inotropic agents produced by the  body are norepinephrine released from the sympathetic nerves  supplying the heart and epinephrine released by the adrenal  cortex. Other positive inotropes include thyroid hormone and  dopamine. The most important negative inotropic agent is ace-  tylcholine released from the vagus nerve. Many medications  have positive or negative inotropic properties that can have  profound effects on cardiac function.   Myocardial contractility is dependent on oxygen supply with  hypoxia contributing to a decrease in contractility. However,  because hypoxia also stimulates coronary artery dilation, the  impact of hypoxia will vary with activity level and the actual  level of hypoxia. Preload, afterload, and contractility all interact  with one another to determine stroke volume and cardiac out-  put. Changes in any one of these factors can result in deleterious  effects on the others, resulting in heart failure (see Chapter 32).  In persons with sepsis, a variety of cytokines, including tumor  necrosis factor-alpha (TNF-a), interleukin-beta, lysozyme  C and endothelin-1, have been shown to impair myocardial  contractility.!?    The average heart rate in healthy adults is about 70 beats/  min. The average heart rate is significantly greater in children.  Heart rate diminishes by 10 to 20 beats/min during sleep and  can accelerate to more than 100 beats/min during muscular  activity or emotional excitement. In well-conditioned athletes  the resting heart rate is about 50 to 60 beats/min. In highly  trained or elite athletes the resting heart rate can be less than  50 beats/min. The low resting heart rate is the result of increased  vagal stimulation and lower sympathetic stimulation.   Neural factors, including neural reflexes, and hormonal  and chemical factors influence the heart rate. Neural control is  exerted by the central and autonomic nervous systems. Hor-  monal factors include the catecholamines (i.e., norepinephrine  and epinephrine), thyroid hormones, growth hormones, and    endocannabinoids, such as anandamide.”” (Hormonal function  is described in Chapter 21.) Stimulation by the sympathetic  nervous system increases the frequency of the cardiac pace-  maker (SA node), whereas parasympathetic stimulation has a  bradycardic effect (heart rate less than 60 beats/min).  Cardiovascular Control Centers in the Brain. The major  cardiovascular control center is in the brainstem in the  medulla with secondary areas in the hypothalamus, the cerebral    cortex, the thalamus, and complex networks of exciting or  inhibiting interneurons (connecting neurons) throughout  the brain. The hypothalamic centers regulate cardiovascular  responses to changes in temperature; the cerebral cortex centers  adjust cardiac reaction to a variety of emotional states; and  the medullary control center regulates heart rate and blood  pressure (see page 1114 for blood pressure regulation). The  medullary neurons often are classified as cardiac and vasomotor    CHAPTER 31 Structure and Function of the Cardiovascular and Lymphatic Systems    (vasoconstrictor or vasodilator) centers; however, because these  centers are not discrete anatomic areas and actually constitute  diffuse networks of interneurons, it is preferable to call the  entire area the cardiovascular control center.   The nerve fibers from the cardiovascular control cen-  ter synapse with the autonomic neurons (see Chapter 15 and  Table 15-7). When the parasympathetic nerves to the heart are    Right subclavian  Superior vena cava  Right pulmonary  Small cardiac  Inferior vena cava  Hepatic    stimulated, the sympathetic nerves to the heart, arterioles, and  veins usually are inhibited. The opposite also is true: when the  sympathetic nerves are stimulated, the parasympathetic nerves  usually are inhibited. Because parasympathetic excitation and  simultaneous sympathetic inhibition generally depress cardiac  function (e.g., decrease the heart rate), these interneurons often  are referred to as the cardioinhibitory center. Excitation occurs    FIGURE 31-19, cont'd B, Principal veins of the body. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8,    with parasympathetic inhibition and sympathetic stimulation,  and these interneurons are collectively called the cardioexcit-  atory center. Therefore, heart rate can be slowed by two simul-  taneous events that begin in the cardiovascular control center:  (1) inhibition of sympathetic stimulation of the SA node, and  (2) activation of parasympathetic stimulation of the SA node.  Conversely, heart rate can be increased by activation of sympa-  thetic nerves and inhibition of parasympathetic nerves.   The resting heart rate in healthy individuals is primarily  under the control of parasympathetic stimulation. While the  individual is at rest, parasympathetic effects from the vagus  nerves override sympathetic effects in the SA node. Interrup-  tion of the vagus nerves causes significant tachycardia (abnor-  mally fast heart rate) because the inhibitory parasympathetic  influence is lost.   Neural Reflexes. Heart rate varies naturally with respiration,  the rate increasing with inspiration and decreasing with  expiration. This normal alteration in rhythm pattern, called  sinus arrhythmia, is caused by changes that occur within the  chest cavity because of respiration. Inspiration results in stretch  and an associated increase in firing of the SA node that increases  heart rate. With expiration the stretch is reduced and the SA  node firing rate slows, resulting in a decrease in heart rate.”!   Two neural reflexes that can affect heart rate and rhythm are  the baroreceptor reflex and the Bainbridge reflex. The baro-  receptor reflex is important in blood pressure control and is  mediated by stretch receptors in the aortic arch and carotid  arteries. (Because the receptors respond to mechanical factors,  they are also called aortic and carotid mechanoreceptors.) When  blood pressure falls, the baroreceptor reflex accelerates heart  rate and causes constriction of arterioles in the systemic circu-  lation. These responses raise blood pressure back toward nor-  mal and are critical to maintaining adequate tissue perfusion.  Aging is associated with dysfunction of the baroreceptor reflex  (baroreflex) and can result in postural hypotension (orthostatic  hypotension, see p. 1140).”7   The baroreflex also can reduce high blood pressure. The  mechanoreceptors increase their rate of discharge when  stretched by blood pressure elevations. Neural impulses are  then transmitted over the glossopharyngeal nerve (ninth cranial  nerve) from the carotid artery and through the vagus nerve from  the aorta to the cardiovascular control centers in the medulla.  These centers initiate an increase in parasympathetic activity  and a decrease in sympathetic activity, causing blood vessels to  dilate and heart rate to decrease. Responses to the baroreceptor  reflex return the blood pressure to its previous level, which may  or may not have been normal.   Bainbridge reflex is the name for the changes in the heart  rate that occur after intravenous infusions of blood or other flu-  ids.?> The change in heart rate is thought to be caused by a reflex  mediated by volume receptors in the atria that are innervated by  the vagus nerves (volume receptors are thought to respond to  increased plasma volume). Although this reflex can be elicited  in humans, its relevance is uncertain at this time.”°   Hormones and Biochemicals. Hormones and biochemicals  affect the arteries, arterioles, venules, capillaries, and contractil-  ity of the myocardium. Norepinephrine increases heart rate,    enhances myocardial contractility, and constricts blood vessels.  Epinephrine dilates vessels of the liver and skeletal muscle  and causes an increase in myocardial contractility. Some  adrenocortical hormones, such as hydrocortisone, potentiate the  effects of the catecholamines.   Thyroid hormone, specifically triiodothyronine, causes  increases in both heart rate and contractility, resulting in an  increase in cardiac output; it also decreases systemic vascular  resistance. Triiodothyronine acts directly on the cardiac myo-  cytes to cause gene transcription and cellular changes that result  in more calcium release from the sarcoplasmic reticulum.**  Awareness of these changes helps to understand the cardiovascu-  lar changes that occur with thyroid diseases. Growth hormone,  working together with insulin-like growth factor 1 (IGF-1), also  has been shown to increase myocardial contractility.” Decreases  in levels of growth hormone or thyroid hormone may result in  bradycardia, reduced cardiac output, and low blood pressure.    The arteries and veins of the systemic circulation are illus-  trated in Figure 31-19. Oxygenated blood from the left side of  the heart flows through the aorta and into the systemic arter-  ies. The arteries branch into small arterioles that branch into  the smallest vessels, the capillaries, where nutrient exchange  between the blood and tissues occurs. Blood from the capillar-  ies then enters tiny venules that join to form the larger veins,  which return venous blood to the right heart. Peripheral vas-  cular system is the term used to describe the part of the sys-  temic circulation that supplies the skin and the extremities,  particularly the legs and feet.    Blood vessel walls are composed of three layers: the tunica  intima (innermost or intimal layer), the tunica media (middle  or medial layer), and the tunica externa or adventitia (outer-  most or external layer). These structures are illustrated in Figure  31-20. The tunica intima is composed of a layer of squamous  epithelium or endothelium, a layer of connective tissue, and a  basement membrane. (These cellular structures are described  in Chapter 1.) The tunica media is composed of smooth muscle  fibers mixed with elastic fibers. The tunica externa, or adven-  titia, is an active layer of connective tissue containing nerves,  lymphatic vessels that influences both vessel development,  and muscle tone (see What’s New? New Roles for the Arterial  Adventitia). Blood vessel walls vary in thickness depending on  the thickness or absence of one or more of these three layers.  Cells of the larger vessels are nourished by the vasa vasorum,  small vessels located in the tunica externa, and innervated by  perivascular nerves. The vasa vasorum arise from the blood ves-  sel itself or from other vessels nearby. In the large elastic vessels  the tunica media is separated from the adventitia by the exter-  nal elastic lamina.   Adults are capable of growing new blood vessels through  three processes, all of which are important in wound heal-  ing but also contribute to tumor growth. The three processes  are angiogenesis, arteriogenesis, and vasculogenesis. Both    CHAPTER 31 Structure and Function of the Cardiovascular and Lymphatic Systems    Internal elastic  membrane  Smooth muscle  Tunica externa  External elastic  membrane  Fibrous connective  tissue    an Artery and Vein. A, Structure of blood vessels. The tunica externa    of the veins are color-coded blue and the arteries red. B, Artery and vein. Light micrograph of a cross section of similar-sized  artery (left) and vein (right). Notice the thick muscular wall of the artery as compared to the thin-walled vein. (From Patton KT,  Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    The adventitia or tunica externa, once thought to be a simple fibrous sheath, is  now recognized as a dynamic player in the life of the vessel and the surrounding  tissues. The adventitia has roles in vessel response to injury, immune function,  and vascular tone. Some of the cell types found include fibroblasts, stem/pro-  genitor cells, mast cells, macrophages, B cells, T cells, and dendritic cells. Other  components of this layer include the vasa vasorum, perivascular nerves (nervi  vasorum), lymphatic vessels, and extracellular matrix (see Figure 31-20). Stud-  ies of labeled cells after arterial injury have shown that new cells migrate from  the adventitia into the media and intima to repair and maintain the vessel. It is  also possible that, in some cases, these migrating cells may contribute to a  rial disease. The vasa vasorum, which forms a miniature circulatory system  supplies blood to walls or larger arteries and veins, also provides a means for  transporting cells of the inflammatory response, such as macrophages, across  the blood vessel walls. Adventitia fibroblasts have the capacity to become myo-  fibroblasts, which can then influence the vascular tone of the vessel. Research  continues on the roles of the adventitia both in health and in a wide variety of  vascular diseases such as atherosclerosis and pulmonary hypertension.    Data from Hu Y, Xu Q: Arterioscler Thromb Vasc Biol 31(7):1523-1529;  Majesky MW et al: Arterioscler Thromb Vasc Bio! 31(7):1530-1539;  Majesky MW et al: Cells Tissues Organs 195(1-2):73-81, 2012;  Stenmark KR et al: Ann Rev Physiol 2012 Dec 3. [Epub ahead of print.].    angiogenesis and arteriogenesis occur by growth of new vessels  that branch from existing vessels. Angiogenesis is branching of  small vessels, such as capillaries, whereas arteriogenesis occurs  by branching from larger vessels, such as arterioles. Vasculo-  genesis is a term that refers to the growth of vessels from pro-  genitor or stemlike cells that originate in the bone marrow and  other body tissues.”°    Arterial walls are composed of elastic connective tissue, fibrous  connective tissue, and smooth muscle. There are two types  of arteries: elastic and muscular. The elastic arteries have a  very thick tunica media that contains more elastic fibers than  smooth muscle fibers. Elastic arteries include the aorta and its  major branches and the pulmonary trunk. Elasticity enables the  vessel to absorb energy imparted to the blood by ventricular  contraction and they stretch as blood is ejected from the heart  during systole. During diastole, elasticity promotes recoil of  the arteries, which is important for maintaining blood pressure  within the vessels, and retransfers the energy from the elastic  artery walls to the blood.   The muscular arteries are medium and small size arter-  ies farther from the heart than the elastic arteries. They con-  tain fewer elastic fibers and more muscle fibers than the elastic  arteries and their function is to distribute blood to arterioles  throughout the body. Because their smooth muscle can be  stimulated to contract or relax, they play a role in controlling  blood flow and in directing flow to the parts of the body with  the highest need at any time. During exercise more blood is sent  to the skeletal muscles, while after a meal more blood is directed  to the gut and liver. Contraction narrows the vessel lumen (the  internal cavity of the vessel), which diminishes flow through  the vessel. This condition is termed vasoconstriction. When    the smooth muscle layer relaxes, more blood flows through the  vessel lumen, a state called vasodilation.   An artery becomes an arteriole at the point where the diam-  eter of its lumen narrows to less than 0.5 mm. The arterioles  are composed almost exclusively of smooth muscle, with little  elastic tissue. Arterioles regulate the flow of blood into the cap-  illaries by vasoconstriction, which retards the flow of blood  into the capillaries, and vasodilation, which permits blood to  enter the capillaries freely (Figure 31-21). The thick, smooth  muscle layer of the arterioles is a major determinant of the  resistance blood encounters as it flows through the systemic  circulation.   The capillary network is composed of connective channels  called metarterioles, and “true” capillaries (see Figure 31-21).  Metarterioles have discontinuous smooth muscle cells in their  tunica media whereas capillaries lack any smooth muscle cells.  The capillaries branch from the metarterioles, meeting at a ring  of smooth muscle called the precapillary sphincters. As the  sphincters contract and relax, they regulate blood flow through  the capillaries. Appropriately stimulated, the precapillary  sphincters help maintain arterial pressure and regulate selective  flow to vascular beds.   Capillaries are composed solely of a layer of endothelial  cells surrounded by a basement membrane. Their thin walls  and unique structure make possible the rapid exchange of  water; small (low molecular weight) soluble molecules; some  larger molecules, such as albumin; and cells of the innate and  adaptive immune system between the blood and the interstitial  fluid.! Based on their structure, three types of capillaries have  been described: continuous, sinusoid, and fenestrated. In the  renal glomerulus, for example, the endothelial cells contain oval  windows or pores termed fenestrations, which are covered by  a thin diaphragm.’’ Sinusoid capillaries are found in the liver  and bone marrow.   Substances pass between the capillary lumen and the inter-  stitial fluid in several ways: (1) through junctions between  endothelial cells, (2) through fenestrations in endothelial cells,  (3) in vesicles moved by active transport across the endothelial  cell membrane, or (4) by diffusion through the endothelial cell  membrane. (Movement across cell membranes is described in  Chapter 1.) A single capillary may be only 0.5 to 1 mm in length  and 0.01 mm in diameter, but the capillaries are so numerous  that their total surface area may be more than 600 m.    Once thought to be simply the cellular layer lining blood ves-  sels, the vascular endothelium is now recognized as impor-  tant to several body functions and is considered by some to  be a separate organ (Figure 31-22). In addition to substance  transport, the vascular endothelium has important roles in  coagulation, antithrombogenesis, and fibrinolysis; immune  system function; tissue growth and wound healing; and  vasomotion, the contraction and relaxation of vessels. The  endothelium performs these vital functions through syn-  thesis and release of vasoactive chemicals. Figures 31-23 and  31-24 and Box 31-1 summarize some of the more important  functions. Because of its varying roles, the actual structure    FIGURE 31-21 Capillary Wall and Microcirculation. Control of blood flow through a capillary network is regulated by  the relative contraction of precapillary sphincters surrounding arterioles and metarterioles. A, Sphincters are relaxed, permitting  blood flow to enter the capillary bed. B, With sphincters contracted, blood flows from the metarteriole directly into the thorough-  fare channel, bypassing the capillary bed. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    FIGURE 31-22 Endothelium. This schematic shows the endothelium in con-  text with the entire blood vessel. Practically imperceptible, the endothelial cells  arrange themselves as a fine lining that has numerous life support functions.    of the endothelium may vary in different vascular beds. For  example, within lymph nodes the endothelial cells of special-  ized venules, called “high endothelial venules,” are uniquely  structured to support the movement of lymphocytes from the  blood into the lymph node.”* Endothelial injury and dysfunc-  tion are central processes in many of the most common and  serious cardiovascular disorders including hypertension and  atherosclerosis (see Chapter 32).    The smallest venules downstream from the capillaries have an  endothelial lining surrounded by fibrous tissue. The largest  venules, those farthest from the capillaries, are surrounded by a  few smooth muscle fibers comprising a thin tunica media.   Compared with arteries, veins are thin walled and fibrous  with a larger diameter (see Figure 31-20). A given vein is larger  than the artery that lies within the same sheath. Veins are more  numerous than arteries. In veins the tunica externa has less  elastic tissue than in arteries, so veins do not recoil after dis-  tention as quickly as arteries. Like arteries, veins receive nour-  ishment from the tiny vasa vasorum. Some veins, typically in  the legs, contain valves that regulate the one-way flow of blood  toward the heart (Figure 31-25). These valves are folds of the  tunica intima and are structurally similar to the semilunar  valves of the heart. Backflow in veins of the legs is stopped as the  flaps of the valves fill with blood and block the vessel. The posi-  tion of the valves also facilitates blood flow in the proper direc-  tion during venous compression. When a person stands up,  contraction of the skeletal muscles of the legs compresses the  deep veins of the legs and assists the flow of blood toward the  heart. This important mechanism of venous return is called  the muscle pump (see Figure 31-25).    Blood flow, the amount of fluid moved per unit of time, is usu-  ally expressed as liters or milliliters per minute (ml/min). The  factors that influence blood flow include pressure, resistance,  velocity, turbulent vs. laminar flow, and compliance.    FIGURE 31-23 Factors Causing Endothelium-Dependent Vasodilation. A variety of exogenous pharmacologic sub-  stances, platelet-derived factors, and shear stress can promote release of nitric oxide by stimulating nitric oxide synthase  (NOS). Prostacyclin (PGI) causes relaxation of vascular smooth muscle cells by a cyclic adenosine monophosphate (cAMP)—  dependent mechanism, and both nitric oxide and PGI, inhibit platelet aggregation. 5-H7, Serotonin; ADP adenosine diphosphate;  ATP adenosine triphosphate.    FIGURE 31-24 Endothelium Regulation of Vasomotion (Constriction and Dilation) and Platelet Aggregation by  Release of a Variety of Constricting and Dilating Substances. Constricting factors include arachidonic acid and metabolites,  such as thromboxane A, (which aspirin inhibits), and a potent amino acid peptide called endothelin. The endothelium also converts  angiotensin | into angiotensin II by the membrane-bound angiotensin-converting enzyme that also metabolizes the endogenous  endothelium-dependent vasodilator bradykinin. ACE, Angiotensin-converting enzyme.   Prostacyclin: A prostaglandin formed from arachidonic acid that can relax vas-  cular smooth muscle through increases in cAMP. The primary function is to  inhibit platelet adherence to the endothelium.   Nitric oxide (NO): Bradykinin and shear stress prompt the endothelium to syn-  thesize and release NO, a potent vasodilator. NO is also anti-inflammatory  and antithrombotic.   C-type natriuretic hormone: Made throughout the vasculature and works with  NO and prostacyclin as a vasodilator.   Endothelium-derived relaxing factor: A potent vasodilator made by vascular  endothelial cells.   Angiotensin II (Ang Il): ls a potent vasoconstrictor produced both hormonally  via the renin-angiotensin-aldosterone system and locally in vascular tissues.  Ang II blocks the release of NO and prostacyclin. Ang I! is also proinflam-  matory: it increases vascular permeability, recruits infiltrating monocytes,  increases expression of adhesion molecules, and stimulates release of  growth factors.   Platelet and monocyte adhesion: The endothelium helps regulate clotting  and inflammation by modulating the number of platelets and inflammatory  cells (monocytes and macrophages) that bind to the vessel wall. Endothelial-  derived substances include von Willebrand factor, platelet-activating factor,  heparan sulfate, t-PA, thrombomodulin, and others.    Filtration and permeability: The endothelium facilitates movement of large  molecules through intercellular junctions and small molecules via vesicles  and junctions.   Cell growth and inhibition: NO and prostacyclin inhibit cellular growth; Ang  Il stimulates growth.    levels of angiotensin Il are increased  and nitric oxide levels are decreased    ACE, Angiotensin-converting enzyme; CAMP, cyclic adenosine monophosphate; t-PA, tissue-type plasminogen activator.  Data from Esper RJ et al: Adv Cardio! 45:17-43, 2008; Schafer A, Bauersachs J: Curr Vasc Pharmacol 6(1):52-60, 2008; Thijssen DH et al: J Physiol  586(2):319-324, 2008. Figure adapted from Rocket JL: Am J Nurs 99(10):44, 1999.    The two main factors influencing blood flow are pressure and  resistance, whereas viscosity, type of flow pattern, and compli-  ance have a lesser impact. Pressure in a liquid system is the force  exerted on the liquid per unit area and is expressed as dynes  per square centimeter (dynes/cm7), millimeters of mercury  (mmHg), or torr (1 torr = 1 mmHg). Blood flow to a specific  organ depends partly on the pressure difference between the  arterial and venous vessels supplying that organ. Fluid moves  from the arterial “side” of the capillaries, a region of greater  pressure, to the venous side, a region of lesser pressure. Blood  flow varies directly with pressure; that is, the greater the pres-  sure differential across a vascular bed, the greater will be the  blood flow.   Resistance is the opposition to blood flow. In the cardio-  vascular system most opposition to blood flow is a result of the  diameter and length of the blood vessels. Changes in blood flow  through an organ, therefore, result from changes in the vascu-  lar resistance within the organ. The major mechanisms caus-  ing changes in vascular resistance are increases or decreases in    vessel diameter and the opening or closing of vascular chan-  nels. The mathematical description of this resistance in a tube  is known as the Hagen-Poiseuille equation, sometimes also  referred to as Poiseuille’s law. This equation indicates that resis-  tance is directly related to tube length and fluid viscosity (blood  viscosity) and inversely related to the radius of the tube to the  fourth power (r+). Blood flow is inversely related to resistance  so that the greater the resistance in a vascular bed or tissue, the  lower the blood flow.   Clinically the most important factor determining resistance  in a single vessel is the caliber of the vessel’s lumen, which can  be measured either as its radius or, as in Figure 31-26, as its  diameter. Small changes in the lumen’s radius lead to large  changes in vascular resistance. Clinically, vasoconstriction will  contribute to an increase in resistance whereas vasodilation will  cause a decrease that may be reflected by a decrease in blood  pressure. Because vessel length is relatively constant and lumen  size is quite variable, length is not as important as lumen size  in determining flow through a single vessel. Because viscosity  is relatively constant, except in the following circumstances,    FIGURE 31-25 Muscle Pump. As blood returns from downstream and the  surrounding muscles contract, the venous valves only allow blood to flow in one  direction, back towards the heart.    blood vessel radius is usually the key factor in determining total  peripheral resistance.   Generally, resistance to flow is greater in longer tubes because  resistance increases with length. That resistance increases with  increased length is demonstrated by comparing flow of the  same amount of blood under the same pressure through vessels  arranged in different configurations. Blood flowing through the  distributing arteries, beginning with branches off the aorta and  ending at arterioles in the capillary bed, encounters more resis-  tance than blood flowing through the capillary bed itself, where  flow is distributed among many short, tiny branches arranged  in parallel. This is because the distributing arteries comprise a  long system of tubes connected in series (end-to-end), whereas  the arterioles and capillaries comprise a short system of many  vessels arranged in parallel (side-by-side) (see Figure 31-26).  Although the arterioles are arranged in series with the distribut-  ing arteries and the capillaries, they are arranged in parallel with  other arterioles. Similarly, the capillaries are in series with the  metarterioles, but they are in parallel with other capillaries.   Resistance to flow through a system of vessels, or total resis-  tance, depends not only on characteristics of individual ves-  sels but also on whether the vessels are arranged in series or in    parallel. For vessels arranged in series, total resistance equals the  sum obtained by adding all the individual resistances. For ves-  sels arranged in parallel, total resistance equals the sum of the  reciprocals (I/R) of the individual resistances.   Total resistance is related to the total cross-sectional area of  a system of vessels in parallel and to the number of vessels in  parallel that make up the total cross-sectional area. The larger  the total cross-sectional area, as in the capillary system, the  lower the resistance. However, if a cross-sectional area consists  of a very large number of parallel vessels, the overall resistance  will be greater than it would be if the cross-sectional area were  made up of only two or three parallel vessels. Therefore, resis-  tance is greater in smaller vessels than in larger vessels. The  total cross-sectional area of the arteriolar system is greater than  that of the arterial system (see Figure 31-26); the greater num-  ber of arterioles arranged in parallel, however, leads to greater  resistance to flow in the arteriolar system. The pressure drop is  greatest across the arterioles. Many capillaries arise from each  arteriole so that the total cross-sectional area of the capillary  bed is very large and resistance is low, despite the fact that the  cross-sectional area of each capillary is less (which normally  increases resistance) than that of each arteriole. As a result,  blood flow becomes quite slow in the capillaries, analogous to  water flow in a river. A narrow river whose bed widens flows  more slowly through the wide section than through the narrow  section. The slow velocity of flow in each vessel is optimal for  capillary-tissue exchange.   Both pressure and resistance impact the velocity of the blood  within a vessel. Blood velocity is the distance blood travels in  a unit of time, usually centimeters per second (cm/sec). Blood  velocity is directly related to blood flow (amount of blood  moved per unit of time) and inversely related to the cross-  sectional area of the vessel in which the blood is flowing.   The relationship between velocity and flow can again be  understood by thinking of a river. The volume of water flowing  in a river is the same whether the river is narrow or wide. Where  the river narrows, the water flows quickly; where it widens, the  water flows slowly. The volume of water moving between the  riverbanks does not change. In the body, as blood moves from  the aorta to the capillaries, the total cross-sectional area of the  vessels increases and the velocity of flow decreases.   Flow varies inversely with the viscosity—thick, sticky consis-  tency of the fluid. Thick fluids move more slowly and cause  greater resistance to flow than thin fluids—just think of honey  as compared to water. The viscosity of blood depends on red  cell content. The greater the percentage of red cells in the blood,  the more viscous the blood. This relationship is expressed as the  hematocrit—the ratio of the volume of red blood cells to the  volume of whole blood (see Chapter 27). A high hematocrit  value reduces flow through the blood vessels, particularly the  microcirculation (arterioles, capillaries, venules). Conditions in  which the hematocrit value is elevated, such as a lack of body  water, cyanotic congenital heart disease (see Chapter 33), or  polycythemia (see Chapter 27), can lead to increased cardiac  work as a result of increased vascular resistance.    FIGURE 31-26 Relationship Between Cross-Sectional Area and Flow Rate of Blood. As can be seen in the simple    diagram (A) and the blood vessel chart (B), blood flows with    vessels increases the total cross-sectional area of the arterioles and capillaries, reducing the flow rate. When capillaries    merge into venules and venules merge into veins, the total cr  (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8,    Flow through any tubular system can be either laminar or tur-  bulent. Blood flow through the vessels, except where vessels split  or branch, is mainly laminar. In laminar flow, concentric layers  of molecules move “straight ahead.” Each concentric layer flows  at a different velocity (Figure 31-27). The cohesive attraction  between the fluid and the vessel wall prevents the molecules of  blood that are in contact with the wall from moving. The next  thin layer of blood is able to slide slowly past the stationary layer  and so on until, at the center, the blood velocity is greatest. The  centermost concentric layer of fluid is not slowed by friction  against the vessel wall. Large vessels have room for a large cen-  ter layer; therefore, they have less resistance to flow and greater  flow and velocity than smaller vessels.   Where flow is obstructed, the vessel turns, or blood flows  over rough surfaces, it becomes turbulent with whorls or eddy  currents that produce noise, causing a murmur to be heard on  auscultation, such as occurs during blood pressure measure-  ment with a sphygmomanometer. Resistance increases with    oss-sectional area decreases, causing the flow rate to increase.  St Louis, 2013, Mosby.)    turbulence. Arterial areas of turbulence also are places where  atherosclerotic plaques are found (see Chapter 32).    Vascular compliance is the increase in volume a vessel is able  to accommodate for a given increase in pressure. Compliance  depends on the factors related to the nature of a vessel wall,  such as the ratio of elastic fibers to muscle fibers in the vessel  wall. Elastic arteries are more compliant than muscular arteries;  the veins are more compliant than either type of artery because  they have less smooth muscle. Because they are more compli-  ant, veins serve as storage areas for the circulatory system.   Compliance determines a vessel’s response to pressure  changes. For example, with a very small increase in pressure,  a large volume of blood can be accommodated by the venous  system. In the less compliant arterial system, where smaller vol-  umes and higher pressures are normal, small variations in pres-  sure cause little or no change in the volume of blood within the  arterial vessels.    FIGURE 31-27 Laminar and Turbulent Flow. A, Laminar flow. Fluid flows  in long smooth-walled tubes as if it is composed of a large number of concentric  layers. B, Turbulent flow is caused by numerous small currents flowing crosswise  or oblique to the long axis of the vessel, resulting in flowing whorls and eddy cur-  rents. (Adapted from Seeley RR, Stephens TD, Tate P: Anatomy and physiology,  ed 3, St Louis, 1995, Mosby.)    Stiffness is the opposite of compliance. Several conditions  and disorders can increase vascular stiffness, with the most  common being aging and arteriosclerosis (see Chapter 32 and  section on aging at the end of this chapter). Arteriosclerosis  increases the rigidity or stiffness of arterial walls, which in turn  increases peak arterial pressure at a given volume of blood.    Regulation of Blood Pressure (Arterial Pressure)  During a wide range of physiologic conditions, including  changes in body position, muscular activity, and circulating  blood volume, arterial pressure is regulated within a fairly nar-  row range to maintain tissue perfusion, or blood supply to the  capillary beds, Systemic arterial blood pressure is a regulated  variable, which means that the cardiovascular control systems  are designed to maintain blood pressure within these limits.  Very low pressures are not consistent with survival because  body tissues will not be perfused whereas very high pressures  increase the risk of stroke and damage to other organs, such as  the kidneys, heart, and retinas. Arterial pressure is a function of  and varies directly with both cardiac output (heart rate x stroke  volume) and peripheral resistance. Increases in one or both will  raise arterial pressure, and decreases in one or both will lower  the arterial pressure (Table 31-3). The major factors and rela-  tionships that regulate arterial blood pressure are summarized  in Figure 31-28.    TABLE 31-3 FACTORS THAT AFFECT  MEAN ARTERIAL PRESSURE  AND CAPILLARY FLOW    The mean arterial pressure (MAP), which is the average  pressure in the arteries throughout the cardiac cycle, depends  on the elastic properties of the arterial walls and the mean vol-  ume of blood in the arterial system. MAP can be approximated  from the measured values of the systolic (Ps) and diastolic (Pd)  pressures by means of the following formula:    The difference between the systolic pressure and diastolic  pressure (Ps — Pd) is called the pulse pressure. Pulse pressure is  directly related to arterial wall stiffness and stroke volume.   The cardiac output (minute volume) of the heart can be  changed by alterations in heart rate, stroke volume (volume of  blood ejected during each ventricular contraction), or both. An  increase in cardiac output without a decrease in peripheral resis-  tance will cause mean blood pressure and flow rate to increase.  The higher arterial pressure increases blood flow through the  arterioles. On the other hand, a decrease in the cardiac output  causes an immediate drop in mean arterial blood pressure and  flow rate (see Table 31-3).    Effects of Total Peripheral Resistance and Blood Volume  Total resistance in the systemic circulation, often referred to as  either systemic vascular resistance (SVR) or total peripheral resis-  tance (TPR), is primarily a function of the diameter of the arte-  rioles. If cardiac output remains constant, arteriolar constriction  raises mean arterial pressure by reducing the flow of blood into  the capillaries and arteriolar dilation has the opposite effect.  Neural Control of Total Peripheral Resistance. Reflex  control of cardiac output and peripheral resistance includes:  (1) sympathetic stimulation of heart, arterioles, and veins;    and (2) parasympathetic stimulation of the heart. The  cardiovascular center in the medulla receives input from  pressure and blood composition sensors throughout the  vascular system and then modifies vagal and sympathetic  output to control heart rate and contractility, plus vascular  diameter (see Figure 31-10). Another input to the system  comes from hypothalamic centers that regulate vascular (and  cardiac) responses to changes in temperature. When the  body’s core temperature exceeds normal, the hypothalamus  reflex initiates dilation of arterioles and veins in the skin.  This vasodilation shunts blood to the skin, where heat is lost  through sweating, radiation, conduction, and/or convection.  When body core temperature decreases below normal,  surface vessels constrict, shunting blood to the vital organs.  Vasoconstriction is regulated by an area of the brainstem that  maintains a constant (tonic) output of norepinephrine from  sympathetic fibers in the peripheral arterioles. This tonic  activity is essential for maintenance of blood pressure.   During exercise and stress, the sympathetic fibers that stimu-  late vasodilation of skeletal muscle arterioles are thought to be  under the direct control of the cerebral cortex and hypothala-  mus and not the medullary centers. Information about pres-  sure, resistance, and blood composition is sensed by neural  receptors (baroreceptors and chemoreceptors) in arterial walls  and delivered to the medullary centers.   Baroreceptors. Baroreceptors (stretch receptors), located  in the aorta, the carotid sinus (Figure 31-29), as well as  other locations in the vasculature, influence both heart  rate and vascular resistance, and therefore blood pressure.  Baroreceptors respond to changes in smooth muscle fiber    length by altering their rate of discharge and supply sensory  information to the cardiovascular center that regulates blood  pressure.’ (Technically they are mechanoreceptors but they  usually are called baroreceptors or pressoreceptors.) The rate  of firing of the baroreceptors increases and decreases with  changes in blood pressure. An increase in arterial pressure  increases the rate of firing of the carotid sinus and aortic arch  baroreceptors. These impulses travel up the afferent nerves  to the medulla (e.g., the cardiac control center) and (1) slow  heart rate by decreasing sympathetic discharge and increasing  parasympathetic discharge (vagus nerve), (2) decrease  myocardial contractility by inhibiting sympathetic discharge,  and (3) increase arteriolar and venous dilation by decreasing  sympathetic discharge to smooth muscle. The net effect of  this major blood pressure—-regulating reflex is to reduce blood  pressure to normal by decreasing cardiac output (heart rate  and stroke volume) and peripheral resistance. Conversely,  the baroreceptor response to decreased blood pressure  results in an increase in heart rate, an increase in myocardial  contractility, and peripheral vasoconstriction, thus raising the  blood pressure. (Postural changes and the baroreceptor reflex  are discussed in Chapter 32.)   Arterial Chemoreceptors. Specialized areas within the  medulla oblongata and aortic and carotid arteries are sensitive  to concentrations of oxygen (Pao,), carbon dioxide (Pacoy),  and hydrogen ions (pH) in the blood. Although these receptors,  called chemoreceptors, are more important for respiratory  control, they also transmit impulses to the medullary  cardiovascular centers that regulate blood pressure. A decrease  in arterial oxygen concentration or an increase in Paco, causes    Chemoreceptors in the  carotid and aortic  bodies: LO,, TCO,,  JpH (TH*)    FIGURE 31-29 Baroreceptor and Chemoreceptor Reflex Control of Blood Pressure. A, Baroreceptor reflexes. Baro-  receptors located in the carotid sinuses and aortic arch detect changes in blood pressure. Action potentials are conducted to  the cardioregulatory and vasomotor centers. The heart rate can be decreased by the parasympathetic system; the heart rate  and stroke volume can be increased by the sympathetic system. The sympathetic system also can constrict or dilate blood  vessels. B, Chemoreceptor reflexes. Chemoreceptors located in the medulla oblongata and in the carotid and aortic bodies  detect changes in levels of blood oxygen, carbon dioxide, or pH. Action potentials are conducted to the medulla oblongata. In  response, the vasomotor center can cause vasoconstriction or dilation of blood vessels by the sympathetic system, and the  cardioregulatory center can cause changes in the pumping activity of the heart through the parasympathetic and sympathetic  systems. (From Seeley RR, Stephens TD, Tate P: Anatomy & physiology, ed 3, St Louis, 1995, Mosby.)    a reflexive increase in heart rate, stroke volume, and blood  pressure, whereas an increase in carbon dioxide concentration  causes decreases in these variables. The major chemoreceptive  reflex is caused by alterations in arterial oxygen concentration.  The effects of altered pH or carbon dioxide levels are minor.  Effect of Hyperemia. When metabolic activity is increased in  the heart, skeletal muscle, and other muscular organs, it causes  an increase in blood flow termed hyperemia. For example, the  blood flow to exercising skeletal muscle increases in proportion  to the activity of the muscle. This condition, known as active    (exercise) hyperemia, is the result of arteriolar dilation and  autoregulation of blood flow within the active organ. Reactive  hyperemia refers to vasodilation in response to restoration of  blood flow after a period of tissue ischemia and results from a  buildup of vasodilatory metabolic byproducts in the ischemic  tissue. After an infarction in a vascular bed, the subsequent  reactive hyperemia that may occur has been associated with  damage known as ischemia reperfusion injury.   Effects of Hormones. Hormones influence total peripheral  resistance and blood volume by changing either vascular    tone or blood volume. Certain hormones cause contraction  or relaxation of arteriolar smooth muscle. By constricting  or dilating arterioles in specific vascular beds, hormones can  (1) increase the blood supply to vital organs that require more  blood flow in times of stress, (2) redistribute blood volume  during hemorrhage or shock, and (3) regulate heat loss.   The vasoconstrictor hormones include angiotensin II, vaso-  pressin (also known as antidiuretic hormone), epinephrine,  and norepinephrine. Epinephrine, the catecholamine hormone  released from the adrenal medulla, causes vasoconstriction in  most vascular beds except the coronary, liver, and skeletal mus-  cle circulations. Norepinephrine mainly acts as a neurotrans-  mitter; however, some is also released from the adrenal medulla  and is actually a more potent vasoconstrictor than epinephrine.  Both angiotensin II and vasopressin are vasoconstrictors but  they are not thought to have a major role in blood pressure con-  trol in normal circumstances.   Both vasopressin and aldosterone influence blood pressure  by increasing blood volume through their influence on fluid  reabsorption in the kidney and by stimulating thirst. Vaso-  pressin causes the reabsorption of water from tubular fluid in  the distal tubule and collecting duct of the nephron. Aldoste-  rone, part of the renin-angiotensin-aldosterone system, stimu-  lates the reabsorption of sodium, chloride, and water from the  same locations. The natriuretic hormones, which include brain  natriuretic peptide (BNP), C-type natriuretic peptide (CNP),  and urodilatin, all cause loss of sodium, chloride, and water  through their effects on kidney function.°!   Adrenomedullin (ADM) is a recently discovered, widely dis-  persed peptide present in numerous tissues with powerful vaso-  dilatory activity, and is a member of the calcitonin gene-related  peptide family. Although it has been found to have numerous  cardiovascular effects in animals, including a role in fetal car-  diovascular system development and vasodilation, its exact role  in adult human cardiovascular function has not been identified.  It is likely that it has a role in cardiovascular disease but those  links remain to be explored.**   Effects of Other Mediators. Several mediators produced by  the vascular endothelium have been demonstrated to cause  arteriolar vasodilation. These mediators include nitric oxide  (NO), prostaglandins, endothelium-derived relaxing factor,  and possibly other molecules. The velocity of blood movement  within the arterioles causes shear stress at the vascular  endothelial surface that in turn is the stimulus that causes  the endothelial cells to produce these vasodilator substances.  The flow-mediated dilation (FMD) test is used to evaluate  endothelial function and to predict the risk of cardiovascular  disease. A reduction in FMD is predictive of increased risk.**    The main determinants of venous blood pressure are: (1) the  volume of fluid within the veins, and (2) the compliance (dis-  tensibility) of the vessel walls. Veins have much thinner walls  than arteries and are more distensible. Typically, the venous  system accommodates approximately 66% of the total blood  volume with venous pressure averaging less than 10 mmHg.  The systemic arteries accommodate about 11% of the total    blood volume, with an average arterial pressure (blood pres-  sure) of about 100 mmHg, whereas the rest of the blood volume  is within the heart, capillaries, and pulmonary circulation.!®   The sympathetic nervous system controls compliance. The  walls of the veins are highly innervated by sympathetic fibers  that control venous smooth muscle. When the sympathetic  nerves to the veins fire, the result is an increase in smooth mus-  cle tone rather than vasoconstriction, which would be the result  in arterial vessels. This increased smooth muscle tone stiffens  the walls of the veins, reducing distensibility and increasing  venous blood pressure, thus forcing more blood through the  veins and into the right heart.   Two other mechanisms that increase venous pressure and  venous return to the heart are: (1) the skeletal muscle pump, and  (2) the respiratory pump. During skeletal muscle contraction  the veins within the muscles are partially compressed, causing  a decrease in venous capacity and increased return to the heart.  The respiratory pump acts during inspiration, when the veins of  the abdomen are partially compressed by the downward move-  ment of the diaphragm. Increased abdominal pressure moves  blood toward the heart.    Flow of blood in the coronary circulation, as in all vascular beds,  is directly proportional to the perfusion pressure and inversely  proportional to the vascular resistance of the bed. Coronary  perfusion pressure is the difference between pressure in the  aorta and pressure in the coronary vessels. Thus aortic pressure  is the driving pressure that propels the perfusion of myocardial  vessels. Mechanisms of vasodilation and vasoconstriction nor-  mally maintain coronary blood flow despite stresses imposed by  the constant contraction and relaxation of the heart muscle and  despite shifts (within a physiologic range) of coronary perfu-  sion pressure.   Several unique anatomic factors influence coronary blood  flow. Because of their location, the aortic valve cusps can  obstruct coronary blood flow by pushing against the openings  of the coronary arteries during systole. Also during systole, the  coronary arteries are compressed by ventricular contraction.  These anatomic factors have a systolic compressive effect,  which is particularly evident in the subendocardial layers of the  left ventricular wall and can greatly increase resistance to coro-  nary blood flow. Therefore, most coronary blood flow in the left  ventricle occurs during diastole. During the period of systolic  compression, when flow is slowed or stopped, oxygen is sup-  plied by myoglobin, a protein in heart muscle (also smooth and  skeletal muscle) that binds oxygen during contraction, diastole  in the heart, and then releases it when blood levels of oxygen fall  during relaxation or systole. Myoglobin is structurally different  than hemoglobin although both contain a heme group.**    Autoregulation (automatic self-regulation) enables organs to  regulate blood flow by altering the resistance in their arteri-  oles. Autoregulation in the coronary circulation maintains  the blood flow at a nearly constant rate at perfusion pressures  (mean arterial pressure) between 60 and 180 mmHg when    FIGURE 31-30 Role of the Lymphatic System in Fluid Balance. Fluid from  plasma flowing through the capillaries moves into interstitial spaces. Although  most of this interstitial fluid is either absorbed by tissue cells or resorbed by blood  capillaries, some of the fluid tends to accumulate in the interstitial spaces. As  this fluid builds up, it usually drains into lymphatic vessels (green) that eventually  return the fluid to the venous blood. Lymphatic structures are not actually green.  Green is used in diagrams to contrast lymphatic structures with nearby blood  vessels (red, blue). (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8,  St Louis, 2013, Mosby.)    other influencing factors are held constant. Thus autoregu-  lation helps to ensure constant coronary blood flow despite  shifts in the perfusion pressure within the stated range. Given  that blood flow is directly related to pressure and inversely  related to resistance, we know that for flow to stay constant  as pressure decreases, resistance also has to decrease; thus  the mechanism(s) underlying autoregulation must relate to  control of smooth muscle contraction in the arteriolar walls.  Although the exact mechanisms underlying autoregulation  are not known, some research has indicated that G-protein—  coupled receptors that influence calcium release with the myo-  cardium are involved.°°    The lymphatic system is a one-way network of vessels that is  important for fluid balance, immune function, and transport  of lipids, hormones, and cytokines. Every day about 3 liters of  fluid filters out of venous capillaries in body tissues and is not  reabsorbed. This fluid becomes the lymph that is carried by the  lymphatic vessels to the chest where it enters the venous circu-  lation. The lymphatic vessels run in the same sheaths with the  arteries and veins (Figure 31-30). The lymphatic system con-  sists of lymphatic vessels and the lymph nodes (Figure 31-31).  (Lymph nodes and lymphoid tissues are described in Chapters  7 and 27.) In this pumpless system a series of valves ensures  one-way flow of the excess interstitial fluid (then called lymph)  toward the heart. The lymphatic capillaries are closed at the dis-  tal ends (Figure 31-32).    FIGURE 31-31 Principal Organs of the Lymphatic System. The inset  shows the areas drained by the right lymphatic duct (green) and the thoracic duct  (blue). (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013,  Mosby.)    Lymph consists primarily of water and small amounts of dis-  solved proteins, mostly albumin, that are too large to be reab-  sorbed into the less permeable blood capillaries. Lymph also  carries two types of cells—lymphocytes and antigen-presenting  cells. The antigen-presenting cells are carried to the next  lymph node in the system whereas lymphocytes traffic between  lymph nodes. Once within the lymphatic system, lymph trav-  els through lymphatic venules and veins that drain into one of  two large ducts in the thorax—the right lymphatic duct and the  thoracic duct. The right lymphatic duct drains lymph from the  right arm and the right side of the head and thorax, whereas  the larger thoracic duct receives lymph from the rest of the  body (see Figure 31-31). The right lymphatic duct and the tho-  racic duct drain lymph into the right and left subclavian veins,  respectively.   The lymphatic veins are thin walled, like the veins of the car-  diovascular system. In the larger lymphatic veins, endothelial  flaps form valves similar to those in the circulatory veins. The  valves permit lymph to flow in only one direction because lym-  phatic vessels are compressed intermittently by contraction of  skeletal muscles, pulsatile expansion of an artery in the same  sheath, and contraction of the smooth muscles in the walls of  the lymphatic vessel.    FIGURE 31-32 Lymphatic Capillaries. A, Schematic representation of lym-  phatic capillaries. B, Anatomic components of microcirculation.    As lymph is transported toward the heart, it is filtered  through thousands of bean-shaped lymph nodes clustered  along the lymphatic vessels (see Figure 31-31). Lymph enters  the nodes through several afferent lymphatic vessels, filters  through the sinuses in the nodes, and leaves by way of efferent  lymphatic vessels. Lymph flows slowly through a node, which  facilitates the phagocytosis of foreign substances within the  node by antigen-presenting cells and the entry of mature but  naive B and T lymphocytes, which then circulate through the  body, moving from one lymph node to the next while waiting  for a chance encounter with the antigen to which they are pro-  grammed to respond (see What’s New? Growth of New Lym-  phatic Vessels from Macrophages). (Phagocytosis is described  in Chapter 7.)    Assessment of the individual with suspected cardiovascular dis-  orders begins with a thorough history for determination of risk    During inflammation and wound healing in adults, new lymphatic vessels  sprout from existing vessels in the affected area, a process known as lym-  phangiogenesis. When inflammation occurs, inflammatory cytokines, such  as vascular endothelial growth factors A and C (VEGF-A and VEGF-C), bind  to receptors, such as the VEGF receptor 3 (VEGFR-3), on macrophages and  stimulate the division of lymphatic endothelial cells and the formation of new    lymphatic capillaries that will drain the affected tissue. Some macrophages  in the area differentiate into a new subtype, known as a macrophage-derived  lymphatic endothelial cell progenitor, that is capable of working with the lym-  phatic endothelial cells to create the new lymphatic capillaries. Understanding  the factors that stimulate and control this growth of new lymphatic vessels  may allow treatment of conditions such as lymphedema, as well as some  heart conditions, impaired wound healing, and some types of cancer.    Data from Ji R-C: Cell Mol Life Sci 69(6):897-914, 2012; Ran S,  Montgomery KE: Cancers (Basel) 4(3):618-657, 2012.    factors and symptoms. A careful physical examination looking  for evidence of tissue ischemia, pulmonary congestion, and car-  diac dysfunction is next. Blood samples are taken and sent for  a variety of tests. For many individuals, these basic steps will  be complemented with methods that measure heart and vas-  cular function with greater specificity. Cardiac function can be  evaluated using indicators calculated from pressures and flow  rates in the heart and vessels. Table 31-4 defines the indicators  most often used in the clinical setting. The normal values for  several testing methods are different for men and women.*°*”  This textbook’s inside back cover includes normal blood values  for common laboratory tests.    Many sophisticated tests are used to evaluate and diagnose car-  diac or coronary artery diseases, and new ones are being tested  each year. Some of the more commonly used modalities include  chest x-ray, electrocardiography, echocardiography, stress test-  ing, computed tomography (CT) and magnetic resonance  imaging (MRI), technetium scanning, electrophysiology stud-  ies, and catheterization with angiography.   Chest x-rays allow for the examination of the size and con-  tour of the heart and related structures. Evidence of chamber  enlargement, pericardial disease, pulmonary edema, valvular  calcification, ventricular hypertrophy, and pathology of the  great vessels may be visualized. Chest x-ray also is useful to  assess for appropriate placement of invasive cardiac conduc-  tion devices and for any complications caused by these devices  (e.g., pneumothorax or hemothorax; see Chapter 35). A chest  x-ray examination is a routine part of a cardiac examination.  The most commonly obtained views are posteroanterior (PA)  and lateral, with the individual standing upright and the lungs  fully expanded. In those individuals confined to bed, an antero-  posterior (AP) view may be obtained but is usually of lesser  quality than the PA view.    Number of heartbeats (cardiac cycles) per minute  Normal adult value: 70 beats/min   Cardiac output (CO) Amount of blood (in L) moved by the heart in 1 min  Normal range: 4-8 L/min    Cardiac index (Cl) Relationship between cardiac output and body  surface area (BSA, in m?)  Normal range: 2.8-4.2 L/min/m?  Stroke volume (SV) Amount of blood (in ml) ejected by the left ventricle  during systole (i.e., per beat)  Normal range: 60-100 ml/beat  Stroke volume index (SVI) Relationship between stroke volume and body  surface area  Normal range: 33-47 ml/beat/m?  Oxygen consumption Amount of oxygen (in ml) consumed per minute in  index (VO;) relation to BSA  Stroke work index (SWI) unt of work (expressed as done) by the left or   Systemic mean arterial blood pressure (in mmHg) in the systemic  pressure (MAP) ies    Electrocardiography, typically a 12-lead electrocardiogram  (ECG), gives information about heart rate and rhythm; the effects  of activities of daily life, exercise, electrolytes, drugs, and disease  on electrical activity in the heart; and the electrical orientation of  the cardiac muscle. An ECG provides no direct information about  the contractile state or mechanical performance of the heart.  Serial 12-lead ECGs are of primary importance in establishing  the presence of myocardial ischemia and infarction or conduc-  tion defects and dysrhythmias. This examination has become  part of the routine hospital preadmission/admission assessment,  even when the admitting diagnosis is not cardiac in nature,  because it establishes baseline information about the electrical  function of the heart. Also, recent ECGs can be compared with  ECGs obtained from the same individual in the past. Changes in  the ECG over time assist in determining the cause, amount, or  nature of changes in cardiac anatomy and physiology. Ambula-  tory electrocardiographic or Holter monitoring is used to evalu-  ate rhythm changes that may occur in persons during activities  of daily living. Cell phone technology also is rapidly advancing  to enable ECG recording and relaying to healthcare providers.   Echocardiography is the most effective and widely used nonin-  vasive modality for evaluating the structures of the heart. Ultra-  sound beams reflected by cardiovascular structures produce   Decreases within specific ranges indicate cardiogenic or hypovolemic shock  (see Chapter 48)    ncreased: acute respiratory distress syndrome (ARDS), pneumonia, primary  pulmonary hypertension, congestive heart failure  Decreased: late shock    shapes that can be visualized and allow for recognition of altered  cardiac anatomy.”* It is used to evaluate for suspected coronary  artery disease, heart failure, valvular disease, infective endocar-  ditis, cardiomyopathies, pericardial disease, prosthetic valve  function, congenital heart disease, and aortic diseases. Through  the use of M-mode, two- and three-dimensional techniques  with Doppler and color flow imaging, accurate assessments of  cardiac output, ejection fraction, and valvular function can be  obtained.***° Advances in technology now allow both intra-  cardiac and transesophageal echocardiography for evaluation  of the heart anatomy, although anesthesia is required for the  transesophageal technique.*”    Cardiac activity during exercise is examined during a stress  test when an intervention is used to increase myocardial work.  Stress testing elicits signs and symptoms of heart disease and  coronary artery disease that may not appear at rest. Echocar-  diography or continuous 12-lead ECG and blood pressure  measurements are obtained before, during, and after the study.  Cardiac stress from exercise is usually induced by having the  individual walk on a treadmill. Other, less frequently used forms  of exercise include static exercise (hand ergometry or chemi-  cal stress), stair climbing (the Stairmaster’s double two-step),  arm ergometry, and bicycle ergometry. The individual exercises  until the maximal heart rate for gender and age is reached or    until other subjective or objective indicators of cardiac dysfunc-  tion or distress appear. Subjective indicators include chest pain,  extreme fatigue, extreme dyspnea, leg pain, or the individual’s  request to stop the test. Objective criteria are ST-segment eleva-  tion or depression, SA node or atrial dysrhythmias, AV node  dysrhythmias, ventricular dysrhythmias, elevated or decreased  blood pressure, signs of cerebral hypoxia, and signs of circula-  tory insufficiency. One limitation of this test is that it cannot be  used in persons whose capacity for exercise is limited.   Stress testing also may be used to evaluate either fitness for  noncardiac surgery or progress in recovery after myocardial  infarction or cardiac surgery. Graded exercise in individuals  with low- to moderate-risk chest pain evaluated in an emer-  gency department can be used as a prognostic indicator of  adverse cardiac events. When a differential diagnosis for chest  pain has been difficult to determine, stress testing may help  distinguish coronary artery insufficiency from other causes of  pain. The risks associated with stress testing include dysrhyth-  mias, myocardial infarction, and death. The risk is greater when  the test is performed soon after an acute ischemic event.   Stress testing with ECG monitoring may not be sensitive  enough to detect and localize areas of the myocardium at risk for  ischemia and infarction. Currently, most stress testing includes  the injection of a radiotracer that is absorbed by active heart  cells. When the heart is scanned, during and after stress testing,  areas where the radiotracer is not taken up by ischemic cells can  be seen and those locations indicate areas of myocardial damage.    Single-photon emission computed tomography (SPECT) is typ-  ically used to evaluate individuals for coronary artery disease and  myocardial ischemia during stress testing. A radiotracer (usu-  ally thalium-201) is injected intravenously and is absorbed and  retained for a while by healthy myocytes.*! Photons are emitted  from the radiotracer in the myocardium in proportion to per-  fusion of the tissue. A gamma camera visualizes the photons,  and views are taken from 360 degrees by CT, which digitizes the  information and provides a three-dimensional view of myo-  cardial perfusion. Data about where the myocardium absorbs  the tracer normally, slowly, or not at all can be correlated with  existing myocardial disease and can help quantify ischemic risk.  A new development, high-speed SPECT, has the advantage of  taking less time and, thereby, requiring less radiotracer, which  decreases radiation exposure for the person being examined.*!   Computed tomography (CT) and magnetic resonance imaging  (MRI) are used to evaluate cardiac anatomy and physiology. New  techniques, including ECG gating (timing of data gathering to the  cardiac cycle), electron beam CT, and spiral CT, have improved  the ability of tomography to visualize cardiac structures. The high  resolution of CT can provide information about calcification of  coronary vessels and cardiac valves. Information about coronary  artery calcification is being used to improve risk classification  for coronary artery disease.” It also is a tool for evaluating large-  vessel disease. Concerns and debate continue, however, about the  radiation risks and use of variable protocols. The International    Commission on Radiological Protection (ICRP) recently released  a report on radiological protection in cardiology.”   MRI is based on the principle that the frequency of energy  (resonant frequency) given up by a nucleus is exactly propor-  tional to the surrounding magnetic field (see Chapter 15). The  anatomy and physiology of the great blood vessels and myo-  cardium are depicted in three dimensions with excellent reso-  lution. Ventricular function can be evaluated using indexes of  ventricular function, such as ejection fraction. Rapidly moving  sequences (MRI) can determine regional wall motion and myo-  cardial deformation. Flow direction and velocity also can be  quantitatively determined. Stress testing also can be done with  MRI using the drug dobutamine to increase the cardiac work-  load instead of exercise.“4    Radiopharmaceuticals labeled with »?™technetium prepara-  tions, such as sestamibi, teboroxime, and tetrofosmin, are used  to image the coronary arteries and myocardium. Technetium  pyrophosphate (??™TcPYP) is injected intravenously into a rest-  ing individual during a “hot spot” imaging examination. Two  hours after injection the distribution pattern of the radioactive  solution is recorded by nuclear scan. During the 2-hour delay,  the injected material will have been taken up by infarcted areas  of the myocardium, particularly 1 to 3 days after the onset of  symptoms. This type of scanning also is done with stress testing  using exercise or dobutamine.” Study results are not definitive  during the first 12 hours after an infarct.   Technetium scanning is used when (1) there is a conflict-  ing history for myocardial infarction, (2) there are equivocal  ECG abnormalities, or (3) an individual’s cardiac enzymes  have been elevated because of surgery or trauma. Ongoing  research is determining any risks associated with radioactive  substances.    In-depth evaluation of electrical conduction within the heart can  provide important information about the nature and causes of  dysrhythmias, such as atrial and ventricular tachycardias and  heart block. This evaluation is often referred to as electrophysi-  ologic mapping of the myocardium. There are many types of  electrophysiology studies that are specific to certain conduction  disorders but they have the common goal of documenting abnor-  mal conduction pathways. Furthermore, the techniques used may  also allow for ablation of unwanted pathways or the appropriate  placement of pacemakers and implantable defibrillators. Map-  ping can include the use of echocardiography and CT scanning.*°   One example of an electrophysiology study is AV bundle elec-  trocardiography. Two electrode-tipped catheters are inserted  percutaneously into the femoral vein, floated up the inferior  vena cava, and positioned in or near the right atrium during  AV bundle (His bundle) electrocardiography. AV bundle elec-  trocardiography can detect secondary sites of impulse genera-  tion (ectopic foci), as well as accessory pathways of conduction.  Other conduction defects and the effects of drugs on conduc-  tion also can be illuminated. Risks related to this procedure can  be grave and include dysrhythmias, death, vessel or heart perfo-  ration, clot or plaque embolization, and kidney failure.    One or both sides of the heart can be examined using cardiac cathe-  terization. This invasive procedure requires the use of fluoroscopy  and strict sterile techniques and takes place in a specially equipped  catheterization laboratory. Local anesthetic is administered, and  a catheter is introduced percutaneously into the vasculature and  passed caudally into the atrium and ventricle. For a right-heart  catheterization, the catheter is placed in either the jugular, subcla-  vian, brachial, or femoral veins. The femoral artery is commonly  used for a left-heart study. Once the catheter has been guided into  the heart chambers, pressures are recorded, blood samples are  obtained to examine oxygen content, and a contrast medium is  injected to visualize chamber function and valve patency.   Cardiac catheterization provides a means to visualize the  chambers of the heart continuously, although for a short time.  A great deal of information can be obtained about heart struc-  ture and function. Pressures in each chamber and across heart  valves can be precisely measured, along with timing of events in  the cardiac cycle. Of particular value is the ability to compare  the oxygen content of blood in each heart chamber. Risks for  this procedure that have decreased over time include the devel-  opment of dysrhythmias. Death can occur secondary to cardiac  arrest after ventricular fibrillation.   Fluoroscopic visualization of the coronary arteries and left-  heart structures using contrast dye is called coronary angiogra-  phy or arteriography. Like cardiac catheterization, this study takes  place in a catheterization laboratory using local anesthesia and a  sterile field. A catheter is threaded into the left ventricle through  the femoral artery. A ventriculogram generally is performed first.  Contrast dye is injected into the apex of the ventricle, and the next  few cardiac cycles are visualized and filmed. Like cardiac catheter-  ization, coronary angiography is used to gain information about  the structure and function of the ventricles and related valves. After  the ventriculogram, catheters are introduced individually into the  ostia of the coronary arteries. When the catheter is in position, a  small volume of contrast dye is mechanically and rapidly injected  into the artery and the results are visualized and filmed. Dye injec-  tion is repeated with the individual tilted at various angles to afford  views of the artery other than the anteroposterior view.   The risks of for coronary angiography are similar to those  of cardiac catheterization, with exceptions. Because the blood  supply to the cardiac muscle is briefly interrupted when dye  is introduced into the coronary arteries, angina (chest pain)  caused by ischemia (lack of oxygen) is much more common.  Coronary artery spasms also can occur. Interrupted flow also  causes decreased heart rate (bradycardia), as well as some tachy-  dysrhythmias, hypotension, and ST-segment depression.   The systemic vascular system can be studied by a variety of  techniques in order to evaluate for adequate flow rates, vascular  obstruction, and structural defects. These techniques include  Doppler ultrasonography, CT and MRI, venography, and  arteriography.    Pulsation, described by the flow of blood through an artery  during the cardiac cycle, can be drawn as a waveform plotting    pressure against time (Figure 31-33). The waveform can be  obtained noninvasively by placing a transducer on the skin over  the carotid artery while the individual’s head is turned slightly  away from the transducer. The amplitude and shape of arterial  waveforms can provide information about the elasticity of the  arterial wall, or its inverse—the stiffness of the wall.    A Doppler study is done using a microphone that amplifies  and records the sounds made by blood flowing in periph-  eral vessels. The Doppler microphone is placed over the  vessel to be studied, and sounds related to obstructions to  flow, vessel wall mobility, and heart murmurs are transmit-  ted through a lubricating gel to the microphone. The audio  findings can be digitized into visual findings that can be ana-  lyzed for flow velocity and volume. These studies are useful  in the evaluation for abnormalities of venous flow (e.g., deep  venous thrombosis) and arterial flow (e.g., embolism). Ultra-  sound also is used to calculate the thickness of arterial walls,  yielding a reading called intimal-medial thickness. Carotid  intimal-medial thickness is used to assess for atherosclero-  sis.*’ Many people are familiar with ultrasound measure-  ments because they are commonly used to assess fetal growth  and development.   CT and MRI are used to evaluate the systemic circulation, pro-  viding information about the structure of the great vessels.  Either can be used to evaluate for aneurysms and dissections  of the thoracic or abdominal aorta. CT also is used to assess  for vessel calcification and provide some insights into the risk  for stroke and myocardial infarction through evaluation of the  carotid and coronary vessels.   Radiopaque dye can be injected through intravenous or intra-  arterial catheters to allow for visualization of the internal struc-  ture, diameter, and patency of veins and arteries. Venography  is performed primarily in the lower extremity to assess for the  presence of thrombi in the large veins of the leg. Arteriogra-  phy (angiography) can be used in almost any vascular system,    CHAPTER 31 Structure and Function of the Cardiovascular and Lymphatic Systems    TABLE 31-5 CARDIOVASCULAR FUNCTION IN OLDER ADULTS  DETERMINANT RESTING CARDIAC PERFORMANCE EXERCISE CARDIAC PERFORMANCE    Cardiac index Unchanged or slightly decreased in women only Declines because of a decrease in heart rate and stroke volume   Heart rate Slight decrease Increases less than in younger people, possibly because of decreased  cardiovascular response to catecholamines; overall slight decrease   Increases less from rest to exercise in older people than in younger people   Declines because of a decline in skeletal muscle mass and increase in body fat    Data from Najjar SS, Gerstenblith G, Lakatta EG: Aging and the cardiovascular system. In Willerson JT et al, editors: Cardiovascular medicine, ed 3,    *As measured by end-systolic volume/systolic blood pressure (ESV/SBP), an index of contractility.    including the great vessels and the pulmonary, coronary (see  previously in this chapter), cerebral, mesenteric, renal, hepatic,  and peripheral arteries. Risks include rupture, dissection,  thrombosis, embolization, or organ infarction involving the  arterial system being studied.    Cardiovascular disease is the most common cause of morbidity  and mortality in older adults in Western society and in much  of the rest of the world.** In addition, age is a key driver of car-  diovascular risk, which explains why it is the primary cause of  death in persons older than age 65.” The most common cardio-  vascular disease condition is hypertension followed by coronary  atherosclerosis for which hypertension is a risk factor.   It is challenging to determine the normal physiologic  changes in cardiac function with aging because many patho-  logic changes are usually present and physical fitness is vari-  able in older people as well. Studies of the effect of age on  cardiovascular function must be rigorous in their distinc-  tion between persons who are free of disease and those who  have disease that may be evident only during testing. There is  a wide range in the older population for nearly every cardio-  vascular variable. These variations are related to an increase  in the prevalence of hypertension and coronary disease with  advancing age; the growth in the segment of the population  older than age 65; and major age-associated changes in life-  style (e.g., fitness status).“? The most relevant age-associated  physiologic changes in cardiovascular performance include  myocardial and blood vessel stiffening, changes in neurogenic  control over vascular tone, increased occurrence of atrial  fibrillation, and loss of exercise capacity plus left ventricular  hypertrophy and fibrosis.*?°° These changes pose considerable  consequences with increased demand for flow, changes in pos-  ture, or with disease.   Arterial stiffening occurs with aging even in the absence of  clinical hypertension. It can, however, be an important contrib-  utor to systolic hypertension and its associated risks for cardio-  vascular events, dementia, and death. These changes result from  alterations within the vascular media, including age-associated    changes in cross-linking of collagen, an increase in the amount  of collagen, deposition of calcium, and changes in the nature  of elastin, the extracellular matrix, inflammatory molecules,  endothelial cell function, and reactive oxygen species.*° The  increased arterial stiffness may not be related strictly to an age-  associated change in vascular structure but may be caused by  changes in baroreceptor activity. Baroreceptor activity may  decrease with age, slowing physiologic adjustment to changes in  blood pressure, and posture. In persons older than age 60, pulse  pressure, which is directly influenced by arterial stiffness, is a  better predictor of cardiovascular disease than either diastolic  or systolic blood pressure.°!   Left ventricular hypertrophy and fibrosis also are more  common in the aging population, even in the absence of high  blood pressure. As the arterial system becomes stiffer the ven-  tricles must work harder to pump blood throughout the body,  thus contributing to hypertrophy. Fibrosis, calcification, and  increase in stiffness also impact valvular function, particu-  larly the function of the atrioventricular valves. These changes  make valvular disease a greater risk for the elderly, along with  an increased risk of heart failure related to the left ventricular  hypertrophy and stiffness.   The advent of genomic medicine and a deeper exploration of  molecular changes with aging continue to enhance our under-  standing of the myriad changes in our bodies as we age.*”*° The  ongoing hope is that as we better understand the causative fac-  tors related to cardiovascular decline with aging, we may be able  to develop therapeutics that arrest or slow these changes.   Stress testing is used to uncover functional capacity losses  that are not apparent at rest. In contrast to the subtle age effects  on resting cardiac tests, more dramatic changes occur during  exercise. Table 31-5 summarizes age-associated changes at rest  and during exercise. Overall, long-term exercise conditioning  in older individuals increases aerobic capacity and decreases  arterial stiffness and left ventricular function so that cardio-  vascular diseases may be prevented or delayed in older adults.  Although the risks and benefits of pharmacologic and invasive  strategies must always be assessed carefully, many older adults  can live longer and healthier lives if appropriate preventive and  treatment regimens are offered, even quite late in life.    The circulatory system is the body’s transport system and a  part of its communication system. It delivers oxygen, nutri-  ents, metabolites, hormones, neurochemicals, proteins,  and blood cells, including lymphocytes and leukocytes,  throughout the body and carries metabolic wastes to the  kidneys and lungs for excretion.    and the lymphatic vessels and is made up of two separate  but conjoined, serially connected pump systems: the pul-  monary circulation and the systemic circulation, plus the  lymphatics.    right side of the heart. The function of the pulmonary cir-  culation is to deliver blood to the lungs for oxygenation.    . The higher pressure systemic circulation is driven by the left    side of the heart, and its function is to move oxygenated  blood to body tissues and to deliver waste products to the  lungs, kidneys, and liver.    and return the fluids to the circulatory system. Another  important function of the lymphatic system is the move-  ment of lymphocytes and leukocytes between different  components of the immune system.    The heart consists of four chambers (two atria and two  ventricles), four valves (two AV valves and two semilunar  valves), a muscular wall, a fibrous skeleton, a conduction  system, nerve fibers, systemic vessels (the coronary circula-  tion), and openings where the great vessels enter the atria  and ventricles.    . The heart wall, which encloses the heart and divides it into    chambers, is made up of three layers: the epicardium (outer  layer), the myocardium (muscular layer), and the endocar-  dium (inner lining). The heart is contained within the peri-  cardium, a double-walled sac.    . The myocardial layer of the two atria, which receive blood    entering the heart, is thinner than the myocardial layer of  the ventricles, which is stronger because it generates the  pressure that causes the blood to circulate through the  lungs or the systemic circulation.    . The right and left sides of the heart are separated by por-    tions of the heart wall called the interatrial septum and the  interventricular septum.    tion enters the right atrium through the superior and infe-  rior venae cavae. From the right atrium the blood passes  through the right AV (tricuspid) valve into the right ventri-  cle. In the ventricle the blood flows from the inflow tract to  the outflow tract and then through the pulmonic semilunar  valve (pulmonary valve) into the pulmonary artery, which  delivers it to the lungs for oxygenation.    and two from the right lung). From the left atrium the  blood passes through the left AV valve (mitral valve) into  the left ventricle. In the ventricle the blood flows from the  inflow tract to the outflow tract and then through the aortic  semilunar valve (aortic valve) into the aorta, which delivers  it to systemic arteries of the entire body.    . The heart valves that ensure the one-way flow of blood    from the atria to the ventricles are called the atrioventric-  ular valves. The valves that ensure one-way flow from the  ventricles to either the pulmonary artery or the aorta are  called semilunar valves.    openings within the semilunar valves at the entrance to the  aorta, and deoxygenated blood from the coronary veins  enters the right atrium through the coronary sinus.    . The pumping action of the heart consists of two phases:    diastole, during which the myocardium relaxes and the  chambers fill with blood; and systole, during which the  myocardium contracts, forcing blood out of the ventricles.  A cardiac cycle consists of one systolic contraction and the  diastolic relaxation that follows it. Each cardiac cycle makes  up one heartbeat.   The sinoatrial (SA) node generates electrical impulses and  the conduction system of the heart transmits these electrical  impulses (cardiac action potentials) that stimulate systolic  contraction. The autonomic nerves (sympathetic and para-  sympathetic fibers) can adjust heart rate and systolic force,  but they do not stimulate the heart to beat.   The normal ECG is the sum of all cardiac action potentials.  The P wave represents atrial depolarization; the QRS com-  plex is the sum of all ventricular cell depolarizations. The  ST interval occurs when the entire ventricular myocardium  is depolarized.   Cardiac action potentials are generated by the SA node at  the rate of between 60 to 100 impulses per minute. The  impulses travel through the conduction system of the heart,  stimulating myocardial contraction as they travel.   Cells of the cardiac conduction system possess the proper-  ties of automaticity and rhythmicity. Automatic cells return  to threshold and depolarize rhythmically without an out-  side stimulus. The cells of the SA node depolarize faster  than other automatic cells, making it the natural pacemaker  of the heart. If the SA node is disabled, the next fastest pace-  maker, the AV node, assumes control.   Each cardiac action potential travels from the SA node to  the AV node to the bundle of His (AV bundle), through the  bundle branches, and finally to the Purkinje fibers and the  ventricular myocardium. There the impulse is stopped. It is  prevented from reversing its path by the refractory period  of cells that have just been polarized. The refractory period  ensures that diastole (relaxation) will occur, thereby com-  pleting the cardiac cycle.   Adrenergic receptor number, type, and function govern  autonomic (sympathetic) regulation of heart rate, contrac-  tile force, and dilation or constriction of coronary arteries.    The presence of specific receptors (0), O2, B,, Bz, 3) in the  myocardium and coronary vessels determines the effects of  the neurotransmitters norepinephrine and epinephrine.  Unique features that distinguish myocardial cells from skel-  etal cells enable myocardial cells to transmit action poten-  tials faster (through intercalated disks), synthesize more  ATP (because of a large number of mitochondria), and  have readier access to ions in the interstitium (because of  an abundance of transverse tubules). These combined dif-  ferences enable the myocardium to work constantly, which  is not required of skeletal muscle.   Cross-bridges between actin and myosin enable contrac-  tion to occur. Calcium and its interaction with the troponin  complex facilitate the contraction process. With troponin  release of calcium, myocardial relaxation begins.   Cardiac performance is affected by preload, afterload, heart  rate, and myocardial contractility.   Preload, or pressure generated in the ventricles at the end of  diastole, depends on the amount of blood in the ventricle.  Afterload is the resistance to ejection of the blood from the  ventricle. Afterload depends on pressure in the aorta.  Contractility is the potential for myocardial fiber shorten-  ing during systole. It is determined by the amount of stretch  during diastole (i.e., preload) and by sympathetic stimula-  tion of the ventricles.   The Frank-Starling law of the heart states that the myocar-  dial stretch determines the force of myocardial contraction  (the greater the stretch, the stronger the contraction).  Laplace’s law states that the amount of contractile force  generated within a chamber depends on the radius of the  chamber and the thickness of its wall (the smaller the radius  and the thicker the wall, the greater the force of contraction).    Blood flows from the left ventricle into the aorta and from the  aorta into arteries that eventually branch into arterioles and  capillaries, the smallest of the arterial vessels. Oxygen, nutri-  ents, and other substances needed for cellular metabolism  pass from the capillaries into the interstitium, where they  are available for uptake by the cells. Capillaries also absorb  products of cellular metabolism from the interstitium.    the venules the venous blood flows into larger and larger  veins until it reaches the venae cavae, through which it  enters the right atrium.    . Vessel walls consist of three layers: the tunica intima (inner    layer), the tunica media (middle layer), and the tunica  externa (outer layer).    . Layers of the vessel wall differ in thickness and composi-    tion from vessel to vessel, depending on the vessel’s size  and location within the circulatory system. In general, the  tunica media of arteries close to the heart contains a greater  proportion of elastic fibers because these arteries must  be able to distend during systole and recoil during dias-  tole. Distributing arteries farther from the heart contain a    greater proportion of smooth muscle fibers because these  arteries must be able to constrict and dilate to control blood  pressure and volume within specific capillary beds.    . Blood flow into the capillary beds is controlled by the con-    traction and relaxation of smooth muscle bands (precap-  illary sphincters) at junctions between metarterioles and  capillaries. The endothelium is probably a source of pros-  taglandins that control vasomotion.    . Blood flow through the veins is assisted by the contraction    of skeletal muscles (the muscle pump), and backwards flow  in the lower body is prevented by one-way valves, particu-  larly in the deep veins of the legs.    . Blood flow is affected by blood pressure; resistance to flow    within the vessels; blood consistency (which affects veloc-  ity); anatomic features that may cause turbulent or laminar  flow; and compliance (distensibility) of the vessels.    pressure, and resistance as the difference between pressure  at the inflow end of the vessel and pressure at the outflow  end divided by resistance within the vessel.    radius and on the viscosity of the blood. The greater a  vessel’s length and the blood’s viscosity and the narrower  the radius of the vessel’s lumen, the greater the resistance  within the vessel.   Total peripheral resistance, or the resistance to flow within  the entire systemic circulatory system, depends on the com-  bined lengths and radii of all the vessels within the system  and on whether the vessels are arranged in series (greater  resistance) or in parallel (lesser resistance).   Blood flow is influenced also by neural stimulation (of  vasoconstriction or vasodilation) and by autonomic fea-  tures that cause turbulence within the vascular lumen  (e.g., protrusions from the vessel wall, twists and turns,  bifurcations).   Arterial blood pressure is influenced and regulated by fac-  tors that affect cardiac output (heart rate and stroke vol-  ume), total resistance within the system, and blood volume.  Many hormones and other endothelial mediators alter  vasomotion including epinephrine, norepinephrine, anti-  diuretic hormone, renin-angiotensin system, natriuretic  peptides, adrenomedullin, nitric oxide, prostaglandins, and  endothelium-derived relaxing factor.   Venous pressure is influenced by blood volume within the  venous system and compliance of the venous walls.   Blood flow through the coronary circulation is governed  not only by the same principles as flow through other vas-  cular beds but also by two adaptations dictated by cardiac  dynamics. First, blood flows into the coronary arteries dur-  ing diastole rather than systole because during systole, the  cusps of the aortic semilunar valve block the openings of  the coronary arteries. Second, systolic contraction inhibits  coronary artery flow by compressing the coronary arteries.   Autoregulation enables the coronary vessels to maintain  optimal perfusion pressure despite systolic effects, and    myoglobin in heart muscle stores oxygen for use during the  systolic phase of the cardiac cycle.    The vessels of the lymphatic system run in the same sheaths  as those of the arteries and veins.   Lymph (interstitial fluid plus cells of the immune system)  is absorbed by lymphatic venules in the capillary beds and  travels through ever larger lymphatic veins until it empties  into the right lymphatic duct and the thoracic duct, which  drain into the right and left subclavian veins, respectively.  As lymph travels toward the thoracic ducts, it passes through  lymph nodes clustered around the lymphatic vessels. The  lymph nodes are sites of immune function and are ideally  placed to sample fluid and cells moving from the periphery  into the central circulation.    The evaluation of an individual with known or suspected  cardiovascular disease must include a careful history and  physical examination including assessment of risk fac-  tors, symptoms, vital signs, level of consciousness, mucous  membrane color, and cardiopulmonary functioning.  Important tests for cardiac disorders are ECG and Holter  monitoring, which detect disturbances of impulse genera-  tion or conduction.   Stress tests elicit clinical manifestations of cardiovascular  disease that might not be present at rest.   The sensitivity of stress testing is improved by the use of  radiotracer imaging techniques such as SPECT.  Echocardiography detects structural and functional cardiac  abnormalities over time.    Cardiac catheterization is used to measure the oxygen con-  tent and pressure of blood in the heart’s chambers and to  inject contrast media for x-ray examination of the size and  shape of the chambers and valves. Injection of contrast  medium into the coronary arteries (coronary angiogra-  phy), on the other hand, permits visualization of the coro-  nary circulation and every tissue perfused by the coronary  arteries.   Evaluation of the systemic vascular system can include arte-  rial pressure pulse waveform analysis, Doppler ultrasonog-  raphy, venography, and arteriography.    Controversy exists regarding the effects of normal aging on  the cardiovascular system. Separating the physiologic from  the pathologic alterations is difficult because of the wide  range of physical fitness in the elderly and the presence of  arteriosclerosis in a majority of older adults.   Studies have documented no change in cardiac output, a  slight decrease in heart rate, and a slight increase in stroke  volume in healthy (lack of ischemic heart disease) older  adults at rest. No changes were noted at rest in ejection frac-  tion. A slight increase in afterload (e.g., as systolic blood  pressure) and prolonged left ventricular relaxation was  noted.   The most relevant age-associated changes in cardiovascu-  lar performance are myocardial and blood vessel stiffening,  changes in neurogenic control over vascular tone, and left  ventricular hypertrophy and fibrosis.   With active risk reduction, physical activity, and disease  management, older adults can have markedly improved  cardiovascular health.    Cardioexcitatory center, 1106  Cardioinhibitory center, 1105  Cardiovascular control center, 1104  Chordae tendineae, 1088  Circumflex artery, 1090   Epinephrine, 1117  Excitation-contraction coupling, 1099  External elastic lamina, 1106  Fenestration, 1108    CHAPTER 31 Structure and Function of the Cardiovascular and Lymphatic Systems   Left ventricular end-diastolic pressure (LVEDP), 1103  Left ventricular end-diastolic volume (LVEDV), 1103  Lumen, 1108   Myocardial contractility, 1099 :  Myocardial oxygen consumption (MVO3), 1099  Myocardium, 1085   Peripheral vascular system, 1106  Posterior vein of the left ventricle, 1092   QRS complex, 1095  QT interval, 1095  Repolarization, 1094  Resistance, 1111  Rhythmicity, 1095  Right atrium, 1086   Right lymphatic duct, 1118  Right pulmonary artery, 1088  Right ventricle, 1086  Semilunar valve, 1087   1. Mehta D, Malik AB: Signaling mechanisms regulating endothelial perme-  ability, Physiol Rev 86(1):279-367, 2006. 18.   2. 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CHAPTER 31 Structure and Function of the Cardiovascular and Lymphatic Systems    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Diseases of the Veins, 1129  Varicose Veins and Chronic Venous Insufficiency, 1129  Deep Venous Thrombosis, 1130  Superior Vena Cava Syndrome, 1131  Diseases of the Arteries, 1132  Hypertension, 1132  Orthostatic (Postural) Hypotension, 1140  Aneurysm, 1140  Arterial Thrombus Formation, 1142  Embolism, 1143  Peripheral Vascular Diseases, 1144  Atherosclerosis, 1145  Peripheral Artery Disease, 1148    Cardiovascular disease is the leading cause of death worldwide  (Table 32-1).! The pathophysiology of heart disease is much  more complicated than just structural and hemodynamic  changes. Today the focus is on the genetic, neurohumoral, and  inflammatory mechanisms that underlie tissue and cellular pro-  cesses, such as endothelial injury, remodeling, stunning, reper-  fusion injury, and autoimmune disease.   Varicose veins are a common condition affecting more than  25 million Americans, women nearly twice as often as men.”  A varicose vein is a superficial vein in which blood has pooled.    Coronary Artery Disease, Myocardial Ischemia, and Acute  Coronary Syndromes, 1148  Disorders of the Heart Wall, 1163  Disorders of the Pericardium, 1163  Disorders of the Myocardium: The Cardiomyopathies, 1165  Disorders of the Endocardium, 1167  Cardiac Complications in Acquired Immunodeficiency  Syndrome, 1175  Manifestations of Heart Disease, 1175  Heart Failure, 1175  Dysrhythmias, 1182    Varicose veins typically involve the saphenous veins of the legs  and are distended, tortuous, and palpable (Figure 32-1). Vari-  cose veins are caused by (1) trauma to the saphenous veins that  damages one or more valves, or (2) gradual venous distention  caused by the action of gravity on blood in the legs.   Veins are thin-walled, highly distensible vessels. Normally  the muscular pump in the legs moves venous blood up toward  the heart, and valves prevent backflow and pooling of blood  (see Figures 31-35 and 31-31). In individuals who habitually  stand for long periods, wear constricting garments, or cross  the legs at the knees, distention progresses until the pressure in  the vein damages venous valves, rendering the valves incompe-  tent. Damaged valves cannot maintain normal venous pressure,  which causes hydrostatic pressure in the vein to increase. As the    DEATH RATES AND PERCENT OF TOTAL DEATHS FOR THE 15 LEADING CAUSES    OF DEATH IN THE UNITED STATES ALL RACES, BOTH SEXES, ALL AGES (FINAL    Data from Murphy SL, Xu J, Kochanek KD: Deaths: final data for 2010. National vital statistics reports; vol 61, no 4. Hyattsville, MD: National  Center for Health Statistics, 2013. Available at www.cdc.gov/nchs/data/dvs/Icwk1_210.pdf. Accessed July 2, 2013.    FIGURE 32-1 Varicose Veins of the Leg (arrow). (Courtesy of Dr. Magruder C.  Donaldson, Brigham and Women’s Hospital, Boston. From Kumar V et al: Robbins basic  pathology, ed 8, Philadelphia, 2007, Saunders.)    vein distends further, it becomes tortuous, and edema develops  in the extremity.   Evidence has been emerging that varicose veins are not just  the result of mechanical pressures. Altered connective tissue  proteins, increased proteolytic enzyme activity, and decreased  transforming growth factor-beta (TGF-$) in vein walls prob-  ably precede the development of valvular damage and the  development of varicosities.* Inflammatory changes that affect  autonomic innervation of veins has also been implicated.?    Varicose veins can progress to chronic venous insufficiency  (CVI), which is defined as sustained inadequate venous return.  Venous hypertension, circulatory stasis, and tissue hypoxia lead  to an inflammatory reaction in vessels and tissue. This causes  fibrosclerotic remodeling of the skin and then ulceration.  Symptoms include edema of the lower extremities and hyper-  pigmentation of the skin of the feet and ankles.   Circulation to the extremities can become so sluggish that  the metabolic demands of the cells for oxygen, nutrients, and  waste removal are barely met. Any trauma or pressure can  therefore lower the oxygen supply and cause cell death and  necrosis (venous stasis ulcers). Infection can occur because  poor circulation impairs the delivery of the cells and biochemi-  cals for the immune and inflammatory responses. This same  sluggish circulation makes infection following reparative sur-  gery a significant risk. Treatment of varicose veins and CVI  begins conservatively, and wound healing often occurs follow-  ing noninvasive treatments, such as leg elevation, compression  stockings, and physical exercise. New management techniques  include endovenous ablation (radiofrequency and laser) and  ultrasound-guided foam sclerotherapy. These techniques are  as effective and safer than surgical ligation and vein stripping.*    A thrombus is a blood clot that remains attached to a ves-  sel wall (Figure 32-2). A detached thrombus is a thromboem-  bolus. Venous thrombi are more common than arterial thrombi  because flow and pressure are lower in the veins than in the arter-  ies. Deep venous thrombosis (DVT) refers to clot formation in  the large veins, primarily of the lower extremities and may result  in venous thromboembolism (VTE) to the pulmonary circula-  tion. The American Heart Association (AHA) estimates that    FIGURE 32-2 Multiple Venous Thrombi. (From Rosai J: Ackerman’s surgical  pathology, ed 8, vol 2, St Louis, 1996, Mosby.)    more than 900,000 incident or recurrent VTE events occur annu-  ally in the United States, of which approximately one third are  fatal.° Three factors (triad of Virchow) promote venous throm-  bosis: (1) venous stasis (e.g., immobility, obesity, prolonged leg  dependency [e.g., air travel], age, heart failure [HF]), (2) venous  endothelial damage (e.g., trauma, medications), and (3) hyperco-  agulable states (e.g., inherited disorders, malignancy, pregnancy,  oral contraceptives, hormone replacement, hyperhomocystein-  emia, antiphospholipid syndrome).° Virtually everyone who is  hospitalized is at significant risk for DVT, especially those with  orthopedic trauma or surgery, spinal cord injury, and obstetric/  gynecologic conditions. Numerous genetic abnormalities are  associated with an increased risk for venous thrombosis primarily  related to states of hypercoagulability. These inherited abnormal-  ities include factor V Leiden mutation; prothrombin mutations;  and deficiencies of protein C, protein S, and antithrombin. Inher-  ited hypercoagulability states should be suspected in individuals  who develop thrombi in the absence of the usual risk factors.*”   Accumulation of clotting factors and platelets leads to  thrombus formation in the vein, often near a venous valve.  Inflammation around the thrombus promotes further platelet  aggregation and the thrombus propagates or grows proximally.  This inflammation may cause local symptoms, but because the  vein is deep in the leg it is usually not accompanied by clinical  symptoms or signs. If the thrombus creates significant obstruc-  tion to venous blood flow, increased pressure in the vein behind  the clot may lead to edema of the extremity.   Most thrombi eventually dissolve without treatment, but  untreated DVT is associated with a high risk of thromboembo-  lization of a part of the clot from the leg to the lung (pulmonary  embolism) (see Chapter 35).° In up to one third of individu-  als with DVT, persistent venous outflow obstruction may lead  to post-thrombotic syndrome (PTS), a frequent complication  of DVT characterized by chronic, persistent pain; edema; and  ulceration of the affected limb.*    Because DVT is usually asymptomatic and difficult to detect  clinically, prevention for at-risk individuals is crucial. If pos-  sible, individuals should be mobilized as soon as possible after  illness, injury, or surgery. Prophylactic treatment can include  low-molecular-weight heparin, antithrombin agents, warfarin,  or pneumatic devices.”'? Unfortunately, even these measures  may not prevent embolism in high-risk individuals such as those  who have undergone hip replacement surgery.'! In individuals  at high risk for pulmonary embolism, but for whom anticoagu-  lation is contraindicated, placement of an inferior vena caval  filter may be necessary to prevent pulmonary embolism.   Diagnosis is most often made by combining measurement of  serum D-dimer concentration with lower extremity ultrasonog-  raphy. p-dimer is an indirect measure of the presence of throm-  bosis that is very sensitive but is not specific. If the p-dimer is  negative, DVT is ruled out. If it is positive, the diagnosis must  be confirmed with ultrasonography.®!” In selected individuals,  computed tomography (CT) or magnetic resonance imaging  (MRI) may be needed to make the diagnosis. If noninvasive  testing is nondiagnostic, a venogram may be indicated.   DVT is treated with low-molecular-weight heparin, unfrac-  tionated intravenous heparin, antithrombin agents, or adjusted-  dose subcutaneous heparin.° Thrombolytic therapy may be  used to dissolve the clot more quickly and reduce the risk of  postphlebotic syndrome, especially when a large clot is located  in a proximal vein.'? However, bleeding risk is increased, and  many people have contraindications to the use of thrombolyt-  ics. Pharmacomechanical treatment involves catheter-mediated  removal of clots that can be used in selected individuals and  so far has a good safety record.'4 DVT has a recurrence rate of  26% 5 years after discontinuation of anticoagulant therapy,  especially if it was unprovoked and no identifiable underly-  ing condition can be reversed.'° In these individuals aspirin  therapy can reduce recurrence rates after discontinuation of  anticoaglulants.!°    Superior vena cava syndrome (SVCS) is a progressive occlu-  sion of the superior vena cava (SVC) that leads to venous dis-  tention in the upper extremities and head. The leading cause  of SVCS is bronchogenic cancer (approximately 70% of cases),  followed by lymphomas and metastasis of other cancers.'”  Benign causes of SVCS include thrombosis, histoplasmosis,  tuberculosis, mediastinal fibrosis, cystic fibrosis, and benign  tumors, such as retrosternal goiter.'* Invasive therapies, includ-  ing pacemaker wires, central venous catheters, and pulmonary  artery catheters, can lead to acute and chronic SVCS.   The SVC is a relatively low-pressure vessel that lies in the  closed thoracic compartment; therefore, tissue expansion can  easily compress the SVC. The right mainstem bronchus abuts  the SVC so that cancers occurring in this bronchus may press  on the vessel and obstruct venous return to the right atrium.  Additionally, the SVC is surrounded by lymph nodes and  lymph chains that commonly become involved in thoracic  cancers and compress the SVC during tumor growth. Because  onset of SVCS is slow, collateral venous drainage to the azygos  vein usually has time to develop.    Clinical manifestations of SVCS include edema and venous dis-  tention in the upper extremities and face, including the ocular beds.  Individuals may complain of a feeling of fullness in the head, or  tightness of shirt collars, necklaces, and rings. Cerebral and central  nervous system (CNS) edema may cause headache, visual distur-  bance, and impaired consciousness. The skin of the face and arms  may become purple and taut, and capillary refill time is prolonged.  Respiratory distress may be present because of edema of bronchial  structures or compression of the bronchus by a carcinoma.   Diagnosis is made by chest x-ray, Doppler studies, CT,  MRI, and ultrasound. With slow onset and the development  of collateral venous drainage, SVCS is generally not a vascular  emergency but rather an oncologic emergency.'’ Treatment  for malignant disorders can include radiation therapy, surgery,  chemotherapy, and the administration of diuretics, steroids,  and anticoagulants, as necessary. Treatment for nonmalignant  causes may include bypass surgery using various grafts, throm-  bolysis (both locally and systemically), balloon angioplasty, and  placement of intravascular stents.'®    Hypertension  Hypertension is consistent elevation of systemic arterial blood  pressure. Hypertension is the most common primary diagnosis  in the United States—approximately 1 in 3 adults greater than  20 years of age has hypertension; this increases to nearly two  thirds in those older than age 60. The prevalence of hyperten-  sion is nearly equal between men and women. Black adults have  among the highest rates of hypertension in the world (44%).  Approximately 80% of hypertensive adults are aware of their  condition, 71% are using antihypertensive medication, but only  48% of those have their hypertension controlled.° Hypertension  is defined in the Seventh Report of the Joint National Com-  mittee on Prevention, Detection, Evaluation, and Treatment  of High Blood Pressure (JNC7)!° as a sustained systolic blood  pressure of 140 mmHg or greater or a diastolic pressure of 90  mmHg or greater (Table 32-2). Normal blood pressure is asso-  ciated with the lowest cardiovascular risk, whereas those who  fall into the prehypertension category (which includes between  25% and 37% of the U.S. population) are at risk for developing  hypertension and many associated cardiovascular complications  unless lifestyle modification and treatment are instituted.*°  Some individuals with hypertensive disease have isolated  systolic hypertension. Isolated systolic hypertension (ISH) is    TABLE 32-2 CLASSIFICATION OF BLOOD  PRESSURE FOR ADULTS AGE  18 YEARS OR OLDER    Prehypertension 120-139 80-89  Stage 1 hypertension 140-159 90-99  Stage 2 hypertension =160 =100    elevated systolic blood pressure accompanied by normal dia-  stolic blood pressure (less than 90 mmHg). ISH is becoming  more prevalent in all age groups and is strongly associated with  cardiovascular and cerebrovascular events.”!   Approximately 95% of cases of hypertension have no known  cause and therefore are diagnosed as primary hypertension.°  Secondary hypertension accounts for 5% of cases and is caused  by altered hemodynamics associated with an underlying pri-  mary disease. Hypertension is a complex disorder that affects  the entire cardiovascular system, and all types and stages of  hypertension are associated with increased risk for target organ  disease events, such as myocardial infarction (MI), kidney  disease, and stroke.°   A combination of genetic and environmental factors is thought  to be responsible for the development of primary hypertension.  Genetic predisposition to hypertension is thought to be poly-  genic. The inherited defects are associated with renal sodium  excretion, insulin and insulin sensitivity, activity of the sympa-  thetic nervous system (SNS) and renin-angiotensin-aldosterone  system (RAAS), and cell membrane sodium or calcium trans-  port.”* In blacks, variants of the apolipoprotein L1 (APOL1)  gene are associated with hypertension and renal disease.”*   Risk factors associated with primary hypertension include:  (1) family history of hypertension; (2) advancing age; (3) gender  (men younger than 55 and women older than 70 years); (4) black  race; (5) high dietary sodium intake; (6) glucose intolerance  (diabetes mellitus); (7) cigarette smoking; (8) obesity; (9) heavy  alcohol consumption; and (10) low dietary intake of potassium,  calcium, and magnesium.!? Many of these factors are also risk  factors for other cardiovascular disorders. In fact, hypertension,  dyslipidemia, and glucose intolerance often are found together  in a condition called metabolic syndrome (see Chapter 22).   Although populations with high dietary sodium intake have  long been shown to have an increased incidence of hyper-  tension, recent studies indicate that low dietary potassium,  calcium, and magnesium intakes are also risk factors because  without their intake, sodium is retained. The nicotine in ciga-  rette smoke is a vasoconstrictor that can elevate systolic and dia-  stolic blood pressure acutely. In habitual smokers an individual  cigarette may not raise blood pressure, yet habitual smoking is  associated with a high incidence of severe hypertension, myo-  cardial hypertrophy, and death resulting from coronary artery  disease (CAD). The incidence of hypertension is higher among  heavy drinkers of alcohol (more than three drinks per day) than  among abstainers, but moderate drinkers (two to four drinks  per week) appear to have the lowest average blood pressures and  cardiovascular mortality. Obesity is recognized as an important  risk factor for hypertension, even in children and adolescents.   PATHOPHYSIOLOGY. Hypertension is caused by increases in car-  diac output or total peripheral resistance, or both. (The many  factors affecting cardiac output and peripheral resistance are  described in Chapter 31.) Cardiac output is increased by any  condition that increases heart rate or stroke volume, whereas  peripheral resistance is increased by any factor that increases  blood viscosity or reduces vessel diameter (vasoconstriction).    Primary Hypertension. Primary hypertension is the result of  a complicated interaction between genetics and the environment  that increase vascular tone (increased peripheral resistance)  and blood volume, thus causing sustained increases in blood  pressure. Multiple pathophysiologic mechanisms mediate  these effects including the sympathetic nervous system (SNS),  the RAAS, and natriuretic peptides. Inflammation, endothelial  dysfunction, obesity-related hormones, and insulin resistance  also contribute to both increased peripheral resistance and  increased blood volume. Increased vascular volume is related to  a decrease in renal excretion of salt, often referred to as a shift  in the pressure-natriuresis relationship. This means that for  a given blood pressure, individuals with hypertension tend to  secrete less salt in their urine. The pathophysiology of primary  hypertension is summarized in Figure 32-3.   The SNS contributes to the pathogenesis of hypertension in  many people. In the healthy individual the SNS contributes to  the maintenance of adequate blood pressure and tissue perfusion    by promoting cardiac contractility and heart rate (maintenance  of adequate cardiac output) and by inducing arteriolar vasocon-  striction (maintenance of adequate peripheral resistance). In  individuals with hypertension, overactivity of the SNS can result  from increased production of catecholamines (epinephrine and  norepinephrine) or from increased receptor reactivity involv-  ing these neurotransmitters.** Increased SNS activity causes  increased heart rate and systemic vasoconstriction, thus raising  the blood pressure. Efferent sympathetic outflow stimulates renin  release, increases tubular sodium reabsorption, and reduces renal  blood flow. Additional mechanisms of SNS-induced hyperten-  sion include structural changes in blood vessels (vascular remod-  eling), insulin resistance, increased renin and angiotensin levels,  and procoagulant effects. The SNS is implicated in the cardio-  vascular and renal complications of hypertension, and new  techniques such as renal denervation are being explored to treat  hypertension.”>”° The role of the SNS in the pathogenesis of car-  diovascular disease is summarized in Figure 32-4.    FIGURE 32-3 Pathophysiology of Hypertension. Numerous genetic vulnerabilities have been linked to hypertension and  these, in combination with environmental risks, cause neurohumoral dysfunction (sympathetic nervous system [SNS], renin-  angiotensin-aldosterone system [RAAS], adducin, and natriuretic hormones) and promote inflammation and insulin resistance.  Insulin resistance and neurohumoral dysfunction contribute to sustained systemic vasoconstriction and increased peripheral  resistance. Inflammation contributes to renal dysfunction, which, in combination with the neurohumoral alterations, results in  renal salt and water retention and increased blood volume. Increased peripheral resistance and increased blood volume are  two primary causes of sustained hypertension.    FIGURE 32-4 Role of the Sympathetic Nervous System in the Pathogenesis of Hypertension. Increased activity of  the sympathetic nervous system (SNS) not only increases heart rate and peripheral resistance but also causes vascular remod-  eling with narrowing and vasospasm of arteries. The SNS contributes to insulin resistance, which is associated with endo-  thelial dysfunction and decreased production of vasodilators, such as nitric oxide. The SNS also has procoagulant properties,  making vascular spasm and thrombosis more likely. All of these factors contribute to sustained increases in blood pressure.    The RAAS has multiple effects on the cardiovascular system. There are two  primary RAA systems. The best known includes the release of renin, the  synthesis of angiotensin II (Ang Il) through angiotensin-converting enzyme  (ACE), stimulation of the AT1 receptor (AT1R), and secretion of aldosterone.  Ang II causes systemic vasoconstriction and renal salt and water retention,  and stimulates tissue growth and inflammation. When present in abnormal  amounts, Ang II contributes to insulin resistance, remodeling of blood vessels,    and decreased release of endothelial vasodilators and anticoagulants. In the  heart, Ang Il and aldosterone contribute to hypertensive hypertrophy and fibro-  sis of heart muscle, decreased contractility, and an increased susceptibility to  arrhythmias and heart failure. In the kidney these hormones cause a shift in the  pressure natriuresis curve, inflammation, and glomerular remodeling and are a  major contributor to renal failure in individuals with hypertension and diabe-  tes. Drugs that block this RAAS include ACE inhibitors, direct renin inhibitors,    Ang II receptor blockers (ARBs), and aldosterone inhibitors. These medications  are used widely in managing hypertension, myocardial infarction, and heart  failure to lower blood pressure and to protect and improve cardiovascular  and renal function. In contrast, the second RAAS serves a counterregulatory  system. Activation of a second ACE pathway (ACE2) leads to the synthesis  of angiotensin 1-7 from Ang Il. Angiotensin 1-7 stimulates Mas receptors in  the brain, blood vessels, heart, kidney, gut, pancreas, and inflammatory cells  and has vasodilatory, antiproliferative, antifibrotic, and antithrombotic effects.  These protective effects lead to lower blood pressure, less vascular inflam-  mation and clotting, and decreased tissue remodeling and damage to target  organ tissues. This pathway appears to be especially important in protecting  renal tissue in those with diabetes and hypertension. Research is under way  to develop genetic and pharmacologic interventions that will stimulate these  protective RAAS pathways.    Data from Daien V et al: Am J Hypertens 25(1):126-132, 2012; Ferrario CM: ACE2: Curr Opin Nephrol Hypertens 20(1):1-6, 2011; Jia L  et al: Front Biosci 17:221-231, 2012; Patel SK et al: Am J Hypertens 25(2):216-222, 2012; Putnam K et al: Am J Physiol Heart Circ Physiol  302(6):H1219-H1230, 2012; Souza LL, Costa-Neto CML: J Cell Physiol 227(5):2117-2122, 2012; Steckelings UM et al: Exp Opin Emerging Drugs    In the healthy individual the RAAS provides an important  homeostatic mechanism for maintaining adequate blood pres-  sure and therefore tissue perfusion (see Chapter 31). In hyper-  tensive individuals, overactivity of the RAAS contributes to salt  and water retention and increased vascular resistance. High  levels of angiotensin II contribute to endothelial dysfunction,  insulin resistance, dyslipidemia, and platelet aggregation and  play an important role in the complications associated with the  metabolic syndrome.’”* Further, angiotensin II mediates arte-  riolar remodeling, which is structural change in the vessel wall  that results in permanent increases in peripheral resistance’  (see Figures 31-28 and 32-5). Angiotensin II is associated with  end-organ effects of hypertension, including atherosclerosis,  renal disease, and cardiac hypertrophy.*° Finally, aldosterone  not only contributes to sodium retention by the kidney but also  has other deleterious effects on the cardiovascular system.°!  Medications, such as angiotensin-converting enzyme (ACE)  inhibitors and angiotensin-receptor blockers (ARBs), oppose  the activity of the RAAS and are effective in reducing blood  pressure and protecting against target organ damage.°* A sec-  ond RAAS has also been described. This system uses ACE 2 to  create Ang 1-7, which has cardiovascular protective effects. Its  discovery may lead to new and more effective medications****  (see What’s New? The Renin-Angiotensin-Aldosterone System  (RAAS) and Cardiovascular Disease).   The natriuretic hormones modulate renal sodium (Na+)  excretion and require adequate potassium, calcium, and  magnesium to function properly. The natriuretic hormones  include atrial natriuretic peptide (ANP), brain natriuretic  peptide (BNP), C-type natriuretic peptide (CNP), and urodi-  latin. These hormones induce diuresis; enhancement of renal  blood flow and glomerular filtration rate, systemic vasodila-  tation, and suppression of aldosterone; and inhibition of the  SNS.*° Dysfunction of these hormones, along with alterations  in the RAA system and the SNS, cause an increase in vascular  tone and a shift in the pressure-natriuresis relationship. When    there is inadequate natriuretic function, serum levels of the  natriuretic peptides are increased. In hypertension, increased  ANP and BNP levels are linked to an increased risk for ven-  tricular hypertrophy, atherosclerosis, and heart failure.°*° Salt  retention leads to water retention and increased blood vol-  ume, which contributes to an increase in blood pressure. Sub-  tle renal injury results, with renal vasoconstriction and tissue  ischemia. Tissue ischemia causes inflammation of the kidney  and contributes to dysfunction of the glomeruli and tubules  and promotes additional sodium retention.” In addition to  increasing dietary intake of potassium, calcium, and magne-  sium in order to enhance natriuretic peptide function, a drug  that mimics the effect of one of these hormones (nesiritide)  is used to treat heart failure.°* Newer and safer agonists are  being studied.*°   As mentioned, renal inflammation contributes to sodium  retention. Inflammation also plays a role in the vascular dys-  function of hypertension. Endothelial injury and tissue ische-  mia result in the release of vasoactive inflammatory cytokines.  Although many of these cytokines (e.g., histamine, prostaglan-  dins) have vasodilatory actions in acute inflammatory injury,  chronic inflammation contributes to vascular remodeling and  smooth muscle contraction.*? Endothelial injury and dys-  function in primary hypertension is further characterized by  decreased production of vasodilators, such as nitric oxide, and  increased production of vasoconstrictors, such as endothelin.*°  Endothelin blockade has been shown to reduce blood pressure  and prevent proteinuria.*!   Obesity is recognized as an important risk factor for hyper-  tension in both adults and children and contributes to many  of the neurohumoral, metabolic, renal, and cardiovascular  processes that cause hypertension. Obesity causes changes in  what are called the adipokines (leptin and adiponectin) and is  associated with increased activity of the SNS and the RAAS.*7-4°  Obesity is linked to inflammation, small artery remodeling,  endothelial dysfunction, and insulin resistance and an increased    the classical pathway of biosynthesis that generates the renin and angiotensin |. Angio-  "4 a Smooth tensinogen is synthesized in the liver and is released into the blood where it is cleaved to    ene form angiotensin | by renin secreted by cells in the kidneys. Angiotensin-converting enzyme  Th : : eon (ACE) in the lung catalyzes the formation of angiotensin II from angiotensin I, and destroys  rombosis T Platelet aggregation migration    the potent vasodilator, bradykinin. Further cleavage generates the angiotensins III and IV.  The reddish shading shows the organs affected by angiotensin II including the brain, heart,  adrenals, kidney, and the kidney’s efferent arterioles. The dashed line (on the left) shows the  inhibition of renin by angiotensin Il. B, Summary of angiotensin II effects on blood vessel  structure and function leading to arteriosclerosis. (Redrawn from Goodfriend TL et al: N Eng/  J Med 334:2649-2654, 1996.)    Obesity is a well-known risk factor for hypertension. Adipocytes (fat cells)  secrete leptin and adiponectin. Leptin’s primary function is to interact with  the hypothalamus to control body weight and fat deposition through appe-  tite inhibition and increased metabolic rate. However, chronically high  levels of leptin associated with obesity result in resistance to these weight-    reducing functions and have been found to increase sympathetic nervous  system activity, decrease renal sodium excretion, promote inflammation,  and stimulate myocyte hypertrophy. Adiponectin is a protein that is pro-  duced by adipose tissue but is reduced in obesity. Decreased adiponectin  is associated with insulin resistance, decreased endothelial-derived nitric  oxide (vasodilator) production, and activation of the sympathetic nervous    and renin-angiotensin-aldosterone systems. Taken together, these obesity-  related changes result in vasoconstriction, salt and water retention, and  renal dysfunction that may contribute to the development of hypertension.  Obese individuals also have been found to have hypertrophic remodeling  of subcutaneous small arteries, and endothelial dysfunction in response to  acetylcholine. Microvascular dysfunction is linked to both the pathogenesis  of hypertension and hypertension-related target organ damage. Obesity also  is linked with insulin resistance, which also affects vascular function and  contributes to the development of sustained hypertension. Further studies  aimed at achieving a better understanding of these mechanisms may lead to  new treatments for obesity-related hypertension.    P et al: Microcirculation 19(1):5-18, 2012; Dorresteijn JA, Visseren FL, Spiering W: Obesity Rev 13(1):17-26, 2012; Kalil GZ,    Haynes WG: Hypertens Res 35(1):4—16, 2012; Rizzoni D et al: Basic Clin Pharmacol Toxicol 110(1):56-62, 2012.    FIGURE 32-6 Shift in the Pressure-Natriuresis Relationship. Numerous factors have been implicated in the pathogen-  esis of sodium retention in individuals with hypertension. These factors cause less renal excretion of salt than would normally  occur with increased blood pressure. This is called a shift in the pressure-natriuresis relationship and is believed to be a  central process in the pathogenesis of primary hypertension. RAAS, Renin-angiotensin-aldosterone system; SNS, sympathetic    risk for cardiovascular complications from hypertension (see  What’s New? Obesity and Hypertension).   Finally, insulin resistance is common in hypertension, even  in individuals without clinical diabetes. Insulin resistance is  associated with decreased endothelial release of nitric oxide and  other vasodilators. It also affects renal function and causes  renal salt and water retention. Insulin resistance is associated  with overactivity of the SNS and the RAAS. It is interesting to  note that in many individuals with diabetes treated with drugs  that increase insulin sensitivity, blood pressure often declines,  even in the absence of antihypertensive drugs. The interactions  between obesity, hypertension, insulin resistance, and lipid dis-  orders in the metabolic syndrome result in a high risk of cardio-  vascular disease.*®   It is likely that primary hypertension is an interaction  between many of these factors leading to sustained increases  in blood volume and peripheral resistance. The role of these  mechanisms in increasing blood volume in the pathophysiol-  ogy of primary hypertension is summarized in Figure 32-6.    Secondary Hypertension. Secondary hypertension is  caused by an underlying disease process that raises peripheral  vascular resistance or cardiac output. If the cause is identified  and removed before permanent structural changes occur,  blood pressure returns to normal. In addition, medications  are an important and often unrecognized cause of secondary  hypertension.** Table 32-3 summarizes the pathogenesis of  major forms of secondary hypertension.   Complicated Hypertension. Chronic hypertension damages  the walls of systemic blood vessels. Within the walls of arteries and  arterioles, smooth muscle cells undergo hypertrophy and hyper-  plasia with associated fibrosis of the tunica intima and media in  a process called vascular remodeling (Figure 32-7). Endothelial  dysfunction, angiotensin II, catecholamines, insulin resistance,  and inflammation contribute to this process. Once significant  fibrosis has occurred, reduced blood flow and dysfunction of  the organs perfused by these affected vessels is inevitable. Target  organs for hypertension include the kidney, brain, heart, extrem-  ities, and eyes (these effects are summarized in Table 32-4).    TABLE 32-3 PATHOGENESIS OF MAJOR FORMS OF SECONDARY HYPERTENSION BY CAUSE   Elevated intracranial pressure (brain tumor, encephalitis,  respiratory acidosis of pulmonary or central nervous  system [CNS] origin)   Surgery, psychogenic hyperventilation, hypoglycemia,  burns, pancreatitis, alcohol withdrawal, sickle cell  crisis, resuscitation, increased intravascular volume    From Cheng J et al: PLoS Pathog May 5(5), 2009. (Epub ahead of print.); Kaplan NM: Clinical hypertension, ed 8, Baltimore, 2002, Lippincott Williams &    Disturbances in filtration and reabsorption of serum sodium, potassium, and calcium initiate the  hemodynamics of early hypertension   Impaired blood flow and renal ischemia invoke the compensatory renin-angiotensin-aldosterone  mechanism in an effort to raise the renal perfusion pressure   Elevated blood renin levels invoke elevations in angiotensin and aldosterone, which causes blood  pressure to rise   Disturbances in filtration and reabsorption of serum sodium, potassium, and calcium initiate the  hemodynamics of early hypertension   Disturbance in filtration and/or reabsorption of serum sodium initiates the hemodynamics of early  hypertension   Calcium ion directly affects vascular tonicity; elevated serum calcium levels increase vascular tone  and peripheral resistance   Increased inotropic effect on the heart elevates systolic pressure; diastolic pressure decreases as a  result of decreased peripheral resistance   Glucocorticoids facilitate sodium and water retention, initiating the hemodynamics of early  hypertension    Excess aldosterone promotes sodium retention and initiation of the hemodynamics of early  hypertension    Decreased blood flow in distal areas initiates maximum peripheral resistance as an autoregulatory  effort to adjust perfusion pressure  Loss of elasticity in vessel walls results in increased peripheral resistance    Interface with neural control of blood pressure initiates increased systemic blood pressure    Unknown; possibly caused by sodium retention, plasma retention, weight gain, changes in levels and  actions of renin, angiotensin, and aldosterone    Contains glycerrhizic acid, a mineralocorticoid that causes salt and water retention  Hypertension may develop in an individual who routinely takes a monoamine oxidase (MAO) inhibitor  with ingestion of a food containing tyramine, such as aged cheese    Cardiovascular complications include left ventricular hyper-  trophy, angina pectoris, congestive heart failure (left heart fail-  ure), CAD, MI, and sudden death. Myocardial hypertrophy in  response to hypertension is mediated by several neurohormonal  substances, including the SNS and angiotensin I. Hypertrophy  is characterized by changes in the myocyte proteins, apoptosis  of myocytes, and deposition of collagen in heart muscle, which  causes it to become thickened, scarred, and less able to relax  during diastole leading to diastolic heart failure.*° In addition,  the increased size of the heart muscle increases demand for oxy-  gen delivery over time, contractility of the heart is impaired,  and the individual is at increased risk for systolic heart failure.  Vascular complications include the formation, dissection, and  rupture of aneurysms (outpouchings in vessel walls); intermit-  tent claudication; and gangrene resulting from vessel occlusion.  Renal complications are parenchymal damage, nephrosclerosis,  renal arteriosclerosis, and renal insufficiency or failure.*”   Microalbuminuria (small amounts of protein in the urine) is  an early sign of impending renal dysfunction and significantly  increased risk for cardiovascular events.**    FIGURE 32-7 Dramatic Hypertension Change in Small Arterioles. Fibrous  intimal proliferation  with reduction in lumen vessel caliber (radius) (L) and nor-  mal media (M). (From Stevens A, Lowe JS, Scott |: Core pathology, ed 3, London,    Increased workload combined with diminished blood flow  Accelerated atherosclerosis (coronary artery disease)    Changes in the vascular beds can be estimated by viewing  the arterioles of the retina. Complications specific to the retina  include retinal vascular sclerosis, exudation, and hemorrhage.*”  Cerebrovascular complications are similar to those of other  arterial beds and include transient ischemia, stroke, cerebral  thrombosis, aneurysm, and hemorrhage. Chronic hypertension  also has been linked to cognitive decline with aging.°°*7   Malignant hypertension (rapidly progressive hypertension  in which diastolic pressure is usually greater than 140 mmHg)  can cause encephalopathy. Encephalopathy occurs because  high arterial pressure renders the cerebral arterioles incapable  of regulating blood flow to the cerebral capillary beds. Capil-  lary permeability is increased by high hydrostatic pressures in  the capillaries, and vascular fluid exudes into the interstitial  space. If blood pressure is not reduced, cerebral edema and  cerebral dysfunction increase until death occurs. Organ dam-  age resulting from malignant hypertension is life threatening.  Besides encephalopathy, malignant hypertension can cause  papilledema, cardiac failure, uremia, retinopathy, and cerebro-  vascular accident.   CLINICAL MANIFESTATIONS. The early stages of hypertension  have no clinical manifestations other than elevated blood pres-  sure. Most important, the lack of signs and symptoms means  the individual is unlikely to seek health care; thus hypertension  is called a lanthanic (silent) disease. The likelihood of developing  primary hypertension increases with age, over and above the  natural rise in blood pressure associated with aging. Although  hypertension usually is thought to be an adult health problem,  it is important to remember that hypertension does occur in  children and is being diagnosed with increasing frequency. If  elevated blood pressure is not detected and treated, it becomes  established and may begin to accelerate its effect on tissues when  the individual is 30 to 50 years of age. This sets the stage for the  complications of hypertension that begin to appear during the  fourth, fifth, and sixth decades of life. The clinical manifesta-  tions of chronic hypertension tend to be specific for the organs  or tissues affected. Evidence of heart disease, renal insufficiency,   Retention of sodium and water, leading to increased blood  volume and perpetuation of hypertension    central nervous system dysfunction, impaired vision, impaired  mobility, vascular occlusion, or edema can be caused by sus-  tained hypertension. (See appropriate chapters for specific clin-  ical manifestations of organ dysfunction.)   EVALUATION AND TREATMENT. A single elevated blood pressure  reading does not mean that a person has hypertension. Diagno-  sis requires the measurement of blood pressure on at least two  separate occasions averaging two readings at least 2 minutes  apart, with the individual seated, the arm supported at heart  level, after 5 minutes rest, with no smoking or caffeine intake in  the past 30 minutes.!? Some individuals benefit from 24-hour  ambulatory blood pressure monitoring because of better cor-  relation with end-organ damage and the ability to screen out  “white coat hypertension” (elevated blood pressure that occurs  only in a clinic setting) and “masked hypertension” (normal  blood pressure in the clinic setting but elevated elsewhere).°***  Ambulatory measurement also detects those who fail to have a  nocturnal decrease in blood pressure and who may be at higher  cardiovascular risk. It is especially recommended for individu-  als with drug resistance, hypotensive symptoms with medica-  tions, episodic hypertension, and autonomic dysfunction.>*   Evaluation of the hypertensive individual should include a  complete medical history and assessment of lifestyle and other  risk factors for hypertension and cardiovascular disease, as  well as evidence of possible secondary causes of hypertension.  Physical examination should include examination of the optic    NOT AT GOAL BP  (<140/90 mmHg or <130/80 mmHg for those with  diabetes or chronic kidney disease)    fundi; calculation of body mass index; auscultation for carotid,  abdominal, and femoral bruits; examination of the heart and  lungs; palpation of the abdomen; assessment of lower extremity  pulses and edema; and neurologic examination. Further rou-  tine diagnostic tests for the evaluation of hypertension include  hematocrit, urinalysis, biochemical blood profile (fasting glu-  cose, sodium, potassium, calcium, creatinine, total cholesterol,  high-density cholesterol, triglycerides), and an electrocardio-  gram (ECG). Optional tests include urinary albumin excre-  tion or albumin/creatinine ratio. Individuals who have elevated  blood pressure are assumed to have primary hypertension  unless their history, physical examination, or initial diagnostic  screening indicates secondary hypertension.   Treatment of primary hypertension depends on its sever-  ity. Figure 32-8 illustrates an overview of the JNC7 recom-  mendations.’? Treatment begins with reducing or eliminating  risk factors. Lifestyle modification can prevent hypertension  from developing in those individuals who fall into the prehy-  pertension category, may control the blood pressure in stage  I hypertension, and can enhance the effects of drug treatment  for those with more significant blood pressure elevation. The  usual dietary recommendations are to restrict sodium intake  to 2.4 g/day, to increase potassium intake, to restrict saturated  fat intake, and to adjust calorie intake as required to maintain  optimum weight. The Dietary Approaches to Stop Hyperten-  sion (DASH) diet is recommended.°>*° Although it has been    Stage 1 hypertension  (Systolic BP 140-159 mmHg or  diastolic BP 90-99 mmHg)  Thiazide-type diuretics for most  May consider ACE inhibitor, ARB,  beta-blocker, CCB, or combination    Stage 2 hypertension  (Systolic BP =160 mmHg or  diastolic BP =100 mmHg)  Two-drug combination for most (usually  thiazide-type diuretic and ACE inhibitor  or ARB or beta-blocker or CCB)    Optimize dosages or add additional drugs until goal BP is achieved  Consider consultation with hypertension specialist    Drugs for the compelling  indications (see JNC7 report)  Other antihypertensive drugs (diuretics,  ACE inhibitor, ARB, beta-blocker, CCB)  as needed    FIGURE 32-8 Summary of Treatmentfor Hypertension. ACE, Angiotensin-converting enzyme; AAB, angiotensin-receptor  blocker; BP blood pressure; CCB, calcium channel blocker. (Data from Chobanian AV et al: JAMA 289:2560-2572, 2003.)    widely recommended since 1998, the DASH diet continues to  be studied with beneficial effects extending to reduced coronary  risks, increased insulin sensitivity, and improved lipid profiles,  especially in those with diabetes.°’? An exercise program that  promotes endurance and relaxation usually is recommended.  Physical training increases stroke volume, which has the effect  of lowering heart rate and hence systolic blood pressure, and  should consist of regular aerobic physical activity. Relaxation is  expected to reduce levels of circulating catecholamines, which  has the effect of reducing vascular tone and blood pressure.  Individuals are counseled to stop smoking to eliminate vaso-  constrictor effects of nicotine.   Pharmacologic treatment of hypertension reduces the risk of  end-organ damage and prevents major diseases, such as myo-  cardial ischemia and stroke. Thiazide diuretics and beta-blockers  have been shown to be safe and effective medications for lowering  blood pressure and preventing the cardiovascular complications  of hypertension for many individuals. However, these medica-  tions are associated with lipid disorders and glucose intoler-  ance.°* Many individuals will have “compelling indications” for  choosing a particular antihypertensive as a first-line medication.  For example, individuals with heart failure or those who have  chronic kidney disease, are postmyocardial infarction, or have  had recurrent stroke should begin antihypertensive treatment  with an ACE inhibitor, ARB, or aldosterone antagonist.'? It is  widely anticipated that the new report from the National Com-  mittee on the Prevention, Detection, Evaluation and Treatment  of High Blood Pressure (JNC8) will have a greater emphasis on  managing the RAAS in hypertension as a first-line intervention;  however, diuretics and beta-blockers will continue to be effective  choices for many individuals.°’ If a person requires two drugs  for blood pressure control, the recommendation is combina-  tions of thiazide diuretics and other antihypertensives, such as  beta-blockers and ACE inhibitors. As described on page 1133, a  new development is the use of renal denervation, which is being  investigated for the treatment of selected individuals with severe  or refractory hypertension.2>™    Orthostatic (postural) hypotension means a decrease in sys-  tolic and diastolic arterial blood pressure on standing. The  American Autonomic Society (AAS) and the American Acad-  emy of Neurology (AAN) define orthostatic hypertension as  a systolic blood pressure decrease of at least 20 mmHg or a  diastolic blood pressure decrease of at least 10 mmHg within  3 minutes of standing up. It can be categorized as arteriolar,  venular, or mixed.°! Compensatory changes during stand-  ing normally increase sympathetic activity mediated through  stretch receptors (baroreceptors) in the carotid sinus and the  aortic arch (see Chapter 31). This reflex response to shifts in  volume caused by postural changes leads to a prompt increase  in heart rate and constriction of the systemic arterioles, which  maintains a stable blood pressure. These compensatory mecha-  nisms are not effective in maintaining a stable blood pressure in  individuals with orthostatic hypotension.   Orthostatic hypotension may be acute or chronic. Acute  orthostatic hypotension (temporary type) may result from:    (1) altered body chemistry, (2) drug action (e.g., antihyper-  tensives or antidepressants), (3) prolonged immobility caused  by illness, (4) starvation, (5) physical exhaustion, (6) any con-  dition that produces volume depletion (e.g., massive diure-  sis, potassium or sodium depletion), and (7) venous pooling  (e.g., pregnancy, extensive varicosities of the lower extremi-  ties). Older adults are susceptible to this type of orthostatic  hypotension, in which postural reflexes are slowed as part of  the aging process.   Chronic orthostatic hypotension can be categorized as  (1) secondary to a specific disease, and (2) idiopathic or pri-  mary. The diseases that cause secondary orthostatic hypoten-  sion are endocrine disorders (e.g., adrenal insufficiency, diabetes  mellitus), metabolic disorders (e.g., porphyria), or diseases of the  central or peripheral nervous system (e.g., intracranial tumors,  cerebral infarcts, Wernicke encephalopathy, peripheral neu-  ropathies). Cardiovascular autonomic neuropathy is a common  cause of orthostatic hypotension in diabetes and is a serious and  often overlooked complication. Severe chronic autonomic fail-  ure may result from multiple system atrophy (MSA), in which  there are multiple central nervous system degenerative changes,  and Parkinson disease. Individuals with these disorders also may  exhibit supine hypertension, altered drug sensitivity, hyperre-  sponsiveness of blood pressure to hypo/hyperventilation, sleep  apnea, and other neurologic disturbances.°»   Idiopathic, or primary, orthostatic hypotension is the term  for hypotension in which there is no known initial cause. It  affects men more often than women and usually occurs between  the ages of 40 and 70 years. Up to 18% of the older adult popu-  lation may be affected by chronic orthostatic hypotension.*' It  is a significant risk factor for falls and associated injuries and  has been associated with an increased risk for cardiovascular  events. In addition to cardiovascular symptoms, impotence and  bowel and bladder dysfunction often are found in this type.   Orthostatic hypotension often is accompanied by dizzi-  ness, blurring or loss of vision, and syncope or fainting. To  assess hypotensive episode frequency, severity, and correlation  with symptoms, 24-hour blood pressure monitoring is rec-  ommended. No curative treatment is available for idiopathic  orthostatic hypertension. In the secondary form, postural hypo-  tension improves when the underlying disorder is corrected.  Several treatments can help acute and chronic orthostatic  hypotension, including liberalization of salt intake, raising the  head of the bed, thigh-high stockings, volume expansion with  mineralocorticoids, and vasoconstrictors such as midodrine.°!    An aneurysm is a localized dilation or outpouching ofa vessel wall  or cardiac chamber. Laplace’s law can provide an understanding  of the hemodynamics of an aneurysm (Figure 32-9). (Laplace’s  law is discussed in detail in Chapter 31.) True aneurysms involve  all three layers of the arterial wall and are best described as a weak-  ening of the vessel wall. Most are fusiform and circumferential  (Figure 32-10). False aneurysm is an extravascular hematoma  that communicates with the intravascular space. A common  cause of this type of lesion is a leak between a vascular graft and a  natural artery. Saccular aneurysms are basically spherical.    Arteriosclerosis and hypertension are found in more than __ erodes the vessel wall. Infections, such as syphilis, collagen dis-  half of all individuals with aneurysms. Chronic hyperten- orders (such as Marfan syndrome), and traumatic injury to the  sion results in mechanical and shear forces that contribute to chest or abdomen, also can cause aortic aneurysms. Genetic  remodeling and weakening of the vessel wall. Atherosclerosis susceptibilities have been identified including gene polymor-  is a common cause of aneurysms because plaque formation phisms for the production of growth factors, myosin, and    FIGURE 32-9 Pressure-Tension and Wall Thickness Relations in Blood Vessels or Cardiac Chambers (Laplace's Law).    Fusiform, circumferential Fusiform, saccular  Tuni Tunica  Tunica media  intima -  Adventitia  Lumen  Dissecting, saccular  Clot  A    FIGURE 32-10 Longitudinal Sections Showing Types of Aneurysms. A, The fusiform circumferential and fusiform  saccular aneurysms are true aneurysms, caused by weakening of the vessel wall. False and saccular aneurysms involve a  break in the vessel wall, usually caused by trauma. B, Dissecting aneurysm of thoracic aorta. (B from Damjanov I, Linder J,  editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.)    proteases. Inflammation (with the production of toxic oxygen  radicals) and changes in cytokines, such as TGF-f, activate  matrix degrading proteins and smooth muscle cell apoptosis  resulting in loss of medial elastic lamellae and thinning of the  tunica media.   Aneurysms most commonly occur in the thoracic or  abdominal aorta. The aorta is particularly susceptible to aneu-  rysm formation because of constant stress on the vessel wall  and the absence of penetrating vasa vasorum in the media layer  (Figure 32-11, A). The prevalence of abdominal aortic aneu-  rysms 2.9 to 4.9 cm in diameter ranges from 1.3% in men 45  to 54 years of age to 12.5% in men 75 to 84 years of age. For  women, the prevalence ranges from zero in the youngest to  5.2% in the oldest age group.° The prevalence of aneurysms  has decreased in men ages 65 years and older likely because of  improvements in risk factor management.°°   Formation of a ventricular wall aneurysm occurs when  intraventricular tension stretches the noncontracting infarcted  muscle (see Figure 32-11, B). The stretching produces infarct  expansion, a weak and thin layer of necrotic muscle, and  fibrous tissue that bulges with each systole. With time the  aneurysm becomes more fibrotic but continues to bulge with  each systole, thus acting as a “reservoir” for some of the stroke  volume.   Clinical manifestations depend on where the aneurysm is  located. Aneurysms in the heart present with dysrhythmias,  heart failure, and embolism of clots to the brain or other vital  organs. Aortic aneurysms often are asymptomatic until they  rupture, when they become painful. Symptoms of dysphagia  (difficulty in swallowing) and dyspnea (breathlessness) are  caused by the pressure of a thoracic aneurysm on surrounding  organs. An abdominal aneurysm can impair flow to an extrem-  ity and cause symptoms of ischemia. Aneurysms that occur  elsewhere in the body have variable symptoms and signs related  to the size of the aneurysm and the potential for rupture and  hemorrhage.    FIGURE 32-11 Aneurysms. A, Abdominal aortic atherosclerotic aneurysm. B, A three dimensional CT scan shows the    The diagnosis of an aneurysm is usually confirmed by ultra-  sonography, CT, MRI, or angiography. The goals of medical  treatment of aneurysms are to maintain a low blood volume  and low blood pressure to decrease mechanical forces thought  to contribute to vessel wall dilation. Medical treatment is  indicated for slow-growing aortic aneurysms, particularly in  early stages, and includes smoking cessation, reducing blood  pressure and blood volume, and f-adrenergic blockage.“ For  those aneurysms that are dilating rapidly, surgical treatment  often is indicated. Surgery or endovascular repair should be  done when aortic aneurysms reach 5 cm in diameter. The  risk for eventual rupture approaches 20% for abdominal aor-  tic aneurysms greater than 5 cm, and greater than 50% for  aneurysms more than 7 cm in diameter.’ New endovascular  surgical techniques with placement of a stent make aneurysm  repair possible even in those individuals with acute symptoms  or complications.°°   Aortic aneurysms can be complicated by the acute aortic  syndromes that include aortic dissection, hemorrhage into the  vessel wall, or vessel rupture. Aortic dissection is a devastat-  ing complication that can involve any part of the aorta (ascend-  ing, arch, or descending) and can disrupt flow through arterial  branches, thus creating a surgical emergency. Dissection of  the layers of the arterial wall occurs when there is a tear in the  intima and blood enters the wall of the artery (see Figure 32-10).  This occurs most commonly when there is trauma to the aorta  or when there is tissue ischemia and necrosis at the edge of an  atherosclerotic plaque that weakens the intima. Persistent  chronic hypertension and inflammation contribute to further  degradation of the vessel wall with fibrotic obstruction of ves-  sels that feed the arterial wall. Emergent evaluation and surgical  intervention are indicated.°’    As in venous thrombosis, arterial thrombi tend to develop  wherever intravascular conditions promote activation of the    aneurysm. (A) involves the ascending thoracic aorta. D, descending aorta; LY, left ventricle. (A from Damjanov I, Linder J,    coagulation, or clotting, cascade. These conditions include inti-  mal irritation and roughening, inflammation, traumatic injury,  infection, and low blood pressures or obstructions that cause  blood stasis and pooling within the vessels. (Mechanisms of  coagulation are described in Chapter 27.) In the arteries, acti-  vation of the coagulation cascade usually is caused by rough-  ening of the tunica intima by atherosclerosis. Invasion of the  tunica intima by an infectious agent also roughens the nor-  mally smooth lining of the artery, causing platelets to adhere  readily. Anatomic changes of an artery (such as an aneurysm)  can stimulate thrombus formation, particularly if the change  results in pooling of arterial blood. Thrombi form also on heart  valves altered by calcification or bacterial vegetation. Valvular  thrombi are associated most commonly with inflammation of  the endocardium (endocarditis) and rheumatic heart disease.   Widespread arterial thrombus formation can occur in shock,  particularly shock resulting from septicemia. In septic shock, sys-  temic inflammation activates the intrinsic and extrinsic pathways  of coagulation resulting in microvascular thrombosis through-  out the systemic arterial circulation (see Chapters 29 and 48).   Arterial thrombi pose two potential threats to the circula-  tion. First, the thrombus may grow large enough to occlude the  artery, causing ischemia in tissue supplied by the artery. Second,  the thrombus may dislodge, becoming a thromboembolus that  travels through the vascular system until it occludes flow into a  distal systemic vascular bed.   Diagnosis of arterial thrombi is usually accomplished  through the use of Doppler ultrasonography and angiography.  Pharmacologic treatment involves the administration of hepa-  rin, warfarin derivatives, thrombin inhibitors, or thrombolyt-  ics. A balloon-tipped catheter also can be used to remove or  compress an arterial thrombus. Various combinations of drug  and catheter therapies are sometimes used concurrently.    Embolism is the obstruction of a vessel by an embolus—a  bolus of matter that is circulating in the bloodstream. The  embolus may consist of a dislodged thrombus; an air bubble;  an aggregate of amniotic fluid; an aggregate of fat, bacteria, or  cancer cells; or a foreign substance. An embolus travels in the  bloodstream until it reaches a vessel through which it cannot  fit. No matter how tiny it is, an embolus eventually will lodge  in a systemic or pulmonary vessel. The source of the embolus  determines whether the embolus will lodge in a vessel of the  pulmonary or systemic circulation. Pulmonary emboli origi-  nate in the venous circulation (mostly from the deep veins of  the legs) or in the right heart (see p. 1275). Arterial emboli most  commonly originate in the left heart and are associated with  thrombi after MI, valvular disease, left heart failure, endocardi-  tis, and dysrhythmias.   Embolism causes ischemia or infarction in tissues distal  to the obstruction. A limb that is ischemic because of arterial  occlusion is characterized (1) by an almost waxy whiteness of  the skin because the vasculature is devoid of erythrocytes, and  (2) by numbness and pain resulting from neural ischemia.   Embolism to a central organ causes organ dysfunction and  pain. For example, pulmonary artery embolism causes chest    pain and dyspnea; renal artery embolism causes abdominal pain  and oliguria; and mesenteric artery embolism causes abdomi-  nal pain and a paralytic, ischemic bowel. In the coronary, cere-  bral, and peripheral arterial systems, embolism may occur as a  result of rupture or mechanical disruption of an atherosclerotic  plaque. This phenomenon is sometimes referred to as choles-  terol embolization syndrome or atheroembolism.®°? Embo-  lism to a coronary or cerebral artery is an immediate threat to  life if the embolus severely obstructs a major vessel. Occlusion  of a coronary artery causes an MI (see p. 1157), whereas occlu-  sion of a cerebral artery causes a stroke (see Chapter 18).   Infarction and subsequent necrosis of a central organ are  life threatening, not only because of organ dysfunction but  also because of sepsis. Necrotic tissue is a rich medium for the  growth of bacteria from the lungs, bowel, and occasionally,  bladder, and can quickly lead to septicemia.    Thromboembolism is a vascular obstruction resulting from  a dislodged thrombus. The most common source of arterial  thromboemboli to the systemic circulation is the heart. Mitral  or aortic valvular disease, especially that associated with abnor-  mal heart rhythms (atrial fibrillation and flutter), causes throm-  bus formation on roughened vascular surfaces and in atrial  blood as a result of stasis. More than half of these thromboem-  boli lodge in the lower extremities (in the femoral and popliteal  arteries). Others lodge in the coronary arteries and the cerebral  vasculature. Heart failure also is associated with an increased  risk of thrombotic complications, although the mechanism for  this increased risk is unclear.    Room air that enters the circulation through intravenous lines  is probably the most common cause of air embolism. Room air  is about 70% nitrogen. Although nitrogen dissolves quickly in  blood, large amounts of air cannot be dissolved rapidly enough  to prevent the displacement of blood in the arterioles and capil-  lary beds. Ischemia and necrosis occur when air totally blocks  a vessel.   Air also can be introduced into the bloodstream if trauma  to the chest causes air from the lungs to enter the vascular  space. For example, gunshot wounds and puncture wounds of  the thorax sometimes introduce air emboli. Treatment for air  embolism is supportive, including bed rest and supplemental  oxygen, once the connection between the source of air and the  vascular system is eliminated.    The great intra-abdominal pressures generated during labor  and delivery may force amniotic fluid into the mother’s  bloodstream through the highly vascular uterine wall. Amni-  otic fluid not only displaces blood, reducing oxygen, nutri-  ent, and waste exchange, but also introduces antigens, cells,  and protein aggregates that trigger inflammation, coagulation,  and the immune response within the bloodstream. Capillary  beds usually are affected by amniotic fluid emboli, especially  the capillary beds of the lungs and kidneys. Treatment is    supportive and may include dialysis, particularly after a cesar-  ean delivery or hysterectomy.    Isolated bacteria in the bloodstream do not cause embolism,  but aggregates of bacteria may be large enough to do so. The  most common cause of bacterial embolism is subacute bacterial  endocarditis, during which clumps of vegetation are dislodged  from infected cardiac valves and ejected into the pulmonary  or systemic circulation. A less common cause is erosion of an  artery or vein by bacteria at a source of infection, such as an  abscess. Treatment for bacterial embolism includes bed rest,  supplemental oxygen, and antibiotics to eradicate the source of  infection.    Trauma to the long bones is associated with fat embolism,  particularly in the lungs. Two mechanisms have been pro-  posed to account for the generation of fat emboli after skeletal  trauma. The first is that trauma to the bones initiates defective  fat metabolism, causing globules of fat to form in the blood.  Platelets adhere to these globules until the conglomerate is large  enough to lodge in a capillary bed. The second possible explana-  tion is that globules of fat are released from fatty bone marrow  exposed by fracture. Again, platelets adhere to the fat globules,  and embolism occurs.   Treatment for fat embolism consists of prompt immobiliza-  tion of fractures and supportive measures that include admin-  istration of supplemental oxygen, steroids, and glucose. Steroid  administration may decrease the inflammation that occurs with  vascular occlusion. Inflammation in the pulmonary bed is espe-  cially dangerous because it can cause acute respiratory distress  syndrome (ARDS) (see Chapter 35).    Foreign matter can enter the bloodstream during trauma or  through an intravenous or intra-arterial line. Small particles,  such as drug precipitates, small glass shards, or fibers from  linen, are sometimes introduced unintentionally into a vessel  through intravenous injections or manipulation of monitor-  ing lines. Once in the blood, these small particles initiate the  coagulation cascade. The thromboemboli that form around the  particles are large enough to occlude a vessel and result in ische-  mia. Treatment is aimed at preventing thrombus formation  around the particle, dissolution of the particle, and supportive  measures to alleviate ischemia. If the bolus of foreign matter is  relatively large, it usually is removed surgically.   Thromboangiitis Obliterans (Buerger Disease)  Thromboangiitis obliterans (Buerger disease) is an inflamma-  tory disease of the peripheral arteries. It is associated with smok-  ing in approximately 95% of cases—the other 5% are related  to frostbite, trauma, or the use of sympathomimetic drugs.”?  The incidence of Buerger disease has been steadily declin-  ing, presumably because of a decrease in cigarette smoking in  men. Inflammatory lesions are accompanied by thrombi and    sometimes by vasospasm of arterial segments. The pathogen-  esis of thromboangiitis obliterans is still being explored. There  is evidence of significant T-cell activation and autoimmunity, as  well as a lack of appropriate production of endothelial precur-  sor cells in the bone marrow.’! Inflammation, thrombus for-  mation, and vasospasm eventually can occlude and obliterate  portions of small and medium-size arteries. Typically affected  are the digital, tibial, and plantar arteries of the feet and the  digital, palmar, and ulnar arteries of the hands.   The chief symptoms of thromboangiitis obliterans are pain  and tenderness of the affected part. Clinical manifestations are  caused by sluggish blood flow and include rubor (redness of the  skin), which is caused by dilated capillaries under the skin, and  cyanosis, which is caused by blood that remains in the capillar-  ies after its oxygen has diffused into the interstitium. Chronic  ischemia causes the skin to thin and become shiny and the nails  to become thickened and malformed. In advanced disease,  ischemia resulting from vessel obliteration can cause gangrene,  which may require amputation.   There are five primary criteria for the diagnosis of Buerger  disease: (1) onset before age 50; (2) history of tobacco use; (3)  ischemia of the digits; (4) typical arteriographic findings; and  (5) exclusion of autoimmune disease, thrombophilia, diabe-  tes, and proximal embolic source.’? The most important part  of treatment is cessation of cigarette smoking. All other mea-  sures are aimed at improving circulation to the foot or hand  and include exercise and dependent positioning to improve  circulation, vasodilators to alleviate vasospasm, and antithrom-  botics to prevent thrombus formation. If vasospasm persists,  sympathectomy may be performed. Newer therapies include  immunomodulation, spinal cord stimulation, and bone mar-  row transplantation.”°”    Raynaud phenomenon and Raynaud disease are characterized  by attacks of vasospasm in the small arteries and arterioles of  the fingers and, less commonly, the toes. Although the clini-  cal manifestations of the phenomenon and the disease are the  same, their causes differ.   Raynaud phenomenon is secondary to systemic diseases,  such as collagen vascular disease (e.g., scleroderma), chemo-  therapy, cocaine use, hypothyroidism, pulmonary hyperten-  sion, thoracic outlet syndrome, serum sickness, vasculitis,  malignancy, or long-term exposure to environmental condi-  tions, such as cold or vibrating machinery in the workplace.  Raynaud phenomenon associated with malignancy can be espe-  cially severe and is an important clue to finding a previously  undiagnosed cancer.”*   Raynaud disease is a primary vasospastic disorder of  unknown origin. Blood vessels in affected individuals dem-  onstrate endothelial dysfunction with an imbalance in  endothelium-derived vasodilators (e.g., nitric oxide) and vaso-  constrictors (e.g., endothelin-1). Platelet activation also may  play a role. It tends to affect young women and to consist of  vasospastic attacks triggered by brief exposure to cold or by  emotional stress. Genetic predisposition may play a role in its  development.    The clinical manifestations of the vasospastic attacks of either  disorder are changes in skin color and sensation caused by ische-  mia. Vasospasm occurs with varying frequency and severity and  causes pallor, numbness, and the sensation of cold in the digits.  Attacks tend to be bilateral, and manifestations usually begin  at the tips of the digits and progress to the proximal phalanges.  Sluggish blood flow resulting in ischemia may cause the skin to  appear cyanotic. Rubor follows as vasospasm ends and the cap-  illaries become engorged with oxygenated blood. Rubor often is  accompanied by throbbing and paresthesias. Skin color returns  to normal after the attack, but frequent, prolonged attacks inter-  fere with cellular metabolism, causing the skin of the fingertips  to thicken and the nails to become brittle. In severe, chronic  Raynaud phenomenon or disease, ischemia eventually can cause  ulceration and gangrene. This outcome is rare, however.   The diagnostic criteria for Raynaud disease include not  only the characteristic clinical manifestations described previ-  ously but also the absence of necrosis, no detectable underlying  cause, normal capillaroscopy findings, normal laboratory tests  for inflammation, and negative tests for antinuclear factors.”*   Treatment for Raynaud phenomenon consists of remov-  ing the stimulus or treating the primary disease process. When  Raynaud phenomenon is associated with malignancy, surgical  removal of the tumor may resolve the ischemia. For Raynaud  phenomenon not associated with malignancy, treatment is  limited to amelioration of symptoms with arm exercises and  medications, such as calcium channel blockers, alpha-blockers,  prostaglandin analogs, or endothelin antagonists.”   Treatment of Raynaud disease is limited to prevention or  alleviation of vasospasm itself, because no underlying disorder  has been identified. Stimuli that trigger attacks (e.g., emotional  stress, cold) are avoided, and cigarette smoking is stopped to  eliminate the vasoconstricting effects of nicotine. Exercises that  build centrifugal force in the extremities also are helpful in the  early stages of vasospasm. If attacks of vasospasm become fre-  quent or prolonged, pharmacologic management can include  calcium channel blockers, nitric oxide agonists, alpha-blockers,  prostaglandin analogs, and selective serotonin reuptake inhibi-  tors. Biofeedback may be helpful.”> Sympathectomy may be  recommended in severe cases but is not always effective and has  a high rate of recurrence.’° If ischemia leads to ulceration and  gangrene, amputation is necessary.    Atherosclerosis is a form of arteriosclerosis in which thicken-  ing and hardening of the vessel are caused by the accumulation  of lipid-laden macrophages within the arterial wall, which leads  to the formation of a lesion called a plaque. Atherosclerosis  is not a single disease but rather a pathologic process that can  affect vascular systems throughout the body, resulting in ische-  mic syndromes that can vary widely in their severity and clinical  manifestations. It is the leading cause of coronary artery and  cerebrovascular disease. (Atherosclerosis of the coronary arter-  ies is described on p. 1148; atherosclerosis of the cerebral arter-  ies is discussed in Chapter 18.)   PATHOPHYSIOLOGY. Atherosclerosis is an inflammatory disease  that develops and proceeds in the presence of elevated plasma    cholesterol levels.’” Both innate and adaptive immunity play  a role in the development and progression of atherosclerotic  lesions.’”® Pathologically, the lesions progress from endothe-  lial injury and dysfunction to fatty streak to fibrotic plaque  to complicated lesion (Figures 32-12 and 32-13). Atheroscle-  rosis begins with injury to the endothelial cells that line artery  walls. Possible causes of endothelial injury include the com-  mon risk factors for atherosclerosis, such as smoking, hyper-  tension, diabetes, increased levels of low-density lipoprotein  (LDL), decreased levels of high-density lipoprotein (HDL), and  autoimmunity.’?*° Other causes of endothelial injury include  inflammatory factors that are being explored as nontraditional  cardiovascular risk factors, such as elevated C-reactive protein  (CRP), increased serum fibrinogen, infection, and periodontal  disease. These risk factors are discussed in more detail in the fol-  lowing section on coronary artery disease (see p. 1148). Recent  evidence indicates that individuals with a defect in the produc-  tion of precursor endothelial cells in the bone marrow are at  greater risk for atherosclerotic disease because these precursor  cells are not available to repair injured endothelium.*!   Once injury has occurred, endothelial dysfunction and  inflammation lead to the following pathophysiologic events:   make normal amounts of antithrombotic and vasodilat-  ing cytokines (see Figure 31-23).   2. Numerous inflammatory cytokines are released, includ-  ing tumor necrosis factor-alpha (TNF-a), interferon-  gamma (IFN-y), interleukin-1 (IL-1), toxic oxygen  radicals, CRP, and heat shock proteins.   3. Macrophages adhere to injured endothelium by way of  adhesion molecules, such as vascular cell adhesion mol-  ecule-1 (VCAM-1).   4, These macrophages then release enzymes and toxic oxy-  gen radicals that create oxidative stress, oxidize LDL, and  further injure the vessel wall.   5. Growth factors also are released, including angiotensin  Il, fibroblast growth factor, TGF-f, and platelet-derived  growth factor, which stimulate smooth muscle cell prolif-  eration in the affected vessel.   LDL penetrates into the subintima of arterial walls, where  it is trapped by proteoglycans. Inflammation, oxidative stress,  and activation of macrophages cause the aggregated LDL to  become oxidized (see Figure 32-13). Diabetes, smoking, and  hypertension (especially with increased levels of angiotensin I)  contribute to increased LDL oxidation. Oxidized LDL is toxic  to endothelial cells and causes smooth muscle proliferation.  Oxidized LDL also increases endothelial adhesion molecule  expression, which recruits more monocyte/macrophages that  penetrate the vessel wall. Several types of receptors on these  macrophages (Toll-like receptors [TLRs], LDL receptor-related  protein [LRP]) enable detection and engulfment of the LDL,  which contributes to activation of additional innate and adap-  tive immune responses.***? Macrophages filled with oxidized  LDL are called foam cells (see Figure 32-13).   Once these lipid-laden foam cells accumulate in significant  amounts, they form a lesion called a fatty streak (see Figure  32-12). These lesions can be found in the walls of arteries of most    FIGURE 32-12 Progression of Atherosclerosis. A, Damaged endothelium. B, Diagram of fatty streak and lipid core for-  mation (see Figure 32-13 for a diagram of oxidized low-density lipoprotein [LDL]). C, Diagram of fibrous plaque. Raised plaques  are visible: some are yellow; others are white. D, Diagram of complicated lesion; thrombus is red; collagen is blue. Plaque is  complicated by red thrombus deposition.    FIGURE 32-13 Low-Density Lipoprotein Oxidation. (1) Low-density lipoprotein (LDL) enters the arterial intima through  an intact endothelium. In hypercholesterolemia, the influx of LDL exceeds the eliminating capacity and an extracellular pool  of LDL is formed. This is enhanced by association of LDL with the extracellular matrix. (2) Intimal LDL is oxidized through the  action of free oxygen radicals formed by enzymatic or nonenzymatic reactions. (3) This generates proinflammatory lipids that  induce endothelial expression of the adhesion molecule; vascular cell adhesion molecule-1 activates complement and stimu-  lates chemokine secretion. All of these factors cause adhesion and entry of mononuclear leukocytes, particularly monocytes  and T lymphocytes. (4) Monocytes differentiate into macrophages. Macrophages up-regulate and internalize oxidized LDL and  transform into foam cells. Macrophage update of oxidized LDL also leads to presentation of fragments of it to antigen-specific  T cells. (5) This induces an autoimmune reaction that leads to production of proinflammatory cytokines. Such cytokines include  interferon-gamma, tumor necrosis factor-alpha, and interleukin-1, which act on endothelial cells to stimulate expression of  adhesion molecules and procoagulant activity; on macrophages to activate proteases, endocytosis, nitric oxide (NO), and  cytokines; and on smooth muscle cells (SMCs) to include NO production and inhibit growth, collagen, and actin expression.    (Modified from Crawford MH, DiMarco JP, Paulus WJ: Cardiology, ed 3, London, 2010, Mosby.)    people, even young children. Once formed, fatty streaks produce  more toxic oxygen radicals and cause immunologic and inflam-  matory changes, resulting in progressive damage to the vessel wall.  At this point, smooth muscle cells proliferate, produce collagen,  and migrate over the fatty streak forming a fibrous plaque (see  Figure 32-12). This process is mediated by many inflammatory  cytokines, including growth factors (e.g., TGF-B).** The fibrous  plaque may calcify, protrude into the vessel lumen, and obstruct  blood flow to distal tissues, especially during exercise, which may  cause symptoms (e.g., angina or intermittent claudication).  Many plaques, however, are “unstable,” meaning they are  prone to rupture even before they affect blood flow and are clini-  cally silent until they rupture. Plaque rupture occurs because of  the inflammatory activation of proteinases (matrix metallopro-  teinases and cathepsins), apoptosis of cells within the plaque, and  bleeding within the lesion (plaque hemorrhage).*? Plaques that  have ruptured are called complicated plaques (see Figure 32-12).  Once rupture occurs, exposure of underlying tissue results in plate-  let adhesion, initiation of the clotting cascade, and rapid thrombus  formation that may suddenly occlude the affected vessel, resulting  in ischemia and infarction. Aspirin or other antithrombotic agents  are used to prevent this complication of atherosclerotic disease.  CLINICAL MANIFESTATIONS. Atherosclerosis presents with symp-  toms and signs that result from inadequate tissue perfusion    because of obstruction of the vessels that supply them. Partial  vessel obstruction may lead to transient ischemic events, often  associated with exercise or stress. Once the lesion becomes com-  plicated, increasing obstruction with superimposed thrombosis  may result in tissue infarction. CAD caused by atherosclerosis is  the major cause of myocardial ischemia and is one of the most  important health issues in the United States. Atherosclerotic  obstruction of the vessels supplying the brain is the major cause  of stroke. Similarly, any part of the body may become isch-  emic when its blood supply is compromised by atherosclerotic  lesions. Often more than one vessel is involved with this disease  process; consequently, an individual may present with symp-  toms from several ischemic tissues at the same time, and disease  in one area may indicate that the individual is at risk for other  ischemic complications elsewhere.   EVALUATION AND TREATMENT. In evaluating individuals for the  presence of atherosclerosis, a complete health history (includ-  ing risk factors and symptoms of ischemia) is essential. Physical  examination may reveal arterial bruits and evidence of decreased  blood flow to tissues. Laboratory tests include measurement of  lipids, blood glucose, and high sensitivity CRP (hs-CRP). Judi-  cious use of x-ray films, electrocardiography, ultrasonography,  nuclear scanning, CT, MRI, and angiography may be necessary  to identify affected vessels, particularly coronary vessels. New    modalities aimed at identifying vulnerable plaques before the  rupture are being evaluated.*°   Current management of atherosclerosis is focused on  detecting and treating preclinical lesions with drugs aimed at  stabilizing and reversing plaques before they rupture.*” Once a  lesion obstructs blood flow, the primary goal in managing ath-  erosclerosis is to restore adequate blood flow to the affected  tissues. If an individual has presented with acute ischemia  (e.g., MI, stroke), interventions are specific to the diseased  area and are discussed further under those topics. In situa-  tions in which the disease process does not require immediate  intervention, management focuses on reducing risk factors,  removing the initial causes of vessel damage, and preventing  lesion progression. This includes exercise, smoking cessation,  and control of hypertension and diabetes when appropriate  while reducing LDL cholesterol by diet or medications or  both. (Management of atherosclerotic risk factors is discussed  further starting on p. 1154.)    Peripheral artery disease (PAD) refers to atherosclerotic dis-  ease of arteries that perfuse the limbs, especially the lower  extremities. PAD affects approximately 8 to 12 million Ameri-  cans, 12% to 20% of whom are 65 years of age or older, and is  associated with significant morbidity and mortality. Prevalence  increases with age, and PAD disproportionately affects blacks.°  The risk factors for PAD are the same as those for atheroscle-  rotic disease, and it is especially prevalent in individuals who  smoke and those with diabetes. PAD is a significant predictor  of systemic atherosclerotic disease such that those with docu-  mented PAD have nearly double the risk of coronary artery dis-  ease than those without.   Lower-extremity ischemia, resulting from arterial obstruc-  tion in PAD, can be gradual or acute. In most individuals grad-  ually increasing obstruction to arterial blood flow to the legs  caused by atherosclerosis in the iliofemoral vessels results in  pain with ambulation called intermittent claudication. How-  ever, only 10% of people with PAD have the classic symptom  of intermittent claudication, and 40% do not complain of leg  pain.° If a thrombus forms over the atherosclerotic lesion, per-  fusion can cease acutely with severe pain, loss of pulses, and skin  color changes in the affected extremity.   Evaluation for PAD requires a careful history and physi-  cal examination that focuses on looking for evidence of ath-  erosclerotic disease (e.g., bruits), ankle-brachial index, and  noninvasive Doppler measurement of blood flow. Treat-  ment includes risk factor reduction (smoking cessation and  treatment of diabetes, hypertension, and dyslipidemia) and  antiplatelet therapy. Symptomatic PAD should be managed  with vasodilators in combination with antiplatelet or anti-  thrombotic medications (aspirin, cilostazol, ticlopidine, or  clopidogrel), cholesterol-lowering medications, and exer-  cise rehabilitation.** If acute or refractory symptoms occur,  emergent percutaneous or surgical revascularization may be  indicated. Newer treatment modalities that are being explored  include autologous stem cell therapies, gene therapy, and  angiogenesis.°””0    FIGURE 32-14 Atherosclerosis. A, Concentric coronary plaque. The lumen is  central. Multiple new small blood vessels are shown within the plaque, the late  result of disruption. B, Cell types in a fibrolipid plaque. The plaque cap (brownish)  contains numerous elongated smooth muscle cells; some contain lipid. Macro-  phages are clustered on the edge of the core. (From Damjanov |, Linder J, editors:  Andersons pathology, ed 10, St Louis, 1996, Mosby.)    CAD, myocardial ischemia, and MI form a pathophysiologic  continuum that impairs the pumping ability of the heart by  depriving the heart muscle of blood-borne oxygen and nutri-  ents. The earliest lesions of the continuum are those of coronary  artery disease (CAD) which occludes the coronary arteries. By  far the most common cause of coronary artery obstruction is  atherosclerosis (Figure 32-14). CAD can diminish the myocar-  dial blood supply until deprivation impairs myocardial metab-  olism enough to cause ischemia, a local state in which the cells  are temporarily deprived of blood supply. They remain alive  but cannot function normally. Persistent ischemia or the com-  plete occlusion of a coronary artery causes acute coronary syn-  drome. Infarction (irreversible myocardial injury) constitutes  the often-fatal event known as a heart attack.    The American Heart Association estimates that approximately 7%  of the U.S. population older than age 20 years has CAD, resulting  in approximately 610,000 new and 325,000 recurrent heart attacks  each year (one every 25 seconds) causing 1 of every 6 deaths.°    Data from Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults, JAMA 285:2486-2497, 2001.    Risk factors for CAD are the same as those for atheroscle-  rosis and can be categorized as conventional (major) versus  nontraditional (novel) and modifiable versus nonmodifiable.  Much new information has been obtained about the conven-  tional risk factors that has markedly improved the prevention  and management of CAD.’! In addition, the more recently  identified nontraditional risk factors have provided insight in  to the pathogenesis of CAD and may lead to more effective  interventions.   Conventional or major risk factors for CAD that are non-  modifiable include: (1) advanced age, (2) male gender or women  after menopause, and (3) family history. Aging and menopause  are associated with increased exposure to risk factors and poor  endothelial healing. Family history may contribute to CAD  through genetics and shared environmental exposures. Many  gene polymorphisms have been associated with CAD and its  risk factors.”* Blood type also has been linked to cardiovascular  risk, with type O associated with the lowest risk and type AB the  highest.?°   Major modifiable conventional risks include: (1) dyslipid-  emia, (2) hypertension, (3) cigarette smoking, (4) diabetes and  insulin resistance, (5) obesity, (6) sedentary lifestyle, and (7) an  atherogenic diet. In individuals with known CAD, the majority  have the growing epidemic of obesity in the United States. If  individuals receive appropriate preventive care, modification of  these factors can significantly reduce the risk for CAD. Of great  concern is the finding that exposure to particulate matter air  pollution is associated with an increase in myocardial infarction  risk and air pollution is a worsening global problem.”*   Dyslipidemia. The link between CAD and elevated plasma  lipoprotein concentrations is well documented.° The term  lipoprotein refers to lipids, phospholipids, cholesterol, and  triglycerides bound to carrier proteins. Lipids (cholesterol in  particular) are required by most cells for the manufacture and  repair of plasma membranes. Cholesterol is also a necessary  component for the manufacture of such essential substances  as bile acids and steroid hormones. Although cholesterol can  easily be obtained from dietary fat intake, most body cells also  can manufacture cholesterol.   The cycle of lipid metabolism is complex. Dietary fat is  packaged into particles known as chylomicrons in the small  intestine. Chylomicrons are required for absorption of fat; they  function by transporting exogenous lipid from the intestine to  the liver and peripheral cells. Chylomicrons are the least dense  of the lipoproteins and primarily contain triglyceride. Some of  the triglyceride may be removed and either stored by adipose  tissue or used by muscle as an energy source. The chylomicron    remnants, composed mainly of cholesterol, are taken up by the  liver. A series of chemical reactions in the liver results in the  production of several lipoproteins that vary in density and func-  tion. These include very-low-density lipoproteins (VLDLs),  primarily triglyceride and protein; low-density lipoproteins  (LDLs), mostly cholesterol and protein; and high-density lipo-  proteins (HDLs), mainly phospholipids and protein.   Dyslipidemia (or dyslipoproteinemia) refers to abnormal  concentrations of serum lipoproteins as defined by the Third  Report of the National Cholesterol Education Program (Table  32-5). It is estimated that nearly half of the U.S. population  has some form of dyslipidemia, especially among white and  Asian populations.” These abnormalities are the result of a  combination of genetic and dietary factors. Primary or famil-  ial dyslipoproteinemias result from genetic defects that cause  abnormalities in lipid-metabolizing enzymes and abnormal  cellular lipid receptors (Table 32-6). Secondary causes of dys-  lipidemia include several common systemic disorders, such as  diabetes, hypothyroidism, pancreatitis, and renal nephrosis, as  well as the use of certain medications such as certain diuretics,  beta-blockers, glucocorticoids, interferons, and antiretrovirals.   An increased serum concentration of LDL is a strong indi-  cator of coronary risk. LDL is responsible for the delivery of  cholesterol to the tissues. Serum levels of LDL are normally  controlled by hepatic receptors for LDL that bind LDL and limit  liver synthesis of this lipoprotein. High dietary intake of choles-  terol and fats, often in combination with a genetic predisposi-  tion to accumulations of LDL in the serum (e.g., dysfunction of  the hepatic LDL receptor), results in high levels of LDL in the  bloodstream. LDL oxidation, migration into the vessel wall, and  phagocytosis by macrophages are key steps in the pathogene-  sis of atherosclerosis (see p. 1145 and Figure 32-13). LDL also  plays a role in endothelial injury, inflammation, and immune  responses that have been identified as being important in ath-  erogenesis.’”? The term LDL actually describes several types of  LDL molecules. Measurement of LDL subfractions allows for  better prediction of coronary risk. For example, LDL-C mea-  surements allow for detection of the small dense LDL particles  that are the most atherogenic, and apolipoprotein B (structural  protein found in both LDL and VLDL) levels are a very strong  predictor of future coronary events.”°   Low levels of HDL cholesterol also are a strong indicator of  coronary risk. HDL is responsible for “reverse cholesterol trans-  port,” which returns excess cholesterol from the tissues to the  liver, where it binds to hepatic receptors (including the LDL  receptor) and is processed and eliminated as bile or converted  to cholesterol-containing steroids.”” Recent evidence shows that    HDL can remove excess cholesterol from the arterial wall through  several pathways, including mediating the efflux of cholesterol  from lipid-laden macrophages (foam cells) through the activa-  tion of adenosine triphosphate (ATP)—binding cassette trans-  porter proteins (ABC proteins).”* This discovery has resulted in    the initiation of a whole new area of pharmacologic investigation  into optimizing HDL function. HDL also participates in endothe-  lial repair and decreases thrombosis. As HDL cholesterol is trans-  ported, it progresses through three subtypes of HDL: pre-B HDL,  HDL3, and HDL2. Apolipoprotein (ApoA-I) on the pre-f HDL    IDL, Intermediate-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.  aCholestyramine (Questran), anion exchange resin; binds bile acids; enhances cholesterol excretion.   ’Colestipol (Colestid), same as cholestyramine.  °Lovastatin, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor; decreases cholesterol synthesis in the liver.    4Nicotinic acid (niacin), decreases release of free fatty acids from adipose tissue; increases lipogenesis in liver; decreases glucagon release; most    ‘Clofibrate (Atromid-S), decreases release of free fatty acids from adipose tissue; decreases hepatic secretion of VLDL and increases catabolism of    3Gemfibrozil (Lopid), similar to clofibrate but increases HDLs more.  Estrogens, decrease IDL levels in type III disorders; experimental.  ‘Progesterone, decreases plasma triglycerides in type V disorders; experimental.    binds cholesterol where it is converted to cholesteryl ester creating  HDL3. HDL3 then increases in size to form HDL2, which is fully  loaded with cholesterol. The smaller HDL3 molecule is the most  protective in preventing atherosclerosis, and research continues  to explore the best approach to increasing this type of HDL.”   Despite the wealth of evidence that HDL plays an important  role in preventing atherosclerotic coronary disease, studies have  suggested that raising overall levels of HDL is not adequate to  prevent cardiovascular disease. A study of individuals who have  a rare genetic trait that increases their HDL levels dramatically  failed to show any reduced cardiovascular risk in that popu-  lation.”? Furthermore, niacin and fibrates are drugs that can  cause modest increases in HDL, but are not correlated with an  improvement in cardiovascular risk in individuals without doc-  umented coronary disease (primary prevention) (see What’s  New? Controversies in the Use of Medications for the Primary  Prevention of Cardiovascular Disease). Drugs that are being  developed are aimed specifically at increasing HDL and include  recombinant apolipoprotein A-I (ApoA-I) mimetics, thiazoli-  dinediones (used to treat diabetes), and cholesteryl ester trans-  fer protein inhibitors, although their effectiveness in preventing  heart disease and their safety are still being evaluated.!° At pres-  ent, experts recommend exercise, weight loss, fish oil consump-  tion, and moderate alcohol to increase HDL levels.   Other lipoproteins associated with increased cardiovascular  risk include elevated serum VLDL (triglycerides) and increased  lipoprotein (a). Triglycerides are associated with an increased  risk for CAD, especially in combination with other risk factors  such as diabetes.'°! Because of this, the measurement of “non-  HDL cholesterol” (LDL plus VLDL) is frequently used to assess  cardiovascular risk rather than just LDL or HDL levels alone.  Lipoprotein (a) (Lp[a]) is a genetically determined molecular  complex between LDL and a serum glycoprotein called apopro-  tein (a) that has been shown to be an important risk factor for  coronary atherosclerosis, especially in women. !°?    Hypertension. Hypertension is responsible for a two- to  threefold increased risk of atherosclerotic cardiovascular  disease including MI.!° It contributes to endothelial injury, a  key step in atherogenesis (see p. 1145), and causes myocardial  hypertrophy, which increases myocardial demand for coronary  flow. The overactivity of the SNS and RAAS commonly found in  hypertension also contributes to the genesis of coronary artery  disease. Drugs that block the effects of the SNS and RAAS to treat  hypertension have many positive effects on the vasculature.   Cigarette Smoking. Direct and passive (environmental)  smoking increase the risk of CAD. The mechanism by which  smoking increases atherosclerosis is uncertain. Nicotine stimulates  the release of catecholamines (epinephrine and norepinephrine),  which increases heart rate and causes peripheral vascular  constriction. As a result blood pressure increases, as do cardiac  workload and oxygen demand. Cigarette smoking is associated  with an increase in LDL and a decrease in HDL, and contributes  to vessel inflammation and thrombosis. The risk of CAD increases  with heavy smoking and decreases when smoking is stopped.   Diabetes Mellitus. Diabetes mellitus and insulin resistance  are extremely important risk factors for CAD. Insulin resistance,  hyperinsulinemia, and hyperglycemia have multiple effects on  the cardiovascular system. These effects can include endothelial  damage, thickening of the vessel wall, increased inflammation  and leukocyte adhesion, increased thrombosis, glycation of  vascular proteins, and decreased production of endothelial-  derived vasodilators such as nitric oxide!%! (diabetes and  atherogenesis are described in more detail in Chapter 22).  Diabetes is also associated with dyslipidemia because of the  resulting alteration of hepatic lipoprotein synthesis and increases  triglycerides and in LDL oxidation.'°° Aggressive management  of this additional risk factor can significantly improve CAD risk  in individuals with diabetes.   Obesity and Sedentary Lifestyle. It is estimated that nearly  two thirds of the U.S. adult population is overweight or obese    Controversies in the Use of Medications for the Primary Prevention of Cardiovascular Disease    Despite clear evidence for the benefit of the use of medications to improve  lipid levels in individuals who already have documented atherosclerotic disease  (secondary prevention), primary prevention of cardiovascular disease through  pharmacologic modulation of lipid levels remains controversial. Although some  clinical trials and meta-analyses have shown a reduction in primary cardiovas-  cular events with the use of the 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA)  reductase drugs (statins), niacin, and other cholesterol-lowering medications,   her studies have provided mixed results, especially in women. In addition,  tatin use is linked to several significant complications including muscle sore-  ss, elevation in liver enzymes, cognitive impairment, and diabetes. For exam-  e, in a recent large study exploring the role of statins in primary prevention,  atin therapy lowered low-density lipoprotein (LDL) and C-reactive protein and    reduced overall cardiovascular risk by 39% and overall mortality by 17%. But  it also increased the risk for diabetes by 28% among individuals with risk fac-  tors for diabetes at baseline. Overall, women demonstrate less cardiovascular    benefit than men, and have no improvement in mortality with the use of statins  for primary prevention. The ability to weigh the risks and benefits of medication  use for primary prevention is complicated by these mixed results.   Low levels of high-density lipoprotein (HDL) also have been strongly correlated  with increased cardiovascular risk, yet several primary prevention trials in which  drugs such as niacin and fibrates raised HDL levels failed to demonstrate benefit.  In fact, use of the cholestery! ester transfer protein (CETP) inhibitor torcetrapib,  which is highly effective at increasing HDL levels, actually resulted in an increase  in cardiovascular risk. Subsequent clinical studies found that this adverse risk  response to torcetrapib was “molecule specific” and independent of its CETP inhi-  bition effect. The other two CETP inhibitors, dalcetrapib and anacetrapib, have so  far been well tolerated in phase | and II clinical trials and do not adversely affect  blood pressure and aldosterone as torcetrapib did. It is clear from these studies  that despite decades of research, there is still much work needed to fully under-  stand the proper role of medications in the prevention of cardiovascular disease.    Data from Badimon L, Vilahur G: Ann N Y Acad Sci (1):18-32, 2012; Boden WE et al: N Eng! J Med 365(24):2255-2267, 2011; Cholesterol Treat-  ment Trialists’ (CTT) Collaborators: Lancet 380:581-590, 2012; Gutierrez J et al: Arch Intern Med 172(12):909-919, 2012; Johns DG et al: Drugs  72(4):491-507, 2012; Michos ED et al: J Am Coll Cardiol 59(23):2058-2064, 2012; Prasad V, Vandross A: Arch Intern Med 172(8):656-659, 2012;  Ridker PM et al: Lancet 380:565-571, 2012; Sampson UK, Fazio S, Linton MF: Curr Atheroscler Rep 14(1):1-10, 2012.    resulting in a much increased risk for CAD and stroke. An  estimated 47 million residents have a combination of obesity,  dyslipidemia, and hypertension (called metabolic syndrome)  (see Chapter 22), which is associated with an even higher  risk for CAD events.!°” Obesity is caused by genetics, diet,  and inadequate physical exercise. Abdominal obesity has  the strongest link with increased CAD risk and is related to  insulin resistance, decreased HDL, increased blood pressure,  and inflammation.'°* Obesity also is associated with changes  in the adipokines (see following) that affect cardiovascular  risk. A sedentary lifestyle not only increases the risk of obesity  but also has an independent effect on increasing CAD risk.  Physical activity and weight loss offer substantial reductions in  risk factors for CAD. There is emerging evidence that bariatric  surgery procedures, such as gastric bypass, can provide sustained  improvement in risk factors for cardiovascular disease such as  hypertension, dyslipidemia, and diabetes!°%!!° (see What’s  New? Cardiovascular Risk Reduction with Bariatric Surgery).  Nontraditional Risk Factors. Nontraditional, or novel,  risk factors for CAD include: (1) increased serum markers  for inflammation and thrombosis, (2) troponin I, (3)  hyperhomocysteinemia, (4) adipokines, (5) infection, (6) air  pollution, and (7) coronary artery calcification and carotid  wall thickness. The amount of risk conferred by these relatively  newly identified factors is still being explored, although the  preponderance of evidence suggests that the traditional risk  factors continue to be more predictive of cardiovascular disease  and should remain the focus of risk factor reduction efforts.!"!  Markers of Inflammation and Thrombosis. Of the numer-  ous markers of inflammation that have been linked to an  increase in CAD risk (hs-CRP, fibrinogen, protein C, plasmino-  gen activator inhibitor), the relationship between serum lev-  els of CRP and CAD has been explored in the greatest depth.  Highly sensitive C-reactive protein (hs-CRP) is an acute phase  reactant or protein mostly synthesized in the liver and is an  indirect measure of atherosclerotic plaque-related inflamma-  tion. Elevated levels of hs-CRP are associated with numerous  other CAD risk factors including smoking, obesity, and diabe-  tes, and have been found to be an independent risk factor for  coronary disease. However, as a nonspecific serum marker for    inflammation, its utility as a screening tool for cardiovascular  risk continues to be debated. A recent study demonstrated that  hs-CRP levels can be used to better assign individuals into car-  diovascular risk categories that aid in decision-making about  pharmacologic interventions for individuals with other risk  factors for coronary disease.!!* Other markers of inflammation  associated with CAD include erythrocyte sedimentation rate,  von Willebrand factor concentration, uric acid, IL-6, IL-18,  TNF-a, fibrinogen, and YKL-40 is a 40 kDa (mass) glycoprotein  produced by inflammatory cells, cancer cells, and stem cells.   Troponin I. Troponin I (TnI) is a serum protein whose  measurement is used as a sensitive and specific diagnostic test  to help identify myocardial injury during acute coronary syn-  dromes. Highly sensitive TnI assays are used in individuals  without a history of CAD to assess risk for future CHD events,  mortality, and heart failure.”°   Hyperhomocysteinemia. Hyperhomocysteinemia occurs  because of a genetic lack of the enzyme that breaks down homo-  cysteine (an amino acid) or because of a nutritional deficiency  of folate, cobalamin (vitamin Bj), or pyridoxine (vitamin B,).  Although it has not been identified by the AHA as a major risk factor  for CAD, hyperhomocysteinemia is associated with increased LDL  oxidation, decreased endogenous vasodilators, increased smooth  muscle proliferation, and an increased tendency for thrombosis.  Elevated levels of homocysteine may interact with other risk factors  (such as dyslipidemia and hypertension) in certain populations to  further increase coronary risk.'!’ Routine serum measurement of  homocysteine is not currently recommended, and prevention and  management have been focused on increasing the dietary intake  of folate and B vitamins. Unfortunately, no controlled treatment  study has shown that folic acid supplements reduce the risk of ath-  erosclerosis or that taking these vitamins affects the development  or recurrence of cardiovascular disease.   Adipokines. Adipokines are a group of hormones released  from adipose cells. The two that are most studied are adiponectin  and leptin. Leptin is primarily implicated in obesity, hypertension,  and diabetes (see p. 1134) but is also being explored as a factor  in autoimmune responses affecting blood vessels.'!* Decreased  adiponectin in obese individuals has been linked to a significant  increase in cardiovascular risk. Its antiatherogenic effects include    With the devastating increase in obesity-related diabetes and cardiovascular  disease, bariatric surgical procedures for weight loss are being used in more and  more individuals. Although there are surgery-related risks, including bleeding,  leakage at the surgical site, and hernias, the number of bariatric procedures is  increasing rapidly, and safer surgical techniques are being developed. Bariatric    surgery has been shown to be effective in reversing diabetes, metabolic syn-  drome, hypertension, and dyslipidemia with associated risk reduction for cardio-  vascular disease. For example, one large study documented a 72% reversal of  diabetes with gastric bypass surgery as compared to 21% of those who under-  went medically managed weight loss. Similarly, more than 80% of individuals    with dyslipidemia treated with surgery were found to have significant improve-  ments in low-density lipoprotein, high-density lipoprotein, and triglycerides such  that they were able to discontinue their drug regimens. These changes have  been found to be sustained (over 6 years) in a large proportion of surgically  treated individuals. Although approximately 7% of weight is regained, and some  individuals have recurrence of their diabetes, overall mortality is reduced after  bariatric surgery as compared with medically managed weight loss. The Ameri-  can Heart Association recommends bariatric surgery for individuals who have  severe obesity in whom efforts at medical therapy have failed and an acceptable  operative risk is present.    Data from Adams TD et al: JAMA 308(11):1122-1131, 2012; Apovian CM, Gokce N: Circulation 125(9):1178-1182, 2012; Benraouane F, Litwin SE:  Curr Opin Cardio! 26(6):555-561, 2011; Mingrone G et al: N Eng! J Med 366(17):1577-1585, 2012; Olbers T, Svensson PA, Carlsson LM: JAMA  307(1):56-65, 2012; Poirier P et al: Circulation 123(15):1683-1701, 2011; Sjostrom L et al: N Eng! J Med 366(17):1567-1576, 2012.    anti-inflammatory, insulin-sensitizing enhancement of nitric  oxide generation, attenuation of reactive oxygen species produc-  tion in endothelial cells, and reduced vascular smooth muscle cell  proliferation.'!° A more recently described adipokine is resistin,  which has been linked to inflammation, endothelial dysfunction,  thrombosis, and smooth muscle cell dysfunction.'!° Emerging  evidence suggests that adipokine changes occurring in perivas-  cular adipose cells may play a significant role in metabolic and  vascular disorders.!'’ Weight loss and exercise improve adipo-  kine levels and are correlated with improved cardiovascular risk.   Infection. Infections with various microorganisms, includ-  ing Chlamydia pneumoniae, Helicobacter pylori, and cytomega-  lovirus, have been linked to an increased risk for CAD, although  cause and effect have not been proven. Periodontal disease also  has been linked to an increased risk for CAD.!!* One hypothesis  is that systemic infection results in increased inflammation of  vessels and therefore contributes to vascular disease. Unfortu-  nately, the use of antibiotics for the prevention and treatment of  CAD has not yielded consistently positive results.   Air Pollution. Exposure to air pollution, especially roadway  exposures, is strongly correlated with coronary risk. It is postu-  lated that toxins in pollution contribute to macrophage activation,  oxidation of LDL, thrombosis, and inflammation of vessel walls.!!?   Coronary Artery Calcification (CAC) and Carotid Artery  Wall Thickness (CAWT). Coronary risk related to changes in  vessel walls can be assessed using various types of vascular imag-  ing techniques. CAC, as detected by CT scanning, and CIMT,  as detected by ultrasonography, are two important imaging  modalities in widespread use for determining coronary heart  disease risk.'2°!7!    PATHOPHYSIOLOGY. The coronary arteries normally supply  blood flow sufficient to meet the demands of the myocar-  dium as it labors under varying workloads. Oxygen extraction  from these vessels occurs with maximal efficiency. If efficient  exchange does not meet myocardial oxygen needs, healthy cor-  onary arteries are able to dilate to increase the flow of oxygen-  ated blood to the myocardium. Narrowing of a major coronary    artery by more than 50% impairs blood flow sufficiently to  hamper cellular metabolism under conditions of increased  myocardial demand (see Figure 32-14).   Myocardial ischemia develops if the supply of coronary  blood cannot meet the demand of the myocardium for oxygen  and nutrients. Imbalances between myocardial demand and  coronary blood supply can result from a number of conditions.  Common causes of increased myocardial demand for blood  include tachycardia, exercise, hypertension (hypertrophy), and  valvular disease. The most common cause of decreased coro-  nary blood flow and resultant myocardial ischemia is the for-  mation of atherosclerotic plaques in the coronary circulation.  As the plaque increases in size, it may partially occlude the ves-  sel lumina, thus limiting coronary flow and causing ischemia  especially during exercise. Some plaques are “unstable,” mean-  ing they are prone to ulceration or rupture (see p. 1156 and  Figure 32-20). When this ulceration or rupture occurs, under-  lying tissues of the vessel wall are exposed, resulting in platelet  adhesion and thrombus formation. Thrombus formation can  suddenly cut off blood supply to the heart muscle, resulting in  acute myocardial ischemia, and if the vessel obstruction cannot  be reversed rapidly, ischemia will progress to infarction. Myo-  cardial ischemia also can result from other causes of decreased  blood and oxygen delivery to the myocardium, such as coro-  nary spasm, hypotension, dysrhythmias, and decreased oxygen-  carrying capacity of the blood (anemia, hypoxemia).   Myocardial cells become ischemic within 10 seconds of  coronary occlusion. After several minutes the heart cells lose  the ability to contract, and cardiac output decreases. Ischemia  also causes conduction abnormalities that lead to changes in  the electrocardiogram and may initiate dysrhythmias. Anaer-  obic processes take over, and lactic acid accumulates. Cardiac  cells remain viable for approximately 20 minutes under ische-  mic conditions. If blood flow is restored, aerobic metabolism  resumes, contractility is restored, and cellular repair begins. If  the coronary artery occlusion persists beyond 20 minutes, MI  occurs (Figure 32-15).   CLINICAL MANIFESTATIONS. Individuals with reversible myocar-  dial ischemia present clinically in several ways. Chronic coronary    Less than 20 min: Greater than 20 min:  ischemic attack myocardial infarction    FIGURE 32-16 Angiogram. A, Baseline (arro  ing branch of the left coronary artery after mental stress (arrow). C, After administration of nitrates and nifedipine, artery  reopened to same diameter as baseline (arrow). (From Stern S, editor: Silent myocardial ischemia, St Louis, 1998, Mosby.)    obstruction usually results in recurrent predictable chest pain  called stable angina. Abnormal vasospasm of coronary vessels  results in unpredictable chest pain called Prinzmetal angina.  Myocardial ischemia that does not cause detectable symptoms  is called silent ischemia.   Stable Angina. Angina pectoris is chest pain caused by  myocardial ischemia. Stable angina is caused by gradual luminal  narrowing and hardening of the arterial walls, so that affected  vessels cannot dilate in response to increased myocardial  demand associated with physical exertion or emotional stress.  If demand is decreased, no necrosis of myocardial cells results.  Angina pectoris is typically experienced as transient substernal  chest discomfort, ranging from a sensation of heaviness or  pressure to moderately severe pain. Individuals often describe  the sensation by clenching a fist over the left sternal border.  The discomfort may be mistaken for indigestion. The pain is  caused by the buildup of lactic acid or abnormal stretching  of the ischemic myocardium that irritates myocardial nerve  fibers. These afferent sympathetic fibers enter the spinal cord  from levels C3 to T4, accounting for the variety of locations and  radiation patterns of anginal pain. Pain may radiate to the neck,  lower jaw, left arm, and left shoulder or occasionally to the back  or down the right arm. Pallor, diaphoresis, and dyspnea may be  associated with the pain. The pain is usually relieved by rest and  nitrates; lack of relief indicates an individual may be developing  infarction.   Myocardial ischemia in women may not present with typi-  cal anginal pain. Common symptoms in women include atypi-  cal chest pain, palpitations, sense of unease, and severe fatigue.  Similarly, in individuals who have autonomic nervous system  dysfunction, such as older adults or those with diabetes, angina  may be mild, atypical, or even silent (see following).   Prinzmetal Angina. Prinzmetal angina (also called variant  angina) is chest pain attributable to transient ischemia of the  myocardium that occurs unpredictably and almost exclusively  at rest. Pain is caused by vasospasm of one or more major  coronary arteries with or without associated atherosclerosis. The  angina may result from decreased vagal activity, hyperactivity  of the sympathetic nervous system, and decreased nitric oxide  activity. Other causes include altered calcium channel function  in arterial smooth muscle and endothelial dysfunction with  release of inflammatory mediators, such as serotonin, histamine,  endothelin, or thromboxane. Serum markers of inflammation,  such as CRP and IL-6, may be elevated in individuals with  this form of angina. The pain often occurs at night during    rapid eye movement sleep and may have a cyclic pattern of  occurrence. If the spasm persists long enough, infarction or  serious dysrhythmias may occur. However, most individuals  are successfully treated with vasodilators and overall prognosis  is good.!?2   Silent Ischemia and Mental Stress (Induced Ischemia).  Myocardial ischemia does not always cause angina and may  be associated only with nonspecific symptoms such as fatigue,  dyspnea, or feeling of unease. Some individuals only have silent  ischemia, whereas episodes of silent myocardial ischemia may  occur in individuals who also experience angina. Silent ischemia  and atypical symptoms are more common in women, although  the pathophysiologic mechanisms are poorly understood.!?*  Global or regional abnormalities in left ventricular sympathetic  afferent innervation have been implicated in autonomic  dysfunction in diabetes mellitus, following surgical denervation  during coronary artery bypass grafting (CABG) or cardiac  transplantation, or following ischemic local nerve injury by  MI.!*4 Silent ischemia also may occur in some individuals  during mental stress (Figures 32-16 and 32-17). Mental stress  has been linked to increased markers of inflammation, such as  CRP, decreased activity of vasodilators, such as nitric oxide, and  a hypercoagulable state that may contribute to acute ischemic  events.!*° Although stress management has been associated  with a reduction in CAD events in men, further research into  the brain-heart pathways is under way to better elucidate  appropriate interventions.   Screening for silent ischemia is based on the presence of risk  factors and is most often detected using stress radionucleotide  imaging. Detection of silent ischemia is important because it is  an indicator of increased risk for serious cardiovascular disease  (CVD) events, and aggressive treatment may be indicated.!*4   EVALUATION AND TREATMENT. Many individuals with reversible  myocardial ischemia exhibit a normal physical examination  between episodes. Physical examination of an individual expe-  riencing myocardial ischemia may disclose tachycardia, extra  heart sounds (gallops or murmurs), and pulmonary congestion  indicating impaired left ventricular function. The presence of  xanthelasmas (small fat deposits) around the eyelids or arcus  senilis of the eyes (a yellow lipid ring around the cornea) sug-  gests dyslipidemia and possible atherosclerosis. The presence of  peripheral or carotid arterial bruits suggests probable atheroscle-  rotic disease and increases the likelihood that CAD is present.   Electrocardiography is a critical tool for diagnosing myo-  cardial ischemia. Because many individuals have normal ECGs    FIGURE 32-17 Pathophysiologic Model of Acute Stress Effects Triggering Cardiac Clinical Events. Acting via the  central and autonomic nervous systems, stress can produce a cascade of physiologic responses that may lead to myocardial  ischemia, potentially fatal dysrhythmia, plaque rupture, or coronary thrombosis. LV, Left ventricular; M/, myocardial infarction;  VE ventricular fibrillation; V7, ventricular tachycardia. (From Kranz DS et al: Mental stress as a trigger of myocardial ischemia  and infarction. In Deedwania PC, Tofler GH, editors: 7riggers and timing of cardiac events, ed 2, London, 1996, Saunders.)    Normal ECG deflections ECG alterations associated with ischemia  R ST segment depression T wave inversion ST segment elevation  R R  7 P T Pp T P  Atrial ; Ventricular Q Qs Q  depolarization repolarization S  A Ventricular depolarization B    in the absence of pain, diagnosis may require that electrocar-  diography be performed during an attack of angina. Transient  ST-segment depression and T-wave inversion are characteris-  tic signs of subendocardial ischemia frequently seen in angina.  ST elevation, indicative of transmural ischemia, can be seen in  individuals with Prinzmetal angina but is more common in  infarction (Figure 32-18). The ECG also can give some indica-  tion of which coronary artery is involved. Approximately 30%  of individuals with angina have nondiagnostic ECG tracings  and require other diagnostic studies.   Stress radionucleotide imaging is indicated to detect ischemic  changes in asymptomatic individuals with multiple risk factors  for coronary disease, such as diabetes and dyslipidemia, and for  older individuals who plan to start vigorous exercise. Stress test-  ing is made more sensitive when radioisotope imaging is added  to the ECG as an indicator of myocardial ischemia. Currently,  the modality of choice for the diagnosis of myocardial ischemia  is single-photon emission computed tomography (SPECT),  which is effective at identifying ischemia and estimating risk for  coronary events. Radioisotope imaging with thallium-201 and    stress echocardiography also are used. Unfortunately, although  all of these tests are helpful in documenting coronary obstruc-  tion, they cannot detect the presence of unstable plaques, which  are the cause of the majority of acute coronary syndromes.   Imaging the coronary arteries for the evaluation of ath-  erosclerotic plaques involves the use of CT with and without  angiography, MRI, or intravascular ultrasound. Coronary angi-  ography is useful in determining the anatomic extent of CAD.  The procedure is expensive and carries some risk; thus it is used  primarily to evaluate for possible percutaneous coronary inter-  vention (PCI) or CABG surgery for individuals whose noninva-  sive studies suggest severe disease.   The primary aim of therapy for myocardial ischemia and  angina is to increase delivery of oxygen by improving coronary  artery blood flow and to reduce myocardial oxygen consump-  tion. Recommendations for appropriate diet, exercise, and  risk reduction strategies have been widely distributed. Coro-  nary blood flow is improved by reversing vasoconstriction,  preventing clotting, and reducing plaque growth and rupture.  Myocardial oxygen consumption is reduced by manipulation    of blood pressure, heart rate, contractility, and left ventricular  volume. Many different classes of drugs are available to man-  age stable angina, including nitrates, B-adrenergic receptor  blockers, and calcium channel blockers. Therapy should be  individualized.!?%!?”   Nitrates improve coronary blood flow and reduce myocar-  dial demand by decreasing peripheral vascular resistance and  venous return to the heart (preload) and thereby reduce cardiac  workload. Nitrates can be used for short-term symptom relief,  and long acting nitrates are available in several forms.!°   B-Adrenergic receptor blockers are first-line therapy to  reduce the myocardial oxygen requirements that occur with  physical exertion. Beta-blockers diminish catecholamine-  induced elevations of heart rate, myocardial contractility, and  blood pressure. Reduction in heart rate provides additional dia-  stolic filling time for coronary perfusion, leading to enhanced  oxygen delivery to the heart.   Calcium channel blockers decrease the influx of calcium  into myocardial cells and vascular smooth muscle cells. They  also modify the pacemaker activity of the sinoatrial (SA)  node and conduction properties of the atrioventricular (AV)  node so that myocardial oxygen demand is reduced. How-  ever, short-acting formulations should be used with caution  because of potentially harmful effects on cardiac contractility  and heart rate.!*°   Combinations of nitrates, beta-blockers, and calcium antag-  onists may provide dramatic relief from clinical manifestations  of ischemic heart disease, which improves quality of life and may  make more invasive interventions unnecessary. However, they  do not reverse the atherosclerotic process; thus the individual  remains at risk for persistent or worsening CAD. Antianginal  medications have not been shown to prolong life or prevent MI  in individuals with stable angina. Medications aimed at plaque  stabilization, regression, and prevention of clotting also are  indicated in the majority of individuals. These include statins,  ACE inhibitors or receptor blockers, and antithrombotics.!*°   Coronary revascularization is indicated for those individu-  als who do not respond adequately to antianginal drugs or who  have high-risk atherosclerotic lesions. Percutaneous coronary  intervention (PCI) is a procedure whereby stenotic (narrowed)  coronary vessels are dilated with a catheter. Several different  types of catheters can be used to open the blocked vessel. PCI  is most often used to treat single-vessel disease, but it can be  effective with multiple-vessel disease or restenosis of a coro-  nary artery bypass graft in selected individuals. Restenosis of  the artery is the major complication of the procedure; how-  ever, placement of a coronary stent can reduce this risk (see  What’s New? Medical Devices—Are They Safe and Effective?)  Antithrombotic treatment such as aspirin, clopidogrel, or gly-  coprotein IIb/IIa receptor antagonists after stenting also can  improve outcomes.!7°   Severe CAD can be surgically treated by CABG, usually using  the saphenous vein from the lower leg. In selected individuals,  a modified CABG procedure called minimally invasive direct  coronary artery bypass (MIDCAB) can be used with much less  surgical morbidity and more rapid recovery. Investigational  therapies for refractory angina that stimulate angiogenesis    There have been many medical technology advances for individuals with  cardiovascular problems, such as stents, defibrillators, and mechanical  heart valves. Although many of these treatments are lifesaving, many of  these cardiovascular medical devices are approved for use before they are  adequately tested. Although the same is true for numerous new drugs,  because these devices require invasive procedures or because once they  are implanted they are necessary to sustain life, they are considered high    risk. Between January 1, 2000, and December 31, 2011, only 48% of devices  were tested using an active control group prior to approval by the U.S. Food  and Drug Administration (FDA) and 35% were approved without any control  group at all. Thus about half of high-risk cardiac devices were approved  without determining if they provide better outcomes than other treatme  As more devices are approved, concern is increasing about the relative ri  and benefits of these interventions.    Data from Chen CE, Dhruva SS, Redberg RF: JAMA 308(17):1740-1742,  2012; Goldberg NH et al: JAMA 305(17):1786-1789, 2011.    include transmyocardial laser revascularization (TMR), gene  therapy for myocardial angiogenesis, spinal cord stimulation,  laser revascularization, and percutaneous in situ coronary  venous arterialization. New drugs being evaluated in the medi-  cal management of myocardial ischemic syndromes include  ranolazine, trimetazidine, nicorandil, and ivabradine.!*°    The process of atherosclerotic plaque progression can be  gradual. However, when there is sudden coronary obstruc-  tion caused by thrombus formation over a ruptured or ulcer-  ated atherosclerotic plaque, acute coronary syndromes result  (Figure 32-19). Unstable angina is the result of reversible myo-  cardial ischemia and is a harbinger of impending infarction.  Myocardial infarction (MI) results when prolonged ischemia  causes irreversible damage to the heart muscle. MI can be fur-  ther subdivided into non—ST-elevation MI (non-STEMI) and  ST-elevation MI (STEMI). Sudden cardiac death can occur as a  result of any of the acute coronary syndromes.   An atherosclerotic plaque that is prone to rupture is called  “unstable” and has a core that is especially rich in deposited oxi-  dized LDL and a thin fibrous cap (Figure 32-20). These unstable  plaques may not extend into the lumen of the vessel and may  be clinically silent until they rupture. Plaque disruption (ulcer-  ation or rupture) occurs because of shear forces, inflammation  with release of multiple inflammatory mediators, secretion of  macrophage-derived degradative enzymes, and apoptosis of  cells at the edges of the lesions. Exposure of the plaque substrate  activates the clotting cascade. In addition, platelet activation  results in the release of coagulants and exposure of platelet gly-  coprotein IIb/IIIa surface receptors, resulting in further platelet  aggregation and adherence. The resulting thrombus can form  very quickly (Figure 32-21, A). Vessel obstruction is further  exacerbated by the release of vasoconstrictors, such as throm-  boxane A2 and endothelin. The thrombus may break up before  permanent myocyte damage has occurred (unstable angina) or  it may cause prolonged ischemia with infarction of the heart    muscle (myocardial infarction) (see Figure 32-21, B). Diagnos-  tic tests aimed at identifying unstable plaques before they rup-  ture include intravascular ultrasound or MRI, angioscopy, and  spectroscopy. Medications such as statins, ACE inhibitors, and  beta-blockers can help stabilize plaques and prevent rupture.    Hibernating myocytes ee |  Myocardial remodeling  FIGURE 32-19 Pathophysiology of Acute Coronary Syndromes. The ath-  erosclerotic process can lead to stable plaque formation and stable angina or can  result in unstable plaques that are prone to rupture and thrombosis. Thrombus  formation on a ruptured plaque that disperses in less than 20 minutes leads to  transient ischemia and unstable angina. If the vessel obstruction is sustained,  myocardial infarction with inflammation and necrosis of the myocardium result. In    addition, myocardial infarction is associated with other structural and functional  changes, including myocyte stunning and hibernation and myocardial remodeling.    Atherosclerotic plaque  with a lipid-rich core  and a thin fibrous cap    Shear forces, inflammation,  apoptosis, macrophage-derived  degradative enzymes  Rupture of plaque  Increased inflammation with 2 eas    Acute decrease in coronary  blood flow  Unstable angina or  myocardial infarction  FIGURE 32-20 Pathogenesis of Unstable Plaques and Thrombus  Formation.    Unstable Angina. Unstable angina is a form of acute coronary  syndrome that results in reversible myocardial ischemia. It is  important to recognize this syndrome because it signals that the  atherosclerotic plaque has ruptured, and infarction may soon  follow.   PATHOPHYSIOLOGY. Unstable angina occurs when fissuring or  superficial erosion of the plaque leads to transient episodes of  thrombotic vessel occlusion and vasoconstriction at the site of  plaque damage. This thrombus is labile and occludes the vessel  for no more than 10 to 20 minutes, with return of perfusion  before significant myocardial necrosis occurs.   CLINICAL MANIFESTATIONS. Unstable angina presents as new-  onset angina, angina that is occurring at rest, or angina that is  increasing in severity or frequency (Box 32-1). Individuals may  experience increased dyspnea, diaphoresis, and anxiety as the  angina worsens.   EVALUATION AND MANAGEMENT. Physical examination may  reveal evidence of ischemic myocardial dysfunction such as  tachycardia or pulmonary congestion. The ECG most com-  monly reveals ST-segment depression and T-wave inversion  during pain that resolves as the pain is relieved. The serum  cardiac biomarkers (troponins, creatine phosphokinase-myo-  cardial bound [CPK-MB] and lactate dehydrogenase [LDH1])  remain normal. Approximately 20% of people with unstable  angina progress within hours to days to MI or death. Manage-  ment of unstable angina requires immediate hospitalization  with administration of oxygen, aspirin (if not contraindicated),  nitrates, and morphine if pain is still present. Additional anti-  thrombotic therapy with clopidogrel or IIb/IIa platelet receptor  antagonists may be indicated. Beta-blockers and ACE inhibitors  also may be used. Anticoagulants, such as low-molecular-weight  heparin, or direct thrombin inhibitors (e.g., fondaparinux) also  can be given. Individuals with refractory angina and those with  electrical or hemodynamic instability require immediate inter-  vention with PCI or CABG.!2%!°0   Myocardial Infarction. When coronary blood flow is  interrupted for an extended period, myocyte necrosis occurs.  This results in MI. In the majority of cases of MI, the decrease  in coronary flow is the result of atherosclerotic CAD; other  causes include coronary spasm and coronary artery embolism.  Pathologically there are two major types of MI: subendocardial  infarction and transmural infarction. Clinically, however, MI is  categorized as non-STEMI or STEMI.   PATHOPHYSIOLOGY. Plaque progression, disruption, and subse-  quent clot formation is the same for myocardial infarction as  it is for unstable angina (see Figures 32-19, 32-20, and 32-21).  In this case, however, the thrombus is less labile and occludes  the vessel for a prolonged period, such that myocardial ische-  mia progresses to myocyte necrosis and death. The duration of  ischemia determines the size and character of the infarction.'*!  If the thrombus breaks up before complete distal tissue necro-  sis has occurred, the infarction will involve only the myocar-  dium directly beneath the endocardium (subendocardial MI).  This infarction usually presents with ST depression and T-wave  inversion and is termed non-STEML. It is especially important  to recognize this form of acute coronary syndrome because  recurrent clot formation on the disrupted atherosclerotic    FIGURE 32-21 Plaque Disruption and Myocardial Infarction. A, Plaque disruption. The cap of the lipid-rich plaque    has become torn with the formation of a thrombus, mostly inside the plaque. B, Myocardial infarction. This infarct is 6 days  old. The center is yellow and necrotic with a hemorrhagic red rim. The responsible coronary artery occlusion is probably in the  right coronary artery. The infarct is on the posterior wall. (From Damjanov I, Linder J, editors: Anderson's pathology, ed 10, St    New-onset angina—new-onset angina of at least Canadian Cardiovascular  Society (CCS) class Ill severity   Increasing angina—previously diagnosed angina that has become distinctly  more frequent, longer in duration, or lower in threshold (i.e., increased by  >1 CCS class to at least CCS class Ill severity)    From Anderson J et al: J Am Coll Cardio! 50:e1-e157, 2007. Originally  adapted from Braunwald E: Circulation 80:410-414, 1989.   * Individuals with non-ST-elevation myocardial infarction (non-STEMI)  usually present with angina at rest.    plaque is likely to occur unless some intervention is undertaken  as soon as possible. If the thrombus lodges permanently in the  vessel, the infarction will extend through the myocardium all  the way from endocardium to epicardium (transmural MI),  resulting in severe cardiac dysfunction. Transmural infarction  usually causes marked elevations in the ST segments on ECG.  Individuals with elevations are categorized as having STEMI.  Clinically it is important to identify those with STEMI because  they are at highest risk for serious complications and require  immediate intervention.   Cellular Injury. Cardiac cells can withstand ischemic condi-  tions for about 20 minutes before cellular death takes place. After  only 30 to 60 seconds of hypoxia, ECG changes are visible. Yet  even if cells are metabolically altered and nonfunctional, they can  remain viable if blood flow returns within 20 minutes. Reports  suggest previous recurrent episodes of myocardial ischemia can  result in myocyte adaptation to oxygen deprivation and preser-  vation of myocardium. This process, termed ischemic precon-  ditioning, is being studied to determine whether it has potential  prophylactic or therapeutic uses.!°?    After 8 to 10 seconds of decreased blood flow, the affected  myocardium becomes cyanotic and cooler. Myocardial oxy-  gen reserves are used very quickly (within about 8 seconds)  after complete cessation of coronary flow. Glycogen stores  decrease as anaerobic metabolism begins. Unfortunately, gly-  colysis can supply only 65% to 70% of the total myocardial  energy requirement and produces much less ATP than aerobic  processes. Hydrogen ions and lactic acid accumulate. Because  myocardial tissues have poor buffering capabilities and myo-  cardial cells are very sensitive to low cellular pH, accumula-  tion of these products further compromises the myocardium.  Acidosis may make the myocardium more vulnerable to the  damaging effects of lysosomal enzymes and may suppress  impulse conduction and contractile function, thereby leading  to heart failure.   Oxygen deprivation also is accompanied by electrolyte dis-  turbances, specifically, loss of potassium, calcium, and mag-  nesium from cells. Myocardial cells deprived of necessary  oxygen and nutrients lose contractility, thereby diminishing  the heart’s pumping ability. Ischemic myocardial cells release  catecholamines (epinephrine and norepinephrine), predispos-  ing the individual to serious imbalances of sympathetic and  parasympathetic function, irregular heartbeats (dysrhythmia),  and heart failure. Catecholamines mediate the release of glyco-  gen, glucose, and stored fat from body cells. Therefore, plasma  concentrations of free fatty acids and glycerol rise within 1  hour after onset of acute MI. Excessive levels of free fatty acids  can have a harmful detergent effect on cell membranes. Nor-  epinephrine elevates blood sugar levels through stimulation  of liver and skeletal muscle cells. It also suppresses pancreatic  B-cell activity, which reduces insulin secretion and elevates  blood glucose further. Hyperglycemia is noted approximately  72 hours after an acute MI and is associated with an increased  risk of death; therefore, careful glucose monitoring and control  after MI is essential.    FIGURE 32-22 Myocardial Infarction. A, Local infarct confined to one region. B, Massive large infarct caused by occlu-  sion of three coronary arteries. (From Damjanov |, Linder J, editors: Andersons pathology, ed 10, St Louis, 1996, Mosby.)    Note: Processes of tissue healing are described and illustrated in Chapter 7.    Ischemic injury can be exacerbated by what is termed reper-  fusion injury once blood flow is restored. This process involves  the release of toxic oxygen radicals, calcium flux, and pH changes  that cause a sustained opening of mitochondrial permeability  transition pores (mPTP) and contribute to resultant cellular  death. Therapies aimed at reducing reperfusion injury are being  explored, including endovascular cooling, adenosine, atrial  natriuretic peptide, cyclosporine, nicorandil, and incretins.'°!)!°?   Angiotensin II is released during myocardial ischemia and  contributes to the pathogenesis of MI in several ways. First, it  results in the systemic effects of peripheral vasoconstriction and  fluid retention. These homeostatic responses are counterpro-  ductive in that they increase myocardial work and thus exacer-  bate the effects of the loss of myocyte contractility. Angiotensin  Il is also released locally, where it is a growth factor for vascular  smooth muscle cells, myocytes, and cardiac fibroblasts; pro-  motes catecholamine release; and causes coronary artery spasm.   Cellular Death. After about 20 minutes of myocardial ische-  mia, irreversible hypoxic injury causes cellular death and tissue  necrosis. (Types of necrosis are described in Chapter 2.) Necrosis    Inflammatory response; intercellular enzyme release  Proteolytic enzymes remove debris; catecholamines, lipolysis,  and glycogenolysis elevate plasma glucose and increase    of myocardial tissue results in the release of certain intracellular  enzymes through the damaged cell membranes into the intersti-  tial spaces. The lymphatics pick up the enzymes and transport  them into the bloodstream, where they can be detected by sero-  logic tests. Recent evidence has found that along with necrosis  myocardial tissue also is destroyed by the tightly controlled pro-  cess of apoptosis. An increased understanding of the steps of the  apoptotic pathway of MI may lead to new therapies aimed at  limiting infarct size.'°°   Structural and Functional Changes. MI results in struc-  tural and functional changes of cardiac tissues (Figure 32-22).  Table 32-7 outlines the tissue changes that may follow MI.  Gross tissue changes in the area of infarction may not become  apparent for several hours, despite almost immediate onset  (within 30 to 60 seconds) of ECG changes. The infarcted myo-  cardium is surrounded by a zone of hypoxic injury, which  may progress to necrosis, undergo remodeling, or return to  normal.   Cardiac tissue surrounding the area of infarction also  undergoes pathophysiologic changes. Myocardial stunning,    a temporary loss of contractile function that persists for hours  to days after perfusion, has been restored. This pathophysi-  ologic state can occur both with MI and in individuals who  suffer ischemia during cardiovascular procedures such as  cardiac surgery. Stunning is caused by the alterations in elec-  trolyte pumps, calcium homeostasis, and the release of toxic  oxygen radicals. It is characterized by decreased contraction  and conduction and can contribute to heart failure, shock,  and dysrhythmias. Stunning is less severe in individuals who  have experienced ischemic preconditioning. New thera-  pies are being explored that can simulate ischemic precon-  ditioning prior to cardiovascular procedures, or that can be  used after ischemic events to reduce the effects of stunning  (post-conditioning).!°!)!*4   Hibernating myocardium refers to tissue that is persistently  ischemic and undergoes metabolic adaptation to prolong myo-  cyte survival until perfusion can be restored. Restoring adequate  perfusion to the myocardium with revascularization therapies  can improve myocardial function.!°°   Myocardial remodeling is a process mediated by angioten-  sin II, aldosterone, catecholamines, adenosine, oxidative stress,  and inflammatory cytokines, which causes myocyte hypertro-  phy, scarring, and loss of contractile function in the areas of the  heart distant from the site of infarction.!°° These changes can be  limited and even reversed (reverse remodeling) through rapid  restoration of coronary flow and the use of ACE inhibitors,  beta-blockers, statins, sequential pacemakers, and ventricular  assist devices after MI.!°7   Repair. MI causes a severe inflammatory response that ends  with wound repair (see Chapter 7). Repair consists of degrada-  tion of damaged cells, proliferation of fibroblasts, and synthesis  of scar tissue. Many cell types, hormones, and nutrient sub-  strates must be available for optimal healing to proceed. Within  24 hours, leukocytes infiltrate the necrotic area and proteolytic  enzymes from scavenger neutrophils degrade necrotic tissue. A  collagen matrix is deposited and is initially weak, mushy, and  vulnerable to reinjury. Unfortunately it is at this time in the    recovery period (10 to 14 days after infarction) that individuals  feel more capable of increasing activities and thus may stress  the newly formed scar tissue. After 6 weeks the necrotic area is  completely replaced by scar tissue, which is strong but unable to  contract and relax like healthy myocardial tissue.   CLINICAL MANIFESTATIONS. The first symptom of acute MI is  usually sudden, severe chest pain. It is not possible to distin-  guish between angina and MI by symptoms alone, although the  pain associated with MI tends to be more severe and prolonged.  It may be described as heavy and crushing, such as an “elephant  sitting on my chest.” Radiation to the neck, jaw, back, shoul-  der, or left arm is common. Some individuals (especially older  adults or those with diabetes) experience no pain, thereby hav-  ing a “silent” infarction. Infarction often simulates a sensation  of unrelenting indigestion. Nausea and vomiting may occur  because of reflex stimulation of vomiting centers by pain fibers.  Vasovagal reflexes from the area of the infarcted myocardium  also may affect the gastrointestinal tract. Various cardiovascular  changes are found on physical examination:   1. The SNS is reflexively activated to compensate, resulting  in a temporary increase in heart rate and blood pressure,  although severe myocardial damage may cause hypoten-  sion despite elevated catecholamine activity.   4. Pulmonary findings of congestion including dullness to  percussion and inspiratory crackles at the lung bases can  occur if the individual develops heart failure.   5. Peripheral vasoconstriction may cause the skin to become  cool and clammy.   EVALUATION AND TREATMENT. The diagnosis of acute MI is made  on the basis of history, physical examination, ECG, and serial  cardiac biomarker alterations (Box 32-2). It is important to note  that nearly half of MIs are not preceded by any previous angina  symptoms and up to one-third present with STEMI as the first  symptomatic manifestation of coronary disease.’ MI can occur    The term myocardial infarction should be used when there is evidence of myocar-  dial necrosis ina clinical setting with myocardial ischemia. Under these conditions  any one of the following criteria meets the diagnosis for myocardial infarction:  © Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with  at least one value above the 99th percentile of the upper reference limit  (URL) together with evidence of myocardial ischemia with at least one of the  following:  Symptoms of ischemia  Electrocardiographic changes indicative of new ischemia (new ST-T changes  or new left bundle branch block ([LBBB])  Development of pathologic O waves in the electrocardiogram  Imaging evidence of new loss of viable myocardium or new regional wall  motion abnormality  Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms  suggestive of myocardial ischemia, and accompanied by presumably new ST ele-  vation, or new LBBB, and/or evidence of fresh thrombus by coronary angiography    and/or at autopsy; but death occurring before blood samples could be obtained,  or at a time before the appearance of cardiac biomarkers in the blood.  For percutaneous coronary interventions (PCls) in patients with normal base-  line troponin values, elevations of cardiac biomarkers above the 99th percen-  tile URL are indicative of periprocedural myocardial necrosis. By convention,  increases of biomarkers greater than 3 x 99th percentile URL have been des-  ignated as defining PCl-related myocardial infarction. A subtype related to a  documented stent thrombosis is recognized.  For coronary artery bypass grafting (CABG) in patients with normal baseline tro-  ponin values, elevations of cardiac biomarkers above the 99th percentile URL  are indicative of periprocedural myocardial necrosis. By convention, increases  of biomarkers greater than 5 x 99th percentile URL plus either new pathologic  Q waves or new LBBB, or angiographically documented new graft or native  coronary artery occlusion, or imaging evidence of new loss of viable myocar-  dium have been designated as defining CABG-related myocardial infarction.    Data from Thygesen K, Alpert J, White H: J Am Coll Cardio! 50:2173-2195, 2007.    FIGURE 32-23 Site of Myocardial Infarction (MI) and Vessel Involve-  ment. Ao, Aorta; /VC, inferior vena cava; LA, left atrium; LV left ventricle; PA,  pulmonary artery; PV pulmonary vein; AA, right atrium; AV right ventricle; SVC,  superior vena cava. (From Stevens A, Lowe JS, Scott |: Core pathology, ed 3, Lon-  don, 2009, Mosby.)    in various regions of the heart wall and may be described as  anterior, inferior, posterior, lateral, subendocardial, or trans-  mural depending on its location and extent of tissue damage  from infarction. Twelve-lead ECGs help localize the affected  area through identification of changes in ST segments and T  waves (Figure 32-23). The infarcted myocardium is surrounded  by a zone of hypoxic injury, which may progress to necrosis or  return to normal, and adjacent to this zone of hypoxic injury is  a zone of reversible ischemia (Figure 32-24). In STEMI, a char-  acteristic Q wave often develops on ECG some hours later.   Cardiac troponin I (cTnI) is the most specific indicator of  MI and should be obtained on admission to the emergency  department. cTnI elevation is detectable 2 to 4 hours after onset  of symptoms. Additional measurements within 6 to 9 hours and  again at 12 to 24 hours are recommended if clinical suspicion is  high and previous samples were negative. cTnI has a sensitivity  of more than 95% and a negative predictive value of 99% for  the diagnosis of acute MI.'** Troponin levels also can be used to  estimate infarct size and therefore the likelihood of complica-  tions.!°? Other biomarkers released by myocardial cells include  CPK-MB and LDH. These isoenzymes exist in several differ-  ent active molecular forms called isoenzymes and are present  in different amounts within particular tissues. Blood is drawn  for troponin and isoenzyme determinations as soon as possible  after the onset of symptoms; serial serum levels of these bio-  markers are assessed for several days.   Additional laboratory data may reveal leukocytosis and ele-  vated CRP, both of which indicate inflammation. The individ-  ual’s blood sugar is usually elevated and the glucose tolerance  level may remain abnormal for several weeks. Hypoxemia may  accompany heart failure.   Acute MI requires admission to the hospital. The individual  should be placed on supplemental oxygen and given an aspirin  immediately (clopidogrel or prasugrel if intolerant to aspirin).  Pain is treated with morphine sulfate. Continuous monitoring  of cardiac rhythms and biomarker changes is essential because  the first 24 hours after onset of symptoms is the time of highest  risk for sudden death. Non-STEMI is treated in the same way  as unstable angina including antithrombotics, anticoagulation    FIGURE 32-24 Electrocardiographic Alterations Associated with the Three Zones of Myocardial Infarction.    or PCI, or both.!°° STEMI is best managed with emergent PCI  and antithrombotics.!°** Thrombolytics may be used if PCI is  not readily available. Hyperglycemia is treated with insulin.'*°  Once the person is stabilized, further management includes  ACE inhibitors, beta-blockers, and statins.!°°'4!)!4? Individuals  who are in shock require aggressive fluid resuscitation, inotro-  pic drugs, and possible emergent invasive procedures. !**   Bed rest, followed by gradual return to activities of daily liv-  ing, reduces the myocardial oxygen demands of the compro-  mised heart. Individuals not receiving thrombolytic or heparin  infusion must receive DVT prophylaxis as long as their activity  is significantly limited. Stool softeners are given to eliminate the  need for straining, which can precipitate bradycardia and can  be followed by increased venous return to the heart, causing  possible cardiac overload. Education on diet, caffeine, smok-  ing cessation, exercise, and other aspects of risk factor reduc-  tion is crucial for secondary prevention of recurrent myocardial  ischemia.   Approximately 1% to 2% of people initially diagnosed with  STEMI do not have myocardial infarction, but rather have a  stress-induced syndrome known as the broken heart syndrome  or Takotsubo cardiomyopathy. These individuals present with  the acute onset of chest pain, ST elevation, elevated troponins,  and BNP after emotional stress, but generally do not have cor-  onary artery disease and must be managed differently!“ (see  What’s New? The Broken Heart Syndrome).   COMPLICATIONS. The number and severity of postinfarction  complications depend on the location and extent of necrosis,  the individual’s physiologic condition before the infarction,  and the availability of swift therapeutic intervention.   Dysrhythmias (arrhythmias), which are disturbances of  cardiac rhythm, are the most common complication of acute  MI. Dysrhythmias can be caused by ischemia, hypoxia, auto-  nomic nervous system (ANS) imbalances, lactic acidosis,  electrolyte abnormalities, alterations of impulse conduction  pathways or conduction defects, drug toxicity, or hemodynamic    abnormalities. Dysrhythmias may originate from the atria, ven-  tricles, nodal regions, or conduction tissues. The seriousness  of dysrhythmias depends on the hemodynamic consequences.  (Dysrhythmias are described in Table 32-12.) Prophylactic use  of antiarrhythmics, such as lidocaine and amiodarone, do not  improve mortality; however, individuals at high risk should be  considered for implantable cardioverter-defibrillators (ICDs).   Acute MI is accompanied by functional impairment of the  myocardium. The severity of functional impairment depends  on the size and the site of infarction. Functional changes can  include: (1) decreased cardiac contractility with abnormal wall  motion, (2) altered left ventricular compliance, (3) decreased  stroke volume, (4) decreased ejection fraction, (5) increased left  ventricular end-diastolic pressure (LVEDP), and (6) SA or AV  node malfunction. Many infarctions result in some degree of  left ventricular failure (congestive heart failure), which is char-  acterized by pulmonary congestion, reduced myocardial con-  tractility, and abnormal heart wall motion. Anterior infarction  is associated with more severe left heart failure than is inferior  infarction. If cardiac output is insufficient to maintain normal  arterial pressure and to perfuse the kidneys and other organs  adequately, cardiogenic shock develops.'*’ (Cardiogenic shock  is discussed in Chapter 48.)   Inflammation of the pericardium (pericarditis) is a com-  mon complication of acute MI. Pericardial friction rubs  often are noted 2 to 3 days after MI and are associated with  anterior chest pain that worsens with respiratory effort. Spe-  cific treatment is not required; however, corticosteroids  dramatically relieve symptoms. Dressler postinfarction  syndrome, which is a delayed form of acute pericarditis,  can occur from 1 week to several months after acute MI.  Although poorly understood, the syndrome is thought to be  an immunologic (antigen-antibody) response to the necrotic  myocardium. Pain, fever, friction rub, pleural effusion, and  arthralgiasmayaccompanythissyndrome. Steroids mayalleviate  symptoms.    Episodes of extreme mental stress, like the loss of a loved one, have been linked  to sudden onset of myocardial ischemia, arrhythmias, heart failure, shock, and  even death. This has been called the “broken heart syndrome.” This phenom-  enon, now called Takotsubo cardiomyopathy, was first described in Japan in  1991, where it was found to occur most often in postmenopausal women at  times of acute stress. Since then it has been found to occur in women and  men of all ages, and many other stressful triggers have been identified such as  earthquakes, lightning strikes, noncardiac surgery, seizures, trauma, anesthe-  sia, and alcohol withdrawal to name just a few. Although the manifestations  are variable, it has been found that many individuals have weakening and bal-  looning of the left ventricular apex during systole that begins within minutes  to hours after the stressful episode. Although the pathophysiology is still being  explored, catecholamines play an important role in the pathogenesis causing  coronary artery spasm, coronary microvascular abnormalities, direct myocar-  dial damage, and neurogenic myocardial stunning. Postmenopausal women    may be especially vulnerable because of estrogen deficiency—mediated effects  on the microvasculature. On myocardial biopsy, most people have inflamma-  tion without necrosis. People with Takotsubo cardiomyopathy present clini-  cally with the same symptoms as acute ST-elevation myocardial infarction  (STEMI), including chest pain, dyspnea, ST-segment elevation, and moderately  elevated cardiac biomarkers, such as troponins and brain natriuretic peptide.  The American Heart Association/May Criteria for the diagnosis describe tran-  sient dyskinesis of the left ventricle in the absence of acute coronary ar  disease, acute head trauma, myocarditis, or other forms of cardiomyopa  Management usually includes aspirin, beta-blockers, angiotensin-converti  enzyme inhibitors, and statins, although targeted emotional support and s  dard psychologic counseling have the greatest effect on recovery and reduc-  ing the risk for recurrence. An interprofessional team that includes a social  worker, pastor, and mental health care providers has been found beneficial for  those suffering from this cardiomyopathy.    Data from Ahmed KA, Madhavan M, Prasad A: Coron Artery Dis 23(4):259-264, 2012; Golabchi A, Sarrafzadegan N: J Res Med Sci 16(3):340-345,  2011; Neil CJ et al: Exp Rev Cardiovasc Ther 10(2):215-221, 2012; Shah RM et al: Am J Ther 19(3):e105-e113, 2012.    Organic brain syndrome may occur in acute or chronic  form if blood flow to the brain is impaired secondary to MI.  Transient ischemic attacks or an outright cerebrovascular acci-  dent may result from thromboemboli that have broken loose  from the wall of the left ventricle or from cardiac valves.   Cardiac complications of MI can include rupture of heart  structures. Tissue necrosis in or around the papillary muscles  can cause rupture of these muscles or of the chordae tendin-  eae. Factors that lead to rupture of the free wall of the infarcted  ventricle include thinning of the wall, poor collateral flow,  shearing effect of muscular contraction against the stiffened  necrotic area, marked necrosis at the terminal end of the  blood supply, and aging of the myocardium with laceration  of the myocardial microstructure. Infarctions around septal  structures that separate the heart chambers can lead to septal  rupture. Ruptures are associated with audible, harsh cardiac  murmurs; increased LVEDP; and decreased systemic blood  pressure.   Weakening of the wall of the infarcted ventricle can cause  ventricular aneurysm formation. According to Laplace’s law,  with decreased muscle mass at the infarcted site, the wall is  weakened and tension stretches the noncontracting infarcted  heart muscle, thus producing infarct expansion or aneurysm  formation (see p. 1140 for a discussion of aneurysm). Decreased  muscle mass causes an increase in the radius of the ventricle,  and because the radius is directly proportional to pressure and  tension, both increase with time. The wall of the aneurysm  becomes more fibrotic but continues to bulge with systole. The  bulge results in impaired pump function. Although rare, rup-  ture may occur when the tension becomes too great. Death in  individuals with a left ventricular aneurysm is usually related to  ventricular tachydysrhythmias and not to ventricular rupture.  Left ventricular aneurysm is a late complication of MI, occur-  ring months or years after the acute event.   Thromboembolism is commonly found during postmortem  examinations of individuals who have died of MI. Thromboem-  boli may disseminate from debris and clots that collect inside  dilated aneurysmal sacs or from the infarcted endocardium and  travel to the pulmonary or systemic vascular systems. Pulmo-  nary emboli also may result from the breaking loose of deep  venous thrombi of the legs in individuals who are confined to  bed (see p. 1275). Early mobilization and prophylactic antico-  agulation therapy are essential to reduce the incidence of this  complication.   Sudden death resulting from cardiac arrest is often caused  by dysrhythmias, particularly ventricular fibrillation. Other  dysrhythmias may be equally lethal. Widespread knowledge  of cardiopulmonary resuscitation has increased the probabil-  ity of survival during the first few hours after cardiac insult.  Immediate intervention and careful monitoring also have  reduced mortality and have improved chances for long-term  survival. Several factors, however, contribute to the risk of  death during acute infarction or reduce the chances of long-  term survival, despite the best possible treatment. They are:  (1) degree of left ventricular dysfunction, (2) degree of left  ventricular ischemia, (3) potential for ventricular dysrhyth-  mias, and (4) the individual’s age.    Pericardial disease is often a manifestation of another disorder,  such as infection (bacterial, viral, fungal, rickettsial, parasitic);  trauma or surgery; neoplasm; or a metabolic, immunologic, or  vascular disorder (uremia, rheumatoid arthritis, systemic lupus  erythematosus, periarteritis nodosa). The pericardial response  to injury from these diverse causes may consist of acute pericar-  ditis, pericardial effusion, or constrictive pericarditis.    Acute pericarditis is acute inflammation of the pericardium. The  etiology of acute pericarditis is most often idiopathic or caused  by viral infection by coxsackievirus, influenza, hepatitis, measles,  mumps, or varicella viruses. It also is the most common cardio-  vascular complication of human immunodeficiency virus (HIV)  infection. Other causes include MI, trauma, neoplasm, surgery,  uremia, bacterial infection (especially tuberculosis), connec-  tive tissue disease (especially systemic lupus erythematosus and  rheumatoid arthritis), or radiation therapy.'*? The pericardial  membranes become inflamed and roughened, and a pericardial  effusion may develop that can be serous, purulent, or fibrinous  (Figure 32-25). Possible sequelae of pericarditis include recurrent  pericarditis, pericardial constriction, and cardiac tamponade.   Most individuals with acute pericarditis describe several days  of fever, myalgias, and malaise followed by the sudden onset of  severe chest pain that worsens with respiratory movements and  with lying down. Although the pain may radiate to the back, it is  generally felt in the anterior chest and may be confused initially  with the pain of acute MI. Individuals with acute pericarditis  also may report dysphagia, restlessness, irritability, anxiety, and  weakness.   Physical examination often discloses low-grade fever and  sinus tachycardia. A pericardial friction rub—a short, scratchy,  grating sound—may be heard at the cardiac apex and left sternal    FIGURE 32-25 Acute Pericarditis. Note shaggy coat of fibers covering sur-  face of heart. (From Damjanov |, Linder J: Pathology: a color atlas, St Louis, 2000,  Mosby.)    border and is highly specific for pericarditis. The rub is caused  by the roughened pericardial membranes rubbing against each  other. Friction rubs are not always present and may be intermit-  tently heard. ECG changes may reflect inflammatory processes  through diffuse ST-segment elevation that is concaved upward  without Q waves.!*° The ECG may remain abnormal for days or  even weeks. Echocardiography may reveal a pericardial effusion.   Treatment for uncomplicated acute pericarditis consists of  relieving symptoms. Rest is helpful during episodes of acute  pain. Salicylates and nonsteroidal anti-inflammatory drugs  (NSAIDs) reduce inflammation. Combined nonsteroidals and  colchicine (prevents fibrosis) is a highly effective regimen.'*°  Additional analgesics may be given to relieve pain. Exploring  the underlying cause is important. If pericardial effusion devel-  ops, aspirating the excessive fluid may be necessary.    Pericardial effusion, the accumulation of fluid in the pericar-  dial cavity, can occur in all forms of pericarditis. The fluid may  be a transudate, such as the serous effusion that develops with  left heart failure, overhydration, or hypoproteinemia. More  often, however, the fluid is an exudate, which indicates pericar-  dial inflammation like that seen with acute pericarditis, heart  surgery, some chemotherapeutic agents, infections, and auto-  immune disorders, such as systemic lupus erythematosus. '4>)'4¢  (Types of exudate are described in Chapter 7.) If the fluid is  serosanguineous, the underlying cause is likely to be tubercu-  losis, neoplasm, uremia, or radiation. Idiopathic serosanguine-  ous (cause unknown) effusion is possible, however. Effusions  of frank blood are generally related to aneurysms, trauma, or  coagulation defects. If chyle leaks from the thoracic duct, it may  enter the pericardium and lead to cholesterol pericarditis.  Pericardial effusion, even in large amounts, is not necessarily  clinically significant, except that it indicates an underlying dis-  order. The important consideration is whether the fluid creates  sufficient pressure to cause cardiac compression, which is a seri-  ous condition known as tamponade.'*° If an effusion develops  gradually, the pericardium can stretch to accommodate large  quantities of fluid without compressing the heart. If the fluid  accumulates rapidly, however, even a small amount (50 to 100  ml) may cause serious tamponade. The danger is that pressure  exerted by the pericardial fluid eventually equals diastolic pres-  sure within the heart chambers, thus preventing chamber filling.  The first structures to be affected by tamponade are the right  atrium and ventricle, where diastolic pressures are normally  lowest. Compression by pericardial fluid interferes with right  atrial filling during diastole, resulting in increased venous pres-  sure, systemic venous congestion, and signs and symptoms of  right heart failure (distention of the jugular veins, edema, hepa-  tomegaly). Decreased atrial filling leads to decreased ventricular  filling, decreased stroke volume, and reduced cardiac output. If  the left atrium collapses because of lack of filling, life-threaten-  ing circulatory collapse may occur.'*>!“° Individuals with car-  diac tamponade most often present with dyspnea, tachycardia,  jugular venous distention, cardiomegaly, and pulsus paradoxus.  Pulsus paradoxus means that the arterial blood pressure during  expiration exceeds arterial pressure during inspiration by more    than 10 mmHg. This clinical finding reflects impairment of dia-  stolic filling of the left ventricle plus reduction of blood volume  within all four cardiac chambers. Presence of a large pericar-  dial effusion or tamponade magnifies the normally insignificant  effect of inspiration on intracardiac flow and volume.   Other clinical manifestations of pericardial effusion are  distant or muffled heart sounds, poorly palpable apical pulse,  dyspnea on exertion, and dull chest pain. A chest x-ray may dis-  close a “water-bottle” configuration of the cardiac silhouette.  An echocardiogram can detect an effusion as small as 20 ml and  is considered the most accurate and reliable method of diagno-  sis, although CT also is commonly used.!*°   Treatment of pericardial effusion or tamponade generally  consists of pericardiocentesis (aspiration of excessive pericar-  dial fluid). Pericardiocentesis is diagnostic and therapeutic: the  fluid is analyzed to identify the cause of the effusion, and its  removal alone may bring dramatic relief from symptoms. Per-  sistent pain may be treated with analgesics, anti-inflammatory  medications, or steroids. Surgery may be required if the under-  lying cause of tamponade is trauma or aneurysm. If an effusion  is neoplasm induced, chemotherapeutic agents may be injected  into the pericardial space.'*° If the effusion recurs, a pericar-  dial “window” can be created or the individual may require  pericardectomy.    Constrictive pericarditis, or restrictive pericarditis (chronic  pericarditis), was synonymous with tuberculosis years ago, and  tuberculosis continues to be an important cause of pericarditis  in immunocompromised individuals.'4° In the United States  this form of pericardial disease is more often idiopathic or asso-  ciated with radiation exposure, rheumatoid arthritis, uremia, or  CABG. In constrictive pericarditis, fibrous scarring with occa-  sional calcification of the pericardium causes the visceral and  parietal pericardial layers to adhere, obliterating the pericar-  dial cavity. The fibrotic lesions encase the heart in a rigid shell  (Figure 32-26). Like tamponade, constrictive pericarditis com-  presses the heart and eventually reduces cardiac output. Unlike  tamponade, however, constrictive pericarditis never develops  suddenly.   Because the onset of constrictive pericarditis is gradual, clini-  cal manifestations seldom include pulsus paradoxus. Symptoms  tend to be exercise intolerance, dyspnea on exertion, fatigue, and  anorexia. Clinical assessment shows weight loss, edema, jugular  vein distention, and hepatic congestion. Restricted ventricular  filling may cause a pericardial knock (early diastolic sound).   ECG findings include T-wave inversions and atrial fibrilla-  tion. Chest x-ray often discloses prominent pulmonary vessels  and calcification of the pericardium. CT, MRI, and transesoph-  ageal echocardiography are used to detect pericardial thick-  ening and constriction. Pericardial biopsy may be needed to  determine the etiology.   Initial treatment for constrictive pericarditis consists of  dietary sodium restriction, digitalis glycosides, and diuretics  to improve cardiac output.'*>'4° If these modalities are not  successful, surgical excision of the restrictive pericardium is  indicated.    FIGURE 32-26 Constrictive Pericarditis. The fibrotic pericardium encases  the heart in a rigid shell. (From Damjanov |, Linder J: Pathology: a color atlas,  St Louis, 2000, Mosby.)    The cardiomyopathies are a diverse group of diseases that affect  the myocardium. Most are the result of remodeling caused by the  effect of the neurohumoral responses to ischemic heart disease  or hypertension on the heart muscle. Cardiomyopathies also can  be secondary to inherited disorders, infectious disease, exposure  to toxins, systemic connective tissue disease, infiltrative and pro-  liferative disorders, or nutritional deficiencies. Many cases of  cardiomyopathy are idiopathic. The cardiomyopathies are cat-  egorized as dilated, hypertrophic, or restrictive depending on  their tissue characteristics, genomics, and hemodynamic effects  (Figure 32-27 and Table 32-8). An individual may display charac-  teristics of more than one type.    Dilated cardiomyopathy is characterized by diminished myo-  cardial contractility, which is reflected in diminished systolic  performance of the heart. This impaired systolic function  leads to increases in intracardiac volume, ventricular dilation,  and systolic heart failure (Figure 32-28). This form of cardio-  myopathy is usually the result of ischemic heart disease, val-  vular disease, diabetes, renal failure, hyperthyroidism, alcohol  or drug toxicity, peripartum complications, genetic disorder,  or infection. Idiopathic dilated cardiomyopathy often has a  familial origin with associated alterations in genes coding for  contractile proteins, mitochondrial dysfunction, and immune  defects.'47148   Ischemic cardiomyopathy is the most common and can  occur as the direct result of myocardial infarction or can result  from repetitive ischemic insults in those with poorly controlled  angina.'“? Valvular heart disease causes cardiac chamber volume  and pressure overload that can result in long-term myocardial    FIGURE 32-27 Diagram Showing Major Distinguishing Pathophysiologic  Features of the Types of Cardiomyopathy. A, The normal heart. B, In the  dilated type of cardiomyopathy, the heart has a globular shape, and the largest  circumference of the left ventricle is not at its base but midway between apex and  base. C, In the hypertrophic type of cardiomyopathy the wall of the left ventricle  is greatly thickened; the left ventricular cavity is small, but the left atrium may be  dilated because of poor diastolic relaxation of the ventricle. D, In the restrictive  type the left ventricular cavity is of normal size, but again, the left atrium is dilated  because of the reduced diastolic compliance of the ventricle. (From Kissane JM,  editor: Anderson’s pathology, ed 9, St Louis, 1990, Mosby.)    dysfunction. Diabetes and uremia are associated with decreased  myocardial contractility and dilated cardiomyopathy. Alcohol  can be directly toxic to the myocardium, as can many drugs  such as some chemotherapeutic, inotropic, and antidysrhythmic  agents. Many nutritional deficiencies can cause cardiomyopathy  including niacin, vitamin D, and selenium. Peripartum cardio-  myopathy occurs in previously healthy women in the final month  of pregnancy and up to 5 months after delivery. Although the  incidence is less than 0.1% of pregnancies, morbidity and mor-  tality rates are high at 5% to 32%.!°° Dilated cardiomyopathies  also may be the late autoimmune consequences of previous viral  infections resulting in myocarditis and subsequent decreases in  contractility.'°! Hyperthyroidism may present with atrial fibril-  lation and dilated cardiomyopathy, which may be reversible with  treatment of the thyroid disorder. (Pathophysiologic effects of  the cardiomyopathies are summarized in Table 32-8.)   The most common symptoms of dilated cardiomyopathy  are dyspnea and fatigue. Pulmonary congestion is expected,  although fulminant pulmonary edema is uncommon. Pal-  pitations and associated dysrhythmias may cause dizziness  (syncope). Systemic and pulmonary emboli are common com-  plications. Chest pain may be present but it is usually nonspecific  and unlike anginal pain.    FIGURE 32-28 Dilated Cardiomyopathy. The dilated left ventricle has a thin  wall (V). (From Stevens A, Lowe JS, Scott |: Core pathology, ed 3, London, 2009,  Mosby.)    In the presence of dilated heart failure, blood pressure may  be elevated initially; however, hypotension indicates progres-  sive decreases in contractility. Extra heart sounds and cardiac  murmurs may be present as well. Echocardiography and MRI  can confirm the diagnosis; however, careful evaluation for  potentially reversible underlying causes is essential.   General treatment for dilated cardiomyopathy consists  of salt restriction and the careful use of vasodilators, diuret-  ics, and inotropic agents. Anticoagulants are given to pre-  vent pulmonary and systemic embolism. Corticosteroids and    immunosuppressants can benefit individuals with documented  inflammatory disease. Myocardial pacemakers (pacing) can  improve cardiac output in many individuals. Cardiac transplan-  tation may be lifesaving. The use of cardiac stem cells to restore  myocardial contractility is an area of promising research.!°7    Hypertrophic Cardiomyopathy  Hypertrophic cardiomyopathy refers to two major categories of  thickening of the myocardium: (1) hypertrophic obstructive car-  diomyopathy (asymmetric septal hypertrophic cardiomyopathy  or subaortic stenosis), and (2) hypertensive or valvular hyper-  trophic cardiomyopathy. These two categories are very different  in their etiology, pathophysiology, and clinical presentation.  Hypertrophic obstructive cardiomyopathy is the most com-  mon inherited heart defect, occurring in 1 of 500 individuals  through autosomal dominant inheritance.° It is characterized by  thickening of the septal wall (Figure 32-29), which may cause  outflow obstruction to the left ventricle outflow tract. Addi-  tional changes include abnormalities of collagen deposition and  altered contractile proteins in the myocytes.'°? The thickening  of the septum results in a hyperdynamic state, especially with  exercise. Diastolic relaxation also is impaired and ventricular  compliance is decreased. Obstruction of left ventricular outflow  can occur when heart rate is increased and intravascular volume  is decreased. Individuals complain of angina, syncope, palpita-  tions, and symptoms of MI and left heart failure. Examination  may reveal extra heart sounds and murmurs. Echocardiography  and cardiac catheterization can confirm the diagnosis.!** This  type of hypertrophic cardiomyopathy is a significant risk for  serious ventricular arrhythmias and sudden death. Management  includes beta-blockers or verapamil to slow the heart rate, surgi-  cal resection of the hypertrophied myocardium, septal ablation,  and prophylactic placement of an ICD in high-risk individuals.'*>    FIGURE 32-29 Hypertrophic Cardiomyopathy. There is marked left ven-  tricular hypertrophy. This often affects the septum (S). (From Stevens A, Lowe JS,  Scott |: Core pathology, ed 3, London, 2009, Mosby.)    Hypertensive or valvular hypertrophic cardiomyopathy  occurs because of increased resistance to ventricular ejection  commonly seen in hypertension or in valvular stenosis (usually  aortic). In this case, hypertrophy of the myocytes is an attempt to  compensate for increased myocardial workload. Long-term dys-  function of the myocytes develops over time, with first diastolic  dysfunction leading eventually to systolic dysfunction of the  ventricle (see Heart Failure, p. 1175). Individuals with hypertro-  phic cardiomyopathy may be asymptomatic or may complain of  angina, syncope, dyspnea on exertion, and palpitations. Exami-  nation may reveal extra heart sounds and murmurs. Echocar-  diography and cardiac catheterization can confirm the diagnosis.    Restrictive cardiomyopathy is characterized by restrictive filling  and reduced diastolic volume of either or both ventricles with  normal or near-normal systolic function and wall thickness.'°° It  may occur idiopathically or as a cardiac manifestation of systemic  diseases, such as scleroderma, amyloidosis, sarcoidosis, lym-  phoma, and hemochromatosis, or a number of inherited stor-  age diseases. The myocardium becomes rigid and noncompliant,  impeding ventricular filling and raising filling pressures during  diastole. The overall clinical and hemodynamic picture mimics  and may be confused with that of constrictive pericarditis.   The most common clinical manifestation of restrictive car-  diomyopathy is right heart failure with systemic venous conges-  tion. Cardiomegaly and dysrhythmias are common. A thorough  evaluation for the underlying cause should be initiated (and  may include myocardial biopsy).!°° Treatment is aimed at the  underlying cause. Death occurs as a result of heart failure or  dysrhythmias.   Disorders of the endocardium, the innermost lining of the heart  wall, all damage the heart valves, which are made up of endo-  cardial tissue. Endocardial damage can be either congenital or    Cusp Fused cusps Cusp  Orifice Orifice  Normal A Normal Stenosed PB  Stenosed  valve valve valve valve  (open) (closed) (open) (closed)    FIGURE 32-30 Valvular Stenosis and Regurgitation. A, Normal position of  the valve leaflets, or cusps, when the valve is open and closed. B, Open position  of a stenosed valve (/eft) and open position of a closed regurgitant valve (right). C,  Hemodynamic effect of mitral stenosis. The stenosed valve is unable to open suf-  ficiently during left atrial systole, inhibiting left ventricular filling. D, Hemodynamic  effect of mitral regurgitation. The mitral valve does not close completely during left  ventricular systole, permitting blood to reenter the left atrium.    acquired. The acquired forms cause inflammatory, ischemic,  traumatic, degenerative, or infectious alterations of valvular  structure and function. Structural alterations of the heart valves  lead to stenosis, incompetence, or both. Although all four heart  valves may be affected, those of the left heart (mitral and aortic  semilunar valves) are more commonly affected than those of  the right heart (tricuspid and pulmonic semilunar valves).   In valvular stenosis the valve orifice is constricted and nar-  rowed, impeding the forward flow of blood and increasing the  workload of the cardiac chamber proximal to the diseased valve  (Figure 32-30). Intraventricular or atrial pressure increases in  the chamber to overcome resistance to flow through the valve.  Increased pressure causes the myocardium to work harder, caus-  ing myocardial hypertrophy. In valvular regurgitation (also  called insufficiency or incompetence) the valve leaflets, or cusps, fail  to shut completely, permitting blood flow to continue even when  the valve is supposed to be closed (see Figure 32-30). During sys-  tole or diastole some blood leaks back into the chamber proximal  to the incompetent valve. Valvular regurgitation increases the  volume of blood the heart must pump and increases the work-  load of the affected heart chamber. Increased volume leads to  chamber dilation, and increased workload leads to hypertrophy.   Valvular dysfunction stimulates chamber dilation and/  or myocardial hypertrophy, both of which are compensatory  mechanisms intended to increase the pumping capability of  the heart. Eventually, myocardial contractility is diminished,  the ejection fraction is reduced, diastolic pressure increases,  and the affected heart chamber fails from overwork. Depend-  ing on the severity of the valvular dysfunction and the capacity  of the heart to compensate, valvular alterations cause a range  of symptoms and some degree of incapacitation (Table 32-9).    Left ventricular  hypertrophy followed  by left heart failure;  decreased coronary  blood flow with  myocardial ischemia   Systolic murmur heard  best at the right  parasternal second  intercostal space and  radiating to the neck    Left atrial hypertrophy and  dilation with fibrillation,  followed by right  ventricular failure    Pulmonary edema: dyspnea  on exertion, orthopnea,  paroxysmal, nocturnal  dyspnea, predisposition  to respiratory infections,  hemoptysis, pulmonary  hypertension, and edema   Low rumbling diastolic  murmur heard best at the  apex and radiating to the  axilla, accentuated first  heart sound, opening snap    Infective endocarditis;  aortic root disease  (connective tissue  diseases, Marfan  syndrome); dilation of  the aortic root due to   Diastolic murmur heard  best at the right  parasternal second  intercostal space and  radiating to the neck   Murmur throughout  systole heard best  at the apex and  radiating to the  axilla   Murmur throughout  systole heard best  at the left lower  sternal border    Data from Braunwald E, editor: Heart disease: a textbook of cardiovascular medicine, ed 7, Philadelphia, 2005, Saunders; Carabello BA, Paulus WJ:  Valvular heart disease. In Crawford MH, DiMarco JP, editors: Cardiology, London, 2001, Mosby-Wolfe.    In general, valvular disease is diagnosed by echocardiography,  which can be used to assess the severity of valvular obstruction  or regurgitation before the onset of symptoms. Management  almost always includes careful fluid management, valvular  repair, or valve replacement with a prosthetic valve followed by  long-term anticoagulation.!*” In the case of mechanical valve  replacement, lifelong antibiotic prophylaxis prior to invasive  procedures is required.!**   Aortic Stenosis. Aortic stenosis is the most common val-  vular abnormality affecting nearly 2% of adults older than 65  years.” The three common causes are: (1) congenital bicuspid  valve, (2) calcific degeneration related to aging, and (3) inflam-  matory damage caused by rheumatic heart disease (less than  10% of cases). Numerous gene abnormalities have been associ-  ated with aortic stenosis. Aortic stenosis is also associated with  many risk factors for coronary artery disease. In the United  States, 29% of adults were found to have degenerative sclerotic  aortic valves, and approximately 2% to 5% progress to aortic  stenosis.*!°? Aortic valve degeneration with aging is associated  with lipoprotein deposition in the tissue with chronic inflam-  mation and leaflet calcification. Evidence suggests that degen-  erative aortic stenosis is linked to hyperlipidemia and that its    prevalence might be decreased by more aggressive lipid lower-  ing in adults. Disorders in calcium transport, apoptosis of endo-  cardial cells, and decreased nitric oxide synthesis also have been  implicated. In aortic stenosis from any cause, the orifice of the  aortic semilunar valve narrows, causing diminished blood flow  from the left ventricle into the aorta (Figures 32-31). Outflow  obstruction increases pressure within the left ventricle as it tries  to eject blood through the narrowed opening. Left ventricular  hypertrophy develops to compensate for the increased work-  load. Eventually, hypertrophy increases myocardial oxygen  demand that the coronary arteries may not be able to supply.  If this occurs, ischemia may cause attacks of angina. Untreated  aortic stenosis can lead to dysrhythmias, myocardial infarction,  and heart failure.   Aortic stenosis tends to develop gradually. The classic mani-  festations of aortic stenosis are angina, syncope, and heart fail-  ure. Clinical manifestations include decreased stroke volume,  reduced systolic blood pressure, and narrowed pulse pressure  (difference between systolic and diastolic pressure). Heart rate  is often slow, and pulses are faint. Resistance to flow through  the stenotic valve gives rise to a crescendo-decrescendo systolic  heart murmur heard best at the second intercostal space and  may radiate to the neck. Echocardiography is used to follow    FIGURE 32-31 Aortic Stenosis. Mild stenosis in valve leaflets of a young  adult. (From Damjanov |, Linder J: Pathology: a color atlas, St Louis, 2000, Mosby.)    FIGURE 32-32 Mitral Stenosis with Classic “Fish Mouth” (Arrows) Ori-  fice. (From Kumar V, et al: Robbins & Cotran pathologic basis of disease, ed 8,  St Louis, 2010, Mosby.)    valve orifice and cardiac functioning. Medical management  with careful monitoring for complications, such as heart fail-  ure and myocardial ischemia, may be indicated for selected  individuals, but most require valve repair or replacement with  a prosthetic valve followed by long-term anticoagulation.'°”  Transcatheter aortic valve implantation is used increasingly to  avoid major heart surgery in selected individuals.'°? The prog-  nosis is poor once an individual becomes symptomatic from  aortic stenosis.!°?   Mitral Stenosis. Mitral stenosis impairs the flow of blood  from the left atrium to the left ventricle. Mitral stenosis is most  commonly caused by acute rheumatic fever (see p. 1171) and is  two to three times more common in women than in men. Con-  genital mitral valve stenosis is less common and includes a wide  range of anatomic variants.'°! Autoimmunity in response to  group A beta-hemolytic streptococcal M protein antigens leads  to inflammation and scarring of the valvular leaflets. Scarring  causes the leaflets to become fibrous and fused and the chordae  tendineae cordis becomes shortened (Figure 32-32).   Clinical manifestations depend on the size of the valvular ori-  fice. Impedance to blood flow results in incomplete emptying of  the left atrium and elevated atrial pressure as the chamber tries    to force blood through the stenotic valve. Continued increases  in left atrial volume and pressure cause chamber dilation and  hypertrophy. The risk of developing atrial dysrhythmias (espe-  cially fibrillation) and dysrhythmia-induced thrombi is high.  As mitral stenosis progresses, symptoms of decreased cardiac  output occur, especially during exertion. Continued elevation  of left atrial pressure and volume causes pressure to rise in the  pulmonary circulation. The outcomes of untreated chronic  mitral stenosis are pulmonary hypertension, edema, and right  ventricular failure.   Blood flow through the stenotic valve gives rise to a rum-  bling decrescendo diastolic murmur heard best over the car-  diac apex and radiating to the left axilla. If the mitral valve is  forced open during diastole, it may make a sharp noise called  an opening snap. The first heart sound (S;) is often accentuated  and somewhat delayed because of increased left atrial pressure.  Other signs and symptoms result from pulmonary congestion  and right heart failure. Atrial enlargement is demonstrated by  chest x-rays and electrocardiography. Mitral stenosis can often  be repaired surgically but may require valve replacement in  advanced cases.!°7   Aortic Regurgitation. Aortic regurgitation results from  an inability of the aortic valve leaflets to close properly during  diastole resulting from abnormalities of the leaflets or the aortic  root, or both. It can be congenital (bicuspid valve) or acquired.  Acquired aortic regurgitation can be caused by rheumatic heart  disease, bacterial endocarditis, syphilis, hypertension, con-  nective tissue disorders (e.g., Marfan syndrome and ankylos-  ing spondylitis), appetite-suppressing medications, trauma, or  atherosclerosis. More than a third of cases of aortic regurgita-  tion are idiopathic. The hemodynamic repercussions depend  on the size of the “leak.” During systole, blood is ejected from  the left ventricle into the aorta. If the aortic semilunar valve fails  to close completely, some of the ejected blood flows back into  the left ventricle during diastole. Volume overload occurs in the  ventricle because it receives blood from the left atrium and the  aorta during diastole. Over time, the end-diastolic volume of  the left ventricle increases and myocardial fibers stretch to  accommodate the extra fluid. Compensatory dilation permits  the left ventricle to increase its stroke volume and maintain  cardiac output. Ventricular hypertrophy also occurs as an adap-  tation to the increased volume and increased afterload created  by the high stroke volume and resultant systolic hypertension.  Ventricular dilation and hypertrophy eventually cease to com-  pensate for aortic incompetence, and heart failure develops.   Clinical manifestations include widened pulse pressure  resulting from increased stroke volume and diastolic backflow.  Turbulence across the aortic valve during diastole produces a  decrescendo murmur heard best in the second, third, or fourth  intercostal spaces parasternally and may radiate to the neck.  Large stroke volume and rapid runoff of blood from the aorta  cause prominent carotid pulsations and bounding peripheral  pulses (Corrigan pulse). Other symptoms are usually associ-  ated with heart failure that occurs when the ventricle can no  longer pump adequately. Dysrhythmias and endocarditis are  common complications of aortic regurgitation. The severity of    FIGURE 32-33 Mitral Valve Prolapse. A, Prolapsed mitral valve. Prolapse permits the valve leaflets to billow back    (arrow) into the atrium during left ventricular systole. The billowing causes the leaflets to part slightly, permitting regurgitation  into the atrium. B, Looking down into the mitral valve, the ballooning (arrows) of the leaflets is seen. (From Kumar V, et al:  Robbins & Cotran pathologic basis of disease, ed 8, St Louis, 2010, Mosby.)    regurgitation can be estimated by echocardiography, and valve  replacement may be delayed for many years through careful use  of vasodilators and inotropic agents.!°7   Mitral Regurgitation. Mitral regurgitation has a variety of  causes. The most common are mitral valve prolapse and rheu-  matic heart disease. Other causes include infective endocarditis,  CAD, connective tissue diseases (Marfan syndrome), and con-  gestive cardiomyopathy. Mitral regurgitation permits backflow  of blood from the left ventricle into the left atrium during ven-  tricular systole, giving rise to a loud pansystolic (throughout sys-  tole) murmur heard best at the apex that radiates into the back  and axilla. Because of increased volume in the left atrium that  then enters the ventricle, the left ventricle becomes dilated and  hypertrophied to maintain adequate cardiac output. The vol-  ume of backflow reentering the left atrium gradually increases,  causing atrial dilation and associated atrial fibrillation. As the  left atrium enlarges, the valve structures stretch and become  deformed, leading to further backflow. As mitral valve regurgita-  tion progresses, left ventricular function may become impaired  to the point of failure. Eventually, increased atrial pressure also  causes pulmonary hypertension and failure of the right ventricle.  Mitral incompetence is usually well tolerated—often for years—  until ventricular failure occurs. Most clinical manifestations are  caused by heart failure. The severity of regurgitation can be esti-  mated by echocardiography, and surgical repair or valve replace-  ment may become necessary.!°”!® In acute mitral regurgitation  caused by MI, surgical repair must be done emergently.   Tricuspid Regurgitation. Tricuspid regurgitation is more  common than tricuspid stenosis and usually is associated with  dilation and failure of the right ventricle secondary to pulmo-  nary hypertension. Rheumatic heart disease and infective endo-  carditis are less common causes. Tricuspid valve incompetence    leads to volume overload in the right atrium and ventricle,  increased systemic venous blood pressure, and right heart fail-  ure.!® Pulmonic valve dysfunction can have the same conse-  quences as tricuspid valve dysfunction.   Mitral Valve Prolapse Syndrome. Mitral valve prolapse  syndrome is a condition in which the anterior and posterior  cusps of the mitral valve billow upward (prolapse) into the  atrium during systole (Figure 32-33). The most common  cause of mitral valve prolapse is myxomatous degeneration of  the leaflets in which the cusps are redundant, thickened, and  scalloped because of changes in tissue proteoglycans, increased  proteinases, and infiltration by myofibroblasts. The chordae  tendineae may be elongated, permitting the valve cusps to  stretch upward. Mitral regurgitation occurs if the ballooning  valve permits blood to leak into the atrium.'*   Mitral valve prolapse is the most common valve disorder in  the United States, with a prevalence estimated at 2.4%.° Mitral  valve prolapse tends to be most prevalent in young women. Stud-  ies suggest an autosomal dominant and X-linked inheritance  pattern. Because mitral valve prolapse often is associated with  other inherited connective tissue disorders (Marfan syndrome,  Ehlers-Danlos syndrome, osteogenesis imperfecta), it is thought  to result from a genetic or environmental disruption of valvular  development during the fifth or sixth week of gestation. There  may be a relationship between symptomatic mitral valve pro-  lapse and hyperthyroidism. Other neuroendocrine abnormalities  have been suggested, including polymorphisms of the angioten-  sin II type 1 (AT,) receptor and alterations in ANS function.!°4   Many cases of mitral valve prolapse are completely asympto-  matic. Cardiac auscultation on routine physical examination may  disclose a regurgitant murmur or midsystolic click in an otherwise  healthy individual, or echocardiography may demonstrate the    condition in the absence of auscultatory findings. Symptomatic  mitral valve prolapse can cause palpitations related to dysrhyth-  mias, tachycardia, lightheadedness, syncope, fatigue (especially  in the morning), lethargy, weakness, dyspnea, chest tightness,  hyperventilation, anxiety, depression, panic attacks, and atypical  chest pain. Many symptoms are vague and puzzling and are unre-  lated to the degree of prolapse. Although severe sequelae—such  as chordae rupture, ventricular failure, systemic emboli, and sud-  den death—are possible, the disorder is actually associated with  minimal mortality and morbidity. Most individuals with mitral  valve prolapse have an excellent prognosis, do not develop symp-  toms, and do not require any restriction in activity or medical  management. Occasionally, beta-blockers are needed to alleviate  syncope, severe chest pain, or palpitations. However, a subset of  individuals have an increased risk for complications such as infec-  tive endocarditis, cardioembolic stroke, and sudden death. These  high-risk individuals can be identified by clinical and echocardio-  graphic findings. If regurgitation is present, medical treatment  includes afterload reduction, diuresis, anticoagulation for associ-  ated atrial fibrillation, and other medications for heart failure.'    Rheumatic fever is a systemic, inflammatory disease caused  by a delayed immune response to infection by group A beta-  hemolytic streptococci.'© In its acute form rheumatic fever is a  febrile illness characterized by inflammation of the joints, skin,  nervous system, and heart.!°° If untreated, rheumatic fever can  cause scarring and deformity of cardiac structures, resulting in  rheumatic heart disease (RHD).   The incidence of acute rheumatic fever declined in the  United States during the 1960s, 1970s, and early 1980s because  of medical and socioeconomic improvements, as well as changes  in the virulence of group A streptococci.!°’ Because crowding  and poor hygiene are environmental risk factors for acute rheu-  matic fever, the disease continues to be a major cause of death  and disability for underprivileged populations.   The acute disease occurs most often in children between 5  and 15 years of age.'®° Because beta-hemolytic streptococcus  infection must persist for some time to cause acute rheumatic  fever, appropriate antibiotic therapy given within the first 9 days  of infection usually prevents rheumatic fever. Initiation of anti-  biotic therapy 2 weeks after the start of streptococcal infection  does not prevent rheumatic fever in susceptible individuals.   Rheumatic fever tends to run in families, lending support  to the concept of genetic predisposition, including changes in  major histocompatibility antigens.'®° Individuals who have  experienced one attack of acute rheumatic fever are more sus-  ceptible than the general population to recurrent attacks.   PATHOPHYSIOLOGY. Acute rheumatic fever can develop only asa  sequel to pharyngeal infection by group A beta-hemolytic strep-  tococci. Streptococcal skin infections do not progress to acute  rheumatic fever because the strains of the microorganism that  infect the skin do not have the same antigenic molecules in their  cell membranes as do those that cause pharyngitis and there-  fore do not elicit the same kind of immune response. However,  both skin infections and pharyngeal infections can cause acute  glomerulonephritis.    FIGURE 32-34 Pathogenesis and Structural Alterations of Acute Rheu-  matic Heart Disease. Beginning usually with a sore throat, rheumatic fever can  develop only as a sequel to pharyngeal infection by group A beta-hemolytic strep-  tococcus. Suspected as a hypersensitivity reaction, it is proposed that antibodies  directed against the M proteins of certain strains of streptococci cross-react with  tissue glycoproteins in the heart, joints, and other tissues. The exact nature of cross-  reacting antigens has been difficult to define, but it appears that the streptococcal  infection causes an autoimmune response against self-antigens. Inflammation is  found in various sites including (1) endocardium, (2) myocardium, and (3) pericar-  dium. The most distinctive inflammatory lesions within the heart are called Aschoff  bodies. The chronic sequelae result from progressive fibrosis because of healing of  the inflammatory lesions and the changes induced by valvular deformities. (From  Damjanov |: Pathology for the health professions, ed 4, Philadelphia, 2012, Saunders.)    Acute rheumatic fever affects the heart, joints, CNS,  and skin through an abnormal humoral and cell-mediated  immune response to the M proteins on the microorganisms  that cross-react with normal tissues (Figure 32-34). Antibodies  against a streptococci bacterial wall antigen (GlcNAc) display    cross-reactivity against laminin, a protein present in extracel-  lular tissues around heart cells and in the valves. Cardiac myo-  sin is another target antigen. Antibodies also cross-react within  neuronal cells triggering dopamine release.'°” These antibodies  also affect skin, muscles, and synovial joints.   Autoimmunity and associated intense inflammation result  in diffuse, proliferative, and exudative lesions in the connective  tissues, especially in the heart, joints, and skin.'°” The inflam-  mation may subside before treatment, leaving behind damage  to the heart valves and increasing the individual’s susceptibility  to recurrent acute rheumatic fever after any subsequent strep-  tococcal infections. Repeated attacks of acute rheumatic fever  cause chronic proliferative changes in the previously mentioned  organs as a result of scarring, granulomas, and thromboses.!°°   Approximately 10% of cases of rheumatic fever develop  RHD.!® Several genes have been implicated in RHD, includ-  ing the HLA-DR 1 antigen and HLA-DR 6 antigen, which sug-  gests that genetically determined immune response factors may  play a role in the pathogenesis of severe chronic RHD.° RHD  begins as carditis, or inflammation of the heart. Although rheu-  matic fever can cause carditis in all three layers of the heart wall  (endocardium, myocardium, pericardium) (see Chapter 31,  Figure 31-2), the primary lesion usually involves the endocar-  dium, which includes the heart valves.'°” Endocardial inflam-  mation causes swelling of the valve leaflets, with secondary  erosion along the lines of leaflet contact. Small beadlike clumps  of vegetation containing platelets and fibrin are deposited on  eroded valvular tissue and on the chordae tendineae (Figure  32-35). (The chordae tendineae anchor the valve leaflets; see  Chapter 31, Figure 31-3). The valves lose their elasticity, and  the leaflets may adhere to each other. Scarring and shortening  of the involved structures occur over time.   If inflammation penetrates the myocardium, localized fibrin  deposits develop that are surrounded by areas of necrosis. These  fibrinoid necrotic deposits are called Aschoff bodies. Pericardial  inflammation is usually characterized by serofibrinous effusion  within the pericardial cavity.   CLINICAL MANIFESTATIONS. The common symptoms of acute  rheumatic fever are fever, lymphadenopathy, arthralgia, nausea,  vomiting, epistaxis (nose bleed), abdominal pain, and tachycar-  dia. The major clinical manifestations of acute rheumatic fever  (carditis, acute migratory polyarthritis, chorea, and erythema  marginatum) usually occur singly or in combination 1 to 5  weeks after streptococcal infection of the pharynx.   Carditis. Carditis occurs a few weeks after the initial infection in  about 50% of patients with acute rheumatic fever.!® The earliest  cardiac manifestation of acute rheumatic fever may be a previously  undetected murmur caused by mitral or aortic semilunar valve  dysfunction. Chest pain is caused by pericardial inflammation.  Pericardial effusion produces an audible friction rub. Extra  heart sounds, heart block (see p. 1181), atrial fibrillation, and a  prolonged PR interval are often associated with chronic rheumatic  heart disease. Endocardial inflammation may be manifested years  later with serious valvular diseases (stenosis and regurgitation)  and recurrent infective endocarditis.   Polyarthritis. Acute migratory polyarthritis (inflammation  of more than one joint) occurs in 60% to 80% of individuals    FIGURE 32-35 Valvular Vegetations in Mitral Stenosis. Mitral stenosis  and clumps of vegetation (V) containing platelets and fibrin. Mitral leaflets are  thickened and fused and have clumps of vegetation containing platelets and fibrin.  (From Stevens A, Lowe JS, Scott |: Core pathology, ed 3, London, 2009, Mosby.)    with rheumatic fever.!©° Although all of the synovial joints may  be involved, the large joints of the extremities are most often  affected. Two or more joints are usually involved simultaneously  or in succession, with each joint being symptomatic for  approximately 2 to 3 days while the overall polyarthritis  continues for up to 3 weeks. Exudative synovitis causes heat,  redness, swelling, severe pain, and tenderness but no permanent  disability. Palpable subcutaneous nodes often develop over  bony prominences and along extensor tendons. They do not  interfere with joint function and often go unnoticed.   Chorea. Sydenham chorea, or St. Vitus dance, is a disorder  of the CNS characterized by sudden, aimless, irregular,  involuntary movements. (Chorea is described in Chapter 17.)  It is the most common acquired chorea in children and is  more common in girls than in boys. The chorea is self-limiting,  although severe cases may require the use of dopamine receptor  blockers and antiepileptic medications. It resolves within 1 to 6  months and has no permanent neural sequelae.   Erythema Marginatum. Erythema marginatum is a  distinctive truncal rash that often accompanies acute rheumatic  fever. It consists of nonpruritic, pink, erythematous macules  that never occur on the face or hands. The rash is transitory and  may change in appearance within minutes or hours. Heat (e.g.,  bathing) darkens the rash. The macules may fade in the center  and be mistaken for ringworm.   EVALUATION AND TREATMENT. Criteria for the diagnosis of rheu-  matic fever have been developed and updated by both the AHA  and the World Health Organization! (‘Table 32-10). When cor-  related with findings from physical assessment, laboratory values  lend significant support to the diagnosis of acute rheumatic fever.  A throat culture positive for group A beta-hemolytic streptococci  can be an important finding when associated with certain physi-  cal signs. Cultures may be negative when the rheumatic attack  begins, however. Most strains of group A beta-hemolytic strepto-  cocci produce a hemolytic factor called streptolysin-O. Antibodies  against this hemolytic factor increase as an individual’s immune  system fights the disease. A high or rising antistreptolysin-O  (ASO) antibody titer is an accurate means of diagnosing the    Evidence of streptococcal infection (increased titer of  streptococcal antibodies: antistreptolysin-O [ASO];  positive throat culture for group A streptococci; recent   Laboratory: increased C-reactive protein, increased  white blood cell count, increased erythrocyte  sedimentation rate    presence of a streptococcal infection. Several other antibody tests  are sensitive indicators of streptococcal infection. These include  antideoxyribonucleotidase (anti-DNase B), antihyaluronidase,  and antistreptozyme (ASTZ).   Elevated white blood cell count, erythrocyte sedimenta-  tion rate, and CRP indicate inflammation. All three are usu-  ally increased at the time cardiac or joint symptoms begin to  appear. They are more useful in identifying an acute inflamma-  tory process and suggesting prognosis than in diagnosing acute  rheumatic fever. The levels of these tests decrease as the inflam-  matory process resolves.   Therapy for acute rheumatic fever is aimed at eradicating the  streptococcal infection using a 10-day regimen of antibiotics.  NSAIDs are used as anti-inflammatory agents for rheumatic  carditis and arthritis and help relieve symptoms, but do not  prevent complications.'°’ Unfortunately there is little evidence  that anti-inflammatory medications (including corticosteroids)  are effective in treating acute carditis.'°’ Serious carditis may  require that cardiac glycosides, diuretics, and bed rest be added  to the regimen. Surgical repair of damaged valves may be neces-  sary in cases of chronic recurrent rheumatic fever or carditis.  Active disease is considered resolved when (1) the murmur has  disappeared or cardiac status becomes stable, (2) major mani-  festations are no longer present, (3) the individual is afebrile,  and (4) the erythrocyte sedimentation rate is normal or stabi-  lized. This may take 1 to 6 months.   A rheumatic recurrence will develop in 50% to 65% of chil-  dren with known rheumatic fever if they have another group  A streptococcal infection. Recurrence rates decline with the  length of time elapsed since the last infection. Continuous pro-  phylactic antibiotic therapy for as long as 5 years is necessary to  prevent recurrence of acute rheumatic fever. Several group A  streptococcus vaccines are in development.!®    Infective endocarditis is a general term used to describe infec-  tion and inflammation of the endocardium, especially the  cardiac valves. There are approximately 15,000 new cases of  infective endocarditis per year in the United States that account    Acquired valvular heart disease (especially mitral valve prolapse)  Implantation of prosthetic heart valves   Congenital lesions associated with highly turbulent flow (e.g., ventricular  septal defect)   Long-term indwelling intravenous catheterization (e.g., for pressure moni-  toring, feeding, hemodialysis)    for approximately 1 in 1000 admissions to the hospital. Bacte-  ria are the most common cause of infective endocarditis, espe-  cially streptococci, staphylococci and enterococci. Other causes  include viruses, fungi, rickettsia, and parasites. Infective endo-  carditis was once a lethal disease, but morbidity and mortal-  ity diminished significantly with the advent of antibiotics and  improved diagnostic techniques (Box 32-3).   PATHOPHYSIOLOGY. The pathogenesis of infective endocarditis  requires at least three critical elements (Figure 32-36):   1. Endocardial damage. Trauma, congenital heart disease,  valvular heart disease, and the presence of prosthetic  valves are the most common risk factors for endocardial  damage that leads to infective endocarditis. Turbulent  blood caused by these abnormalities usually affects the  atrial surface of atrioventricular valves or the ventricular  surface of semilunar valves. Endocardial damage exposes  the endothelial basement membrane, which contains a  type of collagen that attracts platelets and thereby stimu-  lates sterile thrombus formation on the membrane. This  causes an inflammatory reaction (nonbacterial throm-  botic endocarditis).   2. Blood-borne microorganism adherence to the damaged  endocardial surface. Bacteria may enter the bloodstream  during injection drug use, trauma, dental procedures  that involve manipulation of the gingiva, cardiac surgery,  genitourinary procedures and indwelling catheters in the  presence of infection, or gastrointestinal instrumentation,  or they may spread from uncomplicated upper respira-  tory or skin infections. Bacteria adhere to the damaged  endocardium using adhesins.   3. Formation of infective endocardial vegetations (Figure  32-37). Bacteria infiltrate the sterile thrombi and accel-  erate fibrin formation by activating the clotting cascade.  These vegetative lesions can form anywhere on the endo-  cardium but usually occur on heart valves and surround-  ing structures. Although endocardial tissue is constantly  bathed in antibody-containing blood and is surrounded  by scavenging monocytes and polymorphonuclear leuko-  cytes, bacterial colonies are inaccessible to host defenses  because they are embedded in the protective fibrin clots.  Embolization from these vegetations can lead to abscesses  and characteristic skin changes, such as petechiae, splin-  ter hemorrhages, Osler nodes, and Janeway lesions.    FIGURE 32-37 Bacterial Endocarditis of Mitral Valve. Lesion (arrow) in combination with old rheumatic valvulitis.  (From Damjanov I, Linder J: Pathology: a color atlas, St Louis, 2000, Mosby.)    CLINICAL MANIFESTATIONS. Infective endocarditis may be acute,  subacute, or chronic. It causes varying degrees of valvular dys-  function and may be associated with manifestations involving  several organ systems (lungs, eyes, kidneys, bones, joints, CNS),  making diagnosis exceedingly difficult. Signs and symptoms of  infective endocarditis are caused by infection and inflamma-  tion, systemic spread of microemboli, and immune complex  deposition. The “classic” findings are fever; new or changed  cardiac murmur; and petechial lesions of the skin, conjunctiva,  and oral mucosa.'’° Characteristic physical findings include  Osler nodes (painful erythematous nodules on the pads of the  fingers and toes) and Janeway lesions (nonpainful hemorrhagic  lesions on the palms and soles). Other manifestations include  weight loss, back pain, night sweats, and heart failure. CNS,  splenic, renal, pulmonary peripheral arterial, coronary and  ocular emboli may lead to a wide variety of signs and symp-  toms. Sudden onset of severely debilitating symptoms indicates  acute disease.   EVALUATION AND TREATMENT. The criteria for the diagnosis of  infective endocarditis include persistent bacteremia, new heart  murmurs, vascular complications, and appropriate electrocar-  diographic and echocardiographic findings.'’! If emboli are sug-  gested, organ scans can be performed to confirm their presence.  Antimicrobial therapy is generally given for 4 to 6 weeks, begin-  ning with intravenous and ending with oral administration.'!7°!7!  In some cases two different antibiotics are given simultaneously  to eliminate the offending microorganism and prevent the devel-  opment of drug resistance. Other drugs may be necessary to treat  left heart failure secondary to valvular dysfunction, and surgical  intervention to repair or replace the valve may be required.!7!   In the past, individuals with valvular heart disease received  prophylactic antibiotics for dental, genitourinary, or gastroin-  testinal procedures to prevent infective endocarditis; however,  evidence has shown that the risk of endocarditis is low in most  individuals. For example, infective endocarditis resulting from  dental procedures in individuals with mitral valve prolapse is  estimated at only 1 case per 1.1 million dental procedures.° In  2008 the recommendations were changed such that only “high  risk” individuals (history of infective endocarditis, prosthetic  valves, cyanotic congenital heart disease, heart transplant with  valvular defect) receive antibiotic prophylaxis, and only in the  setting of gingival procedures or in the presence of documented  acute gastrointestinal or genitourinary infection.!°*   Individuals infected with HIV and resultant acquired immuno-  deficiency syndrome (AIDS) are at risk for numerous cardiac  complications. Pericardial effusion and left heart failure are the  most common complications of HIV infection. Other conditions  include cardiomyopathy, myocarditis, tuberculous pericarditis,  infective and nonbacterial endocarditis, heart block, pulmonary  hypertension, and non-antiretroviral drug-related cardiotoxic-  ity. Malignancies, such as lymphoma and Kaposi sarcoma, are  often seen in individuals with AIDS and can affect the heart. Fur-  thermore, treatment with combination antiretroviral therapy  (cART) can cause hyperlipidemia and atherosclerotic disease.    Heart failure is defined as the pathophysiologic condition  in which the heart is unable to generate an adequate cardiac  output such that there is inadequate perfusion of tissues or  increased diastolic filling pressure of the left ventricle, or both,  so that pulmonary capillary pressures are increased. It is esti-  mated that nearly 10% of Americans older than age 65 have  symptomatic heart failure and approximately 20% of asymp-  tomatic individuals older than age 40 have some evidence of  myocardial dysfunction.° Ischemic heart disease and hyperten-  sion are the most important predisposing risk factors. Other  risk factors include age, obesity, diabetes, renal failure, valvular  heart disease, cardiomyopathies, myocarditis, congenital heart  disease, and excessive alcohol use. Numerous genetic polymor-  phisms have been linked to an increased risk for heart failure,  including genes for cardiomyopathies, myocyte contractil-  ity, and neurohumoral receptors. Genetic changes in kinases,  phosphatases, and cellular calcium cycling are being explored.  Most causes of heart failure result in dysfunction of the left  ventricle (systolic and diastolic heart failure). The right ven-  tricle also may be dysfunctional, especially in pulmonary dis-  ease (right ventricular failure). Finally, some conditions cause  inadequate perfusion despite normal or elevated cardiac out-  put (high-output failure).   Left Heart Failure (Congestive Heart Failure). Left heart  failure, commonly called congestive heart failure, is categorized  as heart failure with reduced ejection fraction (systolic heart  failure) or heart failure with preserved ejection fraction (diastolic  heart failure). These two types of heart failure can occur together  in one individual or singly.   Heart Failure with Reduced Ejection Fraction (HFrEF)  (Systolic Heart Failure). Heart failure with reduced ejection  fraction (systolic heart failure) is defined as an ejection fraction  of <40% and an inability of the heart to generate an adequate  cardiac output to perfuse vital tissues.°* Cardiac output depends  on the heart rate and stroke volume. Stroke volume is influenced  by three major factors: contractility, preload, and afterload (see  Chapter 31). Contractility is reduced by diseases that disrupt  myocyte activity. Myocardial infarction is the most common  cause of decreased contractility; other causes include myocar-  ditis and cardiomyopathies. Secondary causes of decreased con-  tractility, such as myocardial ischemia and increased myocardial  workload, contribute to inflammatory, immune, and neurohu-  moral changes (activation of the SNS and RAAS) that mediate  a process called ventricular remodeling. Ventricular remodeling  results in disruption of the normal myocardial extracellular  structure with resultant dilation of the myocardium and causes  progressive myocyte contractile dysfunction over time (Figure  32-38). When contractility is decreased, stroke volume falls, and  left ventricular end-diastolic volume (LVEDV) increases. This  causes dilation of the heart and an increase in preload.   Preload, or LVEDV, increases with decreased contractility or  when there is an excess of plasma volume (intravenous fluid    Baroreceptors activated Renin-angiotensin-aldosterone system activated  © Left ventricle  ¢ Aortic arch  ° Carotid sinus    FIGURE 32-38 Pathophysiology of Ventricular Remodeling. Myocardial dysfunction activates the renin-angioten-  sin-aldosterone and sympathetic nervous systems, releasing neurohormones (angiotensin II, aldosterone, catecholamines,  and cytokines). These neurohormones contribute to ventricular remodeling. (Redrawn from Carelock J, Clark AP: Am J Nurs  101[12]:27, 2001.)    FIGURE 32-39 The Effect of Elevated Preload on Myocardial Oxygen  Supply and Demand. LVEDV, Left ventricular end-diastolic volume.    administration, renal failure, mitral valvular disease). Increases  in LVEDV can actually improve cardiac output up to a certain  point, but as preload continues to rise, it causes a stretching of  the myocardium that eventually can lead to dysfunction of the  sarcomeres and decreased contractility (Figure 32-39).   Increased afterload is most commonly a result of increased  peripheral vascular resistance (PVR), such as that seen with  hypertension (Figure 32-40). Nearly 75% of cases of heart fail-  ure have antecedent hypertension.” Although much less com-  mon, it also can be the result of aortic valvular disease. With  increased PVR, there is resistance to ventricular emptying  and more workload for the left ventricle, which responds with  hypertrophy of the myocardium. This process differs from the  physiologic myocyte response to increased workload (exercise)  in which the workload is intermittent rather than sustained,  resulting in an increase in muscle mass but no distortion of the  cardiac architecture.!”* Sustained afterload leads to pathologic  hypertrophy mediated by angiotensin II and catecholamines.  This pathologic increase in muscle mass results in an increase in  oxygen and energy demand. The myocardium consumes a huge  amount of metabolic energy and relies on the efficient produc-  tion of ATP. This production of ATP depends on the myocytes  getting enough fuel, having adequate mitochondrial function,  and using an effective creatine kinase system. When demand  for energy is greater than the ability of these systems to supply  the necessary ATP, contractility of the myocardium is compro-  mised. An energy-starved state develops that further contributes  to changes in the myocytes themselves and ventricular remod-  eling that significantly impairs contractility and therefore ven-  tricular function (see Figure 32-38).'7> Remodeling also results  in the deposition of collagen between the myocytes, which can  disrupt the integrity of the muscle, decrease contractility, and  make the ventricle more likely to dilate and fail.'”* Weakness of  the cardiac muscle due to hypertension-induced hypertrophy is  called hypertensive hypertrophic cardiomyopathy.   As cardiac output falls, renal perfusion diminishes with acti-  vation of the RAAS, which acts to increase PVR and plasma vol-  ume, thus increasing afterload and preload further. In addition,  baroreceptors in the central circulation detect the decrease in    FIGURE 32-40 The Role of Increased Afterload in the Pathogenesis of  Heart Failure. RAA, Renin angiotensin aldosterone, SNS, sympathetic nervous  system.    perfusion and stimulate the SNS to cause yet more vasocon-  striction and to cause the hypothalamus to produce antidiuretic  hormone. This vicious cycle of decreasing contractility, increas-  ing preload, and increasing afterload causes progressive wors-  ening of left heart failure (Figure 32-41).  In addition to these hemodynamic interactions, systolic con-  gestive heart failure is characterized by a complex constellation  of neurohumoral, inflammatory, and metabolic processes:  1. Catecholamines. Sympathetic nervous system activation  initially compensates for a decrease in cardiac output by  increasing heart rate and peripheral vascular resistance.  However, catecholamines cause numerous deleterious  effects on the myocardium, including direct toxicity to  myocytes, induction of myocyte apoptosis, myocardial  remodeling, down-regulation of adrenergic receptors,  facilitation of dysrhythmias, and potentiation of autoim-  mune effects on the heart muscle.  2. RAAS  a. Angiotensin II (Ang II). Activation of the RAAS causes  not only increases in preload and afterload but also  direct toxicity to the myocardium (see Figure 32-38).  Ang II mediates remodeling of the ventricular wall,  contributing to sarcomere death, loss of the normal  collagen matrix, and interstitial fibrosis. This leads to  decreased contractility, changes in myocardial compli-  ance, and ventricular dilation.   b. Aldosterone. Aldosterone not only causes salt and  water retention by the kidney but also contributes to    myocardial fibrosis, autonomic dysfunction, and dys-  rhythmias. It also has been implicated in endothelial  dysfunction and prothrombotic effects.!”°   3. Arginine vasopressin. Arginine vasopressin is also known  as antidiuretic hormone and causes both peripheral vaso-  constriction and renal fluid retention. These actions exac-  erbate hyponatremia and edema in heart failure.   4. Natriuretic peptides. Atrial and BNPs are increased and  may have some protective effect by decreasing preload;  however, their compensatory mechanisms are inadequate  in heart failure.!”°   constrictor and is associated with a poor prognosis in  individuals with heart failure.   b. TNF-a and IL-6. TNF-a is elevated in heart failure and  contributes to myocardial hypertrophy and remodel-  ing.!”7!78 It down-regulates the synthesis of the vaso-  dilator nitric oxide (NO), induces myocyte apoptosis,  and may contribute to weight loss and weakness in  individuals with heart failure (cardiac cachexia). IL-6   FIGURE 32-41 The Vicious Cycle of Systolic Heart Failure. Although the  initial insult may be one of primary decreased contractility (e.g., myocardial infarc-  tion), increased preload (e.g., renal failure), or increased afterload (e.g., hyperten-  sion), all three factors play a role in the progression of left heart failure. LVEDV, Left  ventricular end-diastolic volume.    also is elevated in individuals with severe heart failure  and cardiogenic shock and may contribute to further  deleterious immune activation.   6. Myocyte calcium transport. Calcium transport into, out  of, and within myocytes is critical to normal contractile  function. Changes in calcium ion channels, intracellular  transport mechanisms in the sarcoplasmic reticulum,  and calcium cycling have all been implicated in decreased  myocardial contractility and heart failure.!”’   7. Insulin resistance and diabetes. Insulin resistance is a likely  contributor to, as well as complication of, heart failure.  Insulin resistance causes abnormal myocyte fatty acid  metabolism and generation of ATP, which contributes to  decreased myocardial contractility and remodeling'*? (see  What’s New? Metabolic Changes in Heart Failure). Heart  failure activates the SNS and RAAS, which contribute to  insulin resistance. Diabetes contributes to heart failure  through disturbed calcium metabolism, oxidative stress,  changes in fatty acid and glucose metabolism, and mito-  chondrial dysfunction. In addition, receptors on myocytes  for damaging advanced glycation end-products (RAGE)  (see Chapter 22) are up-regulated in injuries to the heart,  including ischemia and reperfusion injury. Measurement  of levels of RAGE in plasma or serum may correlate with  the degree of heart failure.'*' Unfortunately, many of the  new medications used to treat diabetes and insulin resis-  tance have deleterious side effects on cardiac functioning;  however, newer agents that modify fatty acid metabolism  and insulin activity are being explored.!*   The interaction of these metabolic, neurohumoral, and  inflammatory processes results in a gradual decline in myo-  cardial function. Pathologically, the heart muscle exhibits  progressive changes in myocyte myofilaments, decreased con-  tractility, myocyte apoptosis and necrosis, abnormal fibrin  deposition in the ventricle wall, myocardial hypertrophy, and  changes in the ventricular chamber geometry. These changes  reduce myocardial function and cardiac output and lead to  increased morbidity and mortality. These discoveries have led  to the routine use of ACE inhibitors, aldosterone blockers, and  beta-blockers in the management of heart failure, which has    The heart is the largest consumer of energy in the body and relies on the efficient  production of adenosine triphosphate (ATP). The heart has very little capacity for  energy storage. In the failing heart, increased demand for oxygen and energy  is coupled with a decreased ability to use fatty acids as an energy source. As  a result, there is activation of several genes that alter the ability of myoctyes    to use lipids and glucose as fuel sources, the most studied of which are the  peroxisome proliferator-activated receptor (PPAR) family of genes. These genes  control fatty acid oxidation and are of particular importance in heart failure asso-  ciated with insulin resistance and diabetes. Energy starvation and high levels of  catecholamines associated with heart failure lead to altered fatty acid oxida-  tion and decreased effective ATP generation and use. This results in decreased    myocardial contractility and structural changes in the myocardium (remodel-  ing). Increasing knowledge of these mechanisms has led to the exploration of  potential therapies for heart failure. For example, PPAR agonists have been  shown to enhance fatty acid oxidation, improve endothelial cell function, and  decrease myocardial fibrosis and hypertrophy in animal models of heart failure.  Unfortunately currently available PPAR-gamma agonists (thiazolidinediones) are  contraindicated in worsening heart failure because of increased fluid retention  at the renal tubule. Many new potential pharmacologic interventions are under  investigation, including trimetazidine, a partial fatty-acid-oxidation inhibitor that  may decrease hospitalization for cardiac causes, improve clinical symptoms and  cardiac function, and reduce left ventricular remodeling in people with CHF.    Data from Abel E et al: Arterioscler Throm Vasc Biol 32(9):2068-2076, 2012; Ardehali H et al: Eur J Heart Fail 14(2):120-129, 2012; Sarma S, Arde-  hali H, Gheorghiade M: Heart Fail Rev 17(1):35-43, 2012; Zhang L et al: J Am Coll Cardiol 59(10):913-922, 2012.    Brain natriuretic peptide (BNP) is produced and released in response to pressure  and volume overload of the cardiac chambers. This occurs in both systolic and dia-  stolic heart failure (HF). BNP causes arterial and venous dilation, natriuresis, and  suppression of the renin-angiotensin-aldosterone system and the sympathetic  nervous system. BNP inhibits myocardial fibrosis and hypertrophy and enhances  diastolic function. There are currently four uses for BNP: three are measures of  serum levels of endogenous BNP and one is a therapeutic use for exogenous BNP:  1. Diagnosis of heart failure: Significantly elevated serum levels of BNP have  a sensitivity ranging from 93% to 98% in diagnosing heart failure in symp-  tomatic patients, and negative predictive values ranging from 92% to 98%,  demonstrating BNP ability to rule out heart failure. BNP also can be used to  diagnose diastolic heart failure.  2. Prognosis in HF: Serum levels of BNP are correlated with the American  Heart Association/American College of Cardiology class of heart failure  morbidity and mortality, and risk for future acute exacerbations.    3. Monitoring treatment of HF: Serum levels of BNP-guided treatment of  heart failure reduced total cardiovascular events, mortality, and hospital  readmission with heart failure.   . Treatment of HF: Approved in August 2001 by the U.S. Food and Drug  Administration, nesiritide is the first of a new class of drugs, human B-type  natriuretic peptide (hBNP); it is manufactured from Escherichia coli using  recombinant deoxyribonucleic acid (DNA) technology. Intravenous adminis-  tration of nesiritide (recombinant BNP) also improves preload and contractil-  ity; however, results of this therapy have been mixed and a new natriuretic  peptide (ularitide) is being evaluated. In a limited number of studies, human  recombinant ANP (hANP) has been shown to improve pulmonary capillary  wedge pressure and cardiac output, but not mortality.    Data from Florea VG, Anand |S: Heart Fail Clin 8(2):207-224, 2012; Gassanov N et al: Eur J Clin Pharmacol 68(3):223-230, 2012; Januzzi JL Jr: Arch  Cardiovasc Dis 105(1):40-50, 2012; Kobayashi D et al: Can J Cardiol 28(1):102-199, 2012; Richards AM, Troughton RW: Clin Chem 58(1):62-71,  2012; Saremi A, Gopal D, Maisel AS: Exp Rev Cardovasc Ther 10(2):191—203, 2012; Sato Y, Fujiwara H, Takatsu Y: J Cardiol 59(1):1-7, 2012.    resulted in significant decreases in morbidity and mortality.'°”  Individuals selected for use of these medications may soon be  facilitated through the use of pharmacogenetics that can iden-  tify those genotypes most likely to respond favorably to specific  treatment options.!*°   EVALUATION. The clinical manifestations of HFrEF are the  result of pulmonary vascular congestion and inadequate per-  fusion of the systemic circulation. Individuals experience dys-  pnea, orthopnea, cough of frothy sputum, fatigue, decreased  urine output, and edema. Physical examination often reveals  pulmonary edema (cyanosis, inspiratory crackles, pleural  effusions), hypotension or hypertension, an S; gallop, and  evidence of underlying CAD or hypertension.'** An ECG  and serum troponin should be obtained to evaluate for acute  ischemia. A chest x-ray should be obtained to assess heart size  and evidence of pulmonary congestion, and echocardiogra-  phy, to confirm decreased cardiac output and cardiomegaly.°*  Invasive catheterization to monitor hemodynamics or to doc-  ument underlying coronary disease may be needed. Serum  BNP levels should be measured to assist in diagnosing heart  failure and to give some insight into its severity and response  to treatment>*!*° (see What’s New? Brain Natriuretic Peptide  and Heart Failure). Numerous other biomarkers are emerg-  ing that may aid in the diagnosis and management of heart  failure.!°°   Management of HFrEF is aimed at interrupting the wors-  ening cycle of decreasing contractility, increasing preload, and  increasing afterload, as well as blocking the neurohormonal  mediators of myocardial toxicity.!°’ The acute onset of left  heart failure is most often the result of acute myocardial isch-  emia and must be managed in conjunction with the underlying  coronary disease. Oxygen, nitrates, and morphine admin-  istration improve myocardial oxygenation and help relieve  coronary spasm while lowering preload through systemic  venodilation. Diuretics reduce preload and are the mainstay of    therapy. Intravenous inotropic drugs, such as dobutamine and  milrinone, increase contractility and can help raise the blood  pressure in hypotensive individuals; however, long-term use is  associated with a high mortality.'** Calcium-sensitizing inotro-  pic drugs (e.g., levosimendan) have shown promise for acute  heart failure in selected individuals.!®° ACE inhibitors (which  reduce preload and afterload) and intravenous beta-blockers  (which reduce myocardial demand) have been found to reduce  mortality but must be used with caution in hypotensive indi-  viduals. Intravenous administration of nesiritide (recombinant  BNP) also improves preload and contractility; however, results  of this therapy have been mixed and new natriuretic peptides  (human recombinant ANP and ularitide) are being evalu-  ated.!°°!°! Individuals with severe systolic failure because of  myocardial ischemia may benefit from acute coronary bypass  or PCI. Those with refractory hypotension may be supported  with the intra-aortic balloon pump (IABP) until they can be  taken safely to the operating room; the IABP is positioned in  the aorta just distal to the aortic valve and is inflated during  diastole to improve coronary perfusion and deflated during  systole to reduce afterload.   Management of chronic left heart failure also relies on  increasing contractility and reducing preload and afterload.  In all patients with reduced ejection fraction, ACE inhibitors  and beta blockers are indicated to reduce mortality.**!°” Salt  restriction, loop diuretics, and aldosterone-blockers such as  spironolactone and eplerenone are effective in reducing pre-  load and improving outcomes.'?*!*? ACE inhibitors reduce  preload and afterload and have been shown to significantly  reduce mortality in chronic left heart failure. ARBs do not  improve morbidity or mortality in individuals with heart  failure and should be used only in those who do not tolerate  ACE inhibitors.!** Beta-blockers, especially some of the newer  drugs, such as bisoprolol, improve symptoms and increase  survival.!°° Catheter-based renal sympathetic denervation is    The effectiveness and safety of recent gene therapy trials for heart failure have  led to an explosion of interest in these innovative methods for restoring cardiac  function. The most studied of the potential gene targets include sarcoendoplas-  mic reticulum calcium ATPase (SERCA2a) and S100A1, which affect intracellular  myocyte calcium handling. Another exciting target is adenylyl cyclase 6 (AC6), the    enzyme catalyzing cAMP formation and beta-adrenergic receptor function. Other  targets include SDF1/CXCR4 complex, which promotes homing of stem cells to  infarcted myocardium, microRNAs, and genes that code for critical neurohumoral  factors, including insulin-like growth factor-1 (IGF-1), growth hormone, and  B-type natriuretic peptide. Gene delivery vectors fall into one of two categories:    nonviral or viral. Nonviral gene delivery vectors are safe and have minimal immu-  nogenicity, but do not appear to be efficient at delivering the genes to the tissues.  Viral vectors are more efficient at delivering genes to cells, but safety concerns  persist. Today the viruses most widely used for cardiovascular gene transfer are  adenovirus, sendai virus, and adeno-associated virus (AAV). These viruses exhibit  fairly good cardiotropism, and various methods are being explored for delivering  these gene vectors most efficiently to the myocardium, including antegrade or  retrograde coronary infusion, intravenous infusion, direct myocardial injection,  and pericardial injection. It is clear that the future will reveal many new and  potentially lifesaving gene therapies for individuals with intractable heart failure.    Data from Hulot JS, Senyei G, Hajjar RJ: Gene Ther 19(6):596-599, 2012; Kairouz V et al: Ann N Y Acad Sci 1254:42-50, 2012; Ritterhoff J, Most P:  Gene Ther 19(6):613-621, 2012; Tang T, Gao MH, Hammond HK: Gene Ther 19(6):606-612, 2012; Tilemann L et al: Circ Res 110(5):777-793, 2012.    Adapted from Jessup M, Brozena S: N Engl J Med 348(20):2007-2018, 2003.    being explored for heart failure.!°° The inotropic drug digoxin  may be considered in some individuals, especially those with  atrial fibrillation. Statins are not indicated for the treatment of  heart failure unless other comorbid conditions (e.g., CAD) are  present. Anticoagulants and antithrombotics may be indicated  in selected individuals, particularly those with intracardiac  thrombi or atrial fibrillation. Although many individuals with  left heart failure die suddenly from dysrhythmias, prophylac-  tic administration of antidysrhythmics has not been shown  to improve survival. In individuals with sustained ventricular  tachycardia, amiodarone or ICDs are indicated. Cardiac resyn-  chronization therapy is proving to be an important modality  in selected individuals.!°” Coronary bypass surgery or PCI may  improve perfusion to ischemic myocardium (hibernating myo-  cardium) and improve cardiac output. Other types of surgical  intervention that improve ventricular geometry may be con-  sidered. Heart transplant may be the only remaining option.  Experimental therapies, including gene and stem cell therapies,  are being explored!”*!° (see What’s New? Gene Therapy for  Heart Failure).   Diastolic Heart Failure. Diastolic heart failure (also called  heart failure with preserved ejection fraction) can occur sin-  gly or along with systolic heart failure. Isolated diastolic heart  failure is defined as pulmonary congestion despite a normal  stroke volume and cardiac output. It is the cause of approxi-  mately 50% of all cases of left heart failure and is more common    in women. The major causes of diastolic dysfunction include  hypertension-induced myocardial hypertrophy and myocar-  dial ischemia with resultant ventricular remodeling. Hypertro-  phy and ischemia cause a decreased ability of the myocytes to  actively pump calcium from the cytosol, resulting in impaired  relaxation. Other causes include aortic valvular disease, mitral  valve disease, pericardial diseases, and cardiomyopathies. Dia-  betes also increases the risk for diastolic dysfunction. Like sys-  tolic heart failure, diastolic failure is characterized by sustained  activation of the RAAS and the SNS.   Two areas of pathophysiologic changes in the ventricle have  been identified in diastolic dysfunction: decreased compliance  of the left ventricle and abnormal diastolic relaxation (lus-  itropy). Decreased ventricular compliance has been linked to  changes in myocardial structure such as that seen with molecu-  lar alterations in collagen, which forms the extracellular matrix  for myocytes. Another recently identified structural change is  because of abnormalities in an intracellular protein compo-  nent of the myocyte cytoskeleton called titin. Abnormal lus-  itropy is caused by changes in calcium transport from myocytes  and may be related to the activity of sarcoplasmic reticulum—  calcium adenosine triphosphatase (ATPase).”°° The resultant  noncompliant and poorly lusitropic ventricle cannot accept  filling with blood without significant resistance and an increase  in wall tension. Thus HFpEF occurs because a normal LVEDV  is associated with an increased LVEDP. The resultant increase    FIGURE 32-42 Right Heart Failure (Cor Pulmonale) Caused By Lung Disease. The presence of peripheral edema in  cor pulmonale is caused by lung disease. RA, Right atrial; AV, right ventricular.    in left atrial pressure is then reflected back into the pulmonary  circulation and results in pulmonary edema. The increase in  pressure is made worse when ventricular filling is rapid so  symptoms worsen with tachycardia (e.g., with exercise).  Individuals with diastolic dysfunction most often present  with dyspnea on exertion and fatigue. If diastolic dysfunction  is severe, there may be evidence of pulmonary edema (inspi-  ratory crackles on auscultation, pleural effusions). Pulmonary  hypertension and right ventricular failure may develop.*”! Late  in diastole, atrial contraction with rapid ejection of blood into  the noncompliant ventricle may give rise to an S, gallop. Elec-  trocardiography often reveals evidence of left ventricular hyper-  trophy, and chest x-ray shows pulmonary congestion without  cardiomegaly (Table 32-11).There also may be evidence of  underlying coronary disease, hypertension, or valvular disease.  Diagnosis is based on three factors: signs and symptoms of  heart failure, normal left ventricular ejection fraction, and evi-  dence of diastolic dysfunction. The diagnosis is initially made  by echocardiography, which demonstrates poor ventricular fill-  ing with normal ejection fractions.*°* Management is aimed at  improving ventricular relaxation and prolonging diastolic fill-  ing times to reduce diastolic pressure. Physical training (aerobic  and weight training) improves endurance and quality of life.*°°  Beta-blockers, ACE inhibitors, ARBs, and aldosterone block-  ers have been used with varying success,”°*?°> however current  guidelines focus on treating hypertension or valvular disease.>*  Inotropic drugs are not indicated in isolated diastolic heart fail-  ure because contractility and ejection fraction are not affected.    Outcomes for individuals with HFpEF can be as poor as those  with systolic heart failure, and there has been little improve-  ment in prognosis despite numerous new treatment trials.  Right Heart Failure. Right heart failure is defined as the  inability of the right ventricle to provide adequate blood flow  into the pulmonary circulation at a normal central venous  pressure. It most often results from left heart failure when  the increase in left ventricular filling pressure that is reflected  back into the pulmonary circulation is severe enough.*°° As  pressure in the pulmonary circulation rises, the resistance to  right ventricular emptying increases. The right ventricle is  poorly prepared to compensate for this increased workload  and will dilate and fail. When this happens, pressure will  rise in the systemic venous circulation, resulting in jugular  venous distention, peripheral edema, and hepatosplenomegaly.  Treatment relies on management of the left ventricular dysfunction  as just outlined. When right heart failure occurs in the absence  of left heart failure, it is caused most commonly by pulmonary  hypertension resulting from diffuse hypoxic pulmonary disease  such as chronic obstructive pulmonary disease (COPD), cystic  fibrosis, and ARDS*” (Figure 32-42). The mechanisms for this  type of right ventricular dysfunction (cor pulmonale) are discussed  in Chapter 35. Finally, right heart failure can result from right  ventricular MI, cardiomyopathies, and pulmonic valvular disease.  High-Output Failure. High-output failure is the inability  of the heart to adequately supply the body with blood-borne  nutrients, despite adequate blood volume and normal or  elevated myocardial contractility. In high-output failure the    heart increases its output but the body’s metabolic needs are  still not met. Common causes of high-output failure are anemia,  septicemia, hyperthyroidism, and beriberi (Figure 32-43).   Anemia decreases the oxygen-carrying capacity of the blood  (see Chapter 28). Metabolic acidosis occurs as the body’s cells  switch to anaerobic metabolism (see Chapter 3). In response to  metabolic acidosis, heart rate and stroke volume increase in an  attempt to circulate blood faster. If anemia is severe, however,  even maximum cardiac output does not supply the cells with  enough oxygen for metabolism.   In septicemia, disturbed metabolism, bacterial toxins, and  the inflammatory process cause systemic vasodilation and fever.  Faced with a lowered systemic vascular resistance (SVR) and an  elevated metabolic rate, cardiac output increases to maintain  blood pressure and prevent metabolic acidosis. In overwhelming  septicemia, however, the heart may not be able to raise its output  enough to compensate for vasodilation. Body tissues show signs  of inadequate blood supply despite a very high cardiac output.   Hyperthyroidism accelerates cellular metabolism through  the actions of elevated levels of thyroxine from the thyroid  gland. This may occur chronically (thyrotoxicosis) or acutely  (thyroid storm). Because the body’s increased demand for  oxygen threatens to cause metabolic acidosis, cardiac output  increases. If blood levels of thyroxine are high and the meta-  bolic response to thyroxine is vigorous, even an abnormally  elevated cardiac output may be inadequate.    In the United States, beriberi (thiamine deficiency) usually is  caused by malnutrition secondary to chronic alcoholism. Beriberi  actually causes a mixed type of heart failure. Thiamine deficiency  impairs cellular metabolism in all tissues, including the myocar-  dium. In the heart, impaired cardiac metabolism leads to insuf-  ficient contractile strength. In blood vessels, thiamine deficiency  leads mainly to peripheral vasodilation, which decreases SVR. Heart  failure ensues as decreased SVR triggers increased cardiac output,  which the impaired myocardium is unable to deliver. The strain of  demands for increased output in the face of impaired metabolism  may deplete cardiac reserves until low-output failure begins.   A dysrhythmia, or arrhythmia, is a disturbance of heart rhythm.  Normal heart rhythms are generated by the SA node and travel  through the heart’s conduction system, causing the atrial and  ventricular myocardium to contract and relax at a regular rate  that is appropriate to maintain circulation at various levels  of physical activity (see Chapter 31). Dysrhythmias range in  severity from occasional “missed” or rapid beats to serious dis-  turbances that impair the pumping ability of the heart, contrib-  uting to heart failure and death. Dysrhythmias can be caused by  either an abnormal rate of impulse generation (Table 32-12) by  the SA node or other pacemaker or the abnormal conduction of  impulses (Table 32-13) through the heart’s conduction system,  including the myocardial cells themselves.    Decreased cardiac output from  loss of atrial contribution to  ventricular preload    Decreased cardiac output from  loss of atrial contribution to  ventricular preload for that  beat   Decreased cardiac output from  loss of atrial contribution to  ventricular preload    Same as idiojunctional rhythm  Vagal hyperactivity  Hyperkalemia (6-5.4 mEq/L)  Hypercalcemia, hypoxia, and  elevated preload (see PACs)    Depolarization and contraction  not coupled: electrical activ-  ity present with little or no  mechanical activity    P waves present and independent  of ORS, but not always because  of block (e.g., ventricular  tachycardia)    Decreased cardiac output  from loss of atrial con-  tribution to ventricular  preload   PR interval >0.12 and ORS >0.11  because of presence of delta  wave in PR interval    Hypokalemia (<3.5 mEq/L)  Faulty cell metabolism low in bundle  of His  MI, especially inferior wall, as  nodal artery interrupted; results  in ischemia of AV node  May result from third-degree block  or accelerated junctional or  ventricular rhythm, or be caused  by sinus, atrial, and junctional  bradycardias    Faulty cell metabolism in right and  eft bundle branches  RBBB more common than LBBB  because of dual blood supply to  eft bundle branch  Congestive heart failure, mitral  regurgitation, especially anterior  |, because of infarct of fascicles  Left anterior hemiblock more  common than left posterior hemi-  block, since posterior fascicles  have dual blood supply  Conduction of impulse through  intercalated disks because  conduction system transiently  blocked because of hypoxia,  electrolyte imbalances, digoxin  toxicity, excessively rapid rates of  discharge  Congenital presence of accessory  pathways (bundle of Kent and  iber of Mahaim) that conduct  very rapidly and bypass the AV  node, causing early ventricular  depolarization in relation to atrial  depolarization  Prone (reason unknown) to tachy-  cardias and atrial fibrillation that  can result in very rapid ventricular  rates  Faulty cell metabolism in right and  eft bundle branches  RBBB more common than LBBB  because of dual blood supply to  eft bundle branch  Congestive heart failure, mitral  regurgitation, especially anterior  |, because of infarct of fascicles  Left anterior hemiblock more  common than left posterior hemi-  block, because posterior fascicles  have dual blood supply   Temporary pacing if caused  by inferior MI because  ischemia usually resolves   Pacemaker or reducing  rate of AV or ventricular  discharge, or increasing  rate of sinus or AV node  discharge    Isolated right bundle branch  block (RBBB) or left bundle  branch block (LBBB) or  hemiblock not treated   If acute and/or associated  with acute anterior MI,  treated with permanent  pacer and vigorous phar-  macology   If acute and/or associated  with acute anterior MI,  treated with permanent  pacer and vigorous phar-  macology    syndromes (Wolff- PR interval >0.12 and ORS >0.11  Parkinson-White because of presence of delta  and Lown- wave in PR interval  Ganong-Levine)    Conduction of impulse through Correct underlying cause  intercalated disks because  conduction system transiently  blocked because of hypoxia,  electrolyte imbalances, digoxin  toxicity, excessively rapid rates of  discharge  Congenital presence of accessory Aimed at lining up refrac-  pathways (bundle of Kent and tory periods of accessory  fiber of Mahaim) that conduct pathway and AV node to  very rapidly and bypass the AV prevent reentry  node, causing early ventricular May slow rate with pharma-  depolarization in relation to atrial cology  depolarization May surgically cut pathways  Prone (reason unknown) to tachy-  cardias and atrial fibrillation that  can result in very rapid ventricular  rates   1. Varicosities are areas of veins in which blood has pooled,  usually in the saphenous veins. Varicosities may be caused  by damaged valves as a result of trauma to the valve or by  chronic venous distention involving gravity and venous  constriction.   2. Chronic venous insufficiency is inadequate venous return  over a long period that causes pathologic ischemic changes  in the vasculature, skin, and supporting tissues.   3. Venous stasis ulcers follow the development of chronic  venous insufficiency and probably develop as a result of  the borderline metabolic state of the cells in the affected  extremities.   4. DVT occurs in individuals who have venous stasis (immobil-  ity, age, left heart failure), spinal cord injury, vein wall dam-  age (trauma, intravenous medications), or hypercoagulable  states (pregnancy, oral contraceptives, malignancy, genetic  coagulopathies).   5. DVT is often asymptomatic but may lead to fatal pulmonary  emboli; prevention and careful assessment in individuals at  risk are crucial.   1. Hypertension is a sustained elevation of the systemic arte-  rial blood pressure resulting from increases in cardiac output  or total peripheral resistance, or both. Hypertension can be  primary (without known cause) or secondary (caused by dis-  ease or drugs). Systolic hypertension is the most significant  factor in causing target organ damage.   2. The risk factors for hypertension include a positive family  history; male gender; advanced age; black race; obesity; high    sodium intake; low potassium, calcium, and magnesium  intake; diabetes mellitus; labile blood pressure; cigarette  smoking; and heavy alcohol consumption.   . Primary hypertension is the result of extremely complicated  interactions of genetics and the environment mediated by a  host of neurohumoral effects. These genes interact with diet,  smoking, age, and the other risk factors to cause chronic  changes in vasomotor tone and blood volume.   . The most frequently cited theories of the pathogenesis of  primary hypertension include overactivity of the SNS; over-  activity of the RAAS; alterations in other neurohumoral  mediators of blood volume and vasomotor tone such as ANP,  BNP, and adrenomedullin; inflammation; a complex inter-  action involving insulin resistance and endothelial function;  and obesity-related hormonal changes.   . Clinical manifestations of hypertension result from damage of  organs and tissues outside the vascular system. These include  heart disease, renal disease, CNS problems, and retinal changes.   . Hypertension is managed pharmacologically, using diuret-  ics, adrenergic blockers, calcium channel blockers, ACE  inhibitors, and Ang II receptor blockers. Nonpharmacologic  methods include cessation of smoking, dietary modifica-  tions, and exercise.   7. Orthostatic hypotension is a drop in blood pressure that  occurs on standing. The compensatory vasoconstriction  response to standing is altered by a marked vasodilation  and blood pooling in the muscle vasculature.   8. Orthostatic hypotension may be acute or chronic. The  acute form is caused by a delay in the normal regulatory  mechanisms. The chronic forms are secondary to a specific  disease or are idiopathic.    The clinical manifestations of orthostatic hypotension  include fainting and may involve cardiovascular symptoms,  as well as impotence and bowel and bladder dysfunction.  An aneurysm is a localized dilation of a vessel wall to which  the aorta is particularly susceptible.   A thrombus is a clot that remains attached to a vascular  wall.   An embolus is a mobile aggregate of a variety of substances  that occludes the vasculature. Sources of emboli include  thrombi, air, amniotic fluid, bacteria, fat, and foreign  matter.   The most common sources of arterial thrombotic emboli  from the heart are mitral and aortic valvular disease and  atrial fibrillation. Tissues affected include the lower extrem-  ities, the brain, and the heart.   Emboli to the central organs cause tissue death in lungs,  kidneys, and mesentery.   The generation of air emboli requires a connection between  the vascular compartment and a source of air. These emboli  cause ischemia and necrosis when a vessel is totally blocked.  Amniotic fluid may be forced into the bloodstream and  generate an embolus during the labor and delivery of  pregnancy.   Aggregates of bacteria in the vasculature may be large  enough to form an embolus.   Fat emboli are caused mainly by trauma to the long bones,  either through defective fat metabolism after trauma or  through the release of fat globules from bone marrow  exposed by fracture.   The introduction of foreign matter into the vasculature  can occur with trauma and also can occur in a hospital set-  ting in which intravenous and intra-arterial lines are being  used.   Vasospastic disorders include Raynaud disease, involving  arterioles of the extremities; variant angina, involving coro-  nary arteries; and Buerger disease, involving arteries of the  hands and feet.   Atherosclerosis is a form of arteriosclerosis and is the lead-  ing cause of coronary artery and cerebrovascular disease.  Atherosclerosis is an inflammatory disease that begins with  endothelial injury and progresses through several stages to  become a fibrotic plaque.   Traditional risk factors include age, family history, gender,  smoking, dyslipidemia, hypertension, and diabetes.   Novel risk factors include elevated CRP, increased serum  fibrinogen, oxidative stress, infection, and periodontal  disease.   Once a plaque has formed it can rupture, resulting in throm-  bosis and vasoconstriction that leads to obstruction of the  lumen and inadequate perfusion of distal tissues.   PAD is atherosclerosis of arteries that perfuse the limbs,  especially the lower extremities.   PAD is often asymptomatic but can present with inter-  mittent claudication (pain in leg on walking). Treatment  includes risk factor reduction and antiplatelet therapy.    CAD is spasm or occlusion of the coronary arteries and is  most often the result of atherosclerotic lesions that limit the  flow of blood to the heart.   Many risk factors contribute to the onset and escalation of  CAD, including advanced age, male gender (younger than  age 60), hypertension, dyslipidemia (including elevated  Lp[a]), diabetes mellitus, smoking, obesity, sedentary life-  style, psychosocial factors, elevated CRP, and possibly  infectious agents.   CAD results in an imbalance between coronary supply of  blood and myocardial demand for oxygen and nutrients  such that reversible myocardial ischemia or irreversible  infarction may result.   Reversible myocardial ischemia presents clinically in sev-  eral ways. Chronic coronary obstruction results in recur-  rent predictable chest pain called stable angina. Abnormal  vasospasm of coronary vessels results in unpredictable chest  pain called Prinzmetal angina. Myocardial ischemia that  does not cause detectable symptoms is called silent ischemia.  Stable angina is evaluated by noninvasive techniques of  assessing coronary flow with or without exercise (stress  ECG, thallium, or SPECT). Management may include life-  style changes, vasodilators, antithrombotics, PCI, or CABG  surgery.   When there is sudden coronary obstruction because of  thrombosis formation over a ruptured atherosclerotic  plaque, the acute coronary syndromes result. Unstable  angina causes reversible myocardial ischemia and is a har-  binger of impending infarction. MI results when prolonged  ischemia causes irreversible damage to the heart muscle.  Sudden cardiac death can occur in any of the acute coro-  nary syndromes.   Unstable angina occurs because of transient episodes of  thrombotic vessel occlusion and vasoconstriction at the  site of plaque damage, with return of perfusion before sig-  nificant myocardial necrosis occurs. This must be managed  aggressively with antithrombotic agents to prevent MI.  When coronary blood flow is interrupted for an extended  period, myocyte necrosis occurs; this is called MI. Patho-  logically, there are two major types of myocardial infarc-  tion: subendocardial infarction and transmural infarction.  In addition to myocyte necrosis, other changes in the heart  with MI include hibernating, stunning, and remodeling of  the myocardium.   Acute coronary syndromes are assessed by measuring  serum enzymes, such as creatinine kinase and troponins, as  well as looking for characteristic changes in the ECG. Those  individuals at highest risk for complications present with  ST-segment elevations on the ECG (STEMI) and require  immediate intervention. Smaller subendocardial infarc-  tions are not associated with ST-segment elevations (non-  STEMI) but suggest that additional myocardium is still at  risk for recurrent ischemia and infarction. Management  may include thrombolytic drugs, antithrombotic drugs,  vasodilators, PCI, or immediate surgery.    Dysrhythmias, congestive heart failure, and sudden death  are the most common complications of the acute coronary  syndromes.    Inflammation of the pericardium (pericarditis) may  result from innumerable sources (infection, drug therapy,  tumors). Pericarditis presents with symptoms that are  physically troublesome, but in and of themselves they are  not life threatening.    effusion). Cardiac function may be severely impaired if a  large volume of fluid accumulates rapidly.    dial disorders that are poorly understood. The cardiomy-  opathies are categorized as dilated (congestive), restrictive  (rigid and noncompliant), and hypertrophic (asymmetric).  Size of the cardiac muscle walls and chambers may increase  or decrease, depending on the type of cardiomyopathy,  thereby altering contractile activity.    depends to a great extent on properly functioning cardiac  valves. Congenital or acquired disorders that result in ste-  nosis or incompetence or both can structurally alter the  valves.    temic complaints assist in determining which valve is  abnormal. If severely compromised function exists, a pros-  thetic heart valve may be surgically implanted to replace the  faulty one.    young women. Although not grossly abnormal, the mitral  valve leaflets do not position themselves properly during  systole. Mitral valve prolapse may be a completely asymp-  tomatic condition or it may result in severe subjective  symptoms. Afflicted valves may be at greater risk for devel-  oping infective endocarditis.    a delayed autoimmune response to a streptococcal infection.  The disorder usually resolves without sequelae if treated early.    inflammation of the endocardium, especially the cardiac  valves. A wide range of conditions predisposes one to the  development of this disorder. In the mildest cases, val-  vular function may be slightly impaired by vegetations  that collect on the valve leaflets. If infective endocardi-  tis is left unchecked, severe valve abnormalities, chronic  bacteremia, and systemic emboli may occur as vegeta-  tions break off the valve surface and travel through the  bloodstream. Antibiotic therapy can limit the extent of  this disease.    HIV is associated with cardiac abnormalities, includ-  ing myocarditis, endocarditis, pericarditis, and cardio-  myopathy. Left heart failure is the most common clinical  manifestation.    Heart failure is an inability of the heart to supply the metab-  olism with adequate circulatory volume and pressure.    . Left heart failure can be categorized as systolic heart failure    . Systolic heart failure is defined as an inability of the heart to    . Cardiac output depends on the heart rate and stroke vol-    ume. Stroke volume is influenced by contractility, preload,  and afterload. MI is the most common cause of decreased  contractility. Myocardial ischemia results in ventricular  remodeling that causes progressive myocyte contractile  dysfunction over time.    increased peripheral vascular resistance. This increase in  resistance decreases ventricular emptying and makes more  workload for the left ventricle, resulting in hypertrophy  and ventricular remodeling. The vicious cycle of decreasing  contractility, increasing preload, and increasing afterload  causes progressive worsening.    in the SNS, RAAS, arginine vasopressin, natriuretic pep-  tides, inflammatory cytokines, and myocyte metabolism.    . The clinical manifestations of left heart failure are the result   Diastolic heart failure can occur singly or with systolic heart  failure. The major causes of diastolic dysfunction include  hypertension-induced myocardial hypertrophy and ische-  mia with resultant ventricular remodeling.   Right heart failure can result from left heart failure and/  or diffuse hypoxic pulmonary disease, such as COPD, cys-  tic fibrosis, and ARDS (these mechanisms are discussed in  Chapter 35).   High output failure is the inability of the heart to ade-  quately supply the body with blood-borne nutrients despite  adequate volume and normal or elevated myocardial con-  tractility. Common causes are anemia, septicemia, hyper-  thyroidism, and beriberi.   A dysrhythmia (arrhythmia) is a disturbance of heart  rhythm. Dysrhythmias range in severity from occasional  missed beats or rapid beats to disturbances that impair  myocardial contractility and are life threatening.  Dysrhythmias can occur because of an abnormal rate of  impulse generation or the abnormal conduction ofimpulses.   Highly sensitive C-reactive protein (hs-CRP), 1152  High-output failure, 1181  Hyperhomocysteinemia, 1152   Orthostatic (postural) hypotension, 1140  Percutaneous coronary intervention (PCI), 1156  Pericardial effusion, 1164   Superior vena cava syndrome (SVCS), 1131  Sydenham chorea (St. Vitus dance), 1172  Systolic heart failure, 1175   Thromboangiitis obliterans (Buerger disease), 1144  Thromboembolism, 1143  Thromboembolization, 1131  Thromboembolus, 1143    11. Januel JM et al: Symptomatic in-hospital deep vein thrombosis and    World Health Organization: Global atlas on cardiovascular disease pre-  vention and control, updated 2013. 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Drazner MH: The progression of hypertensive heart disease, Circulation  123(3):327-334, 2011.    Ohara T, Ohte N, Little WC: Pulmonary hypertension in heart failure  with preserved left ventricular ejection fraction: diagnosis and manage-  ment, Curr Opin Cardiol 27(3):281-287, 2012.   Hayley BD, Burwash IG: Heart failure with normal left ventricular  ejection fraction: role of echocardiography, Curr Opin Cardiol  27(2):169-180, 2012.   Haykowsky M, Brubaker P, Kitzman D: Role of physical training in  heart failure with preserved ejection fraction, Curr Heart Fail Rep  9(2):101-106, 2012.   Crouse M et al: Clinical inquiries. Which medications benefit patients  with diastolic heart failure? J Fam Pract 60(2):101—102, 2011.  Oghlakian GO, Sipahi I, Fang JC: Treatment of heart failure with  preserved ejection fraction: have we been pursuing the wrong paradigm?  Mayo Clin Proc 86(6):531-539, 2011.   Sayer GT, Semigran MJ: Right ventricular performance in chronic con-  gestive heart failure, Cardiol Clin 30(2):271-282, 2012.   Rich S: Right ventricular adaptation and maladaptation in chronic  pulmonary arterial hypertension, Cardiol Clin 30(2):257-269, 2012.    As part of your Pageburst Digital Book, you can access the following Integrated Resources:  Animations    Development of the Cardiovascular System, 1194  Developmental Anatomy, 1194  Transitional Circulation, 1196  Postnatal Development, 1198  Congenital Heart Defects, 1198  Classification of Congenital Heart Defects and Associated  Conditions, 1199  Defects Increasing Pulmonary Blood Flow, 1202    Cardiovascular disease in children can be classified as con-  genital or acquired heart disease. Congenital heart disease is  the most common. The diagnosis and management of con-  genital heart defects continue to improve with the use of fetal  echocardiography, early interventional catheterization, and  refined surgical repair. Acquired heart defects in children  continue to present challenges to the practitioner; although  guidelines for diagnosing acquired defects are available, work  is needed in developing standards of treatment and long-term  follow-up.    Cardiogenesis begins at approximately 3 weeks of gestation;  however, most cardiovascular development occurs between    Defects Decreasing Pulmonary Blood Flow, 1207  Obstructive Defects, 1210  Mixing Defects, 1214   Acquired Cardiovascular Disorders, 1218  Kawasaki Disease, 1218  Systemic Hypertension, 1218  Childhood Obesity, 1221    the fourth and seventh weeks.' The heart arises from the mes-  enchyme and begins development as an enlarged blood vessel  with a large lumen and a muscular wall (Figure 33-1, A). Ini-  tially, two lateral endocardial heart tubes fuse to form a single  structure (Figure 33-1, B). During the fifth week of gestation,  the midsection of this tube begins to grow faster than its ends.  This single heart tube elongates and rotates to the right (D-loop  formation), creating a bulboventricular loop by approximately  the twenty-eighth day! (Figure 33-1, C). Also at this time the first  fetal heart contractions occur. At this stage the primitive heart  structures include a common atrium; common ventricle; the  sinus venosus, which eventually evolves into the superior and  inferior venae cavae; the bulbus cordis, which eventually evolves  into the ventricular outflow tracts; and the truncus arteriosus,  which eventually yields the main pulmonary artery (PA) and  aorta (Figure 33-1, D). By the fourth week of gestation, cardio-  vascular septation, ventricular development, aortic arch evolu-  tion, and circulation begin.    FIGURE 33-1 Embryologic Development of the Heart. A, The earliest heart structure consists of a muscular tube with  a large lumen. About the fifth week of gestation, the tube, B, bulges and, C, twists until, D, the ends come together and fuse.    Separation first begins when collections of mesenchymal cells  cause the endocardial lining of the heart to bulge into the inter-  nal lumen. These changes, known as endocardial cushions, are  instrumental in closing the lower portion of the atrial septum,  dividing the atrioventricular (AV) canals into the right and left  AV orifices, and forming the upper portion of the interventric-  ular septum. Altered formation of the endocardial cushions can  result in ostium primum atrial septal defects, inlet ventricular  septal defects (VSDs), malformation of the AV valves, or a com-  plete AV defect (also known as atrioventricular septal defect).  Atrial septation begins when two thin membranelike  structures, known as the septum primum and the septum    secundum, grow toward the area of the endocardial cushions  (Figure 33-2). The septum primum forms along the posterior  wall of the common atrium and grows downward toward the  center portion of the heart. The gap between the two struc-  tures, known as the ostium primum, normally closes by exten-  sions from the endocardial cushions. At the time of closure,  fenestrations or openings develop in the superior portion of  the septum primum, creating the ostium secundum. Failure  of the septum primum to fuse with the endocardial cushions  results in an ostium primum defect in the atrial septum near  the AV valve area.   The septum secundum is also a fenestrated, membranelike  structure located anteriorly that grows toward the endocardial    cushions. During fetal development this structure does not  completely fuse with the endocardial cushions to achieve com-  plete atrial septal closure. The nonfused septum secundum and  ostium secundum result in the formation of a flapped orifice  known as the foramen ovale, which allows the right-to-left  shunting necessary for fetal circulation. Altered development in  any of these structures can lead to an atrial septal defect.   Ventricular septation develops when the muscular ridge  located at the apex, the endocardial tissue, and the bulbar ridges  in the bulbus cordis fuse (Figure 33-3). Closure of the inter-  ventricular septum ensures communication between the right  ventricle (RV) and the PA and between the left ventricle (LV)  and the aorta. Further evolution of the endocardial tissue gives  rise to the membranous ventricular septum and the AV valves.  The conal portion of the ventricular septum that separates the  aorta from the PA forms from the bulbus cordis.   When the single primitive heart tube begins to form the  D-loop, the venous and arterial poles of the heart are fixed,  resulting in torsion within the anterosuperior region of the  loop, known as the truncus arteriosus. This torsion creates a spi-  ral ridgelike structure or septum within the truncus arteriosus  that divides it into the PA and the aorta. The semilunar valves  evolve from tubercles after this division is complete.   Before this division occurs, however, two large arteries form  at the distal end of the truncus arteriosus. Over time they give  rise to a series of arterial vessels, collectively called the six aortic  arches. By the fifth week of gestation, the first two pairs disap-  pear and the third eventually evolves into the common carotid  artery, the external carotid artery, and part of the internal  carotid artery. The fourth pair of aortic arches will form part  of the true aortic arch and the proximal segment of the right  subclavian artery. The fifth pair disappears; however, the sixth  pair yields the proximal and branch pulmonary arteries within  the lung parenchyma and the ductus arteriosus.   Swellings in the conal region at the base of the main  trunk separate the right ventricular outflow (pulmonary out-  flow) tract from the left ventricular outflow (aortic outflow)  tract. The conus also contributes to complete closure of the    interventricular septum, and normal reabsorption of the sub-  aortic conal region ensures rotation of the great arteries so that  the aorta is posterior and to the right of the PA and the PA is  anterior and to the left of the aorta. Despite division of the trun-  cus arteriosus and separation of the right and left outflow tracts,  a communication exists between the aorta and the PA known as  the ductus arteriosus.   In order to deliver maximally oxygenated blood to the  developing brain, fetal circulation differs from the adult pat-  tern by the presence of alternate pathways known as fetal  shunts (Figure 33-4). Fetal oxygenation occurs in the pla-  centa instead of the fetal lungs. The fetal lungs are not aerated,  although the fetus does make breathing motions.   In utero the fetus receives blood carrying oxygen and nutri-  ents from the placenta through the umbilical vein. Fetal arterial  oxygen tension is much lower than that found in the postnatal  period—approximately 20 to 30 torr (mmHg pressure). Yet,  despite this hypoxemic state, tissue hypoxia does not occur  because of high fetal cardiac output and high fetal hemoglobin  levels. The blood travels to the liver, where a portion enters the  portal and hepatic circulation; approximately half the flow is  diverted away from the liver through the ductus venosus and  into the inferior vena cava. Because the blood received from  the inferior vena cava yields a higher pressure, blood entering  the right atrium (RA) from the inferior vena cava is shunted  through the foramen ovale and into the left atrium (LA) and  is then pumped through the LV and into the aorta. Approx-  imately two thirds of the blood flows to the head and upper  extremities. Because this blood is mainly from the placenta, the  brain and coronary arteries receive the blood with the high-  est oxygen concentration. The remaining blood flows into the  descending aorta.   Less-saturated blood, with an oxygen tension of 15 to 19  torr, returns from the upper body, head, neck, and arms and  travels from the superior vena cava into the RA. A small por-  tion of this blood flows into the RV and out the PA and enters  the nonfunctioning lungs. Most of the blood, however, bypasses  the lungs by flowing through the ductus arteriosus and into the  descending aorta. Blood from the descending aorta returns to  the placenta through two umbilical arteries.!   The nonaerated lungs and low oxygen tension induce vaso-  constriction, creating high pulmonary vascular resistance. This  is transmitted to the right side of the heart and the PAs. Con-  versely, fetal systemic resistance is low because of the large-vol-  ume placenta and ductus arteriosus. Therefore, because blood  flow follows the path of least resistance, high pulmonary resis-  tance diverts most of the blood flow into the PA, through the  ductus arteriosus, and into the aorta. From there it travels into  the low-resistance placenta.    At birth a series of circulatory changes occur that affect blood  flow, vascular resistance, and oxygen tension. The most impor-  tant change that takes place in the circulation is the shift of gas  exchange from the placenta to the lungs. In addition, altera-  tions in pressure and volume of blood flowing through the  heart chambers functionally close the ductus arteriosus, ductus    venosus, and foramen ovale. A decrease of pulmonary vascular  resistance and an increase of systemic vascular resistance lead to  changes in the size and shape of the heart chambers.   Clamping of the umbilical cord and expansion of the lungs at  birth shift gas exchange from the placenta to the lungs. Removal  of the low-resistance placenta from circulation also causes an  immediate increase in systemic vascular resistance to about twice  that before birth. Conversely, pulmonary vascular resistance  decreases because of expansion of the lungs, which result from  the infant’s respirations and exposure to more oxygen-rich blood.    Once the umbilical cord is clamped, the umbilical arteries and  vein, which comprise the cord, vasoconstrict and undergo  fibrous changes. Therefore, blood flow through the ductus  venosus falls instantly; absence of fetal shunting through this  vessel usually occurs within the first 7 days of life. Once the duc-  tus venosus closes, its remnants form the ligamentum veno-  sum, or round ligament of the liver.    Internal iliac  (hypogastric) arteries  FIGURE 33-4 Fetal Circulation. Circulation of the fetus reflects the fact that oxygenation of fetal blood does not take  place in the lungs, but rather in the placenta. Therefore, the pulmonary circulatory system is essentially “bypassed.” Instead of  traveling from the right heart to the lungs, as occurs after birth, most blood entering the right heart passes through the ductus  arteriosus and into the systemic circulation.    Increased pulmonary venous return and decreased inferior  vena cava return cause functional closure of the foramen ovale  within the first month of life. In the fetus the foramen ovale is  held open by the blood flow from the higher-pressure right side,  reflecting pulmonary vascular resistance, to the lower-pressure  area on the left side of the heart, reflecting systemic vascular  resistance. At birth the pressure gradients reverse (left atrial  pressure exceeds right atrial pressure by a small degree), causing  the valve flaps of the foramen ovale to close. Functional closure  occurs by the adherence of these flaps to the atrial septum. Ana-  tomic closure occurs within the first month of life after depo-  sition of fibrin tissue and cell products permanently seals the  flaps closed. Until this occurs, any condition that stimulates an  increase in the right-sided pressures or causes dilation of the  RA can reopen the foramen ovale. Conditions in which a patent  foramen ovale may continue past the first month of life include  pulmonary hypertension, RV failure, and tricuspid atresia.   The ductus arteriosus closes more gradually. Increased oxy-  gen saturation in the systemic arterial blood is thought to be    the major stimulus causing vasoconstriction of the ductus arte-  riosus. In addition, a decrease in the amount of endogenous  prostaglandins promoting dilation and the release of vasoactive  substances stimulate further ductal closure. Vasoconstriction  of the ductal medial smooth muscle shortens and thickens the  intima of the ductal wall within 15 to 18 hours after birth. Per-  manent closure is complete 10 to 21 days after birth. Fibrous  tissue adheres to the remaining structure, and the ductus arte-  riosus eventually evolves into the ligamentum arteriosum.  Conditions that involve low arterial oxygen saturations, such as  cyanotic heart disease, decreased medial muscle layer within the  ductus, or increased levels of circulating vasodilating substances  in the blood, may delay or prevent ductal closure.’    Compared to the adult, the infant’s cardiopulmonary system  is proportionally larger in relation to body surface area. The  infant’s heart points at a transverse angle, but as the lungs and  heart mature, the heart shifts lower in the chest and is rotated at  a more oblique angle. Unlike the adult heart, the newborn heart  has RV dominance with a thickened RV wall. This is because of  the high pulmonary vascular resistance in the fetal circulation that  subjects the RV to high afterload, which in turn causes the right  ventricular myocardium to become as thick and strong as the LV  myocardium.   After birth the right ventricular myocardium becomes less  dominant as pulmonary vascular resistance drops. As systemic  vascular resistance increases, the left ventricular myocardium  becomes thicker. By 1 month of age, the newborn’s ventricles  are approximately equal in weight. As the child grows, the heart  size increases accordingly. The weight of the heart doubles dur-  ing the first year of life and increases six times that by 9 years  of age.”   Postnatal changes involve a rise in arterial oxygen tension  and an increase in alveolar oxygenation that stimulates vasodi-  lation, resulting in a decrease in pulmonary vascular resistance.  During the first 2 to 9 weeks of life, the inner medial linings  of the small pulmonary arterioles become thinner in response  to decreased pulmonary arterial pressure. This increased diam-  eter of the pulmonary vessels, along with further development  of the pulmonary bed in response to lung growth, results in a  decrease in pulmonary vascular resistance. By 2 months of age,  pulmonary resistance may approximate adult levels. During the  neonatal period the pulmonary vascular bed remains hyperac-  tive. Adverse conditions, such as alveolar hypoxia, acidosis, and  hypothermia, may trigger pulmonary vasoconstriction and lead  to pulmonary hypertension.    As stated, systemic vascular resistance begins to rise once the pla-  centa is removed from the circulation. Normal levels in the infant  range from approximately 10 to 15 Wood units x body surface  area (in square meters) and gradually increase to 15 to 30 Wood  units x body surface area (in square meters) by childhood.*  Likewise, the systolic pressure is low in the full-term newborn  (approximately 39 to 59 mmHg), reflecting the low systemic  vascular resistance. As the systemic vascular resistance increases,    the LV becomes more developed and the systolic pressure rises  steadily until it equals adult levels once the child reaches puberty.   The heart rate of the newborn ranges from 100 to 180 beats/  minute, which gradually decreases as the child grows. Similarly,  the newborn’s cardiac output is high, which is a reflection of the  fetal circulation described earlier. Oxygen consumption dou-  bles at birth; to maintain adequate oxygen delivery, the cardiac  output also remains high. These changes, however, cause mini-  mal cardiac reserve in the newborn. Additional stressors could  increase oxygen demands and result in acute deterioration. By  2 months of age, oxygen consumption decreases by half. As  the newborn grows, stroke volume steadily increases while the  heart rate decreases, thus maintaining cardiac output.’    Postnatal circulation allows the lungs to oxygenate the venous  blood and allows fully saturated blood to be delivered to the sys-  temic circulation. Desaturated blood returning from the supe-  rior vena cava, inferior vena cava, and coronary veins enters the  RA and is pumped to the RV through the tricuspid valve. The  RV then pumps the blood through the pulmonic valve to the  PA; the blood flows to the lungs, where it is oxygenated. The  oxygenated blood returns from the lungs through the pulmo-  nary veins and enters the LA, which pumps blood to the LV  through the mitral valve. The LV then pumps blood through the  aortic valve and into the aorta. The coronary arteries receive the  saturated blood along with delivery to the systemic circulation.    Congenital heart disease is the leading cause of death, excluding  prematurity, during the first year of life.° It is estimated that  as many as 35% of deaths caused by congenital heart defects  occur in the first year of life and that one third of children born  with congenital heart disease will die as a result of their cardiac  disease (Box 33-1). There are more than 35 documented types    Until 2008 it was common to prescribe an antibiotic to be administered before  dental, gastrointestinal, or genitourinary procedures for almost all children with  congenital heart defects. This practice started in the 1950s and continued until  a committee of the American Heart Association (AHA) reviewed all of the major  literature related to infectious endocarditis (IE), a serious and sometimes fatal  condition in which the heart valves become infected with bacteria. The AHA  committee concluded that: (1) IE is more likely to result from bacteremia from  daily activities, such as brushing one’s teeth, than from procedures; (2) prophy-  laxis was not effective in preventing IE; (3) there are significant risks to giving  antibiotics; and (4) good oral health and hygiene is most important in the pre-  vention of IE. Current recommendations suggest administration of prophylactic  antibiotics before dental procedures only to the most high-risk children and  adults: those with prosthetic cardiac valves, cyanotic congenital heart disease,  repaired heart defects for the first 6 months after the procedure, repaired heart  defects with certain residual defects, and those with previous IE. The best thing  we as healthcare providers can teach our patients and their parents is to take  excellent care of their teeth!    of congenital heart defects, and the frequency of occurrence in  the United States is on the rise. Although researchers have not  determined the reason for this increase, one explanation is that  it may be the result of improved methods of detection.°   The underlying cause of congenital heart disease is known  in only 10% of cases. Several factors place the fetus at risk for  developing congenital heart disease, including prenatal, envi-  ronmental, and genetic factors. Among the prenatal factors are  maternal rubella, maternal insulin-dependent diabetes, mater-  nal alcoholism, maternal age (older than 40 years), maternal  phenylketonuria, and maternal hypercalcemia (Table 33-1).  The use of some drugs during pregnancy is associated with an  above-average incidence of congenital heart disease. Examples    Studies of cancer survivors reveal  radiation can cause atherosclerosis;  myocardial, endocardial, and pericardial  disease; conduction disturbances; and  endothelial vessel disease    of these drugs include thalidomide, lithium, phenytoin (Dilan-  tin), and warfarin. The incidence of heart defects also has been  found to be higher in stillbirths, spontaneous abortions, and  low-birth-weight or small-for-gestational-age infants.” In gen-  eral, the likelihood of unaffected parents having a child with  congenital heart disease is about 1% with a recurrence risk of  2% to 6%.   Genetic factors also have been implicated in the develop-  ment of congenital heart disease, although the mechanism of  causation is often multifactorial. Recent progress, accelerated  through the Human Genome Project, has resulted in the rapid  identification of some genes causing congenital heart disease.°   ETIOLOGY. The etiology of most congenital heart disease is  unknown. Early epidemiologic studies report a multifactorial  influence to be the cause of up to 90% of cardiac anomalies,  with a recurrence rate of 2% to 6%.’ Associated risk factors  include maternal, gestational, and familial conditions. (Mater-  nal risk factors are discussed in the previous section.) Exposure  to teratogens in utero also may be a risk factor. Likewise, fetal  exposure to active maternal infections, such as rubella, herpes-  virus, coxsackievirus B5, and cytomegalovirus, may be a risk.   Chromosomal aberrations account for about 6% of all con-  genital heart defects (Table 33-2). Many genetic and hereditary  diseases are associated with congenital heart defects, although  the mechanism of causation is unknown (Table 33-3). As  many as 50% of infants with trisomy 21 have a congenital heart  defect, either an AV canal defect or a VSD. Extracardiac defects  are noted in as many as 35% of infants with cardiac lesions.  Prospective studies using chromosomal analysis have suggested  that congenital cardiac malformations may be the result of a  single gene defect.°   Because of improved screening methods, surgical interven-  tions, and management, children with congenital heart defects  are now surviving into adulthood and bearing children of their  own. Studies report a 5% to 15% incidence of congenital heart  disease in offspring of a parent having a congenital heart lesion.  If two siblings have a congenital cardiac anomaly, the recur-  rence risk is 9%, and if three siblings have a congenital cardiac  anomaly, the rate jumps to a 50% chance that the next child also  will have a cardiovascular malformation.   There are more than 35 different types of congenital anomalies  that can be classified into 4 categories based on blood flow pat-  tern: (1) lesions increasing pulmonary blood flow; (2) lesions  decreasing pulmonary blood flow; (3) obstructive lesions, in  which right- or left-sided outflow tract obstructions curtail or  prohibit blood flow out of the heart; and (4) mixing lesions, in  which desaturated blood and saturated blood mix within the  chambers or great arteries of the heart (Table 33-4). By clas-  sifying lesions in this way, the clinical manifestations, as well as  associated sequelae, are more predictable.   Associated conditions and their clinical manifestations are  lesion dependent. The two most common conditions associ-  ated with congenital heart disease are heart failure (HF) and  hypoxemia. Lesions increasing pulmonary blood flow include    Ventricular septal defect (VSD), atrial septal defect (ASD),  patent ductus arteriosus (PDA), anomalous pulmonary  venous connection, bicuspid aorta, overriding aorta   Endocardial cushion defects, VSD, PDA, ASD, transposition  of great vessels, tetralogy of Fallot, persistent truncus  arteriosus, coarctation of aorta, endocardial fibroelastosis   Coarctation of aorta, pulmonary stenosis, subaortic and  aortic stenosis, PDA, septal defects    defects that allow blood flow to shunt from the high-pressure  left side to the lower-pressure right side, resulting in pulmo-  nary congestion. Lesions that cause decreased pulmonary blood  flow are generally complex and result in cyanosis. Obstructive  lesions increase the pressure needed to eject the blood from the  ventricles. The two types of obstructive lesions are right-sided  lesions that may result in hypoxemia and cyanosis, and left-  sided lesions that may result in HF. Mixing lesions are variable  in their physiology and clinical manifestations.    Heart failure (HF), sometimes called congestive heart failure  (CHF), is classified as an acquired condition. HF occurs when    Aortic or mitral regurgitation, aortic aneurysm  Pseudoatherosclerosis  Pseudoatherosclerosis, hypertension  Incompetent aortic valve   Atrial septal defect (ASD), ventricular septal defect (VSD)  Defect or absence of atrial septum    Cardiomegaly, left heart failure, supraventricular tachycardia  Thromboembolic episodes, pulmonic and aortic regurgitation    the heart is unable to maintain sufficient cardiac output to meet  the metabolic demands of the body. HF can occur as the result of  decreased myocardial function or excessive metabolic demands.  The most common causes of HF in infancy and childhood are car-  diomyopathy or the result of poor ventricular function. Table 33-5  lists the congenital heart defects that cause HF by age. Pulmonary  overcirculation from large left-to-right shunts (mixing) is often  called CHF but is not usually associated with decreased ventricu-  lar function and failure to meet metabolic demands. However, the  clinical manifestations are similar, such as failure to thrive (FTT),  tachypnea, tachycardia, and respiratory tract infections.  PATHOPHYSIOLOGY. In general, the pathophysiologic mecha-  nisms of HF in infants and children are very similar to those    Patent ductus arteriosus, atrial septal defect, ventricular  septal defect, complete atrioventricular canal defect  Tetralogy of Fallot, tricuspid atresia    Coarctation of the aorta, hypoplastic left heart  syndrome, aortic stenosis, pulmonary stenosis   Transposition of the great arteries, total anomalous  pulmonary venous connection, truncus arteriosus    *If patent ductus arteriosus closes, newborns with hypoplastic left heart syndrome, coarctation of the aorta, or critical aortic stenosis will present  with shock. Newborns with aortic stenosis or pulmonary stenosis may have only mild symptoms depending on severity of stenosis.  ‘Transposition of the great arteries and truncus arteriosus will present with cyanosis as patent ductus arteriosus closes. Total anomalous pulmo-    in adults. The same compensatory mechanisms are activated  in the face of inadequate cardiac output. An acute decrease in  blood pressure stimulates stretch receptors and baroreceptors  in the aorta and carotid arteries, which in turn stimulate the  sympathetic nervous system. With the release of catecholamines  and the stimulation of B receptors, heart rate and the force of  myocardial contraction increase. Venous smooth muscle tone  also increases, which increases return of venous blood to the  heart. Sympathetic stimulation also decreases blood flow to the  kidneys, skin, spleen, and extremities so that maximum flow to    the brain, heart, and lungs can be maintained. Decreased blood  flow to the kidneys causes the release of renin, angiotensin, and  aldosterone. If chronic, this cycle results in retention of sodium  and fluid by the kidneys, which in turn increases volume in the  circulatory system.   These neurohumoral and hemodynamic changes create  abnormal ventricular wall stress and cause the myocardium to  hypertrophy. The myocardial fibers also stretch to accommodate  the increased volume. Hypertrophy and fiber stretch temporarily  increase contractility and hence the force of ventricular contrac-  tion. These mechanisms eventually fail to maintain cardiac out-  put as HF progresses. A review of the Frank-Starling law of the  heart (see Chapter 31) is useful for an understanding of the cycle  of compensation and decompensation that occurs in HF.   CLINICAL MANIFESTATIONS. Symptomatic HF in children has  many causes. It is not usually necessary to determine if it is right-  or left-sided HF. When assessing a child with HF, a combination  of symptoms generally is present. Pulmonary overcirculation is  the predominant cause associated with congenital defects.   HF in infants is manifested as poor feeding and sucking,  often leading to failure to thrive (FIT). Dyspnea, tachypnea,  and diaphoresis may be accompanied by retractions, grunting,  and nasal flaring. Wheezing, coughing, and rales are rare even  with significant HF. Common skin changes, such as pallor or  mottling, are often present.   Hepatomegaly (enlargement of the liver) is atypically attrib-  utable to systemic venous congestion. In infants the normal liver  is soft, sharp-edged, and palpable 1 to 2 cm below the costal mar-  gin. However, the absence of hepatomegaly does not rule out HF.   Periorbital edema and weight gain without caloric increase  are uncommon manifestations of right ventricular failure in  infants. Peripheral edema, which is a common finding in adults,  is rare in infants and young children and more often signifies  renal disease rather than cardiac disease. The clinical manifesta-  tions of HF are listed in Box 33-2.   EVALUATION AND TREATMENT. A thorough physical examina-  tion with an emphasis on cardiac and pulmonary findings often  will reveal the degree of HF. Plotting the child’s growth (height,  weight, head circumference) is an important method for moni-  toring a child’s health. Infants with HF and pulmonary overcir-  culation usually have low weight with normal length and head    From Hockenberry MJ, Wilson D: Wong's nursing care of infants and  children, ed 9, St Louis, 2011, Mosby.    circumference. FTT is usually the result of increased meta-  bolic expenditure relative to caloric intake. An electrocardio-  gram (ECG) should be performed to determine the presence of  dysrhythmias or hypertrophy. A chest radiograph is useful in  assessing the presence of cardiomegaly and signs of increased  pulmonary circulation.   Treatment is aimed at decreasing cardiac workload and  increasing the efficiency of heart function. Medical man-  agement initially consists of diuretics, such as furosemide.  Depending on the degree of HF, other diuretics can be used in  combination with furosemide to counteract potassium losses.  Agents that reduce afterload, such as angiotensin-converting  enzyme (ACE) inhibitors and beta-blockers, have recently been  used to further manage severe HF.*° Caloric supplementation  is routinely prescribed.   Heart defects that allow desaturated blood to enter the systemic  system without passing through the lungs result in hypoxemia  and cyanosis. Hypoxemia occurs when arterial oxygen tension is  below normal and results in low oxygen arterial saturations and  cellular function alteration. Cyanosis, a blue discoloration of the  mucous membranes and nail beds, results from deoxygenated  hemoglobin in a concentration of at least 5 g/dl of blood or from  arterial saturations less than 85%.7* Anemia may mask the signs  of hypoxemia, whereas children who are polycythemic with a  normal arterial saturation may appear cyanotic. Older children  who have an unrepaired septal defect with a left-to-right shunt  may become cyanotic because of pulmonary vascular changes  secondary to increased pulmonary blood flow. Because of these  progressive pulmonary vascular changes, pulmonary vascular    resistance increases to exceed or equal vascular resistance, result-  ing in a reversal of shunting known as Eisenmenger syndrome.  Three types of defects cause hypoxemia and cyanosis:   1. Lesions that cause right ventricular outflow tract obstruc-  tion and shunting from the right side of the heart to the  left side, as in tetralogy of Fallot (see p. 1207)   2. Defects involving the mixing of saturated and unsatu-  rated blood within the heart chambers, as in a univen-  tricular heart (also referred to as a single ventricle)   3. Defects in children with transposition of the great arter-  ies (see p. 1214), in which two parallel circulations exist  and survival depends on the existence of a patent ductus  arteriosus or septal defect   CLINICAL MANIFESTATIONS. Infants with mild hypoxemia may  show signs of cyanosis only occasionally when stressed; oth-  erwise, they may exhibit near-normal age-projected growth  and development. Infants with severe hypoxemia may display  signs of feeding intolerance, poor weight gain, tachypnea, and  dyspnea. Children with chronic hypoxemia are small for their  age, may display cognitive and motor skill delays, experience  shortness of breath with exertion, fatigue easily, and have exer-  cise intolerance. Acute, severe hypoxemia will lead to tissue  hypoxia, metabolic acidosis, hyperventilation, poor perfusion,  and eventually shock.   In response to chronic hypoxemia, polycythemia occurs as  the body generates additional red blood cells to increase the  oxygen-carrying capacity of the blood. In some infants, how-  ever, microcytic anemia may result because of limited stores  of iron. Polycythemia and the associated platelet dysfunction  also place children at risk for thromboembolic events, espe-  cially infants with severe cyanosis and iron deficiency anemia.  In addition to the 2% risk of cerebrovascular accidents, there  is a small chance that children with right-to-left shunting will  develop a brain abscess.‘ Clubbing of the nail beds occurs  because of chronic tissue hypoxemia and polycythemia.    Cardiac lesions that increase pulmonary blood flow include  defects that involve septal abnormalities or communications  between the great arteries. These allow the shunting of blood  from the high-pressure left side to the lower-pressure right side.  Infants with left-to-right shunts are acyanotic and, depend-  ing on the degree of shunting, may develop signs and symp-  toms of CHF. Children with significant left-to-right shunts left  untreated are at risk for development of irreversible pulmonary  hypertension.    The patent ductus arteriosus (PDA) is a vessel located between  the junction of the main and left pulmonary arteries and the  lesser curvature of the descending aorta, usually just distal to the  left subclavian artery (Figure 33-5, A). During fetal circulation  the PDA allows blood to shunt from the PA to the aorta. At birth,  once the placenta is removed and the lungs are expanded, the  PDA will start to constrict within the first hours of life. Closure  of the PDA in full-term infants is usually noted between 15 hours  of life and 2 weeks of age.’ As an isolated defect, PDA occurs in    FIGURE 33-5 Patent Ductus Arteriosus (PDA). A, PDA with left-to-right shunt. B, PDA (asterisk) in an adult with pulmo-  nary hypertension. C, Changes in oxygen saturation, left ventricular volume, and the myocardium caused by left-to-right shunt  through a PDA. Ao, Aorta; LA, left atrium; LPA, left pulmonary artery; LV left ventricle; P7 pulmonary trunk; AA, right atrium; APA,  right pulmonary artery; RY right ventricle; SCV, subclavian vein. (A from Hockenberry Mu, Wilson D: Wong's essentials of pediat-  ric nursing, ed 9, St Louis, 2013, Mosby; B from Damjanov |, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.)    5% to 10% of all congenital cardiac defects. Studies have shown  that the incidence of PDA is high in premature infants.*  PATHOPHYSIOLOGY. Failure of the PDA to close results in per-  sistent patency of the ductus arteriosus. The hemodynamic  effects of PDA depend on the size of the lumen and the resis-  tance in the pulmonary and systemic circulations. At birth the  pulmonary and systemic vascular resistances are almost equal  and are reflected in the PA and aorta, respectively; therefore,  shunting is minimal. However, as pulmonary vascular resis-  tance falls, a reversal of fetal shunting occurs. Blood now begins  to shunt left to right, from the aorta to the PA. The hemody-  namic effect is increased pulmonary blood flow, resulting in    increased pulmonary venous return to the LA and LV with  increased workload on the left side of the heart. The increased  workload is caused by increased pulmonary venous return to  the LA and, potentially, an increase in right ventricular pres-  sure if pulmonary vascular changes occur in response to the  increased blood flow, leading to an increase in pulmonary vas-  cular pressure (see Figure 33-5, B).   CLINICAL MANIFESTATIONS. If pulmonary vascular resis-  tance has fallen, infants with PDA will characteristically have  a continuous-machinery type murmur heard best at the left  upper sternal border throughout systole and diastole. If the  PDA is significant, the infant also will have bounding pulses,    FIGURE 33-6 Atrial Septal Defect (ASD). A, Abnormal opening between the atria causing blood from the higher-pressure  left atrium to flow into the lower-pressure right atrium. B, Complete ASD (asterisk) form in children. Ao, Aorta; LA, left atrium;  LV, left ventricle; P7, pulmonary artery trunk. (A from Hockenberry MJ, Wilson D: Wong's essentials of pediatric nursing, ed 9,  St Louis, 2013, Mosby; B from Damjanov |, Linder J, editors: Anderson’ pathology, ed 10, St Louis, 1996, Mosby.)    an active precordium, a thrill upon palpation, and signs and  symptoms of pulmonary overcirculation. Infants with a small  PDA will usually remain asymptomatic.   EVALUATION AND TREATMENT. Chest radiograph will reveal car-  diomegaly and increased pulmonary vascular markings. An  ECG may demonstrate ventricular enlargement, particularly on  the left, but in most cases it is within the normal range. Echo-  cardiography and auscultation confirm the diagnosis based on  the characteristic continuous-machinery type of murmur.   PDA closure in asymptomatic children with a murmur is  recommended by 2 years of age because of the risk of subacute  bacterial endocarditis. No treatment is recommended for small  PDA in the absence of a murmur or other cardiac conditions.  Premature infants who develop respiratory distress are initially  given indomethacin, a prostaglandin inhibitor, to close the  duct. If this is unsuccessful, surgical ligation and division may  be warranted.   Historically the most widely used method for PDA closure  is surgical closure involving ligation and division of the duc-  tus with complete closure in nearly 100% of cases. Mortality  associated with surgical intervention nears 0%; however, there  continues to be some morbidity associated with the approach  through a left thoracotomy incision.   Several other options for PDA closure are available depend-  ing on the size of the child and the PDA. Many specialists per-  form interventional closure of the PDA during catheterization.  The catheter is advanced into the ductal opening whereby  multiple coils or other devices are placed into the lumen that  prohibit flow through the duct. The greatest advantages to this  procedure are the avoidance of a surgical procedure and thora-  cotomy pain and a brief observation stay in the hospital.   Another option is closure through video-assisted thoraco-  scopic surgery. This procedure involves making three small  incisions in the left lateral wall, through which a probe is    inserted. A clip is then placed around the vessel to occlude it.  An advantage of this procedure over open surgical procedures is  that there is less associated morbidity because of the avoidance  of a thoracotomy incision.®    An atrial septal defect (ASD) is an abnormal communication  between the atria (Figure 33-6, A and B). Although it is an iso-  lated lesion, it is the fourth most common congenital heart  defect, occurring in 5% to 10% of all congenital cardiac defects.  The three major types are: (1) an ostium primum defect,  an opening found low in the septum that may be associated  with AV valve abnormalities, especially mitral insufficiency;  (2) an ostium secundum defect, an opening in the center of  the septum (this is the most common type of atrial defect); and  (3) a sinus venosus defect, an opening that occurs high up in  the atrial septum near the superior vena cava and RA junction.  This defect is often associated with partial anomalous pulmo-  nary venous connection.   PATHOPHYSIOLOGY. Although the pressure difference between  the two atria is minimal, the ASD allows blood to be shunted  from left to right because of the slightly higher pressure of the  left atrial chamber and lower pulmonary vascular resistance as  compared with systemic vascular resistance. Right atrial and  ventricular enlargement develops as a result of left-to-right  shunting. Children with ASD are generally asymptomatic and  rarely display signs of pulmonary overcirculation. Moderate to  large ASDs allow an increase in pulmonary blood flow and, over  time, pulmonary vascular changes can occur that may, although  rarely, result in pulmonary hypertension.   CLINICAL MANIFESTATIONS. Because most children with ASD  are asymptomatic, diagnosis usually is made during a rou-  tine physical examination by the auscultation of a crescendo-  decrescendo systolic ejection murmur that reflects increased    blood flow through the pulmonary valve. The location of the  murmur is between the second and third intercostal spaces  along the left sternal border. A wide fixed splitting of the sec-  ond heart sound is also characteristic of ASD, reflecting volume  overload to the RV, causing prolonged ejection time and delay  of pulmonic valve closure.   EVALUATION AND TREATMENT. In most cases an echocardio-  gram is sufficient to confirm the diagnosis of an ASD. A chest  radiograph may reveal cardiomegaly and increased pulmonary  vascular markings in an asymptomatic child. An ECG may  demonstrate right-axis deviation and diastolic overload of the  RV manifested as right ventricular hypertrophy.’   ASD closure, generally before the child reaches school age,  results in improved health later in life. If left unrepaired, right  ventricular compliance decreases with age, and pulmonary  hypertension and right ventricular hypertrophy may occur,  placing the person at risk for the development of HF, atrial  dysrhythmias, or embolic events later in life. Surgical closure  is one method of closure and involves a pericardial patch or  suture closure of the defect, depending on the size of the open-  ing. Repair is done through a midsternal approach with the use  of cardiopulmonary bypass. Minimally invasive techniques are  being used on near—adult-sized patients. Sinus venosus defects  require a slightly different approach that consists of a synthetic  patch to close the opening and baffle the anomalous right pul-  monary venous drainage to the LA. Operative mortality associ-  ated with ASD closure is near 0%, with minimal morbidity.”!°  Device closure performed in the catheterization laboratory is  becoming a routine alternative to open surgical procedures.’    A ventricular septal defect (VSD) is an abnormal communica-  tion between the ventricles (Figure 33-7, A). VSDs are the most  common type of congenital heart lesion and account for 25%  to 33% of all congenital heart defects. The four types of VSDs  are based on location in the septum. The perimembranous type,  which occurs in the outflow tract of the LV immediately below  the aortic valve, is the most common type, accounting for up to  80% of all VSDs that require treatment. Muscular VSDs, which  occur low or anterior in the ventricular septum between the tra-  beculae (see Figure 33-7, B) are most likely to close spontane-  ously and are difficult to close surgically because of their location  low in the ventricular apex. Most muscular VSDs are hemody-  namically insignificant and require no medical or surgical treat-  ment. Supracristal VSDs (also called outlet VSD) occur in the  right ventricular outflow tract or infundibulum, below the pul-  monary valve. AV canal or inlet VSDs occur posterior and infe-  rior to the membranous system, beneath the septal cusp of the  tricuspid valve and inferior to the papillary muscles of the conus.   PATHOPHYSIOLOGY. The direction of shunting in a child with  a VSD is from the high-pressure left side to the lower-pressure  right side. The amount of shunting depends on the size of the  defect and the degree of pulmonary vascular resistance. Small  VSDs present increased resistance to shunting and limit blood  flow through the defect; thus the degree of pulmonary vascular  congestion and ventricular chamber enlargement is minimal  (see Figure 33-7, C).    After 1 to 2 weeks of life, when pulmonary vascular resis-  tance has decreased, moderate-sized to large VSDs allow a large  amount of shunting from left to right. The shunted blood flows  directly out the RV outflow tract and into the PA rather than  remain in the RV cavity (see Figure 33-7, D). Therefore, the  main PA, LA, and LV all enlarge. LV hypertrophy occurs to  effectively pump the additional volume. Pulmonary overcircu-  lation accounts for the symptoms associated with a large VSD  in most cases.   Over time the pulmonary bed also undergoes changes  because of increased pulmonary blood flow caused by the left-  to-right shunting. The smooth muscle layer in the arteriolar  walls thickens and proliferation of the intimal layer occurs. The  effect of these changes is a decrease in the diameter of the pul-  monary vessels, which increases the resistance to blood flow.  If the pulmonary vascular resistance is severely increased these  changes eventually become irreversible, and pulmonary vas-  cular resistance continues to rise. In some cases it exceeds sys-  temic vascular resistance, causing the shunt through the VSD to  reverse direction. Deoxygenated blood now flows into the sys-  temic circulation, and cyanosis occurs, a phenomenon known  as Eisenmenger syndrome.   CLINICAL MANIFESTATIONS. Clinical manifestations in children  with VSDs depend on the age of the child, size of the defect, and  level of pulmonary vascular resistance. Newborns with small  VSDs are relatively asymptomatic. Initially no murmur is pres-  ent because the newborn’s high pulmonary vascular resistance  causes equalization of the pressures between both ventricles.  Once pulmonary vascular resistance has dropped, left-to-right  shunting occurs, creating a murmur. Infants with large VSDs  display symptoms of HF and poor weight gain. Adults who  develop pulmonary vascular obstructive disease as a result of  unrepaired VSD will be cyanotic and have clubbing.   On physical examination a loud, harsh, holosystolic mur-  mur and systolic thrill can be detected at the left lower sternal  border. The intensity of the murmur reflects the pressure gradi-  ent across the VSD. An apical diastolic rumble may be present  with a moderate to large defect, reflecting increased flow across  the mitral valve.   EVALUATION AND TREATMENT. ECG and chest radiographs  reflect the amount of shunting through the defect. The ECG  of an individual with a small VSD may be normal, whereas the  ECG of an individual with a large VSD may reveal biventricu-  lar hypertrophy and LA enlargement. Chest roentgenographic  findings are significant for cardiomegaly and increased pulmo-  nary vascular markings; again, the severity is directly related to  the magnitude of shunting. An echocardiogram identifies the  position, size, direction of shunting, and dimensions of the LA,  LV, and RV chambers. It also can provide an estimate of PA  and RV pressures. Cardiac catheterization may be performed to  determine hemodynamics and, in some instances, the location  of other defects and additional VSDs.   Many VSDs spontaneously close during the first year of life.  Infants with symptoms of HF and poor weight gain despite  medical management should have their VSD corrected as soon  as possible. Left-to-right shunting with a pulmonary flow/  systemic flow (Q,/Q,) ratio of greater than 2:1 or evidence of    M=5 =  70% 98%  RA l iA |  M=5 M=8  70% 98%    L tu  M=5 M=2  70% 98%  aan |  M=5 M=8  70% 98%  Tal la al  85% aw  98% Hypertrophy    FIGURE 33-7 Ventricular Septal Defects (VSDs). A, VSD with left-to-right shunt. B, Muscular (asterisk) defect (opened  left ventricle). C, Hemodynamics of a small VSD with left-to-right shunt. Mean (M) indicates mean of pressure; systolic/diastolic  pressures are in mmHg; and percentages indicate oxygen saturation. D, Hemodynamics of a large VSD with left-to-right shunt.  Like the shunting that occurs in preductal coarctation of the aorta, the shunting pictured here causes left ventricular overload  and hypertrophy. Ao, Aorta; LA, left atrium; LV, left ventricle; RA, right atrium; AV right ventricle. (A from Hockenberry MJ,  Wilson D: Wong‘ essentials of pediatric nursing, ed 9, St Louis, 2013, Mosby; B from Damjanov I, Linder J, editors: Anderson's    elevated pulmonary vascular resistance are indications for clo-  sure. Closure of the VSD at this time is to prevent the develop-  ment of pulmonary vascular obstructive disease.   Placement of a PA band to decrease the amount of pulmo-  nary blood flow was initially used as a palliative procedure but is  now rarely used unless the presence of an additional lesion makes  complete repair difficult. Patch closure, using a synthetic mate-  rial or pericardium, is accomplished through a sternotomy and  with the use of cardiopulmonary bypass. A transatrial approach  is preferable to a right ventriculotomy because of the increased    incidence of conduction disturbances associated with ventricu-  lotomy. Contraindications for VSD closure include evidence of  pulmonary vascular obstructive disease or Eisenmenger syn-  drome.”’ Occlusion devices for VSD closure performed in the  cardiac catheterization laboratory are now in early clinical use.”""!   An atrioventricular canal (AVC) defect results from nonfusion  of the endocardial cushions during fetal life, yielding abnormal-  ities in both the atrial and ventricular septa and the AV valves    FIGURE33-8 Atrioventricular Canal Defect. (FromHockenberry MJ, Wilson D:  Wong‘s essentials of pediatric nursing, ed 9, St Louis, 2013, Mosby.)    (Figure 33-8). This defect accounts for as many as 5% of all con-  genital heart defects, and approximately 30% of AVC defects  occur in children with Down syndrome.’ The three types of  AVC defects are based on the cardiac components involved.  Complete AVC (CAVC) defects consist of an inlet VSD, a pri-  mum type of ASD, and defects in both the mitral and tricuspid  valves. Partial AVC (PAVC) defects consist of a primum type  of ASD and a cleft in the septal or anterior leaflet of the mitral  valve. Transitional AVC (TAVC) defects involve partial fusion  of the endocardial cushions, resulting in variable AV valve  abnormalities.”   PATHOPHYSIOLOGY. Hemodynamic abnormalities seen in AVC  defects depend on the components of the lesion and the level  of pulmonary vascular resistance. Shunting is minimal dur-  ing the neonatal period when pulmonary vascular resistance is  high. However, once pulmonary vascular resistance drops, left-  to-right shunting occurs through the septal defects, resulting in  increased pulmonary blood flow and HF.   PAVC defects mimic the hemodynamics of secundum ASD  in which the left-to-right shunting through the primum ASD  causes RA and RV dilation and increased pulmonary blood  flow. The mitral regurgitation that occurs, caused by the cleft  mitral valve, is usually hemodynamically insignificant.   CAVC defects reflect the hemodynamics of an ASD and a  VSD, resulting in biatrial and biventricular enlargement. RA  and RV volume overload occurs because of shunting through  the primum ASD and tricuspid regurgitation. Likewise, LA  and LV volume overload occurs because of shunting through  the VSD, increased pulmonary venous return, and mitral  regurgitation.   CLINICAL MANIFESTATIONS. Children with PAVC defects are  generally asymptomatic. Findings on physical examination are  similar to those of secundum ASD with the addition of a holo-  systolic, regurgitant murmur of mitral regurgitation at the apex.    At 4 to 12 weeks of age, when pulmonary vascular resistance  drops, children with CAVC defects usually begin to show symp-  toms of HF. Physical findings are similar to those found in indi-  viduals with VSDs with the addition of a holosystolic murmur  radiating to the back and apex, reflecting mitral regurgitation.  A mid-diastolic rumble at the left lower sternal border or apex  reflects relative stenosis of the mitral or tricuspid valve from  increased flow. Infants with CAVC may have signs of HF and  frequent respiratory tract infections.   EVALUATION AND TREATMENT. The ECG generally demonstrates  a superior left-axis deviation (—90 to —180 degrees), first-degree  AV block, and RV hypertrophy or right bundle branch block.  The ECG of CAVC defects also may show LV hypertrophy.  Chest radiograph shows cardiomegaly, increased pulmonary  vascular markings, and a prominent main PA. Echocardiog-  raphy allows visualization of the components of the defect,  including continuity between the AV valves, their sizes, and  chordal attachments. Cardiac catheterization may be electively  performed and can confirm the location of septal defects, AV  valve abnormalities, degree of left-to-right shunting, and pres-  ence of pulmonary hypertension.   Timing of surgical repair depends on the severity of symp-  toms, degree of shunting, and level of pulmonary vascular resis-  tance. The trend is to perform complete repair between 3 and  6 months after birth to avoid the development of pulmonary  vascular changes. Surgical repair is performed through a mid-  sternotomy implementing a one- or two-patch repair to close  the septal defects and repair the involved AV valves. Mortal-  ity has declined below 10% unless the child is a newborn, has  severe AV valve incompetence, or has a small LV (unbalanced  AV canal). Postoperative complications include heart block,  dysrhythmias, or mitral regurgitation requiring further surgical  intervention or valve replacement.”!    Defects decreasing pulmonary blood flow involve obstruction  to pulmonary blood flow and septal communications. Because  of RV outflow tract obstruction, right-sided pressures exceed  left-sided pressures, resulting in right-to-left shunting. Chil-  dren with these defects have hypoxemia and cyanosis.    Tetralogy of Fallot (TOF) consists of four defects: a large VSD  that is high in the septum, an overriding aorta that straddles  the VSD, pulmonary stenosis (PS), and RV hypertrophy (Figure  33-9, A and B). It is the most common cyanotic congenital heart  defect and accounts for 10% of all defects.’   PATHOPHYSIOLOGY. TOF develops during two phases of embry-  ologic growth: (1) during the division of the truncus arteriosus  by the spiral septum in the third or fourth week of gestation,  and (2) during the division of the ventricles between the fourth  and eighth weeks of gestation. Normally as these events prog-  ress, the truncal septum fuses with the bulbar ridges and in turn  with the endocardial cushions. The membranous portion of the  interventricular septum grows upward to meet the endocardial  cushions, and ultimately all of these tissues unite to complete  the interventricular septum.    The embryologic error that causes TOF is not definitively  known, but two theories have been proposed.! The first is that  the truncus arteriosus divides unevenly, resulting in great ves-  sels of unequal size. The second theory proposes that infundib-  ular overgrowth in the RV is the major developmental anomaly.  Defects in ventricular septation also occur, producing the large  VSD, which allows the aorta to override the VSD.   The pathophysiology associated with TOF varies widely,  depending primarily on the degree of pulmonary stenosis, the  size of the VSD, and the pulmonary and systemic resistance to  flow. Because the VSD is usually large, pressures are equal in the  RV and LV. Therefore, the major determinant of shunt direc-  tion through the VSD is the difference between pulmonary and    systemic vascular resistance (see Figure 33-9, C). Infants who  have little or no right-to-left shunting are acyanotic and are  known as “pink tets.” They may have a net left-to-right shunt  similar to a large VSD. If pulmonary vascular resistance is higher  than systemic resistance, the shunt is from right to left. Because  many factors can alter the balance between pulmonary and sys-  temic resistance, shunt direction is not necessarily constant.  Pulmonary stenosis decreases blood flow to the lungs and,  consequently, the amount of oxygenated blood that returns to  the left heart. If blood also shunts from right to left through  the VSD, deoxygenated blood mixes with the oxygenated blood  returning from the lungs. The result is low oxygen saturation  (hypoxemia) in the systemic circulation. The body attempts    FIGURE 33-9 Tetralogy of Fallot. A, Anatomic defects in tetralogy of Fallot. B, Complete transposition of the aorta and  pulmonary artery. €, Hemodynamics of tetralogy of Fallot with right-to-left shunt. Ao, Aorta; LA, left atrium; LV left ventricle;  PT, pulmonary artery trunk; AA, right atrium; AV right ventricle. (A from Hockenberry MJ, Wilson D: Wong's essentials of  pediatric nursing, ed 9, St Louis, 2013, Mosby; B from Damjanov |, Linder J, editors: Andersons pathology, ed 10, St Louis,    to compensate for chronic hypoxemia by producing more red  blood cells (thereby causing polycythemia) and by increasing  blood flow to the lungs through collateral bronchial vessels in  long-standing cases.   CLINICAL MANIFESTATIONS. In cases with decreased pulmonary  flow through the right ventricular outflow tract as long as the  ductus arteriosus remains open, the newborn’s pulmonary  blood flow may be adequate. As the ductus closes, however, cya-  nosis becomes apparent. Chronic hypoxemia causes clubbing of  the fingers and toes (see Chapter 35).   A rare manifestation of TOF is the sudden onset of dyspnea,  cyanosis, and restlessness, sometimes called a hypercyanotic spell  or a “tet spell,” that generally occurs with crying and exertion.  The cause of these episodes is unknown, but it is theorized that  the RV outflow tract goes into spasm or the systemic resistance  drops suddenly. In either case the relative or actual increase in  pulmonary vascular resistance increases the right-to-left shunt  and the cyanosis. Hypercyanotic spells are often the event that  initiates surgical intervention. If the spells are frequent or do  not terminate spontaneously, they are considered a medical-  surgical emergency.’   Infants with TOF may have difficulty with feeding because  the exertion required increases hypoxia, and therefore they  experience slow growth and FTT. Most infants with TOF grow  normally.   Squatting is a spontaneous compensatory mechanism used  by older children with unrepaired TOF to alleviate hypoxic  spells. Squatting and its variants increase systemic resistance  while decreasing venous return to the heart from the inferior  vena cava. The decrease of systemic return makes relatively more  oxygenated blood available to the body. The increase of systemic  resistance also reverses the shunt through the VSD to a left-to-  right shunt, which has the effect of increasing pulmonary blood  flow. Through both of these mechanisms, squatting temporarily  decreases the degree of hypoxemia. It is uncommon to witness  this because most cases are surgically corrected in early infancy.   The typical heart murmur of TOF is a pulmonary systolic  ejection murmur caused by the obstruction in the outflow tract,  which creates turbulence during systole. More obstruction to  flow (e.g., smaller orifice for the flow of blood) produces a  louder murmur. This explains why the murmur often disap-  pears during a hypoxic spell, when obstruction increases and  pulmonary blood flow decreases to a minimal amount. The  second heart sound seems to be single, but in fact it is not. The  pulmonary component is very soft and delayed and usually is  not heard, although it is present. The enlarged RV may cause  the left side of the chest to be more prominent, and a “heave”  also may be palpated.   EVALUATION AND TREATMENT. The ECG indicates RV hypertro-  phy. Chest radiographic examination shows that the heart is  shaped like a boot (upturned apex because of a small main PA)  and that pulmonary vascular markings are decreased. Echocar-  diograms and angiograms enable the clinician to see the size  and position of the VSD, the stenotic pulmonary infundibulum  or valve, the smaller-than-normal PA, and the overriding aorta.  Measurements made during cardiac catheterization (electively  done in rare cases) demonstrate equal systemic pressure in the    RV and LV, decreased pressure in the PA distal to the obstruc-  tion, and low oxygen saturation in the aorta if there is right-to-  left shunting.   The current practice is to repair TOF before 1 year of age.  Triggers for repair include increasing cyanosis and hypercya-  notic spells. Palliative procedures include the placement of a  pulmonary-to-systemic artery shunt known as the Blalock-  Taussig shunt to increase pulmonary blood flow or a modi-  fication of the shunt using prosthetic graft material placed  from either the subclavian or the innominate artery to the PA.  These shunts may cause PA distortion but may be necessary  in a very small symptomatic child. Corrective repair involves  patch closure of the VSD, resection of infundibular or valvu-  lar stenosis, and patch augmentation of the RV outflow tract.  The procedure is done through a median sternotomy while the  child is on cardiopulmonary bypass. The operative mortality is  less than 5%. Complications include dysrhythmias and occa-  sionally heart block. Many children require further surgery to  relieve recurrent pulmonary stenosis or treat severe pulmonary  insufficiency!    Tricuspid atresia consists of an imperforate tricuspid valve,  resulting in no communication between the RA and RV (Figure  33-10). This defect accounts for 2% to 3% of congenital heart  defects and is the third most common cyanotic heart defect. Tri-  cuspid atresia is a combination of defects, including the imper-  forate tricuspid valve as well as a septal defect, hypoplastic or  absent RV, enlarged mitral valve and LV, and varying degrees of  pulmonic stenosis. Tricuspid atresia also may be associated with  transposition of the great vessels. The most common type of tri-  cuspid atresia involves a hypoplastic RA with decreased pulmo-  nary blood flow, ASD, VSD, and normally related great vessels.   PATHOPHYSIOLOGY. Systemic blood returns through the supe-  rior and inferior venae cavae to the RA. Venous return flows  through the ASD into the LA, mixing with blood returning  from the pulmonary circulation. The blood then enters the  LV. Most of this blood passes into the systemic circulation  through the aorta, but varying amounts flow through the VSD  into the hypoplastic RV and to the lungs. Pulmonary circula-  tion depends on the presence of a VSD and the presence of a  functioning RV of reasonable capacity. If the RV is absent, the  pulmonary valve is usually imperforate as well. If this is the case,  a PDA is necessary to ensure that some blood flows into the  pulmonary circulation.’   Pulmonary circulation also depends on the relationship  between pulmonary and systemic vascular resistance. As long  as pulmonary resistance is lower than systemic resistance,  blood flows through the VSD from left to right, feeding the  pulmonary circulation. If pulmonary resistance rises above  systemic resistance, pulmonary blood flow will be significantly  diminished.   CLINICAL MANIFESTATIONS. Some degree of central cyanosis is  common in tricuspid atresia, depending on the amount of pul-  monary blood flow. Growth failure also is common. Children  experience exertional dyspnea, tachypnea, and hypoxemia.  Long-term effects of hypoxia are polycythemia and clubbing.    FIGURE 33-10 Tricuspid Atresia. A, No communication from the right atrium to the right ventricle. B, Tricuspid atresia  with absent right atrioventricular connection with a hypoplastic right ventricle (four-chamber view). LA, Left atrium; LV, left  ventricle; RA, right atrium; RV right ventricle. (A from Hockenberry MJ, Wilson D: Wong's essentials of pediatric nursing, ed 9,  St Louis, 2013, Mosby; B from Damjanov |, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.)    These children also may display hypercyanotic spells. Hepato-  megaly may be present if the ASD is restrictive or CHF occurs  as a result of increased pulmonary blood flow.   The murmur heard with tricuspid atresia may have several  components. The VSD causes a systolic regurgitant murmur;  the murmur is likely to be softer and shorter as the VSD enlarges.  A narrowly split second heart sound caused by decreased pul-  monary blood flow may be present, or the second heart sound  may be single if there is pulmonary atresia.   EVALUATION AND TREATMENT. Chest radiographic examination  shows a heart size that is normal or slightly increased. ECG usu-  ally shows RA, LA, and LV hypertrophy with left-axis deviation.  Echocardiography and cardiac catheterization, if performed,  depict left-to-right shunting at the ventricular level, inability of  blood flow to enter the RV from the absent tricuspid opening,  and the presence of associated defects.   Newborns with ductal dependent pulmonary blood flow  are immediately given prostaglandins to maintain adequate  pulmonary perfusion. Initial surgical intervention involves  the placement of a Blalock-Taussig shunt (or its modifi-  cation). If the ASD is restrictive, a Rashkind procedure  (balloon atrial septostomy) may be performed during cath-  eterization. Children who experience increased pulmonary  blood flow may require the placement of a PA band. Correc-  tive repair involves closing the septal defects, removing the  previous shunts or band, and connecting the superior and  inferior venae cavae to the PA to separate the pulmonary sys-  temic circulation (Fontan procedure and its modifications).  Postoperative complications include pleural effusions, ele-  vated pulmonary vascular resistance, LV dysfunction, and  dysrhythmias.!°    Obstructive defects are conditions in which anatomic stenosis  (narrowing) in either the right or the left outflow tract causes  obstruction to blood flow and results in a pressure load on the  ventricles. The gradient reflects the severity of the narrowing;    the higher the gradient the more obstruction to flow and more  afterload on the ventricle. The location is classified according to  the location of the narrowing in relation to the valve. Valvular  stenosis refers to stenosis of the valve itself; subvalvular indi-  cates that the obstruction is below the valve or in the ventricular  outflow tract; and supravalvular is the area above the valve in  the great artery. The great vessel itself can be narrowed and the  site of obstruction can be the same as that in coarctation of the  aorta. The obstructive defects include coarctation of the aorta,  aortic stenosis, pulmonary stenosis, and hypoplastic left heart  syndrome. Symptoms associated with the defect depend on the  site and severity of stenosis.    Coarctation of the aorta (COA) is a narrowing of the lumen of  the aorta that impedes blood flow. This defect accounts for 8%  to 10% of all congenital heart defects. COA is almost always in  a juxtaductal position, although it can occur anywhere between  the origin of the aortic arch and the bifurcation of the aorta in  the lower abdomen. About 50% of individuals with COA have a  bicuspid aortic valve (Figure 33-11).?   PATHOPHYSIOLOGY. COA may develop because of abnormal  contractile ductal tissue that constricts at the time of ductal  closure. COA causes a condition in which there are higher pres-  sures proximal to the site of stenosis and lower pressures distal  to the site. In preductal COA the RV acts as a systemic pump,  sending unoxygenated blood through the ductus into the  descending aorta below the coarctation (Figure 33-12). In post-  ductal COA the RV cannot pump enough blood through the  ductus to the descending aorta because of pressure caused by  the narrowed aorta. Systolic pressure increases in the ascending  aorta and LV and decreases in the descending aorta beyond the  COA (Figure 33-13). In long-standing COA, collateral circula-  tion, which involves small arteries arising from the subclavian  arteries, joins intercostal arteries that flow into the descend-  ing aorta. These collateral vessels bypass the COA and sup-  ply blood to the lower extremities. The direction of shunting    through the ductus, if present, depends on the pressure differ-  ence between the PA and aorta and the location of the ductus.  When blood pressure is greater in the aorta than in the PA,  blood flow through the ductus will be left to right toward the  lungs, resulting in increased pulmonary venous return to the    left side of the heart. This may place an additional strain on the  LA and LV, leading to increased volume and workload. With  time, LV hypertrophy develops because of increased afterload  and obstruction to flow caused by the coarctation. HF also may  develop.    FIGURE 33-11 Postductal and Preductal Coarctation of the Aorta. A, Postductal coarctation occurs distal to (“after”)  the insertion of the closed ductus arteriosus into the aortic arch. Preductal coarctation occurs proximal to (“before”) insertion  of the patent ductus arteriosus. The coarctation consists of a flap of tissue that protrudes from the tunica media of the aortic  wall. B, Coarctation of the aorta with typical indentation of the aortic wall (arrow) opposite the ductal arterial ligament (aster-  isk). Ao, Aorta. (A from Hockenberry MJ, Wilson D: Wong's essentials of pediatric nursing, ed 9, St Louis, 2013, Mosby; B from  Damjanov |, Linder J, editors: Anderson’s pathology, ed 10, St Louis, 1996, Mosby.)    FIGURE 33-12 Hemodynamics of Preductal Coarctation of the Aorta  with a Patent Ductus Arteriosus. The left-to-right shunt through the ductus  arteriosus increases the volume of blood in the pulmonary circulation. Afterload  (small black arrows) is increased in the left heart by increased return from the  lungs and decreased ventricular outflow caused by the coarctation. The outcome is  heart failure. LA, Left atrium; LV left ventricle; RA, right atrium; AV, right ventricle.    @ Oxygenated blood  FIGURE 33-13 Hemodynamics of Postductal Coarctation of the Aorta.  Blood pressure increases in the ascending aorta and subclavian artery and  decreases in the descending aorta. These pressure changes eventually occur in  the parts of the systemic circulation served by arteries that branch from the aorta  before and after the coarctation.    CLINICAL MANIFESTATIONS. Clinical manifestations vary depend-  ing on the severity of the coarctation and age of presentation.  In newborns the onset of symptoms depends on the timing of  ductal closure after a fall in pulmonary vascular resistance, the  location of the COA, and the presence of associated defects. The  newborn usually presents with CHF symptoms. Once the ductus  closes, these infants will deteriorate rapidly from the develop-  ment of hypotension, acidosis, and shock. Older children may  not be diagnosed until hypertension is noted. Hypertension is  noted in the upper extremities with decreased or absent pulses  in the lower extremities. Children may have cool, mottled skin  and occasionally leg cramps during exercise. A systolic ejection  murmur, heard best at the left interscapular area, is caused by  rapid blood flow through the narrowed area.   EVALUATION AND TREATMENT. A chest radiograph shows an  enlarged heart with congested lung fields in newborns. Rib  notching between the fourth and eighth ribs may be seen in  children older than 5 years, reflecting erosion of the ribs as a  result of enlarged collateral vessels from the ascending aorta  to the descending aorta, bypassing the coarctation. An ECG  may be normal or reveal LV hypertrophy. An echocardiogram  will confirm the diagnosis and rule out other intracardiac  defects. Cardiac catheterization and/or magnetic resonance  imaging (MRI) is performed only if the echocardiogram is  inconclusive.   The first step in treatment of the symptomatic infant is sta-  bilization, which may require prostaglandin administration,  mechanical ventilation, and inotropic support to maintain  adequate cardiac output. Once this is achieved, surgical inter-  vention is indicated. Surgical repair for infants younger than 1  year consists of either a subclavian flap aortoplasty technique  to enlarge the constricted area or a resection with end-to-end  anastomosis of the arch segments. Depending on the arch mor-  phology, a modification of this procedure enlarges the aorta  beyond the area of constriction. For children older than 1 year,  surgical repair consists of resection with end-to-end anastomo-  sis.!> Cardiopulmonary bypass is not required because of the  extracardiac nature of the lesion, and the approach is accom-  plished through a left thoracotomy.   Postoperative complications include recoarctation and  paradoxical postoperative hypertension. Residual permanent  hypertension requiring continued medical therapy is related to  age at repair; therefore, surgical intervention is recommended  at the time of diagnosis. Operative mortality for infants is less  than 5%, and for children older than 1 year, it is less than 1%.  Balloon dilation angioplasty in newborns has been successfully  performed. However, aortic aneurysm formation and resteno-  sis have been noted; therefore, surgical repair remains the cor-  rection of choice for the newborn.!*"!°    Aortic stenosis (AS) is a narrowing of the aortic outflow tract  (Figure 33-14). The lesion accounts for 5% of all congenital  heart defects.* Valvular stenosis is caused by malformation or  fusion of the cusps. It is the most common type of AS, tends  to be progressive, and, in rare cases, can lead to sudden death  as a result of low cardiac output or myocardial ischemia. For    FIGURE 33-14 Aortic Stenosis. Narrowing of the aortic valve causing resis-  tance to blood flow in the left ventricle, decreased cardiac output, left ventricular  hypertrophy, and pulmonary congestion. (From Hockenberry MJ, Wilson D: Wong's  essentials of pediatric nursing, ed 9, St Louis, 2013, Mosby.)    children with mild AS, no exercise restrictions may be needed.  For those with moderate AS, some exercise limitations may  be advised. Severe AS is an indication for limiting exercise  until the repair is accomplished. Less common forms of AS  are subvalvular stenosis caused by a constricting fibrous ring  below the valve and supravalvular stenosis that occurs above  the valve.”   PATHOPHYSIOLOGY. Obstruction to blood flowing out of the  aorta causes an increased workload on the LV, resulting in  left ventricle hypertrophy (LVH). LV failure may develop,  leading to an increase in LA pressure and a backup in the  system, eventually resulting in pulmonary vascular conges-  tion and pulmonary arterial hypertension. LVH can decrease  coronary artery perfusion, resulting in myocardial ischemia,  and it can alter the LV papillary muscle, causing mitral  insufficiency.   CLINICAL MANIFESTATIONS. Most children with mild to moder-  ate AS are asymptomatic. Signs of exercise intolerance may not  appear until preadolescence. Syncopal episodes, epigastric pain,  and exertional chest pain may occur in more severe forms of  AS. A systolic ejection murmur at the right upper sternal border  that transmits to the neck and left lower sternal border is pro-  duced by blood flow through the stenotic area. An ejection click  may be heard with valvular AS. Severe forms of AS, especially  critical AS in the newborn, result in shock and require immedi-  ate intervention.   EVALUATION AND TREATMENT. Diagnosis may be made based on  previous medical history and physical findings. Chest radio-  graphic examination may reveal a dilated ascending aorta or LV  enlargement. Increased pulmonary vascular markings may be  seen in severe forms. In mild cases the ECG is normal. LVH  with strain pattern (features of LVH with inverted T waves in  the lateral precordial leads) may be seen in severe forms. An    FIGURE 33-15 Pulmonary Stenosis. A, Obstruction of right ventricular outflow caused by pulmonary stenosis. Pressure  on the ventricular side of the pulmonic semilunar valve (pulmonary valve) is much greater than that on the pulmonary arterial  side. This difference disrupts the normal pressure gradient across the valve. Pulmonary stenosis increases ventricular afterload  by decreasing blood flow through the valve, which causes ventricular hypertrophy. B, The backup of ventricular afterload into  the right atrium reopens the foramen ovale. Venous blood then flows from the area of higher pressure (the right atrium) to  the area of lower pressure (the left atrium), causing a right-to-left shunt. Cyanosis occurs if enough venous blood shunts from  right to left to reduce oxygen saturation in the systemic circulation by 3% to 5%. LA, left atrium; RA, right atrium. (A from  Hockenberry MJ, Wilson D: Wong’s essentials of pediatric nursing, ed 9, St Louis, 2013, Mosby.)    echocardiogram may reveal a thickened and poorly functioning  LV with abnormal structure, opening and closure of the aortic  valve. Cardiac catheterization may be performed to augment  echocardiographic data or perform intervention.   The presence of ST-segment changes on ECG, manifesta-  tion of severe CHF, and evidence of discrete severe stenosis at  the aortic outflow tract are indications for intervention. Bal-  loon aortic valvuloplasty is a palliative procedure performed  for valvular AS; however, it is associated with complications,  including aortic insufficiency and dysrhythmia.!’ Aortic val-  votomy, under inflow occlusion or cardiopulmonary bypass, is  performed for valvular AS. Operative mortality remains high  in infants (up to 20%), although older children have a mortal-  ity close to 0%.'° As many as 25% of individuals require a sec-  ond surgery within 10 years for restenosis, at which time valve  replacement may be the procedure of choice.   Subvalvular AS and supravalvular AS require surgical repair  involving excision of the area causing the constriction. For sub-  valvular AS involving a small LV outflow tract and aortic annu-  lus, a Konno procedure may be done to enlarge the LV outflow  tract and aortic annulus with a patch.!*!   Pulmonary stenosis (PS) is the narrowing of the pulmonary  outflow tract. This may be in the form of abnormal thickening  of the valve leaflets or narrowing of the arterial (supravalvular)  or ventricular (subvalvular) side of the valve (Figure 33-15, A).  Pulmonary atresia is the severe form of PS and involves com-  plete fusion of the commissures, allowing no blood flow out of  the RV to the PA. PS accounts for 5% to 8% of all congenital  heart defects.’    PATHOPHYSIOLOGY. PS creates resistance to blood flow from the  RV to the PA. The narrowed orifice (valve) produces increased  resistance (afterload) to ejection. In order for the RV to main-  tain adequate cardiac output, the myocardium hypertrophies. If  the RV outflow tract obstruction is severe, blood may back up  into the RA, causing dilation. This may result in reopening of  the foramen ovale with resultant unoxygenated blood shunting  to the LA, causing cyanosis (see Figure 33-15, B).   CLINICAL MANIFESTATIONS. Clinical manifestations depend on  the severity of PS. A systolic ejection murmur at the left upper  sternal border reflects obstruction to flow through the nar-  rowed pulmonary valve. In some children a variable systolic  ejection click is present with valvular stenosis at the upper left  sternal border. A thrill also may be palpated at the upper left  sternal border. Children with moderate PS may have exertional  dyspnea and fatigability because of the inability of the body to  increase pulmonary blood flow to meet demands for increased  cardiac output. Severe PS will produce cyanosis and HF.   EVALUATION AND TREATMENT. A chest radiograph shows a  normal-size heart with a prominent main PA caused by post-  stenotic dilation. An ECG is usually normal but may reveal  right-axis deviation and RV hypertrophy with moderate PS.  Echocardiography confirms the diagnosis and detects associ-  ated defects. Cardiac catheterization, if performed for interven-  tional purposes, further demonstrates PA anatomy.   Mild to moderate PS will not likely require intervention but  should be observed closely. Most mild PS is not progressive.  Treatment is indicated when a significant pressure gradient is  detected across the RV outflow tract.   Critical (severe) PS must be addressed immediately. The  treatment of choice is balloon angioplasty. This procedure is    FIGURE 33-16 Hypoplastic Left Heart Syndrome. (From Hockenberry MJ,  Wilson D: Wong’s essentials of pediatric nursing, ed 9, St Louis, 2013, Mosby.)    considered highly effective in decreasing the pressure gradient  across the pulmonic valve and is noted to have few associated  complications.!’ Surgical correction involves a pulmonary val-  votomy incising the fused commissures. Operative mortality  is less than 1%.? Both valvotomy and balloon angioplasty may  result in some pulmonary valve incompetence, and long-term  follow-up may reveal the need for further intervention.   Hypoplastic left heart syndrome (HLHS) refers to the abnor-  mal development of the left-sided cardiac structures, resulting  in obstruction to blood flow from the LV outflow tract. HLHS  involves underdevelopment of the LV, aorta, and aortic arch,  as well as mitral atresia or stenosis (Figure 33-16). Therefore,  infants with HLHS must have a well-functioning RV and the  presence of a PDA and atrial septal communication for sur-  vival. HLHS accounts for 1% of all congenital heart defects and  is considered the most complex congenital defect.’   PATHOPHYSIOLOGY. Because of the high pressures caused  by LV outflow tract obstruction, saturated blood enters the  LA and mixes with desaturated blood in the RA through an  atrial septal communication. Blood flow follows the normal  pathways through the right side of the heart. Exiting the PA,  the mixed-saturation blood flows through the ductus and to the  descending aorta. The amount of blood flow that travels to the  pulmonary and systemic circulations depends on vascular resis-  tance in the respective systems. Retrograde blood flow through  the hypoplastic ascending aorta provides coronary and cerebral  blood flow if there is complete aortic atresia.   CLINICAL MANIFESTATIONS. Newborns with HLHS generally  are born full-term and initially appear healthy. As the ductus  closes, systemic perfusion is decreased, resulting in hypoxemia,  acidosis, and shock. Usually no heart murmur is detected.  The second heart sound is loud and single because of aortic  atresia.    EVALUATION AND TREATMENT. A chest radiograph shows car-  diomegaly and increased pulmonary venous congestion. ECG  shows RV hypertrophy and diminished left-sided forces.  Echocardiography reveals the components of the defect with  a diminutive LV cavity, hypoplastic aortic valve and arch, and  hypoplastic or absent mitral valve with an enlarged RV cavity.  Interventional cardiac catheterization with balloon septostomy  may be necessary if the atrial communication is inadequate.  This procedure is very high risk.”   Prostaglandin infusion to maintain patency of the ductus  arteriosus is essential for newborn infant survival. Immedi-  ate correction of acidosis, inotropic support for adequate car-  diac output, and ventilatory manipulation to balance systemic  and pulmonary blood flow prevent further deterioration and  achieve stabilization.   Surgical intervention includes a three-stage approach that  classically begins with a Norwood procedure. The Norwood pro-  cedure consists of an atrial septectomy, placement of a pulmo-  nary-to-systemic artery shunt to maintain adequate pulmonary  blood flow, creation of a permanent communication between the  RV and aorta, and patch augmentation of the hypoplastic aorta.  The Sano modification utilizes a graft between the RV and the PA  to provide stable pulmonary blood flow rather than a pulmonary  to systemic arterial shunt.”” Postoperative complications include  imbalance of systemic and pulmonary blood flow, leading to inad-  equate cardiac output and persistent HF. In most centers, survival  after the initial procedure is now averaging greater than 70%.   The second stage is the bidirectional Glenn procedure, which  is performed between 2 and 9 months of age, depending on the  child’s clinical status, pulmonary vascular resistance, and ven-  tricular function. This involves joining the superior vena cava  to the PA and take-down of the shunt to the lungs. Complica-  tions include superior vena cava obstruction, pleural effusion,  and low cardiac output.   The third stage is the Fontan procedure, described earlier,  which separates the systemic from the pulmonary circulation.  Timing for surgical repair depends on the child’s ventricular  function, presence of AV valve regurgitation, and pulmonary  vascular resistance. Most surgeons perform the Fontan proce-  dure when the child is approximately 2 to 4 years of age.”   Cardiac transplant also may be an option for these newborns.  Most surgical centers offer the three-staged palliative surgeries  as an initial approach, with an option for cardiac transplanta-  tion later in life.”?!   Many complex defects are classified as mixing defects because  of their dependence on the mixing of pulmonary and systemic  circulations for survival during the postnatal period. This mix-  ing results in desaturated systemic blood flow and cyanosis. Pul-  monary congestion occurs because of preferential pulmonary  blood flow. Clinically each defect has varying degrees of cyano-  sis and HF depending on the various components of the lesion.    Transposition of the great arteries (TGA) refers to a condition  in which the aorta arises from the RV and the PA from the LV    FIGURE 33-17 Hemodynamics in Transposition of the Great Arteries (TGA). A, Complete transposition of the great  vessels with an intact interventricular septum. The aorta arises from the right ventricle and the pulmonary artery from the left.  B, Oxygen saturation in the two parallel circuits. Ao, Aorta; ASD, atrial septal defect; LA, left atrium; LV left ventricle; PA,  pulmonary artery; PDA, patent ductus arteriosus; AA, right atrium; AV right ventricle; VSD, ventricular septal defect. (A from  Hockenberry MJ, Wilson D: Wong’s essentials of pediatric nursing, ed 9, St Louis, 2013, Mosby.)    (Figure 33-17, A). The result is two separate, parallel circuits in  which unoxygenated blood circulates continuously through the  systemic circulation and oxygenated blood circulates repeatedly  through the pulmonary circulation. This condition is incom-  patible with extrauterine life unless a communication exists  between the two circuits to provide the necessary oxygen to the  body. Communication is accomplished by mixing of pulmo-  nary and systemic circulations through a PDA, ASD, or VSD  (see Figure 33-17, B). Dextro-transposition of the great arteries  (p-TGA) is the most common cyanotic congenital heart defect  and accounts for 10% of all congenital heart defects; “dextro”  refers to the aorta remaining to the right of the PA.*”   Two factors allow newborns with complete transposition to  survive long enough to be treated. First, blood from the two  closed systems can mix through the ductus arteriosus for a short  time after birth if pulmonary vascular resistance remains high.  Some mixing also may occur through the foramen ovale. If the  child has a VSD, mixing occurs through that opening as well.   PATHOPHYSIOLOGY. It is not known precisely which embryo-  logic events lead to transposition, but researchers have pro-  posed that the fault lies in the development of conal tissue in  the fibrous skeleton of the heart.! The conus is a segment of  muscle that separates the AV (tricuspid and mitral) valves from  the semilunar (aortic and pulmonic) valves. (The fibrous skel-  eton and heart valves are described and illustrated in Chapter  31; see Figure 31-4.) The interventricular septum is intact in  about 60% of cases of transposition; a VSD is present in the  remaining 40%. PS is associated with the transposition in about  4% to 6% of children with intact septa and in 28% to 31% of  children with VSDs.*7   The discussion that follows is limited to the pathophysiol-  ogy of complete transposition with an intact interventricular  septum.   CLINICAL MANIFESTATIONS. The degree of mixing permitted  by fetal structures determines the type and severity of clinical    manifestations. Cyanosis may be mild shortly after birth and  worsen during the first day because of functional closure of the  ductus arteriosus. Low oxygen levels in the blood (hypoxemia)  cause metabolic acidosis, tachycardia, and tachypnea. The pres-  ence of a PDA or large ASD allows for more mixing and results  in only mild cyanosis, but the infant may develop CHF.   The first heart sound is normal, and the second sound  may be heard as a single sound even though both the aortic  and pulmonic valves are functioning. The loud single S, may  occur because transposition places the aortic valve closer to the  chest wall than the pulmonic valve. No murmur is noted with  transposition of the great arteries with an intact ventricular  septum.   EVALUATION AND TREATMENT. On chest radiograph the heart  has a characteristic shape—like an egg on its side—and pul-  monary vascular markings are increased. The heart may be  enlarged if the infant is a few weeks old and has a VSD. ECG  findings reveal a right-axis deviation and some RV hypertro-  phy. Echocardiography confirms the diagnosis of transposition  of the great arteries. Cardiac catheterization may be necessary  to define the coronary anatomy; measure ventricular ratios;  and, if necessary, perform a balloon septostomy. Balloon sep-  tostomy is done only if the situation is critical because there are  risks involved.”   Surgical repair during the newborn period involves the  arterial switch operation that moves the great arteries. The  coronary arteries are removed from the aorta before the arte-  rial switch is performed and reimplanted without torsion or  kinking into the aorta. This establishes normal blood flow  with the LV as the systemic pump. Results are approach-  ing 100% survival. Complications include narrowing at the  sites of the great artery anastomoses and, rarely, coronary  insufficiency.”   Mustard and Senning operations (the creation of an intra-  atrial tunnel to baffle the systemic venous blood flow to the    FIGURE 33-18 Hemodynamics of Total Anomalous Pulmonary Venous  Connection (TAPVC). In the form of TAPVC represented here, the pulmonary  veins enter the left anomalous vertical vein instead of the left atrium. From the  left anomalous vertical vein, the mixed blood from the lungs flows into the superior  vena cava through an innominate vein (literally, a “vein without a name”). Oxygen  saturation within the four heart chambers, the pulmonary artery, and the aorta is  the same. Blood pressure in the right heart exceeds that in the left heart because  the right heart is receiving blood from both the pulmonary and systemic circulatory  systems. (Abnormal vessels are shaded.) (From Hockenberry MJ, Wilson D: Wong's  essentials of pediatric nursing, ed 9, St Louis, 2013, Mosby.)    mitral valve and the pulmonary venous blood flow to the tri-  cuspid valve) are no longer the procedures of choice because the  RV must perform as the systemic pump. Long-term follow-up  of children with Mustard and Senning operations revealed sig-  nificant rates of RV failure and dysrhythmias.’   The Rastelli procedure is used in children with transposition,  VSD, and severe PS. This procedure involves closing the VSD  with a baffle by rerouting LV blood through the VSD to the  aorta. The pulmonary valve is closed, and an RV-to-PA pros-  thetic or homograft valve conduit is placed. This procedure  requires prosthetic conduit replacement as the child grows and  is associated with ventricular failure and dysrhythmias in the  postoperative period.’   Total anomalous pulmonary venous connection (TAPVC),  or total anomalous pulmonary venous return, occurs when the  pulmonary veins abnormally connect to the right side of the  heart either directly or through one or more systemic veins that  drain into the RA (Figure 33-18). An ASD generally is present  also. This defect is extremely rare, accounting for only 1% of all  congenital heart defects. The four types of TAPVC are based on  the site of drainage. Supracardiac TAPVCs are the most com-  mon form (50%) and drain to the superior vena cava through  the vertical or innominate vein. Cardiac TAPVCs (20%) drain  directly into the RA or through the coronary sinus. Infracar-  diac TAPVCs (20%) traverse the diaphragm and drain into the    portal or hepatic vein or the inferior vena cava. Mixed TAPVCs  (10%) are a combination of the various types. Partial anoma-  lous venous connection is a condition in which only one or two  of the pulmonary veins, usually the right-sided veins, drains  into the RA or one of its tributaries.’   PATHOPHYSIOLOGY. Physiologically TAPVC can be differenti-  ated into two groups: nonobstructive and obstructive, depend-  ing on the absence or presence of obstruction to pulmonary  venous drainage. The hemodynamics of the nonobstructive  group involve the RA receiving the oxygenated blood that  would normally flow into the LA. The amount of blood shunted  into the LA vs. the volume entering the RV depends on the size  of the ASD and compliance of the RV. Therefore, if the ASD is  restrictive and RV compliance approaches normal, more blood  will enter the RV than the LA, resulting in RA and RV enlarge-  ment, as well as increased pulmonary blood flow. This causes  increased pulmonary venous blood return and larger amounts  of saturated blood. If the ASD is unrestrictive and the RV does  not become thinner to increase compliance, the majority of  mixed saturated blood is shunted from the higher-pressure RA  to the LA.   The hemodynamics of obstructed TAPVC cause pulmo-  nary venous hypertension because of resistance caused by the  obstruction resulting in an elevation in pulmonary vascular and  RV pressures. Pulmonary edema occurs from hydrostatic capil-  lary pressure exceeding the osmotic pressure of the blood and  eventually contributing to the development of HF. This group  has a strong association with the infracardiac type of TAPVC  and is a surgical emergency.   CLINICAL MANIFESTATIONS. The predominant clinical manifes-  tation in infants with TAPVC is cyanosis caused by mixture  of oxygenated and deoxygenated blood entering the systemic  circulation. The degree of cyanosis is inversely related to the  amount of pulmonary blood flow. Children with unobstructed  TAPVC may be asymptomatic until pulmonary vascular resis-  tance drops, at which time pulmonary blood flow will increase,  resulting in signs of pulmonary overcirculation, particularly  growth retardation and frequent pulmonary infections, in addi-  tion to mild cyanosis. Obstructed TAPVC results in cyanosis  and rapid deterioration necessitating immediate surgical cor-  rection, or death will occur.   Physical examination may reveal a systolic murmur at  the left upper sternal border and a mid-diastolic murmur  at the left lower sternal border. A murmur may be absent in  obstructed TAPVC. A characteristic quadruple rhythm, con-  sisting of S,, widely split S,, and S; or Sy, or a gallop rhythm  also is present.   EVALUATION AND TREATMENT. The ECG shows a right-axis  deviation, RV hypertrophy, and occasionally RA hypertro-  phy. The chest radiograph of unobstructed TAPVC reveals  cardiomegaly, increased pulmonary vascular markings, and  a snowman or figure-eight appearance in the supracardiac  type. A chest roentgenogram of obstructed TAPVC shows a  normal-size heart and a ground-glass appearance of the lung  fields, reflecting pulmonary venous congestion or edema.  The echocardiogram reveals the abnormal pulmonary venous  connections.    FIGURE 33-19 Truncus Arteriosus. A, Persistent truncus arteriosus. The truncus arteriosus fails to divide into the pulmo-  nary artery and aorta, and the interventricular septum fails to close at the top. Blood from both ventricles mixes in the truncus  arteriosus and then enters the pulmonary and systemic circuits. B, Alterations of hemodynamics and oxygen saturation by  persistent truncus arteriosus. LA, Left atrium; LY left ventricle; RA, right atrium; RV right ventricle. (A from Hockenberry Mu,  Wilson D: Wong’s essentials of pediatric nursing, ed 9, St Louis, 2013, Mosby.)    Surgical repair varies with the type of TAPVC and whether  the defect is obstructed or unobstructed. Obstructed lesions  are repaired at the time of diagnosis, whereas the unobstructed  type generally is repaired during infancy. The procedure is per-  formed while the patient is on cardiopulmonary bypass and  involves anastomosis of the common pulmonary vein to the LA  and closing the ASD, as in the supracardiac and infracardiac  types. Repair of the supracardiac type involves baffling the pul-  monary venous drainage to the LA. This repair has the high-  est success rate because of the low technical difficulty, whereas  infracardiac repair is associated with a high mortality (up to  25%) and morbidity. Potential complications include reob-  struction; atrial dysrhythmias, including sick sinus syndrome;  PA hypertension; and LV dysfunction.!°    Truncus arteriosus is the failure of the large embryonic artery,  the truncus arteriosus, to divide into the PA and the aorta. This  results in a single vessel arising from both ventricles, providing  blood flow to the pulmonary and systemic circulations (Figure  33-19, A). This common trunk straddles the VSD (always pres-  ent) and has a single valve with three or four leaflets, which may  result in stenosis, regurgitation, or both. The incidence is 2%  of all congenital heart defects, and a right aortic arch is pres-  ent 50% of the time. There are four types of truncus arteriosus.  Type I is the most common (60%) and involves the main PA  arising from the truncus and then dividing into the right and left  PAs. Type I is less common (20%) and involves the PAs arising  from the posterior aspect of the truncus. Type III is the least  common (10%) and involves the PAs arising from the lateral  aspect of the truncus. Type IV, also known as pseudotruncus, is    now considered a severe form of TOF with the bronchial arter-  ies arising from the descending aorta to supply the lungs.”   PATHOPHYSIOLOGY. Blood flow from the RV and LV is pumped  into the main truncus, resulting in mixing of the pulmonary  and systemic circulations (see Figure 33-19, B). The differential  flow out to either the pulmonary bed or the systemic circulation  depends on the pulmonary and systemic vascular resistances.  Generally the pulmonary vascular resistance is less than the sys-  temic vascular resistance, resulting in the majority of blood flow  traveling to the lungs. This may be altered, however, because of  PS, small pulmonary arteries, or increased pulmonary vascular  resistance. Pulmonary vascular disease develops early with this  defect because of increased pulmonary blood flow.   CLINICAL MANIFESTATIONS. Physical findings depend on the  amount of pulmonary blood flow and the presence of other car-  diac anomalies. If PS is present, a newborn will present with cya-  nosis, caused by already elevated pulmonary vascular resistance,  but no HF. Conversely, if PS is not present, the newborn initially  will have mild to moderate cyanosis that worsens with activity.  Once pulmonary vascular resistance drops, the pulmonary bed  will receive preferential flow and the infant will have signs of HF.  A harsh systolic regurgitant murmur is usually present along the  left sternal border as a result of the VSD, and a systolic click at  the apex and left upper sternal border may be present, reflecting  opening of the truncal valve. An apical rumble with or without  a gallop rhythm also may be present because of increased pul-  monary blood flow. If truncal valve insufficiency exists, an early  diastolic, high-pitched decrescendo murmur may be present.   EVALUATION AND TREATMENT. An ECG generally reveals biven-  tricular hypertrophy and occasionally LA enlargement. A chest  radiograph reveals cardiomegaly with biventricular and LA    enlargement, as well as increased pulmonary vascular markings.  When PS is present, the heart size is normal and the pulmonary  vascular markings are decreased. Echocardiography and cardiac  catheterization, if performed, determine the type of truncal defect,  competency of the truncal valve, and differential blood flow.   Surgical repair in early infancy is recommended to prevent  the sequelae of severe HF and pulmonary vascular disease. The  definitive repair consists of a modified Rastelli procedure involv-  ing VSD patch closure to divert the blood flow from the LV out-  flow tract into the truncus. The pulmonary arteries are excised  from the aorta and connected to the RV through a tissue homo-  graft—namely, aortic and PA segments or cadaver tissue that  is specially preserved. Synthetic conduits may be used but tend  to calcify and develop narrowing within the lumen, leading to  obstruction and the need for early replacement. Mortality varies  depending on the type of truncal anomaly (20% to 50%). Post-  operative complications include HF, residual VSD, truncal valve  (now the aorta) stenosis or insufficiency, dysrhythmias, and pul-  monary hypertension. The RV to PA homograft requires replace-  ment because it becomes inadequate for somatic growth.!°    Acquired heart diseases are those disease processes or abnor-  malities that occur after birth. They result from various causes,  such as infection, genetic disorders, autoimmune processes in  response to infection, environmental factors, or autoimmune  diseases. Examples of acquired heart diseases include Kawasaki  disease, myocarditis, rheumatic heart disease, cardiomyopathy,  and systemic hypertension. This chapter discusses Kawasaki  disease and systemic hypertension. Myocarditis, rheumatic  heart disease, and cardiomyopathy are discussed in Chapter 32.    Kawasaki disease, formerly known as mucocutaneous lymph  node syndrome, is an acute, self-limiting systemic vasculitis  that may result in cardiac sequelae. Although Kawasaki disease  occurs throughout the world, the greatest number of cases are  reported in Japan.   Kawasaki disease is primarily a condition of young children:  80% of cases are seen in children younger than 5 years of age,  with the incidence peaking in the toddler age group. Males are  affected slightly more than females. Its peak incidence is in win-  ter and spring.   The etiology of Kawasaki disease remains unknown. Theo-  ries center on an immunologic response to an infectious, toxic,  or antigenic substance (including superantigen).””°   PATHOPHYSIOLOGY. Kawasaki disease progresses pathologically  and clinically in the following stages:   Stage I (days 1 to 12): Small capillaries, arterioles, and venules   Stage II (days 13 to 25): Inflammation spreads to larger ves-   granulation process, causing coronary artery thickening;  inflammation resolves in the microcirculation; and there  is risk of thrombus formation.    The child must exhibit five of the following six criteria, including fever:   1. Fever for 5 or more days (often diagnosed with shorter duration of fever if  other symptoms are present)    3. Changes in the oral mucous membranes, such as erythema, dryness, and  fissuring of the lips; oropharyngeal reddening; or “strawberry tongue”   4. Changes in the extremities, such as peripheral edema, peripheral erythema,  and desquamation of palms and soles, particularly periungual peeling    Modified from Hockenberry MJ, Wilson D: Wong's nursing care of  infants and children, ed 9, St Louis, 2011, Mosby.    Stage IV (day 41 and beyond): Vessels develop scarring, inti-  mal thickening, calcification, and stenosis of coronary  arteries.   CLINICAL MANIFESTATIONS. The clinical course of the disease  progresses in three stages: acute, subacute, and convalescent. In  the acute phase the child has fever, conjunctivitis, oral changes  (“strawberry” tongue), rash, and lymphadenopathy and is often  irritable. During this phase myocarditis in addition to the vas-  culitis may develop. The subacute phase begins when the fever  ends and continues until the clinical signs have resolved. It is  at this time that the child is most at risk for coronary artery  aneurysm development. Desquamation of the palms and soles  occurs at this time, as well as marked thrombocytosis. The con-  valescent phase is marked by the continued elevation of the  erythrocyte sedimentation rate and platelet count. Arthritis still  may be present. This phase continues until all laboratory values  return to normal—usually about 6 to 8 weeks after onset.   EVALUATION AND TREATMENT. The diagnosis is based on the  diagnostic criteria for Kawasaki disease, which state that the  child must exhibit five of six criteria, including fever (Box 33-3).  These children usually have leukocytosis, increased erythrocyte  sedimentation rates, marked thrombocytosis, and elevated lev-  els of liver enzymes. An echocardiogram is obtained at the time  of diagnosis as a baseline to assess for coronary aneurysms or  inflammation. Serial echocardiograms are obtained after treat-  ment to assess for future development of coronary aneurysms.   The use of aspirin and intravenous immunoglobulin during  the acute phase has decreased the mortality of Kawasaki dis-  ease and has reduced the incidence of coronary abnormalities  from approximately 20% to less than 2% at 6 to 8 weeks after  initiation of therapy. Most children recover completely from  Kawasaki disease, including the regression of aneurysms. The  most common, although rare, cardiovascular sequela is coro-  nary thrombosis. Studies are investigating long-term results of  the disease.>7°   Hypertension (HTN) in children differs from adult HTN in  etiology and presentation. Children diagnosed with HTN are  often found to have some underlying disease, such as renal dis-  ease or COA (Box 33-4). In recent years an increased prevalence   Acquired disorders  Glomerulonephritis—acute or chronic  Pyelonephritis  Nephritis associated with collagen disease   Space-occupying lesions of cranium (increased intracranial pressure)  Tumors, cysts, hematoma  Cerebral edema  Encephalitis (including Guillain-Barré and Reye syndromes)    From Hockenberry MJ, Wilson D: Wong's essentials of pediatric nursing, ed 9, St Louis, 2013, Mosby.    FIGURE 33-20 Mechanisms Believed to Influence Blood Pressure in Children. According to this model, a critical  factor in the development of hypertension is obesity during childhood. Increased body mass, coupled with excessive sodium  intake, can cause primary hypertension in children or set the stage for its development later in life.    TABLE 33-6 SUGGESTED NORMAL BP  VALUES (mmHg) BY  AUSCULTATORY METHOD  (SYSTOLIC/DIASTOLIC K5)    11-11*  12-13*  14-15  Boys 116/66  Girls 112/68  16-18  Boys 121/70  Girls 110/68    From Park MK: Pediatric cardiology for practitioners, ed 4, Philadelphia,  2002, Mosby; modified from Goldring D et al: J Pediatr 91:884, 1977;  Prineas RJ et al: Hypertension 1(Suppl):18, 1980.   *Values for ages 10 to 13 years have been extrapolated from these  two studies using age-related increments from other studies.    of primary HTN in older children has been noted. Researchers  are now focusing on primary HTN in older children in relation  to morbidity and mortality and the presence of early atheroscle-  rotic disease.»7742°   Systemic hypertension in children is defined as systolic  and diastolic blood pressure levels greater than the 95th per-  centile for age and gender on at least three occasions. The  Fourth Task Force on Blood Pressure Control in Children  uses height as an additional criterion to the blood pressure  guide.*°   PATHOPHYSIOLOGY. Hypertension is classified as (1) primary  (or essential) hypertension, in which a specific cause cannot be  identified; or (2) secondary hypertension, in which a cause is  secondary to another alteration (see Box 33-4). In infants and  children a cause of HTN is almost always found. In general, the  younger the child with significant hypertension, the more likely  that a correctable cause can be found. Therefore, a thorough  evaluation needs to be done.?’   The pathophysiology of primary HTN in children is not  clearly understood but may result from a complex interaction  of a strong disposing genetic component with disturbances  in sympathetic vascular smooth muscle tone, humoral agents  (angiotensin, catecholamines), renal sodium excretion, and  cardiac output (Figure 33-20). Ultimately these factors impair  the ability of the peripheral vascular bed to adjust its own resis-  tance to meet tissue perfusion needs.”*   CLINICAL MANIFESTATIONS. Most children with systemic  HTN are asymptomatic. It is necessary that a thorough his-  tory (including family history of HTN and heart disease) and  physical examination be obtained. The examination should  include an accurate blood pressure measurement on three  separate occasions using a cuff of appropriate size (Tables 33-6  and 33-7).    TABLE 33-7 NORMATIVE BP LEVELS  (SYSTOLIC/DIASTOLIC  [MEAN]) BY DINAMAP/  MONITOR IN CHILDREN  5 YEARS OLD AND YOUNGER    1-3 days 64/41 (50) 75/49 (50) 78/52 (62)  1 month-2 95/58 (72) 106/68 (83) 110/71 (86)  years  2-5 years 101/57 (74)    From Park MK: Pediatric cardiology for practitioners, ed 5, Philadelphia,  2008, Mosby; modified from Park MK, Menard SM: Am J Dis Child  143:860, 1989.    From Park MK: Pediatric cardiology for practitioners, ed 5, Philadelphia,  2008, Mosby; adapted from Report of the Second Task Force on Blood  Pressure Control in Children: Pediatrics 79:1, 1987.    Certain factors influence blood pressure in children. Smok-  ing is also associated with an increased risk for HTN. Obesity is  emerging as one of the most important factors in the increasing  prevalence of HTN in children.   EVALUATION AND TREATMENT. In children the history and physi-  cal examination should be directed at determining the etiology  of HTN, such as COA or renal disease (Table 33-8). If COA is  found, surgical or interventional correction is initiated. A com-  plete blood count, serum chemistry levels, urinalysis, urine cul-  ture, lipid profile, and renal ultrasound are part of the routine  evaluation for renal disease (Table 33-9).   Although the criteria for the diagnosis of hypertension are  based on the use of a standard blood pressure cuff, some chil-  dren have what is termed “white coat hypertension.” Elevated  blood pressure readings in these children occur only when mea-  sured in the clinic and may be caused by fear and anxiety. The  use of ambulatory blood pressure monitoring (ABPM) records  the blood pressure over a 24-hour period. In addition to iden-  tifying children with white coat hypertension, ABPM has been    Urinalysis, urine culture, blood urea nitrogen, creatinine, uric acid  Serum electrolyte levels (hypokalemia)    ECG, chest x-ray studies, and possibly echocardiography  Intravenous pyelogram (or ultrasonography, radionuclide studies, computed  tomography, or magnetic resonance imaging of the kidneys)    24-hour urine collection for 17-ketosteroids and 17-hydroxycorticosteroids  24-hour urine collection for catecholamine levels and vanillylmandelic acid   High-renin hypertension (renovascular hypertension, renin-producing tumors,  some Cushing syndrome, some essential hypertension)    found to be useful in children with hypertension that is resis-  tant to treatment (see What’s New? Ambulatory Blood Pressure  Monitoring in Children).”°   If HTN is found to be essential, or primary, in nature, non-  pharmacologic therapy is used initially. Moderate weight loss    Ambulatory blood pressure monitoring (ABPM) records blood pressure over  a 24-hour period. Its use in children was endorsed by the Fourth Report of  the National High Blood Pressure Education Program Working Group on High  Blood Pressure in Children primarily to help identify those children with “white  coat hypertension.” Paradoxically, some children have normal blood pressure  readings in the clinic but are hypertensive during other parts of the day. This  is called “masked hypertension” and also can be identified by ABPM. ABPM    is useful in documenting what is called the “BP load,” which is the total  amount of time the blood pressure (BP) is elevated above normal limits during  a 24-hour period. By measuring BP load, ABPM may be able to identify those  children who are at greatest risk for target organ damage. It can also help with  management of children who suffer hypotensive episodes in response to phar-  macologic therapy for their hypertension. Finally, ABPM facilitates medication  changes in those with hypertension resistant to medication.    Data from Flynn JT, Urbina EM: J Clin Hypertens 14(6):372-382, 2012;  National High Blood Pressure Education Program Working Group on  High Blood Pressure in Children: Pediatrics 114:555-576, 2004.    can decrease systolic and diastolic pressures in many children.  Appropriate diet, regular physical activity, and avoidance of  smoking have been shown to be effective in reducing blood  pressure.?®   Drug therapy is controversial in children with primary  hypertension; however, when nonpharmacologic therapy fails,  a staged approach with the use of diuretics and/or beta-blockers  and afterload reduction is indicated. The emphasis on preven-  tive cardiology, especially for children, is significant because  many investigators believe signs of atherosclerosis and other  cardiovascular risk factors are present from childhood.’?*?    Childhood obesity is considered an epidemic not only in the United  States but also in other countries such as Australia.°>°° Despite  attention from U.S. federal and state initiatives, the prevalence of  obesity in children and young adults has steadily increased over  the past four decades, with estimates as high as 25% of children  considered obese.°’ Although not without controversy, percentile  of body mass index (BMI) expressed as weight/height” (BMI-kg/  m7”) is used to identify overweight and obesity in children and ado-  lescents. The Centers for Disease Control and Prevention (CDC),  the supplier of national growth charts and prevalence data, avoids  characterizing children and adolescents as “obese”; instead, the  CDC suggests two levels of overweight: (1) the 85th percentile, an  “at risk” level; and (2) the 95th percentile, the more severe level.*°    Causes of obesity in young children and adolescents are  multivariable and multidimensional. Risk factors associated  with developing childhood obesity include race, socioeconomic  status, and lack of health insurance. Children of black and His-  panic race are at higher risk, as well as children with no insur-  ance.** The presence of parental obesity also is associated with  childhood obesity.°” In addition, early childhood nutrition,  level of physical activity, and engagement of sedentary activities,  such as watching television and computer use, is associated with  the development of overweight and obese children.**“°   Similar to obese adults, overweight and obese children are  at risk for acquiring numerous other serious and potentially  life-threatening illnesses, such as asthma, sleep apnea, hyperten-  sion, type 2 diabetes, dyslipidemia, and cardiovascular disease.’    Researchers also have reported a multitude of social and economic  consequences in adolescents as a result of being overweight. Over-  weight adolescents are more likely to complete fewer years of edu-  cation, are less likely to marry, and have a lower household income  in adulthood, independent of familial socioeconomic status.*!   As in other acquired diseases, efforts should be focused  on prevention. The initial approach is a combined program  of physical activity with nutritional improvements. Health-  care professionals play a vital role in recognizing the need for  intervention, immediate referral, and support. Successful out-  comes for most overweight and obese children require support,  change in lifestyle at home, and involvement of family mem-  bers. Researchers are involving school-based programs in pro-  moting and preventing obesity in the young.*”   1. The heart arises from the mesenchyme and begins as an  enlarged blood vessel with a large lumen and a muscu-  lar wall. By approximately the eighth week of gestation,  all structures of the fetal heart and vascular system are  present.   2. The endocardial cushions are instrumental in closing the  atrial septum, dividing the AV canals into the right and left  AV orifices, and closing the septum.   3. In the fetus the pulmonary and systemic circulatory systems  are connected by the foramen ovale, an opening between  the atria; by the ductus arteriosus, a fetal vessel that joins  the PA to the aorta; and by the ductus venosus, a fetal vessel  that connects the inferior vena cava to the umbilical vein.   4. Fetal circulation is different from postnatal circulation  because of the presence of fetal shunts and altered meta-  bolic needs of the various organs.   5. Fetal blood flow depends on resistance for its distribution  through the body. Resistance in the pulmonary circula-  tion is higher than resistance in the systemic circulation, so  myocardial thickness is about the same in the right heart  and the left heart.   7. Pulmonary vascular resistance drops suddenly at birth  because the lungs expand and the pulmonary vessels dilate.  It continues to decrease gradually during the first 6 to 8  weeks after birth. Decreased resistance causes the right  myocardium to become thinner.   8. Systemic vascular resistance increases markedly at birth  because severance of the umbilical cord removes the low-  resistance placenta from the systemic circulation. Increased  systemic resistance causes the left myocardium to become  dominant and thicken over time.   9. Changes in resistance cause disappearance of the fetal con-  nections between the pulmonary and systemic circulatory  systems. The foramen ovale closes functionally at birth  and anatomically several months later; the ductus arte-  riosus closes functionally 15 to 18 hours after birth and    anatomically within 10 to 21 days; and the ductus venosus  closes within 1 week after birth.   10. At birth a series of circulatory changes occur that affect  blood flow, vascular resistance, and oxygen tension. The  most important change is the shift of gas exchange from the  placenta to the lungs.   11. After birth, significant postnatal changes occur, including  thinning of the right ventricular myocardium as the pul-  monary vascular resistance drops. As the systemic vascu-  lar resistance increases, the left ventricular myocardium  becomes thicker and more dominant as it is in the adult  heart.   1. Most congenital cardiovascular defects have begun to  develop by the eighth week of gestation, and most have  many causes, both environmental and genetic.   2. Environmental risk factors associated with the incidence of  congenital heart defects typically are maternal conditions.  Among these are viral infections, diabetes, drug intake, alco-  hol intake, metabolic disorders, and advanced maternal age.   3. Genetic factors associated with congenital heart defects  include but are not limited to Down syndrome, trisomy 13,  trisomy 18, cri du chat syndrome, and Turner syndrome.  It now appears, however, that most genetic mechanisms of  causation are multifactorial.   4. Classification of congenital heart defects is based on  whether they: (a) cause blood flow to the lungs to increase  or decrease, (b) obstruct ventricular blood flow patterns, or  (c) cause mixing of unoxygenated and oxygenated blood.   5. Symptoms of HF are usually the result of congenital heart  defects that increase blood volume and pressure in the  pulmonary circulation. Clinical manifestations are almost  the same as the manifestations of CHF in adults. A unique  manifestation in children is FTT.   6. Cyanosis, a bluish discoloration of the skin, indicates that  the tissues are not receiving fully adequate oxygenated  blood. Cyanosis can be caused by defects that (a) reduce  pulmonary blood flow; (b) overload the pulmonary    circulation, causing pulmonary hypertension, pulmo-  nary edema, and respiratory difficulty; and (c) cause large  amounts of unoxygenated blood to shunt from the pulmo-  nary to the systemic circulation.    nication between the pulmonary and systemic circulatory  systems cause blood to shunt from one system to another,  mixing oxygenated and unoxygenated blood and increasing  blood volume and pressure on the receiving side of the shunt.    nication depends on differences in pressure and resistance  between the two systems. Flow is always from an area of  high pressure to an area of low pressure. The resistance to  flow determines the volume of the shunting.    flow consist of abnormal openings (PDA, ASD, VSD, AVC  defect, or truncus arteriosus) that permit blood to shunt  from left (systemic circulation) to right (pulmonary circu-  lation). Cyanosis does not occur because the left-to-right  shunt does not interfere with the flow of oxygenated blood  through the systemic circulation.   If the abnormal communication between the left and right  circuits is large, volume and pressure overload in the pul-  monary circulation leads to CHF.   In truncus arteriosus the main trunk fails to divide longi-  tudinally into the aorta and PA. All blood from both ven-  tricles enters the truncus, so that mixed blood is delivered  by both circulatory systems, causing varying degrees of cya-  nosis and HF.   In heart defects that decrease pulmonary blood flow (TOF,  tricuspid atresia), myocardial hypertrophy cannot com-  pensate for restricted right ventricular outflow. Flow to the  lungs decreases, and cyanosis is caused by mixing of sys-  temic and pulmonary venous return.   Obstruction of ventricular outflow commonly is caused by  PS, AS, COA, interrupted aortic arch, or hypoplastic left  heart syndrome.   Despite obstruction, ventricular output remains normal  for a long time because of compensatory ventricular hyper-  trophy stimulated by increased afterload and, in postduc-  tal COA, development of collateral circulation around the  coarctation.    Signs of HF can occur with pulmonary overcirculation or  myocardial failure.   Complex congenital defects that depend on mixing of the  pulmonary and systemic circulations for survival during  the postnatal period include complete transposition of the  great arteries and total anomalous pulmonary venous con-  nection. This mixing results in desaturated systemic blood  flow and cyanosis.   In complete transposition of the great vessels, the circula-  tory systems are not connected serially or through a shunt,  so that oxygenated blood remains permanently in the pul-  monary circulation and unoxygenated blood remains in  the systemic circulation. Survival depends on patency of  the ductus arteriosus; in the absence of patency, surgical  intervention is mandatory.   Total anomalous pulmonary venous connection is caused  by abnormal pulmonary vein development and the lack of  direct pulmonary venous return to the LA. All blood from  the pulmonary and systemic circulations enters the RA.  Mixed blood enters the LA through an ASD; it then flows  into the systemic circulation and causes cyanosis.  Treatment for all hemodyamically severe congenital defects  is surgical or interventional correction of the anomaly and  management of cyanosis and HF.    The most common acquired cardiovascular disorders of  childhood are Kawasaki disease, rheumatic heart disease,  and hypertension.    may result in the development of coronary artery aneu-  rysms and thrombosis.    . Essential or primary hypertension in children is the same as    that in adults, except that it is more likely to be diagnosed  in an early, asymptomatic stage. Most cases of hypertension  in young children are secondary to an underlying cause.    . Obesity in childhood is epidemic in the United States and    serious and potentially life-threatening illnesses, such as  asthma, sleep apnea, hypertension, type 2 diabetes mellitus,  and cardiovascular disease.   Atrial septal defect (ASD), 1204  Atrioventricular canal (AVC) defect, 1206  Bulbus cordis, 1196   Coarctation of the aorta (COA), 1210  Complete AVC (CAVC) defect, 1207  Conus, 1215    Clark EB, Nakazawa M, Takao A, editors: Etiology and morphogenesis of  congenital heart disease: twenty years of progress in genetics and develop-  mental biology, Mount Kisco, NY, 2000, Futura Publishing.   Park MK: Pediatric cardiology for practitioners, ed 5, Philadelphia, 2008,  Mosby.   Wilson D, Hockenberry MJ: Wong’s clinical manual of pediatric nursing,  ed 7, St Louis, 2008, Mosby.   Hazinski MF: Manual of pediatric critical care, ed 2, St Louis, 1999,  Mosby.   American Heart Association: Heart disease and stroke statistics, 2013  update, Dallas, 2012, Author. Circulation 2013:e6—e245.   Ziegler VL: Congenital heart disease and genetics, Crit Care Nurs Clin  North Am 20:159-169, 2008.   Allen HD: Moss and Adam’s heart disease in infants, children, and  adolescents: including the fetus and young adult, ed 8, Philadelphia, 2013,  Wolters Kluwer Health/Lippincott Williams & Wilkins.   Mezu-Ndubuisi OJ et al: Patent ductus arteriosus in premature neonates,  Drugs 72:907-916, 2012.   Moake L, Ndinjkat SK: Transcatheter device closure for ASD: safety effi-  cacy, complications and costs, Crit Care Nurs Clin North Am 23:339-348,  2011.   Moodie DS, Sterba R: Long-term outcomes excellent for atrial septal  defect repair in adults, Cleve Clin J Med 67(8):591-597, 2000.    2190-2197, 2006.  El-Najdawi EK et al: Operation for partial atrioventricular septal defect: a  forty-year review, J Thorac Cardiovasc Surg 119(5):880-889, 2000.    . Mavroudis C, Backer CL, editors: Pediatric cardiac surgery, ed 3, St Louis,   Thanopoulos BD et al: Initial and six-year results of stent implantation  for aortic coarctation in children, Am J Cardiol 109(10):1499-1503, 2012.  Walhout RJ et al: Comparison of surgical repair with balloon angioplasty  for native coarctation in patients from 3 months to 16 years of age, Eur   Tanous D, Benson LN, Horlick EM: Coarctation of the aorta: evaluation  and management, Curr Opin Cardiol 24(6):509-515, 2009.   Hrasja V et al: Ross and Ross-Konno procedure in children and adoles-  cents: mid-term results, Eur J Cardiothorac Surg 25(5):742—747, 2004.  Poon LK, Menahem S: Pulmonary regurgitation after percutaneous  balloon valvoplasty for isolated pulmonary valvar stenosis in childhood,  Cardiol Young 13(5):444—450, 2003.    . Feinstein JA et al: Hypoplastic left heart syndrome current considerations    and expectations, J Am Coll Cardiol 59(Suppl 1):S1-S42, 2012.  Newburger JW et al: Early developmental outcome in children with  hypoplastic left heart syndrome and related anomalies: the single ven-  tricle reconstruction trial, Circulation 125(17):2081—2091, 2012.  McQuillen PS: Balloon atrial septostomy is associated with preoperative  stroke in neonates with transposition of the great arteries, Circulation  113(2):280-285, 2006.    Rowley AH: Kawasaki disease genetics, pathology, and a need for earlier  diagnosis and treatment, Contemp Pediatr 29(12):18-24, 2012.  Malatesta-Muncher R, Mitsnefes MM: Management of blood pressure in  children, Curr Opin Nephrol Hypertens 21(3):318-322, 2012.   Roley M, Bluhm B: High blood pressure in children and adolescents, Am  Fam Physician 85(7):693-700, 2012.   National High Blood Pressure Education Program Working Group on  High Blood Pressure in Children: The fourth report on the diagnosis,  evaluation, and treatment of high blood pressure in children and adoles-  cents, Pediatrics 114:555—576, 2004.   Nguyen M, Mitsnefes M: Evaluation of hypertension by the general  pediatrician, Curr Opin Pediatr 19(2):165—169, 2007.   Garin EH, Araya CE: Treatment of systemic hypertension in children and  adolescents, Curr Opin Pediatr 21(5):600-604, 2009.   Flynn JT, Urbina EM: Pediatric ambulatory blood pressure monitoring:  indications and interpretations, J Clin Hypertens 14(6):372-382, 2012.  Brady TM et al: Racial differences among children with primary hyper-  tension, Pediatrics 126(5):931—937, 2010.   Meininger JC et al: Overweight and central adiposity in school-age chil-  dren and links with hypertension, J Pediatr Nurs 25(2):119-125, 2010.  Din-Dzietham R et al: High blood pressure trends in children and ado-  lescents in national surveys, 1963-2002, Circulation 116(13):1488-1496,  2007.   Beilin L, Huang RC: Childhood obesity, hypertension, the metabolic  syndrome and adult cardiovascular disease, Clin Exp Pharmacol Physiol  35(4):409-411, 2008.   Ness M et al: Correlates of overweight and obesity among American  Indian/Alaska Native and non-Hispanic white children and ado-  lescents: national survey of children’s health, Matern Child Health J  16(Suppl):268-277, 2012.   van Emmerik NM et al: High cardiovascular risk in severely obese young  children and adolescents, Arch Dis Child 97(9):818-821, 2012.   Rudolf MC, Krom AJ, Cole TH: How good are BMI charts for monitoring  children’s attempts at obesity reduction? Arch Dis Child 97(5):418—422, 2012.  Liu J, Zhang A, Li L: Sleep duration and overweight/obesity in chil-  dren: review and implications for pediatric nursing, J Spec Pediatr Nurs  17(3):193—204, 2012.   Crespo CJ et al: Television watching, energy intake, and obesity in U.S.  children: results from the third National Health and Nutrition Examina-  tion Study, 1988-1994, Arch Pediatr Adolesc Med 155(3):360—-365, 2001.  Gordon-Larsen P, McMurray RG, Popkin BM: Adolescent physical activ-  ity and inactivity vary by ethnicity: The National Longitudinal Study of  Adolescent Health, J Pediatr 135(3):301—306, 1999.   Long JM et al: Overweight and obesity among white, black, and Mexican  American children: implications for when to intervene, J Spec Pediatr  Nurs 17(1):41-50, 2012.   Foltz JL et al: Population-level intervention strategies and examples for  obesity prevention in children, Annu Rev Nutr 32:391-415, 2012.  Centers for Disease Control and Prevention: Guidelines for school health  programs to promote lifelong healthy eating: Centers for Disease Con-  trol, MMWR Recomm Rep 45(RR-9):1-41, 1996.    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:  Case Study    Structures of the Pulmonary System, 1225  Conducting Airways, 1225  Gas-Exchange Airways, 1229  Pulmonary and Bronchial Circulation, 1229  Chest Wall and Pleura, 1231    The pulmonary system consists of upper and lower airways, the  chest wall, and pulmonary circulation. The primary function  of the pulmonary system is the exchange of gases between the  environmental air and the blood. There are three steps in this  process: (1) ventilation, the movement of air into and out of the  lungs; (2) diffusion, the movement of gases between air spaces  in the lungs and the bloodstream; and (3) perfusion, the move-  ment of blood into and out of the capillary beds of the lungs  to body organs and tissues. The first two functions are carried  out by the pulmonary system and the third by the cardiovascu-  lar system (see Chapter 31). Normally the pulmonary system  functions efficiently under a variety of conditions and with little  energy expenditure.    The pulmonary system is made up of the upper airways, two  lungs, the lower airways, and the blood vessels that serve them  (Figure 34-1); the chest wall, or thoracic cage; and the dia-  phragm. The lungs are divided into lobes: three in the right  lung (upper, middle, lower) and two in the left lung (upper,  lower). Each lobe is further divided into segments and lobules.    Functions of the Pulmonary System, 1232  Ventilation, 1232  Gas Transport, 1238   Tests of Pulmonary Function, 1243  AGING and the Pulmonary System, 1244    The space between the lungs, which contains the heart, great  vessels, and esophagus, is called the mediastinum. A set of con-  ducting airways, called bronchi, deliver air to each section of  the lung. The lung tissue that surrounds the airways supports  them, preventing their distortion or collapse as gas moves in  and out during ventilation. The diaphragm is a dome-shaped  muscle that separates the thoracic and abdominal cavities and is  involved in ventilation.   The lungs are protected from a variety of exogenous con-  taminants by a series of mechanical and cellular defenses  (Table 34-1). These defense mechanisms are so effective that  in the healthy individual, contamination of the lung tissue  itself is unusual. (Other defense mechanisms are discussed in  Chapters 7 and 8.)   The conducting airways are the portion of the pulmo-  nary system that provides a passage for the movement of  air into and out of the gas-exchange portions of the lung.  They consist of upper and lower airways. The nasophar-  ynx, oropharynx, and related structures often are called  the upper airway (Figure 34-2). These structures are lined    FIGURE 34-1 Structural Plan of the Respiratory System. /nset shows alveolar sacs where the interchange of oxygen  and carbon dioxide takes place through the walls of the grapelike alveoli. Capillaries surround the alveoli. (From Patton KT,  Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    Upper respiratory tract mucosa Maintains constant temperature and humidification of gas entering the lungs; traps and removes foreign  particles, some bacteria, and noxious gases from inspired air  Trap and remove foreign particles, some bacteria, and noxious gases from inspired air    Protects trachea and bronchi from injury; traps most foreign particles and bacteria that reach the lower airways    Cilia Propel mucous blanket and entrapped particles toward the oropharynx, where they can be swallowed or   Ingest and remove bacteria and other foreign material from alveoli by phagocytosis (see Chapter 7)   Enhance phagocytosis of pathogens and allergens in alveoli; down-regulate inflammatory responses   Stimulation by chemical or mechanical irritants triggers sneeze reflex, which results in rapid removal of  irritants from nasal passages   Stimulation by chemical or mechanical irritants triggers cough reflex, which results in removal of irritants from  the trachea and large airways    with a ciliated mucosa with a very rich vascular supply. The  mucosal lining warms and humidifies inspired air to 100%  and removes foreign particles from it as it passes into the  lungs. During quiet breathing, gas usually flows through the  nose, nasopharynx, and oropharynx to the lower airways.  The mouth and oropharynx provide for ventilation when the  nose is obstructed or when increased flow is required, such as  during exercise. Filtering and humidifying are not as efficient  with mouth breathing.    The larynx connects the upper and lower airways. The  structure of the larynx consists of the endolarynx and its sur-  rounding triangular-shaped bony and cartilaginous structures.  The endolarynx is formed by two pairs of folds that form the  false vocal cords (supraglottis) and the true vocal cords. The  slit-shaped space between the true cords forms the glottis (see  Figure 34-2). The vestibule is the space above the false vocal  cords. The laryngeal box is formed by three large cartilages—  the epiglottis, thyroid, and cricoid—and three smaller    FIGURE 34-2 Structures of the Upper Airway. (Redrawn from Thompson JM et al: Mosby's clinical nursing, ed 5,  St Louis, 2002, Mosby.)    FIGURE 34-3 Conducting Airways and Respiratory Unit. A, Structures of respiratory airways. B, Changes in bronchial  wall with progressive branching. €, Electron micrograph of alveoli: long white arrow identifies type Il pneumonocyte (secretes  surfactant); short white arrow identifies pores of Kohn; red arrow identifies alveolar capillary. D, Plastic cast of pulmonary  capillaries at high magnification. (A redrawn from Thompson JM et al: Mosby% clinical nursing, ed 5, St Louis, 2002, Mosby;  B from Wilson SF, Thompson JM: Respiratory disorders, St Louis, 1990, Mosby; € from Mason Ri et al: Murray and Nadel’s  textbook of respiratory medicine, ed 5, Philadelphia, 2010, Saunders; D courtesy A. Churg, MD, and J. Wright, MD, Vancouver,  Canada. From Leslie KO, Wick MR: Practical pulmonary pathology: a diagnostic approach, ed 2, Philadelphia, 2011, Saunders.)    cartilages—the arytenoid, corniculate, and cuneiform—that  are connected by ligaments. The supporting cartilages prevent  collapse of the larynx during inspiration and swallowing. The  internal laryngeal muscles control vocal cord length and ten-  sion, and the external laryngeal muscles move the larynx as a  whole. Both sets of muscles are important to swallowing, respi-  ration, and vocalization.! The internal muscles contract during  swallowing to prevent aspiration into the trachea and contrib-  ute to voice pitch.   The trachea, which is supported by U-shaped cartilage, con-  nects the larynx to the bronchi, the conducting airways of the  lungs. The trachea divides into the two main airways, or bron-  chi, at the carina (see Figure 34-1). This area is very sensitive and  when stimulated can cause coughing and airway narrowing. The    left mainstem bronchus branches from the trachea at about a 45°  angle. The right mainstem bronchus is slightly larger and more  vertical than the left (branches at about a 20° to 30° angle from the  trachea). Aspirated fluids or foreign particles thus tend to enter  the right lung rather than the left. The right and left main bron-  chi enter the lungs at the hila, or “roots” of the lungs, along with  the pulmonary blood and lymphatic vessels. From the hila the  main bronchi branch into lobar bronchi, then to segmental and  subsegmental bronchi, and finally end at the sixteenth division in  the smallest of the conducting airways, the terminal bronchioles  (Figure 34-3). With these multiple divisions, the cross-sectional  area of the airways increases to 20 times that of the trachea. This  results in decreased velocity of airflow into the gas-exchange por-  tion of the lung and allows for optimal gas diffusion.”    The bronchial walls have three layers: an epithelial lining, a  smooth muscle layer, and a connective tissue layer. In the large  bronchi (to approximately the tenth division), the connective  tissue layer contains cartilage. The epithelial lining of the bron-  chi contains single-celled exocrine glands—the mucus-secreting  goblet cells—and ciliated cells. High columnar pseudostrati-  fied epithelium lines the larger airways, changing to columnar  cuboidal epithelium in the bronchioles (types of epithelia are  illustrated in Chapter 1). The submucosal glands of the bron-  chial lining also produce mucus, contributing to the mucous  blanket that covers the bronchial epithelium. The ciliated epi-  thelial cells rhythmically beat this mucous blanket toward the  trachea and pharynx, where it can be swallowed or expectorated  by coughing. Foreign particles and microorganisms that are not  expelled by mucociliary clearance and coughing are attacked by  cellular components of the inflammatory response and anti-  bodies of the secretory immune system (see Chapter 8).° The  biochemical mediators released early in inflammation also play  a part in antibody-mediated hypersensitivity reactions, such as  asthma, because they stimulate bronchial smooth muscles to  constrict. With branching, the layers of epithelium that line the  bronchi become thinner (see Figure 34-3). Ciliated cells and  goblet cells become more sparse, and smooth muscle and con-  nective tissue layers thin toward the terminal bronchioles."    Gas-Exchange Airways  The bronchioles terminate in gas-exchange airways, where oxy-  gen (O,) enters the blood and carbon dioxide (CO}) is removed  from it. The gas-exchange airways consist of respiratory bron-  chioles, alveolar ducts, and alveoli (see Figure 34-3). These  structures together are sometimes called the acinus, and all of  them participate in gas exchange.°   The bronchioles from the sixteenth through the twenty-third  divisions contain increasing numbers of alveoli and are called  respiratory bronchioles. The walls of the respiratory bronchioles  are very thin, consisting of an epithelial layer devoid of cilia and  goblet cells, very little smooth muscle fiber, and a very thin and  elastic connective tissue layer. These bronchioles end in alveolar  ducts, which lead to alveolar sacs made up of numerous alveoli.   The alveoli are the primary gas-exchange units of the  lung, where oxygen enters the blood and CO, is removed  (Figure 34-4). Tiny passages called pores of Kohn permit some  air to pass through the septa from alveolus to alveolus, promot-  ing collateral ventilation and even distribution of air among the  alveoli. The lungs contain approximately 50 million alveoli at  birth and about 480 million by adulthood.*°   The alveolar septa consist of an epithelial layer and a thin, elas-  tic basement membrane but no muscle layer (see Figure 34-3).  Two major types of epithelial cells appear in the alveolus. Type I  alveolar cells provide structure, and type II alveolar cells secrete  surfactant, a lipoprotein that coats the inner surface of the alveo-  lus and facilitates its expansion during inspiration, lowers alveo-  lar surface tension at end-expiration, and, thereby, prevents lung  collapse.’ Surfactant also contributes to control of lung inflam-  mation and innate and adaptive immunity.”   Like the bronchi, alveoli contain cellular components of  inflammation and immunity, particularly the mononuclear    FIGURE 34-4 Alveoli. Bronchioles subdivide to form tiny tubes called a/ve-  olar ducts that end in clusters of alveoli called a/veolar sacs. (From Patton KT,  Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    phagocytes. The mononuclear phagocytes of the lungs are  called alveolar macrophages. These cells ingest foreign material  that reaches the alveolus and prepare it for removal through  the lymphatics.* (Phagocytosis and the mononuclear phagocyte  system are described in Chapters 7 and 8.)   The pulmonary circulation facilitates gas exchange, delivers  nutrients to lung tissues, acts as a blood reservoir for the left  ventricle, and serves as a filtering system that removes clots, air,  and other debris from the circulation (Figure 34-5).   Although the entire cardiac output from the right ventricle  goes into the lungs, the pulmonary circulation has a lower pres-  sure and resistance than the systemic circulation. Pulmonary  arteries are exposed to about one fifth the pressure of the systemic  circulation and have a much thinner muscle layer. (Systemic  vessels are described in Chapter 31.) Mean pulmonary artery  pressure is 18 mmHg; mean aortic pressure is 90 mmHg. About  one third of the pulmonary vessels are filled with blood (per-  fused) at any given time.’ More vessels become perfused when  right ventricular cardiac output increases. Therefore, increased  delivery of blood to the lungs does not normally increase mean  pulmonary artery pressure.   The pulmonary artery divides and enters the lung at the  hilus, travels with each main bronchus, and branches with the  bronchus at every division so that every bronchus and bron-  chiole has an accompanying artery or arteriole. The arterioles,  less than 1 mm in diameter, regulate blood flow through their  respective capillary beds.’   The arterioles divide at the terminal bronchiole to form a  network of pulmonary capillaries around the acinus. The cap-  illaries are an integral part of the alveolar septa. Capillary walls    FIGURE 34-5 The Pulmonary Circulation. The right and left pulmonary veins and arteries and the branching capillaries  are illustrated. Note the pulmonary artery carries venous blood, and the pulmonary vein carries arterial blood.    consist of an endothelial layer and a thin basement membrane,  which often fuses with the basement membrane of the alveolar  septum (see Figure 34-3). This results in very little separation  between blood in the capillary and gas in the alveolus.   The shared alveolar and capillary walls compose the alveo-  locapillary membrane, a very thin membrane made up of the  alveolar epithelium, the alveolar basement membrane, an inter-  stitial space, the capillary basement membrane, and the capil-  lary endothelium (Figure 34-6). These extremely thin alveolar  walls are easily damaged and can leak plasma and blood into  the alveolar space. Gas exchange occurs across the alveolocapil-  lary membrane. With normal perfusion approximately 100 ml  of blood in the pulmonary capillary bed is spread very thinly  over about 140 m? of alveolar surface area.’ The alveolocapillary  membrane efficiently exposes large quantities of blood to gas in  the alveoli. Any disorder that thickens the membrane impairs  gas exchange.   Each pulmonary vein drains several pulmonary capillar-  ies. Unlike the pulmonary arteries, which follow the branching  bronchi, pulmonary veins are dispersed randomly throughout  the lung and then leave the lung at the hila and enter the left  atrium. They are similar to veins in the systemic circulation, but  they have no valves.   The bronchial circulation is part of the systemic circulation.  It supplies nutrients to the conducting airways, nerves, lymph  nodes, large pulmonary vessels, and membranes (pleurae) that  surround the lungs and moistens inspired air.!° The bronchial  circulation is unique in that not all of its capillaries drain into  its own venous system. Some of the bronchial capillaries empty    into the pulmonary vein and contribute to the normal venous  admixture (mixing of oxygenated and deoxygenated blood) or  right-to-left shunt (right-to-left shunts [ventilation-perfusion  abnormalities] are described in Chapter 35). The bronchial cir-  culation does not participate in gas exchange.   Lung vasculature also includes deep and_ superficial  pulmonary lymphatic capillaries. The deep lymphatic capil-  laries begin at the level of the terminal bronchioles; there are  no lymphatic structures in the acinus. Fluid and alveolar mac-  rophages migrate from the alveoli to the terminal bronchi-  oles, where they enter the lymphatic system. The superficial  lymphatic capillaries drain the membrane that surrounds the  lungs. Both deep and superficial lymphatic vessels leave the lung  at the hilus through a series of mediastinal lymph nodes. The  lymphatic system plays an important role in keeping the lung  free of fluid and providing immune defense. (The lymphatic  system is described in Chapter 31.)    The caliber of pulmonary artery lumina decreases as smooth  muscle in arterial walls contracts. Contraction increases pul-  monary artery pressure. Caliber increases as these muscles  relax, decreasing blood pressure. Contraction (vasoconstric-  tion) and relaxation (vasodilation) occur in response to local  humoral conditions, even though the pulmonary circulation is  innervated by the autonomic nervous system (ANS) in the same  manner as the systemic circulation.   The most important cause of pulmonary artery con-  striction is a low alveolar partial pressure of oxygen (Paoy).    FIGURE 34-6 Section Through the Alveolar Septum (Gas-Exchange Membrane). /nset shows a magnified view of  the respiratory membrane composed of the alveolar wall (fluid containing surfactant, epithelial cells, basement membrane),  interstitial space, and wall of a pulmonary capillary (basement membrane, endothelial cells). The gases—carbon dioxide (CO,)  and oxygen (0,/ diffuse across the respiratory membrane. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8,    Vasoconstriction caused by alveolar and pulmonary venous  hypoxia, often termed hypoxic pulmonary vasoconstriction,  can affect only one portion of the lung or the entire lung. If  only one segment of the lung is involved, the arterioles to that  segment constrict, shunting blood to other, well-ventilated por-  tions of the lung. This reflex improves the lung’s efficiency by  better matching ventilation and perfusion. If alveolar hypoxia  affects all segments of the lung, however, vasoconstriction  occurs throughout the pulmonary vasculature, and pulmonary  hypertension (elevated pulmonary artery pressure) can result.  The pulmonary vasoconstriction caused by low Pao, is revers-  ible if the Pao, is corrected. Chronic alveolar hypoxia can result  in permanent pulmonary artery hypertension, which eventu-  ally leads to cor pulmonale and heart failure (see What’s New?  Update on Hypoxic Pulmonary Vasoconstriction).!!   Acidemia also causes pulmonary artery constriction. If  the acidemia is corrected, the vasoconstriction is reversed.  (Respiratory acidosis and metabolic acidosis are described in  Chapter 3.) It is important to note that an elevated Paco, with-  out a drop in pH does not cause pulmonary artery constriction.  Other biochemical factors that affect the caliber of vessels in    pulmonary circulation are histamine, prostaglandins, endothe-  lin, serotonin, nitric oxide, and bradykinin.    The chest wall (skin, ribs, intercostal muscles) protects the  lungs from injury, and its muscles, in conjunction with the  diaphragm, perform the muscular work of breathing. The tho-  racic cavity is contained by the chest wall and encases the lungs  (Figure 34-7). A serous membrane called the pleura adheres  firmly to the lungs. It then folds over itself and attaches firmly  to the chest wall. The membrane covering the lungs is the vis-  ceral pleura; that lining the thoracic cavity is the parietal pleura.  The area between the two pleurae is called the pleural space,  or pleural cavity. Normally only a thin layer of fluid secreted  by the pleura (pleural fluid) fills the pleural space. About 18  ml of fluid is in the pleural space with a pH of about 7.6, a few  cells, about 1 g/dl protein, and glucose and electrolyte concen-  trations that approximate those of the plasma.’ This lubricates  the pleural surfaces, allowing the two layers to slide over each  other without separating. Pressure in the pleural space is usually  negative or subatmospheric (—4 to -10 mmHg).    Hypoxic pulmonary vasoconstriction is a physiologic response to changes in  the environment and pulmonary pathologic conditions that affect alveolar  oxygen content (Pao,). Decreases in Pao, to less than 12% of normal induce  a locally controlled constriction of preacinar arteriolar smooth muscle and  endothelial cells and therefore decrease blood flow through those vessels.  When a pulmonary disorder is characterized by localized areas of acutely  decreased alveolar oxygen content, vasoconstriction of the arterioles per-  fusing those areas is a positive compensatory mechanism that reduces  shunt (wasted perfusion). However, in diffuse and chronic lung disorders  (e.g., chronic obstructive pulmonary disease [COPD] or cystic fibrosis), wide-  spread and persistent hypoxic pulmonary vasoconstriction creates resistance  to pulmonary blood flow and raises the pressure in the pulmonary artery,  causing a condition known as secondary pulmonary artery hypertension. Pul-  monary hypertension can become severe enough to impede right ventricular  ejection and eventually cause right heart failure known as cor pulmonale. |n  addition, lung hypoxia activates many hypoxia-dependent genes in pulmonary  vascular endothelial cells to produce a variety of chemicals and growth fac-  tors. Recent studies have shown that alveolar hypoxia causes the production  of reactive oxygen species (toxic oxygen radicals), vasoconstrictors (such as  endothelin), and vascular endothelial growth factor that in conjunction with  vascular fibroblasts cause deleterious changes in the pulmonary arteriolar  walls called remodeling. Remodeling is a process by which the vascular wall  becomes scarred and thickened, thus resulting in permanent decreases in  luminal diameter, increased resistance to blood flow, and permanent pulmo-  nary artery hypertension. Research is in progress to inhibit and potentially  reverse this remodeling.    Data from Evans AM et al: Curr Opin Anaesthesiol 24(1):13-20, 2011;  Kummer W: Proc Am Thorac Soc 8(6):471-476, 2011; Orr R, Smith   LJ, Cuttica MJ: Curr Opin Pulm Med 18(2):138-143, 2012; Pitsiou G,  Papakosta D, Bouros D: Respiration 82(3):294-304, 2011; Sylvester JT  et al: Physiol Rev 92(1):367-520, 2012.    Esophagus  FIGURE 34-7 Thoracic (Chest) Cavity and Related Structures. The tho-  racic cavity is divided into three subdivisions (left and right pleural divisions and  mediastinum) by a partition formed by a serous membrane called the pleura.  (From Thibodeau GA, Patton KT: Anatomy & physiology, ed 3, St Louis, 1996,  Mosby.)    The pulmonary system functions to (1) ventilate the alveoli, (2)  diffuse gases into and out of the blood, and (3) perfuse the lungs  so that the organs and tissues of the body receive blood that is  rich in oxygen and low in CO). Each component of the pul-  monary system contributes to one or more of these functions  (Figure 34-8).   Ventilation is the mechanical movement of gas or air into and  out of the lungs. Ventilation often is misnamed respiration,  which is actually the exchange of O, and CO, during cellular  metabolism. “Respiratory rate” is actually the ventilatory rate,  or the number of times gas is inspired and expired per minute.  The amount of effective ventilation is calculated by multiply-  ing the ventilatory rate (breaths per minute) by the volume of  air per breath (liters per breath, tidal volume). This is called  the minute volume (or minute ventilation) and is expressed in  liters per minute.   CO,, the gaseous form of carbonic acid (H,CO3), is a prod-  uct of cellular metabolism. The lung eliminates about 10,000  milliequivalents (mEq) of carbonic acid per day in the form of  CO), which is produced at the rate of approximately 200 ml/  minute. CO, elimination is necessary to maintain a normal par-  tial pressure of arterial CO, (Paco,) of 40 mmHg and normal  acid-base balance (see Chapter 3 for a discussion of acid-base  regulation).?   The adequacy of alveolar ventilation cannot be accurately  determined by observation of ventilatory rate, pattern, or effort.  If a healthcare professional needs to determine the adequacy of  ventilation, an arterial blood gas analysis must be performed to  measure Paco.    Mechanics of Breathing  (major and accessory muscles, lung elasticity, airway resistance,  alveolar surface tension, work of breathing)    Gas Transport  (distribution of ventilation and perfusion, oxygen transport,  carbon dioxide transport)    FIGURE 34-8 Functional Components of the Respiratory System. The  central nervous system responds to neurochemical stimulation of ventilation  and sends signals to the chest wall musculature. The response of the respiratory  system to these impulses is influenced by several factors that affect the mecha-  nisms of breathing and therefore affect the adequacy of ventilation. Gas transport  between the alveoli and pulmonary capillary blood depends on a variety of physical  and chemical activities. The control of the pulmonary circulation plays a role in the  appropriate distribution of blood flow.   The mechanisms that control respiration are very complex.  Breathing is usually involuntary because homeostatic changes  in the ventilatory rate and volume are adjusted automatically  by the nervous system to maintain normal gas exchange. Vol-  untary breathing is necessary for talking, singing, laughing, and  holding one’s breath.   The respiratory center in the brainstem controls respi-  ration by transmitting impulses to the respiratory muscles,  causing them to contract and relax (Figure 34-9). The respira-  tory center is composed of several groups of neurons located  bilaterally in the brainstem: the dorsal respiratory group  (DRG), the ventral respiratory group (VRG), the pneumo-  taxic center, and the apneustic center.!° The basic automatic  rhythm of respiration is set by the DRG, a cluster of inspi-  ratory nerve cells located in the medulla that sends efferent    impulses to the diaphragm and inspiratory intercostal mus-  cles. The DRG also receives afferent impulses from periph-  eral chemoreceptors in the carotid and aortic bodies, which  detect the Paco, and the amount of oxygen in the arterial  blood (Pao,). In addition, several different types of recep-  tors in the lungs stimulate the VRG through afferent nerves.  The VRG, also located in the medulla, contains inspiratory  and expiratory neurons. It is almost inactive during normal,  quiet respiration, becoming active when increased ventila-  tory effort is required. The pneumotaxic center and apneustic  center, situated in the pons, do not generate primary rhythm,  but rather act as modifiers of the inspiratory depth and rate  established by the medullary centers.!° Breathing can be  modified by input from the cortex, the limbic system, and  the hypothalamus, and the pattern of breathing can be influ-  enced by emotion and by disease.   1. Irritant receptors (rapidly adapting receptors) are found  in the epithelium of the conducting airways. They are sen-  sitive to noxious aerosols (vapors), gases, and particulate  matter (e.g., inhaled dusts), which cause them to initiate  the cough reflex. When stimulated, irritant receptors also  cause bronchoconstriction and increased ventilatory rate.  These receptors are located primarily in the proximal  larger airways and are nearly absent in the distal airways;  thus it is possible for secretions to accumulate in the distal  respiratory tree without initiating cough.   2. Stretch receptors (slowly adapting receptors) are located  in the smooth muscles of airways and are sensitive to  increases in the size or volume of the lungs. They decrease  ventilatory rate and volume when stimulated, an occur-  rence sometimes referred to as the Hering-Breuer expira-  tory reflex. This reflex is active in newborns and assists  with ventilation.!” In adults, this reflex is active only at  high tidal volumes (such as with exercise and mechani-  cal ventilation) and may play a role in protecting against  excess lung inflation. Stretch receptors called rapidly  adapting receptors (RARs) have been found to be an  important mediator of cough.!®   3. J-receptors (juxta-pulmonary capillary or pulmonary  C fiber receptors) are located near the capillaries in the  alveolar septa. They are sensitive to increased pulmonary  capillary pressure, which stimulates them to initiate rapid,  shallow breathing; laryngeal constriction on expiration  and mucus secretion; hypotension; and bradycardia.”   (ANS). Fibers of the sympathetic division of the ANS in the  lung branch from the upper thoracic and cervical ganglia of the  spinal cord. Fibers of the parasympathetic division of the ANS  travel in the vagus nerve to the lung. (Structures and function  of the ANS are discussed in detail in Chapter 15.) The parasym-  pathetic and sympathetic divisions of the ANS control airway  caliber (interior diameter of the airway lumen) by stimulating  bronchial smooth muscle to contract or relax. The parasym-  pathetic receptors cause smooth muscle to contract, whereas  sympathetic receptors cause it to relax. Bronchial smooth mus-  cle tone depends on equilibrium, that is, equal stimulation of  contraction and relaxation. The parasympathetic division of  the ANS is the main controller of airway caliber under normal  conditions.” Constriction occurs if the irritant receptors in the  airway epithelium are stimulated by irritants in inspired air, by  inflammatory mediators (e.g., histamine, serotonin, prosta-  glandins), by many drugs, and by humoral substances.   Pao. Central chemoreceptors monitor arterial blood indirectly  by sensing changes in the pH of cerebrospinal fluid (CSF).  They are located near the respiratory center and are sensitive  to hydrogen ion concentration in the CSF. (Chapter 3 describes  the relationship between ions and the pH, or acid-base status,  of body fluids.) The pH, or concentration of hydrogen ions in  the CSF, reflects Paco, because, unlike H* ions, CO, in arterial  blood diffuses across the blood-brain barrier (the capillary wall    separating blood from cells of the central nervous system) into  the CSF until the partial pressure of CO, (Pco) is equal on both  sides. CO, that has entered the CSF combines with H,O to form  carbonic acid, which subsequently dissociates into hydrogen  ions that are capable of stimulating the central chemoreceptors.  In this way Paco, regulates ventilation through its effect on the  pH (hydrogen ion content) of the CSF.!*!>!   If alveolar ventilation is inadequate, Paco, increases. CO,  diffuses across the blood-brain barrier until Pco, in the blood  and CSF reaches equilibrium. As the central chemoreceptors  sense the resulting decrease in pH (increase in hydrogen ion  concentration), they stimulate the respiratory center to increase  the depth and rate of ventilation. Increased ventilation causes  the Paco, to decrease below that of the CSF, and CO), diffuses  back out of the CSF, returning its pH to normal.   The central chemoreceptors are sensitive to very small  changes in the pH of CSF (equivalent to a 1 to 2 mmHg change  in Pco) and are able to maintain a normal Paco, under many  different conditions, including strenuous exercise. If inadequate  ventilation, or hypoventilation, is long term (e.g., in chronic  obstructive pulmonary disease), these receptors become insen-  sitive to small changes in Paco, and regulate ventilation poorly.  In addition, prolonged increases in Paco, result in renal com-  pensation through bicarbonate retention. This bicarbonate  gradually diffuses into the CSF, where it normalizes the pH and  negates the effect on ventilatory drive.”   The peripheral chemoreceptors are located in aortic bod-  ies, the aortic arch, and carotid bodies at the bifurcation of the  carotids, near the baroreceptors (see Chapter 31). Although the  peripheral chemoreceptors are sensitive to changes in Paco,  and pH, they are primarily sensitive to oxygen levels in arterial  blood (Pao) and are responsible for all of the increase in venti-  lation that occurs in response to arterial hypoxemia.”* As Pao,  and pH decrease, peripheral chemoreceptors, particularly in the  carotid bodies, send signals to the respiratory center to increase  ventilation. The peripheral chemoreceptors are not as sensitive  as the central chemoreceptors. The Pao, must drop well below  normal (to approximately 60 mmHg) before the peripheral  chemoreceptors have much influence on ventilation.’ If Paco,  is elevated as well, however, ventilation increases much more  than it would in response to either abnormality alone. The  peripheral chemoreceptors become the major stimulus to ven-  tilation when the central chemoreceptors are “reset” by chronic  hypoventilation.    The mechanical aspects of inspiration and expiration are  known collectively as the mechanics of breathing and involve:  (1) major and accessory muscles of inspiration and expiration,  (2) elastic properties of the lungs and chest wall, and (3) resis-  tance to airflow through the conducting airways. Alterations in  any of these properties increase the work of breathing, or the  metabolic energy that must be exerted to achieve adequate ven-  tilation and oxygenation of the blood.   Major and Accessory Muscles. The major muscles of  inspiration are the diaphragm and the external intercostal  muscles (muscles between the ribs) (Figure 34-10). The    A  Serratus  posterior  Intercostal superior  muscles  Diaphragm  X Serratus  Transversus posterior  thoracis interior  B    FIGURE 34-10 Muscles of Ventilation. A, Anterior view. B, Posterior view.  (Modified from Thompson JM et al: Mosby’ clinical nursing, ed 5, St Louis, 2002,  Mosby.)    diaphragm is a dome-shaped muscle that separates the  abdominal and thoracic cavities. When the diaphragm contracts,  it flattens downward, increasing the volume of the thoracic  cavity, and creates a negative pressure that draws gas into the  lungs through the upper airways and trachea. Contraction of  external intercostal muscles elevates the anterior portion of  the ribs. This increases the volume of the thoracic cavity by  increasing its front-to-back (anteroposterior [AP]) diameter.  Although the external intercostal muscles may contract during  quiet breathing, inspiration at rest usually is assisted by the  diaphragm only.   The accessory muscles of inspiration are the sternocleido-  mastoid and scalene muscles. Like the external intercostal  muscles, these muscles enlarge the thorax by increasing its AP  diameter. The accessory muscles of inspiration assist inspiration  when the minute volume (volume of air inspired and expired  per minute) is very high, such as during strenuous exercise or  when the work of breathing is increased because of disease. The    accessory muscles do not increase the volume of the thorax as  efficiently as the diaphragm does.   There are no major muscles of expiration because normal,  relaxed expiration is passive and requires no muscular effort.  The accessory muscles of expiration, the abdominal and inter-  nal intercostal muscles, assist expiration when minute volume  is high, during coughing, or when airway obstruction is pres-  ent. When the abdominal muscles contract, intra-abdominal  pressure increases, pushing up the diaphragm and decreas-  ing the volume of the thorax. The internal intercostal muscles  pull down the anterior ribs, decreasing the AP diameter of the  thorax.   Alveolar Surface Tension. Surface tension occurs at any  gas-liquid interface and refers to the tendency for liquid  molecules that are exposed to air to adhere to one another. This  phenomenon can be seen, for example, in a glass of liquid that  is about to overflow or in the way liquids “bead” when splashed  on a waterproof surface. In both examples this phenomenon  decreases the surface area exposed to the air.   Within a sphere, such as an alveolus, surface tension tends to  make expansion difficult. According to the law of Laplace, the  pressure (P) required to inflate a sphere is equal to two times  the surface tension (2T) divided by the radius (r) of the sphere,  or P = 2T/r.” As the radius of the sphere (or alveolus) becomes  smaller, more and more pressure is required to inflate it. If the  alveoli were lined with a water-like fluid, taking breaths would  be extremely difficult.   Alveolar ventilation, or distention, is made possible by sur-  factant, which lowers the surface tension by coating the air-  liquid interface in the alveoli (see Figure 34-3). Surfactant, a  lipoprotein (90% lipids and 10% protein) produced by type  II alveolar cells, includes two groups of surfactant proteins.  One group (SP-B and SP-C) consists of small hydrophobic  molecules that have a detergent-like effect that separates the  liquid molecules, thereby decreasing alveolar surface tension.  The second group (SP-A and SP-D) consists of large hydro-  philic molecules called collectins (pattern recognition mol-  ecules) that are capable of inhibiting foreign pathogens” (see  Chapter 7).   Surfactant lines the alveolar side of the alveolocapillary  membrane and, in effect, reverses Laplace’s law. As the radius  of a surfactant-lined sphere (alveolus) grows smaller, the sur-  face tension decreases, and as the radius grows larger, the surface  tension increases. This occurs because the surfactant molecules  have much weaker intermolecular attraction compared with  the liquid molecules. The surfactant molecules occupy most  of the air-fluid interface and disrupt the intermolecular forces  that tend to collapse the alveoli. Therefore, the alveoli are much  easier to inflate at low lung volumes (.e., after expiration) than  at high volumes (i.e., after inspiration). The decrease in surface  tension caused by surfactant also is responsible for keeping  the alveoli free of fluid. If surfactant production is disrupted  or surfactant is not produced in adequate quantities, alveolar  surface tension increases, causing alveolar collapse, decreased  lung expansion, increased work of breathing, and severe gas-  exchange abnormalities (see What’s New? Update on Surfac-  tant and Immunity).    Surfactant is produced from alveolar type Il cells and is a complex molecule  made up of glycophospholipid, cholesterol, and protein. Surfactant's primary  role is to form a lipid monolayer between the surface of the alveoli and the  inspired air and therefore reduce surface tension, preventing expiratory alveo-  lar collapse. More recent investigations have found multiple roles for surfac-  tant in immune function, preventing infection and acting as an antioxidant  both in the alveoli and in extrapulmonary mucosal tissues. The protein com-  ponent of surfactant includes surfactant proteins A, B, C, and D (SP-A, SP-B,  SP-C, SP-D). SP-A and SP-D are collectins, which are involved in initiating  the immune response and clearing pathogens and allergens. SP-A and SP-D  appear to decrease the growth of certain bacteria and viruses. SP-A is also  called an opsonin, which means it makes microorganisms more vulnerable  to phagocytosis, including viruses, bacteria, and fungi. SP-D is postulated to  activate macrophages and enhance their recognition of pathogens by increas-  ing their cell surface receptors. Both SP-A and SP-D regulate the inflammatory  response in the lung, have antioxidant properties, and down-regulate allergic  reactions. These findings are leading to exciting developments in the synthesis  of therapeutic forms of surfactant that may be useful in treating a broad range  of pulmonary disorders.    Data from Glasser JR, Mallampalli RK: Microbes Infect 14(1):17-25,  2012; Nayak A et al: Front Immunol 3:131, 2012; Silveyra P, Floros J:  Front Biosci 17:407-429, 2012.    The decrease in surface tension caused by surfactant is also  responsible for keeping the alveoli free of fluid. In the absence  of surfactant, the surface tension tends to attract fluid into  the alveoli. In addition, surfactant participates in host defense  against respiratory pathogens.”   Elastic Properties of the Lung and Chest Wall. The lung and  chest wall have elastic properties that permit expansion during  inspiration and return to resting volume during expiration.  The elasticity of the lungs is caused both by elastin fibers in  the alveolar walls and surrounding the small airways and  pulmonary capillaries and by surface tension at the alveolar air-  liquid interface.’ The elasticity of the chest wall is the result of  the configuration of its bones and musculature.   Elastic recoil is the tendency of the lungs to return to the  resting state after inspiration. Normal elastic recoil permits pas-  sive expiration, eliminating the need for major muscles of expi-  ration. Passive elastic recoil may be insufficient during labored  breathing (high minute volume), in which case the accessory  muscles of expiration may be needed. The accessory muscles  also are used if disease comprises elastic recoil (e.g., in emphy-  sema) or blocks the conducting airways.   Normal elastic recoil depends on an equilibrium between  opposing forces of recoil in the lungs and chest wall. Under nor-  mal conditions the chest wall tends to recoil by expanding out-  ward. This can be observed readily during open heart surgery.  When the sternum is split to open the thoracic cavity, the chest  wall moves outward laterally. The tendency of the chest wall to  recoil by expanding is balanced by the tendency of the lungs  to recoil or collapse around the hila. This reaction is caused by  elastic recoil and surface tension in the alveoli. The tendency of  the lungs to collapse can be demonstrated if the chest is opened  without mechanically ventilating the lungs (e.g., at postmortem    examination). As the thorax is opened, the lungs immediately  collapse, like inflated balloons that have been released. The  opposing forces of the chest wall and lungs create, in part, the  small negative intrapleural pressure.   Balance between the outward recoil of the chest wall and the  inward recoil of the lungs occurs at the resting level, at the end  of expiration. During inspiration the diaphragm and intercostal  muscles contract, air flows into the lungs, and the chest wall  expands. Muscular effort is needed to overcome the resistance  of the lungs to expansion. During expiration the muscles relax  and the elastic recoil of the lungs causes the thorax to decrease  in volume until, once again, balance between the chest wall and  lung recoil forces is reached”® (Figure 34-11).   Compliance is the measure of lung and chest wall disten-  sibility. It represents the relative ease with which these struc-  tures can be stretched. Compliance is therefore the reciprocal  of elasticity. Compliance is determined by the alveolar surface  tension and the elastic recoil of the lung and chest wall. It can be  measured with the following formula:    where C = compliance in liters per centimeter of water, AV  = volume change (usually tidal volume), and AP = pressure  change (airway or pleural pressure) in centimeters of water.’   Increased compliance indicates that the lungs or chest wall  is abnormally easy to inflate and has lost some elastic recoil. A  decrease indicates that the lungs or chest wall is abnormally stiff  or difficult to inflate. Compliance is increased in emphysema  and decreased in acute respiratory distress syndrome, pneu-  monia, pulmonary edema, and fibrosis. (These disorders are  described in Chapter 35.)   Airway Resistance. Airway resistance, which is similar to  resistance to blood flow (described in Chapter 31), is determined  by the length, radius, and cross-sectional area of the airways  and by the density, viscosity, and velocity of the gas (Poiseuille’s  law). Resistance is computed by dividing change in pressure (P)  by rate of flow (F), or R = P/F (Ohm’s law), and can easily be  measured in the pulmonary function laboratory.’   Airway resistance is normally very low. One half to two  thirds of total airway resistance occurs in the nose. The next  highest resistance is in the oropharynx and larynx. There is very  little resistance in the conducting airways of the lungs because  of their large cross-sectional area. Resistance increases as the  diameter of the airways (total cross-sectional area) decreases;  airway resistance increases when the diameter of the airways  decreases. Bronchoconstriction, which increases airway resis-  tance, can be caused by stimulation of parasympathetic recep-  tors in the bronchial smooth muscle and by numerous irritants  and inflammatory mediators.’’   Bronchodilation, which decreases resistance to airflow, is  caused by B,-adrenergic receptor stimulation. Airway resistance  also can be increased by edema of the bronchial mucosa and by  airway obstructions such as mucus, tumors, or foreign bodies.   Work of Breathing. The work of breathing is determined by  the muscular effort (and therefore oxygen and energy) required  for ventilation. The work of breathing is normally very low,   FIGURE 34-11 Interaction of Forces During Inspiration and Expiration. A, Outward recoil of the chest wall equals  inward recoil of the lungs at the end of expiration. B, During inspiration, contraction of respiratory muscles, assisted by chest  wall recoil, overcomes tendency of lungs to recoil. C, At the end of inspiration, respiratory muscle contraction maintains lung    expansion. D, During expiration, respiratory muscles relax, allowing elastic recoil of the lungs to deflate the lungs.    but may increase considerably in disease states that disrupt  the equilibrium between forces exerted by the lung and chest  wall. More muscular effort is required when lung compliance  is decreased (e.g., in pulmonary edema), chest wall compliance  is decreased (e.g., in spinal deformity or obesity), or airways  are obstructed by bronchospasm or mucous plugging (e.g., in  asthma or bronchitis).”* An increase in the work of breathing  can result in a marked increase in oxygen consumption and  metabolic demand, which can cause significant morbidity in  individuals with severe lung disease.    A gas is made up of millions of molecules moving randomly. As  they move, they collide with each other and the wall of the space  in which they are contained. These collisions exert pressure. If  more molecules are present in the space, the pressure, or num-  ber of collisions, increases (Figure 34-12). If the same number  of gas molecules is contained in a small and a large container,  the pressure is greater in the small container because more colli-  sions occur in the smaller space. Heat increases the speed of the  molecules, which increases the number of collisions. Therefore,  pressure also increases at higher temperatures.    Barometric pressure (Pg) (atmospheric pressure) is the pres-  sure exerted by gas molecules in air at specific altitudes. At sea  level, barometric pressure is 760 mmHg. This number is the  sum of the pressure exerted by each gas in the air at sea level.  The portion of the total pressure exerted by any individual gas  is its partial pressure (see Figure 34-12). At sea level the air is  made up of oxygen (20.9%), nitrogen (78.1%), and a few other  trace gases. The partial pressure of oxygen is equal to the per-  centage of oxygen in the air (20.9%) times the total pressure  (760 mmHg), or 159 mmHg (760 x 0.209 = 158.84). (Symbols  used in the measurement of gas pressures and pulmonary ven-  tilation are defined in Table 34-2.)   The amount of water vapor contained in a gas mixture is  determined by the temperature of the gas and is unrelated to  barometric pressure. Gas that enters the lungs becomes satu-  rated with water vapor (humidified) as it passes through the  upper airway. At body temperature (37° C, 98.6° F), water  vapor exerts a pressure of 47 mmHg. Because this is true  regardless of total (barometric) pressure, the partial pres-  sure of water vapor (always 47 mmHg) must be subtracted  from the barometric pressure before the partial pressure of  other gases in the mixture can be determined. In saturated    FIGURE 34-12 Relationship Between Number of Gas Molecules and Pressure Exerted by the Gas in an Enclosed  Space. A, Theoretically 10 molecules of the same gas exert a total pressure of 10 within the space. B, If the number of mol-  ecules is increased to 20, total pressure is 20. C, If there are different gases in the space, each gas exerts a partial pressure:  here the partial pressure of nitrogen (N,) is 18, that of oxygen (O,) is 6, and total pressure is 24.   Pacds Partial pressure of carbon dioxide in arterial blood  a  a   Pvoo Partial pressure of oxygen in mixed venous or  pulmonary artery blood   Difference between alveolar and arterial partial  pressure of oxygen (A-a gradient)   Forced expiratory volume in 1 second  Expiratory reserve volume  Inspiratory reserve volume  Inspiratory capacity    From Kacmarek RM, Stoller JK, Jeuer AJ: Egan's fundamentals of  respiratory care, ed 10, St Louis, 2013, Mosby.  *Subscripts identify the particular gas, volume, or pressure being    discussed. A dot, such as above V/O, means measurement over time,  usually 1 minute.    air at sea level, the partial pressure of oxygen is therefore  (760 — 47) x 0.209 = 149 mmHg.’ All pressure and volume  measurements made in pulmonary function laboratories  specify the temperature and humidity of a gas at the time of  measurement.    Many pressure measurements are stated as variations from  barometric pressure, rather than percentages of it. On such  scales, barometric pressure is considered zero, and pressure var-  ies up or down from zero. Physiologic pressure measurements  that involve fluids, rather than gases, are measured as variations  from barometric pressure. For example, a systolic blood pres-  sure of 120 mmHg indicates that systolic pressure is 120 mmHg  above barometric pressure.    Gas transport, the delivery of oxygen to the cells of the body  and the removal of CO;, has four steps:  1. Ventilation of the lungs  2. Diffusion of oxygen from the alveoli into the capillary  blood  3. Perfusion of systemic capillaries with oxygenated blood  4. Diffusion of oxygen from systemic capillaries into the cells  Steps in the transport of CO) occur in reverse order:  1. Diffusion of CO, from the cells into the systemic  capillaries  2. Perfusion of the pulmonary capillary bed by venous blood  3. Diffusion of CO, into the alveoli  4. Removal of CO, from the lung by ventilation  If any step in gas transport is impaired by a respiratory or  cardiovascular disorder, gas exchange at the cellular level is  compromised.    Effective gas exchange depends on an approximately even dis-  tribution of gas (ventilation) and blood (perfusion) in all por-  tions of the lungs. The lungs are suspended from the hila in the  thoracic cavity. When the individual is in an upright position  (sitting or standing), gravity pulls the lungs down toward the  diaphragm and compresses their lower portions or bases. The  alveoli in the upper portions, or apexes, of the lungs contain a  greater residual volume of gas and are larger and less numer-  ous than those in the lower portions. Because surface tension  increases as the alveoli become larger, the larger alveoli in the  upper portions of the lung are more difficult to inflate (less    FIGURE 34-13 Pulmonary Blood Flow and Gravity. The greatest volume of pulmonary blood flow will normally occur  in the gravity-dependent areas of the lungs. Body position has a significant effect on the distribution of pulmonary blood flow.    compliant) than the smaller alveoli in the lower portions of  the lung. Therefore, during ventilation most of the tidal vol-  ume is distributed to the bases of the lungs, where compliance  is greater.   The heart pumps against gravity to perfuse the pulmonary  circulation. As blood is pumped into the lung apexes of a sit-  ting or standing individual, some blood pressure is dissipated  in overcoming gravity. As a result, blood pressure at the apexes  is lower than that at the bases. Because greater pressure causes  greater perfusion, the bases of the lungs are better perfused than  the apexes (Figure 34-13). Thus ventilation and perfusion are  greatest in the same lung portions: the lower lobes. Ventilation  and perfusion depend on body position. Ifa standing individual  assumes a supine or side-lying position, the areas of the lungs  that are then most dependent become the best ventilated and  perfused.   Distribution of perfusion in the pulmonary circulation also  is affected by alveolar pressure (gas pressure in the alveoli). The  pulmonary capillary bed differs from the systemic capillary bed  in that it is surrounded by gas-containing alveoli. If the gas  pressure in the alveoli exceeds the blood pressure in the capil-  lary, the capillary collapses and flow ceases. This is most likely    to occur in portions of the lung where blood pressure is lowest  and alveolar gas pressure is greatest, that is, the apex of the lung.   The lungs are divided into three zones on the basis of the  relationships among all the factors affecting pulmonary blood  flow. Alveolar pressure plus the forces of gravity, arterial blood  pressure, and venous blood pressure affect the distribution of  perfusion (Figure 34-14).   Zone | is where alveolar pressure exceeds pulmonary arterial  and venous pressures. The capillary bed collapses, and normal  blood flow ceases. Normally zone I is a very small part of the  lung at the apex. Zone II is the portion where alveolar pres-  sure is greater than venous pressure, but not greater than arte-  rial pressure. Blood flows through zone I, but it is impeded to  a certain extent by alveolar pressure. Zone I] is normally above  the level of the left atrium. In zone III arterial and venous pres-  sures are greater than alveolar pressure and blood flow is not  affected by alveolar pressure. Zone II] is in the base of the lung.  Blood flow through the pulmonary capillary bed increases in  regular increments from the apex to the base.   Although blood flow and ventilation are greater at the base  of the lungs than at the apexes, they are not perfectly matched  in any of the zones. Perfusion exceeds ventilation in the bases    FIGURE 34-14 Gravity and Alveolar Pressure. Effects of gravity and alveolar pressure on pulmonary blood flow in the  three lung zones. In zone |, alveolar pressure (P,) is greater than arterial and venous pressure, and no blood flow occurs. In  zone Il, arterial pressure (P,) exceeds alveolar pressure, but alveolar pressure exceeds venous pressure (Py). Blood flow occurs  in this zone, but alveolar pressure compresses the venules (venous ends of the capillaries). In zone Ill, both arterial and venous  pressures are greater than alveolar pressure and blood flow fluctuates, depending on the difference between arterial and    of the lungs, and ventilation exceeds perfusion in the apexes of  the lung. The relationship between ventilation and perfusion  is expressed as a ratio called the ventilation-perfusion ratio,  or V/Q.° The normal V/Q ratio is 0.8. This is the amount by  which perfusion exceeds ventilation under normal conditions.    Oxygen Transport  Approximately 1000 ml (1 L) of oxygen is transported to the  cells each minute. Oxygen is transported in the blood in two  forms. A small amount dissolves in plasma, and the remainder  binds to hemoglobin molecules. Without hemoglobin, oxygen  would not reach the cells in amounts sufficient to maintain nor-  mal metabolic function. (Hemoglobin is discussed in detail in  Chapter 27; cellular metabolism is discussed in Chapter 1.)  Diffusion Across the Alveolocapillary Membrane. The  alveolocapillary membrane is the ideal medium for oxygen  diffusion, because it has a large total surface area (70 to 100 m*)  and is very thin (0.5 um). In addition, the partial pressure of  oxygen molecules (Po;) is much greater in alveolar gas than in  capillary blood, a condition that promotes rapid diffusion down  the concentration gradient from the alveolus into the capillary.”  The amount of oxygen in the alveoli (Pao,) depends on the  amount of oxygen in the inspired air and on the amount of air  that remains in the alveoli and tracheobronchial tree between  breaths (physiologic dead space).’? The Pao, can be estimated  by using the alveolar gas equation:    This value is approximately 104 mmHg at sea level with  relaxed breathing; therefore a pressure gradient of approxi-  mately 60 mmHg facilitates the diffusion of oxygen from the  alveolus into the capillary (Figure 34-15). Different values for  Pao, can be calculated if there are changes in the inspired oxy-  gen content or the Paco, which are common occurrences in  clinical settings.   Blood remains in the pulmonary capillary for about 0.75 sec-  ond, but only 0.25 second is required for oxygen concentration  to equilibrate (equalize) across the alveolocapillary membrane.’  Therefore, oxygen has ample time to diffuse into the blood,  even during increased cardiac output, which speeds blood flow,  shortening the time the blood remains in the capillary.   Determinants of Arterial Oxygenation. As oxygen diffuses  across the alveolocapillary membrane, it dissolves in the  plasma, where it exerts pressure (the partial pressure of oxygen  in arterial blood, or Pao). As the Pao increases, oxygen moves  from the plasma into the red blood cells (erythrocytes) and  binds with hemoglobin molecules. Oxygen continues to bind  with hemoglobin until the hemoglobin binding sites are filled  or saturated. Oxygen then continues to diffuse across the  alveolocapillary membrane until the Pao, and Pao, equilibrate,  eliminating the pressure gradient across the alveolocapillary  membrane. At this point diffusion ceases (see Figure 34-15).   Normally approximately 20 ml of oxygen is transported per  100 ml of blood. Because oxygen is not very soluble in plasma,  most of the oxygen molecules bind with hemoglobin. Plasma  carries only about 0.3 ml of oxygen per 100 ml of blood (at sea    Pog = 159 mmHg  Pco, = 0.3 mmHg  PH,0 = 3.7 mmHg  PNy = 597 mmHg    Pog = 40 mmHg  Pco, = 46 mmHg  PH20 = 47 mmHg  PNy = 573 mmHg    Po, = 40 mmHg  PCO = 46 mmHg  PHO = 47 mmHg  PNz = 573 mmHg    FIGURE 34-15 Partial Pressure of Respiratory Gases in Normal Respiration. These are average values. The values  of Po», Peds, and PN» fluctuate from breath to breath. CO,, Carbon dioxide; 02, oxygen; Peoz, partial pressure of carbon dioxide;  Pu20, partial pressure of water; PN, partial pressure of nitrogen; Poy, partial pressure of oxygen.    level). Although the remaining 19.7 ml is carried by hemoglo-  bin, it is the small amount of oxygen dissolved in plasma that  is responsible for oxygen’s partial pressure (Pao,) in the blood.   Although Pao, is important in that it provides the driving  pressure that loads the hemoglobin with oxygen, it gives little  information about the amount of oxygen carried in the blood.  This amount, which is measured in milliliters per deciliter  (1 dl = 100 ml) of blood, is the oxygen content of the blood.  The total oxygen content of the blood depends on the amount  of oxygen chemically combined with hemoglobin, as well as  that dissolved in the blood. To calculate the total arterial oxy-  gen content, we must know (1) hemoglobin concentration, or  the amount of hemoglobin that is available to bind with oxygen  (hemoglobin [Hb] in grams per deciliter); (2) the oxygen satu-  ration or percentage of available hemoglobin that is bound to  oxygen (Sao); and (3) the partial pressure of oxygen (Pao).  The maximum amount of oxygen that can be transported by  hemoglobin is 1.34 ml/g. The amount of oxygen that can be  physically dissolved in blood is 0.003 ml/dl per mmHg. If these  specific values are known, the oxygen content of arterial blood  can be calculated.’ To calculate the oxygen content of venous  blood, the partial pressure of mixed venous blood (Pvo;) and  venous oxygen saturation (Svo,) are substituted for the arterial    values in the basic formula. Normal venous oxygen content is  15 to 16 ml/dl.   Because hemoglobin transports all but a small fraction of the  oxygen carried in arterial blood, increases in hemoglobin con-  centration affect the oxygen content of the blood. Decreases in  hemoglobin concentration below the normal value of 15 ml/  dl of blood reduce oxygen content, and increases in hemoglo-  bin concentration may minimize the effect of impaired gas  exchange. In fact, an increase in hemoglobin concentration is  a major compensatory mechanism in pulmonary diseases that  impair gas exchange. For this reason, measurement of hemo-  globin concentration is important in assessing individuals with  pulmonary disease. If cardiovascular function is normal, the  body’s initial response to low oxygen content is to accelerate  cardiac output. In individuals who also have cardiovascular  disease, this compensatory mechanism does not work, making  increased hemoglobin concentration an even more important  compensatory mechanism. (Hemoglobin structure and func-  tion are described in Chapter 27.)   Oxyhemoglobin Association and Dissociation. When  hemoglobin molecules bind with oxygen, oxyhemoglobin  (HbO,) is formed. Binding occurs in the lungs and is called  oxyhemoglobin association or hemoglobin saturation with oxygen    Acute alkalosis (TpH)  Decreased Pco,  Decreased temperature  Low levels of 2,3-BPG  Carboxyhemoglobin  Methemoglobin  Abnormal hemoglobin  (left shift)    FIGURE 34-16 Oxyhemoglobin Dissociation Curve. The horizontal or flat segment of the curve at the top of the graph  is sometimes called the arterial portion, or that part of the curve where oxygen is bound to hemoglobin. This portion of the  curve Is flat because partial pressure changes of oxygen between 60 and 100 mmHg do not significantly alter the percent  saturation of hemoglobin with oxygen. The wide range of partial pressures of oxygen (Pao, of 60 to 100 mmHg), represented  by the flat part of the curve, allows adequate hemoglobin saturation at a variety of a/titudes. For example, a Pao, of 100 mmHg  at sea level results in a hemoglobin saturation with oxygen of 98%. At an altitude of 5000 feet the Pao, is about 70 mmHg  and hemoglobin saturation is 94%, only 4% less than at sea level. If the relationship between Sao, and Pao, were linear (in a  downward-sloping straight line) instead of flat between 60 and 100 mmHg, there would be inadequate saturation of hemoglo-  bin with oxygen. For example, with a Pao of 70 mmHg the saturation would be only 70%, which is equivalent to normal venous  oxygen saturation, and life could not be sustained at altitudes much higher than sea level. The steep part of the oxyhemoglobin  dissociation curve occurs after the Pao drops below 60 mmHg and represents the rapid dissociation of oxygen from hemoglo-  bin. During this phase oxygen diffuses rapidly from the blood into tissue cells. Conditions associated with altered affinity of  hemoglobin for 0 are listed. Ps is the Paoz at which hemoglobin is 50% saturated, normally 26.6 mmHg. A lower than normal  Pg represents increased affinity of hemoglobin for O,; a high Psp is seen with decreased affinity. Note that variation from the  normal is associated with decreased (low Ps9) or increased (high Pq) availability of Oz to tissues (dashed lines). The shaded  area shows the entire oxyhemoglobin dissociation curve under the same circumstances. 2,3-BPG, 2,3-Biphosphoglycerate.    (From Lane EE, Walker JF: Clinical arterial blood gas analysis, St Louis, 1987, Mosby.)    (Sao). The reverse process, in which oxygen is released from  hemoglobin, occurs in the body tissues at the cellular level and  is called hemoglobin desaturation. When hemoglobin saturation  and desaturation are plotted ona graph, the result is a distinctive  S-shaped curve known as the oxyhemoglobin dissociation  curve (Figure 34-16).   Several factors can change the relationship between Pao, and  Sao), causing the oxyhemoglobin dissociation curve to shift to  the right or left (see Figure 34-16). A shift to the right depicts  hemoglobin’s decreased affinity for oxygen or an increase in the  ease with which oxyhemoglobin dissociates and oxygen moves  into the cells. A shift to the left depicts hemoglobin’s increased  affinity for oxygen, which promotes association in the lungs and  inhibits dissociation in the tissues.    The oxyhemoglobin dissociation curve is shifted to the right by  acidosis (low pH) and hypercapnia (increased Paco,). In the tis-  sues the increased levels of CO, and hydrogen ions produced by  metabolic activity decrease the affinity of hemoglobin for oxygen.  The curve is shifted to the left by alkalosis (high pH) and hypocap-  nia (decreased Paco;). In the lungs, as CO, diffuses from the blood  into the alveoli, the blood CO, level is reduced and the affinity of  hemoglobin for oxygen is increased. The shift in the oxyhemoglo-  bin dissociation curve caused by changes in CO) and hydrogen ion  concentration in the blood is called the Bohr effect.’   The oxyhemoglobin curve is shifted also by changes in  body temperature and increased or decreased levels of 2,3-  biphosphoglycerate (2,3-BPG), a substance normally present in  erythrocytes. Hyperthermia and increased 2,3-BPG levels shift    the curve to the right. Hypothermia and decreased 2,3-BPG  levels shift the curve to the left.   Approximately 200 ml of CO) is produced by the tissues per min-  ute as a byproduct of cellular metabolism. This CO, equilibrates  with carbonic acid (H,O + COz = H,CO3 = H+ HCO; ) and  must be eliminated continuously to prevent acidosis. The elimi-  nation of CO, by the lungs plays an important role in the regula-  tion of acid-base balance (see Chapter 3).   CO, is carried in the blood in three ways: (1) dissolved in  plasma, (2) as bicarbonate, and (3) as carbamino compounds.  As CO, diffuses out of the cells into the blood, it dissolves in the  plasma. Approximately 10% of the total CO, in venous blood  and 5% of the CO, in arterial blood are carried dissolved in the  plasma. As CO, moves into the blood, it diffuses into the red  blood cells. Within the red blood cells, CO, with the help of the  enzyme carbonic anhydrase, combines with water to form car-  bonic acid and then quickly dissociates into Ht and HCO;~. As  carbonic acid dissociates, the H* binds to hemoglobin, where it  is buffered, and the HCO; moves out of the red blood cell into  the plasma. Approximately 60% of the CO, in venous blood and  90% of the CO, in arterial blood are carried in the form of bicar-  bonate. The remainder combines with blood proteins, hemo-  globin in particular, to form carbamino compounds (see Figure  3-12). Approximately 30% of the CO, in venous blood and 5% of  the CO, in arterial blood are carried as carbamino compounds.’   CO, is 20 times more soluble than O, and diffuses quickly  from the tissue cells into the blood.? The amount of CO, that is  able to enter the blood is enhanced by diffusion of oxygen out  of the blood and into the cells. Reduced hemoglobin (hemoglo-  bin that is dissociated from oxygen) is able to carry more CO,  than hemoglobin that is saturated with O. Therefore, the drop  in Sao, at the tissue level increases the ability of hemoglobin to  carry CO, back to the lung.   The diffusion gradient for CO, in the lung is only approxi-  mately 6 mmHg (venous Pvco, = 46 mmHg; alveolar Paco, =  40 mmHg), yet CO, is so soluble in the alveolocapillary mem-  brane that the CO, in the blood quickly diffuses into the alveoli,  where it is removed from the lung with each expiration.” Dif-  fusion of CO) in the lung is so efficient that diffusion defects  that cause hypoxemia (low oxygen content of the blood) do not  cause hypercapnia (excessive CO, in the blood).   The diffusion of CO, out of the blood also is enhanced by  oxygen binding with hemoglobin in the lung. As hemoglo-  bin binds with O,, the amount of CO, carried by the blood is  decreased. Thus in the tissue capillaries, O, dissociation from  hemoglobin facilitates the pickup of CO), and the binding of O,  to hemoglobin in the lungs facilitates the release of CO, from  the blood. This effect of oxygen on CO, transport is called the  Haldane effect and can have significant clinical implications for  the management of lung disease.??”    Several laboratory tests aid in the diagnosis and evaluation of  pulmonary system abnormalities. Most of them are easy to    perform at hospitals and clinics. They provide valuable infor-  mation about the possible cause of a respiratory abnormality  and evaluate the progression or resolution of disease.   Spirometry is used to measure forced expiration, which often  is affected by diffuse pulmonary disease. Because the pulmonary  system has remarkable reserves, disease may become well estab-  lished before clinical manifestations appear. Spirometry enables  clinicians to detect restrictive or obstructive deficits early in the  course of disease. Restrictive lung diseases restrict the lungs’ vol-  ume: the lungs are unable to expand normally, diminishing the  amount of gas that can be inspired. Obstructive diseases affect  gas flow: airflow into and out of the lungs is obstructed.   Spirometry measures both volume and flow. The test is per-  formed with a spirometer, which is a water-filled cylinder into  which an inverted cylinder or bell has been inserted. A length  of tubing runs from the inverted bell to a mouthpiece through  which a person breathes during testing. The bell is attached  to a pen that writes on calibrated paper rotating at a constant  speed. As a person performs various breathing maneuvers, the  inverted bell moves up and down, causing the pen to move on  the calibrated paper. This produces a spirogram, which is a  record of the individual’s ventilation in relation to time (Figure  34-17). Clinically the most important spirometric tests are the  forced vital capacity (FVC) and the forced expiratory volume in  1 second (FEV)).*! (These tests and other important measures  are described in Table 34-3.)   Lung capacities, such as vital capacity and total lung capac-  ity, are always the sum of two or more volumes. Norms for vol-  umes and capacities are based on age, gender, and height and  are referred to as predicted values. Changes from predicted or  baseline values are taken into account in diagnosing and assess-  ing respiratory disorders.   Diffusing capacity is a measure of the rate of gas diffusion  across the alveolocapillary membrane. Oxygen, or more com-  monly carbon monoxide, is used to measure diffusing capacity.  The measurement is made by determining how much carbon  monoxide is taken up by the blood and dividing this amount  by the pressure gradient across the alveolocapillary membrane.  Helium often is added to the gas mixture to obtain a simultane-  ous measurement of residual volume (RV), functional reserve  capacity (FRC), and total lung capacity (TLC). Individuals  are asked to perform ventilatory maneuvers similar to those  of spirometry. A decreased diffusing capacity can be the result  of an abnormal ventilation-perfusion ratio or an actual diffu-  sion defect. Diffusing capacity is decreased in individuals with  emphysema.   Arterial blood gas analysis commonly is performed for indi-  viduals with suggested or diagnosed pulmonary disease. Direct  analysis of the pH and gas concentrations in arterial blood pro-  vides valuable information about an individual’s gas exchange  and acid-base status. Acidosis (low pH), alkalosis (high pH),  ventilatory alterations, and decreased Pao, can be diagnosed  accurately only by arterial blood gas analysis. A blood gas report  may be divided into an acid-base/ventilation portion and an  oxygenation portion. (Normal values for arterial blood gases  are given in Table 34-4; acid-base alterations are described in  Chapter 3.) Oximetry can be used to monitor oxygen saturation    Total lung capacity (TLC) (5700-6200 ml)  Vital capacity (VC) (4500-5000 ml)    (1200 ml)  Tne =>  A  x Anatomical dead space  Residual volume  Expiratory 7]  reserve volume T Total lung  capacity  Tidal volume —_—F Vital  it’  Inspiratory pial  B reserve volume | =  FIGURE 34-17 Pulmonary Ventilation and Lung Capacities. A, Spirogram.  During normal, quiet respirations the atmosphere and lungs exchange about 500 ml  of air (V7). With a forcible inspiration, about 3300 ml more air can be inhaled (/RV).    After a normal inspiration and normal expiration, approximately 1000 ml more air  can be forcibly expired (ERV). Vital capacity is the amount of air that can be forcibly  expired after a maximal inspiration and indicates, therefore, the largest amount  of air that can enter and leave the lungs during respiration. Residual volume (RV)  is the air that remains trapped in the alveoli. B, Lung capacities. (From Patton KT,  Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    once the arterial blood gas analysis has accurately measured the  Pao,, but it does not measure Paco, or pH.   Signs and symptoms of most respiratory abnormalities first  appear when the system is stressed during exercise. Therefore,  if pulmonary disease is suspected, the individual is evaluated at  rest and during exercise. During exercise the usual procedures  are spirometry and withdrawal of arterial blood for gas analy-  sis. The exercise usually consists of riding a stationary bicycle  or walking on a treadmill. Exercise testing enables clinicians  to detect early changes in respiratory function and thus begin  treatment. Exercise tests also are used in planning and evaluat-  ing exercise and rehabilitation programs.   Chest radiographs are among the most common exami-  nations of the pulmonary system. A few of the abnormalities  detected in chest radiographs are air trapping in the alveoli  and airways (e.g., in asthma or emphysema), consolidation of    FVC Forced vital capacity: maximum amount of gas that can  be displaced from the lung during a forced expiration   FEV, Forced expiratory volume in 1 second: maximum  amount of air that can be expired from the lung in 1  second   Percentage of maximum inspiration that is expired in 1  second, usually 80% of FVC   FEV; Forced expiratory volume in 3 seconds; maximum  amount of gas that can be expired in 3 seconds   Percentage of FVC that is expired in 3 seconds; usually  95% of FVC   Forced expiratory flow rate during the middle 50%  of expiration; sometimes reported as maximum  midexpiratory flow rate (MIMFR)    lung tissue (e.g., in pneumonia or pulmonary edema), cavities  (e.g., abscesses or tuberculosis), and nodules (e.g., lung cancer).  Often pulmonary abnormalities are detected in routine chest  radiographs of asymptomatic individuals. Various radiographic  techniques are available for the diagnosis and evaluation of  respiratory disorders.    Most knowledge about pulmonary structure and function  is based on norms for the middle years. Less is known about  structure and function in the very young (see Chapter 36) and  older adults, but a few normal physiologic (developmental and  degenerative) changes are known to occur from birth to old age.  An understanding of these changes is needed to provide appro-  priate care and to differentiate between normal alterations and  disease. Normal alterations include: (1) loss of elastic recoil, (2)  stiffening of the chest wall, (3) changes in gas exchange, and (4)  increases in flow resistance (Figure 34-18). These changes are  gradual and usually without adverse consequences in healthy  individuals. They are influenced by environmental and socio-  cultural factors, nutritional status, respiratory disease, body  size, gender, and race.°?-*4   During adulthood and as age advances, the alveoli tend to lose  alveoli wall tissue and capillaries. This process diminishes alveo-  lar surface area available for gas diffusion and decreases airway  support provided by normal lung tissues. Mechanical changes  involve elastic properties of the lungs and chest wall. Chest  wall compliance decreases with age, because the ribs become  ossified (less flexible) and joints become stiffer. As a result the  chest wall loses some of its ability to expand. In addition, respi-  ratory muscle strength and endurance decrease by up to 20%  by age 70.°? These mechanical changes in the lung and chest  wall, along with structural changes in the alveoli, reduce ven-  tilatory capacity in older adults.*° Vital capacity decreases and  residual volume increases; however, total lung capacity remains  unchanged. These changes decrease ventilatory reserves and  lead to decreased ventilation-perfusion ratios. With advancing    TABLE 34-4 NORMAL RANGES FOR ARTERIAL AND MIXED VENOUS BLOOD GASES  MEASUREMENT ARTERIAL BLOOD MIXED VENOUS BLOOD* _CLINICAL NOTES    Acid-base status (pH) 7.35-7.45 7.33-7.43 Most important acid-base value; detects acidosis or  alkalosis  Partial pressure of carbon 35-45 mmHg 41-57 mmHg Measures adequacy of ventilation and respiratory  dioxide (Pco,) contribution of acid-base abnormality (respiratory acidosis)  Bicarbonate (HCO'3) 22-26 mEq/L 24-28 mEq/L Measures metabolic contribution to acid-base abnormality  (metabolic acidosis); calculated from pH and Pco,    Base excess (BE) -2 to +2 0 to +4 Reflects deviation of bicarbonate concentration from  normal  Partial pressure of oxygen 80-100 mmHg 35-40 mmHg Indicates driving pressure that causes oxyhemoglobin  (Po) (sea level) binding; varies with age and barometric pressure  Saturation of hemoglobin 96-98% 70-75% Indicates abnormalities of oxyhemoglobin association and  with oxygen (Soy) dissociation; may be measured directly or calculated  from PcO, pH, and body temperature  Concentration of hemoglobin 15 g/dl 15 g/dl Detects alterations of gas transport caused by anemia  in the blood    *Mixed venous (pulmonary artery) blood is analyzed for critically ill individuals and those undergoing cardiac catheterization (it is not practical to withdraw  samples except from a pulmonary artery catheter). Mixed venous blood gas analysis, in conjunction with arterial analysis, provides important information  about the adequacy of cardiac output and tissue oxygenation.    age there is also increased immune dysregulation, asymptomatic  low-grade inflammation, and increased risk of infection.*°*°*?   Alterations in gas exchange are reflected by blood gas analy-  sis. With advancing age, pH and Paco, do not change much,  even though it has been documented that the chemoreceptors  become less sensitive to gas partial pressures with age.*° Older  adults have a decreased compensatory response to hypercapnia  and hypoxemia; however, the perception of dyspnea remains  intact and is even enhanced. Pao, declines with age as a result  of structural and mechanical changes, such as loss of alveolar  surface area and increased ventilation-perfusion mismatch. The  maximum Pao, in an older adult at sea level can be estimated by  multiplying the person’s age by 0.3 and subtracting the product  from 100. For example, an 80-year-old individual would have an  estimated maximum Pao, of 76 mmHg (0.3 x 80 = 24; 100 — 24  = 76)."! There is also a decrease in the capillary network.   The decrease in Pao, and diminished ventilatory reserve in  an older adult lead to a decrease in exercise tolerance. Respi-  ratory muscle strength and endurance decrease with age.*”    reserve volume Total lung Furthermore, older adults are at greater risk for respiratory   Expiratory , structure and function can vary considerably from person to   ticularly the decrease in vital capacity and the increase in residual volume. one who has been sedentary.   Structures of the Pulmonary System 3. Gas exchange occurs in structures beyond the sixteenth   1. The pulmonary system consists of the lungs, airways, chest division: the respiratory bronchioles, alveolar ducts, and  wall, diaphragm, and pulmonary and bronchial circulation. alveoli. Together these structures comprise the acinus.   2. Air is inspired and expired through the conducting air- 4. The chief gas-exchange units of the lungs are the alveoli. The   ways, which include the nasopharynx, oropharynx, trachea, membrane that surrounds each alveolus and contains the    bronchi, and bronchioles to the sixteenth division. pulmonary capillaries is called the alveolocapillary membrane.    culation, a separate division of the circulatory system. The  bronchi and other lung structures are served by a branch of  the systemic circulation called the bronchial circulation.    vasodilation and vasoconstriction are controlled mainly by  local and humoral factors, particularly arterial oxygenation  and acid-base status.    by alveolar hypoxia, acidemia, and inflammatory mediators  (histamine, serotonin, prostaglandins, and bradykinin).    . The chest wall, which contains and protects the contents of    the thoracic cavity, consists of the skin, ribs, and intercostal  muscles, which lie between the ribs.    . The chest wall is lined by a serous membrane called the parietal    pleura; the lungs are encased in a separate membrane called  the visceral pleura. The area where these two pleurae come into  contact and slide over each another is called the pleural space.    The pulmonary system enables oxygen to diffuse into the  blood and CO, to diffuse out of the blood.    . Ventilation is the process by which air flows into and out of    . Ventilation is involuntary most of the time. It is controlled    by the respiratory center in the brainstem and by the sym-  pathetic and parasympathetic divisions of the ANS, which  adjust airway caliber (by causing bronchial smooth mus-  cle to contract or relax) and control the rate and depth of  ventilation.    mechanical aspects of ventilation. Irritant receptors sense the  needtoexpelunwantedsubstances,stretchreceptorssenselung  volume (lung expansion), and J-receptors sense alveolar size.    sense the effectiveness of ventilation by monitoring the pH  status of cerebrospinal fluid and the oxygen content of arte-  rial blood (Pao,).    ing: the interaction of forces and counterforces involving  the muscles of inspiration and expiration, alveolar surface  tension, elastic properties of the lungs and chest wall, and  resistance to airflow.    . The major muscle of inspiration is the diaphragm. When the    diaphragm contracts, it moves downward in the thoracic cav-  ity, creating a vacuum that causes air to flow into the lungs.    lar cells. It is a lipoprotein that lines the alveoli. Surfactant  reduces alveolar surface tension and permits the alveoli to  expand more easily with air intake.    . Compliance is the ability of the lungs and chest wall to   Elastic recoil is the tendency of the lungs and chest wall to  return to their resting state after inspiration. The elastic  recoil forces of the lungs and chest wall are in opposition  and pull on each other, creating the normally negative pres-  sure of the pleural space.   Gas transport depends on ventilation of the alveoli, dif-  fusion across the alveolocapillary membrane, perfusion  of the pulmonary and systemic capillaries, and diffusion  between systemic capillaries and tissue cells.   Efficient gas exchange depends on an even distribution of ven-  tilation and perfusion within the lungs. Ventilation and perfu-  sion are greatest in the bases of the lungs because the alveoli  in the bases are more compliant (their resting volume is low),  and perfusion is greater in the bases as a result of gravity.  Almost all of the oxygen that diffuses into pulmonary cap-  illary blood is transported by hemoglobin, a protein con-  tained within red blood cells. The remainder of the oxygen  is transported dissolved in plasma.   Oxygen enters the body by diffusing down the concentra-  tion gradient, from high concentrations in the alveoli to  lower concentrations in the capillaries. Diffusion ceases  when alveolar and capillary oxygen pressures equilibrate.  Oxygen is loaded onto hemoglobin by the driving pressure  exerted by Pao, in the plasma. As pressure decreases at tissue  level, oxygen dissociates from hemoglobin and enters tissue  cells by diffusion, again down the concentration gradient.  CO) is more soluble in plasma than oxygen is and diffuses  readily from tissue cells into plasma. CO, returns to the  lungs dissolved in plasma, as bicarbonate, or in carbamino  compounds (e.g., bound to hemoglobin).    . Diffusing capacity is a measure of the gas diffusion rate at    . Arterial blood gas analysis can be used to determine pH and    Aging affects the mechanical aspects of ventilation by  decreasing chest wall compliance and elastic recoil of the  lungs. Changes in these elastic properties reduce ventilatory  reserve.   Aging causes the Pao, to decrease but does not affect the  Paco).   Alveolar ventilation, 1232  Alveoli (sing., alveolus), 1229  Alveolocapillary membrane, 1230  Arterial blood gas analysis, 1243  Bohr effect, 1242   Bronchiole, 1228  Bronchoconstriction, 1236  Bronchodilation, 1236  Bronchus (pl., bronchi), 1228  Carina, 1228   Oxyhemoglobin (HbO,), 1241  Oxyhemoglobin dissociation curve, 1242  Partial pressure (of a gas), 1237   Rapidly adapting receptor (RAR), 1234  Residual volume (RV), 1243  Respiration, 1232   Ventilation, 1232 on  Ventilation-perfusion ratio (V/Q), 1240  Work of breathing, 1236    McCulloch TM, Van Daele D, Ciucci MR: Otolaryngology head and neck  surgery: an integrative view of the larynx, Head Neck 33(Suppl 1):S46-S53,    Meurs H et al: Muscarinic receptors on airway mesenchymal cells: novel  findings for an ancient target, Pulm Pharmacol Ther 26(1):145-155,  2013.   Guyenet PG, Stornetta RL, Bayliss DA: Central respiratory chemorecep-  tion, J Comp Neurol 518(19):3883—3906, 2010.   Madias NE: Renal acidification responses to respiratory acid-base disor-  ders, J Nephrol 23(Suppl 16):S85-S91, 2010.   Forster HV, Smith CA: Contributions of central and peripheral chemore-  ceptors to the ventilatory response to CO,/H*, J Appl Physiol 108(4):989-   Glasser JR, Mallampalli RK: Surfactant and its role in the pathobiology of  pulmonary infection, Microbes Infect 14(1):17—25, 2012.    Chitano P: Models to understand contractile function in the airways,  Pulm Pharmacol Ther 24(5):444—451, 2011.   Des Jardins T, Burton GC: Clinical manifestations and assessment of respi-  ratory disease, ed 6, St Louis, 2011, Mosby.   Cavaliere F et al: Comparison of two methods to assess blood CO) equili-  bration curve in mechanically ventilated patients, Resp Physiol Neurobiol  146(1):77-83, 2005.   Chien JW et al: Uncontrolled oxygen administration and respiratory  failure in acute asthma, Chest 117(3):728—733, 2000.   Mason RJ et al: Murray and Nadel’s textbook of respiratory medicine, ed 5,  St Louis, 2010, Elsevier.   Becklake MR, Kauffmann F: Gender differences in airway behaviour over  the human life span, Thorax 54(12):1119-1138, 1999.   Sharma G, Goodwin J: Effect of aging on respiratory system physiology  and immunology, Clin Interven Aging 1(3):253—260, 2006.   Vaz Fragoso CA, Gill TM: Respiratory impairment and the aging lung: a  novel paradigm for assessing pulmonary function, J Gerontol A Biol Sci  Med Sci 67(3):264—275, 2012.   Miller MR: Structural and physiological age-associated changes in aging  lungs, Semin Respir Crit Care Med 31(5):521-527, 2010.   Dyer C: The interaction of ageing and lung disease, Chron Respir Dis  9(1):63-67, 2012.   Ely KH et al: Aging and CD8+ T cell immunity to respiratory virus infec-  tions, Exp Gerontol 42(5):427—431, 2007.   Haas CF, Loik PS, Gay SE: Airway clearance applications in the elderly  and in patients with neurologic or neuromuscular compromise, Respir  Care 52(10):1362—1381, 2007. discussion 1381.   Taylor BJ, Johnson BD: The pulmonary circulation and exercise  responses in the elderly, Semin Respir Crit Care Med 31(5):528-558,    Dyer C: The interaction of ageing and lung disease, Chron Respir Dis  9(1):63-67, 2012.    2011. 21.  2. Barash PG et al: Clinical anesthesia, ed 6, Philadelphia, 2009, Lippincott  Williams & Wilkins. 22.  3. Vareille M et al: The airway epithelium: soldier in the fight against respi-  ratory viruses, Clin Microbiol Rev 24(1):210-229, 2011. 23.  4. Barrett KE et al: Ganong’s review of medical physiology, ed 24, Philadelphia,  2012, McGraw-Hill. 994, 2010.  5. Corrin B, Nicholson A: Pathology of the lungs, ed 3, London, 2011, 24,  Churchill Livingstone. 25;  6. Ochs MD et al: The number of alveoli in the human lung, Am J Respir  Crit Care Med 169:120-124, 2004. 26.  7. Raghavendran K, Willson D, Notter RH: Surfactant therapy for acute Elsevier.  lung injury and acute respiratory distress syndrome, Crit Care Clin 27.  27(3):525-559, 2011.   7a. Nayak A et al: An insight into the diverse roles of surfactant proteins, SP-A 28.  and SP-D in innate and adaptive immunity, Front Immunol 3:131, 2012.   8. Miyata R, van Eeden SF: The innate and adaptive immune response 29.  induced by alveolar macrophages exposed to ambient particulate matter,  Toxicol Appl Pharmacol 257(2):209-226, 2011.   9. Kacmarek RM, Stoller JK, Jeuer AJ: Egan’s fundamentals of respiratory 30.  care, ed 10, St Louis, 2013, Mosby.   10. Osiro S et al: A friend to the airways: a review of the emerging clini- 31.  cal importance of the bronchial arterial circulation, Surg Radiol Anat  34(9):791-798, 2012. 32.   11. Sylvester JT et al: Hypoxic pulmonary vasoconstriction, Physiol Rev  92(1):367-520, 2012. 33.   12. Housley GD: Recent insights into the regulation of breathing, Auton  Neurosci 164(1-2):3—5, 2011. 34.   13. Moreira TS et al: Central chemoreceptors and neural mechanisms of  cardiorespiratory control, Braz J Med Biol Res 44(9):883-889, 2011.   14. Ramirez JM et al: The role of spiking and bursting pacemakers in the B55  neuronal control of breathing, J Biol Phys 37(3):241-261, 2011.   15. Smith JC et al: Structural and functional architecture of respiratory 36.  networks in the mammalian brainstem, Philos Trans R Soc Lond B Biol Sci  364(1529):2577-2587, 2009. 37.   16. Spyer KM, Gourine AV: Chemosensory pathways in the brainstem  controlling cardiorespiratory activity, Philos Trans R Soc Lond B Biol Sci 38.  364(1529):2603-2610, 2009.   17. Landolfo F et al: Hering-Breuer reflex, lung volume and position in  prematurely born infants, Pediatr Pulmonol 43(8):767—771, 2008. 39.   18. Canning BJ: Anatomy and neurophysiology of the cough reflex, Chest  129:33s—47s, 2006. 2010.   19. Anand A, Srivastava N, Raj H: Effect of sublingual nitrate on respiratory 40.  reflexes arising from stimulation of juxta-pulmonary capillary (J) recep-  tors by i.v. lobeline and short duration exercise, Respir Physiol Neurobiol 41.    Hardie JA et al: Reference values for arterial blood gases in the elderly,  Chest 125(6):2053—2060, 2004.    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Clinical Manifestations of Pulmonary Alterations, 1248  Signs and Symptoms of Pulmonary Disease, 1248  Conditions Caused by Pulmonary Disease or Injury, 1251   Disorders of the Chest Wall and Pleura, 1253  Disorders of the Chest Wall, 1253  Pleural Abnormalities, 1254    Pulmonary disease is often classified as acute or chronic,  obstructive or restrictive, and infectious or noninfectious.  Because skillful and knowledgeable care plays a major role in  decreasing respiratory morbidity and mortality, the clinician  with a clear understanding of the pathophysiology of common  respiratory problems can greatly affect the outcome for each  individual.   Signs and Symptoms of Pulmonary Disease  Pulmonary disease is associated with many signs and symp-  toms and their specific characteristics often help in identifying    the underlying disorder. The most common are dyspnea and  cough. Others include abnormal sputum, hemoptysis, altered    Pulmonary Disorders, 1255  Restrictive Lung Disorders, 1255  Obstructive Pulmonary Disease, 1263  Respiratory Tract Infections, 1271  Viral Pneumonia, 1273  Pulmonary Vascular Disease, 1275  Malignancies of the Respiratory Tract, 1278    breathing patterns, hypoventilation and hyperventilation, cya-  nosis, clubbing of the digits, and chest pain.    Dyspnea  Dyspnea is a subjective experience of breathing discomfort  that is comprised of qualitatively distinct sensations that vary  in intensity. The experience derives from interactions among  multiple physiologic, psychologic, social, and environmental  factors, and it may induce secondary physiologic and behavioral  responses. It is often described as breathlessness, air hunger,  shortness of breath, increased work of breathing, chest tight-  ness, and preoccupation with breathing.! Dyspnea may be the  result of pulmonary disease or many other conditions, such as  pain, heart disease, trauma, and anxiety.   The severity of the experience of dyspnea may not directly  correlate with the severity of underlying disease.*’ Either    diffuse or focal disturbances of ventilation, gas exchange, or  ventilation-perfusion relationships can cause dyspnea, as can  increased work of breathing or diseases that damage lung tis-  sue (lung parenchyma). One proposed mechanism involves an  impaired sense of effort where the perceived work of breathing  is greater than the actual motor response generated. Stimulation  of many receptors can contribute to the sensation of dyspnea  including mechanoreceptors (the stretch receptors, irritant  receptors, and J-receptors), upper airway receptors, and central  and peripheral chemoreceptors that interact with the sensory  and motor cortex.*?   The more severe signs of dyspnea include flaring of the nos-  trils, use of accessory muscles of respiration, and retraction  (pulling back) of the intercostal spaces. In dyspnea caused by  parenchymal disease (e.g., pneumonia), retractions of tissue  between the ribs (subcostal and intercostal retractions) are  observed more often than supercostal retractions (retractions  of tissues above the ribs), which predominate in upper airway  obstruction. Retractions of any type are more commonly seen  in children or in adults who are thin and have poorly developed  thoracic musculature. Dyspnea can be quantified by the use of  ordinal rating scales or visual analog scales.’   Dyspnea can occur transiently or can become chronic.  The first episode commonly occurs with exercise and is called  dyspnea on exertion. Orthopnea is dyspnea that occurs when  an individual lies flat and is common in individuals with heart  failure. The recumbent position redistributes body water, causes  the abdominal contents to exert pressure on the diaphragm,  and decreases the efficiency of the respiratory muscles. Sitting  in a forward-leaning posture or supporting the upper body  on several pillows generally relieves orthopnea. Paroxysmal  nocturnal dyspnea (PND) occurs when individuals with heart  failure or lung disease wake up at night gasping for air and must  sit up or stand to relieve the dyspnea.    Cough  Cough is a protective reflex that helps clear the airways by an  explosive expiration. Inhaled particles, accumulated mucus,  inflammation, or the presence of a foreign body initiates the  cough reflex by stimulating irritant receptors in the airway.  There are few such receptors in the most distal bronchi and the  alveoli; thus it is possible for significant amounts of secretions  to accumulate in the distal respiratory tree without cough being  initiated. The cough reflex consists of inspiration, closure of the  glottis and vocal cords, contraction of the expiratory muscles,  and reopening of the glottis, causing a sudden, forceful expira-  tion that removes the offending matter. The effectiveness of the  cough depends on the depth of the inspiration and the degree  to which the airways narrow, increasing the velocity of expi-  ratory gas flow. Stimulation of cough receptors is transmitted  centrally through the vagus nerve, and central modulation of  the cough reflex can be influenced by opiates and serotonergic  agents.°” Cough occurs frequently in healthy individuals; how-  ever, those with an inability to cough effectively are at greater  risk for pneumonia.   Acute cough is cough that resolves within 2 to 3 weeks of  the onset of illness or resolves with treatment of the underlying    condition. It is most commonly the result of upper respiratory  tract infections, allergic rhinitis, acute bronchitis, pneumonia,  congestive heart failure, pulmonary embolus, or aspiration.  Chronic cough is defined as cough that has persisted for more  than 3 weeks, although some researchers have suggested that 7  or 8 weeks is a more appropriate timeframe because acute cough  and bronchial hyperreactivity can be prolonged in some cases  of viral infection. In nonsmokers, chronic cough is commonly  caused by postnasal drainage syndrome, nonasthmatic eosino-  philic bronchitis, asthma, gastroesophageal reflux disease, or  heightened cough reflex sensitivity. In smokers, chronic bron-  chitis is the most common cause of chronic cough, although  lung cancer must always be considered. Individuals taking  angiotensin-converting enzyme inhibitors for hypertension  may develop chronic cough that resolves with discontinuation  of the drug.    Changes in the amount, consistency, color, and odor of sputum  provide information about progression of disease and effec-  tiveness of therapy. The gross and microscopic appearances of  sputum enable the clinician to identify cellular debris or micro-  organisms that aid in diagnosis and choice of therapy.   Hemoptysis is the coughing up of blood or bloody secre-  tions. This is sometimes confused with hematemesis, which  is the vomiting of blood. Blood that is coughed up is usually  bright red, has an alkaline pH, and is mixed with frothy sputum.  Blood that is vomited is dark, has an acidic pH, and is mixed  with food particles.   Hemoptysis usually indicates infection or inflammation that  damages the bronchi (bronchitis, bronchiectasis) or the lung  parenchyma (pneumonia, tuberculosis, lung abscess). Other  causes include cancer and pulmonary infarction. The amount  and duration of bleeding provide important clues about its  source. Bronchoscopy, combined with chest computed tomog-  raphy (CT), is used to confirm the site of bleeding.’    Normal breathing (eupnea) is rhythmic and effortless. Ventila-  tory rate is 8 to 16 breaths per minute, and tidal volume ranges  from 400 to 800 ml. A short expiratory pause occurs with each  breath, and the individual takes an occasional deeper breath or  sigh. Sigh breaths, which help maintain normal lung function,  are usually 1.5 to 2 times the normal tidal volume and occur  approximately 10 to 12 times per hour.   The rate, depth, regularity, and effort of breathing undergo  characteristic alterations in response to physiologic and patho-  physiologic conditions. Patterns of breathing automatically  adjust to minimize the work of respiratory muscles. Strenuous  exercise or metabolic acidosis induces Kussmaul respirations  (hyperpnea). Kussmaul respirations are characterized by a  slightly increased ventilatory rate, very large tidal volume, and  no expiratory pause.   Labored breathing occurs whenever there is an increased  work of breathing, especially if the airways are obstructed,  as in chronic obstructive pulmonary disease (COPD). If the  large airways are obstructed, a slow ventilatory rate, increased    effort, prolonged inspiration or expiration, and stridor (high-  pitched sounds made during inspiration) or audible wheezing  (whistling sounds on expiration) are typical. In small airway  obstruction, like that seen in asthma and chronic obstructive  pulmonary disease, a rapid ventilatory rate, small tidal volume,  increased effort, prolonged expiration, and wheezing are often  present.   Restricted breathing is commonly caused by disorders such  as pulmonary fibrosis that stiffen the lungs or chest wall and  decrease compliance. Restricted breathing is characterized by  small tidal volumes and rapid ventilatory rate (tachypnea).   Shock and severe cerebral hypoxia (insufficient oxygen in  the brain) contribute to gasping respirations that consist of  irregular, quick inspirations with an expiratory pause. Anxiety  can cause sighing respirations that consist of irregular breathing  characterized by frequent, deep sighing inspirations.   Cheyne-Stokes respirations are characterized by alternat-  ing periods of deep and shallow breathing. Apnea lasting 15 to  60 seconds is followed by ventilations that increase in volume  until a peak is reached, after which ventilation (tidal volume)  decreases again to apnea. Cheyne-Stokes respirations result  from any condition that slows the blood flow to the brainstem,  which in turn slows impulses sending information to the respi-  ratory centers of the brainstem. Neurologic impairment above  the brainstem is also a contributing factor (see Table 17-4 and  Figure 17-1).    Hypoventilation is inadequate alveolar ventilation in relation  to metabolic demands. It is caused by alterations in pulmonary  mechanics or in the neurologic control of breathing such that  minute volume (tidal volume x respiratory rate) is reduced.  When alveolar ventilation is normal, carbon dioxide (CO;) is  removed from the lungs at the same rate at which it is produced  by cellular metabolism. This maintains arterial CO, pressure  (Paco) at normal levels (40 mmHg). With hypoventilation,  CO, removal does not keep up with CO, production and Paco,  increases, causing hypercapnia (Paco, greater than 44 mmHg).  (Table 34-2 contains the definition of gas partial pressure and  other pulmonary abbreviations.) This results in an increase in  hydrogen ion in the blood, termed respiratory acidosis, which  can affect the function of many tissues throughout the body.   Hypoventilation is often overlooked until it is severe  because breathing pattern and ventilatory rate may appear  normal. Blood gas analysis (i.e., measurement of the Paco, of  arterial blood) reveals the hypercapnia. Pronounced hypoven-  tilation can cause somnolence or disorientation. In addition,  alveolar hypoventilation with hypercapnia results in secondary  hypoxemia because the accumulation of alveolar CO) displaces  oxygen (see Hypercapnia, p. 1251).   Hyperventilation is alveolar ventilation that exceeds meta-  bolic demands. The lungs remove CO, at a faster rate than it is  produced by cellular metabolism, resulting in decreased Paco,  or hypocapnia (Paco, less than 36 mmHg). Hypocapnia results  in a respiratory alkalosis that also can interfere with tissue func-  tion. Like hypoventilation, hyperventilation can be determined  only by arterial blood gas analysis. Hyperventilation commonly    occurs with severe anxiety, acute head injury, and conditions  that cause insufficient oxygenation of the blood.   Cyanosis is a bluish discoloration of the skin and mucous  membranes caused by increasing amounts of desaturated or  reduced hemoglobin (which is bluish) in the blood. It gener-  ally develops when 5 g of hemoglobin is desaturated, regardless  of hemoglobin concentration. For example, if total hemoglobin  concentration is 15 g/dl of blood, 5 g/dl must be desaturated to  cause cyanosis. If total hemoglobin level is 11 g/dl, 5 g/dl must  still be desaturated for cyanosis to occur.   Peripheral cyanosis (slow blood circulation in fingers and toes)  is most often caused by poor circulation resulting from intense  peripheral vasoconstriction, like that seen in Raynaud’s disease,  cold environments, or severe stress. Peripheral cyanosis is best  seen in the nail beds. Central cyanosis is caused by decreased  arterial oxygenation (low Pao,) from pulmonary diseases or pul-  monary or cardiac right-to-left shunts. Central cyanosis is best  seen in buccal mucous membranes and lips.   Lack of cyanosis does not necessarily indicate that oxygen-  ation is normal. In adults, cyanosis is not evident until severe  hypoxemia is present and, therefore, is an insensitive indication  of respiratory failure. For example, severe anemia (inadequate  hemoglobin concentration) and carbon monoxide poisoning  (in which hemoglobin binds to carbon monoxide instead of  binding to oxygen) can result in inadequate oxygenation of tis-  sues without causing cyanosis. Individuals with polycythemia  (an abnormal increase in numbers of red blood cells), how-  ever, may have cyanosis when tissue oxygenation is adequate.  Because polycythemia causes hemoglobin concentration to be  greater than normal, 5 g/dl can be desaturated, causing cyano-  sis, without having much effect on oxygenation. Therefore, the  significance of cyanosis as a clinical finding must be interpreted  in relation to the underlying pathophysiology. If cyanosis is  suggested, the Pao, should be measured.    Clubbing is the selective bulbous enlargement of the end (distal  segment) of a digit (finger or toe) (Figure 35-1) whose severity  can be graded from 1 to 5 based on the extent of nail bed hyper-  trophy and the amount of changes in the nails themselves. It is  usually painless. Clubbing is commonly associated with diseases  that interfere with oxygenation, such as bronchiectasis, cystic  fibrosis, pulmonary fibrosis, lung abscess, and congenital heart  disease. It is rarely reversible with treatment of the underlying  pulmonary condition. It can sometimes be seen in individuals  with lung cancer even without hypoxemia, because of the effects  of inflammatory cytokines and growth factors (hypertrophic  osteoarthropathy).'°   Pain caused by pulmonary disorders originates in the pleurae,  airways, or chest wall.'! Pleural pain is the most common pain  caused by pulmonary disease and is usually sharp or stabbing  in character. Infection and inflammation of the parietal pleura  (pleuritis or pleurisy) cause pain when the pleurae stretch    FIGURE 35-1 Clubbing of Fingers Caused by Chronic Hypoxemia. (From  Seidel HM et al: Mosby’ guide to physical examination, ed 6, St Louis, 2006, Mosby.)    during inspiration. The pain is usually localized to a portion  of the chest wall, where a unique breath sound called a pleu-  ral friction rub may be heard over the painful area. Laughing  or coughing makes pleural pain worse. Pleural pain is also  common with pulmonary infarction (tissue death) caused by  pulmonary embolism and emanates from the area around the  infarction.   Pulmonary pain can be central chest pain that is pronounced  after coughing and occurs in individuals with infection and  inflammation of the trachea or bronchi (tracheitis or tracheo-  bronchitis). Central chest pain can be difficult to differentiate  from cardiac pain (see Chapter 32). High blood pressure in the  pulmonary circulation (pulmonary hypertension) can cause  pain during exercise that is often mistaken for cardiac pain  (angina pectoris).   Pain in the chest wall is muscle pain or rib pain. The com-  mon causes of chest wall pain are rib fractures and excessive  coughing, which make the muscles sore. Inflammation of the  costochondral junction (costochondritis) also can cause chest  wall pain. Chest wall pain can often be reproduced by pressing  on the sternum or ribs.   Hypercapnia, or increased CO, concentration in the arterial  blood (increased Paco), is caused by hypoventilation of the  alveoli.!? As discussed in Chapter 34, CO, is easily diffused  from the blood into the alveolar space; thus minute volume  (respiratory rate x tidal volume) determines not only alveolar  ventilation, but also Paco. Hypoventilation is often overlooked  because breathing pattern and ventilatory rate may appear nor-  mal; it is important to obtain blood gas analysis to determine  the severity of hypercapnia and resultant respiratory acidosis  (acid-base balance is described in Chapter 3).    There are many causes of hypercapnia.!* Most are a result of  a decreased drive to breathe or an inadequate ability to respond  to ventilatory stimulation. Causes include: (1) depression of the  respiratory center by drugs; (2) diseases of the medulla, including  infections of the central nervous system or trauma; (3) abnor-  malities of the spinal conducting pathways, as in spinal cord  disruption or poliomyelitis; (4) diseases of the neuromuscular  junction or of the respiratory muscles themselves, as in myasthe-  nia gravis or muscular dystrophy; (5) thoracic cage abnormali-  ties, as in chest injury or congenital deformity; (6) large airway  obstruction, as in tumors or sleep apnea; and (7) increased work  of breathing or physiologic dead space, as in emphysema.   Hypercapnia and the associated respiratory acidosis can  result in several important clinical manifestations. Of greatest  concern are electrolyte abnormalities that occur in response to  the low pH that may cause dysrhythmias. Individuals also may  have somnolence and even be in a coma because of changes  in intracranial pressure associated with high levels of arterial  carbon dioxide, which causes cerebral vasodilation. Alveolar  hypoventilation with increased alveolar carbon dioxide limits  the amount of alveolar oxygen available for diffusion into the  blood, leading to secondary hypoxemia.   Hypoxemia, or reduced oxygenation of arterial blood (reduced  Pao,), is caused by respiratory alterations, whereas hypoxia, or  reduced oxygenation of cells in tissues, may be caused by altera-  tions of other systems as well. Although hypoxemia can lead to  tissue hypoxia, tissue hypoxia can result from other abnormalities,  such as low cardiac output or cyanide poisoning.   Hypoxemia results from problems with one or more of the  major mechanisms of oxygenation:   a. Oxygen content of the inspired air (Fio,)  2. Ventilation of the alveoli  3. Diffusion of oxygen from the alveoli into the blood  a. Balance between alveolar ventilation and perfusion  (V/Q mismatch)  b. Diffusion of oxygen across the alveolocapillary  membrane   4. Perfusion of pulmonary capillaries  Table 35-1 lists some of the common clinical causes of these  problems.   The amount of oxygen in the alveoli is called the Pao, and is  dependent on two factors. The first factor is the presence of ade-  quate oxygen content of the inspired air. The amount of oxygen  in inspired air is expressed as the percentage or fraction of air  that is composed of oxygen, called the Fio,. The Fio, of air at  sea level is approximately 21% or 0.21. Anything that decreases  the Fio, (such as high altitude) decreases the Pao . The second  factor is the amount of alveolar minute ventilation (tidal vol-  ume X respiratory rate). Hypoventilation results in an increase  in Paco, and a decrease in Pao such that there is less oxygen  available in the alveoli for diffusion into the blood. This type  of hypoxemia can be completely corrected if alveolar ventila-  tion is improved by increases in the rate and depth of breathing.  Hypoventilation causes hypoxemia in unconscious persons; in   Lack of neurologic stimulation of the respiratory  center (oversedation, drug overdose,  neurologic damage)   Defects in chest wall mechanics (neuromuscular  disease, trauma, chest deformity, air trapping)    people with neurologic, muscular, or bone diseases that restrict  chest expansion; and in individuals who have COPD.   Diffusion of oxygen from the alveoli into the blood is also  dependent on two factors. The first is the balance between the  amount of air getting into alveoli (V) and the amount of blood  perfusing the capillaries around the alveoli (Q). An abnormal  ventilation-perfusion ratio (V/Q) is the most common cause of  hypoxemia (Figure 35-2). Normally, alveolocapillary lung units  receive almost equal amounts of ventilation and perfusion. The  normal V/Q is 0.8 to 0.9 because perfusion is somewhat greater  than ventilation in the lung bases and because some blood is  normally shunted to the bronchial circulation. V/Q mismatch  refers to an abnormal distribution of ventilation and perfusion.  Hypoxemia can be caused by inadequate ventilation of well-  perfused areas of the lung (low V/Q). Mismatching of this type,  called shunting, occurs in atelectasis, in asthma as a result of  bronchoconstriction, and in pulmonary edema and pneumonia  when alveoli are filled with fluid. When blood passes through  portions of the pulmonary capillary bed that receive no ventila-  tion, right-to-left shunt occurs, resulting in decreased systemic  Pao, and hypoxemia. Hypoxemia also can be caused by poor  perfusion of well-ventilated portions of the lung (high V/Q),  resulting in wasted ventilation. The most common cause of  high V/Q is a pulmonary embolus that impairs blood flow to  a segment of the lung. An area where alveoli are ventilated but  not perfused is termed alveolar dead space.   The second factor affecting diffusion of oxygen from the  alveoli into the blood is the alveolocapillary barrier. Diffusion  of oxygen through the alveolocapillary membrane is impaired  if the alveolocapillary membrane is thickened or the surface    FIGURE 35-2 Ventilation-Perfusion Abnormalities. (Data from Glenny RW:  Adv Physiol Educ 32[3]:192—195, 2008.)    area available for diffusion is decreased. Abnormal thickness, as  occurs with edema (tissue swelling) and fibrosis (formation of  fibrous lesions), increases the time required for diffusion across  the alveolocapillary membrane. If diffusion is slowed enough,  the oxygen in the alveolar gas (Pao,) and capillary blood does  not have time to equilibrate during the fraction of a second that  blood remains in the capillary. Destruction of alveoli, such as that  which occurs in emphysema, decreases the surface area available  for diffusion. Hypercapnia is rarely produced by impaired diffu-  sion, because carbon dioxide diffuses so easily from capillary to  alveolus that the individual with impaired diffusion would die  from hypoxemia before hypercapnia could occur.   Hypoxemia most often is associated with a compensa-  tory hyperventilation and resultant respiratory alkalosis  (i.e., decreased Paco, and increased pH). However, in individu-  als with associated ventilatory difficulties, hypoxemia may be  complicated by hypercapnia and respiratory acidosis. Hypox-  emia results in widespread tissue dysfunction and, when severe,  can lead to organ infarction. In addition, hypoxic pulmonary  vasoconstriction can contribute to increased pressures in the  pulmonary artery (pulmonary artery hypertension) and lead to  right-sided heart failure and cor pulmonale (see p. 1276). Clini-  cal manifestations of acute hypoxemia may include cyanosis,  confusion, tachycardia, edema, and decreased renal output.   Respiratory (lung) failure is defined as inadequate gas  exchange, that is, hypoxemia, in which Pao, is <50 mmHg,  or hypercapnia, in which Paco, is >50 mmHg with a pH of  <7.25. Respiratory failure can result from direct injury to the  lungs, airways, or chest wall or indirectly because of injury to  another body system, such as the brain or liver.!4 It can occur  in individuals who have an otherwise normal respiratory system    or in those with underlying chronic pulmonary disease. Most  pulmonary diseases can cause episodes of acute respiratory  failure. If the respiratory failure is primarily hypercapnic, it is  the result of inadequate alveolar ventilation (see Hypercapnia,  p. 1251) and the individual must receive ventilatory support,  such as with a bag-valve mask, noninvasive positive pressure  ventilation, or intubation and placement on mechanical ven-  tilation. If the respiratory failure is primarily hypoxemic, it is  the result of inadequate exchange of oxygen between the alveoli  and the capillaries (see Hypoxemia, p. 1251) and the individual  must receive supplemental oxygen therapy. Many individuals  have a combined hypercapnic and hypoxemic respiratory fail-  ure and require both kinds of support.   Respiratory failure is an important potential complication  of any major surgical procedure, especially those that involve  the central nervous system, thorax, or upper abdomen. Smok-  ers are at risk, particularly if they have preexisting lung disease.  Limited cardiac reserve, chronic renal failure, chronic hepatic  disease, and infection also increase the tendency to develop  postoperative respiratory failure. The most common postop-  erative pulmonary problems are atelectasis, pneumonia, pul-  monary edema, and pulmonary emboli (these conditions are  discussed later in this chapter).   Prevention of postoperative respiratory failure includes fre-  quent turning and position changes, deep breathing exercises,  and early ambulation to prevent atelectasis and accumulation  of secretions. Humidification of inspired air can help loosen  secretions. Incentive spirometry gives individuals immedi-  ate feedback about tidal volumes, which encourages them to  breathe deeply. Supplemental oxygen is given for hypoxemia,  and antibiotics are given as appropriate to treat infection. If  respiratory failure develops, the individual may require con-  ventional mechanical ventilation, high-frequency ventilation,  or extracorporeal membrane oxygenation.'°    There are many conditions that can affect the chest wall and/or  pleura and impact the function of the respiratory system. Chest  wall disorders primarily affect tidal volume and therefore result in  hypercapnia. Pleural diseases affect ventilation and oxygenation.   If the chest wall is deformed, traumatized, immobilized, or  made heavy by fat, the work of breathing is increased and ven-  tilation may be compromised because of a decrease in tidal  volume. The degree of ventilatory impairment depends on the  severity of the chest wall abnormality. Grossly obese individuals  are often dyspneic on exertion or when recumbent. Individu-  als with severe kyphoscoliosis (lateral bending and rotation of  the spinal column with distortion of the thoracic cage) often  have dyspnea on exertion that can progress to respiratory fail-  ure. Such individuals also are susceptible to lower respiratory  tract infections. Obesity and kyphoscoliosis are risk factors for  respiratory disease in individuals admitted to a hospital for  other problems, particularly those who require surgery. Other    FIGURE 35-3 Flail chest. Normal respiration: A, inspiration; B, expiration.  Paradoxical motion: C, inspiration, area of lung underlying unstable chest wall  sucks in on inspiration; D, expiration, unstable area balloons out. Note movement  of mediastinum toward opposite lung during inspiration.    musculoskeletal abnormalities that can impair ventilation are  ankylosing spondylitis and pectus excavatum (a deformity char-  acterized by depression of the sternum) (see Chapters 44 and  45, respectively). Pain from chest wall injury, surgery, or dis-  ease is also an important cause of restriction and decreased tidal  volume. This can cause significant hypoventilation, especially in  those with underlying lung disease.   Impairment of respiratory muscle function caused by  neuromuscular disease also can restrict the chest wall or  impair pulmonary function. Muscle weakness can result in  hypoventilation and hypercapnia, inability to remove secre-  tions, and hypoxemia. The most common cause of hospital  admission for individuals with neuromuscular diseases, such  as muscular dystrophy, myasthenia gravis, and Guillain-Barré  syndrome, is respiratory difficulty. (See Unit V for a more  complete discussion of these disorders.)   Trauma to the thorax or upper abdomen can restrict chest  expansion because of pain. Trauma to the chest also can cause  structural and mechanical changes that impair the ability of the  chest to expand normally. Flail chest results from the fracture  of several consecutive ribs in more than one place, or the frac-  ture of the sternum and several consecutive ribs. These multiple  fractures result in instability of a portion of the chest wall, caus-  ing paradoxical movement of the chest with breathing. During  the negative intrathoracic pressure of inspiration, the unstable  portion of the chest wall moves inward and during expiration it  moves outward, impairing movement of gas in and out of the  lungs (Figure 35-3). Flail chest is usually associated with signifi-  cant underlying lung contusion. The clinical manifestations of  flail chest are pain, dyspnea, unequal chest expansion, hypoven-  tilation, and hypoxemia. Treatment is internal fixation by con-  trolled mechanical ventilation until the chest wall has stabilized.   Chest wall restriction results in decreased tidal volume. An  increase in respiratory rate can temporarily compensate and    restore minute ventilation, but many individuals will eventually  progress to hypercapnic respiratory failure. Diagnosis of chest  restriction is made by pulmonary function testing (reduction  in forced vital capacity [FVC]), arterial blood gas measure-  ment (hypercapnia), and radiographs. Treatment is aimed at  any reversible underlying cause, but is otherwise supportive. In  severe cases, mechanical ventilation may be indicated.   Pneumothorax is the presence of air or gas in the pleural space  caused by a rupture in the visceral pleura (which surrounds the  lungs) or the parietal pleura and chest wall (see Chapter 34).  As air separates the visceral and parietal pleurae, it destroys the  negative pressure of the pleural space. This disrupts the state of  equilibrium that normally exists between elastic recoil forces of  the lung and chest wall. No longer held in check by the recoil  forces of the chest wall, the lung fulfills its tendency to recoil by  collapsing toward the hilum.   Primary (spontaneous) pneumothorax, which occurs unex-  pectedly in healthy individuals (usually men) between ages 20  and 40 years, is most often caused by the spontaneous rupture of  blebs (blister-like formations) on the visceral pleura, although  there may be underlying pleural disease with emphysema-like  changes.!° Approximately 10% of affected individuals havea sig-  nificant family history of primary pneumothorax that has been  linked to mutations in the folliculin gene (Birt-Hogg-Dubé-  syndrome), which influences cell-cell adhesion.!’ Bleb rupture  can occur during sleep, rest, or exercise. The ruptured bleb or  blebs are usually located in the apexes of the lungs. Secondary  (traumatic) pneumothorax can be caused by chest trauma, such  as a rib fracture, stab or bullet wounds, or a surgical procedure  that tears the pleura; rupture of a bleb or bulla (larger vesicle)  as occurs in COPD; or mechanical ventilation, particularly if it  includes positive end-expiratory pressure (PEEP).'® Iatrogenic  pneumothorax is most commonly caused by transthoracic  needle aspiration.”   Spontaneous and traumatic pneumothorax can present as  either open or tension. In open pneumothorax (communicating  pneumothorax), air pressure in the pleural space equals baro-  metric pressure because air that is drawn into the pleural space  during inspiration (through the damaged chest wall and parietal  pleura or through the lungs and damaged visceral pleura) is forced  back out during expiration. In tension pneumothorax, however,  the site of pleural rupture acts as a one-way valve, permitting air  to enter on inspiration, but preventing its escape by closing dur-  ing expiration. As more and more air enters the pleural space, air  pressure in the pneumothorax begins to exceed barometric pres-  sure. The pathophysiologic effects of tension pneumothorax are  life threatening. Air pressure in the pleural space pushes against  the already recoiled lung, causing compression atelectasis, and  against the mediastinum, compressing and displacing the heart  and great vessels (Figure 35-4).   Clinical manifestations of spontaneous or secondary pneu-  mothorax begin with sudden pleural pain, tachypnea, and pos-  sibly mild dyspnea. Manifestations depend on the size of the  pneumothorax. Physical examination may reveal absent or    FIGURE 35-4 Tension Pneumothorax. Air in the pleural space causes the  lung to collapse around the hilus and may shift trachea and mediastinal contents  (heart and great vessels) toward the other lung.    decreased breath sounds and hyperresonance to percussion  on the affected side. Diagnosis of pneumothorax is made with  chest radiographs, ultrasound, and CT. Tension pneumothorax  may be complicated by severe hypoxemia, tracheal deviation  away from the affected lung, and hypotension (low blood pres-  sure). Deterioration occurs rapidly and immediate treatment  is required. Pneumothorax is treated with insertion of a chest  tube that is attached to a water-seal drainage system with suc-  tion. After the pneumothorax is evacuated and the pleural rup-  ture is healed, the chest tube is removed. For individuals with  persistent air leaks, other interventions may be needed includ-  ing surgery, pleurodesis (instillation of a caustic substance,  such as talc, into the pleural space), or thoracoscopic surgical  techniques.?°    Pleural effusion is the presence of fluid in the pleural space.  The source of the fluid is usually blood vessels or lymphatic  vessels lying beneath either pleura, but occasionally an abscess  or other lesion may drain into the pleural space. Because the  pleura is a relatively permeable membrane, fluids that accumu-  late in the lung can cross into the pleural space. Pleural effusions  that enter the pleural space from the intact blood vessels can be  transudative or exudative. In transudative effusion, the fluid,  or transudate, is watery and diffuses out of the capillaries as a  result of disorders that increase intravascular hydrostatic pres-  sure or decrease capillary oncotic pressure. Examples are con-  gestive heart failure, in which venous and left atrial pressures are  increased, and liver or kidney disorders that cause hypoprotein-  emia. Hypoproteinemia decreases capillary oncotic pressure,  which promotes diffusion of water out of the capillaries. (This  mechanism is discussed in Chapter 3).   Exudative effusion is less watery and contains high con-  centrations of white blood cells and plasma proteins. Exuda-  tive effusion occurs in response to inflammation, infection, or  malignancy and involves inflammatory processes that increase  capillary permeability (see Chapter 7). When stimulated by  biochemical mediators of inflammation, junctions in the cap-  illary endothelium separate slightly, enabling leukocytes and  plasma proteins to migrate out into affected tissues. Other    Watery fluid that diffuses out of capillaries beneath the  pleurae (i.e., capillaries in lung or chest wall)    Fluid rich in proteins (leukocytes, plasma proteins of all  kinds; see Chapter 7) that migrates out of the capillaries    Detritus of infection (microorganisms, leukocytes, cellular  debris) dumped into the pleural space by blocked    Chyle (milky fluid containing lymph and fat droplets) that  is dumped by lymphatic vessels into the pleural space  instead of passing from the gastrointestinal tract to the  thoracic duct    Cardiovascular disease that causes high blood pressure; liver  or kidney disease that disrupts plasma protein production,  causing hypoproteinemia (decreased oncotic pressure in  the blood vessels)   Infection, inflammation, or malignancy of the pleurae that  stimulates mast cells to release biochemical mediators that  increase capillary permeability    *Note: The principles of diffusion are discussed in Chapter 1; mechanisms that increase capillary permeability and cause exudation of cells and    types of pleural effusion are characterized by the presence of  pus (empyema), blood (hemothorax), or chyle (chylothorax).  Mechanisms of pleural effusion are summarized in Table 35-2.   Small pleural effusions may not affect lung function and  remain undetected. Most will be removed by the lymphatic  system once the underlying condition is resolved. Dyspnea,  compression atelectasis with impaired ventilation, and pleural  pain are common. Mediastinal shift and cardiovascular mani-  festations occur in a large, rapidly developing effusion. Physical  examination reveals decreased breath sounds and dullness to  percussion on the affected side. A pleural friction rub can be  heard over areas of inflamed pleura.   Diagnosis is confirmed by chest x-ray and thoracentesis  (needle aspiration), which can determine the type of effusion  and provide symptomatic relief. If the effusion is large, drainage  usually requires the placement of a chest tube and surgical inter-  ventions may be needed to prevent recurrence of the effusion.”°   Empyema (infected pleural effusion) is the presence of pus in  the pleural space. It is thought to develop when the pulmonary  lymphatics become blocked, leading to an outpouring of contam-  inated lymphatic fluid into the pleural space. Empyema occurs  most commonly in older adults and children and usually develops  as a complication of pneumonia, surgery, trauma, or bronchial  obstruction from a tumor.?! Commonly documented infectious  microorganisms include Staphylococcus aureus, Escherichia coli,  anaerobic bacteria, and Klebsiella pneumoniae.   Individuals with empyema present clinically with cyanosis,  fever, tachycardia (rapid heart rate), cough, and pleural pain.  Breath sounds are decreased directly over the empyema. Diag-  nosis is made by chest radiographs, thoracentesis, and sputum  culture. Treatment for empyema includes the administration  of appropriate antimicrobials and drainage of the pleural space  with a chest tube. In severe cases, ultrasound-guided pleural    drainage, instillation of fibrinolytic agents, or deoxyribonucle-  ase (DNase) injected into the pleural space may be needed to  achieve adequate drainage.’   Restrictive lung disorders are characterized by decreased com-  pliance of lung tissue. This means that it takes more effort to  expand the lungs during inspiration, which increases the work  of breathing. Individuals with lung restriction complain of  dyspnea and have an increased respiratory rate and decreased  tidal volume. Pulmonary function testing reveals a decrease in  FVC. Restrictive lung diseases can cause ventilation and perfu-  sion mismatch and affect the alveolocapillary membrane, which  reduces the diffusion of oxygen from the alveoli into the blood  and results in hypoxemia. Some of the most common restrictive  lung diseases in adults are aspiration, atelectasis, bronchiectasis,  bronchiolitis, pulmonary fibrosis, inhalational disorders, pneu-  moconiosis, allergic alveolitis, pulmonary edema, and acute  respiratory distress syndrome.   Aspiration is the passage of fluid and solid particles into the  lung. It tends to occur in individuals whose normal swallow-  ing mechanism and cough reflex are impaired by a decreased  level of consciousness or central nervous system abnormali-  ties. Predisposing factors include altered level of conscious-  ness caused by substance abuse, sedation, or anesthesia; seizure  disorders; cerebrovascular accident; and neuromuscular dis-  orders that cause dysphagia. There is a risk of aspiration and  development of pneumonia in individuals who require enteral  feeding (through a nasogastric feeding tube).*° The right lung,  particularly the right lower lobe, is more susceptible to aspira-  tion than the left lung because the branching angle of the right    mainstem bronchus is straighter than the branching angle of  the left mainstem bronchus.   Aspiration of large food particles or gastric fluid with pH  of less than 2.5 has serious consequences. Solid food particles  can obstruct a bronchus, resulting in bronchial inflammation  and collapse of airways distal to the obstruction. If the aspi-  rated solid is not identified and removed by bronchoscopy, a  chronic, local inflammation develops that may lead to recur-  rent infection and bronchiectasis (permanent dilation of the  bronchus). Once the pathologic process has progressed to  bronchiectasis, surgical resection of the affected area is usually  required.   Aspiration of oral or pharyngeal secretions can lead to aspi-  ration pneumonia, especially if the oral cavity is colonized with  bacteria (e.g., individuals with poor dentition). Intubation of  the trachea also can cause aspiration and bacterial pneumonia.  Aspiration of acidic gastric fluid may cause severe pneumonitis.  Bronchial damage includes inflammation, loss of ciliary func-  tion, and bronchospasm. In the alveoli, acidic fluid damages the  alveolocapillary membrane. This allows plasma and blood cells  to move from capillaries into the alveoli, resulting in hemor-  rhagic pneumonitis. The lung becomes stiff and noncompliant  as surfactant production is disrupted, leading to further edema  and collapse. Hypoventilation may develop as this process pro-  gresses, and systematic complications, such as hypotension,  may occur.   Clinical manifestations of aspiration include the sudden  onset of choking and intractable cough with or without vomit-  ing, fever, dyspnea, and wheezing. Some individuals have no  symptoms acutely; instead they have recurrent lung infections,  chronic cough, or persistent wheezing over months and even  years.   Preventive measures for individuals at risk are more effec-  tive than treatment of known aspiration. The most important  preventive measures include use of a semirecumbent position,  surveillance of enteral feeding, use of promotility agents, and  avoidance of excessive sedation. Individuals being adminis-  tered general anesthetics should not receive food or fluid for  several hours before or after surgery. Antacids are sometimes  given to individuals at risk for aspiration to keep gastric pH  greater than 2.5. Individuals who have difficulty swallowing  are fed with extreme caution and positioned to minimize the  likelihood of aspiration. Nasogastric tubes, which often are  used to remove stomach contents and reduce the risk for aspi-  ration, also can cause aspiration, if fluid and particulate mat-  ter are regurgitated as the tube is being placed. For those who  suffer from swallowing difficulties, speech-language patholo-  gists can often improve swallowing abilities that may prevent  recurrence.   Treatment of aspiration, pneumonia, or pneumonitis  includes supplemental oxygen and may require mechanical ven-  tilation with positive end-expiratory pressure (PEEP). Fluids are  restricted to decrease blood volume and minimize pulmonary  edema. Corticosteroids may be administered during the first  72 hours after aspiration. Bacterial pneumonia may develop as  a complication of aspiration pneumonitis and must be treated  with broad-spectrum antibiotics.”4    Atelectasis is the collapse of lung tissue. There are three types of   or by fluid or air in the pleural space. Atelectasis at the   pressing on a portion of the lung, causing the alveoli to  collapse.   2. Absorption atelectasis results from gradual absorption  of air from obstructed or hypoventilated alveoli or from  inhalation of concentrated oxygen or anesthetic agents.   3. Surfactant impairment results from decreased produc-  tion or inactivation of surfactant, which is necessary to  reduce surface tension in the alveoli and thus prevent  lung collapse during expiration. Surfactant impairment  can occur because of premature birth, acute respiratory  distress syndrome, anesthesia, or mechanical ventilation.   Atelectasis tends to occur after surgery and with use of general   anesthesia.”° In addition, individuals are often in pain, breathe  shallowly, are reluctant to change position, and produce viscous  secretions that tend to pool in dependent portions of the lung  after surgical procedures, especially those involving the thorax  or upper abdomen.”°   pulmonary infection: dyspnea, cough, fever, and leukocytosis.  Prevention and treatment of postoperative atelectasis usually  include deep breathing exercises (often with the aid of an incen-  tive spirometer), frequent position changes, and early ambula-  tion. Deep breathing is beneficial because it (1) promotes the  ciliary clearance of secretions, (2) stabilizes the alveoli by redis-  tributing surfactant, and (3) permits collateral ventilation of the  alveoli through pores of Kohn in the alveolar septa. The pores of  Kohn, which open only during deep breathing, allow air to pass  from well-ventilated alveoli to obstructed alveoli, minimizing  their tendency to collapse and facilitating expectoration of the  bronchial obstruction (Figure 35-5).    Bronchiectasis is persistent abnormal dilation of the bronchi. It  usually occurs in conjunction with other respiratory conditions  that are associated with chronic bronchial inflammation, such  as obstruction of an airway with mucous plugs, atelectasis, aspi-  ration of a foreign body, infection, cystic fibrosis, tuberculosis,  congenital weakness of the bronchial wall, or impaired defense  mechanisms. Bronchiectasis is also associated with a number of  systemic disorders such as rheumatologic disease, inflammatory  bowel disease, and immunodeficiency syndromes (e.g., acquired  immunodeficiency syndrome [AIDS]).?” Chronic inflamma-  tion of the bronchi leads to destruction of elastic and muscular  components of their walls, bronchial lumen obstruction, trac-  tion from adjacent fibrosis, and permanent dilation. Bronchial  dilation (Figure 35-6) may be cylindrical (cylindrical bronchi-  ectasis), with symmetrically dilated airways, as can be seen after  pneumonia and is reversible; saccular (saccular bronchiectasis),  in which the bronchi become large and balloon-like; or varicose  (varicose bronchiectasis), in which constrictions and dilations    Low inspiratory volume High inspiratory volume  A (shallow breathing) (deep breathing)    FIGURE 35-5 Pores of Kohn. A, Absorption atelectasis caused by lack of collateral ventilation through pores of Kohn.  B, Restoration of collateral ventilation during deep breathing.    FIGURE 35-6 Bronchiectasis. A, Types of bronchiectasis. B, Left posterior oblique projection of a left bronchogram show-  ing cylindrical bronchiectasis affecting the entire lower lobe except for the superior segment. Few side branches fill. The basal  airways are crowded together, indicating volume loss of the lower lobe, a common feature in bronchiectasis. €, Cylindrical bron-  chiectasis. The dilated bronchi (A) and bronchioles (B) can be dissected almost to the pleural surface. (B from Hansell: /maging of  diseases of the chest, ed 5, St Louis, 2009, Mosby; € from Damjanov |, Linder J, editors: Anderson's pathology, ed 10, St Louis,  1996, Mosby.)    deform the bronchi, creating a bulbous appearance. In both  varicose and saccular bronchiectases, the smaller bronchial divi-  sions are plugged with secretions or obliterated by fibrosis. Large  anastomoses (connections) develop between the bronchial and  pulmonary blood vessels, increasing blood flow through the  bronchial circulation. These anastomoses are thought to cause  the hemoptysis experienced by individuals with bronchiectasis.  Airway damage leads to bronchospasm and copious produc-  tion of purulent mucus. Ventilation-perfusion abnormalities  develop and result in hypoxemia. In severe cases, minute ven-  tilation is also compromised and Paco, may become elevated.   The primary symptom of bronchiectasis is chronic produc-  tive cough, which may date back to a childhood illness or infec-  tion. The disease is commonly associated with recurrent lower  respiratory tract infections and expectoration of voluminous  amounts of foul-smelling purulent sputum (measured in cups).  If the individual is not receiving antibiotics, the sputum has a  foul odor. Clubbing of the fingers from chronic hypoxemia is  common. Hemoptysis can occur from mucosal inflammation  and necrosis and, in some instances, can be massive. Pulmo-  nary function studies show decreases in FVC and expiratory  flow rates. Diagnosis is usually confirmed by the use of high-  resolution CT. Bronchiectasis is treated with sputum culture  antibiotics, bronchodilators, anti-inflammatory drugs, chest  physiotherapy, and supplemental oxygen. In selected individu-  als with localized areas of involvement, surgery may be indicated  to remove the affected portion of the lung.”®    Bronchiolitis is diffuse inflammation of the small airways or  bronchioles. It is most common in children (see Chapter 36). In  adults it usually occurs with chronic bronchitis, but can occur  in otherwise healthy individuals in association with an upper  or lower airway viral infection (e.g., respiratory syncytial virus  [RSV]), or with inhalation of toxic gases. Atelectasis or emphy-  sematous destruction of the alveoli may develop distal to the  inflammatory lesion. Bronchiolitis is usually diffuse. The result-  ing decrease in the ventilation-perfusion ratio results in hypox-  emia. A decrease in minute ventilation with resulting carbon  dioxide retention also may occur as lung restriction worsens.   Clinical manifestations include a rapid ventilatory rate;  marked use of accessory muscles; low-grade fever; dry, non-  productive cough; and hyperinflated chest. If bronchiolitis is  caused by an inhalation injury, pulmonary edema occurs rap-  idly. Respiratory distress can develop within 24 to 72 hours with  severe hypoxia. Infiltrates can be seen on chest radiographs.”  A decrease in the ventilation-perfusion ratio results in hypox-  emia. Diagnosis is made by spirometry and bronchoscopy with  biopsy. Bronchiolitis is treated with appropriate antibiotics, ste-  roids, and chest physical therapy (humidified air, coughing and  deep breathing, postural drainage).   Bronchiolitis obliterans is a late-stage fibrotic process that  occludes the airways and causes permanent scarring of the  lungs. This process can occur in all causes of bronchiolitis, but is  most common after lung transplantation and is associated with  acute rejection and infection. Bronchiolitis obliterans can be  further complicated by the development of pneumonia (called    bronchiolitis obliterans organizing pneumonia [BOOP]) in  which the alveoli and bronchioles become filled with plugs of  connective tissue.*? This complication of lung transplant has  a high morbidity. Diagnosis is made by spirometry and bron-  choscopy with biopsy. Treatment includes corticosteroids and  other immunomodulatory agents.°!    Pulmonary fibrosis is an excessive amount of fibrous or con-  nective tissue in the lung. When no specific cause for the devel-  opment of fibrosis is known, it is called idiopathic pulmonary  fibrosis. Although fibrosis can complicate healing after active  pulmonary diseases, such as ARDS or tuberculosis, specific  causes most often include inhalation of harmful substances, such  as toxic gases, inorganic dusts, or organic dusts, and underlying  autoimmune systemic disorders, such as rheumatologic disease.  The fibrotic process results from chronic inflammation, alveo-  lar epithelialization, and myofibroblast proliferation. Fibrosis  causes a marked loss of lung compliance. The lung becomes  stiff and difficult to ventilate, and the diffusing capacity of the  alveolocapillary membrane may decrease, causing hypoxemia.  Diffuse pulmonary fibrosis has a poor prognosis.   Idiopathic Pulmonary Fibrosis. \diopathic pulmonary  fibrosis (IPF) is the most common idiopathic interstitial lung  disorder. It is more common in men than in women and most  cases occur after age 60. The median survival is only 2 to 4 years  after diagnosis. IPF is thought to result from multiple injuries at  different sites of the lung followed by aberrant repair.*” Chronic  inflammation and fibroproliferation of the interstitial lung tissue  occur around the alveoli with disruption of the alveolocapillary  basement membrane. This causes decreased oxygen diffusion  across the alveolocapillary membrane and hypoxemia. As the  disease progresses decreased lung compliance leads to increased  work of breathing, decreased tidal volume, and resultant  hypoventilation with hypercapnia. Acute exacerbations of IPF  can occur with rapid decompensation and a death rate as high  as 50%.°° The primary symptom of IPF is increasing dyspnea on  exertion; examination reveals diffuse inspiratory crackles and  diagnosis is confirmed by pulmonary function testing (decreased  FVC), high-resolution CT, and lung biopsy. Treatment with  corticosteroids alone causes remission in approximately 50%  of individuals. Combined treatment with cytotoxic drugs  has a higher success rate, but also higher toxicity. Newer  therapies include antifibrotic drugs (such as N-acetylcysteine  and pirfenidone), interferon, and anticoagulation. Selected  individuals may benefit from lung transplantation.*#   Exposure to Toxic Gases. Inhalation of gaseous irritants  can cause significant respiratory dysfunction. Commonly  encountered toxic gases include ammonia, hydrogen chloride,  sulfur dioxide, chlorine, phosgene, and nitrogen dioxide.  Inhalation injuries in burns can include toxic gases from  household or industrial combustants, heat, and smoke particles.  Inhaled toxic particles cause damage to the airway epithelium,  cilia, and alveoli. There is increased mucus secretion, promotion  of inflammation, and mucosal and pulmonary edema.  Surfactant and other protective buffers and antioxidants are  inactivated.°° The cellular effects of toxic gases are described in    Chapter 2. Acute toxic inhalation is frequently complicated by  the development of ARDS and pneumonia. Initial symptoms  include burning of the eyes, nose, and throat; coughing; chest  tightness; and dyspnea. Hypoxemia is common. Treatment  includes supplemental oxygen, mechanical ventilation with  PEEP, and support of the cardiovascular system. Corticosteroids  sometimes are used, although their effectiveness has not been  well documented. Most individuals respond quickly to therapy.  Some, however, may improve initially and then deteriorate as a  result of bronchiectasis or bronchiolitis.   Prolonged exposure to high concentrations of supplemen-  tal oxygen can result in a relatively rare iatrogenic condition  known as oxygen toxicity. The basic underlying mechanism  of injury is a severe inflammatory response mediated primarily  by oxygen free radicals. The result is damage to alveolocapillary  membranes, disruption of surfactant production, interstitial  and alveolar edema, and decrease in compliance.*° Treatment  involves ventilatory support and reduction of inspired oxygen  concentration to less than 60%, as soon as tolerated.   Pneumoconiosis. Pneumoconiosis represents any change in  the lung caused by inhalation of inorganic dust particles, which  usually occurs in the workplace. As in all cases of environmentally  acquired lung disease, the individual’s history of exposure  is important in determining the diagnosis. Pneumoconiosis  often occurs after years of exposure to the offending dust with  progressive fibrosis of lung tissue.   The dusts of silica, asbestos, and coal are the most com-  mon causes of pneumoconiosis. Others include talc, fiber-  glass, clays, mica, slate, cement, cadmium, beryllium, tungsten,  cobalt, aluminum, and iron. Deposition of these materials in  the lungs cause the release of proinflammatory cytokines (e.g.,  interleukin-1-beta). This leads to chronic inflammation with  scarring of the alveolocapillary membrane, resulting in pulmo-  nary fibrosis and progressive pulmonary deterioration. Clini-  cal manifestations with advancement of disease may include  cough, sputum production, dyspnea, decreased lung volumes,  and hypoxemia. In most cases, diagnosis is made by performing  chest x-ray or CT and by obtaining careful occupational his-  tory.°’ Treatment is usually palliative and focuses on prevent-  ing further exposure and improving working conditions, along  with pulmonary rehabilitation and management of associated  hypoxemia and bronchospasm.   Silicosis is a type of pneumoconiosis resulting from the  inhalation of free silica (silicon dioxide) and silica-containing  compounds as occurs in mining and industries involved with  the extraction and processing of ores; preparation and use of  sand; and manufacture of pipe, building, and roofing mate-  rials. Silica exposure activates innate and adaptive immune  mechanisms, and triggers inflammation with subsequent fibro-  sis.°° Acute inflammation contributes to bronchospasm and  wheezing. Release of proteolytic enzymes and toxic oxygen free  radicals increases the risk for lung cancer. Exposed individu-  als may remain asymptomatic long after the nodules are visible  on chest radiography. When clinical manifestations do appear,  they include cough and dyspnea. There is no curative treatment  for the disease, although corticosteroids may produce some  improvement in the early, more acute stages.    Coal worker pneumoconiosis (coal miner lung, black  lung) is caused by coal dust deposits in the lung. Although  coal dust itself is relatively well tolerated by the lung, it is fre-  quently inhaled as a mixture of coal, silica, and quartz, which  is strongly inflammatory. Its mild form is asymptomatic,  except for possible chronic bronchitis. Its advanced form  manifests as severe pulmonary fibrosis. Individuals usually  are seen with a productive cough and wheezing. Symptoms  are more severe with advanced disease and mimic those of  chronic bronchitis and emphysema.’ Diagnosis is made by  obtaining a history of exposure and observing chest radio-  graphs for characteristic signs. There is no specific treatment  for coal worker pneumoconiosis. Individuals with the mild  form of the disease usually have a favorable prognosis. Those  with more complicated forms often develop marked cardio-  pulmonary dysfunction.   Asbestos exposure affects not only factory workers but also  individuals who live in areas of asbestos emission. Asbestos  exposure can result in a type of pulmonary fibrosis called asbes-  tosis, but can also cause lung cancer, mesothelioma (cancer of  the pleura), or pleural plaques, especially in those also exposed  to cigarette smoke.*”   Asbestosis is caused by inhalation of hydrous silicates of var-  ious metals in fibrous form. Asbestos fibers cause inflammation  and alveolitis. Activated macrophages release toxic oxygen free  radicals and cause cellular apoptosis, leading to both fibrosis  and malignancy. The most prominent clinical manifestations of  asbestosis with fibrosis are dyspnea on exertion, a nonproduc-  tive cough, diffuse inspiratory crackles on examination, hypox-  emia, and decreased lung volume. Progressive disease may take  years and leads to respiratory failure and cardiac complications.  Diagnosis is made by chest x-ray, pulmonary function testing,  and CT. Therapy is supportive.   Hypersensitivity Pheumonitis. Hypersensitivity pneumonitis  (extrinsic allergic alveolitis) is an allergic, inflammatory disease  of the lungs caused by inhalation of organic particles or fumes.  Many allergens (antigens) can cause this disorder, including  grains, silage, bird droppings or feathers, wood dust (particularly  redwood and maple), cork dust, animal pelts, coffee beans, fish  meal, mushroom compost, grain molds, mists from standing  water, and fumes from paints and resins. A type III immune  response (see Chapter 9) is initiated by alveolar macrophages  and results in immunoglobulin G (IgG) antibody production.  Continued exposure results in a type IV cellular immune  activation. The inflammatory response causes pneumonitis.*!  Granuloma formation is common. Lung capacity and  alveolocapillary diffusion are reduced. A genetic predisposition  may increase the risk for this disease.   Allergic alveolitis can be acute, subacute, or chronic. The  acute form causes a fever, cough, dyspnea, and chills a few hours  after exposure that resolve without treatment in 1 to 3 days.  With continued exposure, the disease becomes chronic and pul-  monary fibrosis develops. (The mechanisms of hypersensitivity  reactions are discussed in Chapter 9.) Chronic allergic alveoli-  tis causes weight loss, fever, fatigue, and gradually progressive  respiratory failure. Diagnosis is made by obtaining a history of  allergen exposure and by performing serum antibody testing,    Movement of fluid and plasma  proteins from capillary to  interstitial space (alveolar septum)  and alveoli    chest x-ray, bronchoscopy, CT, and in some cases lung biopsy.*”  Treatment consists of avoidance of the offending agent and  corticosteroid administration.    Several systemic diseases affect the airways, pleurae, or lung  parenchyma, causing fibrosis, vasculitis, pulmonary hemor-  rhage, or granuloma formation. Clinical manifestations of  lung involvement are usually nonspecific, and the diagnosis is  based on involvement of other organs. There is usually no spe-  cific treatment, although corticosteroids often are used. Some  of the systemic diseases affecting the lung are granulomatous  disorders such as sarcoidosis, Wegener granulomatosis, lym-  phomatoid granulomatosis, and eosinophilic granuloma;  connective tissue diseases such as rheumatoid arthritis, sys-  temic lupus erythematosus, scleroderma, polymyositis or der-  matomyositis, Sjogren syndrome, and polyarteritis nodosa;  angioimmunoblastic or immunoblastic lymphadenopathy  (a disease of the lymph nodes); cystic fibrosis (see Chapter  36); and Goodpasture syndrome (a pulmonary and renal  disorder).    Pulmonary edema is excess water in the lung. The normal  lung contains very little fluid. It is kept dry by lymphatic  drainage and a balance among capillary hydrostatic pressure,  capillary oncotic pressure, and capillary permeability. In addi-  tion, surfactant lining the alveoli repels water, keeping fluid  from entering the alveoli. Predisposing factors for pulmonary  edema include heart disease, ARDS, and inhalation of toxic  gases. The pathogenesis of pulmonary edema is illustrated in  Figure 35-7.   The most common cause of pulmonary edema is left-sided  heart disease (see Chapter 32). When the left ventricle fails,    filling pressures on the left side of the heart increase and cause  a concomitant increase in pulmonary capillary hydrostatic  pressure. When the hydrostatic pressure exceeds oncotic pres-  sure, fluid moves into the interstitium, or interstitial space  (the space within the alveolar septum between alveolus and  capillary). Fluid moves to the lymphatic vessels and is then  removed from the lung. When the flow of fluid out of the  capillaries exceeds the lymphatic system’s ability to remove it,  pulmonary edema develops. Pulmonary edema usually begins  to develop at a pulmonary capillary wedge pressure or left  atrial pressure of 20 mmHg. If the capillary oncotic pressure  is decreased for any reason (e.g., anemia or decreased levels  of plasma proteins), pulmonary edema develops at a lower  hydrostatic pressure.   Another cause of pulmonary edema is capillary injury that  increases capillary permeability. Capillary injury causes edema  in cases of adult respiratory distress syndrome (ARDS) or inha-  lation of toxic gases, such as ammonia. Capillary injury causes  water and plasma proteins to leak out of the capillary and move  into the interstitium. When plasma proteins move into the lung  interstitium, they increase the interstitial oncotic pressure, which  is usually very low. As the interstitial oncotic pressure begins to  equal capillary oncotic pressure, water moves out of the capil-  lary and into the lung. (Mechanisms of edema are discussed in  Chapter 3.)   Pulmonary edema also can result from obstruction of the  lymphatic system. Drainage can be blocked by compression of  lymphatic vessels caused by edema, tumors, and fibrotic tis-  sue or by increased systemic venous pressure that elevates the  hydrostatic pressure of the large pulmonary veins into which  the pulmonary lymphatic system drains. This can happen in  left-sided heart failure.   Postobstructive pulmonary edema (POPE, or negative pres-  sure pulmonary edema) is a rare life-threatening complication    that can occur after relief of upper airway obstruction (e.g.,  postextubation laryngospasm after anesthesia, epiglottitis,  laryngeal tumor, or obstructive tonsils). Attempted inspiration  against an occluded airway creates excessive intrathoracic nega-  tive pressure, causing increased venous return and blood flow  to the right side of the heart and decreased outflow from the left  side of the heart from the increased afterload. This combination  of events causes increased pulmonary blood volume and venous  pressure and leads to pulmonary edema.**   Clinical manifestations of pulmonary edema include dys-  pnea, orthopnea, hypoxemia, and increased work of breathing.  Physical examination may reveal inspiratory crackles (rales),  dullness to percussion over the lung bases, and evidence of ven-  tricular dilation (S; gallop and cardiomegaly). In severe edema,  pink, frothy sputum is expectorated, hypoxemia worsens, and  hypoventilation with hypercapnia may develop.   The treatment of pulmonary edema depends on its cause. If  the edema is caused by increased hydrostatic pressure result-  ing from heart failure, therapy is geared toward improving  cardiac output and volume status with diuretics, vasodilators,  and drugs that improve the contraction of the heart muscle. If  edema is the result of increased capillary permeability resulting  from injury, the treatment is focused on removing the offend-  ing agent and supportive therapy to maintain adequate oxygen-  ation, ventilation, and circulation. POPE is treated with positive  end-expiratory pressure ventilation. Individuals with any type  of pulmonary edema require supplemental oxygen. Mechanical  ventilation may be needed if edema significantly impairs venti-  lation and oxygenation.    Acute Lung Injury/Acute Respiratory Distress Syndrome  Acute lung injury (ALI)/acute respiratory distress syndrome  (ARDS) represents a spectrum of acute lung inflammation and  diffuse alveolocapillary injury. In the United States, ALI/ARDS  is estimated at 64 to 78 cases per 100,000 people.** Advances in  therapy have decreased the overall death rate to approximately  42% to 47%, although older people and those who have severe  infections or are immunocompromised continue to have a  much higher mortality.*? Most survivors have almost normal  lung function 1 year after the acute illness, but may have other  health problems, including neurocognitive disorders up to  5 years later.*° The most common predisposing factors for  ARDS are genetic factors, sepsis, and multiple trauma (espe-  cially when multiple transfusions are received); however,  there are many other causes, including pneumonia, burns,  aspiration, cardiopulmonary bypass surgery, pancreatitis,  drug overdose, smoke or noxious gas inhalation, oxygen  toxicity, radiation therapy, and disseminated intravascular  coagulation.*7*°   PATHOPHYSIOLOGY. All disorders that result in ARDS cause  acute injury to the alveolocapillary membrane producing  massive pulmonary inflammation, increased capillary per-  meability, severe pulmonary edema, shunting, V/Q mis-  match, and hypoxemia. The alveolocapillary injury can occur  directly, as with the aspiration of highly acidic gastric con-  tents or the inhalation of toxic gases; or indirectly, as from  circulating inflammatory mediators released in response to    systemic disorders, such as sepsis and trauma. Lung inflam-  mation and injury damages the alveolar epithelium and the  vascular endothelium. Because the pulmonary edema is not  secondary to heart failure, ARDS is often referred to as non-  cardiogenic pulmonary edema. ARDS progresses through three  overlapping phases characterized by histologic changes in the  lung: exudative (inflammatory), proliferative, and fibrotic  (Figure 35-8).   Exudative (Inflammatory) Phase (Within 72 Hours). The  initial lung injury damages the alveolocapillary membrane.  Lung injury activates neutrophils, platelets, macrophages,  lung epithelial and endothelial cells, and uncontrolled  inflammation. Inflammatory mediators include complement,  cytokines, arachidonic acid metabolites, platelet-activating  factor, reactive oxygen species, and other mediators (specifically  tumor necrosis factor [TNF], interleukin-1 [IL-1], and IL-6).*?  Activated complement factors and platelet aggregation result  in intravascular microthrombus formation and further damage  to lung capillaries.*° In ARDS caused by sepsis, bacterial toxins  are recognized by the CD14 receptors on macrophages and  lead to chemotaxis of large numbers of neutrophils to the  lungs. A cascade of inflammatory mediators is released by the  macrophages, including TNF, IL-1, alpha and beta chemokines,  and other interleukins.   The role of neutrophils is central to the development and  progression of ARDS. Activated neutrophils release a battery  of harmful inflammatory mediators, among them proteolytic  enzymes, oxygen free radicals (superoxide radicals, hydrogen  peroxide, hydroxyl radicals), arachidonic acid metabolites  (prostaglandins, thromboxanes, leukotrienes), and_platelet-  activating factor. These mediators cause extensive damage to  the alveolocapillary membrane and greatly increase capillary  membrane permeability. Increased capillary permeability, a  hallmark of ARDS, allows fluids, proteins, and blood cells to  leak from the capillary bed into the pulmonary interstitium and  alveoli (hemorrhagic exudate). The resulting pulmonary edema  and hemorrhage severely reduce lung compliance and impair  alveolar ventilation (Figure 35-9).   Mediators released by neutrophils, and to a certain extent by  macrophages, also cause pulmonary vasoconstriction. Because  vasoconstriction occurs more in some vascular beds than others,  blood flow to selected areas of the lungs is decreased, resulting in  V/Q mismatching. Pulmonary hypertension occurs early in the  course of the disease secondary to vasoconstriction. Thrombi  composed of aggregated neutrophils, macrophages, platelets,  and fibrin are formed.   Surfactant is inactivated, and its production by type I alveo-  lar cells is impaired as alveoli and respiratory bronchioles fill  with fluid or collapse.°! The lungs become less compliant, the  work of breathing increases, ventilation of alveoli decreases,  and hypercapnia develops.   Proliferative Phase (4 to 21 Days). Within 1 to 3 weeks after  the initial lung injury, there is resolution of the pulmonary  edema and proliferation of type II pneumocytes, fibroblasts,  and myofibroblasts. The intra-alveolar hemorrhagic exudate  becomes a cellular granulation tissue appearing as hyaline  membranes and there is progressive hypoxemia.    Neutrophil aggregation and release of mediators  (ROS, proteolytic enzymes, cytokines, PAF)    Pulmonary edema and  hemorrhage with severe  impairment of alveolar  ventilation  (Exudative phase)    Proliferation of type Il pneumocytes,  fibroblasts, and myofibroblasts  Formation of hyaline membranes    Progressive fibrosis and tissue remodeling  (destruction of alveoli and bronchioles)  (Fibrotic phase)    FIGURE 35-8 Pathogenesis of Acute Respiratory Distress Syndrome (ARDS). /L-7, Interleukin-1; /L-6, interleukin-6;  PAF platelet-activating factor; RBCs, red blood cells; ROS, reactive oxygen species; 7NF tumor necrosis factor.    Fibrotic Phase (14 to 21 Days). About 2 to 3 weeks  after the initial injury, remodeling and fibrosis occur. The  fibrosis progressively obliterates the alveoli, respiratory  bronchioles, and interstitium, leading to a decrease in  functional residual capacity (FRC) and continuing V/Q  mismatch with severe right-to-left shunt. The result of this  overwhelming inflammatory response by the lungs is acute  respiratory failure.    The same chemical mediators responsible for the alveolo-  capillary damage of ARDS often cause inflammation, endothe-  lial damage, and capillary permeability throughout the body,  resulting in the systemic inflammatory response syndrome  (SIRS). SIRS then leads to multiple organ dysfunction syn-  drome (MODS). In fact, death may not be caused by respiratory  failure alone, but by MODS associated with ARDS. (MODS is  discussed in Chapter 48.)    FIGURE 35-9 Acute Respiratory Distress Syndrome (ARDS). Cross-  sectional view of alveoli in ARDS. (Modified from Des Jardins T, Burton GG: Clinical  manifestations and assessment of respiratory disease, ed 3, St Louis, 1995, Mosby.)    CLINICAL MANIFESTATIONS. The clinical manifestations of ARDS  are progressive as follows:    Dyspnea and hypoxemia with poor response to oxygen  supplementation  J  Hyperventilation and respiratory alkalosis  J  Decreased tissue perfusion, metabolic acidosis, and organ  dysfunction  J  Increased work of breathing, decreased tidal volume, and  hypoventilation  1  Hypercapnia, respiratory acidosis, and worsening hypoxemia  d,  Decreased cardiac output, hypotension, and death    The new Berlin definition of ARDS provides categories of  severity based on hypoxemia: mild (200 mmHg < PaO,/FIO, <  300 mmHg), moderate (100 mmHg < PaO,/FIO, < 200 mmHg),  and severe (PaO,/FIO; < 100 mm Hg).°!*   Worsening hypoxemia and hypercapnia lead to respiratory  failure. Decreased oxygen delivery to tissues results in metabolic  acidosis and organ dysfunction (e.g., decreased urine output  and a decline in cognitive functioning). Decreased cardiac out-  put and hypotension eventually lead to death.   EVALUATION AND TREATMENT. Diagnosis is made on the basis of  a history of lung injury, physical examination, analysis of arte-  rial blood gases, and chest radiographs. ALI/ARDS is defined as:  (1) the acute onset of bilateral infiltrates on chest radiograph,  (2) a low ratio of partial pressure of arterial oxygen to the frac-  tion of inhaled oxygen, and (3) the absence of clinical evidence of  left atrial hypertension.” Initial physical examination may show  fine inspiratory crackles. Over the first 24 to 48 hours after injury,  interstitial and alveolar infiltrates appear on chest radiographs.  Serum biomarkers, such as TNF, brain natriuretic peptide (BNP),  IL-6 and IL-8, and surfactant proteins, are being studied.°?    Treatment strategies include early detection and manage-  ment of contributing etiologies, supportive therapy to prevent  progression of lung injury, and prevention of complications such  as pneumonia and stress ulcer.**°° Traditional therapy includes  mechanical ventilation with PEEP and high oxygen concentra-  tions. Alternative modalities of ventilation are being evaluated,  including low-volume ventilation, noninvasive positive-pressure  ventilation, permissive hypercapnia, prone positioning, extra-  corporeal gas exchange, and partial liquid ventilation; some of  these methods have shown reductions in death rates.“*   Many studies are investigating new ways to prevent or treat  ARDS.°*° Although recombinant human activated protein C was  initially found to improve outcomes in individuals with shock and  ARDS, more recent reviews found it to have no effect on mortal-  ity and the drug was removed from the market.°” Prophylactic  immunotherapy, antibodies against endotoxins, antioxidants,  surfactant replacement, nitric oxide inhalation, and inhibition  of various inflammatory mediators are among other possibilities  being tested. High-dose corticosteroid administration is no lon-  ger recommended, but low-dose therapy improves outcomes.”®    Obstructive pulmonary disease is characterized by airway  obstruction that is worse with expiration. More force (i.e., use  of accessory muscles of expiration) or more time is required to  expire a given volume of air and emptying of the lungs is slowed.  The unifying symptom of obstructive pulmonary disease is  dyspnea; the unifying sign is wheezing. Individuals have an  increased work of breathing, ventilation-perfusion mismatch-  ing, and a decreased forced expiratory volume in one second  (FEV,). The most common obstructive diseases are asthma,  chronic bronchitis, and emphysema. Because many individu-  als have chronic bronchitis with emphysema, these diseases  together are often called COPD.    Asthma is a chronic inflammatory disorder of the bronchial  mucosa that causes bronchial hyperresponsiveness, constric-  tion of the airways, and variable airflow obstruction that is  reversible.’ Asthma occurs at all ages, with approximately half  of all cases developing during childhood (see Chapter 36) and  another third before age 40. In the United States, it is estimated  that 24.6 million people have asthma and the prevalence con-  tinues to increase. Death rates are highest for adult females,  black persons, and adults older than 65.   Asthma is most commonly a familial disorder and more than  100 genes have been identified that may play a role in the suscep-  tibility and pathogenesis of asthma, including those that influ-  ence the production of IL-4, IL-5, and IL-13; IgE; eosinophils;  mast cells; adrenergic receptors; leukotrienes; nitric oxide; and  transmembrane proteins in the endoplasmic reticulum.°! Spe-  cific gene expression may impart associated phenotypes, such  as inflammation, sensitization to allergens, airway fibroblasts,  airway remodeling, and responsiveness to asthma therapies®”°?  (see Chapter 36, p. 1309, for What’s New? Asthma Phenotypes).  Other risk factors include allergen exposure; urban residence;  exposure to air pollution, tobacco smoke, and environmental    tobacco smoke; recurrent respiratory tract viral infections;  esophageal reflux; and obesity.°”°* These factors cause epi-  genetic changes that influence the function of asthma suscep-  tibility genes.°°°” Exposure to high levels of certain allergens  during childhood increases the risk for asthma. Furthermore,  decreased exposure to certain infectious organisms appears to  create an immunologic imbalance that favors the development  of allergy and asthma in some individuals. This complex rela-  tionship has been called the hygiene hypothesis (see the Asthma  section on p. 1308 in Chapter 36 for more detail).   PATHOPHYSIOLOGY. Airway epithelial exposure to antigen initi-  ates both an innate and an adaptive immune response in sen-  sitized individuals (see Chapter 9).° Many cells and cellular  elements contribute to the persistent inflammation of the bron-  chial mucosa and hyperresponsiveness of the airways, including  macrophages (dendritic cells), T helper 2 (Th2) lymphocytes,  B lymphocytes, mast cells, neutrophils, eosinophils, and baso-  phils. There is both an immediate (early asthmatic response)  and a late (delayed) response.   During the early asthmatic response, antigen exposure to the  bronchial mucosa activates dendritic cells (antigen-presenting  cells) to present the antigen to CD4+ T cells, which differentiate  into Th2 cells (see Chapter 9). These Th2 cells release numer-  ous cytokines including IL-4, IL-5, IL-8, IL-13, IL-17, and  IL-22. IL-4 stimulates B-cell activation, proliferation, and pro-  duction of antigen-specific IgE. IL-5 stimulates the activation,  migration, and proliferation of eosinophils, which cause direct  tissue injury and release of toxic neuropeptides that contrib-  ute to increased bronchial hyperresponsiveness, fibroblast pro-  liferation, epithelial injury, and airway scarring. IL-8 activates  neutrophils that contribute to a more exaggerated inflamma-  tory response. IL-13 impairs mucociliary clearance, enhances  fibroblast secretion, and contributes to bronchoconstriction  and airway remodeling.”” IL-17 increases neutrophilic inflam-  mation and IL-22 stimulates airway epithelial cells, which play  an important role in stimulating further innate and adaptive  immune responses.’!)72   The Fc portion of preformed IgE binds to receptors on the  surface of mast cells. Once bound to antigen, the IgE causes the  mast cells to degranulate, releasing a large number of inflamma-  tory mediators’? (see Figure 7-11 for additional details regard-  ing mast cells). Together these mediators cause vasodilation,  increased capillary permeability, mucosal edema, bronchial  smooth muscle contraction (bronchospasm), and tenacious  mucus secretion from mucosal goblet cells with narrowing of  the airways and obstruction to airflow” (Figures 35-10, 35-11,  and 35-12).   The late asthmatic response begins 4 to 8 hours after the early  response. Chemotactic recruitment of lymphocytes, eosino-  phils, and neutrophils during the acute response causes a latent  release of inflammatory mediators, again inciting broncho-  spasm, edema, and mucus secretion with obstruction to airflow.  Synthesis of leukotrienes contributes to prolonged smooth  muscle contraction. Eosinophil mediators cause direct tissue  injury with fibroblast proliferation and airway scarring. Release  of toxic neuropeptides contribute to increased bronchial hyper-  responsiveness. Damage to ciliated epithelial cells contributes    of alveoli  FIGURE 35-10 Bronchial Asthma. Thick mucus, mucosal edema, and smooth  muscle spasm cause obstruction of small airways; breathing becomes labored and  expiration is difficult. (Modified from Des Jardins T, Burton GG: Clinical manifesta-  tions and assessment of respiratory disease, ed 3, St Louis, 1995, Mosby.)    to impaired mucociliary function with accumulation of mucus  and cellular debris forming plugs in the airways (increased syn-  thesis of nitric oxide contributes to oxidative injury and chronic  inflammation).’* A decrease in the number or function of  T regulatory (Treg) cells are associated with asthma.°’ Untreated  inflammation can lead to long-term airway damage that is irre-  versible, known as airway remodeling (subepithelial fibrosis,  smooth muscle and mucous gland hypertrophy).’°   Airway obstruction increases resistance to airflow and  decreases flow rates, especially expiratory flow. Impaired expi-  ration causes air trapping, hyperinflation distal to obstructions  and increased work of breathing. Changes in resistance to air-  flow are not uniform throughout the lungs and the distribu-  tion of inspired air is uneven, with more air flowing to the less  resistant portions. Continued air trapping increases intrapleu-  ral and alveolar gas pressures and causes decreased perfusion  of the alveoli. Increased alveolar gas pressure, decreased ven-  tilation, and decreased perfusion lead to variable and uneven  ventilation-perfusion relationships within different lung seg-  ments. Hyperventilation is triggered by lung receptors respond-  ing to increased lung volume and obstruction. The result is early  hypoxemia without CO, retention. Hypoxemia further increases  hyperventilation through stimulation of the respiratory center,  causing Paco, to decrease and pH to increase (respiratory alka-  losis). With progressive obstruction of expiratory airflow, air  trapping becomes more severe and the lungs and thorax become  hyperexpanded, putting the respiratory muscles at a mechanical  disadvantage. This leads to a fall in tidal volume with increas-  ing CO, retention and respiratory acidosis. Respiratory acidosis  signals respiratory failure, especially when left ventricular fill-  ing and, thus, cardiac output become compromised because of  severe hyperinflation.   CLINICAL MANIFESTATIONS. Individuals are asymptomatic  between attacks and pulmonary function tests are normal. No  clinical symptoms are present during partial remission, but  pulmonary function tests are abnormal. At the beginning of an  attack, the individual experiences chest constriction, expiratory    Vasoactive mediators Chemotactic mediators  Vasodilation Cellular infiltration  Increased capillary permeability (neutrophils, lymphocytes, eosinophils)  Bronchospasm Autonomic  Vascular congestion dysregulation    remodeling)  FIGURE 35-11 Pathophysiology of Asthma. Allergen or irritant exposure results in a cascade of inflammatory events    Bronchial hyperresponsiveness  Airway obstruction  leading to acute and chronic airway dysfunction. /gF, Immunoglobulin E; /L, interleukin.    FIGURE 35-12 Acute Asthmatic Responses. Inhaled antigen (1) binds to mast cells covered with preformed IgE.  Mast cells degranulate (2) and release inflammatory mediators such as histamine, bradykinins, leukotrienes, prostaglan-  dins, platelet-activating factor, and interleukins. Secreted mediators (3) induce active bronchospasm (airway smooth muscle  constriction), edema from increased capillary permeability, and airway mucus secretion from goblet cells. At the same time,  antigen is detected by (4) dendritic cells that process and present it to Th2 cells (5), which produce interleukin-4 (/L-4) and  many other interleukins (see text). IL-4 promotes switching of B cells to favor immunoglobulin E (/g£) production. Th2 cells  also produce IL-5 (6), which activates eosinophils. Eosinophil products, such as major basic protein and eosinophilic cationic  protein, damage the respiratory epithelium. Many inflammatory cells, including neutrophils (7), also contribute to the inflam-  matory process. /gF, Immunoglobulin E.    wheezing, dyspnea, nonproductive coughing, prolonged expi-  ration, tachycardia, and tachypnea. Severe attacks involve the  use of accessory muscles of respiration, and wheezing is heard  during both inspiration and expiration. A pulsus paradoxus  (decrease in systolic blood pressure during inspiration of more  than 10 mmHg) may be noted. Peak flow measurements should  be obtained. Because the severity of blood gas alterations is dif-  ficult to evaluate by clinical signs alone, arterial blood gas ten-  sions should be measured if oxygen saturation falls below 90%.  Usual findings are hypoxemia with an associated respiratory  alkalosis. In the late asthma response, symptoms can be even  more severe than the initial attack.   If bronchospasm is not reversed by usual measures, the  individual is considered to have severe bronchospasm or  status asthmaticus. If status asthmaticus continues, hypoxemia  worsens, expiratory flows decrease further, and effective venti-  lation decreases. Acidosis develops as arterial Paco, begins to  rise. Asthma becomes life threatening at this point if treatment  does not reverse this process quickly. A silent chest (no audible  air movement) and a Paco; greater than 70 mmHg are ominous  signs of impending death.   EVALUATION AND TREATMENT. The diagnosis of asthma is sup-  ported by a history of allergies and recurrent episodes of  wheezing, dyspnea and cough, or exercise intolerance. Further  evaluation includes spirometry, which may document revers-  ible decreases in FEV, during an induced attack.   The evaluation of an acute asthma attack requires the  rapid assessment of arterial blood gases and expiratory flow  rates (using a peak flowmeter) and a search for underlying  triggers, such as infection. Hypoxemia and respiratory alka-  losis are expected early in the course of an acute attack. The  development of hypercapnia with respiratory acidosis signals  the need for mechanical ventilation. Management of the acute  asthma attack requires immediate administration of oxygen  and inhaled beta-agonist bronchodilators. In addition, oral  corticosteroids should be administered early in the course of  management.°”’° Careful monitoring of gas exchange and air-  way obstruction in response to therapy provides information  necessary to determine whether hospitalization is necessary.  Antibiotics are not indicated for acute asthma unless there is a  documented bacterial infection.   Management of asthma begins with avoidance of allergens  and irritants. Individuals with asthma tend to underestimate  the severity of their asthma and extensive education is impor-  tant, including use of a peak flowmeter and adherence to an  action plan should symptoms worsen. In the mildest form  of asthma (intermittent), short-acting beta-agonist inhalers  are prescribed. For all categories of persistent asthma, anti-  inflammatory medications are essential and inhaled corti-  costeroids are the mainstay of therapy. In individuals whose  symptoms are not adequately controlled using inhaled corti-  costeroids, leukotriene antagonists can be considered. In more  severe asthma, long-acting beta agonists can be used to control  persistent bronchospasm; however, these agonists can actu-  ally worsen asthma in some individuals with certain genetic  polymorphisms (see What’s New? Pharmacogenetics and Beta  Agonists in the Treatment of Asthma). Immunotherapy has    In the recent third report of the National Asthma Education and Prevention  Program (NAEPP), long-acting beta agonists (LABAs) (salmeterol and for-  moterol) are recommended to be used in conjunction with inhaled cortico-  steroids as step 3 therapy for persistent asthma. LABAs have been found to  improve symptoms in many individuals, and exert a long-term bronchodilatory  and anti-inflammatory effect on the airways. However, the safety of LABAs  has been questioned because of the increased mortality in some populations  using these drugs and it is recommended they be withdrawn once asthma i  controlled by combination therapy. One explanation is that those individua  who had worsening symptoms while taking LABAs were using them instea  of (rather in conjunction with) inhaled corticosteroids and thus were simp  masking ongoing inflammation and airway damage. LABAs should not be use  in the absence of inhaled corticosteroids. New evidence suggests that som  persons have a polymorphism of the B-adrenergic receptor gene (ADRB2). Thi  is known as the Arg16Arg genotype and places those individuals at risk for  worsening bronchospasm, increased hospitalizations, and increased mortality  when using LABAs. This genotype is more frequent in blacks and may explain  some of the differences in asthma treatment response and mortality among  these individuals. Studies continue to evaluate other genes and their relation-  ship to medication response, a field of study known as pharmacogenetics.    Data from Erding M, Brozek JL et al: Long-acting §2-agonist step-off in  patients with controlled asthma, Arch Intern Med 172(18):1365-1375,   2012; Mysore S, Ruffin RE: Drugs 71(16):2091-2097, 2011; Wechsler  ME et al: Am J Respir Crit Care Med 184(11):1247-1253, 2011; Wells  KE et al: J Allergy Clin Immunol 129(5):1274-1279, 2012.    been shown to be an important tool in reducing asthma exac-  erbations and can now be given sublingually. Monoclonal anti-  bodies to IgE (omalizumab) have been found to be helpful in  selected individuals.’”’”* The National Asthma Education and  Prevention Program offers stepwise guidelines for the diagnosis  and management of chronic asthma based on clinical severity,  and they may be reviewed at www.nhlbi.nih.gov/guidelines/asth  ma/asthgdln. htm. Biomarkers and epigenetic markers are being  evaluated to personalize treatment and reduce mortality.”    Chronic obstructive pulmonary disease (COPD) is defined  as a “preventable and treatable disease with some significant  extrapulmonary effects that may contribute to the severity in  individual patients. Its pulmonary component is characterized  by airflow limitation that is not fully reversible. The airflow  limitation is usually progressive and associated with an abnor-  mal inflammatory response of the lung to noxious particles or  gases.”°? COPD is the third leading cause of death in the United  States and is the sixth leading cause of death worldwide.*?  Overall mortality from COPD has increased in the United  States over the past 30 years; however, mortality in women has  increased more than twice that much.*! Risk factors for COPD  include tobacco smoke (cigarette, pipe, cigar, and environmen-  tal tobacco smoke), occupational dusts and chemicals (vapors,  irritants, and fumes), indoor air pollution from biomass fuel  used for cooking and heating (in poorly vented dwellings),  outdoor air pollution, and any factor that affects lung growth    FIGURE 35-13 Chronic Bronchitis. Inflammation and thickening of mucous  membrane with accumulation of mucus and pus leading to obstruction characterized  by productive cough. (Modified from Des Jardins T, Burton GG: Clinical manifesta-  tions and assessment of respiratory disease, ed 3, St Louis, 1995, Mosby.)    during gestation and childhood (low birth weight, respiratory  tract infections).°° Genetic susceptibilities have been identified,  including polymorphisms of genes that code for tumor necrosis  factor, surfactant, proteases, antiproteases, and risks for lung  cancer. The clinical phenotypes of COPD are chronic bronchitis  and emphysema.*” An inherited mutation in the o-antitrypsin  gene results in the development of COPD (emphysema) at an  early age, even in nonsmokers.*?*4   The pathologic changes of COPD occur in large central  airways, small peripheral airways, and the lung parenchyma,  the dominant features of chronic bronchitis and emphysema.  Chronic irritant exposure recruits macrophages, neutrophils,  and lymphocytes to the lung, resulting in progressive damage  from oxidative stress, inflammation, extracellular matrix pro-  teolysis, and apoptotic and autophagic cell death.*>*° Systemic  abnormalities, such as renal and hormonal abnormalities,  malnutrition, muscle wasting, osteoporosis, and anemia, are  associated with COPD.*”   Chronic Bronchitis. Chronic bronchitis is defined as  hypersecretion of mucus and chronic productive cough that  continues for at least 3 months of the year (usually the winter  months) for at least 2 consecutive years.   PATHOPHYSIOLOGY. Inspired irritants result in airway inflam-  mation with infiltration of neutrophils, macrophages, and  lymphocytes into the bronchial wall. Tobacco smoke directly  injures airway epithelial cells. Continual bronchial inflamma-  tion causes bronchial edema and increases the size and num-  ber of mucous glands and goblet cells in the airway epithelium.  Thick, tenacious mucus is produced and cannot be cleared  because of impaired ciliary function (Figure 35-13). The lung’s  defense mechanisms are, therefore, compromised, increasing  susceptibility to pulmonary infection, which contributes to air-  way injury.** Frequent infectious exacerbations are complicated  by bronchospasm with dyspnea and productive cough.*? The  pathogenesis of chronic bronchitis is shown in Figure 35-14.   Initially chronic bronchitis affects only the larger bronchi,  but eventually all airways are involved. The thick mucus and    hypertrophied bronchial smooth muscle narrow the airways  and lead to obstruction, particularly during expiration when  the airways are constricted. Obstruction eventually leads to  ventilation-perfusion mismatch with hypoxemia. The airways  collapse early in expiration, trapping gas in the distal portions of  the lung (Figure 35-15). Air trapping expands the thorax, putting  the respiratory muscles at a mechanical disadvantage. This leads  to decreased tidal volume, hypoventilation, and hypercapnia.   CLINICAL MANIFESTATIONS. The common symptoms of chronic  bronchitis include decreased exercise tolerance, wheezing,  and shortness of breath. Individuals usually have a productive  cough (“smoker’s cough”), and evidence of airway obstruction  (decreased FEV,) is shown by spirometry. Hypoxemia may  occur with exercise. As the disease progresses, copious amounts  of sputum are produced, accompanied by frequent pulmo-  nary infections.”” FVC and FEV, values become markedly  reduced, and FRC and residual volume (RV) measurements are  increased as airway obstruction and air trapping become more  pronounced.   Airway obstruction results in decreased alveolar ventilation  and increased Paco . Marked hypoxemia leads to polycythemia  (overproduction of erythrocytes) and cyanosis. If not reversed,  hypoxemia leads to pulmonary hypertension and eventually  results in cor pulmonale (see p. 1278) and can lead to severe  disability or death. (Table 35-3 lists the common clinical mani-  festations of chronic bronchitis.)   EVALUATION AND TREATMENT. Diagnosis is based on history of  symptoms, physical examination, chest radiograph, pulmonary  function tests, and blood gas analyses; these tests reflect the pro-  gressive nature of the disease. Prevention of chronic bronchitis  is the best treatment because pathologic changes are not revers-  ible. By the time an individual seeks medical care for symptoms,  considerable airway damage is present. If the individual stops  smoking, disease progression can be halted.   Bronchodilators (long-acting inhaled anticholinergics or  long-acting inhaled beta agonists for symptomatic persons  with COPD and FEV, <60% predicted) and expectorants are  prescribed to reduce dyspnea and control cough. Chest physi-  cal therapy may be helpful and includes deep breathing and  postural drainage. During acute exacerbations (infection and  bronchospasm), individuals require treatment with antibiot-  ics and corticosteroids and may need mechanical ventilation.  Chronic oral corticosteroids may be needed late in the course of  the disease, but should be considered a last resort. Individuals  with severe hypoxemia will require continuous oxygen therapy.  Teaching includes nutritional counseling, respiratory hygiene,  recognition of the early signs of infection, and techniques that  relieve dyspnea, such as pursed-lip breathing, all of which may  be useful in the treatment of chronic bronchitis in selected  individuals.°!°? (see Nutrition & Disease: Chronic Obstruc-  tive Pulmonary Disease). Oxygen is administered with care to  individuals with severe hypoxemia and CO, retention. Chronic  elevation of Paco, diminishes the sensitivity of central chemo-  receptors and they no longer act as the primary stimulus for  breathing. (Chemoreceptors are described in Chapter 34.) This  role is taken over by the peripheral chemoreceptors, which are  sensitive to changes in Pao . Peripheral chemoreceptors do not    stimulate breathing if the Pao, is much more than 60 mmHg.  Therefore, if oxygen therapy causes Pao, to exceed 60 mmHg,  the stimulus to breathe decreases, Paco, increases, and apnea  results. However, severe hypoxemia must be reversed, especially  if there are comorbidities (e.g., heart disease, tissue injury) that  require adequate tissue oxygenation. If titration of oxygen ther-  apy cannot be achieved without causing respiratory depression,  the individual’s lungs must be mechanically ventilated.”°  Emphysema. Emphysema is abnormal permanent enlarge-  ment of gas-exchange airways (acini) accompanied by  destruction of alveolar walls without obvious fibrosis. The  major mechanism of airflow limitation in emphysema is loss of  elastic recoil. Some degree of emphysema is considered normal    in older adults, but results in a slow and predictable decline in  lung function with aging.   Primary emphysema, which accounts for 1% to 3% of all  cases of emphysema, is commonly linked to an inherited defi-  ciency of the enzyme o.,-antitrypsin.?* Normally o,-antitrypsin  inhibits the action of many proteolytic enzymes (enzymes that  break down proteins). Individuals who have a,-antitrypsin  deficiency (an autosomal recessive trait) have an increased  likelihood of developing emphysema, because proteolysis in  lung tissues is not inhibited. Homozygous individuals have a  70% to 80% likelihood of developing lung disease. (Mecha-  nisms of genetic inheritance are described in Chapter 4.) Per-  sons with o,-antitrypsin deficiency who smoke are even more    Infiltration of inflammatory  cells and release of cytokines  (neutrophils, macrophages,  lymphocytes, leukotrienes,  interleukins)    Increased protease activity  with breakdown of elastin  in connective tissue of lungs  (elastases, cathepsins, etc.)    Airway obstruction  Air trapping  Loss of surface area for gas exchange  Frequent exacerbations  (infections, bronchospasm)    FIGURE 35-14 Pathogenesis of Chronic Bronchitis and Emphysema (Chronic Obstructive Pulmonary Disease    susceptible to emphysema than those with the deficiency alone.  o.,-Antitrypsin deficiency is suggested in nonsmokers and indi-  viduals who develop emphysema before age 40 years (or in their  early forties).   The major cause of secondary emphysema is the inhalation  of cigarette smoke, although air pollution, occupational expo-  sures, and childhood respiratory tract infections are known to  be contributing factors. Not all smokers develop emphysema,  but approximately 15% to 20% are especially susceptible and  develop significant lung damage, if they continue to smoke.”    Alveolar walls  FIGURE 35-15 Mechanisms of Air Trapping in Chronic Obstructive Pul-  monary Disease (COPD). Mucous plugs and narrowed airways cause air trapping  and hyperinflation on expiration. During inspiration the airways are pulled open,  allowing gas to flow past the obstruction. During expiration decreased elastic  recoil of the bronchial walls results in collapse of the airways and prevents normal  expiratory airflow.    PATHOPHYSIOLOGY. Emphysema is characterized by destruction  of alveoli through the breakdown of elastin within the septa by an  imbalance between proteases and antiproteases, oxidative stress,  and apoptosis of lung structural cells®*”° (see Figure 35-14). Cel-  lular apoptosis and early cellular senescence contribute to loss of  alveolar cells and reduced surface area for gas exchange. Alveolar  destruction also produces large air spaces within the lung paren-  chyma (bullae) and air spaces adjacent to pleurae (blebs). Bul-  lae and blebs are not effective in gas exchange and combined  with loss of portions of the pulmonary capillary bed, there is sig-  nificant ventilation-perfusion (V/Q) mismatching and hypox-  emia. Expiration becomes difficult because loss of elastic recoil  reduces the volume of air that can be expired passively and air  is trapped in the lungs (see Figure 35-15). Air trapping causes  hyperexpansion of the chest, which puts the muscles of respira-  tion at a mechanical disadvantage. This results in increased work  of breathing, so that many individuals will develop hypoventila-  tion and hypercapnia late in the course of the disease. Persis-  tent inflammation in the airways can result in hyperreactivity of  the bronchi with bronchoconstriction, which may be partially  reversible with bronchodilators. Chronic inflammation also can  have significant systemic effects including weight loss, muscle  weakness, and increased susceptibility to comorbidities, such as  infection.   Emphysema can be centriacinar (centrilobular) or panacinar  (panlobular) (Figure 35-16), depending on the site of involve-  ment. In centriacinar emphysema septal destruction occurs  in the respiratory bronchioles and alveolar ducts, usually in  the upper lobes of the lung. The alveolar sac (alveoli distal to  the respiratory bronchiole) remains intact. It tends to occur    Malnutrition occurs in up to one third of individuals with chronic obstructive  pulmonary disease (COPD) and is a major concern because these individuals  have increased work of breathing and energy expenditure, decreased energy  intake, and impaired oxygenation. The disproportionate muscle wasting is  similar to what occurs with other chronic diseases, such as cancer, heart fail-  ure, and acquired immunodeficiency syndrome (AIDS). Systemic inflammatory  mediators may impair appetite and contribute to hypermetabolism. Malnutri-  tion (1) adversely affects exercise tolerance by limiting skeletal and respira-  tory muscle strength and aerobic capacity, (2) limits surfactant production,  (3) reduces cell-mediated immune responses, (4) decreases protein synthesis,  and (5) increases morbidity and mortality. The medical nutrition therapy goal is  to maintain an acceptable and stable weight for the person. This can be accom-  plished through high-energy foods, oral nutritional support, frequent snacking,  soft foods and beverages, assistance with shopping, and meal preparation.  Reducing the amount of carbohydrates while providing adequate protein and  lipids may improve carbon dioxide balance. Increasing omega-3 fatty acids  and antioxidant intake may modulate the effects of systemic inflammation.  Vitamin D and calcium supplementation is indicated to improve bone health.  Serum phosphate levels also should be monitored to prevent hypophosphate-  mia, which can contribute to muscle weakness.    Data from Collins PF, Stratton RJ, Elia M: Am J Clin Nutr 95(6):1385-  1395, 2012; Criner GJ et al: Am J Respir Crit Care Med 184(7):763-770,  2011; Kelly RU, Giaccone G: Cancer J 17(5):302-308, 2011; Raguso CA,  Luthy C: Nutrition 27(2):138-143, 2011.    in smokers with chronic bronchitis. Panacinar emphysema  involves the entire acinus, with damage more randomly distrib-  uted and involving the lower lobes of the lung (Figure 35-17). It  tends to occur in older adults and in those with a,-antitrypsin  deficiency.°’   CLINICAL MANIFESTATIONS. Dyspnea on exertion that later  progresses to marked dyspnea, even at rest, is the most com-  mon symptom of emphysema (see Table 35-3). Little cough-  ing and very little sputum are produced. Often the individual  is thin, has tachypnea with prolonged expiration, and must use  accessory muscles for ventilation. The anteroposterior diam-  eter of the chest is increased (barrel chest), and the chest has    FIGURE 35-16 Emphysema. Enlargement and destruction of alveolar walls  with loss of elasticity and trapping of air. A, Panlobular emphysema showing abnor-  mal weakening and enlargement of all air spaces distal to the terminal bronchioles  (normal alveoli shown for comparison only); B, centrilobular emphysema showing  abnormal weakening and enlargement of the respiratory bronchioles in the proxi-  mal portion of the acinus. (Modified from Des Jardins T, Burton GG: Clinical mani-  festations and assessment of respiratory disease, ed 3, St Louis, 1995, Mosby.)    a hyperresonant sound with percussion. To increase lung capac-  ity, the individual often leans forward with arms extended and  braced on knees when sitting. In addition, people with emphy-  sema often exhale through pursed lips which helps prevent  expiratory airway collapse.   EVALUATION AND TREATMENT. Emphysema is usually diagnosed  and staged by pulmonary function measures. In COPD, pulmo-  nary function tests indicate obstruction to gas flow during expi-  ration with a marked decrease in FEV). Airway collapse and air  trapping in distal portions of the lung lead to a decrease in FVC  (but less so than FEV,) and an increase in FRC, residual vol-  ume (RV), and total lung capacity (TLC). Diffusing capacity is  decreased because of destruction of the alveolocapillary mem-  branes. On radiographs the diaphragm appears flattened and  the lung fields appear overdistended. In individuals for whom  pulmonary function testing is not definitive for the diagnosis,  high-resolution CT scanning may be indicated.”* Arterial blood  gas measurements reveal varying degrees of hypoxemia and/  or hypercapnia. The disease course is usually prolonged, with  increasing dyspnea and intermittent bouts of infection that cul-  minate in failure of the right side of the heart (cor pulmonale)  and death.”   Management of acute exacerbations of emphysema is simi-  lar to that for chronic bronchitis and requires obtaining a chest  radiograph, serum white blood cell count, arterial blood gas,  and sputum sample. Individuals should receive oxygen and may  require noninvasive positive-pressure ventilation or mechani-  cal ventilation. Inhaled bronchodilators should be administered  by either inhaler or nebulizer. Oral corticosteroids and antibiot-  ics should be prescribed immediately.*” Chronic management    FIGURE 35-17 Micrographs of Types of Emphysema. A, Centriacinar emphysema. B, Panacinar emphysema. (Micro-  graphs from Damjanov |, Linder J, editors: Andersons pathology, ed 10, St Louis, 1996, Mosby.)    of emphysema begins with smoking cessation. Pharmacologic  management is based on clinical severity, defined by the Global  Initiative for Chronic Obstructive Lung Disease (GOLD), as  mild, moderate, severe, or very severe. Inhaled anticholinergic  agents and beta agonists should be prescribed. Inhaled corti-  costeroids added to long-acting anticholinergics of beta ago-  nists diminish the number of acute exacerbations, slow the rate  of decline in quality of life, and reduce the rate of decline in  FEV,; however, their use must be weighed against the poten-  tial side effects (oropharyngeal candidiasis and hoarseness, and  risk of pneumonia).!°° Long-term therapy with oral corticoste-  roids should be avoided, if possible. Pulmonary rehabilitation,  improved nutrition, and breathing techniques can all improve  symptoms. Oxygen therapy is indicated in chronic hypoxemia,  but must be administered with care. Progressive pulmonary  dysfunction with hypoxemia and hypercapnia may require  long-term oxygen therapy and ventilation, if indicated.'°!  In selected patients, lung volume reduction surgery or trans-  plantation can be considered.!°* The recently approved phos-  phodiesterase E4 (PDE4) inhibitor roflumilast reduces airway  inflammation and is proving to be effective in selected individu-  als with severe COPD.!° a,-Antitrypsin augmentation may be  indicated for primary emphysema.?!)!°*    Respiratory tract infections are the most common cause of  short-term disability in the United States. Most of these infec-  tions—the common cold, pharyngitis (sore throat), and laryn-  gitis—involve only the upper airways. Although the lungs have  direct contact with the atmosphere, they remain sterile under  most circumstances. Infections of the lower respiratory tract  occur most often in the very young, the very old, or individuals  with impaired immunity or underlying disease. In all cases the  body’s normal defense mechanisms are impaired.    Pneumonia is infection of the lower respiratory tract caused  by bacteria, viruses, fungi, protozoa, or parasites. It is the sixth  leading cause of death in the United States and is responsible for  more disease and death than any other infection.!°° More than  half of those hospitalized for pneumonia are older than age 65;  mortality from pneumonia is highest in older adults. Risk factors  for pneumonia include advanced age, immunocompromised  status, underlying lung disease (especially COPD), alcoholism,  altered consciousness, impaired swallowing, smoking, endo-  tracheal intubation, malnutrition, immobilization, underlying  cardiac or liver disease, and residence in a nursing home.  Pneumonia can be categorized as community-acquired  (CAP), healthcare-associated (HCAP), hospital-acquired (HAP),  or ventilator-associated (VAP). CAP is one of the most common  reasons for hospitalization in the United States. HCAP is defined  as occurring in individuals with recent hospitalization, residence  in a nursing home or extended care facility, home infusion ther-  apy; chronic dialysis, or home wound care. It is estimated that  nearly one third of all hospital admissions for pneumonia are  now considered HCAP. HAP is the second most common noso-  comial infection (urinary tract infection [UTI] most common),    but has the greatest mortality (overall 20% to 50% mortality).  VAP occurs in 9% to 27% of individuals who require intubation  and mechanical ventilation. !°%!°* The microorganisms that most  commonly cause CAP are different from those infections that  cause HCAP, HAP, and VAP (Box 35-1). In addition, the char-  acteristics of the individual are important in determining which  etiologic microorganism is likely; for example, immunocompro-  mised persons tend to be susceptible to opportunistic infections  that are uncommon in normal adults (see Box 35-1).   PATHOPHYSIOLOGY. Aspiration of oropharyngeal secretions is  the most common route of lower respiratory tract infection;  thus the nasopharynx and oropharynx constitute the first line  of defense for most infectious agents. Another route of infec-  tion is through the inhalation of microorganisms that have  been released into the air when an infected individual coughs,  sneezes, or talks, or from aerosolized water, such as that from  contaminated respiratory therapy equipment. This route of  infection is most important in viral and mycobacterial pneu-  monias and in Legionella outbreaks. Endotracheal tubes become  colonized with bacteria that form biofilms (protected colonies  of bacteria that are resistant to host defenses and treatment with  antibiotics) and can seed the lung with microorganisms, espe-  cially during endotracheal suctioning.'!°? Pneumonia also can  occur when bacteria are spread to the lungs in the blood from  bacteremia that can result from infection elsewhere in the body  or from intravenous drug use.   In healthy individuals, pathogens that reach the lungs are  expelled or held in check by mechanisms of self-defense (see  Chapters 7, 8, and 34). Ifa microorganism enters the upper air-  way defense mechanisms, such as the cough reflex and muco-  ciliary clearance, the next line of defense is the airway epithelial    Streptococcus  pneumoniae  Haemophilus  influenzae  Staphylococcus  aureus  Mycoplasma  pneumoniae  Chlamydia  pneumoniae  Moraxella  catarrhalis  Legionella  pneumophila  Influenza  Rhinovirus  Coronavirus    Pseudomonas  aeruginosa  Staphylococcus aureus  (including methicillin-  resistant strains)  Klebsiella  pneumoniae  Enterobacter  species    CAP Community-acquired pneumonia; HAP hospital-acquired  pneumonia; HCAP healthcare-associated pneumonia; VAP  ventilator-associated pneumonia.    Resolution of infection:  macrophages in alveoli ingest  and remove degenerated neutrophils,  fibrin, and bacteria    cell. Airway epithelial cells can recognize some pathogens  directly (e.g., Pseudomonas aeruginosa and Staphylococcus  aureus). However, the most important guardian cell of the  lower respiratory tract is the alveolar macrophage and it rec-  ognizes pathogens through its pattern-recognition receptors  (e.g., Toll-like receptors). Macrophages present infectious  antigens to the adaptive immune system, activating T cells and  B cells with the induction of cellular and humoral immunity.  Release of TNF-a and IL-1 from macrophages and chemokines  and chemotactic signals from mast cells and fibroblasts con-  tributes to widespread inflammation in the lung with recruit-  ment of neutrophils from the capillaries of the lungs into the  alveoli. Neutrophils are critical phagocytes that kill microbes  through the formation of phagolysosomes filled with degra-  dative enzymes, antimicrobial proteins, and toxic oxygen free  radicals.!!°   Neutrophils have also been found to extrude a meshwork  of proteins called a neutrophil extracellular trap (NET) that  can capture any bacteria that have not yet been phagocytosed.  Unfortunately, many pathogens, such as the pneumococcus,  can release a DNase that cleaves the NET and thus escape neu-  trophil defense.''! The release of inflammatory mediators and  immune complexes can damage bronchial mucous membranes  and alveolocapillary membranes, causing the acini and terminal  bronchioles to fill with infectious debris and exudate. In addi-  tion, some microorganisms release toxins from their cell walls  that can cause further lung damage. The accumulation of exu-  date in the acinus leads to dyspnea and to V/Q mismatching  and hypoxemia.    Pneumococcal Pneumonia. The pathogenesis of pneumo-  coccal pneumonia (Streptococcus pneumoniae) has been well  documented and serves as a model for understanding other  forms of bacterial pneumonia (Figure 35-18). S. pneumoniae  microorganisms initiate innate and adaptive immune responses  (see Chapters 7 and 8). The immune response includes  complement activation and the production of antibodies,  which are crucial for opsonizing the encapsulated bacterium.  Rapid lysis of pneumococcal bacteria (as occurs with antibiotic  treatment) results in the release of intracellular bacterial  proteins that can be toxic. The best known of these proteins  is pneumolysin, which is cytotoxic to virtually every cell in the  lung and is partially responsible for the worsening in clinical  symptoms sometimes seen in individuals immediately after  they begin antibiotic treatment.!!? Inflammatory cytokines and  cells are released that cause alveolar edema. Edema creates a  medium for the multiplication of bacteria and aids in the spread  of infection into adjacent portions of the lung. The involved  lobe undergoes consolidation, which alveoli fill with blood cells,  fibrin, edematous fluid, and pneumococci, giving lung tissue  a red appearance. This passes into the stage in which affected  tissues become gray because of fibrin deposition over the  pleural surfaces and the presence of fibrin and neutrophils in the  consolidated alveoli, where phagocytosis is rapidly taking place.  With resolution, increasing numbers of macrophages appear in  the alveolar spaces, the neutrophils degenerate, and the fibrin  threads and remaining bacteria are digested by macrophages  and removed by lymphatic vessels. Usually infection is limited  to one or two lobes.    Viral pneumonia is seasonal, usually mild and self-limiting, but  it can set the stage for a secondary bacterial infection (especially  by S. aureus and Streptococcus pneumoniae) by providing an  ideal environment for bacterial growth and by damaging cili-  ated epithelial cells, which normally prevent pathogens from  reaching the lower airways.''’ Viral pneumonia can be a pri-  mary infection (e.g., influenza pneumonia) or a complication  of another viral illness (e.g., chickenpox, measles). Influenza  virus is the most common viral cause of pneumonia. The virus  not only destroys the ciliated epithelial cells, but also invades  the goblet cells and bronchial mucous glands. Sloughing of  destroyed bronchial epithelium occurs throughout the respi-  ratory tract, preventing mucociliary clearance. Bronchial walls  become edematous and infiltrated with leukocytes.!!*   Some forms of viral pneumonia can progress to severe sys-  temic illness with many complications and a high morbidity  and mortality. Severe viral pneumonia can include common  types of influenza that can be fatal, especially in older adults.'!°  Other severe viral infections are considered opportunistic infec-  tions, such as cytomegalovirus pneumonia in immunocompro-  mised individuals. New or atypical forms of viral infection, such  as swine influenza A (H1N1) virus, avian influenza A (H5N1)  virus, and the coronavirus that causes severe acute respiratory  syndrome (SARS), are affecting previously healthy populations  and pose a considerable threat for pandemics.!!°!!”   CLINICAL MANIFESTATIONS. Most cases of pneumonia are pre-  ceded by an upper respiratory tract infection, which is usually  viral. This is then followed by the onset of cough, dyspnea, and  fever. The cough is often productive, but may be nonproductive,  especially in viral pneumonia. Other symptoms include chills,  malaise, and pleuritic chest pain. Physical examination may  reveal signs of pulmonary consolidation, such as inspiratory  crackles, increased tactile fremitus, egophony, and whispered  pectoriloquy. Individuals also may demonstrate symptoms and  signs of underlying systemic disease or sepsis.   EVALUATION AND TREATMENT. Diagnosis is made on the basis of  history, physical examination (tachypnea, tachycardia, crackles,  bronchial breath sounds, and findings of pleural effusion), white  blood cell count, chest x-ray, stains and cultures of blood, and  cultures of respiratory secretions. The white blood cell count  is usually elevated, although it may be low if the individual is  debilitated, immunocompromised, or has overwhelming infec-  tion.!'® Chest radiographs show infiltrates that may involve a  single lobe of the lung or may be more diffuse. Once the diagno-  sis of pneumonia has been made, the pathogen is identified by  means of sputum characteristics (Gram stain, color, odor) and  cultures or, if sputum is absent, blood cultures. Because many  pathogens exist in the normal oropharyngeal flora, the speci-  men may be contaminated with pathogens from oral secretions.  If sputum studies fail to identify the pathogen, the individual  is immunocompromised, or the individual’s condition wors-  ens, further diagnostic studies may include molecular testing of  blood or urine, bronchoscopy, or lung biopsy.!!?!?°   Prevention of pneumonia includes prevention of aspira-  tion, respiratory isolation of inmunocompromised individu-  als, vaccination for appropriate populations, and reduction of    ventilator-associated pulmonary infections through a variety of  dental and endotracheal tube interventions.'°”!*!:!”? The first  step in the management of pneumonia is establishing adequate  ventilation and oxygenation. Most individuals have hypoxemia  and a respiratory alkalosis, although persons with underlying  lung disease may require ventilation. Adequate hydration and  good pulmonary hygiene (e.g., deep breathing, coughing, chest  physical therapy) are also important.   Antibiotics are used to treat bacterial pneumonia; however,  resistant strains of Pneumococcus are becoming more preva-  lent.'?° In individuals for whom a specific microorganism is not  identified, empirical antibiotics are chosen based on the likely  causative microorganism.!**!?° Viral pneumonia is usually  treated with supportive therapy alone (unless secondary bac-  terial infection is present); however, antivirals may be needed  in severe cases. Infections with opportunistic microorganisms  may be polymicrobial and require multiple drugs, including  antifungals.    Tuberculosis  Tuberculosis (TB) is an infection caused by Mycobacterium  tuberculosis, an acid-fast bacillus that usually affects the lungs,  but may invade other body systems. TB is the leading cause of  death from a curable infectious disease throughout the world.  TB cases increased greatly during the mid-1990s because of  AIDS. Individuals with AIDS are highly susceptible to respi-  ratory tract infections, including multidrug-resistant TB.'7°  Many ambitious programs for prevention and treatment have  been initiated worldwide and the World Health Organiza-  tion (WHO) 2011 Global Tuberculosis Control Report indicates  that global TB incidence and prevalence have declined in most  regions of the world in recent years.'”’ In the United States,  the incidence of TB has reached its lowest level since 1953, but  the rate of decline has begun to slow with more than half of  new cases of TB occurring in foreign-born individuals, espe-  cially among non-Hispanic Asians, non-Hispanic blacks, and  Hispanics.!7°   PATHOPHYSIOLOGY. TB is highly contagious and is transmitted  from person-to-person in airborne droplets. Host susceptibil-  ity to infection is influenced by host and parasite genetic poly-  morphisms, including those that affect macrophages, tumor  necrosis factor, and interleukins.'”? In immunocompetent indi-  viduals, the microorganism usually is contained by the inflam-  matory and immune response systems, and latent TB infection  (LTBI) develops with no clinical evidence of disease.!°° Micro-  organisms lodge in the lung periphery, usually in the upper  lobe. Once the bacilli are inspired into the lung, they multiply  and cause nonspecific pneumonitis (lung inflammation). Some  bacilli migrate through the lymphatics and become lodged in  the lymph nodes, where they encounter lymphocytes and ini-  tiate the immune response. Inflammation in the lung causes  neutrophils and macrophages to migrate to the area. These cells  are phagocytes that engulf the bacilli and begin the process by  which the body’s defense mechanisms isolate the bacilli, pre-  venting their spread. However, the bacterium is successful as  a pathogen because it can survive within macrophages, resist  lysosomal killing, multiply within the cell, form well-organized    granulomas creating a confined environment, terminate its  own central metabolism, stop replication, and transit into a  stage of dormancy rendering itself extremely resistant to host  defense and drug treatment.!*!)!°* In defense, macrophages and  lymphocytes release interferon, which inhibits the replication  of the microorganisms and stimulates more macrophages to  attack the bacterium. Apoptotic infected macrophages also can  activate cytotoxic T cells (CD8). Neutrophils, lymphocytes, and  macrophages seal off the colonies of bacilli, forming a granu-  lomatous lesion called a tubercle.'° Infected tissues within the  tubercle die, forming cheeselike material called caseation necro-  sis. (Necrosis is described in Chapter 2.) Collagenous scar tis-  sue then grows around the tubercle, completing isolation of the  bacilli. The immune response is complete after about 10 days,  preventing further multiplication of the bacilli.   Once the bacilli are isolated in tubercles and immunity devel-  ops, TB may remain dormant for life.'°+ If the immune system  is impaired, progressive active disease occurs and may spread  through the blood and lymphatics to other organs. Infection  with human immunodeficiency virus (HIV) is the single great-  est risk factor for reactivation of tuberculosis infection. Cancer,  immunosuppressive medications, poor nutritional status, renal  failure, and other debilitating diseases can reactivate disease.   CLINICAL MANIFESTATIONS. Latent TB infection is asymptomatic.  Symptoms of active disease develop so gradually that they are  not noticed until the disease is advanced. However, symptoms  can appear in immunosuppressed individuals within weeks  of exposure to the bacillus. Common clinical manifestations  include fatigue, weight loss, lethargy, anorexia (loss of appetite),  a low-grade fever that usually occurs in the afternoon, and night  sweats. (These are common signs and symptoms of all chronic  infections.) A cough that produces purulent sputum devel-  ops slowly and becomes more frequent over several weeks or  months. Dyspnea, chest pain, and hemoptysis also may occur as  the disease progresses. Extrapulmonary TB disease is common  in HIV-infected individuals and may cause neurologic deficits,  meningitis symptoms, bone pain, and urinary symptoms.   EVALUATION AND TREATMENT. TB is diagnosed by a positive  tuberculin skin test (TST; purified protein derivative [PPD]),  sputum culture, immunoassays, and chest radiographs.!*>'°° A  positive tuberculin skin test indicates the need for yearly chest  radiographs to detect active disease. The skin test does not dif-  ferentiate between past, latent, or active forms of the disease.  In addition, those individuals who have received the TB vac-  cine with bacille Calmette-Guérin (BCG) will have a positive  TST even if they have never had TB. When active pulmonary  disease is present, the tubercle bacillus can be cultured from  the sputum and may be seen with an acid-fast stain. How-  ever, sputum culture can take up to 6 weeks to become posi-  tive. Chest radiographs of individuals with current or previous  active disease demonstrate characteristic changes. Nodules, cal-  cifications, cavities, and hilar enlargement (enlarged mediasti-  nal lymph nodes) commonly are seen in the upper lobes. Two  immunoassays (enzyme-linked immunospot and quantitative  blood interferon-gamma assay) are available. These new tests  are more sensitive and specific for the diagnosis of latent TB and  are not confounded by previous BCG vaccination. However,    they are often not available in high poverty populations and  new techniques need to be developed for cost-effective and sim-  ple to use diagnostic tests.!°” Prevention of tuberculosis infec-  tion is a complex challenge. Isolating individuals with active  tuberculosis, limiting use of immunosuppressive medications,  and treating underlying inmunocompromising diseases, such  as AIDS, are all critical steps. Development of an effective TB  vaccine has been elusive and vaccines are currently in clinical  development.!°*   Treatment consists of combinations of antibiotics (isoniazid,  rifampin, pyrazinamide, and ethambutol) to control active dis-  ease or prevent reactivation of latent TB infection. The choice  of drugs and the duration of treatment depend on the indi-  vidual’s health history, the likelihood of bacterial resistance to  certain drugs, and the presence of active disease. The waxy coat  of M. tuberculosis renders it impermeable to many common  drugs. For drug-resistant bacilli, the recommended treatment  is administration for an 18-month timeframe of a combination  of at least four drugs to which the microorganism is suscep-  tible, including a review of drug effectiveness at 6 months.!°’  New drugs and drug combinations are being tested to overcome  drug resistance, including immune amplifiers. !4'4!    An abscess is a circumscribed area of suppuration and destruction  of lung parenchyma. Abscess formation follows consolidation  of lung tissue, in which inflammation causes alveoli to fill with  fluid, pus, and microorganisms. Necrosis (death and decay) of  consolidated tissue may progress proximally until it communi-  cates with a bronchus. If this occurs, the abscess empties into  the bronchus, leaving a cavity that has a radiographic appear-  ance similar to that of a lesion of tuberculosis.   Pneumonia caused by aspiration or by exposure to Klebsiella  or Staphylococcus is the most common cause of abscess forma-  tion. Aspiration abscess is usually associated with alcohol abuse,  seizure disorders, general anesthesia, and swallowing disorders.  Immunocompromised individuals also are at greater risk for  lung abscesses and may be infected with opportunistic microor-  ganisms, such as fungi and mycobacteria. The clinical manifes-  tations of abscess formation are similar to those of pneumonitis:  fever, cough, chills, excessive sputum production, and pleural  pain. Abscess communication with a bronchus causes a severe  cough, copious amounts of often foul-smelling sputum, and  occasionally hemoptysis. Cavitation is the process of abscess  emptying and cavity formation. Diagnosis is made by radiog-  raphy. Treatment includes the administration of appropriate  antibiotics and chest physical therapy, including chest percus-  sion and postural drainage. Bronchoscopy may be performed to  drain the abscess. !47    Acute bronchitis is acute infection or inflammation of the air-  ways or bronchi. The vast majority of cases of acute bronchi-  tis are caused by viruses. Many of the clinical manifestations  are similar to those of pneumonia (i.e., cough, fever, chills,  malaise), but physical examination does not reveal signs of  pulmonary consolidation and chest radiographs do not show    , A 7 By cig a Ef 4 Ce Tf, Ogee Ge 3 ‘i  FIGURE 35-19 Pulmonary Embolus. The embolus extends into major  branches of the pulmonary artery. (From Kumar V et al: Robbins & Cotran pathologic  basis of disease, ed 8, Philadelphia, 2010, Saunders.)    infiltrates. Individuals with viral bronchitis usually have a non-  productive cough that occurs in paroxysms and is aggravated  by cold, dry, or dusty air. However, purulent sputum may be  produced with some viral infections. Chest pain often develops  from the effort of coughing. Treatment consists of rest, aspirin,  humidity, and a cough suppressant, such as codeine.   Individuals with bacterial bronchitis have a productive  cough, fever, and pain behind the sternum (breast bone) that  is aggravated by coughing. It is rare in previously healthy adults  except after viral infection, but is common in those with COPD.  Bacterial bronchitis is treated with rest, aspirin, humidity, and  antibiotics. !*°    Blood flow through the lungs can be disrupted by a number  of disorders that result in occlusion of the vessels, an increase  in pulmonary vascular resistance, or destruction of the vascu-  lar bed. The consequences of altered pulmonary blood flow  may be of no functional significance or can result in severe  and life-threatening changes in ventilation-perfusion ratios.  Major disorders that result from pulmonary vascular diseases  include pulmonary embolism, pulmonary hypertension, and  cor pulmonale.   Pulmonary embolism (PE) is occlusion or partial occlusion of  the pulmonary artery or its branches by an embolus. PE most  commonly results from embolization ofa clot from deep venous  thrombosis involving the lower leg (see Chapter 32). Other less  common nonthrombotic emboli include tissue fragments, lip-  ids (fats), a foreign body, or an air bubble (Figure 35-19). Risk  factors for PE include conditions and disorders that promote  blood clotting as a result of venous stasis (immobilization, heart  failure), hypercoagulability (inherited coagulation disorders,  malignancy, hormone replacement, oral contraceptives, preg-  nancy), and endothelial injury to the cells that line the vessels  (trauma, caustic intravenous infusions). Increased risk for  thrombosis associated with hemodynamic stasis, hypercoagula-  bility, and endothelial injury is known as Virchow’s triad'“* (see    Chapter 32). Genetic risks include factor V Leiden mutation  (activated protein C resistance), antithrombin II deficiency,  protein S deficiency, protein C deficiency, and prothrom-  bin 20210 gene mutations. No matter its source, a blood clot  becomes an embolus when all or part of it breaks away from the  site of formation and begins to travel in the bloodstream. '*>'4°  Thromboembolism is described further in Chapter 32.   PATHOPHYSIOLOGY. The effect of the embolus depends on the  extent of pulmonary blood flow obstruction, the size of the  affected vessels, the nature of the embolus, and the secondary  effects.'4”7 Pulmonary emboli can result in any of the following:   cause permanent lung injury (perfusion of the affected  lung segment is maintained by the bronchial circulation)   As a result of the thrombus lodging in the pulmonary cir-  culation, there is a release both of neurohumoral substances,  such as serotonin, histamine, catecholamines, and angiotensin  II, and of inflammatory mediators, such as endothelin, leukotri-  enes, thromboxanes, and toxic oxygen free radicals. This causes  widespread vasoconstriction that further impedes blood flow to  the lung. Hemodynamically, this results in increased pulmonary  artery pressures and can lead to right heart failure.'4* Absent  blood flow to a lung segment causes a ventilation-perfusion  mismatch (increased dead space) and a decrease in surfactant  production. The resulting atelectasis of the affected lung seg-  ments further contributes to hypoxemia. If the thrombus is large  enough, infarction of lung tissue, dysrhythmias, decreased car-  diac output, shock, and death are possible.'*? The pathogenesis  of venous thromboembolism is summarized in Figure 35-20.   If the embolus does not cause infarction, the clot is dissolved  by the fibrinolytic system (see Chapter 27) and pulmonary  function returns to normal. If pulmonary infarction occurs,  shrinking and scarring develop in the affected area of the lung.  The risk of recurrent venous thromboembolism is 30% over the  next 10 years, and is much higher in those individuals who have  irreversible risk factors for the disease.!°°   CLINICAL MANIFESTATIONS. In most cases the clinical manifesta-  tions of PE are nonspecific; therefore, evaluation of risk factors  and predisposing factors is an important aspect of diagnosis.  Consequently, the recognition of individuals at high risk for PE  is crucial to assessing the clinical presentation. A list of an indi-  vidual’s predisposing factors for venous thromboembolism can  be inserted into one of several clinical prediction models (e.g.,  Wells Prediction Rule model) to obtain a prediction score that  helps determine risk probability.!°! In suspected PE, assessment  for DVT may indicate the presence of a lower extremity source  for the thromboembolism. Calf pain and tenderness, along with  calf asymmetry when documented with a tape measure, are  some of the most important findings in DVT. Unfortunately,  DVT is often asymptomatic and clinical examination has low    Tachypnea  Dyspnea  Chest pain  Increased dead space  V/Q imbalances  Decreased PaO»  Pulmonary infarction  Pulmonary hypertension  Decreased cardiac output  Systemic hypotension  Shock    FIGURE 35-20 Pathogenesis of Massive Pulmonary Embolism Caused  by a Thrombus (Pulmonary Thromboembolism).    sensitivity for the presence of a clot, especially in the thigh and  pelvis. Therefore, the lack of clinical indicators for DVT does  not rule out the possibility for PE.   An individual with PE usually presents with the sudden  onset of pleuritic chest pain, dyspnea, tachypnea, tachycardia,  and unexplained anxiety. Occasionally syncope (fainting) or  hemoptysis occurs. With large emboli, a pleural friction rub,  pleural effusion, fever, and leukocytosis may be noted. Recur-  rent pulmonary emboli occur in individuals with a history of  previous emboli. Recurrent small emboli may not be detected  until progressive incapacitation, precordial pain, anxiety, dys-  pnea, and right ventricular enlargement are exhibited. Mas-  sive occlusion causes profound shock, hypotension, tachypnea,  tachycardia, severe pulmonary hypertension, and chest pain.   EVALUATION AND TREATMENT. When an individual is suspected  of having a PE based on the presence of risk factors, symptoms,  and physical findings, a chest x-ray, arterial blood gas, and elec-  trocardiogram (ECG) are obtained immediately. Chest x-ray  findings are nonspecific in PE and often can be normal for the  first 24 hours until atelectasis occurs in the lung. The arterial    blood gas results commonly reveal hypoxemia with a respira-  tory alkalosis (most individuals will hyperventilate in response  to PE). The ECG may show evidence of strain on the right side  of the heart. The serum p-dimer level measures a product of  thrombus degradation by the fibrinolytic system and, if normal,  makes the presence of a PE highly unlikely. Further evaluation  is conducted using single or multidetector spiral CT arteriogra-  phy.!>?!>> This highly sensitive and specific test has replaced the  radionucleotide ventilation-perfusion scan in most hospitals.  Magnetic resonance imaging (MRI) is used in some centers. In  rare cases, a pulmonary angiogram is necessary to confirm the  diagnosis of PE. Recently, the measurement of elevated serum  troponin I levels has been useful in stratifying the risk and sever-  ity of PE because it increases with right ventricular strain or fail-  ure.'*+ Diagnostic algorithms guide diagnosis and treatment.!*°   The ideal treatment of PE is prevention through risk factor  recognition and elimination of predisposing factors. Venous  stasis in hospitalized individuals is minimized by bed exercises,  frequent position changes, early ambulation, and pneumatic  calf compression.'°° Most at-risk individuals also will receive  prophylactic anticoagulation with unfractionated heparin,  low-molecular-weight heparin, warfarin, or fondaparinux.'°°  In individuals who have contraindications to anticoagulation,  the placement of a filter in the inferior vena cava can prevent  emboli from reaching the lungs.!°”   Management of PE begins with administration of oxygen  and hemodynamic stabilization with fluids, if needed, followed  by rapid administration of anticoagulation, usually unfraction-  ated or low-molecular-weight heparin and factor Xa inhibitors  (fondaparinux, idraparinux, rivaroxaban, and apixaban).!°°>!°”  If a massive life-threatening embolism occurs, a fibrinolytic  agent, such as streptokinase, can be used and may be infused  through a pulmonary artery catheter. Some individuals require  emergent percutaneous or surgical embolectomy.!°* Reversal of  the underlying cause of the thrombus is important in preventing  recurrent venous thromboembolism.    Pulmonary artery hypertension (PAH) is defined as a mean  pulmonary artery pressure greater than 25 mmHg at rest.!°”  Pulmonary artery pressure is lower than systemic arterial  pressure and is normally 15 to 18 mmHg. Box 35-2 contains  the WHO clinical categories for PAH. Idiopathic PAH (IPAH)  is rare and usually occurs in women between the ages of 20  and 40 years.'°”!° Familial PAH (FPAH) is caused by muta-  tions in the gene encoding the bone morphogenetic protein  receptor type I] (BMPR2).!°!°! Associated PAH (APAH) is  a leading cause of mortality in many connective tissue disor-  ders (e.g., scleroderma) and affects up to 1 in 200 individuals  infected with HIV.'°° Diet drugs, amphetamines, and cocaine  also have been linked to an increased risk for PAH. Pulmonary  artery hypertension associated with left heart failure or valvu-  lar disease is caused by increased pulmonary venous pressure  and is discussed in Chapter 32. COPD is the most common  lung disease associated with PAH, but any condition that  causes chronic hypoxemia can result in pulmonary hyperten-  sion. Recurrent pulmonary embolism may be subclinical in    1. Pulmonary artery hypertension (PAH)  1.1 Idiopathic (IPAH)  1.2 Heritable  1.2.1 BMPR2  1.2.2 ALK1, endoglin (with or without hereditary hemorrhagic  telangiectasia)  1.2.3 Unknown  1.3 Drug and toxin induced  1.4 Associated with (APAH)  1.4.1 Connective tissue disease  1.4.2 HIV infection  1.4.3 Portal hypertension  1.4.4 Congenital heart disease  1.4.5 Schistosomiasis  1.4.6 Chronic hemolytic anemia  1.5 Persistent pulmonary hypertension of the newborn  ’, Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary  hemangiomatosis (PCH)  . Pulmonary hypertension associated with left-sided heart diseases  2.1 Systolic dysfunction  2.2 Diastolic dysfunction  2.3 Valvular disease  . Pulmonary hypertension associated with lung diseases and/or hypoxia  3.1 Chronic obstructive pulmonary disease  3.2 Interstitial lung disease  3.3 Other pulmonary diseases with mixed restrictive and obstructive  pattern  3.4 Sleep-disordered breathing  3.5 Alveolar hypoventilation disorders  3.6 Chronic exposure to high altitude  3.7 Developmental abnormalities  . Chronic thromboembolic pulmonary hypertension  . Pulmonary hypertension with unclear multifactorial mechanisms  5.1 Hematologic disorders: myeloproliferative disorders, splenectomy  5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocyto-  sis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis  5.3 Metabolic disorders: glycogen storage disease, Gaucher disease,  thyroid disorders  5.4 Others: tumoral obstruction, fibrosing mediastinitis, chronic renal  failure on dialysis    Data from Simonneau G et al: J Am Coll Cardio! 54(1 Suppl):S43-S54,  2009.  HIV, Human immunodeficiency virus.    its presentation and unrecognized until the signs and symp-  toms of PAH are detected.   PATHOPHYSIOLOGY. Idiopathic PAH is characterized by endo-  thelial dysfunction with overproduction of vasoconstrictors  (e.g., thromboxane and endothelin) and decreased production  of vasodilators (e.g., nitric oxide and prostacyclin).!°”!©° Release  of growth factors causes proliferation of endothelial cells, smooth  muscle cells, and fibroblasts, resulting in patchy changes in pre-  capillary pulmonary arteries (resistance vessels). This process  results in luminal narrowing and abnormal vasoconstriction and  is called remodeling.'°* Increased cytosolic calcium (vasocon-  striction), phosphodiesterases (modulate cellular proliferation),    Intimal fibrosis and hypertrophy  of medial smooth muscle layer  of pulmonary arteries    FIGURE 35-21 Pathogenesis of Pulmonary Hypertension and Cor Pul-  monale Caused by Disease of the Respiratory System or Hypoxia. COPD,  Chronic obstructive pulmonary disease.    serotonin (vasoconstrictor), and adrenomedullin (vasodila-  tor) also play a role in the pathogenesis of this disorder. These  combined changes cause resistance to pulmonary artery blood  flow, thus increasing the pressure in the pulmonary arteries. As  resistance and pressure increase, the workload of the right ven-  tricle increases and subsequent right ventricular hypertrophy,  followed by failure, may occur (cor pulmonale). Gas exchange  is reduced with restriction in lung volumes. In individuals with  BMPR2 gene mutations, intracellular signaling abnormalities  result in vascular proliferation. Eventually death results in most  individuals with PAH. The pathogenesis of pulmonary artery  hypertension and cor pulmonale, resulting from disease of the  respiratory system or hypoxia, is shown in Figure 35-21.   Pulmonary hypertension associated with lung respiratory  disease or hypoxia, or both, is a serious complication of many  acute and chronic pulmonary disorders, such as COPD and  hypoventilation associated with obesity. These conditions are  complicated by hypoxic pulmonary vasoconstriction, which  further increases pulmonary artery pressures. '°°   CLINICAL MANIFESTATIONS. Pulmonary artery hypertension may  not be detected until it is quite severe. The symptoms are often  masked by primary pulmonary or cardiovascular disease. The  first indication of pulmonary hypertension is often an abnor-  mality seen on a chest radiograph (enlarged pulmonary arteries    and right heart border) or an electrocardiogram that shows  right ventricular hypertrophy. Symptoms of fatigue, chest dis-  comfort, tachypnea and dyspnea on exertion, palpitations, and  cough are common. Examination may reveal peripheral edema,  jugular venous distention, a precordial heave, and accentuation  of the pulmonary compartment of the second heart sound.!“   EVALUATION AND TREATMENT. Definitive diagnosis and accurate  assessment of pulmonary artery pressure can be made only with  right-sided heart catheterization. Common diagnostic modali-  ties used to determine the cause include chest x-ray, echocar-  diography, and computed tomography. The diagnosis of IPAH  is made when all other causes of pulmonary hypertension have  been ruled out.   Laboratory studies, including arterial blood gas testing, liver  function testing, HIV serology, electrocardiography, chest x-ray  and CT scanning, pulmonary function testing, polysomnogra-  phy, ventilation-perfusion scanning, and echocardiography, are  used to detect underlying causes of PAH.!°?!® Disease severity  is quantified using the New York Heart Association or WHO  classification of functional status of patients with pulmonary  artery hypertension.'©   General therapies for PAH include administration of oxy-  gen, diuretics, and anticoagulants and avoidance of contrib-  uting factors such as air travel, decongestant medications,  nonsteroidal anti-inflammatory medications, pregnancy, and  tobacco use. Medications used in the treatment of PAH include  prostacyclin analogs (epoprostenol, beraprost, iloprost), endo-  thelin receptor antagonists (bosentan, ambrisentan), and phos-  phodiesterase-5 inhibitors.!°° Those who fail medical therapy  may be candidates for lung transplantation.   The most effective treatment for secondary pulmonary  artery hypertension is treatment of the primary disorder. How-  ever, once pulmonary hypertension has persisted long enough  for hypertrophy of the medial smooth muscle layer to develop  (as it does with chronic hypoxemia), it is no longer reversible.  Treatment relies on the use of supplemental oxygen to reverse  hypoxic vasoconstriction.    Cor pulmonale is secondary to pulmonary artery hypertension  and consists of right ventricular enlargement (hypertrophy,  dilation, or both).!°”   PATHOPHYSIOLOGY. Cor pulmonale develops as pulmonary  artery hypertension creates chronic pressure overload in the  right ventricle similar to that created in the left ventricle by  systemic hypertension. (Systemic hypertension is discussed in  Chapter 32.) Pressure overload increases the work of the right  ventricle, causes hypertrophy of the normally thin-walled heart  muscle, and compromises right ventricular myocardial perfu-  sion. Acute hypoxemia, such as might occur with pneumonia,  can exaggerate pulmonary hypertension and dilate the ventricle  as well. Right ventricular filling pressures are normal until fail-  ure occurs. The right ventricle usually fails when pulmonary  artery pressure equals systemic blood pressure.   CLINICAL MANIFESTATIONS. The clinical manifestations of cor  pulmonale may be obscured by primary respiratory disease and  appear only during exercise testing. The heart appears normal    at rest, but with exercise, cardiac output falls. The electrocardio-  gram shows right ventricular hypertrophy. Chest pain is com-  mon. The pulmonary component of the second heart sound,  which represents closure of the pulmonic valve, may be accen-  tuated, and a pulmonic valve murmur also may be present. Tri-  cuspid valve murmur may accompany the development of right  ventricular failure. Peripheral edema, hepatic congestion, and  jugular venous distention often may be detected.   EVALUATION AND TREATMENT. Diagnosis is made on the basis of  physical examination, radiologic examination, and electrocar-  diogram or echocardiogram, or both. The goal of treatment for  cor pulmonale is to decrease the workload of the right ventricle  by lowering pulmonary artery pressure. Treatment is the same  as for pulmonary artery hypertension, and its success depends  on reversal of the underlying lung disease.   Cancer of the larynx represents approximately 2% to 3% of all  cancers in the United States. There were an estimated 12,260  new cases and 3630 deaths in 2013.1   The risk of laryngeal cancer is increased by the amount of  tobacco smoked; risk is further heightened with the combina-  tion of smoking and alcohol consumption. Gastroesophageal  reflux disease is also a risk factor.'°? The human papillomavirus  (HPV) has been linked to both benign and malignant disease of  the larynx.'”? The highest incidence is in men between 50 and  75 years of age.   PATHOPHYSIOLOGY. Carcinoma of the true vocal cords (glottis)  is more common than that of the supraglottic structures (epi-  glottis, aryepiglottic folds, arytenoids, and false cords). Tumors  of the subglottic area are rare. Squamous cell carcinoma is the  most common cell type, although small cell carcinomas also  occur (Figure 35-22). Laryngeal dysplasia has a high risk of  progressing to malignancy. Metastasis develops by spreading to  the draining lymph nodes, and distant metastasis, usually to the  lung, is rare.   CLINICAL MANIFESTATIONS. The presenting symptoms of laryn-  geal cancer include hoarseness, dyspnea, and cough. Progres-  sive hoarseness is the most significant symptom and can result  in voice loss. Dyspnea is rare in the case of supraglottic tumors,  but can be severe in subglottic tumors. Cough occurs less com-  monly and may follow swallowing. Laryngeal pain or a sore  throat is likely to be present with supraglottic lesions.   EVALUATION AND TREATMENT. Evaluation of the larynx includes  external inspection and palpation of the larynx and the lymph  nodes in the neck. Indirect laryngoscopy provides a stereoscopic  view of the structure and movement of the larynx. A biopsy also  can be obtained during this procedure. Direct laryngoscopy  provides specific visualization of the tumor. Plain films of the  larynx and CT facilitate the identification of tumor boundar-  ies and the degree of extension to surrounding tissue. Magnetic  resonance imaging (MRI) and positron-emission tomography  (PET) can be used for staging.   Combined chemotherapy and radiation can result in cure in  selected cases; however, sequelae such as swallowing and speech  difficulties may result.'!’! Photodynamic therapy improves    FIGURE 35-22 Laryngeal Cancer. A, Mirror view of carcinoma of right false cord partially hiding true cord. B, Lateral  view. (From del Regato JA, Spjut HJ, Cox JD: Ackerman and del Regato’s cancer, ed 2, St Louis, 1985, Mosby.)    outcomes while preserving function in many individuals with  early stage disease. Partial laryngectomies are the preferred  treatment for small supraglottic and subglottic malignancies.  Total laryngectomy is required when lesions are extensive and  involve the cartilage.!”*!7° Swallowing and speech therapy after  treatment can significantly improve recovery.    Lung Cancer  Lung cancers (bronchogenic carcinomas) arise from the epi-  thelium of the respiratory tract. As such, the term lung cancer  excludes other pulmonary tumors, including sarcomas, lym-  phomas, blastomas, hematomas, and mesotheliomas. Impor-  tant trends in lung cancer are summarized in Box 35-3. The  most common cause of lung cancer is tobacco smoking, and  approximately 10% to 15% of active smokers will develop lung  cancer. About 10% to 25% of lung cancers occur in never-  smokers and it is estimated that one fourth of lung cancer cases  among never-smokers could be attributed to exposure to pas-  sive tobacco smoke.'”* Tobacco smoke contains several organ-  specific carcinogens, and smoking has been causally related to  carcinogenesis at several sites, including the larynx, oral cav-  ity, esophagus, and urinary bladder. Many genetic mechanisms  have been implicated in the risk for lung cancer including gene  mutations, gene amplification, increases in protein expres-  sion, losses in protein expression, tumor-suppressing altera-  tions, tumor-acquired DNA methylation, and chromosomal  aberrations!”° (see What’s New? Genetic and Immunologic  Breakthroughs in Lung Cancer Treatment). Theories of carci-  nogenesis are discussed in Chapter 12. Currently there are no  specific tools for predicting risk for or rate of progression of  lung cancer.!7°   Environmental or occupational risk factors associated with  lung cancer include benzopyrene, radon gas, metals (chro-  mium, cadmium, arsenic), asbestos fibers, diesel exhaust,  nitrogen mustard gases, nickel, silica, vinyl chloride, and chlo-  romethyl methyl ether.'°° Primary lung cancers arise from cells  that line the bronchi within the lungs and are therefore called  bronchogenic carcinomas. It is now believed that most of these    Incidence  An estimated 22,190 new cases in 2013: 118,080 in men and 110,100 in women.   An estimated 159,480 deaths in 2012: 87,260 in men and 72,200 in women.  The death rate in men is declining but continues to rise for women, and lung  cancer remains by far the greatest cancer killer of men and women.   Cigarette smoking is the number one risk factor. Environmental smoke expo-  sure (exposure to someone else's cigarette smoke) increases the risk of lung  cancer. Occupational risk factors include exposure to asbestos dust, arsenic,  chromium, nickel, ionizing radiation, chloromethyl methyl ether, coal products,  mustard gas, and vinyl chloride.    Warning Signs  A persistent cough, sputum streaked with blood, chest pain, recurring attacks    of pneumonia or bronchitis, weight loss, hard nodes in neck or axilla.   Lung cancer is very difficult to detect early. Periodic chest x-ray films, sputum  cytologic analysis, and computed tomography can detect presymptomatic,  early stage lung cancers, particularly of the squamous cell type; however, no  conclusive evidence of reduction in lung cancer mortality as a consequence of  screening has been found.   Surgical resection of the entire tumor is the only treatment that results in  cure; however, the disease is often too advanced by the time of diagnosis for  surgery to be indicated. Radiation therapy and chemotherapy can be used as  adjunctive or palliative treatment modalities. New treatments include gene  and immunotherapies.    Survival  Although the stage of cancer progression at the time of diagnosis greatly affects  prognosis, overall only 20% of individuals live 5 or more years after diagnosis.    Data from American Cancer Society: Cancer facts and figures 2013.  Available at www.cancer.org/research/cancerfactsfigures/cancerfacts  figures/cancer-facts-figures-2013.    New chemotherapeutic agents have slightly improved outcomes in the man-  agement of lung cancer, but overall survival rates for advanced stage dis-  ease remain poor and the toxicities of these regimens limit their use. New  understandings of the genetic and immunologic features of lung cancer cells  have led to new treatments. Gene therapy is emerging as a way of inducing  tumor apoptosis, restoring normal tumor-suppressor gene function (e.g., 253),  promoting tumor-suicide gene expression, and increasing tumor responsive-  ness to chemoradiation through gene transfer, thereby restoring normal DNA  methylation patterns and altering microRNA function. Immunologic therapies  include vaccines that stimulate tumor-specific antibodies, antibodies to epi-  dermal growth factor receptors (erlotinib, gefitinib, and cetuximab), and anti-  angiogenesis drugs; direct tumor delivery of activating cytokines; and blocking  tumor immunosuppression. The effectiveness of these strategies, the timing  of delivery, optimal drug combinations and their side effects are still being  evaluated, but new knowledge is leading to new opportunities for treatment.    Data from Amos SM et al: Blood 118(3):499-509, 2011; Gonzalez Mari-  nello GM, Santos ES, Raez LE: Expert Rev Anticancer Ther 12(4):  439-445, 2012; Kelly RJ, Giaccone G: Cancer J 17(5):302-308, 2011;  Vachani A et al: Clin Chest Med 32(4):865-885, 2011; Zarogoulidis P    cancers arise from mutated epithelial stem cells. Although there  are many types of lung cancer, they are divided into two major  categories based on cell histology: non-small cell lung carci-  noma (NSCLC, about 85% of all lung cancers) and neuroen-  docrine tumors (about 14% of all lung cancers). NSCLC can be  subdivided into three common types of lung cancer: squamous  cell carcinoma, adenocarcinoma, and large cell undifferentiated  carcinoma, and they each have cellular subtypes.'’? Neuroen-  docrine tumors of the lung can be divided into small cell car-  cinoma, large cell neuroendocrine carcinoma, typical carcinoid  tumors, and atypical carcinoid tumors. Small cell carcinoma is  the most common of these neuroendocrine tumors. The clini-  cal and pathologic features that most commonly characterize  these cancer types are illustrated in Figure 35-23 and described  in Table 35-4. Many cancers that arise in other organs of the  body metastasize to the lungs; however, these are not considered  lung cancers and are categorized by their primary site of origin.   Squamous Cell Carcinoma. Squamous cell carcinoma  (SCC) accounts for about 30% of bronchogenic carcino-  mas, representing a sharp decline in incidence in the past two  decades. SCC has the strongest association with smoking.  Smokers with COPD have a higher incidence of this tumor  type.'7° The tumors are typically located centrally near the hila  and project into bronchi. Because of this central location, non-  productive cough or hemoptysis is common. Pneumonia and  atelectasis are often associated with squamous cell carcinoma  (Figure 35-24, A). Chest pain is a late symptom associated with  large tumors. These tumors can remain fairly well localized and  tend not to metastasize until late in the course of the disease.   Adenocarcinoma. Adenocarcinoma (tumor arising from  glands) of the lung constitutes 35% to 40% of all bronchogenic  carcinomas (Figure 35-24, B). Adenocarcinoma occurs more    Cc EN D-™ i  FIGURE 35-23 Cancer of the Lung. A, Squamous (epidermoid) cell carcinoma.  B, Small cell (oat cell) carcinoma. C, Adenocarcinoma. D, Large cell carcinoma.  (From Des Jardins T, Burton GG: Clinical manifestations and assessment of respira-  tory disease, ed 3, St Louis, 1995, Mosby.)    frequently in women, in non-smokers, and in Asians. Envi-  ronmental tobacco smoke, occupational carcinogens, viruses,  hormones, and positive family history are associated with this  tumor type.!”? Epidermal growth factor receptor (EGFR) muta-  tions are also common in this type of lung cancer.'*” These  tumors, which are usually smaller than 4 cm, more commonly  arise in the peripheral regions of the pulmonary parenchyma.  Pulmonary adenocarcinoma develops in a stepwise fashion  through atypical adenomatous hyperplasia, adenocarcinoma in  situ, and minimally invasive adenocarcinoma to invasive carci-  noma. They may be asymptomatic and discovered by routine  chest roentgenogram in the early stages, or the individual may  seek treatment for pleuritic chest pain and shortness of breath  from pleural involvement by the tumor.   Included in the category of adenocarcinoma is bronchoalveo-  lar cell carcinoma. These tumors tend to arise from the terminal  bronchioles and alveoli. They are slow-growing tumors with an  unpredictable pattern of metastasis. Metastasis occurs through  the pulmonary arterial system and mediastinal lymph nodes.  This cell type has the weakest association with smoking.'*!   Diagnosis of NSCLC requires cytologic analysis from biopsy,  and therapy is based on histologic and molecular markers  (e.g., EGFR tyrosine kinase inhibitors for adenocarcinoma) for a  targeted approach to therapy. Surgical resection is possible in a  high proportion of adenocarcinoma cases, but because metasta-  sis occurs early (70% of lung cancers present in advanced stages),  the 5-year survival rate remains below 15%.!*? Clinical trials are  in progress to develop immunotherapies/vaccines for NSCLC.!*°    FIGURE 35-24 Lung Cancer. A, Squamous cell carcinoma. This hilar tumor originates from the main bronchus. B, Periph-    Radiography, sputum analysis,  bronchoscopy, electron microscopy,  immunohistochemistry, and clinical  manifestations (cough, chest pain,  dyspnea, hemoptysis, localized  wheezing)   Chest wall pain, pleural effusion,  cough, sputum production,  hemoptysis, airway obstruction  resulting in pneumonia (if airways  involved); treated surgically   Airway obstruction, signs and  symptoms of excessive hormone  secretion; treated by chemotherapy  and ionizing radiation to thorax and  central nervous system    eral adenocarcinoma. The tumor shows prominent black pigmentation, suggestive of having evolved in an anthracotic scar.  C, Small cell carcinoma. The tumor forms confluent nodules. On cross sectioning, the nodules have an encephaloid (like brain  tissue) appearance. (From Damjanov I, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.)    Large cell  carcinomas constitute 10% to 15% of bronchogenic  carcinomas. This cell type has lost all evidence of differentiation  and is therefore commonly referred to as undifferentiated  large cell anaplastic cancer. Because large cell carcinomas show  none of the histologic findings of squamous cell carcinoma or  adenocarcinoma, they are diagnosed by a process of exclusion.    The cells are generally larger than leukocytes and contain  large, darkly stained nuclei. These tumors commonly arise  peripherally but are found centrally and can grow to distort the  trachea and cause widening of the carina.   Once metastasis has occurred, surgical therapy is limited to  palliative procedures (comfort measures) designed to relieve  obstructive pneumonitis or prevent recurrence of pleural    effusion. Neither radiation therapy nor chemotherapy has been  successful in increasing survival.   Small Cell (Oat Cell) Carcinoma. Small cell lung carcinomas  (SCLCs) are the most common type of neuroendocrine lung  tumors and constitute about 14% of bronchogenic carcino-  mas, but cause 25% of lung cancer deaths.!** Most tumors arise  from the central part of the lung (see Figures 35-23 and 35-24,  C). Cell sizes range from 6 to 8 um. This cell type has the stron-  gest correlation with tobacco smoking. Because these tumors  show a rapid rate of growth and tend to metastasize early and  widely, this type of carcinoma has the worst prognosis of all  lung cancers. Staging for small cell carcinoma is divided into  only two categories: limited disease (TNM stages I to III: 20%  to 30%) and extensive disease (TNM stage IV: 70% to 80%).!®°  Survival time for untreated small cell carcinoma is less than 5%  at 5 years.!°°   Small cell carcinoma arises from neuroendocrine cells that  contain neurosecretory granules and exist throughout the tra-  cheobronchial tree. Thus small cell carcinoma is often asso-  ciated with tumor-derived hormone production. Hormone  production is important to the clinician because resulting  signs and symptoms (called paraneoplastic syndromes) may  be the first manifestation of the underlying cancer. Examples  include hyponatremia (antidiuretic hormone), Cushing syn-  drome (adrenocorticotropic hormone), hypocalcemia (calcito-  nin), gynecomastia (gonadotropins), and carcinoid syndrome  (serotonin).!°7   Bronchial Carcinoid Tumors. Bronchial carcinoid tumors  are rare, represent about 1% of all lung tumors, are not related  to smoking, are slow growing, and have a low potential to metas-  tasize. Carcinoid tumors can occur from childhood through  older age. They arise more commonly in the main or segmental  bronchi, are easily visualized bronchoscopically, and are found  on routine chest radiographs. The tumor cells have dense gran-  ules containing neuroendocrine-like hormones, but they rarely  produce endocrine symptoms. Cells are not recovered from  bronchial washings, because the tumor is covered with normal  mucosa. Fifty percent of individuals with bronchial carcinoid  tumors are asymptomatic. Local surgical resection is curative if  metastasis has not occurred; this can often be done by broncho-  scopic resection, !85:189   Other Lung Cancers. Adenocystic tumors (cylindromas) and  mucoepidermoid carcinomas are rare bronchial gland tumors.  They arise predominantly in the trachea or large airways and  cause obstruction. They can be malignant and metastasize early,  although distal pulmonary metastases are usually slow growing.  Thus it is not unusual for an individual to survive 10 to 15 years  after diagnosis.   Mesotheliomas are rare tumors associated with asbestos  exposure (80%). Most tumors are aggressive malignant tumors  arising from mesothelial cells that line the pleural cavities. A  long latent interval between exposure to asbestos and appear-  ance of mesothelioma usually occurs, and onset of symptoms  may take 20 to 40 years. Clinical manifestations include dyspnea  and chest pain that result from tumor-derived pleural fluid and  invasion of the chest wall. Early detection is difficult because    radiologic studies do not reveal the tumor at an early stage.  Diagnosis is made by chest x-ray, CT scan, and thoracentesis  with cytologic examination of the pleural fluid. Thoracoscopy  also may be used for biopsy. Osteopontin and mesothelin are  being explored as potential tumor markers for early diagnosis.  Current management of malignant mesothelioma includes a  combination of pleuropneumonectomy, chemotherapy, radia-  tion, and hyperthermia.!°°9!   PATHOGENESIS. Environmental carcinogens found in tobacco  smoke and asbestos are associated with malignant transforma-  tions. Tobacco smoke contains as many as 30 lung carcinogens  and is responsible for the vast majority of lung cancers. These  carcinogens, along with inherited genetic predisposition to can-  cers, result in tumor development.'”” Once lung cancer is ini-  tiated by these carcinogen-induced mutations, further tumor  development is promoted by growth factors that alter cell  growth and differentiation, such as epidermal growth factor,  and by production of inflammatory mediators, such as toxic  oxygen free radicals. The bronchial mucosa suffers multiple  carcinogenic “hits” because of repetitive exposure to tobacco  smoke, and eventually epithelial cell changes begin to be visible  on biopsy. These changes progress from metaplasia to carci-  noma in situ and finally to invasive carcinoma.!”* Tumor pro-  gression includes invasion of surrounding tissues and, finally,  metastasis to distant sites, including the brain, bone marrow,  and liver.   CLINICAL MANIFESTATIONS. Symptoms of early stage, localized  disease are nonspecific and are likely to be attributed by the  individual to the effects of smoking. The clinical manifesta-  tions are ambiguous and insidious; they include coughing,  chest pain, excessive sputum production, hemoptysis, pneu-  monia, airway obstruction, pleural effusions, and weight loss.  By the time manifestations are severe enough to motivate  the individual to seek medical advice, the disease is usually  advanced. Symptoms and signs of metastatic disease (e.g.,  neurologic deficits, bone pain) or paraneoplastic syndromes  may be evident.!4   EVALUATION AND TREATMENT. Although it is clear that diagnos-  ing and treating lung cancer early in its development are crucial  for long-term survival, screening for the presence of asymp-  tomatic tumors in high-risk individuals remains controversial.  The latest guidelines state that the evidence remains insufficient  to recommend screening of asymptomatic individuals with  sputum cytologic examination, chest x-ray, or spiral CT. How-  ever, many clinicians and researchers continue to examine these  and other modalities in an effort to find more effective ways  of catching this deadly disease when it is still curable. Screen-  ing using low-dose spiral CT scans decreases risk of dying from  lung cancer in heavy smokers.!°   The diagnosis of lung cancer relies on the history of risk fac-  tors and symptoms, a careful physical examination, and a con-  stellation of diagnostic tests including sputum cytology, chest  x-ray, low-dose CT scanning in high-risk individuals, PET  scanning, bronchoscopy, biopsy, testing for epidermal growth  factor mutations and other molecular markers, and search  for potential metastatic disease.!°° The goal of these evalua-  tions is to (1) establish the presence of a primary lung cancer,    (2) determine its cell type, and (3) stage the tumor. As stated,  SCLC is staged as either limited or extensive. The staging of  NSCLC uses the TNM classification system in which T denotes  the extent of the primary tumor, N indicates nodal involve-  ment, and M describes the extent of metastasis, and is illus-  trated in Figure 35-25.'°’ The use of biomarkers is advancing  as an approach to early detection and staging of lung cancer and  targeted therapies. !°*   For all types of early stage lung carcinoma, the preferred treat-  ment is surgical resection. Once metastasis has taken place, total  surgical resection is more difficult and survival rates dramati-  cally decrease. NSCLC is less responsive to chemotherapy than  is small cell carcinoma, but chemotherapy (e.g., platinum) and  radiation are commonly used as adjuvant or palliative care.!??-70!  Small cell carcinoma is usually widely metastasized by the time  of diagnosis. Palliative chemotherapy or radiation can improve    FIGURE 35-25 Staging of Lung Cancer by the TNM Classification System. A, B, Stage | disease includes tumors clas-  sified as T1, with or without metastasis to the lymph nodes in the ipsilateral hilar region. C, Also included in stage | are tumors  classified as T2 but having no nodal or distant metastases. D, Stage II disease includes those tumors classified as T2, with  metastasis only to the ipsilateral hilar lymph nodes. E, Stage Ill includes all tumors more extensive than T2 or any tumor with  metastasis to the lymph nodes in the mediastinum or adjacent organs. Stage IV (not shown) involves spread to other organs.    survival.”°? New treatment modalities, such as dose-intensified  radiation radiofrequency ablation, microwave ablation, cryo-  therapy, and brachytherapy, may be available as primary or pal-  liative treatment for those for whom surgical removal is not an  option.?”*.704 New and exciting treatments for lung cancer are  under investigation, including antiangiogenic therapy, target-  ing of growth factor receptors, tumor sensitizing agents, gene  therapy, and immunotherapy.””°° Prevention of lung cancer  relies primarily on reduction of exposure to carcinogens. For  most individuals this means smoking cessation, and numerous  governmental and private organizations are working toward the  complete end of cigarette smoking. Other forms of prevention  also are being explored, including chemoprevention in the form  of dietary supplements and pharmaceuticals.!?*?°” Work is in  progress to establish the best methods for screening and early  detection.2°80”   1. Dyspnea is a feeling of breathlessness and increased respira-  tory effort. Orthopnea is dyspnea when a person lies flat.  Paroxysmal nocturnal dyspnea occurs at night and requires  the person to sit or stand for relief.   2. Coughing is a protective reflex that expels secretions and  irritants from the lower airways.   3. Abnormal sputum is a change in the amount, consistency,  color, and odor of sputum.   4. Hemoptysis is expectoration of bloody mucus that can be  caused by bronchitis, TB, abscess, neoplasms, and other  conditions that cause hemorrhage from damaged vessels.   5. Abnormal breathing patterns are adjustments made by the  body to minimize the work of respiratory muscles. They  include Kussmaul, obstructed, restricted, gasping, and/or  Cheyne-Stokes respirations, and sighing.    6. Hypoventilation is decreased alveolar ventilation caused  by airway obstruction, chest wall restriction, or altered  neurologic control of breathing. Hypoventilation causes  increased Paco).   7. Hyperventilation is increased alveolar ventilation produced  by anxiety, head injury, or severe hypoxemia. Hyperventila-  tion causes decreased Paco).   8. Cyanosis is a bluish discoloration of the skin caused by  desaturation of hemoglobin, polycythemia, or peripheral  vasoconstriction.   9. Clubbing of the fingertips is associated with diseases that  interfere with oxygenation of the tissues.   10. Chest pain can result from inflamed pleurae, trachea, bron-  chi, or respiratory muscles.   11. Hypercapnia is increased Paco, caused by a decrease in  minute volume (respiratory rate x tidal volume).    Hypoxemia is a reduced Pao, caused by (a) decreased oxy-  gen content of inspired gas, (b) hypoventilation, (c) diffu-  sion abnormality, (d) ventilation-perfusion mismatch, or  (e) shunting.   Acute respiratory failure is caused by inadequate gas  exchange or ventilation (Pao, <50 mmHg or Paco, 250  mmHg and pH 27.25).    Chest wall compliance is diminished by obesity and kypho-  scoliosis, which compress the lungs, and by neuromuscular  diseases that impair chest wall muscle function.    . Flail chest results from rib or sternal fractures that disrupt    space. It can be caused by spontaneous rupture of weakened  areas of the pleura or can be secondary to pleural damage  caused by disease, trauma, or mechanical ventilation.    . Pleural effusion is the accumulation of fluid in the pleu-    ral space, usually resulting from disorders that promote  transudation or exudation from capillaries underlying the  pleura but occasionally resulting from blockage or injury  that causes lymphatic vessels to drain into the pleural space.    . Empyema is the presence of pus in the pleural space    (infected pleural effusion). The source of the pus is usually  lymphatic drainage from sites of bacterial pneumonia.    Aspiration is passage of fluid and solid particles into the  lung, usually from impaired swallowing and coughing. It  frequently results in pneumonitis and pulmonary infection.    sion of the lung tissue or absorption of gas from obstructed  alveoli.    tissue in the lung. It diminishes lung compliance and may  be idiopathic or caused by disease.    concentrations of oxygen can damage the bronchial mucosa  or alveolocapillary membrane and cause inflammation or  acute respiratory failure.    particles in the workplace, including coal dust, silica, and  asbestos, can cause chronic inflammation, pulmonary  fibrosis, and susceptibility to lower airway infection and  tumor formation.    . Silicosis is a type of pneumoconiosis caused by inhalation of   Pulmonary edema is excess water in the lung caused by dis-  turbances of capillary hydrostatic pressure, capillary oncotic  pressure, or capillary permeability. A common cause is left-  sided heart failure that increases the hydrostatic pressure in  the pulmonary circulation.   ARDS results from an acute, diffuse injury to the alveolo-  capillary membrane and decreased surfactant production,  which increases membrane permeability and causes edema  and atelectasis.   Obstructive pulmonary disease is characterized by airway  obstruction that causes difficult expiration. Obstructive dis-  ease can be acute or chronic and includes asthma, chronic  bronchitis, and emphysema.   Asthma is a chronic inflammatory disorder of the bronchial  mucosa that causes bronchial hyperresponsiveness, muco-  sal edema, airway constriction, and variable obstruction to  airflow. Obstruction is caused by episodic attacks of bron-  chospasm, bronchial inflammation, mucosal edema, and  increased mucus production.   Chronic bronchitis is a chronic inflammation of the bron-  chi that causes airway obstruction resulting from bronchial  smooth muscle hypertrophy and production of thick, tena-  cious mucus.   Emphysema results from destruction of the alveolar septa  and loss of passive elastic recoil, leading to airway col-  lapse and obstruction to gas flow during expiration and air  trapping.   Emphysema in which septal deterioration is caused by o,-  antitrypsin deficiency or old age tends to be panacinar.  Emphysema in which septal deterioration results from  smoking tends to be centriacinar.   Upper respiratory tract infections are the most com-  mon cause of short-term disability in the United States  and include rhinitis (the common cold), pharyngitis, and  laryngitis.   Serious lower respiratory tract infections, which occur  most often in older adults and individuals with impaired  immunity or underlying disease, include pneumonia and  tuberculosis.   Pneumonia can be categorized as community-acquired  (CAP), healthcare-associated (HCAP), hospital-acquired  (HAP), or ventilator-associated (VAP).   Pneumococcal pneumonia is an acute lung infection result-  ing in an inflammatory response with four phases: (a) con-  solidation, (b) red hepatization, (c) gray hepatization, and  (d) resolution.   Viral pneumonia is an acute, self-limiting lung infection  usually caused by the influenza virus.   TB is a lung infection caused by M. tuberculosis (tubercle  bacillus).    In TB the inflammatory response isolates colonies of bacilli  by enclosing them in tubercles and surrounding the tuber-  cles with scar tissue.   Bacilli may remain dormant within the tubercles for life,  or if the immune system becomes compromised, they may  cause recurrence of active disease.   Abscesses are circumscribed areas of destruction of lung  parenchyma with suppuration usually resulting from aspi-  ration pneumonia.   Acute bronchitis is acute infection or inflammation of the  airways or bronchi usually caused by a virus.   Pulmonary vascular diseases are caused by embolism or  hypertension in the pulmonary circulation.   PE is occlusion of a portion of the pulmonary vascular bed  by a thrombus (most common), a tissue fragment, or an air  bubble. Depending on its size and location, the embolus can  cause hypoxic vasoconstriction, pulmonary edema, atelec-  tasis, pulmonary hypertension, shock, and even death.  Pulmonary artery hypertension (pulmonary artery pres-  sure 5 to 10 mmHg greater than normal) is caused by  (a) elevated left ventricular pressure, (b) increased blood  flow through the pulmonary circulation, (c) oblitera-  tion or obstruction of the vascular bed, or (d) active   Cor pulmonale is right ventricular enlargement caused  by chronic pulmonary hypertension. Cor pulmonale pro-  gresses to right ventricular failure if the pulmonary hyper-  tension is not reversed.   Laryngeal cancer occurs primarily in men and represents  2% to 3% of all cancers. Squamous cell carcinoma of the  true vocal cords is most common and manifests with a clin-  ical symptom of progressive hoarseness.   Lung cancer, the most frequent cause of cancer death in  the United States, is commonly caused by cigarette tobacco  smoking.   Cancer cell types include non-small cell lung cancer (squa-  mous cell carcinoma, adenocarcinoma, large cell undiffer-  entiated carcinoma) and neuroendocrine tumors (small cell  carcinoma and bronchial carcinoid tumors). Other tumors  include small cell (oat cell) carcinoma, bronchial adenoma,  adenocystic tumors (cylindromas), mucoepidermoid carci-  nomas (bronchial tumors), and mesothelioma. Each type  arises in a characteristic site or type of tissue, causes dis-  tinctive clinical manifestations, and differs in likelihood of  metastasis and prognosis.   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As part of your Pageburst Digital Book, you can access the following Integrated Resources:  Animations  Asthma  Atelectasis  Hypercapnia  Hypoxemia  Pleural Effusion  Pulmonary Embolism  Pulmonary Hypertension  Tension Pneumothorax  Case Study  Case Study with Answers    Structure and Function, 1290  Upper Airway, 1290  Lower Airways and Lung Parenchyma, 1290  Chest Wall Dynamics, 1292  Metabolic Characteristics, 1292  Immunologic Incompetence, 1292  Physiologic Control of Respiration, 1293  Disorders of the Upper Airways, 1293  Upper Airway Obstruction, 1293    Alterations of respiratory function in children are influenced by  age, development, gender, race, genetic dominance, and envi-  ronmental conditions. Newborns, premature newborns in par-  ticular, are especially vulnerable to a variety of upper and lower  airway infections caused by immaturity of the airways, circula-  tion, chest wall, and the immune system. Structural differences  in infants and children also render them less competent to tol-  erate conditions that cause increased work of breathing. Access  to health care and timeliness of immunizations influence the  incidence and severity of pulmonary disorders.    A number of structural characteristics of the pulmonary sys-  tem influence the way in which infants and children respond  to respiratory disturbances. These include structural character-  istics of the upper and lower respiratory tracts, chest wall and  lung dynamics, metabolic requirements, immunologic imma-  turity, and physiologic control of respiration.    Disorders of the Lower Airways, 1301  Respiratory Distress Syndrome of the Newborn, 1301  Bronchopulmonary Dysplasia, 1303  Respiratory Tract Infections, 1305  Aspiration Pneumonitis, 1308  Bronchiolitis Obliterans, 1308  Asthma, 1308  Acute Lung Injury/Acute Respiratory Distress Syndrome, 1310  Cystic Fibrosis, 1310  Sudden Infant Death Syndrome, 1313   All conducting airways (the portions of airway that do not par-  ticipate in gas exchange) are present at birth and change only in  size throughout childhood. Branching of the bronchial tree is in  fact complete by the sixteenth week of fetal life.   Because infants and children naturally have smaller-diameter  airways than adults, they suffer more obstruction for a given  degree of mucosal edema or secretion accumulation. The rela-  tive sizes of tonsils, adenoids, and epiglottis likewise are propor-  tionately greater in the young child and with swelling can impose  a significant site of obstruction. Infants up to 2 to 3 months of  age are “obligatory nose breathers” and are unable to breathe in  through their mouths. Nasal congestion is therefore a serious  threat to a young infant.   During fetal development the lung is transformed from a some-  what dense organ to one that is more delicately structured to  facilitate air exchange. Beginning in the second trimester, there    is loss of interstitial (mesenchymal) tissue with concomitant the alveoli increase in size and complexity. In addition to the  expansion of the future air spaces. Capillaries grow into the distal structural development of the lung in utero, there is accompa-  respiratory units that keep subdividing (alveolarization) to max- —_nying functional maturation during which specialized cell types,  imize surface area for gas exchange. The number of alveoli con- such as type II cells, manifest. (Figure 36-1 contains a summary  tinues to increase during the first 5 to 8 years of life, after which — of alveolar development and stages of fetal lung development.)    FIGURE 36-1 Prenatal Development of the Alveolar Unit and Stages of Lung Development. A, Epithelial cells differ-  entiate into type Il and type | cells. Mature type Il cells are cuboidal, have apical microvilli, and contain lamellar bodies for sur-  factant storage and secretion. Type | cells are derived from type II cells and consist of flattened epithelium overlying capillaries,  thus forming part of the desired thin air-blood barrier. During fetal development the pulmonary capillaries initially are randomly  distributed in mesenchyme. They progressively arrange around the epithelial tubes and establish close contacts to the lining  epithelium. Overall the volume of mesenchyme decreases and that of the potential air space increases. B, Stages of fetal lung  development. (B adapted from Gleason CA, Devaskar S: Avery's diseases of the newborn, ed 9, Philadelphia, 2012, Saunders.)    Surfactant is a lipid-protein mix that is produced by type II  alveolar cells and is critical for maintaining alveolar expan-  sion (thus allowing normal gas exchange). It lines alveoli and  reduces surface tension, preventing alveolar collapse at the end  of each exhalation. Without surfactant the alveoli tend to stay  closed, demanding greater inspiratory force and work of breath-  ing to reexpand on the next breath. Deficiency of surfactant is  often seen in premature infants and causes respiratory distress  syndrome (RDS), also known as hyaline membrane disease.  Surfactant is produced by 20 to 24 weeks of gestation and is  secreted into the fetal airways by 30 weeks. The more premature  the infant, the higher the risk of RDS.   Chest wall compliance is high in infants, particularly premature  infants. The cartilaginous structures of the thoracic cage are not  yet well ossified (ossification continues to occur throughout    FIGURE 36-2 Developmental Differences in the Chest Wall and Lung  Mechanics. A, Changes in chest wall shape with age. B, Differences in lung  mechanics caused by differences in chest wall compliance (degree of rigidity) in  premature infants and adults. (Arrows indicate direction of airflow, chest wall  movement, and diaphragm movement.)    childhood), and the chest wall is easily collapsible. During inspi-  ration in the young child, air is drawn in by the downward move-  ment of the diaphragm, but the resulting negative pressure causes  the “soft” chest wall to be drawn inward (Figure 36-2); this pro-  duces so-called paradoxic breathing, or diaphragmatic breathing.  Paradoxic breathing is especially seen during rapid eye movement  (REM) sleep of premature infants. With pulmonary compromise  the accessory muscles are drawn inward, creating retraction of  the intercostal and supraclavicular spaces (Figure 36-3).   Resting lung volume, or functional residual capacity  (FRC), represents the balance point between the natural elas-  tic recoil of the lungs (to collapse) and the elastic recoil of  the chest wall (to expand). In the face of an overly compli-  ant chest wall, infants up to about 1 year of age are thought  to maintain their FRC and avoid atelectasis by muscular  “braking” of their expiration. This may occur either by active  glottic narrowing or by increased activity of the inspiratory  intercostal muscles.    The basal metabolic rate of a child is greater than that of an  adult, and thus oxygen consumption (VO) is greater per  unit of body weight. The VO, of the child’s normal breathing  accounts for up to 25% of the total VO. The work of breathing  increases VO, exponentially with respiratory distress. Children  have less muscle glycogen reserve, which limits the efficiency  of accessory muscles, such that fatigue with lactic acidosis can  occur quickly. Children also have a high proportion of extracel-  lular fluid and therefore more quickly lose fluid and become  dehydrated as a result of fever, from environmental heat, or in  association with tachypnea (which causes evaporation from the  respiratory tract).    Passive immunity with immunoglobulin G (IgG) is nor-  mally conveyed transplacentally from the mother to the fetus    beginning at 20 weeks of gestation; thus IgG levels are lower  in preterm than term infants. Breast-feeding allows transfer  of secretory IgA, IgG, and IgM after birth. Because IgG has a  half-life of approximately 21 days, the placentally transferred  antibodies are depleted after just a few months. Infants are  able to synthesize IgG, IgM, and IgA, and the levels of these  immunoglobulins increase slowly with age. Cell-mediated  immunity is also not fully developed in the neonate, which  creates a situation of enhanced susceptibility to viral and fun-  gal infections.   For up to 3 weeks of age, the newborn has a blunted ventila-  tory response to hypoxia compared with older children and  adults. The mechanisms for this are not well understood but  may reflect reduced activity of the peripheral chemorecep-  tors (in the carotid body) and nonadaptive responses in the  respiratory center (in the brainstem). Ventilatory response to  hypercarbia is normal in term infants but may be reduced in  premature infants. Congenital or acquired lesions of the central  nervous system may cause hypoventilation or apnea. Exposure  to maternal smoking both during and after fetal development  can have significant deleterious effects on lung development  and subsequent susceptibility to pulmonary disorders (see  What’s New? Maternal Smoking: Fetal Lung Development and  Lung Disease).    Pulmonary dysfunction can be categorized into disorders of  either the upper airway or the lower airway. Signs of acute    Maternal smoking during pregnancy is a risk factor for several adverse  developmental outcomes, including abnormal fetal lung development. Lung  development is most critical during late fetal and early postnatal life—the  saccular and alveolar developmental phases. Abnormalities occurring during  these stages can have long-term effects on lung function, contributing to  the development of asthma in children and lung disease in adults. Maternal  smoking and altered fetal pulmonary structure are related to nicotine that  crosses the placenta and is expressed in breast milk. There is up-regulation  of nicotinic acetylcholine receptors in the fetal lung. Animal models have  demonstrated alterations in lung structure including decreased alveolar-  ization, thickening of the alveolocapillary membrane, decreased synthesis  of surfactant, decreased airway diameter, decreased vessel density, and  increased airway hyperresponsiveness. Smoke exposure also changes the  genetics that control lung growth and maintenance of lung structure, and  accelerates lung aging. Prevention of maternal smoking during pregnancy  and lactation is required and nicotine replacement therapy is not advised  for these women.    Data from Abbott LC, Winzer-Serhan UH: Crit Rev Toxicol 42(4):279-303,  2012; Harding R, Maritz G: Semin Fetal Neonatal Med 17(2):67-72, 2012;  Kajeka R: Pharmacol Ther 114:129-145, 2007; Maritz GS, Harding R: /nt  J Environ Res Public Health 8(3):875-898, 2011; Wongtrakool C et al: Am  J Respir Cell Mol Biol 46(5):695-702, 2012.   * Increased respiratory effort with retractions (see Figure  36-3) or gasping (apnea in some conditions)   + Physiologic compromise reflected by hemoglobin desatura-  tion, hypoxemia, hypercarbia, and acidosis    The crucial issue in the upper airways is patency. The most  common causes of acute-onset upper airway obstruction  (UAO) in children are infections, foreign body aspiration,  angioedema, obstructive sleep apnea, and trauma. Chronic  UAO has many etiologies, including congenital malforma-  tions affecting the airway, cartilaginous weakness, vocal cord  paralysis, and subglottic stenosis. Chronic upper airway symp-  toms should prompt referral to a pediatric pulmonologist or  an otolaryngologist because specialized diagnostic studies may  be needed. A list of causes of pediatric UAO can be found in  Box 36-1.   The site and nature of the obstruction are often discernible  by assessing the noise associated with breathing, the quality of  the voice or cry, and the presence of feeding difficulties. This  assessment often can be made without even touching the child.  Likewise, the severity of the problem often can be judged by  visual observation of signs, including retractions, nasal flaring,  gasping or obstructed breaths, anxiety, restlessness, or need to  maintain a specific head or body position. Agitation should be  regarded as a likely sign of hypoxemia or obstruction. In acute  UAO, increasing the child’s anxiety by excessive physical exami-  nation can worsen the condition. The child should be kept as  calm as possible. The clinician should never attempt a pharyn-  geal examination if there is any suspicion of epiglottitis or retro-  pharyngeal abscess because this maneuver may precipitate acute  obstruction of the airway.   The sounds of the child’s breathing can provide key clues  (Figure 36-4). A sonorous, snoring noise is typical for nasopha-  ryngeal obstruction, such as adenotonsillar hypertrophy. A com-  mon sign of pediatric UAO is stridor, a harsh, vibratory sound  of variable pitch caused by turbulent flow through the partially  obstructed airway. A diagnostic approach to stridor is outlined  in Figure 36-5. Whether it is present in inspiration, expiration,  or both reflects the site of the problem. In general, inspiratory  stridor is generated with obstruction of the extrathoracic airway  (above the thoracic inlet), which includes the supraglottic struc-  tures, the larynx, the subglottic space, and the upper trachea.  Expiratory stridor or a monophonic wheeze may be generated  by an obstruction in the intrathoracic airway (the middle to  lower trachea and central bronchi). Biphasic stridor typically  reflects obstruction at the glottis (e.g., vocal cord paralysis) itself  or a fixed rather than a dynamic lesion in the subglottic space  (e.g., hemangioma or subglottic stenosis). Biphasic noise may  sometimes mean abnormalities of both the extrathoracic and  intrathoracic trachea (long-segment stenosis or malacia).    CAUSES OF UPPER AIRWAY  OBSTRUCTION IN CHILDREN  ACCORDING TO SITE OF  OBSTRUCTION   Laryngeal web, cyst, or laryngocele  Laryngotracheobronchitis (viral croup)  Acute spasmodic laryngitis (spasmodic croup)   Cystic hygroma  Subglottic hemangioma  Laryngeal papilloma  Angioneurotic edema  Laryngospasm (hypocalcemic tetany)  Psychogenic stridor    Adapted with permission from Diagnosis of Stridor in Children, November  15, 1999, American Family Physician. Copyright 1999 American Academy  of Family Physicians. All rights reserved.    Abnormalities of voice or cry (weak or hoarse) suggest prob-  lems at the larynx, such as vocal cord paralysis. Muffling of the  voice, especially in an acute condition, suggests supralaryngeal  obstruction, such as epiglottitis or retropharyngeal abscess.  Pronounced cough may be an irritative symptom, such as that  produced by an aspirated foreign body, or may be a sign of tra-  cheal obstruction. The cough associated with croup or tracheal  foreign body is usually harsh and barking.   Airway obstruction occurs sooner in infants than in older  children. Obviously, airway luminal size is smaller in accordance  with smaller body size, but any decrease in luminal diameter  will be much more significant. This is because airway resistance  is proportional to the inverse of the fourth power of the radius;  thus a decrease to half the original diameter increases resistance  16-fold. Furthermore, an infant’s cartilaginous structures are  more collapsible and thus are prone to creating or contributing  to a situation of UAO.    Infections of the upper airway (Table 36-1) are common in  children; some have the potential to cause life-threatening    PN  FIGURE 36-4 Listening Can Help Locate the Site of Airway Obstruction.  A loud, gasping snore suggests enlarged tonsils or adenoids. Stridor during inspira-  tion suggests the airway is compromised at the level of the supralaryngeal structures  (epiglottis and arytenoid cartilages), vocal cords, subglottic region, or upper trachea.  With forced inspiration, intrathoracic pressure becomes quite negative and is less  than atmospheric pressure, promoting collapse at or just above the site of obstruction.  Expiratory stridor or central wheeze results from narrowing or collapse of the lower  trachea or bronchi. During forced exhalation, rising pleural pressure may exceed intra-  tracheal pressure. Airway noise during both inspiration and expiration often repre-  sents a fixed obstruction of the vocal cords or subglottic space. Hoarseness or a weak  cry is a byproduct of obstruction at the vocal cords. If a cough is croupy or low pitched,  suspect tracheal pathology. (Redrawn from Eavey RD: Contemp Pediatr 3[6]:78, 1986;  used with permission; original illustration by Paul Singh-Roy.)    emergencies. Recognition and rapid evaluation of these prob-  lems are crucial pediatric care skills.   Croup. Croup illnesses can be divided into two categories:  (1) acute laryngotracheobronchitis (croup) and (2) spasmodic  croup. Diphtheria can be considered a croup illness but is  now rare because of vaccinations. Croup illnesses are all  characterized by infection and obstruction of the upper  airways.!   Croup is an acute laryngotracheobronchitis and most  commonly occurs in children from 6 months to 3 years of age,  with peak incidence at 2 years of age.” In 85% of cases, croup  is caused by a virus, most commonly parainfluenza; however,  other viruses such as influenza A virus, respiratory syncytial  virus (RSV), rhinovirus, adenovirus, and rubella virus (mea-  sles) as well as the atypical bacterium Mycoplasma pneumoniae  has been associated with causation. The incidence of croup is  highest in late autumn and winter, corresponding to the parain-  fluenza and RSV seasons, respectively. Croup is more common  in boys than girls. In a significant portion of affected children,  croup is a recurrent problem during childhood, and there is a  family history of croup in about 15% of cases. Spasmodic croup  is characterized by similar hoarseness, barking cough, and stri-  dor, but is of sudden onset, usually at night and without viral    Macroglossia Subglottic Foreign body  Neoplasm stenosis Asthma  Adenotonsillar Vocal cord Possible foreign  hypertrophy paralysis body  Congenital Probable foreign  disorders body  Spasmodic Tracheal mass Asthma  croup  Acute tonsillitis  Mononucleosis .  Epiglottitis Viral croup  Abscess Epiglottitis  * Peritonsillar Retropharyngeal  abscess    * The age of the patient must be considered in making a specific diagnosis    t Laryngeal problems are frequently associated with inspiratory and expiratory stridor    FIGURE 36-5 Diagnostic Approach to Stridor. (Adapted from Handler SD: Stridor. In Fleisher GR, Ludwig S, editors:  Textbook of pediatric emergency medicine, Baltimore, 1993, Williams & Wilkins.)    prodrome. It often resolves as quickly as it develops and usu-  ally occurs in older children. The etiology is unknown although  association with viruses, allergies, asthma, and gastroesopha-  geal reflux disease (GERD) is being investigated.’   PATHOPHYSIOLOGY. The pathophysiology of viral croup is  caused primarily by subglottic edema from the infection. The  mucous membranes of the larynx are tightly adherent to the  underlying cartilage, whereas those of the subglottic space are  looser and thus allow accumulation of mucosal and submuco-  sal edema (Figure 36-6). Furthermore, the cricoid cartilage is  structurally the narrowest point of the airway, making edema  in this area critical. As illustrated in Figure 36-7, increased resis-  tance to airflow leads to increased work of breathing, which  generates more negative intrathoracic pressure, which in turn  may exacerbate dynamic collapse of the upper airway.    CLINICAL MANIFESTATIONS. Typically there is a prodrome of rhi-  norrhea, sore throat, and low-grade fever for a few days. The  child then develops the characteristic harsh (seal-like) barking  cough, hoarse voice, and inspiratory stridor. Most cases are  mild and resolve spontaneously after several more days. Occa-  sionally, however, UAO becomes severe and requires urgent  management.   EVALUATION AND TREATMENT. The degree of symptoms deter-  mines the level of treatment. Most children have a barking  cough and viral symptoms and may need no specific treatment.  However, the presence of stridor (especially at rest), retractions,  or agitation suggests a sicker child. The tool most often used for  estimating croup severity is the Westley croup score, which pro-  vides a cumulative score for the degree of stridor, retractions, air  entry, cyanosis, dyspnea, and level of consciousness in the child.*    6mo-3yr Usually gradual Viral (parainfluenza 1 and 3, influenza  A, respiratory syncytial virus)    resistant Staphylococcus aureus  (MRSA)  Haemophilus influenzae type B  Group A streptococci  Haemophilus influenzae type B (Hib)  Group A streptococci    appearance; thick  harsh cough; purulent  secretions; may  prefer head elevation  Severe sore throat;  high fever; toxic  appearance; muffled  voice; may drool; sits  erect and quietly  Similar to epiglottitis    FIGURE 36-6 The Larynx and Subglottic Trachea. A, Normal. B, Narrowing  and obstruction from edema caused by croup. (From Hockenberry MJ, Wilson D:  Wong ‘s nursing care of infants and children, ed 9, St Louis, 2011, Mosby.)    Severity also is classified as mild, moderate, and severe.  Most children with croup require no treatment. Inhalation of  humidified air does not improve symptoms in mild to moder-  ate croup.” Glucocorticoids, either injected or oral (dexametha-  sone) or nebulized (budesonide), have been shown to improve  symptoms within 6 hours. Less sleep is lost by children, less  stress is experienced by parents, and fewer children have a need  for return healthcare visits or hospitalization when cortico-  steroids are used.° The use of nebulized racemic epinephrine  improves outcomes with moderate to severe croup.”” Epineph-  rine stimulates a- and $-adrenergic receptors and is thought to  decrease airway secretions and mucosal edema. It is a temporiz-  ing measure until concomitantly given corticosteroids begin to  take effect. Thus children who are given nebulized epinephrine  should be closely observed for 2 to 3 hours to ensure that they  will remain stable. Oxygen also should be administered. Heliox    (helium-oxygen mixture of 80:20 or 70:30) may be used for  severe cases of croup, although there is lack of scientific evi-  dence to establish use in routine clinical practice.®   Acute Epiglottitis. Historically, acute epiglottitis was caused  by Haemophilus influenzae type B (Hib). Since the advent of  Hib immunization, the overall incidence of acute epiglottitis  in children has decreased significantly, although Hib still  accounts for approximately 25% of the cases seen in children.  Infants less than 1 year of age are at greater risk.? Current  pediatric cases usually represent Hib vaccine failures or are  caused by alternative pathogens, such as groups A, B, C, F, and    G streptococci, Streptococcus pneumoniae, Candida species,  Staphylococcus aureus, and viral pathogens. Thermal injuries,  trauma, and posttransplant lymphoproliferative disorder also  have been reported as causes of epiglottitis.!°   PATHOPHYSIOLOGY. The epiglottis arises from the posterior  tongue base and covers the laryngeal inlet during swallowing.  It has a rich blood and lymphatic circulation. Bacterial invasion  of the mucosa with associated inflammation leads to the rapid  development of edema causing severe, life-threatening obstruc-  tion of the upper airway.'°   CLINICAL MANIFESTATIONS. In the classic form of the disease, a  child between 2 and 6 years of age suddenly develops high fever,  irritability, sore throat, a “hot potato voice,” inspiratory stridor,  and severe respiratory distress. The child appears ill and clas-  sically will adopt a forward-leaning position (tripod position)  with drooling and dysphagia (inability to swallow). Examination  of the throat may trigger laryngospasm and cause respiratory  collapse. Death may occur in a few hours. Pneumonia, cervical  lymph node inflammation, otitis, and, rarely, meningitis or sep-  tic arthritis may occur during the course of epiglottitis.   EVALUATION AND TREATMENT. Acute epiglottitis is a life-  threatening emergency. The essentials are early recognition,  avoidance of disturbing the child (which could worsen the  obstruction), and securing the airway. Examination of the throat  should not be attempted because it may trigger laryngospasm and  cause respiratory collapse. Tracheal intubation should be accom-  plished by the most experienced personnel (usually an anesthe-  siologist and/or otolaryngologist) using fiberoptic laryngoscopy.  Subsequent culture of the airway is obtained and intravenous  broad-spectrum antibiotics are administered promptly. Therapy  is reevaluated after culture results return. Corticosteroids also  are generally used in treatment regimens although there are no  published randomized trials to support this practice.!°!* Despite  the severe presentation of epiglottitis, resolution with treatment  is usually rapid, with intubation rarely needed for more than a  couple of days. When Hib epiglottitis is diagnosed, the Ameri-  can Academy of Pediatrics (AAP) recommends that postexpo-  sure prophylaxis with rifampin be administered to household  contacts (specific to certain ages of children present).!2 When  caused by microorganisms other than H. influenzae, as is now  the usual situation, epiglottitis may present in ages outside the  typical range and with more gradual rather than fulminant onset,  thus making diagnosis less obvious. Such cases also may respond  more slowly to treatment.   Tonsillar Infections. Tonsillar infections (tonsillitis) are  occasionally severe enough to cause UAO.! As with other  infections of the upper airway, the incidence of tonsillitis  secondary to group A beta-hemolytic Streptococci (GABHS) and  methicillin-resistant S. aureus (MRSA) has risen notably in the  past 15 years.'* Significant swelling of the tonsils and pharynx  occurs, and a tenacious membrane may cover the mucosa. UVAO  because of tonsillitis is a well-known complication of infectious  mononucleosis, especially in a young child. The development  of UAO in tonsillar infections requires the use of appropriately  selected antibiotics and may require the use of corticosteroids,  especially in the case of mononucleosis.'° Some children with  recurrent tonsillitis benefit from tonsillectomy.    is evident. (From Whiting JL, Chow AW: J Crit /// 2[7]:36, 1987.)    Peritonsillar abscess is usually unilateral and is most often  a complication of acute tonsillitis.'° The most common caus-  ative microorganism is GABHS. Children have fever, sore  throat, dysphagia, trismus, pooling of saliva, and muffled  voice. Peritonsillar bulging (Figure 36-8) and cervical ade-  nopathy on the same side are usually visible. The abscess must  be drained and the child given antibiotics.!’ Death can occur  from spontaneous abscess rupture with aspiration or airway  obstruction. !*   Bacterial Tracheitis. Bacterial tracheitis is the most  common potentially life-threatening upper airway infection  in children. It is most often caused by Staphylococcus aureus  (S. aureus) (including methicillin-resistant [MRSA] strains),  H. influenzae, group A beta-hemolytic Streptococcus (GABHS  [Streptococcus pyogenes]), or Moraxella catarrhalis.'° It accounts  for 5% to 14% of UAOs in children requiring intensive care.”°  A virus or a fungus is more likely to be seen as the source of  tracheitis in immunocompromised children.?! Treatment  of viral croup with corticosteroids has increased the risk for  serious bacterial tracheitis (especially by GABHS), resulting  in death rates between 18% and 40%.’° The presence of  airway edema and copious purulent secretions leads to airway  obstruction that can be worsened by the formation of a tracheal  pseudomembrane and mucosal sloughing. Increased morbidity  can occur because of respiratory and cardiopulmonary arrest,  respiratory failure, pneumonia, septic shock, toxic shock  syndrome, acute respiratory distress syndrome (ARDS), and  multiple organ dysfunction syndrome (MODS). The onset of  symptoms may be sudden or may be preceded by a pre-existing  viral upper respiratory tract infection or croup. The acute  clinical presentation frequently includes tachypnea, stridor,  hoarse voice, fever, cough, and/or increased secretions from  the mouth and nose. There may be evidence of concurrent  infections, such as sinusitis, otitis, pneumonia, or pharyngitis.”  Children with chronic gastroesophageal reflux are more likely to  experience difficulty with these types of concurrent infections.  Management requires the rapid administration of broad-  spectrum intravenous antibiotics. The majority of children with  tracheitis require endotracheal intubation in order to prevent  airway obstruction. Corticosteroids (parenteral and inhaled)    are used to decrease tracheal inflammation. Many children  recover adequately to be extubated within 72 to 96 hours.?°   Retropharyngeal Abscess. Retropharyngeal abscess can  be caused by aerobic, anaerobic, or polymicrobial infection. A  decrease in retropharyngeal abscess has been noted in the past  several years that is likely related to the use of corticosteroids  in the treatment of influenza and croup. There also has been  an increase in GABHS strains associated with this condition,  and the emergence of MRSA as the offending microorganism is  increasingly noted.*4   Retropharyngeal abscess usually occurs more commonly  in male children about 4 years of age and as a consequence of  either nasopharyngeal infection or penetrating local injury.”  Clinical signs include fever, dysphagia, drooling, stridor, respi-  ratory distress, and stiff neck. This condition requires intrave-  nous antibiotics targeted at the suspected microorganism, and  sometimes incision and drainage.”°    Most children who aspirate a foreign object (foreign body  aspiration) are between 1 and 3 years of age. More than  100,000 cases occur each year.’’ Often the aspiration either is  not witnessed or does not seem significant to the parent; thus  medical care is often not pursued until after the first 24 hours.  At the time of aspiration, the child may cough, choke, gag,  or wheeze, and stridor or cyanosis occasionally occurs. This  may be followed by a quiescent interval of minutes to even  weeks or months before symptoms reappear from resulting  local irritation, granulation, bronchial obstruction, or infec-  tion (pneumonia or bronchiectasis). Pronounced inspira-  tory stridor, cough, and wheezing are typical symptoms that  prompt the parents to seek medical attention. Examples of  common aspirated objects include nuts, sunflower seeds, hot  dog chunks, popcorn, coins, and small toys or toy parts. Meat  or food impactions are more common in adolescents. Items  of particular concern are batteries and multiple magnets. In  general, foreign bodies require early intervention secondary  to their propensity to cause respiratory symptoms and com-  plications, including esophageal erosions or aortoesophageal  fistula (rare).   The symptom history is often the most critical aid in diagno-  sis.?° Symptoms are determined by the size of the object and the  site in which it is located, as well as the child’s age and size (see  Figure 36-4). Foreign bodies lodged in the upper trachea typi-  cally produce inspiratory stridor, whereas those located in the  lower intrathoracic airways more commonly produce wheezing.  About 75% of aspirated foreign bodies lodge in a bronchus. Chil-  dren with an unexplained persistent cough and refractory paren-  chymal infiltrates also should be considered for unrecognized  foreign body aspiration.”? Many objects are not radiopaque;  however, if the object has completely occluded a lung segment,  atelectasis will be visible on a chest radiograph. Occasionally, air  will accumulate distal to the obstruction if the object is causing  a ball-valve effect. This effect can sometimes be documented by  inspiratory and expiratory chest films (Figure 36-9). In a younger  child, bilateral decubitus films may show failure to compress the  obstructed lung when in the “down” position.    FIGURE 36-9 Foreign Body Aspiration. Inspiratory (/eft)and expiratory (right)  chest radiographs of a child who aspirated a portion of a potato into the left main-  stem bronchus. Left lung field is hyperaerated and the mediastinum is shifted to the  right on expiration because of left-sided obstructive emphysema. (From Kenna MA,  Bluestone CD: Pediatr Rev 10[1]:25, 1988.)    Most foreign bodies can be removed by bronchoscopy and  only rarely is a pulmonary lobectomy required. Soft particles  such as food, as well as hard objects, must be removed because  infectious processes will otherwise occur.*” Objects lodged in the  laryngeal or subglottic regions are particularly dangerous because  of their potential for complete or near-complete airway occlusion.    Angioedema is a localized edema involving the deep, subcuta-  neous layers of skin or mucous membranes. Generally, angio-  edema causes facial swelling first, particularly around the eyes  and lips, and may progress to airway swelling.*! Angioedema is  usually secondary to allergic phenomena (e.g., allergy to peanuts,  cow’s milk, chicken eggs).°** If airway compromise is apparent,  standard treatment includes epinephrine (subcutaneous), anti-  histamines, and corticosteroids. An occasional cause of pediatric  angioedema is use of angiotensin-converting enzyme inhibitors  for treatment of hypertension or heart disease. Increased levels  of bradykinin appear to mediate this adverse effect by causing  vasodilation, increased vascular permeability, and histamine  release.*?   An inherited deficiency of the plasma protein C-1 inhibi-  tor (C-1 INH) causes hereditary angioneurotic edema (HAE), a  rare but serious problem in children. About 50% of cases occur  during childhood.** The mean age of onset of initial symptoms  is 8 to 12 years but it also may occur as early as the first year  of life. This condition is characterized by recurring attacks of  angioedema involving subcutaneous tissues (especially limbs,  genitalia, and face); abdominal and pelvic viscera; and, much  less often, the airway. Laryngeal attacks in these individuals may  be life threatening and do not respond reliably to standard mea-  sures for airway edema. Complement studies usually provide  an accurate diagnosis.** The mortality of undiagnosed HAE can  be as high as 50%. The mainstays of supportive care are airway  monitoring, hydration, pain relief, and control of nausea. Con-  centrates of C-1 INH appear to produce rapid improvement  within 15 to 60 minutes. Short- and long-term prophylaxis can  be instituted using antifibrinolytic agents, attenuated andro-  gens, and C-1 INH concentrates.*°    Laryngomalacia  FIGURE 36-10 Laryngomalacia. In the normal larynx (left), supralaryn-  geal structures maintain their upright orientation during inspiration. In contrast,  in infants with laryngomalacia (right), there is inward prolapse of the arytenoid  masses, which include the prominent cuneiform tubercles and the arytenoid carti-  lages. The glottis becomes partially covered, and airflow is impeded. Sometimes  the edges of the epiglottis curl inward, further exacerbating the obstruction. In  expiration, these structures are “blown” aside passively.    Congenital malformations can occur at multiple sites from  the nasal openings to the subglottis. Anatomic or functional  obstruction can cause severe respiratory distress.   Laryngomalacia and Tracheomalacia. Laryngomalacia  results from abnormally soft laryngeal cartilages and is the most  common cause of chronic stridor in infants. Boys are twice as  likely as girls to present with symptoms. In laryngomalacia,  the epiglottis or arytenoids, or both, fold inward with  inspiration, partially covering the glottis (Figure 36-10). The  pathophysiology of these abnormalities is still not completely  understood. Two primary hypotheses are anatomic or  neuromuscular.*° Anatomically there may be foreshortened or  tight aryepiglottic folds or there may be redundant soft tissue in  the supraglottis.°? The neuromuscular hypothesis suggests that  there is an abnormality of the sensorimotor integrative function  of the brainstem and peripheral reflexes are responsible  for laryngeal tone and airway patency.*® Laryngeal nerve  hypertrophy also has been documented.*? Gastroesophageal  reflux disease (GERD) and other comorbidities are associated  with laryngomalacia.*”   Typical signs of laryngomalacia include inspiratory stridor  beginning in the first days or weeks of life, accentuated with  activity, and sometimes with positional changes (worse in  supine or head-flexed positions). Feeding difficulties may be  noted, but they are usually mild. Cry is normal. Laryngoscopy  is used to confirm the diagnosis. Laryngomalacia is usually  mild and improves spontaneously over the first year of life as  the supralaryngeal cartilage structures stiffen; thus most cases  are managed with watchful waiting. A late-onset variant of this  disease has been noted in the literature and should be suspected  if the following occurs: potential cause of feeding difficulties in  toddlers, sleep apnea in children, and exercise intolerance in  teenagers.*!42    In tracheomalacia, or tracheobronchomalacia, the tracheo-  bronchial cartilages are flaccid and tend to collapse during the  expiratory cycle, causing stridor. This may be classified as pri-  mary (idiopathic) or secondary. When malacia is caused by a  secondary source, it is usually related to extrinsic compression  of the trachea from a vascular malformation (congenital tra-  cheomalacia). Tracheobronchomalacia presents clinically as a  spectrum of respiratory illnesses that range from life-threatening  conditions to chronic cough and wheeze conditions. In some  cases symptoms may be more subtle than in laryngomalacia.  Low-pitched inspiratory stridor may be a sign of malacia of the  upper trachea or centrally located, single-pitch (monophonic)  wheeze may be present in malacia of the middle to distal trachea.  Tracheomalacia can be suspected clinically and confirmed by  bronchoscopy. Depending on the type and severity of the lesion,  surgical approaches for repair may be indicated.   Vocal Cord Paralysis. Vocal cord paralysis is second  to laryngomalacias as a cause of stridor and is a relatively  uncommon congenital disorder. The vocal cords should move  apart to facilitate inspiration and move together to facilitate  vocalization. Paralysis of one or both vocal cords may affect  breathing, swallowing, and speech. The etiology of the congenital  abnormality is unclear but may be caused by immaturity of the  vagus nerve or brainstem, or both. Iatrogenic injury is frequently  cited as the major secondary cause of vocal cord paralysis, such  as surgical trauma to the recurrent laryngeal nerve during  cardiac surgery. Other secondary causes include Arnold-  Chiari malformation (the region of the brainstem in which  the nucleus ambiguus acts as the “relay station” for laryngeal  function), cerebral palsy, hydrocephalus, myelomeningocele,  spina bifida, or hypoxia.** Other associations include infectious  and neoplastic causes, trauma, and inflammatory conditions.”  In older children and adolescents, exercise has been known to  precipitate vocal cord dysfunction (VCD).*°   Clinical findings of vocal cord paralysis in children less than  1 year include dysphonia, glottic incompetence, GERD, and  stridor.*° It sometimes resolves spontaneously (most often dur-  ing the first year of life) or with correction of the underlying  problem. Flexible laryngoscopy and chest x-ray are common  evaluative tools that may help determine the cause. In some  individuals, VCD may be misdiagnosed as asthma.*” Medi-  cal therapy may include use of corticosteroids, proton pump  inhibitors, and speech therapy. Recurrent pulmonary infections  secondary to aspiration may occur and require treatment until  the cords are repaired.** Severe cases may necessitate endotra-  cheal intubation and tracheostomy. Tracheostomy may be used  until the vocal cords are surgically repaired or can be used as a  permanent measure for bilateral vocal cord paralysis.*®   Subglottic Stenosis. Congenital subglottic stenosis is the  third most common laryngeal anomaly and is defined as a  subglottic airway diameter of less than 4 mm at the cricoid region  ina full-term infant, and less than 3 mm ina premature infant.*®  Incomplete recanalization of the laryngotracheal tube during  the third month of gestation results in this defect. Subglottic  stenosis also is associated with eosinophilic esophagitis, Wegener  granulomatosis, and neurofibromatosis.*?°! Traumatic injury  to the upper airway with development of subglottic stenosis    is a well-described complication of endotracheal intubation.°?  Factors that contribute to subglottic stenosis include utilization  of long-term assisted ventilation, use of an endotracheal  tube that is too large, excessive movement of the tube, and  susceptibility of the individual.’ Neonates can tolerate  long periods of endotracheal intubation; the overall rate of  symptomatic subglottic stenosis in neonates is 0.2%.°> The  occurrence of subglottic stenosis can be minimized by ensuring  that the tube size allows a small air leak during inspiration (at a  peak inspiratory force of approximately 25 mmHg) and that the  tube is securely taped. Sedation is generally required to reduce  head movement for children who are intubated. Because of the  rapid growth of the lumen of the trachea and cricoid cartilage  in the first year (which triples in size), infants may outgrow the  obstruction, particularly if mild or moderate.™ Serial balloon  dilation can be effective.’ For severe subglottic stenosis,  laryngotracheal reconstruction (LTR) along with cricotracheal  resection and thyrotracheal anastomosis may be required.°°   Other Congenital Malformations. Congenital malformations  ofthe upper airways, trachea, and bronchial tree are rareand cause  airway obstruction. Lesions include coanal atresia; laryngeal  atresias, webs, cysts, clefts, and subglottic hemangiomas; and  tracheal stenosis. Coanal atresia can be unilateral or bilateral  and causes lack of patency of the nasal cavity within the  nasopharynx. Bilateral coanal atresia can be life threatening in  newborns because they are obligate nasal breathers.°’ Laryngeal  atresias and webs are caused by failure of the larynx to recanalize  during embryogenesis. Most of these disorders are in the area  of the glottis with extension into the subglottis.’* Tracheal  stenosis is a rare malformation characterized by inspiratory  and expiratory stridor within the first few weeks of birth. It  is usually associated with pulmonary, cardiovascular, and  gastrointestinal malformations.°® Structural abnormalities such  as pectus excavatum or abnormalities involving the great vessels  also can result in tracheal compression. For example, absent  pulmonary valve syndrome dilates the pulmonary artery, which  can compress the trachea and bronchi.°’ Tracheal or bronchial  compression results in airway symptoms or feeding difficulties,  or both, ranging from dysphagia, recurrent respiratory tract  infections, wheezing, and stridor to acute respiratory distress  or “dying spells.” Many older children are first thought to have  gastroesophageal reflux or asthma as the principal problem.  Surgical management is usually required for these conditions,  and some infants may require mechanical ventilation while  awaiting surgery.”    Obstructive sleep apnea syndrome (OSAS) is a breathing dis-  order defined by prolonged partial and/or intermittent com-  plete UAO during sleep with disruption of normal ventilation  and normal sleep patterns. Childhood OSAS is common with  an estimated prevalence of 2% to 3% among middle-school  children and as many as 13% of children ages 3 to 6 years.  Prevalence is estimated to be two to four times higher in vul-  nerable populations (blacks, Hispanics, and preterm infants).°°  Unlike adults, OSAS in children occurs equally among males  and females. Infants are at risk because they have both anatomic    and physiologic predispositions toward airway obstruction and  gas-exchange abnormalities, including a superiorly placed lar-  ynx, increased chest wall compliance, ventilation-perfusion  mismatching, and ventilatory control instability. Congenital  abnormalities of the airway, as described previously in this  chapter, may have adverse effects on airway patency. Neck flex-  ion, airway secretions, gastroesophageal reflux, and sleep depri-  vation can be associated with airway obstruction. Obstructive  sleep apnea in infants has been associated with failure to thrive,  behavioral deficits, and sudden infant death.°!   PATHOPHYSIOLOGY. The pathophysiology of childhood OSAS is  likely to be multifactorial in origin. The most common predis-  posing factor is adenotonsillar hypertrophy, which causes phys-  ical impingement on the nasopharyngeal airway. OSAS often  occurs more frequently in overweight or obese children, as  well as in those with orthodontic/craniofacial anomalies, neu-  rologic disorders, allergy, asthma, abnormalities in the motor  tone of the upper airways (frequently an issue in neurologi-  cally impaired children), abnormal arousal mechanisms, and  genetic susceptibility.°* Recent studies have documented that  children with sleep disordered breathing (SDB) have increased  inflammation in the upper airway and elevated serum levels of  C-reactive protein, particularly in obese children.®’ Activation  of inflammatory pathways contributes to end-organ injury with  cardiovascular and metabolic morbidities.   CLINICAL MANIFESTATIONS. Common manifestations of OSAS  include snoring and labored breathing, restlessness, and sweat-  ing during sleep, which can be continuous or intermittent.  There may be episodes of increased respiratory effort, but no  audible airflow, often terminated by snorting, gasping, reposi-  tioning, or arousal. Affected children are often chronic mouth  breathers and have large tonsils. They also may exhibit noctur-  nal enuresis.®° It appears that there also may be a correlation  between OSAS and elevated blood pressure similar to adults.  This is further linked to increased body mass index (BMI) and  episodes of desaturation and apnea/hypopnea.°”   OSAS can result in chronic hypoxemia and hypercapnia  affecting multiple organ systems. Significant morbidity is asso-  ciated with OSAS including cognitive problems, neurobehav-  ioral impairment (e.g., inattention, hyperactivity, aggression,  conduct problems, attention-deficit/hyperactivity disorder  [ADHD]/emotional [mood]), excessive daytime sleepiness,  impaired school performance, and poor quality of life.°° Left  untreated it also can cause cardiovascular disease, particularly  left ventricular hypertrophy, and insulin resistance, as well as  pulmonary complications (upper and lower respiratory tract  infections) and reduced somatic growth.®-7!   EVALUATION AND TREATMENT. All parents should be asked if  their child exhibits snoring, a symptom that is often not spon-  taneously reported to a healthcare provider. The history and  physical examination are the most effective means of diagno-  sis. Screening tools and sleep questionnaires may be helpful  in evaluating the presence of SDB.’”* Radiographic images of  the upper airway may reveal upper airway narrowing caused  by adenoidal hypertrophy, and magnetic resonance imag-  ing (MRI) and acoustic reflectometry may detect reduced  upper airway dimensions.”* The most definitive evaluation    (“gold standard”) is the polysomnographic sleep study, which  documents obstructed breathing and physiologic impair-  ment and may be combined with nocturnal oximetry stud-  ies. If obstructive sleep apnea caused by tonsillar enlargement  is documented or strongly suspected clinically, children are  most often referred for tonsillectomy and adenoidectomy  (T&A). For severely affected children who do not respond to  T&A or who have different problems, such as obesity that can-  not be rapidly remedied, continuous positive airway pressure  (CPAP) delivered through a tight-fitting nasal mask may be  used during sleep. Treatment is important to prevent asso-  ciated morbidities. Successful medical or surgical treatment  results in improvement in physical, behavioral, and emotional  difficulties as well as quality of life.”*"7°    Lower airway disease is one of the leading causes of morbid-  ity in the first year of life and continues to be an important  component of other illnesses. Pulmonary disorders commonly  observed include perinatal conditions, such as neonatal RDS,  congenital malformations, asthma, cystic fibrosis, infections,  aspiration syndrome, and ARDS.    Respiratory distress syndrome (RDS) of the newborn (previ-  ously known as hyaline membrane disease [HMD]) is a major  cause of neonatal morbidity and mortality. It occurs almost  exclusively in premature infants and the incidence has increased  in the United States over the past two decades. Preterm births  account for about 12% ofall births. Black mothers have 1.5 times  the risk of preterm birth and 3.4 times the risk of preterm-  related mortality.’” RDS occurs in 50% to 60% of infants born  at 29 weeks of gestation and decreases significantly by 36 weeks.  Infants of diabetic mothers and those with cesarean delivery  (especially elective C-section) are more likely to develop RDS  because the labor-associated catecholamine and steroid surge  do not occur, causing decreased pulmonary surfactant release.’®  It is more common in boys than girls and in one cohort it was  more common in black infants.’”*° Death rates have declined  significantly since the introduction of antenatal steroid therapy  and postnatal surfactant therapy. The major predisposing factor  is prematurity because the immature lung is not well structured  for gas exchange and has not yet developed adequate surfactant  production and secretion. Death rates have declined signifi-  cantly since the introduction of antenatal steroid therapy and  postnatal surfactant therapy. The epidemiology, pathophysiol-  ogy, and clinical presentation of RDS are outlined in Box 36-2.   PATHOPHYSIOLOGY. RDS is caused by surfactant deficiency,  which decreases the alveolar surface area available for gas  exchange. Surfactant lipoproteins have a detergent-like effect  that separates the liquid molecules inside the alveoli, thereby  decreasing alveolar surface tension. Without surfactant, alveoli  collapse at the end of each exhalation.*! Surfactant normally is  not secreted by the alveolar cells until approximately 20 to 24  weeks of gestation (see Figure 36-1). Premature infants also are  born with underdeveloped and small alveoli that are difficult to    inflate. Additionally, the alveoli have thick walls and an inad-  equate capillary blood supply such that gas exchange is sig-  nificantly impaired. The infant’s chest wall is weak and highly  compliant and, thus, the rib cage tends to collapse inward with  respiratory effort. The net effect is atelectasis (Figure 36-11),  resulting in significant hypoxemia. Atelectasis is difficult for  the neonate to overcome because it requires a significant nega-  tive inspiratory pressure to open the alveoli with each breath.  The increased work of breathing and a decrease in tidal vol-  ume cause alveolar hypoventilation and hypercapnia. Hypoxia  and hypercapnia cause pulmonary vasoconstriction, which  increases intrapulmonary resistance and shunting. Increased  pulmonary vascular resistance causes a partial return to fetal  circulation, with right-to-left shunting of blood through the  ductus arteriosus and foramen ovale further compromising  pulmonary perfusion. There is decreased surfactant production  with inadequate pulmonary perfusion and alveolar ventilation.   Prolonged hypoxemia and inadequate tissue perfusion  activates anaerobic glycolysis, producing lactic acid and thus  causing metabolic acidosis. Alveolar hypoventilation causes  respiratory acidosis. Inadequate alveolar ventilation can be  further complicated by increased pulmonary capillary per-  meability. Additionally, many premature infants with RDS  require positive pressure mechanical ventilation with high  oxygen content, which damages the alveolar epithelium (e.g.,  barotrauma and oxygen toxicity). Together these conditions  result in the leakage of plasma proteins into the alveoli and  pulmonary edema. Fibrin deposits in the air spaces create  the appearance of hyaline membranes for which the disorder  was originally named. The plasma proteins leaked into the air  space have the additional adverse effect of inactivating any sur-  factant that may be present. The pathogenesis of RDS is sum-  marized in Figures 36-11 and 36-12.   CLINICAL MANIFESTATIONS. Signs of RDS appear within min-  utes of birth. Some neonates require immediate resuscita-  tion because of asphyxia or initial severe respiratory distress.  Characteristic signs are tachypnea (respiratory rate more than  60 breaths per minute), expiratory grunting, intercostal and  subcostal retractions, nasal flaring, and cyanosis. The natural  course is characterized by progressive hypoxemia and dyspnea  with severity progressing over the first 2 days of life. Apnea and  irregular respirations occur as the infant tires. The severity of  the hypoxemia and the difficulty in providing adequate supple-  mental oxygenation result in the Vermont Oxford Neonatal  Network definition of RDS as a Pao, less than 50 mmHg in  room air, central cyanosis in room air, or a need for supplemen-  tal oxygen to maintain Pao, greater than 50 mmHg, as well as  the classic chest film appearance.*” Typically, a chest radiograph  shows diffuse, fine granular densities within the first 6 hours of  life. This “ground glass” appearance is associated with alveolar  flooding. In most cases the clinical manifestations reach a peak  within 3 days, after which there is gradual improvement with  appropriate treatment.   EVALUATION AND TREATMENT. Diagnosis is made on the basis  of clinical manifestations, chest radiographs, and, if needed,  analysis of amniotic fluid or tracheal aspirates to estimate  lung maturity (lecithin/sphingomyelin ratio [L/S ratio]). The    Clinical Signs  Onset near the time of birth  Tachypnea  Increased work of breathing:  Nasal flaring  Retractions of respiratory muscles  Expiratory grunt  Cyanosis  Systemic hypotension  Characteristic chest film  Course to death or improvement in 3 to 5 days  Fine inspiratory rales  Hypothermia  Peripheral edema  Pulmonary edema   If hypotensive and hypoxic, poor peripheral perfusion, poor renal perfusion,  myocardial malfunction    Prevention  Prenatal glucocorticoids for more than 24 hours  Prevention of asphyxia  Surfactant replacement:  Prophylactically—within 15 minutes after birth  Early rescue—within 60 minutes after birth  Established RDS—within 12 hours after birth  Continuous positive airway pressure    From Jackson JC: Respiratory distress in the preterm infant. In Gleason CA, Devaskar SU, editors: Avery's diseases of the newborn, ed 9, Philadelphia,    DPL, Dipalmitoyl lecithin; FRC, functional residual capacity; /UGR, intrauterine growth restriction; L/S, lecithin/sphingomyelin; PROM, prolonged    FIGURE 36-11 Patchy Atelectasis of Neonatal Lungs with Respiratory  Distress Syndrome (RDS). (From Damjanov |, Linder J, editors: Anderson's  pathology, ed 10, St Louis, 1996, Mosby.)    ultimate treatment for RDS would be prevention of premature  birth. For women in preterm labor, antenatal treatment with  glucocorticoids induces a significant and rapid acceleration of  lung maturation and stimulation of surfactant production in  the fetus. There is extensive evidence that when there is risk of  preterm labor antenatal corticosteroid therapy given between  26 and 34 weeks of gestation reduces the incidence of RDS  and death. Repeated courses of corticosteroids may be safe in  this setting.*** Glucocorticoids induce a significant and rapid  acceleration of lung maturation and stimulation of surfac-  tant production in the fetus. There is extensive evidence that  maternal steroid therapy significantly reduces the incidence of  RDS, central nervous system hemorrhage, and neonatal mortal-  ity.°>8° Glucocorticoids may not significantly affect respiratory  outcomes when given after 34 weeks of gestation.°”**   Current recommendations for infants weighing less than  1000 g include prophylaxis beginning within 15 to 30 min-  utes of birth by administration of exogenous surfactant (either    FIGURE 36-12 Pathogenesis of Respiratory Distress Syndrome (RDS) of the Newborn. RDS is also known as hya-    synthetic or natural) through a nebulizer or nasal continuous  positive airway pressure (CPAP) ventilation.®! Repeat doses are  given every 12 hours for the first few days. There is usually a  dramatic improvement in oxygenation, as well as a decreased  incidence of RDS death, pneumothorax, and pulmonary inter-  stitial emphysema.*?° For infants weighing more than 1000 g,  surfactant replacement is based on clinical need. Surfactant  therapy should be considered complementary to antenatal  glucocorticoids. The two therapies together appear to have an  additive effect on improving lung function.’?! Supplemental  inositol also may promote maturation of surfactant and prevent  adverse neonatal outcomes.”   Supportive care includes oxygen administration and  mechanical ventilation. Mechanical ventilation can result in a  proinflammatory state that may contribute to the development  of chronic lung disease, such as bronchopulmonary dysplasia  (BPD). Strategies that are lung protective, such as greater reli-  ance on nasal continuous positive airway pressure (NCPAP)    to prevent lung injury, permissive hypercapnia, lower oxygen  saturation targets, modulation of tidal volume (V,) settings,  and use of high-frequency oscillation, are being evaluated.’*”*  Mechanical ventilation with mixtures of oxygen and nitric  oxide or helium may improve gas exchange and reduce air-  flow resistance and have improved outcomes.”*?’ Most infants  survive RDS and, in many cases, recovery may be complete  within 10 to 14 days. However, the incidence of subsequent  chronic lung disease is significant among very low birth weight  infants.”>°    Bronchopulmonary dysplasia (BPD), also known as chronic  lung disease of prematurity, is the major cause of pulmo-  nary disease in infants. It is associated with premature birth  (usually before 28 weeks of gestation), perinatal supplemental  oxygen, and positive pressure ventilation. There are approxi-  mately 60,000 infants born weighing less than 1500 g in the    FIGURE 36-13 Pathophysiology of Bronchopulmonary Dysplasia (BPD). (From Polin RA, Fox WW, Abman SH: Fetal    United States on an annual basis. About 20% to 30% of very  low and extremely low birth weight infants develop BPD.10!0!  In the current era of neonatology, the widespread use of ante-  natal glucocorticoids, postnatal surfactant, and NCPAP has less-  ened the incidence and severity of RDS and thus also reduced  the incidence of BPD. Surprisingly, some of the tiny infants who  develop BPD have shown few or no clinical signs of RDS at birth  or have initially received only low levels of supplemental oxygen  or ventilatory support for apnea.!°? The presence of antenatal  chorioamnionitis, postnatal sepsis, a patent ductus arteriosus, and  genetic susceptibility confer additive risk of developing BPD.'”  BPD is a multisystem condition and is associated with devel-  opmental disorders in other systems, such as growth retardation,  pulmonary hypertension, neurodevelopmental delays (e.g., cere-  bral palsy), hearing defects, and retinopathy of prematurity. !°°  PATHOPHYSIOLOGY. Lung immaturity and inflammation con-  tributes to the development of BPD. In preterm infants born at  less than 28 weeks of gestation, the fetal lung is in the canalicular  stage of development (16 to 28 weeks), a critical period dur-  ing which type II epithelial cells appear, capillaries grow into  the future distal alveolar regions, and the interstitium begins  to condense (see Figure 36-1). Ultimately the alveoli must  have a very thin interface between the air space and the cap-  illary for appropriate gas exchange. The extensive network of  alveoli develops by septation within the terminal respiratory    unit, beginning in the saccular stage, starting at approximately  26 to 28 weeks. The alveoli are vulnerable to inflammation and  impaired growth during this stage.!°*   Before the widespread use of surfactant therapy, BPD was  a disease characterized by airway injury, inflammation, and  parenchymal fibrosis (classic BPD). Now, after the initiation of  surfactant therapy, what is called new BPD is most often a form  of arrested lung development with poor formation of the alveo-  lar architecture. Alveoli are large and fewer in number, thereby  presenting decreased surface area for gas exchange. There is  abnormal vascular endothelial growth factor that results in  abnormal pulmonary capillary development and mild fibrosis  accompanied by persistent inflammation contributing to perfu-  sion mismatch and pulmonary hypertension.'”° Genetic influ-  ences on surfactant proteins and inflammatory regulation have  been documented in association with the “new BPD.”!°°   Levels of proinflammatory cytokines, such as tumor necrosis  factor-alpha (TNF-c), interleukin 1 (IL-1), interleukin 6 (IL-6),  and interleukin 8 (IL-8), are all elevated in the amniotic fluid or  tracheal aspirates, or both, of preterm infants who later develop  BPD. Inflammation invites neutrophils and macrophages to  release reactive oxygen species and proteolytic enzymes. Interest-  ingly, the predominant mediators of new BPD are profibrotic and  angiogenic cytokines rather than proinflammatory cytokines. !*!0”  Figure 36-13 illustrates the pathophysiology of BPD.    CLINICAL MANIFESTATIONS. The current clinical definition of  BPD includes the need for supplemental oxygen at 36 weeks of  postmenstrual age (estimated time of conception to birth plus  weeks since birth) and for at least 28 days after birth, with a  graded severity dependent on required respiratory support at  term (divided into mild, moderate, and severe based on oxy-  gen requirements and ventilatory needs). Clinically, the infant  exhibits hypoxemia caused by ventilation-perfusion mismatch  and diffusion defects. Work of breathing is elevated, resulting in  hypercapnia. The ability to feed may be impaired. Intermittent  bronchospasm with wheezing, mucus plugging, and pulmo-  nary hypertension characterizes the clinical course of the most  severely affected babies.   EVALUATION AND TREATMENT. Infants with severe BPD require  prolonged, assisted ventilation with cautious weaning. Preven-  tion of lung damage with “gentle ventilation” (see lung protective  strategies of ventilation in RDS section, p. 1303) or early nasal  CPAP, or both, is used in clinical situations when permitted.  Use of CPAP prevents airway collapse and results in fewer days  of oxygen and ventilator requirement by reducing the amount  of lung injury as compared with mechanical ventilation.'°°  Additionally, oxygen supplementation at lower than previously  accepted values (89% to 94% saturations) is a means to reduce  oxidant injury to the lungs and retinal vasculature. Diuretics  are used to control pulmonary edema, bronchodilators reduce  airway resistance, and inhaled corticosteroids improve the rate  of extubation and reduce the time that mechanical ventilation  is required. Caffeine citrate is used to prevent apnea and for  neuroprotection.'!? Supplementation with vitamin A provides  antioxidant protection and stimulates lung growth and sur-  factant production.'!° Careful nutritional and fluid and elec-  trolyte support is routinely used and has resulted in improved  outcomes.    Infections may be localized to the bronchioles, bronchi, alve-  oli, interstitium, or pleura. The cause and site of infections are  related to the age of the child, seasonal variables, and environ-  mental exposures. Infants and young children tend to have  more viral infections, especially during late autumn to early  spring. Environmental factors may play a role, such as the pres-  ence of siblings and daycare exposure.    Bronchiolitis is a common viral-induced lower respiratory tract  infection of the small airways that occurs in children younger  than 2 years of age. The most common associated pathogen is  RSV, but it also may be associated with adenovirus, rhinovi-  rus (older children), influenza, parainfluenza virus (PIV), and  human metapneumovirus.! Bronchiolitis has a peak incidence  during winter (late December) and a spike in February, and  then tapers off in the spring, paralleling the RSV season. There  are distinct regional differences in the United States depending  on variation in the viral season based on geography. It is a major  reason for hospital admission of children younger than 1 year,  particularly children of lower socioeconomic status.'!! Healthy  infants usually make a full recovery from RSV bronchiolitis, but    infants who are premature (birth weight <2500 g) or who have  underlying lung disease, heart disease, or immune deficiency  may have a much more severe or even deadly course. Bronchi-  olitis has been linked to an increased risk for asthma later in  childhood.!!*!'° Bronchiolitis has a worldwide annual death  rate between 160,000 and 600,000 deaths. !!4   PATHOPHYSIOLOGY. Viral infection causes inflammation and  necrosis of the bronchial epithelium and destruction of ciliated  epithelial cells. There is infiltration with lymphocytes around  the bronchioles and a cell-mediated hypersensitivity to viral  antigens with release of lymphokines causing inflammation, as  well as activation of eosinophils, neutrophils, and monocytes.  The submucosa becomes edematous, and cellular debris and  fibrin form plugs within the bronchioles. Edema of the bron-  chiolar wall, accumulation of mucus and cellular debris, and  possibly bronchospasm narrow or occlude many peripheral  airways. Areas of atelectasis and uneven ventilation lead to  ventilation-perfusion mismatch and hypoxemia.   The mechanics of breathing are disrupted by bronchiolitis.  Airway narrowing causes obstruction of airflow that is worse  with expiration. This leads to air trapping, hyperinflation, and  an increase in FRC. Airway resistance and hyperinflation result  in decreased lung compliance and increased work of breathing  and may cause hypercapnia in severe cases.   CLINICAL MANIFESTATIONS. Symptoms usually begin with sig-  nificant rhinorrhea followed by a tight cough over the next  several days, along with systemic signs of decreased appetite,  lethargy, and fever. Infants may have tachypnea, expiratory  wheezing, cough, rhinorrhea, mild fever, varying degrees of  respiratory distress, and abnormal auscultatory findings of the  chest. In severe cases, chest radiographs reveal hyperexpanded  lungs, patchy or peribronchial infiltrates, and atelectasis.  Severely affected infants appear anxious and distressed because  of dyspnea or hypoxemia. The thoracic cage is overexpanded,  particularly in its anteroposterior diameter. The infant takes  rapid, short breaths, and wheezing and rales are often heard on  auscultation. With overexpansion of the lungs, the diaphragm  is flattened, causing downward displacement of the liver and  spleen. Abdominal distention results from air swallowing.  Genetic tendencies have been noted that correlate RSV bron-  chiolitis with asthma.!!°   EVALUATION AND TREATMENT. Diagnosis of bronchiolitis is  made by review of signs and symptoms (e.g., rhinitis, cough,  wheezing, crackles, chest retractions and/or hyperinflation,  tachypnea) and radiologic examination. Nasal washings/swab-  bings may be tested for specific viral agents, such as RSV. RSV  swabs are positive in 70% of cases of bronchiolitis. In severe  cases, chest imaging may be required for diagnosis and follow-  up. Ultrasound is a reliable option without risk of irradiation.''°   Treatment is determined by the severity of the disease and  the age of the child.''” Most cases are mild and are managed at  home with supportive care. In more severe cases, supplemental  oxygen and increased hydration are commonly used. Inhaled  hypertonic saline has been found to decrease clinical severity  and length of hospital stay.°” Inhaled bronchodilators or bron-  chodilators and corticosteroids benefit infants with underly-  ing lung disease or wheezing.'!*!2° Mechanical ventilation    is occasionally necessary and clinical indicators for CPAP are  being evaluated.!?!:!?? Preventive treatment with RSV-specific  monoclonal antibody, provided as a monthly injection through  the RSV season, is recommended for high-risk infants less than  2 years old who meet specific criteria (e.g., bronchopulmonary  dysplasia, recurrent aspiration pneumonitis, cystic fibrosis, or  pulmonary malformation). Development of other immuno-  therapies and a RSV vaccine is in progress. !?°)!*4    Pneumonia is infection and inflammation in the terminal air-  ways and alveoli. Community-acquired pneumonia (CAP)  is one of the most common global infections in the pediatric  age group and the leading cause of morbidity and mortality in  infants.!*° The incidence of viral and bacterial pneumonia var-  ies according to age, time of year, and geographic location. Viral  pneumonias are most common in young children and infec-  tions occur most often in winter to early spring. Mortality from  respiratory viruses in developed countries is rare but morbid-  ity is significant. In less developed countries, viral pneumonia  results in nearly 5 million deaths annually in children younger  than the age of 5.'*° Bacterial pneumonias are less common and  occur across all age groups. Fungal and anaerobic pneumonias  are rare in children.!*’ Risk factors for developing CAP include  age younger than 2 years, overcrowded living conditions, winter  season, recent antibiotic treatment, attendance at daycare cen-  ters, and passive smoke exposure. Nutritional status, age, and  underlying disease process influence morbidity and mortality  related to CAP.   PATHOPHYSIOLOGY. Viral pneumonia is two to three times  more likely in children than in adults. Viral-bacterial co-infec-  tions are common. The most common cause in infants and  young children is respiratory syncytial virus (RSV). A number  of other viruses are important, including parainfluenza, Hae-  mophilus influenzae types A and B, coronaviruses, rhinoviruses,  enteroviruses, human metapneumovirus (hMPV), bocavirus,  and adenoviruses.   Viral infection is acquired by direct contact, droplet trans-  mission, or aerosol transmission. Viral infection of the lower  respiratory tract results in destruction of ciliated epithelium of  the distal airway, with sloughing of cellular material. A mono-  nuclear-predominant inflammatory response occurs first in the  interstitium and may later involve the alveoli. Certain serotypes  of adenovirus can cause necrotizing disease, sometimes leading  to obliterative bronchiolitis and significant lung disability.   Early in the course of illness, it is often difficult to determine  whether the pneumonia is of viral or bacterial origin. In bacte-  rial pneumonia, the degree of elevated temperature, absolute  neutrophil counts, and percent of bands are consistently higher  than in those cases of viral etiology.'** Diagnosis of a viral eti-  ology requires laboratory confirmation (immunofluorescence  tests). Development of safe agents to treat and prevent viral  pneumonias continues to be a priority, as is development of  more effective vaccines. |”?   Bacterial pneumonia beyond the neonatal period is most  commonly the result of infection with streptococcal and  staphylococcal microorganisms (Table 36-2). Pneumococcal    (S. pneumoniae) pneumonia is the most common cause of  bacterial pneumonia; other causative microorganisms include  Staphylococcus aureus group A streptococci and atypical bacte-  ria. Bacterial pneumonia most often presents acutely and with  variable severity. Pneumococci have specific virulence factors  (such as capsules) that increase their survival and proliferation  while causing insult to the host.'°° A polyvariant pneumococ-  cal conjugate vaccine (PCV7 or PCV13) is incorporated into  routine childhood immunizations and appears to have lessened  the incidence of pneumococcal pneumonia in children younger  than 2 years of age.!°!   Bacterial pneumonia usually begins with aspiration of one’s  own nasopharyngeal bacteria into the trachea. A preceding  viral infection sometimes sets the stage for bacterial infec-  tion by causing epithelial damage and reduced mucociliary  clearance in the trachea and major bronchi. Colonization of  the trachea then ensues, with the microorganism, host, and  environment all playing a role in the development of pneu-  monia. Once in the alveolar region, bacteria encounter local  host defenses, such as antibodies, complement, phagocytes,  and cytokines, that prepare bacteria for ingestion by alveolar  macrophages.   If these mechanisms fail, neutrophils will be recruited and an  intense cytokine-mediated inflammation will ensue. Vascular  engorgement, edema, and a fibrinopurulent exudate with tissue  damage occur. Alveolar filling precludes gas exchange and, if  extensive, can lead to respiratory failure. If sepsis occurs at the  same time, shock and end-organ hypoperfusion may develop.  Staphylococcal and group A streptococcal pneumonia can be  particularly fulminant and necrotizing, with a high incidence of  accompanying empyema, pneumatoceles, and sepsis. Empyema  is increasingly associated with pneumococcal infections and  antibiotic-resistant microorganisms. !°*!°?   The clinical presentation of bacterial pneumonia, particu-  larly pneumococcal, may include a preceding viral illness fol-  lowed by fever with chills and rigors, shortness of breath, and  an increasingly productive cough. Occasionally there is blood  streaking of the sputum. Respiratory rate and oxygen saturation  are important clinical indicators. Auscultation usually reveals  such abnormalities as crackles or decreased breath sounds.  Other less specific findings may include malaise, emesis,  abdominal pain, and chest pain. Chest film will usually present  with a lobar pattern in older children and adolescents but may  appear patchier with a bronchopneumonic pattern in younger  children. !*4   Atypical pneumonia (Mycoplasma pneumoniae, Chla-  mydophila pneumoniae) is the most common cause of CAP  for school-age children (ages 5 and older) and young adults!”  Chlamydophila pneumonia is clinically indistinguishable from  and is typically grouped with Mycoplasma as “atypical pneu-  monia.” Transmission is from person-to-person with a 2- to  3-week incubation period.   Mycoplasma is known to cause a wide spectrum of disease  and has more extensive complications than previously rec-  ognized. Studies reveal that macrolide-resistant Mycoplasma  pneumoniae is seen increasingly in infants and younger chil-  dren.'°>'°° Children experiencing recurrent respiratory tract    Respiratory syncytial  virus (RSV), influenza  (A and B), adenovirus,  parainfluenza, human  metapneumovirus  (hMPV)    Mild to high fever, cough,  rhinorrhea, malaise, rales,  rhonchi, or wheezing;  variable radiographic  pattern    High fever, productive cough,  pleuritic pain, increased  respiratory rate, decreased  breath sounds in area of  consolidation; lobar pattern  or “round pneumonia” on  radiograph    infections often have been found to be infected with atypical  bacteria.   Mycoplasma microorganisms lack cell walls but have a lim-  iting membrane and a specialized tip for attaching to ciliated  respiratory epithelial cells. Local sloughing of cells occurs. Peri-  bronchial lymphocytic infiltration develops, along with neutro-  phil recruitment to the airway lumen. The pattern resembles  bronchitis or bronchopneumonia.   Onset of symptoms is usually gradual, resembling a typical  upper respiratory tract infection with low-grade fever and prom-  inent cough. There may be accompanying sore throat, myal-  gia, and headache. Cases are not usually clinically severe, and  full recovery should be expected without complications. When  complications do occur, they can include bronchopneumonia,  parapneumonic effusions, and necrotizing pneumonitis. !°”   EVALUATION AND TREATMENT. Diagnosis of pneumonia is based  on clinical, laboratory, and chest radiograph findings. Guide-  lines have been developed to improve and aid assessment and  management of pediatric pneumonia.!** Identifying etiologic  pathogens can be very difficult in children, especially because  there is often overlap between bacterial and viral pathogens.  Biomarkers facilitate more rapid diagnosis and procalcitonin  is most specific to bacterial infection and can guide antibiotic  therapy. The highly sensitive C-reactive protein (hs-CRP) is less  specific and elevated in both viral and bacterial infections.!°’    High fever, cough,  respiratory distress,  toxic appearance, sepsis,  empyema, pneumatoceles  are common; multilobar  consolidation    Other laboratory tests that may be helpful include a white cell-  granulocyte count or erythrocyte sedimentation rate (ESR) but  do not indicate a specific etiology. Several microbiologic tests  are available including polymerase chain reaction (PCR) and  nucleic acid amplification tests (NAATs). On chest radiography,  a bacterial pneumonia initially produces an alveolar infiltrate  and later causes a segmental or lobar disease. A viral infection is  more likely to be associated with an interstitial pattern.   Most pneumonias may be treated on an outpatient basis;  however, some children require oxygen supplementation and,  occasionally, assisted ventilation. This is particularly true with  infants who have a viral interstitial pneumonia, such as RSV.  In addition, adequate hydration, nutrition, and supportive pul-  monary therapy are required to reduce the duration and sever-  ity of illness. Many hospitalized infants are markedly tachypneic  and unable to coordinate their breathing with swallowing such  that they may require enteral feeding. Aspiration is always a risk  with infants in respiratory distress.   Appropriate antibiotic administration, whether oral or  intravenous (IV), for bacterial pneumonias is dependent on age  and severity assessment. Hospitalized children require antibi-  otic therapy.'*° Local patterns of drug resistance must be con-  sidered.'*? Both pneumococcal and mycoplasma pneumonia  present some unique treatment obstacles and often need a mul-  tifaceted approach to care, including vaccine antigens, antibiotic    combinations, and immunoadjuvant therapies.'*! Children  should be vaccinated against influenza and pneumococcus.!*7    Aspiration pneumonitis is caused by a foreign substance, such  as food, meconium, secretions (saliva or gastric secretions),  or environmental compounds entering the lung and causing  inflammation of lung tissue. The aspiration of meconium from  amniotic fluid can occur at birth. Meconium contains bile salts  from the fetal intestinal tract that cause inflammation. Neuro-  logically compromised children or children with chronic lung  disease may have chronic pulmonary aspiration (CPA) because  of failure of protective reflexes. This can cause progressive lung  disease, bronchiectasis, and respiratory failure and is the lead-  ing cause of death in children who are neurologically compro-  mised.!4°)!44 Children undergoing sedation or anesthesia also  may aspirate oral secretions contaminated with anaerobic bac-  teria or stomach contents, which may be acidic.   The severity of lung injury after an acute aspiration incident  is determined by the volume of material aspirated, the pH of  the aspirated material, and the presence of pathogenic bacteria.  Very low pH or very high pH causes a significant inflammatory  response. With hydrocarbon ingestions, lung injury is deter-  mined by the volatility and viscosity of the aspirated substance.  A low-viscosity substance, such as gasoline or lighter fluid, is  the most toxic; high-viscosity hydrocarbons, such as petroleum  jelly or mineral oil, are much less likely to cause pneumonitis.  Treatment for aspiration pneumonitis depends on the mate-  rial aspirated but generally includes broad-spectrum antibiotic  therapy. Children with CPA and a large amount of upper respi-  ratory tract secretions may benefit from salivary gland injection  with botulinum toxin A (BTX-A) to suppress secretion.!*°    Bronchiolitis obliterans (BO) is fibrotic obstruction of the  respiratory bronchioles and alveolar ducts secondary to intense  inflammation. It is relatively rare in children. Two types are  noted in the literature—proliferative and constrictive—with  the latter being the more common form. Most cases of BO in  children are associated with viral pulmonary infections, such  as adenovirus (most common), influenza, pertussis (whoop-  ing cough), measles, parainfluenza, RSV, human immunode-  ficiency virus (HIV), or M. pneumoniae. BO may occur after  allograft transplantation (lung, heart-lung, and bone marrow)  as a manifestation of graft-versus-host disease. It also is asso-  ciated with collagen vascular disease, toxic fume inhalation,  chronic hypersensitivity pneumonitis, Crohn disease, and  Stevens-Johnson syndrome.'*°!47 Initially, cough, respira-  tory distress, and cyanosis occur, followed by a brief period of  improvement. The progression of disease is then reflected by  tachypnea, sputum production, increased anterior/posterior  diameter, crackles, wheezing, and hypoxemia.!**   There is no specific treatment for BO and, because it is so  rare, there have been no randomized clinical trials. Therapeu-  tic options include inhaled corticosteroids, bronchodilators,  antibiotics, and oxygen supplementation. Mechanical ventila-  tion may contribute to the progression of the disease. Use of    antiviral agents may be warranted in managing those with viral  infection. For transplant recipients, augmentation of immuno-  suppressive therapies and treatment with anti-inflammatory  agents are showing promise in reducing airway inflammation,  thus improving pulmonary function.!”? Clinical progression  can be quite variable depending on the predisposing condition.  Some children experience partial recovery, whereas others fol-  low a course of steady decline in lung function. Lung transplan-  tation may be considered.!*”    Asthma is a chronic inflammatory disease characterized by sen-  sitization to allergens, bronchial hyperreactivity, and reversible  airway obstruction. It is the most prevalent chronic disease in  childhood, affecting about 10% of U.S. children between 5 and  17 years of age, with boys more often affected than girls. Asthma  prevalence is increasing, especially among non-Hispanic  blacks,!°° obese children,!°! and children from urban and low-  income populations.'°* The overall asthma-related death rate  is decreasing! and asthma-related deaths almost always occur  outside the hospital setting.   The severity and persistence of asthma are influenced by age  at disease onset, genetics, behavior, atopy, air pollution, level of  allergen exposure, environmental tobacco smoke, gastroesoph-  ageal reflux, and respiratory tract infections.'°* Additional  confounding variables that affect disparity in asthma morbid-  ity and therapy are social stress in the home (e.g., violence and  depressed housing conditions), lack of health insurance, poor  access to asthma specialists, inappropriate utilization of health-  care resources, and inadequate medical care.!°»:!>°   The wide spectrum of clinical disease in asthma and differen-  tial responses to standard treatment reflects a complex interac-  tion between environmental factors and genetic susceptibility.  Environmental factors include early exposure to allergens (e.g.,  air pollution, dust mites, cockroach antigen, cat exposure,  tobacco smoke, and dietary factors); infections, particularly  viral respiratory tract infections (e.g., rhinovirus and RSV); and  stress.!°°!97 Vitamin D insufficiency may be a risk factor for  wheezing in children since vitamin D suppresses Th2-mediated  allergic disease.!°* Environmental exposures interact with an  individual’s genetic vulnerabilities to induce the onset of clinical  asthma and epigenetic mechanisms are being studied. !°4!9%'9?@   The genetics of asthma are complex. Genetic studies have  led to the identification of many candidate genes or chromo-  somal regions that are associated with asthma.!©”'® Included  in the long list of asthma-associated genes are those that code  for increased levels of immune and inflammatory mediators  (e.g., IL-4, IL-5, IL-13, IgE, and leukotrienes), adrenergic recep-  tors, nitric oxide, and transmembrane proteins in the endo-  plasmic reticulum.!®*!° In addition, specific gene expression  may impart associated phenotypes, such as bronchial hyperre-  sponsiveness (BHR), inflammation, sensitization to allergens,  airway fibroblasts, airway remodeling, and responsiveness to  asthma therapies.'©° Linking specific genes to specific asthma  phenotypes is leading to targeted therapies and personalized  approaches to asthma treatment (see What’s New? Asthma  Phenotypes).    The severity and clinical course of asthma in children can vary from mild and  transient to severe and lifelong. Research is now emerging that suggests  genetically influenced differences in inflammatory and immune mechanisms  may explain much of this variability. The majority of asthmatic children have  the well-described allergic (type | hypersensitivity) form of asthma that is  characterized by high levels of Th2 cytokines, IgE synthesis, and activation  of eosinophils (therefore also called eosinophilic asthma), resulting in epi-  sodic bronchospasm that is responsive to inhaled bronchodilators and anti-  inflammatory medications. Other mechanisms have been implicated in children  whose asthma phenotype is characterized by more severe symptoms and rela-  tive unresponsiveness to treatment with inhaled steroids. One of these mech-  anisms is called neutrophilic asthma in which Th1 cytokines and activation of  large numbers of polymorphonucleocytes appear to dominate lung injury. Neu-  trophilic asthma especially involves the cytokines TNF-a, interferon-gamma  (IFN-y), IL-17, and IL-27. Other genotypic changes can lead to diverse asthma  phenotypes. For example, variability in the response to inhaled glucocorticoids  may be related to the role of IL-13. Another example involves a specific poly-  morphism in the gene for the B-adrenergic receptor that is prevalent in black  children and is associated with poor response to B-adrenergic inhaled medica-  tion. Variability of response to leukotriene receptor 1 antagonist is related  to variation in leukotriene pathway candidate genes. Finally, genetic factors  also have been identified that are important to the development of airway  remodeling. Increased understanding of these asthma phenotypes is leading  to new therapies that may provide significant improvements in personalized  management of severe and drug-resistant asthma.    Data from Carolan BJ, Sutherland ER: J Allergy Clin Immunol  131(3):627-634, 2013; Corren J et al: N Eng! J Med 365:1088-1098,  2011; Cowan K, Guilbert TW: Curr Opin Pediatr 24:344-351, 2012;  Ducharme FM, Krajinovic M: Pediatr Resp Rev 12:170-176, 2011;  Kotani H et al: J Clin Pharm Ther 37(1):112-116, 2012; Siroux V,  Garcia-Aymerich J: Curr Opin Allergy Clin Immunol 11:393-399, 2012;  Thomson NC, Patel M, Smith AD: Biologics 6:329-335, 2012; Wenzel S:  Nat Med 18:716-725, 2012.    One hypothesis for the high prevalence of asthma in west-  ernized cultures is called the “hygiene hypothesis.” Allergen  exposure shifts the immune system toward Th2-predominant  phenotype with resultant increase in the production of  antibodies, including IgE. This effect is normally balanced  by exposure to numerous siblings, daycare, farming, endo-  toxin, and certain microorganisms (e.g., Toxoplasma gondii,  hepatitis A virus, and Helicobacter pylori). It is proposed  that children exposed to a highly hygienic environment and  who receive vaccinations to prevent infections lack adequate  exposure to common pathogens and therefore do not achieve  a proper balance of their immune systems.!°°!°” Asthma  develops because the Th2 response (in which CD4 T-helper  [Th] cells produce specific cytokines, such as IL-4, IL-5, and  IL-13) promotes an atopic/allergic inflammatory response  in the airways.'® IL-4 and IL-13 are particularly impor-  tant for B-cell switching to favor IgE production, and IL-5  is crucial for local differentiation and enhanced survival of  eosinophils within the airways. This theory about the origins  of asthma is consistent with many of the epidemiologic and  pathophysiologic features of childhood asthma but is not yet  proved.!°°    PATHOPHYSIOLOGY. The pathophysiology of asthma in chil-  dren is similar to that for adults and is described in Chapter 35  (p. 1264). Asthma is initiated by a type I hypersensitivity reac-  tion primarily mediated by IgE (see Figures 35-10, 35-11, and  35-12, pp. 1264-1265). As in adults, inflammation, broncho-  spasm, and mucus production in the airways lead to ventilation  and perfusion mismatch with hypoxemia and expiratory airway  obstruction with air trapping and increased work of breath-  ing. In young children, airway obstruction can be more severe  because of the smaller diameter of their airways.   CLINICAL MANIFESTATIONS. In a typical acute asthma attack in  children, the major complaints are coughing, wheezing, and  shortness of breath. About 70% to 80% of acute wheezing epi-  sodes are associated with viral respiratory tract infections. As a  result, there may be signs of a preceding upper respiratory tract  infection, such as rhinorrhea, or low-grade fever. In infants and  toddlers younger than 2 years old, the most common of these  is RSV.!® In older children and adults, the major viral trigger  is rhinovirus. !7°   There is expiratory wheezing that is often described as high  pitched and musical, along with prolongation of the expiratory  phase of the respiratory cycle. Breath sounds may become faint  when air movement is poor. Sometimes hyperinflation (barrel  chest) is visible. Respiratory and heart rates are elevated. Nasal  flaring and accessory muscle use are evident, with retractions  in the substernal, subcostal, intercostal, suprasternal, or sterno-  cleidomastoid areas. Infants may appear to be “head bobbing”  because of sternocleidomastoid muscle use. Pulsus paradoxus  (decrease in systolic blood pressure of more than 10 mmHg  during inspiration) may be present. The child may appear anx-  ious or diaphoretic, important signs of respiratory compromise.  The child may speak in clipped sentences or not at all because  of dyspnea.   Findings in chronic asthma may include hyperinflation of  the thorax (barrel chest) or pectus excavatum. Clubbing should  not be seen in those with asthma and, if present, should trigger  evaluation for other conditions, such as cystic fibrosis. Exercise  intolerance may indicate underlying asthma.   EVALUATION AND TREATMENT. Asthma is often underdiagnosed  and untreated, especially in preschool-age children because  asthma symptoms overlap with other respiratory illness, such  as bronchitis or upper respiratory tract infections. Diagnosis is  based on symptom patterns (episodes of wheezing), presence  of risk factors, and therapeutic responses. The major historical  and physical factors that contribute to the diagnosis of asthma  in children are parental history of asthma, physician-diagnosed  atopic dermatitis, evidence of sensitization to aeroallergens,  increased IgE and eosinophil levels, and reversible airflow  obstruction on lung function.!”!   The modified asthma predictive index (API) can be used to  help with asthma diagnosis and is recommended by the National  Institutes of Health (NIH) guidelines.!7! Many children with  less severe asthma outgrow the disease by adulthood.'”7   Confirmation of the diagnosis of asthma relies on pulmo-  nary function testing using spirometry, which can be accom-  plished only after the child is 5 to 6 years of age. Characteristic  abnormalities of spirometry would be reduced expiratory flow    rates that are reversible in response to an inhaled bronchodila-  tor. For younger children, an empirical trial of asthma medica-  tions is commonly initiated.   The goal of asthma therapy is to achieve long-term con-  trol by reduction in impairment and risk.!** Management  of asthma medications in children is often difficult because  fluctuations in severity of symptoms is common. Care pro-  viders must periodically assess asthma control in children to  decide if a “step up” (increase) or “step down” (decrease) is  indicated in their asthma therapy. Algorithms can help assess  asthma control and offer information about how to adjust  therapy accordingly. Before therapy is increased, care pro-  viders need to assess medication administration techniques,  environmental controls, comorbidities, and educational  needs. For a reduction in therapy, the child’s asthma should  be well controlled for a minimum of 3 months.!** The phar-  macologic treatment of asthma in children is essentially the  same as that for adults and is initiated in a stepwise sequence  based on asthma severity and response to treatment (see  Chapter 35).   Acute lung injury (ALI)/acute respiratory distress syndrome  (ARDS) occurs in children of all ages. ALI precedes the devel-  opment of ARDS and can result either from a direct or indi-  rect injury, such as pneumonia, aspiration, near-drowning, and  smoke inhalation, or from a systemic insult, such as sepsis, mul-  tiple trauma, or burns. ARDS is characterized by progressive  respiratory distress, severe hypoxemia refractory to treatment  with supplemental oxygen, decreased pulmonary compliance,  bilateral infiltrates on chest x-ray, and no evidence of heart  failure.'7°   The overall mortality in children is less than that experienced  by the adult population but can be as high as 40%, depending  on age and associated conditions and complications.'’4 Chil-  dren younger than 5 years appear to have diminished mortality  compared with those older than 5 years of age. Children with  underlying disease processes, such as Down syndrome!” or  systemic lupus erythematosus, and those who have undergone  lung transplantation have decreased survival.   PATHOPHYSIOLOGY. The pathophysiology of ARDS in children  is the same as that described for adults in Chapter 35 (see p. 1261  and Figure 35-8).   CLINICAL MANIFESTATIONS. ARDS develops acutely after the  initial insult, usually within 24 hours (although occasionally it  is delayed up to a few days). There is progressive respiratory  distress and severe hypoxemia with poor response to oxygen  supplementation. Initially, hyperventilation occurs, but CO,  retention may ultimately develop because of inadequate func-  tional air space, atelectasis, decreased pulmonary compliance,  and respiratory muscle fatigue. Severity of the clinical course  is modified by the cause of lung injury, comorbid factors (such  as the presence of sepsis or multisystem organ failure), and  the development of complications (such as nosocomial pneu-  monia). Some children who recover have residual pulmonary  abnormalities.    EVALUATION AND TREATMENT. ARDS in older children and ado-  lescents is similar to that in adults. However, infants have more  compliant chest walls, lower hematocrit levels, higher baseline  airway resistance, and lower functional residual capacity. The  maturing lung may be at greater risk for ventilator-induced  lung injury.!”°"’7 These factors have implications for manage-  ment strategies that are different than those for older children  and adolescents. There are few randomized controlled trials  that have been completed to guide clinical management of ALI/  ARDS in infants and very young children.   Treatment of ARDS remains supportive in nature and defin-  itive studies related to infants and children are limited.!7°!””  The goals of therapy are to preserve and restore oxygen deliv-  ery, minimize acute lung injury, and decrease morbidity and  mortality by avoiding iatrogenic pulmonary complications.  Most individuals with ARDS require oxygen administration  with mechanical ventilation and relatively high levels of posi-  tive end-expiratory pressure to promote alveolar recruitment,  stabilization, and redistribution of alveolar edema fluid into the  interstitium. Lung-protective ventilation strategies may be used  for ARDS, such as low tidal volumes, positive end-expiratory  pressure (PEEP) ventilation, prone positioning, inverse inspi-  ratory/expiratory ratio, high-frequency oscillatory ventilation,  and airway pressure release ventilation.'’*!°° Use of corticoste-  roids in children with ARDS is controversial and remains at the  discretion of the clinician. There have been no randomized clin-  ical trials regarding this treatment. Surfactant therapy appears  to improve oxygenation and increase survival time in children  1 week to 21 years of age, particularly in cases of direct lung  injury.'7+!5! Extracorporeal membrane oxygenation (ECMO)  has improved survival in some centers.!°*!*°    Cystic Fibrosis  Cystic fibrosis (CF) is an autosomal recessive inherited dis-  order that is associated with defective epithelial chloride ion  transport. The CF gene is located on chromosome 7. There are  more than 1900 known mutations of this gene!** divided into  6 classes with varying severity of disease expression. Classes 1  through 3 are associated with more severe disease and classes  4 through 6 with milder pulmonary disease (generally pan-  creatic sufficient). Death rates correlate respectively with the  classes noted in the previous sentence.'*° CF affects primarily  whites (approximately 1 in 3200) and is one of the most com-  mon lethal genetic diseases in this ethnic group. Approximately  30,000 individuals in the United States and 70,000 worldwide  manifest the disease. The incidence in blacks is 1:15,000 and in  Asian Americans is 1:31,000.'*° Estimated symptomless carrier  frequency is higher, affecting 10 million or 1 in 29 whites in the  United States. Approximately 1000 new cases of CF are diag-  nosed each year, and the median age at diagnosis is 6 months;  75% of cases are diagnosed by 1 year of age. Approximately 10%  of cases are not diagnosed until after age 10; however, these  cases usually have milder symptoms. The median age of survival  in the United States is 37 years of age (2008 data).!*°  PATHOPHYSIOLOGY. CF is characterized by abnormal secretions  that cause obstructive problems within the respiratory, diges-  tive, and reproductive tracts. However, research suggests that    there may be additional CF-associated primary defects, such as  an intrinsic proinflammatory state and abnormal local immune  defenses in the lungs. The cystic fibrosis transmembrane conduc-  tance regulator (CFTCR) gene mutation results in the abnormal  expression of cystic fibrosis transmembrane conductance  regulator (CFTCR) protein, which is a cyclic adenosine mono-  phosphate (cAMP)-activated chloride channel present on the  surface of many types of epithelial cells, including those lining  airways, bile ducts, the pancreas, sweat ducts, and the vas defer-  ens. Despite knowing that chloride transport is a fundamental  abnormality, the exact disease mechanisms in CF have still not  been clearly defined at the cellular and end-organ levels.!*  Although CF is a multiorgan disease, the lungs are the most  critical site of involvement, and respiratory failure is almost  always the cause of death. The typical features of CF lung dis-  ease are mucus plugging, chronic inflammation, and infection  of the small airways.'*® The disease process causes progressive  bronchiectasis that becomes widespread. Parenchymal involve-  ment occurs much later and includes microabscess formation,  patchy consolidation and pneumonia, peribronchial fibrosis,  and cyst formation (Figure 36-14). The pathophysiology for  these changes is outlined in Figure 36-15. Airway obstruction  and weakening of the airway wall can lead to the development of  peripheral bullae, which may rupture and cause pneumothorax.  Hemoptysis, sometimes life threatening, may occur because of    FIGURE 36-14 Pathology of the Lung in End-Stage Cystic Fibrosis. Key  features are widespread mucous impaction of airways and bronchiectasis (espe-  cially in upper lobe, U), with hemorrhagic pneumonia in the lower lobe (L). Small  cysts (C) are present at the apex of the lung. (From Kleinerman J, Vauthy P: Pathol-  ogy of the lung in cystic fibrosis, Atlanta, 1976, Cystic Fibrosis Foundation.)    erosion of enlarged bronchial arteries that develop in response  to the inflammation associated with bronchiectasis. Over a long  period of time, pulmonary vascular remodeling occurs because  of localized hypoxia and arteriolar vasoconstriction; pulmonary  hypertension and cor pulmonale may develop with end-stage  disease.   The mucus plugging seen in CF probably results from the  combination of increased production of mucus, altered phys-  icochemical properties of the mucus, and reduced mucocili-  ary clearance.!*? Mucus-secreting airway cells (goblet cells  and submucosal glands) are increased in number and size. It  has been postulated that the CFTCR protein mutation results  in dysregulation of the airway epithelial sodium channel  (ENaC), although this relationship has recently been called  into question.!?? What is clear is that abnormal chloride  excretion and exaggerated sodium absorption with depletion  of the airway surface liquid volume result in dehydration of  airway mucus.!”! This facilitates adherence of mucus to the  epithelium, subsequent impairment of ciliary mobility, and  retention of bacteria that can then form biofilms. Finally,  after secretion, CF mucus becomes even more viscous  because of deoxyribonucleic acid (DNA) and filamentous (F)  actin released from the high number of degraded neutrophils  present in CF airways.   There are abnormal cytokine profiles in CF airway flu-  ids, including deficient levels of IL-10 and excessive amounts  of IL-1, IL-8, and TNF-a, all changes conducive to promot-  ing inflammation. Neutrophils are present in great excess in  CF airways and play a critical role in long-term damage!” in  large measure because of their release of damaging oxidants,    FIGURE 36-15 Pathogenesis of Cystic Fibrosis Lung Disease. CF/R, Cystic  fibrosis transmembrane conductance regulator; //-8, interleukin-8.    such as myeloperoxidase!”* and proteases, in massive amounts  that overwhelm local antiprotease defenses. The mutant CFTR  channel does not transport antioxidants to counteract neu-  trophil-associated oxidative stress.'°* One protease in particu-  lar, neutrophil elastase, has the following detrimental effects:  (1) direct damage to lung structural proteins, such as elastin;  (2) induction of airway cells to produce IL-8, a strong attrac-  tant for neutrophils and thus a means for augmenting a local  “vicious cycle” of inflammation; (3) destruction of IgG and  complement components important for opsonization and  phagocytosis of pathogens; and (4) direct stimulation of mucus  secretion by mucus-producing cells.   The majority of children with CF have chronic endobron-  chial infection. It is likely that local factors in the CF airway  microenvironment favor bacterial colonization because no  systemic immune defect has been found. Several bacteria  colonize the CF lung including Staphylococcus aureus and  Burkholderia cepacia.'°? However, Pseudomonas aeruginosa  ultimately colonizes airways in 75% of children with CF.  Infecting colonies of Pseudomonas adopt a mucoid pheno-  type and organize themselves into adherent biofilms, making  it difficult for antibiotics and local defenses to reach them.!”°  Their biofilm resists beta-lactam antibiotics and their rapid  mutation makes them antibiotic resistant.'°” Persistence of  infection incites chronic local inflammation, airway dam-  age, bronchiectasis, microabscess formation, and foci of  hemorrhagic pneumonia. There is progressive damage to the  normal architecture of the lung with decline in pulmonary  function. 19519"   CLINICAL MANIFESTATIONS. The most common manifestations  are respiratory and gastrointestinal (also see Chapter 42).  Respiratory symptoms include persistent cough or wheeze,  sputum production, and recurrent or severe pneumonia.  More subtle respiratory tract presentations of CF include  chronic sinusitis and nasal polyps. With appropriate treat-  ment, cough, sputum production, and exercise limitation do  not usually reach debilitating levels during childhood. Digi-  tal clubbing may appear quite early even in the absence of  significant pulmonary impairment. Development of barrel  chest or persistent crackles occurs much later in the course  of the disease.   The overall severity of CF lung disease is highly variable.  Even affected siblings may have disparate courses despite iden-  tical CFTR mutations, environment, and treatment strategy.  We now know that some genetic variants significantly influence  disease progression and survival among children with the same  mutations.?00!   EVALUATION AND TREATMENT. Screening algorithms for cys-  tic fibrosis include the immunoreactive trypsinogen (IRT)  blood test, which is performed at birth (may be repeated) and  is elevated in CF. This test can have false positives and nega-  tives. Genotyping for CFTR mutations also is available as a  supplemental diagnostic method.*°? The sweat test is a stan-  dard method of diagnosis and reveals sweat chloride concentra-  tion in excess of 60 mEq/L. There are more than 1900 specific  mutations, but most standard laboratory panels include fewer  than 100 mutations.!*° Newborn screening for CF is universal    in the United States.*°? Genetic counseling of CF gene carriers  is important so they understand risk assessment in relation to  disease.?°*   Treatment is primarily focused on pulmonary health and  nutrition. Because the pulmonary decline in CF is slow and  insidious, and because of the early onset of chronic inflam-  mation and infection, treatment strategies begin immediately  at diagnosis and are modified over time as disease progresses.  Pulmonary therapies include techniques to promote mucus  clearance, such as chest physical therapy and related equip-  ment (such as the high-frequency chest wall oscillation vest)  and an assortment of handheld positive expiratory pressure  (PEP) devices. Aerosol therapy includes antibiotics, broncho-  dilators, and nebulized deoxyribonuclease (DNase). DNase  acts to liquefy mucus and may even have anti-inflammatory  effects,20:206   Antibiotic practices vary, with prophylactic and treatment  strategies being used. Increasing emphasis has been placed on  delaying and controlling microbe colonization, particularly  Pseudomonas, such as the maintenance use of inhaled anti-  biotics.?°” Inhaled hypertonic saline also has proven benefi-  cial to improve airway surface water, thus improving mucus  viscosity and airway clearance.*°* Azithromycin, ibuprofen,  and corticosteroids can reduce airway inflammation and  improve lung function.*”’ Intravenous antibiotics are used  to treat major exacerbations of pulmonary infection, which  may be either subacute or acute. Individuals with end-stage  lung disease may consider double lung transplant as a life-  lengthening measure.”!”   Nutritional problems are extremely common in CF and  poor nutrition is correlated with worse outcomes including  progression of lung disease; onset of additional complica-  tions, such as decreased bone mineral density; and growth fail-  ure.”!!2!2 Elements of aggressive nutritional support include  meticulous monitoring of growth parameters, controlling fat  malabsorption, ensuring adequate caloric intake, and keeping  overall health stable. Approximately 90% of children with CF  have pancreatic insufficiency. This is the result of abnormal  ion transport causing decreased fluid and bicarbonate secre-  tion from the pancreatic acinar cells, which leads to thickened  secretions plugging the smaller pancreatic ducts, and eventual  autodigestion or atrophy of the acinar cells. Therefore, patients  must take exogenous pancreatic enzymes with meals and  snacks in order to absorb nutrients and control malabsorptive  symptoms. Fat-soluble vitamins (A, D, E, and K) must be sup-  plemented.”!° Caloric needs are high, especially with advancing  lung disease, and high-calorie supplements or even gastros-  tomy feeding may be warranted (see Nutrition & Disease: Cys-  tic Fibrosis [CF]).   Future treatments for CF in trial phases are aimed at  improving inhaled antibiotic therapy, developing a vaccine  against Pseudomonas, and incorporating growth hormone in  the treatment regimen. Newer approaches to gene therapy are  being developed, including mutation-specific diagnosis and  treatment.*!*   There is a growing contingent of adults with CF living into  their forties and fifties. Care for these individuals shifts away    Chronic inflammation, pancreatic enzyme deficiency, and undernutrition  contribute to growth failure and poor clinical outcomes in CF. Energy needs  to meet normal growth and weight gain in CF require a diet composed of  35% to 40% of calories from fat. Breast-feeding for the first 4 to 6 months  has shown to be protective for the infant with CF, and then supplemental  formula fortified with additional fat increases energy content. Oral pancre-  atic enzyme replacement is important in maintaining adequate nutritional  status, particularly for fat absorption. The Food and Drug Administration  now requires approval for the marketing of these products. Selection of  dose and preparations is based on weight gain and individual response.  High doses of lipase can be associated with fibrosing colonopathy and new  products are being tested in clinical trials. Fecal pancreatic elastase-1 is  a common diagnostic test for evaluating pancreatic insufficiency. Yearly  monitoring of fat-soluble vitamins (A, D, E, and K) is recommended with  supplementation as needed. Vitamin D supplements are needed to maintain  serum concentrations at 30 ng/ml. Current recommendations are to follow  the Cystic Fibrosis Foundation nutrition care guidelines available at www  .Cff.org/treatments/CFCareGuidelines/Nutrition/. The management of CF-  related diabetes mellitus is a particular challenge and guidelines have been  published by the American Diabetes Association. Nutritional counseling is  a necessary component of care for all individuals with CF.    Data from Kalnins D, Wilschanski M: Drug Des Dev Ther 6:151-161,  2012; Moran A et al: Diabetes Care 33(12):2697-2708, 2010; Nakajima  K et al: Core Evid 7:77-91, 2012; Tangpricha V et al: J Clin Endocrinol  Metab 97(4):1082-1093, 2012; Wier HA, Kuhn RJ: Curr Opin Pediatr  23(5):541-544, 2011.    from a pediatric focus because their care needs are unique and  often extremely complex.”!° Challenges noted in this specialty  area are pregnancy and details about balancing disease manage-  ment and adult life issues.*!°    Sudden infant death syndrome (SIDS) remains a disease of  unknown cause and is the most common cause of unexplained  infant death in Western countries.7!77'* It is defined as “sud-  den death of an infant under 1 year of age which remains  unexplained after a thorough case investigation, including  performance of a complete autopsy, examination of the death  scene, and review of the clinical history.”7!”   The incidence of SIDS is low during the first month of life  but sharply increases in the second month of life, peaks at  2 to 4 months of age, and is unusual after 6 months of age.  The incidence of SIDS in the United States is 0.54 per 1000  live births.?!° It is more common in male infants (60%) than  female (40%) infants and among American Indian/Alaskan  Natives and blacks.’° It almost always occurs during night-  time sleep, when infants are least likely to be observed. A  seasonal variation has been noted, with higher frequencies  during the winter months. This has been related to a higher  rate of respiratory tract infection during those months, and  such infections are often reported to have preceded the  death.    Clinical risk groups include babies who were preterm  or low birth weight, multiple births, and siblings of prior  SIDS victims (fourfold to sixfold increased risk). SIDS is  more prevalent among infants of low or adverse socioeco-  nomic status and occurs more frequently when family size  is larger.’*! Nevertheless, about 75% of all SIDS victims  have no known predisposing clinical risk factor. Maternal  factors that predict increased SIDS risk are maternal smok-  ing, young maternal age (younger than 20 years), unmarried  mother, less prenatal care, poverty, and illicit drug use or  binge-drinking.””” Avoidable risk factors that relate to the  baby’s sleeping situation are prone positioning (and to a  lesser extent, side sleeping), sleeping on soft bedding, over-  heating (environmental or overwrapping), and bed sharing  with an adult (particularly one who smokes).”*> Epidemio-  logic studies have shown that SIDS rates decreased where  massive public campaigns warned against prone sleeping for  infants (e.g., the Back-to-Sleep campaign).**+   The etiology of SIDS remains unknown, but probably  involves a combination of predisposing factors including a  vulnerable infant, environmental stressors, a critical develop-  mental period for homeostatic control, and altered cardiorespi-  ratory, circulatory, and arousal characteristics.?*>*° There has  been long-standing interest in hypotheses involving impaired  autonomic regulation and failure of cardiovascular, ventila-  tory, and arousal responses (particularly those regulated by the  hypoglossal nucleus [HGN]) to hypoxemia or hypercarbia.’””  Alternative theories involve airway obstruction events, such as  control of tongue movements related to inspiratory activity;  increased vagal tone; sudden intrapulmonary shunting because  of abnormalities of surfactant or pulmonary vessels; or exag-  gerated inflammation, eosinophil degranulation, and massive  cytokine release causing pulmonary edema in response to either  bacterial pathogens from the nasopharynx or viral respiratory  tract infections.?7°?79   Finally, there is growing evidence that genetic factors may  predispose certain individuals to SIDS. The most important  risk factor genes include those involved in the regulation of the  immune system, cardiac function, and the serotonergic net-  work related to brainstem function.?**! It is estimated that  10% to 20% of SIDS cases may be caused by genetic variation  in either ion channel or ion channel—associated proteins asso-  ciated with primary electrical heart disease (e.g., long-QT and  short-QT syndrome).?°?   Currently, the best strategy to reduce SIDS is avoidance of all  the controllable risk factors. Recommendations include supine  positioning; use of a firm sleep surface; room-sharing without  bed-sharing; routine immunization; consideration of a pacifier;  and avoidance of soft bedding, overheating, and exposure to  tobacco smoke, alcohol, and illicit drugs.*°’ Breast-feeding has  been identified as a specific risk reduction measure.?** Parents  of infants with clinical risk should be taught cardiopulmonary  resuscitation as a precaution. Home monitoring has not been  proven to decrease the incidence of SIDS and more research  is needed.**> Some at-risk infants may warrant cardiorespira-  tory monitoring after careful consideration of the individual  situation.    The airways of infants and children are narrower than those  of adults, thus making them more prone to obstruction.    mental maturity of the fetal lung and is secreted into the  airways by 30 weeks of gestation.    Physical examination can provide important clues in assess-  ing the location and nature of UAO.    of inflammatory edema and airway obstruction, includ-  ing bacterial tracheitis, retropharyngeal abscess, and  peritonsillar infections. Recognition and rapid evalua-  tion are crucial.    cause of acute upper airway obstruction in children and  usually affects children ages 6 months to 5 years. Subglottic  edema may be mild to severe. Parainfluenza is the most com-  mon cause.    now rarely seen because of vaccination against H. influen-  zae, which had been the primary causative microorganism.  Current cases usually represent vaccine failure or are caused  by other bacteria, such as group A streptococci.    there is a sudden onset of stridor, coughing, wheezing, or  hoarseness. This usually occurs in 1- to 3-year-olds. Occa-  sionally diagnosis is delayed and symptoms may be attributed  to asthma, bronchitis, or pneumonia without recognition of  the underlying cause.    wheezing, or dyspnea. The most common cause of stridor  in infants is laryngomalacia. Other causes include subglot-  tic stenosis, vocal cord paralysis, and vascular rings.    dren rather than infants and is underdiagnosed. Typi-  cal symptoms are snoring, gasping, and restless sleep.  The most common cause in children is adenotonsillar  hypertrophy.    infants who are born before surfactant production and  alveolocapillary development are complete. Atelectasis  and hypoventilation cause shunting, hypoxemia, and  hypercapnia.    BPD is a chronic lung disease of infancy that is usually the  consequence of acute respiratory disease in premature infants  who required oxygen and positive pressure ventilatory sup-  port. Contributing factors include structural immaturity,  inflammation, and disordered lung repair processes.  Bronchiolitis occurs in infants and toddlers, usually in  the winter and early spring. It is caused by viruses, most  commonly RSV. There is extensive edema, inflammation,  and damage to the bronchiolar epithelium. Injections of  monoclonal antibody against RSV are recommended as a  preventive measure for high-risk infants.   Childhood pneumonia can be caused by viruses (most  common), bacteria, or Mycoplasma. Lobar pneumonia is  usually bacterial. Certain bacteria, such as S. aureus and  group A streptococci, can cause particularly fulminant  disease, as well as abscesses and empyema.   Aspiration pneumonitis can occur because of lung inflam-  mation from entry of any foreign substance, including food,  drink, or chemicals. Aspiration of oropharyngeal bacteria can  occur because of loss of protective reflexes in neurologically  impaired children, or during induction of anesthesia.  Asthma is an obstructive airway disease with episodes of  acute respiratory symptoms (cough, wheeze, dyspnea) and  intermittent or chronic subacute symptoms. It is the most  common chronic condition in children. It is a disease of  local airway inflammation, with exacerbation in response to  triggers, such as infections or allergens. Inflammatory cell  infiltration, mucosal edema, mucus plugging of airways,  and epithelial damage cause obstruction to airflow, and  there is evidence of long-term remodeling of airways.  ARDS is an acute life-threatening condition characterized  by severe hypoxemia, poor lung compliance, and diffuse  densities on chest radiograph. It can be triggered by acute  pulmonary insults or major systemic illness (e.g., sepsis)  or trauma. High-level ventilatory support is required, and  mortality is significant.   CF is an autosomal recessive disease characterized by thick,  tenacious mucus, plugging of airways, chronic pulmonary  infection, and bronchiectasis related to airway epithelial  chloride and sodium transport. The other major manifes-  tations are digestive and nutritional, related to pancreatic  insufficiency. Median survival is currently 37 years, with  mortality primarily related to lung disease.    SIDS is a diagnosis of exclusion after thorough investigation  and autopsy following sudden death of an infant less than  6 months of age. 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Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Structures of the Renal System, 1319  Structures of the Kidney, 1319  Urinary Structures, 1325  Renal Blood Flow, 1326  Autoregulation of Renal Blood Flow, 1326  Neural Regulation, 1326  Hormones and Other Factors, 1327  Kidney Function, 1327  Nephron Function, 1327  Concentration and Dilution of Urine, 1331  Renal Hormones, 1333    The primary function of the kidney is to maintain a stable  internal environment for optimal cell and tissue metabolism.  The kidneys accomplish these life-sustaining tasks by balanc-  ing solute and water transport, excreting metabolic waste prod-  ucts, conserving nutrients, and regulating acids and bases. The  kidney also has an endocrine function, secreting the hormones  renin, erythropoietin, and 1,25-dihydroxy-vitamin D, for regu-  lation of blood pressure, erythrocyte production, and calcium  metabolism, respectively. The kidney also can synthesize glu-  cose from amino acids, performing the process of gluconeogen-  esis (see What’s New? The Kidney and Glucose Regulation). The  formation of urine is achieved through the processes of filtra-  tion, reabsorption, and secretion by the glomeruli and tubules  within the kidney. The bladder stores the urine that it receives  from the kidney by way of the ureters. Urine is then removed  from the body through the urethra.    Tests of Renal Function, 1334  The Concept of Clearance, 1334  Blood Tests, 1335  Urinalysis, 1335  AGING and Renal Function, 1336    The kidneys are paired organs located in the posterior region  of the abdominal cavity behind the peritoneum (Figure  37-1). They lie on either side of the vertebral column with  their upper and lower poles extending from approximately  the twelfth thoracic to the third lumbar vertebrae. The right  kidney is slightly lower than the left and is displaced down-  ward by the overlying liver. Each kidney is approximately 11  cm long, 5 to 6 cm wide, and 3 to 4 cm thick. A tightly adher-  ing capsule (the renal capsule) surrounds each kidney, and  the kidney then is embedded in a mass of fat. The capsule  and fatty layer are covered with a double layer of renal fas-  cia, fibrous tissue that attaches the kidney to the posterior  abdominal wall.    UNIT XI The Renal and Urologic Systems  Adrenal  gland Spleen  Liver Renal artery  Twelfth rib Renal vein  Left kidney  Right  kidney  Abdominal  aorta  Ureter  Inferior  i vena cava  Urinary  bladder  Common  iliac artery  and vein  Urethra    FIGURE 37-1 Organs of the Urinary System. (From Patton KT, Thibodeau GA:  Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    The human kidney contributes to the regulation of glucose concentration by  making glucose through gluconeogenesis, by taking up glucose from the cir-  culation, and by reabsorbing glucose from the glomerular filtrate. The human  liver and kidneys release approximately equal amounts of glucose through  gluconeogenesis in the postabsorptive state (4 to 12 hours after meal inges-  tion). Other tissues lack the enzyme necessary for gluconeogenesis (glucose-  6-phosphatase) and cannot participate in gluconeogenesis. In the postprandial  state (up to 4 hours after meal ingestion), although overall endogenous glu-  cose release decreases substantially, renal gluconeogenesis increases by  approximately twofold.   About 180 grams of glucose are normally filtered each day by the kidneys.  Almost all of this is actively reabsorbed by means of sodium-glucose cotrans-  porter 2 (SGLT2), a transmembrane protein expressed in the luminal border of  the proximal tubule. This ensures sufficient energy is available during fasting  periods. When plasma glucose concentrations exceed a threshold, the SGLT2  becomes saturated and glucose appears in the urine. Individuals with diabetes  mellitus have an increased transport maximum (Ty) for glucose from enhanced  expression of SGLT2 and this contributes to hyperglycemia when there is poor  glucose control. SGLT2 inhibitors are being evaluated for reducing hyperglyce-  mia associated with diabetes mellitus.   Renal glucose release is stimulated by epinephrine and is inhibited by insu-  lin. Insulin suppresses glucose release in both the liver and the kidney. The  kidneys do not synthesize glycogen and, therefore, do not release glucose  through glycogenolysis. In the postabsorptive state, the kidneys utilize about  10% of all glucose used by the body. When there is hypoglycemia, the liver  initially releases glucose through glycogenolysis and then increases gluconeo-  genesis. The kidney also counter-regulates hypoglycemia through gluconeo-  genesis, which may explain in part why individuals with renal failure tend to  develop hypoglycemia.    Data from DeFronzo RA, Davidson JA, Del Prato S: Diabetes Obes  Metab 14(1):5-14, 2012; Gerich JE: Diabet Med 27(2):136-142, 2010;  Mather A, Pollock C: Kidney Int Supp! (120):S1-S6, 2011; Mitrakou A:  Diabetes Res Clin Pract 93(Suppl 1):S66-S72, 2011.    FIGURE 37-2 Kidney Structure. (From Patton KT, Thibodeau GA: Anatomy  & physiology, ed 8, St Louis, 2013, Mosby.)    The cushion of fat and the position of the kidney between  the abdominal organs and muscles of the back protect it from  trauma. A medial indentation (the hilum) is where the renal  blood vessels, nerves, lymphatic vessels, and ureter enter and  exit the kidney.   The structures of the kidney are summarized in Figure 37-2.  The outer layer of the kidney is called the cortex and contains  all of the glomeruli, most of the proximal tubules, and some  segments of the distal tubule. The medulla forms the inner part  of the kidney and consists of regions called the pyramids. Renal  columns extend from the cortex down between the renal pyra-  mids. The apexes of the pyramids project into minor calyces  (cup-shaped cavities) that unite to form major calyces. The  minor calyces receive urine from the collecting ducts through  the renal papilla. The major calyces join to form the renal pel-  vis, which connects with the proximal end of the ureter. The  walls of the calyces, pelvis, and ureter are lined with epithelial  cells and contain smooth muscle cells that contract to move  urine to the bladder.   The structural unit of the kidney is the lobe. Each lobe is  composed of a pyramid and the overlying cortex. On average,  there are 14 lobes in each kidney.    The nephron is the functional unit of the kidney. Each kidney  contains approximately 1.2 million nephrons. The nephron is  a tubular structure with subunits that include the renal cor-  puscle, proximal convoluted tubule, loop of Henle (nephron  ansa), distal convoluted tubule, and collecting duct, all of which  contribute to the formation of urine (Figure 37-3). The different  epithelial cells lining various segments of the tubule facilitate the  special functions of reabsorption and secretion (Figure 37-4).  The kidney has three kinds of nephrons: (1) superficial cor-  tical nephrons (85% of all nephrons), which extend partially  into the medulla; (2) midcortical nephrons with short or long  loops; and (3) juxtamedullary nephrons, which lie close to and  extend deep into the medulla and are important for the process    CHAPTER 37 Structure and Function of the Renal and Urologic Systems    FIGURE 37-3 Components of the Nephron. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013,  Mosby; Damjanov |: Pathology for health professions, ed 4, St Louis, 2012, Mosby.)    of concentrating urine (Figure 37-5). The glomerulus (Figure  37-6; see also Figure 37-3) is a tuft of capillaries that loop into  the circular Bowman glomerular capsule (Bowman space),  like fingers pushed into bread dough. Mesangial cells and the  mesangial matrix, secreted by mesangial cells, lie between and  support the glomerular capillaries. Different mesangial cells  contract like smooth muscle cells to regulate glomerular capil-  lary blood flow. They also have phagocytic properties similar to  monocytes and release inflammatory cytokines and growth fac-  tors.' Together, the glomerulus, Bowman capsule, and mesan-  gial cells are called the renal corpuscle.   The glomerular filtration membrane filters selected blood  components through its three layers: (1) the inner layer is the  glomerular endothelium, (2) the middle layer is the glomeru-  lar basement membrane (GBM), and (3) the outer layer is the    visceral epithelium, which forms the inner layer of Bowman  capsule. Each layer has unique structural properties that allow  all components of the blood to be filtered, with the exception of  blood cells and plasma proteins with a molecular weight greater  than 70,000 (Figure 37-7; see also Figure 37-6).   Glomerular endothelial cells synthesize nitric oxide (a vaso-  dilator) and endothelin-1 (a vasoconstrictor) that help regulate  glomerular blood flow. The glomerular endothelium is perfo-  rated by many small openings or windows, called fenestrae. The  fenestrae are maintained by vascular epithelial growth factor  (VEGF) produced by the visceral epithelium. The middle base-  ment membrane is composed of a selectively permeable network  of proteoglycans (type IV collagen) secreted and maintained by  the epithelial cells.* The visceral epithelium of the Bowman cap-  sule is composed of cells called podocytes (foot-like processes)*    FIGURE 37-4 Epithelial Cells of the Various Segments of Nephron Tubules. The brush border and high number of  mitochondria in the cells of the proximal convoluted tubule permit reabsorption of 60% of the glomerular filtrate. /ntercalated  cells (blue text) secrete either Ht (reabsorb HCO3) or HCO; and reabsorb K* Principal cells (magenta text) reabsorb Na* and    that radiate and adhere to the basement membrane covering  the glomerular capillaries. The foot processes of one podocyte  interlock with the foot processes of adjacent podocytes, form-  ing an elaborate network of intercellular clefts. These clefts are  called filtration slits (see Figure 37-7) and modulate filtration.  Nephrin, podocin, CD2-associated protein, and other protein  molecules ensure proper function of the fenestrae.‘   The podocytes are endocytic, which allow molecules to enter  the cell without passing through the cell membrane, and they  prevent leakage of proteins into the urine. The visceral epithe-  lium is reflected back at the vascular pole to become the parietal  epithelium. The space between the visceral and parietal epithe-  lia is the Bowman (urinary) space, which is continuous with  the lumen of the renal tubules.   Glomerular filtration occurs when plasma filtrate from the  glomerulus passes through the three layers of the glomerular  membrane into Bowman space to form the primary urine. The  endothelium, basement membrane, and podocytes are covered  with protein molecules bearing anionic (negative) charges that  retard the filtration of anionic proteins and prevent proteinuria.   The glomerulus is supplied by the afferent arteriole and drained  by the efferent arteriole. A group of specialized cells known as jux-  taglomerular cells are located around the afferent arteriole where  it enters the glomerulus (see Figures 37-3 and 37-6). Between the  afferent and efferent arterioles is a portion of the distal convoluted    tubule with specialized sodium- and chloride-sensing cells known  as the macula densa. Together the juxtaglomerular cells and mac-  ula densa cells form the juxtaglomerular apparatus (JGA) (see  Figure 37-6). Control of renal blood flow, glomerular filtration,  and renin secretion occurs at this site.   The proximal convoluted tubule continues from the Bow-  man capsule and has an initial convoluted segment (pars con-  voluta) and then a straight segment (pars recta) that descends  toward the medulla (see Figure 37-3). The wall of the tubule  consists of one layer of cuboidal epithelial cells with a surface  layer of microvilli (a brush border) that increases reabsorp-  tive surface area. This is the only surface inside the nephron  where the cells are covered with microvilli (see Figure 37-4).  The proximal convoluted tubule joins the hairpin-shaped loop  of Henle. The loop is composed of a thin descending segment,  thin ascending segment and a thick ascending segment. The  thin descending segment is composed of squamous cells, and is  highly permeable to water but less permeable to ions. It has no  active transport functions. The thin ascending segment is per-  meable to ions but not to water. The thick ascending segment  actively transports ions into the interstitium and passes urine  into the distal convoluted tubule (see Figure 37-14).   The more numerous cortical nephrons have glomeruli  originating close to the surface of the cortex or in the midcor-  tex, unlike the juxtamedullary nephrons, whose glomeruli are    CHAPTER 37 Structure and Function of the Renal and Urologic Systems    FIGURE 37-5 The Nephron Unit with Its Blood Vessels. Blood flows through nephron vessels as follows: interlobular  artery, afferent arteriole, glomerulus, efferent arteriole, peritubular capillaries (around the tubules), venules, interlobular vein.  (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    located deep in the cortex close to the medulla. The major struc-  tural difference between the glomeruli in the two types of neph-  rons is the length of the loop of Henle. In cortical nephrons the  loop is short and may not extend into the medulla. The loop of  Henle for the juxtamedullary nephrons, however, may extend  the whole length of the medulla (40 mm). Juxtamedullary  nephrons represent about 12% of the total number of nephrons  and are important for the concentration and dilution of urine.    The distal convoluted tubule extends from the distal por-  tion of the loop of Henley to the collecting duct. The collecting  duct is a large tubule that descends down the cortex through the  renal pyramids of the inner and outer medullae, draining urine  into the minor calyx. The collecting duct is composed of two  epithelial cell types: principal cells that reabsorb sodium and  water and secrete potassium, and intercalated cells that secrete  hydrogen and reabsorb potassium (see Figure 34-4).    epithelial Podocyte  cells Podocytes (cell body)  (visceral cells) Pedicel  Proximal (cell process) C  convoluted —_  tubule ; | apsular ;  ° slits (filtration) Capillary  endothelium  FIGURE 37-6 Anatomy of the Glomerulus and Juxtaglomerular Apparatus. A, Longitudinal cross section of glomeru-  lus and juxtaglomerular apparatus. B, Horizontal cross section of glomerulus. €, Enlargement of glomerular capillary filtration  membrane.  Podocyte foot  processes  Podocyte ae .  cell body Filtration slits  Endothelial cell  Podocyte cell body  Filtration  ole Basement  membrane  Podocyte foot  processes Fenestration    FIGURE 37-7 Glomerular Capillary. A, Scanning electron micrograph of normal glomerular capillary (C). B, Glomerular  capillary wall (filtration membrane) (x 40,000). Black arrow indicates direction of urine flow. (From Kissane JM, editor: Ander-  son’s pathology, ed 9, St Louis, 1990, Mosby.)    CHAPTER 37 Structure and Function of the Renal and Urologic Systems    The blood vessels of the kidney closely parallel nephron struc-  ture. The renal arteries arise from the abdominal aorta at the  first lumbar vertebra and supply approximately 20% of the  cardiac output to the kidneys. At the renal hilum they divide  into anterior and posterior branches and then subdivide into  lobar arteries that supply blood to the lower, middle, and upper  portions of the kidney. The interlobar arteries are further sub-  divisions that travel down the renal columns and between the  pyramids. At the cortical-medullary junction, interlobar arter-  ies branch into the arcuate arteries that arch over the base of  the pyramids and run parallel to the surface of the kidney. The  interlobular arteries arise from the arcuate arteries and extend  through the cortex toward the periphery of the kidney and sup-  ply the afferent glomerular arterioles (see Figure 37-5).   The afferent arterioles subdivide into the glomerulus, a fistlike  structure of four to eight glomerular capillaries (see Figure  37-6). The glomerular capillaries feed into the efferent arteriole,  which conveys blood to a second capillary bed, the peritubular  capillaries. This is the only place in the body where an arteriole  is positioned between two capillary beds. Increases or decreases  in the resistance of the afferent and efferent arterioles increase  or decrease glomerular filtration. The peritubular capillaries  surround the the proximal and distal convoluted tubules and  the loop of Henle (see Figure 37-5). The peritubular capillar-  ies are adapted differently for the cortical and juxtamedullary  nephrons. The peritubular capillaries surrounding the tubules  of the cortical nephrons are similar to capillaries in other tis-  sues. For the juxtamedullary nephrons a network of capillaries  called the vasa recta forms loops and closely follows the loops of  Henle. The capillaries of the vasa recta are the only blood sup-  ply to the medulla. They influence the osmolar concentration  of the medullary extracellular fluid, which is important to the  formation of concentrated urine. All capillaries then drain into  the venous system. The renal veins follow the arterial path in a  reverse direction and have the same names as the arteries. The  renal vein empties into the inferior vena cava. The lymphatic  vessels tend also to follow the distribution of the blood vessels.    Urinary Structures  Ureters  The urine formed by the nephrons flows from the distal tubules  and collecting ducts through the duct of Bellini and the renal  papillae (projections of the ducts) into the calyces, where it is col-  lected in the renal pelvis (see Figure 37-2) and then funneled into  the ureters. Each adult ureter is approximately 30 cm long and  is composed of long, intertwining smooth muscle bundles. The  lower ends of the ureters pass obliquely through the posterior  aspect of the bladder wall. The close approximation of smooth  muscle cells permits the direct transmission of electrical stimula-  tion from one cell to another. The resulting downward peristaltic  activity propels urine into the bladder. Contraction of the blad-  der during micturition (urination) compresses the lower end of  the ureter, preventing reflux. Peristalsis is maintained even when  the ureter is denervated, so ureters can be transplanted.   Sensory innervation for the upper part of the ureter arises  from the tenth thoracic nerve roots, with referred pain to the    umbilicus. The innervation of lower segments arises from the  sacral nerves with referred pain to the vulva or penis. The ureters  have a rich blood supply. The primary arteries come from the  kidney with contributions from the lumbar and superior vesical  arteries.    The bladder is a bag composed of a basket weave of smooth  muscle fibers that forms the detrusor muscle and its smooth  lining of transitional epithelium (uroepithelium). As the blad-  der fills with urine, it distends and the layers of transitional epi-  thelial cells within the lining slide past each other and become  thinner as the volume of the bladder increases. The transitional  epithelium forms the interface between the urinary space and  underlying vasculature, connective, nervous, and muscle tissue.  It senses and transduces information about luminal pressure  and urine composition within the urinary tract.° The trigone  is a smooth triangular area lying between the openings of the  two ureters and the urethra (Figure 37-8). The position of the  bladder varies with age and gender. In infants and young chil-  dren the bladder rises above the symphysis pubis, providing  easy access for percutaneous aspiration. In adults it lies in the  true pelvis, in front of the rectum and in front of the uterus in  women. Inferiorly, the bladder sits on the prostate in men and  on the anterior vagina in women. The bladder has a profuse  blood supply, accounting for the bleeding that readily occurs  with trauma, surgery, or inflammation.   The urethra extends from the inferior side of the bladder  to the outside of the body. Two muscles called sphincters con-  trol excretion of urine from the bladder through the urethra. A  ring of smooth muscle forms the internal urethral sphincter at  the junction of the urethra and bladder. The external urethral  sphincter is composed of striated skeletal muscle and is under  voluntary control. The entire urethra is lined with mucus-  secreting glands. The female urethra is short (3 to 4 cm). The  male urethra is long (18 to 20 cm) and has three main segments:  prostatic, membranous, and penile. The prostatic urethra is    FIGURE 37-8 Structure and Location of the Urinary Bladder. Frontal view  of a dissected urinary bladder (male) in a fully distended position. (From Patton KT,  Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    closest to the bladder. It passes through the prostate gland and  contains the openings of the ejaculatory ducts. The membra-  nous urethra is the segment that passes through the floor of the  pelvis. The penile segment forms the remainder of the tube. The  penile segment is surrounded by the corpus spongiosum erectile  tissue and contains the openings of the bulbourethral glands.   The innervation of the bladder and internal urethral sphincter  is supplied by parasympathetic fibers of the autonomic nervous  system that arise from the sacral levels of the spinal cord (S2 to  S4). Sensory fibers from the bladder and urethra may extend as  high as the T6 portion of the spinal cord. Skeletal motor neurons  in the pudendal nerve innervate the external urethral sphincter.  The reflex arc required for micturition is stimulated by mecha-  noreceptors that respond to stretching of tissue. The mechano-  receptors sense bladder fullness and send impulses to the sacral  level of the spinal cord with bladder filling. When the bladder  accumulates 250 to 300 ml of urine, the bladder contracts and  the internal urethral sphincter relaxes through activation of the  spinal reflex arc (known as the micturition reflex). At this time a  person feels the urge to void. In older children and adults, the  reflex can be inhibited or facilitated by impulses coming from  the brain, resulting in voluntary control of micturition.    The kidneys are highly vascular organs and receive about 20%  to 25% of the cardiac output, which in adults is equivalent to  1000 to 1200 ml of blood per minute. With a normal hema-  tocrit of 45%, about 600 to 700 ml of blood flowing through  the kidney per minute is plasma. From the renal plasma flow  (RPF), 20% (approximately 120 to 140 ml/minute) is filtered at  the glomerulus and passes into the Bowman capsule. The filtra-  tion of the plasma per unit of time is known as the glomerular  filtration rate (GFR), which is directly related to the perfusion  pressure in the glomerular capillaries.   The remaining 80% (about 480 ml/minute) of plasma flows  through the efferent arterioles to the peritubular capillaries. The  ratio of glomerular filtrate to RPF per minute (120/600 = 0.20)  is called the filtration fraction. Normally all but 1 to 2 ml per  minute of the glomerular filtrate is reabsorbed and returned to  the circulation by the peritubular capillaries.   The GFR is directly related to renal blood flow (RBF), which  is regulated by intrinsic autoregulatory mechanisms, neural reg-  ulation, and hormonal regulation. In general, blood flow to any  organ is determined by the arteriovenous pressure differences  across the vascular bed. If mean arterial pressure decreases or  vascular resistance increases, renal blood flow decreases.    In the kidney a local mechanism of autoregulation tends to  keep the rate of glomerular perfusion and therefore the GFR  fairly constant over a range of arterial pressures between 80 and  180 mmHg (Figure 37-9). This means that changes in afferent  arteriolar pressure and resistance occur in the same direction.  For example, as systemic blood pressure increases, the afferent  arterioles constrict, preventing an increase in filtration pressure.  Opposite processes occur with a decrease in systemic blood    Arterial blood pressure (mmHg)  FIGURE 37-9 Autoregulation of Renal Blood Flow. Blood flow and glomeru-  lar filtration rate are stabilized with changes in mean arterial pressure between  about 80 and 180 mmHg. (From Berne RM, Levy MN, editors: Principles of physiol-  ogy, ed 4, St Louis, 2006, Mosby.) GFR, Glomerular filtration rate; RBF, renal blood  flow.    pressure. Therefore, renal blood flow and GFR are relatively  constant. The purpose of renal autoregulation is to prevent wide  fluctuations in systemic arterial pressure from being transmitted  to the glomerular capillaries. In this way, large fluctuations in  GFR are prevented and solute and water excretion is constantly  maintained despite arterial pressure changes.° Autoregulation  may also protect the kidney from damage by hypertension.   One mechanism responsible for the autoregulatory  response in the kidney is a myogenic mechanism. As arte-  rial pressure declines, the stretch on the afferent arteriolar  smooth muscle decreases and the arteriole relaxes, causing  an increase in glomerular perfusion; an increase in arteriolar  pressure causes the arteriole smooth muscle to contract and  decreases glomerular perfusion. Tubuloglomerular feed-  back is a second mechanism for keeping renal blood flow and  GFR constant and stable. As the GFR in an individual neph-  ron increases or decreases, the macula densa cells in the distal  tubule sense the increasing or decreasing amounts of filtered  sodium. When sodium filtration increases, the macula densa  cells stimulate afferent arteriolar vasoconstriction to decrease  GFR. The opposite occurs with decreases in sodium filtration  at the macula densa.’ A third unknown mechanism also con-  tributes to autoregulation.®    Neural Regulation  The blood vessels of the kidney are innervated by sympathetic  adrenergic/noradrenergic fibers that cause arteriolar vasocon-  striction to reduce renal blood flow. The innervation of the  kidney comes primarily from the celiac ganglion and greater  splanchnic nerve (see Figure 15-25). The afferent and effer-  ent arterioles are richly innervated, but nerves have not been  observed in the glomerular capillaries.   Renal blood flow is reflexively related to the systemic arterial  pressure. When systemic arterial pressure decreases, increased    CHAPTER 37 Structure and Function of the Renal and Urologic Systems    sympathetic nerve activity is mediated reflexively through feed-  back from the baroreceptors of the carotid sinus and aortic  arch. This is achieved through the baroreceptor reflex, which  stimulates vasoconstriction of the afferent arterioles with acti-  vation of a@,-adrenoreceptors. This decreases glomerular per-  fusion and GFR, although autoregulatory processes dampen  the response. Decreased GFR diminishes excretion of sodium  and water, promoting an increase in blood volume and thus an  increase in blood pressure.   Exercise, body position, and hypoxia also influence renal  blood flow. Exercise and change of body position activate renal  sympathetic neurons and cause mild vasoconstriction. Severe  hypoxia stimulates the chemoreceptors of the carotid and aortic  bodies and decreases renal blood flow by means of sympathetic  stimulation.    Hormonal factors and many mediators can alter the resistance  of the renal vasculature by stimulating vasodilation or vasocon-  striction. A major hormonal regulator of renal blood flow is  the renin-angiotensin-aldosterone system (RAAS), which can  increase systemic arterial pressure and increase sodium reab-  sorption. Renin is an enzyme formed and stored in granular  cells of the afferent arterioles of the JGA (see Figure 37-3). The  release of renin is principally triggered by decreased blood pres-  sure in the afferent arterioles, which reduces stretch of the jux-  taglomerular cells; decreased sodium chloride concentrations in  the distal convoluted tubule; sympathetic nerve stimulation of  B-adrenergic receptors on the juxtaglomerular cells; and release  of prostaglandins.’   When renin is released, it cleaves an a-globulin (angioten-  sinogen produced by liver hepatocytes) in the plasma to form  angiotensin I, which is physiologically inactive. In the presence  of angiotensin-converting enzyme (ACE) produced from the  pulmonary and renal endothelium, angiotensin I is converted  to angiotensin II. Angiotensin II stimulates secretion of aldoste-  rone by the adrenal cortex (see Chapter 21), is a potent vasocon-  strictor, and stimulates antidiuretic hormone (ADH) secretion  and thirst. Vitamin D; is a potent negative endocrine regulator  of renin gene expression.'? Numerous physiologic effects of the  RAAS serve the purpose of stabilizing systemic blood pressure  and preserving the extracellular fluid volume during hypoten-  sion or hypovolemia, including sodium reabsorption, potassium  excretion, systemic vasoconstriction, sympathetic nerve stimu-  lation, thirst stimulation, and drinking. (The combined effects  of the RAAS are summarized in Figure 37-10.) ACE inhibitors  are a class of drugs that reduce blood pressure by inhibiting the  formation of angiotensin II and aldosterone.   Natriuretic peptides are a group of peptide hormones,  including atrial natriuretic peptide (ANP), secreted from myo-  cardial cells in the atria and brain natriuretic peptide (BNP)  secreted from myocardial cells in the cardiac ventricles. When  the heart dilates during volume expansion or heart failure,  ANP and BNP inhibit sodium and water absorption by kidney  tubules, inhibit secretion of renin and aldosterone, vasodilate  the afferent arterioles, and constrict the efferent arterioles. The  result is increased urine formation leading to decreased blood    i} Hypovolemia  Angiotensinogen Hypotension  {Na at macula densa cells of  distal tubule    — Aldosterone (adrenal cortex)  Increases NaCl reabsorption by  collecting ducts, Loop of Henle  and distal tubules    — ADH and thirst (hypothalamus  and posterior pituitary)  Increases water reabsorption  at collecting ducts    FIGURE 37-10 Renin-Angiotensin-Aldosterone System. Activation of tubu-  loglomerular feedback mechanisms stimulates the release of renin with activation  of the renin-angiotensin-aldosterone system. Plasma volume and blood pressure  are increased with the reabsorption of sodium chloride and water from the renal  tubules. The restoration of plasma volume and blood pressure then decrease the  release of renin, forming a negative feedback loop. ADH, Antidiuretic hormone.    volume and blood pressure.'! C-type natriuretic peptide is  secreted from vascular endothelium and in the nephron and  causes vasodilation.!* Urodilatin is secreted by the distal convo-  luted tubules and collecting ducts and causes vasodilation and  natriuretic and diuretic effects. Other hormones and mediators  that influence renal blood flow are summarized in Table 37-1.    The major function of the kidney is urine formation and  involves the processes of filtration, reabsorption, and secre-  tion. These processes are the function of the nephrons. Fluid is  filtered at the glomerulus. Substances are reabsorbed from the  filtrate or secreted into the filtrate by the renal tubules. The final  urine flows into the minor and major calyces, and then is pro-  pelled by the ureters to the bladder for storage and elimination.    The nephron can perform many functions simultaneously. It  filters the plasma at the glomerulus and reabsorbs and secretes  different substances at various parts of its tubular structure  (Figure 37-11). The function of the nephron is to form a filtrate    HORMONES, MEDIATORS, AND RENAL BLOOD FLOW  EFFECT ON RENAL BLOOD FLOW    Adenosine Produced within kidney; causes vasoconstriction of afferent arteriole; decreases RBF and GFR  Angiotensin Il Produced systemically and within kidneys; constricts afferent and efferent arterioles; decreases RBF and GFR  Atrial and brain natriuretic peptides Produced by atria and ventricles of the heart with hypertension and increased blood volume; causes vasodilation of    afferent arteriole and vasoconstriction of efferent arteriole; modest increase in GFR with little change in RBF    Bradykinin Produced in kidney from kininogen and causes vasodilation by release of nitric oxide and prostaglandins; increases RBF    Dopamine Produced by the proximal tubule; increases RBF; inhibits renin secretion  Endothelin Produced by renal vessel endothelial cells, mesangial cells, and distal tubule cells in response to bradykinin,    angiotensin Il, epinephrine, and stretch; most active with renal disease; profound vasoconstriction of afferent and  efferent arterioles; decreases RBF and GFR    Histamine Produced locally within the kidney; modulates RBF in basal state and during inflammation; increases RBF by decreasing    Nitric oxide Produced by renal vessel endothelial cells with increased stretch and by stimulation of acetylcholine, histamine,    Prostaglandins, PGI, PGE, Produced locally within kidney with decreased RBF; dampen vasoconstriction caused by sympathetic nerves and    Urodilatin (a natriuretic peptide) Produced by distal tubule and collecting duct when there is increased circulating volume and increased blood pressure;  inhibits sodium and water reabsorption from medullary part of collecting duct, thereby producing diuresis   Filtration Reabsorption of Concentration of urine | Reabsorption of Reabsorption of  Na* (majority) (countercurrent Nat HO (ADH required)  Glucose mechanism) HO (ADH required)  Kea HCO3 Reabsorption or  Amino acids Descending loop secretion of  HCO3 Water reabsorption | Secretion of Nat  PO - Nat diffuses in Kt K+  Urea Urea H+  H2O (ADH not Ascending loop Ht NHg  required) Nat reabsorped NH3  (active transport) Some drugs Urea reabsorption  Secretion of Water stays in in medulla  Ht+  Foreign substances | Urea secretion in  thin segment  TONICITY OF Isotonic lsotonic——> lsotonic or Final concentration  FLUID (WITHIN DUCTS) Hypertonic —> Hypotonic  Hypotonic    FIGURE 37-11 Major Functions of Nephron Segments. ADH, Antidiuretic hormone. (Modified from Hockenberry MJ:  Wong's nursing care of infants and children, ed 8, St Louis, 2007, Mosby.)    of protein-free plasma. This process, known as ultrafiltration,  occurs across the glomerular membrane. The nephron then  regulates the filtrate to maintain body fluid volume, electrolyte  composition, and pH within narrow limits.   Regulation of the filtrate occurs through two processes: tubu-  lar reabsorption and tubular secretion. Tubular reabsorption    is the movement of fluids and solutes from the tubular lumen  to the peritubular capillary plasma. Transfer of substances from  the plasma of the peritubular capillary to the tubular lumen is  tubular secretion. The mechanisms involve active as well as  passive transport. Excretion is the elimination of a substance in  the final urine (Figure 37-12).    CHAPTER 37 Structure and Function of the Renal and Urologic Systems    FIGURE 37-12 Urine Formation: Glomerular Filtration, Tubular Reabsorp-  tion, and Tubular Secretion. The three processes by which the kidneys excrete  urine. Water, electrolytes, glucose, and organic molecules are filtered at the glomeru-  us. Sodium and glucose are reabsorbed into peritubular capillaries by active transport  from the proximal convoluted tubules and water reabsorption follows by osmosis.  Sodium is reabsorbed by active transport from distal convoluted tubules; more sodium  is conserved when aldosterone is secreted. Osmotic reabsorption of water from them  occurs when ADH is present. Secretion of ammonia (NH3), hydrogen, and potassium  occurs from peritubular capillaries into distal tubules by active transport. (From Patton  KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    The fluid filtered by the glomerular capillary filtration mem-  brane is protein free but contains electrolytes such as sodium,  chloride, and potassium and organic molecules such as cre-  atinine, urea, and glucose in the same concentrations as in  plasma. Like other capillary membranes, the glomerulus is  freely permeable to water and relatively impermeable to large  colloids such as plasma proteins. The size of the molecules and  their electrical charge are important factors affecting the per-  meability of substances crossing the glomerulus. The small size  of the filtration slits in the glomerular epithelium restricts the  passage of proteins and other macromolecules. The negative  charge along the filtration membrane further impedes the pas-  sage of negatively charged macromolecules (because like forces  repel each other). Positively charged macromolecules therefore  permeate the membrane more readily than neutrally charged  particles.   Capillary pressures also affect glomerular filtration. The  hydrostatic pressure within the capillary is the major force for  inducing water and solute movement across the filtration mem-  brane into Bowman capsule. This pressure is determined by the  systemic arterial pressure and the resistances to blood flow in  the afferent and efferent arterioles. Two forces oppose the fil-  tration effects of the glomerular capillary hydrostatic pressure  (Pgc): (1) the hydrostatic pressure in Bowman space (Pg), and  (2) the effective oncotic pressure of the glomerular capillary  blood (atgc). (As explained in Chapter 3, hydrostatic pressure  is a pushing force in relation to water, and oncotic pressure is  a pulling force.) Because the fluid in Bowman space normally    contains only minute amounts of protein, it usually does not  have an oncotic influence on the plasma of the glomerular cap-  illary (Figure 37-13).   The combined effect of forces favoring and forces opposing  filtration determines the filtration pressure. The net filtration  pressure (NFP) is the sum of forces favoring and opposing fil-  tration and is expressed by the following equation:    The estimated values contributing to the forces of net filtra-  tion are presented in Figure 37-13.   As the protein-free fluid is filtered into Bowman capsule, the  plasma oncotic pressure increases and the hydrostatic pressure  decreases. The increase in glomerular capillary oncotic pressure  is great enough to reduce the net filtration pressure to zero at  the efferent end of the capillary and to stop the filtration process  effectively. The low hydrostatic pressure and increased oncotic  pressure in the efferent arteriole then are transferred to the peri-  tubular capillaries and facilitate reabsorption of fluid from the  proximal convoluted tubules.   Filtration Rate. The total volume of fluid filtered by the  glomeruli averages 180 L/day, or approximately 120 ml/minute, a  phenomenal amount considering the size of the kidneys. Because  only 1 to 2 L of urine is excreted per day, 99% of the filtrate is  reabsorbed into the peritubular capillaries and thus is returned to  the blood. The factors determining the GFR are directly related  to the pressures that favor or oppose filtration. Any changes in  afferent or efferent arteriolar resistance will alter glomerular  capillary hydrostatic pressure and GFR. Vasoconstriction of one  or the other of these two arterioles produces opposite effects  on glomerular pressure. For example, if the afferent arteriole  constricts, blood flow decreases, with a corresponding drop in  glomerular pressure. The GFR then decreases, and body fluids  are conserved. Conversely, constriction of the efferent arteriole  increases the net filtration pressure, and the GFR increases.  When both afferent and efferent arterioles constrict, little change  occurs in filtration pressure, but renal blood flow is reduced and  so is the GFR.   Obstruction to the outflow of urine (caused by strictures,  stones, or tumors along the urinary tract) can cause a retro-  grade increase in pressure at Bowman capsule and a decrease  in GFR. Low levels of plasma protein in the blood from severe  malnutrition or liver disease result in a decrease in %gc, which  increases GFR. Excessive loss of protein-free fluid from vomit-  ing, diarrhea, use of diuretics, or excessive sweating can increase  glomerular capillary oncotic pressure and decrease the GFR.  Renal disease also can cause changes in pressure relationships  by altering capillary permeability and the surface area available  for filtration (see Chapter 38).   Tubular Transport. By the time the filtrate reaches the end of  the proximal convoluted tubule, approximately 60% to 70%  of filtered sodium and water and about 50% of urea have been  reabsorbed, along with 90% or more of potassium, glucose,  bicarbonate, calcium, phosphate, amino acids, and uric acid.  All this occurs by active transport. Chloride, water, and urea  are reabsorbed passively but are linked to the active transport of    sodium (a cotransport mechanism). For some molecules, active  transportin the renal tubules is limited as carrier molecules become  saturated, a phenomenon known as transport maximum (T,,,).  The reabsorption of glucose is an important example. Glucose  reabsorption in the proximal convoluted tubule is coupled to  sodium transport and has a maximal transport capacity, or  renal threshold. This means that when the carrier molecules for  glucose become saturated, what is not reabsorbed is excreted in  the urine. Normally the plasma level and filtered glucose load are  not high enough to saturate the carrier mechanism. When the  plasma glucose concentration reaches 180 mg/dl, however, as  occurs in the individual with uncontrolled diabetes mellitus, the  renal threshold for glucose is achieved. Any further increase in  the plasma level causes loss of glucose in the urine.   Proximal Convoluted Tubule. Active reabsorption of  sodium is the primary function of the proximal convoluted  tubule. Water, most other electrolytes, and organic substances  are cotransported with sodium. The osmotic force generated by  active sodium transport promotes the passive diffusion of water  out of the tubular lumen and into the peritubular capillaries.  Passive transport of water is further enhanced by the elevated  oncotic pressure of the blood in the peritubular capillaries. The  reabsorption of water leaves an increased concentration of urea  within the tubular lumen, creating a gradient for its passive dif-  fusion to the peritubular plasma.    As the positively charged sodium ions leave the tubular  lumen, negatively charged chloride ions passively follow to  maintain electroneutrality. Because the inner membrane of the  proximal tubular cell has a limited permeability to chloride,  chloride reabsorption lags behind sodium.   Hydrogen ions are actively exchanged for sodium ions in  the tubular lumen. The hydrogen ions (H*) then combine with  bicarbonate (HCO;) in the tubular lumen to form carbonic  acid (H,CO3). The carbonic acid rapidly breaks down, or dis-  sociates, to carbon dioxide (CO,) and water (HO), which then  diffuse into the tubular cell where carbonic anhydrase catalyzes  the reaction between CO, and H,O to form HCO; and Ht.  HCO; combines with sodium and is transported (reabsorbed)  to the peritubular capillary blood. The H* is not excreted but is  again exchanged for sodium and reenters the lumen to recom-  bine with HCO3. Thus, in the proximal convoluted tubule,  for every H* ion secreted into the tubular lumen, a HCO; ion  enters the blood (see Figure 3-13, p. 126).   Bicarbonate is freely filtered at the glomerulus, but is not  readily reabsorbed because the peritubular capillary mem-  brane is not highly permeable to the molecule. As described  previously, HCO; combines with H* in the tubular cell and  is eventually reabsorbed as CO, and H,O. One of the unusual  aspects of this process is that the bicarbonate molecule filtered  at the glomerulus is not the same molecule that is reabsorbed    CHAPTER 37 Structure and Function of the Renal and Urologic Systems    (because it dissociates) and the hydrogen ion secreted by the  proximal tubule is not excreted in the urine. Bicarbonate is thus  conserved, and in this exchange, bicarbonate and hydrogen  normally do not contribute to the urinary excretion of acid or  the addition of acid to the blood. In the form of CO, and H,O,  approximately 90% of filtered bicarbonate is reabsorbed by the  proximal tubules.   In addition to the proximal tubular secretion of hydrogen  ions, secretory transport maximums (T,,) exist for creatinine,  other organic bases, and endogenous and exogenous organic  acids, including para-aminohippurate (PAH) and _penicil-  lin (Box 37-1). These secretory mechanisms are important  for eliminating drugs and other exogenous chemical products  from the body. Frequently, exogenous substances are conju-  gated with sulfate and glucuronic acid by the liver and then  actively secreted by the renal tubules. This has important clini-  cal implications because many drugs and their metabolites are  eliminated from the body in this way. When the renal tubules  are damaged, metabolic byproducts and drugs may accumulate,  causing toxic levels in the body.   Loop of Henle and Distal Convoluted Tubule. The filtrate  entering and leaving the proximal convoluted tubule is essen-  tially isosmotic with the plasma and has a concentration of about  285 mOsm. Although approximately 65% of salt and water is  reabsorbed along the proximal tubule, they are reabsorbed in  equal amounts, causing only minor changes in the osmotic and  electrolyte concentrations of the fluid flowing into the loop of  Henle. Therefore, any concentration or dilution of urine occurs  at more distal sites of the nephron, principally in the medullary  loop of Henle and collecting ducts. Near the top of the renal  pyramids, the interstitial osmolality reaches 1200 mOsm/L.   These quantitative changes taking place in the loop of Henle  are related to the length of the loop and its depth of penetra-  tion into the medulla. The structural features of the medullary  hairpin loops provide the kidney with the ability to concentrate  urine and conserve water for the body. The transition of the fil-  trate into urine is a function of the concentrating ability of the  loops and final adjustments in urine composition made by the  distal tubule and collecting duct.   The primary function of the loop of Henle is to establish a  hyperosmotic state within the medullary interstitial fluid. This  is achieved by reabsorbing more solute than water into the  interstitium. The fluid leaving the ascending limb of the loop  is therefore hypoosmotic, or more dilute than the fluid that    entered. This dilution allows the distal tubule and collecting  duct to make final adjustments in the concentration or dilu-  tion of the excreted urine according to body needs. The vasa  recta act to maintain the high osmotic gradient established by  the loop of Henle (see Figure 37-14, p. 1332).   Different transport or permeability functions of the loop of  Henle are important for dilution and concentration of urine.  The thin, descending segment of the loop of Henle is highly per-  meable to water and moderately permeable to sodium, urea, and  other solutes. The thin, ascending segment is more permeable  to solutes and almost impermeable to water. The thick portion  of the ascending segment is highly permeable to sodium, potas-  sium, and chloride and significantly less permeable to water and  urea. Tamm-Horsfall glycoprotein, also known as uromodulin,  is formed on the epithelial surface of the thick ascending seg-  ment and the first segment of the distal tubule. It is the most  abundant urinary protein and protects against bacterial adhe-  sion and urolithiasis, and is a ligand for lymphokines.!°   The convoluted portion of the distal tubule has limited per-  meability to water but readily absorbs ions and contributes to  the dilution of the tubular fluid. The later, straight segment of  the distal tubule and the collecting duct are permeable to water  as controlled by ADH. Sodium is readily absorbed by the later  segment of the distal tubule and collecting duct under the regu-  lation of the hormone aldosterone (see Chapter 21). Potassium  is actively secreted by principal cells and is reabsorbed in lesser  amounts by intercalated cells in these segments. Potassium  secretion is controlled by aldosterone and other factors related  to the concentration of potassium in body fluids."   Hydrogen is also secreted by the distal tubule and combines  with non-bicarbonate buffers (ammonium and phosphate) for  the elimination of excess acids in the urine. The distal tubule  thus contributes to the regulation of acid-base balance by  excreting hydrogen ions into the urine and by adding new bicar-  bonate to the plasma (see Figure 3-13, p. 126). The mechanism  is similar to the conservation of bicarbonate by the proximal  tubule, except that the hydrogen ion is excreted in the urine.  (The specific mechanisms of acid-base balance and acid excre-  tion are described in Chapter 3.)   Glomerulotubular Balance. Normally, 99% of the glomerular  filtrate is reabsorbed. When the GFR spontaneously decreases or  increases, the renal tubules and, primarily the proximal tubules,  automatically adjust their rate of reabsorption of sodium and  water to balance the change in GFR. Thus a constant fraction of  filtered sodium and water is reabsorbed from the proximal tubule.  This prevents wide fluctuations in sodium and water excretion  into the urine and maintains sodium and water balance.!°   The production of concentrated urine involves a countercur-  rent exchange system, in which fluid flows in opposite direc-  tions through parallel tubes. A concentration gradient causes  fluid to be exchanged across the parallel pathways. In the neph-  ron the fluid moves up and down the parallel sides of the hairpin  loop of Henle in the medulla. The longer the loop, the greater  the concentration gradient because the concentration gradient  increases from the cortex to the tip of the medulla. The loops  of Henle therefore serve as multipliers of the concentration    FIGURE 37-14 Countercurrent Mechanism for Concentrating and Diluting Urine. A, Urine dilution; B, urine con-  centration. 1, Filtrate isotonic to plasma. 2, Descending thin limb permeable to water. 3, Ascending thin limb impermeable  to water; permeable to ions. 4, Ascending thick limb actively transports NaCl; impermeable to water and urea. 5, DT actively  resorbs NaCl; resorbs water in presence of ADH. 6, Medullary CD actively resorbs NaCl, and slightly permeable to water and  urea. (Note: Numbers on illustration represent milliosmols [mOsm]). (From: Koeppen BM, Stanton BA: Berne and Levy Physiology  (updated), ed 6, St Louis, 2010, Mosby.). ADH, Antidiuretic hormone; CO, collecting duct, NaCi, sodium chloride, H0, water.    gradient, and the vasa recta act as a countercurrent exchanger  for maintaining the gradient.'°    The process is initiated in the thick ascending limb of the loop  of Henle with the active transport of sodium chloride out of  the tubular lumen and into the medullary interstitium (Figure  37-14). Because the lumen of the ascending limb is impermeable  to water, water cannot follow the sodium/chloride transport.  This lack of luminal permeability causes the ascending tubular  fluid to become hypoosmotic and the medullary interstitium to  become hyperosmotic. The descending thin limb of the loop,  which receives fluid from the proximal tubule, is highly perme-  able to water, but it is the only place in the nephron that does  not actively transport either sodium or chloride. Sodium and  chloride may, however, diffuse into the descending tubule from  the interstitium. The hyperosmotic interstitium causes water to  move out of the descending thin limb, and the remaining fluid  in the descending tubule becomes increasingly concentrated as it  flows toward the tip of the medulla. As the tubular fluid rounds  the loop and enters the ascending thin limb, sodium and chlo-  ride are removed and water is retained. The fluid then becomes  more and more dilute as it encounters the distal tubule. The data  tubule resorbs water in the presence of antidiuretic hormone.   The slow rate of blood flow and the hairpin structure of the  vasa recta allow blood to flow through the medullary tissue  without disturbing the osmotic gradient. As blood flows into  the descending limb of the vasa recta, it encounters the increas-  ing osmotic concentration gradient of the medullary intersti-  tium. Water moves out, and sodium and chloride diffuse into  the descending vasa recta. The plasma becomes increasingly  concentrated as it flows toward the tip of the medulla.   As the blood flow passes into the ascending limb and back  toward the cortex, the surrounding interstitial fluid becomes  comparatively more dilute. Water then moves back into the    vasa recta, and sodium and chloride diffuse out. The net result  is a preservation of the medullary osmotic gradient. If blood  were to flow rapidly through the vasa recta, as occurs in some  renal diseases, the medullary concentration gradient would  be washed away and the ability to concentrate urine and con-  serve water would be lost. The efficiency of water conservation  is related to the length of the loops: the longer the loops, the  greater the ability to concentrate the urine. Many desert animals  have very long loops and can reabsorb water so efficiently that  they rarely need to drink.    Urea is an end product of protein metabolism and is the major  constituent of urine along with water. The glomerulus freely fil-  ters urea. Tubular reabsorption depends on urine flow rate with  less reabsorption occurring at higher flow rates. Approximately  50% of urea is excreted in the urine, and 50% is recycled within  the kidney. The recycling of urea from the tubules and collecting  ducts contributes to the osmotic gradient within the medulla and  is necessary for the concentration and dilution of urine. Because  urea is an end product of protein metabolism, individuals with  protein deprivation cannot maximally concentrate their urine.    In response to hemorrhage or extracellular fluid depletion,  sympathetic neurons release norepinephrine, and the adrenal  medulla releases epinephrine and norepinephrine. Norepi-  nephrine and epinephrine promote afferent arteriolar vasocon-  striction and decrease GFR and RBF. Renalase is a hormone  produced by the kidney that degrades catecholamines and regu-  lates blood pressure.!”    The distal tubule in the cortex receives the hypoosmotic urine  from the ascending limb of the loop of Henle. The concentration    CHAPTER 37 Structure and Function of the Renal and Urologic Systems    Freely filtered but not reabsorbed; osmotically  attracts water and diminishes sodium   Thiazides Between end of ascending loop and  beginning of distal tubule    Aquaretics  Vasopressin Distal tubule and collecting ducts  (V2 receptor) blockers  (i.e., conivaptan)    of the final urine is controlled by antidiuretic hormone (ADH),  which is secreted from the posterior pituitary, or neurohypoph-  ysis. ADH increases water permeability in the last segment of the  distal tubule and along the entire length of the collecting ducts,  which pass through the inner and outer zones of the medulla.   In the presence of ADH, water reabsorption is high. Most  of the water is reabsorbed in the medullary collecting ducts  because of the high osmotic gradient in the medullary inter-  stitium. The water diffuses into the ascending limb of the vasa  recta and returns to the systemic circulation. The excreted urine  can have a high osmotic concentration, up to 1400 mOsm. The  volume is normally reduced to about 1% of the amount that  was filtered at the glomerulus.   Excess ADH secretion is therefore one cause of oliguria, or  diminished excretion of urine, clinically defined as less than  400 ml/day or 30 ml/hr. The syndrome of inappropriate secre-  tion of ADH occurs when the posterior pituitary hypersecretes  ADH, resulting in excess water reabsorption and water excess in  the plasma (see Chapters 3 and 22).   Inadequate secretion of ADH occurs in diabetes insipidus,  and causes the distal tubules and collecting ducts to become  impermeable to water. Water remains in the tubular lumen  and is excreted as a dilute and large volume of urine. (The  mechanism for the regulation of ADH and plasma osmolality is  described in Chapter 3 and 21.)    The natriuretic peptides (urodilatin, atrial natriuretic peptide  [ANP], and brain natriuretic peptide [BNP]) promote diuresis  and were described on p. 1327.    A diuretic is any agent that enhances the flow of urine. Clini-  cally, diuretics interfere with renal sodium reabsorption and  reduce extracellular fluid volume. Diuretics are commonly used  to treat hypertension and edema caused by heart failure, cirrho-  sis, and nephrotic syndrome.   Different diuretics affect different sites of tubular function  and may produce side effects that alter acid-base and electro-  lyte balance. Therefore, health professionals need to understand  their indications for use, mechanisms of action, and toxic side  effects. Diuretics are divided into five general categories: (1)  osmotic diuretics, (2) carbonic anhydrase inhibitors (inhibitors  of urinary acidification), (3) inhibitors of loop sodium or chlo-  ride transport, (4) aldosterone antagonists, and (5) aquaretics.  (The physiologic mechanism related to each category is sum-  marized in Table 37-2.)    The kidneys activate or synthesize a series of hormones that  have significant systemic effects and include the active form of    Vitamin D is a hormone that can be obtained in the diet or syn-  thesized by the action of ultraviolet radiation on cholesterol in the  skin. These forms of vitamin D (cholecalciferol) are inactive and  require two hydroxylations to establish a metabolically active form.  The first step occurs in the liver with hydroxylation at carbon-25  (calcifediol), and the second hydroxylation occurs at the first  carbon position in the kidneys and is stimulated by parathyroid  hormone. The end product is 1,25-dihydroxycholecalciferol,  or 1,25-dihydroxy-vitamin D3 (1,25-OH,D3) (calcitriol), the  active form of vitamin D.   Calcitriol (vitamin D3) is necessary for the absorption of cal-  cium and phosphate by the small intestine. A decreased plasma  calcium level (less than 10 mg/dl) stimulates the secretion of  parathyroid hormone. Parathyroid hormone then stimulates a  sequence of events that help restore plasma calcium level back  toward normal including:   Absorption of calcium and phosphate from the intestine  by stimulating renal activation of vitamin D   Serum phosphate level fluctuations also influence the renal  hydroxylation of vitamin D. Decreased levels stimulate active  1,25-OH,D; formation, and increased levels inhibit formation.  This results in compensatory changes in phosphate absorption  from bone and the intestine. The clinical significance of the role  of the kidney in calcium and phosphate metabolism is evident  in renal disease. Patients with renal disease have a deficiency of  1,25-OH,D; and manifest symptoms of disturbed calcium and  phosphate balance!*(see Chapter 38).   Erythropoietin is produced by the fetal liver and the adult  kidney and is essential for normal erythropoiesis. In response  to renal tissue hypoxia, peritubular fibroblasts in the kidneys  release erythropoietin, which stimulates the bone marrow to  increase the rate of red blood cell production (see Chapter 27).  Individuals with chronic renal failure develop anemia related to  reduced erythropoietin secretion. The anemia of chronic renal  failure and cancer chemotherapy is treated with recombinant  human erythropoietin (r-HuEPO). Erythropoietin also affects  the endothelium and promotes angiogenesis, mitogenesis, and  anti-apoptosis and is neurotrophic.'?   A number of specific renal functions can be measured by renal  clearance. Renal clearance techniques determine how much of  a substance can be cleared from the blood by the kidneys per  given unit of time. The application of this principle permits an  indirect measure of GFR, tubular secretion, tubular reabsorp-  tion, and renal blood flow.    Clearance and Glomerular Filtration Rate  The GER provides the best estimate of functioning renal tissue.  Damage to the glomerular membrane or loss of nephrons leads  to a corresponding decrease in GFR. The measurement of GFR  requires use of a substance that has a stable plasma concentra-  tion, is not protein bound, is freely filtered at the glomerulus,  does not influence GFR, and is not secreted, reabsorbed, or  metabolized by the tubules. Inulin (a fructose polysaccharide) is  one substance that meets the criteria for measurement of GFR.  The kidney “clears” inulin from the plasma by filtering it at  the glomerulus, reabsorbing nearly all of the fluid, and excret-  ing the inulin left behind in the urine. The amount of inulin  filtered is equal to the volume of plasma filtered (GFR) multi-  plied by the plasma concentration of inulin (Pyy). The amount  of inulin in the urine is equal to a volume of urine per unit of  time (V) (usually 24 hours) multiplied by the inulin concentra-  tion of urine (Uyy). Because all the inulin filtered is excreted in  the urine,    GFR x Pin = Un =V  GFR can be calculated by rearranging the formula:    The accurate determination of insulin clearance requires  constant infusion to maintain a stable plasma level. This is time  consuming, inconvenient, and prone to error. Therefore, the  clearance of creatinine, a natural substance produced by muscle  and released into the blood at a relatively constant rate, is com-  monly used clinically. It is freely filtered at the glomerulus and  is not reabsorbed by the renal tubules, but a small amount is  secreted by the renal tubules. Therefore, creatinine clearance  overestimates the GFR but within tolerable limits. Creatinine  clearance provides a good estimate of GFR because only one  blood sample is required in addition to a 24-hour volume of  urine. The GFR estimated by creatinine clearance is calculated  as follows:    Numerous formulas have been developed for estimating  GER using creatinine and other indicators such as cystatin C.7°   The standard clearance formula also can be used to estimate  renal plasma flow (RPF) and RBF using a molecule called  para-aminohippuric acid (PAH). Some PAH is filtered at the  glomerulus, and most of the remainder is secreted into the  tubules in one circulation through the kidney. If all the PAH  were removed from the plasma during a single pass through  the kidney, total RPF could be determined. Because the sup-  porting and nonsecreting structures of the kidney receive 10%    CHAPTER 37 Structure and Function of the Renal and Urologic Systems    to 15% of effective renal blood flow (ERBF), clearance of PAH  measures only what is known as the effective renal plasma flow  (ERPF), which is 85% to 90% of the true renal plasma flow:    where Upay = concentration of PAH in urine, and Ppay = con-  centration of PAH in plasma.   The estimation of ERBF can then be calculated by consider-  ing the hematocrit in the following formula:    Evaluation of the biochemical components of the blood and  plasma provides valuable information regarding renal function.   A long-term decline in GFR over weeks or months is reflected in  the plasma creatinine (Pcp) concentration (normal value = 0.7  to 1.2 mg/dl). The Pcp concentration has a stable value when the  GFR is stable because creatinine has a constant rate of produc-  tion as a product of muscle metabolism. The amount filtered  is approximately equal to the amount excreted. When the GFR  declines, the Pcp increases proportionately. Thus the GFR and  Pcp are inversely related. If the GFR were to decrease by 50%,  the filtration and excretion of creatinine would be reduced by  50% and creatinine would accumulate in plasma to twice the  normal value. Therefore, elevated Pcp values represent decreas-  ing GFR. In the new steady-state, however, the total amount of  creatinine excreted in the urine would remain the same because  of the proportionate decrease in GFR and increase in Per.   The application of this principle is simple and useful for  monitoring progressive changes in renal function. The test is  most valuable for monitoring the progress of chronic rather  than acute renal disease because it takes 7 to 10 days for the  plasma creatinine level to stabilize when GFR declines. Serial  measures can be obtained over a long time and plotted as a  curve of glomerular function. Normal Pc, value decreases with  advanced age, since older adults experience a decrease in lean  muscle mass. The Pcr value becomes elevated during trauma or  breakdown of muscle tissue. In such instances the value is then  not useful for estimating GFR.   Serum concentrations of cystatin C (a plasma protein freely fil-  tered at the glomerulus) have been proposed for estimations of  GER.”! The reciprocal of the serum concentrations of cystatin C  can be used as estimates of changes in GFR similar to measures  of plasma creatinine concentration. The National Kidney Foun-  dation publishes calculators for estimating GFR for monitoring  renal failure.’   The concentration of urea nitrogen in the blood reflects glo-  merular filtration and urine-concentrating capacity. Because  urea is filtered at the glomerulus, blood urea nitrogen (BUN)  levels increase as glomerular filtration drops. Because urea is  reabsorbed by the blood through the permeable tubules, the  BUN value rises in states of dehydration and acute and chronic  renal failure when passage of fluid through the tubules is slowed.  BUN value also varies as a result of altered protein intake and  protein catabolism and therefore is a poor measure of GFR. The  normal range for BUN value in the adult is 10 to 20 mg/dl of  blood.   Urinalysis is a noninvasive and relatively inexpensive diagnos-  tic procedure. The best results are obtained from a fresh, cleanly  voided specimen because decay permits changes in the compo-  sition of urine. Urinalysis includes evaluation of color, turbid-  ity, protein, pH, specific gravity, sediment, and supernatant.   Urine color is normally a clear, light yellow because of uro-  chrome and other pigments. When formed substances (crystals,  blood cells, or casts) are in the urine, it appears turbid. Pro-  tein in the urine creates marked foaming when shaken, and the  foam is yellow or orange when the urine contains bile pigments.  Urine does not normally contain protein or bile.   Urine pH normally ranges between 5 and 6.5, but it may  vary from 4.5 to 8. Urine is more alkaline after eating and then  becomes less alkaline before the next meal. Because sleep is  accompanied by intermittent hypoventilation, urine is more  acidic on awakening.   Specific gravity is an estimated measure of the solute con-  centration of the urine. The specific gravity of any solution  is measured by comparing the weight of the solution with an  equal volume of distilled water. Hence specific gravity is not a  true measure of the number or concentration of particles, but it  correlates well with osmolality and is a useful clinical tool. Spe-  cific gravity usually is measured with a hydrometer in a cylinder  of urine; the normal value is 1.016 to 1.022. Dipstick evalua-  tions may be falsely high when urine pH is less than 6 and falsely  low when the pH is more than 7.   The final urine osmolality is primarily a function of ADH,  which controls water reabsorption in the collecting ducts. If the  kidney is unable to concentrate or dilute urine, given a stimulus,  the cause is usually a malfunction of the renal tubules or inappro-  priate ADH secretion by the posterior pituitary gland. The state  of hydration also affects the urine specific gravity, so hydration  status should be evaluated before making a diagnosis. This deter-  mination is helpful for differentiating oliguria caused by intrinsic  renal disease from hypovolemia as a result of dehydration.    Urine Sediment  The urine sediment is examined microscopically and may con-  tain cells, casts, crystals, and bacteria. Epithelial cells may be  seen in the microscopic field because they are shed naturally  throughout the urinary tract.   Red Blood Cells. Normal urine contains few or no red blood  cells. If a large number of red cells are present, this is known    as hematuria, and the sediment may be red. An alkaline or  hypotonic urine causes lysis of red cells, however, so that the  cells will not be seen. Urine then will be positive for hemoglobin,  and the specific gravity will be elevated. Hematuria can occur  with the administration of anticoagulants and with several renal  diseases.   Casts. Casts (accumulations of cellular precipitates) originate  in the renal tubules, from which they take their shape. They are  cylindrical with distinct borders. All casts have a precipitated  microprotein matrix and arise primarily from the ascending  limb of the distal tubule. Red cell casts indicate bleeding into  the tubules; white cell casts are associated with an inflammatory  process. Epithelial cell casts indicate degeneration of the tubular  lumen or necrosis of the renal tubules. The type of cast identified  suggests the disease process occurring in the kidney.   Crystals. Numerous kinds of crystals can be observed in  the urine. They may be composed of cystine, uric acid, calcium  oxalate, or phosphate. They may not be initially observable,  but as the urine cools, crystals will form. Crystals tend to form  in a concentrated acidic or alkaline urine. Generally they are  not clinically significant. Crystal formation is diagnostically  significant, usually indicating inflammation, infection, or a  metabolic disorder.   White Blood Cells. White blood cells (WBCs) in the urine (a  condition termed pyuria) are indicative of urinary tractinfection,  particularly when bacteria are present. Glomerulonephritis and  nephrotic syndrome also may demonstrate pyuria but usually in  combination with proteinuria, red cells, and casts. The finding  of WBC casts reflects a kidney infection because these casts are  not formed in the bladder or prostate. If WBCs are present in  the urine, a culture should be done for specific identification of  bacteria and sensitivity of bacteria to antibiotics.    Dipsticks and reagent strips are available for detecting other  substances in the urine, including glucose, bilirubin, urobilino-  gen, leukocyte esterase and nitrates, ketones, proteins, hemo-  globin, and myoglobin.    Throughout life the kidney responds to an increased workload  by compensatory hypertrophy. This hypertrophy is marked in  individuals who have donated a kidney for transplant or have  lost functioning nephrons from trauma or disease. The glom-  eruli increase in diameter, and the tubules enlarge effectively to  maintain the regulatory functions of the kidney. Hypertrophy  occurs more rapidly and with a larger size increase in younger  individuals and in those with high protein intake.   Changes in the kidneys occur throughout life, resulting in a  reduction in size and a linear decrease in renal blood flow and  GER; however, it is less pronounced in healthy individuals.”    The number of nephrons decreases with aging, possibly  related to oxidative stress, inflammation, and associated clini-  cal conditions (e.g., hypertension and diabetes mellitus).**7°  The primary mechanism appears to be a change in the renal  vasculature and perfusion pattern, which leads to a reduction  in numbers of nephrons. The rate of nephron loss accelerates  between 40 and 80 years of age. By 75 years of age the neph-  ron population is reduced by 30% to 50%, with loss of renal  mass occurring primarily in the cortex. Degenerative changes  within nephrons also occur with aging. The glomerular cap-  illaries become sclerotic and remaining glomeruli become  hypertrophic.” The glomeruli may disappear completely. The  arcuate and interlobular arteries become tortuous, contribut-  ing to ischemia. The loss of the glomerular tuft may cause a  shunt between the afferent and efferent arterioles. Although  loss of juxtaglomerular nephrons still allows the vasa recta  to be perfused, the combination of events contributes to a  reduced ability to excrete a concentrated urine.”’ Thus the  specific gravity of the urine in older individuals tends to be on  the low side of normal.   Tubular transport changes with aging, although under nor-  mal conditions the tubules function adequately. Adaptation  to stressful conditions is more difficult. Glucose, bicarbonate,  and sodium are not as efficiently reabsorbed, and hyperkalemia  is more common because of decreased secretion. Response to  acid or base loads is delayed and prolonged. Sudden or large  changes in pH or fluid load may lead to serious imbalances with  increased risk of hypervolemia or hypovolemia. Acute losses or  chronic fluid deficits can lead to renal insufficiency in the older  adult. Administration of drugs eliminated by renal processes  may require dose modifications and more astute observations  for toxic side effects.7*   The T,,, for glucose reabsorption decreases with age, contrib-  uting to a greater amount of glucose in the urine. This is an  important consideration when glycosuria is used for screening  or monitoring the process of diabetes mellitus in older adults.  These changes occur independently of disease, however, indi-  cating a normal process of aging. An age-related decline in  renal activation of vitamin D decreases intestinal absorption of  calcium, and older adults need more vitamin D to overcome  diminishing renal function.’? Previous or concurrent renal  disease or urinary tract obstruction may amplify age-related  changes in function.   Bladder symptoms are common among older adults and  include frequency, urgency, and nocturia. Neurogenic and  myogenic changes in bladder structure and function may con-  tribute to some symptoms as well as influences outside the  urinary tract. Changes in neurotransmission influence the  micturition reflex and may lead to an overactive or underac-  tive bladder.°° Obstruction related to prostate hypertrophy may  lead to urine retention with frequency, urgency, nocturia, and  slow or intermittent urinary stream.    CHAPTER 37 Structure and Function of the Renal and Urologic Systems    The kidneys are paired structures lying bilaterally between  the twelfth thoracic and third lumbar vertebrae.    . The kidney is composed of an outer cortex containing the    glomeruli and an inner medulla containing the tubules and  collecting ducts that drain into the calyces.    . The calyces join to form the renal pelvis and are continuous    . The nephron is the urine-forming unit of the kidney and    is composed of the glomerulus, proximal tubule, hairpin  loops of Henle, distal tubule, and collecting duct.    the Bowman capsule. The capillary walls serve as a filtra-  tion membrane for the formation of the primary urine.  The layers of the glomerular capillary include the endothe-  lium, basement membrane, and epithelium. The epithe-  lium is composed of podocytes that interlock to provide  filtration slits.    . Mesangial cells and matrix lie between and support the glo-    the afferent arteriole. They are contiguous with the  sodium-sensing macula densa cells of the distal convoluted  tubule.    . The Bowman capsule is the space between the visceral and    . The proximal tubule is lined with microvilli to increase sur-   The hairpin-shaped loops of Henle selectively transport sol-  utes and water, contributing to the hypertonic state of the  medulla.   The distal tubule adjusts acid-base balance by excreting acid  into the urine and forming new bicarbonate ions.   The collecting duct contains principal cells that resorb  sodium and water and excrete potassium and intercalated  cells that secrete hydrogen or bicarbonate and potassium.  The ureters extend from the renal pelvis to the posterior  wall of the bladder. Urine flows through the ureters by  means of peristaltic contraction of the ureteral muscles.  The bladder is a bag composed of the detrusor and trigone  muscles and innervated by parasympathetic fibers. When  accumulation of urine reaches 250 to 300 ml, mechanore-  ceptors, which respond to stretching of tissue, stimulate the  micturition reflex.    Renal blood flows at about 1000 to 1200 ml/min, or 20% to  25% of the cardiac output.   Blood flow through the glomerular capillaries is maintained  at a constant rate in spite of a wide range of arterial pres-  sures (autoregulation).    . The GFR is the filtration of plasma per unit of time and is    directly related to the perfusion pressure of renal blood flow.  Autoregulation of RBF and sympathetic neural regulation  of vasoconstriction maintain a constant GFR.    The renal blood vessels are innervated by the sympathetic  noradrenergic nerves that regulate vasoconstriction.   Renin is an enzyme secreted from the juxtaglomerular appa-  ratus; it causes the generation of angiotensin I, which is con-  verted to angiotensin II by the action of ACE. Angiotensin II  is a potent vasoconstrictor and also stimulates release of aldo-  sterone from the adrenal cortex. Thus the renin-angiotensin-  aldosterone system is a regulator of renal blood flow and  blood pressure.    The major function of the nephron is urine formation, which  involves the processes of glomerular filtration, tubular reab-  sorption, and tubular secretion and excretion.    sure and opposed by oncotic pressure in the capillary and  hydrostatic pressure in the Bowman capsule. The balance of  favoring and opposing filtration forces is the net filtration  pressure (NFP).    . The GFR is approximately 120 ml/minute, and 99% of the    70% of the filtered sodium and water and 90% of other  electrolytes.    the carrier mechanism can become saturated at the T,,,. Mol-  ecules not reabsorbed are excreted with the urine.    secrete potassium and hydrogen for the regulation of fluid,  electrolyte, and acid-base balance.    . The concentration of the final urine is a function of the level    of ADH that stimulates the distal tubules and collecting ducts  to reabsorb water. The countercurrent exchange system of the  long loops of Henle and their accompanying capillaries estab-  lishes a concentration gradient within the renal medulla to  facilitate the reabsorption of water from the collecting duct.    . The kidney secretes or activates a number of hormones that    have systemic effects, including vitamin D3; (1,25-OH,D;)  and erythropoietin, which stimulates erythropoiesis when  there is hypoxia.    Tests that measure renal clearance indicate how much of a  substance can be cleared from the blood by the kidneys per  given amount of time.    plasma and urine to calculate a commonly used clinical mea-  surement of GFR (creatinine clearance).    Plasma creatinine and cystatin C are measured to monitor  progressive renal dysfunction; BUN is an indicator of hydra-  tion status.   PAH clearance is used to determine renal plasma flow and  blood flow.   Urinalysis involves evaluation of color, turbidity, protein,  pH, specific gravity, sediment, and supernatant.   Presence of bacteria, red blood cells, white blood cells,  casts, or crystals in the urine sediment may indicate a renal  disorder.    As a person ages, a decrease occurs in the number of  nephrons. Renal blood flow and glomerular filtration rate  decline.   Tubular transport and reabsorption decrease with age.  Response to acid-base changes and reabsorption of glucose  are delayed. Drugs eliminated by the kidney can accumulate  in the plasma, causing toxic reactions.   Neurogenic and myogenic changes in the bladder may lead  to symptoms of urgency and frequency.   Renal capsule, 1319  Renal column, 1320  Renal corpuscle, 1321  Renal fascia, 1319   Effective renal blood flow (ERBF), 1335  Effective renal plasma flow (ERPF), 1335  Excretion, 1328   Glomerular capillary, 1325  Glomerular endothelium, 1321  Glomerular filtration membrane, 1321  Glomerular filtration rate (GFR), 1326    Juxtaglomerular apparatus (JGA), 1322  Juxtaglomerular cell, 1322  Juxtamedullary nephron, 1320  Kidney, 1319   Superficial cortical nephron, 1320  Transitional epithelium (uroepithelium), 1325  Transport maximum (T,,), 1330  Trigone, 1325   Tubular reabsorption, 1328  Tubular secretion, 1328  Tubuloglomerular feedback, 1326  Ultrafiltration, 1328    2. Miner JH: The glomerular basement membrane, Exp Cell Res 318(9):   Greka A, Mundel P: Cell biology and pathology of podocytes, Annu Rev  Physiol 74:299-323, 2012.   Garg P, Holzman LB: Podocytes: gaining a foothold, Exp Cell Res  318(9):955—963, 2012.   Birder LA et al: How does the urothelium affect bladder function in  health and disease? ICI-RS 2011, Neurourol Urodyn 31(3):293-299, 2012.  Just A: Mechanisms of renal blood flow autoregulation: dynamics and con-  tributions, Am J Physiol Regul Integr Comp Physiol 292(1):R1—R17, 2007.  Singh P, Thomson SC: Renal homeostasis and tubuloglomerular feed-  back, Curr Opin Nephrol Hypertens 19(1):59-64, 2010.   Seeliger E et al: The renin-angiotensin system and the third mecha-   nism of renal blood flow autoregulation, Am J Physiol Renal Physiol  296:F1334—F1345, 2009.    Schweda F et al: Renin release, Physiology (Bethesda) 22:310-319, 2007.  Vaidya A, Williams JS: The relationship between vitamin D and the  renin-angiotensin system in the pathophysiology of hypertension, kidney  disease, and diabetes, Metabolism 61(4):450—458, 2012.    . Gassanov N et al: Natriuretic peptides in therapy for decompensated    . Kalra PR et al: C-type natriuretic peptide production by the human    kidney is blunted in chronic heart failure, Clin Sci (Lond) 118(1):71-77,  2009.    . El-Achkar TM, Wu XR: Uromodulin in kidney injury: an instigator,    bystander, or protector? Am J Kidney Dis 59(3):452—461, 2012.  Rodan AR, Cheng CJ, Huang CL: Recent advances in distal tubular  potassium handling, Am J Physiol Renal Physiol 300(4):F821—F827,  2011.    CHAPTER 37 Structure and Function of the Renal and Urologic Systems    Sands JM, Layton HE, Fenton RA: Chapter 10: Urine concentration and  dilution. In Taal MW et al: Brenner and Rector’s the kidney, ed 9, Philadel-  phia, 2011, Saunders, pp 332-333.   Desir G: Novel insights into the physiology of renalase and its role in  hypertension and heart disease, Pediatr Nephrol 27(5):719-725, 2012.  Dusso AS, Tokumoto M: Defective renal maintenance of the vitamin D  endocrine system impairs vitamin D renoprotection: a downward spiral  in kidney disease, Kidney Int 79(7):715—-729, 2011.   Ponce LL et al: Erythropoietin neuroprotection with traumatic brain  injury, Pathophysiology 20(1):31-38, 2013.   Stevens LA, Padala S, Levey AS: Advances in glomerular filtration rate-  estimating equations, Curr Opin Nephrol Hypertens 19(3):298-307, 2010.  Odutayo A, Cherney D: Cystatin C and acute changes in glomerular  filtration rate, Clin Nephrol 78(1):64—75, 2012.   National Kidney Foundation: Calculators for health care professionals.  Available at www.kidney.org/professionals/kdoqi/gfr_calculator.cfm.  Accessed October 16, 2012.   Esposito C, Dal Canton A: Functional changes in the aging kidney,    Choudhury D, Levi M: Kidney aging—inevitable or preventable? Nat Rev  Nephrol 7(12):706-717, 2011.   Pannarale G et al: The aging kidney: structural changes, J Nephrol  23(Suppl 15):S37-S40, 2010.   Stojanovic VR et al: Morphometric analysis of nonsclerosed glomeruli  size and connective tissue content during the aging process, Scientific-  World Journal 2012:845046, 2012.   Sands JM: Urine concentrating and diluting ability during aging, J Geron-  tol A Biol Sci Med Sci 67(12):1352-1357, 2012.   Corsonello A, Pedone C, Incalzi RA: Age-related pharmacokinetic and  pharmacodynamic changes and related risk of adverse drug reactions,  Curr Med Chem 17(6):571—584, 2010.   Vieth R, Ladak Y, Walfish PG: Age-related changes in the 25-hydroxyvitamin  D versus parathyroid hormone relationship suggest a different reason why  older adults require more vitamin D, J Clin Endocrinol Metab 88(1):185-191,  2003.   Smith PP: Aging and the underactive detrusor: a failure of activity or  activation? Neurourol Urodyn 29(3):408—412, 2010.    CHAPTER 37 Structure and Function of the Renal and Urologic Systems    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Urinary Tract Obstruction, 1340  Upper Urinary Tract Obstruction, 1340  Lower Urinary Tract Obstruction, 1344  Tumors, 1347  Urinary Tract Infection, 1349  Causes of Urinary Tract Infection, 1349  Types of Urinary Tract Infection, 1350  Glomerular Disorders, 1352  Glomerulonephritis, 1352  Nephrotic and Nephritic Syndromes, 1358    Renal and urinary function can be affected by a variety of dis-  orders. The most common type of urinary dysfunction is infec-  tion. Stones, tumors, or inflammation also can obstruct the  urinary tract. Renal function can be impaired by disorders of  the kidney itself or by many other systemic diseases and ulti-  mately may result in acute kidney injury or chronic kidney dis-  ease. Because the kidney filters the blood, it is directly linked  to every other organ system. Renal failure, whether acute or  chronic, is life-threatening.    Urinary tract obstruction is an interference with the flow of urine  at any site along the urinary tract (Figure 38-1). An obstruc-  tion may be anatomic or functional. It impedes flow proximal  to the obstruction, dilates structures distal to the obstruction,  increases risk for infection, and compromises renal function.    Acute Kidney Injury, 1359  Classification of Kidney Dysfunction, 1359  Acute Kidney Injury, 1360   Chronic Kidney Disease, 1364  Creatinine and Urea Clearance, 1366  Fluid and Electrolyte Balance, 1367  Calcium, Phosphate, and Bone, 1368    Anatomic changes in the urinary system caused by obstruc-  tion are referred to as obstructive uropathy. The severity of an  obstructive uropathy is determined by: (1) the location of the  obstructive lesion, (2) the involvement of one or both upper  urinary tracts (ureters and renal pelvis), (3) the completeness of  the obstruction, (4) the duration of the obstruction, and (5) the  nature of the obstructive lesion.!* Obstructions may be relieved  or partially alleviated by correction of the obstruction, although  permanent impairments occur if a complete or partial obstruc-  tion persists over weeks to months or longer.   Common causes of upper urinary tract obstruction include  stricture or congenital compression of a calyx or the uretero-  pelvic or ureterovesical junction (e.g., stones [calculi] ); ureteral  compression from an aberrant vessel, tumor, or abdomi-  nal inflammation and scarring (retroperitoneal fibrosis); or    FIGURE 38-1 Urinary Tract Obstruction and Hydronephrosis. A, Causes of urinary tract obstruction. Terms in italics  are normal structures. B, Hydronephrosis, marked dilation of renal pelvis and calyces with thinning of parenchyma.    ureteral blockage from stones or a malignancy of the renal pel-  vis or ureter.   Obstruction of the upper urinary tract causes dilation of the  ureter, renal pelvis, calyces, and renal parenchyma proximal to  the site of urinary blockage. Dilation of the ureter is referred to  as hydroureter (accumulation of urine in the ureter), and dila-  tion of the renal pelvis and calyces proximal to a blockage leads  to hydronephrosis (enlargement of the renal pelvis and calyces)  or ureterohydronephrosis (dilation of both the ureter and the    pelvicaliceal system) (Figure 38-2). Dilation of the upper uri-  nary tract is an early response to obstruction and reflects smooth  muscle hypertrophy and accumulation of urine above the level  of blockage (urinary stasis/retention). The increased pressure  is transmitted to the glomerulus, which decreases filtration.  Unless the obstruction is relieved, this dilation leads to enlarge-  ment with tubulointerstitial fibrosis and apoptosis affecting the  distal nephron and renal function. Tubulointerstitial fibrosis  is the deposition of excessive amounts of extracellular matrix    FIGURE 38-2 Neurogenic Detrusor Overactivity with Vesicosphincter.  The arrow indicates narrowing of the striated sphincter consistent with electro-  myographic activity (Line 6) noted on the urodynamic tracing. Note the charac-  teristic poor flow pattern (Line 1) with elevated voiding pressures (Lines 4 and 5)  indicating obstruction. Line 7 = Urine flow rate; Line 2 = urine volume; Line 3 =  abdominal pressure (Pabd); Line 4= intravesicular (inside bladder) pressure (Pves);  Line 5= detrusor muscle pressure (Pdet); Line 6= bladder electromyelogram (EMG).    (collagen and other proteins). Deposition of extracellular  matrix is a normal process of organ repair and maintenance,  and the deposition of extracellular matrix is balanced by its  breakdown under the influence of metalloproteinases. Multiple  cytokines and growth factors have been implicated in the pro-  cess of tubulointerstitial fibrosis and irreversible loss of kidney  function, including transforming growth factor-beta-1 (TGF-  61), angiotensin II, aldosterone, and various tumor necrosis  factors. Apoptosis is a normal process that the body uses to    replace damaged or senescent cells with new ones (see Chapter  1), but the imbalance in growth factors provoked by obstruc-  tion leads to excess cellular destruction and death, ultimately  resulting in loss of functioning nephrons and kidney damage.   Tubulointerstitial fibrosis and apoptosis result in detectable  damage to the distal renal tubules within approximately 7 days.  By 14 days, obstruction has adversely affected both distal and  proximal aspects of the nephron. Within 28 days the glomer-  uli of the kidney have been damaged and the renal cortex and  medulla are reduced in size (thinned). Distal tubular damage  occurs initially and decreases the kidney’s ability to concentrate  urine, causing an increase in urine volume despite a decrease in  glomerular filtration rate (GFR). The affected kidney is unable  to conserve sodium, bicarbonate, and water or to excrete hydro-  gen or potassium, leading to metabolic acidosis and dehydra-  tion. The magnitude of this damage, and the kidney’s ability to  recover normal homeostatic function, is affected by the severity  and duration of the obstruction. With complete obstruction,  damage to the renal tubules and compression of the renal vas-  culature occurs in a matter of hours, and irreversible damage  occurs within 3 to 4 weeks. Nevertheless, even in the face of a  complete obstruction, the human kidney may recover at least  partial homeostatic function provided the blockage is removed  within 56 to 69 days.*** This recovery requires approximately 4  months. Partial obstruction, in the absence of renal infection,  leads to subtler but ultimately permanent impairments includ-  ing loss of the kidney’s ability to concentrate urine, reabsorb  bicarbonate, excrete ammonia, or regulate metabolic acid-base  balance if the obstruction is not relieved. Complete bilateral  obstruction causes anuria because the retrograde increase in  tubular hydrostatic pressure completely opposes glomerular  filtration.   The body is able to partially counteract the negative conse-  quences of unilateral obstruction by a process called compen-  satory hypertrophy and hyperfunction.* The compensatory  response is the result of two growth processes: obligatory  growth occurs under the influence of somatomedins, and com-  pensatory growth occurs under the influence of a hormone or  hormones that have not yet been identified. These processes  cause the contralateral (unobstructed) kidney to increase the  size of individual glomeruli and tubules but not the total num-  ber of functioning nephrons. The ability of the body to engage  in compensatory hypertrophy and hyperfunction diminishes  with age, and the process is reversible when relief of obstruction  results in recovery of function by the obstructed kidney. Unilat-  eral obstruction may remain silent for a long time.   Relief of bilateral, partial urinary tract obstruction or com-  plete obstruction of one kidney is usually followed by a brief  period of diuresis (commonly called postobstructive diure-  sis).° It is a physiologic response and is typically mild, repre-  senting a restoration of fluid and electrolyte imbalance caused  by the obstructive uropathy. Alterations in tubular transport  and water reabsorption and volume expansion contribute to  the diuresis. Occasionally relief of obstruction will cause rapid  excretion of large volumes of water, sodium, or other electro-  lytes, resulting in a urine output of 10 L/day or more (minimal  normal daily urine output is approximately 720 ml/day). Rapid    postobstructive diuresis causes dehydration and fluid and elec-  trolyte imbalances if not promptly corrected. Risk factors for  severe postobstructive diuresis include bilateral obstruction,  impairment of one or both kidneys’ ability to concentrate urine  or reabsorb sodium (nephrogenic diabetes insipidus), hyper-  tension, edema and weight gain, congestive heart failure, and  uremic encephalopathy.    Calculi, or urinary stones (urolithiasis), are masses of crystals,  protein, or other substances that are a common cause of urinary  tract obstruction in adults. They can be located in the kidneys,  ureters, and urinary bladder. The prevalence of stones in the  United States is approximately 6% in women and 15% in men,  and is more common in whites.° The recurrence rate is approxi-  mately 30% to 50% within 5 years.’ The risk of urinary calculi  formation is influenced by a number of factors, including age,  gender, race, geographic location, seasonal factors, fluid intake,  diet, occupation, genetic predisposition, and other conditions  including urinary tract infection, hypertension, atherosclero-  sis, metabolic syndrome, obesity, and diabetes.* Most persons  develop their first stone before age 50 years. Geographic loca-  tion influences the risk of stone formation because of indirect  factors, including average temperature, humidity, and rain  fall, and their influence on fluid and dietary patterns. Persons  who regularly consume an adequate volume of water and those  who are physically active are at reduced risk when compared  with people who are inactive or consume lower volumes of  fluid. Most kidney stones are unilateral and are a risk factor  for chronic kidney disease and an increased risk for myocardial  infarction.”'°   Urinary calculi can be classified according to the primary  minerals (salts) that comprise the stones. The most common  stone types include calcium oxalate or phosphate (70% to 80%),  struvite (magnesium, ammonium, and phosphate) (15%), and  uric acid (7%). Cystine stones are rare, less than 1%. Less com-  mon stone elements include cystine, 2,8-dihydroxyadeninuria  (a rare genetic disorder that increases risk of xanthine stones),  triamterene (a diuretic), and indinavir (a protease inhibitor  used in management of human immunodeficiency virus [HIV]  infection). Urinary calculi also can be classified according to  location and size. Staghorn calculi are large and fill the minor  and major calyces. Non-staghorn calculi are of variable size and  are located in the calyces, in the renal pelvis, or at different sites  along the ureter.   PATHOPHYSIOLOGY. Renal calculus formation is complex  and related to: (1) supersaturation of one or more salts in the  urine, (2) precipitation of the salts from a liquid to a solid state  (crystals), (3) growth through crystallization or agglomeration  (sometimes called aggregation), and (4) the presence or absence  of stone inhibitors.!! Supersaturation is the presence of a higher  concentration of a salt within a fluid (in this case, the urine)  than the volume is able to dissolve to maintain equilibrium.  Human urine contains many positively and negatively charged  ions capable of precipitating from solution and forming a vari-  ety of salts. The salts form crystals that are retained and grow  into stones. Crystallization is the process by which crystals grow    from a small nidus or nucleus to larger stones in the presence of  supersaturated urine. Although supersaturation is essential for  free stone formation, the urine need not remain continuously  supersaturated for a calculus to grow once its nidus has pre-  cipitated from solution. Intermittent periods of supersatura-  tion after the ingestion of a meal or during times of dehydration  are sufficient for stone growth in many individuals. In addi-  tion, the apical papillae have interstitial sites where hydroxy-  apatite deposits (Randall plaque) become exposed and serve  as sites for calcium oxalate stone formation (but not calcium  phosphate stone formation).!* Matrix is an organic material  (i.e., mucoprotein) in which the components of a kidney stone  are embedded.!!   The pH of the urine also influences the risk of precipita-  tion and calculus formation. An alkaline urinary pH signifi-  cantly increases the risk of calcium phosphate stone formation,  whereas acidic urine increases the risk of a uric acid stone. Cys-  tine and xanthine precipitate more readily in acidic urine.   Stone or crystal growth inhibiting substances, including potas-  sium citrate, pyrophosphate, and magnesium, are capable of  crystal growth inhibition, thereby reducing the risk of calcium  phosphate or calcium oxalate precipitation in the urine and  preventing subsequent stone formation.   Retention of crystal particles occurs primarily at the papil-  lary collecting ducts. Although most crystals are flushed from  the tract through antegrade urine flow, urinary stasis, anatomic  abnormalities, or inflamed epithelium within the urinary tract  may prevent prompt flushing of crystals from the system, thus  increasing the risk of calculus formation.   The size of a stone determines the likelihood that it will pass  through the urinary tract and be excreted through micturi-  tion.'? Stones smaller than 5 mm have about a 50% chance of  spontaneous passage, whereas stones that are 1 cm have almost  no chance of spontaneous passage. Nevertheless, the person  with ureteral dilation from the previous passage of a stone may  be able to excrete larger stones when compared with the person  experiencing an initial obstructing calculus.   Calcium stones (urolithiasis) account for 70% to 80%  of all stones requiring treatment. Calcium oxalate accounts  for about 80% of these stones and calcium phosphate about  15%.'* Both genetic and environmental factors may increase  susceptibility. Most affected individuals have idiopathic cal-  cium oxalate urolithiasis (ICOU), a condition whose exact  etiology has not yet been defined. Stones can form freely  in supersaturated urine or detach from interstitial sites of  formation.!° Hypercalciuria, hyperoxaluria, hyperuricosuria,  hypocitraturia, mild renal tubular acidosis, crystal growth  inhibitor deficiencies, and alkaline urine are associated with  calcium stone formation.'®!’ Hypercalciuria and hyperox-  aluria are usually attributable to intestinal hyperabsorption  and less commonly to a defect in renal calcium reabsorption.  Hyperparathyroidism and bone demineralization associ-  ated with prolonged immobilization are also known to cause  hypercalciuria.   Struvite stones primarily contain magnesium-ammonium-  phosphate as well as varying levels of matrix. Matrix forms in  an alkaline urine and during infection with a urease-producing    Involuntary loss of urine associated with an abrupt and strong desire to void (urgency). Often    associated with involuntary contractions of the detrusor. When associated with a neurologic  disorder this is called detrusor hyperreflexia. When no neurologic disorder exists this is called  detrusor instability. May be associated with decreased bladder wall compliance.    Stress incontinence (most common in women younger  than 60 years and men who have had prostate surgery)  Overflow incontinence    Involuntary loss of urine during coughing, sneezing, laughing, or other physical activity associated  with increased abdominal pressure.  Involuntary loss of urine with overdistention of the bladder.    Associated with neurologic lesions below S1, polyneuropathies, and urethral obstruction (i.e., an    enlarged prostate).  A combination of stress and urge incontinence.  Involuntary loss of urine caused by dementia or immobility.    Data from Agency for Healthcare Research and Quality: Overview: urinary incontinence in adults, clinical practice guideline update, Rockville, MD,    bacterial pathogen, such as a Proteus, Klebsiella, or Pseudomo-  nas. Struvite calculi may grow quite large and branch into a  staghorn configuration (staghorn calculus) that approximates  the pelvicaliceal collecting system. Women are at greater risk  for struvite stones because they have an increased incidence of  urinary tract infection (see p. 1349).   Uric acid is primarily a product of biosynthesis of endog-  enous purines and is secondarily affected by consumption of  purines in the diet. Persons who excrete excessive uric acid in  the urine, such as those with gouty arthritis, are at particular  risk for uric acid stones. A consistently acidic urine greatly  increases this risk. Cystine and xanthine are amino acids that  precipitate more readily in acidic urine. Cystinuria and xanthin-  uria are genetic disorders of amino acid metabolism, and their  excess in urine can cause cystinuric, or xanthine, stone forma-  tion in the presence of a low urine pH of 5.5 or less.   CLINICAL MANIFESTATIONS. Renal colic, described as moderate  to severe pain often originating in the posterior hypochondrium  (flank) and radiating to the groin, usually indicates obstruction  of the renal pelvis or proximal ureter. Colic that radiates to the  lateral flank or lower abdomen typically indicates obstruction  in the midureter, and bothersome lower urinary tract symp-  toms (urgency, frequent voiding, urge incontinence) indicate  obstruction of the lower ureter or ureterovesical junction. The  pain can be severe and incapacitating and may be accompanied  by nausea and vomiting. Gross (visible blood in the urine) or  microscopic hematuria (three or more red blood cells per high  power microscopic field) may be present.!*   EVALUATION AND TREATMENT. The evaluation and diagnosis of  urinary calculi are based on presenting symptoms and history  combined with a focused physical assessment, imaging stud-  ies, and possibly a functional study of renal pelvic and ureteral  pressures.'° The history queries dietary habits; the age of the  first stone episode; stone analysis; and presence of complicating  factors, including recurrent urinary tract infection, hyperpara-  thyroidism, or recent gastrointestinal or genitourinary surgery.  Urinalysis (including pH) is obtained and a 24-hour urine is  completed to identify calcium oxalate, citrate, and other signifi-  cant constituents. In addition, every effort is made to retrieve  and analyze calculi that are passed spontaneously or retrieved    through aggressive intervention. Additional tests are obtained  in selected individuals, such as those with suspected hyperpara-  thyroidism or cystine or uric acid stones, in order to diagnose  and manage underlying metabolic disorders. Imaging of kid-  ney stones includes plain abdominal radiography, ultrasound,  intravenous pyelogram, computed tomography, and magnetic  resonance imaging.!”   The goals of treatment are to manage acute pain, promote  stone passage, reduce the size of stones already formed, and  prevent new stone formation. The components of treatment  include: (1) administering parenteral and/or oral analgesics  for acute pain, (2) providing medical therapy to promote  stone passage (alpha antagonists or calcium channel blockers),  (3) reducing the concentration of stone-forming substances by  increasing urine flow rate with high fluid intake, (4) decreas-  ing the amount of stone-forming substances in the urine by  decreasing dietary intake or endogenous production or by  altering urine pH,*° and (5) removing stones using percuta-  neous nephrolithotomy, ureteroscopy, or ultrasonic or laser  lithotripsy to fragment stones for excretion in the urine.?!?  Obstructing kidney stones with a suspected proximal urinary  tract infection are urologic emergencies requiring emergent  decompression and antibiotics.”°    Obstructive disorders of the lower urinary tract (LUT) are pri-  marily related to storage of urine in the bladder or emptying  of urine through the bladder outlet. The causes of the obstruc-  tion include neurogenic and anatomic alterations or, in some  instances, a combination of both. Incontinence is a common  symptom. Types of incontinence are reviewed in Table 38-1.   Neurogenic bladder is a general term for bladder dysfunction  caused by neurologic disorders. The types of dysfunction are  related to the sites in the nervous system that control sensory  and motor bladder function (Figure 38-3). Lesions that develop  in upper motor neurons of the brain and spinal cord result in  dyssynergia (loss of coordinated neuromuscular contraction)  and overactive or hyperreflexive bladder function. Lesions in    Stroke, traumatic brain injury,  multiple sclerosis, hydrocephalus,  cerebral palsy, Alzheimer disease,  brain tumors    Spinal cord injury (C2-T12)  MS, transverse myelitis,  Guillain-Barré syndrome,  disk problems    Myelodysplasia, peripheral  polyneuropathies, MS, tabes  dorsalis, spinal injury (T12-S),  cauda equina syndrome,  herpes simplex/zoster    FIGURE 38-3 Causes of Neurogenic Bladder and Reflex Incontinence. (Adapted from Doughty DB, editor: Urinary  and fecal incontinence: current management concepts, ed 3, Philadelphia, 2006, Mosby.)    the sacral area of the spinal cord or peripheral nerves result in  underactive, hypotonic, or atonic (flaccid) bladder function,  often with loss of bladder sensation.   Neurologic disorders that develop above the pontine mic-  turition center result in detrusor hyperreflexia, also known as  an uninhibited or reflex bladder. This is an upper motor neu-  ron disorder in which the bladder empties automatically when  it becomes full and the external sphincter functions normally.  Because the pontine micturition center remains intact, there  is coordination between detrusor muscle contraction and the  relaxation of the urethral sphincter. Stroke, traumatic brain  injury, dementia, and brain tumors are examples of disorders  that result in detrusor hyperreflexia. Symptoms include urine  leakage and incontinence.   Neurologic lesions that occur below the pontine micturition  center but above the sacral micturition center (between C2 and S1)  are also upper motor neuron lesions and result in detrusor  hyperreflexia with vesicosphincter (detrusor sphincter) dys-  synergia. There is loss of pontine coordination of detrusor  muscle contraction and external sphincter relaxation, so both  the bladder and the sphincter are contracting at the same time,  causing a functional obstruction of the bladder outlet.”* Spinal  cord injury, multiple sclerosis, Guillain-Barré syndrome, and  intervertebral disk problems are causes of this disorder. There is  diminished bladder relaxation during storage with small urine  volumes and high intravesicular (inside the bladder) pressures.  This results in an overactive bladder syndrome with symptoms  of urgency, frequency, urge incontinence, and increased risk for  urethral turbulence and urinary tract infection.    Lesions that involve the sacral micturition center (below S1;  may also be termed cauda equina syndrome) or peripheral nerve  lesions result in detrusor areflexia (acontractile detrusor),  a lower motor neuron disorder. The result is an acontractile  detrusor or atonic bladder with retention of urine and disten-  tion. If the sensory innervation of the bladder is intact, the full  bladder will be sensed but the detrusor may not contract. This  is an underactive bladder syndrome and may have symptoms  of stress and overflow incontinence. Myelodysplasia, multiple  sclerosis, tabes dorsalis, and peripheral polyneuropathies are  associated with this disorder.    Overactive bladder syndrome (OAB) is a chronic syndrome  of detrusor overactivity in the absence of infection. It is esti-  mated that 29.8 million adults over the age of 40 have bother-  some OAB symptoms.”° OAB is characterized by urgency with  involuntary detrusor contractions during the bladder filling  phase. The contraction may be spontaneous or provoked and  associated with hyperexcitable nerves or involuntary reflexes.”°  There is coordination between the contracting bladder and the  external sphincter, but the detrusor is too weak to empty the  bladder, resulting in urinary retention with overflow or stress  incontinence. Overactive bladder is defined by the Interna-  tional Continence Society as a symptom syndrome of urgency,  with or without urge incontinence and usually associated with  frequency and nocturia.*’ Overactive bladder syndrome affects  millions of men, women, and children; adults are often reluc-  tant to discuss this syndrome with their healthcare provider.    Sexual dysfunction and bowel problems often accompany OAB.  Diagnosis is usually made by evaluation of symptoms. Urody-  namic evaluation confirms the diagnosis. Treatment options  include lifestyle modifications, behavioral therapy, pharmaco-  therapy (e.g., antimuscarinics), neuromodulation, botulinum  toxin therapy, and surgical interventions. When left untreated,  OAB is costly, impairs health and quality of life, causes depres-  sion, and leads to social isolation.**? OAB is a risk for urinary  tract infection and a risk for falls in older adults.°°    Anatomic causes of resistance to urine flow include urethral  stricture, prostatic enlargement in men, pelvic organ pro-  lapse in women, and tumor compression. Symptoms of lower  urinary tract obstruction are more common in men and include:  (1) frequent daytime voiding (urination more than every  2 hours while awake); (2) nocturia (awakening more than once  each night to urinate for adults less than 65 years of age or more  than twice for older adults); (3) bothersome urgency, often  combined with hesitancy; (4) dysuria; (5) poor force of stream;  (6) intermittency of urinary stream; and (7) feelings of incom-  plete bladder emptying despite micturition.   A urethral stricture is a narrowing of its lumen. It occurs  when infection, injury, or surgical manipulation produces a  scar that reduces the caliber of the urethra. The vast majority  of urethral strictures occur in men; they are rare in women.?!*?  The severity of obstruction is influenced by its location within  the urethra, its length, and the minimum caliber of urethral  lumen within the stricture. Specifically, proximal urethral stric-  tures cause more severe obstruction than do strictures of the  distal urethra, longer strictures tend to be more obstructive, and  the magnitude of blockage is in reverse proportion to the ure-  thral caliber.°°   Prostate enlargement is caused by acute inflammation,  benign prostatic hyperplasia, or prostate cancer (see Chapter 25).  Each of these disorders can cause encroachment on the urethra  with obstruction to urine flow and the symptoms summarized  previously.   Severe pelvic organ prolapse (see Chapter 24) in a woman  causes bladder outlet obstruction when, most commonly, a cys-  tocele (the downward protrusion of the bladder into the vagina)  descends below the level of the urethral outlet.** Cystoceles (see  Figure 24-11) that reach or protrude beyond the vaginal introi-  tus create the greatest risk for obstruction, particularly if the  bladder neck (in females the bladder neck and proximal urethra  constitute the internal sphincter of the bladder) has been surgi-  cally repaired without simultaneous repair of the cystocele.°? In  men the bladder may rarely herniate into the scrotum, causing  a similar type of obstruction.   Partial obstruction of the bladder outlet or urethra initially  causes an increase in the force of detrusor contraction. If the  blockage persists, afferent nerves within the bladder wall are  adversely affected, leading to urinary urgency and, in some cases,  overactive detrusor contractions (a myogenic cause of overac-  tive bladder). When obstruction persists, there is an increased  deposition of collagen within the smooth muscle bundles of  the detrusor muscle (trabeculation), possibly in an attempt to    increase the force of its contraction strength. Ultimately, the  bladder wall loses its ability to stretch and accommodate urine,  a condition called low bladder wall compliance, and the detru-  sor loses its ability to contract efficiently. Low bladder wall  compliance chronically elevates intravesicular pressure, greatly  increasing the problems of hydroureter, hydronephrosis, and  impaired renal function.   EVALUATION AND TREATMENT. Although the history and physical  examination are critical to the evaluation of lower urinary tract  disorders, it must be remembered that no symptom or cluster of  symptoms has been identified that accurately differentiates the  various causes of these disorders. For example, symptoms such  as urgency, urge incontinence, frequent urination, and nocturia  may develop because of overactive bladder or either increased  or decreased bladder outlet resistance. Reduced resistance is  associated with the symptom of stress incontinence (inconti-  nence with coughing or sneezing) and symptoms of increased  resistance are similar to those of bladder outlet obstruction,  including poor force of urinary stream, hesitancy, and feelings  of incomplete bladder emptying.   Various diagnostic tests assist with evaluation. A cystometric  test uses a catheter and manometer to evaluate bladder urine  volume and pressure in relation to involuntary bladder contrac-  tion (the leak point pressure) and the urge to void. The post-  void residual urine is measured by catheterization within 5 to 15  minutes of urination or through a bladder ultrasound machine  that measures bladder height and width to provide an approxi-  mation of urine within the vesicle. This measurement may be  combined with uroflowmetry, a graphic representation of the  force of the urinary stream expressed as milliliters voided per  second. Each of these measurements assesses the lower urinary  tract’s efficiency in evacuating urine through micturition but  neither differentiates poor detrusor contraction strength from  obstruction as a cause of urinary retention. Instead, multichan-  nel urodynamic testing is used to identify obstruction, quantify  its severity, and measure detrusor contraction strength (see  Figure 38-2). Video-urodynamic recordings can also demon-  strate overactive bladder and detrusor sphincter dyssynergia.  An evaluation of renal function, including functional imaging  studies and measurement of serum creatinine level, is com-  pleted particularly when obstruction is severe and associated  with elevated residuals or urinary tract infection. Electromyog-  raphy measures electrical activity in the bladder neck using sur-  face or needle electrodes.   Because the bladder neck consists of circular smooth muscle  with adrenergic innervation, detrusor sphincter dyssynergia  may be managed by a-adrenergic blocking (antimuscarinic)  medications or botulinum toxin.*° Obstruction that is not  adequately managed by pharmacotherapy may require blad-  der neck incision. Detrusor sphincter dyssynergia may be  managed by intermittent catheterization in combination with  higher dose antimuscarinic drugs to prevent overactive detru-  sor contractions and associated dyssynergia while ensuring  regular, complete bladder evacuation through catheterization.  Alternatively, men with dyssynergia may be managed by con-  dom catheter containment, supplemented by an a-adrenergic  blocking drug or transurethral sphincterotomy (surgical    incision of the striated sphincter) in order to relieve obstruc-  tion. Low bladder wall compliance may be managed by anti-  muscarinic drugs and intermittent catheterization; however,  more severe cases may require augmentation enterocystoplasty  (enlargement of the low compliant bladder wall using a detu-  bularized piece of small bowel), urinary diversion, or long-term  indwelling catheterization.*’ Prostate enlargement is managed  by treating the underlying cause of the prostate enlargement  with medication or surgery. Acute prostatitis is initially man-  aged by broad-spectrum antibiotics until the results of a urine  culture are obtained. Urinary retention may require transient  placement of a suprapubic catheter. The management of benign  prostatic hyperplasia and treatment options for prostate cancer  are presented in Chapter 25.   Urethral stricture is treated with urethral dilation accom-  plished by using a steel instrument shaped like a catheter  (urethral sound) or a series of incrementally increasing diam-  eter catheter-like tubes (filiforms and followers). Long, dense  strictures typically require surgical urethroplasty to prevent  recurrence.   A pessary (rubber or silicone device designed to compen-  sate for vaginal wall prolapse) may be inserted to mechani-  cally reverse severe pelvic organ (bladder, uterus, or rectum)  prolapse. Depending on the device, the woman may be able to  remove, cleanse, and replace the pessary, or it may be changed  during a clinic visit. Intravaginal hormone replacement therapy  and regular follow-up visits are critical to the long-term suc-  cess of a pessary.°* Alternatively, pelvic organ prolapse may be  repaired surgically; the procedure may be combined with a ure-  thral suspension to correct stress urinary incontinence or rec-  tocele repair.°*?    Tumors  Renal Tumors  Renal tumors account for about 65,150 (3.9%) new cancer  cases and 13,680 (2.3%) deaths in 2013.*° There are a number  of different types of kidney tumors. Renal adenomas (benign  tumors) are uncommon but are increasing in number. The  tumors are solid and encapsulated and are usually located near  the cortex of the kidney. Because they can become malignant,  they are usually surgically removed. Renal transitional cell car-  cinoma (RTCC) is rare and primarily arises in the renal paren-  chyma and renal pelvis. Renal cell carcinoma (RCC) is the most  common renal neoplasm (85% to 90% of all renal neoplasms)  (Figure 38-4). Renal cell carcinoma usually occurs in men (two  times more often than in women) between 50 and 60 years of  age and the incidence is increasing. Blacks have a higher inci-  dence and mortality. Risk factors include cigarette smoking,  obesity, hypertension, and advanced stage chronic renal failure  (CRF).*! Five-year survival for all stages is about 50% and  about 10% for stage IV cancer (metastatic disease).*°  PATHOGENESIS. Renal cell carcinomas are adenocarcinomas  and the etiology is unknown. They are classified according to  cell type and extent of metastasis. Clear cell tumors, the most  common, are dominated by mutations of the von Hippel-  Lindau (VHL) gene located on chromosome 3p in 90% of  cases. They present a better prognosis than papillary (10%),    FIGURE 38-4 Renal Cell Carcinoma. Renal cell carcinomas usually are sphe-  roidal masses composed of yellow tissue mottled with hemorrhage, necrosis, and  fibrosis. (From Damjanov I, Linder J, editors: Anderson's pathology, ed 10, St Louis,  1996, Mosby.)    chromophobe (5%), oncocytoma (3% to 4%), collecting duct  tumors (1%), or unclassified (rare) tumors.** Clear cell and  papillary tumors arise from proximal tubular epithelium.  Chromophobe, oncocytoma, and collecting duct tumors are  believed to arise from the distal nephron epithelium. Con-  finement within the renal capsule, together with treatment, is  associated with a better survival rate. The tumors usually occur  unilaterally (see Figure 38-4). About 25% to 30% of individu-  als with RCC present with metastasis (stage IV).*°*° The most  common sites of distant metastasis are the lung, lymph nodes,  liver, bone, thyroid, and central nervous system.”   CLINICAL MANIFESTATIONS. The classic clinical manifestations  of renal tumors are hematuria, dull and aching flank pain, and  palpable flank mass in thinner individuals. Systemic manifesta-  tions usually represent an advanced stage of disease and include  weight loss, fatigue, intermittent fever from tumor cytokines,  anemia from hematuria and lack of erythropoietin, polycythe-  mia from tumor secretion of erythropoietin, hypertension from  elevated renin levels, and alterations in liver function tests. All  of these symptoms occur in less than 10% of cases. Further, they  represent an advanced stage of disease, whereas earlier stages  are often silent.   EVALUATION AND TREATMENT. Diagnosis is based on the clini-  cal symptoms, plain x-ray films of the abdomen, intravenous  pyelography, renal angiography, and computed tomogra-  phy (CT). (Staging of renal cell carcinoma is presented in  Table 38-2.) Staging systems using molecular tumor markers  (measurable biologic molecules released from a tumor or the  host tissues that distinguish a malignancy) are rapidly advanc-  ing.” Treatment for localized disease is surgical removal of  the affected kidney (radical nephrectomy) or partial nephron  sparing nephrectomy for smaller tumors. Surgery is combined  with the use of chemotherapeutic agents, although RCC is  resistant to conventional chemotherapy.”” Use of traditional  cytokine therapy, specifically high-dose interleukin-2, is lim-  ited by significant toxicity (hypotension requiring vasopres-  sor support, oliguria, pulmonary congestion, arrhythmias, and  neurologic toxicity).°! Agents targeting the vascular endothelial    | Tumor confined within kidney capsule <7 cm in size.  Invasion through renal capsule and renal vein but within surrounding fascia =7 cm in size.  Involvement of adrenal glands and vena cava and one nearby lymph node:  T3a-T3c, NO, MO: The main tumor has reached the adrenal gland, the fatty tissue around the kidney, the renal vein, and/or the large vein (vena  cava) leading from the kidney to the heart. It has not spread beyond Gerota’s fascia. There is no spread to lymph nodes or distant organs.    T1a-T3c, N1, MO: The main tumor can be any size and may be outside the kidney, but it has not spread beyond Gerota’s fascia. The cancer has  spread to one nearby lymph node but has not spread to distant lymph nodes or other organs.  Distant metastases (e.g., liver, lung, bones, brain) and more than one lymph node:  T4, NO-N1, MO: The main tumor has invaded beyond Gerota’s fascia. It has spread to no more than one nearby lymph node. It has not spread to    Any T, N2, MO: The main tumor can be any size and may be outside the kidney. The cancer has spread to more than one nearby lymph node but has    Any T, Any N, M1: The main tumor can be any size and may be outside the kidney. It has spread to distant lymph nodes and/or other organs.    Adapted from American Cancer Society: Kidney cancer (adult)—renal cell carcinoma, 2013. Available at www.cancer.org/cancer/kidneycancer/    growth factor pathway and the mammalian target of rapamycin  (mTOR) have shown efficacy in randomized clinical trials for  treatment of metastatic disease.**°* There is ongoing research  to identify molecular tumor markers that predict individual  response to targeted molecular therapies.** Radiation therapy  may be used for palliation, and new techniques using stereo-  tactic radiofrequency ablation, cryoablation, and laparoscopy  are promising. Tumor obstruction is relieved by placement of  ureteral catheters or nephrostomy tubes or by completion of  urinary diversion procedures. Survival is related to tumor  grade, tumor cell type, and extent of metastasis.    Bladder tumors represent about 4.5% of all malignant tumors  and are the fourth most common malignancy in men. Approxi-  mately 72,570 people developed bladder cancer with 15,210  deaths (2.5% of all cancer deaths) in 2013.4? The development  of bladder cancer is most common in men older than 60 years.  Urothelial (transitional cell) carcinoma is the most com-  mon bladder malignancy, appearing on the inner lining of the  bladder.   PATHOGENESIS. The risk of primary bladder cancer is greater  among people who smoke or are exposed to any of the  following: metabolites of aniline dyes or other aromatic amines  or chemicals, high levels of arsenic in drinking water, or heavy  consumption of phenacetin.*° Oncogenes of the ras gene fam-  ily and tumor-suppressor genes including TP53 mutations and  inactivation of retinoblastoma gene (pRb) are implicated in blad-  der cancer. Loss of heterozygosity at chromosome 9 has been  found in all stages of urothelial cell carcinoma.*° The tumor is  usually composed of uroepithelial cells (cells lining the blad-  der, ureters, urethra, and renal pelvis), most have a papillary  growth pattern (a tuftlike lesion attached to a stalk), and they  rarely progress to invasive disease (Figure 38-5). Nonpapillary  tumors (10% to 30% of bladder tumors) are not as common as  papillary tumors, but they tend to be more invasive and have a  poorer prognosis. Carcinoma in situ can present with papillary    Location of Tumors Tumor Type  Dome  10% Papillary  80%  Posterior and  lateral wall  70%  Trigone and  bladder neck  20%  Carcinoma  in situ 3%    FIGURE 38-5 Carcinoma of the Bladder. A, Papillary transitional cell carci-  noma arising in the dome of the bladder as a cauliflower-like lesion (black arrow);  location and frequency of bladder tumor types noted. B, Bladder cancer with mor-  phologic patterns of most common tumors. (A from Stevens A, Lowe J, Scott I,  editors: Core pathology, ed 3, London, 2009, Mosby; B from Kissane JM, editor:  Anderson's pathology, ed 9, St Louis, 1990, Mosby.)   Carcinoma in situ (CIS)  Tumor invades connective tissue  Tumor invades detrusor muscle  Invasion of fatty tissue around bladder  Tumor has invaded adjacent structures    Adapted from American Cancer Society: Bladder cancer, 2013. Avail-  able at www.cancer.org/cancer/bladdercancer/detailedguide/bladder-  cancer-staging. Accessed April 2013.    tumors.°’ Worldwide, renal squamous cell carcinoma is the  most prevalent and certain forms present at a higher stage and  with a poorer prognosis.°* Metastasis is usually to lymph nodes,  liver, bones, lungs, and adrenal glands. Staging for bladder car-  cinoma is presented in Table 38-3. Secondary bladder cancer  develops by invasion of cancer from bordering organs, such as  cervical carcinoma in women or prostatic carcinoma in men.   CLINICAL MANIFESTATIONS. Gross painless microscopic hema-  turia is the archetypal clinical manifestation of bladder cancer.  Episodes of hematuria tend to recur, and they are often accom-  panied by bothersome lower urinary tract symptoms including  daytime voiding frequency, nocturia, urgency, and urge urinary  incontinence. Flank pain may occur if tumor growth obstructs  one or both ureterovesical junctions. Bothersome lower urinary  tract symptoms are particularly intense in individuals with car-  cinoma in situ. Metastasis is the cause of death from bladder  cancer, usually from high-grade muscle-invasive tumors.°?   EVALUATION AND TREATMENT. Urinalysis for evidence of hema-  turia in the absence of infection provides a useful screening  tool for high-risk patients. Urine cytology (pathologic analysis  of sloughed cells within the urine) is completed in individu-  als with evidence of hematuria from unknown causes; cystos-  copy or fluorescence cystoscopy with tissue biopsy can confirm  the diagnosis. Biologic markers for the diagnosis and progno-  sis of bladder cancer are under investigation (e.g., cadherins,  cyclooxygenase-2 [COX-2] protein, karyopherin-a2 [KPNA2],  tyrosine kinase HER2 [RTOG-0524], and epidermal growth  factor receptor [EGFR)]).°*!   Newer magnetic resonance techniques are helpful for local  staging and whole-body computed tomography detects metas-  tasis.°° Transurethral resection or laser ablation, combined with    intravesical chemotherapy or immunotherapy, is effective for  superficial tumors. Radical cystectomy with urinary diversion  and adjuvant chemotherapy is required for locally invasive  tumors, and radiation therapy may be used to support palliative  or adjuvant treatment for muscle-invasive tumors.    A urinary tract infection (UTI) is an inflammation of the  urinary epithelium usually caused by bacteria from gut flora.  A UTI can occur anywhere along the urinary tract including  the urethra, bladder, ureter, or kidney. At risk are premature  newborns; prepubertal children; sexually active and pregnant  women; women treated with antibiotics that disrupt vaginal  flora; spermicide users; estrogen-deficient postmenopausal  women; individuals with indwelling catheters; and persons  with diabetes mellitus, neurogenic bladder, or urinary tract  obstruction (see What’s New? Catheter-Associated Urinary  Tract Infections). UTIs are commonly classified by their loca-  tion or complicating factors: cystitis (bladder inflammation),  pyelonephritis (inflammation of upper urinary tract), uncom-  plicated UTI (occur in a normally functioning urinary system),  and complicated UTI (occur with defects in the urinary system    Catheter-associated urinary tract infections are the most common healthcare-  associated infection worldwide, and most individuals are asymptomatic.  Appropriate indications for use of catheters include acute urinary retention or  obstruction; perioperative applications in select procedures; and the frequent,  accurate measurement of urine output in critically ill individuals. Other uses  include sacral or perineal wound healing with incontinence and immobilization  from unstable spine or pelvic fractures. The smallest bore catheter should be  used and inserted under aseptic conditions and removed as soon as possible.  Some reviews recommended the use of silver alloy or antimicrobial-impregnated  catheters. The system is maintained using a closed-drainage system that is  replaced if the system is disconnected. The drainage bag is kept below the level  of the bladder. Prophylactic antibiotics are not recommended except in special  cases (e.g., before traumatic urinary tract interventions). Bacteriuria develops  in several ways: periurethral microorganisms may be introduced at the time of  catheterization; contaminated urine from the drainage bag or tubing may reflux  back into the bladder; and microorganisms can be introduced when there is a  break in the closed system. Additionally, bacterial biofilm develops along the  inside and outside of the tubing, providing an environment that allows for bacte-  rial colonization and spread with protection against host defenses and antibi-  otics. Proteus mirabilis and Providencia stuartii are known to produce greater  amounts of biofilm and their adhesion factors and motility allow them to ascend  more rapidly in the urinary tract. E. col/is the most common pathogen associated  with short-term catheterization.    Data from Agency for Healthcare Research and Quality National  Guideline Clearinghouse: Catheter-associated UTIs. In Guidelines on  urological infections, updated December 23, 2011, available at  www.guideline.gov/content.aspx?id=34100; Tambyah PA, Oon J:   Curr Opin Infect Dis 25(4):365-370, 2012; Beattie M, Taylor J: J Clin  Nurs 20(15-16):2098-2108, 2011; Conway LJ, Larson EL: Heart Lung  41(3):271-283, 2012; Nicolle LE: Infect Dis Clin North Am 26(1):13-27,  2012; Chenoweth C, Saint S: Crit Care Clin 29(1):19-32, 2013.    or in individuals with health problems that compromise host  defenses or response to treatment).    Host defense mechanisms maintain a sterile posterior urethra  and bladder in a healthy individual. Even if bacteria manage to  enter the bladder, these defense mechanisms prevent it from  clinging to the walls of the bladder or ascending to the upper  urinary tracts.°° Several factors normally combine to protect  against UTI. Most bacteria are washed out of the urethra dur-  ing micturition. The low pH and high osmolality of urea, the  presence of Tamm-Horsfall protein, and the presence of secre-  tions from the uroepithelium provide a bactericidal effect. The  ureterovesical junction closes during bladder contraction, pre-  venting reflux of urine to the ureters and kidneys. Periurethral  mucus-secreting glands surround the distal two thirds of the  female urethra. Mucus from these glands traps bacteria before  it can ascend from the proximal urethra to the bladder. In men,  the length of the male urethra and secretions from the prostate  and accessory periurethral glands combine to form a protec-  tive barrier against infection. In addition, the urethral sphincter  mechanism acts as a mechanical barrier to bacterial ascent from  the distal urethra.   Bacteria that successfully ascend the urethra face detection  and destruction by components of the body’s immune system  provided they come into contact with the bladder wall. Protec-  tive uroepithelial immune responses include Toll-like receptor  (e.g., TLR4) recognition of pathogen-associated molecular pat-  terns on the bacteria, neutrophil and macrophage recruitment  and phagocytosis, and the presence of antimicrobial proteins  (defensins, cathelicidin, and Tamm-Horsfall protein). Suscep-  tibility to infection also is influence by genetic variation in the  host immune response to bacterial virulence and to the viru-  lence of the pathogen.®’ Unfortunately, time is required for  the immune system to respond to the potential threat, and this  period may provide adequate time for bacteria or other patho-  gens to reproduce several times.   The efficiency of the bladder’s defenses is also influenced  by the person’s Lewis blood group.® This taxonomy is based  on recognition of inherited antigens associated with the ABO  blood factors. Individuals with certain Lewis blood groups are  more prone to UTIs because they secrete fewer antigens capable  of resisting bacterial adherence by pili formation.   Most people are able to rapidly rid the urinary tract of  invading bacteria, but some show evidence of bacteria in the  urine that does not provoke an infection. This condition, called  asymptomatic bacteriuria, does not harm urinary function or  require intervention except in pregnant women.°” A UTI occurs  when a pathogen circumvents or overwhelms the host’s defense  mechanisms and rapidly reproduces.   Virulence of Uropathogens. Virulence is a pathogen’s  ability to evade or overwhelm the host defense mechanisms  and cause disease in a host (see Chapter 10). Several factors  contribute to bacterial virulence within the urinary tract,  including the ability of uropathic bacteria to adhere (attach)  to the uroepithelium. Uropathic strains of Escherichia coli  have type-1 pili. Type-1 pili have adhesins that allow them to    bind to mucosal cellular receptors and enter uroepithelial cells  and resist flushing during normal micturition. Once inside  the cell, they can persist quiescently for long periods and  cause recurrent infection or multiply rapidly, safe from host  defenses and protected from antibiotic therapy.”° Additionally,  uropathic strains have pyelonephritis-associated fimbriae  (P. fimbriae) that bind to the uroepithelial P-blood group  antigen (present in most of the human population) and  readily ascend the urinary tract. Strains of E. coli also produce  siderophores for acquiring nutrient iron, are resistant to  bactericidal effects of complement, and express toxins including  cytotoxin necrotizing factor-1 and hemolysins. Certain bacterial  species also enhance their virulence by acting together to form  a biofilm that enhances colonization and resists efficiency of  innate host defense mechanisms and antimicrobial therapy,  particularly in catheter-associated UTI.7!)”   Acute cystitis is an inflammation of the bladder and is the  most common site of UTI. Cystitis is more common in women  because of the shorter urethra and the closeness of the urethra  to the vagina and anus (increasing the possibility of bacterial  contamination).’°   The morphologic appearance of the bladder through cystos-  copy describes different types of cystitis. With mild inflamma-  tion, the mucosa is hyperemic (red). More advanced cases may  show diffuse hemorrhage (termed hemorrhagic cystitis), pus  formation, or suppurative exudates (termed suppurative cysti-  tis) on the epithelial surface of the bladder. Prolonged infection  may lead to sloughing of the bladder mucosa with ulcer for-  mation (termed ulcerative cystitis). The most severe infections  may cause necrosis of the bladder wall (termed gangrenous cysti-  tis). Generally, infections are mild, without complications, and  occur in individuals with a normal urinary tract. Acute cystitis  may occur alone or in association with pyelonephritis, prostati-  tis, or kidney stones.   PATHOPHYSIOLOGY. Two factors account for the presence of  a UTI: the efficiency of defense mechanisms within the host  (individual) and the virulence of the pathogen (bacterium, fun-  gus, or parasite). The most common infecting microorganisms  are uropathic strains of E. coli (80% to 85%) and the second  most common is Staphylococcus saprophyticus (10%). Less com-  mon microorganisms include Klebsiella, Proteus, Pseudomonas,  fungi, viruses, parasites, or tubercular bacilli. Bacterial con-  tamination of the normally sterile urine usually occurs by retro-  grade movement of gram-negative bacilli into the urethra and  bladder and then to the ureter and kidney. Some women may  be genetically susceptible to certain strains of E. coli attachment  and may harbor pathogenic strains in their vaginal flora.”’ In  rare instances bloodstream infections (sepsis) can spread to the  bladder tissue.   Fungal infections are comparatively uncommon. The  most common pathogen is Candida, but multiple fungal spe-  cies may colonize the urinary tract or urinary catheters and  produce symptomatic UTIs, particularly in those who are  immunosuppressed.”*    Infection initiates an inflammatory response and the symp-  toms of cystitis. The inflammatory edema in the bladder wall  stimulates discharge of stretch receptors, initiating symptoms  of bladder fullness with small volumes of urine and produc-  ing the urgency and frequency of urination associated with  cystitis.   Schistosomiasis haematobium is the most common cause of  parasitic invasion of the urinary tract on a global basis; it infects  more than 200 million people.’”? Although rare among people  living in the United States, the parasite dwells in waters of the  various rivers of fresh water bodies in Africa, South America,  and Pacific Rim countries. It usually enters the human by swim-  ming up the urethra while the host swims or is partly submerged  in an infected body of water. The parasite burrows into the walls  of the urinary tract, causing inflammation and scarring of the  urinary tract, and an increased risk for urothelial malignancies  or renal failure.”   CLINICAL MANIFESTATIONS. Many individuals with bacteriuria  are asymptomatic. Clinical manifestations of cystitis are related  to the host inflammatory response and usually include fre-  quency, urgency, dysuria (painful urination), and suprapubic  and low back pain. Hematuria, cloudy and foul-smelling urine,  and flank pain are more serious symptoms. Approximately 10%  of individuals with bacteriuria have no symptoms and have  low TLR4 levels,’” and 30% of individuals with symptoms are  abacteriuric. Older adults with cystitis may be asymptomatic or  demonstrate confusion or vague abdominal discomfort. Older  adults with recurrent UTI and other concurrent illness have a  higher risk of morbidity and mortality.”   EVALUATION AND TREATMENT. Infections are diagnosed by urine  culture of specific microorganisms with counts of 10,000/ml  or more from freshly voided urine. Dipstick urinalysis and  microscopy are adequate to diagnose an uncomplicated UTI,  but urine culture is critical for complicated infections.”” Risk  factors, such as a urinary tract obstruction, which are associ-  ated with a complicated UTI, should be identified and treated.  Increased fluid intake and analgesics can relieve symptoms. Evi-  dence of bacteria from urine culture and antibiotic sensitivity  warrants treatment with a microorganism-specific antibiotic to  eradicate the underlying pathogen. A single large dose of anti-  biotic or a 3-day course may be effective when symptoms are  of short duration and there are no complications. A treatment  period of 3 to 7 days is most common depending on antimi-  crobial selection; older adults with obstructive disorders may  require 7 to 14 days of treatment. Frequent, recurrent, acute  uncomplicated UTI requires low-dose antimicrobial therapy  from 6 months to 2 years or prophylactic treatment, depend-  ing on frequency and individual responses.*° Follow-up urine  cultures should be obtained 1 week after initiation of treatment  and at monthly intervals for 3 months. Clinical symptoms are  frequently relieved, but bacteriuria may still be present, par-  ticularly with the development of antimicrobial-resistant bac-  terial strains. Repeat cultures should be obtained every 3 to 4  months until 1 year after treatment for evaluation of recurrent  infection. Urosepsis and septic shock are medical emergen-  cies that usually demand parenteral, broad-spectrum antibi-  otic therapy and may require hospitalization. A UTI caused by    Painful bladder syndrome/interstitial cystitis (PBS/IC) is a  condition that includes nonbacterial infectious cystitis (viral,  mycobacterial, chlamydial, fungal) and noninfectious cys-  titis (radiation, chemical, autoimmune, hypersensitivity).°*  It occurs most commonly in women ages 20 to 40 years who  have symptoms of cystitis, such as frequency, urgency, dysuria,  and nocturia, for more than 6 weeks duration but with nega-  tive urine cultures and no other known etiology. Nonbacte-  rial infectious cystitis is most common among those who are  immunocompromised. Noninfectious cystitis is associated  with radiation or chemotherapy treatment for pelvic and uro-  genital cancers.   The cause of PBS/IC is unknown, but an autoimmune  reaction may be responsible for the inflammatory response,  which includes mast cell activation, altered epithelial perme-  ability, neuroinflammation, and increased sensory nerve sen-  sitivity.*? The inflammation is associated with a derangement  of the glycosaminoglycan layer of the bladder mucosa that  makes it more susceptible to penetration by bacteria and nox-  ious urinary solutes. Inflammation and fibrosis of the bladder  wall are accompanied by the presence of hemorrhagic ulcers  (Hunner ulcers) and bladder volume may decrease as a result  of fibrosis, particularly in older individuals.** More recently,  the identification of antiproliferative factor (APF), a protein  expressed by the bladder uroepithelium in those with IC, is  important. APF appears to block the normal growth of cells  that line the inside wall of the bladder and indirectly increases  bladder sensation.*° Characteristic symptoms of IC include  bladder fullness, frequency (including nocturia), small urine  volume, and chronic pelvic pain with symptoms lasting lon-  ger than 9 months. Chronic pain and sleep deprivation can  lead to depression. Diagnosis of IC requires the exclusion of  other diagnoses, and extensive evaluations are completed.*°  No single treatment is effective. Oral and intravesical thera-  pies, sacral nerve stimulation, and onabotulinumtoxinA are  used for symptom relief. Surgery is used in refractory cases.*”  More research is needed to understand the pathogenesis and  treatment of this disease.    Pyelonephritis is an infection of one or both upper urinary  tracts (ureter, renal pelvis, and kidney interstitium). Common  causes are summarized in Table 38-4. Urinary obstruction and  reflux of urine from the bladder (vesicoureteral reflux) are the  most common underlying risk factors. Most cases occur in  young adult women.   PATHOPHYSIOLOGY. Microorganisms usually associated with  acute pyelonephritis include E. coli, Proteus, or Pseudomonas.  The latter two microorganisms are more commonly associated  with infections after urethral instrumentation or urinary tract  surgery. These microorganisms also split urea into ammonia,  making alkaline urine that increases the risk of stone forma-  tion. The infection is probably spread by ascending uropathic    Obstruction and stasis of urine contributing to  bacteriuria and hydronephrosis; irritation of  epithelial lining with entrapment of bacteria   Vesicoureteral Chronic reflux of urine up the ureter and into kidney  reflux during micturition, contributing to bacterial  infection   Dilation and relaxation of ureter with hydroureter  and hydronephrosis; partly caused by obstruction  from enlarged uterus and partly from ureteral  relaxation caused by higher progesterone levels   Neurologic impairment interfering with normal  bladder and urethral sphincter contraction with  residual urine and ascending infection   Introduction of organisms into urethra and bladder  by catheters and endoscopes introduced into the  urinary tract for diagnostic purposes   Movement of organisms from the urethra into the  bladder with infection and retrograde spread to  kidney    microorganisms along the ureters, but dissemination also may  occur by way of the bloodstream. The inflammatory process is  usually focal and irregular, primarily affecting the pelvis, caly-  ces, and medulla. The infection causes medullary infiltration of  white blood cells with renal inflammation, renal edema, and  purulent urine. In severe infections, localized abscesses may  form in the medulla and extend to the cortex. Primarily affected  are the renal tubules; the glomeruli usually are spared. Necro-  sis of renal papillae can develop. After the acute phase, heal-  ing occurs with deposition of scar tissue, fibrosis, and atrophy  of affected tubules (Figure 38-6). Acute pyelonephritis rarely  causes renal failure.**   CLINICAL MANIFESTATIONS. The onset of symptoms is usually  acute, with fever, chills, and flank or groin pain. Symptoms  characteristic of a UTI, including frequency, dysuria, and cos-  tovertebral tenderness, may precede systemic signs and symp-  toms. Older adults may have nonspecific symptoms, such as  low-grade fever and malaise.   EVALUATION AND TREATMENT. Differentiating symptoms of  cystitis from those of pyelonephritis by clinical assessment alone  is difficult. The specific diagnosis is established by urine culture,  urinalysis, and clinical signs and symptoms. White blood cell  casts indicate pyelonephritis, but they are not always present in  the urine. Complicated pyelonephritis requires blood cultures  and urinary tract imaging.*?   Uncomplicated acute pyelonephritis responds well to 2 to  3 weeks of microorganism-specific antibiotic therapy. Follow-up  urine cultures are obtained at 1 and 4 weeks after treatment  if symptoms recur. Antibiotic-resistant microorganisms or  reinfection may occur in cases of urinary tract obstruction or  reflux.” Intravenous pyelography and voiding cystourethrog-  raphy identify surgically correctable lesions.    FIGURE 38-6 Pyelonephritis. (Right) Small, shrunken, irregularly scarred kid-  ney of an individual with chronic pyelonephritis. (Left) Kidney is of normal size but  also shows scarring on the upper pole. (From Damjanov |: Pathology for the health  professions, ed 4, Philadelphia, 2012, Saunders.)    Chronic pyelonephritis is a persistent or recurrent infection  of the kidney leading to scarring of the kidney. One or both  kidneys may be involved. The specific cause of chronic pyelo-  nephritis may be unknown (idiopathic) or associated with  vesicoureteral reflux or renal stones. Recurrent infections  from acute pyelonephritis may be associated with chronic  pyelonephritis. Causes other than chronic pyelonephritis  include drug toxicity from analgesics such as nonsteroidal  anti-inflammatory drugs, ischemia, irradiation, and immune-  complex diseases.   PATHOPHYSIOLOGY. Chronic urinary tract obstruction pre-  vents elimination of bacteria and starts a process of progres-  sive inflammation, alterations of the renal pelvis and calyces,  destruction of the tubules, atrophy or dilation and diffuse scar-  ring, and, finally, impaired urine-concentrating ability, leading  to chronic kidney failure. The lesions of chronic pyelonephritis  are sometimes termed chronic interstitial nephritis because the  inflammation and fibrosis are located in the interstitial spaces  between the tubules (see Figure 38-6).   CLINICAL MANIFESTATIONS. The early symptoms of chronic  pyelonephritis are often minimal and commonly include fre-  quency, dysuria, and flank pain, and may include hypertension.  Progression of disease leads to renal failure, particularly in the  presence of other risk factors (ie., obstructive uropathy or dia-  betes mellitus). There is an inability to conserve sodium with  loss of tubular function, and development of hyperkalemia and  metabolic acidosis. Risk for dehydration must be considered if  there is loss of the ability to concentrate the urine.   EVALUATION AND TREATMENT. Urinalysis, intravenous pyelog-  raphy, and ultrasound are used diagnostically. Treatment is  related to the underlying cause. Obstruction must be relieved.  Antibiotics may be given, with prolonged antibiotic therapy for  recurrent infection.    Glomerulonephritis is an inflammation of the glomerulus  caused by primary glomerular injury, including immunologic    responses, ischemia, free radicals, drugs, toxins, vascular disor-  ders, and infection. Secondary glomerular injury is a consequence  of systemic diseases, including diabetes mellitus, systemic lupus  erythematosus, and, less commonly, congestive heart failure  and HIV-related kidney disease. Glomerular disease is a signifi-  cant cause of chronic kidney disease and end-stage renal failure  worldwide.?!   Acute glomerulonephritis includes renal diseases in which glo-  merular inflammation is caused by immune mechanisms that  damage the glomerular capillary filtration membrane includ-  ing the endothelium, basement membrane, and epithelium  (podocytes). Mesangial expansion can be a component of the  disease. The classic symptoms include sudden onset of hematu-  ria including red blood cell casts and proteinuria, and in more  severe cases, these symptoms are also accompanied by edema,  hypertension, and impaired renal function. Nonimmune acute  glomerular injury is related to ischemia, toxin exposure, drugs,  vascular disorders, and infection with direct injury to glomeru-  lar cells.   PATHOPHYSIOLOGY. Immune mechanisms and inflammation  are a major cause of injury for both primary and secondary  types of acute glomerulonephritis (Figure 38-7). Immune  injury includes: (1) deposition of circulating antigen-antibody  immune complexes on the glomerulus (type HI hypersensitivity  reaction); (2) antibodies reacting in situ against planted anti-  gens within the glomerulus (type II hypersensitivity); (3)  action of antibodies directed against the glomerular capillary  wall (antiglomerular basement membrane antibodies), the  least common and most severe form of immune injury (type II  hypersensitivity); and (4) cell-mediated immune injury (type  IV hypersensitivity) (Table 38-5). In nearly all types of acute  glomerulonephritis, the epithelial or podocyte layer of the glo-  merular capillary membrane is disturbed with loss of negative  charges and changes in membrane permeability; the mesangial  matrix may be expanded or the basement membrane thick-  ened (see Figure 38-7). Different causes of injury may result in  more than one type of glomerular lesion; thus lesions are not  necessarily disease specific (Table 38-6). Many types of acute  glomerulonephritis occur, most often in children or young  adults, including acute postinfectious glomerulonephritis,  Henoch-Schénlein purpura nephritis, and minimal change  nephropathy (lipoid nephrosis) associated with nephrotic  syndrome. Details of these diseases are presented in Chapter  39. The types, causes, and histopathology of acute glomeru-  lonephritis are summarized in Table 38-7. The mechanisms  of acute glomerulonephritis are presented next and include  IgA nephropathy, membranous glomerulonephritis, crescen-  tic or rapidly progressive glomerulonephritis, mesangial pro-  liferative glomerulonephritis, and membranous proliferative  glomerulonephritis.   IgA nephropathy (Berger disease) is the most common  form of idiopathic acute glomerulonephritis in developed  countries, especially Asia. The cause is unknown and more  commonly affects children and young adults aged 20 to 30  years. It occurs almost twice as often in males as in females    and is rare in blacks. Henoch-Schénlein purpura is a milder  systemic form of the disease that presents with hematuria and  occurs more often in children (see Chapter 39). Abnormal  glycosylated IgA-1 (galactose-deficient IgA-1) is produced by  the bone marrow. Glycan-specific IgG and IgA antibodies are  formed against abnormal IgA-1, can activate complement, and  bind to glomerular mesangial cells, stimulating them to prolif-  erate, secrete extracellular matrix proteins, and release inflam-  matory cytokines and chemokines (interleukin-6, tumor  necrosis factor-alpha, and transforming growth factor-beta 1)  that cause injury. The immune response contributes to dif-  fuse mesangioproliferative glomerular injury and glomerulo-  sclerosis, which is reversible.”? A genetic factor may promote  the overproduction of IgA-1.” B cells that respond to mucosal  infections, particularly tonsillitis, might produce the nephrito-  genic IgA-1 molecule.”   The disease manifests with gross or microscopic (30% to  40%) hematuria 24 to 48 hours after an upper respiratory  or gastrointestinal tract viral infection. Proteinuria, edema,  and hypertension are more severe symptoms and must be  treated to prevent future loss of kidney function.”° Diagno-  sis is made by renal biopsy. Treatment includes angiotensin-  converting enzyme (ACE) inhibitors as first-line therapy,  with glucocorticoids added when severe proteinuria is pres-  ent.”’ The disease is more mild in children than in adults.”®  Tonsillectomy combined with steroid-pulse therapy has pro-  moted clinical remission among individuals with the disease  in Japan.”! The prognosis is variable, with 20% to 40%  of cases progressing to renal failure over a period of years.  Long-term follow-up consists of evaluating blood pressure,  urinalysis, proteinuria levels, and renal function every 6 to  12 months. 10119?   Membranous nephropathy, also known as membranous  glomerulonephritis, is one of the most common causes of  acute glomerulonephritis. Primary membranous nephropathy  is caused by subepithelial deposition of circulating antibodies or  antibodies (IgG4 subclass) formed in situ to antigens (M-type  phospholipase A, receptor [PLA2R] protein) located on glo-  merular podocytes. The antigen-antibody complexes activate  C5b-C9 fragments of complement (the membrane attack com-  plex) with injury and release of inflammatory mediators by  mesangial and epithelial cells, resulting in increased membrane  permeability, thickening of the glomerular membrane, and ulti-  mately glomerular sclerosis. Secondary membranous nephrop-  athy is associated with various disorders including infections  (e.g., hepatitis), systemic lupus erythematosus, drugs, and some  cancers. Proteinuria and nephrotic syndrome are common  manifestations.!°)!04   Rapidly progressive (crescentic) glomerulonephritis  (RPGN), also known as subacute or extracapillary glomerulo-  nephritis, develops over days to weeks. The disease affects pri-  marily adults in their fifties and sixties and may be idiopathic or  associated with a proliferative glomerular disease (diffuse prolif-  eration of extracapillary cells), such as lupus or poststreptococ-  cal glomerulonephritis. Antiglomerular basement membrane  antibodies and antineutrophil cytoplasmic antibodies are asso-  ciated with glomerular injury.!°°!°° There is accumulation of T    FIGURE 38-7 Mechanisms of Glomerular Injury. Ab, Antibody; GBM, glomerular basement membrane; GFA, glomerular    cells and macrophages with extensive proliferation of glomeru-  lar epithelial cells into the Bowman space. The accumulation  of cells promotes crescent formation (the shape of the Bow-  man capsule). Heparin-binding epidermal growth factor—like  growth factor (HB-EGF) released from glomerular epithelial  cells is associated with the proliferation.!°’ Typically the glo-  merular injury is accompanied by a rapid decline in glomerular  function, progressing to renal failure in a few weeks or months.    Hematuria is common and may or may not be accompanied  by proteinuria, edema, or hypertension. There are three types  of RPGN distinguished by immunofluorescence and electron  microscopic study of the renal biopsy (Figure 38-8).!°° They are  summarized in Table 38-7.   RPGN has a relatively poor prognosis if not diagnosed and  treated early. Anticoagulants may be of some benefit in reduc-  ing the fibrin component of crescent formation. Plasmapheresis    Formation of antibodies stimulated by the presence of endogenous or exogenous antigens results in circulating soluble antigen-  antibody complexes, which are deposited in glomerular capillaries, or the in situ formation of immune complexes to planted    antigens or to structural components within the glomerulus; glomerular injury occurring with complement deposition and  activation and release of immunologic substances that lyse cells and increase membrane permeability; immune deposits with  a microscopic appearance that fluoresce in a granular pattern when stained with fluorescein and viewed under ultraviolet  light; severity of glomerular injury related to the number of complexes formed; a type Ill hypersensitivity reaction    Antibodies are formed and act directly against the glomerular basement membrane; immune response that causes crescent  formation and a /inear pattern of immunofluorescence; generally associated with rapidly progressive renal failure such as  Goodpasture syndrome (type II hypersensitivity reaction)   A relatively obscure mechanism associated with low levels of complement and membranoproliferative glomerulonephritis    A delayed hypersensitivity response that damages the glomerulus; actual cellular mechanism not clearly understood but    may involve cytokine secretion, activation of effector cells such as macrophages or by inducing autoantibodies or immune  complexes; cytotoxic CD8+ T-cell responses and failure of regulatory T cells may represent two additional types of antirenal    Relatively uniform involvement of most (>50%) or all glomeruli; most common form of glomerulonephritis    Focal Changes in only some glomeruli (>50%), whereas others are normal    is usually combined with corticosteroids and immunosuppres-  sion therapy. Dialysis or transplantation is required when fail-  ure is irreversible. !0?!!!   Mesangial proliferative glomerulonephritis is usually  idiopathic and involves deposits of immune complex in the  mesangium with mesangial cell proliferation. It can be associ-  ated with IgA nephropathy, lupus nephritis, or early diabetic  nephropathy. Mesangial expansion reduces blood flow and  alters filtration membrane permeability with development of  hematuria, proteinuria, hypertension, and uremia (nephritic  syndrome).   Membranoproliferative glomerulonephritis (MPGN)  is usually idiopathic and involves proliferation of mesangial  cells and formation of crescents related to the deposition of  complement (C3 component) and inflammatory injury. This  disease is rare and occurs more commonly in children and  young adults. Hypocomplementemia is associated with all  types of MPGN and they are differentiated by light micros-  copy. All three types stain positive for complement component  C3. The subtypes are summarized in Table 38-7. Injury to the    A lesion involving the entire glomerulus  Changes in one part of the glomerulus with other parts unaffected   Thickening of the glomerular capillary wall with immune deposits (i.e., IgG and C3)   Accumulation of proliferating cells within Bowman space, making the appearance of a crescent  Scarring between the glomerulus and the tubules    glomerular capillary wall in all types of MPGN can cause pro-  teinuria, hematuria, nephrotic syndrome, and acute or chronic  kidney failure.!!*!!°   The immune injury of acute glomerulonephritis is caused  by activation of biochemical mediators of inflammation (i.e.,  complement cytokines from leukocytes and fibrin) and begins  after the antibody or antigen-antibody complexes have depos-  ited or formed in the glomerular capillary wall. Complement is  deposited with the antibodies, and its activation can cause cell  lysis or serve as a chemotactic stimulus for attraction of neu-  trophils, monocytes, and T lymphocytes.'!* Activated platelets  can further the inflammatory reaction by releasing lysosomal  enzymes, reactive oxygen species, and cytokines. These inflam-  matory mediators injure the glomerular filtration membrane,  including endothelial cells, glomerular basement membrane,  and epithelial cells (podocytes). The injury increases glomeru-  lar membrane permeability and reduces glomerular membrane  surface area (podocyte injury). There also may be swelling and  proliferation of mesangial cells and expansion of the extracel-  lular matrix in the Bowman space, contributing to crescent    Associated with Nephritic Syndrome  Acute postinfectious glomerulonephritis (PIGN) (e.g., group A beta-hemolytic Subepithelial deposits of IgG and complement complexes; infiltration of  streptococci [more common in children]; staphylococcus [more common in neutrophils and monocytes; proliferation of mesangial and epithelial cells  older adults}) with occlusion of glomerular capillary blood flow and decreased glomerular  filtration; usually diffuse lesions  Rapidly progressive or crescentic glomerulonephritis (a clinical syndrome): Accumulation of fibrin, macrophages, and epithelial cell proliferation into the  Type |: Formation of IgG antibodies against pulmonary capillary and glomeru- Bowman space forms crescents and occludes glomerular capillary blood  lar basement membrane (Goodpasture syndrome); activation of comple- flow decreasing glomerular filtration; antiglomerular basement membrane  ment and neutrophils; more common in young men; causes pulmonary antibodies lead to necrotizing, proliferative glomerulonephritis, and renal  hemorrhage and renal failure failure; diffuse lesions  Type Il: Mesangial immune complex deposition (PIGN, SLE, IgA nephropathy)  Type Ill: Pauci-immune, lack of anti-GBM antibodies or immune complexes;  presence of serum antineutrophil cytoplasmic (ANC) antibodies associ-  ated with systemic vasculitides (usually idiopathic); nonspecific response  to glomerular injury; can occur in any severe glomerular disease  Mesangial proliferative glomerulonephritis Deposits of immune complexes in the mesangium with mesangial cell  Can be associated with IgA nephropathy or lupus nephritis proliferation; results in decreased glomerular blood flow and glomerular  filtration; leads to hematuria/proteinuria and nephrotic syndrome    Associated with Nephrotic Syndrome  Minimal change nephropathy (lipoid nephrosis) Glomeruli look normal under light microscopy; electron microscopy reveals    Glomerular basement membrane appears normal uniform diffuse effacement of epithelial (podocyte) foot processes; loss of  Most common cause of nephrotic syndrome in children (see Chapter 39) negative charge in basement membrane and increased permeability lead to  Usually idiopathic severe proteinuria and nephrotic syndrome  Focal segmental glomerulosclerosis Focal proliferation of endothelial and mesangial cells and glomerulosclerosis  Usually idiopathic from hyaline deposits in segmental parts of the glomerular membrane; there  Can be associated with HIV infection, IgA nephropathy is effacement (thinning or deletion) of epithelial podocytes, with a significant  increase in pore size resulting in proteinuria and nephrotic syndrome; can  progress to involve entire glomerulus and development of tubulointerstitial  fibrosis  Membranous nephropathy (autoimmune response to unknown renal antigen) Diffuse thickening of glomerular basement membrane and capillary wall from  Usually idiopathic; can be associated with systemic diseases (i.¢., hepatitis deposits of antibody, complement, and release of inflammatory cytokines;  B virus, hepatitis C virus, systemic lupus erythematosus, solid malignant increased permeability with proteinuria and leading cause of nephrotic  tumors) syndrome in white adults  Membranoproliferative (MPGN) Mesangial cell proliferation; thickening of basement membrane; subendothelial  Usually idiopathic; associated with hypocomplementemia deposits of immune complex occlude glomerular capillary blood flow and  Type |: Activation of classical complement pathway with nephrotic syndrome decrease glomerular filtration; diffuse lesions  (hepatitides B and C, SLE)  Type II: Activation of alternate complement pathway with hematuria (idio-  pathic); no circulating immune complexes  Type Ill: Activation of alternative complement pathway with nephrotic  syndrome; can be familial  IgA nephropathy (Berger disease) Mesangial proliferation with deposition of IgA; release of inflammatory  Usually idiopathic (can be associated with cirrhosis and minimal change mediators with cellular proliferation; crescent formation, glomerulosclerosis,  disease); elevated IgA plasma levels (also see Henoch-Schénlein purpura interstitial fibrosis, decreased GFR and hematuria; usually focal, some diffuse  nephritis in Chapter 39) lesions    GBM, Glomerular basement membrane; GFR, glomerular filtration rate; H/V, human immunodeficiency virus; /gA, immunoglobulin A; /gG, immuno-  globulin G; SLE, systemic lupus erythematosus.    formation (deposition of substances in the Bowman space movement of proteins into the urine. Proteins are normally  forming the shape of a crescent moon) and decreased glomer- __ repelled because they also have a negative charge. Red blood  ular blood flow.!!° The result is decreased driving hydrostatic _ cells also escape if pore size is large enough. Proteinuria (excess  pressure, decreased GFR, and alterations in microcirculatory _ protein in the urine, usually albumin) or hematuria (blood in  blood flow within the renal cortex (hypoxic injury).!'° the urine), or both, develop. The severity of glomerular dam-   Loss of the negative electrical charge across the glomerular age and decline in glomerular function is related to the size,  filtration membrane and increase in filtration pore size enhance number, and location (focal or diffuse) of cells injured, the   FIGURE 38-8 Antiglomerular Basement Membrane Nephritis. Glomerulus  with a fresh crescent consisting of fibrin and cells in the Bowman space (A). There  is disruption of the basement membrane of the Bowman capsule, with migration of  cells from the interstitium into the Bowman space (B). The capillary tufts (C) are dis-  torted and compressed because of the crescent. Note the free erythrocytes in tubu-  lar lumina (D). The interstitium is mildly edematous. (Periodic acid-methenamine  silver stain.) (Modified from Damjanov |, Linder J, editors: Anderson's pathology,  ed 10, St Louis, 1996, Mosby.)   CLINICAL MANIFESTATIONS. The onset of glomerular disease  may be sudden or insidious and significant loss of nephron  function can occur before symptoms develop. Acute glomeru-  lonephritis may be silent, mild, moderate, or severe in symptom  presentation.   Two major symptoms distinctive of more severe glomeru-  lonephritis are: (1) hematuria with red blood cell casts, and  (2) proteinuria exceeding 3 g/day to 5 g/day with albumin  (macroalbuminuria) as the major protein. Nephrotic syndrome  is associated with gross proteinuria (see p. 1358). Red blood cells  escaping through the glomerular membrane produce a smoky,  brown-tinged urine; red blood cell casts; and an accompany-  ing proteinuria, which is associated with nephritic syndrome  (see p. 1358). Glomerular bleeding provides prolonged contact  with the acidic urine and transforms hemoglobin to methemo-  globin, which has a brownish color and no blood clots. In com-  parison, bleeding from sites lower in the urinary tract produces  a pink- or red-colored urine.   Different types of glomerulonephritis may be associated with  different patterns of urinary sediment. Urine with nephrotic  sediment contains massive amounts of protein and lipids and  either a microscopic amount of blood or no blood. Urine in  diseases associated with a nephritic sediment is characterized  by the presence of blood in the urine with red cell casts, white  cell casts, and varying degrees of protein, which usually is not  severe. The sediment of chronic glomerular disease has waxy  casts, granular casts, and less protein and blood than found in  nephrotic or nephritic sediment.   Severe or progressive glomerular disease causes oligu-  ria (urine output of 30 ml/hour or less), hypertension, and  renal failure. Focal lesions tend to produce less severe clinical    symptoms. Salt and water are reabsorbed, contributing to fluid  volume expansion, edema, and hypertension.   EVALUATION AND TREATMENT. The diagnosis of glomerular dis-  ease is confirmed by the progressive development of clinical  manifestations and laboratory findings of abnormal urinalysis  with proteinuria, red blood cells, white blood cells, and casts.  Reduced GFR during glomerulonephritis is evidenced by ele-  vated plasma urea, cystatin C, and creatinine concentrations, or  by reduced renal creatinine clearance (see Chapter 37). Renal  biopsy provides a specific determination of renal injury and type  of pathologic condition. Patterns of antigen-antibody complex  deposition or formation within the glomerular capillary filtra-  tion membrane have been established using light, electron, and  immunofluorescent microscopy. Electron microscopy differen-  tiates morphologic changes within the glomerular capillary wall  (e.g., subendothelial and mesangial electron-dense deposits,  increased mesangial matrix, mesangialization of capillary loops,  and foot process fusion). Staining with fluorescein identifies  different antibodies (i.e., immunoglobulin G [IgG] or IgA) and  their configurations when viewed under ultraviolet light with  light microscopy (see Figure 39-5, C, p. 1382).   Management principles for treating glomerulonephritis are  related to treating the primary cause; preventing or minimizing  immune responses; and correcting accompanying problems,  such as edema and hypertension. Specific treatment regimens  are necessary for particular types of glomerulonephritis. Antibi-  otic therapy is essential for the management of underlying infec-  tions that may be contributing to ongoing antigen-antibody  responses. Corticosteroids decrease antibody synthesis and  suppress inflammatory responses. Cytotoxic agents (e.g., cyclo-  phosphamide) may be used to suppress the immune response  in corticosteroid-resistant cases. Anticoagulants may be useful  for controlling fibrin crescent formation in rapidly progressive  glomerulonephritis.    Chronic glomerulonephritis encompasses glomerular diseases  with a progressive course leading to chronic kidney disease (see  p. 1364). There may be no history of renal disease before the  diagnosis. Proteinuria and hypercholesterolemia have been  associated with progressive glomerulosclerosis, tubulointersti-  tial fibrosis, and tubular atrophy.''” The primary cause may be  difficult to establish because advanced pathologic changes may  obscure specific disease characteristics (Figure 38-9). Renal  insufficiency usually begins to develop after 10 to 20 years, fol-  lowed by nephrotic syndrome and an accelerated progression  to end-stage kidney failure. Symptom patterns vary depending  on the underlying cause. Corticosteroids usually do not change  the course of chronic glomerular disease, and dialysis or kid-  ney transplantation ultimately may be needed. Diabetes mel-  litus and systemic lupus erythematosus are common secondary  causes of chronic glomerular injury.   Diabetic nephropathy develops from metabolic (advanced  glycosylated end products), inflammatory (transforming growth  factor-beta and protein kinase C), and microvascular com-  plications related to chronic hyperglycemia (see Chapter 22).  Changes in the glomerulus are characterized by podocyte    FIGURE 38-9 Chronic Glomerulonephritis. The kidneys appear small, are  uniformly shrunken, and have a finely granular external surface. (From Damjanov |:  Pathology for the health professions, ed 4, Philadelphia, 2012, Saunders.)    injury, progressive thickening and fibrosis of the glomerular  basement membrane, and expansion of the mesangial matrix  (diffuse diabetic glomerulosclerosis) with proteinuria and pro-  gression to chronic renal failure.!'® Diabetic nephropathy is the  most common cause of chronic kidney disease and end-stage  renal failure, but has been declining since 1995,.!!%"!7!   Lupus nephritis is an inflammatory complication of the  chronic autoimmune syndrome systemic lupus erythematosus  (see Chapter 9). The renal component of the disease is caused  by the formation of autoantibodies against double-stranded  DNA and nucleosomes with glomerular deposition of the  immune complexes triggering of alpha-interferon dependent  antiviral immune responses.'?!* There is complement activa-  tion and a cascade of inflammatory events results in damage  to the glomerular membrane with mesangial expansion (see  Chapter 8). Different glomerular lesion patterns are identifi-  able on biopsy including membranous, mesangial, membrano-  proliferative, and diffuse proliferative glomerulonephritis; and  tubular fibrosis can be present (see Table 38-6).!2%!75 Symptom  presentation is variable depending on lesion involvement and  can include proteinuria, microscopic hematuria, edema, and  other signs of nephrotic syndrome. Disease progression may be  silent or may progress to end-stage kidney failure over a period  of years. Treatment includes the use of immunosuppressive  agents, |    Nephrotic syndrome is the excretion of 3.0 g or more of pro-  tein in the urine per day, hypoalbuminemia (less than 3.0 g/  dl), and peripheral edema. Nephrotic syndrome is characteris-  tic of glomerular injury. Primary causes of nephrotic syndrome  include minimal change disease (lipoid nephrosis), membra-  nous glomerulonephritis, and focal segmental glomerulosclerosis  (see Table 38-7). Secondary forms of nephrotic syndrome occur in  systemic diseases including diabetes mellitus, amyloidosis, sys-  temic lupus erythematosus, and Henoch-Schénlein purpura (see  Chapter 39). Nephrotic syndrome also is seen with certain drugs,  infections, malignancies, and vascular disorders. Familial forms    of nephrotic syndrome result from genetic defects that affect the  function and composition of the glomerular capillary wall (i.e.,  Alport syndrome with alterations in basement membrane type  IV collagen).!** It often signifies a more serious prognosis when  present as a secondary complication. Nephrotic syndrome is  more common in children than in adults (see Chapter 39).   In nephritic syndrome, the presenting symptom is hematu-  ria (usually microscopic) and red blood cell casts are present in  the urine in addition to proteinuria, which is not severe. This  syndrome is caused by increased permeability of the glomeru-  lar filtration membrane with pore sizes large enough to allow  the passage of red blood cells and protein. Nephritic syndrome  is associated with postinfectious glomerulonephritis, rapidly  progressive (crescentic) glomerulonephritis, IgA nephropathy  (see Chapter 8 for types of immunoglobulins), lupus nephritis,  and diabetic nephropathy (see Table 38-7). The pathophysiol-  ogy is related to immune injury of the glomerulus as previously  described and can occur simultaneously with nephrotic syn-  drome. Hypertension, uremia, and oliguria occur in advanced  stages of disease. The symptoms and treatment are similar to  those for nephrotic syndrome. !°   PATHOPHYSIOLOGY. Disturbances in the glomerular basement  membrane (GBM) and podocyte injury lead to increased per-  meability to protein and loss of electrical negative charge (see  Chapter 37).!?° Loss of plasma proteins, particularly albumin  and some immunoglobulins, occurs across the injured glomer-  ular filtration membrane (Figure 38-10). Sustained protein-  uria can result in the release of inflammatory mediators and    Hypoalbuminemia (decreased oncotic pressure, sodium and water  retention, increased aldosterone and antidiuretic hormone [ADH]  secretion), unresponsiveness to atrial natriuretic peptides    cytokines by tubular cells with influx of leukocytes resulting  in progressive glomerulosclerosis and renal fibrosis.'*” Hypo-  albuminemia results from urinary loss of albumin combined  with a diminished synthesis of replacement albumin by the  liver. Albumin is lost in the greatest quantity because of its high  plasma concentration and low molecular weight. Decreased  dietary intake of protein from anorexia or malnutrition or  accompanying liver disease may also contribute to lower levels  of plasma albumin. Loss of albumin stimulates lipoprotein syn-  thesis by the liver and hyperlipidemia. Loss of immunoglobu-  lins may increase susceptibility to infections. Sodium retention  also is associated with nephrotic syndrome contributing to the  development of edema and ascites. The exact mechanism is  unknown but the site of retention is the distal tubules and col-  lecting ducts.!°   CLINICAL MANIFESTATIONS. Many clinical manifestations of  nephrotic syndrome are related to loss of serum proteins  (Table 38-8) and retention of sodium. They include edema,  hyperlipidemia, lipiduria, vitamin D deficiency, and hypo-  thyroidism.!?%'°° Vitamin D deficiency is related to loss of  serum transport proteins and decreased vitamin D activation  by the kidney. Hypothyroidism can result from urinary loss  of thyroid-binding protein and thyroxine but there may be no  symptoms. Alterations in coagulation factors cause hypercoag-  ulability and may lead to thromboembolic events, particularly  in young adults. '°!   EVALUATION AND TREATMENT. Nephrotic syndrome is diag-  nosed when the protein level in a 24-hour urine collection is  greater than 3.0 g. Serum albumin level decreases (to less than  3 g/dl), and concentrations of serum cholesterol, phospholip-  ids, and triglycerides increase. Fat bodies may be present in  the urine. The specific pathologic condition is identified by  renal biopsy.   Nephrotic syndrome is commonly treated with a normal-  protein (i.e., 1 g/kg body weight/day) low-fat diet, salt restric-  tion, diuretics, immunosuppression, and heparinoids. When  diuretics are used, care must be taken to observe for hypovo-  lemia and hypokalemia or potassium toxicity in the presence    Sloughing of tubular cells containing fat (oval fat bodies); free fat    The globulin to which 1,25-dihydroxy-vitamin Ds is attached for  transport passes through the glomerulus and is lost in the urine  Loss of thyroid-binding globulin and other thyroid hormone transport    of renal insufficiency. Aldactone may be combined with loop  diuretics to suppress aldosterone activity to conserve potas-  sium. Corticosteroids or cyclophosphamide may be particu-  larly effective for the initial treatment of steroid-dependent  nephrotic syndrome in children. Immunosuppressive drugs  and angiotensin-converting enzyme inhibitors are used with  steroid-resistant nephrotic syndrome.!3!°?   Kidney injury may be acute and rapidly progressive (within  hours), and the process may be reversible. Kidney failure also  can be chronic, progressing to end-stage kidney failure over a  period of months or years. The terms renal insufficiency, renal  failure, uremia, and azotemia are associated with decreas-  ing renal function but are not specific in relation to cause of  kidney disease. Often they are used synonymously, although  with some distinctions. Generally, renal insufficiency refers  to a decline in renal function to about 25% of normal or a  GFR of 25 to 30 ml/minute. Levels of serum creatinine and  urea are mildly elevated. Renal failure refers to significant  loss of renal function. When less than 10% of renal function  remains, this is termed end-stage kidney disease (ESKD).  Specific criteria for acute renal dysfunction are discussed in  the next section. Uremia is a syndrome of renal failure and  includes elevated blood urea and creatinine levels accom-  panied by fatigue, anorexia, nausea, vomiting, pruritus, and  neurologic changes. Uremia represents numerous conse-  quences related to renal failure, including retention of toxic  wastes, deficiency states, electrolyte disorders, and immune  activation promoting a proinflammatory state. Azotemia is  characterized by increased serum urea levels and frequently  increased creatinine levels as well. Renal insufficiency or renal  failure causes azotemia. Both azotemia and uremia indicate  an accumulation of nitrogenous waste products in the blood,  a common characteristic that explains the overlap in defini-  tions of terms.    Risk ncreased creatinine x 1.5 or GFR decrease >25%  Injury ncreased creatinine x 2 or GFR decrease >50%  Failure ncreased creatinine x 3 or GFR decrease >75%  Loss Persistent ARF: complete loss of kidney function >4 weeks    ESKD End-stage kidney disease: complete loss of kidney function >3 months    AKIN 1 ncreased Sc;eat by 1.5-2 x above baseline or by 0.3 mg/dl  AKIN 2 ncreased Scyeat by 2-3 x above baseline  AKIN 3 n    From Crowley ST, Peixoto AJ: Clin Chest Med 30(1):29-43, vii-viii, 2009.    creased Scyeat by >3 x above baseline or by 0.3 mg/dl in patients with baseline Screat >4 mg/dl    UO <0.5 ml/kg/hr x 6 hr  UO <0.5 ml/kg/hr x 12 hr  UO <0.3 ml/kg/hr x 24 hr or anuria    UO <0.5 ml/kg/hr x 6 hr  UO <0.5 ml/kg/hr x 12 hr  UO <0.3 ml/kg/hr x 24 hr or anuria for 12 hr    AKIN, Acute Kidney Injury Network ESKD stages; AAF, acute renal failure; GFR, glomerular filtration rate; Scea, serum creatinine level; UO, urine   Acute kidney injury (AKI) affects about 5% of hospitalized  individuals and has a mortality of 50% to 80%.!** AKI is a sud-  den decline in kidney function with a decrease in glomerular  filtration and accumulation of nitrogenous waste products in  the blood as demonstrated by an elevation in plasma creatinine  and blood urea nitrogen levels. The term acute kidney injury is  preferred to the term acute renal failure because it captures the  diverse nature of this syndrome, ranging from minimal or sub-  tle changes in renal function to complete renal failure requir-  ing renal replacement therapy. Classification criteria have been  developed to guide the diagnosis of renal injury described by  the acronym RIFLE (R = risk, I = injury, F = failure, L = loss,  and E = end-stage kidney disease [ESKD]) representing renal  dysfunction of increasing severity (Table 38-9).!%>1°6   PATHOPHYSIOLOGY. AKI commonly results from extracellular  volume depletion, decreased renal blood flow, or toxic/inflam-  matory injury to kidney cells that results in alterations in renal  function that may be minimal or severe. Even small changes  in renal function may be associated with significant morbidity  and mortality. The etiologies of AKI can be described consid-  ering three categories of injury: (1) renal hypoperfusion (pre-  renal AKI); (2) disorders involving the renal parenchymal or  interstitial tissue (intrarenal or intrinsic AKI); and (3) disorders  associated with acute urinary tract obstruction (postrenal AKI)  (Table 38-10). Most types of AKI are reversible if diagnosed and  treated early.   Prerenal acute kidney injury is the most common cause  of AKI. Reduced effective arterial blood volume causes renal  hypoperfusion that occurs rapidly over a period of hours with  elevation of BUN and plasma creatinine levels. During the early  phases of hypoperfusion protective autoregulatory mecha-  nisms maintain GFR at a relatively constant level through  afferent arteriolar dilation and efferent arteriolar vasoconstric-  tion (mediated by angiotensin I). Tubuloglomerular feedback  mechanisms also maintain GFR and distal tubular nephron  flow (see Chapter 37). The GFR ultimately declines because of  the decrease in filtration pressure. Poor perfusion can result  from renal artery thromobosis, hypotension related to hypo-  volemia (dehydration, diarrhea, fluid shifts) or hemorrhage,  renal vasoconstriction and alterations in renal regional blood  flow, microthrombi, or kidney edema that restricts arterial   Water and electrolyte losses (severe vomiting or  diarrhea, intestinal obstruction, uncontrolled  diabetes mellitus, inappropriate use of diuretics)    blood flow.!°” Sepsis/septic shock and cardiogenic shock fol-  lowing cardiac surgery are the most common causes of AKI in  the intensive care unit.!*° AKI may occur during chronic kidney  failure if a sudden stress is imposed on already marginally func-  tioning kidneys, hastening the progression to end-stage kidney  disease. Failure to restore blood volume or blood pressure and  oxygen delivery can cause cell injury and acute tubular necrosis  and apoptosis or acute interstitial necrosis, a more severe form  of AKI.   Intrarenal (intrinsic) acute kidney injury (AKI) may result  from ischemic acute tubular necrosis (ATN), nephrotoxic ATN    (i.e., exposure to radiocontrast media or antibiotics), acute  glomerulonephritis, vascular disease (malignant hypertension,  disseminated intravascular coagulation, and renal vasculitis),  allograft rejection, or interstitial disease (drug allergy, infec-  tion, tumor growth). Acute tubular necrosis (ATN) caused  by ischemia is the most common cause of intrarenal AKI. It  occurs most often after surgery (40% to 50% of cases) but is  also associated with severe sepsis; obstetric complications; and  severe trauma, including severe burns; or small vessel vascu-  litis. A combination of events and predisposing factors leads  to the greatest risk for acute renal failure. The terms acute  tubular necrosis and acute kidney injury are sometimes used  interchangeably, but the conditions are not the same because  acute kidney injury can occur without ATN. ATN is generally  described as postischemic or nephrotoxic or it can be a com-  bination of both. Postischemic ATN involves persistent hypo-  tension, hypoperfusion, and hypoxemia, producing ischemia  and reduced levels of ATP and generating toxic oxygen-free  radicals with loss of antioxidant protection that causes cell  swelling, injury, and necrosis. Activation of inflammatory cells  (e.g., neutrophils, macrophages, and lymphocytes) and com-  plement and release of inflammatory cytokines contribute to  tubular injury.'°’ Transport of sodium and other molecules is  disrupted with damage primarily to the proximal tubular epi-  thelium and shedding of the brush border with the appearance  of tubular granular casts in the urine. Ischemic necrosis tends to  be patchy and may be distributed along any part of the nephron  tubules. Injury is most severe in the outer medulla with scat-  tered necrosis in the cortex and loss of cells along the tubular  epithelium.'“° Severe disease of the glomeruli (i.e., acute or  rapidly progressive glomerulonephritis) or renal microvascular  disorders can also cause intrinsic kidney injury. Oliguria is com-  mon (urine output less than 30 ml/hour) with intrarenal AKI,  but anuria is rare. Creatinine values in septic renal injury may  not reflect renal injury because sepsis decreases production of  creatinine without major alterations in body weight, hematocrit  level, or amount of extracellular fluid. Creatinine level usually  increases with decreased renal blood flow and decreased GFR.  However, in sepsis-induced AKI, creatinine values can remain  within normal ranges and may be related to alterations in intra-  renal microcirculatory blood flow that are different from the  kidney ischemia that develops related to systemic hypotension  and hypoperfusion of nonseptic AKI.!4))!   Nephrotoxic ATN can be produced by numerous antibiot-  ics, but the aminoglycosides (gentamicin, tobramycin) are the  major culprits. The drugs tend to accumulate in the renal cortex  and may not cause renal failure until after treatment is com-  plete. Radiocontrast media (x-ray media) and cisplatin also may  be nephrotoxic. Dehydration, advanced age, concurrent renal  insufficiency, and diabetes mellitus tend to enhance nephro-  toxicity from either aminoglycosides or radiocontrast media.  Other substances such as carbon tetrachloride, heavy metals  (mercury, arsenic), methoxyflurane anesthesia, or bacterial  toxins may promote renal failure. Endogenous substances toxic  to renal tubules are excessive myoglobin (oxygen-transporting  substance in muscles) and hemoglobin. Necrosis and tubular  cell apoptosis caused by nephrotoxins are usually uniform and    limited to the proximal tubules. The high surface area of the  brush border (microvilli) of the proximal tubular cells and the  reabsorption properties of epithelial cells make them more vul-  nerable to toxic injury.!°   Postrenal acute kidney injury is rare and usually occurs  with urinary tract obstruction that affects the kidneys bilater-  ally (e.g., bilateral ureteral obstruction, bladder outlet obstruc-  tion-prostatic hypertrophy, tumors or neurogenic bladder,  and urethral obstruction). The obstruction causes an increase  in intraluminal pressure upstream from the site of obstruction  with a gradual decrease in GFR. A pattern of several hours of  anuria with flank pain followed by polyuria is a characteristic  finding. This type of AKI can occur after diagnostic catheter-  ization of the ureters, a procedure that may cause edema with  obstruction of the tubular lumen.   Oliguria (less than 400 ml of urine output per day) can  occur in AKI, and three mechanisms have been proposed to  account for the decrease in urine output. All three mechanisms  probably contribute to oliguria in varying combinations and  degrees throughout the course of the disease (Figure 38-11).  These mechanisms are as follows!“*:   1. Alterations in renal blood flow. Efferent arteriolar vaso-  constriction may be produced by intrarenal release of  angiotensin II or by redistribution of blood flow from the  cortex to the medulla. Autoregulation of blood flow may  be impaired, resulting in decreased GFR. Changes in glo-  merular permeability and decreased GFR also may result  from the ischemia.   2. Tubular obstruction. Advanced injury with necrosis of the  tubules causes sloughing of cells, cast formation, or ische-  mic edema that results in tubular obstruction, which in  turn causes a retrograde increase in pressure and reduces  the GFR. Renal failure can occur within 24 hours.   3. Backleak. Glomerular filtration remains normal, but  tubular reabsorption or “leak” of filtrate is accelerated as  a result of permeability caused by ischemia and increased  tubular pressure from obstruction.   CLINICAL MANIFESTATIONS. The clinical progression of acute  kidney injury, particularly acute tubular necrosis, occurs in  three phases: initiation phase, maintenance phase, and recov-  ery phase. The initiation phase is the phase of reduced perfu-  sion or toxicity in which renal injury is evolving, usually lasting  24 to 36 hours. Prevention of injury is possible during this  phase. The maintenance or oliguric phase is the period of estab-  lished renal injury and dysfunction after the initiating event  has been resolved and may last from weeks to months. Urine  output is lowest during this phase, and serum creatinine, blood  urea nitrogen, and serum potassium levels increase; metabolic  acidosis develops; and there is salt and water overload. The  recovery phase is the interval when renal injury is repaired and  normal renal function is reestablished. GFR returns toward  normal but the regenerating tubules cannot concentrate the fil-  trate. Diuresis is common during this phase, with a decline in  serum creatinine and urea levels and an increase in creatinine  clearance. Polyuria can result in excessive loss of sodium, potas-  sium, and water. Fluid and electrolyte balance requires careful  maintenance.    FIGURE 38-11 Acute Kidney Injury and Mechanisms of Oliguria. ADH, Antidiuretic hormone; GFR, glomerular filtra-    Oliguria begins within 1 day after a hypotensive event and  lasts for 1 to 3 weeks, but it may regress in several hours or  extend for several weeks, depending on the duration of ische-  mia or severity of toxic injury and the initiation of treatment.  Anuria (urine output less than 50 ml/day) is uncommon in  ATN, and 10% to 20% of cases have nonoliguric failure. Anuria  involves both kidneys and suggests bilateral renal artery occlu-  sion, obstructive uropathy, or acute cortical necrosis. Non-  oliguric renal failure usually represents less severe injury and  is associated with toxin exposure or drug toxicity. The renal  tubules have impaired reabsorption and concentration and  dilution function. The urine output may be greater than 2 L  per day, but the BUN and plasma creatinine concentrations  increase.   Other early manifestations depend on the underlying cause  of renal failure. Individuals who have experienced trauma or  surgery or people in a catabolic state may have more rapid  elevations in BUN level. They are prone to hyperkalemia and  metabolic acidosis related to decreased potassium level and  hydrogen excretion. Renal phosphate excretion is decreased,  causing hyperphosphatemia. Fluid retention may cause edema.  Symptoms of congestive heart failure develop in persons with  cardiac disease. Nausea, vomiting, and fatigue accompany ure-  mia and electrolyte imbalances. Wound healing is delayed, and  the risk of infection, particularly pneumonia, is greater. Non-  oliguric renal failure generally has a better prognosis because  of fewer complications and regeneration of the tubular epithe-  lium. Individuals with oliguria may require maintenance dialy-  sis to attenuate symptoms of renal failure.   As renal function improves during the recovery phase,  increase in urine volume (diuresis) is progressive. During the  early diuretic phase the tubules are still recovering secretory    and reabsorptive function. Sodium and potassium are lost  in the urine, and the risk for hypokalemia is greater. Volume  depletion may ensue, with fluid losses of 3 to 4 L/day. Fluid and  electrolyte balance must be carefully monitored and excessive  urinary losses replaced. Return to normal status may take 3 to  12 months. Approximately 30% of individuals do not have full  recovery of a normal GFR or tubular function and progress to  end-stage kidney disease.'*°   EVALUATION AND TREATMENT. The diagnosis of AKI is related to  the cause of the disease. The history can help distinguish the  different etiologies of AKI. Prerenal causes are associated with a  history of blood volume depletion or other causes of poor kid-  ney perfusion (e.g., shock, heart failure, renal artery thrombi).  Intrinsic causes include exposure to nephrotoxins and infec-  tion. Postrenal causes are associated with obstructive uropathies  (e.g., an enlarged prostate or stones). The diagnostic challenge  is to differentiate prerenal acute renal injury from acute tubu-  lar necrosis. Urine composition may provide helpful diagnostic  clues to changes in tubular function (Table 38-11).   The ratios of the BUN to plasma creatinine concentration  and fractional excretion of sodium (the ratio of filtered sodium  to excreted sodium) are helpful diagnostic indicators because  the tests reflect renal tubular reabsorption ability. In prerenal  AKI, tubular function is maintained and salt, water, and urea  are reabsorbed. With ATN, reabsorption and urinary concen-  tration abilities are compromised. Other causes of renal failure  also may exhibit similar clinical findings. Cystatin C, a serum  protein constantly produced by nucleated cells, is freely filtered  by the glomerulus, and its concentration can serve as a measure  of GFR and may be useful for detecting early changes in glo-  merular filtration rate.'*° Serial measurements of plasma creati-  nine concentration provide an index of renal function during   FEna <1% (also seen in acute glomerulonephritis  Urine sediment Usually no cells, some hyaline casts   >1% (also seen in urinary tract obstruction and renal parenchymal disease)  Brown granular casts, epithelial cells    ATN, Acute tubular necrosis; BUN, blood urea nitrogen; FEj,, fractional excretion of sodium.    the recovery phase. However, changes in serum creatinine level  occur only if more than 50% of glomerular filtration is lost  and are often delayed by more than 24 hours. Such diagnostic  delays make the implementation of early therapy very difficult,  contributing to disease progression and mortality. Advances  are being made in the use of biomarkers that allow assessment  of kidney injury before elevation of serum creatinine level  (see What’s New? Biomarkers and Acute Kidney Injury).   Prevention of AKI and maintenance of renal perfusion  involve maintenance of fluid volume before and after surgery or  diagnostic procedures or when nephrotoxic drugs or contrast  agents are in use. There is no specific treatment for acute renal  failure. The primary goal of therapy, once AKI has occurred, is  to maintain the individual’s life until renal function has recov-  ered. Management principles directly related to physiologic  alterations generally include (1) correcting fluid and electrolyte  disturbances, (2) managing blood pressure, (3) preventing and  treating infections, (4) maintaining nutrition, and (5) remem-  bering that certain drugs or their metabolites are not excreted  and can be toxic. Fluid and electrolyte replacement must be  carefully calculated with consideration of urine losses, insen-  sible losses (up to 1000 ml/day), and production of endogenous  water by oxidation (450 ml/day). Overhydration of patients  dilutes their plasma sodium concentration. Metabolic acidosis  is usually not treated until serum bicarbonate concentration is  less than 15 mEq/L.!*”   Hyperkalemia can be managed by restricting dietary sources  of potassium, using non—potassium-sparing diuretics, or using  cation ion exchange resins, which may be administered orally  or rectally. These resins exchange potassium for another cat-  ion, such as sodium in the bowel, and the potassium is then  excreted attached to the resin. With severe hyperkalemia (more  than 6.5 mEq/L), dialysis may be required or potassium can be  driven back temporarily into the cells by administering glucose  and insulin or by infusing sodium bicarbonate or albuterol.  Glucose metabolism causes potassium to move to the intracel-  lular fluid, and insulin infusions therefore can be effective in  shifting potassium from the extracellular to intracellular space,  along with the transport of glucose, within 30 minutes. (Glu-  cose metabolism is discussed in Chapter 1 and Chapter 21.)  Using sodium bicarbonate to cause alkalemia also shifts potas-  sium into cells in exchange for hydrogen ions. However, use of  sodium bicarbonate in AKI is controversial.'4* Careful moni-  toring of the electrocardiogram for peaking T waves is essential    Rising serum creatinine concentrations and urine output have conventionally  determined evolving acute kidney injury (AKI). However, these changes may  occur 2 to 3 days after the initiating renal insult and delay potentially effective  therapies that are limited to the early stage of injury. New biomarkers are under  investigation that would enhance the differential diagnosis of kidney injury and  dysfunction and provide guidance for very early treatment before a rise in serum  creatinine level. Candidate molecules include neutrophil gelatinase—associated  lipocalin, urinary cystatin C, kidney injury molecule-1, IL-18, renal vanin-1 pro-  tein, and hematopoietic growth factor—inducible neurokinin 1. A recent multi-  center prospective study in the emergency department found levels of urinary  neutrophil gelatinase—associated lipocalin and urinary kidney injury molecule-1  more predictive than serum creatinine level in identifying risk for AKI. Future  research is necessary to clarify whether serial measurements of a specific bio-  marker or the use of a panel of biomarkers may be more useful for diagnosis and  predicting severity and duration of AKI.    Data from Ferguson MA, Waikar SS: Clin Chem 58(4):680-689, 2012;  Nickolas TL et al: J Am Coll Cardio! 59(3):246-255, 2012; Schiffl H,  Lang SM: Mol Diagn Ther 16(4):199-207, 2012; Slocum JL, Heung  M, Pennathur S: Trans/ Res 159(4):277-289, 2012; Vanmassenhove J  et al: Nephrol Dial Transplant 28(2):254-273, 2013.    for individuals with hyperkalemia. Intravenous infusion of  calcium is the most rapid method of treating cardiac effects of  hyperkalemia. Calcium decreases the threshold potential and  reduces the membrane excitability caused by hyperkalemia  (see Chapter 3). Calcium should be used only in emergencies,  however, because hypercalcemia also may cause cardiac arrest.   Azotemia is generally controlled and nutrition maintained  with a low-protein, high-carbohydrate diet. Essential amino  acid replacement can be given orally or parenterally. Adequate  carbohydrate intake slows protein catabolism and helps prevent  release of potassium from cellular breakdown. Because sepsis is  a common serious and potentially fatal complication of renal  failure, observation for signs of infection and early treatment  with antibiotics are necessary. Drug dosage levels may require  adjustment if they are metabolized or excreted by the kidneys.  Recovery may take up to 1 year.   Continuous renal replacement therapy (CRRT [hemodi-  alysis]) (mechanical removal of water, electrolytes, and toxins  from the blood) is indicated for uncontrollable hyperkalemia or  acidosis or severe fluid overload. CRRT is particularly promis-  ing in critically ill people with multiple organ dysfunction or   ncreasing plasma creatinine and urea  Erythropoietin deficiency, anemia  ncreased plasma creatinine and urea  ncreased triglycerides    Adapted from National Kidney Foundation: Chronic Kidney Disease 2006: a guide to select NKF KDOQI guidelines and recommendations, 2006.    Available at www.kidney.org/professionals/kls/pdf/Pharmacist_CPG.pdf.  *Normal glomerular filtration rate in a 70-kg male is about 120 ml/min.  GFR, Glomerular filtration rate; PTH, parathyroid hormone.    sepsis. The timing and optimal dose-response relationships for  CRRT are under investigation.'4?!*°    Chronic kidney disease (CKD) is the progressive loss of renal  function associated with systemic diseases such as hyperten-  sion, diabetes mellitus, systemic lupus erythematosus, or intrin-  sic kidney disease, including kidney stones, acute kidney injury,  chronic glomerulonephritis, chronic pyelonephritis, obstruc-  tive uropathies, or vascular disorders. The National Kidney  Foundation (www.kidney.org/professionals/) defines kidney  damage as a GER less than 60 ml/min/1.73 m? for 3 months or  more, irrespective of cause. Chronic kidney disease is the pre-  ferred terminology and is referenced to declining GFR. The  terms renal insufficiency and chronic renal failure are still often  used to describe declining renal function, but they do not have  the specificity of the stages recommended by the National Kid-  ney Foundation (Table 38-12). CKD decreases filtration and  tubular functions with consequences manifested throughout all  organ systems (Table 38-13).   PATHOPHYSIOLOGY. The kidneys have a remarkable ability to  adapt to loss of nephron mass. Symptomatic changes result-  ing from increased levels of creatinine, urea, and potassium  and alterations in salt and water balance usually do not become  apparent until renal function declines to less than 25% of nor-  mal when adaptive renal reserves have been exhausted.   Different theories have been proposed to account for the  adaptation to loss of renal function. The intact nephron hypoth-  esis proposes that loss of nephron mass with progressive kidney  damage causes the surviving nephrons to sustain normal kidney  function. These nephrons are capable of a compensatory hyper-  trophy and expansion or hyperfunction in their rates of filtration,  reabsorption, and secretion and can maintain adaptive changes  in solute and water regulation in the presence of overall declining    GFR. Although the urine of an individual with chronic kidney  failure may contain abnormal amounts of protein and red and  white blood cells or casts, the major end products of excretion  are similar to those of normally functioning kidneys until the  advanced stages of renal failure when there is a significant reduc-  tion of functioning nephrons.!°! With severe or repeated injury,  epithelial cells have an impaired proliferative response result-  ing in interstitial capillary loss and fibroblast proliferation. The  progressive process of glomerulosclerosis and tubulointerstitial  fibrosis contributes to end-stage kidney disease.!°* The particu-  lar location of kidney damage also can influence loss of kidney  function. For example, tubular interstitial diseases damage pri-  marily the tubular or medullary parts of the nephron, producing  problems such as renal tubular acidosis, salt wasting, and dif-  ficulty diluting or concentrating the urine. When the damage is  primarily vascular or glomerular, proteinuria, hematuria, and  nephrotic syndrome are more prominent. A summary of factors  involved in the progression of chronic kidney disease is outlined  in Table 38-14 and Figure 38-12.   The factors that contribute to the pathogenesis of CKD are  complex and involve the interaction of many cells, cytokines,  and structural alterations. Two factors that have consistently  been recognized to advance renal disease are proteinuria and  angiotensin II activity. Glomerular hyperfiltration and increased  glomerular capillary permeability lead to proteinuria. Protein-  uria contributes to tubulointerstitial injury by accumulating in  the interstitial space and activating complement proteins and  other mediators and cells, such as macrophages, that promote  inflammation and progressive fibrosis.!°> Angiotensin II activ-  ity is elevated with progressive nephron injury. Angiotensin II  promotes glomerular hypertension and hyperfiltration caused  by efferent arteriolar vasoconstriction and also promotes sys-  temic hypertension. The chronically high intraglomerular pres-  sure increases glomerular capillary permeability, contributing  to proteinuria. Angiotensin II also may promote the activity of    Left ventricular hypertrophy, cardiomyopathy, and ischemic  heart disease; hypertension, dysrhythmias, accelerated  atherosclerosis; pericarditis with fever, chest pain, and  pericardial friction rub   Encephalopathy (fatigue, loss of attention, difficulty with  problem solving); peripheral neuropathy (pain and burning  in the legs and feet, loss of vibration sense and deep  tendon reflexes); loss of motor coordination, twitching,  fasciculations, stupor, and coma with advanced uremia    Anorexia, nausea, vomiting; mouth ulcers, stomatitis,  urinous breath (uremic factor), hiccups, peptic ulcers,  gastrointestinal bleeding, and pancreatitis associated  with end-stage renal failure    Increased risk of infection that can cause death; increased  risk of carcinoma    Sexual dysfunction: menorrhagia, amenorrhea, infertility,  and decreased libido in women; decreased testosterone  levels, infertility, and decreased libido in men    Chronic kidney disease-mineral bone disorder: bone  inflammation with fibrous degeneration related to  hyperparathyroidism; bone resorption associated with  vitamin D and calcium deficiency    Fluid overload associated with pulmonary edema and  metabolic acidosis leading to Kussmaul respirations    Extracellular volume expansion and hypersecretion  of renin associated with hypertension; anemia  increases cardiac workload; hyperlipidemia promotes  atherosclerosis; toxins precipitate into pericardium    Reduced erythropoietin secretion and reduced red  cell production; uremic toxins shorten red blood cell  survival and alter platelet function   Suppression of cell-mediated immunity; reduction in  number and function of lymphocytes, diminished  phagocytosis    Control of hyperphosphatemia to reduce hyperparathyroidism;  administration of calcium and aluminum hydroxide  antacids, which bind phosphate in the gut, together with a  phosphate-restricted diet; vitamin D replacement; avoidance  of magnesium antacids because of impaired magnesium  excretion   ACE inhibitors; combination of propranolol, hydralazine,  and minoxidil for those with high levels of renin; bilateral  nephrectomy with dialysis or transplantation   Volume reduction with diuretics that are not potassium  sparing (to avoid hyperkalemia); lipid lowering drugs; blood  pressure—lowering strategies; dialysis   Dialysis; recombinant human erythropoietin (controversial)  and iron supplementation; conjugated estrogens; DDAVP  (1-deamino-[8-c-arginine] vasopressin); transfusion   Protein-restricted diet for relief of nausea and vomiting; Nat*-  based alkali or alkali-inducing food    Glomerular hyperfiltration of protein contributes to tubular intestinal injury by accumulating in the interstitial space and  promoting inflammation and progressive fibrosis.   In chronic renal failure, the GFR falls and the plasma creatinine concentration increases by a reciprocal amount; because  there is no regulatory adjustment for creatinine, plasma levels continue to rise and serve as an index of changing  glomerular function.   As GFR declines, urea clearance increases. (Note: Urea is filtered and reabsorbed and varies with the state of hydration.)   In chronic renal failure, sodium load delivered to nephrons exceeds normal, so excretion must increase; thus less is  reabsorbed. Obligatory loss occurs, leading to sodium deficits and volume depletion. As GFR is reduced, ability to  concentrate and dilute urine diminishes.   Changes in acid-base balance affect phosphate and calcium balance. The major disorders associated with chronic renal    failure are reduced renal phosphate excretion, decreased renal synthesis of 1,25-(OH),-vitamin D3, and hypocalcemia.  Hypocalcemia leads to secondary hyperparathyroidism, GFR falls, and progressive hyperphosphatemia, hypocalcemia,    Lack of erythropoietin and anemia accompany chronic renal failure. Lethargy, dizziness, and low hematocrit are common.  In chronic renal failure, tubular secretion of potassium increases until oliguria develops. Use of potassium-sparing    diuretics also may precipitate elevated serum potassium levels. As disease progresses, total body potassium levels  can rise to life-threatening levels and dialysis is required.    In early renal insufficiency, acid excretion and bicarbonate reabsorption are increased to maintain normal pH. Metabolic    acidosis begins when GFR reaches 30% to 40%. Metabolic acidosis and hyperkalemia may be severe enough to  require dialysis when end-stage renal failure develops.    FIGURE 38-12 Mechanisms Related to the Progression of Chronic Kidney  Disease.    Chronic hyperlipidemia may induce glomerular and tubulointerstitial injury contributing to the progression of chronic    inflammatory cells and growth factors that participate in tubu-  lointerstitial fibrosis and scarring (see Figure 38-12).!>4   CLINICAL MANIFESTATIONS. The clinical manifestations of  chronic kidney disease are often described using the terms azo-  temia and uremia. Azotemia is manifested by increased levels  of serum urea, serum creatinine, and other nitrogenous com-  pounds related to decreasing kidney function. Uremia is a pro-  inflammatory state with many systemic effects known as uremic  syndrome’? and is associated with the accumulation of urea  and other nitrogenous compounds and toxins. Sources of toxins  include the accumulation of end products of protein metabo-  lism, alterations in fluid and electrolytes, metabolic acidosis,  intestinal absorption of toxins produced by gut bacteria, and  results of altered renal hormone synthesis (i.e., anemia, hyper-  phosphatemia, and hypocalcemia). Generally, the symptoms  include hypertension, anorexia, nausea, vomiting, diarrhea or  constipation, malnutrition and weight loss, pruritus, edema,  anemia, and neurologic, cardiovascular disease, and skeletal  changes. The many systemic manifestations associated with ure-  mia are summarized in Table 38-13, p. 1365, and Figure 38-13.    Creatinine is constantly released from muscle and excreted pri-  marily by glomerular filtration. In CKD, as the GFR declines,  the plasma creatinine level increases by a reciprocal amount to  maintain a constant rate of excretion (Figure 38-14). Because  no significant tubular adjustment occurs for creatinine  (i.e., tubular secretion), the plasma levels continue to increase  as the GFR decreases. Therefore, measures of plasma creatinine  can serve as an index of changing glomerular function. The  clearance of urea follows a similar pattern, but urea is filtered    FIGURE 38-13 Common Signs and Symptoms of Kidney Dysfunction (See  Text for Reference Site). (From Goldman L, Schafer Al: Goldman's Cecil medi-  cine, ed 24, Philadelphia, 2012, Saunders; redrawn from Forbes CD, Jackson WF:  Color atlas and text of clinical medicine, ed 3, London, 2003, Mosby.)    2 =A 8 16  Plasma creatinine (mg/dl)  FIGURE 38-14 Plasma Creatinine (P,,) and Glomerular Filtration Rate (GFR).    as well as reabsorbed and varies with the state of hydration; it  is not a good index of GFR. However, as the GFR decreases,  plasma urea concentration also increases.!°°    Fluid and electrolyte and acid-base balances are significantly  disturbed with chronic kidney disease. A summary of electrolyte  and acid-base balance alterations is presented in Table 38-15.  Levels of sodium must be regulated within narrow lim-  its because sodium is the major extracellular solute. In CKD    sodium and water balance is maintained very close to normal  until the development of stage V ESKD. This occurs because  of the increased fractional excretion of sodium, particularly in  the distal nephron, in relation to decreasing GFR. Hormones  including aldosterone, prostaglandins, and natriuretic peptides  also modulate sodium excretion and their levels are elevated  with progressive renal failure. Individual variation in the under-  lying pathology of CKD must be considered in the management  of sodium intake or restriction. Sodium wasting may be pres-  ent with tubulointerstitial causes of CKD and there may also  be extra renal losses of sodium from vomiting, diarrhea, or  fever. Sodium retention is more likely in ESKD particularly in  the presence of nephrotic syndrome or heart failure. Sodium  retention contributes to hypertension, edema, heart failure, and  mortality. Management of salt and water balance requires indi-  vidual assessment, and both hyponatremia and hypernatremia  require management.!°”   The regulation of water balance and osmolality is normally  achieved by urinary concentration mediated by antidiuretic  hormone (ADH). As GER is reduced, ability to concentrate and  dilute the urine diminishes. In earlier stages of renal failure, this  may be caused by osmotic diuresis produced by increased frac-  tional excretion of solutes by the remaining nephrons or by a  decreased tubular response to ADH. Individual nephrons can  maintain water balance until severe renal failure occurs and GFR  declines to 15% to 20% of normal with extensive loss of neph-  ron and tubular function. At this stage the urinary concentration  becomes fixed and approaches that of the plasma at 285 mOsm/L  with a specific gravity of about 1.010.   Urinary excretion of potassium is related primarily to dis-  tal tubular secretion mediated by aldosterone and sodium-  potassium adenosine triphosphatase (see Chapter 3). In renal  failure there is increased tubular secretion that provides effec-  tive regulation until the onset of oliguria. With hyperkalemia  larger amounts of potassium can be eliminated through the  bowel.!°°   Although nonoliguric patients can maintain potassium excre-  tion with normal dietary intake, they are more prone to develop  hyperkalemia with increased loading (i.e., use of salt substitutes).  Use of potassium-sparing diuretics, such as spironolactone  (aldactone), volume depletion, acute infection, severe acidosis,  or marked hyperglycemia also may precipitate elevated levels of  serum potassium.!°? With progression of disease to end-stage  renal failure (ESRF), total body potassium can increase to life-  threatening levels and must be controlled by dietary restriction,  loop diuretics, cation exchange resins, and dialysis. Severe acute  hyperkalemia is treated with intravenous calcium gluconate,  intravenous dextrose and insulin, and nebulized or intravenous  salbutamol (sympathetic beta, agonist, promotes Na*-K*-  ATPase pump and intracellular movement of potassium). Renal  replacement therapy may be required (support of renal function  using hemodialysis or peritoneal dialysis).'°°   The intake of a normal diet produces 50 to 100 mEq of hydro-  gen per day. These ions are secreted from the renal tubules and  excreted in the urine combined with phosphate and ammonia  buffers (buffering is described in Chapter 3). Metabolic acidosis  (Chapter 3) develops when GFR decreases to less than 20% to 25%    TABLE 38-15 ELECTROLYTE AND ACID-BASE ALTERATIONS OF CHRONIC KIDNEY DISEASE  FACTOR CHARACTERISTICS    Sodium and water balance In chronic renal failure, sodium load delivered to nephrons exceeds normal, so excretion must increase; thus less is  reabsorbed. Obligatory loss occurs, leading to sodium deficits and volume depletion. As GFR is reduced, ability to  concentrate and dilute urine diminishes.   The major disorders associated with chronic renal failure are reduced renal phosphate excretion, decreased renal  synthesis of 1,25-(0H),-vitamin D3 (calcitriol), and hypocalcemia.   Hypocalcemia leads to secondary hyperparathyroidism, GFR falls, and progressive hyperphosphatemia,  hypocalcemia, and dissolution of bone result.   In chronic renal failure, tubular secretion of potassium increases until oliguria develops. Use of potassium-sparing  diuretics also may precipitate elevated serum potassium levels. As disease progresses, total body potassium  levels can rise to life-threatening levels and dialysis is required.   In early renal insufficiency, acid excretion and bicarbonate reabsorption are increased to maintain normal pH.   Metabolic acidosis begins to develop when GFR decreases to 30% to 40% of normal. When end-stage renal failure  develops, the metabolic acidosis may be severe enough to require dialysis.    of normal. The causes of acidosis are primarily related to  decreased hydrogen ion elimination and decreased bicarbonate  reabsorption. With end-stage renal failure, metabolic acidosis  may be severe enough to require alkali therapy and dialysis.  Bicarbonate levels should be maintained at about 22 mEq/L.!°   Bone and skeletal changes develop with alterations in calcium  and phosphate metabolism (Table 38-16). These changes begin  when the GFR decreases to 25% or less. Hypocalcemia is accel-  erated by impaired renal synthesis of 1,25-dihydroxy-vitamin  D; (calcitriol) with decreased intestinal absorption of calcium.  Renal phosphate excretion also decreases and the increased  serum phosphate binds calcium, further contributing to hypo-  calcemia. Acidosis also contributes to a negative calcium bal-  ance. Decreased serum calcium level stimulates parathyroid  hormone secretion with mobilization of calcium from bone and  may cause calcium levels to approach normal. The combined  effect of hyperparathyroidism and vitamin D deficiency can result  in renal osteodystrophies (i.e., osteomalacia and osteitis fibrosa  with increased risk for fractures) (see Chapter 44).!°* Other  consequences of secondary hyperparathyroidism include soft  tissue and vascular calcification, cardiovascular disease, and,  less commonly, calcific uremic arteriolopathy.!”   Osteitis fibrosa, osteomalacia, calcium deposits in soft  tissue (occurs when kidney fails to respond to PTH  secretion because of loss of renal mass and calcium  and phosphate continues to be absorbed from bone)    Protein, carbohydrate, and fat metabolism are altered in chronic  kidney disease (CKD). Proteinuria and a catabolic state contrib-  ute to a negative nitrogen balance. Levels of serum proteins  diminish, including albumin, complement, and transferrin,  and there is loss of muscle mass. Proteinuria may indepen-  dently cause renal damage by promoting tubular inflamma-  tion and fibrosis.!°> The amount of proteinuria is also related  to the extent of renal injury and predicts disease progression.!**  Monitoring of proteinuria using the albumin to creatinine ratio  among all individuals with CKD who are not receiving chronic  dialysis therapy has been recommended as a quality perfor-  mance measure for improving patient outcomes.!°   Hyperinsulinemia and glucose intolerance related to insu-  lin resistance are common and may be related to alterations  in adipokines that interfere with insulin action and oxidative  stress that contribute to renal tubular and vascular injury in  both nondiabetic and diabetic CKD.'°° Hyperparathyroidism  also decreases insulin sensitivity and impairs glucose tolerance.  High levels of adiponectin have been associated with increased  mortality in CKD.!°”   Dyslipidemia is common among individuals with CKD. There  is a high ratio of low-density lipoprotein (LDL) to high-density  lipoprotein (HDL), high levels of triglycerides, and accumulation    of LDL particles with accelerated atherosclerosis and vascular cal-  cification. Uremia causes a deficiency in lipoprotein lipase and  decreased hepatic triglyceride lipase. Decreased lipolytic activity  results in a reduction in HDL level. Apolipoprotein B concentra-  tion is also elevated, thereby accelerating atherogenesis. !°*!    Cardiovascular disease (Chapter 32) is a major cause of morbid-  ity and mortality in CKD. Proinflammatory mediators, oxidative  stress, altered vitamin D metabolism, and metabolic derange-  ments are significant contributors. Declining erythropoietin  production causes anemia, which reduces oxygen delivery to  the myocardium. Elevated renin level stimulates the secretion  of aldosterone, increasing sodium and water reabsorption.  Hypertension is the result of excess sodium and fluid volume.  Dyslipidemia occurs early in CKD. Arterial wall thickness  increases with decreased elastic fibers and increased extracellular  matrix. Atheromatous plaque and arterial calcification contrib-  ute to loss of vessel elasticity and obstruction and are accelerated  by the oxidative stress of CKD. Macrovascular disease is respon-  sible for increased risk for ischemic heart disease, left ventricu-  lar hypertrophy, congestive heart failure, stroke, and peripheral  vascular disease in individuals with uremia.!’? Endothelial cell  dysfunction and calcium deposits lead to a loss of vessel elastic-  ity and vascular calcification.'’! The resulting vascular disease  increases the risk for ischemic heart disease, left ventricular hyper-  trophy, congestive heart failure, stroke, and peripheral vascular  disease in individuals with uremia. Pericarditis can develop from  inflammation caused by the presence of uremic toxins. Accu-  mulation of fluid in the pericardial space can compromise ven-  tricular filling and cardiac output.    Pulmonary edema results from fluid overload and congestive  heart failure. Dyspnea is common in ESKD. Metabolic acidosis  can cause Kussmaul respirations.    Hematologic alterations include normochromic normocytic ane-  mia, impaired platelet function, and hypercoagulability. Inad-  equate production of erythropoietin decreases red blood cell  production and is the most significant factor in contributing to  anemia. Chronic inflammation, iron deficiency, and decreased  half-life of erythrocytes are also contributing factors. Anemia  contributes to decreased tissue oxygenation and contributes to  progression of kidney disease. Low levels of hemoglobin and  symptoms of anemia, such as lethargy, weakness, and dizziness,  are common findings. Treatment of anemia includes erythro-  poiesis stimulating agents (i.e., recombinant human erythro-  poietin) and intravenous iron.!”7   Disorders of hemostasis in CKD are primarily related to  defective platelet aggregation and impaired adhesion of platelets  to the vascular endothelium. The consequence is an increased  bleeding tendency manifested by bruising, epistaxis and other  mucosal bleeding, gastrointestinal bleeding, and cerebrovascu-  lar hemorrhage.!7*'!”4 Adequate dialysis improves platelet func-  tion. Alterations of individual clotting factors, fibrin, thrombin,    and fibrinolysis contribute to alterations of blood coagulation  and can promote a hypercoagulable state and thrombosis with  increased risk for myocardial infarction and stroke.!7>!”°    Immune system dysregulation with immune suppression,  deficient response to vaccination, and increased risk for infec-  tion develops with CKD. Chemotaxis, phagocytosis, antibody  production, and cell-mediated immune responses are sup-  pressed.'7” Malnutrition, metabolic acidosis, hyperglycemia, or  effects of hemodialysis may amplify immunosuppression.   Neurologic symptoms are common and progressive with CKD  and are related to uremic toxicity, chronic hyperkalemic depo-  larization, and anemia.'7* Symptoms may include headache,  drowsiness, pain, sleep disorders, impaired concentration,  memory loss, and impaired judgment. Neuromuscular irrita-  tion can cause hiccups, muscle cramps, and muscle twitching.  In advanced stages of renal failure, symptoms may progress  to seizures and coma. Peripheral neuropathies also develop  with impaired sensations, decreased tendon reflexes, muscle  weakness, and muscle atrophy, most commonly in the lower  extremities.   Gastrointestinal complications are common in individuals with  CKD. Uremic gastroenteritis can cause bleeding ulcer and sig-  nificant blood loss. Nonspecific symptoms include anorexia,  nausea, vomiting, and constipation or diarrhea. Uremic fetor  is a form of bad breath caused by the breakdown of urea by  salivary enzymes. Malnutrition is common.    Endocrine and reproductive alterations develop with progres-  sion of CKD. Males and females have a decrease in the levels  of circulating sex steroid hormones. Males often experience  a reduction in testosterone levels and may be impotent. Oli-  gospermia and germinal cell dysplasia can result in infertility.  Females have reduced estrogen levels, amenorrhea, and dif-  ficulty maintaining a pregnancy to term. A decrease in libido  occurs in both genders. !7!®°   Insulin resistance is common in uremia. Low-grade systemic  inflammation and oxidative stress may be contributing factors  with increased risk for cardiovascular disease. As CKD pro-  gresses the ability of the kidney to degrade insulin is reduced,  and the half-life of insulin is prolonged. Individuals with dia-  betes mellitus and CKD need to carefully manage their insu-  lin dosages. Low-protein diets and renal replacement therapy  improve insulin sensitivity. !°1)1°?   CKD also causes alterations in thyroid hormone metabolism  and low thyroid hormone levels and is known as nonthyroi-  dal illness syndrome (euthyroid sick syndrome). Low-grade  inflammation and oxidative stress may be contributing fac-  tors.!®> Uremia also reduces conversion of T; to T,.!*° A low-  protein, low-phosphorus diet may improve thyroid hormone  function.'**    Skin changes are associated with other complications that  develop with CKD. Anemia can cause pallor and bleeding into  the skin and results in hematomas and ecchymosis. Retained  urochromes manifest as a sallow skin color. Hyperparathyroid-  ism and uremic skin residues (known as uremic frost) are asso-  ciated with irritation and pruritus with scratching, excoriation,  and increased risk for infection.'*°   EVALUATION AND TREATMENT. Early screening and evaluation of  CKD are based on risk factors, history, presenting signs and symp-  toms, and diagnostic testing.'®° Prediction equations are used  for estimating GFR from serum creatinine values or creatinine  clearance may be completed. Markers of kidney damage include  urine protein, particularly albumin, and examination of urine  sediment. New biomarkers for predicting progression of CKD are  being evaluated.'*” Ultrasound, CT scan, or plain x-ray films will  show small kidney size. Renal biopsy confirms the diagnosis.   Management involves dietary control, including management  of protein intake, vitamin D supplementation, sodium and fluid  maintenance, potassium restriction, adequate caloric intake, man-  agement of dyslipidemias, and erythropoietin as needed'**:!*? (see  Nutrition & Disease: Chronic Kidney Disease). ACE inhibitors or  receptor blockers are often used to control systemic hypertension  and provide renoprotection, particularly in the presence of dia-  betes mellitus.!°'?! ESKD related to diabetic nephropathy can  be significantly reduced with control of hyperglycemia, hyper-  tension, and hyperlipidemia.!*!'°? ESKD is treated with dialysis,  supportive therapy, and renal transplantation.    The malnutrition-inflammation complex syndrome or protein-energy wasting  is a common condition associated with renal failure and leads to acceler-  ated atherosclerosis and cardiovascular disease and increased mortality for  individuals on maintenance dialysis. Elevated levels of leptin, ghrelin, and  inflammatory cytokines, including interleukin-6, tumor necrosis factor-alpha,  and interferon, suppress appetite and cause muscle proteolysis, decreased  protein assimilation, and hypoalbuminemia. Reduced renal function, oxida-  tive stress, decreased levels of antioxidants, infection, exposure to dialysis  tubing and membranes during hemodialysis, and back-filtration of contami-  nants during hemodialysis contribute to inflammation. Acidosis also acts  synergistically with inflammatory cytokines and insulin resistance to promote  mitochondrial dysfunction and protein catabolism. The provision of nutrients,  including adequate calories along with protein supplementation that includes  amino acids, in the form of intradialytic parenteral nutrition or enteral feed-  ing during dialysis, assists a person to meet the metabolic requirements.  Dietary supplements of antioxidants, such as vitamins A and C, selenium, and  carotinoids, are required. Low-protein, low-phosphorous, and low-sodium  diets assist with reducing proteinuria, preventing hyperphosphatemia and  secondary hyperparathyroidism, and lowering blood pressure. The vegetarian  nature of renal diets may improve lipid profiles. Adequate nutritional support  promotes renal recovery and may prevent consequences of muscle weakness  and immune dysfunction.    Data from Aparicio M et al: J Ren Nutr 22(2 Suppl):S1-S21, 2012;  Garibotto G, Bonanni A, Verzola D: Curr Opin Clin Nutr Metab Care  15(1):78-84, 2012; Guarnieri G, Barazzoni R: J Ren Nutr 21(1):2-6,  2011; Oner-lyidogan Y et al: J Ren Nutr 21(4):316-321, 2011.   1. Obstruction can occur anywhere in the urinary tract, and  may be anatomic or functional, including renal stones,  tumors, an enlarged prostate gland, or urethral strictures.  The most serious complications are hydronephrosis, hydro-  ureter, ureterohydronephrosis, and infection caused by the  accumulation of urine behind the obstruction.   2. Compensatory hypertrophy and hyperfunction of the  opposite kidney compensate for loss of function of the kid-  ney with obstructive disease.   3. Relief of obstruction is usually followed by postobstructive  diuresis and may cause fluid and electrolyte imbalance.   4. Kidney stones are caused by supersaturation of the urine  with precipitation of stone-forming substances, changes  in urine pH, or urinary tract infection. Most stones are  unilateral.   5. The most common kidney stone is formed from calcium  oxalate and most often causes obstruction by lodging in the  ureter.   6. Obstructions of the bladder are a consequence of neuro-  genic or anatomic alteration of the bladder or both.   7. Aneurogenic bladder is caused by a neural lesion that inter-  rupts innervation of the bladder.   8. Upper motor neuron lesions above the pontine micturition  center result in detrusor hyperreflexia and uninhibited or  reflex bladder.    9. Upper motor neuron lesions between C2 and S1 result in over-  active or hyperreflexive bladder function and vesicosphincter  dyssynergia (lack of coordinated neuromuscular contraction).   10. Lower motor neuron lesions below S1 result in detrusor are-  flexia with underactive, hypotonic, or atonic bladder function.   11. OAB syndrome is an uncontrollable or premature contrac-  tion of the bladder that results in urgency with or without  incontinence, frequency, and nocturia.   12. Anatomic obstructions to urine flow include prostatic enlarge-  ment, urethral stricture, and pelvic organ prolapse in women.   13. Partial obstruction of the bladder can result in overac-  tive bladder contractions with urgency. There is deposi-  tion of collagen in the bladder wall over time, resulting in  decreased bladder wall compliance and ineffective detrusor  muscle contraction.   14. Renal cell carcinoma is the most common renal neoplasm.  The larger neoplasms tend to metastasize to the lung, liver,  and bone.   15. Bladder tumors are commonly composed of transitional cells  with a papillary appearance and a high rate of recurrence.    Urinary Tract Infection  1. UTIs are commonly caused by the retrograde movement  of bacteria into the urethra and bladder. UTIs are uncom-  plicated when the urinary system is normal or complicated  when there is a defect or abnormality.    include high osmolality and acidic pH of urine, mucus,  Tamm-Horsfall and other antimicrobial proteins that acti-  vate the immune response, sphincters that prevent reflux,  and urine flow that washes out bacteria.    promote binding to the uroepithelium. Formation of bio-  films enhances colonization and resists host defenses and  antimicrobial therapy.    caused by bacteria and may be acute or chronic. Manifes-  tations of frequency, urgency, and dysuria are caused by  inflammation.    nonbacterial infectious cystitis (viral, mycobacterial,  chlamydial, fungal), noninfectious cystitis (ie., radiation  injury), and interstitial cystitis, which is probably related  to autoimmune injury.    the renal pelvis often related to ascending infection and  obstructive uropathies and may cause abscess formation  and scarring with an alteration in renal function.    Glomerular disorders are a group of related diseases of the  glomerulus that can be primary and are caused by immune  injury, infection, ischemia, toxins or drugs, or vascular dis-  orders or, secondarily, caused by systemic diseases.    matory damage to the glomerulus as a consequence of  immune reactions including deposition of circulating  immune complexes, antibodies reacting in situ to planted  antigens, and antibodies directed against the glomerular  basement membrane.    (nephrotic sediment) or have red and white blood cells and  protein (nephritic sediment).    ciated with immune complex deposition in the glomerulus  or in situ formation.    tibodies against double-stranded DNA (dsDNA) and  nucleosomes in the glomerulus, causing inflammation and  injury.    gial cells in the glomerulus resulting in injury and mesan-  gial proliferation.    . RPGN is associated with injury that results in the prolif-    eration of glomerular capillary endothelial cells and a rapid  loss of renal function.    Membranoproliferative glomerulonephritis involves mesan-  gial cell proliferation, complement deposition, and crescent  formation.   Chronic glomerulonephritis is related to a variety of dis-  eases that cause deterioration of the glomerulus and a pro-  gressive loss of renal function over a period of months to  years, including diabetic nephropathy and lupus nephritis.   Diabetic nephropathy develops from metabolic, inflam-  matory, and microvascular complications associated with  chronic hyperglycemia.   Lupus nephritis is caused by the formation of autoantibod-  ies against dsDNA and nucleosomes in the glomerulus,  causing inflammation and injury.   Nephrotic syndrome is the excretion of at least 3.5 g of  protein (primarily albumin) in the urine per day primar-  ily because of glomerular injury with increased capillary  permeability and loss of membrane negative charge. The  principal signs are hypoproteinemia, hyperlipidemia, and  edema. The liver cannot produce enough protein to ade-  quately compensate for urinary loss.    AKI is the sudden decline in kidney function with decreased  glomerular filtration and an increase in serum creatinine  and BUN levels.    or postrenal and is usually accompanied by oliguria with  elevated plasma BUN and plasma creatinine levels.    . Prerenal acute renal failure is caused by decreased renal per-    . Oliguria is a urine output of less than 400 ml per day and can be    caused by alterations in renal blood flow, tubular obstruction,  or tubular fluid backleak, or by a combination of these events.    Chronic kidney disease is a progressive loss of renal func-  tion. Plasma creatinine levels gradually become elevated  as GFR declines, sodium is lost in the urine, potassium is  retained, acidosis develops, calcium metabolism and phos-  phate metabolism are altered, and erythropoietin produc-  tion is diminished. All organs systems are affected by CRF.    stitial inflammation and fibrosis contribute to the progres-  sion of chronic kidney disease. Proteinuria and angiotensin  II promote the pathologic changes of chronic renal injury.    mulation of urea and other nitrogenous compounds as well  as toxins and alterations in fluid, electrolyte, and acid-base  balance that result from chronic kidney failure. All organ  systems are affected and contribute to disease symptoms.    1. 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Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Structure and Function of the Urinary System in Children, 1376  Development of the Urinary System, 1376  Fluid and Electrolyte Balance in Children, 1377    Renal and urinary disorders occur in children as well as adults.  In childhood, however, the kidney and genitourinary structures  are continuing to develop, so renal dysfunction may be asso-  ciated with mechanisms and manifestations that are different  from those in adults. In addition, some renal and urinary dis-  orders are congenital and involve structural anomalies of the  kidney and urinary drainage system.   The embryonic urinary system develops as three sets of sequen-  tially replaced organs: the pronephros, mesonephros, and  metanephros. The pronephros is a nonfunctional structure  that arises at the level of the cervical and upper thoracic regions  during the third fetal week and connects the primitive wolffian  duct to the cloaca as the foundation for male sexual develop-  ment (Figure 39-1). The development of the mesonephros and  metanephros is described in Figure 39-1. The Wilms tumor 1  (WT1) gene plays an important role at all stages of kidney devel-  opment and maintenance of kidney function. The wingless type    Alterations in Renal and Bladder Function in Children, 1378  Congenital Abnormalities, 1378  Glomerular Disorders, 1381  Kidney Injury, 1385  Wilms Tumor, 1385  Bladder Disorders, 1386  Urinary Incontinence, 1388   After glomeruli and tubules form, the tissues organize and  progressively differentiate over approximately 30 days. Initial  glomerular development is staggered, so there are glomeruli in  various stages. In fact, a few of the first glomeruli formed degen-  erate and disappear during the later stages of fetal development.  Progressive development continues into the ninth fetal month,  when all metanephrogenic tissue then disappears.   As the embryo develops and the vertebral column straightens,  the kidneys appear to ascend to the sacral area at about 6 weeks,  to the third lumbar area by the third month, and to the first lum-  bar area at term. The kidneys rotate 90 degrees as they ascend  so that renal tissue is lateral and the collecting system is medial.   While the kidneys mature, the cloaca becomes the urogenital  sinus. It then differentiates into the vesicourethral canal, which  forms the bladder and the upper urethra, and the urogenital  sinus, which forms the main part of the urethra.   At birth the kidneys occupy a large portion of the posterior  abdominal wall, and the ureters are proportionately shorter  than those of an adult. All the nephrons are present at birth,  and their number does not increase as the kidney grows and    CHAPTER 39 Alterations of Renal and Urinary Tract Function in Children    FIGURE 39-1 Embryonic Development of the Kidneys. The mesonephros begins development more caudally about  the fourth fetal week and begins excretory function in the sixth week. Most of the mesonephros degenerates and disappears  by the end of the embryonic period. The metanephros, the permanent kidney, arises distal to the bifurcation of the aorta and  develops from two different sources: (1) the ureteric bud(metanephric duct) forms as an outgrowth of the mesonephritic (wolff-  ian) duct and grows dorsocranially and starts subdividing to become the collecting system for the kidneys by forming the ureter,  renal pelvis, and calyces; by the fifth fetal month it will have progressively branched into the collecting ducts; and (2) the meta-  nephrogenic mesenchyme sits atop the terminal branches of the collecting ducts and develops into primitive glomeruli and  uriniferous tubules (A). Genetic information from the metanephrogenic mesenchyme guides the development of the ureteric  bud. Establishing the connection between the uriniferous tubules and the collecting ducts is a vital part of kidney development;  errors in this stage can result in polycystic kidneys. As the embryo grows, the definitive kidneys migrate from the caudal posi-  tion to the lumbar region and the ureters connect with the bladder (B-D). In the 8-week male embryo, the wolffian duct begins  to give rise to the epididymis, the seminal vesicles, and the caudal part of the vas deferens (C). The external genitalia develop  between 8 and 16 weeks, and testicular descent begins in month 7 of gestation (D). (From Goldman L, Schafer Al: Goldman's    matures. The kidney reaches adult size by adolescence and,  because of maturation of the tubular system, increases in weight  10-fold from the time of birth.   Urine formation and excretion begin by the third month  of gestation, contributing to the amniotic fluid. In infancy  the bladder lies close to the abdominal wall, making urinary  bladder aspiration for diagnostic purposes a relatively simple  procedure. The bladder descends into the pelvis with growth,  changing from a cylindrical organ to the adult pyramidal shape.  Although small amounts of urine are found in the bladder at  birth, the newborn may not void for 12 to 24 hours.   Immediately at birth the renal blood flow and glomerular  filtration rate (GFR) increase because of a decrease in vascular    resistance and the need to perform excretory functions no lon-  ger performed by the placenta. Renal vascular resistance remains  higher in newborns and infants, however, which may be attrib-  uted to increased levels of circulating renin. The resistance pro-  gressively declines during the first year of development, with an  increasing fraction of the cardiac output going to the kidney.  The GFR continues to increase, achieving adult levels by 2 years  of age.   Because the kidney develops from the center toward the periph-  ery, renal distribution of blood flow during the newborn period is  primarily to the renal medulla. The result is a preferential flow to    the medullary nephrons, which have comparatively short loops at  this stage of development. The combination of higher blood flow  and shorter loops produces a more dilute urine—approximately  600 to 700 mOsm (compared with 800 to 1200 mOsm in adults)  (see Chapter 3). The immature kidney is also less responsive to  the actions of antidiuretic hormone (vasopressin) (see Figure  3-5).° The dilute urine is accentuated by a low rate of urea excre-  tion, which is necessary to establish the concentration gradient in  the medulla. Urea excretion is low primarily because infants are  in a high anabolic state and use their protein for growth.   Because of a high hydrogen ion concentration, limited abil-  ity to regulate the internal environment, and lowered osmotic  pressure, the infant’s renal system has a narrow chemical  safety margin. The immaturity and smaller surface area of the  tubules also may diminish the water reabsorption response to  antidiuretic hormone (ADH). An immature tubular transport  capacity means that the ability to excrete a potassium load,  reabsorb bicarbonate, or buffer hydrogen with ammonia does  not become efficient until approximately 2 years of age. Conse-  quently, any disturbance such as diarrhea, infection, fasting for  diagnostic tests, or improper feeding can rapidly lead to severe  acidosis and fluid imbalance because the infant can rapidly  develop over- or underhydration, or edema (see Chapter 3).*   After birth the proportion of total body water to body weight  does not change markedly. Considerable change occurs, how-  ever, in the location of that body water as the child matures  (see Chapter 3). Compared to an adult, the percentage of extra-  cellular fluid volume of the newborn infant is nearly double.  Decrease in extracellular fluid volume occurs in two different  periods of rapid growth—infancy and adolescence.   An infant has not only a greater content of extracellular fluid  but also a greater rate of fluid exchange. The adult consumes  and excretes approximately 2000 ml of water daily, representing  5% of the total body fluid and 14% of the extracellular fluid. In  contrast, the infant’s daily exchange of 600 to 700 ml represents  290% of the total or nearly 50% of the extracellular volume, mak-  ing control of dehydration and overhydration more difficult.   The composition of body fluids differs slightly with age. The  total electrolyte concentration in extracellular fluids is greater in  the newborn than in the adult. The concentrations of sodium,  chloride, phosphates, and organic acids are also greater. The  concentration of bicarbonate ions is lower in the infant than  in the older child, with a mild acidosis evidenced by a lowered  pH. These variations, combined with a lowered plasma protein  level, cause a reduced oncotic pressure of the vascular compartt-  ment and favor accumulation of fluid in the tissue spaces and  an increased GFR. In the healthy child these differences remain  for a few weeks or months. The premature infant and the nor-  mal newborn infant are usually in a state of well-compensated  acidosis and potential edema.    Congenital abnormalities of the kidney and urinary tract occur  in about 1 out of 500 newborns.” Structural abnormalities range    from minor, nonpathologic, or easily correctable anomalies to  those that are incompatible with life. For example, the kidneys  may fail to ascend from the pelvis to the abdomen, causing  ectopic kidneys—which usually function normally. The kidneys  also may fuse in the midline as they ascend, causing a single  U-shaped horseshoe kidney, with an incidence rate of 0.25 to  0.61 per 10,000 births.° Approximately one third of individuals  with horseshoe kidneys are asymptomatic, and the most com-  mon problems are hydronephrosis, infection, stone formation,  and tumors.’ Collectively, structural anomalies of the renal sys-  tem account for approximately 45% of cases of renal failure in  children.   Some anomalies are obvious at birth, whereas others remain  silent or become apparent in childhood. The following struc-  tural anomalies are commonly associated with urinary tract  malformations’:    Hypospadias  Hypospadias is a congenital condition in which the urethral  meatus is located on the ventral side or undersurface of the  penis. The meatus can be located anywhere on the glans, the  penile shaft, the base of the penis, the penoscrotal junction, or  the perineum (Figure 39-2). This is the most common anom-  aly of the penis and occurs in about 1 in 125 infant boys. The  etiology is multifactorial and related to disruptions in male  hormones, including testosterone biosynthesis defects, steroid  5a-reductase type 2 mutations, genes associated with penile and  urethral development, hormones administered for in vitro fer-  tilization, advanced maternal age, and other environmental fac-  tors.’ Chordee, or penile torsion, may accompany hypospadias.  In chordee a shortage of skin on the ventral surface causes the  penis to bend or to “bow” ventrally (Figure 39-3). Penile torsion  is a counterclockwise twist of the penile shaft. Partial absence of  the foreskin, inguinal hernia, and cryptorchidism (undescended  testes; see Chapter 25) are associated with the anomaly.'°   The goals for corrective surgery on the child with hypospa-  dias are: (1) a straight penis when erect to facilitate sexual inter-  course as an adult, (2) a uniform urethra of adequate caliber  to prevent spraying during urinations, (3) a cosmetic appear-  ance satisfactory to the individual, and (4) repair completed in  as few procedures as possible. Formerly performed in two or  more stages, hypospadias repairs are now done in one stage.  Improvements in microsurgical techniques have enhanced out-  comes and decreased complications and the need for follow-up  surgery. Surgery is usually performed between 4 and 12 months  of age.!!    CHAPTER 39 Alterations of Renal and Urinary Tract Function in Children    i ey Bene  FIGURE 39-2 Hypospadias. (Courtesy H. Gil Rushton, MD, Children’s National Medical Center, Washington, DC; from  Hockenberry MJ, Wilson D: Wong's nursing care of infants and children, ed 9, St Louis, 2011, Mosby.)    FIGURE 39-3 Perineal Hypospadias with Chordee and Partial Penoscro-  tal Transposition. (From Kliegman RM et al, editors: Ne/son textbook of pediat-  rics, ed 19, Philadelphia, 2011, Saunders.)   Epispadias and exstrophy of the bladder are the same congeni-  tal defect but expressed to a different degree. The dorsal urethra  is not fused in epispadias and has failed to form into a tube. In  male epispadias the urethral opening is on the dorsal surface  of the penis. In females a cleft along the ventral urethra usu-  ally extends to the bladder neck. The incidence of epispadias is  about 1 in 40,000 to 118,000 births. About twice as many boys  as girls present with this defect.   In boys the urethral opening may be small and situated  behind the glans (anterior epispadias), or a fissure may extend  the entire length of the penis and into the bladder neck (poste-  rior epispadias). The majority of children with epispadias can  achieve urinary continence, although surgical intervention may  be necessary. !?    FIGURE 39-4 Exstrophy of Bladder. (Courtesy H. Gil Rushton, MD, Chil-  dren's National Medical Center, Washington, DC; from Hockenberry MJ, Wilson D:  Wong's nursing care of infants and children, ed 9, St Louis, 2011, Mosby.)    Exstrophy of the bladder is a rare extensive congenital anom-  aly of herniation of the bladder through the abdominal wall  with failure of the abdominal muscles, pelvic ring, and pel-  vic floor musculature to fuse in the midline (Figure 39-4).  The posterior portion of the bladder mucosa is exposed and  appears bright red. The prevalence of exstrophy of the bladder  is about 2.07 in 100,000 live births. Boys are predominant with  a ratio of about 2:1 and this complication is more common in  whites. !°   Exstrophy of the bladder is caused by intrauterine failure  of the abdominal wall and the mesoderm of the anterior blad-  der to fuse. Urine seeps onto the abdominal wall from the ure-  ters, causing a constant odor of urine and excoriation of the  surrounding skin. The rectus muscles below the umbilicus are  separated, and the pubic rami (bony projections of the pubic  bone) are not joined. The clitoris in girls is divided into two  halves with the urethra between them. The penis in boys is epi-  spadic. In addition, the posterior aspect of the pelvis is exter-  nally rotated, which retroverts the acetabula and causes external  rotation of the feet. This causes a waddling gait when the child    first learns to walk, but most children quickly learn to com-  pensate. Surgical intervention may be required.'* Because the  exposed bladder mucosa becomes hyperemic and edematous,  it bleeds easily and is painful. It should be covered with Silastic  or a plastic dressing (e.g., kitchen plastic wrap) for protection  from diaper irritation while permitting urine drainage. The  unrepaired exstrophic bladder is cosmetically unacceptable and  prone to cancerous changes as soon as | year after birth. Ideally  the bladder and pubic defect should be closed before the infant  is 72 hours old. Surgical reconstruction is usually performed  within the first year either as a complete primary repair or as  staged procedures. Staged procedures may include bladder aug-  mentation and bladder neck and epispadias repair.!° Objectives  of management include preservation of renal function, attain-  ment of urinary control, prevention of infection, reconstructive  repair of the defect, and improvement of sexual function and  quality of life.   Cloacal exstrophy is the most rare and severe form of blad-  der exstrophy. The intestines, genitourinary tract, and spine  may be involved, and reconstruction with restored urine and  fecal control is difficult.    Ureteropelvic junction (UPJ) obstruction is a blockage of the  tapered point where the renal pelvis transitions into the ure-  ter.'° An intrinsic malformation of smooth muscle hypertrophy  and fibrosis produces obstruction in 90% of cases.'7 It is the  most common cause of hydronephrosis in neonates.!® Diagno-  sis is made by ultrasound. Open or endoscopic surgery to relieve  the obstruction occurs if there is decline of renal drainage or  function.'? During infancy or childhood, secondary uretero-  pelvic junction obstruction is caused by kinking or secondary  scarring in the presence of high-grade vesicoureteral reflux.  Children with UPJ obstruction have an increased risk of vesi-  coureteral reflux. Other defects are sometimes associated with  ureteral duplication including complete ureteral duplication  (abnormal growth of two ureters and ureteral orifices drain-  ing a single kidney), incomplete duplication (bifurcation of the  ureter terminates into one ureteral orifice and serves a single  kidney), and ureterocele (cystic dilation of the intravesical ure-  ter). Obstruction of the distant ureter (ureterovesical junction  obstruction) causes dilation of the entire ureter, renal pelvis,  and calyceal system (megaureter). Megaureter can occur when  a short acontractile segment of the ureter develops just above  the ureterovesical junction or from ureteral reflux.?°    Congenital causes of bladder outlet obstruction are rare and  include urethral valves, urethral polyps, and urethral atresia. A  urethral valve is a thin membrane that occludes the urethral  lumen and obstructs urinary outflow in males. It is the most  common cause of congenital lower urinary tract obstruction  and renal failure. Most valves occur in the posterior urethra,  although a few arise from the embryologically distinct anterior  urethra.”! Urethral polyps arising from the prostatic urethra  are rare. Symptoms of polyps may include hematuria; void-  ing issues, such as urinary retention or straining to void; and    dilation of the upper tracts.”* Urethral atresia is absence of the  urethra and is rare.   Congenital urethral valves or polyps can be diagnosed with  prenatal ultrasound and treated with prenatal bladder shunt-  ing or with resection during the first days of life.” Infants with  significant renal (and pulmonary) hypoplasia who are unable  to undergo primary resection may be managed with a vesicos-  tomy, a small opening created between the bladder wall and the  abdomen.”*    Hypoplastic or Dysplastic Kidneys  During embryologic development the ureteric duct grows into  the metanephric tissue, triggering the formation of the kid-  neys. If this growth does not occur, the kidney is absent—a  condition called renal aplasia. A hypoplastic kidney is small  with a decreased number of nephrons. These conditions may  be unilateral or bilateral; the occurrence may be incidental or  familial.~* Bilateral hypoplastic kidneys are a common cause  of chronic renal failure in children. Segmental hypoplasia (the  Ask-Upmark kidney) may be congenital or secondary to vesi-  coureteral reflux.”°   Renal dysplasia usually results from abnormal differentia-  tion of the renal tissues; for example, primitive glomeruli and  tubules, cysts, and nonrenal tissue (such as cartilage) are found  in the dysplastic kidney. Dysplasia may be secondary to antena-  tal obstruction of the urinary tract from ureteroceles, posterior  urethral valves, or prune-belly syndrome (congenital absence of  abdominal muscles).    Renal agenesis (the absence of one or both kidneys) may be  unilateral or bilateral, and may occur randomly or be heredi-  tary. It may be an isolated entity or associated with anomalies  in other organs.*°   Unilateral renal agenesis occurs in approximately 1 of 1000  live births in the United States. Males are more often affected,  and it is usually the left kidney that is absent. The single kid-  ney is often completely normal so that the child can expect a  normal, healthy life. The normal solitary kidney grows because  of compensatory hypertrophy before?’ and after birth. By the  time the child is several years older, the volume of this kid-  ney may approach twice the normal size. In some instances  the single kidney is abnormally formed and associated with  abnormalities of its collecting system.’* Extrarenal congeni-  tal abnormalities are relatively more common with unilateral  renal agenesis.   Bilateral renal agenesis (also called Potter syndrome) is a  rare disorder incompatible with extrauterine life.?” Approxi-  mately 75% of affected infants are male. Bilateral renal agenesis  results from either an abnormal development of the normal  progression from pronephros to mesonephros to metanephros  or an isolated bilateral failure of development of the ureteral  buds. The term Potter syndrome refers to the association with  a specific group of facial anomalies (wide-set eyes, parrot-beak  nose, low-set ears, and receding chin). Oligohydramnios (low  amount of amniotic fluid) leads to underdeveloped lungs.  Affected infants rarely live more than a few hours because    CHAPTER 39 Alterations of Renal and Urinary Tract Function in Children    of pulmonary insufficiency. Approximately 40% of affected  infants are stillborn. Renal agenesis can be detected prenatally  by ultrasound.   Autosomal dominant polycystic kidney disease (ADPKD) is  an inherited disorder that occurs in about 1 in 1000 live births  in the United States. Mutations of two genes, PKD-1 (chromo-  some 16) and PKD-2 (chromosome 4), account for the disease  most often presenting in late childhood or adulthood. The gene  products (polycystins) regulate growth and differentiation of  the tubular epithelium.°’ Defects in the formation of epithelial  cells and their cilium result in cyst formation and obstruction  accompanied by destruction of renal parenchyma, interstitial  fibrosis, and loss of functional nephrons. Cysts may occur in  other organs including the liver, ovaries, and pancreas. Hyper-  tension, heart valve defects, and cerebral and aortic aneurysms  may develop. Urinary tract infection, hematuria, and flank pain  may occur. Diagnosis is usually confirmed by ultrasound. Indi-  viduals may live for decades before developing symptoms of  renal disease and not all progress to end-stage disease.*! Auto-  somal recessive PKD (ARPKD) with cystic changes in the kid-  ney and liver is often first suspected on a prenatal ultrasound.  The gene mutation for ARPKD (PKHD1) encodes a protein  important to maintaining structural integrity and cellular func-  tion of the kidneys and liver. Renal replacement therapy is usu-  ally required during childhood or adolescence. Biomarkers and  therapies to slow the progression of cyst development and renal  failure are being studied.°?    The most common glomerular disorders in children are glo-  merulonephritis, nephrotic syndrome, and hemolytic uremic  syndrome. Most glomerular diseases are acquired and immu-  nologically mediated. The disease can be acute or chronic. The  likelihood of developing renal failure depends on the specific  condition. The most common glomerular disorders in children  are presented below.    Acute glomerulonephritis includes a number of renal disor-  ders in which proliferation and inflammation of the glomeruli  are secondary to an immune mechanism (Table 39-1). (The  major glomerulopathies and their histologic characteristics can  be reviewed in Chapter 38 and Table 38-7.) The symptoms usu-  ally include the sudden onset of hematuria with red blood cell  casts and proteinuria, and can be accompanied by renal salt and  water retention, edema, hypertension, and in severe cases azo-  temia (i.e., decreased glomerular filtration rate). Chronic glo-  merulonephritis is the causative factor for 30% to 50% of renal  failure in children and is the condition responsible for most  school-age and teenage children requiring dialysis and kidney  transplantation.   Acute Poststreptococcal Glomerulonephritis. Acute  poststreptococcal glomerulonephritis (PSGN) is one of the  most common immune complex—mediated renal diseases  in children ages 5 to 15 years and it is representative of acute    glomerulonephritis. It most commonly occurs after a throat  (pharyngitis) or skin (impetigo) infection with nephritogenic  strains of group A beta-hemolytic streptococci, although other  bacteria (e.g., Staphylococcus) and viruses also may be responsible.  Sporadic occurrences of infectious glomerulonephritis have been  observed after bacterial endocarditis, which may be associated  with streptococcal or staphylococcal microorganisms, or  after viral diseases, such as varicella and hepatitides B and C.  Glomerulonephritis develops with the deposition of antigen-  antibody complexes (immunoglobulin G [IgG], IgA, and C;  complement) (see Chapter 8) in the glomerulus or the antigen  may be trapped within the glomerulus and immune complexes  formed in situ.’ The exact mechanism of immune complex  formation is unknown. The immune complexes initiate  inflammation and glomerular injury. Immunofluorescence  microscopy shows lumpy deposits of immunoglobulin (IgG) and  complement (C3) on the glomerular basement membrane (Figure  39-5). The thickened glomerular membrane contributes to  decreased GFR. Activated complement, inflammatory cytokines,  oxidants, proteases, and growth factors attack epithelial cells, alter  membrane permeability, and cause hematuria and proteinuria.  More severe renal disease is observed after a prolonged infection  and before antibiotic therapy. Hypertension occurs primarily  because of fluid retention.*#   Symptoms usually begin 1 to 2 weeks after an upper respi-  ratory tract infection (more common during cold weather)  and up to 6 weeks after skin infections, such as impetigo  (more common during warm, humid weather). The onset of  symptoms in the child is abrupt, varying with disease sever-  ity. The urine is usually smoky brown or cola colored because  of the presence of red blood cells. The child may complain  of flank or midabdominal pain, irritability, general malaise,  and fever. Acute hypertension may cause headache, vomiting,    FIGURE 39-5 Glomerulonephritis. A, Normal glomerulus; note single-contoured walls, patent capillaries, inconspicuous  mesangium, and degree of cellularity. (Periodic acid-methenamine silver stain.) B, Acute postinfectious glomerulonephritis.  There is considerable increase in cellularity, mainly because of accumulation of numerous polymorphonuclear leukocytes in  capillary lumina. Note numerous subepithelial hump-shaped fuchsinophilic deposits in many capillary walls. Protein precipi-  tates (hyalinization) are in the arteriole. (Masson trichrome stain.) C, Postinfectious glomerulonephritis. Irregular mesangial and  capillary wall immunostaining for C3. (From Damjanov |, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.)    somnolence, and other central nervous system (CNS) mani-  festations, including seizures. Cardiovascular symptoms are  related to circulatory overload and are compounded by hyper-  tension. These include dyspnea, tachypnea, and an enlarged,  tender liver. The most severely affected children develop  acute renal failure with oliguria. As many as half the children  affected are asymptomatic. The disease is usually mild and  runs its course in 1 month, but urine abnormalities may be  found up to 1 year after the onset. Less than 5% of children  become oliguric or develop rapidly progressive glomerulone-  phritis, or progress to chronic glomerulonephritis. Prolonged  proteinuria and abnormal GFR indicate an unfavorable prog-  nosis. More than 95% recover completely.   Acute glomerulonephritis (AGN) may be accompa-  nied by a positive throat or skin culture for Streptococcus.  Antistreptolysin-O titers confirm a recent streptococcal  infection. Antihyaluronidase, antideoxyribonuclease B, and  antistreptokinase antibody are other diagnostic markers.  Serum complement level is decreased, and serum creatinine  concentration and blood urea nitrogen level are elevated. The  urine usually contains red blood cells and proteins. Treat-  ment is supportive and symptom specific. For severe disease  oliguria and hypertension are common, and fluid, sodium,  and potassium intakes are restricted. Antihypertensive    medication and diuretic agents may be indicated during the  acute phase.   Henoch-Schénlein Purpura Nephritis. Henoch-Schénlein  purpura (HSP) nephritis (anaphylactoid purpura) is an  immune-mediated IgA vasculitis that affects glomerular blood  vessels, causing inflammation and damage to the vessel wall  (see Chapter 38 for the pathophysiology of IgA nephropathy).  The disease also involves small vessels in the skin and gut.  Classic symptoms of HSP include palpable purpura, arthritis,  abdominal pain, and renal disease characterized by gross or  microscopic hematuria with mild or no proteinuria. Kidney  biopsy demonstrates IgA deposition in the mesangium’*> (see  Table 38-7 in Chapter 38). The development of interstitial  fibrosis and crescent formation from subepithelial immune  deposits along the glomeruli increases the risk of chronic renal  failure.°° Most children recover with supportive care, although  some progress to kidney failure. Severe symptoms require  corticosteroids and other immunosuppressant drugs.*”    Hemolytic uremic syndrome (HUS) is an acute disorder  characterized by microangiopathic hemolytic anemia, throm-  bocytopenia, and renal impairment. It is the most common  community-acquired cause of acute renal failure in young    CHAPTER 39 Alterations of Renal and Urinary Tract Function in Children    children. The disease occurs most frequently in infants and chil-  dren younger than 4 years of age. The prognosis has improved  dramatically in recent years, with more than 90% of children  surviving and most regaining normal renal function.   PATHOPHYSIOLOGY. HUS has been associated with both bacte-  rial and viral agents, as well as endotoxins, especially those from  Escherichia coli 0157:H7 and recently Escherichia coli 0104:H4  (Shiga toxins).** Potential sources of exposure include animals,  unpasteurized beverages, and contaminated meat and vegeta-  bles. The disease also occurs with cancer and use of chemother-  apeutic agents.*” In HUS, verotoxin (Shiga toxin) from E. coli  is absorbed from the intestines into the blood, binds to poly-  morphonuclear leukocytes, and is transported to the kidney,  causing a cascade of effects, including lysis of glomerular capil-  lary endothelial cells, separation of endothelial cells from the  basement membrane, activation and aggregation of platelets,  and activation of the coagulation cascade. The glomerular arte-  rioles become swollen and occluded with platelets and fibrin  clots. There is decreased glomerular filtration, and the damaged  glomerular membrane results in hematuria and proteinuria.  Oliguria with renal failure occurs in up to 50% of children. Nar-  rowed vessels damage passing erythrocytes. These damaged red  blood cells, identified as burr cells, helmet cells, and fragmented  red blood cells, are removed by the spleen, causing acute hemo-  lytic anemia. Fibrinolysis, the process of dissolution of a clot,  acts on precipitated fibrin, causing the fibrin split products to  appear in serum and urine. The platelet clustering within dam-  aged vessels, combined with the damage and removal of plate-  lets, produces thrombocytopenia. Fibrin-rich thrombi can be  found throughout the microcirculation.*° Other tissues, includ-  ing the brain, liver, heart, and intestines, are often involved,  which portends a poorer prognosis.   CLINICAL MANIFESTATIONS. Typical HUS is preceded by a pro-  dromal gastrointestinal (GI) illness with diarrhea (usually  caused by Shiga toxin—producing E. coli) and is known as D+  HUS. Less frequently atypical or sporadic HUS is preceded by  an unknown event or an upper respiratory tract infection and  is known as D— HUS. A rare familial form is associated with  mutations in complement proteins. P-hemolytic-uremic syn-  drome is associated with Streptococcus pneumoniae respiratory  tract infection and is mediated by neuraminidase that injures  glomerular epithelial cells. It occurs without diarrhea. The  onset of D+ HUS occurs about 1 to 2 weeks after a GI illness  with a symptom-free 1- to 5-day period. There is sudden onset  of pallor, bruising or purpura, irritability, and oliguria. Slight  fever, anorexia, vomiting, diarrhea (with the stool character-  istically watery and blood stained—hemorrhagic diarrhea),  abdominal pain, mild jaundice, and circulatory overload are  accompanying symptoms. Seizures and lethargy indicate CNS  involvement. Renal failure is apparent within 2 days to 2 weeks  of onset. The renal failure causes metabolic acidosis, uremia,  hyperkalemia, and often hypertension.   EVALUATION AND TREATMENT. Clinical evaluation includes his-  tory of preexisting illness, presenting symptoms, and urine  and blood analysis. Antibiotics are not used in the initial treat-  ment because they increase Shiga toxin release and increase the  risk of HUS. Management consists of maintaining nutrition    and hydration (to dilute toxins) and controlling hyperten-  sion, hyperkalemia, and seizures.*! When renal failure occurs,  dialysis is indicated. Blood transfusions with packed red blood  cells are needed to maintain reasonable hemoglobin levels.  Most children recover; however, some will develop hyperten-  sion, proteinuria, or renal insufficiency or failure. Death usu-  ally occurs from complications related to CNS or myocardial  involvement.” Preventing Shiga toxin-producing bacterial  infection (i.e., E. coli) prevents HUS.   Nephrotic syndrome is a term used to describe a symptom  complex characterized by proteinuria, hypoalbuminemia,  hyperlipidemia, and edema. The syndrome is more common  in children than adults. When no identifiable cause is found,  the condition is termed primary (idiopathic) nephrotic syn-  drome. If it results from a systemic disease or other causes (e.g.,  drugs, toxins, diabetes mellitus, lupus nephritis) it is called  secondary nephrotic syndrome. Primary nephrotic syndrome  is usually described by histopathologic results (i.e., minimal  change nephropathy [MCN], focal segmental glomeruloscle-  rosis [FSGS], membranous nephropathy [MN], or membra-  noproliferative glomerulonephritis [MPGN]) (see Table 38-7).  Secondary nephrotic syndrome has the same patterns of histo-  pathology but is associated with an underlying cause.   Approximately 95% of cases of nephrotic syndrome in chil-  dren occur in the absence of systemic or preexisting renal dis-  ease. Primary nephrotic syndrome is found predominantly in  preschool children, with a peak incidence of onset between 2  and 3 years of age. Onset is rare after 8 years of age. Boys are  affected more often than girls. No prevalent racial or geographic  distributions are evident. The incidence is approximately 2 to 3  per 100,000 children per year.**   PATHOPHYSIOLOGY. The cause of nephrotic syndrome in  children is usually idiopathic and includes minimal change  nephropathy (85%), FSGS (10%), and mesangial prolif-  erative nephropathy (MPN) (5%) (see Chapter 38, Table  38-7).** Secondary nephrotic syndrome may develop dur-  ing the course of several different renal or systemic diseases.  The pathophysiology (see Figure 38-10) and common clinical  manifestations of nephrotic syndrome in adults are described  in Chapter 38 (Table 38-8), and are similar in children. The  most common causes of nephrotic syndrome in children are  presented here.   Minimal change nephropathy (MCN), also known as lipoid  nephrosis, is the most common cause of nephrotic syndrome in  children ages 2 to 6 years. A systemic immune mechanism is a  likely cause of the disease, but the true etiology is unknown. The  mechanism of increased glomerular permeability is unknown  but is related, in part, to release of permeability factors from  abnormal circulating T cells that injure the glomerular epithe-  lial cells. The glomeruli appear normal by light microscopy, and  immunoglobulin deposition is usually absent. The only change  is fusion of epithelial cell podocyte foot processes.** There are few  other renal structural abnormalities. Loss of the electrical nega-  tive charge and increased permeability within the glomerular  capillary wall lead to albuminuria.*? Hyperlipidemia leads to    hyperlipiduria and primarily results from increased hepatic  lipid synthesis and decreased plasma lipid catabolism.*°   Focal segmental glomerulosclerosis (FSGS) is present in  approximately 10% to 15% of children with nephrotic syn-  drome and is more common in blacks. The frequency of FSGS  is increasing in children and adults.*”? The primary injury is  effacement (thinning or deletion) of epithelial podocytes, with  a significant increase in pore size leading to impairment of size  selectivity and proteinuria. Progressive disease results in prolif-  eration of endothelial and mesangial cells with occlusion and  sclerosis of glomerular capillaries. The more severe the protein-  uria, the more likely that end-stage renal disease will occur.“®   Edema is the classic symptom of nephrotic syndrome. Several  factors contribute to edema formation with hypoalbuminemia  (decreased plasma oncotic pressure) and sodium retention as  major contributors. The movement of fluid from the vascular  to the interstitial space can decrease blood volume and increase  the activity of aldosterone and antidiuretic hormone (vasopres-  sin), and decrease atrial natriuretic peptide concentration, all of  which promote fluid retention.”   Hyperlipidemia occurs in inverse proportion to the decrease  in plasma proteins, particularly albumin. There are high con-  centrations of triglycerides, low-density lipoprotein (LDL), and  very-low-density lipoprotein (VLDL) cholesterol. High-density  lipoprotein (HDL) cholesterol concentration is decreased.  Hypoalbuminemia leads to a deficiency in the carrier protein  for the transport of fatty acids, and they remain elevated in the  serum. There is hepatic compensation for hypoalbuminemia  with increased synthesis of lipoproteins to maintain plasma  oncotic pressure. Hypoalbuminemia also leads to an increased  hepatic stimulus for synthesis of LDL and VLDL cholesterol by  the liver. Serum lipids may remain elevated from 1 to 3 months  after remission of proteinuria.   Hypercoagulation with risk for arterial or venous thrombo-  sis results from abnormalities in the coagulation pathways dur-  ing nephrotic syndrome. Although rare, thrombosis can occur  in the brain or lung. Family history and predisposing risk fac-  tors should be evaluated. Anticoagulants may be required.*?   Congenital, or infantile, nephrotic syndrome (Finnish  type) is caused by an autosomal recessive mutation of the    NPHS1 gene that encodes an immunoglobulin-like protein,  nephrin, at the podocyte slit membrane. Lack of nephrin causes  heavy proteinuria.°! The disease usually manifests within the  first 3 to 12 months of life, and these infants do not respond to  corticosteroid treatment.°*   CLINICAL MANIFESTATIONS. Onset of nephrotic syndrome is  often insidious, with periorbital edema as the first sign. The  edema is most noticeable in the morning but subsides during  the day as fluid shifts to the abdomen and lower extremities  (Figure 39-6). Parents may notice diminished, frothy, or foamy  urine output; when edema becomes pronounced with ascites,  respiratory difficulty from pleural effusion and labial or scrotal  swelling may develop.   Edema of the intestinal mucosa may cause diarrhea,  anorexia, and poor absorption. Edema often masks the malnu-  trition caused by malabsorption and protein loss. Because of  protein deficiency, changes in the quality of hair indicate a mal-  nourished state. Pallor, with shiny skin and prominent veins,  may be present. Blood pressure is usually normal. The child has  an increased susceptibility to infection, especially pneumonia,  peritonitis, cellulitis, and septicemia. Irritability, fatigue, and  lethargy are common. Infants born with congenital nephrotic  syndrome have large fontanels and separated cranial sutures.   EVALUATION AND TREATMENT. The diagnosis of nephrotic syn-  drome is evident from the clinical presentation and findings  of proteinuria, hyperlipidemia, and edema. Several diagnostic  tests, including kidney biopsy, may be required to determine  whether the cause is an intrinsic renal disease or a consequence  of systemic disease.   The goals of treatment are to reduce the excretion of protein  and to maintain protein-free urine. Prevention or treatment of  infection, control of edema, establishment of a balanced nutri-  tional state, and restoration of normal metabolic processes  also are important in managing the disorder and avoiding  adverse aspects of treatment. Basic management of nephrotic  syndrome includes administering glucocorticosteroids (pred-  nisone); adhering to a low-sodium, well-balanced diet; per-  forming good skin care; and, if edema becomes problematic,  administering diuretics (furosemide, metolazone).> Angioten-  sin-converting enzyme (ACE) inhibitors inhibit formation of    FIGURE 39-6 Nephrotic Syndrome. A, Facial edema. B, Gross edema of scrotum and legs with abdominal distention  from ascites. (From Lissauer T, Clayden G: ///ustrated textbook of paediatrics, ed 4, London, 2012, Mosby.)    CHAPTER 39 Alterations of Renal and Urinary Tract Function in Children    angiotensin II and aldosterone, resulting in decreased blood  pressure and decreased renal sodium reabsorption. Nephrotic  syndrome is often described by the response to steroid therapy  (Table 39-2). Steroid-sensitive nephrotic syndrome usually  results in complete remission without serious adverse effects.  Steroid-resistant nephrotic syndrome is described for chil-  dren (usually infants 3 to 12 months of age or adolescents)  who fail to respond to prednisone within 8 weeks. They may  be treated with noncorticosteroid immunosuppressive agents  (i.e., cyclophosphamide) or combinations of corticosteroids  and noncorticosteroid immunosuppressives to prolong remis-  sion.**°° Children with minimal change disease tend to have a  very favorable prognosis, whereas those with other conditions,  such as FSGS, may develop end-stage kidney disease.°°   Kidney injury, either acute or chronic, is rare in children.  The pathophysiology (see Figure 38-11) and management are  similar to those for kidney injury in adults. A modification  of the RIFLE criteria (R = risk, I = injury, F = failure, L =  loss, and E = end-stage kidney disease [ESKD]) that was pro-  posed to standardize the definition of acute kidney injury in  adults has been used in critically ill children (pRIFLE criteria)  (Table 39-3).°7   May require low-dose prednisone or  treatment with other immunosuppressive  agents to prevent recurrence   Treatment with immunosuppressive and  nonimmunosuppressive medications;  risk for development of end-stage kidney  disease    Risk eCCl decrease by 25%  Injury eCCl decrease by 50%  Failure eCCl decrease by 75% or  eCC! <35 ml/min/1.73 m2  Persistent failure >4 weeks    Data from Akcan-Arikan A et al: Kidney Int 71(10):1028-1035, 2007.  eCCl, Estimated creatinine clearance; GFR, glomerular filtration rate;  PRIFLE, pediatric risk, injury, failure, loss, and end-stage renal disease.    The most common causes of prerenal acute kidney injury  are dehydration, hemorrhage, and sepsis. Glomerulonephri-  tis, hemolytic uremic syndrome, and hypersensitivity reac-  tions to drugs or infectious agents are the most common  causes of intrinsic acute kidney injury. Obstructive uropathies,  such as posterior urethral valves and obstruction of the ure-  teropelvic junction, are associated with postrenal acute kid-  ney injury.°* Chronic kidney failure in very young children  is commonly associated with congenital renal structural  abnormalities. In older children the most common cause is  glomerulonephropathies.°°° Renal replacement modalities  available for children with end-stage renal disease include  peritoneal and hemodialysis and kidney transplant.°'°* The  use of growth hormone before and after transplant has con-  tributed to normal growth and development, particularly in  prepubertal children.”   Wilms tumor is an embryonal tumor of the kidney arising from  epigenetic and genetic changes that lead to abnormal prolifera-  tion of renal stem cells (metanephric blastema). It is also known  by the histologic name of nephroblastoma and is the most  common solid tumor occurring in children.   The incidence of Wilms tumor remains constant in the  United States, with approximately 650 children diagnosed each  year. Most children are between 1 and 5 years of age when they  are diagnosed. The peak incidence occurs between 2 and 3 years  of age. Wilms tumor is slightly more common in females and  in black than in white children, and is less common in Asian  children.°+°   Microscopically, Wilms tumor is composed of three cel-  lular components: stromal, epithelial, and blastemic. This  occurs because blastemic cells, which are primitive and  undifferentiated, may have partially developed into epithe-  lial or stromal tissue. With each of these three cellular com-  ponents, varying stages of differentiation may be evident  within the tumor.   PATHOGENESIS. Wilms tumor (nephroblastoma) has sporadic  and inherited origins. The sporadic form occurs in children  with no known genetic predisposition. Inherited cases, which  are relatively rare (1% to 2% of cases), are transmitted in an  autosomal dominant fashion.   A “two-hit” hypothesis for the development of Wilms  tumor has been proposed wherein children who inherit a  mutation in one allele of a tumor-suppression gene require  just one more somatic mutation for a tumor to form®® (see  Figure 16-18). This hypothesis may not apply to all Wilms  tumors, however, because a number of genetic abnormali-  ties have been identified in Wilms tumors.°”°* Wilms tumor-  suppressor genes WTI and WT2 are located on chromosome  11. Chromosomal abnormalities, including gains, losses, and  rearrangements, are often present in Wilms tumors. Gains  in chromosomes 6, 7, 8, 12, 13, and 18 and losses in chro-  mosomes 11, 16, 22, and X are among the most common  findings, although multiple other chromosomal abnormali-  ties also have been identified.°? WTX is a tumor-suppressor  gene located on the X chromosome.®” Approximately 10%    of children who have Wilms tumor also have loss of other  important genes and therefore have a number of congenital  anomalies. These anomalies include aniridia (lack of an iris  in the eye), hemihypertrophy (an asymmetry of the body),  and genitourinary malformations (i.e., horseshoe kidneys,  hypospadias, ureteral duplication, polycystic kidneys, uter-  ine abnormalities).”°’! Children with congenital anomalies  as well as Wilms tumor are more likely to have the inherited  bilateral form of the disease.   CLINICAL MANIFESTATIONS. Most Wilms tumors (90%) pre-  sent as an enlarging asymptomatic upper abdominal mass in  a healthy, thriving child. Other presenting complaints include  vague abdominal pain, hematuria, fever, and hypertension.”   EVALUATION AND TREATMENT. On physical examination the  tumor feels firm, nontender, and smooth, and generally is a  solitary mass of varying size confined to one side of the abdo-  men. Diagnostic imaging demonstrates a solid intrarenal  mass.   Diagnosis is based on surgical biopsy. Additional labora-  tory and radiologic studies are used to evaluate the presence or  absence of metastasis. The most common sites of metastasis are  regional lymph nodes and the lungs and less commonly liver,  brain, and bone.   Staging systems for Wilms tumor have been developed and  serve as guides to treatment. The most widely accepted system  was developed by the National Wilms Tumor Study Group  (Table 39-4). The system is based on surgical findings and the  extent of disease at diagnosis.”* Children are further classified  as either high or low risk according to favorable or unfavorable  histologic presentation (anaplasia).   Primary treatment is usually (1) surgical exploration and  resection, or (2) chemotherapy followed by surgical resection.  In bilateral disease, surgical intervention may include hemine-  phrectomy of the less involved kidney and nephrectomy of the  other. Radiation therapy has been found to be most effective if    Stage | (40% to 45%) Tumor limited to the kidney,  completely resected   Tumor ascending beyond the kidney  or into vessels of renal sinus, but  appearing to be totally resected   Residual nonhematogenous tumor  confined to the abdomen, positive  lymph nodes in renal hila   Bilateral disease either at diagnosis  or later, but need to stage each  kidney    Data from American Cancer Society: Wilms tumor, 2013. Available at  www.cancer.org/cancer/wilmstumor/detailedguide/wilms-tumor-staging.  Accessed April 2013.   *NoTE: Staging system of the Third National Wilms Tumor Study Group  (NWTS-3).    begun 1 to 3 days after surgery for stages III and IV disease and  metastases. Chemotherapy is specific to histologic presentation  and stage of disease.’4   The overall cure rate is as high as 95% for children with  stage I through stage III disease (Table 39-5). Prognosis is  improving for children with metastases, and this is one of the  few tumors for which lung metastases have been cured. Recur-  rent disease is treated aggressively in children with favorable  histologic results.   Urinary tract infection (UTI) is the colonization of a patho-  gen anywhere along the urinary tract (urethra, bladder,  ureter, kidney) and occurs commonly in children.”> The  incidence of UTI is greater in boys up to 1 year of age, par-  ticularly among those not circumcised.”° Girls have a greater  incidence after 1 year of age with an increasing incidence at  adolescence. UTIs in girls occur as a result of perineal bacte-  ria, especially E. coli, ascending the urethra, which lies close  to the anus. The incidence of UTI in neonates and infants  is low, but the risk is increased because of an immature  immune system.   The pathophysiology of UTIs in children is similar to that  of adults (see Chapter 38). Although nephrolithiasis can be  associated with UTI in adults, nephrolithiasis in children is  rare, but is increasing in incidence (see What’s New? Kidney  Stones in Children). UTIs in children are often clinically cat-  egorized as first or recurrent infection. Individual suscepti-  bility, bacterial virulence, and the host’s anatomy (presence  of reflux, obstruction, stasis, stones, or structural anomalies  of the urinary tract) affect the severity of the disease. The  recurrence rate is approximately 30% to 40%”’ and is highest  in females. Sexually active female adolescents are at increased  risk to have a UTI. Similar to adult women, susceptibility  is increased when genetically controlled blood group anti-  gens (P1 and Lewis blood group nonsecretor) are present on  surface uroepithelial cells and act as receptors for bacterial  attachment.’®    From American Cancer Society: Wilms tumor, 2013. Available at  www.cancer.org/Cancer/WilmsTumor/DetailedGuide/wilms-tumor-  survival-rates. Accessed April 2013.    CHAPTER 39 Alterations of Renal and Urinary Tract Function in Children    Nephrolithiasis in children is rare although the incidence of calcium stones  among children is increasing, particularly in adolescents. There are limited  data available regarding the pathogenesis of kidney stones in children, but the  mechanisms appear different compared to those of adults. Epidemiologic data  indicate nephrolithiasis in children is more common in non-Hispanic white  adolescent females between ages 13 and 18 years (male to female ratio 1:1.4).  Proposed risk factors include obesity; diets high in salt, protein, or fructose,  or low in water or calcium; and use of certain antiseizure, diuretic, vitamin,  or antibiotic medications. Kidney stones also can be associated with urinary  tract malformations (reflux disease and megaureter). Calcium stones are the  most common stone type (72% to 88%). Children who form stones have higher  supersaturation of calcium oxalate; however, the significance to stone forma-  tion is unknown. The most common symptom presentation is pain and gross  hematuria. Prevention and treatment are individualized and any metabolic  cause needs to be evaluated. Stone inhibitors, magnesium, and citrate have  been effective in some groups. Surgical methods include extracorporeal shock  wave lithotripsy, ureteroscopy, and percutaneous nephrolithotomy.    Data from Ayoob R, Wang W, Schwaderer A: Pediatr Nephrol  26(12):2173-2178, 2011; Bergsland KJ et al: Kidney Int 81(11):  1140-1148, 2012; Chahed J et al: Afr J Paediatr Surg 8(2):168-171,  2011; Dwyer ME et al: J Uro/ 188(1):247-252, 2012; Granberg CF,  Baker LA: Pediatr Clin North Am 59(4):897-908, 2012; Sas DJ: Clin  J Am Soe Nephrol 6(8):2062-2068, 2011; Schissel BL, Johnson BK:  Pediatr Emerg Care. 27(7):676-681, 2011.    Cystitis, or infection of the bladder, results in mucosal  inflammation and congestion. This causes detrusor muscle  hyperactivity and a resulting decrease in the bladder capacity.  It also can lead to transient reflux of urine up the ureters, send-  ing bacteria all the way to the kidney, causing acute or chronic  pyelonephritis and renal abscesses or scarring.   Symptoms of UTI in children are nonspecific, and differenti-  ating whether an infection is in the bladder or kidneys is difficult  based on symptoms alone. Infants usually develop vomiting,  diarrhea, or jaundice. Infants and young children may present  only with fever of undetermined origin and others may present  with urinary tract symptoms of frequency; urgency; enuresis  or incontinence in a previously dry child; abdominal, flank,  or back pain; foul-smelling urine; and sometimes hematuria.  Acute pyelonephritis usually causes chills, fever, and flank  or abdominal pain along with enlarged kidney(s) caused by  edema. Chronic pyelonephritis may be asymptomatic.   Diagnosis of UTIs is by urine culture of a pathogen before  antimicrobial treatment. An accompanying urinalysis can  show pyuria, nitrites, and hematuria. The presence of casts  in the urine can indicate pyelonephritis. Ultrasound, voiding  cystourethrography (VCUG) or radionuclide cystography, or  computed tomography (CT) scan may be necessary to rule out  obstructions, abscesses, or reflux, particularly in young children  who do not respond to antimicrobial therapy.   With treatment, UTI symptoms are usually relieved in 1 to 2  days and the urine becomes sterile. A 2- to 4-day course of oral  antibiotics is effective for uncomplicated UTI.” Longer treat-  ment may be required if the child has a recurrent UTI, has a  complicated UTI including congenital abnormalities of the uri-  nary tract, or is immunosuppressed. Imaging of children after a    first UTI is controversial.6°*! The age of the child and serious-  ness of the infection should be considered when making imag-  ing decisions. Repeat urine cultures are not needed ifa child has  responded to treatment.**   Management of constipation, promotion of adequate fluid  intake, and elimination of dysfunctional voiding patterns are  the cornerstones of minimizing the risk of recurrence.** Pro-  phylactic antibiotics may be helpful for some children. Educat-  ing families about signs and symptoms of UTI allows for early  identification and treatment. Surgical correction of vesicoure-  teral reflux or obstruction may be necessary.    Vesicoureteral reflux (VUR) is the retrograde flow of bladder  urine into the kidney or ureters, or both. Reflux allows infected  urine from the bladder to reach the kidneys. Reflux perpetu-  ates infection by preventing complete emptying of the bladder  as refluxed urine drains back into the bladder at the end of each  void. In addition, the reflux allows the maximal intravesical  pressure to be transmitted to the renal calyces and pyramids.  The combination of reflux and infection is an important cause  of pyelonephritis, especially in children younger than 5 years.   Vesicoureteral reflux occurs more often in girls by a ratio of  10:1 and is less common in blacks. Its incidence is approximately  1 in 1000 children, and siblings of those affected have an approxi-  mately 30% chance of developing reflux.*! Reflux nephropathy  in males is associated with congenitally abnormal kidneys.®° The  shortness of the submucosal segment of the ureter during infancy  and childhood renders the antireflux mechanism relatively inef-  ficient and delicate. Thus reflux is seen commonly in association  with infections during early childhood but rarely in older children  and adults. (Among adults with UTIs, the incidence of reflux is  approximately 5%.) Reflux may be unilateral or bilateral, and it  can be classified or graded (Figure 39-7) for comparative purposes:    FIGURE 39-7 Grades of Reflux. (From Feehally J, Floege J, Johnson RJ: Com-  prehensive clinical nephrology, ed 3, Philadelphia, 2008, Mosby.)    FIGURE 39-8 Normal and Abnormal Configuration of the Ureteral Orifices. Left to right: Progressive lateral displace-  ment of the ureteral orifices and shortening of the intramural tunnels. Jop row: Endoscopic appearance. Bottom row: Sagittal  view through the intramural ureter. (From Kliegman RM et al, editors: Ne/son textbook of pediatrics, ed 19, Philadelphia, 2011,   ity and effacement of the calyceal details; occurs almost  exclusively in male infants*°   PATHOPHYSIOLOGY. Primary reflux results from a congenitally  abnormal or ectopic insertion of the ureter into the bladder.  In some infants VUR may be related to inadequate relaxation  of the external urethral sphincter.*” Occasionally the condition  is hereditary. Secondary reflux may be transient or persistent.  It develops in association with infection, malformations of the  ureterovesical (UV) junction, increased intravesical pressures,  voiding disorders, or surgery on the UV junction (Figure 39-8).  Urinary tract infection associated with VUR may lead to perma-  nent renal scarring, particularly when there is pyelonephritis.**  The actual cause of renal cell damage and scarring is unknown  but contributing factors include inflammatory cytokines acti-  vated by bacterial virulence factors.*?   CLINICAL MANIFESTATIONS. Children with reflux may be asymp-  tomatic or may experience recurrent UTIs or unexplained  fever, poor growth and development, irritability, and feeding  problems. The family history may reveal VUR or urinary tract  infections.   EVALUATION AND TREATMENT. Prompt treatment of UTIs in  children with reflux is important to minimize the risk of renal  scar development. Some infants may have renal scarring at  birth from intrauterine damage caused by reflux. In addition  to the history of recurrent UTIs and other symptoms, imag-  ing may be required for diagnosis and assessment of structural  change, scarring, urinary tract function, and risk for future  infection and renal damage. Most children with vesicoureteral  reflux respond to nonoperative management aimed at pre-  vention and treatment of infection. Spontaneous remission of  grades I and II reflux may occur in more than 80% of children.  Resolution of grades III and IV reflux occurs in 46% and 30%,  respectively, over 5 years.” The use of prophylactic antibiotics  for these children is controversial with concerns regarding effi-  cacy and the development of antibiotic resistance.?! Recurrent    infection or high-grade reflux are possible indications for surgi-  cal intervention or endoscopic injection of biomaterials into the  bladder wall below the ureteral orifice. Surgical repair of reflux  has been shown to decrease the incidence of pyelonephritis but  does not decrease the risk of the development or progression of  renal damage.”* The value of screening asymptomatic siblings  of children with vesicoureteral reflux is debatable. One current  recommendation is to perform a renal ultrasound and consider  a VCUG only in children with scarring or otherwise abnormal  appearing kidneys.*4    Urinary incontinence refers to the involuntary passage of urine  by a child who is beyond the age when voluntary bladder control  should have been acquired. Nighttime wetting is called enure-  sis. Bladder control is accomplished by most children before  the age of 5 years, although this is largely influenced by cul-  tural beliefs and parental toilet training practices. Functional  incontinence is urinary incontinence in which no structural  or neurologic abnormality can be identified. The underly-  ing mechanism may include disorders of both the storage and  voiding phases of the bladder cycle. A child may have daytime  incontinence or enuresis, or both.   The incidence of incontinence is difficult to determine  because it is not a problem that parents readily share with oth-  ers and because definitions vary according to cultural norms  and family practices. The incidence of enuresis in children older  than 5 years ranges from 15% to 20%. Boys are more enuretic  than girls by a ratio of 2:1. Less than 2% of adults experience  enuresis. Daytime incontinence occurs in up to 9% of early  school age children.”   PATHOGENESIS. Multiple factors are likely responsible for  incontinence. All or part of each one might be operating in  a given child. A reasonable approach is to eliminate organic,  behavioral, or physiologic causes before exploring the psycho-  logic ones.   Organic causes of incontinence account for 2% to 10% of  cases. The causes include urinary tract infections; neurologic  disturbances; congenital defects of the meatus, urethra, and    CHAPTER 39 Alterations of Renal and Urinary Tract Function in Children    bladder neck; allergies; constipation; obesity;”° or alteration  in renal tubular ion and water transport related to prosta-  glandin secretion. Disorders that increase the normal output  of urine, such as diabetes mellitus and diabetes insipidus, or  disorders that impair the concentrating ability of the kidney  must be considered in the evaluation of enuresis.?° Enure-  sis in children may be associated with a maturational lag.  Studies have demonstrated that some children with enuresis  have smaller functional bladder capacities than nonenuretic  children.?’ Children who do not have the normal nocturnal  elevation of vasopressin produce a higher volume of urine  with a lower osmolality than controls.”* A number of chil-  dren experience bladder overactivity with elevated intra-  vesical pressure and spikelike detrusor contractions during  bladder filling. Incontinence often spontaneously disappears  in children as they get older.   Genetic factors as a cause of enuresis are being investigated.  Linkages have been proposed between nocturnal enuresis and  chromosomes 8, 12, 13, and 22.°? Bed-wetting occurs with  high frequency among parents, siblings, and other near rela-  tives of symptomatic children. These observations are further  supported by a high concordance rate in enuretic monozygotic  twins.   Multiple studies have examined the role of sleep architecture  on enuresis. Findings have ranged from elevated arousal thresh-  olds!°° to increased light sleep with frequent cortical arousal  without complete awakening.!°! Enuresis may be associated with  obstructive sleep apnea. Inspiratory effort against a closed airway  increases intrathoracic negative pressure, causing cardiac disten-  tion and release of atrial natriuretic hormone and decreased levels  of vasopressin and renin-angiotensin-aldosterone complex.!°?   A variety of psychosocial factors also have been postulated  as explanations of enuresis. Enuresis has been associated with  attention-deficit/hyperactivity disorders, anxiety disorders,  depression, and opposition defiant disorders.!°°!0   CLINICAL MANIFESTATIONS. Primary incontinence refers to a  condition in which the child has never been continent. Sec-  ondary incontinence occurs when a child who has experienced  a period of dryness of at least 6 months after toilet training  becomes incontinent again. Secondary enuresis may be diurnal,   Habitual contraction of the urethral sphincter  during voiding; observed by uroflow   Leakage of urine in discrete episodes during the  day and/or night   Leakage of small amounts of urine with exertion  or raised intra-abdominal pressure   Decreased voiding frequency with use of raised  intra-abdominal pressure to void    nocturnal, or a combination of both. (Types of incontinence  are defined in Table 39-6.)   EVALUATION AND TREATMENT. Evaluation of incontinence  includes use of questionnaires, drinking and voiding charts,  physical examination, and urinalysis. Underlying pathology,  including kidney disease, vesicoureteral reflux, urinary tract  infection, or neurogenic bladder, is excluded. Radiologic and  urodynamic evaluation may be required.!0>1°°   Therapeutic management of incontinence or enuresis  begins with education. If the child and family understand the  probable etiology of the child’s condition, they are better able  to choose and participate in therapies that are most likely to  succeed. Treatment of daytime incontinence includes behav-  ioral therapy, including timed voiding; fluid management;  treatment of constipation, urinary tract infections, and other  coexisting conditions if present; and medication (anticholiner-  gic, alpha-blocker).!°”!°* Enuresis treatment also may include  enuresis alarms or other medications (desmopressin acetate  tablets) 109110   1. The Wilms tumor 1 gene and WNT signaling are important  for kidney development, growth, and differentiation.   2. The kidney develops from three sets of structures: the pro-  nephros (nonfunctional by the end of the embryonic period),  mesonephros (nonfunctional), and metanephros (the func-  tional kidney).   3. All nephrons are present at birth. The number does not  increase with maturation, but they do increase in weight and  function.   4. Urine formation begins by the third gestational month and  contributes to the amniotic fluid.    5. Infants have a narrow chemical safety margin because of  high hydrogen ion concentration, limited ability to regulate  the internal environment, and lowered osmotic pressure.   6. Any disturbance, such as diarrhea, infection, fasting, or feed-  ing alterations, can lead rapidly to severe acidosis and fluid  imbalance in infants.   7. The composition of body fluids differs with age, thus making  children more vulnerable to pathophysiologic changes.   8. Because the kidney develops from the medulla to the cor-  tex, blood flow to the medullary nephrons is limited in  infancy, and infants thus have limited urine-concentrating  capacity.   1. Congenital renal disorders affect about 1 out of 500 new-  borns. These disorders range in severity from minor, easily  correctable anomalies to those incompatible with life.  Horseshoe kidney is a single U-shaped kidney that develops 12. Henoch-Schénlein nephritis is an IgA nephropathy that  from fusion of the kidneys as they descend from the mid-    11. IgA nephropathies result from deposition of IgA immuno-  globulins and other immune products in the mesangium of  the glomerular capillaries. It is the most common type of  childhood glomerulonephritis.    line. The kidney may be asymptomatic or associated with 13. Hemolytic uremic syndrome is an acute disorder character-    hydronephrosis, stone formation, or infection.  Hypospadias is a congenital condition in which the urethral    ized by hemolytic anemia, acute renal failure, and throm-  bocytopenia and can be associated with E. coli verotoxin.    meatus is located on the undersurface of the penis; epispa- 14. Nephrotic syndrome is a term used to describe a symptom    dias is a congenital condition in which the urethral opening  is located on the dorsal surface of the penis.   Exstrophy of the bladder is a congenital malformation in  which the pubic bones are separated, the lower portion of  the abdominal wall and anterior wall of the bladder are    complex characterized by proteinuria, hypoalbuminemia,  hyperlipidemia, and edema. Metabolic, biochemical, or  physiochemical disturbance in the glomerular basement  membrane leads to increased permeability to protein. The  most common form is minimal change nephropathy.    missing, and the back wall of the bladder is everted through 15. Acute or chronic renal injury is rare in children and the  most common cause is prerenal acute renal failure related    renal pelvis joins the ureter and is often caused by smooth 16. Wilms tumor is an embryonal tumor of the kidney that usu-    secondary to immune mechanisms characterized by hema-  turia, edema, and hypertension. Poststreptococcal glo-  merulonephritis may occur after infection, especially of the    Renal agenesis is the failure of a kidney to grow or develop.  The condition may be unilateral or bilateral and may occur  as an isolated entity or in association with other disorders.   Polycystic kidney disease is an autosomal dominant or 18. Vesicoureteral reflux, which refers to the retrograde flow of  recessive disorder in which the renal tubule or epithelium  proliferates; excessive fluid transport causes cyst formation    ally presents between birth and 5 years of age as an inherited    (5% to 10%) or sporadic form. The tumor can be success-    A dysplastic kidney is the result of abnormal differentiation 17. Urinary tract infections can result from general sepsis in the    of renal tissues. The hypoplastic kidney is a very small but newborn but are usually caused by bacteria ascending the    cystitis. The infection ascends to the kidney or kidneys in  pyelonephritis. Urinary tract anomalies may need surgical  correction to prevent frequent recurrent infections.    bladder urine into the kidney and/or ureters, provides mech-  anisms for bladder infection in children whose ureters are    shorter than those of adults. It can be unilateral or bilateral.    Glomerulonephritis is an inflammation of the glomeruli 19. Urinary incontinence refers to the involuntary passage of  urine beyond the age when normal continence should have  occurred. This may occur during the day (incontinence)  or night (enuresis). These disorders can have a variety of   Hemolytic uremic syndrome (HUS), 1382  Henoch-Schénlein purpura (HSP) nephritis, 1382  Horseshoe kidney, 1378   Secondary nephrotic syndrome, 1383  Secondary ureteropelvic junction obstruction, 1380  Steroid-resistant nephrotic syndrome, 1385  Steroid-sensitive nephrotic syndrome, 1385  Unilateral renal agenesis, 1380   Urinary tract infection (UTI), 1386  Ureteropelvic junction (UPJ) obstruction, 1380  Vesicoureteral reflux (VUR), 1387    CHAPTER 39 Alterations of Renal and Urinary Tract Function in Children    Fanni D et al: Expression of WT1 during normal human kidney devel-  opment, J Matern Fetal Neonatal Med 24(Suppl 2):44—47, 2011.   Hendry C et al: Defining and redefining the nephron progenitor popula-  tion, Pediatr Nephrol 26(9):1395-1406, 2011.   Bonilla-Felix M: Development of water transport in the collecting duct,  Am J Physiol Renal Physiol 287(6):F1093—F1101, 2004.   Quigley R: Developmental changes in renal function, Curr Opin Pediatr  24(12):184—190, 2012.    . Song R, Yosypiv IV: Genetics of congenital anomalies of the kidney and    . Harris J, Robert E, Kallén B: Epidemiologic characteristics of kidney    . Casas KA, Kamil ES, Rimoin DL: Congenital disorders of the urinary    tract. In Rimon KD et al: Principles and practice of medical genetics, ed 5,  vol 2, Philadelphia, 2007, Churchill Livingstone, Elsevier.    . Blaschko SD, Cunha GR, Baskin LS: Molecular mechanisms of external    . Montag S, Palmer LS: Abnormalities of penile curvature: chordee and    . Macedo A Jr et al: Long-term results with a one-stage complex primary    hypospadias repair strategy (the three-in-one technique), J Pediatr Urol  7(3):299-304, 2011.    . Chalmers D, Ferrer F: Continent urinary diversion in the epispadias-    . 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Akcan-Arikan A et al: Modified RIFLE criteria in critically ill children  with acute kidney injury, Kidney Int 71(10):1028-1035, 2007.   Andreoli SP: Acute kidney injury in children, Pediatr Nephrol  24(2):253-263, 2009.   Harambat J et al: Epidemiology of chronic kidney disease in children,  Pediatr Nephrol 27(3):363-373, 2012.   Mong Hiep TT et al: Clinical characteristics and outcomes of children  with stage 3-5 chronic kidney disease, Pediatr Nephrol 25(5):935—-940,  2010.   LaRosa C, Jorge Baluarte H, Meyers K: Outcomes in pediatric solid-  organ transplantation, Pediatr Transplant 15(2):1228-1241, 2011.   Neu AM, Frankenfield DL: Clinical outcomes in pediatric hemodialysis  patients in the USA: lessons from CMS’ ESRD CPM Project, Pediatr  Nephrol 24(7):1287-1295, 2009.   Fine R: Etiology and treatment of growth retardation in children with  chronic kidney disease and end-stage renal disease: a historical perspec-  tive, Pediatr Nephrol 25(4):725—732, 2010.    Axt J et al: Race disparities in Wilms tumor incidence and biology, J Surg  Res 170(1):112-119, 2011.   Knudson AG Jr, Strong LC: Mutation and cancer: a model for Wilms’  tumor of the kidney, J Natl Cancer Inst 48(2):313-324, 1972.   Md Zin R, Murch A, Charles A: Pathology, genetics and cytogenetics of  Wilm’s tumour, Pathology 43(4):302-312, 2011.   Md Zin R, Murch A, Charles A: Cytogenetic findings in Wilms’ tumour:  a single institute study, Pathology 42(7):643-649, 2010.   Ko EY, Ritchey ML: Current management of Wilms’ tumor in children,  J Pediatr Urol 5(1):56-65, 2009.   Ganesh S, Vennila JJ, Scholz H: An overview and perspectives of Wilm’s  tumor, Int J Cancer Res 7(1):1—7, 2011.   Kaste SC et al: Wilms tumour: prognostic factors, staging, therapy and  late effects, Pediatr Radiol 38(1):2—17, 2008.   Green DM: The evolution of treatment for Wilms tumor, J Pediatr Surg  48(1):14-19, 2013.   Bhat RG, Katy TA, Place FC: Pediatric urinary tract infections, Emerg  Med Clin North Am 29(3):637-653, 2011.   Sadeh SA, Mattoo TK: Managing urinary tract infections, Pediatr  Nephrol 26(11):1967—-1976, 2011.   Brandstrém P et al: The Swedish Reflux Trial in Children: III. Urinary  tract infection pattern, J Urol 184(1):286—291, 2010.   Khunda A, Elneil S: Recurrent urinary tract infections associated with  gynecological disorders, Curr Bladder Dysfunct Rep 7(2):131—-140, 2012.  Michael M et al: Short versus standard duration oral antibiotic therapy  for acute urinary tract infection in children, Cochrane Database Syst Rev  (1):CD003966, 2003.   Newman TB: The new American Academy of Pediatrics urinary tract  infection guideline, Pediatrics 128(3):572-575, 2011.   Wan J et al: Section on urology response to new guidelines for the  diagnosis and management of UTI, Pediatrics 129(4):e1051-e1053,  2012.   Park KH et al: The clinical usefulness of a repeat urine culture 48 hours  after microbial treatment in anatomically normal and abnormal urinary  tract infection, J Korean Soc Pediatr Nephrol 13(1):49-55, 2009.   Yang SS et al: Advances in non-surgical treatments for urinary tract  infections in children, World J Urol 30(1):69-75, 2012.   Skoog SJ et al: Pediatric Vesicoureteral Reflux Guidelines Panel  summary report: clinical practice guidelines for screening siblings of  children with vesicoureteral reflux and neonates/infants with prenatal  hydronephrosis, J Urol 184(3):1145-1151, 2010.   Blumenthal I: Vesicoureteric reflux and urinary tract infection in chil-  dren, Postgrad Med J 82(963):31-35, 2006.   Sung J, Skoog S: Surgical management of vesicoureteral reflux in chil-  dren, Pediatr Nephrol 27(4):551-561, 2012.   Sjéstrém S et al: Change in urodynamic patterns in infants with dilating  vesicoureteral reflux: 3-year follow-up, J Urol 182(5):2446—2454, 2009.  Peters C, Rushton HG: Vesicoureteral reflux associated renal dam-   age: congenital reflux nephropathy and acquired renal scarring, J Urol  184(1):265—-273, 2010.    Tramma D et al: Interleukin-6 and interleukin-8 levels in the urine of  children with renal scarring, Pediatr Nephrol 27(9):1525—1530, 2012.  Coleman R: Early management and long-term outcomes in primary  vesico-ureteric reflux, BJUI 108(Suppl 2):3—8, 2011.   Peters CA et al: Summary of the AUA Guideline on Management of Pri-  mary Vesicoureteral Reflux in Children, J Urol 184(3):1134-1144, 2010.  Fonseca FF, Tanno FY, Nguyen HT: Current options in the manage-  ment of primary vesicoureteral reflux in children, Pediatr Clin North Am  59(4):819-834, 2012.   Buckley BS, Lapitan MC: Prevalence of urinary incontinence in men,  women, and children—current evidence: findings of the Fourth Interna-  tional Consultation on Incontinence, Urology 76(2):265-271, 2010.  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CHAPTER 39 Alterations of Renal and Urinary Tract Function in Children    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:  Case Study    The Gastrointestinal Tract, 1393  Mouth and Esophagus, 1395  Stomach, 1396  Small Intestine, 1400  Large Intestine, 1407  Intestinal Bacteria, 1408   Accessory Organs of Digestion, 1409  Liver, 1409  Gallbladder, 1413  Exocrine Pancreas, 1413    The digestive system breaks down ingested food, prepares it for  uptake by the body’s cells, provides body water, and eliminates  wastes. This system consists of the gastrointestinal tract and  accessory organs of digestion: the liver, gallbladder, and exo-  crine pancreas.   Food breakdown begins in the mouth with chewing and con-  tinues in the stomach, where food is churned and mixed with  acid, mucus, enzymes, and other secretions. From the stomach,  the fluid and partially digested food pass into the small intes-  tine, where biochemicals and enzymes secreted by the liver,  exocrine pancreas, and small intestinal epithelium break it  down into absorbable components of proteins, carbohydrates,  and fats. These nutrients pass through the small intestinal epi-  thelium into underlying blood vessels and lymphatics that carry  them to the liver via the hepatic portal circulation for further  processing and storage.   Ingested substances and secretions that are not absorbed  in the small intestine pass into the large intestine, where fluid    Tests of Digestive Function, 1415  Gastrointestinal Tract, 1415  Liver, 1416  Gallbladder, 1416  Exocrine Pancreas, 1416  AGING and the Gastrointestinal System, 1417    continues to be absorbed. Solid wastes pass into the rectum and  are eliminated from the body through the anus.   Except for chewing, swallowing, and defecation of solid  wastes, the activities of the digestive system are controlled by  hormones and the autonomic nervous system. As ingested  substances move through the gastrointestinal tract, they trig-  ger the release of hormones that stimulate or inhibit (1) the  muscular contractions (gastrointestinal motility) that mix and  propel food from the esophagus to the anus, and (2) the timely  secretion of substances that aid in digestion. The autonomic  innervation, sympathetic and parasympathetic, is controlled by  centers in the brain and by local stimuli that are mediated by  neural plexuses within the gastrointestinal walls.    The gastrointestinal tract (alimentary canal) consists of the  mouth, esophagus, stomach, small intestine, large intestine,    rectum, and anus (Figure 40-1). It carries out the following  digestive processes:   2. Propulsion of food and wastes from the mouth to the   . Secretion of mucus, water, and enzymes  . Mechanical digestion of food particles  . Chemical digestion of food particles  . Absorption of digested food  . Elimination of waste products by defecation   Histologically, the gastrointestinal tract consists of four  layers. From the inside out, they are the mucosa, submucosa,  muscularis, and serosa or adventitia (esophagus only). These  concentric layers vary in thickness, and each layer has sublay-  ers (Figure 40-2). Neurons forming the enteric nervous sys-  tem are located solely within the gastrointestinal tract and are  controlled by local and autonomic nervous system stimuli. The  enteric nervous system comprises three nerve plexuses located  in different layers of the gastrointestinal walls. The submucosal  plexus (Meissner plexus) is located in the muscularis mucosae,  the myenteric plexus (Auerbach plexus) between the inner cir-  cular and outer longitudinal muscle layers in the muscularis,  and the subserosal plexus just beneath the serosa. The enteric  (intramural) plexus neurons regulate motility reflexes, blood  flow, absorption, secretions, and immune response.!    FIGURE 40-2 Wall of the Gastrointestinal (GI) Tract. The wall of the Gl tract is made up of four layers with a network of  nerves between the layers. Shown here is a generalized diagram of a segment of the GI tract. Note that the serosa is continu-  ous with a fold of serous membrane called a mesentery. Note also that digestive glands may empty their products into the  lumen of the GI tract by way of ducts. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)   The mouth is a reservoir for the chewing and mixing of food  with saliva. As food particles become smaller and move around  in the mouth, the taste buds and olfactory nerves are con-  tinuously stimulated, adding to the satisfaction of eating. The  tongue’s surface and soft palate contains thousands of chemo-  receptors, or taste buds, that can distinguish salty, sour, bitter,  umami, and sweet tastes. Tastes and food odors help initiate  salivation and the secretion of gastric juice in the stomach.  There are 32 permanent teeth in the adult mouth, and they are  important for speech and mastication.    The three pairs of salivary glands (the submandibular, sub-  lingual, and parotid glands) (Figure 40-3) secrete about 1 L  of saliva per day. Saliva consists mostly of water that contains  varying amounts of mucus, sodium, bicarbonate, chloride,  potassium, and salivary c-amylase (ptyalin), an enzyme that  initiates carbohydrate digestion in the mouth and stomach.  The sympathetic and parasympathetic divisions of the auto-  nomic nervous system control salivation. Because cholinergic  parasympathetic fibers stimulate the salivary glands, atropine  (an anticholinergic agent) inhibits salivation and makes the  mouth dry. §-Adrenergic stimulation from sympathetic fibers  also increases salivary secretion. The salivary glands are not reg-  ulated by hormones, although hormones are found in saliva.'*    Sublingual  gland  FIGURE 40-3 Salivary Glands. (From Patton KT, Thibodeau GA: Anatomy &  physiology, ed 8, St Louis, 2013, Mosby.)    The composition of saliva depends on the rate of secretion.  Aldosterone can decrease the rate of secretion by increasing an  exchange of sodium for potassium. Sodium and water are con-  served and potassium is excreted. The bicarbonate concentration  of saliva sustains a pH of about 7.4, which neutralizes bacterial  acids and prevents tooth decay. Saliva also contains immunoglob-  ulin A (IgA), which helps prevent infection. Exogenous fluoride  (e.g., fluoride in drinking water) is absorbed and then secreted  in the saliva, providing additional protection against tooth decay.   The esophagus is a hollow muscular tube approximately 25 cm  long that conducts substances from the oropharynx to the  stomach (see Figure 40-1). The pharynx and upper third of the  esophagus contain striated muscle that is directly innervated  by skeletal motor neurons that control swallowing. The middle  third contains a mix of striated and smooth muscle, and the  lower third is smooth muscle that is innervated by pregangli-  onic cholinergic fibers from the vagus nerve. Peristalsis is stim-  ulated when afferent fibers distributed along the length of the  esophagus sense changes in wall tension caused by stretching  as food passes. The greater the tension, the greater the intensity  of esophageal contraction. Occasionally, intense contractions  cause pain similar to “heartburn” or angina.   Each end of the esophagus is opened and closed by a sphinc-  ter. The upper esophageal sphincter (cricopharyngeal muscle)  prevents entry of air into the esophagus during respiration.’  The lower esophageal sphincter (cardiac sphincter) prevents  regurgitation from the stomach. The lower esophageal sphinc-  ter is located near the esophageal hiatus—the opening in the  diaphragm where the esophagus ends at the stomach.*   Swallowing is a complex event mediated by the trigeminal  nucleus, nucleus tractus solitarius, and reticular formation of  the brainstem and also involves other brain regions, including  the insula/claustrum and cerebellum.*   Swallowing occurs in two phases: the oropharyngeal (volun-  tary) phase and the esophageal (involuntary) phase. During the  oral and pharyngeal phases of swallowing, food is segmented  into a bolus by the tongue and forced posteriorly toward the  pharynx as the tongue pushes upward against the hard palate.  The superior constrictor muscle of the pharynx contracts, pre-  venting movement of food into the nasopharynx. At the same  time, respiration is inhibited and the epiglottis folds downward  to prevent the bolus from entering the larynx and trachea. The  movements of the tongue and pharyngeal constrictors propel  the food into the esophagus in a series of coordinated events,  taking less than 1 or 2 seconds.   During the esophageal phase of swallowing, the bolus is  transported to the stomach by the coordinated sequential con-  traction and relaxation of outer longitudinal and inner circular  layers of smooth muscle. The wave of relaxation reduces resis-  tance and allows food to pass, after which the wave of contrac-  tion pushes food farther along. The terminal 1 to 2 cm portion  of the musculature forms the lower esophageal sphincter, which  relaxes just before the arrival of a peristaltic wave. The sphinc-  ter muscles return to their resting tone after the bolus of food  passes into the stomach. The esophageal phase of swallowing    takes 5 to 10 seconds, with the bolus moving 2 to 6 cm/second.  Throughout swallowing, the sphincters and esophagus work  in concert with the peristaltic wave that moves food from the  mouth to the stomach.   Peristalsis that immediately follows the oropharyngeal phase  of swallowing is called primary peristalsis. If a bolus of food  becomes stuck in the esophageal lumen, the distention of the  esophageal wall stimulates secondary peristalsis, a wave of  contraction and relaxation that is independent of voluntary  swallowing. This is in response to stretch receptors that are  stimulated by increased wall tension, causing an increase in  impulses from the swallowing center of the brain.   When it is closed, the lower esophageal sphincter serves as a  barrier between the stomach and esophagus. Cholinergic vagal  stimulation and the digestive hormone gastrin increase sphinc-  ter tone. Nonadrenergic, noncholinergic vagal impulses relax  the lower esophageal sphincter, as do the hormones progester-  one, secretin, and glucagon. Relaxation during swallowing is  mediated by the vagus nerve.°    The stomach is a hollow muscular organ that stores food dur-  ing eating, secretes digestive juices, mixes food with these juices,  and propels partially digested food, called chyme, into the duo-  denum of the small intestine. The anatomy of the stomach is  presented in Figure 40-4. Its major anatomic boundaries are the  lower esophageal sphincter, where food passes through the car-  diac orifice at the gastroduodenal junction into the stomach,  and the pyloric sphincter, which relaxes as food is propelled  into the duodenum. Functional areas of the stomach are the  fundus (upper portion), body (middle portion), and antrum  (lower portion).    The stomach has three layers of smooth muscle: an outer,  longitudinal layer; a middle, circular layer; and an inner,  oblique layer (the most prominent) (see Figure 40-4). These  layers become progressively thicker in the body and antrum,  where food is mixed, churned, and pushed into the duodenum.  The circular layer is most prominent and the oblique layer is  the least complete; the longitudinal layer is absent on the ante-  rior and posterior surfaces. The glandular epithelium is dis-  cussed in the section about secretory functions of the stomach  (see p. 1398).   Blood is supplied to the stomach by branches of the celiac  artery. The blood supply is so abundant that nearly all arterial  vessels must be occluded before ischemic changes occur in the  stomach wall. A series of small veins (short gastric, left and right  gastric, and left and right gastro-omental) drain blood from the  stomach towards the hepatic portal vein.   The stomach is innervated by sympathetic and parasym-  pathetic divisions of the autonomic nervous system. Some of  the autonomic nerves are extrinsic; that is, they originate in the  central nervous system and are controlled by nerve centers in  the brain. The vagus nerve provides parasympathetic innerva-  tion and branches of the celiac plexus innervate the stomach  sympathetically. Other neurons are intrinsic; that is, they origi-  nate within the stomach and respond to local stimuli and are  components of the enteric nervous system. Extrinsic sympa-  thetic fibers reach the stomach through the celiac plexus (solar  plexus), whereas extrinsic parasympathetic fibers enter through  the gastric branch of the vagus nerve.   Few substances are absorbed in the stomach. The stomach  mucosa is impermeable to water, but the stomach can absorb  alcohol and aspirin and other nonsteroidal anti-inflammatory  agents.    FIGURE 40-4 Stomach. A portion of the anterior wall has been cut away to reveal the muscle layers of the stomach wall.  Note that the mucosa lining the stomach forms folds called rugae. The dashed lines distinguish the fundus, body, and antrum  of the stomach. (Modified from Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    In its resting state the stomach is small and contains about  50 ml of fluid. There is little wall tension, and the muscle layers  in the fundus contract very little. Swallowing causes the fundus  to relax (receptive relaxation) to receive a bolus of food from  the esophagus. Relaxation is coordinated by efferent, nonad-  renergic, noncholinergic vagal fibers and is facilitated by gastrin  and cholecystokinin, two polypeptide hormones secreted by the  gastrointestinal mucosa. (The actions of digestive hormones are  summarized in Table 40-1.) Food is stored in vertical or oblique  layers as it arrives in the fundus, whereas fluids flow relatively  quickly down to the antrum.   Gastric (stomach) motility increases with the initiation  of peristaltic waves, which sweep over the body of the stom-  ach toward the antrum. The rate of peristaltic contractions is  approximately three per minute and is influenced by neural  and hormonal activity. Gastrin and motilin (small intestine  hormones) and the vagus nerve increase contraction by mak-  ing the threshold potential of muscle fibers less negative. (The  neural and biochemical mechanisms of muscle contraction  are described in Chapter 43.) Sympathetic activity and secre-  tin (another small intestine hormone) are inhibitory and make  the threshold potential more negative. The rate of peristalsis is    Histamine  Somatostatin  Acetylcholine  Gastrin-releasing  peptide (bombesin)  Mucosa of the Motilin  small intestine    Vagus and local nerves in stomach  Vagus and local nerves in stomach    Presence of chyme (acid, partially digested  proteins, fats) in the duodenum    Presence of chyme (acid, partially digested  proteins, fats) in the duodenum    Presence of chyme in duodenum  Fat and glucose in small intestine    mediated by pacemaker cells that initiate a wave of depolariza-  tion (basic electrical rhythm), which moves from the upper part  of the stomach to the pylorus.   Gastric mixing and subsequent emptying of gastric con-  tents (chyme) from the stomach take several hours (3 to 6  hours depending on the composition and volume of food  intake). Mixing occurs as food is propelled toward the antrum.  As food approaches the pylorus, the velocity of the peristaltic  wave increases, forcing the contents back toward the body of  the stomach. This retropulsion effectively mixes food with  digestive juices, and the oscillating motion breaks down large  food particles. With each peristaltic wave a small portion of the  chyme passes through the pylorus and into the duodenum. The  pyloric sphincter is about 1.5 cm long and is always open about  2 mm. It opens wider during antral contraction. Normally there  is no regurgitation from the duodenum into the antrum.   The rate of gastric emptying (movement of gastric contents  into the duodenum) depends on the volume, osmotic pressure,  and chemical composition of the gastric contents. Larger vol-  umes of food increase gastric pressure, peristalsis, and rate of  emptying. Solids, fats, and nonisotonic solutions delay gastric  emptying.° (Osmotic pressure and tonicity are described in  Chapters 1 and 3.) Products of fat digestion, which are formed    Stimulates gastric glands to secrete hydrochloric acid and  pepsinogen; growth of gastric mucosa; promotes gastric motility    Stimulates pancreas to secrete alkaline pancreatic juice and liver  to secrete bile; decreases gastrointestinal motility; inhibits  gastrin and gastric acid secretion   Stimulates gallbladder to eject bile and pancreas to secrete  alkaline fluid; decreases gastric motility; constricts pyloric  sphincter; inhibits gastrin; delays gastric emptying   Weakly inhibits gastric and pancreatic secretion and enhances  insulin release, lipolysis, ketogenesis, and glycogenolysis;  delays gastric emptying   Inhibits gastric secretion and gastric emptying, stimulates insulin  release; inhibits intestinal motility   Inhibits postprandial gastric acid and pancreatic secretion and  delays gastric and small bowel emptying    Modified from Johnson LR: Gastrointestinal physiology, ed 7, St Louis, 2007, Mosby.   *Data from Schubert ML, Peura DA: Gastroenterology 134(7):1842-1860, 2008; Wren AM, Bloom SR: Gastroenterology 132(6):2116—2130, 2007.  tNote: The digestive hormones are not secreted into the gastrointestinal lumen but rather into the bloodstream, in which they travel to target tis-  sues. There are more than 30 peptide hormone genes expressed in the gastrointestinal tract and more than 100 hormonally active peptides.    in the duodenum by the action of bile from the liver and  enzymes from the pancreas, stimulate the secretion of chole-  cystokinin.’ This hormone inhibits food intake, reduces gas-  tric motility, and decreases gastric emptying so that fats are not  emptied into the duodenum at a rate that exceeds the rate of bile  and enzyme secretion. Osmoreceptors in the wall of the duode-  num are sensitive to the osmotic pressure of duodenal contents.  The arrival of hypertonic or hypotonic gastric contents activates  the osmoreceptors, which delays gastric emptying to facilitate  formation of an isosmotic duodenal environment. The rate at  which acid enters the duodenum also influences gastric empty-  ing. Secretions from the pancreas, liver, and duodenal mucosa  neutralize gastric hydrochloric acid in the duodenum. The rate  of emptying is adjusted to the duodenum’s ability to neutral-  ize the incoming acidity. Peristaltic activity in the stomach is  also affected by blood glucose levels. Low blood glucose levels  stimulate the vagus nerve and gastric smooth muscles, increas-  ing the rate of contraction.®    Stimulated by eating, the stomach produces large volumes of  gastric secretions. Specialized cells located throughout the gas-  tric mucosa produce mucus, acid, enzymes, hormones, intrin-  sic factor, and gastroferrin. Intrinsic factor is necessary for the  intestinal absorption of vitamin B,, and gastroferrin facilitates  small intestinal absorption of iron. The hormones are secreted  into the blood and travel to target tissues in the bloodstream.  The other gastric secretions are released directly into the stom-  ach lumen under neural and hormonal regulation.? Mucus  covering the entire mucosa, intercellular tight junctions, bicar-  bonate secretion, and submucosal acid sensors form a protective  barrier against acid and proteolytic enzymes, which otherwise  would damage the gastric lining.!°   In the fundus and body of the stomach the gastric glands  of the mucosa are the primary secretory units (Figure 40-5).  Several of these glands (three to seven) empty into a common  duct known as the gastric pit. The parietal cells (oxyntic cells)  within the glands secrete hydrochloric acid, intrinsic factor, and  gastroferrin. The chief cells within the glands secrete pepsino-  gen, an enzyme precursor that is readily converted to pepsin  (a proteolytic enzyme) in the gastric fluid. The pyloric gland  mucosa in the antrum synthesizes and releases the hormone  gastrin from G cells. Enterochromaffin-like cells secrete hista-  mine, and D cells secrete somatostatin.   The composition of gastric fluid depends on volume and  flow rate (Figure 40-6). Potassium level remains relatively con-  stant, but its concentration is greater in gastric secretions than  in plasma. The rate of secretion varies with the time of day;  lower in the morning and higher in the afternoon and evening.  Loss of gastric secretions through vomiting, drainage, or suc-  tion may decrease body stores of sodium, potassium, hydrogen,  and chloride.   Acid. The major functions of gastric hydrochloric acid are  to dissolve food fibers, act as a bactericide against swallowed  organisms, and convert pepsinogen to pepsin. The production  of acid by the parietal cells requires the transport of hydrogen  and chloride from the parietal cells to the stomach lumen. Acid    is formed in the parietal cells, primarily through the hydrolysis  of water (Figure 40-7). At a high rate of gastric secretion,  bicarbonate moves into the plasma, producing an “alkaline  tide” in the venous blood, which also may result in a more  alkaline urine.!!    oo y;  Visceral peritoneum  FIGURE 40-5 Gastric Pits and Gastric Glands. Gastric pits are depressions  in the epithelial lining of the stomach. At the bottom of each pit is one or more  tubular gastric glands. Chief cells produce the enzymes of gastric juice, and pari-  etal cells produce stomach acid. (From Patton KT, Thibodeau GA: Anatomy & physi-  ology, ed 8, St Louis, 2013, Mosby.)    Secretory rate  FIGURE 40-6 Relationship Between Secretory Rate and Electrolyte  Composition of the Gastric Secretions. Sodium (Na*) concentration is lower in  the gastric secretions than in the plasma, whereas hydrogen (H*), potassium (K*),  and chloride (Cr) concentrations are higher. Gastric secretions are close to iso-  tonic. Secretory rate increases during the cephalic and gastric phases of digestion.    Acid secretion by parietal cells is stimulated by acetylcholine  (ACh) (a neurotransmitter), gastrin (a hormone), and hista-  mine (a biochemical mediator). The vagus nerve releases ACh  and stimulates the secretion of histamine and gastrin-releasing  peptide (GRP), which stimulates release of gastrin.'* Histamine  secretion is also stimulated by gastrin. Histamine is stored in  enterochromaffin cells (mast cells; see Chapter 7) in the gas-  tric mucosa. Histamine receptors in the gastric mucosa are H2  receptors (unlike those in the bronchial mucosa, which are H1  receptors). Gastric lipase is produced by glands in the fundus  of the stomach and is most effective in an acidic environment.  Caffeine stimulates acid secretion, as does calcium. Prosta-  glandins, enterogastrones (such as gastric inhibitory peptide),  somatostatin, and secretin inhibit acid secretion.!°   Pepsin. Acetylcholine, through vagal stimulation during  the cephalic and gastric phases, is the strongest stimulation    for pepsin secretion. The precursor pepsinogen is quickly  converted to pepsin at a pH of 2. Acid also stimulates a local  cholinergic reflex and stimulates chief cells to secrete pepsin.  Gastrin and secretin are weaker pepsinogen secretagogues.  Pepsin is a proteolytic enzyme that breaks down protein-  forming polypeptides in the stomach. Once chyme has entered  the duodenum, the alkaline environment of the duodenum  inactivates pepsin.   Mucus. The gastric mucosa is protected from the digestive  actions of acid and pepsin by a coating of mucus called the  mucosal barrier. Gastric mucosal blood flow is important to  maintaining mucosal barrier function.'*   The quality and quantity of mucus and the tight junctions  between epithelial cells make gastric mucosa relatively imper-  meable to acid. Prostaglandins and nitric oxide protect the  mucosal barrier by stimulating the secretion of mucus and  bicarbonate and by inhibiting the secretion of acid. A break in  the protective barrier may occur because of exposure to aspi-  rin or other nonsteroidal anti-inflammatory drugs, Helicobacter  pylori, ethanol, regurgitated bile, or ischemia. Breaks cause  inflammation and ulceration.   Intrinsic factor (IF), a mucoprotein produced by parietal  cells, combines with vitamin B,, in the stomach. It is required  for the absorption of vitamin B,, by the ileum. Atrophic gastri-  tis and failure to absorb vitamin B,) result in pernicious anemia  (see Chapter 28).   Phases of Gastric Secretion. The secretion of gastric juice  is influenced by numerous stimuli that together facilitate the  process of digestion. The phases of gastric secretion are the  cephalic phase, gastric phase, and intestinal phase (Figure 40-8).    FIGURE 40-8 Mechanisms for Stimulating Acid Secretion. ACh, Acetylcholine; ECL, enterochromaffin-like cell; GRP    gastrin-releasing peptide. (From Johnson LR: Gastrointestinal physiology, ed 7, St Louis, 2007, Mosby.)    Cephalic Phase. The anticipatory and sensory experiences  of smelling, seeing, tasting, chewing, and swallowing food con-  tribute to the cephalic phase of secretion.!° The cephalic phase  of gastric secretion is mediated by the vagus nerve through the  myenteric plexus. Acetylcholine stimulates the parietal and  chief cells to secrete acid and pepsinogen, respectively. The G  cells in the antrum release gastrin, which circulates through the  bloodstream to the gastric glands and stimulates acid and pep-  sinogen secretion.   Insulin secretion by the endocrine pancreas, stimulated by  hyperglycemia, also is a strong stimulus for gastric secretion  and is mediated by the vagus nerve through sensors located in  the hypothalamus. Maintenance of steady serum glucose levels  suppresses the gastric response to insulin.   Gastric Phase. The gastric phase of secretion begins with  the arrival of food in the stomach. Two major stimuli have a  secretory effect: (1) distention of the stomach, and (2) the pres-  ence of digested protein. The vagus and enteric nerve plexuses  are stimulated by distention and contribute to gastric secre-  tion through a local reflex. Both neural reflexes are mediated  by ACh and can be blocked by atropine. As digestion proceeds,  products of protein break down, stimulating the release of more  gastrin from G cells.   Intestinal Phase. The movement of chyme from the stomach  into the duodenum initiates the intestinal phase of secretion.    This phase represents a deceleration of the gastric secretory  response; however, the presence of digested protein and amino  acids in the duodenum continues to stimulate some gastric  secretion.   Concurrently, in response to low duodenal pH and the pres-  ence of lipids, inhibitory vagal and enteric reflexes decrease  gastric motility when chyme enters the duodenum. The release  of secretin and cholecystokinin stimulate pancreatic secretions  and inhibit gastric secretions.    The small intestine is about 5 to 6 m long and is function-  ally divided into three segments: the duodenum, jejunum,  and ileum (Figure 40-9). The duodenum begins at the pylorus  and ends where it joins the jejunum at a suspensory ligament  called the Treitz ligament. The end of the jejunum and begin-  ning of the ileum are not distinguished by an anatomic marker.  These structures are not grossly different, but the jejunum has  a slightly larger lumen. The ileocecal valve (sphincter) controls  the flow of digested material from the ileum into the large intes-  tine and prevents reflux into the small intestine.   The peritoneum is the serous membrane surrounding the  organs of the abdomen and lining the abdominopelvic cavity.  It is analogous to the pericardium and pleura that surround  the heart and lungs, respectively. The visceral peritoneum lies    on the surface of the organs, and the parietal peritoneum lines  the wall of the body cavity. The space between these two lay-  ers is called the peritoneal cavity. This cavity normally contains  just enough fluid to lubricate the two layers and prevent fric-  tion during organ movement. Inflammation of the peritoneum,  called peritonitis, may occur with perforation of the intestine or  after abdominal surgery. As the inflammatory process resolves,  scar tissue adhesions may form and cause intestinal obstruction.   The duodenum lies behind the peritoneum, or retroperito-  neally, and has an essential role in mixing food with digestive  juices from the liver and pancreas. The ileum and jejunum are  suspended from the posterior abdominal wall by a component  of the peritoneum called the mesentery. The loose folds of the  mesentery facilitate intestinal motility and support blood ves-  sels, nerves, and lymphatics.   The arterial supply to the duodenum arises primarily from  the gastroduodenal artery, a small branch of the celiac artery.  The jejunum and ileum are supplied by branches of the supe-  rior mesenteric artery. Blood flow increases significantly dur-  ing digestion. The superior mesenteric vein drains blood from  the entire small intestine and empties into the hepatic portal  circulation. The regional lymphatics drain into the thoracic  duct. Both divisions of the autonomic nervous system innervate  the small intestine. Secretion, motility, and intestinal reflexes  (e.g., relaxation of the lower esophageal sphincter) are medi-  ated parasympathetically by the vagus nerve. Sympathetic activ-  ity inhibits motility and produces vasoconstriction. Intrinsic  reflexive activity is mediated by the myenteric plexus (Auer-  bach plexus) and the submucosal plexus (Meissner plexus) of  the enteric nervous system.   The smooth muscles of the small intestine are arranged in  two layers: a longitudinal, outer layer; and a thicker, inner cir-  cular layer (see Figure 40-9). Circular folds of the small intestine  mucosa slow the passage of food, thereby providing more time  for digestion and absorption. The folds are most numerous and  prominent in the jejunum and upper ileum.   Absorption occurs through villi, which cover the circular  folds and are the functional units of the intestine (see Figure  40-9). A villus is composed of absorptive columnar epithe-  lial cells (enterocytes) and mucus-secreting goblet cells of the  mucosa. Each villus secretes some of the enzymes necessary for  digestion and absorbs nutrients. Near the surface, columnar  cells closely adhere to each other at sites called tight junctions.  Water and electrolytes are absorbed through these intercellular  spaces. The surface of each columnar epithelial cell on the vil-  lus contains tiny projections called microvilli (see Figure 40-9).  Together the microvilli create a mucosal surface known as the  brush border. The villi and microvilli greatly increase the sur-  face area available for absorption. Coating the brush border is  an “unstirred” layer of fluid that is important for the absorption  of substances other than water and electrolytes. The lamina  propria (a connective tissue layer of the mucosa) lies beneath  the epithelial cells of the villi and contains lymphocytes; plasma  cells, which produce immunoglobulins; and macrophages.   Central arterioles ascend within each villus and branch into  a capillary array that extends around the base of the columnar  cells and cascades down to the venules that lead to the hepatic    portal circulation. The opposing ascending and descend-  ing blood flow provides a countercurrent exchange system  for absorbed substances and blood gases. A central lacteal, or  lymphatic capillary, is also contained within each villus and is  important for the absorption and transport of fat molecules.  Contents of the lacteals flow to regional nodes and channels  that eventually drain into the thoracic duct'® (see Figure 40-9).   Between the bases of the villi are the crypts of Lieberkithn  (intestinal glands), which extend to the submucosal layer. Undif-  ferentiated (stem cells) and secretory cells and Paneth epithelial  cells are located here. The stem cells are precursors of columnar  epithelial and goblet cells. These premature cells produce alkaline  fluids containing electrolytes, mucus, and water. These cells arise  from the base of the crypt and move toward the tip of the villus,  maturing in shape and function as they progress. After becom-  ing columnar cells and completing their migration to the tip of  the villus, they function for a few days and then are shed into the  intestinal lumen and digested. The entire epithelial population  is replaced about every 4 to 7 days. Many factors can influence  this process of cellular proliferation. Starvation, vitamin B,, defi-  ciency, and cytotoxic drugs or irradiation suppress cell division  and shorten the villi. The decreased absorption that results can  cause diarrhea and malnutrition. Nutrient intake and intestinal  resection stimulate cell production. The Paneth cells located at the  base of the crypts produce defensins and other antibiotic peptides  and proteins.'” Other secretory cells produce digestive enzymes.    The process of intestinal digestion is initiated in the stomach by  the actions of gastric hydrochloric acid and pepsin, which break  down food fibers and proteins. The chyme that passes into the  duodenum is a liquid that contains small particles of undigested  food. Digestion is continued in the proximal portion of the small  intestine by the action of pancreatic enzymes, intestinal brush-  border enzymes, and bile salts (Box 40-1). Here carbohydrates  are broken down to monosaccharides and disaccharides; pro-  teins are degraded further to amino acids and peptides; and fats  are emulsified and reduced to fatty acids and monoglycerides  (Figure 40-10). These nutrients, along with water, vitamins, and  electrolytes, are absorbed across the intestinal mucosa and into  the blood by active transport, diffusion, or facilitated diffusion.  Products of carbohydrate and protein breakdown move into  villus capillaries and then to the liver through the hepatic portal  vein. Digested fats move into the lacteals and eventually reach  the liver through the systemic circulation. Intestinal motility  exposes nutrients to a large mucosal surface area by mixing  chyme and moving it through the lumen. Different segments of  the gastrointestinal tract absorb different nutrients. Digestion  and absorption of all major nutrients occur in the small intes-  tine. Sites of absorption are shown in Figure 40-11.   Water and Electrolyte Transport by the Small Intestine. The  epithelial cell membranes of the small intestine are formed of  lipids and therefore are hydrophobic, or tend to repel water.  (The properties of cell membranes are described in Chapter  1.) Therefore, water and electrolytes are transported in both  directions (toward the capillary blood or toward the intestinal  lumen) through the tight junctions and intercellular spaces    Small Intestine  Enterokinase  Disaccharidases  Maltase  Sucrase  Lactase  a,a-Trehalase  lsomaltase  Peptidases  Amino-oligopeptidase  Dipeptidase    From Johnson LR: Gastrointestinal physiology, ed 7, St Louis, 2007,  Mosby.    rather than across cell membranes. Water diffuses passively  across hydrostatic pressure and osmotic gradients established  by the active transport of sodium and other substances.  Approximately 85% to 90% of the water that enters the  gastrointestinal tract each day is absorbed in the small intestine.  The remaining water and electrolytes are absorbed at a constant  rate in the large intestine.'* Sodium passes through the tight  junctions and is actively transported across cell membranes.  Sodium and glucose share a common active transport carrier  (sodium-glucose ligand transporter! [SGLT1]) so that sodium  absorption is enhanced by glucose transport!** (Figure 40-12).  Potassium moves passively across the tight junctions with  changes in the electrochemical gradient. Chloride is actively  secreted throughout the large and small intestines.  Carbohydrates. Carbohydrate (starch, table sugar [sucrose],  milk sugar [lactose], cereal sugar [maltose]) accounts for at  least 50% of the American diet. Because only monosaccharides  (ribose, galactose, glucose, fructose) are absorbed by the  intestinal mucosa, the complex carbohydrates (polysaccharides  and oligosaccharides) must be hydrolyzed to their simplest  form (see Figure 40-10). Salivary and pancreatic amylases break  down starches to oligosaccharides by splitting a-1,4-glucosidic  linkages of long-chain molecules. The major disaccharides are  sucrose (glucose-fructose), maltose (glucose-glucose), and lactose    (glucose-galactose). Approximately half of starch hydrolysis occurs  in the stomach and about half in the duodenum. In the small  intestine, disaccharides are hydrolyzed by brush-border enzymes  (sucrase, maltase, and lactase) to their respective monosaccharides.   The sugars are absorbed primarily in the duodenum and upper  jejunum. The monosaccharides pass through the unstirred layer by  diffusion. At the cell membrane, glucose and galactose are actively  transported with a sodium carrier (SGLT1) and fructose absorp-  tion is facilitated by glucose transporter 5 (GLUT5) and GLUT7."”  Transport of all three monosaccharides from the cytosol to the  bloodstream is facilitated by GLUT2” (see Figure 40-12). Insulin  facilitates glucose transport into fat and muscle cells via glucose  transporter 4 (GLUT4).   Insulin is not required for the intestinal absorption of glucose.  Cellulose is a glucose polysaccharide found in plants. Humans  lack enzymes to digest cellulose, and the undigested fiber con-  tributes to stool volume and stimulates large intestine motility.   Proteins. Adults require 44 to 56 g of protein per day.  Approximately 20 to 30 g of protein is derived endogenously  from shed epithelial cells and small amounts of plasma proteins.  Most ingested protein is absorbed; only 5% to 10% is eliminated  in the stool.   The site of digestion of protein depends on the source of  the protein. For example, casein from bovine milk precipi-  tates in the stomach and is digested by gastric pepsin and acid,  whereas the soluble proteins whey and soy pass rapidly through  the stomach and are digested by pancreatic enzymes.*! Major  protein hydrolysis is accomplished in the small intestine by the  pancreatic enzymes trypsin, chymotrypsin, and carboxypepti-  dase (see Figure 40-10). Trypsin and chymotrypsin (endopep-  tidase) hydrolyze the interior bonds of the large molecules, and  carboxypeptidases cleave the end amino acids (exopeptidase).  Hydrolysis of proteins is also carried out by the brush-border  enzymes and enzymes in the epithelial cytosol (intracellular  fluid). The brush-border enzymes hydrolyze the large oligo-  peptides (proteins composed of three to six amino acids) into  smaller peptides, which can cross cell membranes. Enzymes in  the cytosol then break them down to amino acids. Amino acids  are actively transported from the cytosol into the bloodstream  by a sodium-dependent carrier in the basolateral membrane.  There also are free amino acids that can be absorbed directly  from the intestinal lumen using a membrane transport protein.  Like the sugars, proteins are absorbed primarily in the proximal  area of the small intestine.    Approximately 90 to 100 g of fat is consumed daily by the average  American. Fat is an important source of calories and is a primary  structural component of cell membranes and organelles. Sources  of dietary fat are reviewed in Box 40-2. Although triglycerides  are the major dietary lipids, cholesterol, phospholipids, and fat-  soluble vitamins also have nutritional importance. The digestion  and absorption of fat occur in four phases: (1) emulsification  and lipolysis, (2) micelle formation, (3) fat absorption, and  (4) resynthesis of triglycerides and phospholipids.   The mechanical action of the stomach and small intes-  tine disperses the triglyceride droplets into small particles.    Action Foodstuff  Starch  ~<.  Y  Dextrins, oligosaccharides  lng  Carbohydrate y Y y  digestion and  absorption Lactose Maltose Sucrose  je  Y Y Y  Galactose | | Glucose | | Fructose  Y  Absorbed by capillaries  in the villi and transported  to the liver by portal vein  Proteins  ~«<.  Y  Proteases, peptones  ~«  Protei u  rotein : ee  digestion and Small polypeptides, dipeptides  absorption  le.  y  Amino acids  Y  Absorbed by capillaries in  the villi and transported to  the liver by hepatic portal  vein  Unemulsified fats  Fat a  digestion Monoglycerides Glycerol and  and fatty acids fatty acids    Emulsifying agents (bile  acids, fatty acids, mono-  glycerides, lecithin,  cholesterol, and protein)    in the villi and transported to  the liver in the systemic circula-  tion, which receives lymphatic  flow from the thoracic duct or via the  hepatic portal vein    Glycerol and  short-chain fatty acids  absorbed by capillaries  in the villi and trans-  ported to the liver by  the portal vein    Emulsification is the process by which emulsifying agents (fatty  acids, monoglycerides, lecithin, cholesterol, protein, bile salts)  in the small intestinal lumen cover the small fat particles and  prevent them from re-forming into fat droplets. Emulsified fat  is then ready for lipolysis (lipid hydrolysis) by pancreatic lipase,  phospholipase, and hydrolase. Lipase breaks down triglycerides  to diglycerides, monoglycerides, free fatty acids, and glycerol  (see Figure 40-10). The action of lipase requires the presence of  colipase, a pancreatic enzyme that allows lipase to penetrate the  triglyceride molecule. Phospholipase cleaves fatty acids from  phospholipids, and cholesterol esterase breaks cholesterol  esters into fatty acids and glycerol.   The products of lipid hydrolysis must be made water soluble  if they are to be absorbed efficiently from the intestinal lumen.  This is accomplished by the formation of water-soluble mol-  ecules known as micelles (Figure 40-13). Micelles are formed of  bile salts (see p. 1411), the products of fat hydrolysis, fat-soluble  vitamins, and cholesterol. The fats form the core of the micelle,  and the polar bile salts form an outer shell, with the hydropho-  bic (“water-hating”) side facing the interior and the hydrophilic  (“water-loving”) side facing the aqueous (water-like) content of  the intestinal lumen. Because the unstirred layer of the brush  border is aqueous, the micelles readily diffuse through it. The  micelles maintain the fat molecules in the dissolved or solubi-  lized form, which allows them to move more rapidly from the  micelle toward the absorbing surface of the intestinal epithe-  lium. The fat products of the micelle then readily diffuse through  the epithelial cell membrane, while the bile salts remain in the  lumen and proceed to the ileum, where they are absorbed into    FIGURE 40-12 Monosaccharides and Sodium Transport. Schematic showing monosaccharides and sodium (Na?)  transport through the small intestinal epithelium. Glucose, galactose, and sodium are transported into the epithelial cell by   Each carbon atom in the chain is linked by single bonds to adjacent carbon and  hydrogen atoms; atoms are solid at room temperature and found in animal fat  and tropical oils (coconut and palm oils); they increase low-density lipoprotein  (LDL) cholesterol (“bad” cholesterol) blood levels and increase the risk of coro-  nary artery disease.   Unsaturated fatty acids are soft or liquid at room temperature; omega-6 fatty  acids are found in plants and vegetables (olive, canola, and peanut oils), and  omega-3 fatty acids are found in fish and shellfish.   1. Monounsaturated fatty acids (e.g., oleic acid [C;gH3,0,]): Contain one  double bond in the carbon chain and are found in plants and animals;  may be beneficial in reducing blood cholesterol, glucose levels, and sys-  tolic blood pressure; do not lower high-density lipoprotein (HDL) choles-  terol (“good” cholesterol) level; low HDL levels have been associated  with coronary heart disease.   . Polyunsaturated fatty acids (e.g., linoleic acid [C;gH30]): Contain two or  more double bonds in the carbon chain and are found in plants and fish  oils; omega-6 fatty acids lower total and LDL cholesterol blood levels;  high levels of polyunsaturated fatty acids may lower LDL level; omega-3  fatty acids lower blood triglyceride levels, reduce platelet aggregation  and blood-clotting tendency, are necessary for growth and development,  and may prevent coronary artery disease, hypertension, cancer, and  inflammatory and immune disorders.    FIGURE 40-13 Structure of Bile Acid and Micelle. A, A bile salt molecule  in solution. The molecule is amphipathic in that it has a hydrophilic face and a  hydrophobic face. The amphipathic structure is key in the ability of the bile salts to  emulsify lipids and form micelles. B, A model of the structure of a bile salt—lipid  mixed micelle, an emulsified fat. (From Levy MN, Koeppen BM, Stanton BA: Prin-  ciples of physiology, ed 4, St Louis, 2006, Mosby.)    the circulation and returned to the liver via the enterohepatic  circulation (Figure 40-14 and Figure 40-20, p. 1411). Almost all  of the bile salts are recycled in this way.   When the fat products reach the inside of the epithelial cell,  they are resynthesized into triglycerides and phospholipids. The  triglycerides are covered with phospholipids, lipoproteins, and  cholesterol to become particles called chylomicrons. The chy-  lomicrons travel to the basolateral membrane of the columnar  epithelial cells, where they are extruded into the intercellular  spaces of the villus. From here they enter the lacteals and lym-  phatic channels and, eventually, the systemic circulation.   Minerals and Vitamins. The recommended intake of calcium  ranges from 1000 to 1500 mg/day. Between 500 and 600 mg is  secreted or shed into the lumen with desquamated epithelial  cells. Not all of this calcium is absorbed. Daily absorption of  calcium is approximately 600 mg. This amount increases with  increased intake. When its concentration in the lumen is greater  than 5 mmol/L, calcium is absorbed by passive diffusion. At  concentrations less than 5 mmol/L, calcium is transported actively  across cell membranes, bound to a carrier protein. The carrier  formation requires the presence of the active form of vitamin D,  (1,25-dihydroxy-vitamin D). The calcium-protein complex moves  into the epithelial cell, where the calcium binds to proteins or other  substances. Then these complexes move through the basolateral  membrane to the interstitial fluid by diffusion or active transport.  Calcium is absorbed throughout the small intestine, but primarily  in the ileum. Increased serum calcium concentration inhibits  parathyroid hormone, which in turn decreases the formation of  vitamin D, by the kidney, thus regulating calcium absorption.   Increased demand for calcium results in increased uptake, as  evidenced by the fact that calcium is absorbed more rapidly in  children and pregnant or lactating women. Bile salts enhance  calcium absorption indirectly by facilitating the absorption of  vitamin D, which is fat soluble. In addition, bile salts promote  the absorption of free fatty acids that, at high concentrations,  bind calcium and form soaps in the intestinal lumen. In older  individuals calcium is absorbed less readily because of inade-  quate amounts of the active form of vitamin D.”   The recommended intake of magnesium for adults is 300  to 350 mg/day. Approximately 50% of it is absorbed by active  transport or passive diffusion in the jejunum and ileum. Phos-  phate is also absorbed in the small intestine by passive diffusion  and active transport.   The levels of iron in the body are regulated primarily by intes-  tinal absorption and secretion. The average intake ranges from  15 to 30 mg/day. Of this amount, menstruating women absorb 1  to 1.5 mg and men absorb 0.15 to 1 mg. Generally the amount of  iron absorbed is equal to the amount required. Iron is absorbed  more rapidly if a deficiency exists. A primary source of iron is  heme from animal protein. This iron is rapidly absorbed by the  epithelial cells primarily in the duodenum. Inorganic iron (e.g.,  iron in fruits, cereals, eggs, vegetables) is also readily absorbed.  The presence of vitamin C reduces ferric iron to ferrous iron,  which is the form more easily absorbed. Calcium phosphate and  phosphoproteins (milk and antacids) in the intestinal lumen  bind iron and reduce absorption. Tea also binds iron and inhib-  its absorption by forming iron tannate complexes.    FIGURE 40-14 Lipid Absorption in the Small Intestine. Micelles of bile salts and products of lipid digestion diffuse  through the unstirred layer and among the microvilli. As digestive products are absorbed from free solution by epithelial cells  of the villi, more digestive products dissociate from the micelles. (From Levy MN, Koeppen BM, Stanton BA: Principles of   Bg (pyridoxine, pyridoxamine, pyridoxal phosphate) Passive diffusion  Pantothenic acid Passive diffusion  Biotin Unknown    Iron is bound to intestinal transferrin in the lumen and is  absorbed and bound to the protein ferritin and to amino acid  chelates in the cytosol of the enterocytes. Transport of iron  across the basolateral membrane is determined by the amount  of iron in the circulation. It is transported in the blood by  plasma transferrin, a glycoprotein, and is carried to body tis-  sues. When there is less need for iron, it remains in the entero-  cyte as ferritin and is carried into the lumen when the cell is  sloughed from the end of the villus. Following hemorrhage,  the intestinal cells require 3 days to increase their rate of iron  absorption. This is because the need for iron is perceived by the  precursor stem cells in the crypts of Lieberkiihn, and they take  3 days to mature and migrate to the tips of the villi, where they  absorb more iron. Hepcidin is a protein synthesized by the liver  that inhibits apical uptake of iron by enterocytes and modulates  iron trafficking.”    Passive diffusion; active transport (sodium dependent) lleum  Active transport (sodium dependent)  Active transport (intrinsic factor dependent)    The absorption of vitamins is summarized in Table  40-2. Most of the water-soluble vitamins are absorbed pas-  sively or by sodium-dependent active transport. Most vita-  min B,, (cobalamin) is bound to intrinsic factor (making it  resistant to digestion) and absorbed in the terminal ileum,  although a small amount of the vitamin is absorbed in its free  (unbound) form.    The movements of the small intestine facilitate digestion and  absorption. Chyme coming from the stomach stimulates intes-  tinal movements that mix in secretions from the liver, pancreas,  and intestinal glands. A churning motion brings the luminal  content into contact with the absorbing cells of the villi. Pro-  pulsive movements then advance the chyme toward the large  intestine.    Intestinal motility is regulated by the enteric nervous system,  vagal stimulation, and hormones (see Table 40-1). Two move-  ments promote motility: segmentation and peristalsis. Segmen-  tation consists of localized rhythmic contractions of the circular  smooth muscles and occurs more frequently than peristalsis.**  The contraction waves occur at different rates in different parts  of the small intestine in segments of 1 to 4 cm. Frequency is  greatest (12 per minute) in the upper small intestine and least  (8 per minute) in the distal part of the ileum. Segmentation  divides and mixes the chyme, bringing it into contact with the  absorbent mucosal surface. It also helps to propel the chyme  toward the large intestine. The frequency of the segmentation  is regulated intrinsically by the frequency of the basic electrical  rhythm (BER), which arises in the myenteric plexus of longitu-  dinal smooth muscle and is controlled by the interstitial cells  of Cajal, the pacemaker cells of the gastrointestinal (GI) tract.  Although the basic rate of contraction is controlled intrinsi-  cally, the force of contraction can be enhanced extrinsically by  vagal stimulation.”   Intestinal peristalsis involves short segments (about 10 cm)  of longitudinal smooth muscle and propels chyme through the  intestine. The wave of contraction moves slowly (1 to 2 cm/sec-  ond) to allow time for digestion and absorption.   Peptide hormones, including motilin, gastrin, secretin, and  cholecystokinin, facilitate intestinal motility. Neural reflexes  along the length of the small intestine facilitate motility, diges-  tion, and absorption. Through reflex action, receptors in one part  of the intestine transmit signals that influence the function of  another part. The ileogastric reflex inhibits gastric motility when  the ileum becomes distended. This prevents the continued move-  ment of chyme into an already distended intestine. The intes-  tinointestinal reflex inhibits intestinal motility when one part  of the intestine is overdistended. Both of these reflexes require  extrinsic innervation. The gastroileal reflex, which is activated  by an increase in gastric motility and secretion, stimulates an  increase in ileal motility and relaxation of the ileocecal sphincter.  This empties the ileum and prepares it to receive more chyme.  The gastroileal reflex is probably regulated by the hormones gas-  trin and cholecystokinin or through the autonomic nerves.   During prolonged fasting or between meals, particularly  overnight, slow waves sweep along the entire length of the  intestinal tract from the stomach to the terminal ileum. This is  known as the interdigestive myoelectric complex, and it appears  to propel residual gastric and intestinal contents, including bac-  teria, into the colon.   The intestinal villi move with contractions of the muscu-  laris mucosae, a very thin layer of muscle that separates the  mucosa and submucosa. Absorption is promoted by the sway-  ing of villi in the luminal contents. Contractile activity also  helps to empty the central lacteals, which contain products of  fat digestion.   The ileocecal valve (sphincter) marks the junction between  the terminal ileum and the large intestine. This valve is intrinsi-  cally regulated and is normally closed. The arrival of peristal-  tic waves from the last few centimeters of the ileum causes the  ileocecal valve to open, allowing a small amount of chyme to  pass through. Distention of the upper large intestine causes the    sphincter to constrict, preventing further distention or retro-  grade flow of intestinal contents.    The large intestine is approximately 1.5 m long and consists  of the cecum, appendix, colon, rectum, and anal canal (Figure  40-15). The cecum is a pouch that receives chyme from the  ileum. Attached to the cecum is the vermiform appendix, an  appendage having little or no physiologic function. From the  cecum, chyme enters the colon, a four-part length of intestine  that loops upward, traverses the abdominal cavity, and descends  to the anal canal. The four parts of the colon are the ascending  colon, transverse colon, descending colon, and sigmoid colon.  Two sphincters control the flow of intestinal contents through  the cecum and colon: the ileocecal valve, which admits chyme  from the ileum to the cecum, and the rectosigmoid (O’Beirne)  sphincter, which controls the movement of wastes from the  sigmoid colon into the rectum. A thick (2.5 to 3 cm) portion  of smooth muscle surrounds the anal canal, forming the inter-  nal anal sphincter. Overlapping it distally is the striated skeletal  muscle of the external anal sphincter.   In the cecum and colon the longitudinal muscle layer consists  of three longitudinal bands called teniae coli (see Figure 40-15).  The teniae coli are shorter than the colon, giving the colon its  “gathered” appearance. The circular muscles of the colon sepa-  rate the gathers into outpouchings called haustra. The haus-  tra become more or less prominent with the contractions and  relaxations of the circular muscles. The mucosal surface of the  colon has rugae (folds), particularly between the haustra, and  Lieberkiihn crypts but no villi. Columnar epithelial cells and  mucus-secreting goblet cells form the mucosa throughout the  large intestine. The columnar epithelium absorbs fluid and  electrolytes, and the mucus-secreting cells lubricate the mucosa.   The enteric nervous system regulates motor and secretory  activity independently of extrinsic nervous system control.  Extrinsic parasympathetic innervation occurs through the vagus  nerve and extends from the cecum up to the first part of the trans-  verse colon. Vagal stimulation increases rhythmic contraction  of the proximal colon. Extrinsic parasympathetic fibers reach  the distal colon through the sacral parasympathetic splanchnic  nerves. The internal anal sphincter is usually in a state of contrac-  tion, and its reflex response is to relax when the rectum is dis-  tended. The myenteric plexus provides the major innervation of  the internal anal sphincter, but responds to sympathetic stimula-  tion to maintain contraction and parasympathetic stimulation  that facilitates relaxation when the rectum is full. Sympathetic  innervation of this sphincter arises from the celiac and superior  mesenteric ganglia and the sphincter nerve. The external anal  sphincter is innervated by the pudendal nerve arising from sacral  levels of the spinal cord. Voluntary control of the external anal  sphincter is paralyzed after injury of the lower spinal cord, but  the internal sphincter is still functional. Sympathetic activity in  the entire large intestine modulates intestinal reflexes, conveys  somatic sensations of fullness and pain, participates in the def-  ecation reflex, and constricts blood vessels. The blood supply of  the large intestine and rectum is derived primarily from branches  of the superior and inferior mesenteric artery.”°    FIGURE 40-15 Large Intestine. A, Structure of the large intestine. B, Microscopic cross section illustrating cellular  structures of the large intestine. The wall of the large intestine is lined with columnar epithelium in contrast to the villi char-  acteristics of the small intestine. The longitudinal layer of muscularis is reduced to become the teniae coli. (A modified from  Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby; B from Gartner LP, Hiatt JL: Color textbook of    The primary type of colonic movement is segmental. The cir-  cular muscles contract and relax at different sites, shuttling the  intestinal contents back and forth between the contracting and  relaxing haustra. The movements massage the intestinal con-  tents, then called the fecal mass, and facilitate the absorption of  water. Propulsive movement occurs with the proximal-to-distal  contraction of several haustral units. Peristaltic movements  also occur and promote the emptying of the colon. The gas-  trocolic reflex initiates propulsion in the entire colon, usually  during or immediately after eating, when chyme enters from  the ileum. The gastrocolic reflex causes the fecal mass to pass  rapidly into the sigmoid colon and rectum, stimulating defeca-  tion. Gastrin and cholecystokinin participate in stimulating this  reflex. Epinephrine inhibits contractile activity.   Approximately 500 to 700 ml of chyme flows from the ileum  to the cecum per day. Most of the water is absorbed in the colon  by diffusion and active transport. The electrochemical gradi-  ent established by sodium movement enhances the diffusion of  serum potassium from the capillaries in the lumen. Aldosterone  increases colon membrane permeability to sodium, thereby  increasing both the diffusion of sodium into the cell and the  active transport of sodium across the basolateral membrane to  the interstitial fluid. (See Chapters 3, 21, and 37 for a discussion  of aldosterone secretion.) This increases the cell-to-lumen dif-  fusion gradient for potassium. Potassium moves outward, and  chloride is absorbed with sodium as the complementary anion.  Chloride also enters the cell in exchange for bicarbonate.   By the time the fecal mass enters the sigmoid colon, the  mass consists entirely of wastes and is called the feces. Feces,    or excrement, consists of food residue, unabsorbed gastrointes-  tinal secretions, shed epithelial cells, and bacteria. The move-  ment of feces into the sigmoid colon and rectum stimulates  the defecation reflex (rectosphincteric reflex). The rectal wall  stretches and the tonically constricted internal anal sphincter  relaxes, creating the urge to defecate. The defecation reflex can  be overridden voluntarily by contraction of the external anal  sphincter and muscles of the pelvic floor. The rectal wall gradu-  ally relaxes, reducing tension, and the urge to defecate passes.  Retrograde contraction of the rectum may displace the feces  out of the rectal vault until a more convenient time for evacua-  tion. Pain or fear of pain associated with defecation (e.g., rectal  fissures or hemorrhoids) can inhibit the defecation reflex. The  defecation reflex is regulated by parasympathetic and choliner-  gic fibers. Voluntary inhibition or facilitation of defecation is  mediated from cortical projections onto the medulla and down  to sacral segments of the cord.   Defecation is facilitated by squatting or sitting because these  positions straighten the angle between the rectum and anal  canal and increase the efficiency of straining (increasing intra-  abdominal pressure). Intra-abdominal pressure is increased by  initiating the Valsalva maneuver. This maneuver consists of  inhaling and forcing the diaphragm and chest muscles against  the closed glottis. This increases both intrathoracic and intra-  abdominal pressure, which is transmitted to the rectum.    The type and number of bacterial flora vary greatly throughout  the normal gastrointestinal tract, with an increasing number    FIGURE 40-16 Locations of the Liver, Gallbladder, and Exocrine Pan-  creas, Which Are the Accessory Organs of Digestion.    of bacteria from the stomach to the distal colon. The stomach  is relatively sterile because of the secretion of acid that kills  ingested pathogens or inhibits bacterial growth. Bile acid secre-  tion, intestinal motility, and antibody production suppress  bacterial growth in the duodenum, and in the duodenum and  jejunum there is a low concentration of aerobes (107! to 10~4/  ml), primarily streptococci, lactobacilli, staphylococci, entero-  bacteria, and Bacteroides. Anaerobes are only found distal to the  ileocecal valve. They constitute about 95% of the fecal flora in  the colon and contribute one third of the solid bulk of feces. Bac-  teroides, clostridia, anaerobic lactobacilli, and coliforms are the  most common microorganisms from the ileum to the cecum.?’   The intestinal tract is sterile at birth but becomes colonized  with Escherichia coli, Clostridium welchii, and Streptococcus  within a few hours. Within 3 to 4 weeks after birth, the nor-  mal flora are established. The normal flora do not have the  virulence factors associated with pathogenic microorganisms,  thus permitting immune tolerances. The intestinal mucosal  environment also produces a broad spectrum of protective  antimicrobial agents.”* The intestinal bacteria play a role in the  metabolism of bile salts (contributing to the intestinal reab-  sorption of bile and the elimination of toxic bile metabolites);  the metabolism of estrogens, androgens, and lipids and conver-  sion of unabsorbed carbohydrates to absorbable organic acids;  the synthesis of vitamin K, and B vitamins; and the metabolism  of various nitrogenous substances and drugs.”?    The liver, gallbladder, and exocrine pancreas all secrete sub-  stances necessary for the digestion of chyme. These secretions  are delivered to the duodenum through ducts (Figure 40-16).  The liver produces bile, which contains salts necessary for fat    digestion and absorption. Between meals bile is stored in the  gallbladder. The exocrine pancreas produces enzymes needed  for the complete digestion of carbohydrates, proteins, and fats.  The exocrine pancreas also produces an alkaline fluid that neu-  tralizes chyme, creating a duodenal pH that supports enzymatic  action. The liver receives nutrients absorbed by the small intes-  tine and metabolizes or synthesizes these nutrients into forms  that can be absorbed by the body’s cells. It then releases the  nutrients into the bloodstream or stores them for later use.   The liver, which weighs 1200 to 1600 g, is the largest solid  organ in the body. It is located under the right diaphragm and is  divided into right and left lobes. The larger, right lobe is divided  further into the caudate and quadrate lobes (Figure 40-17). The  falciform ligament separates the right and left lobes and attaches  the liver to the anterior abdominal wall. A fibrous cord called  the round ligament (ligamentum teres) extends along the free  edge of the falciform ligament. The round ligament is the rem-  nant of the umbilical vein and extends from the umbilicus to  the inferior surface of the liver. The coronary ligament branches  from the falciform ligament and extends over the superior sur-  face of the right and left lobes, adhering the liver to the inferior  surface of the diaphragm. The liver is covered by a fibroelas-  tic capsule called the Glisson capsule. When the liver is diseased  or swollen, distention of the capsule causes pain because it is  innervated by afferent neurons.   The metabolic functions of the liver require a large amount  of blood. The liver receives blood from both arterial and venous  sources. The hepatic artery branches from the celiac artery  and provides oxygenated blood at the rate of 400 to 500 ml/  minute (about 25% of the cardiac output). The hepatic portal  vein, which receives deoxygenated blood from the inferior and  superior mesenteric veins and the splenic vein, delivers about  1000 to 1200 ml/minute of blood to the liver. The hepatic portal  vein, which carries 70% of the blood supply to the liver, is rich  in nutrients that have been absorbed from the digestive tract  (Figure 40-18).   Within the liver lobes are multiple, smaller anatomic units  called liver lobules (Figure 40-19). The lobules are formed of  cords or plates of hepatocytes, which are the functional cells  of the liver. These cells are capable of regeneration; therefore,  damaged or resected liver tissue can regrow. Hepatocytes  secrete electrolytes, lipids, lecithin, bile acids, and cholesterol  into the canaliculi. Plasma proteins are also synthesized and  released into the bloodstream. Lipocytes are star-shaped cells  that store lipids, including vitamin A. Small capillaries, or  sinusoids, are located between the plates of hepatocytes. The  sinusoids receive a mixture of venous and arterial blood from  branches of the hepatic artery and hepatic portal vein. Blood  from the sinusoids drains into a central vein in the middle of  each liver lobule. Venous blood from all the lobules then flows  into the hepatic vein, which empties into the inferior vena cava.  The sinusoids of the liver lobules are lined with highly perme-  able endothelium. This permeability enhances the transport of  nutrients from the sinusoids into the hepatocytes, where they  are metabolized.*° The sinusoids are also lined with phagocytic    FIGURE 40-17 Gross Structure of the Liver. A, Anterior view. B, Inferior view. (From Patton KT, Thibodeau GA: Anatomy    FIGURE 40-18 Hepatic Portal Circulation. In this unusual circulatory route,  a vein is located between two capillary beds. The hepatic portal vein collects blood  from capillaries in visceral structures located in the abdomen and empties into the  liver for distribution to the hepatic capillaries. Hepatic veins return blood to the  inferior vena cava. (Organs are not drawn to scale.) (From Patton KT, Thibodeau GA:  Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    cells, known as Kupffer cells, which are part of the mononuclear  phagocyte system (see Chapters 7 and 27) and are the largest  population of tissue macrophages in the body. They are bacte-  ricidal and central to innate immunity.*! Stellate cells contain  retinoids (vitamin A), are contractile in liver injury, regulate  sinusoidal blood flow, may proliferate into myofibroblasts, and    FIGURE 40-19 Diagrammatic Representation of a Liver Lobule. A central  vein is located in the center of the lobule, with plates of hepatocytes disposed radi-  ally. Branches of the portal vein and hepatic artery are located on the periphery of  the lobule, and blood from both vessels perfuses the sinusoids. Peripherally located  bile ducts drain the bile canaliculi that run between the hepatocytes. (Modified  from Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    participate in liver fibrosis.*” They remove foreign substances  from the blood and trap bacteria. Pit cells are natural killer cells  found in the sinusoidal lumen; they produce interferon-y and  are important in tumor defense.** Between the endothelial lin-  ing of the sinusoid and the hepatocyte is the Disse space, which  drains interstitial fluid into the hepatic lymph system.    65% to 85% of bile salts  and secondary bile acids  enter the circulation with  protein binding and are  transported to liver    intestinal lumen or are  deconjugated by bacteria  into secondary  bile acids  that diffuse passively  across the lumen    The liver assists intestinal digestion by secreting 700 to 1200  ml of bile per day. Bile is an alkaline, bitter-tasting yellow-  ish green fluid that contains bile salts (conjugated bile acids),  cholesterol, bilirubin (a pigment), electrolytes, and water. It is  formed by hepatocytes and secreted into the canaliculi, which  are small channels adjacent to hepatocytes. Bile salts, which  are conjugated bile acids, are required for the intestinal emul-  sification and absorption of fats. The bile canaliculi empty  into hepatic bile ducts and eventually drain into the com-  mon bile duct (see Figure 40-19). The union of the common  bile duct and pancreatic duct is at the papilla or ampulla of  Vater, which empties into the duodenum through an open-  ing called the major duodenal papilla and is surrounded by  the sphincter of Oddi.* Having facilitated fat emulsifica-  tion and absorption in the small intestine, most bile salts are  actively absorbed in the terminal ileum and returned to the  liver through the portal circulation for resecretion. The path-  way for recycling of bile salts is termed the enterohepatic cir-  culation (Figure 40-20).*    Bile has two fractional components: the acid-dependent  fraction and the acid-independent fraction. Hepatocytes secrete  the bile acid—dependent fraction of the bile. This fraction con-  sists of bile acids, cholesterol, lecithin (a phospholipid), and  bilirubin (a bile pigment). The bile acid—independent fraction  of the bile, which is secreted by the hepatocytes and epithelial  cells of the bile canaliculi, is a bicarbonate-rich aqueous fluid  that gives bile its alkaline pH.   Bile salts are conjugated in the liver from primary and sec-  ondary bile acids. The primary bile acids are cholic acid and  chenodeoxycholic (chenic acid or chenodiol) acid. These acids  are synthesized from cholesterol by the hepatocytes. The sec-  ondary bile acids are deoxycholic acid and lithocholic acid.  These acids are formed in the small intestine by the action of  intestinal bacteria, after which they are absorbed and flow to  the liver (see Figure 40-20). Both forms of bile acids are conju-  gated with amino acids (glycine or taurine) in the liver to form  bile salts. Conjugation makes the bile acids more water solu-  ble, thus restricting their diffusion from the duodenum and  ileum. The primary and secondary bile acids together form the  bile acid pool.   Bile secretion is called choleresis. A choleretic agent is a  substance that stimulates the liver to secrete bile. One strong  stimulus is a high concentration of bile salts. Other chole-  retics include secretin, which increases the rate of bile flow  by promoting the secretion of bicarbonate from canaliculi  and other intrahepatic bile ducts; cholecystokinin; and vagal  stimulation.    Bilirubin is a byproduct of destruction of aged red blood cells.  It gives bile a greenish black color and produces the yellow tinge  of jaundice. Aged red blood cells are taken up and destroyed  by macrophages of the mononuclear phagocyte system, pri-  marily in the spleen and liver. (In the liver these macrophages  are Kupffer cells.) Within these cells, hemoglobin is separated  into its component parts—heme and globin (Figure 40-21).  The globin component is further degraded into its constituent  amino acids, which are recycled to form new protein. The heme  moiety is converted to biliverdin by the enzymatic (heme oxy-  genase) cleavage of iron. The iron attaches to transferrin in the  plasma and can be stored in the liver or used by the bone mar-  row to make new red blood cells. The biliverdin is enzymatically  converted to bilirubin in the macrophage of the mononuclear  phagocytic system and then is released into the plasma. In the  plasma, bilirubin binds to albumin and is known as uncon-  jugated bilirubin, or free bilirubin, which is lipid soluble.  Bilirubin also may have a role as an antioxidant and provide  cytoprotection.*°°”   In the liver, unconjugated bilirubin moves from plasma  in the sinusoids into the hepatocyte. Within hepatocytes it  joins with glucuronic acid to form conjugated bilirubin,  which is water soluble. Conjugation transforms bilirubin  from a lipid-soluble substance that can cross biologic mem-  branes to a water-soluble substance that can be excreted in  the bile. When conjugated bilirubin reaches the distal ileum  and colon, it is deconjugated by bacteria and converted to    Unconjugated bilirubin  +  Albumin  (bilirubin/albumin complex makes  bilirubin soluble in blood)    urobilinogen. Urobilinogen is then reabsorbed in the intes-  tines and transported to the kidney where it is excreted in  the urine as urobilin, giving urine its yellow color. A small  amount of urobilin is recirculated back into the liver and  eliminated in feces as stercobilin, which contributes to the  stool’s brown pigmentation.    Because of its extensive vascular network, the liver can store  a large volume of blood. The amount stored at any one time  depends on pressure relationships in the arteries and veins. The  liver also can release blood to maintain systemic circulatory vol-  ume in the event of hemorrhage.   Fluid balance Albumin is a major source of plasma oncotic pressure.   Collagen fibers provide structural support to many parts  of the body; keratin strengthens skin, hair, and nails.   Hemoglobin transports oxygen and carbon dioxide  in the blood; plasma proteins serve as transport  molecules; proteins in cell membranes control  movement of materials into and out of cells.    Kupffer cells (macrophages) in the sinusoids of the liver  remove bacteria and foreign particles from blood in the hepatic  circulation. Because the liver receives all of the venous blood  from the gut and pancreas, the Kupffer cells play an important  role in destroying intestinal bacteria and preventing infections.   The liver also has hemostatic functions. It synthesizes most  of the clotting factors (see Chapters 7 and 27). Vitamin K,  (synthesized by plants and ingested in the diet) and vitamin  K, (synthesized by intestinal bacteria) are fat-soluble vitamins  essential for the synthesis of clotting factors (prothrombin  and factors VH, IX, and X). Because bile salts are needed for  absorption of fats, vitamin K absorption depends on adequate  bile production in the liver. Impairment of vitamin K absorp-  tion diminishes production of clotting factors and increases  risk of bleeding.    Fats. Ingested fat absorbed by lacteals in the intestinal  villi enters the liver through the lymphatics, primarily as  triglycerides. In the liver the triglycerides can be hydrolyzed  to glycerol and free fatty acids and used to produce metabolic  energy (ATP), or they can be released into the bloodstream  bound to proteins (lipoproteins). The lipoproteins are carried by  the blood to adipose cells for storage. The liver also synthesizes  phospholipids and cholesterol, which are needed for the hepatic  production of bile salts, steroid hormones, components of  plasma membranes, and other special molecules.   Proteins. Protein synthesis requires the presence of all the  essential amino acids (obtained only from food), as well as  nonessential amino acids. Proteins perform many important  roles in the body and are summarized in Table 40-3.   Within hepatocytes, amino acids are converted to carbohy-  drates by the removal of ammonia (NH;), a process known as  deamination. The ammonia is converted to urea by the liver  and passes into the blood to be excreted by the kidneys. The  plasma proteins, including albumins and globulins (with the  exception of gamma globulin, which is formed in lymph nodes  and lymphoid tissue), are synthesized by the liver. The liver also    synthesizes several nonessential amino acids and serum enzymes  that become elevated with liver injury (and other diseases):  + Aspartate aminotransferase (AST) (previously called  serum glutamate-oxaloacetate transaminase [SGOT]):  also present in red blood cells and skeletal muscle; AST  transfers an a-amino group between aspartate and  glutamate.  + Alanine aminotransferase (ALT) (previously called  serum glutamate-pyruvate transaminase [SGPT]): also  present in small amounts in the kidneys, heart, skeletal  muscle, and pancreas; ALT transfers an amino group  from alanine to a-ketoglutarate to form pyruvate and  glutamate.  + Lactate dehydrogenase (LDH): catalyzes the conversion  of lactate to pyruvate; LDH is widely distributed through-  out the body and different isoenzymes are found in dif-  ferent tissues.  + Alkaline phosphatase: removes phosphate groups, par-  ticularly in an alkaline environment.  * Gamma-glutamyltransferase: transfers the gamma-  glutamyl moiety of glutathione to an acceptor to form  glutamate and is a pro-oxidant.  Reference values for the above enzymes can be reviewed in  Table 40-6 and are summarized on the inside back book cover.   Carbohydrates. The liver contributes to the stability of blood  glucose levels by releasing glucose during states of hypoglycemia  (low blood glucose levels) and taking up glucose during states  of hyperglycemia (high blood glucose levels) and storing it as  glycogen (glyconeogenesis) or converting it to fat. When all  glycogen stores have been used, the liver can convert amino  acids and glycerol to glucose.   The liver alters exogenous and endogenous chemicals (e.g.,  drugs), foreign molecules, and hormones to make them less  toxic or less biologically active. This process, called metabolic  detoxification (biotransformation), diminishes intestinal  or renal tubular reabsorption of potentially toxic substances  and facilitates their intestinal and renal excretion. In this way  alcohol, barbiturates, amphetamines, steroids, and hormones  (including estrogens, aldosterone, antidiuretic hormone, and  testosterone) are metabolized or detoxified, preventing exces-  sive accumulation and adverse effects.   Although metabolic detoxification is usually protec-  tive, sometimes the end products of metabolic detoxification  become toxins. Those of alcohol metabolism, for example, are  acetaldehyde and hydrogen. Excessive intake of alcohol over a  prolonged period causes these end products to damage hepa-  tocytes. Acetaldehyde damages cellular mitochondria, and the  excess hydrogen promotes fat accumulation. This is how alco-  hol impairs the liver’s ability to function (see Chapter 2).   The liver stores certain vitamins and minerals, including iron and  copper, in times of excessive intake and releases them in times of  need. The liver can store vitamins B,, and D for several months  and vitamin A for several years. The liver also stores vitamins    E and K. Iron is stored in the liver as ferritin, an iron-protein  complex, and is released as needed for red blood cell production.    The gallbladder is a saclike organ that lies on the inferior sur-  face of the liver (Figures 40-17 and 40-22). The wall of the gall-  bladder is composed of the mucous membrane, muscularis,  and serosa. The primary function of the gallbladder is to store  and concentrate bile between meals. During the interdigestive  period, bile flows from the liver through the right or left hepatic  duct into the common bile duct and meets resistance at the  closed sphincter of Oddi, which controls flow into the duode-  num and prevents reflux of duodenal contents into the pancre-  atobiliary system. Bile then flows into the gallbladder through  the cystic duct where it is concentrated and stored. The mucosa  of the gallbladder wall readily absorbs water and electrolytes,  leaving a high concentration of bile salts, bile pigments, and  cholesterol. The gallbladder holds about 90 ml of bile.   Within 30 minutes after eating, the gallbladder begins to  contract, forcing stored bile through the cystic duct and into  the common bile duct. The sphincter of Oddi relaxes, and bile  flows into the duodenum through the major duodenal papilla.  During the cephalic and gastric phases of digestion, gallblad-  der contraction is mediated by cholinergic branches of the  vagus nerve. Hormonal regulation of gallbladder contraction is  derived primarily from the release of cholecystokinin secreted by  the duodenal and jejunal mucosa in the presence of fat. Vasoac-  tive intestinal peptide, pancreatic polypeptide, and sympathetic  nerve stimulation relax the gallbladder.    The pancreas is approximately 20 cm long, with its head tucked  into the curve of the duodenum and its tail touching the spleen.  The body of the pancreas lies deep in the abdomen, behind the  stomach (see Figure 40-16). The pancreas is unique in that it  has endocrine as well as exocrine functions. The endocrine pan-  creas secretes insulin, glucagon, somatostatin, and pancreatic  polypeptide (see Chapter 21).   The exocrine pancreas is composed of acinar cells that  secrete enzymes and networks of ducts that secrete alkaline  fluids with important digestive functions. The acinar cells are  organized into spherical lobules (acini) around small secretory  ducts (see Figure 40-22). Secretions drain into a system of ducts  that leads to the pancreatic duct (Wirsung duct), which emp-  ties into the common bile duct at the ampulla of Vater and then  through the duodenal papilla into the duodenum. In some indi-  viduals an accessory duct (the duct of Santorini) branches off  the pancreatic duct and drains directly into the duodenum at  an opening called the minor duodenal papilla (see Figure 40-22).   Arterial blood is supplied to the pancreas by branches of the  celiac and superior mesenteric arteries. Venous blood leaves the  head of the pancreas through the tributaries to the hepatic por-  tal vein, with the body and tail being drained through the splenic  vein. All hormonal pancreatic secretions also pass through the  hepatic portal vein into the liver.   Pancreatic innervation arises from parasympathetic neurons  of the vagus nerve, which stimulate enzymatic and hormonal    secretion. Sympathetic postganglionic fibers from the celiac and  superior mesenteric plexuses innervate the blood vessels and  cause vasoconstriction and inhibit pancreatic secretion.**   The aqueous secretions of the exocrine pancreas are isotonic  and contain potassium, sodium, bicarbonate, magnesium,  calcium, and chloride. Sodium and potassium concentrations  are about equal to those in the plasma. The concentration of  bicarbonate in pancreatic juice varies directly with the secretory  flow rate. As bicarbonate secretion increases, chloride secretion  decreases to maintain a constant anionic concentration. The  highly alkaline pancreatic juice neutralizes the acidic chyme  that enters the duodenum from the stomach and provides the   electrolytes and water  FIGURE 40-22 Associated Structures of the Gallbladder, Pancreas, and Pancreatic Acinar Cells and Duct. (Mod-  ified from Patton KT, Thibodeau GA: Anatomy & physiology, ed 6, St Louis, 2007, Mosby.)    alkaline medium needed for the actions of digestive enzymes  and the absorption of fat in the intestine.   In the pancreas, transport of water and electrolytes through  the ductal epithelium involves active and passive mechanisms.  The ductal cells actively transport hydrogen into the blood and  bicarbonate into the duct lumen. Potassium and chloride are  secreted by diffusion according to changes in electrochemi-  cal potential gradients. As the secretion flows down the duct,  water is osmotically transported into the juice until it becomes  isosmotic. At low flow rates, bicarbonate is exchanged passively  for chloride, but at higher flow rates there is less time for this  exchange and bicarbonate concentration increases. Because    Endoscopy  Esophagoscopy (esophagus)  Gastroscopy (stomach)  Duodenoscopy (duodenum)  Colonoscopy (large intestine)  Sigmoidoscopy (sigmoid colon)  Ultrasound    eating stimulates the flow of pancreatic juice, the juice is most  alkaline when it needs to be—during digestion. Secretion of the  aqueous and enzymatic components of pancreatic juice is con-  trolled by hormonal and vagal stimuli.   The pancreatic enzymes hydrolyze proteins (proteases), car-  bohydrates (amylases), and fats (lipases). The proteases include  trypsin, chymotrypsin, carboxypeptidase, and elastase. These  enzymes are secreted in their inactive forms—that is, as trypsin-  ogen, chymotrypsinogen, and procarboxypeptidase—to pro-  tect the pancreas from the digestive effects of its own enzymes.  For further protection the pancreas produces trypsin inhibi-  tor, which prevents the activation of proteolytic enzymes while  they are in the pancreas. Once in the duodenum, the inactive  forms (proenzymes) are activated by enterokinase, an enzyme  secreted by the duodenal mucosa. Trypsinogen is the first pro-  enzyme to be activated. Its conversion to trypsin stimulates the  conversion of chymotrypsinogen to chymotrypsin and pro-  carboxypeptidase to carboxypeptidase. Each of these enzymes  cleaves specific peptide bonds to reduce polypeptides to smaller  peptides.   Pancreatic a-amylase is secreted in active form and  digests intestinal carbohydrate by cleaving interior a-1,4-  glucosidic bonds to yield glucose and maltose at an optimum  pH of approximately 6.9. Pancreatic lipases hydrolyze tri-  glycerides, cholesterol, and phospholipids to free fatty acids  in the intestine. Secretin stimulates the acinar and duct cells  to secrete the bicarbonate-rich fluid that neutralizes chyme  and prepares it for enzymatic digestion. As chyme enters the  duodenum, its acidity (pH of 4.5 or less) stimulates the S cells  of the duodenum to release secretin, which is absorbed by the  intestine and delivered to the pancreas in the bloodstream. In  the pancreas, secretin causes ductal and acinar cells to release  alkaline fluid. Secretin also inhibits the actions of gastrin,  thereby decreasing gastric hydrochloric acid secretion and    Passage of rigid or flexible (fiberoptic) endoscope into the  gastrointestinal tract for visualization or biopsy    Use of piezoelectric crystal to generate sound waves that are  reflected from tissue interfaces to provide an image    Use of a computer to integrate differences in absorption of a large  number of x-rays to produce a cross-sectional image; may be    Projection of differences in magnetic properties of molecules within  different cells and tissues, using the field of a large magnet   Enhanced visualization of the contours, position,  and size of the gastrointestinal tract to detect  umbilical hernia, ulcers, diverticula, congenital  anomalies, polyps, tumors, strictures, obstructions   Visualization or biopsy of inflamed hernias, polyps,  ulcers, strictures, varices, tumors, sites of  bleeding, mucosal or neoplastic lesions and for  culture of Helicobacter pylori from stomach    Imaging of abdominal organs (gallbladder, liver,  pancreas, spleen), masses, stones, abscesses,  structural abnormalities   Imaging of gallbladder, liver, pancreas, spleen, cysts,  hematomas, abscesses, stones, extrahepatic bile  ducts, and portal vein   Same applications as CT scan; also can detect blood  flow and vessel patency    motility. The overall effect is to neutralize the contents of the  duodenum.   Enzymatic secretion follows, stimulated by cholecystokinin,  which activates ACh from the vagus nerve and release of ACh  from pancreatic stellate cells.°? Cholecystokinin is released in  the duodenum in response to the essential amino acids and  fatty acids already present in chyme. Once in the small intestine,  activated pancreatic enzymes inhibit the release of more cho-  lecystokinin and ACh. This feedback mechanism inhibits the  secretion of more pancreatic enzymes. Pancreatic polypeptide  is released after eating and inhibits postprandial pancreatic exo-  crine secretion. (Table 40-1 summarizes hormonal stimulation  of pancreatic secretions.)    Although important diagnostic information can be obtained  from the patient’s medical history and presenting symptoms,  numerous disease-specific tests must be performed to evalu-  ate the structure and function of the gastrointestinal tract. A  description of selected studies is presented in Tables 40-4  and 40-5. Radiography and imaging techniques—including  radionuclide, positron emission tomography (PET), magnetic  resonance (MR), computed tomography (CT) scanning, and  ultrasound—are procedures for evaluating structure and func-  tion. Plain radiographs using contrast media such as barium- or  iodine-containing compounds can be used to outline the gas-  trointestinal lumen, biliary tree and pancreatic ducts, fistulae,  and arteriovenous systems. CT scanning is particularly useful  for diagnosis of intestinal lesions and pancreatic or hepatic  tumors or cysts. Ultrasonic scanning is a safe, simple, and rela-  tively inexpensive technique used to detect gallstones and intra-  abdominal masses, particularly abscesses.    Manometry (use of water-filled  catheters connected to pressure  transducers passed into the  esophagus, stomach, colon, or  rectum to evaluate contractility)   Glucose or p-xylose breath test  Urea breath test  Lactose breath test    Detection of Salmonella typhi (typhoid fever), Shigella (dysentery), Vibrio  cholerae (cholera), Yersinia (enterocolitis), Escherichia coli (gastroenteritis),  Staphylococcus aureus (food poisoning), Clostridium botulinum (food poisoning),  Clostridium perfringens (food poisoning), Aeromonas (gastroenteritis)   Steatorrhea (increased values) can result from intestinal malabsorption or  pancreatic insufficiency   Large amounts of pus are associated with chronic ulcerative colitis, abscesses,  and anorectal fistula   Differentiation of pancreatic steatorrhea (normal p-xylose absorption) from  intestinal steatorrhea (impaired 0-xylose absorption)   Detection of duodenal ulcers, Zollinger-Ellison syndrome (increased values),  gastric atrophy, gastric carcinoma (decreased values)    May indicate intestinal bacterial overgrowth  Presence of Helicobacter pylori infection  Lactose intolerance    Fiberoptic endoscopy, using flexible endoscopes, allows  direct visualization of the gastrointestinal tract. A biopsy  channel allows tissue sampling, and suction can be applied to  remove gastrointestinal secretions or blood. Analysis of stool,  gastric secretions, tissue, and plasma provides important clues  to infection, malabsorption syndromes, ulcerative lesions, and  tumor growth.    A variety of diagnostic tests can be performed to evaluate liver  function’?! (Table 40-6). Imaging techniques similar to those  described for the gastrointestinal tract also are useful for eval-  uating liver structure and function. Nuclear imaging is useful  after liver transplant.’* Elevated plasma levels of liver enzymes  are associated with many liver diseases because of the release of  cytoplasmic enzymes into the circulation when there is damage  to the hepatocyte. Of particular importance are elevations of  aminotransferases and lactate dehydrogenase (LDH). Obstruc-  tion of bile canaliculi or ducts results in regurgitation of bile  back into the hepatic sinusoids and into the circulation, mani-  festing with elevation of conjugated bilirubin levels. Prothrom-  bin times (a measure of clotting tendency) are often prolonged  with both hepatitis and chronic liver disease. In severe disease,  other plasma proteins, such as albumin and globulins, may be  diminished as a result of hepatocyte damage. Liver biopsies are  often performed to evaluate the extent of liver involvement or  degeneration with cirrhosis, hepatitis, or fatty liver disease.    Evaluation of structural alterations in the gallbladder may be  achieved by the use of various imaging techniques. Table 40-7  summarizes these techniques. Obstruction of the bile ducts  from stones, tumors, or inflammation prevents the flow of  bile from the liver and gallbladder from reaching the gastro-  intestinal tract. Both the conjugated and total serum bilirubin  values are elevated, urine urobilinogen level is increased, stools  are clay colored, and jaundice develops. Fat absorption can be  impaired and the prothrombin time prolonged if vitamin K is  not absorbed. With inflammation of the gallbladder, the white  cell count is elevated.    Tests of pancreatic function are summarized in Table 40-8. Eval-  uation of serum lipase and urinary amylase provides particu-  larly significant measures of pancreatic injury. Inflammation or  obstruction of the pancreas results in an early increase in serum  amylase levels. Serum lipase level remains elevated after serum  amylase has returned to normal levels and provides greater  sensitivity with delayed presentation of pancreatitis. Elevation  of urine amylase level also occurs later (after 48 hours) when  serum amylase may have returned to normal levels. Urinary  trypsinogen 2 (available as dipstick) is used to diagnose acute  pancreatitis and is comparable to serum amylase and lipase.**  Increased stool fat can reflect pancreatic insufficiency caused by  decreased lipase secretion when biliary function is normal.    Bilirubin Metabolism  Serum bilirubin  Unconjugated (indirect)  Conjugated (direct) 0.2-0.4 mg/dl  TOTAL <1.0 mg/dl  Urine bilirubin 0  Urine urobilinogen 0-4 mg/24 hr    Blood-Clotting Functions  Prothrombin time (PT)  control  25-40 sec  <6% retention in 45 min    Increases with biliary obstruction and cholestatic hepatitis  Increases with biliary obstruction and cholestatic hepatitis    Increases with hepatocellular injury (and injury in other tissues, i.e., skeletal  and cardiac muscle)  Increases with hepatocellular injury and necrosis    Isoenzyme LD; is elevated with hypoxic and primary liver injury  Increases with increase in alkaline phosphatase and cholestatic disorders    Increases with hemolysis (lysis of red blood cells)  Increases with hepatocellular injury or obstruction  Increases with biliary obstruction    Liver damage with decreased values, iron deficiency with increased values  Elevated values in primary hepatocellular carcinoma   Oral cholecystogram (use of an oral contrast medium such as iopanoic  acid, which is excreted with bile and concentrated in the gallbladder for  visualization by radiography; may be administered as a double dose)   Intravenous cholangiography (use of intravenous contrast agents for  visualization of gallbladder and bile ducts)    Endoscopic retrograde cholangiography (instillation of contrast medium  through cannulation of ampulla of Vater with a duodenoscope)  Computed tomography (CT)    Age-related changes in gastrointestinal function can begin to  occur before 50 years of age.** Tooth enamel and dentin wear  down, making the teeth vulnerable to cavities. Teeth are lost,  often as a result of periodontal (gum) disease, recession of    Visualization of calcified gallstones  Visualization of gallstones; evaluation of filling and emptying of gallbladder    Diagnosis of acute gallbladder inflammation (cholecystitis) or disease of bile  ducts   Preferred method for detecting gallstones; differentiation of hepatic disease from  biliary obstruction; diagnosis of chronic cholecystitis   Diagnosis of cholecystitis in individuals allergic to iodine-containing contrast  agents; diagnosis of cystic duct obstruction    Diagnosis of biliary obstruction or malignancy when ultrasound is not successful    the gums, osteoporotic bone changes, and more brittle roots  that fracture easily. Taste buds decline in number, and the  sense of smell diminishes.*° Together these losses decrease the  sense of taste. Salivary secretion decreases and contributes to  dry mouth and loss of taste.*° In very old adults these oral and  sensory changes make eating less pleasurable and reduce appe-  tite. Food may not be chewed or lubricated sufficiently, making   Bicarbonate concentration: >80 mEq/L  Bicarbonate output: >10 mEq/L/30 sec  2-5 g/24 hr    swallowing difficult. The esophagus develops decreased motil-  ity, and changes in the upper esophageal sphincter, history of  stroke, and dementia may affect swallowing and contribute to  gastroesophageal reflux.*”   Age also diminishes gastric motility and volume, including  secretion of bicarbonate and gastric mucus in some individu-  als. Acid content of gastric juice is related to gastric atrophy,  which results in hypochlorhydria (insufficient hydrochloric  acid), delayed gastric emptying, and compromise of the gas-  tric mucosal barrier.** Decreased production of intrinsic fac-  tor leads to inadequate small intestinal absorption of vitamin  B, and pernicious anemia.*? Aging may be associated with  a change in the composition of the intestinal microflora and  increased susceptibility to disease.°° The ileal villi of the small  intestine may become broader and shorter, perhaps because of  a decrease in cell turnover. Intestinal absorption, motility, and  blood flow decrease, impairing nutrient absorption.°! Proteins,  fats, minerals (including iron and calcium), and vitamins are  absorbed more slowly and in lesser amounts, and absorption   Elevated levels with pancreatic inflammation (may be elevated with other conditions;  differentiates with amylase isoenzyme study)    of carbohydrates is decreased. Intestinal transit time is delayed.  Constipation is often described as a condition of old age, but  it is probably caused by lifestyle factors (e.g., diet, lack of fluid  intake) rather than physiologic decline although studies dem-  onstrate there can be alterations in intestinal innervation.”   The rate of liver regeneration decreases with advancing age  but the volume of the liver can be maintained.°? Alterations in  liver function in older individuals are usually a sign of a patho-  logic condition. Liver blood flow and enzyme activity decrease  with age and can influence the efficiency of drug and alco-  hol metabolism.** However, liver function test results often  remain within relatively normal ranges. Alterations in liver  function in older individuals are usually a sign of a pathologic  condition. The pancreas undergoes structural changes, such as  fibrosis, fatty acid deposits, and atrophy. Pancreatic secretion  decreases, but there is usually no observable dysfunction.*°  Aging does not cause apparent changes in the structure and  function of the gallbladder and bile ducts, but the incidence of  gallstones increases.°°   1. The major functions of the gastrointestinal tract are the  mechanical and chemical breakdown of food and the  absorption of digested nutrients.   2. The gastrointestinal tract is a hollow tube that extends from  the mouth to the anus.   3. The walls of the gastrointestinal tract have several layers:  mucosa, muscularis mucosa, submucosa, muscularis (cir-  cular muscle and longitudinal muscle), and serosa (adven-  titia in the esophagus).   4, Except for swallowing and defecation, which are controlled  voluntarily, the functions of the gastrointestinal tract are con-  trolled by extrinsic autonomic nerves (vagus, parasympathetic  splanchnic, and sympathetic nerves) and intrinsic autonomic  nerves (enteric nervous system) and intestinal hormones.   5. Digestion begins in the mouth, with chewing and saliva-  tion. The digestive component of saliva is a-amylase, which  initiates carbohydrate digestion.   6. The esophagus is a muscular tube that transports food from  the mouth to the stomach. The muscularis in the upper part  of the esophagus is striated muscle, and that in the lower  part is smooth muscle.    7. Swallowing is controlled by the swallowing center in the  reticular formation of the brain. The two phases of swal-  lowing are the oropharyngeal phase (voluntary swallowing)  and the esophageal phase (involuntary swallowing).   8. Food is propelled through the gastrointestinal tract by peri-  stalsis: waves of sequential relaxations and contractions of  the muscularis.   9. The lower esophageal sphincter opens to admit swallowed  food into the stomach and then closes to prevent regurgita-  tion of food back into the esophagus.   10. The stomach is a baglike structure that secretes digestive  juices, mixes and stores food, and propels partially digested  food (chyme) into the duodenum. The smooth muscles of  the stomach include the outer longitudinal, middle circular,  and internal oblique.   12. The hormones gastrin and motilin stimulate gastric empty-  ing; the hormones secretin and cholecystokinin delay gas-  tric emptying.   13. Gastric glands in the fundus and body of the stomach secrete  intrinsic factor, which is needed for vitamin B,, absorption,    and hydrochloric acid, which dissolves food fibers, kills  microorganisms, and activates the enzyme pepsin.   Chief cells in the stomach secrete pepsinogen, which is  converted to pepsin in the acidic environment created by  hydrochloric acid.   Acid secretion is stimulated by the vagus nerve, gastrin,  and histamine and inhibited by sympathetic stimulation  and cholecystokinin. Acetylcholine stimulates pepsin  secretion.   Mucus is secreted throughout the stomach and protects the  stomach wall from acid and digestive enzymes.   The three phases of acid secretion by the stomach are the  cephalic phase (anticipation and swallowing), the gas-  tric phase (food in the stomach), and the intestinal phase  (chyme in the intestine).   The small intestine is 5 m long and has three segments: the  duodenum, jejunum, and ileum. Digestion and absorption  of all major nutrients and most ingested water occur in the  small intestine.   The peritoneum is a double layer of membranous tissue.  The visceral layer covers the abdominal organs, and the  parietal layer extends along the abdominal wall.   Blood flow to the small intestine is primarily provided by  the superior mesenteric artery.   The duodenum receives chyme from the stomach through  the pyloric valve. The presence of chyme stimulates the liver  and gallbladder to deliver bile and the pancreas to deliver  digestive enzymes and alkaline secretions. Bile and enzymes  flow through an opening guarded by the sphincter of Oddi.  Bile is produced by the liver and is necessary for fat diges-  tion and absorption. Bile’s alkalinity helps neutralize  chyme, thereby creating a pH that enables the pancreatic  enzymes to digest proteins, carbohydrates, and sugars.  Enzymes secreted by the small intestine (maltase, sucrase,  lactase), pancreatic enzymes (proteases, amylase, and  lipase), and bile salts act in the small intestine to digest pro-  teins, carbohydrates, and fats.   Digested substances are absorbed across the intestinal wall  and then transported to the liver through the hepatic portal  vein, where they are metabolized further.   The ileocecal valve connects the small and large intestines  and prevents reflux into the small intestine.   Villi are small fingerlike projections that extend from the small  intestinal mucosa and increase its absorptive surface area.  Carbohydrates, amino acids, and fats are absorbed primar-  ily by the duodenum and jejunum; bile salts and vitamin B,,  are absorbed by the ileum. Vitamin B,, absorption requires  the presence of intrinsic factor.   Bile salts emulsify and hydrolyze fats and incorporate them  into water-soluble micelles that transport them through the  unstirred layer to the brush border of the intestinal mucosa.  The fat content of the micelles readily diffuses through the  epithelium into lacteals (lymphatic ducts) in the villi. From  there fats flow into the lymphatics and into the systemic cir-  culation, which delivers them to the liver.    Minerals and water-soluble vitamins are absorbed by active  and passive transport throughout the small intestine.  Peristaltic movements created by longitudinal muscles pro-  pel the chyme along the intestinal tract, whereas contrac-  tions of the circular muscles (segmentation) mix the chyme  and promote digestion.   The ileogastric reflex inhibits gastric motility when the  ileum is distended.   The intestinointestinal reflex inhibits intestinal motility  when one intestinal segment is overdistended.   The gastroileal reflex increases intestinal motility when gas-  tric motility increases.   The large intestine consists of the cecum, appendix, colon  (ascending, transverse, descending, and sigmoid), rectum,  and anal canal.   The teniae coli are three bands of longitudinal muscle that  extend the length of the colon.   Haustra are pouches of colon that are formed with alternat-  ing contraction and relaxation of the circular muscles.   The mucosa of the large intestine contains mucus-secreting  cells and mucosal folds, but no villi.   The large intestine massages the fecal mass and absorbs  water and electrolytes.   Distention of the ileum with chyme causes the gastrocolic  reflex, or the mass propulsion of feces to the rectum.  Defecation is stimulated when the rectum is distended  with feces. The conically contracted internal anal sphincter  relaxes and, if the voluntarily regulated external sphincter  relaxes, defecation occurs.   The largest numbers of intestinal bacteria are in the colon.  They are anaerobes consisting of Bacteroides, clostridia,  coliforms, and lactobacilli.   The intestinal tract is sterile at birth and becomes totally  colonized within 3 to 4 weeks.   Endogenous infections of the gastrointestinal tract occur by  excessive proliferation of bacteria, perforation of the intes-  tine, or contamination from neighboring structures.    The liver is the largest organ in the body. It has diges-  tive, metabolic, hematologic, vascular, and immunologic  functions.    . The liver is divided into the right and left lobes and is sup-    . Liver lobules consist of plates of hepatocytes, which are the    . The hepatic artery supplies blood to the liver. The portal    vein receives blood from the inferior and superior mesen-  teric veins.    . Hepatocytes synthesize 700 to 1200 ml of bile per day and    secrete it into the bile canaliculi, which are small chan-  nels between the hepatocytes. The bile canaliculi drain  bile into the common bile duct and then into the duode-  num through an opening called the major duodenal papilla  (sphincter of Oddi).    Sinusoids are capillaries located between the plates of hepa-  tocytes. Blood from the hepatic portal vein and hepatic  artery flows through the sinusoids to a central vein in each  lobule and then into the hepatic vein and inferior vena cava. 18.    glucose. The exocrine pancreas secretes an alkaline solution  and the enzymes (trypsin, chymotrypsin, carboxypeptidase,  a-amylase, lipase) that digest proteins, carbohydrates, and fats.  Secretin stimulates pancreatic secretion of alkaline fluid, and  cholecystokinin and ACh stimulate secretion of enzymes. Pan-  creatic secretions originate in acini and ducts of the pancreas  and empty into the duodenum through the common bile duct  or an accessory duct that opens directly into the duodenum.    form bile salts. The secondary bile acids are the product of _ Tests of Digestive Function    . Most bile salts and acids are recycled. The absorption of bile    salts and acids from the terminal ileum and their return to   the liver are known as the enterohepatic circulation of bile.  Bilirubin is a pigment liberated by the lysis of aged red   is fat soluble and can cross cell membranes. Unconjugated 2:  bilirubin is converted to water-soluble, conjugated biliru-   and cholesterol. Fat absorbed by intestinal lacteals is pri-  marily triglyceride, which is hydrolyzed to glycerol and free 3;  fatty acid.    Numerous diagnostic tests can evaluate structure and func-  tion (digestion, secretion, absorption) of the gastrointestinal  tract. Radiographs and scans are most commonly used to eval-  uate structure, in addition to direct observation by endoscopy.  Gastric and stool analysis and blood studies provide impor-  tant information about digestion, absorption, and secretion.  Plasma chemistry levels and imaging procedures are com-  monly used to diagnose alterations in liver function. Of  particular importance are the enzymes LDH, AST, and  ALT. Plasma bilirubin levels reflect alterations in bilirubin  and bile metabolism, and prothrombin times are prolonged  in hepatitis and chronic liver disease.   Obstructive diseases of the gallbladder are evident by ele-  vated serum bilirubin levels, elevated urine urobilinogen  levels, and increased stool fat. The serum leukocyte levels  become elevated with inflammation of the gallbladder.   The most significant indicators of pancreatic dysfunction  are serum amylase and stool fat. Both values are increased  with diseases of the pancreas.    The liver performs many metabolic functions including Aging and the Gastrointestinal System   The gallbladder is a saclike organ located in the inferior sur-   and ejects it when chyme enters the duodenum. 2.  Stimulated by cholecystokinin, the gallbladder contracts and   forces bile through the cystic duct and into the common bile   duct. The sphincter of Oddi relaxes, enabling bile to flow 3:  through the major duodenal papilla into the duodenum.   The pancreas is a gland located behind the stomach. The 4.  endocrine pancreas produces hormones (glucagon and  insulin) that facilitate the formation and cellular uptake of    Advancing age is often associated with the loss or deterio-  ration of teeth, diminished senses of taste and smell, and  diminished salivary secretions, all of which may make eat-  ing difficult and reduce appetite.   Aging reduces gastric motility and secretions, particularly  of hydrochloric acid. These changes slow gastric digestion  and emptying.   Intestinal motility and absorption of carbohydrates, pro-  teins, fats, and minerals decrease with age.   Efficiency of drug and alcohol metabolism decreases with  age and can be related to decreased liver perfusion and  decreased liver enzymes.   Alkaline phosphatase, 1413 Bilirubin, 1411  Ampulla of Vater, 1411, 1413 Biliverdin, 1411  Antrum of stomach, 1396 Body of stomach, 1396  Ascending colon, 1407 Brush border, 1401  Aspartate aminotransferase (AST), 1413 Calcium, 1405   Bile, 1411 Carboxypeptidase, 1402  Bile acid—dependent fraction, 1411 Cardiac orifice, 1396  Bile acid—independent fraction, 1411 Cecum, 1407   Bile acid pool, 1411 Cephalic phase of secretion, 1400  Bile canaliculi, 1411 Chief cell, 1398    Cholecystokinin, 1398, 1415  Choleresis, 1411  Choleretic agent, 1411  Cholesterol esterase, 1404  Chylomicron, 1405  Chyme, 1396  Chymotrypsin, 1402  Colipase, 1404   Enteric nervous system, 1394  Enterochromaffin-like cell, 1398  Enterohepatic circulation, 1411  Enterokinase, 1415   Gastrocolic reflex, 1408  Gastroileal reflex, 1407  Gastrointestinal tract (alimentary canal), 1393  Haustrum (pl., haustra), 1407  Hepatic artery, 1409    Pharyngeal phase of swallowing, 1395  Phases of gastric secretion, 1399  Phosphate, 1405    muscle), 1395  Urobilinogen, 1412  Valsalva maneuver, 1408  Vermiform appendix, 1407  Villus (pl., villi), 1401  Vitamin, 1406    Tarnawski AS, Ahluwalia A, Jones MK: The mechanisms of gastric muco-  sal injury: focus on microvascular endothelium as a key target, Curr Med    Zafra MA, Molina F, Puerto A: The neural/cephalic phase reflexes in the  physiology of nutrition, Neurosci Biobehav Rev 30(7):1032-1044, 2006.  Miller MJ, McDole JR, Newberry RD: Microanatomy of the intestinal  lymphatic system, Ann N Y Acad Sci 1207(Suppl 1):E21—E28, 2010.  Santaolalla R, Abreu MT: Innate immunity in the small intestine, Curr    Ashton KA et al: Basal and meal-stimulated colonic absorption, Dis Colon  Wright EM, Loo DD, Hirayama BA: Biology of human sodium glucose  Cheeseman C: GLUT7: a new intestinal facilitated hexose transporter,  Am J Physiol Endocrinol Metab 295(2):E238—E241, 2008.   Leturque A, Brot-Laroche E, Le Gall M: GLUT2 mutations, translocation,  and receptor function in diet sugar managing, Am J Physiol Endocrinol  Jahan-Mihan A et al: Dietary proteins as determinants of metabolic and physi-  ologic functions of the gastrointestinal tract, Nutrients 3(5):574-603, 2011.  Christakos S et al: Vitamin D and intestinal calcium absorption, Mol Cell    13.  REFERENCES enterol Rep 10(6):523-527, 2008.  1. 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Dockray GJ: Cholecystokinin, Curr Opin Endocrinol Diabetes Obes  19(1):8-12, 2012. 20.  8. Middleton SJ, Balan K: Idiopathic accelerated gastric emptying present-  ing in adults with post-prandial diarrhea and reactive hypoglycemia: a Metab 296(5):E985—E992, 2009.  case series, J Med Case Rep 6(1):132, 2012. 21,  9. Chu S, Schubert ML: Gastric secretion, Curr Opin Gastroenterol  28(6):587-593, 2012. 22.  10. Palileo C, Kaunitz JD: Gastrointestinal defense mechanisms, Curr Opin Endocrinol 347(1-2):25—-29, 2011.  Gastroenterol 27(6):543—-548, 2011. 23.  11. Longkumer T et al: Assessment of vagotomy status with postprandial Science 338(6108):768—772, 2012.  urinary alkaline tide, Trop Gastroenterol 30(2):91—94, 2009. 24,  12. Ramsay PT, Carr A: Gastric acid and digestive physiology, Surg Clin    tions in organic disease and functional disorders, Neurogastroenterol  Motil 11(3):141-161, 1999.    Lubbers T, Buurman W, Luyer M: Controlling postoperative ileus by  vagal activation, World J Gastroenterol 16(14):1683—-1687, 2010.   Byard RW: Acute mesenteric ischaemia and unexpected death, J Forensic  Leg Med 19(4):185-190, 2012.   Manson JM, Rauch M, Gilmore MS: The commensal microbiology of the  gastrointestinal tract, Adv Exp Med Biol 635:15—28, 2008.   Abraham C, Medzhitov R: Interactions between the host innate immune  system and microbes in inflammatory bowel disease, Gastroenterology  140(6):1729-1737, 2011.   Resta SC: Effects of probiotics and commensals on intestinal epithelial  physiology: implications for nutrient handling, J Physiol 587(Pt 17):  4169-4174, 2009.   Yokomori H et al: Recent advances in liver sinusoidal endothelial ultra-  structure and fine structure immunocytochemistry, Micron 43(2-3):  129-134, 2012.   Yang Q et al: The evolving story of macrophages in acute liver failure,  Immunol Lett 147(1-2):1-9, 2012.   Tacke F, Weiskirchen R: Update on hepatic stellate cells: pathogenic role  in liver fibrosis and novel isolation techniques, Expert Rev Gastroenterol  Hepatol 6(1):67-80, 2012.   Tian Z et al: Natural killer cells in liver disease, Hepatol 57(4):1654-1662,  2013.   Horiguchi S, Kamisawa T: Major duodenal papilla and its normal  anatomy, Dig Surg 27(2):90—93, 2010.   Hofmann AF: The enterohepatic circulation of bile acids in mammals:  form and functions, Front Biosci 14:2584—2598, 2009.   Jansen T et al: Conversion of biliverdin to bilirubin by biliverdin reduc-  tase contributes to endothelial cell protection by heme oxygenase-1—  evidence for direct and indirect antioxidant actions of bilirubin, J Mol  Cell Cardiol 49(2):186-195, 2010.   Jiraskova A et al: Association of serum bilirubin and promoter variations  in HMOX1 and UGTIAI genes with sporadic colorectal cancer, Int J  Cancer 131(7):1549-1555, 2012.   Rodriguez-Diaz R et al: Innervation patterns of autonomic axons in the  human endocrine pancreas, Cell Metab 14(1):45-54, 2011.   Chandra R, Liddle RA: Recent advances in pancreatic endocrine and  exocrine secretion, Curr Opin Gastroenterol 27(5):439—443, 2011.    Aranda-Michel J, Sherman KE: Tests of the liver: use and misuse, Gastro-  enterologist 6(1):34—43, 1998.   Johnston DE: Special considerations in interpreting liver function tests,  Am Fam Physician 59(8):2223—2230, 1999.   Hoekstra LT et al: Physiological and biochemical basis of clinical liver  function tests: a review, Ann Surg 257(1):27-36, 2013.   Mayumi T et al: Validity of the urinary trypsinogen-2 test in the diagnosis  of acute pancreatitis, Pancreas 41(6):869-875, 2012.   Grassi M et al: Changes, functional disorders, and diseases in the gastro-  intestinal tract of elderly, Nutr Hosp 26(4):659-668, 2011.   Gupta A, Epstein JB, Sroussi H: Hyposalivation in elderly patients, J Can  Dent Assoc 72(9):841—846, 2006.   Sura L et al: Dysphagia in the elderly: management and nutritional con-  siderations, Clin Interv Aging 7:287—298, 2012.   Salles N: Is stomach spontaneously ageing? Pathophysiology of the ageing  stomach, Best Pract Res Clin Gastroenterol 23(6):805—-819, 2009.   Patel KV: Epidemiology of anemia in older adults, Semin Hematol  45(4):210-217, 2008.   Tiihonen K, Ouwehand AC, Rautonen N: Human intestinal microbiota  and healthy ageing, Ageing Res Rev 9(2):107—116, 2010.   Drozdowski L, Thomson AB: Aging and the intestine, World J Gastroen-  terol 12(47):7578-7584, 2006.   Rayner CK, Horowitz M: Physiology of the ageing gut, Curr Opin Clin  Nutr Metab Care 16(1):33-38, 2013.   Schmucker DL, Sanchez H: Liver regeneration and aging: a current per-  spective, Curr Gerontol Geriatr Res 2011:526379, 2011.   McLachlan AJ, Pont LG: Drug metabolism in older people—a key con-  sideration in achieving optimal outcomes with medicines, J Gerontol A  Biol Sci Med Sci 67(2):175-180, 2012.   Herzig KH et al: Fecal pancreatic elastase-1 levels in older individuals  without known gastrointestinal diseases or diabetes mellitus, BMC Geri-  atr 11:4, 2011.   Stinton LM, Shaffer EA: Epidemiology of gallbladder disease: cholelithia-  sis and cancer, Gut Liver 6(2):172—187, 2012.    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Disorders of the Gastrointestinal Tract, 1423  Clinical Manifestations of Gastrointestinal Dysfunction,  1423  Disorders of Motility, 1428  Gastritis, 1434  Peptic Ulcer Disease, 1435  Malabsorption Syndromes, 1439  Inflammatory Bowel Disease, 1440  Intestinal Vascular Insufficiency, 1446  Disorders of Nutrition, 1446    Disorders of the gastrointestinal tract disrupt one or more of  its functions. Structural and neural abnormalities can slow,  obstruct, or accelerate the movement of intestinal content at  any level of the gastrointestinal tract. Inflammatory and ulcer-  ative conditions of the gastrointestinal wall disrupt secretion,  motility, and absorption. Inflammation or obstruction of the  liver, pancreas, or gallbladder can alter metabolism and result in  local or systemic symptoms, or both. Many clinical manifesta-  tions of gastrointestinal tract disorders are nonspecific and can  be caused by a variety of impairments. These manifestations are  described in the section below.    Disorders of the Accessory Organs of Digestion, 1451  Common Complications of Liver Disorders, 1451  Disorders of the Liver, 1457  Disorders of the Gallbladder, 1463  Disorders of the Pancreas, 1464   Cancer of the Digestive System, 1466  Cancer of the Gastrointestinal Tract, 1466  Cancer of the Accessory Organs of Digestion, 1472   Anorexia is lack of a desire to eat despite physiologic stimuli  that would normally produce hunger. Anorexia is a nonspe-  cific symptom that is often associated with nausea, abdomi-  nal pain, diarrhea, and psychologic distress. Side effects of  drugs and disorders of other organ systems, including cancer,   Vomiting is the forceful emptying of stomach and intestinal  contents through the mouth. The vomiting center lies in the  medulla oblongata and includes the reticular formation and trac-  tus solitarius nucleus. Stimulation of the vomiting center occurs  directly by irritants or indirectly. Indirect stimulation includes  the cerebral cortex and thalamus (anxiety and pain); the vestib-  ular system through the eighth cranial nerve (motion sickness);  several types of intestinal, vagal, or sympathetic input, includ-  ing the presence of ipecac or copper salts in the duodenum; side  effects of many drugs; distention of the stomach or duodenum;  or torsion or trauma affecting the ovaries, testes, uterus, bladder,  or kidney. Serotonin (5-hydroxytryptamine [5-HT]) stimulates  the vomiting center and appears to be released from enterochro-  maffin cells in the intestinal wall, which activate vagal afferents  leading to the chemoreceptor trigger zone (CTZ).! Activation of  the CTZ, which lies in the area postrema between the medulla  and floor of the fourth ventricle, leads to vomiting by triggering  receptors for substances such as dopamine (D,), opioids, ace-  tylcholine, substance P, serotonin (5-hydroxytryptamine type  3), and neurokinin-1. Serotonin and neurokinin-1 antagonists  are effective antiemetics and have been used to treat nausea and  vomiting associated with postoperative vomiting and cancer  chemotherapy. Apomorphine, levodopa, and bromocriptine are  dopamine D, agonists that cause nausea and vomiting. Metoclo-  pramide, domperidone, and haloperidol are D, antagonists and  are effective antiemetics.”   Nausea and retching usually precede vomiting although they  are distinct entities. Nausea is a subjective experience that is  associated with many different conditions, including visceral  pain, labyrinthine stimulation (i.e., motion), and use of opiate  medications. Specific neural pathways have not been identified  for nausea. Hypersalivation and tachycardia are common asso-  ciated symptoms.   With vomiting, the duodenum and antrum of the stomach  produce retrograde peristalsis while the body of the stomach  and the esophagus relax. When the stomach is full of gastric  contents, the diaphragm is forced high into the thoracic cavity  by strong contractions of the abdominal muscles. The higher  intrathoracic pressure forces the upper esophageal sphincter to  open, and chyme is expelled from the mouth. Then the stomach  relaxes and the upper part of the esophagus contracts, forcing  the remaining chyme back into the stomach. The lower esopha-  geal sphincter then closes. The cycle is repeated if there is a  volume of chyme remaining in the stomach.   Retching is the muscular event of vomiting without the  expulsion of vomitus. Retching begins with deep inspiration.  The glottis then closes, intrathoracic pressure falls, and the  esophagus becomes distended. Simultaneously, the abdominal  muscles contract creating a pressure gradient from abdomen to  thorax. The lower esophageal sphincter and body of the stom-  ach relax, but the duodenum and antrum of the stomach spasm.  The reverse peristalsis and pressure gradient force chyme from  the stomach and duodenum up into the esophagus. Because    the upper esophageal sphincter is closed, chyme does not enter  the mouth. As the abdominal muscles relax, the contents of the  esophagus drop back into the stomach. This process may be  repeated several times before vomiting occurs. A diffuse sympa-  thetic discharge causes the tachycardia, tachypnea, and sweating  that accompany retching and vomiting. The parasympathetic  system mediates copious salivation, increased gastric motility,  and relaxation of the upper and lower esophageal sphincters.  Projectile vomiting is spontaneous vomiting that is not  preceded by nausea or retching. Projectile vomiting is caused  by direct stimulation of the vomiting center by neurologic  lesions (e.g., increased intracranial pressure, tumors, or aneu-  rysms involving the brainstem [see Chapters 17 and 20]). The  metabolic consequences of vomiting are fluid, electrolyte, and  acid-base disturbances, including hyponatremia, hypokalemia,  hypochloremia, and metabolic alkalosis (see Chapter 3).    Constipation is difficult or infrequent defecation and is esti-  mated to affect 2% to 28% of the population. Constipation  must be individually defined because patterns of bowel evacu-  ation differ greatly among individuals. Normal bowel habits  range from two or three evacuations per day to one per week.  Constipation is not significant until it causes health risks  (e.g., severe abdominal distention or fecal impaction) or impairs  quality of life.’   PATHOPHYSIOLOGY. Primary constipation is generally classified  into three categories. Normal transit (functional) constipation  involves a normal rate of stool passage but there is difficulty  with stool evacuation. Functional constipation is most common  and is associated with low-residue diet (the habitual consump-  tion of highly refined foods) or low fluid intake, which decreases  the volume and number of stools and can contribute to consti-  pation. Physical activity stimulates peristalsis; therefore, a sed-  entary lifestyle and lack of regular exercise are common causes  of constipation. Lack of access to toilet facilities, consistent sup-  pression of the urge to empty the bowel, and dehydration are  other causes. Slow-transit constipation involves impaired colonic  motor activity with infrequent bowel movements, straining to  defecate, mild abdominal distention, and palpable stool in the  sigmoid colon. Pelvic floor dysfunction (pelvic floor dyssynergia-  anismus) is difficulty expelling stool because of failure of the  pelvic floor muscles or anal sphincter to relax with defecation.   Secondary constipation can be caused by neurogenic disor-  ders (e.g., stroke, Parkinson disease, spinal cord injury, multiple  sclerosis) in which neurotransmitters are altered or neural path-  ways are diseased or degenerated, resulting in delayed colon  transit time. Opiates, particularly codeine, antacids containing  calcium carbonate or aluminum hydroxide; anticholinergics;  iron; and bismuth tend to inhibit bowel motility. Endocrine  or metabolic disorders associated with constipation include  hypothyroidism, diabetes mellitus, hypokalemia, and hyper-  calcemia. Pelvic hiatal hernia (herniation of the bowel through  the floor of the pelvis), diverticuli, irritable bowel syndrome—  constipation predominant, and pregnancy also can be associ-  ated with constipation. Aging can result in constipation caused  from decreased motility related to the degeneration of neurons    in the myenteric plexus, decreased neurotransmitter function,  use of medications, and comorbid medical conditions.* Consti-  pation as a notable change in bowel habits can be an indication  of colorectal cancer.   Many mechanical conditions can slow intestinal transit time.  The abdominal muscles are normally used to create the intra-  abdominal pressure required to evacuate the rectum. Weakness  or pain can interfere with the generation of adequate intra-  abdominal pressure. Lesions of the anus, such as inflamed hem-  orrhoids, fissures, or fistulae, make defecation painful because  of stretching. With the urge to defecate, the sphincter becomes  hypertonic and the stool is not eliminated. Depression often  impairs bowel evacuation, partly because depressed individuals  tend to be sedentary and lack the motivation to eat a healthy  diet. The problem is made worse if antidepressant drugs (e.g.,  anticholinergics) are used to treat the depression.   CLINICAL MANIFESTATIONS. Indicators of constipation include  two of the following for at least 3 months: (1) straining with  defecation at least 25% of the time, (2) lumpy or hard stools at  least 25% of the time, (3) sensation of incomplete emptying at  least 25% of the time, (4) manual maneuvers to facilitate stool  evacuation for at least 25% of defecations, and (5) fewer than  three bowel movements per week.° Changes in bowel evacu-  ation patterns, such as less frequent defecation, smaller stool  volume, hard stools, difficulty passing stools (straining), or a  feeling of bowel fullness and discomfort or blood in the stools,  require investigation. Fecal impaction (hard, dry stool retained  in the rectum) is associated with rectal bleeding, abdominal or  cramping pain, nausea and vomiting, weight loss, and episodes  of diarrhea. Straining to evacuate stool may cause engorgement  of the hemorrhoidal veins and hemorrhoidal disease or throm-  bosis with rectal pain, bleeding, and itching. Passage of hard  stools can cause painful anal fissures.   EVALUATION AND TREATMENT. The history, current use of medi-  cations, physical examination, and stool diaries provide precise  clues regarding the nature of constipation. Sudden-onset con-  stipation can accompany the development of colorectal cancer  and requires careful evaluation. The individual’s description  of frequency, stool consistency, associated pain, and presence  of blood or whether evacuation was stimulated by enemas or  cathartics (laxatives) is significant. Cramping abdominal pain  may be symptomatic of partial bowel obstruction. Palpation  discloses colonic distention, masses, and tenderness. Blood may  be caused by bleeding hemorrhoids or a neoplastic lesion of the  colon.   Digital examination of the rectum and anorectal manometry  are performed to assess sphincter tone and detect anal lesions.  Proctosigmoidoscopy and colonoscopy are used to visualize the  lumen directly. Colonic transit studies and imaging techniques  can assist in identifying the etiology of constipation.   The treatment for constipation is to manage the underlying  cause or disease for each individual. Management usually con-  sists of bowel retraining, in which the individual establishes a  satisfactory bowel evacuation routine without becoming pre-  occupied with bowel movements. Moderate exercise, increased  fluid and fiber intake, stool softeners, and laxative agents are  useful for some individuals. Enemas can be used to establish    bowel routine, but they should not be used habitually. Biofeed-  back training can be effective for dyssynergic defecation.® Drugs  used to treat constipation include the colonic secretagogues  lubiprostone and plecanatide and the 5-HT, agonist prucalo-  pride. Methylnaltrexone is a peripherally acting p-opioid recep-  tor antagonist approved for opioid-induced constipation in  terminally ill individuals.”    Diarrhea is an increase in the frequency of defecation and the  fluid content, volume, and weight of feces. Three or more loose  or liquid stools per day or more frequently than is normal for  the individual are considered abnormal.* Many factors determine  stool volume and consistency, including the water content of the  colon and the presence of unabsorbed food, unabsorbable mate-  rial, and intestinal secretions. Stool volume in the normal adult  averages less than 200 g/day. Stool volume in children depends on  age and size. An infant may pass up to 100 g/day. The adult intes-  tine processes approximately 9 L of luminal contents per day; 2 L  is ingested, and the remaining 7 L consists of intestinal secretions.  Of this volume, 99% of the fluid is absorbed—90% (7 to 8 L)  in the small intestine and 9% (1 to 2 L) in the colon. Normally,  approximately 150 ml of water is excreted daily in the stool.   PATHOPHYSIOLOGY. Diarrhea in which the volume of feces is  increased is called large-volume diarrhea. Large-volume diarrhea  generally is caused by excessive amounts of water or secretions,  or both, in the intestines. Small-volume diarrhea, in which the  volume of feces is not increased, usually results from excessive  intestinal motility. The three major mechanisms of diarrhea are  osmotic, secretory, and motility.’ (Specific mechanisms of diar-  rhea in children are described in Chapter 42.)   In osmotic diarrhea, a nonabsorbable substance in the intes-  tine draws water into the lumen by osmosis. The excess water  and the nonabsorbable substance cause large-volume diarrhea.  Large oral doses of poorly absorbed ions, such as magnesium,  sulfate, and phosphate, can increase intraluminal osmotic  pressure. Excessive ingestion of synthetic, nonabsorbable sug-  ars (e.g., sorbitol); introduction of full-strength tube feeding  formulas; and dumping syndrome associated with gastric resec-  tion draw water into the intestinal lumen (see p. 1440). Osmotic  diarrhea disappears when ingestion of the osmotic substance  stops. Malabsorption related to lactase deficiency, pancreatic  enzyme or bile salt deficiency, small intestine bacterial over-  growth, and celiac disease also cause diarrhea.   Secretory diarrhea is a form of large-volume diarrhea caused  by excessive mucosal secretion of chloride- or bicarbonate-rich  fluid or inhibition of net sodium absorption. Infectious causes  include viruses (e.g., rotavirus), bacterial enterotoxins (e.g.,  Escherichia coli and Vibrio cholerae), or exotoxins from over-  growth of Clostridium difficile following antibiotic therapy.  These infections cause secretion of transmitters from entero-  endocrine cells (e.g., 5-HT) and activation of afferent neurons  that stimulate submucosal secretomotor neurons and altered  sodium and chloride transport resulting in decreased water  absorption.!'! Neoplasms (such as gastrinoma or thyroid car-  cinoma) produce hormones that stimulate intestinal secretion  causing diarrhea.    Small-volume diarrhea usually is caused by an inflammatory  disorder of the intestine, such as ulcerative colitis, Crohn dis-  ease, or microscopic colitis. Inflammation of the colon causes  smooth muscle contraction, cramping pain, urgency, and fre-  quency. Small-volume diarrhea also can be caused by fecal  impaction, a severe form of constipation. This diarrhea consists  of secretions (mucus and fluid) produced by the colon to lubri-  cate the impacted feces and move it toward the anal canal. These  secretions flow around the impaction and cause low-volume,  secretory diarrhea.   Motility diarrhea is caused by resection of the small intestine  (short bowel syndrome), surgical bypass of an area of the intes-  tine, fistula formation between loops of intestine, irritable bowel  syndrome-diarrhea predominant, diabetic neuropathy, hyper-  thyroidism, and laxative abuse. Excessive motility decreases  transit time, mucosal surface contact, and opportunities for  fluid absorption, resulting in diarrhea.   CLINICAL MANIFESTATIONS. Diarrhea can be acute or chronic,  depending on its cause. Systemic effects of prolonged diarrhea  are dehydration, electrolyte imbalance (hyponatremia, hypo-  kalemia), metabolic acidosis, and weight loss. Manifestations  of acute bacterial or viral infection include fever, with or with-  out cramping pain. Fever, cramping pain, and bloody stools  accompany diarrhea caused by inflammatory bowel disease.  Steatorrhea (fat in the stools) and diarrhea are common signs  of malabsorption syndromes. Anal and perineal skin irritation  can occur.   EVALUATION AND TREATMENT. A thorough history is taken to  document the onset, frequency, and volume of stools. Expo-  sure to contaminated food or water is indicated if the individual  has traveled in foreign countries or areas where drinking water  might be contaminated. Iatrogenic diarrhea is suggested if the  individual has undergone abdominal radiation therapy, intesti-  nal resection, or treatment with selected drugs (e.g., antibiotics,  diuretics, antihypertensives, laxatives). Physical examination  helps the clinician to identify underlying systemic disease. Stool  culture, examination of stool specimens for blood, abdominal  roentgenograms, endoscopy, and intestinal biopsies provide  more specific data.!*   Treatment for diarrhea includes restoration of fluid and  electrolyte balance, antimotility (e.g., loperamide [an opiate]  or Lomotil [atropine]) and/or water-absorbent (e.g., attapulg-  ite and polycarbophil) medications, and treatment of causal  factors. Nutritional deficiencies need to be corrected in cases  of chronic diarrhea or malabsorption. Natural bran and com-  mercial preparations of psyllium are inexpensive and effective  treatments for mild diarrhea. Probiotics can be useful for treat-  ing Clostridium difficile-associated diarrhea as an approach to  restoring normal microflora in addition to antibiotic therapy.!°  Fecal transplantation can be used for cases that are resistant to  conventional therapies.'*    Abdominal pain is the presenting symptom of a number of  gastrointestinal (GI) diseases and can be acute or chronic. The  causal mechanisms are mechanical, inflammatory, or ischemic.  (The physiology of pain is described in Chapter 16.) Abdominal    pain may be generalized to the abdomen or localized to a partic-  ular abdominal quadrant. The pain is often described as sharp,  dull, or colicky. Generally the abdominal organs are not sensi-  tive to mechanical stimuli, such as cutting, tearing, or crushing.  These organs are, however, sensitive to stretching and disten-  tion, which activate nerve endings in both hollow and solid  structures. The onset of pain is associated with rapid distention;  gradual distention causes little pain. Traction on the peritoneum  caused by adhesions, distention of the common bile duct, or  forceful peristalsis resulting from intestinal obstruction causes  pain because of increased tension. Capsules that surround solid  organs, such as the liver and gallbladder, contain pain fibers that  are stimulated by stretching if these organs swell.   Biochemical mediators of the inflammatory response, such  as histamine, bradykinin, and serotonin, stimulate pain nerve  endings and produce abdominal pain. The edema and vascular  congestion that accompany chemical, bacterial, or viral inflam-  mation also cause painful stretching. Obstruction of blood flow  from the distention of bowel obstruction or mesenteric vessel  thrombosis produces the pain of ischemia, and increased con-  centrations of tissue metabolites stimulate pain receptors.   Abdominal pain can be parietal (somatic), visceral, or  referred. Parietal pain arises from the parietal peritoneum. This  pain is more localized and intense than visceral pain, which  arises from the organs themselves. Nerve fibers from the pari-  etal peritoneum travel with peripheral nerves to the spinal cord,  and the sensation of pain corresponds to skin dermatomes T6  and L1. Parietal pain lateralizes because, at any particular point,  the parietal peritoneum is innervated from only one side of the  nervous system.   Visceral pain arises from a stimulus (distention, inflam-  mation, ischemia) acting on an abdominal organ. Chronic  low-grade inflammation can cause pain hypersensitivity with  involvement of neurokinins, serotonin, and voltage-gated ion  channels.!>!° Pain is usually felt near the midline in the epi-  gastrium, midabdomen, or lower abdomen. The pain is poorly  localized, is dull rather than sharp, and is difficult to describe.  Visceral pain is diffuse and vague because nerve endings in  abdominal organs are sparse and multisegmented. Pain aris-  ing from the stomach, for example, is experienced as a sensa-  tion of fullness, cramping, or gnawing in the midepigastric  area. Referred pain is visceral pain felt at some distance from  a diseased or an affected organ. Referred pain is usually well  localized and is felt in the skin dermatomes or deeper tissues  that share a central afferent pathway with the affected organ.  Gallbladder pain is, for example, referred to the right shoulder  or scapulae.    Upper gastrointestinal (GI) bleeding is bleeding in the esopha-  gus, stomach, or duodenum and is characterized by frank, bright  red bleeding in emesis or dark, grainy digested blood (“coffee  grounds”) in stool. Upper GI bleeding is caused by esophageal  or gastric varices, a Mallory-Weiss tear at the esophageal-gastric  junction from severe retching, cancer, angiodysplasias, or peptic  ulcers.!’ Lower gastrointestinal (GI) bleeding, bleeding from  the small intestine (jejunum or ileum), colon, or rectum, can be    caused by polyps, inflammatory bowel disease, diverticulosis,  cancer, vascular ectasias, or hemorrhoids.'* Occult bleeding is  usually caused by slow, chronic blood loss that is not obvious  and results in iron deficiency anemia as iron stores in the bone  marrow are slowly depleted. Acute, severe GI bleeding is life  threatening depending on the volume and rate of blood loss,  associated disease, age, and effectiveness of treatment.    Physiologic response to gastrointestinal bleeding depends  on the amount and rate of the loss (Figure 41-1). Changes in  blood pressure and heart rate are the best indicators of massive  blood loss in the gastrointestinal tract. Blood losses of 1000 ml  or more over a short time cause a decrease in blood pressure  and a corresponding increase in heart rate. With losses of 1000  ml or more, the heart rate is greater than 100 beats/minute and    Acute, massive Gl bleeding  (loss of 1000 ml or 20%-25% of  blood volume within a few hours)    { Cardiac output: J Systolic blood pressure (<100 mmHg)  T Pulse rate (>100)    systolic blood pressure is less than 100 mmHg. During the early  stages of blood volume depletion, the peripheral arteries and  arterioles constrict to shunt blood to vital organs, including  the brain (see Chapters 32 and 48). Signs of large-volume blood  loss are postural hypotension (a drop in blood pressure that  occurs with a change from the recumbent position to a sitting or  upright position), lightheadedness, and loss of vision. If blood  loss continues, hypovolemic shock develops. Diminished blood  flow to the kidneys causes decreased urine output and may lead  to oliguria (low urine output), tubular necrosis, and renal failure.  Ultimately, insufficient cerebral and coronary blood flow causes  irreversible anoxia and death.   The presentation of GI bleeding is summarized in Table 41-1.  The accumulation of blood in the gastrointestinal tract is irritat-  ing and increases peristalsis, causing vomiting (hematemesis)  or diarrhea, or both. If bleeding is from the lower GI tract, the  diarrhea is frankly bloody. Bleeding from the upper GI tract  also can be rapid enough to produce bright red stools (hemato-  chezia), but generally some digestion of the blood components  will have occurred, producing melena, black or tarry stools that  are sticky and have a characteristic foul odor. The digestion of  blood proteins originating from massive upper GI bleeding is  reflected by an increase in blood urea nitrogen (BUN) levels  (see Figure 41-1).   The hematocrit and hemoglobin values are not the best indi-  cators of acute gastrointestinal bleeding because plasma and red  cell volume are lost proportionately. As the plasma volume is  replaced, the hematocrit and hemoglobin values begin to reflect  the extent of blood loss. The interpretation of these values is  modified to account for exogenous replacement of fluids and the  hydration status of the tissues. Anemia associated with chronic  GI bleeding is caused by iron depletion. Evaluation and treat-  ment involves identifying and treating the source of the bleeding  and replacing iron losses. Administration of blood products may  be used for massive hemorrhage. Guidelines are available for the  diagnosis and management of gastrointestinal bleeding.'”!   PATHOPHYSIOLOGY. Dysphagia is difficulty swallowing. It  can result from mechanical obstruction of the esophagus    Acute bleeding  Hematemesis Bloody vomitus; either fresh, bright red blood  or dark, grainy, digested blood with “coffee  grounds” appearance  Black, sticky, tarry, foul-smelling stools caused by  digestion of blood in the gastrointestinal tract  Fresh, bright red blood passed from the rectum  Trace amounts of blood in normal-appearing  stools or gastric secretions; detectable only  with a guaiac test    or a functional disorder that impairs esophageal motility.  Mechanical obstructions can be intrinsic or extrinsic. Intrinsic  obstructions originate in the wall of the esophageal lumen.  Tumors, strictures, and diverticular herniations (outpouch-  ings) are all causes of intrinsic mechanical obstruction.  Extrinsic mechanical obstructions originate outside the  esophageal lumen and narrow the esophagus by pressing  inward on the esophageal wall. The most common cause of  extrinsic mechanical obstruction is tumor.   Functional dysphagia is caused by neural or muscular disorders  that interfere with voluntary swallowing or peristalsis. Disorders  that affect the striated muscles of the upper esophagus interfere  with the oropharyngeal (voluntary) phase of swallowing. Typi-  cal causes of functional dysphagia in the upper esophagus are  dermatomyositis (a muscle disease) and neurologic impairments  caused by stroke, multiple sclerosis, Parkinson disease, amyo-  trophic lateral sclerosis, or myasthenia gravis.”   Achalasia is a rare disorder related to loss of inhibitory neu-  rons in the myenteric plexus with smooth muscle atrophy in  the middle and lower portions of the esophagus. The etiology  is unknown but may be related to viral or autoimmune mecha-  nisms.”° This leads to altered esophageal peristalsis and failure  of the lower esophageal sphincter (LES) to relax, causing func-  tional obstruction of the lower esophagus. Food accumulates  above the obstruction, distends the esophagus, and causes dys-  phagia. Cough and aspiration can occur. As hydrostatic pres-  sure increases, food is slowly forced past the obstruction into  the stomach. Chronic inflammation from esophageal food  retention can increase risk for esophageal cancer. Chronic  esophageal distention requires dilation or surgical myomotomy  of the lower esophageal sphincter (LES).”*   CLINICAL MANIFESTATIONS. Clinical manifestations of dyspha-  gia vary according to the location of the obstruction. Distention  and spasm of the esophageal muscles during eating or drinking  may cause a mild or severe stabbing pain at the level of obstruc-  tion. Discomfort occurring 2 to 4 seconds after swallowing is  associated with upper esophageal obstruction. Discomfort  occurring 10 to 15 seconds after swallowing is more common in  obstructions of the lower esophagus. If the cause of obstruction  is a growing tumor, dysphagia begins with difficulty swallow-  ing solids and advances to difficulty swallowing semisolids and  liquids. Retrosternal pain, regurgitation of undigested food,  unpleasant taste, vomiting, and weight loss are common mani-  festations of all types of dysphagia. Aspiration of esophageal  contents can lead to chronic cough and pneumonia.   EVALUATION AND TREATMENT. Knowledge of the individual’s  history and clinical manifestations contributes significantly to a  diagnosis of dysphagia. Videofluoroscopy and high-frequency  ultrasound are used to visualize the contours of the esophagus  and identify structural defects. High-resolution manometry with  topography and intraluminal impedance monitoring documents  the duration and amplitude of abnormal pressure changes associ-  ated with obstruction or loss of neural regulation.”? Esophageal  endoscopy is performed to examine the esophageal mucosa,  obtain biopsy specimens, or perform corrective surgery.   The individual is taught to manage symptoms by eating  slowly, eating small meals, taking fluid with meals, and sleeping    with the head elevated to prevent regurgitation and aspiration.  Oral medications may need to be formulated so they can be  swallowed.”° Tube feedings may be required for some individu-  als, particularly following stroke.’” Anticholinergic drugs may  alleviate symptoms. Definitive treatments include mechanical  dilation of the esophageal sphincter and surgical separation  of the lower esophageal muscles with a longitudinal incision  (myotomy) widening the passage into the stomach.”®   Gastroesophageal reflux disease (GERD) is the reflux of acid  and pepsin from the stomach to the esophagus that causes  esophagitis. Risk factors for GERD include obesity, hiatal her-  nia, and drugs or chemicals that relax the LES (anticholinergics,  nitrates, calcium channel blockers, nicotine).?? GERD may be a  trigger for asthma or chronic cough.*? Gastroesophageal reflux  that does not cause symptoms is known as physiologic reflux.  In nonerosive reflux disease (NERD), individuals have symp-  toms of reflux disease but no visible esophageal mucosal injury  (functional heartburn).*!   PATHOPHYSIOLOGY. The resting tone of the LES tends to be  lower than normal from either transient relaxation or weak-  ness of the sphincter in those who develop GERD. Vomiting,  coughing, lifting, bending, or obesity increases abdominal pres-  sure, contributing to the development of reflux esophagitis.  Delayed gastric emptying contributes to reflux esophagitis by:  (1) lengthening the period during which reflux is possible and  (2) increasing the acid content of chyme. Disorders that delay  emptying include gastric or duodenal ulcers, which can cause  pyloric edema; strictures that narrow the pylorus; and hiatal  hernia, which can weaken the LES.°?   GERD causes inflammatory responses in the esophageal wall  resulting in hyperemia, edema, tissue fragility, erosion, and ulcer-  ations (Figure 41-2). Severity of inflammation is related to compo-  sition of gastric contents and length of exposure time.*? Fibrosis,  basal cell hyperplasia, and elongation of papillae are common.    Precancerous lesions (Barrett esophagus, see p. 1466) with pro-  gression to adenocarcinoma can be a long-term consequence.*>**   CLINICAL MANIFESTATIONS. The clinical manifestations of reflux  esophagitis are heartburn from acid regurgitation, chronic  cough, asthma attacks (see Chapter 35), and laryngitis.°? Upper  abdominal pain usually occurs within 1 hour of eating and can  be relapsing and remitting. Symptoms can worsen if the individ-  ual lies down or if intra-abdominal pressure increases (e.g., as a  result of coughing, vomiting, or straining at stool). Symptoms  may be present when no acid is in the esophagus.*° Heartburn  also may be experienced as chest pain, which requires ruling  out cardiac ischemia. Edema, fibrosis (strictures), esophageal  spasm, or decreased esophageal motility may result in dyspha-  gia. Alcohol or acid-containing foods, such as citrus fruits, can  cause discomfort during swallowing.   EVALUATION AND TREATMENT. Diagnosis of reflux esophagitis  is based on the history and clinical manifestations. Esophageal  endoscopy shows hyperemia, edema, erosion, and strictures.  Dysplastic changes (Barrett esophagus) can be identified by  tissue biopsy. Impedance/pH monitoring measures the move-  ment of stomach contents upward into the esophagus and the  acidity of the refluxate.   Proton pump inhibitors are the most effective monotherapy.  Other therapies include histamine-2 (H2) receptor antagonists,  prokinetics, and antacids. Pain medication may be used in resis-  tant cases. Elevation of the head of the bed 6 inches prevents  reflux. Weight reduction and cessation of smoking also help to  alleviate symptoms. Laparoscopic fundoplication is the most  common surgical intervention when medical treatment fails.°°°”   Eosinophilic esophagitis is a rare, idiopathic inflammatory  disease of the esophagus characterized by esophageal infiltra-  tion of eosinophils associated with atopic disease, including  asthma and food allergies. It occurs in adults and children. Dys-  phagia, food impaction, vomiting, and weight loss are common  symptoms. Endoscopy with biopsy identifies the eosinophilc  infiltration and differentiation from GERD. Treatment is symp-  tomatic including elimination diets, proton pump inhibitors,  and immunosuppression.°®   PATHOPHYSIOLOGY. Hiatal hernia is the protrusion (hernia-  tion) of the upper part of the stomach through the diaphragm  and into the thorax.°’ There are four types: sliding (type I);  paraesophageal (type II); mixed (type III), which include ele-  ments of types I and II (Figure 41-3).4° In type IV the entire  stomach and other abdominal organs slide into the thorax.   In type I, sliding hiatal hernia (the most common type,  90%), the proximal portion of the stomach moves into the tho-  racic cavity through the esophageal hiatus, an opening in the  diaphragm for the esophagus and vagus nerves. A congenitally  short esophagus, fibrosis or excessive vagal nerve stimulation, or  weakening of the diaphragmatic muscles at the gastroesophageal  junction contributes to the hernia. While the individual is in the  supine position, the lower esophagus and stomach are pulled  into the thorax. Standing causes the organs to “slide” back into  the abdomen. Sliding hiatal hernia is exacerbated by factors that  increase intra-abdominal pressure, such as coughing, bending,    wearing tight clothing, ascites, obesity, or pregnancy. This type  of hernia is associated with gastroesophageal reflux because the  hernia diminishes the resting pressure of the LES. In pregnant  women with sliding hiatal hernia, progesterone and estrogen  may lower the resting pressure of the LES further.   In type II, paraesophageal hiatal hernia (rolling hiatal her-  nia), herniation of the greater curvature of the stomach is through  a secondary opening in the diaphragm (see Figure 41-3). A giant  paraesophageal hiatal hernia develops when 30% to 60% of the  stomach moves into the thorax. As the stomach protrudes through  the opening into the thorax, it lies alongside the esophagus. The    FIGURE 41-3 The Three Types of Hiatal Hernia. A, Type |—sliding hernia.  The visceral peritoneum remains intact and restrains the size of the hernia in slid-  ing hiatal hernia. B, Type ||—paraesophageal or rolling hernia. The membrane  becomes thinner or defective in paraesophageal hernia, allowing a true peritoneal  sac to protrude into the posterior mediastinum where negative intrathoracic pres-  sure causes it to enlarge. C, Type II|—mixed hernia. GE, Gastroesophageal. (From  Townsend CM et al: Sabiston textbook of surgery, ed 19, Philadelphia, 2012, Saun-  ders.) Note: Type |V-complex paraesophageal hernia is not shown.    gastroesophageal junction remains below the diaphragm. With  paraesophageal hernia, reflux is uncommon. The position of a  portion of the stomach above the diaphragm, however, causes  congestion of mucosal blood flow and can lead to gastritis and  ulcer formation. A mechanical strangulation of the hernia is a  major complication, and surgical correction is required. Strangu-  lation occludes blood vessels and causes vascular engorgement,  edema, ischemia, and hemorrhage. Type III, mixed hiatal her-  nia, is a combination of both types I and I] and tends to occur in  conjunction with several other diseases, including gastroesopha-  geal reflux, peptic ulcer, cholecystitis (gallbladder inflammation),  cholelithiasis (gallstones), chronic pancreatitis, and diverticulo-  sis. Type IV is an aggravated form of type III.   CLINICAL MANIFESTATIONS. Hiatal hernias are often asympto-  matic. Generally, a wide variety of symptoms develop later in life  and are associated with other gastrointestinal disorders, includ-  ing GERD. Manifestations of the various types of hiatal hernia  are difficult to distinguish. Symptoms include heartburn, regur-  gitation, dysphagia, and epigastric pain.*! Ischemia from hernia  strangulation causes acute, severe chest or epigastric pain, nausea,  vomiting, and GI bleeding.   EVALUATION AND TREATMENT. Diagnostic procedures include  chest x-ray with oral barium and endoscopy. A chest x-ray often  will show the protrusion of the stomach into the thorax, indi-  cating paraesophageal hiatal hernia.   Treatment for sliding hiatal hernia is usually conservative.  The individual can diminish reflux by eating small, frequent  meals and avoiding the recumbent position after eating. Abdom-  inal supports and tight clothing are avoided, and weight control  is recommended for obese individuals. Antacids alleviate reflux  esophagitis. Drugs that relax the LES (anticholinergic, nitrates,  calcium channel blockers) are contraindicated because they  delay gastric emptying. Laparoscopic surgery (i.e., fundoplica-  tion) may be performed for paraesophageal hiatal hernia or if  medical management fails to control symptoms.”    PATHOPHYSIOLOGY. Pyloric obstruction (gastric outlet  obstruction) is the narrowing or blocking of the opening  between the stomach and the duodenum. This condition can  be congenital (ie., infantile hypertrophic pyloric stenosis, see  Chapter 42) or acquired. Acquired obstruction is caused by  peptic ulcer disease or carcinoma near the pylorus. Duodenal  ulcers are more likely than gastric ulcers to obstruct the pylorus.  Ulceration causes obstruction resulting from inflammation,  edema, spasm, fibrosis, or scarring. Tumors cause obstruction  by growing into the pylorus.”   CLINICAL MANIFESTATIONS. Early in the course of pyloric  obstruction, the individual experiences vague epigastric full-  ness, which becomes more distressing after eating and later  in the day. Nausea and epigastric pain may occur as the mus-  cles of the stomach contract in attempts to force chyme past  the obstruction. These symptoms disappear when the chyme  finally moves into the duodenum. As obstruction progresses  anorexia develops sometimes accompanied by weight loss.  Severe obstruction causes gastric distention and atony (lack of  muscle tone and gastric motility). Gastric distention stimulates    gastric secretion, which increases the feeling of fullness. Roll-  ing or jarring of the abdomen produces a sloshing sound called  the succussion splash. At this stage, vomiting is a cardinal sign  of obstruction. It is usually copious and occurs several hours  after eating. The vomitus contains undigested food but no bile.  Prolonged vomiting leads to dehydration, which is accompa-  nied by a hypokalemic and hypochloremic metabolic alkalosis  caused by the respective loss of gastric potassium and acid.  Because food does not enter the intestine, stools are infrequent  and small. Prolonged pyloric obstruction causes severe malnu-  trition and dehydration.   EVALUATION AND TREATMENT. Diagnosis is based on clinical  manifestations, a history of peptic ulcer disease, and examina-  tion of residual gastric contents. Endoscopy for the purpose of  biopsy is performed if gastric carcinoma is the suggested cause  of pyloric obstruction. Barium studies are contraindicated  because the barium may harden and be retained in the stomach.   Obstructions resulting from ulceration often resolve with  conservative management. Gastric drainage is used to decom-  press the stomach and restore normal motility. Gastric secre-  tions that contribute to inflammation and edema can be  suppressed with proton pump inhibitors or histamine-2 (H2)  receptor antagonists. Fluids and electrolytes (sodium chloride  and potassium) are given intravenously to effect rehydration  and correct hypochloremia, alkalosis, and hypokalemia (see  Chapter 3). Severely malnourished individuals may require par-  enteral hyperalimentation (intravenous nutrition). Surgery or  stenting may be required to treat gastric carcinoma or persistent  obstruction caused by fibrosis and scarring.**    Intestinal obstruction can be caused by any condition that pre-  vents the normal flow of chyme through the intestinal lumen  or failure of normal intestinal motility in the absence of an  obstructing lesion (ileus). The small intestine is more com-  monly obstructed because of its narrower lumen. Common  causes of intestinal obstruction are summarized in Table 41-2.  Criteria for classifying intestinal obstruction are summarized  in Table 41-3. Intestinal obstruction is classified by cause as  simple or functional. Simple obstruction is mechanical blockage    of the lumen by a lesion and is the most common type of intes-  tinal obstruction. Paralytic ileus, or functional obstruction, is a  failure of motility after gastrointestinal or abdominal surgery.  Anesthetic agents, local inflammatory reactions, use of opioid  analgesia, and hyperactivity of the sympathetic nervous system  contribute to postoperative ileus.   Simple obstruction of the small intestine from fibrous adhe-  sions is the most common type of intestinal obstruction.”  Acute obstructions usually have mechanical causes, such as  adhesions or hernias (Figure 41-4). Chronic or partial obstruc-  tions are more often associated with tumors or inflammatory  disorders, particularly of the large intestine. Intussusception is  rare in adults compared with the more frequent occurrence in  infants. The most common causes of large bowel obstruction  are colorectal cancer, volvulus (twisting), and strictures related  to diverticulitis. Common causes of intestinal obstruction in  children are presented in Chapter 42.   PATHOPHYSIOLOGY. The consequences of intestinal obstruc-  tion are related to its onset and location, the length of intes-  tinal tract proximal to the obstruction, and the presence and  severity of ischemia. The major pathophysiologic alterations are  presented in Figure 41-5. Postoperative paralytic ileus results  from inhibitory neural reflexes associated with inflammatory  mediators, and the influence of exogenous (meperidine) and  endogenous opioids (endorphins) that affect the entire GI tract,  including the stomach.***” Small intestine obstruction leads  to accumulation of fluid and gas inside the lumen proximal to  the obstruction. Fluids accumulate from impaired water and  electrolyte absorption and enhanced secretion with net move-  ment of fluid from the vascular space to the intestinal lumen.  Gas from swallowed air, and to a lesser extent from bacterial  overgrowth, contributes to the distention. Distention begins  almost immediately, as gases and fluids accumulate proximal  to the obstruction. Distention decreases the intestine’s ability  to absorb water and electrolytes and increases the net secretion  of these substances into the lumen. Within 24 hours, up to 8 L  of fluid and electrolytes enters the lumen in the form of saliva,  gastric juice, bile, pancreatic juice, and intestinal secretions.  Copious vomiting or sequestration of fluids in the intestinal  lumen prevents their reabsorption and produces severe fluid    Protrusion of the intestine through a weakness in the abdominal muscles or through the inguinal ring  Telescoping of one part of the intestine into another; this usually causes strangulation of the blood supply; more common in    the ileocecal area in infants 10 to 15 months of age than in adults    Twisting of the intestine on its mesenteric pedicle, with occlusion of the blood supply; often associated with fibrous    adhesions in the small intestine; occurs most often in the large intestine in older adults    Inflamed saccular herniations (diverticula) of the mucosa and submucosa through the tunica muscularis of the colon;    diverticula are interspersed between thick, circular, fibrous bands; most common in obese individuals older than 60 years    Tumor growth into the intestinal lumen; adenocarcinoma of the colon and rectum is the most common tumoral obstruction;    Loss of peristaltic motor activity in the intestine; associated with abdominal surgery, peritonitis, hypokalemia, ischemic    bowel, spinal trauma, pneumonia, neuropathies, or myopathies; affects small and large intestines    Peritoneal irritation from surgery or trauma leads to formation of fibrin and adhesions that attach to intestine, omentum, or    peritoneum and can cause traction and obstruction; most common in small intestine    Sudden onset; often caused by torsion, intussusception, or herniation  Protracted onset; more commonly from tumor growth or progressive formation of strictures    Intrinsic Obstruction develops within intestinal lumen; examples: luminal edema or hemorrhage, foreign bodies    Extrinsic Obstruction originates outside the intestine; examples: tumors, torsion, fibrosis, hernia, intussusception    Simple Luminal obstruction without impairment of blood supply  Strangulated Luminal obstruction with occlusion of blood supply  Closed loop Obstruction at each end of a segment of the intestine    Blockage of the intestinal lumen by intrinsic or extrinsic lesions; usually treated surgically  Paralysis of the intestinal musculature as a result of accidental or surgical trauma, peritonitis, electrolyte    Volvulus Intussusception  FIGURE 41-4 Intestinal Obstructions. A, Hernia. B, Constriction from adhe-  sions. €, Volvulus. D, Intussusception. (From Kumar V, Abbas AK, Aster J: Robbins  basic pathology, ed 9, Philadelphia, 2013, Saunders.)    and electrolyte disturbances. Extracellular fluid volume and  plasma volume decrease, causing dehydration. Hemoconcen-  tration (decreased plasma volume) elevates hematocrit level  and causes hypotension and tachycardia. Severe dehydration  leads to hypovolemic shock.   If the obstruction is at the pylorus or high in the small  intestine, metabolic alkalosis develops initially as a result of    excessive loss of hydrogen ions that normally would be reab-  sorbed from the gastric juice. With prolonged obstruction or  obstruction lower in the intestine, metabolic acidosis is more  likely to occur because bicarbonate from pancreatic secretions  and bile cannot be reabsorbed. Hypokalemia from vomiting  and decreased potassium absorption can be extreme, promot-  ing acidosis and atony of the intestinal wall. Metabolic acidosis  also may be accentuated by ketosis, the result of declining car-  bohydrate stores caused by starvation. Lack of circulation per-  mits the buildup of significant amounts of lactic acid, which  worsen the metabolic acidosis. If pressure from the distention  is severe enough, it occludes the arterial circulation and causes  ischemia, necrosis, perforation, and peritonitis. Fever and  leukocytosis are often associated with overgrowth of bacteria,  ischemia, and bowel necrosis. Bacterial proliferation and trans-  location across the mucosa to the mesenteric lymph nodes or  systemic circulation cause sepsis. The release of inflammatory  mediators into the circulation causes remote organ failure (see  Chapter 48).   Consequences of large bowel obstruction are related to the  competence of the ileocecal valve, which normally prevents  reflux of colonic contents into the small intestine. When the  ileocecal valve is competent, the cecum cannot decompress  into the small intestine, resulting in distention. Ischemia occurs  when the intraluminal pressure exceeds the capillary pressure  in the lumen. Acute colonic pseudo-obstruction (Ogilvie syn-  drome) is a massive dilation of the large bowel that occurs in  critically ill patients and immobilized older adults. It is char-  acterized by significant dilation of the cecum and absence of  mechanical obstruction, and is related to excessive sympathetic  motor input or decreased parasympathetic motor input.   CLINICAL MANIFESTATIONS. Signs and symptoms of small  intestine obstruction are consistent with the pathophysiology.    Colicky pains caused by intestinal distention followed by nau-  sea and vomiting are the cardinal symptoms. Typically the pain  occurs intermittently. Pain intensifies for seconds or minutes  as a peristaltic wave of muscle contraction meets the obstruc-  tion. The passing of the wave is followed by a pain-free interval.  Pain may be continuous with severe distention and then dimin-  ish in intensity. If ischemia occurs, the pain loses its colicky  character, becoming more constant and severe. Sweating and  tachycardia occur as a sympathetic nervous system response  to hypotension. Fever, severe leukocytosis, abdominal disten-  tion, and rebound tenderness develop as ischemia progresses to  necrosis, perforation, and peritonitis.   Vomiting and abdominal distention vary, depending on the  level and completion of the obstruction. Obstruction at the    pylorus causes early, profuse vomiting of clear gastric fluid.  Obstruction in the proximal small intestine causes mild disten-  tion and vomiting of bile-stained fluid. Obstruction in the distal  small intestine causes more pronounced distention because a  greater length of intestine is proximal to the obstruction. In this  case, vomiting may not occur or may occur later and contain  fecal material. Partial obstruction can cause diarrhea or con-  stipation, but complete obstruction usually causes constipa-  tion only. Complete obstruction increases the number of bowel  sounds, which may be tinkly and accompanied by peristaltic  rushes and crampy, abdominal pain. Signs of hypovolemia and  metabolic acidosis (see Chapter 3) may be observed as early as  24 hours after the occurrence of complete obstruction. Disten-  tion may be severe enough to push against the diaphragm and    decrease lung volume. This can lead to atelectasis and pneumo-  nia, particularly in debilitated individuals.   Large intestine obstruction usually presents with hypogas-  tric pain and abdominal distention. Pain can vary from vague  to excruciating, depending on the degree of ischemia and the  development of peritonitis.   EVALUATION AND TREATMENT. Evaluation is based on clinical  manifestations and includes ultrasound and radiography.*®  Successful management requires early identification of the site  and type of obstruction. Replacement of fluid and electrolytes  and decompression of the lumen with gastric or intestinal suc-  tion are essential forms of therapy. Laparoscopic procedures can  release adhesions. Immediate surgical intervention is required  for strangulation and complete obstruction. Neostigmine, a  parasympathomimetic, is used for colonic pseudo-obstruction  and colonoscopic decompression may be required.”    Gastritis is an inflammatory disorder of the gastric mucosa. It  can be acute or chronic and can affect the fundus or antrum, or  both. Acute gastritis erodes the surface epithelium in a diffuse  or localized pattern. The erosions are usually superficial.   Acute gastritis is usually caused by injury of the protective  mucosal barrier by drugs, chemicals, or Helicobacter pylori  infection (Figure 41-6). Nonsteroidal anti-inflammatory drugs  (NSAIDs [ibuprofen, naproxen, indomethacin, and aspirin]})  inhibit the action of cyclooxygenase-1 (COX-1), and are known  to cause erosive gastritis because they inhibit prostaglandins,  which normally stimulate the secretion of mucus and suppress  inflammation. With the exception of aspirin, NSAIDs also  cause gastric hypermotility, causing mucosal compression and  injury.°° Alcohol, histamine, digitalis, and metabolic disorders  such as uremia are contributing factors. H. pylori—associated  acute gastritis causes inflammation, increased gastric secretion  in antral gastritis, decreased gastric section in fundal gastritis,  pain, nausea, and vomiting*! (Box 41-1).   The clinical manifestations of acute gastritis can include  vague abdominal discomfort, epigastric tenderness, and bleed-  ing. Healing usually occurs spontaneously within a few days.    FIGURE 41-6 Acute Erosive Gastritis. Acute erosive gastritis is shown in  the opened stomach. The mucosa appears hyperemic, and the foci of superficial  ulceration are manifested as scattered, small, red areas termed erosions. (From  Kumar V et al: Pathologic basis of disease, ed 7, Philadelphia, 2006, Saunders.)    Discontinuing injurious drugs, using antacids, or decreasing  acid secretion with a histamine H2-receptor antagonist and  proton pump inhibitor also promote healing.   Chronic gastritis tends to occur in older adults and causes  chronic inflammation, mucosal atrophy, and epithelial meta-  plasia. Chronic gastritis usually is classified as type A, or  immune (fundal), or type B, nonimmune (antral), depending  on the pathogenesis and location of the lesions. Both types of  chronic gastritis can occur and is known as type AB, or pangas-  tritis, with the antrum being more severely involved.   Chronic fundal gastritis is the most rare and severe type and  is associated with loss of T-cell tolerance and development    H. pylori is a gram-negative spiral bacterium with a flagella and is a major  cause of acute and chronic gastritis, peptic ulcer disease in the duodenum and  stomach, gastric adenocarcinoma, and gastric mucosa—associated lymphoid  tissue (MALT) (see p. 1467) in about 20% of infected individuals. H. pylori is  transmitted through the fecal-oral route and is usually acquired in childhood.  Infection is asymptomatic in about 70% of cases. In other cases, inflamma-  tion and immune responses promote mucosal ulcerations or prevent healing of  injured tissue. Gene-environment interaction and different pathogenic strains  of H. pylori increase risk for disease. Patterns of gastritis and disease progres-  sion vary by site of infection and strain of H. pylori. Pathogenic and virulence  factors include the following:  . An ability to colonize and adhere to gastric epithelial cells  . The possession of flagella that allows movement through the luminal  mucous layer to a site of higher pH  . An ability of adherent strains to suppress acid secretion to improve  their survival, particularly CagA and VacA  . Secretion of urease that produces ammonia and carbon dioxide, result-  ing ina more alkaline environment  . Release of vacuolating cytotoxin (VacA) that promotes bacterial sur-  vival and causes epithelial injury  . The presence of cytotoxin-associated gene (CagA) strains that can  escape normal immune responses and cause inflammation with  release of inflammatory cytokines and reactive oxygen metabolites  that damage mucosal epithelial cells and cause loss of the protective  mucosal barrier; they also promote tumor development by degrading  p53 tumor suppression  . Recruitment and activation of neutrophils, macrophages, and mast  cells with release of inflammatory cytokines (tumor necrosis factor-  alpha [TNF-a], interleukin-1 [IL-1], IL-6, IL-8, histamine) that promote  cellular injury  . Down-regulation of antral somatostatin leading to increased gas-  trin, increased acid, impaired mucosal bicarbonate production, and  increased mucosal exposure to acid and pepsin  . Activation or inhibition of T- and B-cell immune responses that may  contribute to mucosal injury  . Release of cytokines and chemokines that promote gastric epithelial  cell death (apoptosis) and cell proliferation that can result in atrophy,  ulcers, or malignant growth    Data from Costa AM et al: FEBS Lett 587(3):259-265, 2013; Peek RM  Jr, Fiske C, Wilson KT: Physiol Rev 90(3):831-858, 2010; Ruggiero P:  Curr Opin Infect Dis 25(3):337-344, 2012; Suzuki R, Shiota S, Yamaoka  Y: Infect Genet Evol 12(2):203-213, 2012; Varbanova M, Malfertheiner P:  Dig Dis 29(6):592-599, 2011.    of autoantibodies to gastric Ht-Kt ATPase. Infection with  H. pylori can trigger the immune response through molecular  mimicry.°* The gastric mucosa degenerates extensively in the  body and fundus of the stomach, leading to gastric atrophy.  Loss of parietal cells diminishes secretion of hydrochloric acid  and intrinsic factor. Because acid secretion is insufficient, the  feedback mechanism that normally inhibits gastrin secretion  is impaired, causing elevated plasma levels of gastrin. Chronic  antral gastritis generally involves the antrum only and is more  common than fundal gastritis. It is caused by H. pylori bacte-  ria or chronic use of alcohol, tobacco, and nonsteroidal anti-  inflammatory drugs. There are high levels of hydrochloric acid  secretion with an increased risk of duodenal ulcers. H. pylori  can also progress to autoimmune atrophic gastritis and involve  the fundus, thus becoming pangastritis. In these cases there is  greater risk for the development of gastric cancer.   Signs and symptoms of chronic gastritis often do not cor-  relate with the severity of the disease. Gastroscopic examination  and biopsy may show a long-standing inflammatory process  and gastric atrophy in an individual with no history of abdomi-  nal distress. The presence of antiparietal cell antibody and ele-  vated plasma ghrelin level are specific for atrophic gastritis.   H. pylori infection is evidence for H. pylori gastritis. In  chronic fundal gastritis, failure to stimulate acid secretion con-  firms achlorhydria (diminished secretion of hydrochloric acid).  The gastric secretions also can be evaluated for the presence of  intrinsic factor. Pernicious anemia can develop because intrin-  sic factor is less available to facilitate vitamin B,, absorption.  Individuals may report vague symptoms, including anorexia,  fullness, nausea, vomiting, and epigastric pain. Gastric bleeding  may be the only clinical manifestation of gastritis. Evaluation  for gastric carcinoma is completed with chronic H. pylori infec-  tion.°° Symptoms can usually be managed with consumption  of smaller meals, including a soft, bland diet; and avoidance  of alcohol and NSAIDs. Combination antibiotics are used to  treat H. pylori, and the emergence of antimicrobial resistance is  a concern.°° Vitamin B,, is administered to correct pernicious  anemia (see Chapter 28).°”   Alkaline reflux gastritis is a stomach inflammation caused  by reflux of bile and alkaline pancreatic secretions that con-  tain proteolytic enzymes and disrupt the mucosal barrier in  the remnant stomach. This form of gastritis occurs in 5% to  20% of individuals who have undergone gastrectomy or pyloro-  plasty. Clinical manifestations include nausea, bilious vomiting  (vomiting in which the vomitus contains bile), and sustained  epigastric pain that worsens after eating and is not relieved  by antacids. Endoscopy shows a hemorrhagic and friable gas-  tric mucosa. Antacids do not consistently improve symptoms.  Avoidance of aspirin and alcohol may decrease gastric irrita-  tion, and a low-fat diet may limit bile secretion. Surgical correc-  tion may ultimately be required.°*    A peptic ulcer is a break, or ulceration, in the protective muco-  sal lining of the lower esophagus, stomach, or duodenum. It is  estimated that 10% to 17% of the population have peptic ulcer  disease; however, the true incidence is unkown.*?    Risk factors for peptic ulcer disease include genetic pre-  disposition, H. pylori infection of the gastric mucosa (see Box  41-1), and habitual use of NSAIDs. Additional factors include  excessive use of alcohol, smoking, acute pancreatitis, chronic  obstructive pulmonary disease, obesity, cirrhosis, and age  greater than 65 years.°°! Psychologic stress may be a risk factor  for peptic ulcer disease but the exact mechanism of causation is  not known.°*   Peptic ulcers can be acute or chronic, and superficial or deep.  Superficial ulcerations are called erosions because they erode the  mucosa but do not penetrate the muscularis mucosae (Figure  41-7). True ulcers extend through the muscularis mucosae and  damage blood vessels, causing hemorrhage or perforating the  gastrointestinal wall.   Chronic use of NSAIDs suppresses mucosal prostaglandin  synthesis, resulting in decreased bicarbonate secretion and mucin  (a component of the gut barrier) production and increased  secretion of hydrochloric acid. The interaction of NSAIDs and  H. pylori can contribute to the pathogenesis of peptic ulcer.  Disruption of the mucosa exposes submucosal areas to gastric  secretions and autodigestion causing erosion and ulceration.    Duodenal ulcers occur with greater frequency than other types  of peptic ulcers. Idiopathic duodenal ulcers are rare and can be  associated with altered mucosal defenses, rapid gastric empty-  ing, elevated serum gastrin levels, or acid production stimulated  by smoking.   PATHOPHYSIOLOGY. Causative factors, singly or in combination,  cause acid and pepsin concentrations in the duodenum to pen-  etrate the mucosal barrier and lead to ulceration® (Figure 41-8).   CLINICAL MANIFESTATIONS. The characteristic manifestation of  a duodenal ulcer is chronic intermittent pain in the epigastric  area. The pain begins 30 minutes to 2 hours after eating, when  the stomach is empty. It is not unusual for pain to occur in the  middle of the night and disappear by morning. The pain results  from sensorineural stimulation by acid or muscle spasm, or both.  Pain is relieved rapidly by ingestion of food or antacids, creating    d 1 y iS i. 5 6  FIGURE 41-7 Chronic Peptic Ulcer. Gross photograph of a chronic peptic  ulcer located in the lesser curvature, straddling the antrum and corpus of the stom-  ach. (From Damjanov |, Linder J, editors: Anderson's pathology, ed 10, St Louis,  1996, Mosby.)    FIGURE 41-8 Duodenal Ulcer. A, A deep ulceration in the duodenal wall extending as a crater through the entire mucosa  and into the muscle layers. B, Duodenal ulcer. C, Bilateral (kissing) duodenal ulcers in a person using nonsteroidal anti-  inflammatory drugs (NSAIDs). (€ courtesy David Bjorkman, MD, Department of Gastroenterology, University of Utah School of  Medicine, Salt Lake City, UT.)    Often present (60-80%)  May be present  Normal or decreased  Normal or decreased  Increased    a typical “pain-food-relief” pattern. Some individuals with duo-  denal ulcer have no symptoms, particularly older adults; the  first manifestation may be hemorrhage or perforation, particu-  larly with a history of NSAID or anticoagulant use. Healing is  accompanied by relief of pain. Constant, unremitting pain may  be caused by complications, such as intestinal obstruction or  perforation. Bleeding from duodenal ulcers causes hematemesis  or melena. It is not clear why individuals infected with H. pylori  duodenal ulcers are negatively associated with gastric cancer.°°   EVALUATION AND TREATMENT. Several diagnostic approaches  are used to differentiate duodenal ulcers from gastric ulcers or  gastric carcinoma. Endoscopic evaluation allows visualization  of lesions and biopsy. Radioimmune assays of gastrin levels are  evaluated to identify ulcers associated with gastric carcinomas.  A urea breath test; measurement of levels of serum antibodies,  stool, and serum antigen; and findings from gastric biopsy are  used to detect H. pylori infection.”   Management of duodenal ulcers is aimed at relieving the  causes and effects of hyperacidity and preventing complications.  Antacids neutralize gastric contents, elevate pH, inactivate pep-  sin, relieve pain, and are cytoprotective.°”* Acid secretion can be  suppressed with drugs that block H2 receptors and inhibit the  secretion of acid. Proton pump inhibitors inhibit acid produc-  tion. Eradication of H. pylori with bismuth and combinations of  antibiotics supplemented with vitamin C usually prevents relapse,  although there is increasing drug resistance. Ulcer-coating  agents, such as sucralfate and colloidal bismuth, promote healing.  Anticholinergic drugs may be used to inhibit gastric secretion,  suppress gastric motility, and delay gastric emptying. Surgical  resection may be required for complications including bleeding,    FIGURE 41-9 Macroscopic Appearance of Benign Gastric Ulcers. (From  Damjanov I, Linder J, editors: Anderson’s pathology, ed 10, St Louis, 1996, Mosby.)    perforation, obstruction, or peritonitis.’”” Risk of duodenal ulcer  may be reduced with a diet high in vitamin A and fiber.’”! Devel-  opment of a vaccine against H. pylori is progressing slowly.”   Gastric ulcers are ulcers of the stomach. They usually occur  between the ages of 55 and 65 years, and are about one fourth  as common as duodenal ulcers (Table 41-4 and Figure 41-9).    PATHOPHYSIOLOGY. Generally gastric ulcers develop in the  antral region, adjacent to the acid-secreting mucosa of the  body, and are frequently caused by H. pylori (see Box 41-1).  The primary defect is an abnormality that increases the mucosal  barrier’s permeability to hydrogen ions. Gastric secretion may  be normal or less than normal and there may be a decreased  mass of parietal cells. Chronic pangastritis is often associated  with development of gastric ulcers and may precipitate ulcer  formation by limiting the mucosa’s ability to secrete a protec-  tive layer of mucus (Figure 41-10).   Duodenal reflux of bile is associated with gastric ulcer (alka-  line reflux gastritis, p. 1435) and may occur after cholecystec-  tomy, pyloroplasty, or gastrojejunostomy. The pyloric sphincter  also may fail to respond to stimuli that normally increase resting  tone, such as entry of acid, protein, and fat into the duodenum,  allowing reflux of bile and pancreatic enzymes to damage the  gastric mucosa. The damaged mucosal barrier permits hydrogen  ions to diffuse into the mucosa, where they disrupt permeabil-  ity and cellular structure. A vicious cycle can be established as  the damaged mucosa liberates histamine, which stimulates the    increase of acid and pepsinogen production, blood flow, and  capillary permeability. The disrupted mucosa becomes edema-  tous and loses plasma proteins. Destruction of small vessels  causes bleeding.   Zollinger-Ellison syndrome is associated with peptic ulcers  related to increased secretion of gastrin, which causes excess  secretion of gastric acid. A gastrinoma (a gastrin-secreting  neuroendocrine tumor or multiple tumors) of the pancreas  or duodenum stimulates a proliferation of gastric parietal cells  and chronic secretion of gastric acid. The resulting excess acid  causes gastric and duodenal ulcers, gastroesophageal reflux with  abdominal pain, and diarrhea. Diagnosis includes secretin- or  calcium-stimulated measures of gastrin levels, gastric pH levels  less than 2, and symptomatic evidence of peptic ulcer disease.  Proton pump inhibitors reduce gastric acid secretion, and sur-  gical removal of tumors limits metastasis.”*”°   CLINICAL MANIFESTATIONS. The clinical manifestations of gastric  ulcers are similar to those of duodenal ulcers (see Table 41-4).  The pattern of pain, food, and relief is common, but the pain of  gastric ulcers also occurs immediately after eating. Gastric ulcers    also tend to be chronic rather than alternate between periods of  remission and exacerbation and cause more anorexia, vomiting,  and weight loss than duodenal ulcers.   EVALUATION AND TREATMENT. The evaluation and treatment  of gastric ulcers are similar to the evaluation and treatment of  duodenal ulcers (see p. 1437).    A stress ulcer (stress-related mucosal disease) is an acute form  of peptic ulcer that tends to accompany the physiologic stress  of severe illness; multisystem organ failure; or major trauma,  including severe burns or head injury. Usually, multiple sites  of ulceration are distributed within the stomach or duodenum.  Stress ulcers may be classified as ischemic ulcers or Cushing  ulcers.   Ischemic ulcers develop within hours of an event—such as  hemorrhage, multisystem trauma, severe burns, heart failure,  or sepsis—that causes ischemia of the stomach and duodenal  mucosa. Stress ulcers that develop as a result of burn injury are  often called Curling ulcers.   Cushing ulcer is a stress ulcer associated with severe head  trauma or brain surgery. This ulcer results from decreased  mucosal blood flow and hypersecretion of acid caused by  overstimulation of the vagal nuclei. Excessive acid damages  the mucosal barrier, initiating the processes summarized in  Figure 41-10.   The primary clinical manifestation of stress-related mucosal  disease is bleeding that occurs more readily with the presence  of coagulopathy.”° Other symptoms may not be present. The  bleeding may be slight or, if a small vessel is perforated, amount  to hundreds of milliliters. Prophylactic treatment regimens are  used to prevent this disease.’””* Stress ulcers seldom become  chronic.    Advances in the medical treatment of peptic ulcer disease with  proton pump inhibitors and eradication of H. pylori, and lapa-  roscopic and endoscopic repair techniques have significantly  reduced the number of cases requiring open surgery.”’ The indi-  cations for ulcer surgery are recurrent or uncontrolled bleeding  and complicated perforation of the stomach or duodenum.*°   Weight loss often follows gastric resection but stabilizes  within 3 months. Inadequate food intake is a common cause  because many individuals cannot tolerate the osmotic effect  of carbohydrates or a normal-size meal. Foods may be poorly  absorbed because the stomach is less able to mix, churn, and  break down food particles. Abdominal pain, vomiting, diar-  rhea, and malabsorption of fats also contribute to weight loss.  In the case of bariatric surgery for extreme obesity, weight loss  is the intended outcome.   Acute complications of gastrectomy or anastomosis, such as  poor wound healing, abscess formation, or suture failure, are  relatively uncommon except in the debilitated person. Chronic  complications, however, occur more often and are likely to  develop if a large portion of the stomach has been removed.  These complications and their pathophysiologic mechanisms  are described in the next section.   Postgastrectomy syndromes are a group of signs and symptoms  that occur after gastric resection. They are caused by changes in  motor and control functions of the stomach and upper small  intestine.*!   Malabsorption syndromes interfere with nutrient absorption.  Historically malabsorption disorders have been classified as  maldigestion or malabsorption. Maldigestion is failure of the  chemical processes of digestion that take place in the intesti-  nal lumen or at the brush border of the intestinal mucosa of  the small intestine. Malabsorption is the failure of the intes-  tinal mucosa to absorb (transport) the digested nutrients.  Often maldigestion and malabsorption are interrelated or  occur together, making classification difficult. Generally, how-  ever, maldigestion is caused by deficiencies of enzymes, such  as pancreatic lipase or intestinal lactase, which are necessary  for digestion. Inadequate secretion of bile salts and inadequate  reabsorption of bile in the ileum also contribute to maldiges-  tion. Malabsorption is the result of mucosal disruption caused  by gastric or intestinal resection, vascular disorders, or intestinal  disease.   The pancreatic enzymes (lipase, amylase, trypsin, chymotryp-  sin) are required for the digestion of proteins, carbohydrates,  and fats. Pancreatic insufficiency is the deficient production  of these enzymes by the pancreas. Causes of pancreatic insuf-  ficiency include chronic pancreatitis, pancreatic carcinoma,  pancreatic resection, and cystic fibrosis. Significant damage to  or loss of pancreatic tissue must occur before enzyme levels  decrease sufficiently to cause maldigestion. Although pancre-  atic insufficiency causes poor digestion of all nutrients, fat mal-  digestion is the chief problem. Salivary amylase and enzymes  secreted by the intestinal brush border assist in carbohydrate  and protein digestion, but these enzymes do not digest fats.  Absence of pancreatic bicarbonate in the duodenum and jeju-  num causes an acidic pH that worsens maldigestion by pre-  venting activation of pancreatic enzymes that are present.  A large amount of fat in the stool (steatorrhea) and weight loss  are the most common signs of pancreatic insufficiency. Lipase  supplementation is usually successful.*?   Deficiency of disaccharidase at the villus brush border of the  small intestine is caused by a congenital defect in the lactase  gene. Lactase deficiency inhibits the breakdown of lactose (milk  sugar) into monosaccharides and therefore prevents lactose  digestion and absorption across the intestinal wall. Lactase defi-  ciency is most common in blacks. Congenital lactase deficiency  causes watery diarrhea in breast milk or lactose-containing for-  mulas in infants. Lactase expression is lost before adulthood in  adult-type lactose intolerance.** Secondary (acquired) lactase  deficiency can be caused by several diseases of the intestine,  including gluten-sensitive enteropathy (see Chapter 42), enteri-  tis, and bacterial overgrowth.    The undigested lactose remains in the intestine, where bac-  terial fermentation causes gases to form. Undigested lactose  also increases the osmotic gradient in the intestine, causing  irritation and osmotic diarrhea. Clinical manifestations of lac-  tose consumption with lactase deficiency are bloating, crampy  pain, diarrhea, and flatulence. The disorder is diagnosed by  genetic testing, a lactose-hydrogen breath test, dietary lactose  withdrawal, or rarely small intestinal biopsy.** Avoiding milk  products and adhering to a lactose-free diet relieve symptoms.  Maintaining an adequate calcium intake with restricted intake  of milk products decreases risk of osteoporosis.    Conjugated bile acids (bile salts) are necessary for the digestion  and absorption of fats. Bile salts are conjugated in the bile that  is synthesized from cholesterol and secreted from the liver.*°  When bile enters the duodenum, the bile salts aggregate with  fatty acids and monoglycerides to form micelles. Micelle for-  mation makes fat molecules more soluble and allows them to  pass through the unstirred layer at the brush border of the small  intestinal villi (see Chapter 40). A minimum concentration of  bile salts, termed the critical micelle concentration, is required  to allow micelles to form. Therefore, conditions that decrease  the production or secretion of bile result in decreased micelle  formation and fat malabsorption. These conditions include  advanced liver disease, which decreases production of bile salts;  obstruction of the common bile duct, which decreases flow of  bile into the duodenum; intestinal stasis (lack of motility), which  permits overgrowth of intestinal bacteria that deconjugate bile  salts; and diseases of the ileum, which prevent the reabsorption  and recycling of bile salts (enterohepatic circulation).°°   poor intestinal absorption of fat and fat-soluble vitamins (A, D,  E, and K). Increased fat in the stools (steatorrhea) leads to diar-  rhea and decreased plasma proteins. The losses of fat-soluble  vitamins and their effects include the following:   2. Vitamin D deficiency results in decreased calcium absorp-  tion with bone demineralization (osteoporosis), bone  pain, and fractures.   3. Vitamin K deficiency prolongs prothrombin time, lead-  ing to spontaneous development of purpura (bruising)  and petechiae.   4, Vitamin E deficiency has uncertain effects but may cause  testicular atrophy and neurologic defects in children.   ciency is to increase the amount of medium-chain triglycerides  in the diet, for example, by using coconut oil for cooking. Vita-  mins A, D, and K are given parenterally.   Dumping syndrome is the rapid emptying of hypertonic  chyme from the surgically created, residual stomach into the  small intestine 10 to 20 minutes after eating (early dumping  syndrome). It occurs with varying severity in 5% to 10% of  individuals who have undergone partial gastrectomy, bariatric  surgical procedures, or pyloroplasty.*'*” It is not as common    in individuals who have undergone a Billroth I] anastomo-  sis (gastrojejunostomy) accompanied by vagotomy. Factors  that promote early dumping syndrome include: (1) loss of gas-  tric capacity, (2) loss of emptying control when the pylorus is  removed, and (3) loss of feedback control by the duodenum  when it is removed. Rapid gastric emptying and creation of a  nonphysiologic, high osmotic gradient within the small intes-  tine cause a sudden shift of fluid from the vascular compart-  ment to the intestinal lumen. Plasma volume decreases, causing  vasomotor responses, such as increased pulse rate, hypotension,  weakness, pallor, sweating, and dizziness. Rapid distention of  the intestine produces a feeling of epigastric fullness, cramp-  ing, nausea, and vomiting. Diarrhea can accompany dumping  syndrome or occur as a solitary symptom. Diarrhea can occur  as frequent, persistent elimination of liquid stool or as inter-  mittent, precipitous, and unpredictable elimination of a large  volume of stool. Both types can be either mild or severe.   A less common form of dumping syndrome, late dump-  ing syndrome occurs 1 to 3 hours after eating. The symptoms  include weakness, diaphoresis, and confusion but they cannot be  explained by rapid gastric emptying. After a high-carbohydrate  meal, individuals who have undergone gastrectomy may develop  hypoglycemia, which causes the symptoms. The hypoglycemia  is caused by an increase in insulin secretion stimulated by the  hyperglycemia that follows eating. Other hormonal responses  also may participate in the development of hypoglycemia.   Most cases of dumping syndrome respond well to dietary  management.®* Frequent small meals that are high in protein  and low in carbohydrates relieve symptoms. Other measures  include drinking fluids between meals instead of at mealtime  and reclining on the left side after eating. Some cases require  surgical intervention, including reconstruction of the pylorus or  a gastrojejunostomy. Octreotide reduces abdominal and vaso-  motor symptoms of dumping syndrome by inhibiting insulin  and gut hormone release, slowing intestinal transit time, and  inhibiting food-induced circulatory changes.*?    Ulcerative colitis and Crohn disease are chronic, relapsing  inflammatory bowel diseases (IBDs) of unknown origin. The  incidence of IBD is increasing around the world and varies from  3 to 300 per 100,000 persons.”° Both diseases are associated with  genetic factors, alterations in epithelial cell barrier functions,  immunopathology related to abnormal T-cell reactions to  commensal microflora and other luminal antigens, and varying  phenotypes.?! Microscopic colitis is increasing in prevalence  and is reviewed in What’s New? Microscopic Colitis.    Ulcerative colitis (UC) is a chronic inflammatory disease  that causes ulceration of the colonic mucosa and extends  proximally from the rectum into the colon (Figure 41-11).  The lesions appear in susceptible individuals between 20 and  40 years of age. Risk factors include family history of disease or  Jewish descent, and the disease is more prevalent among white  populations and Northern Europeans. UC is less common in  smokers.”    Although the cause of UC is unknown, dietary, infectious,  genetic, and immunologic factors are all suggested causes.?°  Inflammation may be caused by commensal or pathogenic  enteric microorganisms with increased mucosal adherence and  invasion and persistent activation of T cells. The familial ten-  dency to develop ulcerative colitis and the occurrence of dis-  ease in identical twins support a genetic theory of causation.  Perhaps most significant are the humoral and cellular immu-  nologic factors associated with the disease. Colonic epithelial    Microscopic colitis is a relatively common cause of diarrhea and occurs primar-  ily in females and older adults. There are two histologic forms: lymphocytic and  collagenous. The symptoms of frequent chronic daily watery diarrhea are the  same for both types and can be accompanied by abdominal pain and weight  loss. The cause is unknown and the prevalence is increasing. There are associa-  tions with numerous drugs and celiac disease. Autoantibodies have been found  in some individuals including intestinal goblet cells, antinuclear antibodies  (ANAs), antineutrophil cytoplasmic antibodies, and anti-Saccharomyces cerevi-  siae antibody (ASCA). The colon mucosa appears normal on endoscopy. Biopsy  reveals histopathologic descriptions. Lymphocytic colitis shows an increase in  intraepithelial lymphocytes of more than 20 lymphocytes per 100 surface colo-  nocytes. Collagenous colitis is characterized by a thickened subepithelial col-  lagen layer of more than 10 ym, alteration of the vascular mucosal pattern, and  mucosal nodularity. Antidiarrheal agents and budesonide (an anti-inflammatory  steroid) are the best documented short-term treatments and new immunosup-  pressive agents are being evaluated. An optimal long-term strategy is yet to be  identified. The disease is negatively associated with colorectal cancer.    Data from Gentile NM et al: Am J Gastroentero/ 108(2):256-259,  2013; laniro G et al: World J Gastroenterol 18(43):6206-6215, 2012;  Koulaouzidis A, Saeed AA: World J Gastroenterol 17(37):4157-4165,  2011; Mahajan D et al: Adv Anat Patho! 19(1):28-38, 2012; Yen EF  et al: Dig Dis Sci 57(1):161-169, 2012.    antibodies of the immunoglobulin G (IgG) class have been  identified in the sera of individuals with ulcerative colitis and a  large number of plasma cells are found in the inflamed colon.  Lymphocytes (T cells) in individuals with ulcerative colitis may  have cytotoxic effects on the epithelial cells of the colon, as well  as damage caused by inflammatory cytokines (interleukin-1  [IL-1], IL-2, IL-6, IL-8, IL-10, tumor necrosis factor-alpha  [TNF-a]), toxic oxygen free radicals, and interferon-gamma  (IFN-y).°* Furthermore, autoimmune disorders, such as sys-  temic lupus erythematosus and erythema nodosum, may  accompany ulcerative colitis.   PATHOPHYSIOLOGY. The primary lesions of UC are continu-  ous with no skip lesions, are limited to the mucosa, and are not  transmural. The mucous layer is thinner than normal and there  is impairment of the epithelial barrier. The rectum is almost  always involved. Inflammation begins at the base of the crypt of  Lieberkiihn in the large intestine, primarily the left colon, with  infiltration and release of inflammatory cytokines from neu-  trophils, lymphocytes, plasma cells, macrophages, eosinophils,  and mast cells. Activated macrophages also contribute cytokines  that cause fever and the acute phase response. The inflammation  damages the epithelial mucosal barrier with leak of fluids into  the gut.” The disease is most severe in the rectum and sigmoid  colon. With milder inflammation, the mucosa is hyperemic and  edematous, and may appear dark red and velvety (Figure 41-12).  In more severe inflammation, the mucosa becomes hemor-  rhagic, and small erosions form and coalesce into ulcers. Abscess  formation occurs in the crypts. Necrosis and ragged ulceration  of the mucosa ensue. Edema and thickening of the muscula-  ris mucosae may narrow the lumen of the involved colon. In  chronic disease, inflammatory polyps (pseudopolyps) develop  in the colon from rapidly regenerating epithelium.   CLINICAL MANIFESTATIONS. The course of UC consists of  intermittent periods of remission and exacerbation. Clinical    FIGURE 41-11 Distribution Patterns of Crohn Disease and Ulcerative Colitis. Comparison of distribution patterns of  Crohn disease and ulcerative colitis as well as different conformations of ulcers and wall thickenings. (From Kumar V et al:    FIGURE 41-12 Acute Ulcerative Colitis. A gross specimen of subtotal ulcer-  ative colitis showing diffuse continuous disease starting from the distal rectum and  continuing up to the midportion of the ascending colon. (From Odze RD, Goldblum  JR, editors: Surgical pathology of the GI tract, liver, biliary tract, and pancreas,  ed 2, Philadelphia, 2009, Saunders.)    manifestations vary with the severity and extent of disease.  Loss of the absorptive mucosal surface and decreased colonic  transit time can cause large volumes of watery diarrhea. Muco-  sal destruction causes bleeding, cramping pain, and an urge  to defecate. There is frequent bloody diarrhea with passage of  purulent mucus.”° Mild UC involves less mucosa and may be  limited to proctitis, so that frequency of bowel movements,  bleeding, and pain is minimal. Severe forms may involve the  entire colon (pancolitis) and are characterized by fever, ele-  vated pulse rate, frequent diarrhea (10 to 20 movements per  day), urgency, obviously bloody stools, and continuous crampy  pain. Dehydration, weight loss, anemia, and fever result from  fluid loss, bleeding, and inflammation. Complications include  toxic megacolon, anal fissures, hemorrhoids, and perirectal  abscess. Severe hemorrhage is rare, but chronic blood loss may  precipitate hypotension and shock. Edema, strictures, or fibro-  sis can obstruct the colon. Perforation is an unusual but pos-  sible complication. The risk of left-sided colon cancer increases  significantly after many years of ulcerative colitis and the pres-  ence of primary sclerosing cholangitis.””   Extraintestinal manifestations of UC and Crohn disease  occur in about 30% of cases and include cutaneous lesions (ery-  thema nodosum and pyoderma gangrenosum), migratory poly-  arthritis and sacroiliitis, osteopenia and osteoporosis, mouth  ulcers, episcleritis or anterior uveitis of the eye, and primary  sclerosing cholangitis in the liver.?® Gallstones are common.  Chronic inflammation causes alterations in coagulation and  can cause life-threatening microthrombi, deep vein thrombosis,  and other thromboembolic events.”   EVALUATION AND TREATMENT. Diagnosis of ulcerative colitis is  based on the medical history, clinical manifestations, imag-  ing procedures, and histologic criteria.!°? Endoscopic evalua-  tion shows an inflamed and hemorrhagic mucosa. Radiologic  assessment may show loss of haustra, ulceration, and irregular  mucosa. The laboratory data include low hemoglobin values,    hypoalbuminemia, and low serum potassium levels. Infectious  causes are ruled out by stool culture. The symptoms of ulcerative  colitis can be very similar to those of Crohn disease, and serologi-  cal markers may be used for differential diagnosis.'°!   Treatment depends on the severity of symptoms and  the extent of mucosal involvement. First-line therapy is  5-aminosalicylic acid (mesalazine). Corticosteroids and  salicylates suppress the inflammatory response and help alle-  viate the cramping pain. Immunosuppressive agents (e.g.,  6-mercaptopurine or azathioprine), cyclosporine, tacrolimus,  and infliximab (a monoclonal anti-TNF-o antibody) are used  for chronic active disease.'°? Broad-spectrum antibiotics may  induce remission.!° For unknown reasons, nicotine may have a  protective effect in ulcerative colitis but not in Crohn disease.!°*  Severe, unremitting disease can require hospital admission and  administration of intravenous fluids. Extreme malnutrition  may require intravenous hyperalimentation. Surgical resection  of the colon or a colostomy may be performed if other forms  of therapy are unsuccessful.!°° Pouchitis is a complication of  restorative proctocolectomy with ileal pouch—anal anastomosis  performed as surgical treatment for both UC and Crohn dis-  ease. Antibiotic treatment is usually successful.!°°    Crohn disease (CD) (granulomatous colitis, ileocolitis, or  regional enteritis) is an idiopathic inflammatory disorder that  affects any part of the gastrointestinal tract from the mouth to  the anus. The distal small intestine and proximal large colon are  most commonly affected by the disease. In a small percentage  of cases, CD is difficult to differentiate from ulcerative colitis  (Table 41-5). Risk factors include family history, smoking, Jew-  ish ethnicity, urban residency, age less than 40 years, and a slight  predominance in women.!"” The CARD15/NOD2 (nucleotide-  binding-oligomerization-domains) gene mutations have the  strongest association with CD (35% to 45% of cases) although  many other genes have been identified.!°° The CARD15 /NOD2  genes code for a protein (a Toll-like receptor; see Chapter 10)  involved in the recognition of gram-negative and gram-positive  bacteria. The pathogenesis of CD may be associated with an  overly aggressive response to normal flora bacteria in geneti-  cally predisposed individuals.!°° Th1-mediated inflammation  with activation of leukocytes and cytokines (TNF-a, IFN-y, and  interleukins) causes injury. Recruited leukocytes release proin-  flammatory substances, including prostaglandins, leukotrienes,  proteases, reactive oxygen species, and nitric oxide, which cause  further injury and inflammation. Elevations in IgG levels are  associated with severity of disease.!!°   PATHOPHYSIOLOGY. The inflammatory process of CD begins in  the intestinal submucosa and spreads across the intestinal wall  to involve the mucosa and serosa in areas overlying lymphoid  tissue. Progression of the disease involves neutrophil infiltration  of the crypts, resulting in abscess formation and crypt destruc-  tion. The most common site of the disease is the ileocolon, but  both the large and small intestines may be involved. The inflam-  mation can affect some haustral segments but not others, creat-  ing a pattern called skip lesions. One side of the intestinal wall  may be affected but not the other.    Clinical Manifestations  Abdominal pain Occasional  Diarrhea Common  Bloody stools Common  Abdominal mass Rare  Small intestinal malabsorption Rare  Steatorrhea Rare  Potential for malignancy Common  Antineutrophil cytoplasmic antibodies Common  Anti—Saccharomyces cerevisiae antibodies Rare  Clinical course    The ulcerations of CD produce longitudinal and transverse  fissures that extend inflammation into lymphoid tissue. The  typical chronic lesion is a granuloma having cobblestone pro-  jections of inflamed tissue surrounded by areas of ulceration  (Figure 41-13). (Granulomas are described in Chapter 7.) The  lumen can narrow with inflammation, edema, and fibrotic  strictures. Fistulae may form in the perianal area between loops  of intestine or extend into the bladder.   CLINICAL MANIFESTATIONS. Individuals with CD may have no  specific symptoms other than an “irritable bowel” for several  years. Symptoms vary and are associated with disease location.  Abdominal pain and diarrhea are the most common signs (more  than five stools per day), with passage of blood and mucus. Diar-  rhea can result from decreased colonic absorption, bypass fistu-  lae, medications, bacterial overgrowth, and the presence of bile  in the colon that inhibits water absorption. Other manifestations  are related to the location and extent of intestinal involvement.  Inflammation of the ileum, for example, causes tenderness in  the lower right side of the abdomen. If the ileum is involved, the  individual may be anemic as a result of malabsorption of vita-  min B,. There also may be deficiencies in folic acid, vitamin D  absorption, and calcium leading to bone disease. Proteins may  be lost, leading to hypoalbuminemia. Weight loss is common.  Anal manifestations occur in about 30% of cases, including anal  fissure, perianal abscess, and fistula.!!! Individuals with CD of  long duration are also at risk for intestinal adenocarcinoma.!'”  Complications include obstruction, fistulae, abscess formation,  and chronic blood loss. Extraintestinal manifestations are similar  to those described for UC.    FIGURE 41-13 Crohn Disease. A, The mucosa in Crohn disease demonstrates  a cobblestone pattern as a result of fissured ulcers (U) with intervening areas of  edematous mucosa (M). B, Compared with normal small bowel wall (N), the Crohn  segment (C) shows wall thickening that has caused a stenosis. (From Kumar V et al:  Pathologic basis of disease, ed 7, Philadelphia, 2006, Saunders.)    EVALUATION AND TREATMENT. The diagnosis and treatment of  CD are similar to the diagnosis and treatment of ulcerative coli-  tis. Treatment with immunomodulatory agents can be effective.  TNF-a—blocking agents are used for treatment of fistulae and to  maintain remission.''? Surgery is generally performed to man-  age complications such as strictures, fistulae, abscesses, and per-  foration, or to relieve obstruction.''4 When treatment involves  surgical resection of small intestinal segments, complications  related to short bowel syndrome can occur, including malab-  sorption, diarrhea, and nutritional deficiencies. Symptoms are  related to the extent and location of resection.!!°    Diverticula are herniations or saclike outpouchings of mucosa  through the muscle layers of the colon wall. Diverticulosis is  asymptomatic diverticular disease. Diverticulitis represents  inflammation. The cause of diverticular disease is unknown but  is associated with age greater than 60 years, decreased dietary  fiber, increased intracolonic pressure, abnormal neuromuscu-  lar function, and alterations in intestinal motility.'!°  PATHOPHYSIOLOGY. Diverticula can occur anywhere in the gas-  trointestinal tract but the most common site is the left colon.  They rarely occur in the small intestine.'!” The diverticula form  at weak points in the colon wall, usually where arteries pene-  trate the tunica muscularis to nourish the mucosal layer. The  colonic mucosa herniates through the smooth muscle layers  (Figure 41-14). A common associated finding is thickening of  the circular and longitudinal (teniae coli) muscles surrounding  the diverticula. Hypertrophy and contraction of these muscles  increase intraluminal pressure and degree of herniation. Habitual  consumption ofa low-residue diet reduces fecal bulk, thus reduc-  ing the diameter of the colon. According to Laplace’s law (see  Chapter 31), wall pressure increases as the diameter of a cylin-  drical structure decreases. Therefore, pressure within the narrow  lumen can increase enough to rupture the diverticula. Insoluble    FIGURE 41-14 Diverticular Disease. In diverticular disease, the outpouches  (arrows) of mucosa seen in the sigmoid colon appear as slitlike openings from the  mucosal surface of the opened bowel. (From Townsend CM et al: Sabiston textbook  of surgery, ed 19, Philadelphia 2012, Saunders.)    dietary fiber deficiency also may change the intestinal microflora,  decreasing the immune response and levels of inflammatory  cytokines in the colon.'!®!!° Diverticulitis can cause abscess for-  mation, fistula formation, peritonitis, or obstruction.!7°   CLINICAL MANIFESTATIONS. Symptoms of diverticular disease are  usually vague or absent and about 30% of individuals develop  specific symptoms. Cramping pain of the lower abdomen can  accompany constriction of the hypertrophied colonic muscles.  Diarrhea, constipation, distention, or flatulence may occur.  Diverticula with an obstructed opening become inflamed or  abscesses form, and the individual develops fever, leukocytosis  (increased white blood cell count), and tenderness of the lower  left quadrant. Right lower quadrant pain and severe complica-  tions, such as hemorrhage, perforation with peritonitis, bowel  obstruction, and fistula formation, are rare.!°   EVALUATION AND TREATMENT. Diverticula are often discov-  ered during diagnostic procedures performed for other prob-  lems. Ultrasound, sigmoidoscopy, or barium enema is used for  diagnosis of uncomplicated diverticula. Abdominal computed  tomography (CT) is used for complicated cases.   An increase of dietary fiber intake increases stool weight, low-  ers colonic pressures, improves transit times, and often relieves  symptoms (see Nutrition & Disease: Diverticular Disease and  Diet). Uncomplicated diverticular disease is treated with bowel  rest and antibiotics.!2! Surgical resection may be required if  there are severe complications, including hemorrhage, bowel  stenosis, obstruction, abscesses, fistulae, bowel perforation, and  peritonitis. !?2    Daily consumption of fiber-enriched foods is recommended for the prevention  of diverticula. A high-fiber diet increases fecal bulk, decreases transit time,  lowers intracolonic pressures, and eases stool elimination. The recommenda-  tion for fiber is 20 to 35 g/day. Some examples of high-fiber choices are whole  wheat bread and other grain products, baked potato with skin, fresh fruit with  skins, raw vegetables, beans, peas, legumes, wheat bran, and brown rice.  Side effects may include flatulence, intestinal rumbling, cramps, and diarrhea.  A gradual increase in dietary fiber over 1 or 2 months helps to avoid these  problems. Other potential problems with an excessively high-fiber diet (greater  than 40 to 45 g) might include a decrease in nutrient absorption because of  the increased volume of intestinal contents, which in turn decreases the abil-  ity of the digestive enzymes to come into contact with the food. An increase  of water intake (eight 8-ounce glasses) is important so intestinal blockage  will not occur. For small children and older adults, a high-fiber diet increases  the volume of food needed to meet energy requirements, and that increase  may be difficult to obtain. Although some physicians recommend restricting  nuts, seeds, and foods containing seeds such as berries, kiwi, and tomatoes  that might lodge in the pouches, there is no evidence that this happens. If  the diverticula become inflamed, a low-fiber, low-residue (no milk products),  or elemental diet, or in complicated cases total parenteral nutrition (TPN),  is required to prevent continued irritation of the inflamed tissue. Controlled  clinical trials are needed to evaluate the effectiveness of high-fiber diets in  preventing diverticular disease.    Data from Crowe FL et al: BMJ 343:d4131, 2011; Strate LL: Dig Dis  30(1):35-45, 2012; Unlti C et al: Int J Colorectal Dis 27(4):419-427,  2012; Wick JY: Consult Pharm 27(9):613-618, 2012.    Appendicitis  Appendicitis is an inflammation of the vermiform appen-  dix, which is a projection from the apex of the cecum. It is the  most common surgical emergency of the abdomen and usually  occurs between 20 and 30 years of age, although it may develop  at any age.!*°   PATHOPHYSIOLOGY. The exact cause of appendicitis is contro-  versial. Obstruction of the lumen with stool, tumors, or foreign  bodies with consequent increased intraluminal pressure, ische-  mia, bacterial infection, and inflammation is a common theory.  The obstructed lumen does not allow drainage of the appen-  dix, and as mucosal secretion continues, intraluminal pressure  increases. The resultant increased pressure decreases mucosal  blood flow, and the appendix becomes hypoxic. The mucosa  ulcerates, promoting bacterial or other microbial invasion with  further inflammation and edema. Inflammation may involve  the distal or entire appendix. Gangrene develops from throm-  bosis of the luminal blood vessels, followed by perforation.   CLINICAL MANIFESTATIONS. Epigastric or periumbilical pain is  the typical symptom of an inflamed appendix. The pain may  be vague at first, increasing in intensity over 3 to 4 hours. It  may subside and then recur with a shift of location to the right  lower quadrant with rebound tenderness. Right lower quad-  rant pain is associated with extension of the inflammation to  the surrounding tissues. Nausea, vomiting, and anorexia fol-  low the onset of pain, and fever is common. Diarrhea occurs in  some individuals, particularly children; others have a sensation  of constipation. Perforation, peritonitis, and abscess formation  are the most serious complications of appendicitis. !*4   EVALUATION AND TREATMENT. In addition to clinical manifesta-  tions, the clinician can usually locate the painful site with one  finger. Rebound tenderness is usually referred to the right lower  quadrant. The white blood cell count ranges from 10,000 to  16,000 cells/mm? with elevations in the levels of neutrophils,  C-reactive protein.'?? Abdominal CT scans and ultrasound  assist diagnostic accuracy. The combined information provides  the best discriminating diagnosis.'7°   Antibiotics and appendectomy is the treatment for simple or  perforated appendicitis. Laparoscopic surgery provides quick  recovery for simple appendicitis. Recovery is more complicated  in cases of perforation or abscess formation and in individuals  of older age.!?7!8    Irritable bowel syndrome (IBS) is a functional gastrointestinal  disorder characterized by abdominal pain and altered bowel  habits that affects about 10% of individuals throughout the  world and is more common in women, with a higher prevalence  in youth and middle age. Individuals with IBS are more likely to  have anxiety and depression.!””   PATHOPHYSIOLOGY. There are no specific structural or bio-  chemical alterations as a cause of IBS but there is increasing evi-  dence to explain the varying symptom presentations and they  are summarized as follows:   distention of the rectum but also other areas of the gut:  This occurs in about 30% to 40% of those with IBS. The    cause is unknown; it may originate in either the periph-  eral or the central nervous system. The mechanism may  be related to pain and a dysregulation of the “brain-gut  axis” (alterations in gut or central nervous system pro-  cessing of gut nociceptive information), increased perme-  ability that stimulates nociceptors, the role of serotonin  in the enteric nervous system of the gut, infiltration and  activation of mast cells and T lymphocytes, or alterations  in the autonomic nervous system.!°”   2. Abnormal gastrointestinal permeability, motility, and secre-  tion: Individuals with diarrhea-type IBS have more rapid  colonic transit times and increased intestinal permeabil-  ity, whereas those with bloating and constipation have  delayed transit times and decreased intestinal permeabil-  ity. The mechanisms may be related to visceral hypersen-  sitivity and dysregulation of the brain-gut axis or to the  role of serotonin in the function of the enteric nervous  system and to activity of mast cells.'*!   3. Postinfectious IBS: Two or more of the following symp-  toms are present: fever, vomiting, diarrhea, and a positive  stool culture Intestinal infection (bacterial enteritis) has  been associated with symptoms of IBS and may be related  to altered gut microbiota, ongoing low-grade inflamma-  tion, and an abnormal immune response in gut tissues.!°*   4. Overgrowth of intestinal flora: Small intestinal overgrowth  of normal gut bacteria may precipitate IBS symptoms and  it is proposed that methane gas may slow intestinal transit  time, resulting in constipation and bloating.!*>'**   5. Food allergy or food intolerance: Food antigens may acti-  vate the mucosal immune system, mediating hypersensi-  tivity reactions and IBS symptoms. Individualized food  elimination approaches are helpful in some cases because  different foods alter neural and hormonal small intesti-  nal responses. Allergic conditions, including rhinitis and  asthma, have been associated with IBS.!°°   6. Psychosocial factors: Psychosocial factors including emo-  tional stress influence brain-gut interaction including  neuroendocrine, neuroimmune, autonomic nervous sys-  tem, and pain modulatory responses contributing to the  symptoms of IBS.!°°   CLINICAL MANIFESTATIONS. IBS is characterized by lower  abdominal pain, diarrhea-predominant, constipation-predom-  inant, or alternating diarrhea/constipation (mixed), gas, bloat-  ing, and nausea. Individuals may also describe fecal urgency  and incomplete evacuation. Symptoms are usually relieved with  defecation and usually do not interfere with sleep.   EVALUATION AND TREATMENT. The diagnosis of IBS is based  on signs and symptoms and includes the exclusion of struc-  tural or biochemical causes of disease. In the absence of “alarm  symptoms” such as fever, weight loss, gastrointestinal bleed-  ing, anemia, or abdominal mass, only limited diagnostic tests  are needed. The individual may be evaluated for food allergies,  lactose intolerance, parasites, or bacterial growth. The Rome  Ill criteria for diagnosing IBS have been released to guide  evaluation (Box 41-2).   There is no cure for IBS, and treatment is individualized.  Treatment of symptoms may include laxatives and dietary   For a disorder to be diagnosed as irritable bowel syndrome, at least two or  more of the following conditions will have existed for at least 3 months,  with onset occurring at least 6 months before the beginning of the recurrent  abdominal pain or discomfort:   3. Onset associated with a change in form (appearance) of stool   5. Sensation of incomplete evacuation more than 25% of the time  6. Diarrhea with mucus more than 25% of the time    Modified from Longstreth GF et al: Gastroenterology 130(5):1480-1491,  2006; Suares NC, Ford AC: Discov Med 11(60):425-433, 2011; White-  head WE, Drossman DA: Am J Gastroentero!/ 105(4):814-820, 2010.    fiber, antidiarrheals, antispasmodics, low-dose antidepressants,  and serotonin agonists or antagonists. For severe constipation,  5-hydroxytryptamine-4 agonists (e.g., tegaserod) may be used  (not approved for use in North America since 2007 because of  cardiac ischemic events) or CIC-2 chloride channel activators  (e.g., lubiprostone). For severe diarrhea, 5-hydroxytryptamine-3  receptor antagonists (e.g., alosetron) or rifaximin (an antibiotic)  may be used to normalize bowel habits. Low-dose tricyclic anti-  depressants and selective serotonin reuptake inhibitors (SSRIs)  have been used for severe pain. Alternative therapies including  prebiotics (stimulate growth of healthy gut bacteria), probiot-  ics, selected herbal treatments (e.g., peppermint oil), hypnosis,  and psychotherapy are treatment options. Research continues to  advance the management of this complex syndrome.!*”"!°8    The stomach and intestines are supplied by three branches of  the abdominal aorta: the celiac artery and the superior and infe-  rior mesenteric arteries. Atherosclerotic lesions, thrombi, and  emboli can develop in these vessels, occluding blood flow and  causing ischemia or necrosis in the gastrointestinal tract.  Mesenteric venous thrombosis is the least common of the  causes of mesenteric vascular insufficiency. Malignancies, right-  sided heart failure, and deep vein thrombosis are risk factors.  Acute mesenteric ischemia caused by acute occlusion of the  mesenteric artery results in a significant reduction in mucosal  blood flow to the large and small intestines. Dissecting aortic  aneurysms, arterial thrombi, or emboli can be causes. Embolic  obstruction is associated with atrial fibrillation, mitral valve  disease, heart valve prostheses, or myocardial infarction. The  superior mesenteric artery has a more direct line of flow from  the aorta; therefore, emboli enter it more readily than they enter  the inferior branch, causing ischemia and necrosis of the small  intestine. Ischemia and necrosis alter membrane permeabil-  ity. There is initially increased motility, nausea and vomiting,    urgent bowel evacuation, and severe abdominal pain. Ischemia  leads to decreased motility and distention. The damaged intes-  tinal mucosa cannot produce enough mucus to protect itself  from digestive enzymes. Mucosal alteration causes fluid to move  from the blood vessels into the bowel wall and peritoneum.  Fluid loss causes hypovolemia and further decreases in intesti-  nal blood flow. As intestinal infarction progresses, shock, fever,  bloody diarrhea, and leukocytosis develop. Bacteria invade the  necrotic intestinal wall, causing gangrene and peritonitis. '°?)4°   Chronic mesenteric ischemia is rare. It can develop second-  ary to atherosclerosis (most common), congestive heart failure,  dysrhythmias, hemorrhage, thrombus formation, aortic aneu-  rysm, or any condition that decreases arterial blood flow. Chronic  occlusion is often accompanied by formation of collateral cir-  culation that may be able to nourish the resting intestine. After  eating, however, when the intestine requires more blood, the  arterial supply may be insufficient. Ischemia develops, causing a  cramping abdominal pain, called abdominal angina, after meals.  Progressive vascular obstruction eventually causes continuous  abdominal pain and necrosis of the intestinal tissue. Reperfusion  injury related to reactive oxygen metabolites and inflammatory  mediators contributes to further tissue damage.   Colicky abdominal pain after eating is a cardinal symptom  of chronic mesenteric insufficiency. Some individuals suffer sig-  nificant weight loss because they stop eating to control the pain.   Diagnosis of acute and chronic mesenteric ischemia is based  on clinical manifestations, laboratory findings, and imag-  ing studies. Bruit often can be heard over a partially occluded  artery. Medical management includes antibiotics, anticoagula-  tion, vasodilators, and inhibitors of reperfusion injury. Surgery  is required to remove necrotic tissue, repair sclerosed vessels,  and revascularize tissue. Acute occlusion is a surgical emer-  gency and mortality is high (50% to 90%). Early diagnosis and  aggressive treatment result in the best survival rates.!4!)!47    Disorders of Nutrition  Obesity  Obesity is an increase in body fat mass and a metabolic disorder  that has become an epidemic worldwide. The incidence is rap-  idly increasing among children and adolescents and they tend  to become obese adults.!4?:!“4   Obesity is defined as a body mass index (BMI) that exceeds  30 kg/m? and generally develops when caloric intake exceeds  caloric expenditure in genetically susceptible individuals.'*  Obesity is a major risk factor for morbidity, death, and high  healthcare cost in the United States and worldwide.'“° Three  leading causes of death in the United States are associated with  obesity: cardiovascular disease, type 2 diabetes mellitus, and  cancer (colorectal, breast in postmenopausal women, endo-  metrial, prostate, renal, and esophageal).'*” Obesity is also a  risk factor for hypertension, stroke, hyperlipidemia, gallstones,  nonalcoholic steatohepatitis, gastroesophageal reflux, osteoar-  thritis, infectious disease, asthma, and obstructive sleep apnea.  However, some studies have shown that a BMI between 25 and  34 in older individuals is associated with lower mortality. !4*!°   The causes and consequences of obesity are multiple and  complex and there is rapidly advancing research regarding   Modulating role in reproduction, angiogenesis, immune response,  blood pressure control, and osteogenesis   Inhibits adipocyte differentiation and may function as a feedback  regulator of adipogenesis    Visfatin (from Visceral Fat)  Mimics insulin and binds to insulin receptors in rats   Tumor necrosis factor-alpha  Interleukins (IL-1, IL-6, IL-8, IL-10)  Plasminogen activator inhibitor 1  Monocyte chemoattractant protein 1   FABP4 (fatty acid binding protein 4)—suppresses cardiomyocyte contraction  Insulin-like growth factor    Data from Bluher M: Diabetes Metab J 36(5):317-327, 2012; Maenhaut N, Van de Voorde J: BMC Med 16(9):25, 2011.    causal mechanisms, complications, and treatment. Genotype  and gene-envirnoment interactions are important predispos-  ing factors.!°° Single-gene defects are rare and obesity is usu-  ally polygenic and associated with other phenotypes such as  endocrine disorders (i.e., diabetes and hypothyroidism) and  mental retardation (i.e., Down and Prader-Willi syndromes).  Single-gene defects include the melanocortin-4 receptor gene  (decreases appetite), leptin gene (also known as the obesity gene),  and leptin-receptor gene. All single-gene defects are directly or  indirectly related to leptin and melanocortin pathways.'°! Met-  abolic abnormalities contributing to obesity include Cushing  syndrome, Cushing disease, polycystic ovary syndrome, hypo-  thyroidism, and hypothalamic injury. Environmental factors  include culture, socioeconomic status, food intake, and exer-  cise. Obesity is associated with adverse social and psychologic  consequences. !°*!>9   PATHOPHYSIOLOGY. The pathophysiology of obesity is com-  plex and involves the interaction of numerous cytokines,  hormones, and neurotransmitters. Mechanisms contribut-  ing to the imbalance of energy intake in relation to energy  expenditure and the multiple pathogenic effects of excess  adipose tissue are not completely understood. The adipo-  cyte is the cellular basis of obesity. Adipocytes secrete a  number of hormones and cytokines known as adipokines!**    (Box 41-3). Adipokines participate in regulation of food  intake, lipid storage and metabolism, insulin sensitivity, the  alternative complement system, vascular homeostasis, blood  pressure regulation, angiogenesis, the inflammatory and  immune responses, female reproduction, and regulation of  energy metabolism. Visceral fat accumulation causes dysfunc-  tion of adipocytes and results in alterations in the regulation  and interaction of these hormones. Macrophages infiltrate  excess adipocytes with increased expression of inflammatory  cytokines (e.g., TNF-a and IL-1). The low-grade inflamma-  tion and alterations in adipokines, and other hormones and  neurotransmitters contributes to the causes and complica-  tions of obesity, particularly cardiovascular disease and type  2 diabetes mellitus.!°°   Regulation of appetite and satiety occurs through neuro-  endocrine regulation of eating behavior, energy metabolism,  and body fat mass. The system is complex and controlled by a  dynamic circuit of signaling molecules from the periphery act-  ing on central controls including the brainstem, hypothalamus,  and autonomic nervous system. An imbalance in this system  is usually associated with excessive caloric intake in relation to  exercise with the consequence of weight gain and obesity.   The arcuate nucleus (ARC) in the hypothalamus has two  sets of neurons with opposing effects that interact to regulate    BOX 41-4 EXAMPLES OF HORMONES  AND NEUROPEPTIDES THAT  INFLUENCE EATING BEHAVIOR    Orexins (Appetite Stimulants)  Neuropeptide Y (NPY)  Melanin-concentrating hormone (MCH)  Agouti-related protein (AGRP)    and balance food intake and energy metabolism. One set of  neurons produces neuropeptide Y (NPY) and agouti-related  protein (AGRP), which promotes appetite, stimulates eating,  and decreases metabolism (anabolic). Another set of neurons  synthesizes pro-opiomelanocortin (POMC)-producing peptide  and cocaine-and-amphetamine-regulated transcript (CART),  collectively known as POMC/CART neurons, which suppress  appetite, inhibit eating, and increase metabolism (catabolic).   Molecules that stimulate eating are called orexins (i.e., hypo-  cretins [from the hypothalamus], a peptide family that act  as neurotransmitters for stimulating eating). Molecules that  inhibit eating are called anorexins (Box 41-4). Peripheral effects  of these signaling pathways are transmitted through the auto-  nomic nervous and endocrine systems to regulate appetite, food  intake, and energy metabolism.!°°   Many different hormones also control appetite, satiety, and  body weight. Their sources include ghrelin from the stomach;  peptide YY, cholecystokinin (CCK), and glucagon-like peptide 1  (GLP-1) from the intestines; insulin from pancreatic beta cells;  leptin, adiponectin, and retinol-binding protein 4 (RBP4) from  adipose tissue; and endocannabinoids (arachidonic acid based  lipids) from brain and peripheral nerves. These hormones circu-  late in the blood at concentrations that increase or decrease in  relation to body fat mass, and serve as peripheral signals to the  ARC in the hypothalamus, where appetite (food intake) and  metabolism (energy expenditure) are regulated. Leptin and insu-  lin normally decrease appetite by inhibiting NPY/AGRP neurons  (anabolic circuits) and stimulating POMC/CART neurons (cata-  bolic circuits). Ghrelin and other hormones stimulate appetite by  activating NPY/AGRP-expressing neurons. Intestinal peptide YY    (PYY), CCK, endocannabinoids, and other hormones decrease  appetite. Other peripheral hormones and neurotransmitters also  can influence the hypothalamus and affect appetite and energy  expenditure (see Box 41-4). Obesity is associated with increased  circulating plasma levels of leptin (leptin resistance), retinol-  binding protein 4, insulin (insulin resistance), and ghrelin. There  are decreased levels of adiponectin and peptide YY. Interaction  among these hormones and adipokines at the level of the hypo-  thalamus and in the periphery may be important determinants of  excessive fat mass. Leptin resistance, decreased adiponectin levels,  increased ghrelin levels, insulin resistance, and inflammation are  particularly important in the complications of obesity.   Leptin, a product of the obesity gene (Ob gene) and  expressed primarily by adipocytes, acts on the hypothalamus  to suppress appetite and regulates body weight within a fairly  narrow range. Low leptin levels during fasting normally stimu-  late food intake and reduce energy expenditure and high leptin  levels in the fed state inhibit food intake and increase energy  expenditure. Leptin secretion increases as adipocytes increase  in size or number (hyperleptinemia). The high levels of leptin  in obesity are ineffective at decreasing appetite and increasing  energy expenditure—this is known as decreased leptin sensi-  tivity or leptin resistance. Leptin resistance disrupts hypo-  thalamic satiety signaling, promotes overeating and excessive  weight gain, and is a factor in the development of obesity.!°”   The cause of leptin resistance is unknown. It may be related  to a defect in leptin transport, an inability of leptin to cross the  blood-brain barrier; an alteration in the permissive effect of  leptin on urocortin (a satiety-signaling molecule); or a defect in  the leptin receptor. Hyperleptinemia also stimulates the sympa-  thetic nervous system, chronic inflammation, oxidative stress,  and ventricular hypertrophy and may contribute to the patho-  genesis of hypertension, atherosclerosis, and cardiovascular  disease associated with obesity. !°*!°   Adiponectin, produced primarily by visceral adipose tissue,  has insulin-sensitizing properties and plasma levels decrease  with visceral obesity, contributing to insulin resistance and  type 2 diabetes mellitus. Decreased levels of adiponectin are  associated with complications of obesity, including increased  risk for coronary artery disease resulting from hyperlipidemia,  hypertension, and factors that promote thrombosis and inflam-  mation!®! (see Chapter 32). Decreased adiponectin levels are  associated with increased hepatic gluconeogenesis, decreased  skeletal muscle glucose uptake, and increased levels of inflam-  matory markers, such as IL-6 and TNF-a. Adiponectin may  serve as an anti-inflammatory and anti-atherogenic plasma  protein and has an important role in vascular remodeling that  is limited with obesity. !°%!°°   Insulin resistance is associated with obesity. The mecha-  nisms are not clear but there is an association between hyper-  lipidemia and fat storage, macrophages and inflammation, and  alterations in adipokines. Leptin resistance and decreased adi-  ponectin contribute to insulin resistance.!®* Retinol-binding  protein 4 is an adipokine that is increased in visceral adipos-  ity and contributes to insulin resistance in liver and muscle.'°°  Insulin resistance results in hyperglycemia and predisposition  to type 2 diabetes mellitus.    FIGURE 41-15 Pathophysiology and Common Complications of Obesity. See text for details. CAD, Coronary artery  disease; GERD, gastroesophageal reflux disease; GLP7, glucagon-like peptide 1; /L-6, interleukin-6; PYY intestinal peptide YY;    RBP4, retinol-binding protein 4; TNF-c, tumor necrosis factor-alpha; VLDL, very-low-density lipoprotein.    Ghrelin is produced by the stomach in response to hunger  and stimulates food intake through activation of the ghrelin  receptor (GHS-R) located on neuropeptide Y (NPY)/agouti-  related peptide (AGRP) neurons in the hypothalamus. Ghre-  lin induces metabolic changes leading to an increase in body  weight and body fat mass. Ghrelin also stimulates release of  growth hormone (GH) from anterior pituitary cells, release of  gastric acid, gastrointestinal motility, and pancreatic functions.  It has satiety, vasodilatory, cardioprotective, and antiprolifera-  tive effects.!°°   Leptin and ghrelin are complementary, yet antagonistic sig-  nals reflecting acute and chronic changes in energy balance, the  effects of which are mediated by hypothalamic neuropeptides,  such as NPY and AGRP. In obesity, plasma ghrelin level does  not decrease after eating and its role in contributing to obesity  is yet to be defined. Endocrine and vagal afferent pathways are  also involved in the actions of ghrelin and leptin, adding to the  complexity of mechanisms that can affect obesity.!°”    Glucose-like peptide 1 is an incretin secreted from intestinal  endocrine cells when nutrients enter the small intestine. GLP-1  stimulates pancreatic glucose-dependent insulin secretion,  delays gastric emptying, and suppresses appetite. GLP-1 levels  may be decreased in obese individuals.!°   Peptide YY (PYY) is released from intestinal endocrine cells  in response to nutrients entering the intestine and inhibits gas-  tric motility and decreases appetite. The level of PYY decreases  with increases in adiposity and decreased PYY level is associated  with obesity.!°   Endocannabinoids (i.e., anandamide) are expressed in both  the brain and peripheral nerve tissues and have effects on endocan-  nabinoid receptors in orexigenic pathways. They increase appetite,  enhance nutrient absorption, stimulate lipogenesis, and increase  adipose tissue accumulation by acting at both central (CB1 recep-  tor) and peripheral sites (CB2 receptor). An increase in endocan-  nabinoids is proposed to be associated with obesity.!”° Figure 41-15  summarizes the pathophysiology and complications of obesity.    CLINICAL MANIFESTATIONS. Obesity usually presents with two  different forms or phenotypes of adipose tissue distribution.'7!  Visceral obesity (also known as intra-abdominal, central, or  masculine obesity) occurs when the distribution of body fat  is localized around the abdomen and upper body, resulting in  an apple shape. Visceral obesity is associated with accelerated  lipolysis and has an increased risk for inflammation, meta-  bolic syndrome (hypertriglyceridemia, reduced high-density  lipoprotein, increased low-density lipoproteins, hypertension,  and insulin resistance), type 2 diabetes mellitus, cardiovascular  complications, and cancer. Visceral venous blood drains into  the portal vein, contributing to higher liver synthesis of plasma  lipids.'’*!7> Peripheral obesity (also known as gluteal-femoral,  feminine, or subcutaneous obesity) occurs when the distribu-  tion of body fat is extraperitoneal and distributed around the  thighs and buttocks and through the muscle, resulting in a pear  shape; it is more common in women. Peripheral and subcu-  taneous fat is less metabolically active and less lipolytic and  releases fewer adipocytokines (particularly adiponectin) than  visceral fat. Risk factors are still present for the complications  of obesity but they are less severe than for visceral obesity.!”4   EVALUATION AND TREATMENT. There are several methods for  measuring or estimating body fat mass, including anthropo-  metric measurements, such as skinfold thickness, circumfer-  ences, various body diameters (i.e., waist-to-hip ratios and  waist circumference, BMI tables), underwater weighing, and  bioimpedance analysis.!”°7° The BMI and waist-to-hip ratios  are most commonly used because they are the easiest to measure  and most cost-effective. Overweight is defined as a BMI greater  than 25 kg/m? and obesity is a BMI greater than 30 kg/m?. BMI  charts are available for children ages 2 to 20 years; these can be  used for comparison during adulthood because obese children  generally become obese adults. No specific diagnostic criteria  for obesity have been established.!””   Obesity is a chronic disease for which various treatment  approaches have been used, including correction of metabolic  abnormalities, individually tailored weight-reduction diets, and  exercise programs.'’° A combination of weight reduction and  exercise is the most effective. Self-motivation and support sys-  tems are critical aspects of treatment.!”? Additional treatments  include psychotherapy, behavioral modification, and anti-obesity  drugs.'*° Bariatric surgical procedures (i.e., the Roux-en-Y gastric  bypass, gastric banding, or sleeve gastrectomy) also are prescribed  and when successful result in a significant reduction in weight,  reduction in comorbidities, and a decrease in insulin resistance.  Unraveling the causes of obesity will lead to more specific preven-  tion and pharmacotherapies.!*!"!*    Many young adults and adolescents—as many as 1% of  women and adolescent girls in the United States—are affected  by complex and related eating disorders: anorexia ner-  vosa, bulimia nervosa, and binge eating. These disorders are  included in the proposed DMS-5 classification of eating dis-  orders by the American Psychiatric Association (Box 41-5).  They rarely occur in black women, and only 5% to 10% of   2. Distorted body image: the perception that the body is fat when it is actually  underweight   3. Restriction of energy intake leading to significantly low body weight   1. Recurrent episodes of binge eating during which the individual fears not  being able to stop   2. Self-induced vomiting, use of laxatives, or fasting to oppose the effect of  binge eating   3. One binge eating episode per week for at least 3 months    Binge Eating Disorder  1. Recurrent episodes of binge eating  2. Binge eating associated with three or more of the following:  a. Eating much more rapidly than normal  b. Eating until uncomfortably full  . Eating large amounts of food when not physically hungry  . Eating alone because of being embarrassed  . Feeling disgusted, depressed, or very guilty after overeating  3. Marked distress regarding binge eating  4. One binge eating episode per week for at least 3 months  5. Does not meet criteria for anorexia nervosa or bulimia nervosa    cases are men.'*4 Onset may occur in children and women  over age 50 years.'®° Risk factors include genetic, epigenetic,  familial, biologic, psychologic, and social factors.'®°!*” There  is an association between posttraumatic stress and sexual  assault history and eating disorders.'*® An increasing number  of children, young men, and older adult women are experi-  encing eating disorders, often with an associated depression,  anxiety, or personality disorder.'*?!°° The death rate is highest  among women with anorexia nervosa. !?!    Malnutrition is lack of nourishment from inadequate amounts  of calories, protein, vitamins, or minerals and is caused by  improper diet, alterations in digestion or absorption, chronic  disease, or a combination of these factors. Starvation is a  reduction in energy intake leading to weight loss. Short-term  starvation and long-term starvation have different effects. Ther-  apeutic short-term starvation is part of many weight-reduction  programs because it causes an initial rapid weight loss that  reinforces the individual’s motivation to diet. Therapeutic  long-term starvation is used in medically controlled environ-  ments to facilitate rapid weight loss in morbidly obese individu-  als. Pathologic long-term starvation can be caused by poverty;  chronic diseases of the cardiovascular, pulmonary, hepatic, and  digestive systems; malabsorption syndromes; human immuno-  deficiency virus (HIV) infection; and cancer.!”    Short-term starvation, or extended fasting, consists of sev-  eral days of total dietary abstinence or deprivation. The body  responds with protective mechanisms. For 4 to 6 hours after the  last meal, the body is in a well-fed state and its energy require-  ments are supplied by glucose from recently ingested carbohy-  drates. Once all available energy has been absorbed from the  intestine, glycogen in the liver is converted to glucose through  glycogenolysis, the splitting of glycogen into glucose. This pro-  cess peaks within 4 to 8 hours, and gluconeogenesis begins.  Gluconeogenesis is the formation of glucose from noncarbohy-  drate molecules: lactate, pyruvate, amino acids, and the glycerol  portion of fats. Like glycogenolysis, gluconeogenesis takes place  within the liver. Both of these processes deplete stored nutrients  and thus cannot meet the body’s energy needs indefinitely. Pro-  teins continue to be catabolized to a minimal degree, providing  carbon for the synthesis of glucose.!”°   Long-term starvation begins after several days of dietary  abstinence and eventually causes death. Absolute deprivation  of food causes marasmus or protein-energy malnutrition (loss  of muscle mass and body fat depletion). Protein deprivation in  the presence of carbohydrate intake is called kwashiorkor (loss  of muscle mass with sustained body fat). Marasmic kwashior-  kor (edematous, severe childhood malnutrition) is a combina-  tion of chronic energy deficiency and chronic or acute protein  deficiency and inadequate micronutrients.'°* Anorexia nervosa  is a psychologic cause of long-term starvation (see Box 41-5).  Cachexia (also known as cytokine-induced malnutrition)  is physical wasting with loss of weight and muscle atrophy,  fatigue, and weakness. Inflammatory mediators (i.e., TNF-o,  interferon-y, IL-1, IL-6) and a blunted response to ghrelin and  adiponectin are associated with the cachexia of advanced can-  cer.!°° Cancer, AIDS, tuberculosis, and other major chronic  progressive diseases contribute to cachexia. Anorexia and  cachexia often occur together. Cachexia is not the same as food  deprivation starvation. A healthy person’s body can adjust to  starvation by slowing metabolism; however, in cachexia, the  body does not make this adjustment.   The major characteristic of long-term starvation is a  decreased dependence on gluconeogenesis and an increased  use of ketone bodies (products of lipid and pyruvate metabo-  lism) as a cellular energy source. During long-term starvation,  depressed insulin levels and increased levels of glucagon, cor-  tisone, epinephrine, and growth hormones promote lipolysis  in adipose tissue. Lipolysis liberates fatty acids, which supply  energy to cardiac and skeletal muscle cells, and ketone bodies,  which sustain brain tissue. Fatty acid, or ketone body, oxidation  meets most of the energy needs of the cells. (Some glucose is  still needed as fuel for brain tissue.) Once the supply of adi-  pose tissue is depleted, proteolysis begins. The breakdown of  muscle and visceral protein is the last process the body engages  to supply energy for life. Death results from severe alterations  in electrolyte balance and loss of renal, pulmonary, and cardiac  function.!”°   Adequate ingestion of appropriate nutrients is the obvious  treatment for starvation. In medically induced starvation the  body is maintained in a ketotic state until the desired amount  of adipose tissue has been lysed. Starvation imposed by chronic    Refeeding syndrome occurs in severely malnourished individuals when paren-  teral or enteral nutritional therapy is initiated. During starvation, loss of body  minerals causes the movement of phosphate, magnesium, and potassium ions  out of the cells and into the plasma. When refeeding starts, an increase in  insulin levels stimulates the movement of glucose and these ions back into the  cells, and the plasma concentrations can decrease to dangerously low levels,  causing hypophosphatemia, hypomagnesemia, hypokalemia, hyponatremia,  hypocalcemia, and vitamin deficiency. Rapid expansion of the extracellular  fluid volume also can occur with carbohydrate refeeding and may cause fluid  overload. Hypophosphatemia contributes to alterations in red blood cell shape  and function contributing to tissue hypoxia and increased respiratory drive.  The consequence of these alterations includes life-threatening dysrhythmias,  congestive heart failure, muscle weakness (including respiratory muscles), and  death. Individuals at greatest risk are those with starvation from any cause  including anorexia nervosa, chronic alcoholism, morbid obesity with mas-  sive weight loss, and prolonged fasting. Refeeding syndrome is prevented by  slowly reinstituting feeding (about 20 kcal/kg/day for the first few days) and  monitoring plasma levels of phosphate, potassium, magnesium, and calcium.    Data from Byrnes MC, Stangenes J: Curr Opin Clin Nutr Metab Care  14(2):186-192, 2011; Kohn MR, Madden S, Clarke SD: Curr Opin Pediatr  23(4):390-394, 2011; Skipper A: Nutr Clin Pract 27(1):34-40, 2012.    disease, long-term illness, or malabsorption is treated with  enteral or parenteral nutrition and there is the potential to  develop refeeding syndrome. Perioperative or critical care man-  agement of nutrition is necessary to prevent unnecessary star-  vation.!°’ Care must be taken to prevent refeeding syndrome  during the treatment of long-term starvation (see What’s New?  Refeeding Syndrome).    The accessory organs of digestion (liver, gallbladder, pancreas)  secrete substances necessary for digestion and, in the case of the  liver, carry out metabolic functions needed to maintain life.    Of all the accessory organ disorders, acute or chronic liver  disease leads to the most systemic, life-threatening complica-  tions. Complications of chronic liver disorders include portal  hypertension, ascites, hepatic encephalopathy, jaundice, and  hepatorenal syndrome.    Acute liver failure (fulminant liver failure) is a rare clinical  syndrome (2000 cases in the United States annually)!”® result-  ing from severe impairment or necrosis of liver cells without  preexisting liver disease or cirrhosis. Acetaminophen overdose  is the leading cause of acute liver failure in the United States!”  (see What’s New? Acetaminophen and Acute Liver Failure). It  also may occur as a complication of viral hepatitis, particularly  heptatitis B virus (HBV) infection compounded by infection  with the delta virus, as well as metabolic liver disorders.    Acetaminophen (paracetamol) toxicity from chronic use or intentional over-  dose is the leading cause of acute liver failure in the United States and Great  Britain. Liver injury may occur with doses of 4 to 10 g and hepatotoxicity with  mitochondrial injury and hepatocyte necrosis should be suspected when  doses exceed 4 g/day. The onset is sudden and unpredictable accompanied  by coagulopathy and encephalopathy. Elevated serum aminotransferase lev-    els (may be up to 400 times normal) accompanied by hypoprothrombinemia,  metabolic acidosis, and renal failure support a diagnosis of acute liver failure  caused by acetaminophen. Complications of cerebral edema and infection are  difficult to diagnose and treat and may lead to multiorgan failure and irrevers-  ible brain damage. Early treatment with correct dosing with N-acetylcysteine  provides a 66% chance of recovery and there is 70% survival at 1 year after  liver transplant.    Pathogenic mechanisms of acute liver failure are poorly  understood. Hepatocytes become edematous, and patchy areas  of necrosis and inflammatory cell infiltrates disrupt the paren-  chyma. The hepatic necrosis is irreversible.   Acute liver failure usually develops 6 to 8 weeks after the  initial symptoms of viral hepatitis or a metabolic liver disor-  der (e.g., Wilson disease). Anorexia, vomiting, abdominal pain,  and progressive jaundice are initial signs, followed by ascites  and gastrointestinal bleeding. Coagulopathy and encephalopa-  thy occur in individuals without preexisting liver disease and  can cause cerebral edema manifested as lethargy, altered motor  functions, coma, and death. Liver function tests show elevations  the levels of both conjugated and unconjugated serum biliru-  bin, serum transaminases, and blood ammonia. Prothrombin  time is prolonged.'? Treatment of acute liver failure requires  rapid evaluation and critical care. N-Acetylcysteine is used for  acetaminophen poisoning; antiviral therapy appears to improve  survival in cases of viral hepatitis; and lowering blood ammo-  nia levels may improve prognosis. Liver transplantation may be  lifesaving but needs to be performed early and obtaining a liver  for transplant can be difficult.” Artificial liver support systems  and use of hepatic stem cells are still in experimental stages of  development.!”*°! Survivors usually do not develop cirrhosis  or chronic liver disease.    Portal hypertension is abnormally high blood pressure in the  portal venous system primarily caused by resistance to portal  blood flow. Pressure in this system is normally 3 mmHg; portal  hypertension is an increase to at least 10 mmHg.  PATHOPHYSIOLOGY. Portal hypertension is caused by disorders  that obstruct or impede blood flow through any component of  the hepatic portal system. Intrahepatic causes result from vascu-  lar remodeling with intrahepatic shunts, thrombosis, inflamma-  tion, or fibrosis, as occurs in cirrhosis of the liver, viral hepatitis,  or schistosomiasis (a parasitic infection). Posthepatic causes    FIGURE 41-16 Varices Related to Portal Hypertension. Portal vein, its major  tributaries, and the most important shunts (collateral veins) between the portal and  caval systems. (From Monahan FD et al: Phipps’ medical-surgical nursing: concepts  and clinical practice, ed 8, St Louis, 2007, Mosby.)    occur from hepatic vein thrombosis or cardiac disorders that  impair the pumping ability of the right side of the heart (ie.,  right-sided heart failure).?°” This causes blood to back up and  increase pressure in the portal system. Thrombosis or narrowing  of the hepatic portal vein is the major prehepatic cause. Long-  term portal hypertension causes several pathophysiologic prob-  lems that are difficult to treat and can be fatal. These problems  include varices, splenomegaly, hepatopulmonary syndrome,  ascites, and hepatic encephalopathy.   Varices are distended, tortuous, collateral veins. Prolonged  elevation of pressure in the hepatic portal vein causes collat-  eral veins to open between the portal vein and systemic veins  and their transformation into varices, particularly in the lower  esophagus and stomach but also over the abdominal wall  (known as the caput medusae [Medusa head]) and rectum  (hemorrhoidal varices) (Figure 41-16). Rupture of varices can  cause life-threatening hemorrhage.?"7"   Splenomegaly is an enlargement of the spleen. Portal hyper-  tension contributes to congestive splenomegaly caused by  increased pressure in the splenic vein, a tributary to the hepatic  portal vein. Thrombocytopenia from platelet sequestration is the  most common manifestation and can contribute to an increased  bleeding tendency. Splenomegaly also can be predictive of  esophageal varices severity.?”°    Hepatopulmonary syndrome (intrapulmonary vasodilation,  intrapulmonary shunting, and hypoxia)*”° and portopulmonary  hypertension (pulmonary vasoconstriction and vascular remod-  eling)*°° are common respiratory complications of advanced  liver disease and portal hypertension. Hyperdynamic (high-flow)  state, increased pulmonary venous congestion, and vascular con-  striction or obstruction of the pulmonary arterial bed are con-  tributing factors.?°” There are no specific clinical manifestations,  although dyspnea, cyanosis, and digital clubbing may occur.  Diagnosis is made by contrast echocardiography and right heart  catheterization. In portopulmonary hypertension, pulmonary  artery pressure is greater than 25 mmHg. Treatment may include  systemic vasodilators and endothelin receptor antagonists, which  can reduce pulmonary and portal hypertension.”   CLINICAL MANIFESTATIONS. The most common clinical manifes-  tation of portal hypertension is vomiting of blood from bleed-  ing esophageal varices.*°*”” Bleeding is usually from varices  that have developed slowly over a period of years. Slow, chronic  bleeding from varices causes anemia or melena.   Acute rupture of esophageal varices causes hemorrhage and  voluminous vomiting of dark blood. The ruptured varices are  usually painless. Rupture is caused by a combination of erosion  by gastric acid and elevated venous pressure. Mortality from  ruptured esophageal varices ranges from 15% to 20%. Hem-  orrhoidal varices present as hematochezia and copious rectal  bleeding. Recurrent bleeding of esophageal or gastric varices  indicates a poor prognosis. Most individuals die within 1 year.   EVALUATION AND TREATMENT. Diagnosis of portal hypertension  is often made at the time of variceal bleeding and confirmed by  endoscopy and evaluation of portal venous pressure. Distended  collateral veins may radiate over the abdomen, giving rise to  caput medusae (Medusa’s head) from opening of the paraum-  bilical veins. The individual usually has a history of hepatitis or  alcoholism.   Beta-blockers can be effective in preventing variceal bleed-  ing. Emergency management of bleeding varices includes fluid  resuscitation, prophylactic antibiotics, vasoactive drugs (e.g.,  nonselective }-receptor antagonists and terlipressin, a vasopres-  sin derivative), endoscopic variceal band ligation, compression  of the varices with an inflatable tube or balloon, and injection of  a sclerosing agent. Surgical construction of a transjugular intra-  hepatic portosystemic shunt (TIPS) (anastomosis of the portal  vein to the inferior vena cava) may decompress the varices, but  this treatment can precipitate encephalopathy or liver failure  resulting from reduced hepatic blood flow. There is no defini-  tive treatment for portal hypertension.” Liver transplant is the  most successful option for liver failure.?!°    Ascites is the accumulation of fluid in the peritoneal cav-  ity and is a complication of portal hypertension. Ascites traps  body fluid in the peritoneal cavity from which it cannot escape.  The effect reduces the amount of fluid available for normal  physiologic functions. Cirrhosis is the most common cause  of ascites; ascites is the most common complication of cirrho-  sis. Other diseases associated with ascites include right heart  failure, abdominal malignancies, nephrotic syndrome, and    malnutrition. Twenty-five percent of individuals who develop  ascites caused by cirrhosis die within 1 year. Continued heavy  drinking of alcohol is associated with this mortality because of  increased risk for cirrhosis.   PATHOPHYSIOLOGY. Several factors contribute to the develop-  ment of ascites, including portal hypertension, splanchnic vaso-  dilation, hypoalbuminemia, and sodium and water retention.  The overflow theory proposes that renal sodium retention is  stimulated by portal hypertension with intravascular hypervol-  emia and overflow into the peritoneal cavity (transudative effu-  sion). Portal hypertension also increases capillary hydrostatic  pressures in the intestinal wall, which causes fluid to “weep”  into the peritoneal cavity. Reduced capillary oncotic pressure  adds to the fluid shift. The underfill theory proposes an increase  in hepatic sinusoidal hydrostatic pressure and decreased plasma  oncotic pressure with weeping of lymph fluid from the surface  of the liver. The resulting decrease in effective circulating plasma  volume activates the renin-angiotensin-aldosterone system,  stimulating the kidney to retain more sodium and water and  leading to intravascular volume overload. The peripheral arterial  vasodilation theory, or forward theory, is a synthesis of the over-  flow and underfill theories and the most accepted theory. This  theory proposes that circulating nitric oxide and carbon mon-  oxide causes splanchnic vasodilation. The decrease in systemic  vascular resistance overcomes compensatory cardiac output.  Stimulation of baroreceptors activates renal sodium retention  through activation of the renin-angiotensin-aldosterone sys-  tem, increased sympathetic tone, secretion of antidiuretic hor-  mones, and fluid retention. Combined portal hypertension and  splanchnic vasodilation causes fluid transudation and lymph  formation producing ascites. The release of endotoxin from  translocation of intestinal bacteria also can trigger arterial vaso-  dilation of the splanchnic organs.*!! Ascites can be complicated  by bacterial peritonitis. Figure 41-17 summarizes the mecha-  nisms by which cirrhosis of the liver causes ascites.   CLINICAL MANIFESTATIONS. The accumulation of ascitic fluid  causes abdominal distention, increased abdominal girth, and  weight gain (Figure 41-18). Large volumes of fluid (10 to  20 L) displace the diaphragm and cause dyspnea by decreas-  ing lung capacity. Respiratory rate increases, and the individual  assumes a semi-Fowler position to relieve the dyspnea. Some  peripheral edema is usually present. Dilutional hyponatremia  is a consequence of excess fluid volume. Approximately 10%  of individuals with ascites develop bacterial peritonitis, either  spontaneously or as a result of paracentesis (needle aspiration  of ascitic fluid). Peritonitis causes fever, chills, abdominal pain,  decreased bowel sounds, and cloudy ascitic fluid.   EVALUATION AND TREATMENT. Diagnosis of ascites is usually  based on clinical manifestations and identification of liver dis-  ease. The serum-ascites albumin gradient (SAAG) is the most  specific diagnostic indicator for portal hypertension—related  ascites. Chest and abdominal x-rays, ultrasonography, or CT  scans are used to evaluate the cause and extent of the ascites,  and complications such as peritonitis. The goal of treatment is  to relieve discomfort. If the restoration of liver function is pos-  sible (e.g., in ascites caused by viral hepatitis), the ascites dimin-  ishes spontaneously. In the meantime, dietary salt restriction    FIGURE 41-18 Massive Ascites in an Individual with Cirrhosis. Distended  abdomen, dilated upper abdominal veins, and everted umbilicus are classic manifes-  tations. (From Goldman L, Schafer Al: Goldman’s Cecil medicine, ed 24, Philadelphia,  2012, Saunders.)    and potassium-sparing diuretics can reduce ascites. Strong  diuretics, such as furosemide or ethacrynic acid, may be used  and vasopressin receptor-2 antagonists are effective for dilu-  tional hyponatremia. Albumin may be given.?!? Serum electro-  lyte levels are monitored carefully because the individual is at  risk for hyponatremia and hypokalemia.*!°   Palliative measures include paracentesis to remove 1 or 2 Lof  ascitic fluid and relieve respiratory distress. This procedure can  have serious complications, however. The removal of too much  fluid too fast relieves pressure on blood vessels, causing arterio-  lar vasodilation, which carries the risk of hypotension, shock, or  death. Despite repeated paracentesis, ascitic fluid reaccumulates  in individuals with irreversible disease, drawing more albumin  and electrolytes out of the vascular compartment. Paracentesis    is also likely to cause peritonitis. Peritonitis is treated with long-  term antibiotics. A transjugular intrahepatic portosystemic  shunt or peritoneovenous shunt may be used to treat refrac-  tory ascites. Individuals with ascites and portal hypertension  have a poor prognosis, and liver transplant is the best treatment  option.?!*    Hepatic encephalopathy (portosystemic encephalopathy) is  a complex neurologic syndrome characterized by impaired  cognitive function, flapping tremor (asterixis), and electroen-  cephalogram (EEG) changes. The syndrome may develop rap-  idly during acute fulminant hepatitis (type A) in association  with portosystemic bypass and in the absence of intrinsic liver  disease (type B); or slowly during the course of chronic liver  disease (type C: episodic, persistent, or covert).’!> Risk factors  in the presence of advanced liver disease include gastrointesti-  nal bleeding, increased dietary protein, electrolyte imbalance,  and hypoxia.   PATHOPHYSIOLOGY. Hepatic encephalopathy results from  a combination of biochemical alterations that affect neuro-  transmission. Liver dysfunction and collateral vessels that  shunt blood around the liver to the systemic circulation per-  mit neurotoxins and other harmful substances absorbed from  the gastrointestinal tract to accumulate and circulate freely to  the brain. Substances include inflammatory cytokines, short-  chain fatty acids, serotonin, tryptophan, and false neurotrans-  mitters. The most hazardous substances are end-products of  intestinal protein digestion, particularly ammonia, which  cannot be converted to urea by the diseased liver. The diges-  tion of blood from leaking or ruptured varices adds to the  amount of ammonia present in systemic blood, as does the  action of ammonia-forming bacteria in the colon. Ammonia    Hepatocytes cannot conjugate  and excrete bilirubin as rapidly  as it is formed, so  bilirubin enters the bloodstream    that reaches the brain is metabolized to glutamine with osmotic  disturbances and alterations in cerebral blood flow that inter-  fere with neurotransmitters and cause astrocyte edema (cyto-  toxic edema) and oxidation. Permeability of the blood-brain  barrier also may be increased (vasogenic edema), contributing  to brain edema and intracranial hypertension.?!%?!” Excessive  amounts of gamma-aminobutyric acid (GABA), an inhibitory  neurotransmitter, may contribute to reduced levels of con-  sciousness. Infection, hemorrhage, inflammation, electrolyte  imbalance, sedatives, and analgesics also can precipitate stupor  and coma in the presence of liver disease.?!*7!°   CLINICAL MANIFESTATIONS. Subtle changes in personality, mem-  ory loss, irritability, lethargy, and sleep disturbances are com-  mon initial manifestations of hepatic encephalopathy and can  be invisible (minimal hepatic encephalopathy). In acute liver  failure, symptom onset can be rapid with confusion, flapping  tremor of the hands, stupor, convulsions, and coma. Coma is  usually a sign of severe liver dysfunction and ultimately results  in death.??°   EVALUATION AND TREATMENT. There is no specific diagnostic test  of hepatic encephalopathy. Diagnosis is based on a history of  liver disease, clinical manifestations, and psychometric testing.  Electroencephalography and blood chemistry tests, including  blood ammonia levels, provide supportive data. Tracking lev-  els of serum ammonia assesses treatment effectiveness and liver  function.    Correction of fluid and electrolyte imbalances and with-  drawal of depressant drugs metabolized by the liver are the first  steps in the treatment of hepatic encephalopathy. Reduction of  blood ammonia levels is a major objective. This is accomplished  by restricting dietary protein intake and eliminating intestinal  bacteria. Neomycin is effective in sterilizing the bowel, but it  can be nephrotoxic. Lactulose may be administered to prevent  ammonia absorption in the colon.””! Rifaximin decreases intes-  tinal production and absorption of ammonia by altering gas-  trointestinal flora and is minimally absorbed. Sodium benzoate  and L-ornithine-L-aspartate also detoxify ammonia and lactu-  lose enemas promote ammonia excretion.?””    Jaundice  Jaundice (icterus) is a yellow or greenish pigmentation of the  skin caused by hyperbilirubinemia (total plasma bilirubin con-  centrations greater than 2.5 to 3 mg/dl). Hyperbilirubinemia  and jaundice can result from (1) extrahepatic obstruction to  bile flow (gallstones), (2) intrahepatic obstruction (hepatocel-  lular disease such as cirrhosis or hepatitis), or (3) excessive pro-  duction of bilirubin (excessive hemolysis of red blood cells)??°  (Figure 41-19). Jaundice in newborns is caused by impaired  bilirubin uptake and conjugation (see Chapter 42).  PATHOPHYSIOLOGY. Obstructive jaundice can result from  extrahepatic or intrahepatic obstruction.?”4 Extrahepatic obstruc-  tive jaundice develops if the common bile duct is occluded by    a gallstone, tumor, or compression from edema of pancreatitis.  Because the bile duct is obstructed, bilirubin is conjugated by  the hepatocytes but cannot flow into the duodenum. (Conju-  gated bilirubin is soluble in water and is then soluble in aque-  ous bile.) Therefore, it accumulates in the liver and enters the  bloodstream, causing hyperbilirubinemia. Because conjugated  bilirubin is water soluble, it appears in the urine. The stools may  be light colored or clay colored because they lack bile pigments.  The stools also lack urobilinogen because bile is not available  for conversion to urobilinogen.   Intrahepatic obstructive jaundice involves disturbances in  hepatocyte function and obstruction of bile canaliculi. The  uptake, conjugation, and excretion of bilirubin are affected  with elevated levels of both conjugated and unconjugated bili-  rubin. Hepatocellular damage increases plasma concentrations  of unconjugated bilirubin. The major disorder, however, is  obstruction of bile canaliculi, which diminishes flow of conju-  gated bilirubin into the common bile duct with elevations in the  plasma. In mild cases, some of the bile canaliculi open. Conse-  quently, the amount of bilirubin in the intestinal tract may be  only slightly decreased. The stools may appear normal or light  colored.   Excessive hemolysis (breakdown) of red blood cells or  absorption of hematoma can cause hemolytic jaundice (pre-  hepatic or nonobstructive jaundice). An increased amount  of unconjugated bilirubin is formed through metabolism of  the heme component of destroyed red blood cells. The extra  amount of unconjugated bilirubin exceeds the conjugation  ability of the liver, causing blood levels of unconjugated biliru-  bin to rise. Because unconjugated bilirubin is not water soluble,  it is not excreted in the urine. The reserve conjugation ability of  the liver usually prevents long-term unconjugated hyperbiliru-  binemia greater than 4 to 5 mg/dl. If unconjugated hyperbili-  rubinemia exceeds 5 mg/dl, both hemolytic and liver disorders  are indicated.   Hyperbilirubinemia and jaundice can be caused also by meta-  bolic defects that impair the uptake or conjugation of unconju-  gated bilirubin in the liver. Gilbert disease, for example, causes  an elevation of unconjugated bilirubin level in the plasma but    no other symptoms of liver disease. Gilbert disease is prob-  ably caused by an inherited deficiency of glucuronyl transferase  enzyme, which is required for the hepatic uptake of unconjugated  bilirubin. The causes of jaundice are summarized in Table 41-6.   CLINICAL MANIFESTATIONS. The clinical manifestations of jaun-  dice vary and are related to the underlying pathology. Conju-  gated hyperbilirubinemia may cause the urine to darken several  days before the onset of jaundice. The complete obstruction of  bile flow from the liver to the duodenum causes light-colored  stools. With partial obstruction, stool color is normal and bili-  rubin is present in the urine. Extrahepatic biliary obstruction is  associated with increased intestinal permeability and bacterial  translocation, and may contribute to the pathogenesis of sepsis  and renal failure.*?°   Fever, chills, and pain often accompany jaundice resulting  from viral or bacterial inflammation of the liver (e.g., viral hep-  atitis). Manifestations of liver injury from any cause commonly  include anorexia, malaise, and fatigue. Yellow discoloration  may first occur in the sclera of the eye and then progress to the  skin. Skin xanthomas (cholesterol deposits) and pruritus com-  monly accompany jaundice with an elevation of serum alkaline  phosphatase level.?°   EVALUATION AND TREATMENT. Laboratory evaluation establishes  whether the elevated level is plasma bilirubin is conjugated or  unconjugated or both. The history, physical examination, and  laboratory tests identify underlying disorders, such as alcohol-  ism, exposure to hepatitis virus, or gallbladder disease. The  treatment for jaundice consists of correcting the cause.    Hepatorenal syndrome (HRS) is functional renal failure; it  develops as a complication of advanced liver disease that tends  to occur with ascites. Renal disorders associated with liver dis-  ease can have numerous causes but HRS is usually associated  with alcoholic cirrhosis. The renal failure is not caused by pri-  mary renal disease or other extrinsic factors, but rather by arte-  rial vasodilation of the splanchnic vasculature, reduced effective  blood volume, and renal vasoconstriction.””” There are two  types of HRS: type 1 involves rapid and progressive renal failure   Toxic substances in the circulation (e.g., snake venom)  Transfusion of incompatible blood    Obstruction to passage of conjugated bilirubin from Obstruction of bile duct by gallstones or tumor    Failure of liver cells (hepatocytes) to conjugate bilirubin Genetic defect of hepatocyte (decreased enzymes),  and of bilirubin to pass from liver to intestine    such as occurs in premature infants (see Chapter 42)  Hepatitis or biliary cirrhosis    related to severe reduction in blood volume and decreased car-  diac output; type 2 is slower, is more stable, and is accompanied  by refractory ascites.*7*   PATHOPHYSIOLOGY. Hepatorenal syndrome generally accom-  panies a sudden decrease in blood volume secondary to massive  gastrointestinal or variceal bleeding and hypotension caused  by bleeding and splanchnic vasodilation associated with failing  liver function. Hypotension also can be caused by the excessive  use of diuretics to treat ascites. The decrease in blood volume  and hypotension result in decreased renal perfusion, decreased  glomerular filtration, and oliguria (see Chapter 39). The ability  to concentrate and dilute urine is usually maintained. Intrarenal  vasoconstriction may result from the selective effects of vasoac-  tive substances that accumulate in the blood because of liver  failure. The diseased liver fails to remove excessive angioten-  sin, vasopressin, prostaglandins, and catecholamines from the  blood, which travel to the kidneys and cause vasoconstriction.  Vasoconstriction also may be a compensatory response to por-  tal hypotension and vasodilation in the splanchnic circulation.  The exact reason for the renal vasoconstriction is unknown but  is related to vasoconstrictive mediators and sympathetic nerve  stimulation.”   CLINICAL MANIFESTATIONS. The onset of hepatorenal manifesta-  tions may be gradual or acute. Oliguria and complications of  advanced liver disease, including jaundice, ascites, and gastro-  intestinal bleeding, are usually present. Systolic blood pressure  is usually less than 100 mmHg. Nonspecific symptoms of hepa-  torenal syndrome include anorexia, weakness, and fatigue.   EVALUATION AND TREATMENT. Diagnosis of HRS is made by  excluding all other causes of renal failure. Despite decreased  glomerular filtration, serum potassium levels do not become  dangerously elevated until the terminal stages of the hepa-  torenal syndrome. Serum creatinine values increase rapidly  (within 2 weeks) in type 1 HRS and slowly or not at all in type  2 HRS. Urine osmolality is increased, but urine sodium con-  centrations are below normal (unlike acute tubular necrosis).    Urine specific gravity is greater than 1.015. The prognosis for  hepatorenal syndrome is usually poor and is related to liver  function. Secondary problems, including fluid and electrolyte  disorders, bleeding, infections, and encephalopathy, are vigor-  ously treated. Treatments to increase renal perfusion include  systemic vasoconstrictors (a-adrenergic agonists and telepres-  sin) and albumin, which are effective in 50% of individuals with  type 1 HRS. Vasoconstrictors also may be combined with TIPS  as a bridge to liver transplant. Liver transplant reverses symp-  toms in most individuals and it may be combined with kidney  transplantation.?°°?°?   Autoimmune hepatitis is a rare chronic, progressive T-cell-  mediated inflammatory liver disease that affects females, both  adults and children. Serologically, there is hypergammaglobu-  linemia and an association with human leukocyte antigens DR3  or DR4 and absence of viral hepatitis. Biopsy shows interface  (parenchymal—connective tissue interface) hepatitis. Aspartate  and alanine aminotransferase levels are elevated. There may be  no symptoms or jaundice, fatigue, loss of appetite, and amen-  orrhea. Most individuals respond to immunosuppressive drug  therapy (e.g., corticosteroids or in combination with azathio-  prine) with remission within 24 months. Relapses are common  with treatment withdrawal. About 10% of cases require liver  transplant.?°>-?°>   Viral hepatitis is a relatively common systemic disease that  affects primarily the liver. Different strains of viruses cause dif-  ferent types of hepatitis: hepatitis A virus (HAV), hepatitis B  virus (HBV), hepatitis D virus (HDV) associated with HBV, hep-  atitis C virus (HCV), and hepatitis E virus (HEV) (Table 41-7).  Hepatitis A was previously known as infectious hepatitis, and  hepatitis B as serum hepatitis. Coinfection of HBV, HCV, HDV,    DNA, Deoxyribonucleic acid; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; RNA, ribonucleic acid.    FIGURE 41-20 Course of Infection with the Hepatitis A Virus (HAV).  ALT, Alanine transaminase; /gG, immunoglobulin G; /gM/, immunoglobulin M.    and HIV occurs because these viruses share the same routes of  transmission (contact between infected body fluids, broken skin  or mucous membranes, or intravenously). Progression of liver  disease is more rapid in these cases.**° Characteristics of the vari-  ous types of hepatitis are presented in Table 41-7.   Hepatitis A Virus (HAV). HAV can be recovered from the  feces, bile, and sera of infected individuals. The usual mode  of transmission is the fecal-oral route (contaminated food or  water), but the virus can be spread also by the transfusion of  infected blood. Approximately 45% of adults in urban areas  have HAV antibodies in their blood. The disease spreads  readily in crowded, unsanitary conditions, usually through  contaminated food or water. Person-to-person spread is  more likely to occur in institutional care settings where  there is contact between clients and caregivers who are not  vaccinated.   The incubation period (the time between exposure and onset  of symptoms) for HAV is 4 to 6 weeks (Figure 41-20). Fecal  shedding of the virus is greatest for 10 to 14 days before the  onset of symptoms and during the first week of symptoms and  up to 3 months after onset of symptoms. The disease is most  contagious during this time. Antibodies to HAV (anti-HAV)  develop about 4 weeks after infection. The serum immunoglob-  ulin M (IgM) concentration increases initially and is followed  by an increase of serum IgG, whose levels remain elevated for  several years after infection, creating immunity to the disease.  (See Chapters 7 and 8 for a description of immune functions.)  The administration of immunoglobulin before exposure or  early in the incubation period can prevent hepatitis A. HAV  vaccine and combined HAV and HBV vaccines are available  and effective in preventing the disease and confer long-term  immunity.’ Transmission of HAV is prevented by handwash-  ing and use of gloves when disposing fecal matter. Molecular  procedures are available for direct surveillance of HAV in food  and water.”°*   Hepatitis B Virus (HBV). HBV is transmitted through  blood-blood contact and the sexual route. People who are  immunosuppressed; receive hemodialysis, multiple blood    0 ] 2 3 4 5 6 12  FIGURE 41-21 Course of Infection with the Hepatitis B Virus (HBV). ALT,  Alanine transaminase; anti-HBe, antibody to HBeAg; HBV-DNA, hepatitis B virus  deoxyribonucleic acid; /gG, immunoglobulin G; /gM, immunoglobulin M; HBsAg,  hepatitis B surface antigen; /gG anti-HBs, antibody to HBsAg; HBeAg, hepatitis B  e-antigen; IgM anti-HBc, antibody to hepatitis B core antigen.    transfusions, or immunosuppressive drugs; have multiple sex  partners; or share needles, syringes, or other drug equipment or  infants born to infected mothers have a greater risk of exposure  or less resistance to HBV coinfection with HCV, HDV. HIV  is common because these viruses share the same routes of  transmission.”°?7"   Mother-infant transmission of HBV occurs if the mother  becomes infected during the third trimester of pregnancy. In  women who are seropositive for both hepatitis B surface antigen  (HBsAg) and hepatitis B e antigen (HBeAg), vertical transmis-  sion is approximately 90%.**!4" Transmission among homo-  sexual men may be by oral or genital contact with bleeding  lesions in the rectal mucosa. Up to 400 million people worldwide  carry the hepatitis B surface antigen (HBsAg) marker for active  HBV. HBV is a major cause of chronic hepatitis, cirrhosis, and  hepatocellular carcinoma.’   Three types of viral particles are involved in HBV infection.  The larger (47 nm) Dane particle probably represents the intact  HBV. The Dane particle has a double-layered outer coat and  carries HBsAg, which was originally called the Australia antigen.  HBsAg can be identified in the serum by radioimmunoassay.  Hepatitis B core antigen (HBcAg) usually is not detected in the  serum. The HBeAg is a derivative of HBcAg and is a marker of  HBV replication. The HBV has an incubation period of 6 to  8 weeks. The initial serologic change is a transient increase in  IgM levels. Levels of IgG antibodies to HBsAg rise more slowly  and remain elevated for years (Figure 41-21). Chronic infec-  tion develops in 15% to 30% of those with acute infection.  HBV DNA measures viral load and the efficacy of drug treat-  ment. Persistent liver cell injury and deregulation of cellular  growth control genes lead to increased risk for cirrhosis and  hepatocellular carcinoma.*“* Antiviral and immunomodula-  tory treatment for chronic hepatitis B includes monotherapy,  combination therapy, and prevention of drug resistance. Vac-  cine prevents transmission of hepatitis B, the development of  acute or chronic hepatitis B, and reduction of hepatocellular    carcinoma, particularly in high-risk populations. Mutant  strains can develop with escape from vaccine protection or  diagnosis with HBsAg.**° Hepatitis B immunoglobulin pro-  vides postexposure prophylaxis against HBV after contact with  blood or body fluids of individuals infected with hepatitis B.**°  HBV vaccine or a combined vaccine for HAV and HBV pro-  vides protective immunity.   Hepatitis C Virus (HCV). HCV (previously known as non-A,  non-B hepatitis) is a parenterally transmitted flavivirus with  six genotypes. About 40% of HCV cases involve intravenous  drug users, who also have a high incidence of HIV infection.””  Coinfection with HBV also is prevalent. Approximately 80%  of cases develop chronic liver disease.*** HCV is diagnosed  through detection of anti-HCV IgG.” Persistent infection with  recurring acute symptoms and elevated aminotransferase levels  represent the clinical presentation. Antiviral drug therapy is  available.*°° Progression of disease to cirrhosis or hepatocellular  carcinoma is greatest among individuals with HIV or coexisting  liver disease.*?! The variants of HCV make vaccine development  difficult and resistance to drug therapy is common.’”? There  is no vaccine for HCV. The Centers for Disease Control and  Prevention have recommended that all persons born from 1945  through 1965 be screened for HCV infection.”°?   Hepatitis D Virus (HDV). HDV occurs in individuals  with hepatitis B. The delta virus depends on the HBV for its  replication because the viral coat consists of HBsAg molecules  that are on the surface of HBV. Hepatitis D has been shown  to suppress replication of HBV. Parenteral drug users have a  high incidence of HDV infection. HDV symptoms can be mild  or severe with progression to fulminant liver failure. HDV is  diagnosed by the presence of antibodies directed against HDAg  (anti-HD) and HDV RNA in serum. Treatment for chronic  HDV includes pegylated interferon alpha and it is effective  in about 25% of individuals. New treatments are in clinical  development.?°*7°>   Hepatitis E Virus (HEV). HEV is most common in Asian and  African countries and is transmitted by the fecal-oral route,  usually by way of contaminated water or uncooked meat. It is  also found in developed countries and must be differentiated  from drug-induced liver injury. Animal reservoirs of HEV  include domestic pigs, wild boars, deer, and rodents. It is  more prevalent among adults and has the highest mortality in  pregnant women. Clinically, it resembles HAV and is diagnosed  based on detection of anti-HEV IgM. A vaccine for HEV has  been approved in China but not in other countries.2°°7°”   PATHOPHYSIOLOGY. The pathologic lesions of hepatitis are  similar to those caused by other viral infection. Hepatic cell  necrosis, scarring, Kupffer cell hyperplasia, and infiltration by  mononuclear phagocytes occur with varying severity. Cellular  injury is promoted by cell-mediated immune mechanisms (i.e.,  cytotoxic T cells, T regulatory cells, and natural killer cells).*°*  Regeneration of hepatic cells begins within 48 hours of injury.  The inflammatory process can damage and obstruct bile cana-  liculi, leading to cholestasis and obstructive jaundice. In milder  cases the liver parenchyma is not damaged. Damage tends to be  most severe in cases of hepatitis B and hepatitis C. Hepatitis B  is also associated with acute fulminating hepatitis, a rare form    of the disease that is characterized by massive hepatic necro-  sis. Acute fulminating hepatitis causes severe encephalopathy,  which is manifested as confusion, stupor, and coma. Liver fail-  ure can occur, leading to GI bleeding, cardiorespiratory insuf-  ficiency, and hepatorenal syndrome. Mortality is high, but  recovery can be complete.   CLINICAL MANIFESTATIONS. The clinical manifestations of the  various types of hepatitis are very similar. The spectrum of  manifestations ranges from absence of symptoms to fulminat-  ing hepatitis, with rapid onset of liver failure and coma. Acute  viral hepatitis causes abnormal liver function test results. The  serum aminotransferase values, aspartate transaminase (AST)  and alanine transaminase (ALT), are elevated, but their eleva-  tion may not be consistent with the extent of cellular damage.  The clinical course of hepatitis usually consists of four phases:  incubation, prodromal, icteric, and recovery phases. The  incubation phase and manifestations vary depending on the  virus (see Table 41-7).   Prodromal Phase. The prodromal (preicteric) phase of  hepatitis begins about 2 weeks after exposure and ends with  the appearance of jaundice. Fatigue, anorexia, malaise, nausea,  vomiting, headache, hyperalgia, cough, and low-grade fever  are prodromal symptoms that precede the onset of jaundice.  About 10% of individuals may develop extrahepatic symptoms  including rash, arthralgias, and purpura. HBV and HCV  may cause nephritis related to glomerular immune complex  deposition.2>? Infection with HCV may have no symptoms.  Right upper abdominal pain is common, and a weight loss of  2 to 4 kg is not unusual. The infection is highly transmissible  during this phase.   Icteric Phase (Jaundice). The icteric phase begins about  1 to 2 weeks after the prodromal phase and lasts 2 to 6 weeks.  Individuals who develop chronic HBV infection do not become  jaundiced and may not be diagnosed.”°! Hepatocellular  destruction and intrahepatic bile stasis cause jaundice (icterus).  The urine may be dark and the stools clay colored before the  onset of jaundice from conjugated hyperbilirubinemia. The  icteric phase is the actual phase of illness. The liver is enlarged,  smooth, and tender, and percussion over the liver causes  pain. During the icteric phase, gastrointestinal and respiratory  symptoms subside, but fatigue and abdominal pain may persist  or become more severe. The stools may be lighter in color as  a result of cholestasis. Serum bilirubin levels range from 5 to  10 mg/dl, with conjugated bilirubin fraction increasing. The  jaundice may last 2 to 6 weeks or longer. Mild and transient  itching often accompanies jaundice. The prothrombin time  may be prolonged in individuals with more serious forms of  the disease.   Recovery Phase. The posticteric or recovery phase begins  with resolution of jaundice, about 6 to 8 weeks after exposure.  Although the liver may still be enlarged and tender, symptoms  diminish. In most cases, liver function test results return to  normal within 2 to 12 weeks after the onset of jaundice.   Chronic hepatitis may begin at this point and is associated  with HBV, HCV, and HDV infection. Chronic active hepatitis  is the persistence of clinical manifestations and liver inflamma-  tion after the acute stages. Liver function tests remain abnormal   Nonalcoholic fatty liver disease (NAFLD), also known as nonalcoholic steato-  hepatitis (NASH)   Prolonged exposure to chemicals (e.g., carbon tetrachloride, cleaning and  industrial solvents, copper salts)    for longer than 6 months, and HBsAg persists. Chronic, active  HBV and HBC is a predisposition to cirrhosis and primary  hepatocellular carcinoma. Chronic active hepatitis constitutes  a carrier state, and HBV and HCV can be transmitted from  mothers to infants.?°   EVALUATION AND TREATMENT. Diagnosis and treatment were  previously described for the different types of hepatitis viruses.  Physical activity may be restricted. A low-fat, high-carbohydrate  diet is beneficial if bile flow is obstructed.   There should be no direct contact with blood or body flu-  ids of individuals with hepatitis B or hepatitis C. A combined  vaccine for HAV and HBV is available. Hepatitis B immuno-  globulin provides passive prophylactic immunity against HBV.  Prophylaxis is recommended for healthcare workers, liver  transplant recipients, and others who are at risk for contact with  infected body fluids.?%    Cirrhosis is an irreversible inflammatory, fibrotic liver disease  and the twelfth leading cause of death in the United States. Many  disorders can cause cirrhosis and are summarized in Box 41-6.  Alcohol abuse and viral hepatitis are the most common causes.”  The process of cellular injury depends on the cause of cirrho-  sis; however, not all causes are clearly understood. Structural  changes result from injury (alcoholism, viruses, steatosis, chemi-  cals) and fibrosis. Fibrosis is a consequence of Kupffer cell (liver  macrophages) activation with release of inflammatory media-  tors, reactive oxygen species, and growth factors and activation  of fibrogenic fibroblasts.*°° Chaotic fibrosis alters or obstructs  biliary channels and blood flow, producing jaundice and portal  hypertension. New vascular channels form shunts, and blood  from the portal vein bypasses the liver, contributing to portal  hypertension, metabolic alterations, and toxin accumulation.  The process of regeneration is disrupted by hypoxia, necrosis,  atrophy, and (ultimately) liver failure. The formation of fibrous    bands and regenerating nodules distorts the architecture of the  liver parenchyma and gives the liver a cobbly appearance.” The  liver may be larger or smaller than normal and is usually firm or  hard when palpated. Cirrhosis develops slowly over a period of  years. Its severity and rate of progression depend on the cause.   If alcohol is involved, the rate of cell death and the severity  of inflammation depend on the amount of alcohol present.*°”  Removal of alcohol slows the progression of liver damage and  enhances the process of regeneration.   Alcoholic Liver Disease. Abuse of any type of alcoholic  beverage can cause alcoholic liver disease and the severity  of disease is related to the amount and duration of alcohol  consumed and formation of acetaldehyde (see Chapter 2  and Figure 2-15).*°” The incidence of alcoholic cirrhosis is  greatest in middle-aged men; however, women develop more  severe liver injury than men.”° In the United States, mortality  resulting from cirrhosis is highest among Hispanic white  males and females; however, the death rates for all groups are  declining.*®? Malnutrition may add to the risk of cirrhosis in  alcohol abusers. Many alcoholics are malnourished and the liver  cannot regenerate without adequate nutrition. The spectrum of  alcoholic liver disease includes steatosis, alcoholic hepatitis, and  alcoholic cirrhosis (fibrosis).?”°   PATHOPHYSIOLOGY. Alcoholic fatty liver (steatosis) is the mild-  est form of alcoholic liver disease. It can be caused by chronic  ingestion of relatively small amounts of alcohol (more than one  alcoholic drink [14 grams of alcohol] per day for women and  two alcoholic drinks [28 grams of alcohol] per day for men),  may be asymptomatic, and is reversible with cessation of drink-  ing.’’!”? Fat deposition (deposition of triglycerides) within the  liver is caused primarily by increased lipogenesis and decreased  fatty acid oxidation and fat metabolism by hepatocytes. Lipids  mobilized from adipose tissue or dietary fat intake may contrib-  ute to fat accumulation.   Alcoholic hepatitis (steatohepatitis) is a precursor of cir-  rhosis characterized by inflammation; degeneration and necro-  sis of hepatocytes; infiltration of neutrophils, macrophages,  and lymphocytes; immunologic alterations; and lipid peroxida-  tion. The injured hepatocytes contain Mallory bodies (hyaline  endoplasmic reticulum), indicating the onset of fibrosis. Neu-  trophils infiltrate and surround degenerating hepatocytes. The  mechanism of hepatocyte injury is not clearly understood, but  inflammatory mediators, acetaldehyde, reactive oxygen and  nitrogen species, and genetic factors are involved.’”*:?”* Alcohol  also increases gut permeability, and translocation of bacteria-  derived lipopolysaccharide contributes to inflammation, oxida-  tive stress, and the severity of alcoholic liver disease.?”> Serum  IgA level is often elevated in individuals with alcoholic hepa-  titis, and liver antigens and antibodies have been identified in  persons with progressive alcoholic liver disease.’”° The inflam-  mation and necrosis caused by alcoholic hepatitis stimulate the  fibrosis characteristic of the cirrhotic stage of disease. Cortico-  steroids and pentoxifylline are used for treatment.?””   Alcoholic cirrhosis is caused by the toxic effects of alcohol  metabolism on the liver, immunologic alterations, oxidative  stress from lipid peroxidation, and malnutrition.’”* Alco-  holic cirrhosis is more severe when associated with HCV.2””    Although alcoholic cirrhosis is the most prevalent of the vari-  ous types of cirrhosis, the occurrence of cirrhosis among per-  sons with alcoholism is relatively low (approximately 35%).  Alcohol is transformed to acetaldehyde. Excessive amounts of  acetaldehyde are toxic and induce lipid peroxidation and oxi-  dative stress and disrupt cytoskeletal and membrane function.  Acetaldehyde inhibits export of proteins from the liver, alters  metabolism of vitamins and minerals, promotes liver fibrosis,  and contributes to malnutrition.’*° Mitochondrial function  is impaired, decreasing oxidation of fatty acid. Enzyme and  protein synthesis may be depressed or altered, and hormone  and ammonia degradation is diminished. Alcohol also may  stimulate the formation of autoantibodies specific to hepatic  cells.?”° Alcohol also increases gut permeability, and translo-  cation of bacteria-derived endotoxin from the intestine con-  tributes to progressive injury and inflammation.’”? Cellular  damage initiates an inflammatory response. Inflammatory  cytokines, including TNF-a and IL-6, IL-8, and IL-18, and  activation of complement are associated with alcoholic liver  disease. Inflammation and necrosis result in excessive collagen  formation. Transforming growth factor-beta (TGF-f) contrib-  utes to fibrosis and is produced in part by activated Kupffer  cells. TGF-f activates hepatic stellate cells to produce excess  collagen. Dense bands of fibrosis surround regenerative hepa-  tocellular nodules. Fibrosis and scarring alter the structure of  the liver and obstruct biliary and vascular channels and hepa-  tocytes lose their ability to regenerate.’?”° There is increased  risk for hepatocellular carcinoma. Examples of liver damage  are shown in Figure 41-22.   CLINICAL MANIFESTATIONS. Fatty infiltration causes no specific  symptoms or abnormal liver function test results. The liver is  usually enlarged, however, and the individual has a history of  continuous alcohol intake during the previous weeks or months.  The clinical manifestations of alcoholic hepatitis can be mild  or severe. Nonspecific symptoms include fatigue, weight loss,  and anorexia. Manifestations of acute illness include nausea,  anorexia, fever, abdominal pain, and jaundice.”*! Toxic effects  of alcohol also can cause gynecomastia, testicular atrophy,  reduced libido, azoospermia, and decreased testosterone level  in men.** Cirrhosis is a multiple-system disease and causes  hepatomegaly, splenomegaly, ascites, gastrointestinal hemor-  rhage, portal hypertension, hepatic encephalopathy, and esoph-  ageal varices. Anemia results from blood loss, malnutrition, and  hypersplenism. Hepatorenal syndrome is usually a late compli-  cation. Risk for infection is greater, in part because of innate  immune dysfunction.”*’ The presence of numerous and severe  manifestations increases the risk of death. The clinical features  of alcoholic cirrhosis depend on the duration of the disease and  the severity of liver damage (Figure 41-23).   EVALUATION AND TREATMENT. The diagnosis of alcoholic hepatitis  is based on the individual’s history and clinical manifestations.  The results of liver function tests are abnormal, and serologic  studies show elevated levels of serum enzymes and bilirubin  and decreased serum albumin levels. Prolonged prothrombin  time cannot easily be corrected with vitamin K therapy. Liver  biopsy can confirm the diagnosis of cirrhosis, but biopsy is not  necessary if clinical manifestations of cirrhosis are evident.    FIGURE 41-22 Cirrhosis. A, Micronodular cirrhosis. The nodular appearance  develops from regeneration of hepatocytes projecting through fibrous bands of tis-  sue. B, Macronodular cirrhosis. (From Damjanov |, Linder J, editors: Andersons  pathology, ed 10, St Louis, 1996, Mosby.)    There is no specific treatment for alcoholic liver disease,  but many of the complications are treatable. Rest, a nutritious  diet, corticosteroids, antioxidants, drugs that slow fibrosis, and  management of complications such as ascites, gastrointestinal  bleeding, infection, and encephalopathy slow disease progres-  sion.*** Cessation of alcohol consumption slows the progres-  sion of liver damage, improves clinical symptoms, and prolongs  life. Although the liver damage is irreversible, measures that  halt the inflammation and destruction of liver cells prolong life.  Liver transplant is the treatment for liver failure and artificial  liver support systems are being developed.?*>”°°   Nonalcoholic Fatty Liver Disease and Nonalcoholic  Steatohepatitis. Nonalcoholic fatty liver disease (NAFLD) is  infiltration of hepatocytes with fat, primarily in the form of  triglycerides, but it occurs in the absence of alcohol intake. It is  associated with obesity (including obese children), high levels  of cholesterol and triglycerides, metabolic syndrome, and type 2  diabetes mellitus, and is the most common chronic liver disease  in the United States. Some individuals with NAFLD will develop  nonalcoholic steatohepatitis (NASH) with hepatocellular  injury, inflammation, and fibrosis; this condition is difficult  to distinguish from alcohol-induced liver fibrosis.?”* NAFLD  is usually asymptomatic and may remain undetected for years.  The most severe forms of NASH progress to cirrhosis, end-  stage liver disease, and an increased risk for hepatocellular  carcinoma.?*”    Esophageal varices  Hemorrhoids  Superficial abdominal veins  (caput medusae)  Hepatopulmonary syndrome  Portopulmonary hypertension    FIGURE 41-23 Clinical Manifestations of Cirrhosis. ADH, Antidiuretic hormone; ALT, alanine transaminase; AST, aspartate    Biliary Cirrhosis. Biliary cirrhosis differs from alcoholic  cirrhosis in that the damage and inflammation leading to  cirrhosis begin in bile canaliculi and bile ducts, rather than in  the hepatocytes. The two types of biliary cirrhosis are primary  and secondary. Although both involve bile duct pathology, they  differ with respect to cause, risk factors, and mechanisms of  obstruction and inflammation.   Primary Biliary Cirrhosis. Primary biliary cirrhosis (PBC)  is a T lymphocyte- and antibody-mediated destruction of  the small intrahepatic bile ducts. The disease is thought to be  caused by superimposed environmental antigens (e.g., infec-  tious agents) in genetically susceptible individuals. Women are  affected more commonly (90%) than men. Symptoms rarely  develop before the age of 30 years. Primary biliary cirrhosis  often accompanies other autoimmune diseases.7**   PBC develops insidiously. Antimitochondrial antibody is  the hallmark of the disease and 30% to 50% of individuals have  antinuclear antibodies. Expression of glycoprotein 210 (gp210)  antibodies and anticentromere antibodies confers different  risks for disease progression with anti-gp210 causing the most    severe disease.**? Pathogenesis includes inflammation, destruc-  tion, fibrosis, and obstruction of the intrahepatic bile ducts.  Nodular regeneration, cirrhosis, and portal hypertension can  develop during later stages of the disease.   Diagnosis is based on two of the following three criteria:  (1) biochemical evidence of cholestatic liver disease for at least  6-month’s duration, (2) antimitochondrial antibody (AMA)  positivity, and (3) histologic features of PBC on liver biopsy.’”°  Serologic tests show elevated levels of alkaline phosphatase and  y-glutamyl transpeptidase, hyperbilirubinemia, and hyper-  lipidemia with or without other clinical manifestations. Most  individuals have a circulating IgG antimitochondrial antibody  that is not found in other types of liver disease. Biopsy shows  cholangitis and excludes other inflammatory liver diseases.  Evaluation involves ruling out biliary obstruction caused by  gallstones, tumor, or inflammation of the common bile duct  (i.e., secondary biliary cirrhosis).   Individuals with primary biliary cirrhosis may be asympto-  matic or symptomatic at diagnosis and may have minimal  disease or rapid progression to cirrhosis and liver failure. The    earliest manifestations are pruritus, fatigue, and abdomi-  nal pain. Jaundice and light-colored stools are symptoms of  advanced disease. These symptoms are caused by intrahepatic  obstruction of bile flow. Steatorrhea and fat-soluble vitamin  deficiencies are present in some cases. The malabsorption can  lead to osteomalacia and osteoporosis. Cirrhosis, symptoms of  portal hypertension, encephalopathy, and ultimately liver fail-  ure develop in untreated individuals.   Long-term treatment with ursodeoxycholic acid is highly  effective.*** The distressing pruritus may be relieved by chole-  styramine, which binds bile salts in the intestine. Intramuscular  injections of vitamins D and K alleviate the vitamin deficiency.  The other symptoms of cirrhosis are managed as they develop.  Liver transplant is the only option for those with progressive  disease not responding to medical treatment.”!   Secondary Biliary Cirrhosis. Secondary biliary cirrhosis  develops when there is prolonged partial or complete obstruc-  tion of the common bile duct or its branches. The obstruction  may be caused by gallstones, tumors, fibrotic strictures, or  chronic pancreatitis. Biliary atresia and cystic fibrosis cause sec-  ondary biliary cirrhosis in children.   Chronic obstruction to bile flow increases pressure in the  hepatic bile duct and results in the accumulation of bile in the  centrilobular spaces. Necrotic areas develop and are followed by  proliferation and inflammation of the portal ducts that result  in edema and fibrosis. Pools of bile form when the portal ducts  rupture into surrounding necrotic areas. Injury is accompanied  by regeneration of hepatic cells with the development of finely  nodular cirrhosis.   Clinical manifestations are similar to those of primary biliary  cirrhosis, with jaundice and pruritus the most distressing symp-  toms. Right upper quadrant pain is common, and a low-grade  fever may be present from bile duct inflammation (cholangitis).   Cholangiography provides the most definitive diagnosis.  Laboratory tests usually show elevated conjugated bilirubin and  alkaline phosphatase levels. Aminotransferase level increases  if there is an accompanying cholangitis. Surgery or endos-  copy relieves obstruction, prolongs survival, and diminishes or  resolves symptoms. Continued obstruction leads to advanced  cirrhosis and liver failure.   Primary Sclerosing Cholangitis. Primary _ sclerosing  cholangitis (PSC) is a chronic inflammatory fibrotic disease of  the hepatic bile ducts that leads to secondary biliary cirrhosis.  The disease is immune-mediated but the exact mechanism is  unknown. PSC is associated with inflammatory bowel disease  (75%) and primarily affects genetically susceptible males. There  is no effective sustaining medical or surgical therapy and liver  transplant is required for liver failure.?°>??    Obstruction and inflammation are the most common disor-  ders of the gallbladder. Obstruction is caused by gallstones  (cholelithiasis), which are aggregates of substances in the bile.  The gallstones may remain in the gallbladder or be ejected,  with bile, into the cystic duct. Gallstones that become lodged  in the cystic duct obstruct the flow of bile into and out of the  gallbladder and cause inflammation. Gallstone formation is    FIGURE 41-24 Resected Gallbladder Containing Mixed Gallstones. (From  Kissane JM, editor: Anderson's pathology, ed 9, St Louis, 1990, Mosby.)    termed cholelithiasis. Inflammation of the gallbladder or cystic  duct is known as cholecystitis.    Cholelithiasis is a prevalent disorder in developed countries,  where the incidence is 10% to 15%. The actual incidence is  unknown because many individuals who have gallstones are  asymptomatic. Risk factors include obesity; rapid weight loss in  obese individuals; middle age; female gender; use of oral con-  traceptives; American Indian ancestry; gallbladder, pancreatic,  or ileal disease; low HDL cholesterol level and hypertriglyceri-  demia; and gene-environmental interactions.?**   PATHOPHYSIOLOGY. Gallstones are commonly of two types: cho-  lesterol and pigmented. Cholesterol stones are the most com-  mon. Cholesterol gallstones form in bile that is supersaturated  with cholesterol produced by the liver. Supersaturation sets  the stage for cholesterol crystal formation, or the formation of  “microstones.” More crystals then aggregate on the microstones,  which grow to form “macrostones” within a mucin matrix. This  process usually occurs in the gallbladder. The stones may lie  “silent” or become lodged in the cystic or common duct, causing  pain and cholecystitis. Gallstone formation may be such that the  stones accumulate and fill the entire gallbladder (Figure 41-24).   It is not known why the hepatocytes secrete bile that is super-  saturated with cholesterol. Proposed mechanisms include: (1) an  enzymatic defect that increases the hepatocytes’ synthesis of  cholesterol; (2) diminished secretion of bile acids, which nor-  mally promote cholesterol solubility; (3) decreased resorp-  tion of bile salts from the ileum, which decrease the bile acid  pool; (4) gallbladder smooth muscle hypomotility and stasis;  (5) genetic predisposition; and (6) some combination of these  mechanisms.””° In obese individuals the mechanism appears to  involve cholesterol synthesis, whereas in nonobese individuals,  it appears to involve decreased secretion of bile acids.   Pigmented stones are black (hard) or brown (soft). Black pig-  mented stones are formed in a sterile environment and consist  primarily of calcium bilirubinate polymer. They are associated  with hyperbilirubinbilia (biliary hypersecretion of bilirubin  conjugates) and hemolytic diseases, such as sickle cell anemia  and Gilbert syndrome (hereditary hyperbilirubinemia). The  formation of brown stones is associated with bacterial infec-  tion of the bile ducts with formation of stone composed of cal-  cium soaps, unconjugated bilirubin, cholesterol, fatty acids, and  mucin. They are more common in East Asia.””°    CLINICAL MANIFESTATIONS. Epigastric and right hypochon-  drium pain and intolerance to fatty foods are the cardinal mani-  festations of cholelithiasis. Vague symptoms include heartburn,  flatulence, epigastric discomfort, pruritus, jaundice, and food  intolerances, particularly to fats and cabbage. The pain, often  called biliary colic, is most characteristic and is caused by the  lodging of one or more gallstones in the cystic or common  duct.’*”? The pain can be intermittent or steady. It usually is  located in the right upper quadrant and radiates to the mid-  upper back. Jaundice indicates that the stone is located in the  common bile duct. Abdominal tenderness and fever indicate  cholecystitis. Complications can include pancreatitis from  obstruction of the pancreatic duct.   EVALUATION AND TREATMENT. Diagnosis is based on the indi-  vidual’s medical history, physical examination, and imaging  evaluation. An oral cholecystogram usually outlines the stones.  Intravenous cholangiography is used to differentiate cholelithi-  asis from other causes of extrahepatic biliary obstruction if the  cholecystogram is negative. Endoscopic or percutaneous chol-  angiography and endoscopic or transabdominal ultrasonogra-  phy are diagnostic options.’”*   Laparoscopic cholecystectomy is the preferred treatment for  gallstones that cause obstruction or inflammation. Use of trans-  luminal endoscopic surgery is advancing rapidly. Endoscopic  retrograde cholangiopancreatography and _ sphincterotomy  with stone retrieval is used for the treatment of bile duct stones.  Large stones may be managed with lithotripsy??? An alter-  native treatment is the administration of drugs that dissolve  smaller stones. For example, the bile acid chenodeoxycholic  acid (CDCA) can completely or partially dissolve cholesterol  gallstones. Ursodeoxycholic acid (UDCA), which is structurally  similar to CDCA, is also effective, is less toxic to hepatocytes,  and does not cause fatty diarrhea, as does CDCA.    Cholecystitis can be acute or chronic. Both forms are almost  always caused by the lodging of a gallstone in the cystic duct.  Obstruction causes the gallbladder to become distended and  inflamed. The pain is similar to that caused by gallstones. Pres-  sure against the distended wall of the gallbladder decreases  blood flow. Ischemia, necrosis, and perforation of the gall-  bladder are possible. Fever, leukocytosis, rebound tenderness,  and abdominal muscle guarding are common findings. Serum  bilirubin and alkaline phosphatase levels may be elevated. Nev-  ertheless, the acute abdominal pain of cholecystitis must be  differentiated from the pain caused by other disorders, such as  pancreatitis, intestinal vascular insufficiency, and acute pyelo-  nephritis of the right kidney. Cholescintigraphy tracks the pro-  duction and flow of bile from the liver to the gallbladder and  small intestine and shows if bile is blocked at any point along  the way; it has the highest diagnostic accuracy but involves the  use of ionizing radiation. Ultrasound and magnetic resonance  imaging have a substantial margin of error but can demonstrate  nonspecific morphologic changes.°”!   Treatment includes pain control, replacement of fluid  and electrolytes, and fasting. Antibiotics are often prescribed  to manage bacterial infection in severe cases. Immediate    cholecystectomy is required for complications such as peritoni-  tis from gallbladder perforation. Persistent symptoms or devel-  opment of chronic cholecystitis punctuated by recurrent acute  attacks usually requires cholecystectomy.*°”    Pancreatitis, or inflammation of the pancreas, is a relatively  rare (about 17 cases per 100,000 people in the United States)*°*  and a potentially serious disorder. Incidence is about equal  in men and women and is more common between 50 and 60  years of age. Risk factors include alcoholism, obstructive biliary  tract disease (particularly cholelithiasis), peptic ulcers, abdomi-  nal trauma, hyperlipidemia, certain drugs, and genetic factors  (hereditary pancreatitis, cystic fibrosis). The cause is unknown  in 15% to 25% of cases.°°* Pancreatitis can be acute or chronic.    Acute pancreatitis is usually a mild disease and resolves spon-  taneously, but about 20% of those with the disease develop a  severe acute pancreatitis requiring hospitalization. Pancreati-  tis develops because of obstruction to the outflow of pancre-  atic digestive enzymes caused by bile duct or pancreatic duct  obstruction (e.g., gallstones). Chronic alcohol use may also  cause spasm of the sphincter of Oddi and formation of protein  plugs in pancreatic ducts, resulting in obstruction. Acute pan-  creatitis can also result from direct cellular injury from drugs or  viral infection.°°   PATHOPHYSIOLOGY. In obstructive disease, the backup of pan-  creatic secretions causes activation and release of enzymes  (activated trypsin activates chymotrypsin, lipase, and elastase)  within the pancreatic acinar cells. The activated enzymes cause  autodigestion (e.g., proteolysis, lipolysis) of pancreatic cells and  tissues, resulting in inflammation. The autodigestion causes vas-  cular damage, coagulative necrosis, fat necrosis (see Chapter 2),  and formation of pseudocysts (walled-off collections of pancre-  atic secretions).°°° Edema within the pancreatic capsule leads to  ischemia and can contribute to necrosis.   Systemic effects are associated with severe acute pancreatitis.  Proinflammatory cytokines (e.g., interleukin-6, tumor necro-  sis factor-alpha, transforming growth factor-beta, and platelet-  activating factor) and vasoactive peptides are released into the  bloodstream. Activation of leukocytes, injury to vessel walls, and  coagulation abnormalities with development of vasodilation,  hypotension, and shock occur.*°” These systemic effects can  lead to acute respiratory distress syndrome (ARDS), heart fail-  ure, renal failure, coagulopathies, and the systemic inflamma-  tory response syndrome (SIRS) (see Chapter 48) (Figures 41-25  and 41-26). Translocation of intestinal bacteria to the blood-  stream may cause peritonitis or sepsis. Anti-inflammatory cyto-  kines and specific cytokine inhibitors are produced in response  to the systemic inflammatory response and may increase risk of  infection.°°* As the pancreatitis progresses, pancreatic stellate  cells become activated, causing pancreatic fibrosis, strictures,  and duct obstruction and leading to chronic pancreatitis.   CLINICAL MANIFESTATIONS. Epigastric or midabdominal pain  is the cardinal symptom of acute pancreatitis. The pain may  radiate to the back because of the retroperitoneal location of    the pancreas. The pain is caused by edema, which distends the  pancreatic ducts and capsule; chemical irritation and inflam-  mation of the peritoneum; and irritation or obstruction of the  biliary tract. Fever and leukocytosis accompany the inflamma-  tory response. Nausea and vomiting are caused by hypermotil-  ity or paralytic ileus secondary to the pancreatitis or peritonitis.   Abdominal distention accompanies bowel hypermotility or  paralytic ileus and the accumulation of fluids in the peritoneal  cavity (ascites). Hypotension and shock occur with hypovo-  lemia and SIRS.°°? Tachypnea and hypoxemia are indicative  of ascites, diaphragmatic irritation, or respiratory complica-  tions.°!° In severe cases, hypovolemia decreases renal blood flow  sufficiently to impair renal function.*!!?!° Transient hypergly-  cemia also can occur if glucagon is released from damaged A  cells in the pancreatic islets. SIRS and multiple organ failure  account for most deaths with severe pancreatitis.°°” In severe  acute pancreatitis, some individuals develop flank or perium-  bilical ecchymosis, a sign of poor prognosis.   EVALUATION AND TREATMENT. Diagnosis of pancreatitis is based  on clinical findings, identification of associated disorders, lab-  oratory studies, and imaging techniques (CT scan, MRI, and  ultrasonography). Elevated serum lipase level is the primary  diagnostic marker for acute pancreatitis. Serum lipase levels    FIGURE 41-26 Acute Severe Pancreatitis with Hemorrhage. A, Normal  pancreas. B, Acute hemorrhagic pancreatitis. The pancreas has hemorrhage, fat  necrosis (white patches), and a pseudocyst filled with blood (white arrow). (A from  Klatt EC, editor: Robbins and Cotran atlas of pathology, Philadelphia, 2006, Saunders.  B from Damjanov |, Linder J, editors: Pathology: a color atlas, St Louis, 2000, Mosby.)    increase within 4 to 8 hours of clinical symptom onset and  decrease within 8 to 14 days. Serum amylase level is elevated  but is not diagnostic of severity or specificity of disease. Serum  trypsin levels are very specific for pancreatitis but the test is not  widely available.*'* C-reactive protein, procalcitonin, blood  urea nitrogen, and Bedside Index of Severity in Acute Pancre-  atitis are predictors of severity.*!>°!°   Acute pancreatitis is difficult to diagnose because several  other disorders can cause similar clinical and laboratory find-  ings (e.g., perforating duodenal ulcer, acute cholecystitis, and  kidney stones). Intra-abdominal pressure monitoring assesses  risk for abdominal compartment syndrome*!’ (see What’s  New? Abdominal Compartment Syndrome).   There is no specific treatment for acute pancreatitis. The  goal of treatment is to stop the process of autodigestion and  prevent systemic complications. Hemodynamic monitoring  and parenteral fluids are essential to restore blood volume  and prevent hypotension and shock, particularly in the first  24 hours. Narcotic medications may be needed to relieve pain.  Meperidine hydrochloride (Demerol) is used instead of mor-  phine because it causes less spasm of the sphincter of Oddi  than morphine. Nasogastric suction may not be necessary  with mild pancreatitis but may help relieve pain and prevent    Abdominal compartment syndrome (ACS), also known as intra-abdominal  hypertension, develops when there is abnormally high intra-abdominal pres-  sure associated with organ dysfunction. It occurs in 20% to 40% of intensive  care unit patients. ACS is associated with abdominal injury, including trauma,  ruptured aortic aneurysm, acute pancreatitis, sepsis, significant thermal injury,  liver failure with ascites, and massive fluid volume replacement with mechani-  cal ventilation. Increased intra-abdominal pressure increases intrathoracic,  intracardiac, and intracranial filling pressures and results in decreased cardiac  output, atelectasis, pulmonary edema, oliguria, compromise of splanchnic and  hepatic blood flow, and translocation of bacteria from the gut. The end conse-  quence is multiple organ failure.   Normally intra-abdominal pressure is slightly greater than atmospheric pres-  sure (5 to 7 mmHg, up to 12 mmHg). Organ dysfunction develops at pressures  greater than 20 mmHg that last for more than 6 hours. ACS is difficult to detect  from physical diagnosis alone. Automated serial or continuous monitoring of  pressure inside the bladder provides a reliable estimate of intra-abdominal  pressure. Gastric monitoring is not always feasible and inferior vena cava  monitoring is more invasive. Treatment is tiered medical management and  decompressive laparotomy, which may be performed at the bedside if the indi-  vidual is too unstable to move. Elevating the head of the bed to 30 degrees is  helpful for some individuals.    Data from Luckianow GM et al: Crit Care Res Pract 2012:908169, 2012;  Starkopf J, Tamme K, Blaser AR: Ann Intensive Care 2(Suppl 1):S9,  2012; Yi M et al: J Crit Care 27(2):222.e1e-6, 2012.    paralytic ileus in individuals who are nauseated and vomit-  ing. Feeding is usually initiated within 24 to 48 hours if ileus  is not present. In severe acute pancreatitis, enteral nutrition  with use of jejunal tube feeding is usually well tolerated and  may decrease pancreatic enzyme secretion, prevent gut bacte-  rial overgrowth, and maintain gut barrier function. Parenteral  hyperalimentation should be initiated only when enteral feed-  ing is not tolerated. Drugs that decrease gastric acid produc-  tion (e.g., H2 receptor antagonists) can decrease stimulation  of the pancreas by secretin. Necrotizing pancreatitis requires  surgical resection, and antibiotics may control infection. The  risk of mortality increases significantly with the development of  pulmonary, cardiac, and renal complications.°!®    Chronic alcohol abuse is the most common cause of chronic  pancreatitis because repeated exacerbations of acute pancreati-  tis can lead to chronic changes. Obstruction from gallstones,  autoimmune disease, gene mutations, smoking, occupational  chemical exposure, and obesity are associated with chronic pan-  creatitis. The disease is idiopathic in about 25% of cases. Toxic  metabolites and chronic release of inflammatory cytokines  contribute to the destruction of acinar cells and islets of Lang-  erhans. The pancreatic parenchyma is destroyed and replaced  by fibrous tissues, strictures, calcification, ductal obstruction,  and pancreatic cysts. The cysts are walled-off areas or pockets of  pancreatic juice, necrotic debris, or blood within or adjacent to  the pancreas. Continuous or intermittent abdominal pain is the  classic symptom. Pain is associated with increased intraductal  pressure, increased tissue pressure, ischemia, neuritis, ongoing    injury, and changes in central pain perception. Weight loss and,  less commonly, steatorrhea and diabetes mellitus accompany  disease progression and require treatment with oral lipase and  insulin. Autoimmune chronic pancreatitis is treated with cor-  ticosteroids. Preventing disease progression includes lifestyle  modification to stop alcohol use and smoking. Pain manage-  ment is complex with use of analgesics, endoscopic therapy,  nerve block, and surgical drainage of cysts or partial resection  of the pancreas.°!?*?! Chronic pancreatitis is a risk factor for  pancreatic cancer.°??    Cancer occurs throughout the alimentary tract and the acces-  sory organs of digestion (liver, gallbladder, and pancreas)  (Table 41-8). A genetic predisposition is being evaluated.°”°   Carcinoma of the esophagus is a rare disease with 17,990 new  cases and 15,210 deaths in 2013 in the United States.**4 Squamous  cell carcinoma is more prevalent in China, Iran, South America,  and South Africa. Squamous cell carcinoma is found in the upper  two thirds of the esophagus and is associated with smoking and  alcohol ingestion. Adenocarcinoma accounts for about 58% of  esophageal carcinoma cases in the United States and is increasing.  Adenocarcinoma is found in the distal one third of the esophagus  and is associated with risk factors that include smoking, abdomi-  nal obesity, reflux esophagitis, and sliding hiatal hernia. Carcino-  mas are most common at the gastroesophageal junction.*”°   PATHOGENESIS. The pathogenesis of esophageal carcinoma is  facilitated by (1) chronic inflammation, metaplasia, and dys-  plasia caused by gastroesophageal reflux (Barrett esophagus);  and (2) long-term exposure to irritants, such as alcohol and  tobacco, that cause neoplastic transformation (see Chapter  12). Both genomic and epigenomic events are associated with  Barrett esophagus and mutation of the T’P53 gene is an early  event.°*°°?7 The CagA-positive strain of H. pylori may be a pro-  tection against esophageal adenocarcinoma.*”*   CLINICAL MANIFESTATIONS. Early stages of esophageal car-  cinoma are asymptomatic. The two main manifestations of  esophageal carcinoma are chest pain and dysphagia. The most  common type of pain is heartburn (pyrosis). It is initiated by  eating spicy or highly seasoned foods and by lying down. Dys-  phagia (pain on swallowing), another common symptom, is  usually pressure-like and may radiate posteriorly between the  scapulae. Some individuals with esophageal cancer complain of  a constant retrosternal pain that radiates to the back. Dysphagia  usually progresses rapidly.   EVALUATION AND TREATMENT. Individuals who present with  dysphagia undergo endoscopy so that specimens can be exam-  ined for neoplastic change and type of carcinoma. CT studies  of the thorax also are used for diagnosis. Treatment of gas-  troesophageal reflux is essential for the prevention of Barrett  esophagus. Barrett esophagus with high-grade dysplasia is  treated with endoscopic radiofrequency ablation, cryotherapy,  or resection.°”?    Anorexia  Malaise  Weight loss  Upper abdominal pain  Vomiting  Occult blood  Adenocarcinoma (left colon Pain  grows in ring; right colon Mass  grows as mass) Anemia  Bloody stool  Obstruction  Distention  Hepatomas Pain  Cholangiomas Anorexia  Bloating  Weight loss  Portal hypertension  Ascites + jaundice    Amended with permission from the American Cancer Society: Cancer facts and figures, 2009, Atlanta, GA, 2009, Author.  *Note: Esophageal (men), colorectal, liver, and pancreatic cancers are within the top 10 causes of death from cancer.    Untreated esophageal cancer metastasizes rapidly and has  a poor prognosis. At the time of diagnosis, 50% of esophageal  cancers present with metastatic disease. The lymphatic vessels of  the esophagus are continuous with vital mediastinal structures  (trachea, heart, and great vessels) and drain to the celiac lymph  nodes, making it impossible to remove all the lymph nodes with  the tumor. Removal of the primary lesion and the local lymph  nodes, however, can benefit the individual with esophageal  cancer and cure is likely if there is no metastasis. If spread has  occurred, treatment is combined radiation, chemotherapy, and  palliative care (e.g., self-expanding metal stents).°°°    Although the incidence of gastric cancer has declined in the  United States, it still represents about 2% (21,600 cases) of all  new cancer cases and 10,990 deaths in 2013.°*4 The majority  of cases are adenocarcinoma. The incidence of gastric cancer is  greater in men than in women. In countries such as Eastern Asia,  Eastern Europe, and South America, the incidence of stomach  cancer has remained consistently high.*?! Nonenvironmental  risk factors include a family history of gastric adenocarcinoma;  blood type (blood group A); type A atrophic gastritis; and per-  nicious anemia, which is associated with atrophy of the gastric  mucosa in the same locations where gastric tumors arise.**>*4   The most important environmental risk factors in caus-  ing gastric cancer are: (1) infection with H. pylori that carries    the CagA gene product cytotoxin-associated antigen A (80%  of cases); (2) dietary factors, such as salt added to food, food  additives (e.g., nitrates) in pickled or salted foods (e.g., bacon),  and low intake of fruits and vegetables; and (3) lifestyle, such  as alcohol consumption and cigarette smoking. Infection with  H. pylori and severe chronic gastritis change the mucosal cell  proliferation pattern, destroy cell junctions, inhibit cell prolif-  eration, and promote cell invasive ability, increasing the risk for  gastric and duodenal carcinoma.**>>°”   H. pylori also is causatively linked to mucosa-associated  lymphoid tissue (MALT) lymphoma (a low-grade B-cell  lymphoma) that can originate in the stomach. Dietary salt  enhances the conversion of nitrates to carcinogenic nitrosa-  mines in the stomach. Salt is also caustic to the stomach and  can cause chronic atrophic gastritis. Hypertonic salt solu-  tions delay gastric emptying. Delayed emptying increases the  time during which carcinogenic nitrosamines can exert their  effects on the stomach mucosa. Nitrates interact with amino  acids in the stomach to form nitrosamines. The conversion  of these carcinogenic nitrosamines is enhanced at a low pH  by iodides and thiocyanates. Nitrates are thought to be active  only when converted to nitrites and to cause stomach cancer  once atrophic gastritis has occurred. Smoking decreases the  production of prostaglandins that maintain gastric mucosal  integrity, and smokers have a higher incidence of H. pylori  infection.***    PATHOGENESIS. Gastric adenocarcinoma usually begins in the  glands of the stomach mucosa. Approximately 50% of all gas-  tric cancers develop in the prepyloric antrum (Figure 41-27).  Atrophic gastritis and intestinal metaplasia are strongly linked  to the development of gastric cancer. Insufficient acid secretion  by the atrophic mucosa creates a relatively alkaline environ-  ment that permits bacteria to multiply and act on nitrates. The  resulting increase in nitrosoamines damages the deoxyribo-  nucleic acid (DNA) of mucosal cells further, promoting meta-  plasia and neoplasia. Duodenal reflux also may contribute to  intestinal metaplasia. The reflux contains caustic bile salts that  destroy the mucosal barrier that normally protects the stomach.  Epigenetic alterations (DNA methylation, histone methylation,  and histone acetylation) and multiple genes are involved in gas-  tric cancer including oncogenes, tumor-suppressor genes, DNA  repair genes, and cell cycle regulator genes. Genetics also can  distinguish well-differentiated (intestinal) from undifferenti-  ated (diffuse) gastric adenocarcinomas. About 10% to 15% of  gastric cancers are familial.*°?*4°   CLINICAL MANIFESTATIONS. The early stages of gastric cancer are  generally asymptomatic or produce vague symptoms such as  loss of appetite (especially for meat), malaise, and unexplained  weight loss. Later manifestations include upper abdominal  pain, vomiting, change in bowel habits, and anemia caused by  persistent occult bleeding. The prognosis is poor because symp-  toms usually do not occur until the tumor has penetrated the  muscle layers of the stomach, spread to surrounding tissues,  and entered the draining lymph nodes and veins, causing dis-  tant metastases. Generally the first manifestations of carcinoma  are caused by distant metastases.   EVALUATION AND TREATMENT. The choice of diagnostic tests  depends on the clinical manifestations at the time of presen-  tation. Most symptoms suggest a problem in the upper gas-  trointestinal tract. Direct endoscopic visualization and biopsy  usually establish the diagnosis, or microscopic examination of  exfoliated cells obtained by lavage during endoscopy.   Surgery is the treatment for gastric cancer. Staging is deter-  mined by pathologic findings after resection. Chemotherapy  combined with chemoradiotherapy may provide the best    FIGURE 41-27 Typical Sites of Stomach Cancer. (From del Regato JA,  Spjut HJ, Cox JD: Cancer: diagnosis, treatment, and prognosis, ed 2, St Louis,  1985, Mosby.)    postoperative outcomes. Five-year survival is less than 20%.  Screening and eradication of H. pylori infection is the best  preventive approach to gastric cancer and remission of gastric  MALT lymphoma.*"! Dietary modifications include high intake  of fruits and vegetables, vitamin C, carotenoids, and fiber and  reduced intake of salt, salted food, and red meat.**”    Small intestine carcinoma is rare and represents less than  3% of gastrointestinal cancers (8810 estimated new cases and  1170 deaths in 2013).°?4 Adenocarcinoma is the most common  tumor type followed by carcinoid (neuroendocrine) tumors.**  Carcinoma occurs more frequently in familial adenomatous  polyposis and Crohn disease.*4* Long-term management  includes frequent screening and endoscopic surveillance.*°    Cancer of the lower intestinal tract (colon [78%], rectum  [28%]) is the third most common cause of cancer death in the  United States for men and women. Colon and rectal cancer  (CRC) accounted for an estimated 102,480 colon and 40,340  rectal new cancer cases, and 50,830 deaths (colon and rectal  combined) in 2013. The median age at diagnosis was 69 years  in 2009. It is more common in blacks*** worldwide, and the  prevalence of colorectal cancer is highest in populations with  high socioeconomic standards.*4°**” CRC develops in individ-  uals with an acquired or inherited genetic predisposition who  are exposed to a combination of environmental risk factors  (Box 41-7).   Family history of colorectal cancer  Familial adenomatous polyposis  Inflammatory bowel disease  Smoking or chewing tobacco  Obesity   Diets high in cereal grains, vegetables, milk; fish; folic acid, calcium, and  vitamin D; magnesium and selenium    Data from Aune D et al: Ann Oncol 23(1):37-45, 2012; Aune D et al:  BMJ 343:d6617, 2011; Avivi D et al: Exp Opin Ther Targets 16(Suppl 1):  $51-S62, 2012; Bardou M et al: Gut 62(6):933-947, 2013; Kennedy  DA et al: Cancer Epidemiol! 35(1):2-10, 2011; Méplan C, Hesketh   J: Mutagenesis 27(2):177-186, 2012; Meyerhardt JA: Semin Oncol  38(4):533-541, 2011; Schror K: Best Pract Res Clin Gastroenterol  25(4-5):473-484, 2011; Wu S et al: Am J Med 125(6):551-559, 2012;  Yuhara H et al: Am J Gastroentero! 106(11):1911-1921, 2011; Zhang X,  Giovannucci E: Best Pract Res Clin Gastroenterol 25(4-5):485-494, 2011.    PATHOGENESIS. Genetic and environmental factors (epi- may be inherited or acquired after birth (somatic mutations).  genetics, see Chapter 6)*** are associated with the development — Family history of CRC occurs in about 25% of cases but only  of CRC (Figure 41-28). CRC can develop through molecular 5% to 6% of these are related to highly penetrating gene muta-  pathways, gene mutations, and genomic instability (the cell tions, mostly autosomal dominant (e.g., familial adenomatous  cycle loses control of the gene mutation rate). Gene mutations _ polyposis [FAP] and hereditary nonpolyposis colorectal cancer    Microsatellite instability pathway (MSI) —15% right colon  HNPCC (Lynch Syndrome) 70% — 80% risk  Sporadoc CRC 10% — 15% risk    FIGURE 41-28 Multistage Development of Colonic Cancer. Colorectal carcinoma develops from the sequential pro-  gression of genetic abnormalities in different pathways. These pathways overlap in many tumors. 1, Most CRC arises in the  CIN pathway with imbalances in chromosomal numbers (aneuploidy) and loss of heterozygosity. Abnormalities in oncogenes  and tumor-suppressor genes activate the pathways for CRC initiation and progression. Mutations in the APC gene are the  earliest known event and inactivation of APC accelerates cell cycle progression. K-ras overexpression leads to loss of p53  and transforms an adenoma into a metastatic carcinoma. p53 loss occurs in =75% of colorectal carcinomas, but occurs infre-  quently in benign lesions. Growth factors COX-2 and EGFR promote tumor growth and angiogenesis in response to inflamma-  tory cytokines and proto-oncogenes. 2, The microsatellite instability (MS/) pathway involves the epigenetic mutation of DNA  mismatch repair genes (MMA) that encode key molecules that repair DNA, resulting in replication errors and deactivation of  proteins from other downstream mutations (7GFB, IGFZR, BAX). 3, The epigenetic pathway, CpG island methylator phenotype  (CIMP), involves early hypermethylation of DNA with gene silencing of MMAR genes that then transform into the MSI pathway.  ACF, Aberrant crypt foci; APC, APC gene (a tumor-suppressor gene); BAX, Bcl-2-associated X protein (apoptosis-related pro-  tein); C/N, chromosomal instability; COX-2, cyclooxygenase-2; CpG, cytosine-phosphodiester bond-guanine DNA region; CRC,  colorectal cancer; DCC, deleted in colorectal cancer (located at chromosome 18q); EGFR, epidermal growth factor receptor;  FAP familial adenomatous polyposis; HNPCC, hereditary nonpolyposis colorectal cancer; /GFZA, insulin growth factor type II  receptor; K-ras, a proto-oncogene (promotes cell growth); LOH, loss of heterozygosity; MLH1, MSH2, MSH6, deoxyribonucleic  acid (DNA) mismatch repair genes; MMR, mutation mismatch repair; MSI, microsatellite instability; 953, protein 53 or tumor  protein 53 (a tumor-suppressor protein); SMAD4, a tumor-suppressor gene; 7GFG, transforming growth factor-beta.    [HNPCC or Lynch syndrome]). The remainder of inherited  CRCs are related to less penetrant genes, and environmental  interactions increase risk.*4? About 75% of CRC is sporadic  (nonhereditary or acquired) and the environment contributes  to multiple somatic mutations.   Most CRCs arise from epithelial tissue in the form of adeno-  matous polyps. Progression from polyps to colon cancer (adeno-  carcinoma) involves a multistep cascade of genetic mutations.  The gene mutations include: (1) activation of proto-oncogenes  (promote cell growth; e.g., K-ras [retrovirus-associated DNA  sequence] and BRAF); (2) loss of tumor-suppressor gene activity  (inhibit cell growth [e.g., APC, TP53, TFTB and SMAD4, DCC));  and (3) abnormalities in DNA mismatch repair (MMR) genes  (fix errors in DNA replication and recombination, e.g., TGF,  EGFR, hMSH1, hMSH2, hMSH6).   Three molecular subtypes of genomic instability have been  recognized and they can overlap in tumor development**?°>?  (see Figure 41-28). Chromosomal instability (CIN or the sup-  pressor pathway or adenoma-carcinoma sequence) includes  the autosomal dominant inherited syndrome known as familial  adenomatous polyposis (FAP) coli. Tumors associated with CIN  are primarily located on the left side in the distal colon (50%  to 85% of tumors). Microsatellite instability (MSI) is associated  with epigenetic methylation of DNA MMR genes. These tumors  are located in the right colon proximal to the splenic flexure and  are associated with autosomal dominant hereditary polyposis  colorectal cancer (HNPCC) or sporadic epigenetic alterations  in 15% to 20% of CRCs. CpG (cytosine-phosphate-guanine)  island methylator phenotype (CIMP) involves epigenetic DNA  methylation of promoter CpG islands silencing genes involved  in tumor suppression, cell cycle control, DNA repair, apoptosis,  and invasion. It is found in 35% to 40% of CRCs and serrated  adenomas are associated with this pathway. Cyclooxygenase-2  (COX-2) is variably expressed in right-sided and left-sided  colorectal cancer, but the mechanism of expression is not clear.  COX-2 may participate in regulation of apoptosis, angiogen-  esis, and invasiveness of adenomatous polyposis coli*** (see  Figure 41-28). Understanding the molecular events associated  with CRC is allowing more targeted detection, diagnosis, and  prognosis prediction, and more specific and personalized treat-  ment approaches.°>49°   Most CRC develops from adenomatous polyps (Figure 41-29).  A polyp is a mass or fingerlike projection arising from the intes-  tinal mucosal epithelium. Most polyps are benign. Grossly,  they are described as pedunculated (with a stalk) or sessile  (flat, without a stalk). Histologically, they are classified as tubu-  lar with branched tubular glands (the most prevalent), villous  with fingerlike projections of the epithelium (more related to  CRC), or tubulovillous adenomas. Sessile serrated polyps have  a serrated crypt and include hyperplastic polyps. They gener-  ally lack atypia but when they are large (greater than 1 cm),  numerous (more than 20), and located in the right colon they  are associated with cancer (Figure 41-30). The adenomatous  polyp forms in an area of epithelial cell hyperproliferation and  crypt dysplasia. Once the adenoma traverses the muscularis  mucosae, it becomes invasive and highly malignant. Adeno-  mas can be detected early, however, and the submucosa may    FIGURE 41-29 Development of Cancer of the Colon from Adenomatous  Polyps. A, The tumor becomes invasive if it penetrates the muscularis mucosae  and enters the submucosal layer. B, Endoscopic image of pedunculated polyp in  descending colon. (A from del Regato JA, Spjut HJ, Cox JD: Cancer: diagnosis,  treatment, and prognosis, ed 2, St Louis, 1985, Mosby. B courtesy David Bjorkman,  MD, Department of Gastroenterology, University of Utah School of Medicine, Salt  Lake City, UT.)    not be penetrated for several years. The larger the polyp and  the greater the degree of dysplasia, the greater the risk of CRC.  Thus, screening colonoscopy with polypectomy is important  when polyps are found. Table 41-9 gives other conditions com-  monly confused with colorectal cancer.    as mass,  cnange In . Descending  bowel habits, colon. 5%,  calli Pain, change in  bowel habits,  Rectum 10% bright red  Blood in stool, blood in stool,  change in bowel habits, obstruction  A scar pea Se    FIGURE 41-30 Signs and Symptoms of Colorectal Cancer by Location  of Primary Lesion. A, Clinical manifestations are listed in order of frequency for  each region (lymphatics of colon also shown). B, Tubular adenomas (A)are rounded  lesions 0.5 to 2 cm in size that are generally red and sit on a stalk (S) of normal  mucosa that has been dragged up by traction of the polyp in the bowel lumen.  C, Villous adenomas are frondlike lesions about 0.6 cm thick that occupy a broad  area of mucosa generally 1 to 5 cm in diameter. (B and C from Stevens A, Lowe JS,  Scott |: Core pathology, ed 3, London, 2009, Mosby.)    Most colorectal cancers are moderately differentiated adeno-  carcinomas. These tumors have a long preinvasive phase, and  when they invade they tend to grow slowly (10 to 15 years).  Because the lymphatic channels are located underneath the  muscularis mucosae, the lesions must traverse this layer before  metastasis can occur. Systemic lymphatic spread occurs along  the aorta to the mesenteric and pancreatic lymph nodes. Liver  metastasis follows invasion of the mesenteric veins (left colon)  or superior veins (right colon), which drain into the portal  circulation.   Rectal carcinomas are defined as tumors occurring up to  15 cm from the anal opening. Tumors of the rectum can spread    through the rectal wall to nearby structures: the prostate in men  and the vagina in women. Penetration occurs more readily in  the lower third of the rectum because it has no serosal covering.  Systemic and pulmonary metastases occur through the hemor-  rhoidal plexus, which drains into the vena cava.   CLINICAL MANIFESTATIONS. Symptoms of colorectal cancer  depend on the location, size, shape, and metastasis of the lesion.  Tumors of the right (ascending) and left (descending) colon  evolve into two distinct types. On the right side the lesions are  polypoid and extend along one wall of the cecum and ascend-  ing colon. These tumors may be silent, evolving to pain, with a  palpable mass in the lower right quadrant, anemia, fatigue, and  dark red or mahogany-colored blood mixed with the stool (see  Figure 41-30). These tumors can become large and bulky with  necrosis and ulceration, contributing to persistent blood loss  and anemia. Obstruction is unusual because the growth does  not encircle the colon.   Tumors of the left, or descending, colon are small, elevated,  button-like masses. This type grows circumferentially, encircling  the entire bowel wall, and eventually ulcerating in the middle as  the tumor penetrates the blood supply. Obstruction is common  but occurs slowly and stools become narrow and pencil shaped.  Manifestations include progressive abdominal distention, pain,  vomiting, constipation, need for laxatives, cramps, and bright  blood on the surface of the stool. In 8% to 29% of cases, bowel  obstruction is the primary symptom at diagnosis.*°° Other  symptoms can develop related to distant organ metastasis.   EVALUATION AND TREATMENT. Individuals with hereditary pol-  yposis or a strong family history of CRC should begin screening  at an early age (10 to 12 years) using colonoscopy and biopsy  with a consideration of prophylactic surgery.°°” Fecal immu-  nochemical testing (FIT) may be more accurate than stool  occult blood testing.°°**°’ Screening for nonhereditary CRC  in asymptomatic individuals older than age 50 years includes  fecal occult blood and immunochemical tests, stool DNA and  sigmoidoscopy, colonoscopy, virtual colonoscopy, or double-  contrast barium enema.°*°*°!   The staging of colorectal cancer involves preoperative test-  ing and operative exploration. Preoperative testing begins with  physical examination of the abdomen to detect liver enlarge-  ment and ascites and palpation of appropriate lymph nodes.  Elevations in the level of carcinoembryonic antigen (CEA) are  often detected in the sera of individuals with colorectal carci-  noma. The amount of CEA in the serum is a function of the  stage of the disease and the type of tumor. Operative staging  consists of careful exploration during surgery and biopsy of pos-  sible metastases. The National Cancer Institute*® classification  is widely used for staging of colorectal cancer and is as follows:   Stage I: extension of cancer to the middle layers of the colon   wall, no spread to lymph nodes; stage I colon cancer is  sometimes called Dukes’ A colon cancer   around the colon or rectum, and/or through the perito-  neum; stage II colon cancer is sometimes called Dukes’ B  colon cancer    Left-sided pain similar to that of appendicitis; tender lower left quadrant; associated findings: nausea, vomiting,    fever, obstruction, anorexia, and leukocytosis; mucosa is intact, and perforation, peritonitis, and abscesses occur  more often than in cancer; ultrasound, CT scan, MRI, and proctosigmoidoscopy are used to distinguish from cancer    Younger people with chronic attacks of bloody diarrhea, crampy abdominal pain, fever, malnutrition, and dehydration;    usually involves the left colon and rectum; endoscopy, barium enema, and biopsy performed for definitive diagnosis  Generally involves the right colon; chronic diarrhea with abdominal cramps, fever, weight loss, and often a palpable  abdominal mass; difficult at times to distinguish Crohn disease from ulcerative colitis; endoscopic examination and  CT scan used to distinguish from cancer  Vague abdominal symptoms, often with a tender or nontender mass in the lower right quadrant; associated  symptoms: mild fever and leukocytosis; CT scan used to distinguish cancer of the cecum from appendiceal abscess  Examination shows a tender, swollen, bluish painful mass in the anus; individual has a history of hemorrhoids    Stage III: spread beyond the colon into lymph nodes and  nearby organs and/or through the peritoneum; stage III  colon cancer is sometimes called Dukes’ C colon cancer   Stage IV: spread to nearby lymph nodes and has spread to  other parts of the body, such as the liver or lungs; stage IV  colon cancer is sometimes called Dukes’ D colon cancer   Treatment for cancer of the colon is always surgical. The  location and amount of colon resected depend on the site of  the cancer. Resection and anastomosis can be performed for  early stage tumors and is usually curative. These surgeries are  performed using laparoscopic techniques or through abdomi-  nal incisions, and natural defecation is preserved. Growths in  the lower portion of the rectum require removal of the entire  rectum with formation of a permanent colostomy. Prognosis  after surgery depends on the stage and location of the tumor.  TNM classifications are available from the National Cancer  Institute.°™   Radiation therapy is often given before surgery in the hope  that it will shrink the tumor, alter the malignant cells, or both so  that these cells will not survive after surgery. Adjuvant chemo-  radiotherapy is used to treat metastatic disease and cases with a  high risk of recurrence. Monoclonal antibody therapy may be  added.*°*°°° Vaccines for colon cancer are in clinical trials.°°7°°°  Treatment of rectal cancer includes preoperative chemoradio-  therapy, total mesorectal excision surgery, and adjuvant che-  motherapy with fluorouracil.°°”   Anal carcinoma is rare (estimated 7060 cases and 880 deaths  in 2013).°*4 The most common tumor type is squamous cell  carcinoma, about 80%; other anal cancers are adenocarcinoma,  lymphoma, or sarcoma. The most common risk factor is infec-  tion with human papillomavirus (93%) and less commonly  anal involvement in Crohn disease.*”° Squamous cell anal carci-  noma is more common among the human immunodeficiency  virus-infected population.*”!   Hepatocellular carcinoma represented about 2% of new can-  cers (30,640) and 3.6% of cancer deaths (21,670) in 2013. The  overall 5-year survival rate is 14%.°*+ Blacks and Hispanics are  almost twice as likely to develop these cancers as whites.*”?  In the United States, the incidence of primary hepatocellular    carcinoma is increasing as a result of chronic hepatitis C infec-  tion. Liver cancer is common in densely populated parts of  Southeast Asia and sub-Saharan Africa where hepatitis B virus  infection is endemic.*~* Primary liver cancer is rare before the  age of 40 years and most common during the sixth decade.  Cancer in the liver is usually caused by metastatic spread from  a primary site elsewhere in the body.   1. Infection with HBV, HCV, and HDV, particularly in con-  junction with cirrhosis, acts either as a carcinogen or as a  co-carcinogen in chronically infected hepatocytes*””   2. Chronic alcoholic liver disease and nonalcoholic liver dis-  ease that results in cirrhosis   3. Exposure to mycotoxins; the most significant mycotoxins  are the aflatoxins, particularly those produced by Asper-  gillus flavus, a mold found on spoiled corn, peanuts, and  grain; aflatoxins cause mutation of the TP53 suppressor  gene and activation of WNT signal transduction pathway   cellular or cholangiocellular. Hepatocellular carcinoma devel-  ops in the hepatocytes, whereas cholangiocellular carcinoma  (cholangiocarcinoma) develops in the bile ducts. Hepatocel-  lular carcinoma (hepatocarcinoma) (HCC) can be nodular  (consisting of multiple, discrete nodules), massive (consist-  ing of a large tumor mass having satellite nodules), or diffuse  (consisting of very small nodules distributed throughout most  of the liver). HCC is the type of primary liver cancer that is  closely associated with cirrhosis (Figure 41-31). Chronic hepa-  titis B and hepatitis C and cirrhosis give rise to HCC repeti-  tive cellular proliferation that occurs in the inflamed liver in  response to growth factor and cytokine stimulation and oxida-  tive stress-induced DNA damage. Numerous genetic and epi-  genetic alterations, including activation of oncogenes, failure  of tumor-suppressor genes, and signaling pathways, combine  to promote carcinogenesis.*”° Because carcinoma of the liver  invades the hepatic and portal veins, it often spreads to the  heart and lungs. Other sites of metastases are the brain, kidney,  and spleen.    FIGURE 41-31 Hepatocellular Carcinoma. Macroscopically, hepatocellular  carcinomas may be single or multifocal. They usually develop in a liver already  affected by cirrhosis. Tumor appears as an abnormal mass (M) within the liver.  (From Stevens A, Lowe JS, Scott |: Core pathology, ed 3, London, 2009, Mosby.)    Cholangiocellular carcinomas (cholangiocarcinoma) occur  less often than hepatocellular carcinomas in the United States  and represent about 10% to 25% of hepatobiliary malignan-  cies. The disease predominates in men. Incidence demonstrates  geographic variation and is common in Southeast Asia where  liver fluke infestation is prevalent. The mechanism by which  fluke infestation causes cholangiocellular carcinoma is multi-  factorial and includes parasite secretions, immunopathology,  and mechanical damage. Other risk factors include primary  sclerosing cholangitis, hepatolithiasis, and choledochal cysts.*””  Intrahepatic cholangiocellular carcinoma also is associated with  cirrhosis, HBV and HCV infection, obesity, and diabetes. How-  ever, most individuals diagnosed with cholangiocellular carci-  noma do not have an identifiable risk factor except age.°°°*!  Cholangiocellular carcinoma can occur anywhere along the bile  duct, both within and outside the liver, and usually is a solitary  lesion. It is difficult to distinguish an invasion of cholangiocel-  lular carcinoma from a metastatic adenocarcinoma except by  neoplastic changes found in nearby ducts.   CLINICAL MANIFESTATIONS. The clinical presentation of liver  cancer in adults is characterized by vague abdominal symptoms,  such as nausea and vomiting, fullness, pressure, dull ache in the  right hypochondrium, and weight loss. Manifestations of hepa-  tocellular carcinoma can occur slowly or abruptly. In individuals  with cirrhosis, deepening jaundice or abrupt lack of appetite is  a sign of hepatocellular carcinoma. Obstruction by the tumor  can cause sudden worsening of portal hypertension and devel-  opment of ascites. As the tumor enlarges, it causes pain. Chol-  angiocellular carcinoma more commonly presents insidiously as  pain, loss of appetite, weight loss, and gradual onset of jaundice.  Some carcinomas of the liver rupture spontaneously, causing  hemorrhage. Others are discovered accidentally during evalua-  tion of a bone fracture or surgical exploration.   EVALUATION AND TREATMENT. There is no specific test for the  diagnosis of liver cancer. For HCC high-risk individuals, alpha  fetoprotein and abdominal ultrasound are common screening  tools and can be used for screening in individuals with cirrho-  sis.°°? Additional serum markers are being evaluated.**’ The  diagnosis is based on additional laboratory findings, radiologic  examination, biopsy findings, and exploratory laparotomy.    Serum levels of alkaline phosphatase, aspartate aminotransfer-  ase (AST), and alanine aminotransferase (ALT) are commonly  elevated in individuals with HCC.   Staging of HCC is important to guiding treatment but does  not accurately predict postoperative outcome. Surgical resection  is possible with solitary tumors and the absence of portal hyper-  tension.*** Radiofrequency (thermal) ablation has emerged as  the most effective method for local tumor destruction. Tyrosine  kinase inhibitors (e.g., sorafenib) and monoclonal antibodies  are improving survival; many new therapies are in clinical tri-  als.**° Transarterial embolization and radiation is used for man-  agement of pain and to reduce tumor size.*** Surgical resection  or liver transplantation is the only alternative for cure; however,  very early stage HCC is difficult to diagnose.**” Primary preven-  tion of HCC is vaccination against HBV and antiviral therapy  for HCV.°*°   Cholangiocarcinoma causes duct obstruction, and radiother-  apy, chemotherapy, photodynamic therapy, and stenting can  temporarily relieve the blockage for unresectable disease.°*” >”?    Cancer of the gallbladder and biliary tract is a rare but lethal  disease. An estimated 10,310 new cases and 3230 deaths were  recorded in 2013.°*4 It rarely occurs before age 40 and is most  common between the ages of 50 and 60 years. Risk factors  include gallstones, advancing age, female gender (2:1), anoma-  lous pancreaticobiliary ductal junction, and obesity. Native  populations in North and South America have greater risk of  gallbladder cancer, and it is more common in Chile, Poland,  India, Japan, and Israel.*’!°°* Most cancerous tumors in the  gallbladder are caused by metastasis.   PATHOGENESIS. Most primary cancers of the gallbladder are  adenocarcinomas and, less commonly, squamous cell carcino-  mas. The mechanisms of tumorigenesis are not clear. Multiple  genes and oncogenes are involved in the initiation and progres-  sion of gallbladder cancer. Research is in progress to target these  genes for diagnosis and treatment.*”? Infiltrative tumors are  associated with gallstones, and invasion of the liver and lymph  nodes occurs early. Spreading extends to the pancreas and ret-  roperitoneal lymph nodes. Direct invasion of the stomach and  the duodenum can cause pyloric obstruction. Infection often  accompanies cancer of the gallbladder. Generalized peritonitis,  gangrene, perforation, and liver abscesses are potential compli-  cations of infection.   CLINICAL MANIFESTATIONS. Early stages of gallbladder carci-  noma are asymptomatic. A typical presentation is steady upper  right quadrant pain for about 2 months. Other symptoms  mimic benign gallbladder disease, including diarrhea, belching,  weakness, loss of appetite, weight loss, and vomiting. Obstruc-  tive jaundice can occur if an enlarging tumor presses on the  extrahepatic ducts.   EVALUATION AND TREATMENT. Early diagnosis of gallbladder  cancer is rare and the disease is often found incidentally when  removing gallstones or when an individual presents with an  advanced stage of disease.*”° Individuals with gallstones, espe-  cially older women, are evaluated carefully. Inflammatory  disorders, such as cholangitis (bile duct inflammation) and    peritonitis, often obscure an underlying malignancy. The most  specific diagnostic procedures include ultrasonography, CT,  and MRI.   Complete surgical resection of the gallbladder is the only  effective treatment. Because advanced malignancies cannot be  resected, gallbladders containing stones are removed as a pre-  ventive measure. Palliative chemotherapy or chemoradiation  provides symptom improvement but does not improve sur-  vival.°*’ The prognosis of gallbladder cancer is extremely poor;  most individuals die within 1 to 2 years after surgery.°?°°”?    Pancreatic cancer represents about 2.6% of all new cancers.  There are 45,220 new cases and 38,460 deaths estimated for  2013.°*4 The incidence of pancreatic cancer rises steadily with  age. Men are affected slightly more often than women and  blacks more often than whites.*** Mortality is about 95% within  12 months. Risk factors include cigarette smoking, heavy alco-  hol use, family history of pancreatic cancer, and non-O blood  group.*°° Chronic pancreatitis is associated with about 4% to  5% of pancreatic cancers.40!40   PATHOGENESIS. Cancer of the pancreas can arise from exocrine  or endocrine cells. Most pancreatic tumors arise from exocrine  cells in the ducts and are called ductal adenocarcinomas. Tumors  arising in small ducts invade nearby glandular tissue, penetrate the  covering of the pancreas, and extend into surrounding tissues.*°°  Pancreatic cancer is a disease of inherited and acquired mutations  in cancer-related genes associated with chronic inflammation.‘°**  A K-ras mutation is the most common genetic alteration; tumor-  suppressor gene alterations are also found, including TP53,  CDKN2A, SMAD4, BRCA2, and PALB2.*°* Growth factors are  overexpressed in ductal cancer.40°40°   Ductal adenocarcinomas are the most common tumor and  can occur in the head, body, or tail of the pancreas. Tumors of  the head quickly spread to obstruct the common bile duct and  portal vein (Figure 41-32). These tumors can then infiltrate the  superior mesenteric artery, the vena cava, and the aorta. Cancer  cells that enter the blood vessels can form emboli. Tumors of  the body and tail infiltrate the posterior abdominal wall. Lym-  phatic invasion occurs early and rapidly and involves local and  regional lymph nodes. Venous invasion causes metastases to the  liver. Tumor implants on the peritoneal surface can obstruct  veins and promote development of ascites.   Ductal adenocarcinomas arising in the head of the pancreas  cause biliary obstruction somewhat early in the disease. Indi-  viduals with such tumors survive slightly longer than those with  cancer of the body and tail, presumably because they seek medi-  cal attention earlier.   Tumors of the endocrine pancreas are rare neoplasms of the  islets of Langerhans known as apudomas. The first four letters  in apudoma derive from amine precursor uptake and decarbox-  ylation. The apudomas are so named because they contain neu-  rosecretory granules. Endocrine neoplasms secrete abnormal  amounts of hormones, such as insulin.    FIGURE 41-32 Pancreatic Carcinoma. Tumors appear as gritty, gray, hard nod-  ules (7) irregularly invading the adjacent gland and local structures. (From Stevens A,  Lowe JS, Scott |: Core pathology, ed 3, London, 2009, Mosby.)    CLINICAL MANIFESTATIONS. Cancer of the body and tail of the  pancreas is generally asymptomatic until there is intraductal  obstruction or the tumor invades adjacent tissue. Often vague,  abdominal or mid-back pain is an initial symptom.*°” Jaun-  dice develops in most cases, usually caused by obstruction of  the bile duct. Because obstruction impairs enzyme secretion  and flow to the duodenum, pancreatic cancer causes fat and  protein malabsorption, resulting in weight loss. Some individ-  uals develop diabetes mellitus. Distant metastases are found  in the cervical lymph nodes, the lungs, and the brain. Most  individuals die of hepatic failure, malnutrition, or systemic  complications.   EVALUATION AND TREATMENT. Pancreatic cancer is usually diag-  nosed at an advanced stage and has a poor prognosis. The most  effective screening method for those at risk is endoscopic ultra-  sound because it detects small lesions; the search for biomarkers  is continuing.*°° Autoimmune pancreatitis is a rare, fibroinflam-  matory disorder of the pancreas that mimics and must be differ-  entiated from pancreatic cancer.*°? Contrast CT scans, contrast  MRI, and abdominal and endoscopic ultrasound (EUS) are  used for initial diagnosis. EUS also provides opportunity for  biopsy, or CT-guided fine needle aspiration can confirm diag-  nosis although this is not necessary when cancer suspicion is  high.*!° Laparotomy is used to establish a definitive diagnosis,  evaluate the extent of disease, and determine whether palliative  bypass surgery (i.e., cholecystojejunostomy and gastrojejunos-  tomy) is needed.   Individuals with small tumors and complete resection have  the best possibility of cure (15% to 20% of cases). Pancreati-  coduodenectomy (Whipple procedure) is the most common  procedure and portal or superior mesenteric vein resection  and reconstruction may be performed. Some surgeons rec-  ommend a total pancreatectomy because cancer of the pan-  creas seldom consists of a single lesion.*!'! The dense stromal  structure of the tumor impairs chemotherapeutic drug deliv-  ery, resulting in poor response to chemotherapy.*!” Adjuvant  chemotherapy is used for curative attempts in resected low-  grade tumors. Chemoradiation therapy is used for advanced  disease in some centers. Treatments with molecular targets are  in clinical trials.4!°-4!> Palliative care, including pain manage-  ment and nutrition, are important.*!°    Anorexia (loss of appetite), vomiting, constipation, diar-  rhea, abdominal pain, and evidence of gastrointestinal  bleeding are clinical manifestations of many disorders of  the gastrointestinal tract.    by gastrointestinal contraction and reverse peristalsis of the  esophagus. It is usually preceded by nausea and retching  with the exception of projectile vomiting, which is associated  with direct stimulation of the vomiting center in the brain.    associated with low-residue, low-fluid diet; slow-transit,  related to impaired colonic motor function; and pelvic floor  dyssynergia-anismus. Secondary constipation results from a  neurogenic disease, drugs that decrease intestinal motility,  endocrine or metabolic disorders, or obstruction.    . Diarrhea can be caused by excessive fluid drawn into the    intestinal lumen by osmosis (osmotic diarrhea), excessive  secretion of fluids by the intestinal mucosa (secretory diar-  rhea), or excessive gastrointestinal motility.    ischemia and originates in the peritoneum (parietal pain)  or in the organs themselves (visceral pain). Visceral pain is  often referred to the back.    gastrointestinal tract. Obvious manifestations of gastro-  intestinal bleeding are hematemesis (vomiting of blood),  melena (dark, tarry stools), and hematochezia (frank bleed-  ing from the rectum). Occult bleeding can be detected only  by testing stools or vomitus for the presence of blood.    . Dysphagia is difficulty in swallowing. It can be caused by a    mechanical or functional obstruction of the esophagus. Func-  tional obstruction is an impairment of esophageal motility.    . Achalasia is a form of functional dysphagia caused by loss of    chyme from the stomach into the esophagus, causing  esophagitis from repeated exposure to acids and enzymes  in the regurgitated gastric contents.   Hiatal hernia is the protrusion of the upper part of the  stomach through the hiatus (esophageal opening in the  diaphragm) at the gastroesophageal junction. Hiatal hernia  can be sliding, paraesophageal, or mixed.   Pyloric obstruction is the narrowing or blockage of the pylo-  rus, which is the opening between the stomach and the duo-  denum. It can be caused by a congenital defect, inflammation  and scarring secondary to a gastric ulcer, or tumor growth.  Intestinal obstruction prevents the normal movement of  chyme through the intestinal tract. It is usually mechanical—  that is, caused by torsion, herniation, or tumor. Functional  obstruction is caused by paralytic ileus.   The most severe consequences of intestinal obstruction are  fluid and electrolyte losses, hypovolemia, shock, intestinal  necrosis, and perforation of the intestinal wall.    Gastritis is an acute or a chronic inflammation of the gastric  mucosa.   Regurgitation of bile, use of anti-inflammatory drugs or  alcohol, H. pylori infection, and some systemic diseases are  associated with gastritis.   Chronic fundal gastritis is rare and associated with auto-  antibodies to parietal cells and intrinsic factor, resulting in  gastric atrophy and causing pernicious anemia.   Chronic antral gastritis is the most common and is associ-  ated with H. pylori and NSAIDs.   Alkaline reflux gastritis is stomach inflammation caused by  the reflux of bile and pancreatic secretions from the duode-  num into the stomach. These substances disrupt the muco-  sal barrier and cause inflammation.   A peptic ulcer is a circumscribed area of mucosal inflamma-  tion and ulceration caused by excessive secretion of gastric  acid, disruption of the protective mucosal barrier, or both.  The three types of peptic ulcers are duodenal, gastric, and  stress ulcers and they are usually caused by H. pylori infec-  tion or NSAIDs.   Duodenal ulcers, the most common peptic ulcers, are asso-  ciated with increased numbers of parietal (acid-secreting)  cells in the stomach, elevated gastrin levels, and rapid gas-  tric emptying. Pain occurs when the stomach is empty, and  pain is relieved with food or antacids. Duodenal ulcers tend  to heal spontaneously and recur frequently.   Gastric ulcers develop near parietal cells, generally in the  antrum, and tend to become chronic. Gastric secretions may  be normal or decreased, and pain may occur after eating.  Zollinger-Ellison syndrome is associated with a gastrinoma,  chronic secretion of gastric acid, and gastric and duodenal  ulcers.   Stress ulcer (stress-related mucosal disease) is an acute form of  peptic ulcer associated with severe illness or extensive trauma.  Ischemic stress ulcers develop suddenly after severe illness,  systemic trauma, neural injury, or burns (Curling ulcer).  Ulceration follows mucosal damage caused by ischemia  (decreased blood flow to the gastric mucosa).   Cushing ulcer is a stress ulcer caused by head trauma. Ulcer-  ation follows hypersecretion of hydrochloric acid caused by  overstimulation of the vagal nuclei.   Pancreatic insufficiency causes malabsorption associated  with insufficient amounts of the enzymes that digest pro-  tein, carbohydrates, and fats into components that can be  absorbed by the intestine.   Deficient lactase production in the brush border of the  small intestine inhibits the breakdown of lactose. This pre-  vents lactose absorption and causes osmotic diarrhea.   Bile salt deficiency causes fat malabsorption, including fat-  soluble vitamins, and steatorrhea (fatty stools). Bile salt defi-  ciency can result from inadequate secretion of bile, excessive  bacterial deconjugation of bile, or impaired reabsorption of  bile salts caused by ileal disease.    Dumping syndrome causes malabsorption by the rapid  emptying of hypertonic chyme from the surgically cre-  ated residual stomach into the small intestine. It causes an  osmotic shift of fluid from the vascular compartment to the  intestinal lumen, which decreases plasma volume.  Ulcerative colitis is an inflammatory bowel disease that causes  ulceration, abscess formation, and necrosis of the colonic  and rectal mucosa. Cramping pain, bleeding, frequent diar-  rhea, dehydration, and weight loss accompany severe forms  of the disease. A course of frequent remissions and exacerba-  tions is common.   Crohn disease is similar to ulcerative colitis, but it affects the  large and small intestines, and ulceration tends to involve all  the layers of the lumen. “Skip lesion” fissures and granulomas  are characteristic of Crohn disease. Abdominal tenderness,  nonbloody diarrhea, and weight loss are the usual symptoms.  Diverticula are outpouchings of colonic mucosa through  the muscle layers of the colon wall. Diverticulosis is the  presence of these outpouchings; diverticulitis is inflamma-  tion of the diverticula.   Appendicitis is the most common surgical emergency of the  abdomen. Obstruction of the lumen leads to increased pres-  sure, ischemia, and inflammation of the appendix. Without  surgical resection, inflammation may progress to gangrene,  perforation, and peritonitis.   Vascular insufficiency in the intestine is associated most  often with acute or chronic occlusion or obstruction of the  mesenteric vessels or insufficient mesenteric arterial blood  flow. The resulting ischemia and necrosis produce abdomi-  nal pain, fever, bloody diarrhea, hypovolemia, and shock.  Obesity is defined as a BMI greater than 30 kg/m? and usu-  ally results from energy intake exceeding expenditure.  Single-gene and polygenetic disorders are associated with  obesity, as well as social, cultural, economic, exercise, and  metabolic factors.   Increases in body fat mass are associated with macrophage  infiltration of adipocytes with release of inflammatory  mediators, increased adipocyte lipolysis, increased leptin  (leptin resistance) and RBP4 levels, and decreased adipo-  nectin level. Insulin resistance may develop. Increased lev-  els of ghrelin and endocannabinoids and decreased levels of  PYY and GLP1 are associated with obesity. Alterations in the  expression of these hormones and neurotransmitters affect  appetite and metabolic rate at the level of the hypothalamus.  The eating disorders include anorexia nervosa, bulimia  nervosa, and binge eating disorder. They are psychogenic  disorders that can lead to malnutrition. Anorexia nervosa is  the most serious and can be fatal.   Short-term starvation, or lack of dietary intake for 3 or 4  days, stimulates mobilization of stored glucose by two met-  abolic processes: glycogenolysis (splitting of glycogen into  glucose) and gluconeogenesis (formation of glucose from  noncarbohydrate molecules).   Long-term starvation triggers the breakdown of ketone bod-  ies and fatty acids. Eventually proteolysis (protein break-  down) begins, and death ensues if nutrition is not restored.    Portal hypertension, ascites, hepatic encephalopathy, jaun-  dice, and hepatorenal syndrome are complications of many  liver disorders.    sure to at least 10 mmHg. It is caused by increased resis-  tance to venous flow in the portal vein and its tributaries,  including the sinusoids and hepatic vein.    liver disease because it can cause fatal complications, such  as bleeding varices, ascites, hepatic encephalopathy, and  renal failure.    related to the release of vasodilators that effect pulmonary  arterioles and is associated with portal hypertension and  severe liver disease.    . Ascites is the accumulation and sequestration of fluid in the    peritoneal cavity, often as a result of portal hypertension,  decreased concentrations of plasma proteins, and sodium  retention.    impaired cerebral function caused by blood-borne toxins  (particularly ammonia) not metabolized by the liver.    the skin or sclera of the eyes caused by increases in plasma  bilirubin concentration (hyperbilirubinemia).   Obstructive jaundice is caused by obstructed bile canaliculi  (intrahepatic obstructive jaundice) or obstructed bile ducts  outside the liver (extrahepatic obstructive jaundice). Biliru-  bin accumulates proximal to sites of obstruction, enters the  bloodstream, and is deposited in the skin and other connec-  tive tissues.   Hemolytic jaundice is caused by destruction of red blood  cells at a rate that exceeds the liver’s ability to metabolize  unconjugated bilirubin.   Hepatorenal syndrome is functional renal failure caused  by advanced liver disease, particularly cirrhosis with portal  hypertension. Renal failure is caused by a sudden decrease  in blood flow to the kidneys, usually as a result of massive  gastrointestinal hemorrhage or liver failure. Its chief clinical  manifestation is oliguria.   Autoimmune hepatitis is T cell mediated with hypergam-  maglobulinemia and absence of viral hepatitis.   Viral hepatitis is an infection of the liver caused by  strains of the hepatitis virus: HAV, HBV, HCV, HDV,  and HEV. HAV and HEV are transmitted via the fecal-  oral route. The hepatitis viruses are blood-borne and can  cause hepatic cell necrosis, Kupffer cell hyperplasia, and  infiltration of liver tissue by mononuclear phagocytes.  These changes obstruct bile flow and impair hepatocyte  function.    The clinical manifestations of viral hepatitis depend on  the stage of infection. Fever, malaise, anorexia, and liver  enlargement and tenderness characterize the prodromal  phase (stage 1). Jaundice and hyperbilirubinemia mark the  icteric phase (stage 2). During the recovery phase (stage 3),  symptoms resolve. Recovery takes several weeks.   Chronic active hepatitis can occur with HBV and HCV with  predisposition to cirrhosis and hepatocellular carcinoma.  Fulminant hepatitis is a complication of hepatitis B (with  or without hepatitis D infection) or hepatitis C. It causes  widespread hepatic necrosis and is often fatal.   Cirrhosis is an irreversible inflammatory disease of the liver  that causes disorganization of lobular structure, fibrosis,  and nodular regeneration. Bile obstruction causes jaundice.  Vascular obstruction causes portal hypertension, shunting,  and varices. Cirrhosis can result from hepatitis or expo-  sure to toxins, such as acetaldehyde (a product of alcohol  metabolism). The disease causes progressive irreversible  liver damage, usually over a period of years.   Alcoholic liver disease impairs the hepatocytes’ ability  to oxidize fatty acids, synthesize enzymes and proteins,  degrade hormones, and clear portal blood of ammonia and  toxins. The disease is progressive and includes steatosis, ste-  atohepatitis, and alcoholic cirrhosis.   Nonalcoholic fatty liver disease is fat infiltration of hepato-  cytes associated with obesity.   Primary biliary cirrhosis is an autoimmune disease with  inflammatory destruction of intrahepatic bile ducts. Mito-  chondrial autoantibodies are found in this disease.  Secondary biliary cirrhosis develops from prolonged  obstruction of bile flow (e.g., gallstones) with increased  pressure in the hepatic bile ducts that causes pooling of  bile and necrosis of tissue. Relief of obstruction alleviates  symptoms of jaundice and pruritus. Continued obstruction  causes cirrhosis and liver failure.   Primary sclerosing cholangitis is a fibrotic disease of  medium and large sized bile ducts outside the liver.  Cholelithiasis (the formation of gallstones) is a result of  bile aggregation of cholesterol crystals (cholesterol stones)  or precipitates of unconjugated bilirubin (pigmented  stones). Gallstones that fill the gallbladder or obstruct the  cystic, or common, bile duct cause abdominal pain and  jaundice.   Cholecystitis is an inflammation of the gallbladder. It is  usually associated with obstruction of the cystic duct by  gallstones.   Acute pancreatitis (pancreatic inflammation) is a serious  but relatively rare disorder associated with biliary obstruc-  tion and alcoholism. Injury permits leakage of digestive  enzymes into pancreatic tissue, where they become acti-  vated and begin the process of autodigestion, inflammation,  and destruction of tissues. Release of pancreatic enzymes  into the bloodstream or abdominal cavity causes damage to  other organs.   Chronic pancreatitis results from structural or functional  impairment of the pancreas usually related to alcoholism or    recurrent acute pancreatitis. It causes recurrent abdominal  pain and digestive disorders.    Cancer of the esophagus is rare and tends to occur in people  older than 60 years. Alcohol and tobacco use, reflux esoph-  agitis, radiation exposure, and nutritional deficiencies are  associated with esophageal carcinoma.    esophageal cancer. Early treatment of tumors that have not  spread into the mediastinum or lymph nodes results in a  good prognosis.    . Approximately 50% of all gastric cancers are located in the    prepyloric antrum. Clinical manifestations (weight loss,  upper abdominal pain, vomiting, hematemesis, anemia)  develop only after the tumor has penetrated the wall of the  stomach.    the second most common type of cancer death in the  United States. Small intestinal cancers are rare. Famil-  ial adenomatous polyposis coli is an inherited form of  colon cancer. Preexisting large and numerous polyps are  highly associated with sporadic adenocarcinoma of the  colon.    and bulky; tumors of the left (descending, sigmoid) colon  develop as small button-like masses. Manifestations of  colon tumors include pain, bloody stools, and change in  bowel habits.    . Rectal carcinoma is located up to 15 cm from the opening    of the anus. The tumor spreads transmurally to the vagina  in women or to the prostate in men.    . Metastatic invasion of the liver is more common than pri-    ease (cirrhosis and hepatitides B and C). Hepatocellular  carcinomas arise from the hepatocytes, whereas cholangio-  cellular carcinomas arise from the bile ducts. Primary liver  cancer spreads to the heart, lungs, brain, kidney, and spleen  through the circulation.   Cancer of the gallbladder is relatively rare and tends to  occur in women older than 50 years. Adenocarcinoma is  most common. Because clinical manifestations occur late  in the disease, metastases to lymph channels have usu-  ally occurred by the time of diagnosis, and the prognosis  is poor.   Cancer of the pancreas ranks fifth as a cause of cancer  deaths. The one known risk factor is heavy cigarette smok-  ing. Most tumors are adenocarcinomas that arise in the  exocrine cells of ducts in the head, body, or tail of the pan-  creas. 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Highlights from the    As part of your Pageburst Digital Book, you can access the following Integrated Resources:  Animations    Disorders of the Gastrointestinal Tract, 1486  Congenital Impairment of Motility, 1486  Esophageal Malformations, 1487  Acquired Impairment of Motility, 1492  Impairment of Digestion, Absorption, and Nutrition, 1494  Diarrhea, 1499    Disorders of the gastrointestinal tract, liver, and pancreas in  children include congenital anomalies with structural and func-  tional alterations, enzyme deficiencies, and infections. These  disorders lead to impairment of motility, digestion, nutrition,  and normal growth and development.   Cleft lip (harelip) and cleft palate (CLP) are developmental  anomalies of the first branchial arch (Figure 42-1). The inci-  dence of CLP is estimated at 1 in 1000 live births in the United  States.! Incidence is lower in black populations and higher in  Asian populations.” Cleft lip, with or without cleft palate, is  more common in males and isolated cleft palate is more com-  mon in females. Both anomalies can be unilateral or bilateral,  partial or complete and may also be associated with other mal-  formations. Nonsyndromic (isolated) CLP is a malformation  with an incomplete separation between nasal and oral cavities    Disorders of the Liver, 1500  Disorders of Biliary Metabolism and Transport, 1500  Inflammatory Disorders, 1502  Portal Hypertension, 1502  Metabolic Disorders, 1503    without any associated anomaly. Syndromic CLP is associated  with other malformations (e.g., Crouzon syndrome [craniofa-  cial dysostosis], Treacher Collins syndrome [mandibulofacial  dysostosis], hemifacial microsomia).°   In most cases, cleft lip and cleft palate are caused by multi-  ple gene-environmental interactions, including maternal defi-  ciency of B vitamins (Bg, folic acid, and B,7), maternal smoking  and alcohol use, maternal hyperhomocysteinemia, and mater-  nal diabetes mellitus as well as genetic variations of interferon  regulatory factor-6, fibroblast growth factor, tumor growth  factor-alpha, and other growth factors.‘ (This phenomenon,  called multifactorial inheritance, is discussed in Chapter 4.)  Together these factors reduce the amount of neural crest mes-  enchyme that migrates into the area that will develop into the  face of the embryo.°   PATHOPHYSIOLOGY. Cleft lip (harelip) is caused by the incom-  plete fusion of the nasomedial and intermaxillary processes  beginning during the fourth week of embryonic development,°  a period of rapid fetal growth. The cleft causes structures of  the face and mouth to develop without the normal restraints  of encircling lip muscles. The facial cleft may affect not only    FIGURE 42-1 Variations in Clefts of the Lip and Palate. A, Notch in vermil-  ion border. B, Unilateral cleft lip and palate. C, Bilateral cleft lip and cleft palate.  D, Cleft palate.    the lip but also the external nose, the nasal cartilages, the nasal  septum, and the alveolar processes (bony ridge of maxilla that  contains the tooth sockets).   The cleft is usually just beneath the center of one nostril. The  defect may occur bilaterally and may be symmetric or asym-  metric. The cleft can range in severity from a slight indentation  of the lip to a fissure that extends to the nostril, causing a sag-  ging and flattening of the nose. The failure of lip fusion by 35  days of gestation may impair closure of the palatal shelves. The  more complete the cleft lip, the greater the chance that teeth in  the line of the cleft will be missing or malformed.   Cleft palate is often associated with cleft lip but may occur  without it. Cleft palate results from the failure of the primary  palatal shelves, or processes, to fuse during the third month of  gestation. The fissure may affect only the uvula and soft palate,  or it may extend forward to the nostril and involve the hard  palate and the maxillary alveolar ridge. It may be unilateral or    bilateral, with the cleft occupying the midline posteriorly and  as far forward as the alveolar process, where it deviates to the  involved side. Clefts involving the palate only are usually but  not necessarily in the midline. In some cases the vomer and  nasal septum are partly or completely undeveloped. When these  facial bones are involved, the nasal cavity may freely communi-  cate with the oral cavity. Teeth in the cleft palate area may be  missing or deformed.’   CLINICAL MANIFESTATIONS. Feeding the infant with cleft lip usu-  ally presents no difficulty if the cleft lip is simple and the palate  intact. Nursing at breast or bottle depends on suction developed  by pressing the nipple against the hard palate with the tongue.  Closure of the lips is not necessary, but the tongue must work  harder if the lips cannot be pursed. A baby with cleft palate  usually requires large, soft nipples with cross-cut openings and  better tolerates feeding when in an upright position to prevent  milk escaping through the nose. Although most infants with  cleft palate can be successfully breast-fed, it may be impossible  for some because of an unproductive suck and difficulty swal-  lowing.® An orthodontic prosthesis for the roof of the mouth  may facilitate sucking for some infants.’   EVALUATION AND TREATMENT. Prenatal diagnosis is made  by ultrasound; facial x-ray films confirm the extent of bone  deformity. Soft tissue alterations are evaluated by history and  physical examination.'? The nature and extent of the cleft, the  infant’s condition, and the method of surgical correction pro-  posed determine the course of treatment. Surgical correction is  planned as soon as possible and may be in stages.'! The aim of  surgery is to obtain an airtight closure of the palatal cleft and to  preserve the mobility and length of the soft palate without com-  promising mid-facial growth.'* Children with cleft palate tend  to have repeated infections of the paranasal sinuses and middle  ear both before and after surgery, which require treatment. The  child should be evaluated for hearing loss.!° Excessive dental  decay is not unusual. Speech training and special attention by a  prosthodontist and orthodontist are almost always required.'*  Periconceptual B vitamins, folate, and folic acid intake and  reduced tobacco and alcohol use may prevent orofacial clefts.°  Surgical correction facilitates feeding and normal growth and  development.!°    Congenital malformations of the esophagus are rare and  occur in about 1 in 3000 live births, depending on geographic  region.!° Esophageal atresia is a condition in which the esoph-  agus ends in a blind pouch and is usually accompanied by a  fistula between the esophagus and the trachea. This connection  is called a tracheoesophageal fistula (TEF). Either defect can  occur alone or in association with other defects (Figure 42-2).  Many genes have been implicated.'”   PATHOPHYSIOLOGY. The pathogenesis of esophageal abnormal-  ities is unknown. They are thought to arise from defective dif-  ferentiation as the trachea separates from the esophagus during  the fourth to sixth weeks of embryonic development. Defective  growth of endodermal cells leads to atresia. Incomplete fusion  of the lateral walls of the foregut leads to incomplete closure of  the laryngotracheal tube and fistula formation.'*    es of Esophageal Atresia and Tracheoesophageal Fistulae. A, Simple esophageal atresia.    Proximal esophagus and distal esophagus end in blind pouches, and there is no tracheal communication. Nothing enters    B or D. Note: Type F, esophageal stenosis, is not shown.    CLINICAL MANIFESTATIONS. Polyhydramnios (excessive amni-  otic fluid) is reported to occur in 14% to 90% of mothers of  affected infants.!? The blind end of the proximal esophagus  has a capacity of only a few milliliters. Normally swallowed  amniotic fluid is absorbed into the placental circulation, and  it accumulates in the uterus if the fetus cannot swallow. As the  infant with esophageal atresia swallows oral secretions, the  pouch fills and overflows into the pharynx, resulting in drool-  ing and occasionally in aspiration (see Figure 42-2, A and C).   Ifa fistula connects the trachea with the distal esophagus, the  abdomen fills with air and becomes distended. The distention  may be great enough to interfere with breathing (see Figure  42-2, C to E). If the fistula connects the proximal esophagus to  the trachea, the first feeding after birth will be problematic (see  Figure 42-2, B, D, and E). As the infant drinks, the blind end of  the esophagus and the mouth fill with fluid. When the infant  tries to take a breath, the fluid is aspirated into the lungs, which  triggers protective cough and choke reflexes. Intermittent cya-  nosis may result. Plain water or glucose is recommended for  the initial feeding to minimize the dangers associated with  aspiration. If an abnormality of the esophagus is indicated, oral  feedings are withheld until a diagnosis is confirmed.   Pulmonary complications are compounded by reflux of air  and gastric secretions into the tracheobronchial tree through  the fistula (see Figure 42-2, D and E), causing severe chemical  irritation. The upper lobe of the right lung is most commonly  involved because of its proximity to the tracheoesophageal  (TE) fistula. Infants with esophageal atresia but no fistula have  a scaphoid (boat-shaped), gasless abdomen. In fistula without  atresia (see Figure 42-2, E), the usual symptoms are recurrent  aspiration, pneumonia, and atelectasis that remains “silent” for  days or even months. Late complications of esophageal atresia  or tracheal esophageal fistula include stricture, reflux, dyspha-  gia, chronic cough, and dyspnea on exertion.”    he stomach; regurgitated food and fluid may enter the lungs. B, Proximal and distal esophageal segments end in blind  pouches, and a fistula connects the proximal esophagus to the trachea. Nothing enters the stomach; food and fluid enter the  ungs. €, Proximal esophagus ends in a blind pouch, and a fistula connects the trachea to the distal esophagus. Air enters  the stomach; regurgitated gastric secretions enter the lungs through the fistula. D, Fistula connects proximal and distal  esophageal segments to the trachea. Air, food, and fluid enter the stomach and the lungs. E, Simple tracheoesophageal  istula between otherwise normal esophagus and trachea. Air, food, and fluid enter the stomach and the lungs. Between  85% and 90% of esophageal anomalies are type C; 6% to 8% are type A; 3% to 5% are type E; and less than 1% are type    Other congenital anomalies are present in at least 50% of  infants with esophageal defects. They are known as the VAC-  TERAL association with the letters representing vertebral anoma-  lies, anal atresia, cardiovascular malformations, TE fistula and/or  esophageal atresia, renal anomalies, and limb anomalies.*!   EVALUATION AND TREATMENT. Prenatal diagnosis may include  ultrasound imaging but the findings of polyhydramnios and small  stomach bubble are often nonspecific and associated with other  problems.” Esophageal atresia is usually diagnosed at birth, when  attempts to pass a small-bore orogastric or nasogastric tube into  the stomach fail. Imaging will show displacement of the tube.”*   Initial postnatal treatment is to prevent aspiration. Surgery  restores esophageal continuity, and the fistula is eliminated. Sur-  gery is usually undertaken after birth, sometimes in stages. The  child may continue to have problems with aspiration, gastro-  esophageal reflux, and esophagitis after surgical repair. The over-  all survival rate for infants with esophageal defects exceeds 90%.”*    Pyloric stenosis is an obstruction of the pyloric sphincter  caused by hypertrophy of the sphincter muscle. It is one of the  most common disorders of early infancy and affects infants  between the ages of either 1 and 2 weeks or 3 and 4 months.”°  The incidence of pyloric stenosis among males is approxi-  mately 5 in 1000, whereas among females it is only 1 in 1000.7°  Whites are affected more often than blacks or Asians, and full-  term infants are affected more often than premature infants.  The cause is unknown but increased gastrin secretion by the  mother in the last trimester of pregnancy raises the likelihood  of pyloric stenosis in the infant. The overproduction of gastric  secretions in the infant may be caused by stress-related factors  in the mother. Exogenous administration of prostaglandin E is  associated with an increased incidence of pyloric stenosis. There  is an increased incidence of pyloric stenosis in those children    who have a family member with pyloric stenosis, suggesting a  genetic predisposition.’”   PATHOPHYSIOLOGY. The circular muscle of the pylorus is grossly  enlarged because of an increase in cell size (hypertrophy) and an  increase in cell number (hyperplasia).?” The mucosal lining of  the pyloric opening is folded and the lumen is narrowed by the  encroaching muscle. Because of the extra peristaltic effort neces-  sary to force the gastric contents through the narrow pylorus, the  muscle layers of the stomach may become hypertrophied as well.   CLINICAL MANIFESTATIONS. Between 2 and 3 weeks after birth,  an infant who is fed well and gained weight begins to vomit  without apparent reason and the vomiting becomes more  forceful. The forceful, or projectile, vomiting usually occurs  immediately after eating, and the vomitus consists of the bulk  of the feeding plus some food retained from previous feedings  but is almost always free of bile. Usually infants are hungry and  want to eat again after vomiting.   Prolonged retention of food in the stomach is a characteris-  tic feature of pyloric stenosis and food is present after 4 hours  unless vomiting has occurred. Constipation is the rule because  most food does not reach the intestine.   In severe untreated cases, increased gastric peristalsis and  vomiting lead to severe fluid and electrolyte imbalances (hypo-  kalemic, hypochloremic metabolic alkalosis), chronic malnu-  trition, and weight loss that can be fatal within 4 to 6 weeks.  Infants with pyloric stenosis are irritable because of hunger,  and they may have esophageal discomfort caused by repeated  vomiting and esophagitis. The vomitus may be blood streaked  because of rupture of gastric and esophageal vessels.   EVALUATION AND TREATMENT. Diagnosis is based on the his-  tory of clinical manifestations. Occasionally, gastric peristalsis  is observable over the abdomen. A firm, small, movable mass,  approximately the size of an olive, is felt in the right upper quad-  rant in 70% to 90% of infants with pyloric stenosis. A visible  gastric peristaltic wave after eating is observed in some infants.  Ultrasound clearly shows the hypertrophied pyloric muscles  and narrowed pyloric channel.   The standard treatment for hypertrophic pyloric stenosis is  a pyloromyotomy, in which the muscles of the pylorus are split  and separated. The procedure can be completed with an open  technique or with laparoscopy. The mortality associated with  surgical correction is less than 0.5%. Fluid and electrolyte losses  are managed before surgical intervention and children usually  can tolerate feeding several hours after surgery.”*    During the tenth week of embryonic development, the emerging  ileum and cecum normally rotate, so that the cecum moves into  the lower right quadrant of the abdomen and is fixed there by  the mesentery. Intestinal malrotation is a condition in which  rotation does not occur and the colon remains in the upper right  quadrant, where an abnormal membrane or band may press  on and obstruct the duodenum. The obstructing band over the  duodenum, called a periduodenal band (Ladd’s band), is one  of the most significant findings in malrotation (Figure 42-3).  Genetic factors associated with malrotation are being identified  and most occur with other malformations or abnormalities.’    FIGURE 42-3 Variations of Intestinal Malrotation. A, Nonrotation. B, Incom-  plete rotation. C, Midgut volvulus with duodenal obstruction and obstruction of  superior mesenteric artery blood flow. D, Incomplete rotation with Ladd’s bands  extending from the lateral and posterior abdominal wall to the subhepatic cecum.  LB, Ladd's band; SMA, superior mesenteric artery. (From Gilbert-Barness E et al:  Potter's pathology of the fetus, infant and child, ed 2, Philadelphia, 2007, Mosby.)    Associated abnormalities include 50% of children with duode-  nal atresia and 33% of those with jejunal atresia, as well as biliary  or pancreatic malformations and heart defects.°°   PATHOPHYSIOLOGY. The small intestine lacks a normal poste-  rior fixation in malrotation because it has only a rudimentary  attachment near the origin of the superior mesenteric artery.  Therefore, the entire mass can twist when the mobile loops of  intestine from the duodenojejunal junction to the middle of  the transverse colon twist on themselves. The twisting is termed  volvulus. Intestinal twisting around the rudimentary mesentery  angulates and obstructs the intestinal lumen and partly or com-  pletely occludes the superior mesenteric artery, causing infarc-  tion and necrosis of the entire midgut.   CLINICAL MANIFESTATIONS. Although most cases of malrota-  tion-associated volvulus and infarction develop during the  neonatal period or infancy (younger than 1 year), some develop  during childhood or even adulthood. In one study, 48% of  individuals first diagnosed with malrotation were adults.°*! In  infants the obstruction causes intermittent or persistent bile-  stained vomiting after feedings. Abdominal distention is lim-  ited initially to the epigastrium because only the stomach and  duodenum are dilated. The degree of distention depends on the  pressure of swallowed air and the degree of obstruction caused  by the volvulus. Dehydration and electrolyte imbalance may    occur rapidly because large amounts of pancreatic juice, bile,  and gastric secretions are lost through vomiting. Fever usually  ensues. Pain, scanty stools, diarrhea, bloody stools, and severe  dehydration are associated with progressive volvulus, vascular  compression, and infarction of the intestine in infants.*? Inter-  mittent or partial volvulus may be seen in older children and  adults. This may be asymptomatic (25% to 50% of the time)  and discovered during unrelated abdominal surgery, or it may  cause minor abdominal complaints, such as nausea after meals,  recurrent episodes of vomiting, or abdominal pain.**   EVALUATION AND TREATMENT. Diagnosis of malrotation with  volvulus and infarction is based on a review of the clinical man-  ifestations, upper gastrointestinal contrast imaging, and explor-  ative laparoscopy.*4   Treatment includes laparoscopic or open surgery to reduce  the volvulus.*° Necrotic bowel is resected and a primary anasto-  mosis performed. An enterostomy may be created. Most children  have a good outcome; however, there is risk for adhesion-related  bowel obstruction in about 15% of cases.°°    Meconium is a substance that fills the entire intestine before  birth. It consists of intestinal gland secretions and some amni-  otic fluid. Normally, meconium is passed from the rectum dur-  ing the first 12 to 72 hours after birth.   Meconium ileus (MI) is intestinal obstruction caused by  meconium formed in utero that is abnormally sticky and  adheres firmly to the mucosa of the small intestine, resisting  passage beyond the terminal ileum. The cause is usually a lack of  digestive enzymes during fetal life. This meconium is also found  to contain albumin, which is not normally found in meconium.  MI is associated with cystic fibrosis.°’ In the cases not associ-  ated with cystic fibrosis, genes other than CFTR mutations have  been identified.** The cause usually is unknown. Partial aplasia  of the pancreas is an associated factor, however, and one fifth  of infants with meconium ileus are premature or have a his-  tory of maternal hydramnios (excessive amniotic fluid). After  intestinal atresia and malrotation with volvulus, meconium  ileus is the most common cause of small intestinal obstruction  in newborns.   PATHOPHYSIOLOGY. The terminal ileum is plugged with thick,  viscous meconium resulting from the formation ofan insoluble,  calcium-glycoprotein compound in abnormal mucus. The seg-  ment of the ileum proximal to the obstruction is distended with  liquid contents, and its walls may be hypertrophied. The seg-  ment distal to the obstruction is collapsed and filled with small  pellets of pale-colored stool. Meconium in the obstructed seg-  ment has the consistency of thick syrup or glue. Peristalsis fails  to propel this viscous material through the ileum, so it becomes  impacted. Volvulus, atresia, or perforation of the bowel some-  times accompanies meconium ileus.   CLINICAL MANIFESTATIONS. Abdominal distention usually  develops during the first few days after birth. The infant does  not pass meconium and begins to vomit within hours or days of  birth. Infants with cystic fibrosis may have signs of pulmonary  involvement, such as tachypnea, intercostal retractions, and  grunting respirations. The distended abdomen shows patterns    of dilated intestinal loops that feel doughlike when palpated.  Some of the loops contain scattered, firm, movable masses.  Despite hyperactive peristalsis, the rectal ampulla is empty.   EVALUATION AND TREATMENT. All women of reproductive age  should be offered preconception and prenatal cystic fibrosis  (CF) carrier screening. Prenatal diagnosis of MI can be made by  ultrasound. Radiologic imaging is used to confirm the presence  of MI.°? The sweat test is performed to detect or rule out cystic  fibrosis. It is considered the “gold standard” and is accurate in  90% of infants. The treatment of choice for cases not compli-  cated by volvulus or perforation is a hyperosmolar enema (e.g.,  metglutamine diatrizoate [Gastrografin]) performed under  fluoroscopy. The fluid is drawn into the meconium mass,  hydrating and softening it. Transient osmotic diarrhea follows.  A warm saline enema containing 4% N-acetylcysteine may be  given to help complete the evacuation. Surgical management  includes tube enterostomy (a percutaneous drain), open enter-  ostomy, or resection to remove the meconium mass. Survival of  infants with meconium ileus is improving, with survival rates  approaching 100%.*° The mortality increases if obstruction is  complicated by peritonitis.*!    Distal intestinal obstruction syndrome (DIOS), formerly  called meconium ileus equivalent, affects approximately 15%  of children and adults with cystic fibrosis.*” DIOS is the partial  or complete obstruction of the colon or the terminal ileum by  abnormally viscous intestinal contents, particularly after epi-  sodes of dehydration or lack of pancreatic enzymes. It can occur  in children or adults. The child displays signs and symptoms of  intestinal obstruction. In most cases the obstruction is relieved  by hypertonic enemas.*?    Congenital obstruction of the duodenum can be caused by intrin-  sic malformations (atresia or stenosis) or external pressure. The  obstruction may be partial or complete and usually is located at  or near the major duodenal papilla. Extrinsic obstructions can  be caused by peritoneal bands that constrict the duodenum. The  duodenum can be obstructed by an annular pancreas—a defect  in which the head of the pancreas surrounds part of the duo-  denum. Congenital obstructions of the jejunum and ileum can  be attributable to atresia, stenosis, meconium ileus, megacolon  (Hirschsprung disease), intussusception, Meckel diverticulum,  intestinal duplication, or strangulated hernia.   In ileal atresia or jejunal atresia, the intestine ends blindly  proximal and distal to an interruption in its continuity, with  or without a gap in the mesentery. Stenosis (narrowing of the  lumen) causes dilation proximal to the obstruction and luminal  collapse distal to it.    Meckel diverticulum is an outpouching of all layers of the small  intestinal wall (usually in the ileum) and is the most common  congenital malformation of the gastrointestinal tract. The rules  of 2 are cited in association with Meckel diverticulum: it occurs  in about 2% of the population, 2% develop complications    usually before 2 years of age, there are 2 types of common  ectopic tissue (gastric and pancreatic), and it is located within  2 feet of the ileocecal valve. Meckel diverticulum develops when  there is failure to obliterate the omphalomesenteric duct, which  normally leaves a fibrous band that connects the small intestine  to the umbilicus during the first months of fetal development.  Ectopic gastric mucosal cells are contained in the diverticuli and  may cause peptic ulcer. Although most Meckel diverticuli are  asymptomatic, the most common symptom is painless rectal  bleeding. Intestinal obstruction, intussusception, and volvulus  occur more commonly in adults. Diagnosis is made by symp-  tom presentation and radionucleotide scintingraphy. The scan  shows the gastric mucosal cells in the diverticuli. Treatment in  those with symptoms is surgical resection."*   Congenital aganglionic megacolon (Hirschsprung disease) is a  functional obstruction of the colon caused by the absence of the  enteric ganglia along a variable length of the colon with inad-  equate motility. The incidence is approximately 1 in 5000 live  births with an increased incidence in males, siblings of children  with Hirschsprung disease, and children with Down syndrome or  other congenital malformations.’ The exact cause is unknown  but multiple interacting factors and a complex inheritance pat-  tern with mutations in multiple genes are involved.*°   PATHOPHYSIOLOGY. Congenital aganglionic megacolon is  caused by a malformation of the parasympathetic nervous  system. It is characterized by abnormalities of the basement  membrane and extracellular matrix and absence of the intra-  mural ganglion cells in the enteric nerve plexuses (Meissner  and Auerbach plexuses) along variable lengths of the colon, and  there may be skipped segments. Lacking neural stimulation,  the muscle layers of the colon wall fail to propel feces through  the colon, leading to functional obstruction. In 80% of cases  the aganglionic segment is limited to the rectosigmoid region  (short-segment); in 3% the entire colon lacks ganglion cells  and the ileum may be involved. The abnormally innervated  colon impairs fecal movements, causing the proximal colon to  become distended, hence the term megacolon (Figure 42-4).   The ganglia normally develop from an advancing neu-  ral crest between the muscle layers (tunica muscularis) in the  submucosal area (muscularis mucosae) of the intestinal wall.  In cases of congenital megacolon, neurologic development is  blocked and large, nonmyelinated fibers develop in place of  these ganglion cells. The segment of colon that lacks ganglion  cells has a relatively normal lumen caliber and wall thickness. In  the segment of the colon proximal to it, the lumen is dilated and  the muscle hypertrophied. Therefore, the abnormal portion of  the colon appears to be normal and the normal portion appears  to be diseased.*”   CLINICAL MANIFESTATIONS. The extent of the aganglionic portion  of the colon determines the severity of the symptoms of congeni-  tal aganglionic megacolon. The most distal part of the rectum is  always involved. This is the extent of the aganglionic portion in  some children, and the child is said to have “ultrashort-segment”  Hirschsprung disease and generally has only mild constipation  as a symptom. These individuals may not be diagnosed until    adulthood. Symptoms of chronic constipation, poor feeding,  poor weight gain, and progressive abdominal distention increase  in severity as the aganglionic portion extends proximally. Diar-  rhea may be the first sign, however, because only water can travel  around the impacted feces.   In the neonate there is delayed passage of meconium and  abdominal distention, with or without bilious vomiting. Bowel  dilation stretches and partly occludes the encircling blood  and lymphatic vessels, causing edema, ischemia, infarction of  the mucosa, and significant outflow of fluid into the bowel  lumen. Copious, liquid stools result. In severe cases infarction  and destruction of the mucosa enable enteric microorganisms  to penetrate the bowel wall. Frequently, gram-negative sepsis  occurs, accompanied by fever and vomiting. Severe and rapid  electrolyte changes may take place, causing collapse and rapid  death.*®   EVALUATION AND TREATMENT. Hirschsprung disease in usually  diagnosed in the newborn period and should be suspected with  failure to pass meconium within 24 to 48 hours after birth.  Radiocontrast enema, anorectal manometry, and rectal suction  biopsy are screening tools for the diagnosis of Hirschsprung  disease. Serial manometry measurements may be required  in neonates.*? This test has uncovered ultrashort-segment  Hirschsprung disease in older children with a history of con-  stipation.°” The definitive diagnosis is made by rectal suction  biopsy showing an absence of ganglion cells in the submucosa  of the colon.*!   The involved segment is usually resected within the first few  months of life using a “pull-through” procedure that anastomo-  ses the proximal and distal segments of remaining bowel or rec-  tum. Laparoscopic or open approaches may be used. In skipped  segment disease, the area of normal bowel may be preserved.*?  For children with short-segment Hirschsprung disease, enemas  are given to relieve impaction, and laxatives with a dietary and  bowel training program are used in preference to surgical inter-  vention.” The child is not treated for diarrhea.    Hirschsprung-associated enterocolitis is a postsurgical com-  plication that sometimes recurs. If postoperative enterocolitis  is allowed to persist, pseudopolyps may appear. Because these  are essentially identical to the lesions of ulcerative colitis, they  have malignant potential. Therefore, a colectomy is indicated if  pseudopolyps develop.   In general, the prognosis of congenital megacolon is satisfac-  tory for children who undergo surgical treatment. Bowel train-  ing may be prolonged; however, most children achieve bowel  continence before puberty whereas others have long-term con-  stipation or fecal incontinence.»    Congenital anorectal malformations (ARMs) are rare birth  defects of unknown etiology that range from mild anal steno-  sis, which is corrected by simple dilation, to complex deformi-  ties, such as anal or rectal agenesis, atresia, and rectourethral  fistula (Figure 42-5). Deformities that cause complete obstruc-  tion are known collectively as imperforate anus. The cause is  unknown.*! ARM occurs in approximately 1 in 2500 to 1 in  5000 newborn babies.°°   Approximately 40% of infants with ARMs have other devel-  opmental anomalies, including Down syndrome, congenital  heart disease, renal and urologic abnormalities, cryptorchidism,  esophageal atresia, and malformations of the spine.°° Imper-  forate anus may not be obvious. It can be detected by gentle  insertion of a rectal tube; x-ray films show dilations throughout    the intestinal tract. Anal stenosis can be treated by dilations,  but all other anorectal malformations require surgical correc-  tion. The overall death rate is approximately 10%. More than  90% of children with a low (anal) anomaly and intact sacrum  achieve bowel continence with stenosis as a common complica-  tion. Children with very high anomalies or anomalies associ-  ated with genitourinary fistulae have more difficulty achieving  continence.°”°®    Acquired Impairment of Motility  Intussusception  Intussusception is the telescoping or invagination of one por-  tion of the intestine into another. It is the most common cause  of acquired intestinal obstruction in infants between 5 and 10  months of age, although it can occur at any age. The ileum usu-  ally invaginates the cecum and part of the ascending colon by  collapsing through the ileocecal valve (ileocolic intussuscep-  tion). It can occur anywhere from the duodenum to the rectum.  Intussusception is more common in males and can be idio-  pathic, can be associated with lead points (polyps or tumors,  Meckel diverticulum, intestinal adhesions) or cystic fibrosis, or  can develop immediately after abdominal surgery.”  PATHOPHYSIOLOGY. Most commonly, the proximal portion  of the intestine, the intussusceptum, collapses into the dis-  tal portion, the intussuscipiens, in the direction of peristaltic  flow (Figure 42-6). As this occurs, the intussusceptum drags its  mesentery into the enveloping lumen. Initially, the mesentery    is constricted, obstructing venous return. Compression of the  mesenteric vessels between the two layers of intestinal wall and  at the U-shaped angle at either end of the intussusceptum leads  within hours to venous stasis, engorgement, edema, exudation,  and further vascular compression. Unless the intussusception  is treated, bleeding, necrosis, bowel perforation, and gangrene  ensue. The tension of the mesentery on the intussusceptum  tends to arch the bowel in a curve with its center at the mesen-  teric root. Edema and compression obstruct the flow of chyme  through the intestine.   CLINICAL MANIFESTATIONS. The affected infant suddenly devel-  ops abdominal pain, becomes irritable (colicky), and flexes the  knees. Vomiting occurs soon afterward. A single normal stool  may be passed, evacuating the colon distal to the apex of the  intussusception. Following the passage of normal stool, 60% of  infants pass “currant jelly” stools, which appear dark and gelati-  nous because of their blood and mucus content. In one study,  less than one third of children had this clinical triad of vomiting,  colicky abdominal pain, and bloody stools.°° Most infants have  a tender, sausage-shaped abdominal mass. Abdominal tender-  ness and distention develop as intestinal obstruction becomes  more acute.   EVALUATION AND TREATMENT. Diagnosis is based on clini-  cal manifestations and onset of symptoms. Ultrasound of the  abdomen, computed tomography (CT), and magnetic reso-  nance imaging (MRI) are commonly completed for diagnosis.°!  More than 82% of children have positive ultrasound results in  ileocolic and jejunointestinal intussusception. Reduction is an  emergency procedure involving hydrostatic pressure generated  by an air or a barium enema given using fluoroscopic guidance.  This technique is successful most of the time with about a 10%  to 13% recurrence rate. Surgical reduction is done on chil-  dren who fail or, in rare cases, have perforation.°»** Untreated    intussusception in infants is nearly always fatal. Most infants  recover if the intussusception is reduced within 24 hours. Spon-  taneous reduction of intussusception may occur in sympto-  matic or asymptomatic children.    Gastroesophageal reflux (GER) is the return of stomach  contents into the esophagus because of relaxation or incom-  petence of the lower esophageal sphincter. In newborns, gas-  troesophageal reflux is normal (physiologic reflux) because  neuromuscular control of the gastroesophageal sphincter is not  fully developed. The frequency of reflux is highest in prema-  ture infants and decreases during the first 6 to 12 months of  life. Children usually outgrow their reflux. Gastroesophageal  reflux disease (GERD) occurs when protective mechanisms are  ineffective and persistent reflux results in complications such as  mucosal erosion, bleeding, dysphagia, or failure to thrive.   PATHOPHYSIOLOGY. GERD in children may be related to delayed  maturation of the lower esophageal sphincter or impaired hor-  monal or neurotransmitter response mechanisms (i.e., vasoac-  tive intestinal peptide and nitric oxide). Factors that maintain  lower esophageal sphincter integrity in children include location  of the gastroesophageal junction in a high-pressure zone within  the abdomen, mucosal gathering within the sphincter, and the  angle at which the esophagus is inserted into the stomach. Reflux  persists if any of these pressure-maintaining factors is altered.  Irritation of the mucosa by acidic gastric contents results in  inflammation of the esophageal epithelium (esophagitis) and  stimulation of the vomiting reflex.   GERD may be a factor in the stimulation of reactive airway  disease and otitis media with effusion in some children but the  exact relationships are yet to be defined.°°°’ The relationship  between apnea of prematurity caused by GERD and laryngo-  spasm is controversial.°*   Eosinophilic esophagitis is differentiated from GERD (see  Chapter 41) and can occur in children. It is thought to be an  atopic disease involving immediate as well as delayed hyper-  sensitivity reactions to food ingestion. A mast cell, eosinophil,  and T lymphocyte infiltrate are associated with inflammation of  the entire esophagus that is nonresponsive to acid-suppression  therapy. Eosinophilic inflammation may lead to progressive sub-  epithelial fibrosis with esophageal strictures, narrowing, and dys-  phagia. The esophageal mucosa can appear normal in children  at endoscopy. Dysphagia, food impaction, and vomiting are  common symptoms and other atopic diseases, such as asthma  and eczema, may be present. Treatment includes elimination  diets and oral corticosteroids.©”°   CLINICAL MANIFESTATIONS. The signs and symptoms of GERD  are caused by exposure of the esophageal epithelium to refluxed  gastric contents; 85% of affected infants vomit excessively dur-  ing the first week of life and usually have other symptoms by 6  weeks, including feeding difficulty, feeding refusal, and failure  to thrive.   Vomiting may be forceful and must be differentiated from  pyloric stenosis. Aspiration pneumonia develops in one third of  infants with gastroesophageal reflux (GER). In cases that per-  sist into childhood, chronic cough, wheezing, hoarseness, and    recurrent pneumonia are common.’!”* Repeated vomiting leads  to inadequate retention of nutrients, adversely affecting growth  and weight gain. Esophagitis from exposure of the esophageal  mucosa to acidic gastric contents is manifested by pain, bleed-  ing, and eventually stricture formation and abnormal motility.  Approximately 10% to 25% of children with GERD also have  iron deficiency anemia caused by frank or occult blood loss.”°   EVALUATION AND TREATMENT. The clinical manifestations are  often adequate to confirm a diagnosis of GERD. However, irri-  tability, crying, feeding refusal, and regurgitation can be com-  mon problems in infants and not specific to GERD. Esophageal  pH monitoring with a probe for 24 hours and endoscopy  with biopsy are routinely used for diagnosis.’*’° Mild GER  resolves without treatment. Thickened feedings may help some  infants’’; however, this has not been shown to be consistently  helpful. Techniques for managing infant reflux include small,  frequent feedings; prolonged feeding duration and slower flow  rate; and frequent burping.”*”   Medications are used to treat erosive esophagitis and proki-  netic agents must be used with caution.* If no improvement is  seen with medical management or the child has life-threatening  events with reflux, an antireflux surgical procedure, including  gastropexy and fundoplication, is performed. A fundoplication  recreates a valve by wrapping the fundus of the stomach around  the lower esophagus and can be completed using laparoscopic  techniques. °!   Classic gastrointestinal manifestations of cystic fibrosis include  meconium ileus at birth, which is usually pathognomonic for  cystic fibrosis (CF). Approximately 15% to 20% of individuals  with CF present with this symptom. Rectal prolapse is an occa-  sional presenting sign that should always prompt testing for CF.  About 10% of CF patients do not experience gastrointestinal  problems and are termed “pancreatic sufficient.” Several spe-  cific CFTR mutations are predictive of this milder phenotype.  Males with CF are typically infertile (98%).   Cystic fibrosis of the pancreas, which is also called muco-  viscidosis or fibrocystic disease of the pancreas, is a genetically  transmitted disease (mutation of the long arm of chromosome  7) that involves many organs and systems and usually causes  death in childhood or young adulthood. It is the most common  cause of chronic suppurative lung disease in children and is the  most common life-threatening inherited disease in the white  population. This section focuses on the deficiency of pancreatic  enzymes. (Chapter 36 discusses the pulmonary consequences  of cystic fibrosis.)   PATHOPHYSIOLOGY. The pathophysiologic triad that is the  hallmark of CF includes: (1) pancreatic enzyme deficiency,  which causes maldigestion; (2) overproduction of mucus in  the respiratory tract and inability to clear secretions, which  cause progressive chronic obstructive pulmonary disease; and  (3) abnormally elevated sodium and chloride concentrations  in sweat. Exocrine secretions tend to be abnormally thick and  precipitate in the glandular ducts, obstructing flow. Almost all  clinical manifestations of CF are a result of overproduction of    extremely viscous mucus and pancreatic enzyme deficiency.  The full spectrum of involvement is summarized in Table 42-1.   Pancreatic function may range from normal to completely  ablated. Approximately 85% of patients have pancreatic insuf-  ficiency. Obstruction of the pancreatic ducts with thick mucus  blocks the flow of pancreatic enzymes and causes degenera-  tive and fibrotic changes in the pancreas. Pancreatic damage  eventually can affect the beta cells, resulting in diabetes mel-  litus (10% to 25%). The incidence of diabetes mellitus and cir-  rhosis (13% to 17%) in this population has increased as larger  numbers of people with cystic fibrosis have moved into young  and middle adulthood. Severe problems with maldigestion of  proteins, carbohydrates, and fats occur because of insufficient  secretion of pancreatic enzymes. Failure to thrive, growth fail-  ure, malabsorptive symptoms, metabolic abnormalities, trace  element deficiencies, fat-soluble vitamin alterations, electrolyte  imbalances, and decreased bone mineral density can occur early  in the disease.*?"*4   EVALUATION AND TREATMENT. To determine the extent of pan-  creatic function 72-hour stool fat measurements are used.  Stools also may be examined for absence of pancreatic enzymes,  particularly fecal elastase, trypsin, and chymotrypsin. To opti-  mize treatment, the carbon-13 (!°C) mixed triglyceride breath  test offers a simple, noninvasive way of assessing the need for  pancreatic enzyme supplementation in children with cystic  fibrosis.*° Pancreatic replacement enzymes are administered  before or with meals and high-calorie, high-protein diets with  frequent snacks and vitamin supplements are used to treat mal-  nutrition.®*° However, anorexia is not uncommon in this group  secondary to pulmonary disease and frequently large sputum  output. To combat the worsening problem of growth failure  in children with cystic fibrosis, nasogastric or gastrostomy  tube feedings are used to supplement oral intake and promote  weight gain. Monitoring of growth and body mass index is criti-  cal to treatment evaluation.*”**    Gluten-sensitive enteropathy, formerly called celiac sprue or  celiac disease, is an autoimmune disease of the small intestinal  villous epithelium when there is ingestion of the cereal protein  gluten (gliadin) found in wheat, rye, barley, and oats in geneti-  cally susceptible individuals. The disease has a prevalence of  about 1% worldwide and about 0.71% in the United States;  many cases are undiagnosed.*? Although gluten-sensitive  enteropathy is widely perceived as a malabsorption syndrome  of childhood, the diagnosis is usually made in adulthood. It is  not known why disease presentation varies so widely.”” Numer-  ous genes have been identified and other autoimmune diseases  can be associated with the autoantibodies of gluten-sensitive  enteropathy, including type 1 diabetes mellitus, autoimmune  thyroiditis, and Addison disease.”!   PATHOPHYSIOLOGY. The disease is complex and involves the  interaction of genetic, immune, and environmental factors. Both  cellular immunity and humoral immunity are implicated.’  The major pathophysiologic characteristic is T-cell-mediated    Inspissation and precipitation of pancreatic  secretions, causing obstruction of  pancreatic ducts    Inspissation and precipitation of secretions  in small ducts of submaxillary and  sublingual salivary glands    Viscid genital tract secretions during  embryologic development, causing failure  of formation of normal vas deferens    Absence of pancreatic enzymes, causing  malabsorption of food; fatty, bulky  stools   Decreased bone density and risk of  fractures in adolescents and adults    Data from Gelfond D, Borowitz D: Clin Gastroenterol Hepatol 11(4):333-342, 2013; Javier RM, Jacquot J: Joint Bone Spine (5):445-450, 2011;  Rudolph CD et al: Rudolph’s pediatrics, ed 21, New York, 2003, McGraw-Hill.    autoimmune injury to the intestinal epithelial cells.?! Trans-  glutaminase 2 (TG2) and endomysial autoantibodies closely  correlate with the acute phase of the disease in the presence  of gluten.?? T-cell infiltration results in mucosal cell destruc-  tion with inflammation, atrophy, and flattening of villi in the  upper small intestine (Figures 42-7 and 42-8). The atrophy is  caused by accelerated shedding of epithelial cells from the villi.  To compensate for this loss, epithelial cell production increases,  causing hypertrophy of the crypts of Lieberkiihn. Increased cell  production is not sufficient to keep pace with cell loss, and the  cells are not mature enough to sustain absorptive functions. The  microvilli and brush border disappear, leaving patches of bald  mucosa. The loss of mucosal surface area and brush-border    enzymes leads to severe malabsorption. The pathologic process  is most pronounced in the duodenum and jejunum. The ileum  may be spared. The severity of disease correlates with the length  of the small intestinal mucosa involved.**?°   Damage to the mucosa of the duodenum and jejunum has  secondary effects that exacerbate malabsorption. The secretion  of intestinal hormones, such as secretin and cholecystokinin,  may be diminished. Because these chemical messengers are  scarce, secretion of pancreatic enzymes and expulsion of bile  from the gallbladder decrease.   Destruction of mucosal cells causes inflammation, and water  and electrolytes are secreted, leading to watery diarrhea. In addi-  tion, absorption that normally occurs by sodium-dependent    Gluten-Sensitive Enteropathy. A, Atrophy of villi and elongation of crypts that result in malabsorption    (arrows). B, Recovery of normal villus structure after 6 months of gluten-free diet. (From Damjanov I, Linder J: Pathology: a color    active transport or facilitated diffusion is impaired. Carbohy-  drates, amino acids, dipeptides, water-soluble vitamins, bile  salts, and cations are not absorbed from the intestinal lumen.  Potassium loss, which is more severe than sodium loss, leads  to muscle weakness. Magnesium and calcium malabsorption  can cause seizures or tetany. Unabsorbed fatty acids combine  with calcium, and secondary hyperparathyroidism increases    phosphorus excretion, resulting in bone reabsorption. Cal-  cium is no longer available to bind oxalate in the intestine and  is absorbed, which causes hyperoxaluria. Gallbladder function  may be abnormal, and bile salt conjugation may be decreased.  Fat malabsorption in the jejunum is the major cause of ste-  atorrhea (fatty stools). Malabsorption may be mild early in  the disease. Fecal nitrogen level is elevated because peptidase    deficiencies impair protein absorption. Pancreatic function is  decreased, not only because of decreased hormonal levels but  also because of malnutrition.   Deficiencies of fat-soluble vitamins are common in children  with gluten-sensitive enteropathy. Vitamin K malabsorption  leads to hypoprothrombinemia. In one third of cases, iron and  folic acid malabsorption is manifested as cheilosis; anemia; and  a smooth, red tongue. Vitamin B,, absorption is impaired in  those with extensive ileal disease. Because the absorption of  folate and iron is greatest in the proximal small intestine, defi-  ciencies of these substances are common.   Dermatitis herpetiformis is a cutaneous manifestation of  gluten-sensitive enteropathy that involves transglutaminase  3 IgA autoantibodies. They circulate to the skin and interact  with antigens produced by keratinocytes. The antigen-antibody  complex activates neutrophils in the papillary dermis, causing  blister formation. The lesions present with a symmetric dis-  tribution on the extensor surfaces of the elbows (90%), knees  (30%), shoulders, middle line of the back, or buttocks. The  sacral region, scalp, nuchal area, face, and groin also may be  involved.”   CLINICAL MANIFESTATIONS. The onset of clinical manifesta-  tions of gluten-sensitive enteropathy depends on the age of the  infant when gluten-containing substances are added to the diet.  In 50% of affected children, onset occurs by 18 months of age,  with latent intervals varying from months to years. Severity of  symptoms can vary tremendously, and children older than 3  years of age can present with mild to severe gastrointestinal  symptoms.”   Diarrhea is an early sign in most infants accompanied by fail-  ure to thrive and anemia. The stools are pale, bulky, greasy, and  foul smelling, and may contain oil droplets. Three to five such  movements occur daily. As early as 3 or 4 months of age, growth  failure, anorexia, and constipation can begin. In older children  constipation is occasionally seen despite steatorrhea. Vomit-  ing and abdominal pain are prominent in infants but unusual  in older children. Anorexia is prevalent. The classic physical  manifestations of organic failure to thrive, such as abdominal  protuberance, wasted buttocks and limbs, and hypotonia, occur  in less than 50% of infants with gluten-sensitive enteropathy.  Growth is usually diminished.?*   Manifestations of malabsorption, such as rickets, tetany,  frank or occult bleeding, or anemia, may be obvious. Some chil-  dren urinate more at night. The tongue is smooth and red, and  the child may bruise and bleed easily. Hypomagnesemia and  hypocalcemia cause irritability, tremor, convulsions, tetany,  bone pain, osteomalacia, and dental abnormalities. If vitamin  D deficiency is prolonged, rickets and clubbing of the terminal  phalanges are likely. Eighty-six percent of older children have  fingerprint changes (ridge atrophy). In older children, delayed  puberty and infertility may be a manifestation of otherwise sub-  tle gluten-sensitive enteropathy.”   EVALUATION AND TREATMENT. Diagnosis includes confirma-  tion with serologic antiendomysial and antitransglutaminase  IgA antibodies and HLA-type DQ2 or DQ8 (human leukocyte  antigen class II haplotypes that regulate immunity). Intes-  tinal biopsy detects the classic mucosal changes caused by    gluten-sensitive enteropathy and confirms the diagnosis. The  initial biopsy may be followed by a second intestinal biopsy to  demonstrate regeneration of intestinal villi after treatment with  a gluten-free diet.!°° Most children with celiac disease remain  undiagnosed.   Treatment consists of the immediate and permanent insti-  tution of a gluten-free diet. Lactose (milk sugar) intolerance  is presumed because of damage to the villi; therefore, lactose  is excluded from the diet. With removal of gluten and healing  of the mucosa, lactose may be reintroduced at a later point.!°!  Infants are routinely given vitamin D, iron, and folic acid sup-  plements to treat deficiencies. Breast-feeding at the time of  gluten introduction in the diet delays the appearance of celiac  disease.!°   Most children have complete remission of symptoms with  clearing of serologic markers and an excellent prognosis.  Approximately 25% of children experience recurrent relapses  that interfere with growth. There is an increased incidence of  malignant disease, particularly T-cell lymphoma, in individuals  who fail to respond to gluten-free diets.!°°    Kwashiorkor (nutritional edema) and marasmus, or a combi-  nation of both, are the most common types of malnutrition in  children. These disorders are known collectively as severe acute  malnutrition (SAM), previously known as protein-energy  malnutrition (PEM). Both are states of starvation associated  with food shortages (see Chapter 41). Kwashiorkor is severe  protein deficiency, and marasmus is severe deficiency of all  nutrients. Kwashiorkor is a widespread nutritional problem  among children in developing countries and economically des-  titute populations particularly when associated with human  immunodeficiency virus (HIV) infection.!°* The disease usu-  ally occurs in infants or children from 1 to 4 years of age who  have been weaned from breast milk to a high-starch, protein-  deficient diet.   Marasmus can occur at any age, but it is common in children  younger than 1 year. In marasmus, starvation is attributable to  lack of protein and carbohydrates. One third of the world’s chil-  dren suffer from PEM, with the highest concentrations in Asia,  Africa, Latin America, and the Carribbean.!°   The mortality risk for children in developing countries has  been found to be inversely related to anthropometric indica-  tors (height, weight, head circumference, skinfold thickness,  midarm muscle circumference). There is elevated risk even in  the mild to moderate range of malnutrition.!°° Poor sanitation,  early weaning of breast-fed infants, use of overdiluted com-  mercial formulas, and infection (measles, malaria, pneumonia,  HIV, tuberculosis, and diarrheal disease) are major risk factors  for SAM.   SAM is a complication of some diseases, such as chronic  fever, malignancy, digestive and malabsorptive disorders, and  psychogenic illness. Radiation therapy, chemotherapy and long-  term dialysis also can contribute to SAM. Acute and chronic  malnutrition is common in hospitalized children.'°”   PATHOPHYSIOLOGY. In kwashiorkor, the deficit of dietary amino  acids reduces protein synthesis in all tissues. Physical growth    and mental growth are stunted, and maintenance of minimal  life processes is in jeopardy. The lack of sufficient plasma pro-  teins, particularly albumin, causes systemic pressure changes  that result in generalized edema. The volume of total body  water and extracellular fluid increases. Life-threatening hypo-  kalemia, hyponatremia, and hypophosphatemia can occur.!°°  The liver swells with stored fat because no hepatic proteins are  synthesized to form and release lipoproteins. Pancreatic atro-  phy and fibrosis may be present. Kwashiorkor also causes mal-  absorption, reduced bone density, and impaired renal function.  If the condition is not reversed, the prognosis is very poor.   Because the intake of all dietary nutrients is reduced to a min-  imum in marasmus, metabolic processes, including liver func-  tion, are preserved but growth is severely retarded. Caloric intake  is too low to support protein synthesis for growth or the storage  of fat. If more protein is needed than is ingested, muscle wasting  occurs. Fat wasting and anemia are common and can be severe.  The volume of total body water is high. Serum triglyceride and  phospholipid levels increase with increasing severity of malnu-  trition, but other serum values, such as cholesterol, are normal  or slightly reduced. High fasting phospholipid and triglyceride  concentrations are predictive of a poor prognosis for these chil-  dren.'” Severe vitamin A deficiency contributes to blindness.!!°   CLINICAL MANIFESTATIONS. Retarded physical, mental, and psy-  chologic development; muscle wasting; diarrhea; dermatosis;  low hemoglobin level; and infection characterize marasmus.  The presence of subcutaneous fat, hepatomegaly, and fatty liver  distinguishes kwashiorkor from marasmus. These manifesta-  tions are missing in marasmus because caloric intake is not suf-  ficient to support fat synthesis and storage.'!!   EVALUATION AND TREATMENT. Evaluation of SAM is based on  nutritional history and clinical manifestations. Providing defi-  cient nutrients resolves clinical symptoms in 4 to 6 weeks. Phys-  ical and mental retardation may not be reversible, however.  Nutritional rehabilitation with appropriate environmental  stimulation for infants and young children resolves or improves  cerebral shrinkage, physical growth, and psychomotor develop-  ment.!!*!!5 Advances are being made in the local preparation of  ready-to-use therapeutic food for both home- and community-  based malnutrition management.'!* Breast-feeding needs to be  encouraged and some infants and children require intensive  inpatient treatment.!'° High morbidity and mortality occur  in some regions of the world.''° Routine use of antibiotics for  uncomplicated SAM needs investigation.!!®*    Failure to thrive (FTT) is the inadequate intake, insufficient  absorption, or excessive expenditure of calories. It is manifested  as a deceleration in weight gain, a low weight/height ratio, or a  low weight/height/head circumference ratio. FIT is a common  problem and can present at any time in childhood.  PATHOPHYSIOLOGY. Organic FTT has a pathophysiologic cause,  such as GERD, pyloric stenosis, gastroenteritis, cystic fibrosis,  malabsorption syndromes, infection by intestinal parasites,  congenital anomalies, very low birth weight, or chronic dis-  eases of major body systems. All these factors either reduce the  availability of nutrients for maintenance and growth or increase    nutrient requirements, particularly when there is chronic infec-  tion. A chronic disease or congenital anomaly that causes weak-  ness or reduced stature can create developmental, psychosocial,  and emotional problems for the child.   Nonorganic FTT occurs in the absence of any gastrointesti-  nal, endocrine, or other chronic diseases. It is usually associated  with psychosocial deprivation, although behavioral problems  may contribute to its occurrence in the absence of maternal  pathologic findings. Behavioral and psychosocial problems may  be compounded by inadequate economic resources and lack of  knowledge. Generally the problem in nonorganic FTT is inef-  fective nurturing or neglect by parents and primary caregivers.  A variety of parental stressors may be involved and include the  following:   * Inability to bond with the infant because of health or   The first few postnatal months appear to be a sensitive  period in the relationship between growth and mental develop-  ment, suggesting a critical need for early diagnosis and aggres-  sive interventions.!!7-!!?   CLINICAL MANIFESTATIONS. Clinical manifestations of organic  FIT are delayed growth accompanied by manifestations of  the underlying disease (e.g., diarrhea). Manifestations of non-  organic FTT are delayed growth plus reduced energy level,  reduced responsiveness and interaction with the environment,  social isolation, spasticity or rigidity when held or touched,  inability to make eye contact or smile, refusal to eat, and rejec-  tion of foods. Weight loss and decelerated growth are accompa-  nied by restricted development in many areas. Nonorganic FTT  is a complex syndrome involving psychosocial, emotional, and  parent-child problems that compound the pathophysiologic  abnormalities.!*°!?! Children with primarily organic FTT have  been found to have lower developmental skills, and their par-  ents have been found to have higher emotional distress. Infant  stress, vomiting, feeding disorders, and psychosocial factors  have been noted in children with organic and inorganic FTT,  making the distinction between the two complex.!?   EVALUATION AND TREATMENT. Failure to thrive is suggested if a  child falls below the third percentile on the growth curve or is  lagging in a previously established growth curve. Organic FTT  is manifested in infancy by weight, height, and head circum-  ference growth that may be parallel to but below the normal  ranges. If no genetic, endocrine, or other systemic disorder is  identified and if the physical and laboratory examinations show  no abnormalities other than delayed growth, an environmental  cause is indicated!   Hospital admission is recommended if the diagnosis is  unclear or the child is in nutritional or emotional jeopardy. Eat-  ing patterns, food preferences, caloric intake, and family inter-  actions can be assessed during the hospital stay. If the cause is  environmental, the hospitalized child with FTT usually begins    to gain weight. Organic and nonorganic FTT can coexist, mak-  ing the distinction between them more difficult.   If an organic problem has been identified, management of  FTT consists of treating the cause. Management of nonorganic  FTT involves the immediate total care of the child and mea-  sures to address: (1) the psychosocial and emotional problems  of the caregivers, (2) parent-child interactions, and (3) access to  adequate nutritional resources. Counseling, parental modeling,  and long-term family support are sometimes required. Clinical  manifestations of organic FIT have inorganic components in  the majority of children. The most successful interventions not  only treat the underlying organic cause but also address ways to  assist parents with feeding practices and management of psy-  chosocial symptoms. !?4)!°    Necrotizing enterocolitis (NEC) is an ischemic, inflamma-  tory condition that causes bowel necrosis and perforation, and  infant death if untreated. It is the most common gastrointesti-  nal emergency in the newborn. The overall death rate is between  12% and 30% and is higher for infants requiring surgery.!*°  The incidence of NEC is increasing, causing 1500 to 2000 infant  deaths every year in the United States.!*” NEC primarily occurs  in premature very low birth weight infants.'*° The risk of NEC  decreases as the gastrointestinal tract matures.   PATHOPHYSIOLOGY. The exact etiology of NEC is unclear. Mul-  tiple factors contribute to the development of NEC including  premature birth (<28 weeks), low birth weight, immature immu-  nity, immature intestinal motility and barrier function, abnor-  mal bacterial colonization, infections, maternal age greater than  35 years, maternal hypertensive disease of pregnancy, perinatal  stress and low Apgar scores, effects of medications, enteral feed-  ing, and genetic predisposition.'?”!*° The immature mucosal  barrier delays digestion and motility is slower, allowing for the  accumulation of noxious substances that damage the intestine  and increase permeability and increase the risk for infection.  Translocation of intestinal bacteria and other substances con-  tributes to injury, inflammation, and development of systemic  inflammatory disease. Immature intestinal innate immunity  and an unfavorable balance between normal and pathogenic  bacteria promote intestinal inflammation and release of proin-  flammatory mediators.'°! Accumulation of gas in the intestine  can cause pressure that decreases blood flow and an imbalance  between vasodilator and vasoconstrictor inputs in the imma-  ture gut may lead to vasoconstriction, promoting ischemia,  necrosis, and perforation. Injury to Paneth cells located in the  intestinal crypts has also been proposed.!*!* The terminal ileum  and proximal colon are most often involved.!°!°°   CLINICAL MANIFESTATIONS. Manifestations of NEC appear  suddenly and usually within 2 weeks of birth after introduc-  tion of enteral feeding. Symptoms may appear earlier in full-  term infants (5.3 days compared with 15.3 days in premature  infants).'** They range from mild abdominal distention to  bowel perforation, sepsis, and death. Abdominal pain, unsta-  ble temperature, bradycardia, and apnea are nonspecific signs.  Affected infants have abdominal distention, occult or grossly  bloody stools, retained gastric contents, and septicemia with    elevated white blood cell and falling platelet counts. The more  premature the infant, the greater the incidence of NEC and  related diseases of prematurity, such as respiratory distress syn-  drome and immunocompromised status.   EVALUATION AND TREATMENT. Diagnosis is based on clinical  manifestations, laboratory results, and plain films of the abdo-  men that show gas accumulation in the intestine. Preventive  strategies include following written feeding guidelines; encour-  aging feeding with breast milk; ensuring judicious fluid man-  agement to prevent patent ductus arteriosus; and administering  arginine, glutamine, and lactoferrin supplements, epidermal  growth factor to support intestinal epithelial cell growth, and  enteral prebiotics and probiotics to support commensal gut  bacteria.!*>'°’ Treatments include cessation of feeding formula  milk, avoidance of H2-receptor antagonists, use of gastric suc-  tion to decompress the intestines, maintenance of fluid and  electrolyte balance, and administration of antibiotics to con-  trol sepsis.'°*!4° Enteral feeding should be started as soon as  possible. !4!)!4   Surgical resection is the treatment of choice for intestinal  perforation, and the mortality is high at about 60%, particu-  larly for small bowel resection.'** For very ill infants peritoneal  drainage may be used as an adjunct to laparotomy.'“* Following  treatment of NEC, infants treated by medical and surgical man-  agement are at risk for the following complications: intestinal  obstruction related to the development of strictures, short bowel  syndrome, and neurodevelopmental delay.'*? Infants who have  extensive resection of necrotic bowel may develop short bowel  syndrome, requiring chronic total parenteral nutrition. Pre-  serving bowel length with stents and intestinal transplantation  are available as a lifesaving option for these children.!4°'4”    Diarrhea is an increase in the water content, volume, or fre-  quency of stools and can be acute or chronic. Diarrhea is a  common gastrointestinal problem during infancy and early  childhood, and infectious diarrhea is the leading cause of death  in young children, particularly in developing countries. Severe  diarrhea occurs one to three times during the first 3 years of  life. Most episodes are self-limiting and resolve within 72 hours.   The pathophysiologic mechanisms of diarrhea in children  are similar to those for adults, including osmotic, secretory,  or increased motility (see Chapter 41). Prolonged diarrhea is  more dangerous in children, because they have much smaller  fluid reserves than those of adults. Therefore, dehydration can  develop rapidly if any disturbance increases fluid secretion into  the gastrointestinal lumen (secretory diarrhea), draws fluid into  the lumen by osmosis (osmotic diarrhea), or increases motility  and prevents fluid absorption in the intestine.   Infant diarrhea is of special concern because its cause  may be a congenital or metabolic anomaly. Common causes  of acute diarrhea in infants include infections, congenital  aganglionic megacolon, milk-protein allergies, and NEC.  Less common causes are adrenogenital syndrome, impaired  chloride-bicarbonate exchange, congenital lactase deficiency,  glucose-galactose malabsorption, and sucrase-isomaltase defi-  ciency. Infants have low fluid reserves and relatively rapid    peristalsis and metabolism. Therefore, the danger of dehy-  dration is great. Causes of diarrhea in young children are  unknown in about 40% of cases.!“*    Acute infectious diarrhea in infants and young children is  usually associated with acute viral or bacterial gastroenteri-  tis. Viral causes of diarrhea include rotaviruses, noroviruses,  astroviruses, and certain types of adenoviruses. Rotavirus is  the leading cause of severe diarrhea in infants and young chil-  dren worldwide. Rotavirus invades enterocytes of the intestinal  mucosa and releases an enterotoxin that damages these cells.  Damage decreases viable absorptive surface area, causing an  imbalance of secretion and absorption, and increases motility,  resulting in diarrhea and dehydration. Recovery from mucosal  damage may take several weeks. Rotavirus is transmitted by the  fecal-oral route among humans. Rotavirus vaccine is an effec-  tive preventive strategy and is reducing disease burden in both  developed and developing countries. Monitoring is ongoing to  evaluate resistant strains. '*? By 5 years of age most children have  developed resistance to rotavirus infection. Viral gastroenteritis  tends to be self-limiting.   Bacterial causes of diarrhea include Escherichia coli, Kleb-  siella, staphylococci, Salmonella, Shigella, and Vibrio cholerae.  Giardia intestinalis, Cryptosporidium parvum or hominis, and  Strongyloides stercoralis are parasites that cause diarrhea in  tropical areas. Infectious diarrhea has a rapid onset, and aci-  dosis and shock can occur quickly. Clostridium difficile is often  associated with previous antibiotic therapy and can cause  acute, profuse, watery diarrhea, and symptoms of colitis (pseu-  domembranous colitis). The symptoms are more severe in  immunosuppressed children. Use of probiotics can be helpful  in preventing C. difficile-associated diarrhea.!?)'9!   Bacterial gastroenteritis is treated with antibiotics if the causal  pathogen can be identified. Other causes of acute diarrhea in  the older child include antibiotic therapy, appendicitis, chemo-  therapy, inflammatory bowel disease, parasitic infestation, and  ingestion of toxic substances. Children with acute gastroenteritis  often remain mildly symptomatic for up to 2 weeks; therefore,  diarrhea that persists longer than 2 weeks is considered to be  chronic.   Causes of chronic diarrhea in children include persis-  tent infectious diarrhea (viral, bacterial, or parasitic), chronic  osmotic diarrhea (lactose intolerance or ingestion of large  amounts of poorly absorbable sugars), and disease that impairs  absorption (e.g., celiac disease, pancreatic insufficiency, or  inflammatory bowel disease). Persistent diarrhea is a significant  factor in causing malnutrition and growth failure.   Treatment of diarrhea requires rehydration with fluids, elec-  trolytes, and glucose; maintenance of nutrition; and treatment  of associated conditions and antibiotics as indicated. Intrave-  nous solutions are used only when oral rehydration solutions  are not tolerated. Antiemetics can facilitate oral rehydration!  Zinc supplements (not used in children less than 6 months of  age), yogurt-based or amino acid-based diets, and probiot-  ics may accelerate recovery!?>!°° (see What’s New? Pediatric  Inflammatory Bowel Disease).    Pediatric inflammatory bowel disease (IBD) includes both Crohn disease  (CD) and ulcerative colitis (UC) (see Chapter 41). The incidence in children is  unknown, but CD appears to be increasing across the world. It is often diag-  nosed in late childhood or during adolescence. The etiology is unknown, but  there are suspected genetic, epigenetic, and environmental factors involved,  and children with IBD are more likely to have parents with the disease. Male  children more commonly develop CD; the disease is more extensive and pro-  gressive than in adults, involving both the ileum and the colon; growth failure  is common and associated with corticosteroid treatment; there are higher  rates of hospitalizations and surgery; and growth failure is more common. A  recent large population-based study of IBD in children reported an increased  risk associated with any antianaerobic antibiotic exposure in a dose-response  manner, further emphasizing the need for caution in prescribing antibiotics for  children. Fecal calprotectin (FC) level is elevated in IBD and can be used as a  marker for IBD diagnosis in children. Treatment for childhood IBD is currently  the same as that for adults, but new treatment approaches are needed. Nutri-  tional management is required to maintain normal growth and development.  The risk of cancer and death is low in children with IBD.    Data from Abraham BP, Mehta S, El-Serag HB: J Clin Gastroenterol  46(7):581-589, 2012; Benchimol El et al: Inflamm Bowel Dis 17(1):  423-439, 2011; Henderson P et al: Am J Gastroentero! 107(6):941-949,  2012; Kronman MP et al: Pediatrics 130(4):e794-e803, 2012; Sauer  CG, Kugathasan S: Gastroenterol Clin North Am 38(4):611-628, 2009;  Sherlock ME, Griffiths AM: Curr Gastroenterol! Rep 14(2):166-173,  2012; Tsang J et al: BWC Pediatr 12:162, 2012.    Primary Lactose Intolerance. Lactose intolerance is the  inability to digest lactose (milk sugar). It is caused by inadequate  production of lactase and is a common cause of diarrhea in  children, particularly nonwhite children younger than 7 years of  age. The malabsorption of lactose results in osmotic diarrhea, in  which fluids move by osmosis from the vascular compartment  into the intestinal lumen. The undigested sugar is processed by  the colonic bacteria, and intestinal gas is produced. The diarrhea  is accompanied by abdominal pain, bloating, and flatulence.  Diagnosis includes elimination of dietary lactose or hydrogen  breath testing. Treatment consists of using lactase-treated dairy  products or lactase supplements or reducing dairy product  consumption. Other sources of dietary calcium or supplements  need to be provided if dairy products are eliminated. Some  children can tolerate lactose in fermented forms, such as cheese  and yogurt.!9° 18   Physiologic jaundice (hyperbilirubinemia) of the newborn is  usually a transient, benign icterus that occurs during the first week  of life in otherwise healthy full-term infants. It is caused by mild  unconjugated (indirect-reacting) hyperbilirubinemia. Pathologic  jaundice appears within 24 hours after birth with total serum bil-  irubin level greater than 20 mg/dl or an indirect bilirubin level  greater than 15 mg/dl. Risk factors include fetal-maternal blood  type incompatibility (ABO and Rh incompatibility), prematurity,    exclusive breast-feeding, maternal age greater than or equal to  25 years, an infant of male gender, delayed meconium passage,  and excessive birth trauma such as bruising or cephalhemato-  mas.!°? Prediction tools for hyperbilirubinemia are available to  reduce risk associated with early hospital discharge (within 48  hours) when hyperbilirubinemia may not yet be evident.   PATHOPHYSIOLOGY. Pathologic jaundice results from the com-  plex interaction of factors that cause: (1) increased bilirubin  production (e.g., hemolysis), (2) impaired hepatic uptake or  excretion of unconjugated bilirubin, and (3) delayed matura-  tion of liver conjugating mechanisms.'®? The most common  cause is hemolytic disease of the newborn, also known as eryth-  roblastosis fetalis (ABO blood incompatibility; see Chapters 9  and 30). Unconjugated bilirubin (indirect bilirubin) is lipid  soluble, bound to albumin in the blood, and in the free form  readily crosses the blood-brain barrier in infants. Chronic bili-  rubin encephalopathy (kernicterus) is caused by the deposi-  tion of toxic, unconjugated bilirubin in brain cells and usually  does not occur in healthy full-term infants.!°! Elevated level  of conjugated bilirubin is a sign of underlying disease. A late  rising indirect bilirubin level also may be a manifestation of  glucose-6-phosphate dehydrogenase (an enzyme important  in red blood cell metabolism) deficiency, a hereditary X-linked  genetic defect.'°*!°> Elevated unconjugated bilirubin levels also  can cause hemolysis, further increasing neonatal jaundice.   CLINICAL MANIFESTATIONS. Physiologic jaundice develops during  the second or third day after birth and usually subsides in 1 to 2  weeks in full-term infants and in 2 to 4 weeks in premature infants.  After this, increasing bilirubin values and persistent jaundice  indicate pathologic hyperbilirubinemia. Manifestations include  yellowing skin, dark urine, light-colored stools, and weight loss.  Premature infants with respiratory distress, acidosis, or sepsis are  at greater risk for encephalopathy. The resulting disabilities include  athetoid cerebral palsy and speech and hearing impairment.'°°   EVALUATION AND TREATMENT. Total and direct (conjugated) bil-  irubin levels are monitored and the bilirubin/albumin ratio is  being evaluated as a corollary to unbound serum bilirubin level  for predicting neurotoxicity.!°° Pathologic jaundice should be  suspected with serum bilirubin values that increase greater than  5 mg/dl per day, persistent jaundice (more than 7 to 10 days  in the full-term infant), or conjugated bilirubin values greater  than 2 mg/dl. Other causes of jaundice must be eliminated to  confirm physiologic jaundice.   Treatment depends on the degree of hyperbilirubinemia.  Physiologic jaundice is usually treated by phototherapy (ultra-  violet light) with good eye protection. Phototherapy produces  isomers of bilirubin that are water soluble, can be more rapidly  excreted in the stools and urine, and do not cross the blood-brain  barrier. Pathologic jaundice requires high-intensity phototherapy,  exchange transfusion, and treatment of the underlying cause.  Advances are being made to improve transcutaneous bilirubin  monitoring and use of drugs to reduce serum bilirubin levels.!°” 1°   Biliary atresia is a rare congenital or acquired (perinatal) mal-  formation characterized by the absence or obstruction of intra-  hepatic or extrahepatic bile ducts. Extrahepatic ducts may end    in a blind pouch. The cause is unknown. The congenital form  may be related to a chromosomal abnormality. The acquired  form may be related to a viral infection (cytomegalovirus),  chronic inflammatory disease, or autoimmune injury to bile  duct epithelium.!”° The points of destruction are influenced by  the stage of intrauterine development in which injury occurs.  The atresia or progressive destruction leads to inflammation,  fibrosis, and plugging of the bile canaliculi and extrahepatic bil-  iary tree with obstruction to bile flow. Progressive obstruction  may lead to biliary cirrhosis and portal hypertension (see Chap-  ter 41), which can develop within a few weeks after birth. Liver  failure can lead to death within 2 years without treatment.!7!)'77   Jaundice is the primary clinical manifestation of biliary atre-  sia. Other signs are hepatomegaly and acholic (clay-colored)  stools. Fat absorption is impaired because of the lack of bile  salts, and the infant may fail to gain weight and requires nutri-  tional support.!’° Early diagnosis of biliary atresia is manda-  tory and is based on clinical manifestations and liver biopsy.  Liver function test results are abnormal. Serum transaminase  and alkaline phosphatase values are elevated and conjugated  (direct) serum bilirubin levels rise progressively.   Extrahepatic atresia can be relieved by surgical drainage  and correction in approximately 10% of cases. Some infants  benefit from the Kasai portoenterostomy, in which a hepatic  duct remnant is anastomosed to the jejunum or a jejunal seg-  ment is anastomosed to the porta hepatis if the patent hepatic  duct remnant is not available (Figure 42-9). Even with initial  restoration of bile flow, however, fibrosis and obliteration of  intrahepatic bile ducts can continue, resulting in cirrhosis.    Rest of intestine stitched to  side of small intestine  (Roux-en-Y connection)    FIGURE 42-9 Kasai Procedure. Surgical correction for extrahepatic biliary  atresia. The jejunal segment between the liver and the bowel may be externalized,  creating a double-barrel portoenterostomy.    Liver transplantation is the long-term therapy when surgery  fails. Approximately 40% of children with biliary atresia are  immediate candidates for transplantation. Approximately 90%  of children who receive transplants for biliary atresia become  long-term survivors with good physical and mental develop-  ment.'”4 The use of reduced and split livers from living, related  donors has increased the number of children who survive after  transplantation.!”°   The pathophysiology of viral and fulminant hepatitis is described  in Chapter 41 (see Table 41-7).   Hepatitis A. Approximately one third to one half of the  reported cases of hepatitis A virus (HAV) occur in children.'”°  Incidence is highest among young children of preschool age.  Outbreaks tend to occur in daycare centers with large numbers  of children who are not toilet trained and staff members who  practice poor handwashing techniques.!’” HAV replicates in the  liver and is excreted through the biliary system into the stool.  HAV in young children is usually mild and asymptomatic.  Clinical manifestations, however, may include nausea, vomiting,  and diarrhea. Because jaundice is absent, infected children  appear to have the “flu.” Almost all children recover from  hepatitis A without residual liver damage.'’* Vaccination for  hepatitis A should begin at 12 to 23 months of age.!””   Hepatitis B. Risk factors for hepatitis B virus (HBV) infection  include infants of mothers who are chronic hepatitis B surface  antigen (HBsAg) carriers, hemophiliacs who receive frequent  blood transfusions, children who abuse parenteral drugs, and  children who live in residences for the mentally handicapped.  Of newborns infected by their mothers (vertical transmission),  most develop chronic hepatitis and become carriers.'*° Hepatitis  B is endemic in China and other parts of Asia where most  infections occur in infants and children as a result of maternal-  neonatal transmission.!*!   Chronic hepatitis may develop more often in young children  because of their immature immune systems. Infected infants and  children are at risk for cirrhosis and hepatocellular carcinoma.  The most serious consequence of HBV infection is fulminant  hepatitis, which occurs in 1% of cases. Hepatitis D virus (HDV)  infection depends on active infection with HBV. There is evidence  that the risk of fulminant hepatitis is higher in individuals with  combined infections of HBV, HDV, HCV, or human immuno-  deficiency virus (HIV) than in those with HBV infection alone.!*”  Infants should receive passive-active immunoprophylactic treat-  ment at birth. Most children are treated conservatively and antivi-  rals are used for chronic disease. Aggressive vaccination programs  reduce the incidence of HBV. Maternal antiviral therapy during  pregnancy and lactation is a treatment option.'*°:!*4   Hepatitis C. Hepatitis C virus (HCV) in children is most  commonly transmitted vertically and is enhanced with  maternal coinfection with HIV. It also is transmitted with blood  transfusions. Between 10% and 50% of affected children develop  chronic liver disease. Antivirals are effective in the treatment of  hepatitis C and liver transplant is required for liver failure.'®°  There is currently no vaccination available for hepatitis C.    Chronic Hepatitis. Hepatitis B (HBV) andhepatitis C (HCV) are  the main causes of chronic hepatitis in children. Manifestations of  chronic hepatitis include malaise, anorexia, fever, gastrointestinal  bleeding, hepatomegaly, edema, and transient joint pain. Often  there are no symptoms. Serum transaminase and bilirubin  levels are elevated. There may be evidence of impairment of  synthetic functions of the liver: prolonged prothrombin time  and hypoalbuminemia. Diagnosis is based on the clinical  manifestations and liver biopsy. There is no curative therapy  for chronic HBV or chronic HCV and children are treated with  antiviral drugs and should continue to be monitored. There also  is an autoimmune form of chronic hepatitis that is treated with  immunosuppression therapy.'®° Liver transplant may ultimately  be required for chronic hepatitis.!°71°°   Cirrhosis is fibrotic scarring of the liver in response to inflam-  mation and tissue damage (see Chapter 41). Most forms of  chronic liver diseases in children can progress to cirrhosis, but  they seldom do. Causes include cystic fibrosis, biliary atresia,  infectious hepatitis, and Wilson disease. Nonalcoholic fatty  liver disease (steatohepatitis) is increasing in children in corre-  lation with an increase in childhood obesity and it can progress  to cirrhosis and liver cancer.!*?   The complications of cirrhosis in children are the same as  those in adults: portal hypertension, the opening of collateral  vessels between the portal and systemic veins, and varices. In  addition, children with cirrhosis experience growth failure  caused by nutritional deficits and developmental delay, particu-  larly in gross motor function because of ascites and weakness.  The cause of cirrhosis may influence its severity and course.  Some types of cirrhosis can be stabilized if the cause is identi-  fied and treated early.   The two basic causes of portal hypertension in children are:  (1) increased resistance to blood flow within the portal sys-  tem, and (2) increased volume of portal blood flow. Increased  resistance to flow can occur anywhere in the portal circula-  tory system. Portal hypertension can accompany cirrhosis,  intra-abdominal infections, portal vein thrombosis, congenital  anomalies of the portal vein, and congenital hepatic fibrosis.   Extrahepatic Portal Hypertension. Extrahepatic (prehepatic)  portal venous obstruction causes 50% to 70% of extrahepatic  portal hypertension in children. For at least half of these  children, no specific cause can be found. Obstruction is almost  always in the portal vein and is usually caused by thrombosis.  Umbilical infection with or without a history of catheterization  of the umbilical vein may be a cause in neonates. Portal vein  thrombosis can occur as a complication of intra-abdominal  infections, pancreatitis, and blunt abdominal trauma. It also has  been associated with neonatal dehydration, inflammatory bowel  disease, and hypercoagulable states, such as protein C and protein  S deficiencies.!”° Life-threatening variceal bleeding can require  banding or sclerotherapy. Mesoportal bypass (anastomosis    of mesenteric vein to portal vein) restores normal physiologic  portal flow to the liver and corrects portal hypertension.!”!   Intrahepatic Portal Hypertension. Cirrhosis is the primary  cause of intrahepatic portal hypertension. The most common  finding is cirrhosis and congenital hepatic fibrosis, which  increases resistance to portal blood flow by constricting and  reducing the compliance of the hepatic sinusoids. No underlying  cause is found in half of cases.'?”   CLINICAL MANIFESTATIONS. The clinical manifestations of portal  hypertension are: (1) splenomegaly, (2) upper gastrointestinal  bleeding, (3) ascites, and (4) hepatic encephalopathy (see Chap-  ter 41). Severe liver disease is characterized by hypoalbuminemia,  prolonged prothrombin times, hyperbilirubinemia, electrolyte  imbalance, and hypoglycemia. Splenomegaly is the most com-  mon sign of portal hypertension in children. The spleen may  be firm or hard, depending on the duration of portal hyperten-  sion. In children, most episodes of gastrointestinal bleeding are  caused by rupture of esophageal varices. Hematemesis, possibly  associated with abdominal pain, often accompanies sudden pal-  lor. Melena is observed, either at the time of hematemesis or  soon afterward. Clotting abnormalities caused by altered liver  function promote the bleeding. If plasma volume is increased,  esophageal varices readily rupture during activities that increase  blood pressure, such as coughing. Acetylsalicylic acid (aspirin),  which should not be administered to children, can trigger bleed-  ing. Severe bleeding episodes can cause hypovolemic shock  and death. Symptoms of ascites include weight gain, protrud-  ing abdomen, and reduced tidal volumes if the ascites is severe.  Hepatic encephalopathy in children can be acute or chronic.  Acute encephalopathy is characterized by major disorders of  consciousness, which may progress to coma. This may follow an  acute episode of variceal bleeding as the impaired liver attempts  to metabolize the large protein (nitrogenous) load from the    blood. Chronic, or minimal, encephalopathy is characterized by  emotional or psychiatric disorders, decreased intellectual func-  tioning, personality disorders caused by minimal brain dysfunc-  tion, and spatial disorientation.   EVALUATION AND TREATMENT. Assessment of portal hyperten-  sion in children must be thorough because the cause dictates  the management. The objectives of the clinical investigation  are to locate the site of the venous block and identify the dis-  ease responsible for the portal hypertension. Thorough physical  examination, laboratory tests of liver function, imaging proce-  dures, and biopsy may be included in the diagnostic evaluation  (see Chapter 40). Sclerotherapy, banding, and transjugular intra-  hepatic portosystemic shunt (TIPS procedure) are treatments for  severe esophageal varices in children.'?!)!°°   The indications for surgical shunting include gastrointesti-  nal hemorrhage not responsive to sclerotherapy. Portosystemic  shunts are rarely performed in children but it can be a bridge to  liver transplant.!°* The outcome of portal hypertension depends  almost entirely on its cause. Children with extrahepatic disease  are expected to recover with little morbidity. For children with  intrahepatic disease, the prognosis varies.    More than 5000 genetically determined metabolic pathways  have been identified in liver tissue. The earliest possible iden-  tification of metabolic disorders is essential because: (1) early  treatment may prevent permanent damage to vital organs,  such as the liver or brain; (2) precise genetic counseling may be  possible with prenatal diagnosis; and (3) complications can be  minimized, even if cure is not possible. Galactosemia,!”° fruc-  tosemia, and Wilson disease are rare treatable metabolic disor-  ders that have hepatic clinical manifestations. These disorders  are summarized in Table 42-2; Wilson disease is discussed next.   Presence of reducing substances  in urine when infant is receiving  lactose   Cannot metabolize fructose, sucrose,  or honey; occurs when breast milk is  replaced with cow's milk   |mpaired transport of copper in blood caused by  diminished transport protein (ceruloplasmin)    Chelation therapy to remove copper from body  Decreased dietary intake of copper  Liver transplant    Wilson disease (hepatolenticular degeneration) is an autoso-  mal recessive defect of copper metabolism related to loss of  ATP7B gene expression that causes toxic amounts of copper to  accumulate in the liver, brain, kidneys, and corneas. ATP7B is  localized on chromosome 13 and encodes copper-transporting  P-type adenosinetriphosphatase (ATPase) membrane-spanning  protein. It is highly expressed in the liver, kidney, and placenta  and is expressed in lower levels in the brain, heart, muscle, and  pancreas.!°° This defect in the uptake and excretion of copper  by hepatocytes is an important cause of progressive liver disease  in children and young adults. Wilson disease is very rare, with  an incidence of 1 in 30,000 live births worldwide.'”” Between 1  in 200 and 1 in 500 persons are carriers.!”°   PATHOPHYSIOLOGY. Two major abnormalities in copper metab-  olism have been identified: (1) diminished biliary excretion of  copper, and (2) failure to insert copper into ceruloplasmin (a  glycoprotein that transports copper in the blood). A positive  copper balance is present from birth in children with Wilson  disease, despite increased excretion of copper in the urine.  Copper toxicity with accumulation in the liver and brain is  the major abnormality. Excesses of copper generate free radi-  cals that disrupt cellular organelles, deoxyribonucleic acid  (DNA), microtubules, enzymes, and proteins. Copper overload  is related to impaired biliary excretion of copper and may be  related to failure of hepatocyte lysosomes to eliminate copper  by exocytosis.!°   Early in the disease, intestinal absorption of copper is nor-  mal, as is hepatic clearance of albumin-bound absorbed cop-  per. As copper-binding proteins in the liver become saturated,  hepatic uptake of copper diminishes, with elevated serum cop-  per levels and biochemical and clinical evidence of liver damage  caused by copper accumulation. In later stages of the disease,  copper accumulates in extrahepatic tissues, including the eyes,  brain, and kidneys.   When cerebral copper-binding proteins become saturated,  a characteristic pattern of brain damage develops, particularly  in the basal ganglia. Neural effects include intention tremor,  unsteady gait, dystonia, and behavioral changes. Manifesta-  tions of renal tubular injury usually appear simultaneously. The  uptake of copper by red blood cells is thought to cause hemolytic    anemia, a condition sometimes seen early in the clinical course  of Wilson disease.   CLINICAL MANIFESTATIONS. The clinical manifestations of Wil-  son disease may begin as young as 4 years of age, when control  mechanisms responsible for copper homeostasis and biliary  excretion should have matured. The classic clinical presentation  of Wilson disease is a triad of neuromuscular abnormalities,  intention tremors, dysarthria (indistinct speech), and dysto-  nia (disordered muscular tonicity): (1) Kayser-Fleischer rings  (accumulation of copper in the limbus of the cornea, causing  a greenish yellow ring), (2) cirrhosis associated with elevated  serum copper levels, and (3) low ceruloplasmin levels.!%? Initial  symptoms vary from malaise and abdominal pain to jaundice.  Changes in mental and motor performance may develop at  age 6 years or into adult life. The earliest signs of liver involve-  ment include enlargement of the liver and spleen, jaundice,  and anorexia. Edema and ascites may develop suddenly, or  gastrointestinal hemorrhage may be the initial sign of the dis-  ease. Occasionally Wilson disease begins with a hemolytic crisis  caused by the toxic effects of copper on the red blood cells. Cir-  rhosis develops in all untreated cases. Copper deposition in the  kidneys causes a proximal renal tubular defect that results in  losses of glucose, amino acids, phosphate, and uric acid in the  urine and renal tubular acidosis. All untreated individuals will  develop behavioral or psychiatric disorders.   EVALUATION AND TREATMENT. Because Wilson disease is rare  and has broad clinical manifestations, it may not be diagnosed  until older childhood or adulthood. The mean age at diagnosis  in one large study was 15.5 years.” Laboratory tests detect a  serum ceruloplasmin concentration less than 30 mg/dl. Serum  copper values may be normal or high, and urine copper values  are elevated. Liver biopsy is used to assess structural changes  and measure copper concentrations. ATP7B gene sequencing  can avoid the need for liver biopsy.”°! The goal of therapy is  to decrease copper accumulation by decreasing dietary copper  intake and intestinal copper absorption, and increasing renal  excretion of copper. Medical treatments include p-penicilla-  mine, trientine, zinc (reduces intestinal copper absorption),  and ammonium tetrathiomolybdate.”” Liver transplantation is  the only therapy for Wilson disease and gene therapy and hepa-  tocyte cell transplantation are being investigated.   1. Most alterations of digestive function in children are caused  by congenital anomalies of the intestinal tract; disorders of  digestion, absorption, or nutrition; or liver disease.   2. Cleft lip (harelip) and cleft palate (failure of the bony palate  to fuse in the midline) may occur separately or together,  and both defects are associated with multiple gene-envi-  ronmental interactions and deficiency of B vitamins. The  fissure may affect the uvula, soft palate, hard palate, nostril,  and maxillary alveolar ridge.   3. Esophageal atresia, a condition in which the esopha-  gus ends in a blind pouch, may occur with or without    tracheoesophageal fistula, a connection between the esoph-  agus and the trachea. As the infant swallows oral secretions  or ingests milk, the pouch fills, causing either drooling or  aspiration into the lungs.   4. Pyloric stenosis, an obstruction of the pyloric outlet caused  by hypertrophy and hyperplasia of circular muscles in the  pyloric sphincter, is more common in male infants and may  require surgical correction.   5. Intestinal malrotation occurs with failure of the colon to  rotate during fetal development and an obstructing band or  volvulus (twisting of the bowel on itself) may partly or com-  pletely occlude the gastrointestinal tract and its blood vessels.    Meconium ileus is a condition in the newborn in which  intestinal secretions and amniotic waste products produce  a thick tarry plug that obstructs the intestine, usually from  lack of fetal digestive enzymes. From 10% to 15% of neo-  nates with CF have meconium ileus as neonates.    when intestinal contents become abnormally thick and  obstruct the intestinal lumen. CF, pancreatic enzyme defi-  ciency, and dehydration are common causes.    . Meckel diverticulum is an outpouching of all layers of the    small intestine caused by failure of the fibrous band that  connects the small intestine to the umbilicus.   Congenital aganglionic megacolon (Hirschsprung disease)  is caused by an absence of enteric ganglia and malformation  of the parasympathetic nervous system in a segment of the  colon, resulting in inadequate colon motility and functional  obstruction.   Malformations of the anus and rectum range from mild  congenital stenosis of the anus to complex deformities, all  of which are classified as imperforate anus.   The most common cause of acquired intestinal obstruc-  tion in infants is intussusception, a condition in which  one portion of the bowel telescopes or invaginates into  another. It occurs most commonly in the area of the ileo-  cecal junction.   GERD is caused by the relaxation or incompetence of  the lower esophageal sphincter. Infants are susceptible  to reflux because the sphincter is not fully mature, their  diet consists of liquids, and they are seldom in an upright  position.   Eosinophilic esophagitis involves an eosinophilic inflam-  mation of the esophagus with dysphagia and vomiting that  can be associated with asthma and eczema.   CF is an inherited disease with a pathophysiologic triad  that includes pancreatic enzyme deficiency (which causes  maldigestion), overproduction of mucus in the respiratory  tract, and abnormally elevated sodium and chloride con-  centrations in sweat.   Gluten-sensitive enteropathy is an immune-mediated life-  long disease characterized by the loss of mature villous  epithelium in the presence of a gluten-containing diet. It  results in malabsorption and growth failure.   Severe acute malnutrition is a group of disorders  resulting from a severe dietary deficiency of proteins  (kwashiorkor), carbohydrates, or both (marasmus).  Starvation causes stunted mental and physical develop-  ment. Kwashiorkor occurs most often in toddlers who  have stopped breast-feeding and subsist on a high-  carbohydrate diet.    Failure to thrive is inadequate physical growth of a child.  Organic failure to thrive is caused by genetic, anatomic, or  pathophysiologic factors that restrict normal growth and  development. Nonorganic failure to thrive is caused by  nutritional deficits associated with inadequate nurturing.  Necrotizing enterocolitis is a disorder in neonates, par-  ticularly low birth weight or premature infants, thought to  result from stress and anoxia of an immature bowel wall.  Bacteria invade the mucosa and can result in colitis, necro-  sis, intestinal perforation, sepsis, and death.   Acute diarrhea in infants and children is often caused by  infection and can rapidly cause dehydration and electrolyte  imbalances because fluid reserves are relatively small. The  most common cause of acute diarrhea in children is bacte-  rial or viral enterocolitis.   Chronic diarrhea (diarrhea persisting longer than 4 weeks)  can be caused by a wide variety of underlying conditions  and often leads to growth failure and delayed development.  Lactose intolerance causes diarrhea when failure to produce  lactase results in osmotic diarrhea with ingestion of lactose-  containing dairy products.    Physiologic jaundice of the newborn is caused by mild  hyperbilirubinemia that subsides in 1 to 2 weeks. Patho-  logic jaundice is caused by severe hyperbilirubinemia and  can cause brain damage (kernicterus).    . Biliary atresia is a congenital malformation of the bile ducts    that obstructs bile flow. Atresia causes jaundice, cirrhosis,  and liver failure. Biliary atresia is the most common reason  for liver transplantation in children.    . Acute hepatitis has the same clinical course in children and    adults but children have milder cases of the disease. Hepati-  tis A is the most common form of childhood hepatitis.    . Cirrhosis is fibrotic scarring of the liver and is rare in chil-    dren but can develop from most forms of chronic liver  disease.    hepatic obstruction. Thrombosis of the portal vein is the  most common cause of portal hypertension in children and  splenomegaly is the most common sign.    liver damage in children are galactosemia, fructosemia, and  Wilson disease. All are rare, inherited as genetic traits, and  permit the accumulation of toxins in the liver.    olism. Unexcreted copper accumulates in the liver, brain,  kidney, and corneal cells. Damage from accumulated cop-  per is gradual; the disease is usually not diagnosed before  age 4 or 5 years.   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Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Structure and Function of Bones, 1510  Elements of Bone Tissue, 1511  Types of Bone Tissue, 1517  Characteristics of Bone, 1517  Maintenance of Bone Integrity, 1519   Structure and Function of Joints, 1520  Fibrous Joints, 1520  Cartilaginous Joints, 1520  Synovial Joints, 1522    The way an individual functions in daily life, moves about, or  manipulates objects physically depends on the integrity of the  musculoskeletal system. The musculoskeletal system is actu-  ally composed of two systems: (1) the skeleton proper, which  is composed of bones and joints; and (2) skeletal muscles. Each  of the systems contributes to mobility. The skeleton supports  the body and provides leverage to the skeletal muscles so that  movement of various parts of the body is possible. This move-  ment is accomplished by contraction of the skeletal muscles and  bending or rotation at the joints.    Bones give form to the body, support tissues, and permit move-  ment by providing points of attachment for muscles. Many  bones meet in movable joints that determine the type and  extent of movement possible. Bones also protect many of the    Structure and Function of Skeletal Muscles, 1526  Whole Muscle, 1527  Components of Muscle Function, 1533  Tests of Musculoskeletal Function, 1535  Tests of Bone Function, 1535  Tests of Joint Function, 1535  Tests of Muscular Function, 1535  AGING and The Musculoskeletal System, 1536    body’s vital organs. For example, the bones of the skull, thorax,  and pelvis are hard exterior shields that protect the brain, heart,  lungs, and reproductive and urinary organs.   Bone marrow is one of the sources of mesenchymal stem  cells (MSCs) (Figure 43-1). These nonhematopoietic stem  cells consist of a small proportion of the stromal cell popula-  tion in the bone marrow, and can generate bone, cartilage,  fat, cells that support the formation of blood, and fibrous  connective tissue. Within certain bones, the marrow cavi-  ties also serve as storage site for the hematopoietic stem cells  that form both blood and immune cells. In adults, blood cells  originate exclusively in the marrow cavities of the skull, ver-  tebrae, ribs, sternum, scapulae, and pelvis. Bones also have a  crucial role in mineral homeostasis, and storing and releasing  minerals (i.e., calcium, phosphate, carbonate, magnesium)  that are essential for the proper working of many delicate cel-  lular mechanisms.    FIGURE 43-1 Hematopoietic and Mesenchymal Stromal Cell Differentiation. Undifferentiated hematopoietic and  mesenchymal multipotential cells give rise to a variety of cell types with distinct functions. (Adapted from abcam.com.)    Mature bone is a rigid yet flexible connective tissue consisting  of cells, fibers, a gelatinous material termed ground substance,  and large amounts of crystallized minerals, mainly calcium, that  give bone its rigidity. The structural elements of bone are sum-  marized in Table 43-1.   Bone cells enable bone to grow, repair itself, change shape,  and continuously synthesize new bone tissue and resorb (dis-  solve or digest) old tissue. The fibers in bone are made of col-  lagen, which gives bone its tensile strength (the ability to hold  itself together). Ground substance acts as a medium for the    diffusion of nutrients, oxygen, metabolic wastes, biochemicals,  and minerals between bone tissue and blood vessels.   Bone formation arises during embryonic development  when mesenchymal stem cells begin differentiating into either  chondrocytes or preosteoblasts. Endochondral ossification and  intramembranous bone formation are the two major mecha-  nisms responsible for normal bone development.   Endochondral ossification occurs when mesenchymal  (mesenchyme, or loose tissue found during embryonic devel-  opment) stem cells begin differentiating into chondrocytes (see  Figure 43-1), which in turn develop a mineralized cartilage    scaffold that allows formation of osteoblasts. Most bone ele-  ments are formed this way. With the second mechanism, intra-  membranous bone formation, mesenchymal stem cells  differentiate into a preosteoblast line that then forms osteo-  blasts without any cartilage framework.!   Multiple factors influence normal bone formation, mainte-  nance, and remodeling. The superfamily of signaling factors,  containing more than 40 members including bone morpho-  genic proteins (BMPs), is known as the transforming growth  factor-beta (TGF-f) family. This group is primarily responsible  for initiation, differentiation, and commitment of precursor  cells into osteoblasts. TGF- signals are transmitted across the  plasma membrane, combine with certain proteins that act as  transcription factors (Smads), and then form specific receptors  known as R-Smads. These receptors, in turn, initiate intracel-  lular signaling, interact with other transcription factors, and  regulate other factors that are important in osteoblast forma-  tion, function, and maintenance.’ Crosstalk between signaling  pathways (including TGF-B, BMPs, FGF, Wnt, Notch, MAPK,  and Hedgehog) is critical in regulating osteoblasts.   BMPs have multiple crucial functions in the skeletal system.  BMP activities are regulated at different molecular levels. Table  43-2 summarizes the role of several important BMPs.   Wnt genes belong to a large family of protein-signaling fac-  tors that are required for the development of body systems,  including the musculoskeletal system. They play a significant  role in forming bone, developing bone mass, remodeling, and    Synthesize collagen and proteoglycans; stimulate bone formation and are also involved in some osteoclast    Maintain bone matrix; act as mechanoreceptors; influence osteoblasts and osteoclasts  Resorb bone; major role in mineral homeostasis    Inhibits calcium-phosphate precipitation; promotes bone resorption  Stabilizes basement membranes in bones    Regulates vitamin D and thereby promotes mineralization  Balance of organic and inorganic phosphate required for proper bone mineralization; regulates vitamin D    fracture healing. Wnt signaling regulates production and differ-  entiation of osteoblasts and osteoclasts, and affects bone mass  and density, joint formation, fracture repair, bone remodeling,  and some bone diseases. Other important elements responsible  for bone formation and homeostasis are presented in Table  43-3,   In mature bone the formation of new tissue begins with the  production of an organic matrix by the bone cells. This bone  matrix consists of ground substances, collagen, and other pro-  teins (see Table 43-1) that take part in bone formation and  maintenance.   The next step in bone formation is calcification, when min-  erals are deposited and crystallize. Minerals bind tightly to col-  lagen fibers, producing tensile and compressional strength in  bone, and withstand pressure and weightbearing.    Bone contains three types of cells: osteoblasts, osteocytes, and  osteoclasts (Figure 43-2). Osteoblasts are the bone-forming  cells, whose primary function is to lay down new bone. Once  this function is complete, osteoblasts become osteocytes that  are imbedded in bone. Comprising 90% to 95% of bone cells,  osteocytes develop dendritic processes that extend to either the  bone surface or the bone’s vascular space.* They help maintain  bone by signaling osteoblasts and osteoclasts to form and resorb  bone.° Osteoclasts are the major bone-resorbing cells respon-  sible for remodeling.    Data from Caetano-Lopes J, Canhao H, Fonseca JE: Arthritis Res Ther 9(Suppl 1):S1, 2007; Hojo H et al: J Bone Miner Metab 28(5):489-502, 2010;    Cartilage development; is actually a metalloprotease; key role in extracellular matrix (ECM) formation   Found in osteoblasts; helps maintain adult joint integrity; accelerates bone repair   Major role in osteoblast differentiation, chondrocyte formation, fracture healing; important in renal  development and repair    Cartilage development; tendon and ligament repair  Assists in bone and tendon healing; cartilage formation    Fajardo M, Liu C-J, Egol K: Clin Orthop Relat Res 467(12):3071-3078, 2009; Li Y et al: Zhong Nan Da Xue Xue Bao Yi Xue Ban 37(1):1-5, 2012.    Receptor activator of nuclear factor KB (RANK)  Bone morphogenic protein antagonists    Superfamily of polypeptides; regulates bone formation, many other cellular processes though  signaling   FGF-2 increases osteoblast population, but not function; inhibits alkaline phosphatase activity,  osteocalcin, type 1 collagen, and osteopontin    Increases peak bone mass during adolescence; decreases osteoblast apoptosis; maintains bone matrix   Mediate the signaling cascade of transforming growth factor-beta (TGF-f), especially in embryonic  bone development; play a role in crosstalk between BMP/TGF-B and Wnt signaling pathways   Members of transforming growth factor-beta (TGF-B) superfamily of polypeptides; have many   unctions outside skeletal system; stimulate endochondral bone and cartilage formation and   unction, promote osteoblast maturation; augment bone remodeling by affecting both osteoblasts   Superfamily of cytokines; play major role in regulating bone metabolism, especially osteoclast   nhibits bone remodeling/resorption; produced by several cells, including osteoblasts; is a decoy   receptor for RANKL (binds to RANKL, inhibiting RANK/RANKL interactions, suppressing osteoclast   Multiple effects in and out of skeletal system, but also binds BMP-2, -4, and -7; may play a role in  development of osteoporosis   Affects both osteoblasts and osteoclasts; may promote bone formation and fracture healing;  expressed by both osteoblasts and chondrocytes; helps regulate bone mass   Dominant over activin and BMPs; helps regulate bone mass and strength by affecting formation of  osteoblasts and osteoclasts   Important in differentiating osteoblasts and bone formation; has overlapping effects with BMPs; helps  regulate bone formation and remodeling    Disrupt Wnt signaling, leading to reduced bone mass  Protein secreted by osteocytes, osteoblasts, and osteoclasts; binds to BMP-6 and BMP-7; interferes  with Wnt signaling pathway, inhibiting bone formation by osteoblasts    TABLE 43-3 SELECTED FACTORS AFFECTING BONE FORMATION AND HOMEOSTASIS — cont'd    Matrix metalloproteinases (MMPs)  Family of endopeptidases (enzymes) that includes  collagenases, gelatinases, stromelysins, matrilysins  A disintegrin and metalloproteinase (ADAM)  A disintegrin and metalloproteinase with    Affects embryonic osteoclastogenesis; plays a role in certain osteoclast, osteoblast, and chondroblast    Help maintain equilibrium of extracellular matrix (ECM); break down almost all components of ECM    Proteolytic enzymes; also have cell-signaling functions, usually linked to cell membrane  Similar to ADAMs but are secreted into circulation, are found around cells; various subgroups affect    K-expressed by osteoclasts; assists in bone remodeling by cleaving proteins, such as collagen type |,    MMP Inhibitors  Tetracyclines (especially doxycycline), bisphosphonates  Tissue inhibitors of metalloproteinases (TIMPs)    From Boyce GC, Zhenqiang, Zing L: Ann N Y Acad Sci 1192:367-375, 2010; Canalis E: J Cell Biol 108(4):769-777, 2009; Kim Y-S et al: J Korean  Med Sci 25:985-991, 2010; Moester MJ et al: Calcif Tissue Int 87(2):99-107, 2010; Nicks KN et al: Mol Cell Endocrinol 310(1-2):11-20, 2009;  Pasternak B, Aspenberg P: Acta Orthopaedica 80(6):693-703, 2009; Stewart A, Guan H, Yang K: J Cell Physio! 223(3):658-666, 2010; Tat SK et al:    FIGURE 43-2 Bone Cells. A, Osteoblasts are responsible for the production of collagenous and noncollagenous proteins    that compose osteoid. Active osteoblasts are lined up on the osteoid. Note the eccentrically located nuclei. B, Osteocyte.  Scanning electron micrograph showing an osteocyte within a lacuna. The cell is surrounded by collagen fibers and mineralized  bone. €, Osteoclasts actively resorb mineralized tissue. The scalloped surface in which the multinucleated osteoclasts rest is  termed the Howship lacuna. (A and € from Damjanov |, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.  B from Erlandsen S, Magney J: Color atlas of histology, St Louis, 1992, Mosby.)    Osteoblasts. Osteoblasts are cells derived from mesenchymal  stem cells. Osteoblasts produce several substances, including  osteocalcin, TGF-B, macrophage colony-stimulating factor,  receptor activator of nuclear factor «fi ligand (RANKL),  osteoprotegerin (OPG), and bone matrix® and osteocalcin when  stimulated by 1,25-dihydroxy-vitamin D. Osteoblasts are active  on the outer surface of bones, where they form a single layer of  cells. They initiate the formation of new bone by their synthesis  of osteoid (nonmineralized bone matrix). The mechanism  of osteoblast stimulation is reported to be the production of  so-called coupling factors generated during the resorption  process. Osteoblasts cause the formation of new bone and the  orderly mineralization of bone matrix by concentrating some of  the plasma proteins (growth factors) found in the bone matrix    and by facilitating the deposit and exchange of calcium and other  ions at the site. Osteoblasts alter levels of RANKL and OPG; the  balance of these two cytokines determines overall osteoclast  formation’ (see Figure 44-11). As new bone is formed, it is shaped  and remodeled through TGF-£, as well as other plasma proteins  (growth factors) found in the bone marrow (Table 43-4).   Osteocytes. An osteocyte is a transformed osteoblast that is  trapped or surrounded in osteoid as it hardens from minerals  that enter during ossification (see Figure 43-2, B). It is the final  differentiation stage for an osteoblast. The osteocyte is within  a space in the hardened bone matrix called a lacuna. Each  osteocyte has a high nucleus/cytoplasm ratio with a thin layer  of nonmineralized osteoid around it, similar to the egg white  surrounding an egg yolk.    Transforming growth factor-beta Bone  Transforming growth factor-alpha or epidermal growth factor Bon  Insulin-like growth factor Bon  Fibroblast growth factor Bon  Platelet-derived growth factor Bon  Colony-stimulating factors Bon  Interferon-gamma Bon    +, -, Both stimulatory and inhibitory properties on the specific cell listed; 0,    The cells of the osteoblastic lineage (osteoblasts and osteo-  cytes) form a network of cells in bone that sense the shape  and structure of bone (mechanoreceptors) and determine the  appropriate locations for bone formation or resorption, accord-  ing to Wolff’s law (bone is shaped according to its function).   Osteocytes communicate with other bone cells and instruct  both osteoblasts and osteoclasts about when and where to form  and resorb bone; concentrate nutrients in the matrix; regulate  bone mass and minerals (especially calcium and phosphorus);  and secrete other proteins, such as sclerostin and fibroblast growth  factor-23 (FGF-23), that influence mineral metabolism.°**°  Sclerostin inhibits osteoblasts, thus reducing bone formation.  Additionally, osteocytes seem to function as endocrine receptors in  regulating bone metabolism and are prime target cells of parathy-  roid hormone (PTH).”"!! Through exchanges between these cells,  hormone catalysts, and minerals, optimal levels of calcium, phos-  phorus, and other minerals are maintained in blood plasma. The  osteocyte also aids in modifying bone matrix through release of  enzymes to dissolve the mineralized walls of the lacunae to prepare  the bone for remodeling. (Remodeling is described on p. 1519.)   Osteoclasts. Osteoclasts are large, multinucleated bone  cells derived from hematopoietic stem cells in the bone marrow  stroma and are the major resorptive cells of bone. Considered  to be the major remodelers of bone, osteoclasts contain  lysosomes (digestive vacuoles) filled with hydrolytic enzymes.  Fine projections, or microvilli, fan out from the osteoclast cell’s  surface and are known as ruffled borders; these projections  result from extensive infoldings of the cell membrane adjacent  to the resorptive surface.!* Osteoclasts in regions of bone  resorption lie in pits called Howship lacunae, where the infolded,  ruffled borders of the osteoclasts greatly increase the surface  area of the plasma membrane. The infolds end in numerous  channels and vesicles in the cell cytoplasm, permitting them to  resorb the bone under their ruffled, infolded borders.    Osteoclasts bind to the bone surface of cell attachment pro-  teins called integrins.'* In contact with bone mineral, osteo-  clasts use adhesive structures, called podosomes, to attach  themselves to the bone surface. They then seal their cytoplasm  with the underlying bone and dissolve the bone and matrix  while protecting the surrounding tissue.'? They effect resorp-  tion of bone by secretion of hydrochloric acid (HCl) and  cathepsin K (a protease enzyme), which help dissolve bone  minerals and collagenase, thereby aiding the digestion of colla-  gen along with the action of cytokines (see Table 43-4). Matrix  metalloproteinases (MMPs), a group of proteolytic enzymes,  help control osteoclast-matrix interactions necessary for bone  resorption. Once resorption is completed, the osteoclast disap-  pears by degeneration, either by reverting to its parent cell or  by leaving the site through the process of cell mobility, wherein  the osteoclast then becomes an inactive, or “resting,” osteoclast.  Overall, bone homeostasis is the result of crosstalk between  osteoclasts, osteoblasts, and osteocytes.'* Recent evidence has  indicated that osteoclasts also may play a role in the body’s  immune system.!>-!7    Bone matrix is made of the extracellular elements of bone tis-  sue, composed of about 35% organic and 65% inorganic mate-  rials. The major organic components are collagen fibers, and  the major inorganic components are the calcium and phos-  phate minerals. Other parts of the bone matrix are the pro-  teins, carbohydrate-protein complexes, and ground substances.  Water comprises 5% to 8% of the matrix. Within the matrix  are small particles known as matrix vesicles that “bud” from  chondrocytes, osteoblasts, and odontoblasts. These vesicles are  the initial sites for calcification in skeletal tissues.'® Calcifica-  tion begins as extracellular calcium enters the matrix vesicles  and forms hydroxyapatite crystals.    | Bone, tendon, ligament, intervertebral  disk, muscle*  Cartilage, intervertebral disk  Skin, muscle, often with type |  Basement cell membrane, muscle  Codistributed with type | muscle, most    Collagen Fibers. Collagen fibers are the major organic  component of bone matrix. The fibers are approximately  90% type I collagen, are essential for bone strength, and are  synthesized and secreted by osteoblasts. Once secreted, collagen  molecules assemble into thin chains called a-chains, which  combine in groups of 3 to form fibrils. The fibrils form a  staggered pattern, overlapping nearby fibrils by approximately  one fourth their length. This staggered, overlapping pattern  creates regular gaps, called hole zones, into which mineral  crystals are deposited.!* After mineral deposition, the fibrils link  together and twist to form ropelike fibers. Collagen fibers then  join to form a framework that gives bone its tensile strength and  enables it to bear weight.   Collagen is the most abundant macromolecule in the body,  accounting for approximately one third of all protein and pro-  viding the structural framework for nearly all tissues. Collagen  is one of the extracellular components, along with proteogly-  cans and noncollagenous matrix proteins, of articular cartilage.  To date, more than 20 types of collagen have been identified,  though all their functions are not yet known. Cartilage-specific  collagens include types II (the principal component), VI, IX,  X, and XI. Type IX collagen is thought to be the “glue” that  holds together the type II collagen scaffold of articular cartilage,  helps maintain the structural integrity of cartilage, and resists  tensile forces on the joint cartilage. Type XI regulates the fibril  diameter of type II cartilage. Degradation of type IX collagen by  proteolytic enzymes has been seen in the early stages of osteo-  arthritis and rheumatoid arthritis. Researchers have proposed  that this degradation, or “unplugging,” may be the mechanism  for the degenerative changes seen in osteoarthritic and rheuma-  toid cartilage. Table 43-5 gives the musculoskeletal distribution  of other types of collagen.    Proteoglycans. Proteoglycans are large complexes of  numerous polysaccharides attached to a common protein  core. Hyaline cartilage is primarily composed of the  glycosaminoglycans chondroitin sulfate and keratin sulfate.  They strengthen bone by forming compression-resistant  networks between the collagen fibrils. Proteoglycans also control  the transport and distribution of electrically charged particles  (ions), particularly calcium, through the bone matrix, thereby  playing a role in bone calcium deposition and calcification.   Glycoproteins. Glycoproteins are also carbohydrate-  protein complexes of bone. Glycoproteins control the collagen  interactions that lead to fibril formation. They also play a role  in calcification.   Some of the glycoproteins in bone matrix include bone  sialoprotein, osteocalcin, osteonectin, laminin, albumin, and  a-glycoprotein. Other proteins found in bone matrix are the  compounds currently called bone morphogenic proteins  (BMPs) (see Table 43-2). Sialoprotein (osteopontin) com-  prises about 8% of the noncollagenous matrix of bone and eas-  ily binds with calcium.   Osteocalcin is also a calcium-binding protein that binds  preferentially to calcium that has already crystallized. The  roles of osteocalcin may be to inhibit calcium phosphate pre-  cipitation and to play a part in bone resorption by recruiting  osteoclasts.   Osteonectin is a bone-specific protein that binds selectively  to both hydroxyapatite and collagen in the bone matrix. Lam-  inin is an abundant bone matrix protein in humans that stabi-  lizes basement membranes in bones and is important in neurite  and axon growth.   Bone albumin is identical to serum albumin. In calcified  matrix, bone albumin is permanently fixed to bone mineral  crystals and remains so until the bone is resorbed. Bone albu-  min transports essential elements such as hormones, ions, and  other metabolites to and from the bone cells and maintains the  osmotic pressure of bone fluid (fluid surrounding mineral crys-  tals and osteoblasts).    Mineralization is the final step in bone formation, after collagen  synthesis and fiber formation. Mineralization has two distinct  phases: (1) formation of the initial mineral deposit (initiation),  and (2) proliferation or accretion of additional mineral crystals  on the initial mineral deposits (growth).'? The majority of the  mineral content in the body is an analog of the naturally occur-  ring mineral hydroxyapatite.   Table 43-6 lists the sequence in which calcium and phos-  phate form amorphous (fluid) calcium phosphate compounds  that are converted, in stages, to solid hexagonal crystals of  hydroxyapatite (HAP). As the calcium and phosphorous con-  centrations increase in the bone matrix, the first precipitate to  form is dicalcium phosphate dihydrate (DCPD). Once DCPD  precipitation begins, the remaining phases of bone crystal for-  mation proceed until insoluble HAP is produced, with approx-  imately 80% to 90% of the HAP being incorporated into the  collagen fibers. Amorphous calcium phosphate is distributed  throughout the bone matrix.    TABLE 43-6 SEQUENCE OF CALCIUM  AND PHOSPHATE  COMPOUND FORMATION  AND CRYSTALLIZATION    Dicalcium phosphate dehydrate DCPD  Octacalcium phosphate ocP  Amorphous calcium phosphate ACP  Tricalcium phosphate TCP  Hydroxyapatite HAP    Note: Compounds are listed in order in which precipitation and crystal  formation occur.    Bone consists of two types of bony (osseous) tissue: compact  bone (cortical bone) and spongy bone (cancellous bone) (Fig-  ure 43-3). Compact bone constitutes approximately 85% of  the skeleton; spongy bone comprises the remaining 15%. Both  types of bone tissue contain the same structural elements, and,  with a few exceptions, both compact tissue and spongy tissue  are present in every bone. The major difference between the two  types of tissue is the organization of the elements.   Compact bone is highly organized, solid, and extremely  strong. The basic structural unit in compact bone is the haver-  sian system (Figure 43-4). Each haversian system is made up of  the following:   Each haversian system is a separate cylindrical entity that  looks like a set of concentric rings. In the center of the haversian  system is the haversian canal that runs through the long axis of  bone and contains one or two blood vessels and nerve fibers.  The blood vessels in the canal communicate with blood vessels  in the periosteum (surface cover) and marrow cavity to trans-  port nutrients and wastes to and from the osteocytes contained  within the lacunae. Surrounding each haversian canal are the  concentric lamellae. Between the lamellae are the lacunae, each  of which contains one osteocyte. The lacunae are connected to  each other and to the haversian canal by the canaliculi, which  run parallel to the horizontal axis of the bone. Each canalicu-  lus encloses a small extension (cytoplasmic process) from the  osteocyte contained in the lacuna. The canaliculi transport both  nourishment and molecular signals into the lacunae, a mecha-  nism essential for osteocyte survival.   Spongy bone is less complex and lacks haversian systems. In  spongy bone the lamellae are not arranged in concentric layers  but in plates or bars termed trabeculae that branch and unite  with one another to form an irregular meshwork. The pattern  of the meshwork is determined by the direction of stress on the  particular bone. The spaces between the trabeculae are filled with  red bone marrow. The osteocyte-containing lacunae are distrib-  uted between the trabeculae and interconnected by canaliculi.  Capillaries pass through the marrow to nourish the osteocytes.    FIGURE 43-3 Cross Section of Bone. Longitudinal section of long bone (tibia)  showing cancellous and compact bone. (From Patton KT, Thibodeau GA: Anatomy &  physiology, ed 8, St Louis, 2013, Mosby.)    All bones are covered with a double-layered connective tis-  sue called the periosteum. The outer layer of the periosteum  contains blood vessels and nerves, some of which penetrate to  the inner structures of the bone through channels called Volk-  mann canals (see Figure 43-4). The inner layer of the perios-  teum is anchored to the bone by collagenous fibers (Sharpey  fibers) that penetrate the bone. Sharpey fibers also help hold  or attach tendons and ligaments to the periosteum of bones. !?    The human skeleton consists of 206 bones that constitute the  axial skeleton and the appendicular skeleton (Figure 43-5). The  axial skeleton consists of 80 bones that make up the skull, ver-  tebral column, and thorax. The appendicular skeleton consists  of 126 bones that make up the upper and lower extremities, the  shoulder girdle (pectoral girdle), and the pelvic girdle. The skel-  eton contributes about 14% of the weight of the adult body.  Bones can be classified by shape as long, flat, short (cuboi-  dal), or irregular. Long bones are longer than they are wide and  consist of a narrow tubular midportion (diaphysis) that merges    FIGURE 43-4 Structure of Compact and Cancellous Bone. A, Longitudinal section of a long bone showing cancel-  lous and compact bone. B, A magnified view of compact bone. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8,    into a broader neck (metaphysis) and a broad end (epiphysis)  (see Figure 43-3).   The diaphysis consists of a shaft of thick, rigid compact bone  that can tolerate bending forces. Contained within the diaphysis  is the elongated marrow (medullary) cavity. The marrow cavity  of the diaphysis contains primarily fatty tissue, which is referred  to as yellow marrow. The yellow marrow assists red bone mar-  row in hematopoiesis only during times of stress. The yellow  marrow cavity of the diaphysis is continuous with marrow cavi-  ties in the spongy bone of the metaphysis and diaphysis. The  marrow contained within the epiphysis is red because it con-  tains primarily blood-forming tissue (see Chapter 27). A layer  of connective tissue, the endosteum, lines the outer surfaces of  both types of marrow cavity.    The broadness of the epiphysis allows weightbearing to  be distributed over a wide area. The epiphysis is made up of  spongy bone covered by a very thin layer of compact bone. In  a child the epiphysis is separated from the metaphysis by a car-  tilaginous growth plate, the epiphyseal plate. After puberty  the epiphyseal plate calcifies and the epiphysis and metaphy-  sis merge. By adulthood the line of demarcation between the  epiphysis and metaphysis is undetectable.   In flat bones, such as the ribs or scapulae, two plates of  compact bone are roughly parallel to each other. Between the  compact bone plates is a layer of spongy bone. Short bones  (cuboidal bones), such as the bones of the wrist or ankle, are  often cuboidal in shape. They consist of spongy bone covered  by a thin layer of compact bone.    FIGURE 43-5 Anterior View of Skeleton. (From Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013,    Irregular bones, such as the vertebrae, mandibles, or other  facial bones, have various shapes that include thin and thick  segments. The thin part of an irregular bone consists of two  plates of compact bone with spongy bone between the plates.  The thick part consists of spongy bone surrounded by a layer  of compact bone.   Clusters of bone cells, termed bone-remodeling units, are  responsible for maintaining the structure of bone by remodel-  ing, a three-phase process in which existing bone is resorbed    and new bone is laid down to replace it. The bone-remodeling  units are made up of bone precursor cells that differentiate into  osteoclasts and osteoblasts. Precursor cells are located on the  free surfaces of bones and along the vascular channels (espe-  cially the marrow cavities).   In phase 1 (activation) of the remodeling cycle, a stimulus  (e.g., hormone, drug, vitamin, physical stressor) activates pro-  grammed osteocyte cell death (apoptosis). The distribution of  these apoptotic osteocytes provides osteoclasts with informa-  tion about where to begin resorbing damaged bone. In phase 2  (resorption), the osteoclasts form a “cutting cone,” which grad-  ually resorbs bone, leaving behind an elongated cavity termed    a resorption cavity. The resorption cavity in compact bone follows  the longitudinal axis of the haversian system, and the resorption  cavity in spongy bone parallels the surface of the trabeculae.   Phase 3 (formation) is the laying down of new bone, termed  secondary bone, by osteoblasts lining the walls of the resorption  cavity. Successive layers (lamellae) in compact bone are laid  down until the resorption cavity is reduced to a narrow haver-  sian canal around a blood vessel. In this way, old haversian sys-  tems are destroyed and new haversian systems are formed. New  trabeculae are formed in spongy bone. The entire process of  remodeling takes about 3 to 4 months.   The remodeling process can repair microscopic bone injuries,  but gross injuries, such as fractures and surgical wounds (oste-  otomies), heal by the same stages as soft tissue injuries, except  that new bone, instead of scar tissue, is the final result (see  Chapter 7). In bone the stages of wound healing are as follows:   1. Hematoma formation: This process occurs if vessels have  been damaged, causing hemorrhage. Fibrin and platelets  within the hematoma form a meshwork that is the ini-  tial framework for healing with the help of hematopoietic  growth factors such as platelet-derived growth factor and  TGF-B (see Table 43-3).   2. Procallus formation: Fibroblasts, capillary buds, and  osteoblasts move into the wound to produce granulation  tissue called procallus. Cartilage is formed as a precur-  sor of bone, and types I, I, and III collagen are formed.  Enzymes and growth factors, such as insulin and insulin-  like growth factors, plus bone morphogenic protein and  osteogenin, aid in this stage of healing.   3. Callus formation: Osteoblasts in the procallus form mem-  branous or woven bone (callus). Enzymes increase the  phosphate content and permit the phosphate to join with  calcium to be deposited as mineral to harden the callus.   4. Callus replacement: Osteoblasts continue to replace the  callus with lamellar bone or trabecular bone (Figure 43-6).   5. Remodeling: The periosteal and endosteal surfaces of the  bone are remodeled to the size and shape of the bone  before injury. Synthesis of other types of collagen recedes  in favor of type I, which is the collagen found in bone.  This final stage of healing, or remodeling, is vital because  bone that has not been remodeled does not have good  mechanical properties for weightbearing and mobility.   of the bone disruption; the type and amount of bone tissue  that must be replaced (spongy bone heals faster); the blood  supply and oxygen content at the site; the presence of growth  and thyroid hormones, insulin, vitamins, and other nutrients;  the presence of systemic disease; the effects of aging; and the  effectiveness of treatment, including immobilization and the  prevention of complications such as infection. In general, how-  ever, hematoma formation occurs within hours of fracture or  surgery; formation of procallus by osteoblasts occurs within  days; callus formation occurs within weeks; and replacement  and contour modeling occur within years—up to 4 years in  some cases.    The site where two or more bones meet is called a joint (articula-  tion) (Figure 43-7). The primary function of joints is to provide  stability and mobility to the skeleton. Whether a joint provides  stability or mobility depends on its location and its structure.  Generally, joints that stabilize the skeleton have a simpler struc-  ture than those that enable movement of the skeleton. Most joints  provide stability and mobility to some degree (Figure 43-8).   Joints are classified based on the degree of movement they  permit or on the connecting tissues that hold them together.  Based on movement, a joint is classified as a synarthrosis  (immovable joint), an amphiarthrosis (slightly movable  joint), or a diarthrosis (freely movable joint). On the basis of  connective structures, joints are classified broadly as fibrous,  cartilaginous, and synovial. Each of these three structural classi-  fications can be subdivided according to the shape and contour  of the articulating surfaces (ends) of the bones and the type of  motion the joint permits.    A joint in which bone is united directly to bone by fibrous con-  nective tissue is called a fibrous joint. Generally, fibrous joints  are synarthroses (immovable), but many fibrous joints allow  some movement. The degree of movement depends on the dis-  tance between the bones and the flexibility of the fibrous con-  nective tissue.   Fibrous joints are further subdivided into three types:  sutures, syndesmoses, and gomphoses. A suture has a thin  layer of dense fibrous tissue that binds together interlock-  ing flat bones in the skulls of young children. Sutures form an  extremely tight union that permits no motion. By adulthood  the fibrous tissue has been replaced by bone. A syndesmosis is  a joint in which the two bony surfaces are united by a ligament  or membrane. The fibers of ligaments are flexible and stretch,  permitting a limited amount of movement. The paired bones  of the lower arm (radius and ulna) and the lower leg (tibia and  fibula) and their ligaments are syndesmotic joints. A gompho-  sis is a special type of fibrous joint in which a conical projection  fits into a complementary socket and is held there by a ligament.  The teeth held in the maxilla or mandible are gomphosis joints.   The two types of cartilaginous joints are symphyses and syn-  chondroses. A symphysis is a cartilaginous joint in which  bones are united by a pad or disk of fibrocartilage. A thin layer  of hyaline cartilage usually covers the articulating surfaces  of the two bones, and the thick pad of fibrocartilage acts as a  shock absorber and stabilizer. Examples of symphyses are the  symphysis pubis, which joins the two pubic bones, and the  intervertebral disks, which join the bodies of the vertebrae. A  synchondrosis is a joint in which hyaline cartilage, rather than  fibrocartilage, connects the two bones. The joints between the  ribs and the sternum are synchondroses. The hyaline cartilage  of these joints is called costal cartilage. Slight movement at the  synchondroses between the ribs and the sternum allows the  chest to move outward and upward during breathing.    F  FIGURE 43-6 Bone Remodeling. All bone cells participate in bone remodeli    blasts). Bone remodeling is necessary because it allows the skeleton to respond  trol (repair and prevent microdamage), and allows the skeleton to release growth  stored in bone matrix to the circulation. The cells work in response to signals g  osteoclastic cells mediate the first phase of remode  the osteoblasts begins (B). They form new bone that replaces bone removed by t    ing. They are activated, scoop out bone (A), and resorb it; then th  he resorption process (C). The sequence takes    ng. In the remodeling sequence bone sections  are removed by bone-resorbing cells (osteoclasts) and replaced with a new section laid down by bone-forming cells (osteo-  to mechanical loading, maintains quality con-  actors and minerals (calcium and phosphate)  . Only the    4 to 6 months. D, Micrograph of active bone remodeling seen in the settings of primary or secondary hyperparathyroidism.    Note the active osteoblasts surmounted on red-stained osteoid. Marrow fibrosis  bone (F). Numerous signaling factors are necessary for remodeling. Factors mos  macrophage-colony-stimulating factor (GM-CSF), in    is present. E, Bone remodeling cycle in normal  important for resorption include granulocyte  erleukins-1 and -6 (IL-7 and /L-6), receptor activator for nuclear factor KB    ligand (RANKL), prostaglandin E, (PGE,), and tumor necrosis factor-alpha (7NF-c.). Important factors for bone formation include  osteoprotegerin (OPG), transforming growth factor-beta (7GF-B), and estrogen. (Adapted from Nucleus Medical Art. D from  Damjananov |, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.)   Synovial joints (diarthroses) are the most movable and the  most complex joints in the body (Figure 43-9). A synovial joint  consists of the following parts:   2. A synovial membrane that lines the inner surface of the   3. A joint cavity (synovial cavity), a space formed by the   Joint Capsule. The fibrous joint capsule (articular capsule)  is connective tissue that covers the ends of the bones where they  meet in the joint. Sharpey fibers firmly attach the proximal and  distal capsules to the periosteum and ligaments and tendons,  which also reinforce the capsule. The joint capsule consists of  parallel, interlacing bundles of dense, white fibrous tissue. It is  richly supplied with nerves, blood vessels, and lymphatic vessels.  The nerves in and around the joint capsule are sensitive to the  rate and direction of motion, compression, tension, vibration,  and pain.   Synovial Membrane. The synovial membrane (synovium)  is the smooth, delicate inner lining of the joint capsule (Figure  43-10). It lines the nonarticular portion of the synovial joint  and any ligaments or tendons that traverse the joint cavity. It is  made up of two layers—a vascular layer (subintima) and a thin  cellular layer (intima). The vascular subintima merges with the  fibrous joint capsule and is composed of loose fibrous connective  tissue, elastin fibers, fat cells, fibroblasts, macrophages, and mast  cells. The intima consists of rows of synovial cells embedded in    a fiber-free intercellular matrix. The intima contains two types  of synovial cells: type A and type B. Type A synovial cells ingest  and remove bacteria and particles of debris by phagocytosis in  the joint cavity. (Phagocytosis is described in Chapter 7.) Type  B synovial cells secrete hyaluronate, a binding agent that gives  synovial fluid its viscous quality. The synovial membrane is  richly supplied with blood and lymphatic vessels; therefore, it is  capable of rapid repair and regeneration.   Joint Cavity. The joint cavity (synovial cavity) is an enclosed  fluid-filled space between the articulating surfaces of the two  bones. This small cavity, often called the joint space, enables the  two bones to move “against” one another. The synovial cavity  is surrounded by the synovial membrane and filled with a clear,  viscous, slick fluid called the synovial fluid.   Synovial Fluid. Synovial fluid is superfiltrated plasma  from blood vessels in the synovial membrane. Synovial fluid  lubricates the joint surfaces, nourishes the pad of the articular  cartilage that covers the ends of the bones, and contains free-  floating synovial cells and various leukocytes that phagocytize  joint debris and microorganisms. Loss of synovial fluid leads to  rapid deterioration of articular cartilage.   Articular Cartilage. Articular cartilage is a layer of hyaline  cartilage that covers the end of each bone (Figure 43-11). It  ranges from 2 to 5 mm thick, depending on the size of the joint,  the fit of the two bone ends, and the amount of weight and  shearing force the joint normally withstands. Cartilage strength  and its biologic properties are due to an extensive network  of cross-linked collagen fibers. Figure 43-12 illustrates how  collagen cross-links from cartilage. The function of articular  cartilage is to reduce friction in the joint and to distribute  the forces of weightbearing. Articular cartilage is composed  of chondrocytes (cartilage cells) (making up about 2% of the  tissue) and an intercellular matrix made up of collagen (making    FIGURE 43-8 Types of Joints. Cartilaginous (amphiarthrodial) joints, which are slightly movable, include (A) a synchon-  drosis that attaches ribs to costal cartilage; (B) a symphysis that connects vertebrae; and (C) the symphysis that connects  the two pubic bones. Fibrous (synarthrodial) joints, which are immovable, include (D) the syndesmosis between the tibia and  fibula; (E) sutures that connect the skull bones; and the gomphosis (not shown), which holds teeth in their sockets. The synovial  joints include (F) the spheroid type at the shoulder; (G) the hinge type at the elbow; and (H) the gliding joints of the hand.    up about 10% to 30% of weight), protein polysaccharides  (making up 5% to 10% of weight), and water. The water  content ranges from 60% to almost 80% of the net weight of  the cartilage, and individual molecules rapidly enter or exit the  articular cartilage to contribute to the resiliency of the tissue.  The intercellular matrix is produced by the chondrocytes,  which synthesize and extrude collagen that, like the collagen  produced by bone cells, is distributed throughout the carti-  lage in a highly organized system of fibers. Collagen fibers in    cartilage are made up of many fine fibrils that, like bone fibrils,  are assembled in an orderly fashion that makes them resistant  to physical, metabolic, or chemical breakdown. The main dif-  ferences between bone collagen and cartilage collagen are the  amino acid content of the a-chains and the composition of the  fibrils. Bone collagen fibrils are made up of two type I chains  and one type II chain. Approximately 90% of the cartilage col-  lagen fibrils is made up of three identical type II chains, with the  remaining 10% consisting of types V, VI, IX, X, and XI.    FIGURE 43-10 Synovium. Note the delicate synovial lining resting on a fibro-  adipose subintimal lining rich in capillaries, lymphatics, and nerve endings. (Modi-  fied from Hochberg MC et al: Rheumatology, ed 4, Philadelphia, 2008, Mosby.)    At the surface of articular cartilage, the collagen fibers run par-  allel to the joint surface and are closely compacted into a dense,  protective mat. (Loss of this dense, compacted configuration at  the surface subjects the underlying fibers to splitting and thin-  ning, in which case the cartilage is unable to tolerate weightbear-  ing.) In the middle layer (the proliferative zone) of the cartilage,  the fibers are arranged tangential to the surface, which allows  them to deform and absorb some of the force of weightbearing  (see Figure 43-11). In the bottom layer (the hypertrophic zone)  of the cartilage, the fibers are perpendicular to the joint surface,  allowing them to resist shear forces, and are embedded in a calci-  fied layer of cartilage called the tidemark. The tidemark anchors  the collagen fibers to the underlying (subchondral) bone and    FIGURE 43-11 Collagen Zones. The three collagen zones (reserve, prolifera-  tive, and hypertrophic) are distinctly shown in a growth plate. (From Hjorten R et al:  Bone 41[4]:535, 2007.)    represents the zone between calcified and uncalcified cartilage.  Collagen fibers are important components of the cartilage matrix  because they account for approximately 60% of the dry weight  and because they (1) anchor the cartilage securely to underlying  bone, (2) provide a taut framework for the cartilage, (3) control    FIGURE 43-12 Heterotypic Collagen Fibril. Hierarchical depiction of heterotypic collagen fibril, emphasizing the internal  axial relationships required for mature cross-link formation. A, Three-dimensional concept of the type II/IX/X! heterotypic fibril  of developing cartilage matrix. B, Detail illustrating required nearest neighbor axial relationships for trifunctional intermolecu-  lar cross-links to form in collagens of cartilage, bone, and other high-tensile strength tissue matrices. The exact 3D spatial  pattern of cross-linking bonds is still unclear for any tissue. C, Detail of the axial stagger of individual collagen molecules  required for pyridinoline cross-linking. (From Eyre DA, Weiss MA, Wu JJ: Methods 4[1]:65, 2008.)    the loss of fluid from the cartilage, and (4) prevent the escape of  protein polysaccharides (proteoglycans) from the cartilage.   The proteoglycans are macromolecules consisting of pro-  teins, carbohydrates (glycosaminoglycans), and hyaluronic  acid. One subgroup of proteoglycans, known as heparin sulfate  proteoglycans (HSPGs), binds to many proteins involved in  musculoskeletal development and homeostasis, including FGF,  BMPs, Wnts, chemokines, interleukins, and extracellular matrix  (ECM) proteins.!? The glycosaminoglycans (keratin sulfate and  chondroitin sulfate) are attached to the protein core, and sev-  eral protein cores (with their attached glycosaminoglycans) are  bound to a hyaluronic acid chain by a special protein called link  protein. The proteoglycans give articular cartilage its stiff qual-  ity and regulate the movement of synovial fluid through the  cartilage. Without proteoglycans, normal weightbearing would  rapidly and completely press all the synovial fluid out of the car-  tilage. Proteoglycans act as a pump, permitting enough fluid to  be pressed out to ensure that a fluid film is always present on the  surface of the cartilage, even after hours of weightbearing. The  pumping action of proteoglycans also draws synovial fluid back  into the cartilage after a weightbearing load is released. Mobil-  ity and weightbearing are necessary for the pumping action of  proteoglycans to occur. Nonuse of a joint quickly reduces the  pumping action, which changes the composition of the matrix  and interferes with the nutrition of the chondrocytes.    Normal articular cartilage has no blood vessels, lymph vessels,  or nerves. Therefore, it is insensitive to pain and regenerates slowly  and minimally after injury.2°*! Regeneration occurs primarily at  sites where the articular cartilage meets the synovial membrane,  where blood vessels and nutrients are available. In general, it has  been difficult to enhance cartilage repair, but that may be chang-  ing (see What’s New? Progress in Rebuilding Cartilage).    Efforts to repair damaged cartilage have been difficult because of the poor  vascularity of cartilage. Currently available techniques, such as autologous  chondrocyte transplantation, have not consistently produced good results.  Developments in tissue engineering have been aided by maintaining improved  biologic control of cell growth, differentiation, and metabolic activity. One per-  sistent challenge is developing material with increased amounts of collagen   Techniques known as “functional tissue engineering” not only should pro-  vide a network of chondrocyte cell growth but also should greatly improve  the biomechanical properties of engineered cartilage. By more closely resem-  bling native cartilage, these technologies show great promise for clinically  improved outcomes in cartilage repair and replacement.    Data from Kock L, van Donkelaar CC, Ito K: Cell Tissue Res  347(3):613-627, 2012.    Synovial joints are described as uniaxial, biaxial, or multiaxial  according to the shapes of the bone ends and the type of move-  ment occurring at the joint (Figure 43-13). Usually one of the  bones is stable and serves as an axis for the motion of the other  bone. The body movements made possible by various synovial  joints are either circular or angular (Figure 43-14).    Skeletal muscles arise from mesodermal progenitor cells; the  most numerous are the somites. Actual formation of skeletal  muscle is a complex process controlled by multiple signaling  factors. A critical component of successful embryonic muscle  formation (myogenesis) is protein kinase, an enzyme that adds  phosphate groups to substrate proteins, thereby directing cell  processes.”” In muscle, these factors direct formation of myo-  blasts. Once myoblasts are formed, they fuse with other myo-  blasts and form myotubes, eventually developing into muscle  fibers. At birth, the muscle fibers have completed development    from myoblasts. Final muscle type is determined by tran-  scription factors that regulate both pre- and postnatal muscle  development.”?   All voluntary muscles are derived from the mesodermal  layer of the embryo. Genetic transcription factors, most nota-  bly myoblast determination protein (MyoD), induce skeletal  muscle differentiation. Myoblasts are the main cells responsible  for muscle growth and regeneration. Myoblasts are termed sat-  ellite cells when in a dormant state and are crucial in muscle  growth, maintenance, repair, and regeneration. Once muscle is  injured, satellite cells become activated and increase the num-  ber of transcriptional factors necessary to form myoblasts and  assist in repair.   Skeletal muscles are made up of millions of individual fibers  that by the process of contraction and relaxation do the work  necessary to complete movements as varied as a ballerina’s pir-  ouette or an artist’s deft stroke (Figure 43-15). Muscle consti-  tutes 40% of adults’ body weight and 50% of children’s body  weight. Muscle is 75% water, 20% protein, and 5% organic and  inorganic compounds; 32% of all protein stores for energy and  metabolism is contained in muscle.    There are more than 350 named muscles; almost all are paired.  The body’s muscles vary dramatically; they range from 2 to  60 cm in length and are shaped according to function.** Fusi-  form muscles are elongated muscles shaped like straps and can  run from one joint to another. Pennate muscles are broad,  flat, and slightly fan shaped, with fibers running obliquely to  the muscle’s long axis. The multipennate deltoid muscle, which  flexes and extends the arm, is a good example of a muscle  shaped according to its function.   Each skeletal muscle is a separate organ encased in a three-  part connective tissue framework called fascia. The layers of  connective tissue protect the muscle fibers, attach the muscle  to bony prominences, and provide a structure for a network of  nerve fibers, blood vessels, and lymphatic channels.   The outermost layer, the epimysium, is located on the sur-  face of the muscle and tapers at each end to form the tendon  (Figure 43-16). Tendons allow a short muscle to exert power  on a distant joint, whereas a thick muscle interferes with joint  mobility. The next layer, the perimysium, further subdivides  the muscle fibers into bundles of connective tissue, or fascicles.    Plantar flexion  FIGURE 43-14 Body Movements Provided by Synovial (Diarthrodial) Joints.    The endomysium surrounds the muscle fascicles, the smallest  unit of muscle fibers visible without a microscope. The liga-  ments, tendons, and fascia are made up of connective tissue that  also serves to buffer the limbs from the effects of sudden strains  or changes in speed. The rapid recovery necessary for strenuous  exercise is supported by the elastic property of muscle and its  connective tissue.   Skeletal muscle is described, almost interchangeably, as  voluntary, striated, or extrafusal. “Voluntary” indicates that  the muscle is controlled directly by the central nervous system.  “Striated” describes the striated, or striped, pattern of skeletal  muscle viewed under a light microscope. The striations result  from the organization of the muscle fibers into the contractile  units called sarcomeres. “Extrafusal” distinguishes the skeletal  muscle fibers from other contractile fibers located within the  sensory organs of the muscle.   Other components that are visible on gross inspection of  the whole muscle include the motor and sensory nerve fibers.  These function together with the muscle, innervating portions  of it and providing the electrical impulses needed for motor  function.    FIGURE 43-15 Skeletal Muscles of the Body. A, Anterior view. B, Posterior view.    and Their Coverings. (From Thibodeau GA, Patton KT: Anatomy & physiology,  ed 5, St Louis, 2003, Mosby.)    From the anterior horn cell of the spinal cord, the axons of  motor nerves branch out to innervate a specific group of muscle  fibers. Each anterior horn cell, its axon (part of a lower motor  neuron; see Chapter 15), and the muscle fibers innervated by  it are called a motor unit (Figure 43-17). The motor units are  composed of lower motor neurons, which extend to skeletal  muscles. Often termed the functional unit of the neuromuscular    system, the motor unit behaves as a single entity and contracts  as a whole when it receives an electrical impulse.   The whole muscle may be controlled by several motor nerve  axons. These branch to innervate many motor units within the  muscle. The whole muscle then may consist of many motor  units. The number of motor units per individual muscle varies  greatly. In the calf, for example, 1 motor axon will innervate  approximately 2000 muscle fibers, out of a total of 1,200,000  muscle fibers. This is a high innervation ratio of muscle fibers  to axons, and it contrasts markedly with the low innervation  ratio in the laryngeal muscles. There, two or three muscle fibers  constitute each motor unit, and the innervation ratio can be of  great functional significance. The greater the innervation ratio  of a particular organ, the greater its endurance. Higher innerva-  tion ratios prevent fatigue, and lower innervation ratios allow  for precision of movement.   Sensory Receptors. Although muscles function as effector  organs, they also contain sensory receptors and are involved  in sending different signals to the central nervous system.  Among these are the muscle spindles and Golgi tendon organs.  Spindles are mechanoreceptors that lie parallel to muscle  fibers and respond to muscle stretching. Golgi tendon organs  are dendrites that terminate and branch to tendons near the  neuromuscular junction. Motor and sensory neurons secrete  a proteoglycan called neuroregulin (NRG) that increases the    FIGURE 43-17 Motor Units of a Muscle. Each motor unit consists of a somatic motor neuron and all the muscle fibers    FIGURE 43-18 Myofibrils of a Skeletal Muscle Fiber (Cell) and Overall Organization of Skeletal Muscle. (From  Patton KT, Thibodeau GA: Anatomy & physiology, ed 8, St Louis, 2013, Mosby.)    number of acetylcholine receptors and helps in the formation  of muscle spindle fibers. Muscle spindles, Golgi tendon organs,  and free nerve endings provide a means of reporting changes in  length, tension, velocity, and tone in the muscle. This system of  afferent signals is responsible for the muscle stretch response  and maintenance of normal muscle tone.   Muscle Fibers. Each muscle fiber is a single muscle cell. This  long cell is cylindrical and surrounded by a membrane capable of  excitation and impulse propagation. The muscle fiber contains  bundles of myofibrils, the fiber’s functional subunits, in a parallel  arrangement along the longitudinal axis of the muscle (Figure  43-18). At birth the muscle fibers have completed development  from precursor cells called myoblasts. All voluntary muscles are  derived from the mesodermal layer of the embryo.   The type of peripheral nerve influences the muscle fiber and  motor unit considerably. Whether motor nerves are fast or slow  determines the type of muscle fibers in the motor unit. Type II  fibers, also called white fast-motor fibers, are innervated by relatively  large type II alpha motor neurons with fast conduction velocities.  These fibers rely on a short-term anaerobic glycolytic system for  rapid energy transfer, whereas type I fibers depend on aerobic    oxidative metabolism. Histochemical stains are now routinely  used to describe the structure of muscle fibers and contractile ele-  ments of muscle biopsy specimens. White muscle (type II fibers)  stains dark in the enzyme stain adenosinetriphosphatase (ATPase)  at a pH of 9.4. Red muscle (type I fibers) appears lightly stained.   The overlap of muscle fibers that appear with staining gives  the checkerboard appearance of muscle biopsy specimens and  provides an equal distribution of fiber types throughout the  muscle. This overlap also helps compensate for muscle fiber  loss and fatigue of individual motor units during activity. In  spite of this, some muscles contain proportionally more of  one fiber type than another. The postural muscles have more  type I fibers, allowing them the high resistance to fatigue that is  necessary to maintain the same position for extended periods.  Ocular muscles have more type II muscle fibers, allowing them  to respond rapidly to visual changes. (Table 43-7 describes the  specific characteristics of type I and type II fibers.)   The number of muscle fibers varies according to location. Large  muscles, such as the gastrocnemius, have more fibers (1,200,000)  than smaller muscles, such as the lumbrical muscles in the hand  (10,000). The diameter of muscle fibers also varies. The closely    fibers in soleus  Glycogen content Low  Intensity of contraction Low  Aerobic metabolic capacity High  Fiber diameter Small  Myosin-adenosinetriphosphatase (ATPase) activity Low    From Spence AP, Mason EE: Human anatomy and physiology, ed 4, St Paul, MN, 1992, West Publishing.    packed polygons are small (10 to 20 pm) until puberty, when they  attain the normal adult diameter of 40 to 80 um. Women usually  have smaller-diameter fibers than men. Small muscles, such as  the ocular muscles, are 15 xm in diameter; larger, more proximal  muscles are 40 pm in diameter. Both fiber size and muscle length  have functional significance. Studies have shown that larger fiber  diameter is associated with generation of greater forces. Fiber  diameter can be increased by activities that cause hypertrophied  muscle, such as exercise or occupational overuse.   The major components of the muscle fiber include the muscle  membrane, myofibrils, sarcotubular system, sarcoplasm, and  mitochondria (see Figure 43-18). The muscle membrane is a  two-part membrane. It includes the sarcolemma, which con-  tains the plasma membrane of the muscle cell, and the cell’s base-  ment membrane. The sarcolemma is 7.5 ym thick and is capable  of propagating electrical impulses to initiate contraction. At the  motor nerve end plate, where the nerve impulse is transmitted,  the sarcolemma forms the highly convoluted synaptic cleft. The  sarcolemma is comprised of lipid molecules and protein systems.  The protein systems perform special functions, such as transport  of nutrients and protein synthesis. They also provide the sodium-  potassium pump and include the cell’s cholinergic receptor. The  basement membrane is 50 wm thick and is composed primarily  of proteins and polysaccharides. It serves as the cell’s microskel-  eton and maintains the shape of the muscle cell. The basement  membrane also may function in some way to restrict further dif-  fusion of electrolytes once they have crossed the sarcolemma.   The sarcoplasm is the cytoplasm of the muscle cell and con-  tains the intracellular components that are common to all cells  (see Chapter 1). The sarcoplasm is an aqueous substance that  provides a matrix that surrounds the myofibrils. It contains  numerous enzymes and proteins that are responsible for the cell’s  energy production, protein synthesis, and oxygen storage. The  mitochondria house enzyme systems for energy production, par-  ticularly those that regulate such processes as the citric acid cycle    and adenosine triphosphate (ATP) formation. Many other struc-  tures are present in the sarcoplasm. The ribosomes are composed  primarily of ribonucleic acid (RNA) and participate in the pro-  cess of protein synthesis. The cell nucleus, satellite cells, glycogen  granules, and lipid droplets are suspended in the sarcoplasmic  matrix. Blood vessels, nerve endings, muscle spindles, and Golgi  tendon organs are also directly located within this structure.   Unique to the muscle is the sarcotubular system, a net-  work that includes the transverse tubules and the sarcoplasmic  reticulum, which crosses the interior of the cell. The sarcoplas-  mic reticulum is made in the same manner as the endoplasmic  reticulum in other cells. In the muscle cells the sarcoplasmic  reticulum is involved in calcium transport, which initiates mus-  cle contraction at the sarcomere, a portion of the myofibril.  The sarcoplasmic reticulum is composed of tubules that run  parallel to the myofibrils. The longitudinal tubules are termed  sarcotubules. The transverse tubules, which are closely associ-  ated with the sarcotubules, run across the sarcoplasm and com-  municate with the extracellular space. Together, the tubules of  this membrane system allow for intracellular calcium uptake,  regulation, and release during muscle contraction, and for the  storage of calcium during muscle relaxation.   Myofibrils. Myofibrils, the most abundant subcellular mus-  cle components, are the functional units of muscle contraction.  Each myofibril contains sarcomeres, which, in turn, consist of  repeating protein filaments”? (see Figure 43-18). Sarcomeres  are chiefly composed of the proteins actin, myosin, titin, and  nebulin. The sarcomere is responsible for converting chemical  energy into movement.   On cross section they are irregular polygons with a mean  diameter of less than 1 ym. Each myofibril is composed of seri-  ally repeating sarcomeres, separated by Z lines that give the  muscle its striped, cross-striated appearance. Each sarcomere  has a dark A band and is flanked by two light I bands (Fig-  ure 43-19). Titin functions as a molecular spring that plays a    FIGURE 43-19 Muscle Fibers. A, The Z disks define the end of an individual sarcomere. The M line (which lies within the  H band) is made of cross-connecting elements of the cytoskeleton. B, Actin is the primary protein of the | band (thin filament).  Nebulin(not shown) also extends along the | band and contains binding sites for actin and myosin. Myosin (thick filament) extends  through the A band. Titin extends from the Z disk to the M line, binding with myosin; strong titin anchoring within the | band is  necessary for proper muscle function. During contraction, the | bands and H bands shorten, moving the Z disks closer together.  C, Electron photomicrograph of human muscle tissue corresponding to schematics in A and B. (A modified from Thompson JM  et al: Mosby’ clinical nursing, ed 5, St Louis, 2002, Mosby; € courtesy Louisa Howard.)   Titin Unknown  Creatine kinase Unknown M line  Desmin Unknown Z line  Filamin* Unknown Z line   Regulatory and structural function; links filaments,  controls filament length  Regulatory and structural function; links filaments,  controls filament length  Regulatory and structural function; links filaments,  controls filament length    enzyme creatine kinase  Possible structural role  Interconnects thin filaments in Z line  Catalyzes the phosphorylation of ADP to form ATP  Interconnects thin filaments in Z line  Interconnects thin filaments in Z line; stabilizes  membrane  Determines filament length    Modified from Simon SR, editor: Orthopaedic basic science, Chicago, 1994, American Academy of Orthopaedic Surgeons.  ADP. Adenosine diphosphate; ATP adenosine triphosphate; ATPase, adenosinetriphosphatase.  *Data from Ma K, Wang K: Fed Eur Biochem Soc Lett 532(3):273-278, 2002; Sampson LJ, Leyland ML, Dart D: J Biol Chem 278(43):41988-41997,    significant role in determining muscle stiffness and elasticity.”°  The A band is 1.5 to 1.6 wm long and contains thick myosin  filaments. Included in the A band is a lighter zone called the H  band, and in the center of the H band is the dark M band, or  M line. The I band, which contains actin, is divided at the mid-  point of each sarcomere by the Z line. Its length varies with the  start of muscle contraction.   Myofibrils are composed of myofilaments. Each myofila-  ment is structured in a closely packed hexagonal arrangement,  with two thin filaments for every thick filament. The thick fila-  ment, along with C protein and M line protein, is made up of  myosin. Myosin has two subunits, heavy and light meromyosin,  which resemble twisted golf club shafts. The thin filaments are  twisted double strands made up of actin, troponin, and tropo-  myosin (see Chapter 31 and Figure 31-15).   Muscle Proteins. Table 43-8 summarizes muscle protein  distribution, location, and possible functional significance.  The contractile and regulatory functions of actin, myosin, and  the troponin-tropomyosin complex (associated with actin)  are the most commonly known. They also account for most  of the protein found in the myofibril. The structural and regu-  latory processes of muscle proteins are less well understood.  Alpha actin and beta actin are known to link the filaments. M  protein contains the enzyme creatine kinase (CK). Creatine is  released when muscle cells are damaged, making serum cre-  atine value an important measurement of pathologic condi-  tions of muscles.   The most abundant proteins, actin and myosin, are also  found in other cells, particularly motile cells such as platelets.  The complete amino acid sequences of actin and myosin have    been identified. Noteworthy is the presence of the amino acid  3-methylhistidine, found only in the thin filament, actin; 85%  to 90% of 3-methylhistidine is found in skeletal muscle. The  amino acids lysine and histidine, in addition to leucine, have  been used to study protein synthesis by means of stable isotope  infusion and muscle biopsy analysis.   Nonprotein Constituents of Muscle. Nitrogen, creatine,  creatinine, phosphocreatine, purines, uric acid, and amino  acids serve in the complex process of muscle metabolism. Phos-  phocreatine concentration is an extremely sensitive indicator of  muscle fiber activity.?” Glycogen and its derivatives are present  as energy sources.   Creatine and creatinine metabolism have been used to  measure muscle mass. Plasma creatine is taken up by muscle  and converted into the high-energy phosphate compound  phosphocreatine by the enzyme creatine kinase. Creatinine is  formed in muscle from creatine at a constant rate of 2% per  day. (Tests for plasma creatine are discussed in Chapter 37.)  Creatine excretion is increased in muscle wasting. This change  reflects the reduction in total body creatine stores and loss of  muscle mass.   Inorganic compounds, anions (phosphate, chloride), and  cations (calcium, magnesium, sodium, potassium) are impor-  tant in regulating protein synthesis, muscle contraction, enzyme  systems, and membrane stabilization. Intracellular calcium  levels influence the force and duration of muscle contraction.  Total body potassium (TBK), measured by the Ky) method, has  been used to measure muscle mass, also called Jean body mass.  TBK levels reflect changes in muscle mass seen during growth,  malnutrition, and muscle wasting.    Adenosine triphosphate (ATP) — Adenosine diphosphate (ADP) + Inorganic phosphate (Pi) + Energy    Phosphocreatine + ADP = Creatine + ATP  Glycogen/glucose + Pi + ADP — Lactate + ATP    Glycogen/glucose + ADP + Pi + 02 > H,0 + CO, + ATP  Free fatty acids + ADP + Pi + 02 > H,0 + CO, + ATP    Creatine kinase catalyzes the reversible reaction of ATP to ADP: Creatine phosphate + ADP = Creatine + ATP    From Spence AP, Mason EE: Human anatomy and physiology, ed 4, St Paul, MN, 1992, West Publishing.    The ultimate function of muscle is to accomplish work.  Although variously expressed in such measures as foot-pounds  or kilogram-meters, work usually refers to the amount of  energy liberated or force exerted over a distance (work = force X  distance). Muscles usually contract or tense while doing work.  Muscle contraction occurs on the molecular level and leads to  the observable phenomenon of muscle movement.    Muscle contraction is a four-step process: excitation, coupling,  contraction, and relaxation. The initial contraction process  is the excitation-contraction coupling (ECC) series, which  involves the electrical properties of all cells and the movement  of ions across the plasma membrane (see Chapter 1). At rest  an electrical charge of —90 mV is continually maintained across  the muscle sarcolemma. This resting potential, generated by the  separation of positive and negative charges on either side of the  membrane, creates an electrochemical equilibrium caused by  the selective permeability of the sarcolemma to electrolytes in  the intracellular and extracellular fluids, particularly potassium  and sodium.   Specific intracellular receptors within skeletal muscle sarco-  plasmic reticulum, called ryanodine receptors (RyRs), are the  primary ion channels that control calcium release. RyRs are the  largest known ion channels, allowing for rapid movement of cal-  cium. Three RyRs have been identified: RyR1 is predominantly  found in skeletal muscle; RyR2 is found mostly in cardiac muscle;  and RyR3 is in the diaphragm, smooth muscle, and brain.**°°   Excitation, the first step of muscle contraction, begins with the  spread of an action potential from the nerve terminal to the neu-  romuscular junction. The rapid depolarization of the membrane  initiates an electrical impulse in the muscle fiber membrane called  the muscle fiber action potential. As the action potential advances  along the sarcolemmal membrane, it spreads to the transverse  tubules (T-tubules). (The velocity of conduction is much slower  in muscle fibers than in myelinated nerve fibers—only 3 to  5 m/second compared with 54 to 90 m/second in nerve fibers.)   The generated action potential then triggers voltage-sensitive  receptors in the T-tubule wall; in turn, these receptors open the  RyR channels, causing release of calcium from the sarcoplasmic  reticulum.”®   Following depolarization of the T-tubules, the second stage,  coupling, occurs. This stage consists of the migration of cal-  cium ions to the myofilaments. Calcium affects troponin and    tropomyosin, muscle proteins that bind with actin when the  muscle is at rest. In the presence of calcium, however, both of  these proteins are attracted to calcium ions, leaving the actin  free to bind with myosin.   Contraction begins as the calcium ions combine with tropo-  nin, a reaction that overcomes the inhibitory function of the tro-  ponin-tropomyosin system. The thin filament actin then slides  toward the thick filament myosin. The two ends of the myo-  fibril shorten after contraction when the myosin heads attach  to the actin molecules, forming a cross-bridge that constitutes  an actin-myosin complex. ATP, located on the actin-myosin  complex, is released when the cross-bridges attach. This is the  sliding filament theory and was first described by A.F. Huxley  in the 1950s; however, it is now called the cross-bridge theory  because of the formation of the actin-myosin cross-bridges. The  process is so named because the actin actually slides onto the  myosin, causing the sarcomere to shorten. The useful distance  of contraction of a skeletal muscle is approximately 25% to 35%  of the muscle’s length. When actin and myosin filaments have  maximum interactions, the muscle generates maximum force.”*   The last step, relaxation, begins as the sarcoplasmic reticulum  absorbs the calcium molecules, removing them from interaction  with troponin. Calcium is pumped back into the sarcoplasmic  reticulum by means of an active transport process. The cross-  bridges detach, and the sarcomere lengthens. (The cross-bridge  theory of muscle contraction is discussed in Chapter 31.)    Skeletal muscle requires a constant supply of ATP and phos-  phocreatine. These substances are necessary to fuel the com-  plex processes of muscle contraction, driving the cross-bridges  of actin and myosin together and transporting calcium from  the sarcoplasmic reticulum to the myofibril. Other internal  processes of the muscular system that require ATP include  protein synthesis, which replenishes muscle constituents and  accommodates growth and repair. The rate of protein synthesis  is related to hormone levels (particularly insulin), amino acid  substrates, and overall nutritional status. At rest the rate of ATP  formation by oxidation of glucose or acetoacetate is sufficient  to maintain internal processes, given normal nutritional status.  During activity the need for ATP increases 100-fold. The meta-  bolic pathways for muscle activity in Table 43-9 show reactions  to the immediate need for increased ATP caused by contrac-  tion. Activity lasting longer than 5 seconds expends the avail-  able stored ATP and phosphocreatine.    Stored glycogen and blood glucose are converted anaerobi-  cally to sustain brief activity without increasing the demand for  oxygen. Anaerobic glycolysis is much less efficient than aero-  bic glycolysis, using six to eight times more glycogen to pro-  duce the same amount of ATP. With increased activity, such  as intense exercise, or ischemia, an increase in the level of lactic  acid occurs because of the breakdown of glycogen, thus causing  a shift in muscle pH (see Table 43-9). This short-term mecha-  nism “buys time” by allowing ATP formation in spite of inad-  equate energy stores or oxygen supply. When the anaerobic  threshold is reached and more oxygen is required, physiologic  changes occur, including an increase in lactic acid concentra-  tion and increases in oxygen consumption, heart rate, respira-  tory rate, and muscle blood flow.   Strenuous exercise requires oxygen, which activates the  aerobic glycogen pathway for ATP formation. During maximal  exercise, free fatty acid mobilization and the aerobic glycogen  pathways provide ATP over an extended time. These pathways  require oxygen to maintain maximal activity and return the  muscle to the resting state. Maximal exercise increases oxygen  uptake 15 to 30 times over the resting state.*! When this system  becomes exhausted or unable to respond to the need for ATP,  fatigue and weakness finally force the muscle to reduce activity,  with a resultant buildup of lactic acid in muscle fibers.   The ability to sustain maximal muscular activity leads to the  accumulation of oxygen debt. Oxygen debt is the amount of  oxygen needed to convert the buildup of lactic acid to glucose  and replenish ATP and phosphocreatine stores. For example,  after running at maximal speed for 10 seconds, the average  person has consumed 1 L of oxygen. At rest, oxygen consump-  tion for the same period is approximately 40 ml. As the per-  son recovers, the measured oxygen debt is 4 L greater than the  amount used during activity.   Oxygen consumption is measured to calculate the metabolic  cost of activity in normal and diseased muscle. It is an indirect  measure of energy expenditure, along with timed tests of activ-  ity, heart rate, and respiratory quotient (ratio of carbon dioxide  to expired oxygen consumed). Energy expenditure is measured  directly by heat production because heat is released whenever  work is accomplished.   Another factor that changes energy requirements is muscle  fiber type. Type II fibers rely on anaerobic glycolytic metabo-  lism and fatigue readily. Type I fibers can resist fatigue for lon-  ger periods because of their capacity for oxidative metabolism.    Muscle contraction cannot be viewed in isolation. Several fac-  tors determine how force is transmitted from the cross-bridges  on individual muscle fibers to accomplish whole-muscle con-  traction. First, when a motor unit responds to a single nerve  stimulus, it develops a phasic contraction, also called twitch.  Because the motor unit contracts in an “all or nothing” man-  ner, the contraction that is generated will be a maximal con-  traction. The central nervous system smoothly grades the force  generated by “recruiting” additional motor units and varying  the discharge frequency of each active motor unit. This adding  of motor units within the muscle is called repetitive discharge.    Recruitment and repetitive discharge of motor units allow  the muscle to activate the number of motor units needed to gen-  erate the desired force. The total force developed is the sum of  the force generated by each motor unit. As the strength, speed,  and duration of stimuli increase, the summation of contrac-  tions reaches a critical frequency called tetanus. When tetanus  is reached, no further increase in force can be achieved.   Other variables, such as fiber type, innervation ratio, mus-  cle temperature, and muscle shape, influence the efficiency of  muscular contraction. The two muscle fiber types differ in their  responses to electrical activity. Tetanus and duration of pha-  sic contractions, which take microseconds to accomplish, are  achieved more rapidly in type II than in type I muscle fibers.  Low-innervation ratios promote control and coordination,  whereas high ratios promote strength and endurance. Muscles  work best at normal body temperature, 37° C (98.6° F). Finally,  muscles with a large cross-sectional area, such as the fan-  shaped pennate muscles, develop greater contractile forces than  smaller-diameter muscles. The initial length of a muscle and the  range of shortening that occur when the muscle contracts also  determine the forces it can generate. The long fusiform muscles  have a greater range of shortening and can contract up to 57%  of their resting length. A certain amount of elongation is nec-  essary to generate sufficient tension and muscular force. The  elongation that occurs during the swing of a golf club or tennis  racquet is an example of how stretch improves contractile force.    During isometric contraction (static or holding contraction),  the muscle maintains constant length as tension is increased.  Isometric contraction occurs, for example, when the arm or leg  is pushed against an immovable object. The muscle contracts,  but the limb does not move.   During isotonic contraction (lengthening or shortening  contraction), the muscle maintains a constant tension as it  moves. The terms “eccentric” for lengthening and “concentric”  for shortening are technically inaccurate descriptions of muscle  movement; the respective terms “lengthening” and “shorten-  ing” are more precise. Positive work is accomplished during  shortening, and energy is released to exert force or lift a weight.  In contrast, during lengthening the muscle lengthens and  absorbs energy. Negative work is accomplished on the muscle  by the load. Lengthening requires less energy to accomplish and  may result in the development of pain and stiffness after unac-  customed exercise.    Muscles do not act alone but rather in groups, often under auto-  matic control. When a muscle contracts it acts as. a “prime mover,”  or agonist, and its reciprocal muscle, or antagonist, relaxes. This  is easily tested by holding the right arm in the horizontal position  in front of the body and then bending the elbow while feeling the  upper arm, biceps in the front and the triceps in the back, with  the other hand. The biceps is firm, and the triceps is soft. As the  arm is extended, the muscles change. When the elbow is com-  pletely extended, the biceps is soft and the triceps firm. Complet-  ing this movement causes the agonist and antagonist to change    automatically; only the movement is commanded, not the alter-  nate contraction and relaxation of the specific muscle groups.   Other associated actions may be seen during walking; as the  foot leaves the ground, the paravertebral and gluteal muscles  on the opposite sides of the body contract to maintain balance.  One notices the loss of the associated muscle’s action when  paralysis offsets this process and decreases balance. If a person  is paralyzed, difficulty in maintaining balance is noticeable.    Diagnostic procedures to evaluate bone function include gait  analysis, measurement of serum calcium and phosphorus  levels, and imaging studies. Most imaging techniques pro-  vide morphologic rather than functional information about  bone. Plain radiographs (x-rays) remain the standard initial  imaging tool for bone evaluation because bone absorbs x-ray  beams better than soft tissue. Computed tomography (CT)  provides multiple images that are then processed into single  (2-dimensional) or multiple images taken around a single  axis to form (3-dimensional) pictures. Dual-energy computed  tomography (DECT) utilizes x-ray beams at two different  energy levels to determine different chemical composition of  tissues, thereby expanding CT imaging to include soft tissues,  bone marrow, and crystals.*? Advances in CT technology allow  for detailed visualization of bone microstructure.°?   Magnetic resonance imaging (MRI) provides detailed ana-  tomic information and is useful for evaluating primary or  metastatic bone lesions, infection, marrow edema, bony ero-  sions, osteonecrosis, fractures, and other pathologic changes  of bone. Magnetic resonance arthrography (MRa) involves  injection of a contrast agent into the area of interest but allows  better visualization of small abnormalities. Detailed func-  tional imaging of bone can be attained with positron emission  tomography (PET) scanning. A relatively new technology,  MRI-PET combines MRI with functional imaging of molecu-  lar events seen with PET.   Nuclear medicine studies also provide imaging about meta-  bolic activity in bone and soft tissue. After a small amount of  radioactive tracer is injected, a special camera is used to identify  bone absorption of the tracer. Bone scanning is very sensitive,  but not specific about the cause of increased metabolic activity.   Dual-photon absorptiometry (DXA) is often used to mea-  sure the density of bones in the extremities and the fracture  risk of vertebral bodies, femoral neck, and distal radius (DXA).  Dual-photon absorptiometry allows the soft tissue components  to be subtracted. New technology promises more accurate eval-  uation of bone.   Serum bone-specific alkaline phosphatase (BAP) is a  marker of bone formation. Bone resorption is evaluated with  urinary and serum measurements of cross-linked N-terminal  telopeptides (NTx), a product of osteoclast bone resorption.  NTx is specific for bone because the cross-links assessed are  characteristic of bone collagen alone. Urine NTx is a more sen-  sitive and specific biochemical marker of bone resorption than  serum NTx.**°°    Procedures used to diagnose joint function include arthrogra-  phy, arthroscopy, magnetic resonance imaging, and synovial  fluid analysis. Arthrography (the injection of dye into the joint)  is particularly useful to diagnose tears in the fibrocartilage of the  knee (meniscus) and the rotator cuff of the shoulder. Arthros-  copy is the direct visualization of a joint through an arthro-  scope. Magnetic resonance imaging (MRI) produces images  of body tissues through the use of electromagnetic (radio)  waves that alter the atoms (hydrogen ions) in the nuclei of cells  being examined. When the polarized radiowaves are stopped,  the nuclear atoms return to their original positions, emitting  energy as signals as they move back. The signals produce visible  images for examination and diagnosis. MRI produces excellent  contrast of soft tissues for evaluation of musculoskeletal con-  ditions. Magnetic resonance arthroscopy (MRa) is injection of  contrast into a joint, followed by MRI evaluation.   Analysis of synovial fluid may reveal inflammatory, septic,  and noninflammatory joint diseases, which cause characteristic  changes in the color, clarity, viscosity, and cellular elements of  the fluid. The presence of blood in the joint fluid (hemarthrosis)  usually indicates joint trauma. Normal synovial fluid is sterile,  so the presence of bacteria in the fluid always indicates disease.  Cell fragments and fibrous tissue in the fluid are the result of  inflammation or wear-and-tear on the articular surfaces.    When the individual’s history and physical examination dis-  close abnormalities, such as weakness, atrophy, muscle tender-  ness, cramps, and stiffness, specific tests of muscle function  are in order. One of the most useful tests is the serum creatine  kinase (CK) concentration. CK is found in large quantities in  the muscle fibers, and when these are diseased or damaged, CK  leaks into the serum. Myoglobin is also detectable in the urine  after acute muscle damage caused by crush injury, ischemic dis-  orders, extreme exertion, and some inherited diseases.   Because the muscle membrane tissue is excitable and carries  an electrical charge, its capacity to function can be assessed by  electromyography. Using sensitive needle electrodes, the electro-  myogram (EMG) records the summation of action potentials of  the muscle fibers in each motor unit. The EMG is often compared  with the electrocardiogram (ECG), but the activity recorded on the  EMG is ona much smaller scale. The amplitude of the ECG is mea-  sured in volts, the duration of impulse is recorded in seconds, and  both are recorded as the heart rate (e.g., 80 V/60 seconds). EMG  amplitude is recorded in millivolts and the duration is measured  in milliseconds, with a frequency of about 5 to 50 action poten-  tials per second. Motor unit potentials are measured to determine  rate of firing, duration, and amplitude. Abnormalities in EMG  and nerve conduction velocities help differentiate muscle diseases  (myopathy) from peripheral nerve (neuropathy) and neuromus-  cular junction disorders. The muscle biopsy (using histologic,  histochemical, and electron microscopic studies) is used to fur-  ther define the presence of myopathic and neuropathic disorders,  many of which can be diagnosed only by muscle biopsy. Complex  myography, a relatively new technique, allows a noninvasive way  to gather information on the mechanical characteristics of muscle.    A new area of evaluation is genetics. Recent advances in  molecular genetics, deoxyribonucleic acid (DNA) libraries,  genetic probes, and gene localization techniques have enhanced  our knowledge of neuromuscular diseases, including types of  muscular dystrophy, Charcot-Marie-Tooth disease, and famil-  ial amyotrophic lateral sclerosis.   Aging is accompanied by the loss of bone tissue. Bones become  less stiff, less strong, and more brittle with aging. The bone  remodeling cycle takes longer to complete, and the rate of miner-  alization also decelerates. Studies have shown that an individual’s  bone mass at the end of their growth period helps determine the  significance of bone loss as they age. With aging, women experi-  ence loss of bone density, accelerated by rapid bone loss during  early menopause from increased osteoclastic bone resorption.*°  By age 70, susceptible women have lost an average of 50% of  their peripheral cortical bone mass. Extensive loss of bone mass  leads to deformity, pain, stiffness, and a high risk for fractures.  Asymptomatic vertebral fractures can cause loss of height. Men  also experience bone loss but at later ages and much slower rates  than women. Also, peak bone mass in men is higher than that in  women.°” In general, age-related bone loss is caused by genet-  ics, hormonal factors (decreased estrogen and estradiol levels),  decreased bone formation, vitamin and mineral deficiencies  (vitamin D, magnesium, and calcium), underlying conditions  (malignancy, autoimmune diseases, hyperthyroidism), and life-  style choices (physical inactivity, smoking, certain medications,  and alcohol intake). Men’s peak bone mass is related to race,  heredity, hormonal factors (testosterone and estradiol levels),  physical activity, and calcium intake during childhood.**   Bone mass can be gained in healthy young women up to the  third decade through physical activity and intake of dietary cal-  cium and magnesium. In addition to the positive effects of exer-  cise on bone mineral density (BMD), exercise has been shown  to improve balance, coordination, muscle strength, lean body  mass, and mobility, all of which may decrease the incidence of  falls*’*° (also see Figure 2-22, p. 85).   With aging, cartilage becomes more rigid, fragile, and suscep-  tible to fibrillation because of increasing cross-linking of col-  lagen and elastin, decreasing water content in the cartilage  ground substance, and decreasing concentrations of glycosami-  noglycans. Changes in collagen result in cartilage calcification  and muscle stiffness. Decreased range of motion of the joint  is related to the changes in ligaments and muscles. Bones in  joints develop evidence of osteoporosis with fewer trabeculae  and thinner, less dense bones, making them prone to fractures.  Intervertebral disk spaces decrease in height.    The function of skeletal muscle depends on many factors that  are affected by aging, including the nervous, vascular, and endo-  crine systems. Mitochondrial dysfunction within cells contrib-  utes to oxidative stress and results in increased bone resorption  and apoptosis of muscle cells.*!“? In the young child, develop-  ment of muscle tissue is highly dependent on continuing neuro-  developmental maturation. Muscle function remains trainable  even into advanced age. Muscle diseases have a definite asso-  ciation with specific age groups. Muscular dystrophies occur in  children, and muscle disabilities related to rheumatic diseases  usually occur in advancing age.   Age-related loss in skeletal muscle is referred to as sarcope-  nia and is a direct cause of the age-related decrease in muscle  strength. As the body ages, muscle bulk and strength decline  slowly, beginning as early as age 50, with loss of about 1% per  year thereafter. Muscle strength declines faster than muscle  mass.** Type II fibers decrease to a greater extent than the  slower acting type I fibers. Loss of satellite cells appears to play  a major role in the development of sarcopenia. Although mus-  cle’s regenerative function remains largely intact, satellite cell  numbers are decreased.*? The reduced RNA synthesis, loss of  mitochondrial volume, shortening of telomeres, and reduction  in the size of motor units contribute to sarcopenia. As much as  30% to 40% of skeletal muscle mass and strength may be lost  from the third to ninth decades.   Maximal oxygen intake decreases with age. Reduced basal  metabolic rate and decreased lean body mass are also seen in  the older adult population.   1. Bones provide support and protection for the body’s tissues  and organs and are important sources of minerals and blood  cells.   2. Bone formation begins in utero with the differentiation of  mesenchymal cells into either chondrocytes or osteoblasts.  Bone minerals then either crystallize on a cartilage frame-  work or become bone-forming cells without cartilage.   3. Bone tissue is continuously being resorbed and synthesized  by bone-remodeling units of osteoclasts and osteoblasts.    4. RANKL induces osteoclast activation and bone resorption.  OPG, a protein, binds to a protein called OPG ligand. This  attachment serves as a decoy receptor for RANKL and blocks  osteoclast activity, thus decreasing bone resorption. The bal-  ance between RANKL and OPG determines the quality of  bone.   5. Bones in the body are made up of compact bone tissue and  spongy bone tissue. Compact bone is highly organized into  haversian systems that consist of concentric layers of crys-  tallized matrix surrounding a central canal that contains    blood vessels and nerves. Dispersed throughout the concen-  tric layers of crystallized matrix are small spaces containing  osteocytes. Smaller canals, called canaliculi, interconnect  the osteocyte-containing spaces. The crystallized matrix in  spongy bone is arranged in bars or plates. Spaces contain-  ing osteocytes are dispersed between the bars or plates and  interconnected by canaliculi.    . BMPs are part of the TGF-B superfamily and involved in    . There are 206 bones in the body, divided into the axial skel-    eton and the appendicular skeleton. Bones are classified by  shape as long, short, flat, or irregular. Long bones have a  broad end (epiphysis), broad neck (metaphysis), and nar-  row midportion (diaphysis) that contains the medullary  cavity.    provides the fibrin framework for formation and organiza-  tion of granulation tissue. Granulation tissue provides a car-  tilage model for the formation and crystallization of bone  matrix. Remodeling restores the original shape and size to  the injured bone.    A joint is the site of attachment of two or more bones. Joints  provide stability and mobility to the skeleton.    throses, depending on the degree of movement they allow.  Joints also can be classified by the type of connecting tissue  holding them together. Fibrous joints are connected by dense  fibrous tissue, ligaments, or membranes. Cartilaginous joints  are connected by fibrocartilage or hyaline cartilage. Synovial  joints are connected by a fibrous joint capsule. Within the  capsule is a small fluid-filled space. The fluid in the space  nourishes the articular cartilage that covers the ends of the  bones meeting in the synovial joint.    fibers and proteoglycans. The fibers firmly anchor the car-  tilage to the bone, and the proteoglycans control the loss of  fluid from the cartilage.    Skeletal muscle is the largest organ in the body and is made  up of millions of individual fibers.    . Whole muscles vary in size (2 to 60 cm) and shape (fusiform    and pennate). They are encased in a three-part connective  tissue framework. The fundamental concept of muscle func-  tion is the motor unit, defined as all muscle fibers innervated  by a single motor nerve.    parallel along the longitudinal axis and include the muscle  membrane, myofibrils, sarcotubular system, aqueous sar-  coplasm, and mitochondria. There are two types of mus-  cle fibers, type I and type II, determined by motor nerve  innervation.    4, Myofibrils and myofilaments contain the major muscle  proteins actin and myosin, which interact to form cross-  bridges during muscle contraction. The nonprotein muscle  constituents provide an energy source for contraction and  regulate protein synthesis, enzyme systems, and membrane  stabilization.   6. Muscle strength is graded by the “all or nothing” phenom-  enon and recruitment. Speed of contraction is affected by  several factors: muscle fiber type, temperature, stretch, and  weight of the load.   7. The two types of muscle contraction are isometric and iso-  tonic. Muscle shortening occurs during contraction but can  be seen also during pathologic and physiologic contracture.   8. Actin and myosin filaments form cross-bridges that cause  the sarcomere to shorten, a process now known as the cross-  bridge theory of muscle contraction.   9. Skeletal muscle requires a constant supply of ATP and  phosphocreatine to fuel muscle contraction and for growth  and repair. ATP and phosphocreatine can be generated  aerobically or anaerobically. Phosphocreatine concentra-  tion is an extremely sensitive indicator of muscle fiber  activity.    actin-myosin cross-bridges on individual muscle fibers to  accomplish whole-muscle contraction. When a motor unit  responds to a single nerve stimulus, it develops a phasic  contraction. The central nervous system smoothly grades  the force generated by “recruiting” additional motor units  and varying the discharge frequency of each active motor  unit.    1. Various diagnostic procedures are used to evaluate bone  function, including urinary markers, serum calcium and  phosphorus levels, x-ray films, angiography, bone scan-  ning, and MRI.   2. Procedures used to evaluate joint function include arthrog-  raphy, arthroscopy, MRI, and synovial fluid analysis.   3. Genetic evaluation is useful in detecting, diagnosing, and  developing specific treatment for certain inheritable muscle  diseases such as muscular dystrophy.    1. Muscle bulk and strength slowly decline with aging,  although not to a pathologic degree. The bone remodeling  cycle takes longer to complete, and the rate of mineraliza-  tion slows.   2. Exercise in older adults improves muscle strength, helps  increase bone mineral density, and improves balance, coor-  dination, lean body mass, and mobility.   3. Age-related loss in skeletal muscle is referred to as sarco-  penia. Loss of satellite cells appears to play a major role in the  development of sarcopenia.   Diarthrosis (freely movable joint), 1520  Electromyogram (EMG), 1535  Endochondral ossification, 1511  Endomysium, 1527    Schaffler MB, Kennedy OD: Osteocyte signaling in bone, Curr Osteoporos  Rep 10(2):118-125, 2012.   Buckwalter JA, Einhorn TA, Simon SR, editors: Orthopaedic basic science,  Rosemont, IL, 1999, American Academy of Orthopaedic Surgeons.  Boyce BF, Xing L: Biology of RANK, RANKL, and osteoprotegerin,  Arthritis Res Ther 9(Suppl 1):S1, 2007.   Del Fattore A, Teti A, Rucci N: Bone cells and the mechanisms of bone  remodeling, Front Biosci (Elite Ed) 4:2302—2321, 2012.   Boyce BF, Yao Z, Xing L: Osteoclasts have multiple roles in bone in addi-  tion to bone resorption, Crit Rev Eukaryot Gene Expr 19(3):171-180,    Jones D, Glimcher LH, Aliprantis AO: Osteoimmunology at the nexus of  arthritis, osteoporosis, cancer, and infection, J Clin Invest 121(7):    Nakashima T, Takayanagi H: Osteoclasts and the immune system, J Bone  Miner Metab 27:519-529, 2009.   Golub EE: Biomineralization and matrix vesicles in biology and pathol-  ogy, Semin Immunopathol 33(5):409-417, 2011.   Bishop JR, Schuksz M, Esko JD: Heparan sulphate proteoglycans fine-  tune mammalian physiology, Nature 446(7139):1030-1037, 2007.    Metab 28(5):489-502, 2010. 12;  2. Shapiro F: Bone development and its relation to fracture repair. The role  of mesenchymal osteoblasts and surface osteoblasts, Eur Cell Mater 15:53, 13.  2008.  3. Chen G, Deng C, Li Y- P: TGF-B and BMP signaling in osteoblast dif- 14.  ferentiation and bone formation, Int J Biol Sci 8:272—288, 2012.  4. Bonewald LF: The amazing osteocyte, J Bone Miner Res 26(2):229-238, 15.  2012,  5. Caetano-Lopes J, Canhao H, Fonesca JE: Osteoblasts and bone forma- 2009.  tion, Acta Reum Port 32:103, 2007. 16.  6. Yavropoulou MR, Yovos JG: The role of the Wnt signaling pathway in  osteoblast commitment and differentiation, Hormones 6(4):279, 2008. 2534-2542, 2011.  7. Zaudi M et al: Osteoclastogenesis, bone resorption, and osteoclast-based 17.  therapeutics, J Bone Miner Res 18(4):599-609, 2003.  8. Kennedy OD, Schaffler MB: The roles of osteocyte signaling in bone, 18.  J Am Acad Orthop Surg 20(10):670-671, 2012.  9. Quarles LD: Skeletal secretion of FGF-23 regulates phosphate and vita- 19.  min D metabolism, Nat Rev Endocrinol 8(5):276—286, 2012.  10. Bellido T, Saini V, Pajevic PD: Effects of PTH on osteocyte function, Bone 20.    Kock L, van Donkelaar CC, Ito K: Tissue engineering of functional articu-  lar cartilage: the current status, Cell Tissue Res 347(3):613-627, 2012.    Pesesse L, Sanchez C, Henrotin Y: Osteochondral plate angiogenesis: a  new treatment target in osteoarthritis, Joint Bone Spine 78(2):144-149,  2011.   Knight JD, Kothary R: The myogenic kinome: protein kinases critical to  mammalian skeletal myogenesis, Skeletal Muscle 1:29-46, 2011.   Braun T, Gautel M: Transcriptional mechanisms regulating skeletal  muscle differentiation, growth and homeostasis, Nat Rev Mol Cell Biol  12:349-361, 2011.   Lieber RL, Ward SR: Skeletal muscle design to meet functional demands,  Philos Trans R Soc Lond B Biol Sci 366(1570):1466-1476, 2011.   Myhre JL, Pilgrim DB: At the start of the sarcomere: a previously unrec-  ognized role for myosin chaperones and associated proteins during early  myofibrillogenesis, Biochem Res Int 2012:712315, 2012.   Labiet D et al: Calcium-dependent molecular spring elements in the giant  protein titin, Proc Natl Acad Sci U S A 100(23):13716—-13721, 2003.  Sargeant AJ: Structural and functional determinants of human muscle  power, Exp Physiol 92(2):323, 2007.   Capes EM, Loaiza R, Valdivia HH: Ryanodine receptors, Skelet Muscle  1(1):18, 2011.   Hamilton SL, Serysheva II: Ryanodine receptor structure: progress and  challenges, J Biol Chem 284(7):4047—4051, 2009.   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Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    http://evolve.elsevier.com/McCance/  * Review Questions and Answers  * Online Course: Module 18    Musculoskeletal Injuries, 1540  Skeletal Trauma, 1540  Support Structure Trauma, 1545  Disorders of Bones, 1550  Metabolic Bone Diseases, 1550  Infectious Bone Disease: Osteomyelitis, 1558  Bone Tumors, 1560  Disorders of Joints, 1565  Osteoarthritis, 1565  Classic Inflammatory Joint Disease, 1568    Musculoskeletal injuries include fractures, dislocations, sprains,  and strains. Alterations in bones, joints, and muscles may be  caused by trauma, metabolic disorders, infections, inflamma-  tory or noninflammatory diseases, or tumors. Trauma is the  leading cause of death of people ages 1 to 44 years of all races  and socioeconomic levels.    Skeletal muscles can withstand many penetrating injuries with-  out permanent loss of function. For example, studies of soldiers  with severe combat injuries showed that muscle function was  preserved after the removal of large portions of muscle tis-  sue. Successful regeneration of skeletal muscle fibers depends  primarily on the extent of injury, the preservation of vascular  supply (and source of nutrition), and the availability of satellite  cells and terminal axons for reinnervation.    Disorders of Skeletal Muscle, 1578  Secondary Muscular Dysfunction, 1578  Muscle Membrane Abnormalities, 1581  Metabolic Muscle Diseases, 1582  Inflammatory Muscle Diseases: Myositis, 1583  Myopathy, 1585  Muscle Tumors, 1585   A fracture is a break in the continuity of a bone. A break occurs  when force is applied that exceeds the tensile or compressive  strength of the bone. The highest incidence of fractures occurs  in young males (between ages 15 and 24 years) and in adults 65  years of age and older, and varies for individual bones accord-  ing to age, gender, and possibly race. In a study of more than  158,000 people, fractures were most prevalent among black  males younger than age 65, whereas fractures in whites were  highest in those age 65 and older.! Fractures of healthy bones,  particularly the tibia, clavicle, and lower humerus, tend to occur  in young persons and are often the result of trauma. Frac-  tures of the hands and feet are usually caused by accidents in  the workplace. The incidence of fractures of the upper femur,  upper humerus, vertebrae, and pelvis is highest in older or older  adults and is often associated with osteoporosis (see p. 1550). In    FIGURE 44-1 Examples of Types of Bone Fractures. A, Oblique: frac-  ture at oblique angle across both cortices. Cause: direct or indirect energy, with  angulation and some compression. B, Occult: fracture that is hidden or not read-  ily discernible. Cause: minor force or energy. €, Open: skin broken over fracture;  possible soft tissue trauma. Cause: moderate to severe energy that is continuous  and exceeds tissue tolerances. D, Pathologic: transverse, oblique, or spiral fracture  of bone weakened by tumor pressure or presence. Cause: minor energy or force,  which may be direct or indirect. E, Segmented: fracture with two or more pieces  or segments. Cause: direct or indirect moderate to severe force. F, Spiral: fracture  that curves around cortices and may become displaced by twist. Cause: direct or  indirect twisting energy or force with distal part held or unable to move. G, /rans-  verse: horizontal break through bone. Cause: direct or indirect energy toward bone.  H, Greenstick: break in only one cortex of bone. Cause: minor direct or indirect  energy. I, Impacted: fracture with one end wedged into opposite end of inside  fractured fragment. Cause: compressive axial energy or force directly to distal frag-  ment. (Redrawn from Mourad L: Musculoskeletal system. In Thompson JM et al,  editors: Mosby's clinical nursing, ed 7, St Louis, 2002, Mosby.)    1990, an estimated 1.66 million hip fractures occurred world-  wide; that number is expected to increase to 6.3 million by the  year 2050.   Classification. Fractures can be classified as complete or  incomplete and open or closed (Figure 44-1). In a complete  fracture the bone is broken all the way through, whereas in  an incomplete fracture the bone is damaged but still in one  piece. Complete or incomplete fractures also can be classified  as open (formerly referred to as compound) if the skin is broken  or as closed (formerly called simple) if it is not. A fracture in  which a bone breaks into more than two fragments is termed a    comminuted fracture. Fractures are classified also according to  the direction of the fracture line. A linear fracture runs parallel  to the long axis of the bone. An oblique fracture is a slanted  fracture of the shaft of the bone. A spiral fracture encircles the  bone, and a transverse fracture occurs straight across the bone.   Incomplete fractures tend to occur in the more flexible,  growing bones of children. The three main types of incomplete  fractures are greenstick, buckle or torus, and bowing. A green-  stick fracture perforates one cortex and splinters the spongy  bone and is relatively unstable.’ The name is derived from the  damage sustained by a young tree branch (a green stick) when  it is bent sharply. The outer surface is disrupted, but the inner  surface remains intact. Greenstick fractures typically occur in  the metaphysis or diaphysis of the tibia, radius, and ulna. In a  buckle or torus fracture, the cortex buckles but does not break;  this is a relatively stable fracture. Bowing fractures usually  occur when longitudinal force is applied to bone. This type of  fracture is common in children and usually involves the paired  radius-ulna or fibula-tibia. A complete diaphyseal fracture  occurs in one of the bones of the pair, which disperses the stress  sufficiently to prevent a complete fracture of the second bone,  which bows. A bowing fracture resists correction (reduction)  because the force necessary to reduce it must be equal to the  force that bowed it. Treatment of bowing fractures is difficult  also because the bowed bone interferes with reduction of the  fractured bone. A fracture that results from a low-level trauma  (one that would not normally cause a fracture) is called a fragil-  ity fracture, which is often seen in osteoporosis. Types of frac-  tures are summarized in Table 44-1.   Fractures may be further classified by cause as pathologic,  stress, or transchondral. A pathologic fracture is a break at the  site of a preexisting abnormality (such as a tumor), usually by  force that would not fracture a normal bone. Any disease pro-  cess that weakens a bone (especially the cortex) predisposes the  bone to pathologic fracture, commonly associated with tumors,  osteoporosis, infections, and metabolic bone disorders.   Stress fractures occur in normal or abnormal bone that  is subjected to repeated forces, such as occurs during athlet-  ics. Fatigue fractures are caused by abnormal stress or torque  applied to a bone with normal ability to deform and recover  (e.g., joggers, dancers, military recruits) and are a type of stress  fracture. Insufficiency fractures include fragility fractures of  osteoporosis and osteomalacia, and occur in bones lacking nor-  mal ability to deform and recover (i.e., normal weightbearing or  activity fractures the bone).   A transchondral fracture consists of fragmentation and  separation of a portion of the articular cartilage that covers the  end of a bone at a joint. (Joint structures are defined in Chapter  43.) The fragments may consist of cartilage alone or cartilage  and bone. Typical sites of transchondral fracture are the distal  femur, the ankle, the kneecap, the elbow, and the wrist. Trans-  chondral fractures are most prevalent in adolescents.   PATHOPHYSIOLOGY. When a bone is broken the periosteum  and blood vessels in the cortex, marrow, and surrounding  soft tissues are disrupted. Bleeding occurs from the damaged  ends of the bone and from the neighboring soft tissue. A clot  (hematoma) forms within the medullary canal, between the    The skin overlying the bone is intact  Communicating wound between bone and skin  Multiple bone fragments   Fracture line at an angle to long axis of bone  Fracture line encircling bone (as a spiral staircase)  Fracture line perpendicular to long axis of bone  Fracture fragments are pushed into each other    fractured ends of the bone, and beneath the periosteum. Bone  tissue immediately adjacent to the fracture dies. This necrotic  tissue (along with any debris in the fracture area) stimulates  an intense inflammatory response characterized by vasodila-  tion, exudation of plasma and leukocytes, and infiltration by  inflammatory leukocytes and mast cells. Cytokines, including  transforming growth factor-beta (TGF-f), platelet-derived  growth factor (PDGF), prostaglandins, and other factors that  promote healing are released. Within 48 hours after the injury,  vascular tissue invades the fracture area from surrounding soft  tissue and the marrow cavity, and blood flow to the entire bone  is increased. Bone-forming cells in the periosteum, endosteum,  and marrow are activated to produce subperiosteal procallus  along the outer surface of the shaft and over the broken ends of  the bone (Figure 44-2). Healing generally occurs in three over-  lapping phases. The initial inflammatory phase of healing lasts  3 to 4 days. During the next few days, the repair phase begins  and capillary ingrowth, together with mononuclear cells and  fibroblasts, begins the transformation of a hematoma into  granulation tissue. Osteoblasts within the procallus synthesize  collagen and matrix, which becomes mineralized to form cal-  lus. As the repair process continues, remodeling occurs, dur-  ing which unnecessary callus is resorbed and trabeculae are  formed along lines of stress; at the end of this stage, bone can  withstand normal stresses. The last phase, remodeling, lasts for  months to years. Except for the liver, bone is unique among  all body tissues in that after a fracture it will heal with normal,  not scar, tissue.   CLINICAL MANIFESTATIONS. The clinical manifestations of a  fracture vary according to the type of fracture, site of the frac-  ture, and associated soft tissue injury. In general, the signs and    Fracture occurs at a point in the bone weakened by disease (e.g., bones with tumors or osteoporosis)  A fragment of bone connected to a ligament or tendon breaks off from the main bone   Fracture is wedged or squeezed together on one side of bone   Fracture with one, both, or all fragments out of normal alignment   Fragment is close to the joint but remains outside the joint capsule    Break on one cortex of bone with splintering of inner bone surface (commonly occurs in children and older adults)    Separation of cartilaginous joint surface (articular cartilage) from main shaft of bone    FIGURE 44-2 Exuberant Callus Formation Following Fracture. (From Rosai  J: Ackerman’s surgical pathology, ed 8, St Louis, 1996, Mosby.)    symptoms of a fracture include impaired function, unnatural  alignment (deformity), swelling, muscle spasm, tenderness,  pain, and impaired sensation. The position of the bone seg-  ments is determined by the pull of attached muscles, gravity,  and the direction and magnitude of the force that caused the  fracture. One or both segments may be rotated inward or out-  ward on the bone’s long axis (rotation), be misaligned at an  angle (angulation), slide over the other segment (overriding),  or be out of normal position (displaced).    The immediate pain of a fracture is severe and usually  caused by trauma. Subsequent pain may be produced by mus-  cle spasm, overriding of the fracture segments, or damage to  adjacent soft tissues. Numbness is common and is caused by  swelling, pinching or severing of a nerve, trauma, or by bone  fragments. Pathologic fractures can cause angular deformity,  painless swelling, or generalized bone pain. Stress fractures  are painful, not because of trauma, but because of accelerated  remodeling. The pain occurs during activity and is usually  relieved by rest. Stress fractures also cause local tenderness and  soft tissue swelling. Transchondral fractures may be entirely  asymptomatic or painful during movement. Range of motion  in the joint is limited, and movement may evoke audible click-  ing sounds (crepitus).   EVALUATION AND TREATMENT. Treatment of a displaced frac-  ture involves realigning the bone fragments (reduction) to their  normal or anatomic position and holding the fragments in  place (immobilization) so that bone union can occur. Several  methods are available to reduce a fracture: closed manipula-  tion, traction, and open reduction. Many fractures heal without  manipulation—they require only adequate immobilization. A  fracture that is malaligned, however, requires more aggressive  treatment.   Many fractures can be reduced by closed manipulation:  the skin is not opened, and the bone is moved or manipulated  into place. Closed manipulation is used when the contour of  the bone is in fair alignment and can be maintained well with  immobilization.   Traction is used to accomplish or maintain reduction.  When bone fragments are displaced (not in their anatomic  position), weights are used to apply firm, steady traction (pull)  and countertraction to the long axis of the bone. Traction  stretches and fatigues muscles that pull the bone fragments out  of place, allowing the distal fragment to align with the proxi-  mal fragment. Traction can be applied to the skin (skin trac-  tion), directly to the involved bone, or distal to the involved  bone (skeletal traction). Skin traction is used when only a few  pounds of pulling force are needed to realign the fragments  or when the traction will be used for brief times only, such  as before surgery or, for children with femoral fractures, for  3 to 7 days before applying a cast. In skeletal traction, a pin or  wire is drilled through the bone below the fracture site, and  a traction bow, rope, and weights are attached to the pin or  wire to apply tension and to provide the pulling force needed  to overcome the muscle spasm and help realign the fracture  fragments.   External fixation can be used to reduce and immobilize sig-  nificantly displaced open fractures. Pins are placed in the bone  proximal and distal to the break and then stabilized by an exter-  nal frame of clamps and rods (Figure 44-3).   Open reduction is a surgical procedure that exposes the frac-  ture site; the fragments are brought into alignment under direct  visualization. Some form of prosthesis, screw, plate, nail, or wire  usually is used to maintain the reduction (internal fixation).   Splints and casts are used to immobilize and hold a reduc-  tion in place. Improper reduction or immobilization of a  fractured bone may result in nonunion, delayed union, or    FIGURE 44-3 Example of an External Fixation Device on the Right Leg.  The left leg is in a splint.    Old Man. Multiple fractures had occurred in 2 years previous and necessitated  bone grafting. (From Rosai J: Ackerman’ surgical pathology, ed 8, St Louis, 1996,  Mosby.)    malunion. Nonunion is failure of the bone ends to grow  together (Figure 44-4). The gap between the broken ends of  the bone fills with dense fibrous and fibrocartilaginous tissue  instead of new bone. Occasionally the fibrous tissue contains  a fluid-filled space that resembles a joint and is termed a false  joint, or pseudarthrosis. Delayed union is union that does  not occur until approximately 8 to 9 months after a fracture.  Malunion is the healing of a bone in a nonanatomic position.  Treatment of delayed union and nonunion includes use of  various modalities designed to stimulate new bone formation.  Physical modalities, such as implantable or external electric  current devices, electromagnetic field generations, and low-  density ultrasound, have been effective in stimulating bone  formation.* Stem cells and gene therapy also show promise in  promoting formation of new bone.» Large defects in bone can  be filled with bone graft or synthetic materials, such as calcium  phosphate cement.    FIGURE 44-5 Displaced Fracture. An x-ray showing a displaced fracture of  the base of the first metacarpal, also known as a Bennett fracture.    Dislocation and subluxation are usually caused by trauma but  can also be due to ligamentous laxity, nerve injury, rheuma-  toid disease, or genetic problems. Dislocation is the temporary  displacement of a bone from its normal position in a joint. Ifa  dislocation does not involve a fracture, it is considered a simple  dislocation; if there is an associated fracture, it becomes a com-  plex dislocation. If the contact between the two joint surfaces is  only partially lost, the injury is called a subluxation.   Dislocation and subluxation are most common in persons  younger than 20 years and are generally associated with frac-  tures. Dislocation and subluxation, however, may result from  congenital or acquired disorders that cause (1) muscular imbal-  ance, as occurs with congenital hip dislocation or neurologic  disorders; (2) incongruities in the articulating surfaces of the  bones, such as with rheumatoid arthritis (see p. 1568); or (3)  joint instability.   Most often dislocated or subluxated are the joints of the  shoulder, elbow, wrist, finger, hip, and knee (Figure 44-5).  The shoulder’s glenohumeral joint is a relatively unstable joint  because the articular surface of the glenoid cavity is only one  third as large as the surface of the humeral head. As a result,  the glenohumeral joint is often injured. Physical trauma to the  shoulder can cause anterior, posterior, superior, or inferior dis-  location. Anterior dislocation is the most common and is usu-  ally the result of an indirect force that places the shoulder in  extreme external rotation. Posterior dislocations usually occur  as a result of trauma. A superior dislocation is rare and usu-  ally the result of an extreme forward and upward force on an  adducted arm. Inferior displacement is often seen in persons  with neurologic injuries of the brachial plexus and is believed  to be caused by stretching of the supporting muscles or by joint  effusion.    Traumatic dislocation of the elbow joint is common in the  immature skeleton. In adults an elbow dislocation is usually  associated with a fracture of the ulna or head of the radius. Pos-  terior dislocations occur when the individual falls on an out-  stretched hand with the elbow extended. Anterior dislocations  are usually the result of a direct blow to the flexed elbow.   Traumatic dislocation of the wrist usually involves the distal  ulna and carpal bones. Any one of the eight carpal bones can be  dislocated after an injury. The most common cause is a fall on  the hyperextended hand.   Dislocation in the hand usually involves the metacarpopha-  langeal and interphalangeal joints. Dislocation of the metacar-  pophalangeal joint is often the result ofa fall on the outstretched  hand that forces the joint into hyperextension. Dislocation of  the interphalangeal joint occurs as a result of injury to the fin-  gers in a hyperextended position.   Considerable trauma is needed to dislocate the hip. Anterior  hip dislocation is rather rare and is caused by forced abduction,  for example, when an individual lands on the feet from a high  fall. Posterior dislocation of the hip can occur in an automobile  accident in which the flexed knee strikes the dashboard.   The knee is a relatively unstable joint that depends heavily on  the soft tissue structures around it for support. Because the knee  is an unstable weightbearing joint exposed to many different  types of motion (flexion, extension, rotation), it is one of the  most commonly injured joints. A knee dislocation can be ante-  rior, posterior, lateral, medial, or rotary. It is often the result  of a hyperextension injury that occurs during sports activities.   PATHOPHYSIOLOGY. Dislocations and subluxations are often  accompanied by fracture because stress is placed on areas of  bone not normally subjected to stress. In addition, as the bone  separates from the joint, it may bruise or tear adjacent nerves,  blood vessels, ligaments, supporting structures, and soft tissue.  Dislocation of the shoulder may damage the shoulder capsule  and the axillary nerve. Damage to the axillary nerve causes anes-  thesia in the sensory distribution of the nerve and paralysis of  the deltoid muscle. Torn periosteum, ligaments, and muscle fre-  quently accompany elbow dislocations. Bleeding from the dam-  aged periosteum and muscle puts pressure on adjacent arteries  that stop circulation to and from the forearm and hand. If the  pressure is not promptly relieved, ischemic paralysis develops.  Dislocations of the hand often result in permanent disability  because of damage to the tendons and intricate mechanisms  that allow smooth gliding in the joints. In the hip, avascular  necrosis of the femoral head is a complication seen with dislo-  cations. Knee dislocation usually tears both the collateral and  cruciate ligaments.   CLINICAL MANIFESTATIONS. Signs and symptoms of dislocations  or subluxations include pain, swelling, limitation of motion,  and joint deformity. Pain may be caused by effusion of inflam-  matory exudate into the joint or associated tendon and ligament  injury. Joint deformity is usually caused by muscle contractions  that exert pull on the dislocated or subluxated joint or fluid  within the joint. Limitation of motion may be a result of effu-  sion into the joint or the displacement of bones.   Tenderness and deformity are prominent in dislocations  of the fingers. Unusual muscle pull and pain often result in    abnormal posturing of the fingers; for example, the fingers or  thumb may be abnormally flexed. A dislocated elbow is often  held in a flexed position, and the joint resists active or pas-  sive movement. Pain is the key symptom of shoulder injuries.  Attempts to lift the arm aggravate the pain. In most shoulder  dislocations, the ability to elevate the arm is minimal and the  individual supports the injured arm with the opposite hand.  Pain and an abnormal gait or limp or inability to bear full  weight usually accompanies traumatic dislocation of the hip.  The pain is constant and severe and is often felt in the inguinal  region or thigh. The thigh and leg may assume a position of  inward rotation, adduction, or flexion and appear shortened.  In a rare anterior dislocation, the limb is not shortened and the  joint is fixed in abduction, outward rotation, and flexion.   EVALUATION AND TREATMENT. Evaluation of dislocations and  subluxations is based on clinical manifestations and roentgeno-  grams. Treatment consists of reduction and immobilization for  2 to 6 weeks and exercises to maintain normal range of motion  in the joint. Depending on the joint, healing is usually complete  within months to years.   Tendon and ligament injuries can accompany fractures and dis-  locations. A tendon is fibrous connective tissue that attaches  skeletal muscle to bone. A ligament is a band of fibrous con-  nective tissue that connects bones where they meet at a joint.  Tendons and ligaments support the bones and joints and either  facilitate or limit motion. Tendons and ligaments can be torn,  ruptured, or completely separated from bone at their points of  attachment.   A tear in a tendon is commonly known as a strain. Major  trauma can tear or rupture a tendon at any site in the body.  Most often injured are the tendons of the hands and feet, the  knee (patellar), the upper arm (biceps and triceps), the thigh  (quadriceps), the ankle, and the heel (Achilles). Lifting excessive  weight with the arms can cause traumatic rupture of the biceps  tendon. Rupture of the Achilles tendon occurs when forced  dorsiflexion is applied to the foot when it is in plantar flexion.  Spontaneous tendon ruptures can occur in individuals receiving  local corticosteroid injections or fluoroquinolones and in per-  sons with rheumatoid arthritis or systemic lupus erythematosus.   Ligament tears are commonly known as sprains. Ligament  tears and ruptures can occur at any joint but are most common  in the wrist, ankle, elbow, and knee joints. A complete sepa-  ration of a tendon or ligament from its bony attachment site  is known as an avulsion. An avulsion is the result of abnor-  mal stress on the ligament or tendon and is commonly seen in  young athletes, especially sprinters, hurdlers, and runners.   Strains and sprains are classified as first degree (least severe),  second degree, and third degree (most severe).   PATHOPHYSIOLOGY. When a tendon or ligament is torn, an  extensive cascade of inflammatory processes begins. An inflam-  matory exudate develops between the torn ends. Later, granula-  tion tissue containing macrophages, fibroblasts, and capillary  buds grows inward from the surrounding soft tissue and car-  tilage to begin the repair process. Within 3 to 4 days after the    injury, collagen formation begins. At first, collagen formation is  random and disorganized. As the collagen fibers interweave and  connect with pre-existing tendon fibers, they become organized  parallel to the lines of stress. Eventually vascular fibrous tissue  fuses the new and surrounding tissues into a single mass. As  reorganization takes place, the healing tendon or ligament sepa-  rates from the surrounding soft tissue. Usually a healing tendon  or ligament lacks sufficient strength to withstand strong pull for  4 to 5 weeks after the injury. If strong muscle pull does occur  during this time, the tendon or ligament ends may separate  again, which causes the tendon or ligament to heal in a length-  ened shape with an excessive amount of scar tissue that renders  the tendon or ligament functionless. Scar remodeling may take  months to years before it is complete.’   CLINICAL MANIFESTATIONS. Tendon and ligament injuries are  painful and are usually accompanied by soft tissue swelling,  changes in tendon or ligament contour, and dislocation or  subluxation of bones. The pain is generally sharp and local-  ized, and tenderness persists over the distribution of the ten-  don or ligament. Painful joint swelling usually can be seen in  finger and elbow sprains. Flexion deformities of the fingers and  thumb occur in injuries to the extensor tendons. Crepitus may  accompany tendon injury in the wrist. Pain in the elbow may  be accentuated by flexion, supination, and extension of the  elbow or by extension of the wrist. Lifting small objects requires  extension of the wrist and therefore aggravates the pain. Ten-  don injuries in the upper arm cause weakness when the indi-  vidual tries to flex the forearm. Pain is often the key symptom  of shoulder injuries. It may be referred to the deltoid muscle or  extend down the arm and is aggravated by attempts to actively  raise the arms. Depending on the ligament or tendon involved,  tendon and ligament injuries in the knee may produce pro-  nounced immobility, absence of lateral movement, instability  when walking down stairs, flexion deformity, crepitus, or an  upward or downward shift of the patella.   EVALUATION AND TREATMENT. Evaluation is based on clinical  manifestations, stress radiography, arthroscopy, or arthrog-  raphy. When possible, treatment consists of protection of the  involved structures (splinting), promotion of early motion, and  rehabilitation. Suturing the tendon or ligament ends in close  approximation may be necessary to treat complete rupture. If  this is not possible because of the extent of damage, tendon or  ligament grafting may be necessary. Prolonged rehabilitation  exercises help ensure that the individual regains nearly normal  functions.    Trauma and repetitive stress can cause painful degradation of  collagen fibers (tendinosis), inflammation of tendons (ten-  dinitis), or inflammation in bursal sacs (bursitis). The term  tendinopathy includes tendinitis, tendinosis, and paratendini-  tis. Studies have shown that vascular ingrowth in tendinopa-  thy (neovascularization) is accompanied with nerve ingrowth,  facilitating pain transmission in Achilles and patellar tendinop-  athies.° Other causes of tendinopathy include crystal deposits,  postural misalignment, and hypermobility in a joint. Table 44-2  summarizes classes of tendinopathies.    Symptomatic degeneration of the tendon with  vascular disruption and inflammatory repair  response   “Inflammation” of the outer layer of the tendon  (paratenon) alone, whether or not the paratenon  is lined by synovium    Collagen disorientation, disorganization, and fiber separation  by an increase in mucoid ground substance, increased  preponderance of cells and vascular spaces with or without  neovascularization and focal necrosis or calcification   Degenerative changes as noted above with superimposed  evidence of tear, including fibroblastic and myofibroblastic  proliferation, hemorrhage, and organizing granulation tissue   Mucoid degeneration if the areolar tissue is seen; a scattered  mild mononuclear infiltrate with or without focal fibrin  deposition and fibrinous exudate    degeneration with or without fibrous and scattered  inflammatory cells in the paratenon alveolar tissue    From Maffulli N, Wong J, Almekinders LC: Clin Sports Med 22(4):675-692, 2003.    Epicondylitis is inflammation of a tendon where it attaches  to a bone (at its origin). Most tendon pathology, however, is  caused by tissue degeneration rather than inflammation.’ Epi-  condylar areas of the humerus, radius, or ulna and the area  around the knee are most often involved. Lateral epicondy-  lopathy, commonly called tennis elbow, is the result of tissue  degeneration or irritation of the extensor carpi radialis brevis  tendon at its origin. Medial epicondylopathy, referred to as  golfer’s elbow, is a degenerative process of the pronator teres,  flexor carpi radialis, and palmaris longus tendons at the medial  humeral condyle (Figure 44-6). Epicondylopathy is also related  to smoking, obesity, and work activities that involve forceful  or repetitive cyclic flexion and extension of the elbow, or cyclic  pronation, supination, extension, and flexion of the wrist that  generates loads to the elbow and forearm region.   Bursae are small sacs lined with synovial membrane and  filled with synovial fluid; they are located between tendons,  muscles, and bony prominences. Their primary function is to  separate, lubricate, and cushion these structures. When irritated  or injured, these sacs become inflamed and swell. Because most  bursae lie outside joints, joint movement is rarely compromised  with bursitis. Acute bursitis occurs primarily in the middle years  and is often caused by trauma; repetitive irritation can cause  chronic bursitis. Septic bursitis is caused by wound infection  or bacterial infection of the skin overlying the bursae. Bursitis  commonly occurs in the shoulder, hip, knee, and elbow.   PATHOPHYSIOLOGY. In tendinitis, inflammatory fluid accumu-  lates causing swelling of the tendon and its enclosing sheath.  Inflammatory changes cause thickening of the sheath, which  limits movements and causes pain. Microtears cause bleeding,  edema, and pain in the involved tendons or surrounding struc-  tures. At times, after repeated inflammations, calcium may be  deposited in the tendon origin area, causing a calcific tendinitis.   The typical bursitis is an inflammation that is reactive to  overuse or excessive pressure. The inflamed bursal sac becomes  engorged, and the inflammation can spread to adjacent tis-  sues (Figure 44-7). The inflammation may decrease with rest,  heat, and aspiration of the fluid. (Inflammation is discussed in  Chapter 7.)    FIGURE 44-6 Tendinitis and Epicondylitis. A, Medial or lateral epicondyles  of humerus, site of epicondylitis. B, Achilles tendon, site of commonly occurring  tendinitis.    CLINICAL MANIFESTATIONS. Tendinopathy may be asympto-  matic, but generally there is localized pain that worsens with  active more than passive motion. With symptomatic tendinopa-  thy, the pain is localized over the involved tendon and movement  in the affected joint is limited. In bursitis, onset of pain may be    FIGURE 44-7 Olecranon Bursa. A case of olecranon bursitis in a patient with  rheumatoid arthritis. A rheumatoid nodule is also shown. (From Hochberg MC et al:  Rheumatology, ed 5, London, 2011, Mosby.)    gradual or sudden, but movement of the joint itself is normal.  Shoulder bursitis impairs arm abduction because of pain and  swelling of the bursa. Bursitis in the knee produces pain when  climbing stairs, and crossing the legs is painful in bursitis of the  hip. Lying on the side of an inflamed trochanteric bursa is also  very painful. Table 44-3 summarizes common sites of bursitis.  Signs of infectious bursitis may include the presence of a punc-  ture site, prior corticosteroid injection, severe inflammation, or  an adjacent source of infection.   EVALUATION AND TREATMENT. Evaluation of tendinopathy, epi-  condylopathy, and bursitis is based on clinical manifestations,  physical examination, arthroscopy, arthrography, ultrasound,  and possibly magnetic resonance imaging (MRI). Treatment  includes administration of systemic analgesics, application of  ice or heat, or local injection of an anesthetic and a corticoste-  roid to reduce inflammation. Bursitis may require aspiration to  drain excess fluid. Physical therapy to prevent loss of function  begins after acute symptoms subside.    Mild injury such as muscle strain is usually seen after trau-  matic or sports injuries. Muscle strain is a general term for local  muscle damage. It is often the result of sudden, forced motion  causing the muscle to become stretched beyond normal capac-  ity. Strains often involve the tendon as well. Muscles are rup-  tured more often than tendons in young people; the opposite  is true in older adults. Muscle strain may be chronic when the  muscle is repeatedly stretched beyond its usual capacity. There  is evidence of tissue disruption with subsequent signs of muscle  regeneration and connective tissue repair when a biopsy is per-  formed. Hemorrhage into the surrounding tissue and signs of  inflammation also may be present. Knife and gunshot wounds  also cause traumatic rupture. Regardless of the cause of trauma,  muscle cells usually can regenerate. Regeneration may take up  to 6 weeks, and the affected muscle should be protected during  this time. Types of muscle strain, together with their manifesta-  tions and treatment, are summarized in Table 44-4.   A late complication of localized muscle injury is abnormal  bone formation in soft tissue, often called myositis ossificans  or heterotopic ossification (HO). Its exact pathophysiology    Repetitive overhead activities  Rheumatoid arthritis (RA), gout,  tuberculosis, leaning on elbow  Acute trauma, chronic stress  Overuse (runner, ballet dancers),  lumbosacral disease, RA,  osteoarthritis (OA)    remains unknown, but the basic problem seems to be the  inability of mesenchymal cells to differentiate into osteoblas-  tic stem cells and the improper development of fibroblasts into  bone-forming cells. Though uncommon, HO is associated with  burns, joint surgery, and trauma to the musculoskeletal system  or central nervous system. HO may involve muscle or tendons,  ligaments, or bones near a muscle.'° Examples include “rider’s  bone,” in which the adductor muscle of the thigh of equestri-  ans becomes calcified, as well as in football players after muscle  injury to thigh muscles; and “drill bone,” in which the same  complication is seen in the deltoid and pectoral muscles of fenc-  ers and infantry soldiers.    Once used interchangeably with the term myoglobinuria, rhab-  domyolysis is the rapid breakdown of muscle that causes the  release of intracellular contents, including protein pigment  myoglobin, into the extracellular space and bloodstream. Phys-  ical interruptions in the sarcolemmal membrane, called delta  lesions, suggest that the sarcolemmal membrane is the route  through which muscle constituents are released. Myoglobin-  uria, first described in victims of crush injuries in London dur-  ing World War I, refers to the presence of the muscle protein  myoglobin in the urine. More recently, myoglobinuria has been  reported in individuals found unresponsive and immobile for  long periods, such as drug and alcohol overdoses.  PATHOPHYSIOLOGY. Rhabdomyolysis is sometimes incorrectly  used interchangeably with crush injury (a description of injuries  resulting from crushing of a body part), compartment syndrome  (the consequences of increased intracompartmental pressures  of a muscle), or crush syndrome (the pathophysiologic events  caused by rhabdomyolysis, primarily involving the kidneys and  coagulation syndrome).'! Although relatively rare, rhabdo-  myolysis has many causes (Box 44-1) and can result in serious  complications, including hyperkalemia (because of the release  of intracellular potassium into the circulation), metabolic  acidosis (from liberation of intracellular phosphorus and sul-  fate), acute renal failure (myoglobin precipitates in the tubules,  obstructing flow through the nephron and producing injury),    First degree (e.g., bench press in Muscle overstretched, painful Ice should be applied 5 or 6 times in the first 24-48 hours; complete rest for up to  untrained athlete) 2 weeks, followed by weightbearing 3 times per week and range of motion daily  Second degree (e.g., any muscle Muscle intact with some tearing Treatment similar to that for first-degree strains, with added mild analgesia; cryokinetics  strain with bruising and pain) pain, mild bruising; fascia is (a treatment system of alternating applications of cold with progressive exercise)  intact  Third degree (e.g., traumatic Caused by tearing of fascia; Surgery to approximate ruptured edges; immobilization and rest for 6 weeks, followed  injury) muscle rupture palpable, by an individualized rehabilitation regimen of strengthening exercises  bleeding present    Medications and Toxic Substances That Increase Traumatic, Heat-Related, Ischemic, and Exertional   HMG-CoA reductase inhibitors (statins), especially in combination with fibrate- Direct trauma  derived lipid-lowering agents such as niacin (nicotinic acid; Nicolar) Lightning strike   Antipsychotics and antidepressants (amitriptyline, doxepine, fluoxetine, halo-  peridol, lithium, protriptyline, perphenazine, promethazine, chlorpromazine,  trifluoperazine)    Hypnotics and sedatives (benzodiazepines, barbiturates) Delirium Hemnens ,  Peraiy Heat dissipation impairment   Miscellaneous medications (amphotericin B, azathioprine, epsilon-aminocaproic  acid, quinidine, penicillamine, salicylates, theophylline, terbutaline, thiazides,  vasopressin)   Lactate dehydrogenase deficiency (characteristic elevation of creatine kinase  level with normal lactate dehydrogenase level)   Viruses: influenza virus B, parainfluenza virus, adenovirus, coxsackievirus, echo-  virus, herpes simplex virus, cytomegalovirus, Epstein-Barr virus, human immu-  nodeficiency virus   Compounds containing ma huang, guarana, and garcinia cambogia  Ephedra-based compounds, especially weight-loss supplements    Data from Acharya S et al: Ann Indian Acad Neurol 13(3):221—222, 2010; Cervellin G, Comelli |, Lippi G: Clin Chem Lab Med 48(6):749-756, 2010;  Croce F et al: Int J STD AIDS 21(11):783-785, 2010; Halpern P et al: Hum Exp Toxicol 29(5):259-266, 2010; Mammen AL, Amato AA: Curr Opin  Rheumatol 22(6):644-650, 2010; Sauret JM, Narinides G, Wang GK: Am Fam Physician 65(3):907, 2002.    FIGURE 44-8 Pathogenesis of Compartment Syndrome and Crush Syndrome Caused by Prolonged Muscle Com-    and even disseminated intravascular coagulation (DIC) (likely  caused by activation of the clotting cascade by sarcolemma  damage and release of intracellular components from the dam-  aged muscles). Even the weight of a limp extremity can generate  enough pressure to produce muscle ischemia (Figure 44-8).  Malignant hyperthermia (MH) is a potentially life-threat-  ening hereditary disorder of skeletal muscle ryanodine recep-  tors (RyR1), allowing large quantities of calcium to be released    from the sarcoplasmic reticulum (SR) after exposure to certain  volatile anesthetics. The sustained elevation of calcium concen-  tration allows excessive stimulation of aerobic and anaerobic  glycolytic metabolism, causing a hypermetabolic state resulting  in respiratory and metabolic acidosis, muscle rigidity, altered  cell permeability, and hyperkalemia.!* Dantrolene, a skeletal  muscle relaxant, inhibits calcium release from the SR and is  used to reverse the effects of MH.    Compartment syndromes occur when blood flow to the  affected area is compromised because of increased venous pres-  sure, leading to decreased arterial inflow, ischemia, and edema.  Emergency treatment may be required to save an affected limb.  Classic symptoms of compartment syndrome are: (1) pain out  of proportion to the injury, (2) paresthesia, (3) pallor, (4) pulse-  lessness (uncommon), and (5) paralysis (a late finding). Of  these symptoms, pain is the most sensitive clinical sign.!   When clinical evaluation is inconclusive, the rising com-  partment pressure can be directly measured by inserting a wick  catheter, needle, or slit catheter into the muscle. Immediate fas-  ciotomy and débridement are advocated for reducing elevated  intracompartmental pressures.!> Compartments frequently  affected are the compartments of the leg, the volar compart-  ment of the hand, the abdomen, and the gluteal compartments.   CLINICAL MANIFESTATIONS. A classic triad of muscle pain, weak-  ness, and dark urine is considered typical of rhabdomyolysis,  but those affected may have no complaint of pain or muscle  weakness.'! Abnormally dark urine caused by myoglobinuria  may be the first and only symptom. The renal threshold for  myoglobin is low (approximately 0.5 mg/dl of urine), so only  200 g of muscle need to be damaged to cause visible changes in  the urine. Myoglobin is rapidly cleared and levels may return  to normal within 24 hours of injury. Along with the release  of myoglobin, creatine kinase (CK) and other serum enzymes  are released in massive quantities. The efflux of proteins and  enzymes also includes loss of potassium, phosphate, nucleo-  tides, creatinine, and creatine. Serum hypocalcemia is seen  early in the course of myoglobinuria and is followed by late  hypercalcemia.   EVALUATION AND TREATMENT. The most important and clinically  useful measurement in rhabdomyolysis is serum creatine kinase  (CK) level. With normal CK serum levels of 5 to 25 units/L for  women and 5 to 35 units/L for men, a level five times the upper  limit of normal (about 1000 units/L) is used to identify rhab-  domyolysis. Once CK levels exceed 5000 units/L, acute renal  failure is likely. A recent study evaluated the ultrasonographic  appearance of rhabdomyolysis in damaged muscle from earth-  quake victims and found abnormalities in muscle texture and  subcutaneous tissue, as well as areas of liquid in the damaged  tissue.!4   Maintaining adequate urinary flow and prevention of kid-  ney failure are goals of treatment. Rapid intravenous hydration  maintains adequate kidney flow. Other issues, such as hyperka-  lemia, may require temporary hemodialysis. Other treatments,  such as using mannitol to cause an osmotic diuresis or bicar-  bonate to alkalinize the urine, have not been shown to consis-  tently improve outcomes.    Metabolic bone disease is characterized by abnormal bone  structure that is caused by altered or inadequate biochemi-  cal reactions resulting in disorders of bone strength. Abnor-  malities include genetic, mineral, vitamin, and structural  abnormalities.   Osteoporosis, or porous bone, is a disease in which bone tis-  sue is normally mineralized but the mass—density of bone—  is decreased and the structural integrity of trabecular bone is  impaired. Two types of osteoporosis are generally considered.  Postmenopausal, or primary, osteoporosis is most common. Sec-  ondary osteoporosis is osteoporosis caused by other conditions,  including hormonal imbalances (endocrine disease, diabetes,  hyperparathyroidism, hyperthyroidism), medications (such as  heparin, corticosteroids, phenytoin, barbiturates, lithium), and  other substances (including tobacco and ethanol). Other condi-  tions, including rheumatoid disease, human immunodeficiency  virus (HIV), malignancies, malabsorption syndromes, liver or  kidney disease, also increase the risk for developing osteoporo-  sis (Box 44-2). Cortical bone becomes more porous and thin-  ner, making bone weaker and prone to fractures (Figure 44-9).  The World Health Organization (WHO) has defined osteopo-  rosis based on bone density:   Osteoporosis is a complex, multifactorial chronic disease  that often progresses silently for decades until fractures occur.  It is the most common disease that affects bone. It is not neces-  sarily a consequence of the aging process because some older  adults retain strong, relatively dense bones. In osteoporosis, old  bone is being reabsorbed faster than new bone is being made,  causing the bones to lose density, becoming thinner and more  porous. A progressive loss of bone mass may continue until the  skeleton is no longer strong enough to support itself. Eventu-  ally, bones can fracture spontaneously. As bone becomes more  fragile, fractures occur from falls or bumps that would not pre-  viously have caused fracture.   Severe or established osteoporosis is identified when there  has been a fragility fracture. The disease can be (1) generalized,  involving major portions of the axial skeleton, or (2) regional,  involving one segment of the appendicular skeleton.   Throughout a lifetime, old bone is removed (resorption)  and new bone is added (formation) to the skeleton. During  childhood and teenage years, new bone is added faster than  old bone is removed. Consequently, bones become larger,  heavier, and denser. Bone formation continues at a pace faster  than resorption until peak bone mass, or maximum bone den-  sity and strength, is reached, around age 30, after which bone  resorption slowly exceeds bone formation. In women, bone loss  begins before menopause, and is most rapid in the first years  after menopause but persists throughout the postmenopausal  years. Though osteoporosis is most common in women, it is  estimated that one in five men will experience an osteoporosis-  related fracture at some point in his lifetime.!° In adults over  age 50, the prevalence of osteoporosis at either the spine or the  femoral neck by age ranges from 3% to 10% in men and from  7% to 35% in women. One study showed that in men the preva-  lence of osteoporosis did not increase with age until age 80 years  and older, but in women it increased for each decade after age  50 years.'°    FIGURE 44-9 Vertebral Body. Osteoporotic vertebra (right) shortened by  compression fractures compared with normal vertebral body (/eft). Note that the  osteoporotic vertebra has characteristic loss of horizontal trabeculae and thickened  vertebral trabeculae. (From Kumar V et al: Robbins & Cotran pathologic basis of  disease, ed 8, Philadelphia, 2010, Saunders.)    Approximately 52 million people in the United States are  affected by osteoporosis or low bone density.!’ The major risks  for persons with osteoporosis are fractures. Men lose bone den-  sity with aging but because they begin with a higher bone density,  they reach osteoporotic levels at an older age than do women. '®  Osteoporotic fractures affect 1 in 2 women and 1 in 5 men  older than the age of 50.'® In 2011 the United States Preventive  Services Task Force (USPSTF) issued a recommendation that   Renal insufficiency, hypocalciuria  Rheumatoid arthritis  Spinal cord injury  Systemic lupus erythematosus    women age 65 and older be routinely screened for osteoporo-  sis.!° Hip fractures, in particular, can have devastating effects on  an individual’s life. In addition to direct medical costs, studies  have shown decreased quality of life as well as excess loss of life-  years for those experiencing hip or osteoporotic fractures.”°7!   Vertebral fractures are the most common osteoporotic frac-  ture but may be asymptomatic. Even if the fracture does not  cause pain, vertebral fractures can cause deformity, reduced  pulmonary function, and loss of height. The degree of com-  pression necessary to define a vertebral fracture has not been  standardized.   Osteoporosis affects all races and both sexes. Recent data  from the National Health and Nutrition Examination Survey  (NHANES) showed that Mexican-Americans had higher risk  for osteoporosis, whereas non-Hispanic black persons had  lower risk of osteopenia or osteoporosis at the lumbar spine or  femoral neck.!° Multiple genetic factors also influence develop-  ment of osteoporosis.”   Whites are more susceptible than other races to osteoporosis  caused by loss of bone density with age. Blacks have only about  half the fractures found in whites, probably related to their  higher peak bone mass, but black women remain at a high risk  because of factors such as decreased dietary calcium intake, a  high percentage of lactose intolerance, and increased prevalence  of diseases, such as sickle cell disease and lupus, that increases    the risk of developing osteoporosis.” Both black women and  black men have generally been undertreated for osteoporosis.”*  Decreased bone strength with aging is partly due to lower bone  mass, but other factors such as deterioration of type I collagen  likely contribute to increased fracture risk.   Measuring bone mineral density (BMD) by using dual x-ray  absorptiometry (DXA) continues to be the most common  method of estimating bone mass. Bone quality relates not just  to bone mass (as measured by bone density) but also to the  microarchitecture of the bone. Other variables include crystal  size and shape, brittleness, vitality of the bone cells, structure  of the bone proteins, water volume, integrity of the trabecular  network, vascular supply, and the ability to repair tiny cracks.”°   Because bone density relates to quantity of bone, bone qual-  ity is not accurately identified by bone density testing. There-  fore, bone density testing may or may not accurately identify  individuals with increased fracture risk. An online tool called  FRAX incorporates clinical risk factors with BMD at the femoral  neck to predict an individual’s 10-year probability of fracture.  This tool is available at www.shef.ac.uk/FRAX/. Postmeno-  pausal osteoporosis occurs in middle-aged and older women.  It can occur because of estrogen deficiency as well as estrogen-  independent age-related mechanisms (e.g., secondary causes  such as hyperparathyroidism and decreased mechanical stimu-  lation). Recent studies indicate that increased oxidative stress  (OS) and increased intracellular reactive oxygen species (ROS)  play a significant role in the development of age-related bone  loss, as well as other age-related changes in the body.”° Hor-  monal deficiency also can increase with stress, excessive exer-  cise, and low body weight. Postmenopausal changes include a  substantial increase in bone turnover—that is, an imbalance  between the remodeling activity of osteoclasts and osteo-  blasts. Increased formation and longevity of osteoclasts results  in increased bone resorption and is associated with a cascade  of proinflammatory cytokines. Increased cytokine activation,  especially tumor necrosis factor (TNF), can occur with declin-  ing estrogen levels.*° In addition, estrogen helps protect against  the effects of OS and osteoclast apoptosis. Biologically, these  processes involve the receptor activator nuclear factor kp ligand  (RANKL), transcription factors such as forkhead proteins, the  Wnt and osteoprotegerin (OPG) signaling pathways (see the  following Pathophysiology section), and insulin-like growth  factor (IGF). Other causes may include a combination of inad-  equate dietary calcium intake and lack of vitamin D, possibly  decreased magnesium level, lack of exercise, low body mass,  and family history. IGF is known to help in fracture healing and  collagen synthesis and improves conditions for bone mineral-  ization. IGF levels significantly decline by age 60.   Sex hormones, especially estrogen and testosterone, are sig-  nificant in premenopausal bone maintenance; however, when  estrogen levels drop after menopause, it appears that circulating  androgens become significant effectors on bone metabolism.  In clinical studies of women, data have suggested that serum  androgens influence bone density in pre-, peri-, and postmeno-  pausal women. Androgens (1.e., testosterone and dihydrotestos-  terone) have long been recognized to stimulate bone formation.  Other risk factors are identified in Box 44-2.    Poor nutrition and insufficient intake or malabsorption of  dietary minerals, particularly calcium, are factors in the devel-  opment of osteoporosis. Calcium absorption from the intestine  decreases with age, and studies of individuals with osteoporosis  show that their calcium intake is lower than that of age-matched  controls. Deficiencies of vitamins, particularly vitamins C, D, E,  and K, also contribute to bone loss.””   Skeletal homeostasis depends on a very narrow range of  plasma calcium and phosphate concentrations, which are  maintained by the endocrine system.** Therefore, endocrine  dysfunction ultimately can cause metabolic bone disease.  In addition to declining levels of sex steroids, the hormones  most commonly associated with osteoporosis are parathyroid  hormone, cortisol, thyroid hormone, and growth hormone.  Excessive intakes of caffeine, alcohol, and nicotine along with  low body fat have been considered risk factors. In addition, sig-  nificant differences in the levels of trace elements (zinc, copper,  manganese) were noted in the bones and hair of unaffected  individuals compared with those with osteoporosis. Devel-  opment of selective androgen receptor modulators (SARMs)  promises novel treatment for osteoporosis through increas-  ing bone formation and building more muscle mass. In the-  ory, selectively affecting bone, muscle mass, and other desired  sites while not affecting lipid or estrogen levels or blood pres-  sure, side effects can be controlled but since the direct effects  of SARMs on bone are not yet known, this remains a clinical  challenge.*?*°   Secondary osteoporosis sometimes develops temporarily in  individuals receiving large doses of heparin, perhaps because  heparin promotes bone resorption by decreasing collagen  synthesis or by increasing collagen breakdown. Osteoporosis  caused by heparin therapy usually resolves when therapy ceases.  Treatment with other medications may lead to the development  of osteoporosis, such as the use of glucocorticoid treatment for  rheumatoid arthritis. Other medications increasing the risk of  osteoporosis include lithium, methotrexate, anticonvulsants,  cyclophosphamide, and cyclosporine.   One form, transient osteoporosis of the hip, is associated  with the third trimester of pregnancy or the immediate postpar-  tum period. However, most transient osteoporosis is a typically  self-limiting syndrome affecting the lower extremity joints of  middle-aged men. The etiology is unknown and although most  cases spontaneously resolve, some occurrences of bone demin-  eralization may be related to osteonecrosis.°!   Regional osteoporosis—osteoporosis confined to a region  or segment of the appendicular skeleton—usually has a known  cause. Transient regional osteoporosis has no known etiology,  is characterized by bone marrow edema, and can cause severe  pain. The lower extremity is most often affected, but other areas  also may be involved.** Fortunately, it is usually self-limited.  It tends to occur in middle-aged men and women in their late  second or third trimester of pregnancy.** It is characterized  by bone marrow edema, seen on magnetic resonance imaging  (MRI), and areas of localized bone demineralization are seen on  plain radiographs. Treatment is primarily symptomatic and the  condition usually resolves spontaneously over 3 to 6 months,  with no long-term adverse effects.    Classic regional osteoporosis is associated with disuse or  immobilization of a limb because of fractures, motor paralysis,  or bone or joint inflammation (see Figure 44-13, p. 1555). A neg-  ative calcium balance develops early and continues throughout  the period of immobilization. After 8 weeks of immobilization,  significant osteoporosis is present, although it may develop ear-  lier in persons younger than 20 years or older than 50 years. A  uniform distribution of osteoporosis also has been observed in  astronauts and in individuals treated with air suspension therapy  as a result of weightlessness and lack of mechanical strain.   PATHOPHYSIOLOGY. Whatever the cause, osteoporosis develops  when the remodeling cycle—the process of bone resorption and  bone formation—is disrupted, leading to an imbalance in the  coupling process. The explosion of new information in the field  of bone biology has led to new understanding of the roles of  hormones, growth, and signaling factors, and cellular biology  in osteoporosis. Although hormonal influences remain impor-  tant in maintaining bone health, genetic factors and the role  of oxidative stress are receiving increased attention as critical  determinants of bone homeostasis.**”° Reactive oxygen species  are normal byproducts of aerobic metabolism, and although  they can cause cell damage, at levels below which they cause OS,  ROS serve as signaling molecules for many cell types, includ-  ing osteocytes, osteoblasts, and osteoclasts. When excess ROS  accumulate, OS occurs and can result in loss of bone mass and  bone strength.”   The osteoclast differentiation pathway is directed by a series  of processes that include proliferation, differentiation, fusion,  and activation. These processes are controlled by hormones,  cytokines, and paracrine stromal-cell microenvironment inter-  actions. Thus the intercellular communication in bone and the  key molecular regulators are necessary for bone homeostasis.  Certain transcription factors, known as Forkhead box (FoxO),  help protect against the effects of OS by preventing excess  accumulation of ROS and regulating certain genes that affect  DNA repair and cell life span. FoxOs help remove damaged and  abnormal cells by inducing apoptosis.”°   Interleukins (IL-1, IL-4, IL-6, IL-7, IL-11, IL-17), tumor  necrosis factor-alpha (TNF-a), transforming growth factor-  beta (TGF-f), prostaglandin E,, and hormones interact to con-  trol osteoclasts** (Figure 44-10). Normal bone homeostasis is  dependent on the balance between the cytokine receptor acti-  vator of nuclear factor «pf ligand (RANKL), its receptor RANK,  and its decoy receptor osteoprotegerin (OPG); understanding  this has led to a tremendously increased knowledge of osteoclast  biology and pathogenesis of bone loss.*°   RANKL, a member of the TNF family, is expressed by osteo-  blasts and their immature precursors and is necessary for osteo-  clast development. RANKL activates the receptor RANK, which  is expressed on osteoclasts and their precursors and suppresses  apoptosis, which leads to activation and prolongation of osteo-  clast survival.*° The effects of RANKL are blocked by OPG, a  glycoprotein that acts as a decoy receptor for RANKL that pre-  vents it from binding and activating RANK (see Figure 44-10).  Cytokines and hormones regulate the balance between RANKL  and OPG. Alterations of the RANKL/RANK/OPG system can  lead to dysregulation and pathologic conditions including    osteoporosis, immune-mediated bone diseases, malignant bone  disorders, and inherited skeletal diseases (see Figure 44-10).   Postmenopausal osteoporosis is characterized by increased  bone resorption relative to the rate of bone formation, lead-  ing to sustained bone loss resulting from estrogen deficiency.  Bone loss resulting from estrogen deficiency also contributes to  osteoporosis in men.°”°*   Increased bone resorption results from enhanced develop-  ment of osteoclasts and decreased osteoclast apoptosis (see  Figure 44-10). Estrogen stimulates OPG secretion and down-  regulates RANKL; drugs known as selective estrogen response  modifiers (SERMs) also stimulate OPG production. In estro-  gen deficiency, the exact role of OPG is less clear.** Postmeno-  pausal women express higher levels of RANKL on bone marrow  stromal cells, T cells, and B cells than premenopausal women.  Importantly, RANKL expression is increased when estrogen  levels are decreased, leading to increased formation of osteo-  clasts while reducing osteoclast apoptosis.!*° Other factors, such  as sclerostin (SOST), a glycoprotein secreted by osteocytes, are  powerful inhibitors of osteoblast formation by binding to low-  density lipoprotein (LDL) receptor—related protein 5 (LRP5)  and prevent binding with frizzled protein and Wnt signaling,  important factors in osteoblast and bone formation.**   Sex steroids (e.g., estrogens) exert anti-apoptotic effects on  osteoblasts but exert pro-apoptotic effects on osteoclasts; in  both scenarios this is accomplished by activating the extracel-  lular signal regulated kinases (ERKs). Estrogen activates ERKs  outside the nucleus; ERKs then accumulate in the nucleus and  activate downstream transcription factors.°’ This confusing and  complicated data eventually revealed that the important deter-  minant of whether pro-apoptosis or anti-apoptosis was exhibited  was the length of time that the phosphorylated ERKs remained in  the nucleus. Prolonged nuclear accumulation of activated ERKs  converted the anti-apoptotic effect of estradiol to pro-apoptotic.  In addition to ERKs, RANKL promotes the anti-apoptotic effects  on osteoclasts, thus increasing their life span.*° Wnt signaling  induces a biochemical series of events that increases osteoblast  and bone formation. Alterations in Wnt signaling account for  critical pathophysiologic changes in most acquired metabolic  bone diseases including postmenopausal osteoporosis, aging  effects, and glucocorticoid (1.e., cortisone) excess. Agents such as  parathyroid hormone and bisphosphonates, used for treatment  of bone loss, exert their positive effects by altering the formation  of osteoblasts or osteoclasts or by inducing osteoclast apoptosis.   Glucocorticoid (e.g., cortisone)-induced osteoporosis is  characterized by increased bone resorption and decreased bone  formation. Glucocorticoids increase RANKL expression and  inhibit OPG production by osteoblasts (see Figure 44-10). The  use of immunosuppressive drugs (e.g., cyclosporine A) to reduce  rejection of transplanted organs also alters the OPG/RANKL/  RANK system and can lead to posttransplantation osteoporo-  sis. Other conditions affected by OPG/RANKL/RANK include  rheumatoid arthritis, myeloma, vascular diseases, and skeletal  metastases from neoplastic disorders.   Age-related bone loss begins in the third to fourth decade.  The cause remains unclear, but it is known that decreased serum  growth hormone (GH) and IGF levels along with increased    =e OPG production  expression Increased by Decreased by  Increased by IL-1, IL-13, IL-18 PTH  IL-1, IL-11, IL-17 TNF-a Prostaglandin E,  TNF-a TGF-B, BMP-2 Glucocorticoids  PTH ; 17£-estradiol Cyclosporine A  Prostaglandin E, Leptin  Glucocorticoids Mechanical strain    OPG production  Increased by Decreased by  PDGF-BB Glucocorticoids  Cyclosporine A  Troglitazone    FIGURE 44-10 OPG/RANKL/RANK System. Receptor activator of nuclear factor «B ligand (RANKL), a cytokine and  part of the tumor necrosis factor (TNF) family, expression and osteoprotegerin (OPG), a glycoprotein receptor antagonist, are  modulated by various cytokines, hormones, drugs, and mechanical strains (see inserts). A, In bone, RANKL is expressed by both  stromal cells and osteoblasts. RANKL stimulates the receptor RANK on osteoclast precursor cells and mature osteoclasts, and  activates intracellular signaling pathways to promote osteoclast differentiation and activation and cytoskeletal reorganization  and survival (PKB/Akt pathway) that increases resorption and bone loss. OPG, secreted by stromal cells and osteoblasts, acts  as a “decoy” receptor and blocks RANKL binding to and activation of RANK. B, In the immune system, RANKL is expressed  and secreted by T cells. T-cell-derived RANKL also can activate RANK on osteoclasts, T cells, and dendritic cells (antigen-  presenting cells), which enhances bone loss that occurs in inflammatory bone diseases such as rheumatoid arthritis. Dendritic  cells may regulate these processes by secreting OPG. €, In the vascular system, endothelial cells express RANKL and the  RANK receptor. RANKL/RANK interactions contribute to endothelial and smooth muscle cells and can block RANKL binding.  The physiologic significance of the OPG/RANKL/RANK system in endothelial and smooth muscle cells is being studied. BMP-  2, Bone morphogenic protein 2; /L, interleukin, POGF-BP platelet-derived growth factor-beta polypeptide; P7H, parathyroid  hormone; 7GF-a, tumor necrosis factor-alpha; 7GF-8, transforming growth factor-beta. (Adapted from Hofbauer LC, Schoppet  M: JAMA 292[4]:490-495, 2004.)    FIGURE 44-12 Mechanism of Loss of Trabecular Bone in Women and  Trabecular Thinning in Men. Bone thinning predominates in men because of  reduced bone formation. Loss of connectivity and complete trabecular loss pre-  dominates in women.    binding of RANKL and decreased OPG affect osteoblast and  osteoclast function. Loss of trabecular bone in men proceeds  in a linear fashion, with thinning of trabecular bone rather than  complete loss as is noted in women (Figure 44-11). Men have  approximately 30% more bone mass than women, which may  be a factor in their later involvement with osteoporosis (Figure  44-12). Androgens promote osteoprotegerin production, thus  inhibiting the osteoclastic effect of RANKL.*! Reduction in  physical activity in older persons also may be a major factor  in the degree of bone loss because preservation of bone mass  depends on skeletal stress (mechanical) through muscle con-  traction and weightbearing.**   CLINICAL MANIFESTATIONS. The specific clinical manifestations  of osteoporosis depend on the bones involved. The most com-  mon manifestation, however, is bone deformity. Pain tends to  occur only when there is a fragility fracture. Fractures are likely  to occur because the trabeculae of spongy bone become thin  and sparse and compact bone becomes porous. As the bones  lose volume, they become brittle and weak and may collapse  or become misshapen. Vertebral collapse causes kyphosis  (hunchback) and diminished height (Figure 44-13). Fractures  of the long bones (particularly the femur and humerus), distal    FIGURE 44-13 Kyphosis. This older adult woman's condition was caused by  a combination of spinal osteoporotic vertebral collapse and chronic degenerative  changes in the vertebral column. (From Kamal A, Brocklehurst JC: Color atlas of  geriatric medicine, ed 2, St Louis, 1992, Mosby.)    radius, ribs, and vertebrae are most common. The most seri-  ous fractures associated with osteoporosis are hip fractures  because of their resultant chronic pain, disability, diminished  quality of life, and premature death. Fracture of the neck of the  femur (intertrochanteric fracture) tends to occur in older adult  women with osteoporosis.‘” Fatal complications of fractures  include fat or pulmonary embolism, hemorrhage, and shock.  Approximately 20% of persons with a hip fracture die as a result  of surgical complications.   EVALUATION AND TREATMENT. Generally, osteoporosis is  detected radiographically as increased radiolucency of bone. By  the time abnormalities are detected by x-ray examination, as  much as 25% to 30% of bone tissue may have been lost.   Types of radiologic examinations include single- or  dual-photon absorptiometry (SXA, DXA) and computed    tomography (CT) scans. Because osteoporosis is asymptomatic  unless a fracture occurs, diagnosis is often delayed. At pres-  ent, DXA is the current examination of choice for diagnosis.  Unfortunately, DXA does not provide information about bone  strength or fracture risk.   Because fractures are the primary complication of osteoporo-  sis, the World Health Organization has developed an assessment  tool to estimate an individual’s 10-year risk of fracture. The  WHO’s Fracture Risk Assessment (FRAX) is a downloadable  computer-drive questionnaire that has been developed for use  in Europe, North America, Asia, and Australia. Once completed,  the imbedded algorithms predict the 10-year probability of hip,  spine, forearm, or shoulder fractures. This tool can be down-  loaded from www.shef.ac.uk/FRAX. Other evaluation proce-  dures include tests for levels of serum calcium, phosphorus, and  alkaline phosphatase as well as protein electrophoresis. Body  calcium levels also can be measured by neuron activation analy-  sis, a procedure involving use of radioactive calcium-49, whose  gamma activity can be measured with a whole-body counter.   Though prevention of osteoporosis is paramount, treatment  is more common and is focused on preventing fractures and  maintaining optimal bone function. The role of calcium intake  to prevent and treat osteoporosis is controversial. It is well  accepted that oral calcium intake sufficient to maintain nor-  mal calcium balance is necessary during adolescence to ensure  development of peak bone mass, and that calcium-deficient  diets can aggravate bone loss associated with menopause and  aging. Although recommendations have been established for  young women of 1000 mg of calcium daily (particularly from  dietary sources) and for postmenopausal women of 1500 mg  daily (with vitamin D), it has been difficult to translate these rec-  ommendations into clear-cut clinical outcomes (see Nutrition  & Disease: Postmenopausal Women Should Not Take Calcium  and Vitamin D to Prevent Fractures). A significant relation-  ship has been observed between an individual’s lifetime history  of calcium intake and peak bone mineral density. Diets with  higher fruit and vegetable intake seem to correlate with higher  BMD.* Other nutrients that appear to have a positive impact  on bone health include magnesium, vitamin K,, and docosa-  hexaenoic acid or DHA (from purified fish oil).“    Postmenopausal Women Should Not Take  Calcium and Vitamin D to Prevent Fractures    The beneficial effects of vitamin D on fracture risk are attributed to two expla-  nations: (1) the decrease in bone loss in older adults, and (2) the increase in  muscle strength and balance mediated through vitamin D receptors in muscle  tissue. Vitamin D alone, however, does not appear to reduce fracture risk.  In fact, the U.S. Preventive Services Task Force (USPSTF) has made the rec-    ommendation that postmenopausal women should not take supplementary  calcium (1000 mg or less) and vitamin D (400 IU or less) because, at these  doses, it appears that it does not prevent primary fracture risk and poses a  small increased risk for renal stones. The USPSTF also concluded there is not  enough evidence either supporting or opposing the use of higher doses of  calcium and vitamin D for men or premenopausal women.    Magnesium (Mg**), another mineral important for skeletal  development, is an essential mineral in many biochemical and  physiologic functions, including activation of enzymes, involve-  ment in adenosine triphosphate (ATP) synthesis and protein  synthesis, regulation of membrane channels, and contraction of  muscle. Mg** is important to bone quality because it helps con-  trol hydroxyapatite crystal growth and thereby prevents forma-  tion of brittle bones. It seems reasonable that Mg** is required  for normal calcium (Ca**) absorption because severe Mg*tt  deficiency results in hypocalcemia.   Regular, moderate weightbearing exercise can slow the rate of  bone loss and, in some cases, reverse demineralization because  the mechanical stress of exercise stimulates bone formation. It  is important to reduce the risk of falls and enhance bone qual-  ity. Therefore, an exercise program to enhance muscle strength  is advised. Important new findings suggest that estrogen may  prevent excessive bone loss before and after menopause by lim-  iting osteoclast life span through promotion of apoptosis.   SERMs and SARMs have been developed to provide the  positive effects of estrogen on bone but minimize estrogen’s  negative effect on breast and endometrial tissues. As a result,  in addition to reducing vertebral fractures, SERMs reduce risk  of estrogen receptor breast cancer and improve lipid profiles.”  Raloxifene and tamoxifen are examples of SERMs.   Bisphosphonates are a class of inorganic pyrophosphate  derivatives that bind bone mineral and improve osteoblast and  osteocyte survival while promoting osteoclast apoptosis, thus  slowing the bone remodeling process.*° Nitrogen-containing  bisphosphonates are highly effective in reducing both verte-  bral and nonvertebral osteoporotic fractures; because of this,  bisphosphonates are the mainstay of osteoporosis treatment.  Side effects include alterations in TGF-f signaling that may  cause osteonecrosis of the jaw.*” There also is a small risk of  atypical femoral fractures, atrial fibrillation, and possibly  esophageal cancer associated with bisphosphonates.**°! The  optimal length of treatment with bisphosphonates has not yet  been determined.”   One of the most promising treatments for osteoporosis is  denosumab, a monoclonal antibody that that binds the cyto-  kine receptor activator of NF-«B ligand (RANKL). RANKL  inhibition blocks the maturation, function, and survival of  osteoclasts, thus reducing bone resorption.°*   Teriparatide, also called PTH 1-34, is a biosynthetic form of  parathormone and contains the first 34 amino acids of para-  thyroid hormone; PTH 1-84 is a recombinant PTH that con-  tains all 84 amino acids of naturally occurring PTH. Both work  by stimulating osteoblasts when administered intermittently.>*  Given by subcutaneous injection, PTH reduces vertebral frac-  tures but use is limited to a period of 24 months because of the  risk of developing osteosarcoma. A recent large meta-analysis  of osteoporosis treatment found improved BMD and reduced  fractures with bisphosphonates, SERMs, and denosumab,  though each regimen has potential adverse effects.*° Restora-  tion of a balanced RANKL/OPG ratio (see p. 1553) or inhibi-  tion of RANK responsiveness is known to prevent osteoclast  activation and bone resorption. Anti-RANKL therapy signifi-  cantly reduces bone resorption. Other biologic agents under    investigation include cathepsin K inhibitors, antisclerostin, and  anti-dickkopf antibodies that affect the Wnt/B-catenin signal-  ing pathway in osteoblasts.°°    Osteomalacia is a metabolic disease characterized by inad-  equate and delayed mineralization of osteoid in mature com-  pact and spongy bone. In osteomalacia the remodeling cycle  proceeds normally through osteoid formation, but mineral  calcification (hydroxyapatite formation) does not occur. Bone  volume remains unchanged, but the replaced bone consists of  soft osteoid instead of rigid bone. The result is abnormal bone  matrix mineralization. Rickets is similar to osteomalacia in  pathogenesis, but it occurs in the growing bones of children,  whereas osteomalacia occurs in adult bone. Chronically low  serum phosphate levels can be caused by tumors resulting in  osteomalacia.*” Fibroblast growth factor-23 (FGF-23) plays a  significant role in maintaining normal serum phosphate levels.  Primarily produced by osteocytes, FGF-23 functions to inhibit  reabsorption of phosphate in the renal proximal tubule.°*  (Rickets is described in Chapter 45.)   Osteomalacia and rickets are rare in the United States and  Western Europe but are significant health problems in Great  Britain, Ethiopia, Pakistan, Iran, and India. In the United States  these diseases occur in older adults, in premature infants of  very low birth weight, and in individuals adhering to rigid mac-  robiotic vegetarian diets. Breast-fed black infants who do not  receive vitamin D supplementation have been shown to be at  risk for developing nutritional rickets.°?°   Many factors contribute to the development of osteomala-  cia, but the most important is a deficiency of vitamin D. The  major causes of vitamin D deficiency are diets deficient in  vitamin D, decreased endogenous production of vitamin D,  intestinal malabsorption of vitamin D, renal tubular diseases,  and anticonvulsant therapy. Classic vitamin D deficiency is rare  in the United States because of the addition of synthetic vita-  min D to dairy products and bread. Still, disorders of the small  bowel, kidneys, hepatobiliary system, and pancreas do cause  vitamin D deficiency in the United States. In malabsorptive dis-  ease of the small bowel, vitamin D and calcium absorption are  decreased, so vitamin D is lost in feces. Liver disease interferes  with the metabolism of vitamin D to its more active form, and  diseases of the pancreas and biliary system cause a deficiency of  bile salts, which are necessary for normal intestinal absorption  of vitamin D.   The mechanism by which anticonvulsant drug therapy  results in decreased bone mineral density is not completely  understood, but appears to be from direct impact on bone or  effects on other regulators of bone metabolism such as calcium,  vitamin D, and parathyroid hormone.*®! The anticonvulsants  phenobarbital and phenytoin interfere with calcium absorption  and increase degradation of vitamin D metabolism in the liver  through activation of the cytochrome P-450 pathway.   PATHOPHYSIOLOGY. Crystallization of minerals in osteoid  requires adequate concentrations of calcium and phosphate.  When the concentrations are too low, crystallization (and hence  ossification) does not proceed normally.    Vitamin D deficiency disrupts mineralization because vita-  min D normally regulates and enhances the absorption of cal-  cium ions from the intestine. A lack of vitamin D causes the  plasma calcium concentrations to fall. Low plasma calcium  levels stimulate increased synthesis and secretion of parathy-  roid hormone (PTH). Although the increase in the level of cir-  culating PTH raises the plasma calcium concentration, it also  stimulates increased renal clearance of phosphate. When the  concentration of phosphate in the bone decreases below a criti-  cal level, mineralization cannot proceed normally.   Abnormalities occur in spongy as well as compact bone.  Trabeculae in spongy bone become thinner and fewer, whereas  haversian systems in compact bone develop large channels and  become irregular. Because osteoid continues to be produced  but not mineralized, abnormal quantities of osteoid accumu-  late, coating the trabeculae and the linings of the haversian  canals. Excessive osteoid also can accumulate in areas beneath  the periosteum. The excess of osteoid leads to gross deformities  of the long bones, spine, pelvis, and skull.   CLINICAL MANIFESTATIONS. Osteomalacia causes varying  degrees of diffuse skeletal pain and tenderness. Bone pain is  typically between joints, rather than within them.°’ Pain is  noted particularly in the hips, and the individual may be hesi-  tant to walk. Muscular weakness, particularly of the proximal  muscles, is common and may contribute to a waddling gait.  Facial deformities and bowed knees, or “knock-knees,” may be  present. Bone fractures and vertebral collapse occur with mini-  mal trauma. Low back pain may be an early complaint, but pain  also may involve ribs, feet, other areas of the vertebral column,  and other sites. Uremia may be present in renal osteodystrophy.   EVALUATION AND TREATMENT. Laboratory data may include ele-  vated blood urea nitrogen (BUN) and creatinine levels, normal  or low serum calcium levels, and a serum inorganic phosphate  level that is usually higher than 5.5 mg. Alkaline phosphatase  and PTH levels are usually elevated. Radiographic findings  show pseudofractures and radiolucent bands perpendicular to  the surface of involved bones. Bone biopsy is useful in deter-  mining bone structure and remodeling. Diagnosis of certain  types of osteomalacia is becoming easier because of the abil-  ity to measure an individual’s serum FGF-23 level. Elevated  FGF-23 levels are common in X-linked hypophosphatemic and  tumor-induced osteomalacia.”   phosphatemia  5. Adding dietary supplements of vitamin D  6. Performing renal dialysis  7. Considering renal transplant for renal osteodystrophy   Paget disease of bone (PDB or osteitis deformans) is a state of  increased metabolic activity in bone characterized by abnormal  and excessive bone resorption and formation (remodeling).    Genetic manipulations involving the RANK-NF-«f signaling  pathways are significant in the development of Paget disease,  resulting in increased osteoclast activity.°° Chronic accelerated  remodeling eventually enlarges and softens the affected bones.  Classic PDB arises as a consequence of disorderly bone resorp-  tion and formation.   PDB most often affects the axial skeleton, especially the ver-  tebrae, skull, sacrum, sternum, pelvis, and femur. The disease  process may occur in one or more bones without causing sig-  nificant clinical manifestations.   The disease is seldom found before age 40 years, but its inci-  dence almost doubles each decade from age 50. It affects men  more than women in a proportion of 1.8:1. Because it is often  symptomless and can be diagnosed only by invasive procedures,  few epidemiologic data are available. Autopsy data from Eng-  land and Germany indicate that approximately 3% to 4% of  persons older than 40 years have Paget disease. It is most preva-  lent in Australia, Great Britain, New Zealand, and the United  States.   The cause of PDB is unknown; however, studies have impli-  cated both genetic and environmental factors. About 10%  to 30% of individuals with PDB have mutations of a specific  gene, sequestosome-1.°°°* Even viral etiologies have been  proposed.   PATHOPHYSIOLOGY. Paget disease begins with excessive resorp-  tion of spongy bone and deposition of disorganized bone. The  trabeculae diminish, and bone marrow is replaced by extremely  vascular fibrous tissue. The resorption phase of Paget disease is  followed by the formation of abnormal new bone at an acceler-  ated rate. The collagen fibers are disorganized, and glycoprotein  levels in the matrix decrease. Mineralization may extend into  the bone marrow. Bone formation is excessive around par-  tially resorbed trabeculae, causing them to thicken and enlarge.  Eventually, Paget disease progresses to an inactive phase, in  which abnormal remodeling is minimal or absent. Osteoclasts  of individuals with Paget disease have increased responses to  RANKL.®   CLINICAL MANIFESTATIONS. In the skull, abnormal remodel-  ing is first evident in the frontal or occipital regions, and then  encroaches on the outer and inner surfaces of the entire skull.  The skull thickens and assumes an asymmetric shape (Figure  44-14). Thickened segments of the skull may compress areas of  the brain, producing altered mentality and dementia. Impinge-  ment of new bone on cranial nerves causes sensory abnormali-  ties, impaired motor function, deafness, atrophy of the optic  nerve, and obstruction of the lacrimal duct. Headache is com-  monly noted.   Extensive alterations of the facial bones are rare except in  the jaw, where sclerosis and thickening of the maxilla and man-  dible displace teeth and produce malocclusion. In long bones,  resorption begins in the subchondral regions of the epiphysis  and extends into the metaphysis and diaphysis. Warmth over  the affected area, bone and joint pain, and bone deformity may  occur. Occasionally, Paget disease affects both ends of a long  bone. In the femur, PDB produces an exaggerated lateral curva-  ture. In the tibia, anterior curvature is also exaggerated. Stress  fractures are common in the lower extremities.    FIGURE 44-14 Paget disease of the skull A, Active Paget disease of the  skull, with marked cortical thickening and an area of osteoporosis circumscripta  (arrows). B, The same individual several years later (after bisphosphonate treat-  ment), with the lytic lesion largely replaced by sclerotic bone. (From Walsh JP: Med  J Aust 181[5]:263, 2004.)    Clinical manifestations of PDB in the vertebral column  depend on the level of involvement and are caused by com-  pression of adjacent structures. In the cervical spine, cord com-  pression can lead to spastic quadriplegia. Approximately 1% of  persons with PDB develop osteogenic sarcoma. Paget-related  sarcoma has a poor prognosis.   EVALUATION AND TREATMENT. Evaluation of PDB is made on the  basis of radiographic findings of irregular bone trabeculae with  a thickened and disorganized pattern. A typical V-shaped lesion  in long bones and rounded areas of thinning bone in the skull  are often seen on plain x-ray. Bone scanning can more readily  detect early disease as well as extent of PDB through increased  uptake of bone radionuclides. Serum total alkaline phosphatase  and urinary hydroxyproline levels are elevated.   Most individuals require no treatment because the disease  is localized and does not cause symptoms. Treatment during  active disease is for pain relief, prevention of deformity, or frac-  ture. Bisphosphonates (alendronate, risedronate, and pamidro-  nate) and calcitonin (salmon and human) are the mainstays of  treatment. Surgery is indicated if there are neurologic compli-  cations or severe bony deformities.    Osteomyelitis is a bone infection most often caused by bacteria;  however, fungi, mycobacteria, parasites, and viruses also can  infect bone (Figure 44-15). Exogenous osteomyelitis is an infec-  tion that enters from outside the body, for example, through    open fractures, penetrating wounds, or surgical procedures.  In exogenous osteomyelitis, infection spreads from soft tis-  sues into adjacent bone. Endogenous osteomyelitis is caused by  pathogens carried in the blood from sites of infection elsewhere  in the body. In hematogenous osteomyelitis, infection spreads  from bone to adjacent soft tissues. Hematogenous osteomyeli-  tis is commonly found in infants, children, and older adults.  (Osteomyelitis in children is discussed in Chapter 45.) In  infants, incidence rates among males and females are approxi-  mately equal. In children and older adults, however, males are  most commonly affected. Osteomyelitis is a common compli-  cation of sickle cell anemia and low oxygen tension.   Staphylococcus aureus (including methicillin-resistant Staph-  ylococcus aureus [MRSA]) is the primary cause of hematog-  enous osteomyelitis.”” Other microorganisms include group B  streptococci, Haemophilus influenzae, Salmonella, and gram-  negative bacteria. Group B streptococci and H. influenzae tend  to infect young children; Salmonella infection is associated with  sickle cell anemia; and gram-negative infections are most com-  mon in older adults and individuals with impaired immunity.  Mycobacterial and fungal infections occur in immunocompro-  mised individuals.   Cutaneous, sinus, ear, and dental infections are the primary  sources of bacteria in hematogenous bone infections. Soft tis-  sue infections, disorders of the gastrointestinal tract, infections  of the genitourinary system, and respiratory tract infections are  also sources of bacterial contamination. In addition, infections  contracted after total joint replacement surgeries can be causes  of osteomyelitis. The vulnerability of specific bone depends on  the anatomy of its vascular supply. In adults, hematogenous  osteomyelitis is more common in the spine, pelvis, and small  bones.   Microorganisms reach the vertebrae through arteries, veins,  or lymphatic vessels. The spread of infection from pelvic organs  to the vertebrae is well documented. Vaginal, uterine, ovar-  ian, bladder, and intestinal infections can lead to iliac or sacral  osteomyelitis.   Exogenous osteomyelitis can be caused by human bites or  fist blows to the mouth. Superficial animal or human bites inoc-  ulate local soft tissue with bacteria that later spread to under-  lying bone. Deep bites can introduce microorganisms directly  onto bone. The most common infecting organism in human  bites is S. aureus. In animal bites the most common infecting    organism is Pasteurella multocida, which is part of the normal  mouth flora of cats and dogs.   Direct contamination of bones with bacteria also can occur  in open fractures or dislocations with an overlying skin wound.  Intervertebral disk surgery and operative procedures involving  implantation of large foreign objects, such as metallic plates or  artificial joints, are associated with exogenous osteomyelitis.  Local injections and venous punctures are significant causes of  exogenous osteomyelitis. Exogenous osteomyelitis of the arm  and hand bones tends to occur in drug abusers. S. aureus is the  most common pathogen. In general, persons who are chroni-  cally ill, have diabetes or alcoholism, or are receiving large doses  of corticosteroids or immunosuppressive drugs are particularly  susceptible to exogenous osteomyelitis or recurring episodes of  this disease.   PATHOPHYSIOLOGY. Regardless of the source of the pathogen,  the pathologic features of bone infection are similar to those in  any other body tissue (see Chapter 10). First, the invading patho-  gen provokes an intense inflammatory response. Inflamma-  tion in bone is characterized by vascular engorgement, edema,  leukocyte activity, small blood vessel thrombosis, and abscess  formation.’! Once inflammation is initiated, the small termi-  nal vessels thrombose and exudate seals the bone’s canaliculi.  Inflammatory exudate extends into the metaphysis and the  marrow cavity and through small metaphyseal openings into  the cortex. In children, exudate that reaches the outer surface of  the cortex forms abscesses that lift the periosteum off underlying  bone. Lifting of the periosteum disrupts blood vessels that enter  bone through the periosteum, which deprives underlying bone  of its blood supply; this leads to necrosis and death of the area  of bone infected, producing sequestrum, an area of devitalized  bone (see Figure 44-15). Lifting of the periosteum also stimu-  lates an intense osteoblastic response. Osteoblasts lay down  new bone that can partially or completely surround the infected  bone. This layer of new bone surrounding the infected bone is  called an involucrum. Openings in the involucrum allow the  exudate to escape into surrounding soft tissue and ultimately  through the skin by way of sinus tracts. Involucrum in adults is  rare because the periosteum is firmly attached to the cortex and  resists displacement. Instead, infection disrupts and weakens  the cortex, which predisposes the bone to pathologic fracture.   CLINICAL MANIFESTATIONS. Clinical manifestations of osteomy-  elitis vary with the age of the individual, site of involvement,    initiating event, infecting organism, and whether the infec-  tion is acute, subacute, or chronic. Acute osteomyelitis causes  an abrupt onset of inflammation. If an acute infection is not  completely eliminated, the disease may become subacute or  chronic. In subacute osteomyelitis, signs and symptoms are  usually vague. In the chronic stage, infection is indolent or  silent between exacerbations. The microorganisms persist in  small abscesses or fragments of necrotic bone and produce  occasional flare-ups of acute osteomyelitis. The progression  from acute to subacute osteomyelitis may be the result of inad-  equate or inappropriate therapy or the development of drug-  resistant microorganisms.   In the adult, hematogenous osteomyelitis has an insidi-  ous onset. The symptoms are usually vague and include fever,  malaise, anorexia, and weight loss. Recent infection (urinary,  respiratory, skin) or instrumentation (catheterization, cystos-  copy, myelography, diskography) usually precedes onset of  symptoms.   Back pain is the primary symptom in vertebral osteomyelitis.  Pain may be intermittent or constant, aggravated by motion,  and throbbing at rest. It may radiate in a radicular distribu-  tion and is commonly accompanied by spinal tenderness and  rigidity. Hip contracture can occur in the presence of soft tissue  inflammation as a result of irritation of the psoas muscle.”   Signs and symptoms of sacroiliac osteomyelitis are generally  severe and include local pain, tenderness, and a limp. The pain  may radiate to the buttock or the abdomen.   Single or multiple abscesses (Brodie abscesses) characterize  subacute or chronic osteomyelitis. Brodie abscesses are painless,  circumscribed lesions 1 to 4 cm in diameter, usually in the ends  of long bones, and surrounded by dense ossified bone matrix.  The abscesses are thought to develop when the infectious micro-  organism has become less virulent or the individual’s immune  system is resisting the infection somewhat successfully.   In exogenous osteomyelitis, signs and symptoms of soft tis-  sue infection predominate. Inflammatory exudate in the soft  tissues disrupts muscles and supporting structures and forms  abscesses. Low-grade fever, lymphadenopathy, local pain, and  swelling usually occur within days of contamination by a punc-  ture wound. Osteomyelitis in the hand causes exquisite tender-  ness over the course of tendon sheaths. The fingers are usually  in a semiflexed position, and extension usually causes severe  pain. Palmar swelling or symmetric swelling of the fingers may  be present.   EVALUATION AND TREATMENT. Laboratory data show an elevated  white cell count. Radiographic studies include radionuclide  bone scanning, CT, and MRI. MRI is especially useful in detect-  ing early bone changes associated with infection.”   Infectious bone disease is expensive and difficult to treat and  often culminates in extensive physical disability. The following  factors contribute to the difficulty in treating bone infection:   1. Bone contains multiple microscopic channels that are  impermeable to the cells and biochemicals of the body’s  natural defenses. Once bacteria gain access to these chan-  nels, they are able to proliferate unimpeded.   2. The microcirculation of bone is highly vulnerable to dam-  age and destruction by bacterial toxins. Vessel damage    causes local thrombosis (blockage) of the small vessels,  which leads to ischemic necrosis (death) of bone.   3. Bone cells have a limited capacity to replace bone  destroyed by infections. Initially, osteoclasts are stimu-  lated by infection to resorb bone, which opens up iso-  lated bone channels so that cells of the inflammatory and  immune system can gain access to the infected bone. At  the same time, however, resorption weakens the struc-  tural integrity of the bone. New bone formation usually  lags behind resorption, and the haversian systems in the  new bone are incomplete.   Treatment of osteomyelitis includes surgical débridement  with bone biopsy and culture before or as soon after initiating  antibiotics as possible. Initial antibiotic therapy should be intra-  venous. Chronic conditions may require surgical removal of the  inflammatory exudate followed by continuous wound irriga-  tion with antibiotic solutions in addition to systemic treatment  with antibiotics. Hyperbaric oxygen therapy of 100% oxygen,  given at 2 atmospheres of pressure for 2 hours’ duration per day  for 30 treatments, is also beneficial for chronic refractory osteo-  myelitis. Implanted hardware may require removal to more  thoroughly treat an infected joint.    Primary bone cancer is rare but metastatic disease commonly  affects bone. Many different types of tumors involve the skel-  eton. Based on the tissue of origin, bone tumors are classified  as osteogenic, chondrogenic, collagenic, or myelogenic. Each of  the four types arises from one of the four stem cells that are ulti-  mately derived from the primitive mesoderm (Figure 44-16). In  addition, bone tumors may be classified as being of histiocytic,  notochordal, lipogenic, and neurogenic origins (Box 44-3).   The mesoderm contributes the primitive fibroblast and retic-  ulum cells. The fibroblast is the progenitor of the osteoblast and  the chondroblast. Each cell synthesizes a specific type of intercel-  lular ground substance, and the type of ground substance pro-  duced by the cell generally characterizes the tumor derived from  the cell. For example, osteogenic tumors usually contain cells  that have the appearance of osteoblasts and produce an intercel-  lular substance that can be recognized as osteoid. Chondrogenic  tumors contain chondroblasts and produce an intercellular sub-  stance similar to chondroid (cartilage). Collagenic tumors con-  tain fibrous tissue cells and produce an intercellular substance  similar to the type of collagen found in fibrous connective tissue.   Tumors are also classified as benign or malignant. The crite-  ria used to identify tumor cells as malignant are: (1) an increased  nuclear/cytoplasmic ratio, (2) an irregular nuclear border, (3)  an excess of chromatin, (4) a prominent nucleolus, and (5) an  increase in the number of cells undergoing mitosis. However,  many young, rapidly growing, normal cells and cells subjected  to inflammation and change in their blood supply also exhibit  many of these same characteristics. (Tumor characteristics in  general are described in Chapter 12.)    Epidemiology  The incidence of bone tumors varies with age. Osteosarcoma is  the most common primary malignant bone tumor in children    Fibrogenic Tumors (Often Produce Collagen; Do Not Have  a Mineralizing Matrix)  Fibrosarcoma (M)    Fibrohistiocytic Tumors (Comprised of Fibroblasts)  Benign fibrous histiocytoma (B)  Malignant fibrous histiocytoma (M)    Giant Cell Tumor  Giant cell tumor (B, but can grow aggressively)  Malignancy in giant cell tumor (M; very rare tumor)    Miscellaneous Tumors  Adamantinoma (M; almost exclusively found in tibia)  Metastatic malignancy (M; most common skeletal malignancy)   Chest wall hamartoma (B; is excessive growth of mesenchymal tissue  [mostly cartilage])    Data from Dorfman HD et al: WHO classification of tumours of bone: introduction. In Christopher DM et al, editors: World Health Organization clas-  sification of tumours, International Agency for Research on Cancer (IARC) pathology and genetics of tumours of soft tissue and bone, p 226, Lyon,    and young adults.’”*”° Adolescents have the highest incidence  of bone tumors, and adults between 30 and 35 years of age have  the lowest incidence. After age 35, the incidence slowly increases  until, at age 60, it equals the incidence in adolescents, primarily  related to metastatic tumors.    The general pathologic features of bone tumors include bone  destruction, erosion or expansion of the cortex, and periosteal    response to changes in underlying bone. The least amount of  pathologic damage occurs with benign bone tumors that push  against neighboring tissue. Because they usually have a sym-  metric, controlled growth pattern, benign bone tumors tend to  compress and displace neighboring normal bone tissue, which  weakens the bone’s structure until it is incapable of withstand-  ing the stress of ordinary use, leading to pathologic fracture.  Other tumors invade and destroy adjacent normal bone tissue  by producing substances that promote resorption by increasing    osteoclast activity or by interfering with a bone’s blood supply.  Three patterns of bone destruction by bone tumors have been  identified: (1) the geographic pattern, (2) the moth-eaten pat-  tern, and (3) the permeative pattern (Table 44-5).   Tumors that erode the cortex of the bone usually stimulate  a periosteal response, that is, new bone formation at the inter-  face between the surface of the bone and the periosteum. Slow  erosion of the cortex usually stimulates a uniform periosteal  response. Additional layers of bone are added to the exterior  surface of the bone to buttress the cortex. Eventually the addi-  tional layers expand the bone’s contour. Aggressive penetration  of the cortex usually elevates the periosteum and stimulates  erratic patterns of new bone formation. Examples of erratic pat-  terns include concentric layers of new bone; a sunburst pattern,  in which delicate rays of new bone radiate toward the perios-  teum from a single focus on the underlying surface; and rays of  new bone that grow perpendicularly, creating a brush or bristle  pattern.    Diagnosis  Malignant bone tumors account for less than 0.2% of all can-  cers.’° A tumor must be identified early to allow survival of the  individual and the preservation of the affected limb. However,  individuals often have only vague symptoms that may be attrib-  uted to minor trauma, degenerative changes, or inflammatory  conditions. In addition, other conditions may obscure the  diagnosis.   Thorough diagnostic studies are needed to determine the  exact type and extent of bone tumor present, which also helps    Well-defined margins separated from  surrounding normal bone; well-  defined lytic area in affected bone   Less-defined margin not easily  separated from normal bone; areas  of partially destroyed bone adjacent  to completely lytic areas   Poorly demarcated margins; abnormal  lytic bone merges imperceptibly with  surrounding normal bone    Intracompartmental (T,)  Extracompartmental (T,)  Intracompartmental (T;)  Extracompartmental (T,)  Intracompartmental or extracompartmental (T, or T,)  Intracompartmental or extracompartmental (T, or T,)    determine the optimal treatment regimen. Staging of any bone  tumor is critical to determine future treatment and results. The  American Joint Committee on Cancer (AJCC) staging system  (also known as Enneking or TNM Staging System) is the most  commonly used arrangement (Table 44-6). This system clas-  sifies tumors as to grade (G), tumor site (T), and metastasis  (M). Benign tumors are given a numeric value of zero, whereas  malignant tumors are low grade (G;) or high grade (G)).   Serum alkaline phosphatase levels are elevated in bone lytic  tumors, and they are significantly elevated in osteosarcoma and  Ewing sarcoma. Radiologic studies include plain radiologic  film, technetium-99 bone scan, CT scan, and MRI, which has  become the examination of choice for the local staging of bone  tumors, especially the staging of peripheral osteosarcomas (see  Table 44-5). MRI is also used to monitor the response of osteo-  sarcomas to radiation or chemotherapy and to detect recurrent  disease. A CT scan can evaluate involvement of osteosarcoma  in flat bones when the tumor is not well defined on a plain film,  can assist in differentiating the tumor, and can locate pulmo-  nary metastases. Radionucleotide bone scans show an increased  uptake at the tumor site. Before any surgical procedure, bone  biopsy or core needle biopsy should be performed. Core needle  biopsy has less risk of tumor seeding.’°   Additional diagnostic studies performed for specific bone  tumors include a complete blood count and erythrocyte sedi-  mentation rate (to rule out infection, myeloma, or Ewing  sarcoma) and measurement of serum levels of calcium and  phosphorus to detect hypercalcemia. Serum glucose levels may  be elevated in chondrosarcoma. Acid phosphatase level may  be moderately elevated in bone metastases, multiple myeloma,  and advanced Paget disease. Serum protein electrophoresis and  immunoelectrophoresis are done to rule out multiple myeloma.  Fine-needle biopsy is done, usually at the time of surgery, to  determine the exact tumor type.   A very large number of lesions are classified as bone tumors. The  bone tumors most representative of the four derivative types  (see Figure 44-16)—osteogenic, chondrogenic, collagenic, and  myelogenic tumors—are described here.   Osteogenic Tumors: Osteosarcoma. Osteogenic (bone-  forming) tumors are characterized by the formation of bone  or osteoid tissue with a sarcomatous tissue. The tissue can  have the appearance of compact or spongy bone. The most  common malignant primary bone tumor is osteosarcoma.    None (Mb)  None (Mb)  None (Mb)  None (Mb)  Regional or distant (M,)  Regional or distant (M,)    Data from National Comprehensive Cancer Network: Recent updates to NCCN clinical practice guidelines in oncology: bone cancer, National  Comprehensive Cancer Network, Version 1, Fort Washington, PA, 2013, Author.    FIGURE 44-17 Osteosarcoma. A, Common locations of osteosarcoma.  B, Femur has a large mass involving the metaphysis of the bone; the tumor has  destroyed the cortex, forming a soft tissue component. (From Damjanov I, Linder J,  editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.)    Osteosarcomas account for 38% of bone tumors. The male/  female ratio is 3:2, and osteosarcoma occurs predominantly in  adolescents and young adults; 60% of osteosarcomas occur in  persons younger than 20 years. A secondary peak incidence for  osteosarcoma occurs in the 60 and older age group, primarily  in individuals with a history of radiation therapy several years  previously for pelvic or other malignancies (Figure 44-17).   An osteosarcoma is a malignant bone-forming tumor. It is  aggressive and most often found in bone marrow; it has a moth-  eaten pattern of bone destruction. The borders of the tumor are  indistinct and merge into adjacent normal bone. Osteosarco-  mas always contain osteoid and callus (osteoblastic sarcoma)  produced by anaplastic stromal cells, which are atypical, abnor-  mal cells not seen in normal developing bone; they are neither  normal nor embryonal. The osteosarcoma also may contain  chondroid (cartilage) (chondroblastic sarcoma) and fibrinoid  tissue (fibroblastic sarcoma) that may form the bulk of the  tumor. The osteoid is deposited in thick masses or “stream-  ers” between the trabeculae of callus, which infiltrate the nor-  mal compact bone, destroy it, and replace it with dense callus  and masses of osteoid. Demonstrating the presence of osteoid  aids in the diagnosis of osteosarcoma. Bone tissue produced by  osteosarcomas never matures to compact bone.   Ninety percent of osteosarcomas are located in the metaphy-  ses of long bones, especially the distal femur and proximal tibia,  with 50% around the knee area. The tumor typically breaks  through the cortex, lifts the periosteum, and forms a soft tissue  mass that is not covered by a smooth shell of new bone. Lift-  ing of the periosteum stimulates bizarre patterns of new bone  formation called a periosteal reaction. Distinct osteosarcomas  occur on the surface of long bones, called parosteal, periosteal,  or high-grade surface osteosarcomas; dedifferentiated parosteal  and central osteosarcomas also occur.    The most common initial symptoms are pain and swelling.  Initially the pain is slight and intermittent, but within a short  time it increases in severity and duration. Pain is usually worse at  night and gradually requires medication. Systemic symptoms are  uncommon. Usually a coincidental history of trauma is noted.  Occasionally the individual may have a pathologic fracture.   Systemic chemotherapy and surgery are the treatments of  choice, with the location of the tumor and its size, malignancy  grade, and evidence of metastasis dictating the type and extent  of surgery. Preoperative chemotherapy has greatly increased the  number of individuals qualifying for limb salvage surgery. Limb  salvaging procedures have been made possible by advances in  reconstructive techniques and endoprosthetics. Limb salvage  ultimately may be successful in as many as 80% of persons.  Individuals must have achieved most of their bone growth to be  candidates for limb salvage procedures, which are preferred to  amputation. Skeletally immature individuals may have a limb  salvage operation, referred to as a rotationplasty, in which the  major portions of the thigh, the tumor, and contaminated knee  are resected while preserving the nerve supply (sciatic) to the leg  and foot. The proximal tibia is internally fixed to the stump of the  proximal femur after it has been rotated 180 degrees. The foot is  positioned at a desired spot or direction, allowing the ankle joint  to function as a knee joint with the foot supplying the traditional  role of the tibial stump in a below-knee amputation.   If an amputation is done, individuals are monitored closely  with chest roentgenograms and CT. Pulmonary metastases are  surgically resected, and chemotherapy is now a common ther-  apy given both before and after surgery, using combinations  of chemotherapeutic agents. Promising agents under investi-  gation include monoclonal antibodies, hormone antagonists,  gene therapy, and other biologic agents that may dramatically  improve survival.””7   Chondrogenic Tumors: Chondrosarcoma. Chondrogenic  (cartilage-forming) tumors produce cartilage or chondroid,  a primitive cartilage or cartilage-like substance. The most  common chondrogenic tumor is chondrosarcoma, accounting  for 20% of bone tumors.   Chondrosarcoma, the second most common primary  malignant bone tumor, is a tumor of middle-age and older  adults; incidence peaks in the sixth decade of life.’? The tumor  is found more commonly in men than in women. Pre-existing  chondral lesions, such as osteochondromas, can give rise to  secondary chondrosarcoma, which, generally, has a fairly good  prognosis.®°   A chondrosarcoma is a large ill-defined malignant tumor  that infiltrates trabeculae in spongy bone. It produces carti-  lage-forming cells but there is no ossification, as in normal  endochondral bone formation.*! It occurs most often in the  metaphysis or diaphysis of long bones, especially the femur, and  in the bones of the pelvis (Figure 44-18). The tumor contains  large lobules of hyaline cartilage that are separated by bands of  fibrous tissue and anaplastic cells. Chondrosarcomas typically  implant in surrounding tissue (“seeding”).   Symptoms associated with chondrosarcoma have an insidi-  ous onset. Local swelling and pain are the usual symptoms that  cause a person to seek treatment. At first the pain is dull and    FIGURE 44-18 Chondrosarcoma. A, Common locations of chondrosarcoma.  B, Chondrosarcoma of humerus. (From Damjanov |, Linder J, editors: Andersons  pathology, ed 10, St Louis, 1996, Mosby.)    intermittent, then gradually intensifies and becomes constant.  It may awaken the person at night.   Diagnostic studies include radiographs, which must be  reviewed carefully for an accurate diagnosis. Biopsy is done at  the time of surgery. (If biopsy is done before scheduled surgical  incision, seeding of tumor cells could occur.) Sufficient tumor  material must be obtained to facilitate an accurate diagnosis.   Wide surgical excision is generally regarded as the treatment  of choice because chemotherapy and radiation seem to have  little effect.*! Many surgically treated individuals demonstrate  recurrences, however, so amputation is becoming one treat-  ment of choice. Therefore, individuals with tumors located in  the limbs have a better prognosis than those with pelvic lesions.   Collagenic Tumors: Fibrosarcoma. Collagenic (collagen-  forming) tumors produce fibrous connective tissue. The most  typical collagenic tumor is the fibrosarcoma.   Fibrosarcomas come from fibroblasts that originate from  mesenchymal stem cells and represent 4% of primary malignant  bone tumors, with a broad age distribution. They may occur at  any age but are most common in adults between 30 and 50 years  of age. Fibrosarcoma also may be a secondary complication of  radiation therapy, Paget disease, and long-standing osteomyeli-  tis; secondary fibrosarcoma tends to be more aggressive, with  poorer outcome.   Fibrosarcoma is a solitary tumor that most often affects the  metaphyseal region of the femur or tibia. The tumor is com-  posed of a firm fibrous mass of tissue that contains collagen,  malignant fibroblasts, and occasional osteoclast-like giant cells.   The tumor begins in the marrow cavity of the bone and  infiltrates the trabeculae. It demonstrates a permeative growth  pattern, destroys the cortex, and extends into the soft tissue.  Metastasis to the lung is common.   Symptoms associated with the tumor have an insidious onset,  which delays diagnosis. Pain and swelling, the usual symptoms    FIGURE 44-19 Giant Cell Tumor of Bone. A, Common skeletal locations.  B, Gross picture of cell tumor of bone (epimetaphysis). (From Damjanov |, Linder J,  editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.)    that cause the individual to seek treatment, usually indicate that  the tumor has broken through the cortex. Local tenderness, the  presence of a palpable mass, and limitation of motion also may  be present. A pathologic fracture in the affected bone is often  the reason for seeking medical help. Diagnostic studies include  radiographs and MRI.   Radical surgery and amputation are the treatments of choice  for fibrosarcoma. Radiation therapy is generally considered  ineffective treatment for this tumor.   Myelogenic Tumors. Myelogenic tumors originate from  various bone marrow cells. Two types of myelogenic tumors  are giant cell tumor and myeloma. Myeloma is discussed in  Chapter 29.   Giant Cell Tumor. Giant cell tumor is the sixth most com-  mon of the primary bone tumors, accounting for 4% to 5% of  bone tumors. Giant cell tumors have a wide age distribution;  however, they are rare in persons younger than 10 years or  older than 70 years. Most giant cell tumors are found in persons  between 20 and 40 years of age. Unlike most other bone tumors,  giant cell tumors affect females more often than males.*?   Giant cell tumors are generally benign, solitary, circum-  scribed tumors that cause extensive bone resorption because  of their osteoclastic origin (Figure 44-19). There is a high    rate of recurrence but metastasis is rare. The tumor is rich in  osteoclast-like giant cells and anaplastic stromal cells. It also may  contain osteoid, callus, and collagen. Overexpression of several  genes, including osteoprotegerin ligand (OPGL), occurs in  giant cell tumors. The giant cell tumor is typically located in the  center of the epiphysis in the femur, tibia, radius, or humerus.  The tumor has a slow, relentless growth rate and is usually con-  tained within the original contour of the affected bone. Tumors  are often associated with pathologic fractures because of aggres-  sive bone resorption.** It may, however, extend into the articu-  lar cartilage. When the tumor extends, it is usually covered by  periosteum or periosteal bone growth.   The most common symptoms associated with giant cell  tumor are pain, local swelling, and limitation of movement.  Diagnostic studies include radiographs, CT, and MRI. Cryo-  surgery and resection of the tumor with the use of adjuvant  polymethylmethacrylate (PMMA) for bone grafts decrease  recurrence and are more successful treatments than curet-  tage and radiation.** Amputation may be necessary but is not  common.    The American College of Rheumatology (ACR) recognizes 13  groups of joint disease—arthropathies. Most of these disorders  can be placed into two major categories: noninflammatory joint  disease and inflammatory joint disease. With recent improve-  ments in detection methods, conditions such as osteoarthritis  that were previously classified as noninflammatory have now  had inflammatory pathways identified.    Osteoarthritis (OA) is a common age-related disorder of syno-  vial joints. It is characterized by local areas of loss and dam-  age of articular cartilage, new bone formation of joint margins  (osteophytosis), subchondral bone changes, variable degrees  of mild synovitis, and thickening of the joint capsule (Figure  44-20). OA has been commonly classified as noninflamma-  tory joint disease. However, it is clear that specific markers of  inflammation are present in OA and inflammation is an impor-  tant feature of OA. The use of MRI and arthroscopy has made  it clear that osteoarthritic changes are not defined by changes  noted on x-ray films alone.   The exact cause of OA is uncertain; however, pathology  centers on load-bearing areas. Advancing disease reveals nar-  rowing of the joint space because of cartilage loss, bone spurs  (osteophytes), and sometimes changes in the subchondral  bone. It is uncommon in people younger than 40 years but  rises in incidence with age. Low-grade inflammation, calcifi-  cation of articular cartilage, genetic alterations, and metabolic  disorders combined with the interaction of transcription fac-  tors, cytokines, growth factors, matrix molecules, and enzymes  affect development and progression of OA.*>*° OA is generally  distributed throughout the peripheral and central joints of the  body (hips, hands, knees, and spine). With aging, the quality  and quantity of the proteoglycans in cartilage decrease in direct  proportion to the severity of OA.    OA can be caused by any condition that damages carti-  lage directly; subjects the joint surfaces or underlying bone to  chronic, excessive, or abnormal forces; or causes instability in  the joint. Specific risk factors include the following:   ing which inflammatory cells release enzymes capable of  digesting cartilage cells   cot neuropathic joint) in which pain and proprioceptive  reflexes are diminished or lost, increasing the tendency  for abnormal movement, positioning, or weightbearing   which causes chronic bleeding into the joints, or hyper-  parathyroidism, which causes bone to lose calcium   All of these factors alter articular cartilage in some way and  accelerate the rate of cartilage loss.   PATHOPHYSIOLOGY. The primary defect in OA is loss of articular  cartilage. Early in the disease, the articular cartilage loses its glis-  tening appearance, becoming yellow-gray or brownish gray. As  the disease progresses, surface areas of the articular cartilage flake  off and deeper layers develop longitudinal fissures (fibrillation).  The cartilage becomes thin and may be absent over some areas,  leaving the underlying bone (subchondral bone) unprotected.  Consequently, the unprotected subchondral bone becomes scle-  rotic (dense and hard). Cysts sometimes develop within the sub-  chondral bone and communicate with the longitudinal fissures  in the cartilage. Pressure builds in the cysts until the cystic con-  tents are forced into the synovial cavity, breaking through the  articular cartilage on the way. As the articular cartilage erodes,  cartilage-coated osteophytes may grow outward from the under-  lying bone and alter the bone contours and joint anatomy. These  spur-like bony projections enlarge until small pieces, called joint  mice, break off into the synovial cavity. If osteophyte fragments  irritate the synovial membrane, synovitis and joint effusion  result. The joint capsule also becomes thickened and at times  adheres to the deformed underlying bone, which may contribute  to the limitation of movement (see Figure 44-20).   Articular cartilage is lost through a cascade of cytokine and  anabolic growth factor pathways.*’ Enzymatic processes, partic-  ularly those involving matrix metalloproteinases, break down  the macromolecules of proteoglycans, glycosaminoglycans, and  collagen into large, diffusible fragments. The fragments are then  taken up by the cartilage cells (chondrocytes) and digested by  the cell’s own lysosomal enzymes. (Processes of cellular uptake  and lysosomal digestion are described in Chapter 1.) The loss of    Irregular thickening and  remodeling of subchondral bone,  with sclerosis and cysts    FIGURE 44-20 Osteoarthritis (OA). A, Cartilage and degeneration of the hip joint resulting from osteoarthritis.  B, Heberden nodes and Bouchard nodes. €, Characteristics of OA. Normal vs. osteoarthritic synovial joint.    proteoglycans from articular cartilage is a hallmark of the osteo-  arthritic process.   Enzymatic destruction of articular cartilage begins in the  matrix, with destruction of proteoglycans and collagen fibers.  Enzymes, particularly stromelysin and matrix metalloprotein-  ases (collagenase), affect proteoglycans by interfering with  assembly of the proteoglycan subunit or the proteoglycan  aggregate (see Chapter 43); levels of these enzymes are markedly  elevated in OA. Changes in the conformation of proteoglycans  disrupt the pumping action that regulates movement of water  and synovial fluid into and out of the cartilage. Without the  regulatory action of the proteoglycan pump, cartilage absorbs  too much fluid and becomes less able to withstand the stresses    of weightbearing. Also with aging, the proteoglycan content is  decreased and the water content in cartilage can be increased by  as much as 8%, affecting the strength of the cartilage. Persons  with OA, even those with fairly extensive cartilage destruction,  have elevated levels of proteoglycans or fragments of proteo-  glycans in their synovial fluid, perhaps indicative of a more  pronounced reparative phase. Inflammatory cytokines, such as  IL-1 and TNF (see Chapter 8 for a discussion of cytokines), play  a major role in cartilage degradation in part through induction  of nitric oxide synthase (iNOS) and nitric oxide (NO) increased  generation. Cytokines release and activate proteolytic and col-  lagenolytic enzymes, causing an imbalance of cell responses to  growth factor activity.*”    FIGURE 44-21 Possible Mechanisms Driving Artery and Cartilage Calcification. All specified factors have been dem-  onstrated to promote calcification in either arteries and/or cartilage (see text). MGP Matrix GLA-protein; OPG, osteoprotegerin;  Pi, inorganic phosphate; PPi, inorganic pyrophosphate. (From Rutsch F, Terkeltaub R: Joint Bone Spine 72:110-118, 2005.)    Crosstalk between signaling pathways contributes to the  development and progression of OA.** Some of the enzymes that  degrade collagen (e.g., chemokines and metalloproteinases) are  produced by the synovium. Chondrocyte apoptosis is increased  in OA cartilage and is directly correlated with hydroxyapatite  crystal deposition. Nitric oxide (NO) stimulates apoptosis in  chondrocytes. The resultant cartilage destruction initiates the  IL-18 and TNF-a pathways of inflammation. Genetic defi-  ciencies of inhibitors of calcification also may contribute to  “run away” calcification (Figure 44-21). Collagen breakdown  destroys the fibrils that give articular cartilage its tensile strength  and exposes the chondrocytes to mechanical stress and enzyme  attack. Thus a cycle of destruction begins that involves all the  components of articular cartilage—proteoglycans, collagen  fibers, and chondrocytes.   CLINICAL MANIFESTATIONS. Clinical manifestations of OA typi-  cally appear during the fifth or sixth decade of life, although  asymptomatic articular surface changes are common after age  40. Pain and stiffness in one or more joints, usually weightbear-  ing or load-bearing joints, are the first symptoms of the disease.  Use-related joint pain relieved by rest is a key feature. Exami-  nation usually shows general involvement of peripheral and  central joints. Peripheral joints most often involved are in the  hands, wrists, knees, and feet. Central joints most often affected  are in the lower cervical spine, lumbosacral spine, shoulders,  and hips.   Pain and stiffness are the predominant symptoms of OA;  others include swelling, tenderness, or enlargement/deformity  of joints. Symptoms are usually aggravated by weightbearing  or use of the joint and relieved by resting the joint. Sometimes  pain is referred to another part of the body. For example, osteo-  arthritis of the lumbosacral spine may mimic sciatica, causing  severe pain in the back of the thigh along the course of the sci-  atic nerve. OA in the lower cervical spine may cause brachial  neuralgia (pain in the arm) aggravated by movement of the  neck. Osteoarthritic conditions in the hip cause pain that may  be referred to the lower thigh and knee area.    The actual mechanisms of joint pain are complex and poorly  understood, but several explanations are possible. Subchon-  dral bone changes, weightbearing stress, and inflammatory  mediators may be sources of joint pain in OA.°?°° Nonetheless,  there is little correlation between radiologic appearance of OA  and an affected person’s pain level.’! Articular distention and  stretching of the fibrous joint capsule, which has an abundant  nerve supply may also contribute to pain. In addition, inflam-  mation of the joint capsule causes fibrous shrinking, so that  movement of the joint in any direction causes painful stretching  (Figure 44-22).   The origin of joint stiffness is unknown. Joint stiffness is  generally defined as difficulty in initiating joint movement,  immobility, or a loss of range of motion. The extent of carti-  lage degeneration also limits range of motion to some degree.  The stiffness usually occurs as joint movement begins and dis-  sipates within 30 minutes. Enlargement and bulging of joint    contour, commonly described as swelling, may be caused by  bone enlargement or the proliferation of osteophytes around  the margins of the joint. These types of typical joint swelling in  the fingers are termed Heberden and Bouchard nodes. Swelling  also occurs if inflammatory exudate or blood enters the joint  cavity, thereby increasing the volume of synovial fluid. This  condition, termed joint effusion, is caused by (1) the presence  of osteophyte fragments in the synovial cavity, (2) drainage of  cysts from diseased subchondral bone, or (3) acute trauma to  joint structures, resulting in hemorrhage and inflammatory  exudation into the synovial cavity.   Abnormal knee alignment (either varus or valgus of more  than 5 degrees) has been shown to increase progression of  OA.”? Gait abnormalities may ensue attributable to knee  malalignment.   EVALUATION AND TREATMENT. Evaluation consists of clinical  assessment and radiologic studies, CT scan, arthroscopy, and  MRI. Treatment is based on severity of symptoms. Research is  ongoing to evaluate the use of specific biomarkers to allow ear-  lier detection of OA and monitor its progress.*> Conservative  treatment includes rest of the involved joint until inflammation,  if present, subsides; participation in aerobic exercise and range-  of-motion exercise to prevent joint capsule contraction; use of  a cane, crutches, or walker to decrease weightbearing; weight  loss if obesity is present; and analgesic and anti-inflammatory  drug therapy to reduce pain and swelling. Glucosamine and  chondroitin, so-called nutraceuticals, are not currently rec-  ommended.” Other alternative therapies, including magnetic  bracelets and acupuncture, seem to improve symptoms in some  people as do intra-articular injection of high-molecular-weight  viscosupplements, particularly hyaluronic acid. New technolo-  gies, including tissue engineering, hold promise for reversing  degenerative joint changes (see What’s New? Tissue Engineer-  ing for Cartilage and Tendon).   Surgery is used to improve joint movement, correct defor-  mity or malalignment, or create a new joint with artificial  implants. There are nearly 250,000 total hip replacements yearly  in the United States, most of which are related to OA.    Inflammatory joint disease commonly is called arthritis.  Inflammatory joint disease is characterized by damage or  destruction in the synovial membrane or articular cartilage and  by systemic signs of inflammation (fever, leukocytosis, malaise,  anorexia, hyperfibrinogenemia).   Inflammatory joint disease can be infectious or noninfec-  tious. In infectious inflammatory joint disease, inflammation  is caused by invasion of the joint by bacteria, mycoplasmas,  viruses, fungi, or protozoa. These agents can invade the joint  through a traumatic wound, surgical incision, or contami-  nated needle, or they can be delivered by the bloodstream  from sites of infection elsewhere in the body, typically bones,  heart valves, or blood vessels. In noninfectious inflammatory  joint disease, inflammation is caused by the deposition of crys-  tals of monosodium urate in and around the joint (gout) or  by immune reactions (rheumatoid arthritis and ankylosing  spondylitis).    Chronic musculoskeletal disorders involving joints and soft tissue cause sig-  nificant disability and loss of productivity. Articular cartilage degeneration  related to osteoarthritis affects a majority of people over the age of 65 and  often results in chronic pain and disability. After laceration or rupture of a  tendon, healing can take months to occur and return of normal function is  often limited.   Efforts to surgically repair or replace damaged cartilage and tendon have  been frustrated by inferior mechanical and functional qualities of repaired tis-  sue compared to healthy, noninjured tissue. New techniques, however, prom-  ise improved return of preinjury characteristics.   Nanotechnology has allowed development of a scaffold for cartilage repair  that mimics the body's natural endochondral framework for cartilage and bone  development. This biomimetic structure has been used to treat osteochondral  cartilage defects in a recent clinical trial. Future nanocomposites that mimic  bone are also under exploration.   Tendon scaffolds using nanofibers are being investigated. In soft tissue such  as tendon, use of scaffolds for implanting mesenchymal stem cells (MCSs)  and growth factors can increase tendon strength and improve biomechanical  properties of healing tissue. Other ongoing research is focusing on combining  MCSs, type | collagen sponges, and constructs treated with mechanical stimu-  lation to improve mechanical and cellular properties of tissue.    Data from Grande DA et al: J Am Acad Orthop Surg 19:59-62, 2011;  Hogan MV et al: J Am Acad Orthop Surg 19:134-142, 2011; Kock L,  van Donkelaar CC, Ito K: Cell Tissue Res 347:613-627, 2012; Pleshko  N, Grande DA, Myers KR: J Am Acad Orthop Surg 20:60-62, 2012.    Rheumatoid arthritis (RA) is a chronic, systemic inflammatory  autoimmune disease distinguished by joint swelling and ten-  derness and destruction of synovial joints, leading to disability  and premature death.”> (Autoimmune disease is described in  Chapter 9.) The first joint tissue to be affected is the synovial  membrane, which lines the joint cavity (see Chapter 43 and  Figure 43-9). Multiple immunoregulatory cytokines (such as  interleukins, B cells, and matrix metalloproteinases) contrib-  ute to joint damage. Eventually, inflammation may spread to  the articular cartilage, fibrous joint capsule, and surrounding  ligaments and tendons, causing pain, joint deformity, and loss  of function (Figure 44-23). The joints most commonly affected  are in the fingers, feet, wrists, elbows, ankles, and knees, but the  shoulders, hips, and cervical spine also may be involved, as well  as the tissues of the lungs, heart, kidneys, and skin.   Over the past five decades, the incidence and prevalence of  RA have decreased, and RA now affects between 0.5% and 1%  of the adult population in developed countries.”° The frequency  of RA increases with age. Besides inflammation of the joints, RA  can cause fever, malaise, rash, lymph node or spleen enlarge-  ment, and Raynaud phenomenon (transient lack of circulation  to the fingertips and toes).   Despite intensive research, the cause of RA remains obscure.  It is likely a combination of genetic factors interacting with  inflammatory meditators. The intricate interplay of chemokines  (powerful mediators of inflammation) is largely responsible for  RA’s chronic inflammatory characteristics. Ligand/receptor  chemokines attract T cells and produce inflammatory changes.”    A key genetic element has been localized to the human  leukocyte antigen-death receptor 4 (HLA-DR4), HLA-DRB1  (death receptor beta), and HLA-DP genes of the major histo-  compatibility complex in all ethnic groups. A surprising new  discovery is the presence of T-cell abnormalities in individuals  with RA, indicating a defect in telomere repair that may result  in faster aging of telomeres with subsequent loss of efficient    FIGURE 44-23 Rheumatoid Arthritis of the Hand. Note swelling from  chronic synovitis of metacarpophalangeal joints, marked ulnar drift, subcutaneous  nodules, and subluxation of metacarpophalangeal joints with extension of proxi-  mal interphalangeal joints and flexion of distal joints. Note also deformed position  of thumb. Hand has wasted appearance. (From Mourad L: Orthopedic disorders,  St Louis, 1991, Mosby.)    Spirochete Borrelia burgdorferi  Transmitted via ticks (Ixodes scapularis or |. pacificus)    Bacterial infections with Gonococcus, Staphylococcus, Streptococcus,  Haemophilus influenzae, and gram-negative bacilli; H. influenzae arthritis more  common in children younger than 2 years; S. aureus in older children and adults   Many viruses including parvovirus B19, rubella, hepatitis C virus, human  immunodeficiency virus    immune function.?’ Types of infectious arthritis are sum-  marized in Table 44-7. With long-term or intensive exposure  to the antigen, normal antibodies (immunoglobulins [Igs])  become autoantibodies—antibodies that attack host tissues  (self-antigens). Because they are usually present in individu-  als with rheumatoid arthritis, the altered antibodies are termed  rheumatoid factors (RFs). RFs usually consist of two classes  of immunoglobulin antibodies (antibodies for IgM and IgG)  but occasionally involve antibodies for IgA. Their main anti-  genic targets are portions of the immunoglobulin molecules.  RFs bind with their target self-antigens in blood and synovial  membrane, forming immune complexes (antigen-antibody  complexes) (see Chapter 8).   Environmental factors including geographic area of birth,  length of breast-feeding, socioeconomic status, and especially  smoking have been identified as risk factors for developing  RA.*® RA and other autoimmune diseases have a higher prev-  alence among women.” The reasons for this are unclear, but  hormones and genetics play a role as shown by RA symptom  improvement during pregnancy and flares with breast-feeding.   PATHOPHYSIOLOGY. Although no specific events (such as  trauma, illness, or environmental conditions) have been identi-  fied that would cause immune abnormalities to develop into  localized tissue and joint inflammation, the pathology of RA  is fairly well understood. During inflammation, arginine (an  a-amino acid) can be enzymatically modified into another  a-amino acid, citrulline. This process (citrullination) changes  the structure and function of the protein. Other proteins, like  fibrin and vimentin, can become citrullinated during cell death  and tissue inflammation.! In turn, the citrullinated proteins  can be seen as antigens by the body’s immune system. Thus,  both T and B cells play a role in the autoimmune response.  T cells express receptor activator of nuclear factor «kB ligand  (RANKL), which promotes osteoclast formation, causing bony  erosion.””   Inflammatory cytokines, particularly tumor necrosis  factor-alpha (TNF-a), interleukin-1 beta (IL-1), interleukin-6    Initial infection of skin followed by spreading to other sites including joints in  days or weeks   Arthritis is a predominant feature involving mainly large joints; possibly  caused by immune reactions against Borrelia antigens (such as Osp A) that  cross-react with tissue antigens in joints   Fibrous ankylosis and destruction of joint space; onset is insidious and  gradual   Classic is a sudden onset of symptoms—painful, hot, swollen joint with  decreased range of motion    Symptoms vary from acute to subacute  Unclear if effects are from direct invasion of the virus or an autoimmune  reaction    FIGURE 44-24 Emerging Model of Pathogenesis of Rheumatoid Arthritis. Rheumatoid arthritis is an autoimmune  disease of a genetically susceptible host triggered by an unknown antigenic agent. Chronic autoimmune reaction with activa-  tion of CD4+ helper T cells and possibly other lymphocytes and the local release of inflammatory cytokines and mediators  eventually destroys the joint. T cells stimulate cells in the joint to produce cytokines that are key mediators of synovial damage.  Apparently immune complex deposition also plays a role. Tumor necrosis factor (TNF) and interleukin-1 (/L-7), as well as some  other cytokines, stimulate synovial cells to proliferate and produce other mediators of inflammation, such as prostaglandin E,  (PGE;), matrix metalloproteinases, and enzymes, which all contribute to destruction of cartilage. Activated T cells and synovial  fibroblasts also produce receptor activator of nuclear factor KB ligand (RANKL), which activates the osteoclasts and promotes  bone destruction. Pannus is a mass of synovium and synovial stroma with inflammatory cells, granulation tissue, and fibro-  blasts that grows over the articular surface and causes its destruction.    (IL-6), interleukin-7 (IL-7), and interleukin-21 (IL-21), that  induce enzymatic (metalloproteinase) breakdown of cartilage  and bone and T cells also interact with synovial fibroblasts (syn-  oviocytes) through TNF-a, converting synovium into a thick,  abnormal layer of granulation tissue known as pannus (see Fig-  ures 44-25 and 44-26, A). Composed of these macrophages, plus  osteoclasts and fibroblast-like synoviocytes, the pannus acts like  a locally invasive tumor.!°!!°2 Macrophages, components of  pannus (Figure 44-24), stimulate the release of IL-1, platelet-  derived growth factor (PDGF), and fibronectin. The pathogen-  esis of rheumatoid arthritis is summarized in Figure 44-24.  Several types of leukocytes are attracted out of the cir-  culation and into the synovial membrane. The phagocytes  of inflammation (neutrophils and macrophages) ingest the  immune complexes and, in the process of doing so, release    powerful enzymes that degrade synovial tissue and articular  cartilage (Figure 44-25). The immune system’s B and T lym-  phocytes are also activated. The B lymphocytes are stimulated  to produce more RFs, and the T lymphocytes eventually cause  release of enzymes that amplify and perpetuate the inflam-  matory response. Cartilage destruction is mediated by matrix  metalloproteinases (MMPs) that activate the synoviocytes to  invade and attack the synovium and matrix.!% In addition,  RANKL is expressed by various cells in the synovium and  induces osteoclast maturation and activation, thus producing  increased bone resorption (see p. 1553).   Inflammatory and immune processes have several damag-  ing effects on the synovial membrane. Along with the swelling  caused by leukocyte infiltration, the synovial membrane under-  goes hyperplastic thickening as its cells proliferate and become    FIGURE 44-25 Synovitis. Inflamed synovium showing typical arrangements of  macrophages and fibroblastic cells.    abnormally large. As synovial inflammation progresses to  involve its blood vessels, small venules become occluded by the  hypertrophied endothelial cells, fibrin, platelets, and inflamma-  tory cells, which decrease vascular flow to the synovial tissue.  Compromised circulation, coupled with increased metabolic  needs because of hypertrophy and hyperplasia, causes hypoxia  and metabolic acidosis. Acidosis stimulates the release of hydro-  lytic enzymes from synovial cells into the surrounding tissue,  initiating erosion of the articular cartilage and inflammation  in the supporting ligaments and tendons. Inflammation causes  hemorrhage, coagulation, and fibrin deposition on the synovial  membrane, in the intracellular matrix, and in the synovial fluid.  (Figure 44-26, A and B).   CLINICAL MANIFESTATIONS. The onset of RA is usually insidi-  ous, although as many as 15% of cases have an acute onset.  RA begins with general systemic manifestations of inflamma-  tion, including fever, fatigue, weakness, anorexia, weight loss,  and generalized aching and stiffness. Local manifestations also  appear gradually over weeks or months. Typically the joints  become painful, tender, and stiff. Pain early in the disease is  caused by pressure from swelling; later it is caused by sclerosis  of subchondral bone and new bone formation. Stiffness usu-  ally lasts for about 1 hour after arising in the morning and may  be caused by synovitis. Initially most commonly involved joints  are the metacarpophalangeal (MCP), proximal interphalangeal  (PIP), and wrists, with later involvement of larger weightbear-  ing joints.   Widespread and symmetric joint swelling is caused by  increasing amounts of inflammatory exudate (leukocytes,  plasma, plasma proteins) in the synovial membrane, hyper-  plasia of inflamed tissues, and formation of new bone. On    te  FIGURE 44-26 Rheumatoid Arthritis. A, Schematic view of the joint lesion.  B, Advanced rheumatoid arthritis involving femur. There is prominent prolifera-  tion of synovium and almost complete destruction of overlying articular cartilage.  (A modified from Feldmann M: Nat Rev Immunol 2:364, 2002; B from Rosai J:  Ackerman’s surgical pathology, ed 10, Philadelphia, 2011, Mosby.)    palpation, the swollen joint feels warm and the synovial mem-  brane feels “boggy.” The skin over the joint may have a ruddy  or cyanotic hue and may look thin and shiny.   An inflamed joint may lose some of its mobility; even  mild synovitis can lead to loss of range of motion. Extension  becomes limited and is eventually lost if flexion contractures  form. Chronic synovitis weakens ligamentous structures lead-  ing to deformities of the fingers, toes, and limbs, including ulnar  deviation of the hands, boutonniére and swan-neck deformi-  ties of the finger joints,!°4 plantar subluxation of the metatarsal  heads of the foot, and hallux valgus (angulation of the great toe  toward the other toes). Flexion contractures of the knees and  hips are also common.   Joint deformities cause the physical limitations experienced  by persons with RA. Loss of joint motion is quickly followed by  secondary atrophy of the surrounding muscles. With secondary    muscle atrophy the joint becomes unstable, which further  aggravates joint pathology.   Two complications of chronic RA are caused by an excessive  amount of inflammatory exudate in the synovial cavity. One  complication is the formation of cysts in the articular cartilage  or subchondral bone. Occasionally these cysts communicate  with the skin surface (usually the sole of the foot) and can drain  through passages called fistulae. The second complication is  rupture of a cyst or of the synovial joint itself, usually caused  by strenuous physical activity that places excessive pressure on  the joint.   Extrasynovial rheumatoid nodules, or swellings, are  observed in areas of pressure or trauma in 20% of individu-  als with RA. Each nodule is an aggregate of inflammatory cells  surrounding a central core of fibrinoid and cellular debris.  T lymphocytes are the predominant leukocytes in the nodule;  B lymphocytes, plasma cells, and phagocytes are found around  the periphery. Nodules are found most often in subcutaneous  tissue over the extensor surfaces of elbows and fingers. Less  common sites are the scalp, back, feet, hands, buttocks, and  knees.   Rheumatoid nodules also may invade the skin, cardiac valves,  pericardium, pleura, lung parenchyma, and spleen. These nod-  ules are identical to those encountered in some individuals with  rheumatic fever and are characterized by central tissue necro-  sis surrounded by proliferating connective tissue. Also noted  are large numbers of lymphocytes and occasional plasma cells.  Acute glaucoma may result, with nodules forming on the sclera.  Pulmonary involvement may result in diffuse pleuritis or multi-  ple intraparenchymal nodules. Together, the occurrence of pul-  monary nodules and pneumoconiosis (chronic inflammation  of the lungs from inhalation of dust) creates Caplan syndrome.  Diffuse pulmonary fibrosis may occur because of immunologi-  cally mediated immune complex deposition.   Rheumatoid nodules within the heart may cause valvular  deformities, particularly of the aortic valve leaflets. Pericardial  effusion or other pericardial problems occur in almost 50% of  individuals with RA. Lymphadenopathy of the nodes close to  the affected joints may develop. Rheumatoid nodules within  the spleen result in splenomegaly. Involvement of blood vessels  results in an acute necrotizing vasculitis, characteristic of that  noted in other immunologic/inflammatory states. Thrombo-  ses of such involved vessels may give rise to myocardial infarc-  tions, cerebrovascular occlusions, mesenteric infarction, kidney  damage, and vascular insufficiency in the hands and fingers  (Raynaud phenomenon). Vascular changes are noted primar-  ily in individuals receiving corticosteroid therapy; thus there is  some concern that the therapy may play a role in initiating these  lesions. Changes in skeletal muscle are often noted in the form  of nonspecific atrophy secondary to joint dysfunction.   EVALUATION AND TREATMENT. The autoantibodies rheumatoid  factor (RF) and the much more specific serum marker anti—  citrullinated protein antibody (ACPA) can be present for years  to decades before synovial or radiographic changes become  apparent.?*!0!95 Early, aggressive treatment of RA can prevent  disability and joint destruction. In 2010 the American College  of Rheumatology (ACR) and the European League Against    Rheumatism (EULAR) revised their classification criteria to  better identify early stages of RA.?? Box 44-4 summarizes the  criteria for diagnosing RA.   Early treatment of RA begins with disease-modifying anti-  rheumatic drugs (DMARDs) such as methotrexate (MTX), aza-  thioprine, sulfasalazine, hydroxychloroquine, leflunomide, and  cyclosporine. MTX remains the first line of treatment. More  recently, targeted treatment of RA has involved use of agents  aimed at interrupting the pathogenesis of the disease. Known  as biological DMARDs (bDMARDs), these medications affect  specific processes in the development of RA and include tumor  necrosis factor inhibitors such as etanercept, adalimumab, and  infliximab. They recently have been augmented by the mono-  clonal antibodies golimumab and certolizumab. Other agents  interfere with cytokine function (anakinra inhibits IL-1 func-  tion; tocilizumab targets IL-6), inhibit T-cell activation (abata-  cept), or deplete B cells (rituximab). Combination therapy with  a DMARD and a biologic agent, such as infliximab (a TNF  inhibitor), is more effective than using a single agent.!°°   Education is fundamental in treating RA. Other treatments  and therapies include nonsteroidal anti-inflammatory drugs  (NSAIDs), glucocorticoids, intra-articular steroid injections,  physical and occupational therapy with therapeutic exercise,  and use of assistive devices. Surgery is used to treat deformities  or mechanical deficiencies of joints and can include synovec-  tomy or joint replacement.   Ankylosing spondylitis (AS) is the most common of a group of  inflammatory arthropathies known as spondyloarthropathies.  It is a chronic inflammatory joint disease characterized by stiff-  ening and fusion (ankylosis) of the spine and sacroiliac joints.  The exact cause of AS is unknown but its high association with  the histocompatibility antigen human leukocyte antigen (HLA-  B27) has been known for decades. New research has shown that  misfolding of HLA-B27 occurs in the endoplasmic reticulum  (ER). As misfolded proteins accumulate, it results in a stress  response of the ER and increased production of interleukin-23  (IL-23), a potent cytokine that may also act on T-helper 17 cells,  promoting their survival.'°’ Th17 cells, in turn, produce the  inflammatory cytokine IL-17.   Although inflammation is the primary pathologic process  in both RA and AS, the two diseases possibly differ in the pri-  mary site of inflammation and the end result. In RA the pri-  mary site of inflammation is the synovial membrane, resulting  in the destruction and instability of synovial joints. In AS, the  primary pathologic problem is uncontrolled bone formation,  rather than bone destruction seen with most other types of  arthritis.!°° The end results of AS are fibrosis, ossification, and  fusion of the joint, primarily the sacroiliac joints and the verte-  bral column. MRI studies demonstrate changes in the sacroiliac  joints before they become clinically apparent or visible on plain  radiographs. !0”   The prevalence of AS in the United States is approximately  0.5% to 1% among whites, 3% to 4% among blacks, and 18%  to 50% in various nations of American Indians. Worldwide, the  disease appears to be most prevalent in whites. The prevalence    BOX 44-4 THE 2010 AMERICAN COLLEGE OF RHEUMATOLOGY/EUROPEAN LEAGUE  AGAINST RHEUMATISM CLASSIFICATION CRITERIA FOR RHEUMATOID ARTHRITIS    Target population (Who should be tested?) Individuals:  1. who have at least one joint with definite clinical synovitis (swelling)*  2. who have synovitis not better explained by another disease!  Classification criteria for RA (score-based algorithm: add scores of categories  A to D; a score of =6/10 is needed for classification of a patient as having defi-  nite RA)?  Clinical Finding Score  A. Joint involvement®  1 large joint!  2-10 large joints  1-3 small joints (with or without involvement of large joints)*  4-10 small joints (with or without involvement of large joints)  >10 joints (at least 1 small joint)**    joint involvement.  I Large joints” refer to shoulders, elbows, hips, knees, and ankles.    of AS in males is at least 10 times greater than previously consid-  ered. It affects men three times as often as women. In women,  AS may affect the peripheral joints of the appendicular skeleton  rather than the axial skeleton, progress less rapidly, and cause  less dramatic spinal changes. Many individuals with AS remain  undiagnosed.   Primary AS usually develops in late adolescence or young  adulthood, with peak incidence at about 20 years of age. Sec-  ondary AS affects older age groups and is often associated  with other inflammatory diseases (e.g., psoriatic arthropathy,  inflammatory bowel disease, Reiter syndrome).   PATHOPHYSIOLOGY. AS has a strong association with the histo-  compatibility antigen HLA-B27. Several hypotheses have been  suggested to explain this association including the arthritogenic  peptide theory that proposes that certain HLA-B27 alleles bind  certain arthritogenic peptides because of their specific anchor-  ing proteins. Cartilage antigens are proposed as the targets for  the immune response and the presentation of such antigens    Clinical Finding Score  B. Serology (at least 1 test result is needed for classification)'*    C. Acute-phase reactants (at least 1 test result is needed for classification)**  Normal CRP and normal ESR  Abnormal CRP or abnormal ESR    *The criteria are aimed at classification of newly presenting patients. In addition, patients with erosive disease typical of rheumatoid arthritis (RA)  with a history compatible of prior fulfillment of the 2010 criteria should be classified as having RA. Patients with longstanding disease, including  hose whose disease is inactive (with or without treatment), who, based on retrospectively available data, have previously fulfilled the 2010    Differential diagnoses vary among patients with different presentations, but may include conditions such as systemic lupus erythematosus,  psoriatic arthritis, and gout. If it is unclear about the relevant differential diagnoses to consider, an expert rheumatologist should be consulted.  Although patients with a score 26/10 are not classifiable as having RA, their status can be reassessed and the criteria might be fulfilled    SJoint involvement refers to any swollen or tender joint on examination, which may be confirmed by imaging evidence of synovitis. Distal interpha-  angeal joints, first metacarpophalangeal joints, and first metatarsophalangeal joints are excluded from assessment. Categories of joint distribution  are classified according to the location and number of involved joints, with placement into the highest category possible based on the pattern of    #"Small joints” refer to the metacarpophalangeal joints, proximal interphalangeal joints, second through fifth metatarsophalangeal joints, thumb    “In this category, at least 1 of the involved joints must be a small joint; the others can include any combination of large and additional small joints,  as well as other joints not specifically listed elsewhere (e.g., temporomandibular, acromioclavicular, sternoclavicular, etc.).   tNegative refers to IU values that are less than or equal to the upper limit of normal (ULN) for the laboratory and assay; low-positive refers to  values that are higher than the ULN but <3 times the ULN for the laboratory and assay; high-positive refers to IU values that are >3 times the ULN  or the laboratory and assay. Where rheumatoid factor (RF) information is only available as positive or negative, a positive result should be scored    *Normal/abnormal is determined by local laboratory standards. CRP. C-reactive protein; ESR, erythrocyte sedimentation rate.  58Duration of symptoms refers to patient self-report of the duration of signs and symptoms of synovitis (e.g., pain, swelling, tenderness) of joints  hat are clinically involved at the time of assessment, regardless of treatment status.    to CD8+ T cells. In the early phases of AS, T cells and mac-  rophages invade and cause erosion of the cartilage at different  sites. Based on these observations, it is thought that the carti-  lage is the primary target for the immune response. Aggrecan, a  proteoglycan, forms a major part of the extracellular matrix of  cartilage and helps maintain its stability. A specific CD4+ T-cell  response to proteins derived from aggrecan has been found in  animals and humans. Although these T cells have been found  in AS, their role as a causative agent in AS remains unclear and  necessitates future study.   AS involves inflammation of fibrocartilage in cartilaginous  joints, primarily the vertebrae. The fibrous tissue of the joint  capsule, the cartilage that surrounds intervertebral disks, the  entheses, and the periosteum are infiltrated by inflammatory  cells. As inflammatory cells (chiefly macrophages) and lympho-  cytes infiltrate and erode bone and fibrocartilage in joint struc-  tures, repair begins. Repair of cartilaginous structures begins  with the proliferation of fibroblasts. Fibroblasts synthesize and    FIGURE 44-27 Ankylosing Spondylitis. Characteristic posture and primary  pathologic sites of inflammation and resulting damage.    secrete collagen. The collagen becomes organized into fibrous  scar tissue that eventually undergoes calcification and ossifica-  tion. With time, all the cartilaginous structures of the joint are  replaced by ossified scar tissue, causing the joint to fuse, or lose  flexibility.   Repair of eroded bone begins with osteoblast activation and  proliferation. Osteoblasts lay down new bone (callus), which  is remodeled and replaced by compact, lamellar bone. Bone  repair changes the contour of the bone’s surface because the  new bone grows outward to form a new enthesis with the end  of the eroded ligament. The new enthesis, which forms on top  of the old one, is called a syndesmophyte. As calcification of  the spinal ligaments progresses, the vertebral bodies lose their  concave anterior contour and appear square. On radiographs  the spine assumes the classic “bamboo spine” appearance of AS.   CLINICAL MANIFESTATIONS. The most common signs and symp-  toms of early AS are low back pain and stiffness. Typically the  individual with primary disease develops low back pain during  the early twenties. The pain is at first insidious but progressively  becomes persistent. It is often worse after prolonged rest and is  alleviated by physical activity. Early morning stiffness usually  accompanies the low back pain, and the individual typically has  difficulty sitting up or twisting the spine. Forward flexion, rota-  tion, and lateral flexion of the spine are restricted and painful.  Early pain and resultant loss of motion are caused by the under-  lying inflammation and reflex muscle spasm rather than by soft  tissue or bony fusion.   As the disease progresses, the normal convex curve of the  lower spine (lumbar lordosis) diminishes and concavity of  the upper spine (kyphosis) increases. The individual becomes  increasingly stooped. The thoracic spine becomes rounded, the  head and neck are held forward on the shoulders, and the hips  are flexed (Figure 44-27).    Inflammation in the tendon insertions of the many cos-  tosternal and costovertebral muscles can cause pleuritic chest  pain and restricted chest movement. The pain is usually worse  on inspiration. Movement in the diaphragm is normal and full.  Pressure on the anterior chest wall over the sternum, ribs, and  costal cartilages may cause tenderness. Tenderness over the  pelvic brim may cause discomfort at night and interfere with  sleep because turning onto the iliac crests causes pain. Tender-  ness over the ischial tuberosities may make sitting on hard seats  unbearable. Tenderness in the heels may contribute to a limp or  the cautious placement of the feet during walking.   Along with low back pain, many individuals have periph-  eral joint involvement, uveitis, fibrotic changes in the lungs,  cardiomegaly, aortic incompetence, amyloidosis, and Achilles  tendinitis. Symptoms may include fatigue, weight loss, low-  grade fever, hypochromic anemia, and an increased erythrocyte  sedimentation rate.   EVALUATION AND TREATMENT. Diagnosis of AS is made on the  basis of both clinical and radiologic findings. Low back pain and  stiffness lasting more than 3 months that improves with exer-  cise but is not relieved by rest, limited spine range of motion  (ROM) in both frontal and sagittal planes, and limited chest  expansion relative to normal values for age and gender are the  classic clinical criteria. Radiologic changes at the sacroiliac joint  are graded according to severity of abnormality; abnormalities  include sclerosis, widening, narrowing, or ankylosis.'!° Labo-  ratory tests, including serum analysis for the presence of the  histocompatibility antigen HLA-B27, elevated erythrocyte sedi-  mentation rate (ESR) (normal is 0 to 9 mm/hr in males, 0 to  2 mm/hr in females), and elevated alkaline phosphatase levels,  can be used to help monitor the course of the disease.   Treatment of individuals with AS consists of a multidisci-  plinary approach: physical therapy to maintain skeletal mobil-  ity and prevent the natural progression of contractures, support  groups, nonsteroidal anti-inflammatory drugs (NSAIDs) to  provide relief of symptoms, analgesic medications to suppress  some of the pain and stiffness and to facilitate exercise, and  corticosteroid injections to locally inflamed joints. The medica-  tions do not prevent disease progression, but they do provide  relief from symptoms. DMARDs such as gold, methotrex-  ate, and sulfasalazine have little or no effect in AS. Three TNF  inhibitors (etanercept, infliximab, and adalimumab) have been  approved for severe AS. Surgery can help if there is severe dis-  abling deformity.!!°    Gout is a syndrome caused by an inflammatory response to  uric acid production or excretion resulting in high levels of  uric acid in the blood (hyperuricemia) and in other body flu-  ids, including synovial fluid. Although hyperuricemia is essen-  tial for the development of gout, it is not the only factor. Other  factors include age (rare before 30 years), genetic predisposi-  tion (X-linked alteration of the enzyme hypoxanthine-guanine  phosphoribosyltransferase [HGPRT]), excessive alcohol con-  sumption, obesity, certain drugs (especially thiazides), and  lead toxicity. When the uric acid concentration is >6.8 mg/dl  in fluids, it crystallizes and forms insoluble precipitates of   Steep rise to 5.2 mg/dl  Slow rise to =4 mg/dl  4.7 mg/dl    Males (at puberty)  Females (puberty to premenopause)  Females (after menopause)  Hyperuricemia    monosodium urate (MSU) that are deposited in connective  tissues throughout the body. Crystallization in synovial fluid  causes acute, painful inflammation of the joint, and triggers an  inflammatory response by macrophages. When macrophages  phagocytize MSU crystals, they form a protein scaffold known  as an inflammasome. Inflammasomes then convert inactive  interleukins of IL-1B and IL-18 into their active forms.!!!!!?  Prolonged accumulation results in joint damage, a condition  known as gouty arthritis. With time, crystal deposition in sub-  cutaneous tissues causes the formation of small, white nodules,  or tophi, that are visible through the skin. Crystal aggregates  deposited in the kidneys can form urate renal stones and lead  to renal failure.   In classic gouty arthritis, monosodium urate crystals form  and cause joint inflammation. Pseudogout is caused by the for-  mation of calcium pyrophosphate dihydrate (CPPD) crystals.  The effect of either crystal is the same—the onset of a cytokine-  mediated acute inflammatory response (see Chapter 7).   Gout is rare in children and premenopausal women and is  uncommon in males younger than 30 years. The peak age of  onset in males is between 40 and 50 years, whereas it is some-  what later in females. The risk of developing gouty arthritis is  similar in males and females for a particular urate concentra-  tion. The plasma urate concentration is an important determi-  nant of the risk of developing gout (Table 44-8).   Uric acid (UA) is a byproduct of protein metabolism that  normally assists with removal of nitrogen waste from the body.  At lower levels, UA is an important antioxidant but at higher  levels it acts as a pro-oxidant where it increases levels of free  radicals and causes other inflammatory changes.'!> When ion-  ized, uric acid can form salts with various cations but 98% of  extracellular uric acid is in the form of monosodium urate (uric  acid salt). At any time the proportion of uric acid or urate is pH  dependent, so the ratio of these two forms varies considerably  in urine (Figure 44-28).   The solubility of urate and uric acid is critical to the develop-  ment of crystals. Urate is more soluble in plasma, synovial fluid,  and urine than in aqueous solutions; solubility in urine rises  dramatically as the pH increases to more than 4. There is little  change, however, in the solubility of urate within the normal  pH range that exists in the plasma, synovial fluid, and other tis-  sues. Decreasing temperatures cause both urate and uric acid  solubility to fall. The pathways of production of uric acid are  shown in Figure 44-29.    FIGURE 44-28 Effect of pH on Uric Acid and Urate Equilibrium. At pH 5.7,  equal amounts of uric acid and urate are present in the solution. (Redrawn from  Klippel JH, Dieppe PA, editors: Rheumatology, ed 2, London, 1998, Mosby-Wolfe.)    PATHOPHYSIOLOGY. The pathophysiology of gout is closely  linked to purine metabolism and kidney function. At the cel-  lular level, purines are synthesized to purine nucleotides, which  are used in the synthesis of nucleic acids, adenosine triphos-  phate, cyclic adenosine monophosphate (cAMP), and cyclic  guanosine monophosphate (GMP). Uric acid is a breakdown  product of purine nucleotides (uric acid synthesis and elimi-  nation are illustrated in Figure 44-30). Some individuals with  gout have an accelerated rate of purine synthesis accompanied  by an overproduction of uric acid. Other individuals break  down purine nucleotides at an accelerated rate that also results  in an overproduction of uric acid. A deficiency of the enzyme  HGPRT (see earlier) can lead to an increased production of  uric acid. A complete absence of HGPRT is uncommon but can  occur in the X-linked Lesch-Nyhan syndrome, with males at  risk for hyperuricemia, neurologic alterations, and sometimes  gouty arthritis. The majority of individuals with gout, how-  ever, have an unknown metabolic defect, which is referred to as  primary gout. When the etiology is known, it is referred to as  secondary gout.   Most uric acid is eliminated from the body through the kid-  neys. Urate is filtered at the glomerulus and undergoes reab-  sorption and excretion within the proximal renal tubules. In  primary gout, urate excretion by the kidneys is sluggish; this  may be the result of a decrease in glomerular filtration of urate  or acceleration in urate reabsorption. In addition, MSU crys-  tals deposited in renal tubules can cause acute nephropathy. !!*  (Kidney function is described in Chapter 37.)   Monosodium urate crystals can stimulate and perpetuate the  inflammatory response (Figure 44-31). The presence of MSU  crystals triggers the acute inflammatory response. Initiation of  the complement system activates cytokines and produces other    FIGURE 44-29 Production of Uric Acid. The major pathways involved in purine nucleotide synthesis. (Redrawn from  Klippel JH, Dieppe PA, editors: Rheumatology, ed 2, London, 1998, Mosby-Wolfe.)    FIGURE 44-30 Uric Acid Synthesis and Elimination. Uric acid is derived  from ingested purines or synthesized from ingested foods, as well as being recy-  cled following cell breakdown. Uric acid is then eliminated through the kidneys and  gastrointestinal tract. (Redrawn from Klippel JH, Dieppe PA, editors: Rheumatol-  ogy, ed 2, London, 1998, Mosby-Wolfe.)    substances, called chemoattractants, that draw neutrophils out  of the circulation to begin phagocytizing (ingesting) the crystals.   A variety of inflammatory mediators are released dur-  ing the crystal/cell response, of which IL-16 appears to be of  prime importance. Other factors including chemotactic fac-  tors, lysosomal enzymes, eicosanoids, prostaglandin E (PGE)),  reactive oxygen species, and collagenase also are released (see  Figure 44-31, B). Some of these mediators stimulate the influx    of neutrophils, monocytes, and lymphocytes. (Acute inflamma-  tion and phagocytosis are described in Chapter 7.)   Within the joint fluid, urate crystals react particularly with  neutrophils and monocytes. Tissue damage begins to occur,  principally when the neutrophils release the contents of their  phagolysosomes. These contents also perpetuate inflammation.  At an early phase of an acute gouty attack, synovial microto-  phi have been demonstrated. As the process continues, numer-  ous microtophi may be present on the synovial membrane (see  Figure 44-31, C).   CLINICAL MANIFESTATIONS. Gout is manifested by (1) an increase  in serum urate concentration (hyperuricemia); (2) recurrent  attacks of monoarticular arthritis (inflammation ofa single joint);  (3) deposits of monosodium urate monohydrate (tophi) in and  around the joints; (4) renal disease involving glomerular, tubular,  and interstitial tissues and blood vessels; and (5) the formation of  renal stones. These manifestations appear in three clinical stages:   1. Asymptomatic hyperuricemia: The serum urate level is  elevated but arthritic symptoms, tophi, and renal stones  are not present; may persist throughout life.   2. Acute gouty arthritis: Attacks develop with increased  serum urate concentrations; tends to occur with sudden  or sustained increases of hyperuricemia but also can be  triggered by trauma, drugs, and alcohol.   3. Tophaceous gout: The third and chronic stage of disease;  can begin as early as 3 years or as late as 40 years after  the initial attack of gouty arthritis. Progressive inability to  excrete uric acid expands the urate pool until urate crystal  deposits (tophi) appear in cartilage, synovial membranes,  tendons, and soft tissue.    FIGURE 44-31 Pathogenesis of Acute Gouty Arthritis. A, Depending on the urate crystal coating, a variety of cells    may be stimulated to produce a wide range of inflammatory mediators. B, Sequence of events in the production of inflamma-  tory response to urate crystals. C, Gouty tophus on right foot. Apo-E, Apolipoprotein E; /gG, immunoglobulin G; /L, interleukin;  LTB,, leukotriene By; PGE, prostaglandin E. (€ from Dieppe P et al: Arthritis and rheumatism in practice, London, 1991, Gower.)    Attacks of gouty arthritis occur abruptly, usually in a periph-  eral joint. The primary symptom is severe pain. Approximately  50% of the initial attacks occur in the metatarsophalangeal  joint of the great toe. The other 50% involve the heel, ankle,  and instep of the foot; knee; wrist; or elbow. The pain is usually  noticed at night. Within a few hours the affected joint becomes  hot, red, and extremely tender and may be slightly swollen.  Lymphangitis and systemic signs of inflammation (leukocyto-  sis, fever, elevated sedimentation rate) occasionally are present.  Untreated, mild attacks usually subside in several hours but    may persist for 1 or 2 days. Severe attacks may persist for sev-  eral days or weeks. After recovery, the symptoms resolve com-  pletely. Intervals between acute attacks of gouty arthritis are  called intercritical periods. Some individuals never have a second  attack; others experience subsequent attacks within days to as  long as 5 to 10 years after the first.   The helix of the ear is the most common site of tophi, which  are the characteristic diagnostic lesions of chronic gout. Each  tophus consists of a deposit of urate crystals, surrounded by a  granuloma made up of mononuclear phagocytes (macrophages)    that have developed into epithelial and giant cells. (Granuloma  formation is described in and illustrated in Chapter 7.)   Tophaceous deposits produce irregular swellings of the  fingers, hands, knees, and feet. Tophi commonly form lumps  along the ulnar surface of the forearm, the tibial surface of the  leg, the Achilles tendon, and the olecranon bursa. Tophi may  produce marked limitation of joint movement and eventually  cause grotesque deformities of the hands and feet. Although the  tophi themselves are painless, they often cause progressive stiff-  ness and persistent aching of the affected joint. Tophi in the  upper extremities may cause nerve compressions such as carpal  tunnel syndrome; in the lower extremities tophi may cause tar-  sal tunnel syndrome. They also may erode and drain through  the skin.   Renal stones are 1000 times more prevalent in individuals with  primary gout than in the general population. Renal stones can  form in the collecting tubules, pelvis, or ureters, causing obstruc-  tion, dilation, and atrophy of the more proximal tubules and  leading eventually to acute renal failure. Stones deposited directly  in renal interstitial tissue initiate an inflammatory reaction that  leads to chronic renal disease and progressive renal failure.   EVALUATION AND TREATMENT. The goals of gout treatment are  to terminate the acute gouty attack as promptly as possible;  avoid recurring attacks; prevent or reverse complications asso-  ciated with urate deposits in the joints, soft tissues, and kidneys;  and prevent formation of kidney stones. Acute gouty arthritis  is treated with anti-inflammatory drugs. The drugs of choice  are NSAIDs and xanthine oxidase inhibitors, such as allopuri-  nol and febuxostat. Colchicine and NSAIDs are used for acute  episodes of gout. Hydrocortisone may be injected into the joint  to relieve pain. Drugs that block IL-1 have shown promise and  investigation into certain plant-based extracts may lead to new  therapies.!!!1!41!> Ice also may relieve some of the inflamma-  tion of the joint. Weightbearing on the involved joint is avoided  until the acute attack subsides. Reducing body weight, avoiding  alcohol, and increasing consumption of low-fat dairy products,  cherries, soybeans, and vegetable sources of protein may reduce  recurrent gouty episodes. |!    Common symptoms of disorders of skeletal muscle are weak-  ness and fatigue. In many cases, neural, traumatic, and psycho-  genic causes provide an adequate explanation for the failure  to generate force (weakness) or sustain force (fatigue) seen  in myopathies. The pathophysiologic mechanisms in some of  the metabolic and inflammatory muscle diseases have been  explored, but the cause of many of the myopathies remains  obscure. Recognition and improved understanding of ryano-  dine receptor (RyR1) function has allowed identification of  therapeutic targets in treating central core disease (CCD). The  term CCD refers to the mitochondrial lack of oxidative enzyme  activity in the central cytoplasmic area of the muscle caused by a  genetic abnormality on chromosome 19. Complex interactions  between muscles and nerves affect muscular function as well.  Only inherited and acquired disorders of skeletal muscles are  discussed here.    Muscular symptoms arise from a variety of causes unrelated to  the muscle itself. Secondary muscular phenomena (contrac-  ture, stress-related muscle tension, immobility) are common  disorders that influence muscular function.   Contractures are termed pathologic or physiologic. A physio-  logic muscle contracture occurs in the absence ofa muscle action  potential in the sarcolemma. Muscle shortening is explained on  the basis of failure of the calcium pump in the presence of ATP.  A physiologic contracture is seen in McArdle disease (muscle  myophosphorylase deficiency) and malignant hyperthermia.  The contracture is usually temporary if the underlying pathol-  ogy is reversed.   A pathologic contracture is a permanent muscle shorten-  ing caused by muscle spasm or weakness. Heel cord (Achilles  tendon) contractures are examples of pathologic contractures.  They are associated with plentiful ATP and occur in spite of a  normal action potential. The most common form of contrac-  ture is seen in such conditions as muscular dystrophy, cere-  bral palsy (see Chapter 45), and central nervous system (CNS)  injury. Contractures also may develop secondary to scar tissue  contraction in the flexor tissues of a joint, for example, con-  tracture of burned tissues in the antecubital area of the forearm  leading to a flexion contracture.    Abnormally increased muscle tension has been associated with  chronic anxiety, as well as a variety of stress-related muscular  symptoms, including neck stiffness, back pain, and headache.!'°  Abnormalities in the CNS, reticular activating system, and auto-  nomic nervous system (ANS) have been implicated. The under-  lying pathophysiology may be related to the fact that as a muscle  contracts, the muscle spindle is activated. This gamma-feedback  system produces a series of impulses that are transmitted to the  brain by the sensitive 1A afferent fibers. Unconscious tension is  thought to increase the activity of the reticular activating system  as well. This influences increasing firing of the efferent loop of  the gamma fibers and produces further muscle contraction and  increases muscle tension. ANS function that regulates increased  blood flow to the muscle during sympathetic activity may be  related to increased muscle contraction tension.   Various forms of treatment have been used to reduce the  muscle tension associated with stress. Progressive relaxation  training, yoga, meditation, and biofeedback are examples of  stress reduction therapies. Biofeedback uses an integrated elec-  tromyogram (EMG) to make recordings from the skin surface.  The goal is to teach the individual to control tension that has  been functioning maladaptively. It is particularly useful in indi-  viduals who have a connection between skeletal muscle tension  and pain.   Progressive relaxation training emphasizes the individual’s  ability to perceive the difference between tension and relaxation.  This technique involves sequential tensing and a relaxing envi-  ronment. The individual is taught to practice this routine daily,  often with the use of audiotaped instructions. By teaching the    FIGURE 44-32 Location of Specific Tender Points for Diagnostic Classification of Fibromyalgia. (Redrawn from  Freundlich B, Leventhal L: The fibromyalgia syndrome. In Schumacher HR Jr, Klippel JH, Koopman W4J, editors: Primer on the  rheumatic diseases, ed 11, Atlanta, 1997, Arthritis Foundation. Copyright ©1997. Reprinted with permission of the Arthritis    individual to recognize excessive contraction of skeletal muscle,  one hopes to enhance the ability to relax specific muscle groups  to relieve tension and thus reduce CNS as well as ANS arousal.    Fibromyalgia  Fibromyalgia (FM) is a chronic musculoskeletal syndrome  characterized by widespread joint and muscle pain, fatigue, and  tender points. Increased sensitivity to touch (i.e., tender points);  the absence of systemic or localized inflammation, fatigue, and  nonrestorative sleep; and anxiety and depression are common.  FM and its symptoms are viewed as the result of CNS dysfunc-  tion, where pain transmission and interpretation are amplified,  a condition known as central sensitization. In the past, a com-  mon misdiagnosis has been chronic fatigue syndrome and there  is overlap of symptoms between these two conditions. From  80% to 90% of individuals affected are women, and the peak  age is 30 to 50 years. Although the incidence is unknown, the  prevalence is reported to be 2% to almost 6% and increases with  age. The ACR classification criteria include diffuse soft tissue  pain of at least 3 months’ duration and pain on palpation of at  least 11 of 18 tender points (Figure 44-32). It is more common  than RA, but its cause is still unknown.   The etiology of fibromyalgia has been debated for more than  a century. It is unlikely that it is caused by a single factor. The  most common precipitating factors include the following:   Certain rheumatic diseases, such as RA or systemic lupus  erythematosus, may coexist if not initially manifested with  fibromyalgia. In addition, fibromyalgia may overlap with myo-  fascial pain syndromes!” (Table 44-9).   PATHOPHYSIOLOGY. Fibromyalgia as a chronic pain syndrome  is defined by subjective symptoms and not unique pathophysi-  ologic characteristics. Altered circadian activity of several neuro-  endocrine axes and ANS dysfunction have been reported.!!®!!”  Genetic factors are increasingly being suggested as important in  developing FM. Aggregation of fibromyalgia within families and  other coexisting conditions, such as irritable bowel syndrome,  chronic fatigue, and mood disorders, suggest a major role for  neuroendocrine and stress-response alterations (see Chapter 11).    Studies of genetic factors have implicated alterations in genes  affecting serotonin, catecholamines, and dopamine—all of these  substances are involved in stress response and sensory process-  ing.!?°!?! In spite of these studies, the role of genetic factors in  EM has not yet been fully identified. External stressors such as  infection, psychosocial stress, and physical or emotional trauma  may precipitate onset of FM.   Functional magnetic resonance imaging (fMRI) and molecu-  lar imaging techniques of positron emission tomography (PET)  of the brains of persons with FM have shown activity in different  areas of the brain than in healthy individuals when exposed to  painful stimuli.!?? Individuals with fibromyalgia have lowered  mechanical and thermal pain thresholds, high pain ratings for  provoking stimuli, and altered temporal summation of pain  stimuli. Functional abnormalities within the CNS are shown  in Figure 44-32. Other pathophysiologic evidence includes  hypothalamic-pituitary-adrenal (HPA) axis alterations that  demonstrate abnormal response to pain;!*> recent investiga-  tions suggest cytokines are involved in the pathogenesis of FM.  Corticotropin-releasing hormone (CRH) and locus ceruleus—  norepinephrine (LC/NE), their peripheral effectors, and the  hypothalamic-pituitary-adrenal axis are the main components  of the stress system. Impaired functioning of the HPA axis and  LC/NE system may be associated with fibromyalgia.   CLINICAL MANIFESTATIONS. The prominent symptom of fibro-  myalgia is diffuse, chronic pain. The locations of nine pairs of  tender points for diagnostic classification of fibromyalgia are  shown in Figure 44-32. Along with a history of diffuse pain,  tenderness in 11 of these 18 points is necessary for diagnosis.  Tender points must include areas on both sides of the spine as  well as above and below the waist. In an effort to simplify and  more accurately diagnose FM, the American College of Rheu-  matology (ACR) recently expanded the diagnostic criteria to  include a widespread pain index (WPI) as “axial pain, left- and  right-sided pain, and upper and lower segment pain.”!*+ Pain  often begins in one location, especially the neck and shoulders,  but then becomes more generalized. Some investigators have  found that the majority of women experienced pain and fatigue  for more than 90% of their time awake. Fatigue is most notable  when arising from sleep and during the midafternoon. Head-  aches, symptoms of irritable bowel syndrome, and excess sensi-  tivity to cold (Raynaud-like) are reported in 50% of individuals.   Almost 25% of individuals seek psychologic support for  depression. Anxiety, particularly in regard to their diagnosis  and future, is almost universal. Again, the only reliable finding  on examination is the presence of multiple tender points.   EVALUATION AND TREATMENT. Because the manifestations of  chronic, generalized pain and fatigue are present in many mus-  culoskeletal (e.g., rheumatic) disorders, these disorders should  be considered in the diagnosis of fibromyalgia (Tables 44-10  and 44-11).   No single regimen of medication has proved successful for  fibromyalgia. Medications that improve sleep may be helpful as  well as vitamin D supplementation. Anti-inflammatories have  been used despite the fact there is no evidence of tissue inflam-  mation, but these medications have not been effective. Certain  CNS-active medications, most notably pregabalin, were better    Data from Klippel JH, Dieppe PA, editors: Rheumatology, ed 2,  London, 1998, Mosby-Wolfe.  *Fibromyalgia may also more commonly coexist with these conditions.    Data from Klippel JH, Dieppe PA, editors: Rheumatology, ed 2,  London, 1998, Mosby-Wolfe.    than placebo in controlled trials.!?? Probably the best approach  is a combination of modalities, including education, medica-  tion, exercise, and cognitive-behavioral therapy.'*° Box 44-5  lists some of these modalities.    Chronic Fatigue Syndrome  Chronic fatigue syndrome (CFS), also known as myalgic  encephalomyelitis (ME), is a debilitating and complex disorder  characterized by profound fatigue, neurologic energy produc-  tion, and immune impairments. Though controversy about its  etiology persists, recent evidence indicates symptoms are the  result of central nervous system dysregulation, cardiovascular  and immune system abnormalities, and dysfunction of cellular  energy metabolism and ion transport.'”’ As a result, CFS/ME  is less a musculoskeletal disorder than one related to hypersen-  sitivity of the central nervous system, a condition also known  as central sensitization. Although individuals with CFS have  widespread pain and fatigue, they do not have the tender points  associated with fibromyalgia. !”°   PATHOPHYSIOLOGY. A recent International Consensus Crite-  ria have recommended use of the term myalgic encephalomy-  elitis (ME) rather than chronic fatigue syndrome, because ME  indicates an underlying pathophysiology.'?’ In support of this,   Explain that fibromyalgia is not a deforming or deteriorating condition.  Explain that fibromyalgia is neither life threatening nor markedly debilitat-  ing, although it is an irritating presence.   Discuss the role of sleep disturbances and the relationship of neurohor-  mones to pain, fatigue, abnormal sleep, and mood.   Reassure that although the cause is unknown, some information is known  about the physiologic changes responsible for the symptoms.   Assist individual to use aerobic exercise to reduce stress and increase rapid  eye movement (REM) sleep.    functional MRI (fMRI) has shown lower blood perfusion to the  brainstem in individuals affected by CFS.!?° Other researchers  have shown apparent central nervous system abnormalities,  immunologic dysregulation, and higher-than-normal levels of  proinflammatory cytokines. Certain points in skeletal muscle  may be affected by oxidative stress reactions (see Chapter 2),  accounting for the muscle pain and fatigue associated with CFS;  but other research implicates central sensitization of the CNS.!”°   CLINICAL MANIFESTATIONS. Unrestful sleep is a hallmark of CFS.  Defining symptoms include debilitating fatigue made worse  by physical or mental exercise (postexertional fatigue), muscle  pain, noninflammatory joint pain, headaches, flu-like symp-  toms, and memory or concentration problems. Other com-  mon symptoms include bloating, morning joint stiffness, chest  or jaw pain, chills and night sweats, visual disturbances, sore  throat, and tender axillary or cervical lymph nodes. Symptoms  and their consequences can be severe.   EVALUATION AND TREATMENT. Diagnosis of CFS is often delayed  or missed because there is no biologic marker or specific labo-  ratory test for CFS, many CFS symptoms are shared with other  illnesses, individuals with CFS do not necessarily look sick, and  symptoms typically have a variable course. Currently, the CDC  recommends considering a diagnosis of CFS if the following  two criteria are met!*”:   1. Unexplained, persistent fatigue is not due to ongoing  exertion, is not substantially relieved by rest, is of new  onset (not lifelong), and results in a significant reduction  of previous levels of activity.   2. Four or more of the following symptoms are present for 6  months or more:   * Postexertional malaise (extreme, prolonged exhaus-  tion and exacerbation of symptoms following physical  or mental exertion)    Treatment of CFS is primarily based on the person’s indi-  vidual needs and involves consideration of psychosocial factors  as well as symptomatic and supportive care. Acknowledging  the validity of the person’s symptoms is important. Collabora-  tive decision-making between the individual and healthcare  provider with regard to treatment, professional counseling,  medication, diet, and activity helps CFS sufferers deal with the  limitations imposed by the disease. Alternative therapies such  as acupuncture, massage, and therapeutic touch can relieve  anxiety.   The term disuse atrophy describes the pathologic reduction  in normal size of muscle fibers after prolonged inactivity from  bed rest, trauma (casting), or local nerve damage. The effects of  muscular deconditioning associated with lack of physical activ-  ity may be apparent in a matter of days. Oxidative stress from  lack of muscle activity causes decreased protein synthesis and  increased proteolysis, leading to muscle atrophy.'*! The nor-  mal individual on bed rest loses muscle strength from baseline  levels at a rate of 3% per day. Bed rest also is associated with  cardiovascular, skeletal, and other organ system changes. As  muscles age, they lose strength and mass, a condition known  as sarcopenia.   Certain genes and transcription factors play a role in muscle  atrophy.'**!°> Measures to prevent atrophy include adequate  nutrition, frequent forceful isometric muscle contractions, and  passive lengthening exercises. If reuse is not restored within 1  year, regeneration of muscle fibers becomes impaired.    Two defects of the muscle membrane (plasma membrane of the  muscle fiber) have been linked to clinical syndromes: the hyper-  excitable membrane seen in the myotonic disorders and the  intermittently unresponsive membrane seen in periodic paraly-  ses. Although these are infrequent disorders, research into the  pathologic processes has led to an improved understanding of  the cell membrane.    Generally speaking, skeletal muscle channelopathies can be  divided into two primary groups: those presenting with myo-  tonia (nondystrophic myotonias) and those associated with  episodes of weakness (periodic paralysis). In myotonic chan-  nelopathies, muscle relaxation is delayed after voluntary  contractions such as handgrip or eye closure. With periodic  paralysis, depolarization of the sarcolemma is severe enough  that the muscle cannot be “fired” again, resulting in paralysis. '**  (Ion channels are discussed in Chapter 1.)   Myotonia can be reproduced by removing extracellular  chloride, thus reducing chloride conductance across the plasma  membrane. The delicate balance in which sodium diffuses into  the intracellular fluid, potassium diffuses out of the intracellular  fluid, and chloride is in flux is thus interrupted. Because the  normal diffusion processes (described in Chapter 3) stabilize  the membrane, the shift in chloride ions is thought to increase  membrane excitability. The chloride abnormality may explain    the resting membrane hyperexcitability, but it does not explain  the delayed relaxation present in myotonia and has not been  detected in human myotonia.   Myotonia is seen in several disorders: myotonia congenita,  paramyotonia congenita, myotonic muscular dystrophy, and  some forms of periodic paralysis. Most are inherited disorders  and are mild in symptomatology, with the exception of myotonic  muscular dystrophy (see Chapter 45). Myotonia is treated by  drugs that reduce muscle fiber excitability, such as procaine, pro-  cainamide, and phenytoin. Other treatments include the carbonic  anhydrase inhibitors acetazolamide and dichlorphenamide.   Central core disease (CCD) is another inherited channelo-  pathy that involves mutations in ryanodine receptors (RyR1)  and affects calcium channels. In CCD, RyR1 channels are defec-  tive and either too much or too little calcium is released from  the cell’s sarcoplasmic reticulum. Classified as a neuromuscular  disorder, CCD typically manifests during infancy as decreased  muscle tone, delayed motor development, muscle weakness  (particularly around the hip girdle), and other skeletal defor-  mities, such as scoliosis.'°° Associated malignant hyperthermia  susceptibility is common. Thought to be the most common  congenital myopathy, pathology relates to the lack of “cores”  within skeletal myofibers that do not contain mitochondria and  their oxidative enzymes.    Periodic paralysis (PP) is caused by autosomal dominant inher-  ited mutations of skeletal muscle sodium, calcium, or potas-  sium channels.'*° During an attack of PP the muscle membrane  is unresponsive to neural stimuli and the resting membrane  potential is reduced from —90 to —45 mV. Periodic paralysis  can be either hyper- or hypokalemic. As the name implies, PP  is usually transient.   The paralysis, which leaves the individual flaccid and weak,  does not affect the respiratory muscles. In most cases the weak-  ness is accompanied by a change in serum potassium level,  although in some individuals the change may be negligible.  Cardiac dysrhythmias have been present during attacks.   Hypokalemic periodic paralysis is most often triggered by  thyrotoxicosis caused by alterations in potassium ion chan-  nels that are regulated by triiodothyronine (T;).'°” (The effect  of potassium on the resting membrane potential is discussed  in Chapter 3.) Glucose and insulin infusions and oral potas-  sium loading are used as provocative tests; oral and intrave-  nous potassium can relieve acute attacks. Treatment includes  potassium-sparing diuretics and a high-salt diet. Acetazolamide,  dichlorphenamide, and a low-salt diet are useful for long-term  therapy. Hyperkalemic periodic paralysis is caused by a genetic  mutation of sodium channels. Attacks are usually less severe than  the hypokalemic form. Treatment includes small carbohydrate-  rich meals, light exercise, and intravenous calcium gluconate.    Disorders in muscle metabolism can be caused by endocrine  abnormalities or diseases of energy metabolism, such as glyco-  gen storage disease, enzyme deficiencies, and abnormalities in  lipid metabolism and mitochondrial function.    Often the systemic effects of hormonal imbalance overshadow  the individual’s muscular symptoms. For example, individuals  with thyrotoxicosis may have signs of proximal weakness, pare-  sis of the extraocular muscles (exophthalmic ophthalmoplegia),  and, rarely, hypokalemic periodic paralysis. Hypothyroidism is  often associated with a decrease in muscle mass and strength,  with weak, flabby skeletal muscles and sluggish movements.  Thyroid hormone is believed to regulate muscle protein syn-  thesis and electrolyte balance. Changes in muscle protein syn-  thesis and electrolyte balance may therefore explain the changes  in muscle mass and contractility seen in endocrine disorders.  The muscle symptoms subside with appropriate treatment of  the primary hormonal disorder.   Familial hypomagnesemia is an autosomal recessive disease  that primarily affects the renal system, causing hypomagnese-  mia and secondary hypocalcemia and can result in tetany and  convulsions.'** Other endocrine disorders affecting the muscu-  loskeletal system include Dent disease, a syndrome that causes  bone deformities, rickets or osteomalacia, and elevated urine  calcium levels. Osteopetrosis (also known as Albers-Schénberg  disease), caused by failure of osteoclasts to resorb bone, results  in increased bone mass but increased bone fragility; growth  abnormalities; and in the infantile form, bone marrow failure  as bone marrow is replaced by bone.!°?   Muscle relies on carbohydrates, such as glycogen and lipids  (free fatty acids), for energy. When stored glycogen or lipids  cannot be used because of a lack of the enzyme necessary to  convert energy for contraction, the individual experiences  cramps, fatigue, and exercise intolerance. Disorders of muscle  metabolism can be self-limiting, such as is seen in McArdle dis-  ease and some lipid disorders, or cause widespread irreparable  muscle destruction, as in acid maltase deficiency.   McArdle Disease. McArdle disease, or glycogen myopho-  sphorylase deficiency, was the first myopathy in which a single  enzyme defect was identified (Figure 44-33). Individuals  with McArdle disease lack muscle phosphorylase, which is  responsible for the breakdown of glycogen in muscle. Normally  after the body uses the short-term ATP and phosphocreatine  stores, intramuscular lactic acid accumulates as glycogen is used  (see Chapter 43). The individual with McArdle disease is not  able to break down glycogen or produce lactic acid.   The altered energy production manifests itself in exercise  intolerance, fatigue, and painful muscle cramps. When exercise  is carried to an extreme, painful muscle contracture and myo-  globinuria develop. Some individuals describe a “second wind”  phenomenon, in which exercise tolerance increases if they slow  their pace once the initial sensation of fatigue commences. This  is caused by the use of free fatty acids as a secondary source  of energy.'*° As the disease progresses, some individuals have  pronounced muscle weakness and wasting. Other organs are  not involved because the absence of phosphorylase is limited  to muscle. Generally, individuals with McArdle disease learn to  adapt their daily routine to avoid muscle symptoms. Usually  the diagnosis of McArdle disease is made by the histochemical    FIGURE 44-33 McArdle Disease. A, Normal muscle fibers. B, Muscle fibers of McArdle disease. Note the enlarged    (white) peripheral vacuoles. (From Damjanov |, Linder J, editors: Anderson's pathology, ed 10, St Louis, 1996, Mosby.)    evaluation of myophosphorylase activity in frozen sections.  There is no staining of myofibrils in affected individuals.   Acid Maltase Deficiency. Acid maltase deficiency is  an uncommon glycogen storage disease associated with an  accumulation of glycogen in the lysosomes of muscle and other  tissue cells. The usual pathways of glycogen degradation are  preserved. The absence of the enzyme acid maltase is responsible  for the abnormality in glycogen metabolism, although the exact  mechanism is unknown. It is an autosomal recessive disorder,  with the gene located on the long arm of chromosome 17.   The infantile form, Pompe disease, is an autosomal reces-  sive disease that causes lysosomal glycogen accumulation. The  adult form tends to be less dramatic than the infantile type.  The infantile form is recognized shortly after birth by hypo-  tonia, dysreflexia, and an enlarged heart, tongue, and liver.  Hypertrophy of these tissues is thought to be the result of gly-  cogen deposition. Until recently, children often died of cardiac  or respiratory failure before age 2; now enzyme replacement  therapy (ERT) with recombinant human acid a-glucosidase  and physical therapy can markedly improve symptoms.'*! The  adult variety becomes evident subacutely and muscular symp-  toms resemble those of muscular dystrophy or polymyositis.  A distinguishing feature in adults may be severe respiratory  muscle weakness.   Myoadenylate Deaminase Deficiency. Myoadenylate  deaminase deficiency (MDD) is a fairly common enzyme  deficiency that causes changes in skeletal muscles and is  associated with exercise intolerance. Because these individuals  lack myoadenylate deaminase, they have a poor capacity for  sustained energy production. Myoadenylate deaminase is the  catalytic enzyme that forms phosphocreatine and ATP during  exercise through a metabolic pathway that binds the purine  and phosphate molecules that constitute ATP. Persons with  MDD differ from those with McArdle disease in that during  the ischemic exercise test, lactate production is normal when  ATP and phosphocreatine are synthesized. Symptoms range  from minimal complaints to exercise-induced muscle pain, to  rhabdomyolysis.!“   Lipid Deficiencies. Inherited disorders of lipid metabolism  are uncommon but account for severe changes in muscle    metabolism. The lipid content of muscle cells consists of free  fatty acids, which are oxidized in the mitochondria. These acids  require carnitine and the enzyme carnitine palmitoyltransferase  (CPT); there are two CPT enzymes, I and II. Both are necessary  to transport long-chain fatty acids to the mitochondria.  Individuals with CPT deficiency often have mild muscular  symptoms but can experience bouts of renal failure caused by  rhabdomyolysis. Individuals with a deficiency of carnitine alone  have progressive muscle weakness and can experience sudden  exacerbations.   Measuring the CPT and carnitine content in muscle aids in  the diagnosis. Cells in the muscle biopsy show vacuoles and lipid  deposits. Treatments with riboflavin, medium-chain triglycer-  ides, oral carnitine, and prednisone have been suggested.!**   Viral, bacterial, and parasitic infections of varying severity are  known to produce inflammatory changes in skeletal muscle, a  group of conditions collectively described by the term myo-  sitis. In tuberculosis and sarcoidosis, chronic inflammatory  changes and granulomas are found in muscle, as well as in  other affected tissues. In trichinellosis, Trichinella larvae reside  in infected pork and, after ingestion, migrate to the intestinal  mucosa and from there to the lymphatics. Symptoms include  severe pain, rash, and muscle stiffness. Treatment includes  administration of corticosteroids and antiparasitic agents, such  as mebendazole or albendazole. Unfortunately, once trichinella  larvae are established they may reside for years in the muscles.  Toxoplasmosis, a common parasitic infection, is also associ-  ated with a generalized polymyositis that responds rapidly to  therapy.   In the tropics, more prevalent disorders include bacterial  infections with Staphylococcus aureus and parasites such as cys-  ticercus, the larva of the tapeworm Taenia solium. Viral infec-  tions can be associated with an acute myositis. Muscle pain,  tenderness, signs of inflammation, and elevation of CK level  are common manifestations of viral myositis. The self-limiting  symptoms of muscle aches and pains during a bout of influenza  may actually be a subacute form of viral myopathy.    FIGURE 44-34 Distribution of CD4+ and CD8+ Lymphocytes in Different  Types of Myositis. Dermatomyositis shows perivascular and CD4+ T cells (helper  T cells). Polymyositis shows mostly CD8+ T cells (cytotoxic T cells).   Idiopathic inflammatory myopathies (IIMs) are a group of  autoimmune diseases that target skeletal muscle. IIMs are char-  acterized by symmetric proximal muscle (pelvic and shoul-  der girdle) weakness and myalgia that develops over weeks  to months. The three principle types are polymyositis (PM),  dermatomyositis (DM), and inclusion-body myositis (IBM).  Non-white women over age 50 are most often affected by IIM;  however, DM includes a juvenile form (JDM). Interstitial lung  disease is common in both PM and DM. The incidence of IIM  appears to be increasing, but this may simply reflect improved  diagnosis.   PATHOPHYSIOLOGY. Polymyositis and dermatomyositis are  characterized by inflammation of connective tissue and muscle  fibers. Polymyositis is mediated by T cells, whereas dermatomy-  ositis is humorally-mediated.'*4 CD8* T cells and macrophages  are typically found in PM-affected muscles. Figure 44-34 shows  the distribution of CD4+ and CD8+ lymphocytes in myositis.  Innate and adaptive immune responses are activated in these  myopathies, including myositis-specific antibodies and cyto-  kines.'*° Inflammatory cells, including T cells, macrophages,  and plasma cells, surround, displace, and even invade muscle  fibers in PM. Perimysial and perivascular sites are selectively  enriched in B cells and helper T cells in those with DM. DM is    FIGURE 44-35 Dermatomyositis. Heliotrope (violaceous) discoloration  around the eyes and periorbital edema. (From Habif TP: Clinical dermatology,  ed 3, St Louis, 1996, Mosby.)    thought to be a microvascular disorder that includes deposits  of complement in capillaries; however, recent research also has  shown up-regulation of interferon signaling in muscle, blood,  and skin of people with DM.'“° Ability to demonstrate elevated  interferon levels can aid in both diagnosis and determination of  targets to treat these diseases.   CLINICAL MANIFESTATIONS. The acute symptoms include many  of those seen in any inflammatory process: malaise, fever, mus-  cle swelling, pain and tenderness, lethargy, and listlessness. In  adults, weakness of the shoulder and pelvic girdle muscles is a  primary manifestation of PM. Both PM and DM often are asso-  ciated with symmetric proximal muscle weakness and initially  can be confused with other myopathies. A thorough evaluation  is required to exclude other disorders. Clinical features com-  mon to both are dysphagia, reduced esophageal motility, vas-  culitis, Raynaud phenomenon, cardiomyopathy, and interstitial  pulmonary fibrosis. Some individuals have other coexisting col-  lagen vascular disorders, such as RA, systemic lupus erythema-  tosus (SLE), and progressive systemic sclerosis (formerly called  scleroderma).   Although PM and DM have similar histories of onset, DM  includes cutaneous manifestations. The two most classic signs  of skin involvement are rashes: (1) a heliotrope (reddish pur-  ple) rash that generally covers the eyelids and periorbital area  (Figure 44-35), and often includes the chest; and (2) erythema-  tous, scaly lesions (Gottron lesions) that cover joints, such as  the knees and elbows. DM is slightly more common in children  and older adults, with onset before age 15 or after age 50. The  adult with DM occasionally has underlying malignancies.   IBM differs from both PM and DM in several important  ways. Muscle biopsy and histopathologic studies of IBM show  degenerative changes of muscle, accumulation of multiple pro-  teins within muscle fibers, and evidence of endoplasmic reticu-  lar stress with misfolding of proteins.'*”!4° Clinically, IBM may  show weakness of the wrist and finger flexors as well as asym-  metric atrophy and quadriceps weakness. !“?    EVALUATION AND TREATMENT. Muscle biopsy is striking in DM,  with most individuals showing inflammatory cells grouped  around blood vessels and atrophy of cells in muscle fascicles.  This change, perifascicular atrophy, is absent in PM. Creatine  kinase (CK) and other muscle enzymes, including aspartate  transaminase (AST), lactate dehydrogenase (LDH), and ala-  nine transaminase (ALT), and sedimentation rate are often  extremely elevated in both disorders. The presence of serum  antinuclear antibodies also may be helpful in diagnosing DM.  EMG abnormalities include signs of muscle irritability and  myopathic changes—usually large numbers of low-amplitude  action potentials of brief duration. The EMG also shows a typi-  cal “myopathic” pattern, with short, low-amplitude polypha-  sic potentials, as well as signs of marked muscle irritability.  Muscle biopsy is indispensable for determining a diagnosis of  polymyositis or dermatomyositis as opposed to other myo-  tonic diseases. MRI reveals inflammation and edema of the  muscles.   Treatment primarily includes immunosuppressive drugs,  although they are not always successful if uniformly applied.  Most clinicians choose corticosteroids initially, though their  utility has recently come into question.'*? High-dose intrave-  nous immunoglobulin administration is sometimes used dur-  ing active disease. Successful treatment with azathioprine and  methotrexate has been reported. Creatine supplements and  physical therapy may improve muscle strength.   Myopathy is the term applied to a primary muscle disorder.  Many pathologic processes affect muscles and cause loss of  functional muscle cells. Myopathies affect muscle strength,  tone, and bulk. Primary muscle disease is invariably associ-  ated with weakness—usually marked weakness. The distri-  bution of the weakness in myopathy is usually symmetric  and proximal, although occasionally the weakness is pre-  dominantly distal, such as in myotonic dystrophy. The  weakness is associated with mild fatigue. Tone is decreased,  as are the tendon reflexes. Atrophy may be present. Some  myopathies are associated with muscle hypertrophy as in  cretinism and the familial progressive muscular dystrophies  of childhood, in which hypertrophied muscles are rubbery  and weak. Fasciculations are not present with myopathy  because no denervation is present. No sensory changes are  found. (Specific neurologic-associated myopathies are dis-  cussed in Chapter 17.)    Toxic Myopathies  A number of agents, including corticosteroids, chloroquine,  alcohol, phenytoin, azathioprine, organophosphates, and  reverse transcriptase inhibitors, have been shown to cause toxic  myopathy. Alcohol remains the most common cause of toxic  myopathy. The incidence of acute alcoholic myopathy has been  estimated at up to 20% of individuals admitted with acute alco-  holic withdrawal.   The mechanisms by which alcohol affects the muscle  include disturbances of energy cell turnover, gene dysregu-  lation, and initiation of apoptosis. Pathologic abnormalities    include necrosis of individual muscle fibers, particularly type II  fibers; whole segments can be found in the same stage of  degeneration.   Acute alcoholic myopathy can range from benign cramps  and pain resolving in a matter of hours to severe weakness and  markedly increased CK level associated with myoglobinuria  and renal failure. Individuals are prone to repeated attacks fol-  lowing recovery. The only treatment is abstinence from alcohol  and improved nutrition. An individual with chronic alcoholic  myopathy often has a coexisting peripheral neuropathy that  complicates the diagnosis.   Repeated intramuscular injections have been associated  also with changes in muscle fibers. Local necrosis of muscle  fiber and elevated CK concentration have been reported after  intramuscular injections of certain cephalosporins, lidocaine,  diazepam, and digoxin; these effects were not produced with  injections of saline. When drugs are injected over long periods,  a chronic focal myopathy develops. Proliferation of connective  tissue both in the muscle fiber and in the overlying skin and  subcutaneous tissue has been reported. Over time, segments  of the muscles, particularly the deltoid and quadriceps, are  converted into fibrotic bands. Pathophysiologic mechanisms  for these changes include repeated needle trauma and infec-  tion, along with the nonphysiologic acidity and alkalinity of  the injected material. Box 44-6 lists some of the causes of toxic  myopathy.   Rhabdomyoma is an extremely rare benign tumor of striated  muscle that generally occurs in the tongue, neck muscles, lar-  ynx, uvula, nasal cavity, axilla, vulva, and heart. These tumors  are usually treated by surgical excision and do not recur.    A rare malignant tumor of striated muscle is called rhabdo-  myosarcoma, which is a subgroup of sarcoma. These tumors  are highly malignant, with rapid metastasis. They are located  in the muscle tissue of the head, neck, and genitourinary  tract in 75% of cases. The remaining 25% of these tumors are  located in the trunk and extremities. Rhabdomyosarcomas are  the most common soft tissue tumors in children and young  adults.   Three types of rhabdomyosarcoma are differentiated on  pathologic section: pleomorphic, embryonal, and alveolar.  The pleomorphic, or spindle cell, type is considered to be one  of the most highly malignant tumors of the extremities seen in  adulthood, but has a better outcome in children. Embryonal  tumors are most commonly seen in childhood and appear on  biopsy to be shaped like a tadpole or tennis racquet. Alveolar-  type tumors, which appear lattice-like and look like lung tissue  alveoli, have the poorest outcome.!*!   The diagnosis of rhabdomyosarcoma is made by history,  physical examination, serologic testing, CT, and MRI, and is  confirmed by incisional biopsy and examination of the speci-  men by a pathologist. On electron microscopy the tissue dem-  onstrates myofilaments and Z-band material; CT scan helps   Steroids (especially with prolonged high doses; doses >25 mg/day; fluorinated  steroids)    Hyperthyroidism (CK may be normal)  Hypothyroidism (CK may be mildly elevated)   Any medication that alters serum concentrations of sodium, potassium, calcium,  phosphorus, or magnesium    Data from Kuncl RW: Curr Opin Neurol 22(5):506-515, 2009; Valiyil R, Christopher-Stine L: Curr Rheumatol Rep 12(3):213-220, 2010.    define the tissue borders. Staging is based on pathologic grade  of the tumor and is helpful in determining prognosis and  treatment.   Treatment consists of a combination of surgical excision,  radiation therapy, and systemic chemotherapy. Overall survival  of childhood rhabdomyosarcoma has improved over the past  decades but adult survival remains poor (see Chapter 45).    Metastatic muscle tumors are rare in spite of the extensive vas-  cular supply of skeletal muscles. It is suggested that local pH  or metabolic changes discourage metastatic involvement from  other tumors. When adjacent carcinomas do cause muscle  damage, it is usually related to the compression of tissue and  resultant muscle atrophy.   1. The most common skeletal injury is a fracture. A bone can  be completely or incompletely fractured. A closed fracture  leaves the skin intact. An open fracture has an overlying  skin wound. The direction of the fracture line can be linear,  oblique, spiral, or transverse. Greenstick, torus, and bowing  fractures are examples of incomplete fractures that occur in  children. Stress fractures occur in normal or abnormal bone  that is subjected to repeated stress. Fatigue fractures occur in  normal bone subjected to abnormal stress. Normal weight-  bearing can cause an insufficiency fracture in abnormal bone.   2. Dislocation is complete loss of contact between the surfaces of  two bones. Subluxation is partial loss of contact between two  bones. As a bone separates from a joint, it may damage adja-  cent nerves, blood vessels, ligaments, tendons, and muscle.   3. Tendon tears are called strains, and ligament tears are called  sprains. A complete separation of a tendon or ligament from  its attachment is called an avulsion.   4. Epicondylopathy is degeneration ofa tendon where it attaches  to a bone. Bursitis is inflammation of the bursae (small sacs  lined with synovial membrane and filled with synovial fluid).  Bursitis can be inflammatory, septic, or hemorrhagic.   5. Muscle strain can range from mild injury to severe damage  that can result in loss of muscle function.    6. Rhabdomyolysis can be a life-threatening complication  of severe muscle trauma wherein muscle cell contents are  released into the circulation. It may result in myoglobinuria,  the presence of myoglobin in the urine, and is often associ-  ated with acute renal failure.   1. Metabolic bone diseases are characterized by abnormal bone  structure. In osteoporosis bone tissue is normally mineral-  ized, but the density or mass of bone is reduced because the  bone remodeling cycle is disrupted. Osteoporosis is a com-  plex, multifactorial, chronic disease that often progresses  silently for decades until fractures occur. It is the most com-  mon bone disease. Multiple factors are involved including  alteration in the OPG/RANKL/RANK system.   2. Postmenopausal osteoporosis occurs in middle-aged and  older women and is caused by increased osteoclast activity,  probably caused by changes in osteoprotegerin, IGF, a com-  bination of inadequate dietary calcium intake and lack of  vitamin D, possibly decreased levels of magnesium, lack of  exercise, decreased levels of estrogen, and family history.   3. Glucocorticoids increase RANKL expression and inhibit  OPG production by osteoblasts, thus leading to lower bone  density.    Osteomalacia is a metabolic bone disease characterized by  inadequate bone mineralization.    . Osteomyelitis is a bone infection caused most often by bacte-    ria (e.g., S. aureus) that can enter bone from outside the body  (exogenous osteomyelitis) or from infection sites within the  body (hematogenous osteomyelitis).    tissue cells, or vascular marrow cells. Each cell produces a spe-  cific type of ground substance that is used to classify the tumor  as osteogenic (bone cell), chondrogenic (cartilage cell), col-  lagenic (fibrous tissue cell), or myelogenic (vascular marrow  cell). Malignant bone tumors are large, aggressively destroy  surrounding bone, invade surrounding tissue, and initiate  independent growth outside the site of origin. Benign bone  tumors are less destructive, limit their growth to the anatomic  confines of the bone, and have a well-demarcated border.    Noninflammatory joint disease is differentiated from inflam-  matory joint disease by the absence of synovial membrane  inflammation, the absence of systemic signs and symptoms,  and the presence of normal synovial fluid.    . OA is now considered an inflammatory joint disease and is    characterized by the degeneration and loss of articular car-  tilage, sclerosis of underlying bone, and formation of bone  spurs (osteophytes).    matory destruction of the synovial membrane, articular car-  tilage, joint capsule, and surrounding ligaments and tendons.  RA involves an aberrant immune response and the trans-  formed antibodies are called rheumatoid factors. The OPG/  RANKL/RANK system is also involved. Rheumatoid nod-  ules may also invade the skin, lung, and spleen and involve  small and large arteries. RA is a systemic disease that affects  the heart, lungs, kidneys, and skin, as well as the joints.    stiffening and fusion of the spine and sacroiliac joints. Recent  data show that synovitis and bone marrow inflammation,  rather than solely enthesis involvement, explain the altera-  tion in sacroiliac joints.    . Gout is a metabolic disorder associated with high levels of    uric acid in the blood and body fluids. Uric acid crystallizes  in the connective tissue of a joint, where it initiates inflam-  matory destruction of the joint.    A pathologic contracture is permanent muscle shortening  caused by muscle spasticity, as seen in CNS injury or severe  muscle weakness.    increased activity in the reticular activating system and gamma  loop in the muscle fiber. Progressive relaxation training and  biofeedback have been advocated to reduce muscle tension.    terized by diffuse pain and tender points. It is unknown but  suspected that muscle is the end organ responsible for the pain  and fatigue of the disease. Comorbidities (e.g., irritable bowel  syndrome, mood disorders, and chronic fatigue) suggest a  major role for neuroendocrine and stress-response alterations.    plex disorder with profound fatigue not improved by bed  rest. The actual cause of CFS is unknown and hypotheses  include central nervous system alterations, immunologic  disruptions, and chronic proinflammatory cytokines.    . Atrophy of muscle fibers and overall diminished size of the    muscle are seen after prolonged inactivity. Isometric con-  tractions and passive lengthening exercises decrease atro-  phy to some degree in immobilized persons.    trical phenomenon of myotonia. The disorder is treated  with drugs that reduce fiber excitability. Periodic paraly-  sis is caused by an unresponsive muscle membrane and is  accompanied by changes in the level of serum potassium.  The biochemical defect is possibly related to changes in the  muscle membrane and sarcoplasmic reticulum.    ders, glycogen storage disease, enzyme deficiencies, and  abnormal lipid function. The muscle depends on a complex  system of carbohydrates and fats converted by enzymes to  produce energy for the muscle cell. Abnormalities in these  pathways can inhibit function or cause damage to the mus-  cle fiber. These illnesses are rare, yet they account for sig-  nificant functional abnormalities.    the characteristic clinical and pathologic changes associated  with inflammation. These are usually treatable and self-  limiting disorders.    matomyositis (polymyositis accompanied with skin rash)  are characterized by inflammation of connective tissue and  muscle fibers, and muscle fiber necrosis. Cell-mediated and  humoral immune factors have been implicated. Treatment  with immunosuppressive agents is effective in many cases.  Primary disorders with weakness and atrophy are known as  myopathies.   The most common toxic myopathy is caused by alcohol  abuse. Direct toxic effects of alcohol-producing necrosis  of muscle fibers and nutritional deficiency have been sug-  gested. The only treatment is abstinence and improved  nutrition. 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As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Musculoskeletal Development in Children, 1591  Bone Formation, 1591  Bone Growth, 1592  Skeletal Development, 1593  Muscle Growth, 1593  Musculoskeletal Alterations in Children, 1593  Congenital Defects, 1593  Abnormal Density or Modeling of the Skeleton, 1597    Musculoskeletal alterations in children are very common. They  may be congenital, such as clubfoot; hereditary, such as muscu-  lar dystrophy; or acquired, such as Legg-Calvé-Perthes disease.  Some of these disorders are acute, and the child will recover  completely; other disorders are chronic or, in some cases,  terminal. An understanding of the pathophysiology of these  alterations will aid in providing the best care possible for these  children.    Bone formation, which begins at about the sixth week of gesta-  tion, involves two phases: (1) the delivery of bone cell precur-  sors to sites of bone formation and (2) the aggregation of these  cells at primary centers of ossification, where they mature and  begin to secrete osteoid (see Chapter 43). Some of the bone cell  precursors are present in fetal connective tissues, whereas oth-  ers migrate in blood to sites of bone formation after blood ves-  sels have grown into the tissue.    Cellular aggregation and maturation occur in two types of  fetal tissue, depending on which bones are being formed. The  cranium, facial bones, clavicles, and parts of the jawbone (clas-  sically called “flatbones”) arise from a fetal membrane termed  the mesenchyme. Bones that develop on or within the mesen-  chyme grow by the process of intramembranous formation of  bone. As the mesenchyme becomes vascularized, the immature  bone cells aggregate and mature into osteoblasts, which form  the centers of ossification and create solid bone or osteoid.   Endochondral formation of bone is the development of new  bone from cartilage (Figure 45-1). First, mesenchymal tissue  forms a cartilage anlage, which defines the shape of the bone.  This is usually found by 6 weeks of gestation. Blood vessel inva-  sion to inside the anlage brings osteoprogenitor cells leading to  primary centers of calcification by 8 weeks. Endochondral bone  formation begins in the outer layer of the cartilage model, which  consists of a layer of dense connective tissue called perichon-  drium. The perichondrium contains cells that develop into  osteoblasts, forming a collar of bone, termed the periosteal col-  lar, around the cartilage model. Cartilage enclosed within the  periosteal collar degenerates, and capillaries from outside the    perichondrium invade the degenerating cartilage cells, carry-  ing with them osteoblast precursors from the inner layer of the  perichondrium and osteoclast precursors from the blood itself.   Endochondral bone formation progresses at the primary  center of ossification in the middle of the cartilage model and  extends toward either end of the developing bone. At the same  time, the periosteal collar thickens and becomes wider toward  the epiphyses. By the end of gestation secondary centers of  ossification (i.e., the epiphyseal centers) begin to lay down  bone at both ends of the cartilage model. Here, too, cartilage  within the periosteal collar degenerates, and blood vessels grow  inward, delivering bone cell precursors. Once the osteoblasts  begin to secrete osteoid, ossification spreads from the secondary  centers in all directions until all the cartilage within the model  is replaced by bone.   Two regions of cartilage remain at the ends of long bones:  (1) articular cartilage over the free ends of the bone, and  (2) the physeal plate, a layer of cartilage between the metaphysis  and epiphysis. (These structures are described and illustrated in  Chapter 43; see Figure 43-3.) The physeal plate retains the abil-  ity to form and calcify new cartilage and deposit bone until the  skeleton matures approximately 1 year after sexual maturity (11  to 15 years of age in females, 15 to 18 in males).    Until adult stature is reached, growth in the length of long  bones occurs at the physeal plate through endochondral ossifi-  cation. Cartilage cells at the epiphyseal side of the physeal plate  multiply and enlarge. As rapidly as new cartilage cells form, car-  tilage cells at the metaphyseal side of the plate are destroyed and  replaced by bone.   In the shaft of new bone, where growth is relatively slow, the  bone produced by accretion is compact and dense. The compact  bone is thickest where it has to withstand the maximal stresses,  which generally occur in the middle of the shaft.   The two physes of the long bone often have varying activity  rates. For example, the distal physis in the femur contributes    80% of the overall length, whereas the proximal physis at the  hip contributes only 20%. The more active of the two has more  power to remodel deformity but also can be more sensitive to  injury. The architecture of the physis also dictates its sensitiv-  ity to injury. The distal femur, for example, has an undulating  pattern that increases its resistance to sheer force; when injured,  however, growth disturbance is highly likely, whereas the distal  radius, which contributes 80% of overall radial length, is a flat,  smooth physis that is far more resistant to traumatic injury.   Growth in the diameter of bone occurs by deposition of new  bone on an existing bone surface. Bone matrix is laid down by  osteoblasts on the periosteal surface and subsequently becomes  calcified. At the same time, bone resorption occurs on the end-  osteal surface. Endosteal resorption increases the diameter of  the medullary cavity, which contains marrow and spongy bone.   Many factors affect the development, physiology, and rate  of growth of the epiphyseal plate. Growth hormone must be  secreted by the pituitary gland at a constant rate to stimulate the  growth plate consistently. Other known factors affecting growth  include peptide regulatory factors (e.g., fibroblast growth factor  [FGF]); changes in cell-to-cell interactions through cell adhe-  sion molecules (CAMs) and cell junctions; and complex inter-  actions or changes in the extracellular matrix (ECM), nutrition,  general health, and other hormones (e.g., thyroid hormone,  adrenal and gonadal androgens, estrogens). When these factors  are poorly controlled, skeletal dysplasias, such as achondropla-  sia, can occur.   Even after physeal closure at skeletal maturity, bone is con-  stantly being destroyed and re-formed (see Chapter 43). This is  a rapid process in young children, allowing them to heal bone  injury more quickly than adults. By adulthood, however, bone  turnover, or remodeling, occurs at a relatively slow rate. Peak  bone mass is achieved by the middle to late twenties and slowly  decreases throughout life; therefore, ensuring appropriate lev-  els of calcium and phosphorous intake, performing weight-  bearing lifting and exercise, and minimizing caffeine intake  are especially important for a young female if she is to avoid    osteoporosis in later life. Recently, the importance of vitamin  D levels also has been emphasized. In one study, nearly 70% of  American children had low levels of vitamin D.!   The axial skeleton changes shape with growth. (The axial skel-  eton and appendicular skeleton are described and illustrated in  Chapter 43; see Figure 43-5). In a newborn the entire spine is  concave anteriorly, or kyphosed. In the first 3 months of life,  with the infant’s ability to control the head, the upper (cervical)  spine begins to arch, or become lordotic. The normal lordotic  curve of the lower (lumbar) spine begins to develop with sitting.   The appendicular skeleton (the extremities) grows faster  during childhood than does the axial skeleton (see Figure 43-5).  The newborn has a relatively large head and long spine with  disproportionately shorter limbs than an adult. By 1 year of age,  50% of the total growth of the spine has occurred and is more  than 70% complete by age 8.” Therefore, failure of the spine  to grow (e.g., spinal fusion) does not limit eventual height as  much as the premature fusion of the growth plates of the lower  extremities. In children with congenital curvature of the spine,  growth tends to worsen the deformity rather than to increase  the length of the spine.   Besides getting longer, growing bones of the extremities  undergo changes in rotation and alignment. In the newborn the  proximal femur is rotated forward up to 40 degrees and the tibia  is rotated inward. With growth the femur assumes its normal  alignment (by 12 years of age) and tibial rotation neutralizes  at 8 years of age.? Bowlegs and knock knees can be normal at  certain stages of growth. At birth the newborn’s legs are bowed  because of stresses in utero. Genu varum (bowleg) reaches a  peak by 30 months of age, whereas genu valgum (knock knee)  maximizes by 5 to 6 years of age. If genu varum or genu val-  gum persists past these ages, a pathologic process rather than  a physiologic phase may be present. Pathologic causes of genu  varum are Blount disease, rickets, skeletal dysplasias (such as  achondroplastic dwarfism), and traumatic injury. Genu val-  gum may persist also as a result of skeletal dysplasia or genetic  predisposition.    The composition and size of muscles vary with age. In the fetus,  muscle tissue contains a large amount of water and much inter-  cellular matrix. After birth, both are reduced considerably as the  muscle fibers (cells) enlarge by accumulating cytoplasm. Little  information is available about the numbers of fibers in a given  muscle at various ages, but the total mass of muscle in the body  can be estimated from the amount of creatinine excreted in the  urine, because the conversion of creatine to creatinine takes  place only in muscle (see Chapter 43). Between birth and matu-  rity the number of muscle nuclei in the body increases 14 times  in boys and 10 times in girls. Muscle fibers reach their maxi-  mal size in girls at approximately 10 years of age and in boys by  14 years. Growth in length occurs at the ends of muscles, and  the increase in length is accompanied by an increase in number  of nuclei in the fibers. Muscle fibers increase in diameter as the  fibrils become more numerous. The fibrils themselves do not    increase in diameter. Connective tissue components of muscle  grow where the tendon and muscle meet.   A potent stimulus to the growth of a muscle is the separation  of its attachments as the skeleton grows. The length of a muscle  fiber is the direct consequence of its intended range of move-  ment. The stimulus for the formation of a tendon is probably  the pull of the muscle rudiment on undifferentiated connective  tissue. If the normal opponents of a muscle are paralyzed, the  muscle fails to grow properly and can result in contracture of  a joint.   Muscle growth during adolescence is a major factor in weight  gain. Gender differences in muscle size and weight are minor in  childhood but become considerable with the onset of puberty.   In the infant, muscle accounts for approximately 25% of  total body weight, compared with 40% in the adult. In the  adult, approximately 55% of muscle weight is in the lower limb  muscles, whereas in the infant the majority of the weight is axial  musculature. The respiratory and facial muscles are well devel-  oped at birth so that the infant can perform the vital functions  of breathing and sucking. Other muscle groups, such as the pel-  vic muscles, take several years to develop fully. Throughout life  the weight of the skeletal muscles can be increased by exercise.   The most common congenital defect of the upper extremity  is syndactyly, or webbing of the fingers (Figure 45-2). Simple  webbing involves the soft tissue envelope alone and is best  released surgically when the child is 6 months to 1 year of age.  Complex syndactyly involves fusion of the bones and nails as  well as the soft tissues; it may be associated with absence or  anomaly of bony or neurovascular units. The primary goal in  surgical correction of these defects is to achieve maximal func-  tion and appearance. Ideally, corrective surgery is deferred until  the child is 1 to 2 years old and completed before the child enters  school. Vestigial tabs, such as an extra digit, however, are best  removed during the immediate neonatal period. Anomalies on  the radial aspect of the arm, such as a foreshortened or absent    radius, are often associated with abnormalities of blood, heart,  or kidneys. Lateral or ulnar-sided defects are less often associ-  ated with systemic anomalies and are far more rare.   Developmental dysplasia of the hip (DDH), formerly known  as congenital dislocation of the hip, is an abnormality in the  development of the proximal femur, acetabulum, or both  (Figure 45-3). Although most often present at birth, it may  occur at any time in the newborn or infant period.   The incidence of true dislocation of the hip or a dislocat-  able hip is 1 in 1000 live births. Some degree of instability of  the hip is present in approximately 10 per 1000 live births. The  left hip is affected in 60% of cases, whereas the right hip alone    FIGURE 45-3 Hip Dysplasia in Children. Developmental dysplasia of the hip  (DDH) with residual acetabular dysplasia. Radiographs at birth, 3, 10, and 19 years  (top to bottom) show persisting dysplasia.    is affected only 20% of the time. Bilateral DDH occurs 20% of  the time.   Risk factors for DDH include family history, female gender  (6:1), metatarsus adductus (20%), torticollis (10%), oligohy-  dramnios, first pregnancy, and breech presentation. First preg-  nancies and oligohydramnios (deficient volume of amniotic  fluid) are thought to limit fetal movement, and breech presen-  tation not only limits movement but also places the hips in a  position of flexion and adduction, which creates a more shallow  socket, or acetabulum. Although only 2% of births have breech  history, as many as 40% of infants with DDH had a breech  birth. Maternal hormones that reportedly increase joint laxity  also have an effect on DDH, although the exact mechanism is  unknown. DDH also is more common in whites and those cul-  tures that swaddle infants with the hips in extension and adduc-  tion. It is almost unknown in African cultures where infants are  carried, with legs abducted, on the back.   PATHOPHYSIOLOGY. The hip can be described as subluxated  (partial contact only), dislocated (no contact between femoral  head and acetabulum), and acetabular dysplasia (the femoral  head is located properly but the acetabulum is shallow) (Figure  45-4). The subluxated hip maintains contact with the acetabu-  lum but is not well seated within the hip joint. The acetabu-  lum is often dysplastic (or shallow) although the femur is often  normal. The dislocatable hip is sometimes located but can be  dislocated easily. The dislocated hip has no contact between the  femoral head and the acetabulum. Some degree of acetabular  dysplasia is present in almost all cases. Typically the acetabu-  lum is shallow or sloping rather than cup shaped.   By approximately 10 weeks of gestation, the femur, acetabu-  lum, and hip joint capsule are well developed. It appears that  most dysplasias occur within the second and third trimesters  and are often the result of positioning factors. Experimen-  tally, DDH can be produced in laboratory animals by placing  the developing hip in adduction and extension, replicating the  breech position. There is, however, a genetic component that is  poorly understood. In addition, 2% of DDH cases are terato-  logic or caused by a systemic syndrome, such as arthrogryposis  or spina bifida, in which muscle contracture or imbalance leads  to DDH.    FIGURE 45-4 Configuration and Relationship of Structures in Developmental Dysplasia of the Hip. (From Hocken-  berry MJ, Wilson D: Wong‘s nursing care of infants and children, ed 9, St Louis, 2011, Mosby.)    If DDH is left untreated in the growing child, secondary  changes occur. If the hip remains subluxated or dislocated, the  acetabulum becomes increasingly shallow and the soft tissues  shorten around the proximal femur. Subluxation leads to early  osteoarthritis (OA), and it is now estimated that at least 60%  of all OA of the hip is related to DDH. If the hip is dislocated,  the bone acetabulum fills with soft tissue and a false acetabu-  lum forms where the femoral head contacts the iliac crest. An  apparent limb length inequity and hip muscle weakness occurs,  leading to a waddling gait. Back pain and hip pain develop in  adulthood. Adult reconstruction of a dislocated hip, even with  an artificial hip, is very difficult.*   CLINICAL MANIFESTATIONS. The clinical manifestations of DDH  vary with the severity of the condition and the age of the child.  Signs and symptoms that should be noted include the following:   (Figure 45-5, A)  5. Positive Ortolani sign (hip dislocated, but reducible)  (Figure 45-5, B)   The child also should be examined for other anomalies, such  as torticollis or metatarsus adductus, which can be associated  with DDH.   EVALUATION AND TREATMENT. In the newborn period clinical  examination is the most important diagnostic tool. Real-time  ultrasound, in which the hip is examined while the ultrasound  is performed, also is extremely valuable in the newborn period,    FIGURE 45-5 Congenital Dislocation of the Hip. A, Barlow maneuver. With  one hand pressing the symphysis in front and the sacral spine in back, lateral pres-  sure is applied to the thigh with the thumb of the other hand while pressure is  applied with the palm to the knee on the side being examined. The hip that has  been flexed to 90 degrees is then adducted. A positive sign is a sensation of abnor-  mal movement, indicating dislocation of the femoral head from the acetabulum.  The hands are reversed for examining the other hip. This sign and Ortolani sign  may be found only in the first weeks of life. B, Ortolani maneuver. Sign of jerking  into correct position. After the Barlow maneuver (A), the hip should be abducted  to about 80 degrees while the femur is lifted anteriorly with the fingers along the  thigh. A positive sign is a sensation of a jerk or snap with reduction into the joint  socket. (Adapted from Specht EE: Am Fam Physician 9:88-96, 1974.)    especially in high-risk infants. The use of ultrasound allows  visualization of the cartilaginous structures of the hip (the fem-  oral head and the outer lip of the acetabulum), which are not  seen on plain roentgenogram. Radiographs are used after age 6  months when the ossific nucleus of the femoral head appears.°  Treatment depends on the age of the child, severity of dys-  plasia, and duration of dysplasia. The earlier that treatment is  begun, the better the result. In children less than 4 months of  age, a Pavlik harness can brace the hip in abduction and flex-  ion, and the acetabulum will remodel as the femoral head rests  centered in the socket (Figure 45-6). With this treatment, up to  98% of children will have an excellent result. A “closed” reduc-  tion (without opening the joint) followed by spica or body cast-  ing for up to 3 months can be done in children up to 12 months  of age. After 12 months, surgical intervention—including  opening the joint and cutting and realigning the femur and/or  acetabulum—may be required. As the child ages, the percentage  of good outcomes decreases. Up to 70% of children treated sur-  gically for DDH after age 3 develop early osteoarthritis.° Early  intervention before age 1 is critical for a good outcome; there-  fore, vigilance for this problem within the first year is essential.    Congenital Deformity. Congenital foot deformity is found in  approximately 4% of all newborns, and metatarsus adductus    FIGURE 45-6 Pavlik Harness for Bilateral Hip Dislocation. (From Wheaton  Brace Co.)    Lateral deviation away from the midline of the body  Lateral deviation toward the midline of the body  Twisting of the foot outward along its long axis  Twisting of the foot inward on its long axis  Bending the foot upward and backward   Plantar flexion of the foot in which the heel is lower  than the toes   Dorsiflexion of the foot in which the heel is lower  than the toes   Elevation of the medial longitudinal arch of the foot  (high arch)    accounts for 75% of these deformities (Table 45-1). Metatarsus  adductus is a forefoot adduction deformity associated with a  normal, plantigrade hindfoot and is believed to be secondary  to intrauterine positioning. It is associated with developmental  dysplasia of the hip in 20% of cases; consequently, the hips of  these infants must be carefully evaluated. Metatarsus adductus is  usually classified by two criteria: flexibility (passively correctable  or rigid) and degree of deformity. The degree of deformity  (mild, moderate, severe) is ascertained by the heel bisection line.  A mild deformity is one in which the heel bisection line passes  medial to the third toe; moderate, through the third or fourth  toes; and severe, lateral to the fourth toe. Serial casts during  the first 6 months of life are suggested for moderate to severe  deformities and those deformities that appear less flexible. Casts  are changed weekly for 6 to 12 weeks. By 6 years of age, 87%  of children usually correct spontaneously, and 95% by 15 years  of age. Even in those children with some residual deformity,  functional symptoms are rare.   Clubfoot: Equinovarus Deformity. Clubfoot describes a range  of foot deformities in which the foot turns inward and downward.  Technically called equinovarus, the heel is positioned varus  (inwardly deviated) and equinus (plantar flexed) (Figures 45-7  and 45-8). The clubfoot deformity can be positional (correctable  passively), idiopathic, or teratologic equinovarus (as a result of  another syndrome, such as spina bifida). These three types are  discussed in the following sections. Overall, the true positional  equinovarus lends itself to rapid correction by application  of serial casts. The idiopathic variety is treated by attempting    B  FIGURE 45-7 Bilateral Clubfoot. A, Infant with bilateral congenital talipes  equinovarus. B, Ponseti casting. (A courtesy of Dr. a.E. Chudley, Section of  Genetics and Metabolism, Department of Pediatrics and Child Health, Children’s  Hospital and University of Manitoba, Winnipeg, Manitoba, Canada. In Moore KL,  et al: The developing human, ed 9, Philadelphia, 2013, Saunders.)    FIGURE 45-8 Idiopathic Clubfoot. Idiopathic clubfoot displaying forefoot  adduction (toward midline of body) and supination (upturning) and hindfoot equinus  (pointed downward). Note skin creases along arch and back of heal.    cast correction, followed by surgical intervention of resistant  deformities. Teratologic equinovarus nearly always requires  surgical correction and/or muscle balancing procedures.   Positional Equinovarus. Positional equinovarus is a defor-  mity in which an infant’s foot is in equinovarus position but  does have flexibility without deep creases at the posterior ankle  or midfoot. The Achilles tendon is still flexible. The foot can be  passively brought to a plantigrade position and is amenable to  casting. In general, 1 to 3 months of serial above-knee casting  corrects this foot without the need for surgical intervention or  lengthy bracing.   Idiopathic Congenital Equinovarus. The etiology of idio-  pathic equinovarus (clubfoot) is unknown. In one human fetal  study, all clubfeet were associated with identifiable anterior horn  cell changes in L5 and S1. Muscle biopsies of both the anterior  tibialis long flexors and the peroneus brevis muscles in clubfoot  reveal that at least 50% of cases show a decreased number of  muscle fibers and/or abnormal fiber histology. The soleus often  has an increase in type 1 fibers, whereas the peroneus brevis has  a fiber type disproportion. The more abnormal the histopathol-  ogy, the more severe the deformity, and the greater the chance  of recurrent deformity after treatment. The genetic component  is unclear and studies are ongoing.   Idiopathic equinovarus occurs in approximately 1 of every  1000 live births, with males being affected twice as often as  females. Historically, these deformities were treated by postero-  medial release, a surgical procedure that lengthened all tight  structures and opened the capsule of all tight joints in the foot.  However, since 1998 the casting technique developed by Igna-  cio Ponseti (see Figure 45-7, B) has been used; the technique  involves six to eight above-knee casts, left on for 5 to 7 days  each, followed by a percutaneous tendoachilles lengthening  procedure performed with local anesthesia. The child then uses  special braces at night until 3 years of age. Noncompliance with  braces leads to increased recurrence and need for additional  casting or surgery. Nearly 30% of children may need an ante-  rior tibialis transfer around age 3.’ Studies comparing opera-  tive posteromedial release with Ponseti techniques show better  long-term results with less invasive Ponseti method® (Box 45-1).   Teratologic Equinovarus. The most common causes of ter-  atologic equinovarus are either neuromuscular (such as spina  bifida) or syndromic, as in arthrogryposis or osteochondrodys-  plasia (such as diastrophic dwarfism). The teratologic clubfoot,  unlike the idiopathic type, more often fails to be corrected with  Ponseti casting and may require operative intervention. The  surgery is often more extensive than that for an idiopathic club-  foot, and revision surgery is also more common (Box 45-1).   Pes Planus (Flatfoot) Deformity. Pes planus (flatfoot)  commonly raises parental concern. Despite medical evidence to  the contrary, it can be very difficult to convince families that a  flexible flatfoot is often as functional as one with a “normal”  arch. The majority of babies are born with flat (or “fat”) feet,  with the arch becoming more apparent with age. The relatively  benign natural history, however, should not overshadow the  importance of accurate diagnosis. Significant ankle valgus, ver-  tical talus, tarsal coalition, and skewfoot must be accurately dif-  ferentiated from flexible pes planus.    Ponseti casting implements toe-to-groin casts changed weekly for 6 weeks.  Casting begins as early as possible after birth and culminates in a percutane-  ous tendoachilles lengthening in the clinic, followed by a final cast worn for    3 weeks. In recalcitrant cases, a full surgical posteromedial release (PMR)  still may be required. The need for PMR in idiopathic clubfoot has decreased  from 90% to less than 20% of infants when this casting technique is used.  Long-term results, presumably because of less scarring and more long-term  flexibility, are better with Ponseti casting than the PMR method.    Flexible flatfoot deformity appears to be familial, with occa-  sional association of generalized ligamentous laxity. Careful eval-  uation of possible occult Achilles contracture is done by holding  the hindfoot in varus position and dorsiflexing the ankle. Achil-  les contracture can signify a more severe flatfoot variant. The  flexibility of the hindfoot is evaluated by having the child stand  on his or her toes facing away from the examiner. In flexible pes  planus, the hindfoot swings into a varus position as the planter  fascia tightens in toe raise. In rigid pes planus, the hindfoot stays  in valgus and the child has more difficulty going up onto tip-toe.   The surgical or orthotic treatment of asymptomatic flexible  pes planus is unnecessary. Custom orthotics, Helfet heelcups,  and corrective orthopedic shoes have no influence over the  natural history (clinically or radiographically) of flat feet. Adult  studies on army recruits have shown that soldiers with flat feet  perform just as well as their counterparts without “fallen” arches.   There is a small subset of children with painful flexible flat  feet. For these children careful attention to the possibility of  Achilles contracture or tarsal coalition (congenital union of  the hindfoot bones) must be made. This group of children is  best treated with inexpensive shoe inserts and then expectantly  watched. If pain continues into adolescence, requiring more  aggressive treatment, calcaneal lengthening will correct the pes  planus without decreasing hindfoot motion. In rigid flat feet, a  computed tomographic (CT) scan often will reveal a coalition,  a bony or cartilaginous connection between the bones—if pain-  ful, this can be resected. Heel cord contractures can be surgi-  cally lengthened if stretching alone is inadequate. All surgery  carries risk; if a foot is flat but nonpainful, treatment is not  required. The painless flatfoot should be viewed as a variation  of normal feet.   Osteogenesis imperfecta (OI) (brittle bone disease) is a spec-  trum of disease caused by genetic mutation in the gene that  codes for type I collagen, the main component of bone and  blood vessels. The disorder was first described in 1840 as a syn-  drome in newborns that consisted of osteoporosis with fractures  and skeletal deformities. The Sillence classification is based on  both models of inheritance and clinical findings (Table 45-2).  In the most severe form of this disorder, the child is usually still-  born or dies soon after birth, although some survive into child-  hood. OI in its more severe forms is evident at birth because  fractures and deformity have occurred in utero. The less severe  forms may not become evident until the child begins to walk.    Substitutions of glycyl residue in  X1 or X2 chains in triple helix    Mild to moderate bone fragility,  osteoporosis, bowing of long bones,  scoliosis   Usually lethal in perinatal period,  delayed ossification of skull,  intrauterine growth restriction    Hearing loss, short stature, blue  sclerae becoming less blue with  age, shortened life expectancy,  dentinogenesis imperfecta, relative  macrocephaly with triangular facies    Reproduced with permission from Vaccaro AR, editor: Orthopaedic knowledge update 8, p 248, Rosemont, IL, 2005, American Academy of Ortho-    Some children with this milder form then experience numerous  fractures and can be mistaken for nonaccidental trauma until  the diagnosis is made.   The prevalence rate of the most common form is about 1 in  30,000. Inheritance is usually autosomal dominant but can be  autosomal recessive. At least four syndromes have been iden-  tified that have various clinical manifestations and prognoses  (see Table 45-2).   PATHOPHYSIOLOGY. The major errors in OI lie in the synthesis  of collagen, a triple helix with two matching alpha chains and  one beta chain. Collagen is present in bone, cartilage, eye tissue,  skin, and the vascular system. The severity of the OI phenotype  and the related anomalies of the eye, dentition, or vascular sys-  tem are all dependent on the severity of the genetic anomaly  and the part of the triple helix that is affected.’ (Genes are dis-  cussed in Chapter 4.)   A number of metabolic abnormalities are associated with OI.  Some individuals have increased serum thyroxine levels, sug-  gesting hyperthyroidism. This is consistent with the findings of  increased sweating, heat intolerance, increased body tempera-  ture, a resting tachycardia, and tachypnea. Studies of leukocyte  metabolism suggest an uncoupling of oxidative phosphoryla-  tion. Reports of alterations of platelet function with defects in  adhesion and clot retraction also exist.   CLINICAL MANIFESTATIONS. The classic clinical manifestations  of OI are osteoporosis and increased rate of fractures, possible    bony deformation, triangular facies, possible vascular weakness  (i.e., aortic aneurysm), possible blue sclerae, and poor denti-  tion. The Sillence classification designated types I through IV  on the basis of severity. The most severe, types II and II, are  comparable to osteogenesis imperfecta congenita. These two  types are characterized by autosomal recessive inheritance and  early onset of manifestations. Both can cause stillbirth or severe  neonatal deformity and a short life expectancy. Less severe are  types I and IV, which are comparable to osteogenesis imperfecta  tarda. Type | is slightly more common than types II and III,  and type IV is quite rare. Types I and IV are inherited as auto-  somal dominant traits and vary in age of onset from birth to  adulthood. Type IV, especially when the sclerae are white, is the  least deforming type and is often confused with nonaccidental  trauma (child abuse).   EVALUATION AND TREATMENT. Evaluation of OI is based primar-  ily on clinical manifestations. Serum alkaline phosphatase level  is elevated in all forms of the disease. OI can be diagnosed pre-  natally by ultrasound or chorionic villi sampling. Quantitative  analysis of cultured skin fibroblast collagen by electrophoresis  shows a decreased quantity of collagen in 95% of individuals.   Type II OI is often terminal in the perinatal period, and  therefore little is known about appropriate treatment for the  few children who survive. For other types of OI, careful posi-  tioning and handling of the newborn help prevent fractures.  Beyond the neonatal period, various orthopedic measures are    FIGURE 45-9 Osteogenesis Imperfecta Treated with Osteotomies and Telescoping Medullary Rods. A, Severe  deformity of both femurs. B, Same individual after multiple osteotomies with telescoping medullary rod fixation. €, Same  individual 4 years later demonstrating growth of femurs, no recurrence of deformity, and elongation of rods. (Plaster casts are  in place for immobilization of tibial osteotomies.) (From Crenshaw AH, editor: Campbell's operative orthopaedics, ed 8, vol 3,    applied, such as prompt splinting of fractures and correction  of deformities arising from the progressive bowing or bending  of the skeleton by intramedullary rodding of the bones (Figure  45-9). Newer, telescoping rods, which grow with the child, have  been shown to reduce the reoperative rate by 30%.!° Scoliosis is  present in up to 50% of Sillence II cases and often requires sur-  gery. A multicenter study of a bisphosphonate therapy showed  promising results in type III OI, with marked improvements of  bone density (up to 30%). Despite these results, there is concern  that the healing of fractures and surgical intervention can be  more difficult. More study is needed to address the efficacy and  safety of these types of drugs. Genetic counseling for affected  families should aim at primary prevention.   Rickets is a disorder in which growing bone fails to become  mineralized (ossified), resulting in “soft” bones and skeletal  deformity (Figure 45-10). Rickets results from either insuffi-  cient vitamin D, insensitivity to vitamin D, wasting of vitamin  D by the kidney, or inability to absorb vitamin D and calcium  in the gut. The most common form is X-linked hypophospha-  temic rickets in industrialized nations. In addition to the severe  form of metabolic rickets, dietary and lifestyle changes in the  United States have led to widespread vitamin D deficiency in  children.'' Although unprotected exposure to ultraviolet rays is  not suggested, children still need 15 to 20 minutes per week of  true sun exposure to activate vitamin D, the mineral necessary    for absorption and metabolism of calcium and phosphate. In  one recent study up to 90% of normal American children had a  low vitamin D level, especially children of color. This can lead  to early fracture or slow bone healing after fracture. '*   Severe metabolic rickets in the immature skeleton leads to  short stature and bowing of the limbs with broad, irregular    growth plates. The rows of cells in the growth plate that are  intended to ossify fail to do so as they reach the metaphysis  since calcification is impeded.   Children with rickets are often listless and irritable. They  have hypotonia and muscle weakness and may be unable to  walk without support. Abnormal parietal flattening and fron-  tal bossing occur in the skull. The calvaria become soft, and  the sutures may widen. Cartilaginous attachments of the ribs  become prominent, and the long bones of the extremities (tibia,  femur, radius, ulna) may be bowed. Growth is restricted, and  fractures are common.   Like osteogenesis imperfecta, surgical treatment of bony  deformity can be required. However, medical management of  calcium, phosphorous, and vitamin D levels must be optimized  before surgical intervention. Deformity often improves with  normalization of bone metabolism.    Scoliosis is a rotational curvature of the spine most obvious in  the anteroposterior plane (Figure 45-11). It can be classified as  nonstructural or structural. Nonstructural scoliosis results from  a cause other than the spine itself, such as posture, leg length dis-  crepancy, or pain. Structural scoliosis is curvature of the spine  associated with vertebral rotation. Nonstructural scoliosis can  become structural if the underlying cause is not found and treated.   Structural scoliosis can be caused by a great variety of con-  ditions. It can result from congenital skeletal abnormalities  (15%), neuromuscular diseases (15%), trauma, extraspinal  contractures, bone infections that involve the vertebrae, meta-  bolic bone disorders (e.g., rickets, osteoporosis, osteogenesis  imperfecta), joint disease, and tumors. Most cases of structural  scoliosis, however, have no known cause, although genetic fac-  tors are suggested. Structural scoliosis with no known cause,  termed idiopathic scoliosis, accounts for at least 70% of cases.   Idiopathic scoliosis is classified as infantile, juvenile, or ado-  lescent, depending on the child’s age at the time of onset. In  infantile scoliosis, spinal curvature develops during the first    FIGURE 45-11 Scoliosis in Children. Normal spinal alignment and abnormal spinal curvatures associated with scoliosis.  A, Normal. B, Mild. €, Severe. D, Rotation and curvature of scoliosis.    3 years of life; in juvenile scoliosis, curvature develops between  the skeletal age of 4 years and the onset of adolescence; and in  adolescent scoliosis, it develops after the skeletal age of 10. Ado-  lescent idiopathic scoliosis is the most common. Scoliosis in its  milder forms occurs equally in boys and girls; once curves mea-  sure more than 15 degrees, however, girls are five times more  likely to have scoliosis than boys.   PATHOPHYSIOLOGY. It has been hypothesized that in individu-  als with adolescent scoliosis, there is an abnormality of the cen-  tral nervous system involving the balance mechanism (reticular  system) in the midbrain. A genetic component is also suggested  because 30% occur within families.   Experimentally it also has been shown that individuals with  adolescent idiopathic scoliosis have an abnormality in the func-  tion of the posterior columns of the spinal cord. This results in  abnormal proprioception and is not evident clinically except in  the presence of scoliosis. The exact cause of scoliosis, however,  remains elusive.!   The earliest pathologic changes, which are probably second-  ary changes, occur in the soft tissues. The muscles, ligaments,  and other soft tissues become shortened on the concave side  of the curve. Vertebral deformity occurs as asymmetric forces  are applied to the epiphyseal center of the ossification by short-  ened and tight soft tissues on the concave side of the curve. True  curves involve not only bending but also twisting of the torso  leading to the “rib hump” seen when the child bends forward.   The curves increase most rapidly during periods of rapid  skeletal growth. If the curve is less than 40 degrees at skeletal  maturity, the risk of progression is quite small. In curves greater  than 50 degrees, the spine is biomechanically unstable, and the  curve usually progresses even after the cessation of growth.  Curves in the thoracic spine greater than 80 degrees result in  decreased pulmonary function, whereas the most common  complication of large curves in the lumbar spine is back pain.   CLINICAL MANIFESTATIONS. The clinical manifestations of non-  structural scoliosis are mild spinal curvature with prominence  of one hip or rounded shoulders. The curvature disappears  with forward flexion of the spine, lying down, or traction of  the head. Treatment for nonstructural scoliosis is correction of  the underlying disorder. The clinical manifestations of struc-  tural scoliosis include asymmetry of hip height, asymmetry of  shoulder height, shoulder and scapular (shoulder blade) promi-  nence, and rib prominence.   EVALUATION AND TREATMENT. Spinal curvature is usually visible  or palpable, and muscles on one side of the lower back (the con-  vex side) may be prominent or bulging. Most cases of idiopathic  scoliosis are noticed during school screening programs. In girls  the deformity may be noticed because clothing does not “hang”  properly on the body. Diagnosis is made by roentgenographic  examinations.   Treatment of curves greater than 20 degrees in the skeletally  immature child is with bracing. In most cases a low-profile  thoracolumbar brace is used. Low-profile braces are worn  for 22 hours per day until skeletal maturity. Bracing will only  prevent progression of the curve; it will not correct the cur-  vature. Bracing is not effective in large curves or in skeletally  mature individuals; the most effective time for bracing is in    infants younger than 1 year the epiphysis is nourished by penetrating arteries  through the physis, allowing development of the condition within the epiphysis.  B, In children up to 15 years of age the infection is restricted to below the physis  because of interruption of the vessels.    growing prepubescents with a small curve.'4 Extensive chiro-  practic manipulations and electrical stimulation have not been  shown to change natural history. Surgical treatment with spinal  fusion with instrumentation is recommended for curves greater  than 40 to 50 degrees. If surgery is indicated, it is better per-  formed during the adolescent years while there is greater flex-  ibility of the curves and less risk of complications.    Osteomyelitis is an infection of the bone. Occurring twice as  often in males as females, acute osteomyelitis may affect infants  and children of any age, but it occurs most often between 3 and  12 years of age.   Bacteria enter the bone through the bloodstream and lodge  in the medullary cavity, where a rich phagocytic mechanism  often prevents most of the bacteria from establishing an infec-  tious state. In some cases, however, the bacteria may lodge at  the end of the venous loops beneath the epiphyseal plate, and  infection then develops because there are no phagocytic cells  present to remove the bacteria'*'” (Figure 45-12).    The microorganism responsible for osteomyelitis varies and  is related to the age of the child (Box 45-2). Osteomyelitis in the  newborn is caused primarily by Staphylococcus aureus. Group B  streptococcus and Escherichia coli infections are responsible for  some cases, especially those of multiple bone involvement and  in high-risk infants.!”   S. aureus is the responsible microorganism in 80% to 90%  of osteomyelitis cases in older children. Haemophilus influen-  zae, a previously common cause of osteomyelitis in children  less than 5 years of age, has become rare with the improve-  ments in immunization. However, cases of methicillin-resistant  Staphylococcus aureus (MRSA) have risen alarmingly in the past  5 years. Once an infrequent cause of childhood osteomyelitis,  MRSA now causes up to 30% of new cases.'* Gram-negative  microorganisms account for an increasing number of infections  of the vertebrae,'””° whereas Salmonella infections are associ-  ated with sickle cell disease.   Factors that predispose an individual to the development of  osteomyelitis include impetigo, furunculosis, infected lesions  of varicella (chickenpox), infected burns, cerebral abscesses,  immunization with bacille Calmette-Guérin (BCG) vaccine,  prolonged intravenous or central parenteral alimentation, drug  addiction, and direct trauma to the area adjacent to the site of  osteomyelitis.   PATHOPHYSIOLOGY. Osteomyelitis usually begins as a bloody  abscess in the metaphysis of the bone. The abscess ruptures  under the periosteum and spreads along the bone shaft or into  the bone marrow cavity if untreated. Infection rarely spreads  down the medullary cavity of the bone but rather first gains  entrance to the subperiosteal space in the metaphysis. The bone  cortex in this area is porous, allowing easier entry for the bac-  teria than the shaft of the bone.’! Because of the accumulation  of debris caused by the infection, the periosteum may separate  and form a shell of new bone around the infected portion of  the shaft. Because the periosteum is separated from an adequate   \ ¥ 3} A ee U. |  FIGURE 45-13 Routes of Infection to the Joint. (1) The hematogenous  route; (2) dissemination from osteomyelitis; (3) spread from an adjacent soft tis-  sue infection; (4) diagnostic or therapeutic measures; (5) penetrating damage by  puncture of cutting.    blood supply, sections of the bone die; these pieces of dead bone  are called sequestra. The periosteum that maintains a blood  supply generates new bone and is responsible for the appear-  ance of the periosteal new bone, or involucrum. The presence  of the sequestra and involucrum indicates that the disease is  highly aggressive or established.   In cases in which the infection in the metaphysis occurs  near the joint, the accumulating pus (bacteria, white blood  cells, fluid) creates increasing pressure that may cause a rup-  ture into the joint cavity. If rupture into the joint occurs, the  pus causes inflammation and a condition called secondary  septic arthritis.!° Studies show that up to 40% of children  will have adjacent joint involvement with osteomyelitis.  The most common joint to be affected is the knee. Osteo-  myelitis is most commonly caused by bacteria that reach the  metaphysis through the bloodstream but may occur through  secondary inoculation of microorganisms caused by trauma  or contagious spread of infection from cellulitis in adjacent  soft tissue.   Osteomyelitis in infants is often associated with septic  arthritis because the infant’s bone has blood vessels that per-  forate the growth plate. Because of the unique nature of the  blood supply to an infant’s bones, the occurrence of osteo-  myelitis and septic arthritis in combination is higher than  50%. Normal anatomic variations in infants allow infection to  spread directly to the epiphysis, which causes both joint dis-  ease and permanent injury to the growth plate. Multiple sites  of osteomyelitis are also common in children younger than 2  years of age. Other areas of osteomyelitis and possibly septic  arthritis must be evaluated through a bone scan of the entire  skeleton.”   Children are susceptible to joint involvement for several rea-  sons (Figure 45-13). In the immature infant, there is no epiphy-  seal plate or an ossific nucleus at the end of the bone and the  cartilage precursor of bone is penetrated by vascular channels.    In these infants the infection begins in the vulnerable cartilage  precursor of the end bone itself and results in rapid destruction  of the joint and arrested growth of the bone. For this reason  the early detection and treatment of osteomyelitis are crucial if  the infant’s joint is to be saved from destruction. As the child  matures and the epiphyseal, or growth, plate forms, a tempo-  rary barrier is established against infection because the arteri-  oles end beneath the epiphyseal plate.!   In children older than 2 years, the epiphyseal plate prevents  the spread of a metaphyseal abscess into the epiphysis and the  cortex of the metaphysis is thicker. These anatomic differences  increase the likelihood that the metaphyseal abscess will extend  into the diaphysis, and the blood supply of the bone will be  disrupted. The periosteum is also more difficult to perforate in  older children; this may lead to a larger subperiosteal abscess  that could endanger the periosteal blood supply as well. This  process results in extensive sequestrum formation and chronic  osteomyelitis.”!   Osteomyelitis is much less common after the physeal plates  are closed, except in the vertebral body. Infection may develop  in any part of a bone, and abscesses spread slowly. Destruc-  tion of the cortex in a localized area may result in a pathologic  fracture,”   Spread of infection to contiguous joints is related to the  child’s age. Metaphyseal infection may spread to contiguous  joints if the fibrous joint capsule includes the metaphysis and  epiphysis. This special situation exists at the hip joint, distal  femur, proximal humerus and radius, and lateral ankle. Care-  ful clinical vigilance helps protect children with osteomyelitis  from suffering permanent joint injury. Unlike bone, the articu-  lar cartilage of joints is unable to repair itself after injury from  infection.’   CLINICAL MANIFESTATIONS. The clinical manifestations of  osteomyelitis are age dependent and are related to the differing  vascular patterns found in the skeletal system at various ages.  Three distinct groups may be identified: (1) infants younger  than 1 year, (2) children from 1 year of age to puberty, and  (3) adolescents after cessation of bone growth and adults.    Osteomyelitis may be an acute illness characterized by fever  and failure to move the affected limb (pseudoparalysis). Infan-  tile osteomyelitis is characterized by involvement of multiple  sites within the same bone or in multiple bones. If untreated,  involvement of the adjacent growth plate can result in growth  arrest.    Osteomyelitis in children between the ages of 1 year and puberty  is characterized by fever and systemic signs of toxicity. The ill-  ness is sometimes subacute, with the child complaining of  swelling, fever, tenderness, and decreasing ability to bear weight  on or move the affected area. Onset can be abrupt. Osteomyeli-  tis during childhood most often affects the long bones but also  may be found in the pelvis and spine. Clinical manifestations  are usually accompanied by elevated white blood cell counts  and elevated erythrocyte sedimentation rates. When the level of    C-reactive protein (CRP) is elevated, it a sensitive sign of osteo-  myelitis and can rapidly decrease with appropriate treatment.  Evidence of infection using roentgenograms can be delayed but  bone scan is positive within 48 hours.    In addition to the sites previously mentioned, osteomyeli-  tis in adolescents and adults may involve the vertebrae. Back  pain, with a duration of several weeks, may be the only clinical  complaint. This age group is less often affected than younger  populations.   EVALUATION AND TREATMENT. White blood cell counts and  erythrocyte sedimentation rates are sometimes elevated, but  this is not a consistent finding. Monitoring of erythrocyte sedi-  mentation rates is an indication of response to management  but can be delayed. CRP is more quickly responsive to appro-  priate treatment. Blood cultures (positive in 30% to 40%) and  aspiration of the soft tissue or bone, or both, should be done  to identify the causative microorganism. Appropriate antibi-  otics should be prescribed after culture and sensitivity studies  have been completed. A tuberculin test also is administered  because Mycobacterium tuberculosis is sometimes responsible  and has had a slight resurgence in incidence. Bone scans can  be quite helpful with diagnosis and in children younger than 1  year are absolutely required to define whether multiple sites are  involved.   Treatment includes intravenous (IV) antibiotics or, in  highly reliable children and families, a combination of IV and  oral antibiotics for 6 weeks. Drainage and margination of bone  is required if changes are present on radiographs signifying  abscess. Immobilization may help with pain control. Ifa joint is  also infected (termed “septic arthritis”), the situation becomes  a surgical emergency; surgery on the affected joint can help pre-  vent damage to the articular cartilage by lysozymes released  from the involved neutrophils.   Death is rare, but serious sequelae may occur. The course of  the disease and prognosis depend on the age of the child, the  rapidity with which the diagnosis is established, the initiation of  early treatment, and maintenance of treatment for an adequate  time. The most serious complications are growth arrest, osse-  ous necrosis, and recurrence. Recurrence with presently avail-  able antibiotic regimens is less than 10%.   The rheumatic diseases are a group of diverse conditions hav-  ing in common the inflammation of connective tissues. They  include juvenile idiopathic arthritis (JIA, formerly known as  juvenile rheumatoid arthritis), systemic lupus erythematosus,  dermatomyositis, and progressive systemic sclerosis (formerly  called scleroderma). The incidence of these disorders in chil-  dren is estimated in Table 45-3.   Juvenile idiopathic arthritis (JIA) is the childhood form of  rheumatoid arthritis (RA) (see Chapter 43). Like adult-onset  RA, JIA is a syndrome that is often accompanied by systemic  manifestations. Approximately 5% of all cases of RA begin in  childhood. An estimated 250,000 children in the United States  have JIA.    Systemic lupus erythematosus 8:1  Dermatomyositis : el  Progressive systemic sclerosis ; 3:1  Polyarteritis ; (s    RACE RATIO PEAK AGE GROUP CHILDHOOD  (WHITE/BLACK) AT RISK (yr) ONSET     Data from Hollingworth P. In Klippel JH, Dieppe PA, editors: Rheumatology, St Louis, 1994, Mosby.    The basic pathophysiology of JIA is the same as that of adult  RA. The clinical manifestations of JIA may differ, however,  beginning with mode of onset. Unlike adult RA, which begins  insidiously with systemic signs of inflammation and generalized  aches, JIA has three distinct modes of onset: arthritis in fewer  than five joints (pauciarticular arthritis), arthritis in more than  five joints (polyarticular arthritis), and systemic or Still disease.  JIA differs from the adult form in the following respects”**:   mon if the disease progresses.  . Joint pain may not be severe, as in the adult type.  . Serologic tests often detect antinuclear antibody (ANA).  Chronic uveitis is common, especially if ANA positive.  . Serologic tests seldom detect rheumatoid factor.   . Rheumatoid nodules are not limited to subcutaneous tissue  but are found in the heart, lungs, eyes, and other organs.  8. Cyclic citrullinated peptide antibody is often positive.   Treatment for children with JIA is supportive but not  curative. Many children with pauciarticular arthritis who are  seronegative for ANA will resolve their symptoms over time.  However, with systemic onset (Still disease) or seropositivity,  JIA may progress to true adult RA. The aims of treatment are to  control inflammation and other clinical manifestations of the  disease and to minimize deformity.    The avascular diseases of the bone, collectively termed osteo-  chondroses, are caused by insufficient blood supply to growing  bones. Disturbances of blood supply to primary and second-  ary centers of ossification during periods of rapid bone growth  result in a variety of skeletal abnormalities.   The cause of the osteochondroses remains obscure. In the  past, infection, nutritional deficiencies, and hormonal imbal-  ances were blamed, but these causes have been largely dis-  proved. Currently, vascular impairment and trauma, coupled  with an underlying developmental or genetic predisposition,  have been identified as probable causes of osteochondroses. The  most common osteochondroses are Osgood-Schlatter disease  (tibial tubercle), Sinding-Larsen-Johansson syndrome (distal  patellar pole), Panner disease (radial head), Kohler disease (the  navicular bone of the foot), and Sever disease (calcaneus). All  are associated with activity-related pain of the affected region  that improves with rest. All are more common in boys than girls  and in athletes more than nonathletes.    The osteochondroses involve areas of significant tensile or  compressing stress that undergo partial osseous necrosis, pro-  gressive bony weakness, and then microfracture. Most of these  are associated with trauma and overuse and improve with rest.  Use of anti-inflammatories, modification of activities, and even  immobilization of the affected area are used during active stages  of the disease. Reparative correction by revascularization is the  rule, although this may be a lengthy process.   Legg-Calvé-Perthes (LCP) disease, commonly called Perthes  disease, is classically thought to be an osteochondrosis like  those previously described. This self-limited disease of the  hip is presumably produced by recurrent interruption of the  blood supply to the femoral head. The ossification center first  becomes necrotic and collapses and then is gradually remodeled  by live bone.   LCP disease is relatively common (1 in 5000 children), usu-  ally occurring in children between 3 and 10 years of age, with  a peak incidence at 6 years. It is more common in boys than in  girls by a ratio of about 5:1. The condition is bilateral in approx-  imately 10% of affected children; however, bilateral cases are  temporally separated. If LCP disease appears at identical stages  and the femoral heads show matched radiographic involve-  ment, then another diagnosis, such as an epiphyseal dysplasia,  should be considered.   The cause of decreased blood supply to the head of the femur  is unknown. Several theories have been proposed, including  trauma, infection, and protein C and S deficiencies, which cause  a hypercoagulable state or vascular anomolies.’? A plausible  theory is that acute synovitis (infection of the synovial mem-  brane) and increased hydrostatic pressure in the hip joint com-  press blood vessels that supply the femoral head.   Constitutional factors definitely play a role. Skeletal matura-  tion is delayed an average of 2 years in children with LCP dis-  ease, and affected children are between 2.5 and 7 cm shorter  than unaffected children of the same age. Familial occurrence is  30% to 40%. The disease is rare in blacks, and it is frequent in  children of Japanese and central European ancestry.   PATHOPHYSIOLOGY. LCP disease runs its natural course in 2  to 5 years. In the initial stage the soft tissues of the hip (syno-  vial membrane and joint capsule) are swollen, edematous,  and hyperemic, often with fluid present in the joint (Figure  45-14). The joint space widens, and the joint capsule bulges.  The first stage lasts only a few weeks. In the second stage, called    fragmentation, the entire epiphysis or the anterior half of  the epiphysis of the femoral head loses blood supply and the  metaphyseal bone at the junction of the femoral neck and capi-  tal epiphyseal plate is softened because of decalcification. Soon  granulation tissue (procallus) and blood vessels invade the dead  bone. This stage lasts several months to 1 year.   The third (or regenerative healing) stage ordinarily lasts 2  to 3 years. The dead femoral head is replaced by procallus, and  new bone is laid down. Collapse and flattening of the femoral  head occur, and the femoral neck becomes short and wide (see  Figure 45-14).   In the fourth (or healed) stage, remodeling takes place and  the newly formed bone is organized into a live spongy bone.  Children less than 6 years of age at onset have more time to  remodel the damage LCP has caused and have the best out-  come. Recent multicenter studies, using the Herring “lateral  pillar” classification,*° have shown that hips younger than 6  years with no involvement of the lateral femoral head (type A)  do better than those with involvement of the lateral femoral  head. Those children with complete collapse of the lateral femo-  ral head (type C) have the worst prognosis. Long-term studies  of type C hips show that 70% to 90% progress to osteoarthritis  by 40 years of age.’”   CLINICAL MANIFESTATIONS. Injury or trauma precedes the onset  of clinical manifestations in approximately one third of children  with LCP disease. Onset of symptoms is insidious unless trauma  aggravates the disease process. The pain often is referred to the  knee and can lead to misdiagnosis as a knee injury. The inner  thigh and groin also can be painful. In some children, pain may  be absent or minimal. If pain is present, it is usually aggravated  by activity and relieved by rest.   The typical physical findings include spasm on inward rota-  tion of the hip and a limitation of internal rotation flexion and  abduction. If the child is walking, an abnormal gait, termed a  Trendelenburg gait or abductor lurch, is apparent. The child  dips the trunk toward the affected side with stance to compen-  sate for weak abductor musculature. If the hip pain or limp has  been present for a prolonged period, muscles of the hip and  thigh atrophy. A limb length inequity may be present if the  proximal femoral physis is involved.   EVALUATION AND TREATMENT. Diagnosis is confirmed by radio-  graphic examination. Principles of treatment are contain-  ment (keeping the ball completely in the socket) and motion  to maintain the articular cartilage. In the past, children were    treated with bed rest and a variety of braces. Most children can  be managed with anti-inflammatory medications and crutches  for episodes of synovitis and with activity modification (avoid-  ance of jumping activities that place increased stress on the hip)  during the active phase of the disease. Serial roentgenograms  monitor the progress of the disease and ensure that the hip  remains congruent. Surgery may be necessary if the femoral  head becomes subluxated or incongruent with the acetabulum  before the reparative process. The ball must be congruent to  take on the shape of the socket as remodeling occurs. Newer  treatments, such as intra-articular injection of bisphosphonates  (that reduce the function of osteoclasts), are being studied.**   Factors affecting the outcome of LCP disease are the age of  the child at onset, the extent of necrosis, and the congruence  of the joint at skeletal maturity. Recent studies have shown  that girls, despite earlier skeletal maturity, do as well as boys.  Outcome is 70% satisfactory with Herring stage A; for Herring  stages B and C or age greater than 8 years, outcome is guarded.  Present prospective studies are evaluating more aggressive early  treatment (i.e., osteotomy of the femur or pelvis) on the more  involved hips to change long-term outcome.    Osgood-Schlatter disease consists of tendinitis of the anterior  patellar tendon, within which the patella (kneecap) is embed-  ded, and associated osteochondrosis of the tubercle of the tibia.  Osgood-Schlatter disease occurs most often in preadolescents  and adolescents who participate in sports. The incidence is  higher in boys than in girls, many of whom have increased out-  ward tibial fusion compared to controls.”   PATHOPHYSIOLOGY. The severity of the lesion varies from mild  tendinitis to a complete separation of the anterior extension  of the tibial epiphysis, which is the part of the epiphysis that  contributes to growth of the tibial tubercle. The underlying  pathologic alterations also vary. The mildest form of Osgood-  Schlatter disease causes ischemic (avascular) necrosis in the  region of the bony tibial tubercle, with hypertrophic cartilage  formation during the stages of repair. In more severe cases the  abnormality involves a true epiphyseal separation of the tibial  tubercle.   CLINICAL MANIFESTATIONS. The child experiences pain and  swelling in the region of the patellar tendon and tibial tubercle,  which becomes prominent and is tender to direct pressure. The  pain is most severe after physical activity that involves vigorous    quadriceps contraction or direct local trauma to the tibial  tubercle area. Often the child experiences sudden acute dis-  comfort referable to the affected region. Sudden onset of pain  can represent a pathologic fracture through an area of ischemic  necrosis.   EVALUATION AND TREATMENT. Diagnosis is confirmed by roent-  genographic examination. The goal of treatment for Osgood-  Schlatter disease is to decrease the stress at the tubercle. Often  a period of 4 to 8 weeks of restriction from strenuous physical  activity is sufficient. If pain relief is not achieved, a cast or brace  is required to immobilize the knee, a situation that is particu-  larly difficult if the condition is bilateral.   Gradual resumption of activity is permitted after 8 weeks,  but return to unrestricted athletic participation requires an  additional 8 weeks to allow for revascularization, healing, and  ossification of the tibial tubercle. All types of osteochondroses  resolve once skeletal maturity is reached.    Cerebral palsy (CP) is a general term that refers to nonprogres-  sive disorders of movement and posture resulting from injury  or malformation of the developing central nervous system. The  resulting disability may be mild, manifesting as a stiff-legged  gait; or severe, where the child is in a wheelchair and needs  lifelong help eating, ambulating, and communicating. There  often are associated conditions, such as intellectual disability,  seizures, scoliosis, and hearing or vision, or both, defects, espe-  cially in children with more severe forms. The overall incidence  is 3% to 5%; this number has stayed approximately the same  although changes in prenatal and newborn care have been asso-  ciated with shifts in the etiologies of CP.°?!   EVALUATION AND DIAGNOSIS. The diagnosis of CP is often made  when gross motor milestones are not met by predicted ages.  In some infants, diagnosis is made at birth because the child  has an underlying diagnosis, such as a major brain malfor-  mation, that is known to be associated with CP, or as early as  4 months in children with more severe forms.*” There are   Percussion myotonia,  cataracts, diabetic  GIT despite  increased insulin,  testicular atrophy,  decreased IgG   Slow, related to  age at clinical  onset, faster  with younger  patients    classic patterns: hemiplegia involves one side of the body, diple-  gia usually involves the lower extremities only, and quadriple-  gia involves all four extremities. All children with CP should  receive speech/language therapy with trials of augmentative  communication devices so that underlying cognitive abilities,  which may not be apparent because of motor problems, are  given a chance to manifest.   TREATMENT. Treatment of CP is multifaceted and undergo-  ing constant evolution. Physical and occupational treatments,  orthotics, spasticity reduction (by selected dorsal rhizotomy,  oral, or intrathecal baclofen), botulinum-A (Botox) toxin injec-  tions, and surgery are often used to maximize a child’s func-  tion. In many centers, a multispecialty approach at “CP clinics”  occurs so that a family may, within one clinic visit, see neurol-  ogy, pediatrics, orthotics, orthopedic surgery, and rehabilita-  tion clinicians.   Children with CP should be carefully followed and given all  possible opportunities to flourish. Although CP is a static disor-  der, progressive deformity because of increased muscle tone can  occur. Monitoring these children as they grow with a multispe-  cialty approach is essential to their optimal outcome.   The muscular dystrophies are a group of inherited disorders  that cause progressive muscle fiber loss leading to weakness,  mostly of the voluntary muscles. The muscular dystrophies are  the most prevalent of the muscle diseases in childhood with  increasing disability and deformity, although severity depends  on the type of dystrophy (Table 45-4).   Although previous classification of the muscular dystrophies  was based on age of onset, rate of progression, distribution of  muscular involvement, and patterns of inheritance, increas-  ingly the molecular mechanism or gene, or both, for the condi-  tion is used for diagnosis. Examples include Duchenne/Becker  muscular dystrophy, both caused by mutations in the gene for  the muscle protein dystrophin; myotonic muscular dystrophy,  because of a genetic mutation in a protein kinase gene; and    FIGURE 45-15 Initial Muscle Groups Involved in Three Types of Muscular Dystrophy. A, Pseudohypertrophic. B,  Facioscapulohumeral. C, Limb girdle. (From Hockenberry MJ, Wilson D: Wong's nursing care of infants and children, ed 9,    facioscapulohumeral muscular dystrophy, for which the muta-  tion is still not well understood, although we know that the  responsible gene is on chromosome 4 (Figure 45-15).   In 1868 the French neurologist G.B.A. Duchenne described  progressive weakness associated with large calf muscles said to  be pseudohypertrophic, because they consisted of fat and con-  nective tissue rather than muscle. Today this form of muscular  dystrophy, called Duchenne muscular dystrophy, is the most  common of the muscular dystrophies. Its incidence is approxi-  mately 1 in 3500 male births.** Classic Duchenne muscular  dystrophy occurs only in boys and has a history of X-linked  inheritance in half of the cases.   PATHOPHYSIOLOGY. The X-linked inherited type of Duchenne  muscular dystrophy is thought to be caused by deletion of a seg-  ment of deoxyribonucleic acid (DNA)*? or a single-gene defect  on the short arm of the X chromosome. A protein encoded by  the Duchenne muscular dystrophy gene, called dystrophin, has  been identified.   Dystrophin is present in normal muscle cells and absent  in Duchenne muscular dystrophy (it is present in reduced  amounts in Becker dystrophy). Dystrophin mediates anchor-  age of the actin cytoskeleton of skeletal muscle fibers to the  basement membrane through a membrane glycoprotein com-  plex. The complete lack of dystrophin in severe Duchenne dys-  trophy means that poorly anchored fibers tear themselves apart  under the repeated stress of contraction. Free calcium then  enters the muscle cells, causing cell death and fiber necrosis**  (Figure 45-16).   Over time, as muscles degenerate, there is increased  endomysial connective tissue and fat; loss of striations; and    concomitant hyaline, granular, and fatty degeneration of fibers.  Disorganization of tendinous insertions is associated with fat  accumulation in these areas. Although fibers regenerate in the  younger child, regeneration is not able to keep up with muscle  cell death.   CLINICAL MANIFESTATIONS. Duchenne muscular dystrophy is  usually identified in children at approximately 3 years of age,  when the parents first notice slow motor development with  progressive weakness and muscle wasting. Sitting, standing, and  walking are delayed, and the child is clumsy, falls frequently,  and has difficulty climbing stairs.   Muscular weakness begins in the pelvic girdle, causing a  “waddling” gait. Hypertrophy of the calf muscles is apparent in  80% of cases. The method of rising from the floor by “climb-  ing up the legs” (Gower sign) is characteristic and is caused by  weakness of the lumbar and gluteal muscles. The foot assumes  an equinovarus position (see Figure 45-7), and the child tends  to walk on the toes because of weakness of the anterior tibial  and peroneal muscles. Within 3 to 5 years, muscles of the shoul-  der girdle become involved. Contractures and wasting of the  muscles contribute to muscular atrophy and deformity of the  skeleton.   Duchenne muscular dystrophy has serious complications,  although these are decreased by treatment with oral corticoste-  roids at diagnosis. The recent addition of oral corticosteroids  early in the disease has dramatically improved outcome. Chil-  dren are able to walk an additional 2 to 5 years and life expec-  tancy has increased.*° Complications, such as compromised  pulmonary function and kyphoscoliosis (“humped” upper  spine combined with scoliosis), are delayed. Full-scale IQ is 85,  which is significantly lower than the average IQ of 100, although  studies suggest this decrease may be caused by specific learning    FIGURE 45-16 Duchenne Muscular Dystrophy. A, Young boy with Duchenne muscular dystrophy but on horseback.    B, Transverse section of gastrocnemius muscle from a healthy boy. C, Transverse section of gastrocnemius muscle from a boy  with Duchenne muscular dystrophy. Normal muscle fiber is replaced with fat and connective tissue. (C from Jorde LB, Carey  JC, Bamshad MJ: Medical genetics, ed 4, Philadelphia, 2010, Mosby.)    disabilities rather than a true decreased intelligence. As the con-  dition develops, constipation and incontinence of urine and  stool may develop, possibly because of smooth muscle involve-  ment. Although the life expectancy of boys with Duchenne  continues to increase, death usually occurs from respiratory  tract infection and a compromised respiratory system, with the  majority living into their middle twenties. Some individuals who  have chosen ventilatory support live a decade or more longer.   EVALUATION AND TREATMENT. Diagnosis is confirmed by  genetic testing, which is informative in 95% of cases. Levels of  serum enzymes, especially creatine phosphokinase (CPK), are  increased to more than 10 times normal, even during infancy  and before the onset of weakness. This test may be done as a  screening test before gene testing. Electrodiagnostic testing and  biopsy are rarely necessary.   Genetic counseling is recommended for all families who  have children with DMD. With X-linked inheritance, male sib-  lings of an affected child have a 50% chance of being affected  and female siblings have a 50% chance of being carriers. Prena-  tal diagnosis is now possible and female carriers can be identi-  fied, especially if there is a known genetic defect in a son with  muscular dystrophy. However, a negative carrier test cannot  exclude the female being a carrier since the female’s germ cells  (her eggs) may be of two different types: one with Duchenne  and one without (mosaicism). About one third of the time,  the mutation in a boy with DMD is sporadic; that is, the boy is    the first person in the family to develop the mutation causing  DMD. Various strategies to develop gene therapy are currently  in development for children with DMD.   Maintaining function in unaffected muscle groups for as  long as possible is the primary goal. Although activity fosters  maintenance of muscle function, very strenuous exercise may  hasten the breakdown of muscle fibers. Range-of-motion exer-  cises, bracing, and surgical release of contracture deformities  are used to maintain normal function as long as possible. To  prolong respiratory function or walking ability, or both, sur-  gery for scoliosis is suggested when curves reach greater than  20 degrees. Children with DMD require a multidisciplinary  approach to care, including attention to heart and breathing  problems, weight loss/gain, constipation, rehabilitative/devel-  opmental problems, psychosocial needs, neurologic issues, and  orthopedic problems (Figure 45-17).    Becker muscular dystrophy is caused by the same mutation in  the gene coding for the muscle structural protein dystrophin;  therefore, it shares the X-linked inheritance pattern and has  similar but milder clinical features. Clinical symptoms often  begin between 5 and 15 years of age. Children with Becker mus-  cular dystrophy remain ambulatory into their teens and early  twenties Heart failure is infrequent but can be a cause of prema-  ture death and disability.    FIGURE 45-17 Multisystem Approach for Evaluation and Treatment of  Duchenne Muscular Dystrophy. (Adapted from Bushby K: Diagnosis and manage-  ment of Duchenne muscular dystrophy part 1: diagnosis and pharmacological and  psychosocial management, 2009; Bushby K: Diagnosis and management of Duch-  enne muscular dystrophy part 2: implementation of multidisciplinary care, 2009.  Available at www.thelancet.com/neurology. Published online November 30, 2009.  [doi: 10.1016/S1474-4422(0970271].)    Maintaining ambulation and ensuring careful follow-up  examinations for evidence of cardiopulmonary complica-  tions are essential for long-term care. If the affected individual  marries and has children, all daughters will be carriers of this  X-linked recessive disorder; however, male children will be  unaffected. Genetic counseling should be offered to the mother,  female siblings, offspring, and any maternal relatives.    Facioscapulohumeral Muscular Dystrophy  Facioscapulohumeral muscular dystrophy (FSHD) is a mild  form of progressive, autosomal dominant muscular dystrophy.  Age at onset varies from early childhood to adulthood, and the  disease affects males and females equally. As the name implies,  clinical manifestations begin with weakness and atrophy of  facial and shoulder girdle (scapulohumeral) muscles. The ill-  ness progresses slowly. Inability to close the eyes completely  may be noted from early childhood. The face is expressionless,  and pouting of the lips makes whistling impossible. The first  symptoms usually include drooping of the shoulders with dif-  ficulty in raising the arms above the head. Onset of weakness  in the lower limbs often is delayed for 20 to 30 years, and pseu-  dohypertrophy of muscles is rare. Contractures and skeletal  deformities develop less often and are less prominent than in  Duchenne muscular dystrophy. FSHD is rare compared to the  other dystrophies in that it often manifests asymmetrically.  Treatment includes supportive physiotherapy to prevent  contractures and prolong ambulation. Lightweight plastic    ankle-foot orthoses (AFOs) for footdrop are extremely helpful.  Shoulder pain is often present and figure-of-eight bracing or  surgery to stabilize the shoulder is sometimes advised.   Bone tumors are uncommon childhood tumors and comprise  less than 5% of all childhood malignancies. Of the malignant  tumors, osteosarcoma and Ewing sarcoma are the most com-  mon. Fortunately, the majority of pediatric tumors are benign,  most commonly nonossifying fibroma, osteochondroma,  simple bone cyst, aneurysmal bone cyst, osteoid osteoma, and  fibrous dysplasia.   Nonossifying Fibroma. Nonossifying fibromas are sharply  demarcated, cortically based lesions of fibrocytes that have  replaced normal bone. These fibromas constitute about 50% of  benign bone tumors. Most fibrous cortical defects are metaphy-  seal and resolve spontaneously or are obliterated by reparative  ossification or remodeling. In some cases, however, the nonos-  sifying fibroma persists and proliferates, affecting the structural  integrity of the bone.   Nonossifying fibromas are usually asymptomatic and found  incidentally on radiographs. In the 1950s, when fluoride was  added to drinking water, random skeletal surveys were done on  hundreds of children. Nonossifying fibromas were discovered  in 20% to 30% of children and were distributed in nearly every  bone of the body.   Nonossifying fibroma is not treated until it occupies more  than 50% of the diameter of the bone or extends more than 3  to 4 cm into the cortex. When the tumor grows to this size, a  pathologic fracture may occur, and curettage and bone grafting  of the defect is undertaken. Quantitative CT scans help define a  large lesion clearly and are used for preoperative planning.   Osteochondroma. Osteochondroma (or exostosis) is a  very common benign tumor that results in a bony protuber-  ance of bone growing near the growth plate. They can occur as  a solitary lesion or as an inherited syndrome of hereditary mul-  tiple exostoses (HMEs). Osteochondromas are covered with a  cartilage cap that, very rarely, can degenerate into malignant  chondrosarcoma. Osteochondromas can occur on any bone  and mature while a child is growing. They are the most com-  monly removed bony tumor.   Hereditary multiple exostosis (HME) occurs in about 1  of every 50,000 live births and results in multiple osteochon-  droma. It is autosomal dominant and caused by inactivation of  EXT1 and EXT2 mutations on chromosomes 8 and 11, respec-  tively. Multiple surgeries are common in affected individuals  because the lesions lead to angulation of the bones, pain from  pressure on nerves or tendons, and growth abnormalities.  The malignant transformation rate is higher, reaching 5%. All  affected children should be screened with a spinal MRI to dis-  cover if the cord is at risk of injury by spinal exostosis. Involve-  ment of the spine in children with multiple hereditary exostoses  is common.*°   Simple Bone Cyst. Simple bone cysts (SBCs) are cystic  lesions of the central region of the metaphyseal area in children.    With growth these lesions may appear within the diaphysis.  Affected children are usually asymptomatic until pathologic  fracture or incidental discovery occurs. Lesions often heal after  a fracture, but large lesions may require treatment. A large pro-  spective, randomized study compared steroid injection (the  classic treatment for these lesions) with bone marrow injection  for treatment. Both treatment modalities were found to have  comparable healing rates if the pseudolining of the lesion was  scraped from the cyst wall.°” Very large lesions in weightbearing  areas may require internal fixation and bone grafting.   Aneurysmal Bone Cyst. Aneurysmal bone cysts (ABCs) are  typically eccentric, metaphyseal lesions that occur in a slightly  older population than SBCs. The etiology remains controver-  sial; many consider ABC a lesion secondary to another process,  such as giant cell tumor. This lesion must be differentiated from  malignant telangiectatic osteosarcoma; thus biopsy is necessary.  Recent findings of genetic aberration in chromosome band  17p13 suggest a neoplastic basis for ABC.** Once diagnosed,  curettage with complete removal of the “pseudolining” must  be done with chemical cautery or electrocautery to minimize  recurrence. Bone graft is placed in the defect. Even with modern  techniques, recurrence can be as high as 21%.°”   Osteoid Osteoma. Osteoid osteoma, or the larger counter-  part osteoblastoma, presents as painful lesions of the diaphysis  or metadiaphysis of long bones. Involvement of the posterior  elements of the spine—with resultant “splinting” scoliosis—  can occur. Night pain is common, as is relief from symptoms  with nonsteroidal anti-inflammatory drugs (NSAIDs), because  these tumors release prostaglandins. When pain is too extreme  to be controlled medically, resection of the “nidus,” or central  portion, of the lesion is uniformly successful. CT guidance to  the lesion is often used and, if possible, CT-guided laser abla-  tion can be done. When present in the spine, surgical resection  must be used since the heat of laser ablation can injure the spi-  nal cord.   Fibrous Dysplasia. Fibrous dysplasia (FD) is a disease that  causes thinning of the bone or the formation of growths or  lesions that can occur in one bone (monostotic) or in multiple  bones (polyostotic). Albright syndrome is a triad of polyostotic  ED, precocious puberty, and cutaneous pigmentation. Although  any bone can be affected, the long bones, ribs, and skull are the  most common. A radiographic “ground glass” appearance is  present primarily in the metaphyseal or metadiaphyseal areas.  Deformity can be marked and necessitate operative interven-  tion. When Albright syndrome is present, endocrine abnormal-  ities also must be addressed.   Osteosarcoma. Osteosarcoma is the most common malig-  nant bone tumor that occurs during childhood; it originates  from bone-producing mesenchymal cells. It accounts for 60%  of all malignant bone tumors and strikes between the ages of 10  and 18.   Molecular analysis has demonstrated deletion of genetic  material on the long arm of chromosome 13, leading to the  identification of a tumor-suppressor gene as part of the mecha-  nism for tumor development. The oncogene src also has been  associated with osteosarcoma.    PATHOPHYSIOLOGY. Osteosarcoma occurs mainly in the  metaphyses of long bones. Most tumors arise in bones involved  with the knee joint at the distal end of the femur or proximal  end of the tibia. As a tumor of mesenchymal cells, osteosarcoma  makes osteoid tissue.   Osteosarcoma is a bulky tumor that extends beyond the  bone into the soft tissues. It may encircle the bone and destroy  the trabeculae of the diseased bone. Osteosarcoma disseminates  through the bloodstream, usually to the lung. As many as 25%  of children diagnosed with osteosarcoma exhibit lung metasta-  ses at diagnosis. Other sites of metastatic spread include other  bones and visceral organs.   CLINICAL MANIFESTATIONS. The most common presenting  complaint is pain. There may be swelling, warmth, and red-  ness caused by the vascularity of the tumor. Symptoms also  may include cough, dyspnea, and chest pain if lung metastasis is  present. If a lower extremity is involved, a limp or even patho-  logic fracture may be present.   Initial evaluation includes roentgenographic examination  that shows the osteosarcoma’s characteristic osteoblastic and  osteolytic changes. “Staging” studies to determine not only the  local extent of the tumor but also possible metastatic spread  must be done. These include bone scan (to assess bony spread),  magnetic resonance imaging (MRI) of the lesion (to plan surgi-  cal resection and to compare with postchemotherapy studies),  and chest roentgenograms or CT, or both. The chest roentgen-  ogram must be done before biopsy because the general anes-  thetic required for biopsy can give false-positive results on the  roentgenogram.   EVALUATION AND TREATMENT. Tissue biopsy confirms the diag-  nosis, although needle biopsy is often sufficient to establish the  diagnosis. There are five histologic types of osteosarcoma, each  determined by the predominant cell type. The tumor is then  graded according to degree of malignancy; the higher the num-  ber, the worse the prognosis.   Surgery and multiagent chemotherapy are the primary treat-  ments for osteosarcoma. Radiation is occasionally used. The  5-year survival rate with modern protocols is 70% to 80%.*°   Chemotherapy is used preoperatively to shrink the size of the  tumor and minimize metastatic growth. Following chemother-  apy; the child is given a short “rest period” to regain strength for  surgery. Following adjunctive chemotherapy, the majority of  children undergo “limb salvage” rather than amputation proce-  dures. The long-term survival rate of children treated with limb  salvage and chemotherapy is now nearly equal to amputation in  5- and 10-year survival.*!   Ewing Sarcoma. Ewing sarcoma is a malignant round cell  tumor of bone and soft tissue that has a poor prognosis. It is the  second most common and most lethal malignant bone tumor  that can occur during childhood. The peak incidence is 10 to 20  years. Like osteosarcoma, Ewing sarcoma is slightly more com-  mon in males than females and is linked with periods of rapid  bone growth. The incidence of Ewing sarcoma is less than 2%  in blacks.”   PATHOPHYSIOLOGY. Ewing sarcoma commonly occurs in the  diaphysis of long bones or in flat bones. The most common sites  include the pelvis, femur, and tibia (Figure 45-18). The femur    is involved in most cases, with the pelvis being the second most  common site. It can occur in any bone.   Arising from bone marrow, Ewing sarcoma can break  through the cortex of the bone to form a soft tissue mass. It  does not form bone, but abundant reactive bone may be present  in an attempt to contain this quickly growing lesion. Metasta-  sis occurs early and is usually apparent at diagnosis or within 1  year. The most common sites are the lung, other bones, lymph  nodes, bone marrow, liver, spleen, and central nervous system,  although invasion of any organ is possible.   CLINICAL MANIFESTATIONS. Like osteosarcoma, the most com-  mon complaint is pain. A soft tissue mass is often present.  Additional symptoms may include fever, malaise, and anorexia.  Known as “the great imitator,” Ewing sarcoma can appear radio-  graphically identical to infection or even benign lesions such as  Langerhans cell granulomatosis. Any pervasive diaphyseal or  rib lesion must be regarded with a high index of suspicion.   EVALUATION AND TREATMENT. In addition to plain roentgeno-  gram, CT and MRI are needed to help establish the diagnosis  and extent of the tumor. Bone scan, chest roentgenogram, and  chest CT scan are also used to detect metastases. No specific lab-  oratory test is diagnostic; however, the sedimentation rate will  be elevated and lactic dehydrogenase (LDH) level often is ele-  vated. An elevated LDH level is a poor prognostic sign. Biopsy is  used to conclusively establish the diagnosis. The identification  of an 11:22 chromosomal translocation within the tumor cells  confirms the diagnosis of Ewing sarcoma.   The use of multidrug chemotherapy has improved survival  rates. Treatment protocols call for preoperative chemother-  apy followed by radiation or surgical resection or both, with    of the tibia. Tumor extends into the soft tissue. (From Damjanov |, Linder J, editors: Anderson's pathology, ed 10, St Louis,  1996, Mosby.)    continuation of chemotherapy for 12 to 18 months afterward.  Surgical resection is essential.   Historically, Ewing sarcoma had a dismal prognosis with  5-year survival rates no better than 5% to 10%. Combinations  of aggressive radiation, chemotherapy, and surgical resection  have improved the survival rate for extremity disease to 65% to  75%.» Disease of the trunk or pelvis continues to have a 5-year  survival of only 40%. The major predictor of prognosis appears  to be the location of the primary tumor and the presence of  metastases at diagnosis.    Most soft tissue tumors in children are benign. Only two malignant  soft tissue tumors occur with any frequency—rhabdomyosarcoma  in the younger child and synovial cell sarcoma in the teenager.  Both of these occur rarely. The annual incidence is 8 cases per  million for white children and 7.7 per million for black chil-  dren. About 230 U.S. children are diagnosed with a soft tissue  tumor each year. Soft tissue tumors originate from the primitive  mesenchymal cells that normally give rise to muscle, tendons,  blood vessels, lymphatic structures, fibrous and connective tis-  sue, and bursa and fascia. Table 45-5 identifies the classification  of soft tissue tumors according to origin. All malignant soft tis-  sue tumors are characterized as highly aggressive tumors that  invade surrounding structures and metastasize early.   Rhabdomyosarcoma (RMS) is the most common soft tissue  sarcoma of childhood and accounts for more than 50% of soft  tissue tumors but less than 3% of all childhood cancers. RMS  arises from embryonal rhabdomyoblasts that normally differ-  entiate into mature striated muscle.    RMS can develop anywhere striated muscle is located. The  primary locations and percentage range of incidence are the  head and neck (including the orbit), 36% to 61%; the trunk,  8% to 33%; the extremities, 14% to 24%; and the genitourinary  tract, 10% to 17%. Two age ranges (2 to 6 years and 15 to 19  years) are associated with RMS. More than two thirds of chil-  dren with RMS are diagnosed by 10 years of age, and RMS is  slightly more common in males than females.   Recent studies demonstrate an association between TP53  (a tumor-suppressor gene) mutations and sporadic rhabdo-  myosarcoma.*! Three oncogenes (src, ras, and c-myb) have been  associated with this tumor.*°   PATHOPHYSIOLOGY. RMS generally appears as a firm, fleshy,  grayish white mass. RMS has various appearances, depending  on the phase of differentiation of the rhabdomyoblast. The cells  may be round, spindle shaped, tadpole shaped, or multinucle-  ated giant cells.   At least 20% of children with RMS have metastatic disease at  diagnosis. The preferred sites of metastases include the lungs,  lymph nodes, bone marrow, liver, brain, and bone. Another  30% have disease that is unresectable, although not widely  spread.   CLINICAL MANIFESTATIONS. The signs and symptoms of RMS  depend on the anatomic location of the primary tumor and  the presence of symptomatic metastases. The tumors are usu-  ally painless, and early detection of RMS is facilitated by the  presence of a palpable or visible mass. Deep-seated tumors may  cause functional impairment but can be silent until they are  very large. The clinical manifestations of RMS are outlined in  Table 45-6.   EVALUATION AND TREATMENT. Diagnostic studies during the  pretreatment phase are used to determine the extent of the pri-  mary tumor and metastases. Specific diagnostic studies depend  on the primary site, but a combination of radiographic, nuclear,  and CT scanning or MRI technology and blood studies is used.  A biopsy of the primary tumor is necessary to confirm the  diagnosis.   RMS is treated by a combination of surgery, radiation, and  chemotherapy. Complete surgical resection combined with  multiagent chemotherapy has increased the overall survival  rate to 70%. If surgical resection leads to serious disfigurement  or functional disability (e.g., enucleation for orbital tumors   Painful mastication  Chronic serous otitis media  Discharge from affected ear  Facial nerve palsy  Conduction hearing loss  Visible polypoid mass    Abnormal vaginal bleeding  Protruding polypoid mass  Urinary tract obstruction  Urinary retention    or cystectomy for bladder tumors), chemotherapy and radia-  tion serve as the primary treatment, and surgery is avoided or  minimized.   The primary prognostic factor in RMS is the degree of resid-  ual disease after surgical resection. Children with localized dis-  ease (stages I and II) have long-term survival rates of 70% to  80%. With widespread disease, long-term survival rates drop  to 20%. Orbital tumors have an overall favorable prognosis,  probably because of the lack of lymphatics in the area and early  physical signs of disease.    Abuse is estimated to occur in more than 1.5 million U.S. chil-  dren per year. The maltreatment may be psychologic, sexual,  or physical. Of children who suffer physical abuse, 30% are ini-  tially seen by an orthopedist. Accurate and appropriate referrals  to child protection services are not only legally mandated but    also essential for the well-being of the child; an abused child  who returns unmonitored to an abusive situation has a 15%  chance of mortality.   ETIOLOGY. Children who are not yet ambulatory and present  with a long bone fracture have a greater than 75% chance of  that fracture being caused by nonaccidental trauma. “Corner”  metaphyseal fractures, caused by a twisting force, are nearly  pathognomonic of abuse but occur only 25% of the time (Figure  45-19). Fractures at multiple stages of healing are also sugges-  tive; however, osteogenesis imperfecta must be ruled out. The  most common presentation is a transverse tibia fracture.*° After  walking age, only 2% of long bone fractures are the result of  nonaccidental trauma.*”   EVALUATION. If suspected, nonaccidental trauma necessitates  early consultation with child protective services. The child  should undergo skeletal radiographic survey, especially if less  than 2 years of age, and have a complete physical examination  to evaluate for patterned bruising, burns, or multiple soft tis-  sue injuries. Ophthalmologic examination and brain CT should  be used to evaluate for retinal or brain hemorrhage caused by  shaking. A thorough history must be obtained for all identified  injuries. Bone scan can be helpful in diagnosing subtle injuries,  especially rib fractures. Posterior rib fractures are especially  likely to be caused by abuse. It is important to remember that  social isolation can lead to increased likelihood of abuse, but no  social stratum is immune.   TREATMENT. A nonjudgmental attitude on the part of the  treating healthcare provider is essential. The child and family  involved in nonaccidental trauma are delicate and require not    FIGURE 45-19 Corner Fracture. Bilateral knee radiograph showing healing  corner fractures of bilateral proximal tibias and distal femurs. Note the varying  amount of callus formation signifying fractures at different stages of healing.    only physical but also emotional care. Social workers need to be  involved early to ensure appropriate medical care to the child.  Fortunately, fractures heal quickly in young children; neuro-  logic injury and social disease, however, are much more diffi-  cult to cure.   1. Skeletal growth and development consists of two phases: (a)  delivery of bone cell precursors to sites of bone formation,  and (b) the aggregation of these cells at primary centers of  ossification where they mature to secrete osteoid.   2. Ossification takes place in two centers in long bones: (a) the  primary center, or the diaphysis (the long, central portion of  the bone); and (b) the secondary center, or the epiphysis (the  end portions of the bone).   3. Peak bone mass is achieved by the middle to late twenties.   4. By 1 year of age 50% of the total growth of the spine has  occurred, and most children have achieved 50% of their  adult height by 2 years of age.   5. The appendicular skeleton (extremities) grows faster during  childhood than does the axial skeleton.   6. Muscle fibers reach their maximal size in females at 10 years  of age and at 14 years of age in males.   1. The most common congenital defect of the upper extremi-  ties is syndactyly (webbing of the fingers).   2. Developmental dysplasia of the hip (DDH) is an abnormal-  ity in the development of the femoral head, acetabulum, or    both. It is a serious and disabling condition in children if not  diagnosed and treated early, preferably in infancy.   3. Clubfoot (equinovarus) is a common deformity in which  the foot is twisted out of its normal shape or position. Club-  foot can be positional, idiopathic, or teratologic.   4. Congenital muscle disorders (myopathies) include absence  of muscles, hypoplasia, hyperplasia, and faulty intrinsic  development.   5. Osteogenesis imperfecta (brittle bone disease) is a genetic  disorder of collagen that affects primarily bones and results  in fractures of many bones.   6. Rickets is a condition caused by deficiencies in vitamin D,  calcium, and usually phosphorus that is characterized by  the failure of bones to become mineralized (ossified) and  results in skeletal deformity.   7. Scoliosis is a lateral curvature of the spinal column that can be  caused by congenital malformations of the spine, neuromus-  cular disease, trauma, extraspinal contractures, bone infec-  tions, metabolic bone disorders, joint disease, and tumors.   8. Osteomyelitis is a local or generalized bacterial infection  of bone and bone marrow. Bacteria are usually introduced  by direct extension from a nearby infection, through the  bloodstream, or by trauma. Septic arthritis (bacteria within    the joint) may be associated with osteomyelitis and is a sur- 18. Ewing sarcoma originates from cells within the bone mar-  gical emergency. row space and is located most often in the midshaft of long  Juvenile idiopathic arthritis is an inflammatory joint dis- bones, in ribs, or in flat bones.  order characterized by pain and swelling. Large joints are 19. Ewing sarcoma is more common in males and is diagnosed  most commonly affected. most often between the ages of 5 and 15 years.  10. Avascular diseases of the bone are collectively referred to 20. Pain is the usual presenting symptom for either osteosar-   as osteochondroses and are caused by an insufficient blood coma or Ewing sarcoma.   supply to growing bones. 21. The primary treatments for osteosarcoma are surgery and  11. Legg-Calvé-Perthes disease is one of the most common chemotherapy. The primary treatment for Ewing sar-  osteochondroses. This disorder is characterized by epiphy- coma is a combination of chemotherapy, radiation, and  seal necrosis or degeneration of the head of the femur fol- surgery.  lowed by regeneration or recalcification. 22. The most common type of childhood soft tissue tumor is  Osgood-Schlatter disease is characterized by inflammation rhabdomyosarcoma.  or partial separation of the tibial tubercle caused by chronic 23. Rhabdomyosarcoma originates from embryonal rhabdo-  irritation, usually as a result of overuse of the quadriceps myoblasts that normally differentiate into mature striated  muscles. The condition is seen primarily in muscular, ath- muscle.  letic adolescent males. 24, Clinical manifestations of rhabdomyosarcoma depend on  The muscular dystrophies are a group of genetically trans- the anatomic location; superficial tumors exhibit a painless  mitted diseases characterized by progressive atrophy of palpable mass, whereas deep-seated tumors cause func-  symmetric groups of skeletal muscles without evidence of tional impairment.  involvement or degeneration of neural tissue. There is an 25. Rhabdomyosarcoma is treated with a combination of sur-  insidious loss of strength in all forms of the disorder with gery, radiation, and chemotherapy.  increasing disability and deformity.  The two most common forms of benign bone tumors  include nonossifying fibroma and osteochondroma. Other  benign bone tumors include simple bone cysts, aneurysmal  bone cysts, osteoid osteoma, and fibrous dysplasia.  15. The two main types of malignant childhood bone tumors  are osteosarcoma and Ewing sarcoma.  Osteosarcoma, the most common malignant childhood  bone tumor, originates in bone-producing mesenchymal  cells and is most often located in the distal end of the femur  or proximal end of the tibia.  Most childhood osteosarcoma tumors occur between the  ages of 10 and 18 years.   1. Nonaccidental trauma must be considered with any long  bone injury in a preambulatory child.   2. Evidence of soft tissue injury, corner fractures, and frac-  tures at different stages of healing are extremely helpful in  making a diagnosis of nonaccidental trauma.   3. When nonaccidental trauma is suspected, a child must be  evaluated radiographically for other fractures, head trauma,  and retinal hemorrhage.   5. The healthcare provider is legally responsible to report sus-  pected nonaccidental trauma.   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Vijermans V et al: Factors determining the final outcome of treatment of  idiopathic scoliosis with the Boston brace: a longitudinal study, J Pediatr  Orthop B 13(3):143-149, 2004.   Caksen H et al: Septic arthritis in childhood, Pediatr Int 42(5):534,   Gillespie WJ et al: Aspects of the microbe:host relationship in staphylo-  coccal hematogenous osteomyelitis, Orthopedics 10(3):475, 1987.  Hedstrém SA, Lidgren L: Septic arthritis and osteomyelitis. In Klippel JH,  Dieppe PA, editors: Rheumatology, ed 2, London, 1998, Mosby-Wolfe.  Stanitski C: Changes in pediatric acute hematogenous osteomyelitis  management, J Pediatr Orthop 24(4):444—445, 2004.   Przybylski GJ, Sharan AD: Single-stage autogenous bone grafting and  internal fixation in the surgical management of pyogenic discitis and  vertebral osteomyelitis, J Neurosurg 94(Suppl 1):1, 2001.    genesis of acute bacterial bone and joint sepsis, Baillieres Best Pract Res  Clin Rheumatol 13(1):1, 1999.    . Perlman M et al: The incidence of joint involvement of adjacent osteo-   Cassidy JT: Textbook of pediatric rheumatology, New York, 1982, Wiley &  Sons.   Hollingworth P: Juvenile chronic arthritis. In Klippel JH, Dieppe PA,  editors: Rheumatology, ed 2, London, 1998, Mosby-Wolfe.   and hypofibrinolysis with Legg-Perthes disease, J Bone Joint Surg Am  78(1):3-13, 1996.   Herring JA et al: The lateral pillar classification of Legg-Calvé-Perthes  disease, J Pediatr Orthop 12(2):143—150, 1992.   Schoenecker PL et al: Legg-Perthes disease in children under 6 years old,  Orthop Rev 22:201, 1993.   Little DG et al: Potential for bisphosphonate treatment in Legg-Calve-  Perthes disease, J Pediatr Orthop 31(Suppl 2):S182-S188, 2011.   Gigante A et al: What is the best treatment for Osgood-Schlatter disease?  J Fam Pract 53(2):153-156, 2004.   Himmelmann K et al: The changing panorama of cerebral palsy in Swe-  den. IX. 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As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Structure and Function of the Skin, 1616  Layers of the Skin, 1616  Subcutaneous Layer, 1618  AGING and Skin Integrity, 1619  Tests of Skin Function, 1619  Clinical Manifestations of Skin Dysfunction, 1619  Disorders of the Skin, 1627  Inflammatory Disorders, 1627  Papulosquamous Disorders, 1629  Vesiculobullous Disorders, 1632  Infections, 1634    The skin covers the entire body and is the body’s largest organ,  accounting for approximately 20% of the body’s weight. Com-  bined with the accessory structures of hair, nails, and glands, it  forms the integumentary system. The primary function of the  skin is to protect the body from the environment by serving as a  barrier against microorganisms, ultraviolet (UV) radiation, loss  of body fluids, and the stress of mechanical forces. The skin also  regulates body temperature within a very narrow range, and is  involved in immune surveillance and the activation of vitamin  D. Touch and pressure receptors provide important protective  functions and pleasurable sensations. The commensal (normal)  microorganisms of the skin protect against pathologic bacteria.    The skin is formed of two major layers: (1) a superficial or outer  layer of epidermis, and (2) a deeper layer of dermis (the true    skin) (Figure 46-1). The subcutaneous layer (hypodermis) is  the lowest lying layer of connective tissue that contains macro-  phages, fibroblasts, fat cells, nerves, fine muscles, blood vessels,  lymphatics, and hair follicle roots. Each skin layer contains cells  that represent progressive stages of skin cell differentiation and  function as the skin grows. These are summarized in Table 46-1.   The epidermis is a defensive barrier that continually renews  itself by shedding the superficial layer of stratum corneum. It is  formed primarily of keratinocytes embedded in a lipid matrix.  These cells are named for the substances they produce. Keratin-  ocytes produce keratin, a scleroprotein that provides protection  from mechanical stress. Keratin is the main constituent of skin,  hair, and nail cells. The thickness of the epidermis varies from  0.3 mm on the eyelids to 1.5 mm on the palms of the hands and  soles of the feet. New cells (keratinocytes) formed in the basal  layer (stratum basale) move upward and differentiate, forming    FIGURE 46-1 Structure of the Skin. A, Cross section showing major skin structures. B, Layers of the epidermis.  (A from Kumar V et al: Robbins & Cotran pathologic basis of disease, ed 8, St Louis, 2009, Saunders; B from Gawkrodger D,  Ardern-Jones MR: Dermatology, ed 5, Philadelphia, 2012, Churchill Livingstone.)    the spinous layer (stratum spinosum). Together they form  the germinative layer (stratum germinativum) and ensure  continual renewal of the skin. The cells enlarge and then  become flattened, stacked, and cornified (stratum corneum)  as they ascend to the skin surface. Cornification, or keratini-  zation, prevents dehydration of deeper skin layers and loss of  body water. The average turnover of the epidermis is about  30 days.   The epidermis has three additional types of cells that facili-  tate its functional characteristics: melanocytes, Langerhans cells,  and Merkel cells. The melanocytes are usually located near the  base of the epidermis. They synthesize and secrete the pigment  melanin with exposure to UV light in response to melanocyte-  stimulating hormone (MSH). Melanin in the epidermis pro-  vides a shield against UV radiation and determines skin color.  Vitiligo is an autoimmune-related loss of melanocytes resulting    in the depigmentation of patches of skin (see “Patch” in Table  44-3, p. 1547). Langerhans cells migrate to the epidermis from  the bone marrow. Langerhans cells (a type of dendritic cell) and  dermal dendritic cells initiate an immune response by present-  ing processed antigen to T cells, thus providing a defense against  environmental antigens.! Merkel cells are associated with touch  receptors and function as slowly adapting mechanoreceptors  when stimulated by deformation of the epidermis.   The dermis is 1 to 4 mm thick and is composed of three types  of connective tissue: (1) collagen, (2) elastin and reticulin, and  (3) a gel-like ground substance. The haphazard arrangement of  connective tissue allows the skin to be mobile and to stretch and  contract with body movement. Hair follicles, sebaceous glands,  sweat glands, blood vessels, lymphatic vessels, and nerves are    Most important layer of skin; normally very thin (0.12 mm) but can thicken and form corns or calluses  with constant pressure or friction; includes rete pegs that extend into papillary layer of dermis   Clear layers of cells containing eleidin, which becomes keratin as cells move up to the corneum layer;  found only in palmoplantar skin   Basal layer where keratinocytes divide and move upward to replace cells shed from the surface   Originate in neural crest and migrate to stratum basale and produce melanin   The function of Merkel cells is not clearly known—have role in light touch   Irregular connective tissue layer with rich blood, lymphatic, and nerve supply; contains sensory receptors  and sweat glands (apocrine, eccrine, sebaceous); macrophages (phagocytic and important for wound  healing) and mast cells (release histamine) have immune functions (see Chapter 7)    Stratum spinosum Keratinocytes  Langerhans cells  Stratum basale (germinativum) Keratinocytes  Melanocytes  Merkel cells  Macrophages  Mast cells    Histiocytes are wandering macrophages that collect pigments and inflammatory debris  Generate connective tissue; imported for wound healing  Subcutaneous tissue or superficial fascia of varying thickness that connects the overlying dermis to    underlying muscle; contains macrophages, fibroblasts, fat cells, nerves, blood vessels, lymphatics, and    contained in the dermis. The conelike projections of the papil-  lary dermis interface with the epidermis. The papillae provide  texture to the surface of the skin by forming rete pegs.   The cells of the dermis include fibroblasts, mast cells, and  macrophages. Fibroblasts secrete the connective tissue matrix  and collagen. Mast cells release histamine and play a role in  hypersensitivity reactions in the skin. Macrophages are phago-  cytic and participate in immune responses. Histiocytes are mac-  rophages that reside in loose connective tissue and phagocytize  pigments and the debris of inflammation.    The third layer of the skin is subcutaneous tissue and consists of  fat cells or adipocytes. The lobules are separated by fibrous walls  (septa) of collagen and large blood vessels. Dermal collagen is  continuous with the collagen found in the subcutaneous tissue.    The dermal appendages include the nails, hair, sebaceous  glands, and the eccrine and apocrine sweat glands. The nails are  protective keratinized plates composed of four structural units:  (1) the proximal nail fold, (2) the matrix from which the nail  grows, (3) the hyponychium (nail bed), and (4) the nail plate  (Figure 46-2). Nail growth is continuous throughout life at a  rate of 1 mm or less per day.   Hair follicles and sebaceous glands are integrated units (see  Figure 46-1). Hair color, density, grain, and pattern of distribu-  tion have considerable variability and depend on age, gender,  and race. Hair follicles arise from the matrix (or bulb) located  deep in the dermis. They extend from the dermis at an angle  and have an erector pili muscle attached near the mid-dermis  that straightens the follicle when contracted, causing the hair to  stand up. Hair growth begins in the bulb, with cellular differen-  tiation of stem cells occurring as the hair progresses up the fol-  licle.? Hair color is determined by melanin-secreting follicular    FIGURE 46-2 Structures of the Nail. (Redrawn from Thompson JM et al:  Mosby’: clinical nursing, ed 5, St Louis, 2002, Mosby.)    melanocytes. Hair is fully hardened, or cornified, by the time it  emerges at the skin surface. Hair growth is cyclic, with periods  of growth and rest that vary over different body surfaces.   The sebaceous glands open onto the surface of the skin  through a canal. They are found in greatest numbers on the  face, chest, and back; modified glands are found on the eyelids,  lips, nipple, glans penis, and prepuce. Sebaceous glands secrete  sebum, composed primarily of lipids, that oils the skin and hair  and prevents drying. Growth of sebaceous glands is stimulated  by androgens, and their enlargement is one of the early signs of  puberty.   The eccrine sweat glands are distributed over the body, with  the greatest numbers in the palms of the hands, soles of the  feet, and forehead. These secretions are important in thermo-  regulation and cooling of the body through evaporation. The  apocrine sweat glands are fewer in number and are located in  the axillae, scalp, face, abdomen, and genital area and have very  limited proven function.    Magnified illumination of the skin using a liquid medium and transparent plate to examine skin lesions  Histologic examination of tissue to determine differential diagnosis of cellular structure (i.e., benign growths vs. carcinoma, chronic    Microscopic \dentification of antibodies, immunoglobulins, and complement components for diseases such as pemphigus, vasculitis, and discoid  immunofluorescence lupus erythematosus using fluorescent light on slide-mounted biopsy specimens    Culture Identification of chronic bacterial and fungal infections by incubating skin specimens in culture media    Examination of skin or hair to identify fungus that fluoresces bright yellow-green under ultraviolet light    Patch and scratch tests Application of suspected allergens to skin by patch or scratch for evaluation of immune system responses to known allergens and    evaluation of cell-mediated immune function (Candida albicans, skin fungus, chemicals, aeroallergens, and foods)    Skin scrapings Application of potassium hydroxide and low heat to skin scrapings on a glass slide to identify dermatophytes and C. albicans    The blood supply to the skin is limited to the papillary capil-  laries, or plexus, of the dermis. These capillary loops arise from  a subpapillary plexus that is supplied by a deeper horizontal  cutaneous arterial plexus. Branches from the deep plexus sup-  ply hair follicles and sweat glands. A subpapillary network of  veins drains the capillary loops. Arteriovenous anastomoses in  the dermis facilitate the regulation of body temperature. Heat  loss can be regulated by varying blood flow through the skin  by opening and closing the arteriovenous anastomoses in con-  junction with evaporative heat loss of sweat. The sympathetic  nervous system regulates vasoconstriction and vasodilation  through a-adrenergic receptors. The lymphatic vessels arise in  the papillary dermis and drain into larger subcutaneous trunks,  removing cells, proteins, and immunologic mediators.    Many age-associated changes in the skin are generalized and  readily observable. Genetics and cumulative environmental  factors, including UV radiation from sun exposure (photoag-  ing), inflammatory responses, tobacco smoke, and gravity con-  tribute to cutaneous changes with aging.** Structurally the skin  becomes thinner, less elastic, drier, and wrinkled with a change  in pigmentation. The cellular alterations contributing to the  changes include a flattening of the dermoepidermal junction  with a shortening and decrease in the number of capillary loops.  There are fewer melanocytes, resulting in decreased protection  against UV radiation. A significant decrease in the number  of Langerhans cells reduces the skin’s immune response with  aging. The thickness of the dermis also decreases and accounts  for the translucent, paper-thin quality of the skin. Loss of the  rete pegs gives the skin a smooth, shiny appearance.°   The decreased vasculature and lymphatic drainage contrib-  ute to loss of barrier protection and the atrophy of eccrine,  apocrine, and sebaceous glands, all of which promote dry skin.  Loss of elastin fibers is associated with wrinkling. Collagen  fibers become fragmented, and fibroblasts decrease in number,    Indirect lighting of the skin using light to the side of the lesions to evaluate patterns of depression and elevation of skin lesions  Use of glass or clear plastic pressed on the skin to differentiate erythema caused by dilated capillaries (blanching) from    A microscopic examination of cellular material from skin lesions to help diagnose vesicular diseases, including herpes simplex virus    resulting in a decreased ability of the skin to stretch and regain  shape. Decreased cell proliferation, diminished blood supply,  and depressed immune responses also delay wound healing in  aging skin. Changes in hair color and distribution also occur.  Graying is caused by loss of melanocytes from hair bulbs, and  thinning occurs from a gradual decline in the number of hair  follicles and growth of finer hair.°   Epidermal cells change shape, and the barrier function of  the stratum corneum is reduced. There is increased permeabil-  ity and decreased clearance of toxic oxidative substances from  the dermis. The accumulation of such substances is related  to decreased vascularity and can cause skin irritation. Tem-  perature regulation is compromised in older adults, with an  increased risk for heat stroke and hypothermia. Loss of cuta-  neous vasomotion and subcutaneous fat, reduced vascularity,  and decreased eccrine sweat production are contributing fac-  tors.’ The pressure and touch receptors and free nerve endings  decrease in number and reduce sensory perception. With aging  many of the protective functions of the skin decrease, whereas  the likelihood of infection and delay in wound healing increase.®    Diagnostic evaluations of skin disorders often can be completed  by gathering historical information, performing a physical  examination, and observing the distribution and characteristics  of the presenting lesions. Additional diagnostic studies are sum-  marized in Table 46-2.   Lesions of the skin are readily observable and easily assessed  for distribution and structure. Identification of the morpho-  logic structure, including a differentiation between the primary  and secondary lesions, and the general appearance of the skin  is critical. The physical exam, in combination with a thorough  health history, is essential to identify the underlying patho-  physiology. Table 46-3 describes and illustrates the primary    A flat, circumscribed area that is a Freckles, flat moles (nevi), petechiae,  change in the color of the skin; measles, scarlet fever  less than 1 cm in diameter    An elevated, firm, circumscribed Wart (verruca), elevated moles, lichen  area less than 1 cm in diameter planus, fibroma, insect bite    Lichen planus®  Patch  A flat, nonpalpable, irregular- Vitiligo, port-wine stains, mongolian  shaped macule more than 1 cm in spots, café-au-lait spots  diameter    Vitiligo’  Plaque  Elevated, firm, and rough lesion Psoriasis, seborrheic and actinic  with flat top surface greater than keratoses  1 cm in diameter   Elevated, firm, circumscribed lesion; Erythema nodosum, lipomas  deeper in dermis than a papule;  1-2 cm in diameter    Elevated, solid lesion; may be Neoplasms, benign tumor, lipoma,  clearly demarcated; deeper in neurofibroma, hemangioma  dermis; greater than 2 cm in  diameter   Elevated, circumscribed, superficial, Varicella (chickenpox), herpes zoster  does not extend into dermis; filled (shingles), herpes simplex  with serous fluid; less than 1 cm  in diameter    Bulla  Vesicle greater than 1 cm in Blister, pemphigus vulgaris  diameter   Elevated, circumscribed, Sebaceous cyst, cystic acne  encapsulated lesion; in dermis or  subcutaneous layer; filled with  liquid or semisolid material    Telangiectasia  Fine (0.5-1.0 mm), irregular red lines — Telangiectasia in rosacea  produced by capillary dilation; can  be associated with acne rosacea  (face), venous hypertension  (spider veins in legs), systemic  sclerosis, or developmental  abnormalities (port-wine  birthmarks)    aFarrar WE et al: Infectious diseases, ed 2, London, 1992, Gower.   bJames WD, Berger T, Elston DMD: Andrews’ diseases of the skin, ed 11, Philadelphia, 2011, Saunders.  °Weston WL, Lane AT: Color textbook of pediatric dermatology, ed 3, Philadelphia, 2002, Mosby.   dHabif TP: Clinical dermatology: a color guide to diagnosis and therapy, ed 5, Philadelphia, 2010, Mosby.  ®Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology, ed 3, Philadelphia, 2012, Saunders.   fWeston WL, Lane AT, Morelli JG: Color textbook of pediatric dermatology, ed 4, Philadelphia, 2007, Mosby.  9Black MM et al: Obstetric and gynecologic dermatology, ed 3, Philadelphia, 2008, Mosby.   hMarks JG, Miller JJ: Lookingbill & Marks’ principles of dermatology, ed 4, London, 2006, Saunders.    LESIONS EXAMPLES  Scale  Heaped-up, keratinized cells; flaky Flaking of skin with seborrheic  skin; irregular-shape; thick or thin; dermatitis following scarlet fever,  dry or oily; variation in size or flaking of skin following a drug  reaction; dry skin    Lichenification  Rough, thickened epidermis Chronic dermatitis  secondary to persistent rubbing,  itching, or skin irritation; often  involves flexor surface of  extremity    Keloid  Irregular-shaped, elevated, Keloid formation following surgery  progressively enlarging scar;  grows beyond the boundaries of  the wound; caused by excessive  collagen formation during healing   Thin to thick fibrous tissue that Healed wound or surgical incision  replaces normal skin following  injury or laceration to the dermis    Loss of the epidermis; linear, Abrasion or scratch, scabies  hollowed-out, crusted area    Linear crack or break from the Athlete's foot, cracks at the corner of    epidermis to the dermis; may be the mouth, anal fissure, dermatitis  moist or dry   Loss of part of the epidermis; Chemical injury  depressed, moist, glistening;  follows rupture of a vesicle or  bulla or chemical injury    Atrophy  Thinning of the skin surface and  loss of skin markings    aBaran R, Dawber RR, Levene GM: Color atlas of the hair, scalp, and nails, St Louis, 1991, Mosby.   bJames WD, Berger T, Elston DMD: Andrews’ diseases of the skin, ed 11, Philadelphia, 2011, Saunders.  Weston WL, Lane AT, Morelli JG: Color textbook of pediatric dermatology, ed 4, Philadelphia, 2007, Mosby.  dNouri K, Leal-Khouri S: Techniques in dermatologic surgery, Philadelphia, 2003, Mosby.   ®Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology, ed 3, Philadelphia, 2012, Saunders.    fRobinson JK et al: Surgery of the skin, ed 2, Philadelphia, 2010, Mosby.    9Seidel HM et al: Mosby's guide to physical examination, ed 7, St Louis, 2011, Mosby.    Comedone A plug of sebaceous and keratin material lodged in the  opening of a hair follicle; an open comedone has a  dilated orifice (blackhead), and a closed comedone has a    narrow opening (whitehead)  A narrow, raised, irregular channel caused by a parasite  A circumscribed area of blood less than 0.5 cm in diameter  A circumscribed area of blood greater than 0.5 cm in  diameter    secondary lesions of the skin. Special skin lesions are described  in Table 46-5.   Pressure Ulcers. Pressure ulcers are ischemic ulcers  resulting from unrelieved pressure, shearing forces, friction,  and moisture. Pressure that consistently interrupts arterial and  venous blood flow to and from the skin or deeper tissue is the  most significant cause.’ The term decubitus ulcer refers to an  ulcer or pressure sore that results when an individual lies or  sits in one position for a long time. The more general terms  of pressure sore or ulcer are used here. Risk factors for pressure  ulcers are summarized in Box 46-1.   Most individuals with darkly pigmented skin are at greater  risk for developing pressure ulcers because early signs of skin  damage may not be clearly visible.!° Pressure sores usually  develop over bony prominences: the sacrum, heels, ischia, and  greater trochanters are the most common sites. Continuous  pressure on tissue between the bony prominence and a resis-  tant outside surface distort capillaries and occlude the blood  flow and oxygen supply. Several scales are available for predict-  ing pressure sore risk; the Braden Scale is one of those most    frequently used.'!"!? One classification of pressure ulcer grades  or stages is summarized as follows!*:   I. Nonblanchable erythema of intact skin usually over bony  prominence; darkly pigmented skin may not have visible  blanching   I. Partial-thickness skin loss (erosion or blistering) involv-  ing epidermis or dermis presenting as a shallow open ulcer  with a red-pink wound bed, without slough   II. Full-thickness skin loss involving damage or necrosis of  subcutaneous tissue that may extend to, but not through,  underlying fascia   IV. Full-thickness tissue loss with exposure of muscle, bone,  or supporting structures (tendons or joint capsules); can  include undermining and tunneling   Suspected deep tissue injury is localized in an area of purple  or maroon discolored intact skin or blood-filled blister caused  by underlying soft tissue damage from pressure and/or shear.   Unstageable is full-thickness tissue loss with base of ulcer  covered by slough or eschar, or both, in the wound bed.   Superficial damage results in a layer of dead tissue that  appears as a blister, erosion, or nonblanchable red/darkened  skin or as a reddish blue discoloration when there is deeper tis-  sue damage. Superficial sores are more common on the sacrum  as a result of shearing or friction forces (forces parallel to the  skin). Deep sores develop closer to the bone as a result of tis-  sue distortion and vascular occlusion from pressure that is per-  pendicular to the tissue (over the heels, trochanter, and ischia)  (Figure 46-3).   The primary goal for those at risk for pressure ulcers is pre-  vention, including frequent skin assessment with repositioning  and turning; use of pressure reduction surfaces and specialty  beds; elimination of incontinence, moisture, and drainage;  and maintenance of fluid, protein, and caloric intakes.!>!°    Prolonged Pressure/Immobilization  Lying in bed or sitting in chair or wheelchair without changing position or reliev-  ing pressure over an extended period  Lying for hours on hard x-ray and operating tables  Neurologic disorders (coma, spinal cord injuries, cognitive impairment, or  cerebrovascular disease)  Fractures or contractures  Debilitation: elderly persons in hospitals and nursing homes  Pain  Sedation  Shearing forces  e Turning by dragging on coarse bed sheets   Chronic diseases accompanied by anemia, edema, renal failure, malnutrition,  peripheral vascular disease, or sepsis    Data from Alderden J et al: Crit Care Nurse 31(4):30-43, 2011; Coleman S et al: /nt J Nurs Stud 50(7):974—1003, 2013; Cowan LJ et al: Wound  Repair Regen 20(2):137-148, 2012; Guihan M, Bombardier CH: J Spinal Cord Med 35(4):240-250, 2012; Jaul E: Drugs Aging 27(4):311-325, 2010;  Thomas DR: J Am Med Dir Assoc 11(6):397-405, 2010; White-Chu EF et al: Clin Geriatr Med 27(2):241-258, 2011.   = gies ce ry  SeiNeeae  FIGURE 46-3 Progression of Decubitus Ulcer. Sustained pressure over a  bony prominence compresses the tissue and reduces blood flow, resulting in pro-  gressive ischemia and necrosis of tissue.    Superficial ulcers should be covered with flat, moisture-retain-  ing dressings that cannot wrinkle and cause increased pressure  or friction; multiple options are available.'’ Successful healing  requires continued adequate relief of pressure; débridement of  dead tissue; use of specialty wound care products (dressings,  foams, gels, cleansers); and repair with skin flaps for large, deep  ulcers. Negative pressure wound healing is a useful technology  in the treatment of stage III/IV pressure ulcers.!*!? Infection  requires treatment with antibiotics and pain should be con-  trolled.”° Randomized controlled trials are needed to determine  the best methods for treating pressure ulcers.*!??   Keloids and Hypertrophic Scars. Keloids are rounded, firm,  elevated scars with irregular clawlike margins that extend beyond  the original site of injury. Hypertrophic scars are elevated  erythematous fibrous lesions that do not expand beyond the  border of injury. Both lesions are genetically influenced and  caused by abnormal wound healing with excessive fibroblast  activity and collagen formation during dermal connective tissue  repair.>*4 A familial tendency for keloid formation has been    found and both autosomal recessive and autosomal dominant  inheritance patterns have been reported.’? Genes regulating  fibroblasts may be up- or down-regulated in keloid tissue.”°   Keloids are most common in darkly pigmented skin types  and burn scars (see Chapter 48). Excessive or poorly aligned  tension on a wound, introduction of foreign material into the  skin, and the occurrence of certain types of trauma (e.g., burns)  are provocative factors. At risk are the shoulders, back, chin,  ears, and lower legs. Keloids can appear within weeks to months  after a stable scar has formed. Individuals 10 to 30 years of age  develop lesions much more commonly than do children before  puberty or older adults. Hypertrophic scars usually regress  within a year.   The amount of type III collagen is increased with keloids.  The increased synthesis of collagen is associated with interleu-  kin-6 (IL-6) signaling and dermal fibroblasts that have high  metabolic and mitotic rates. There is aberrant expression of  transforming growth factor-beta (TGF-f) and platelet-derived  growth factor (PDGF).?’   Myofibroblasts, cells with characteristics of fibroblasts and  smooth muscle cells, are the principal cells in keloids. Colla-  genase activity in keloids is normal or increased, but the col-  lagen may be protected from degradation by proteoglycan, a  glycoprotein present in connective tissue that serves as a bind-  ing (cementing) material, and by specific inhibitors of pro-  teolytic enzymes.”* Keloids first appear as pink or red, firm,  well-defined rubbery plaques that persist for several months  after trauma. Later, uncontrolled overgrowth causes extension  beyond the site of the original wound and the tumor becomes  smoother, irregularly shaped, hyperpigmented, and harder with  clawlike prolongations (Figure 46-4).   Keloids are the most extreme example of cutaneous scar-  ring and the most difficult to treat. Preventive measures such  as avoidance of unnecessary elective surgeries, recognition  of familial tendency, and early detection are of paramount    FIGURE 46-4 Keloid. (Courtesy Department of Dermatology, Schoo! of Medi-  cine, University of Utah.)    importance. Standard management of keloids and hypertrophic  scars includes intralesional corticosteroids, cryotherapy, radio-  therapy, and surgical/laser procedures whereas intralesional  injections of interferon, bleomycin, and 5-fluorouracil (5-FU)  are emerging treatments.’ There remains a need for research to  improve treatment outcome.*”*!    Pruritus, or itching, is the most common symptom associated  with many primary skin disorders, such as eczema, psoriasis, or  lice infestations, or it can be a manifestation of systemic disease  (e.g., xerosis, chronic renal failure, cholestatic liver disease, thy-  roid disorders, iron deficiency, neuropathies, or malignancy) or  drug reactions. Pruritus may be acute (e.g., mosquito bite) or  chronic, and may be localized or generalized and migratory.   Multiple stimuli can produce itching and there is interaction  between itch and pain sensations. Peripheral pruritogenic (itch)  mediators include histamine, neuropeptides, serotonin, prosta-  glandins, bradykinin, substance P, opioids, acetylcholine, inter-  leukin-31, and nerve growth factor. Itch sensation is thought to  be carried by specific unmyelinated C nerve fibers and thinly  myelinated Ad nerve fibers. Specific spinal pathways carry itch  sensations through the spinal cord to the brain.** These nerve  fibers also may interact with dermal eosinophils, lymphocytes,  and mast cells.**   Central nervous system mechanisms also can modulate itch-  ing, which is less perceptible when the mind is distracted by  other stimuli. How the central nervous system influences the  itch sensation is unclear. Neuropathic itch (itch without prurito-  genic stimuli) is related to pathology along an afferent pathway  (i.e., postherpetic neuropathy).** Psychogenic itch is associated  with psychologic disorders (e.g., depression and obsessive-  compulsive disorder).°°   Chronic itching is an unpleasant sensation that may or may  not be relieved by scratching—often done so intensely that  trauma to the skin occurs, resulting in infection, skin thicken-  ing (lichenification), and scarring. Both central and peripheral  sensitization occurs.°? Some individuals become so distraught  with the constant irritation that they apply heat and/or ice with  enough intensity and duration to produce skin injury. Manage-  ment of itching is challenging and depends on the cause; the  primary condition must be treated. Both topical and systemic  therapies are used.*°*”    FIGURE 46-5 Poison Ivy. A, Poison ivy on knee. B, Poison ivy dermatitis.  (Courtesy Department of Dermatology, School of Medicine, University of Utah.)    Disruptions in skin integrity may be precipitated by trauma,  abnormal cellular function, infection and inflammation, and  systemic diseases. Many skin disorders are benign and self-lim-  iting, whereas others are severe and life threatening.    The most common inflammatory disorder of the skin is  eczema, or dermatitis. Eczema and dermatitis are general terms  that describe a particular type of inflammatory response in  the skin—the terms can be used interchangeably. Eczematous  disorders are generally characterized by pruritus, lesions with  indistinct borders, and epidermal changes. These lesions either  can appear as erythema, papules, or scales or can present in an  acute, subacute, or chronic phase. Edema, serous discharge,  and crusting occur with continued irritation and scratching.  In chronic eczema the skin becomes thickened, leathery, and  hyperpigmented from recurrent irritation and scratching. The  location of eczema is related to the underlying cause. Eczema-  tous inflammations need to be differentiated from other der-  matoses, particularly psoriasis.    Allergic contact dermatitis is a common form of T-cell—medi-  ated or delayed hypersensitivity (type IV).°* (See Chapter 9  for various types of allergic responses.) Genetic susceptibility  involves several genes including loss-of-function mutations in  the gene encoding the epidermal protein filaggrin.*? Allergens  (e.g., microorganisms, chemicals, foreign proteins, drugs, met-  als, latex) can form the sensitizing antigen; contact with poi-  son ivy is a common example (Figure 46-5). The response is a    reaction to irritants with release of cytokines, chemokines, and  cytotoxins from keratinocytes, dendritic cells (Langerhans cells),  and natural killer cells. When the allergen comes into contact  with the skin the allergen is bound to a carrier protein, forming  a hapten-specific sensitizing antigen. Langerhans cells process  the antigen and carry it to T cells that then become sensitized to  the antigen, releasing cytokines and chemokines and leading to  leukocyte infiltration and inflammation.*° Latex allergy can be  either a type IV hypersensitivity reaction to chemicals used in  latex rubber processing or a type I immediate hypersensitivity  reaction with IgE antibodies formed in response to latex rubber  protein.*!   In delayed hypersensitivity, several hours pass before an  immunologic response is apparent. The T cells play an impor-  tant role because they differentiate and secrete lymphokines  that affect macrophage movement and aggregation, coagula-  tion, and other inflammatory responses (see Chapter 9). Sensi-  tization usually develops with first exposure to the antigen, and  symptoms of dermatitis occur with reexposure.   The manifestations of allergic contact dermatitis include ery-  thema and swelling with pruritic (itching) vesicular lesions in the  areas of allergen contact. The pattern of distribution provides  clues to the source of the antigen (e.g., hands exposed to chemi-  cal solutions or boundaries from rings and bracelets). Patch  tests with specific antigens may assist with diagnosis. Removal  of the allergen is necessary for resolution of the inflammatory  response and tissue repair. Topical or systemic steroids, as well  as other symptomatic treatment, may be required depending on  the severity of the lesion.”    Irritant contact dermatitis is a common nonimmunologically-  mediated inflammation of the skin. The intensity of the inflam-  mation is related to the concentration of the irritant, exposure  time, disruption of the skin barrier, and age.** Irritation can  occur from almost anything, especially if the epidermal barrier  is compromised in any way (Box 46-2). The skin lesions are  similar in appearance to allergic contact dermatitis. Removing  the source of irritation and using topical agents (i.e., corticoste-  roids and petroleum-based emollients) and nonirritating soaps  constitute effective treatment.    Atopic dermatitis (allergic dermatitis) is more common in  infancy and childhood; however, some individuals are affected  throughout life. See Chapter 47 for details.“4    Stasis dermatitis usually occurs on the legs as a result of venous  stasis and edema. The disorder is associated with varicosities  (incompetent venous valves), phlebitis, and vascular trauma.  Pooling of venous blood traps leukocytes that may release pro-  teolytic enzymes. Increased venous pressure widens interendo-  thelial pores with deposition of red blood cells, fibrin, and other  macromolecules, making them unavailable for repair and pro-  moting inflammation.*° Edema evolves to erythema and pruritus  with progression to scaling, petechiae, and hyperpigmentation.    Alkalis  Soaps  Detergents  Ammonia preparations  Lye  Drainpipe cleaners  Toilet bowl cleaners  Oven cleaners  Acids  Metal salts  Cyanides of calcium, copper, mercury, nickel, silver, zinc  Chlorides of calcium and zinc  Bromine, chlorine, iodine, fluorine  nsecticides  Herbicides  Dusts of lime, zinc, arsenic  Dyes and fragrances  Wood dust from teak, cinchona bark, quinine, pyrethrum  Tobacco dust from cigars  Explosive powders  Hydrocarbons  Crude petroleum, lubricating oil, cutting oil  Paraffins, mineral oils  Asphalt, other tar products  Soot, peat  Preservatives    *For chemicals that cause occupational allergic contact dermatitis see  National Library of Medicine: Haz-map Table 1: Chemicals that cause  occupational allergic contact dermatitis, Bethesda, MD, last updated  April 2013. Available at www.hax-map.com/allergic.htm.    FIGURE 46-6 Stasis Ulcer. (Courtesy Department of Dermatology, School of  Medicine, University of Utah.)    Progressive lesions become ulcerated (stasis ulcers), particularly  around the ankles and tibia (Figure 46-6).   Treatment includes elevating the legs as often as possible,  refraining from wearing tight clothes around the legs, and  avoiding standing for long periods. Defined infections are  treated with antibiotics. Chronic lesions with ulceration are  treated with moist dressings, external compression garments,  and vein ablation surgery.*°    FIGURE 46-7 Seborrheic Dermatitis. (Courtesy Department of Dermatology,  School of Medicine, University of Utah.)    Seborrheic dermatitis is a common chronic inflammation of  the skin involving the scalp, eyebrows, eyelids, ear canals, naso-  labial folds, axillae, chest, and back (Figure 46-7). In infants it  is known as cradle cap. The cause is unknown, but genetic pre-  disposition, the production of specific phospholipases from the  presence of Malassezia yeasts, and immune responses are impli-  cated.*”** The lesions appear from infancy to old age, with peri-  ods of remission and exacerbation. The lesions appear as greasy,  scaly, white, or yellowish inflammatory plaques in sebaceous  areas with mild pruritus. Mild cases are treated with shampoos  containing sulfur, salicylic acid, or tar. Ketoconazole has anti-  fungal and anti-inflammatory effects and has been used with  success along with topical calcineurin inhibitors. Corticosteroid  applications are useful for suppression of severe symptoms but  should not be used for maintenance therapy.”    Psoriasis, pityriasis rosea, and lichen planus are inflamma-  tory disorders characterized by papules, scales, plaques, and  erythema. Collectively they are described as papulosquamous  disorders.    Psoriasis is a chronic, relapsing, proliferative, inflammatory  disorder that involves the skin, scalp, and nails and can occur at  any age. The disease affects about 1% to 8% of the world popu-  lation and is more common in countries north of the equator.°°  The onset is generally established by 20 years of age. A family  history of psoriasis is common. The genetic mechanisms are  complex and the human leukocyte antigen (HLA)-Cwé allele  (PSORS1) is a major susceptibility gene that affects skin bar-  rier function and innate immune responses.*! Psoriasis is a T  helper (Th) cell-mediated autoimmune disease. The interleu-  kin (IL)-23/T helper (Th) 17 cell axis plays an important role  in the pathogenesis of psoriasis.°* Inflammatory cytokines  involved include tumor necrosis factor-alpha (TNF-a), inter-  feron-gamma (IFN-y), IL-6, IL-12, IL-15, IL-17, IL-20, IL-21,  and IL-22 derived from activated T cells, B cells, dendritic cells,  and macrophages.”   The dermis and epidermis are thickened with keratino-  cyte hyperproliferation, altered keratinocyte differentiation,  expanded dermal vasculature, infiltration of neutrophils and    FIGURE 46-8 Psoriasis. Typical oval plaques with well-defined borders and  silvery scale. (Courtesy Department of Dermatology, School of Medicine, University  of Utah.)    lymphocytes, and inflammation.™* The turnover time for shed-  ding the epidermis is decreased from the normal 26 to 30 days  to 3 to 4 days. There are increased numbers of germinative cells  and an increase in transit time of cells through the dermis. The  rapid cellular proliferation does not allow time for cell matura-  tion and keratinization to occur, resulting in a thickened epi-  dermis and plaque formation. The loosely cohesive keratin  gives the lesion a silvery, scaly appearance. There is often cap-  illary dilation and increased vascularization to accommodate  the increased cell metabolism. The increased vascularity causes  erythema.   The types of psoriasis include plaque (psoriasis vulgaris),  inverse, guttate, pustular, and erythrodermic. Plaque psoriasis  is the most common and affects 80% to 90% of individuals with  psoriasis. The disease can be mild, moderate, or severe, depend-  ing on the size, distribution, and inflammation of the lesions.  Early onset psoriasis is an inflammatory lesion with epidermal  hyperproliferation and the presence of activated T lymphocytes.  The typical lesion of plaque psoriasis is a well-demarcated,  thick, silvery, scaly, erythematous plaque surrounded by nor-  mal skin (Figure 46-8). Initial lesions usually develop insidi-  ously as small erythematous papules that enlarge and coalesce  into larger inflammatory lesions that can be painful. The lesions  are commonly located on the scalp, elbows, and knees and at  sites of trauma. The scales are usually loosely adherent and  may cause small bleeding points when removed. Inverse psoria-  sis is rare and involves lesions that develop in skinfolds (i.e.,  axilla or groin). They are large, smooth, dry, and deep red. The  clinical course of psoriasis is characterized by remissions and  exacerbations. Psoriasis may be triggered by drugs including  antimalarials, lithium, nonsteroidal anti-inflammatories, and  beta-blockers.°°   In guttate psoriasis, small papules (1 to 10 mm) appear sud-  denly on the trunk and extremities (Figure 46-9). The lesions  may appear a few weeks after a streptococcal respiratory tract  infection and are more common in children. Guttate psoria-  sis may resolve spontaneously in weeks or months. Pustular  psoriasis appears as blisters of noninfectious pus (collections  of neutrophils) that develop over areas of plaque psoriasis.    FIGURE 46-9 Guttate Psoriasis after Streptococcal Infection. Numerous  uniformly small lesions may abruptly occur after streptococcal pharyngitis. (Cour-  tesy Department of Dermatology, School of Medicine, University of Utah.)    Erythrodermic (exfoliative) psoriasis is characterized by wide-  spread red, scaling lesions that cover a large body surface area  (BSA) and is often accompanied by itching or pain associated  with constitutional symptoms (fever, chills, fatigue) and skin  infections.   Psoriatic arthritis (PsA) and ankylosing spondylitis are  associated with the proinflammatory cytokines that cause pso-  riatic skin lesions. Joints of the hands, feet, knees, and ankles  are involved, and 5% to 50% of individuals with psoriasis have  seronegative joint involvement. Psoriatic arthritis mutilans  involves pronounced bone destruction and there is greater risk  of cardiovascular disease with PsA.°°°’ Psoriatic nail disease  can occur in all psoriasis subtypes with pitting, onycholysis,  subungual hyperkeratosis, and nail plate dystrophy. Psoriasis  also is a risk factor for a number of comorbidities including  inflammatory bowel disease; metabolic syndrome, including  hypertension insulin resistance, dyslipidemias, and abdominal  obesity; and increased risk for atherosclerosis and cardiovas-  cular disease that is independent of traditional risk factors for  these diseases.°*°?   Treatment is individualized and related to maintaining skin  moisture, reducing epidermal cell turnover and itching, and  improving immunomodulation. Mild lesions are usually treated  with emollients, keratolytic agents, and corticosteroids. Mod-  erate lesions may respond to UVB light, tar preparations, or a  combination of both, and to methotrexate, cyclosporine A, and  acitretin. Moderate to severe disease is responsive to the photo-  sensitizing agent oral psoralen in combination with UVA light  (PUVA), although skin cancer risk (melanoma and squamous  cell) with cumulative dose remains a valid concern.® Vitamin  D; (calcitriol) is used to reduce epidermal proliferation. Mod-  erate to severe disease is the indication for biologic treatment  including TNF-a blockers (adalimumab, etanercept, inflix-  imab) and interleukin (IL)-12/-23 inhibitors (ustekinumab).  Clinical trials are evaluating new agents.°!°    Pityriasis rosea is a benign self-limiting inflammatory disorder  that occurs more often in young adults, with seasonal peaks in  the spring and fall. This is a benign disorder except when con-  tracted during pregnancy, when risks are increased for miscar-  riage and premature delivery.®? The cause is unknown but is    FIGURE 46-10 Pityriasis Rosea Herald Patch. A collarette pattern has  formed around the margins. (Courtesy Department of Dermatology, School of Medi-  cine, University of Utah.)    thought to be associated with a virus (e.g., human herpesvirus 6  [HHV-6] and HHV-7) because of the timing and clustering of  the outbreaks.™ Pityriasis rosea begins as a single lesion known  as a herald patch (Figure 46-10) that is circular, demarcated,  and salmon-pink; is approximately 3 to 4 cm in diameter; and is  usually located on the trunk. Early lesions are macular and pap-  ular; secondary lesions develop within 14 to 21 days and extend  over the trunk and upper part of the extremities. Lesions are  rarely located on the face. They emerge as small erythematous  papules that expand into characteristic oval lesions. There may  be few or hundreds of lesions. The pattern of distribution fol-  lows the skin lines around the trunk and resembles a drooping  pine tree. As scales flake off from the margin of the lesions, a  collarette pattern is formed. Itching is the most common symp-  tom. Headache, fatigue, or sore throat may precede the devel-  opment of the lesions.   The diagnosis of pityriasis rosea is made by the clinical  appearance of the lesion. Secondary syphilis, psoriasis, drug  eruption, nummular eczema, and seborrheic dermatitis are  among the differential diagnosis considerations. The disorder  is usually self-limiting and resolves in a few months with symp-  tomatic treatment for pruritus or cosmetic concerns. UV light  (with some risk for hyperpigmentation), antihistamines, or  topical corticosteroids may be used to control itching. Erythro-  mycin and acyclovir also may be used for treatment.”   Lichen planus (LP) is a benign, autoimmune inflammatory  disorder of the skin and mucous membranes with multiple  clinical variations. The cause is unknown, but T cells, adhe-  sion molecules, inflammatory cytokines, perforin, and antigen-  presenting cells are involved.® The infiltrate of T cells mediates  immunoreactivity against basal layer keratinocytes, which have  altered surface antigens and adhesion molecules.” LP is also  linked to hepatitis C virus. Some individuals develop lichen-  oid lesions after exposure to drugs or film-processing chemi-  cals. The age of onset is usually between 30 and 70 years. The  disorder begins with flat purple, polygonal, pruritic, nonscal-  ing papules 2 to 4 mm in size, usually located on the wrists,  ankles, lower legs, and genitalia (Figure 46-11). New lesions are  pale pink and evolve into a dark violet. Persistent lesions may  be thickened and red, forming hypertrophic LP. Oral lesions    FIGURE 46-11 Hypertrophic Lichen Planus on Arms. (Courtesy Department  of Dermatology, School of Medicine, University of Utah.)    (oral lichen planus) appear as lacy white rings that must be dif-  ferentiated from leukoplakia or oral candidiasis and they may  be precancerous lesions.®* Fine white lines, known as Wickham  striae, can be seen throughout the oral lesions on magnification.  These lesions also can develop on the penis and vulvovaginal  area. More commonly, oral lesions do not ulcerate, but local-  ized or extensive painful ulcerations do, and frequently, occur.  Chronic ulcerated lesions become malignant in 1% of individu-  als with the disease. Thinning and splitting of nails are com-  mon, and part or all of the nail may be shed.   Pruritus is the most distressing symptom. The lesions are  self-limiting and may last for months or years, with an average  duration of 6 to 18 months. Postinflammatory hyperpigmen-  tation is a common consequence of the lesion. Approximately  20% of individuals have a recurrence. Diagnosis is commonly    made by the clinical appearance of the lesion; however, his-  topathologic diagnosis is recommended. For cutaneous LP,  treatment is individualized and includes topical, intralesional,  or systemic corticosteroids (second line for resistant LP), and  systemic acitretin with/without adjuvant light therapy. Anti-  histamines are given for itching, and topical or systemic cor-  ticosteroids may be used to control inflammation. Short-term  systemic glucocorticoids are indicated if oral lesions are severe  or for LP involving three or more nails. Mucous membrane  lesions are treated with potent topical steroids, topical reti-  noids, and systemic glucocorticoids.°”*”!    Acne vulgaris is an inflammatory disorder of the pilosebaceous  follicle (the sebaceous gland contiguous with a hair follicle).  It occurs most commonly during adolescence. Details of this  disorder are presented in Chapter 47. Hidradenitis suppura-  tiva (inverse acne) is summarized in What’s New? Hidradenitis  Suppurativa (Inverse Acne).    Acne rosacea is a chronic, readily exacerbated, inflammatory  skin disease with varied presentations and extent of involve-  ment that develops primarily in middle-age adults. There are  four types of lesions: erythematotelangiectatic, papulopustular,  phymatous, and ocular.’”* They occur in the middle third of the  face, including the forehead, nose, cheeks, and chin (Figure  46-12). The cause is unknown, but immune-mediated inflam-  mation may be a factor. The lesions are associated with chronic,    Hidradenitis suppurativa (inverse acne) is a chronic, inflammatory, recurring,  scarring disease of the pilosebaceous follicular ducts involving areas of skin  where there are folds, hair follicles, and apocrine (sweat) glands (i-e., axillary,  inguinal, inframammary, genital, buttocks, and perineal areas of the body) (see  figure). The incidence is unknown but estimated at 1% to 4% of the population  and is more common in females. The pathogenesis of the disease is complex and  includes a combination of genetic, hormonal, immune, and environmental fac-  tors. Aggravating factors include tight clothing, heat and perspiration, obesity,  stress, and smoking. Follicular hyperkeratosis and occlusion obstructs the pilose-  baceous unit, causing perifolliculitis, abscess formation, sinus tracts, and scar-  ring. Bacterial infection is a secondary event. The lesions present as deep, firm,  painful subcutaneous nodules that track and rupture horizontally under the skin.  They are differentiated from “boils” (carbuncles) because boils extend vertically  and discharge onto the skin. Diagnosis can be difficult, delaying effective treat-  ment. Treatment can include administering systemic medications, performing  incision and drainage of nodules, obtaining a culture of the exudate, and giving  antibiotics, with concern about the presence of methicillin-resistant Staphylo-  coccus aureus (MRSA), topical or intralesional corticosteroids, and retinoids.  Lesions often require surgical excision and skin grafting. Complete, spontane-  ous resolution is rare. Deterrence includes avoiding heat and perspiration, losing  weight if obese, wearing loose clothing, refraining from shaving affected areas,  stopping smoking, and using zinc gluconate supplements to reduce inflammation.    The disease can recur for years with negative effects on quality of life. Clinical  trials are needed to identify the best treatment options.    A, Characteristic painful pustules and draining sinus tracts. B, Histology shows  follicular plugging and connection to a dilated apocrine duct. (A courtesy Kalman  Watsky, MD; from Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology, ed 3, Phila-  delphia, 2012, Saunders. B from Bolognia JL, Jorizzo JL, Rapini RP: Dermatology,  ed 2, Philadelphia, 2008, Saunders.)    Data from Alikhan A, Lynch PJ, Eisen DB: J Am Acad Dermatol 60(4):539-561, 2009; Bieniek A et al: Dermatol Surg 36(12):1998-2004, 2010; Danby FW,  Margesson LJ: Dermatol Clin 28(4):779-793, 2010; Danby FW et al: Br J Dermatol 168(5):1034-1039, 2013; Yazdanyar S, Jemec GB: Curr Opin Infect Dis    FIGURE 46-12 Rosacea. Pustules and erythema occur on the forehead,  cheeks, and nose. (Courtesy Department of Dermatology, School of Medicine, Uni-  versity of Utah.)    inappropriate vasodilation resulting in flushing and sensitivity  to the sun. Sebaceous hypertrophy, fibrosis, and telangiecta-  sia may be severe enough to produce an irreversible bulbous  appearance of the nose, known as rhinophyma. The vascular  abnormalities induce local production of transforming growth  factor-61 (TGF-B1) capable of creating fibrosis and, there-  fore, cutaneous thickening.”> Demodex folliculorum (mites)  infection may be a contributing factor.”* Disorders of the eye  often accompany rosacea, particularly conjunctivitis and, more  rarely, keratitis, which can result in visual impairment.” Facial  application of fluorinated topical steroids may precipitate rosa-  cea-like lesions that are difficult to treat.   Hot drinks or alcohol should be taken cautiously because the  heat and vasodilation accentuate erythema. Daily use of photo-  protection, including sunscreens, is recommended; both topi-  cal (metronidazole, azelaic acid) and oral drugs (tetracyclines)  may be effective.”° Surgical excision of excessive tissue may be  required for rhinophyma.    Lupus erythematosus is an inflammatory, autoimmune, sys-  temic disease with cutaneous manifestations. Discoid (or cuta-  neous) lupus erythematosus (DLE) is limited to the skin and  can progress to systemic lupus erythematosus (SLE). DLE may  be described as a subset of SLE, with cutaneous manifestations  as the only symptom”’ (Figure 46-13). (SLE, a diffuse, multisys-  tem disease that also has cutaneous manifestations, is discussed  in Chapter 9.)   Discoid (Cutaneous) Lupus Erythematosus. Discoid  (cutaneous) lupus erythematosus (DLE) usually occurs in  genetically susceptible adults, particularly in women in their  late thirties or early forties. There are three forms of the disease:  acute, subacute, and chronic. The lesions may be single or  multiple and of various sizes. Often the lesions are located on  light-exposed areas of the skin, and photosensitivity is common.  The face is the most common site of lesion involvement. The  characteristic manifestations of the different categories of DLE  are summarized in Table 46-6.   The cause is unknown but thought to be related to genetic  and environmental factors and an altered immune response to    FIGURE 46-13 Subacute Cutaneous Lupus (Discoid Lupus Erythema-  tosus). (Courtesy Department of Dermatology, School of Medicine, University of  Utah.)    an unknown antigen or response to UV wavelengths with the  development of self-reactive T and B cells, decreased number  of regulatory T cells, and increased proinflammatory cytokines.  Autoantibodies and immune complexes cause tissue damage.”®   Diagnosis of DLE is made from the presenting symptoms,  biopsy of skin lesions with direct immunofluorescence, as well  as histologic results. Skin biopsy with immunofluorescent  observation reveals lumpy deposits of immunoglobulins, espe-  cially IgM and C3.”” DLE can progress to systemic lupus erythe-  matosus and individuals with SLE should be regularly screened  for this progression.®°   Individuals with DLE must use sunscreen and sun protec-  tion because direct sun exposure initiates or exacerbates lesions.  Treatment options include topical steroids, calcineurin inhibi-  tors, antimalarial drugs (e.g., hydroxychloroquine sulfate), and  immunosuppressors. These medications must be used with  caution to prevent serious side effects.*!    Vesiculobullous skin diseases share a common characteristic of  vesicle, or blister, formation. Two such diseases are pemphigus  and erythema multiforme.   Pemphigus (meaning to blister or bubble) is a rare autoim-  mune blistering disease of the skin and oral mucous membranes  caused by circulating autoantibodies directed against the cell  surface adhesion molecule desmoglein at the desmosomal cell  junction in the suprabasal layer of the epidermis. Pemphigus    Butterfly pattern of erythema over bridge of nose and malar areas of face (malar rash); may have fine surface scales and underlying  edema; scalp areas may develop alopecia; lasts for hours to days    Diffuse or papular erythema of face, upper trunk, or extremities; develops quickly and lasts hours to days  Erythematous macules and papules that evolve into papu/osquamous or annular plaques developing on sun-exposed areas of the    upper body (V area of neck, upper chest, back, shoulders, extensor surface of arms and hands); can be associated with reaction to  drugs; may be accompanied by mild systemic disease    Classic discoid lupus erythematosus is the most common form; lesions are red to purple macules or papules with a superficial    brownish scale; scale can penetrate hair follicle leaving a carpet-tack appearance when removed; may have residual scarring,  dermal atrophy hypopigmentation, alopecia, and telangiectasia; Raynaud phenomenon occurs in some individuals    Data from Kuhn A, Biji M: Lupus 17(5):389-393, 2008; Rothfield N, Sontheimer RD, Bernstein M: Clin Dermatol 24(5):348-362, 2006; Uva L    can occur in all age groups but is more prevalent between 40  and 50 years of age. There is a genetic predisposition as well as  environmental triggers, most of which are unknown.*? Pemphi-  gus presents in varying forms:   * Pemphigus vulgaris is the most common form with  acantholysis at the suprabasal level. Immunoglobulin G  (IgG) autoantibodies and C3 complement bind to the  desmoglein adhesion molecules, resulting in the destruc-  tion of cell-to-cell adhesion (acantholysis) in the epider-  mis with fluid accumulation and the resulting symptom  of blister formation.*’ Oral lesions precede the onset of  skin blistering, which is more prominent on the face,  scalp, and axilla. The blisters rupture easily because of  the thin, fragile overlying portion of epidermis, resulting  in painful erosions. Pemphigus vegetans is a rare variant  of pemphigus vulgaris with large blisters that progress to  hypertrophic granulomas with tissue erosion and pustules  (vegetating plaques). They usually occur in tissue folds.   + Pemphigus foliaceus is a milder form of the disease and  involves acantholysis at the subcorneal level with blister-  ing, erosions, scaling, crusting, and erythema usually of  the face and chest. Oral mucous membranes are rarely  involved. Pemphigus erythematosus is a subset of pemphi-  gus foliaceus often associated with systemic lupus erythe-  matosus with positive antinuclear antibodies. The lesions  are generally less widely distributed.   + Paraneoplastic pemphigus is the most severe form of  pemphigus and is associated with lymphoproliferative  neoplasms. Internal organs, including lungs, thyroid,  kidney, smooth muscle, and the gastrointestinal tract,  also are involved, leading to the term paraneoplastic auto-  immune multiorgan syndrome. In contrast to pemphigus  vulgaris, the lesions develop from inflammatory papules  or macules rather than normal skin.**   + IgA pemphigus is the most benign form of pemphigus  characterized by tissue-bound and circulating IgA anti-  bodies targeting desmosomal or nondesmosomal cell  surface components in the basement membrane of the  epidermis. Acantholysis is not as severe as that in pem-  phigus vulgaris but there is still blister formation.*°    The diagnosis of pemphigus is made from the clinical mani-  festations and histologic examination of the skin. Immunofluo-  rescence demonstrates the presence of antibodies at the site of  blister formation. The clinical course of the disease may range  from rapidly fatal to relatively benign. The primary treatment  for pemphigus is systemic corticosteroids in combination with  adjuvant immunosuppressants and, in difficult cases, adjuvant  protein A immunoadsorption intravenous immunoglobulins,  plasmapheresis, and anti-CD20 monoclonal antibody therapy.  Newer methods of treatment and a clearer understanding of  the pathogenesis have improved the prognosis and decreased  mortality.®*°    Bullous pemphigoid (BP) is a more benign autoimmune disease  than pemphigus vulgaris, with blistering of the subepidermal  skin layer. Autoantibodies (IgG and IgE) to hemidesmosomal  proteins designated BP 180 and BP 230 have been found. There  are numerous triggers, including drugs and skin trauma. The  autoantibodies activate complement with inflammatory infil-  tration of neutrophils, eosinophils, and lymphocytes. Loss of  dermal-epidermal adhesion is caused by inflammatory cyto-  kines.*”° The lesions of pemphigoid begin with localized  erythema or as pruritic plaques that extend and become edem-  atous. The plaques turn reddish purple by 2 to 3 weeks, with  vesicles and bullae emerging on the surface (Figure 46-14). Oral  lesions can occur. The bullae do not extend with pressure. The  blisters rupture within 1 week and heal rapidly. BP occurs more  commonly after 60 years of age.   Diagnosis is by skin biopsy and immunofluorescent exami-  nation. The presence of subepidermal blistering and eosino-  phils distinguishes pemphigoid from pemphigus. Treatment  usually includes hydroxyzine (Atarax) for itching and topical or  systemic corticosteroids. Adjuvant immunosuppressive drugs  may be prescribed. Relapse may occur with discontinuation of  treatment.*?,”°    Erythema multiforme is not a single disease but rather a syn-  drome characterized by inflammation of skin and mucous    FIGURE 46-14 Bullous Pemphigoid. Generalized eruption with blisters aris-  ing from an edematous, erythematous annular base. (Courtesy Department of Der-  matology, School of Medicine, University of Utah.)    membranes. It often is associated with a T-cell—mediated  immunologic reaction to microorganisms (e.g., herpes simplex  virus, Mycoplasma pneumoniae) or a toxic reaction to drugs in  which TNF-a causes tissue damage.”! Overall, it is relatively  rare and can occur at any age but is more common between  20 and 40 years of age. Immune complex formation and depo-  sition of complement (C3), IgM, and fibrinogen around the  superficial dermal blood vessels, basement membrane, and  keratinocytes are found in most individuals with erythema mul-  tiforme. Edema develops in the superficial dermis, leading to  the formation of vesicles and bullae. The lesions vary in clinical  presentation and may involve the skin or mucous membranes,  or both. The characteristic “bull’s-eye” or “target” lesions occur  on the skin surface with a central dusky region surrounded by  concentric rings or alternating edema and inflammation.”””°  The lesions usually occur suddenly in groups over 2 to 3 weeks.  Urticarial plaques, 1 to 2 cm in diameter, can develop with-  out the target lesion. A vesiculobullous form is characterized  by mucous membrane lesions and erythematous plaques over  elbows and knees. Single or multiple vesicles or bullae may arise  on a part of the plaque, accompanied by pruritus and burning.  In the minor form, there may be tens to hundreds of lesions.”*  The lesions heal within 3 to 4 weeks (Figure 46-15).   Prodromal symptoms of erythema multiform include fever,  headache, malaise, sore throat, and cough in approximately  one third of cases. The bullous lesions form erosions and crusts  when ruptured. The mouth, air passages, esophagus, urethra,  and conjunctiva may be involved when mucous membranes are  affected. Blindness can result from corneal ulcerations. Diffi-  culty with eating, breathing, and urinating may develop with  severe manifestations. Severe forms of the disease can be fatal.   Diagnosis is made by medication history, by recognition of  the target lesion, or by skin biopsy to establish the diagnosis.  Mild, acute forms of the disease last 10 to 14 days, are usu-  ally self-limiting, and require no treatment. Any ongoing drug  therapy should be withdrawn or reevaluated and underlying  infections treated. Treatment is individualized according to  severity.”> Antiviral prophylaxis may be required. Fluid and  electrolyte balance should be monitored in severe forms of the  disease, and mucous membranes must be carefully managed  with a bland diet, warm saline eyewashes, topical anesthetics, or  corticosteroids to maintain comfort and prevent infection. Use    FIGURE 46-15 Erythema Multiforme Caused by Doxepin. (Courtesy  Department of Dermatology, School of Medicine, University of Utah.)    of systemic steroids is controversial. Cutaneous blisters can be  treated with wet compresses of nanocrystalline silver. Ophthal-  mic, kidney, and lung involvement requires special care. Reso-  lution occurs in 8 to 10 days, usually without scarring. Mucosal  lesions may take 6 weeks to heal.?°    Cutaneous infections are common forms of skin disease. They  generally remain localized; however, serious complications can  develop with systemic involvement. The types of skin infec-  tion include bacterial, viral, and fungal. Most infections occur  superficially; however, systemic signs and symptoms occasion-  ally develop and rarely become life threatening. Aerobes, yeast,  and anaerobes comprise the normal flora of the skin and often  provide protection against pathogens that cause skin infections,  including Staphylococcus and Streptococcus.    Most bacterial infections of the skin are caused by local inva-  sion of pathogens. Coagulase-positive Staphylococcus aureus  and, less often, beta-hemolytic Streptococci are the common  causative microorganisms. Community-acquired methicillin-  resistant Staphylococcus aureus (CA-MRSA) is also a cause of  serious skin infection (Box 46-3).   Folliculitis. Folliculitis is an infection of the hair follicle  and can be caused by bacteria, viruses, or fungi. S. aureus is a  common causative microorganism.” The infection develops  from proliferation of the microorganism around the opening  of the follicle and then spreads into the follicle. Inflammation is  caused by the release of chemotactic factors and enzymes from  the bacteria. The lesions appear as pustules with a surrounding  area of erythema. They are most prominent on the scalp and  extremities and rarely cause systemic symptoms. Prolonged  skin moisture, occlusive clothing, topical agents, skin trauma  (e.g., shaving facial hair), and poor hygiene are associated  contributing factors to the development of folliculitis. Cleaning  with soap and water and topical application of antibiotics are  effective forms of treatment.   Furuncles and Carbuncles. A furuncle, or “boil,” is an  inflammation of the hair follicles that may develop from a  preceding folliculitis and spread through the follicular wall  into the surrounding dermis. The invading microorganism is    CA-MRSA is a serious skin and soft tissue infection that includes abscesses, cel-  lulitis, and necrotizing fasciitis, and can serve as a source for bloodstream infec-  tions. Infections are documented among healthy individuals who have no known  risk factors, that is, no recent hospitalization, surgical procedures, or prolonged  antibiotic treatment. Outbreaks have been documented among athletic teams,  among prisoners, and in daycare centers. CA-MRSA strains are epidemiologically  and clonally different from hospital- or nursing home—acquired MRSA. The most  common tests involve genotyping for the staphylococcal chromosomal cassette  mec (SCCmec) type IV and Panton-Valentine leukocidin genes. The USA300-0114  strain has been epidemic in the United States. It also has caused life-threatening  pneumonia, osteomyelitis, and septic arthritis and is spreading internationally.    CA-MRSAs are more sensitive to antibiotic treatment and there is a wider choice  of antibiotic treatment options for CA-MRSA compared with hospital-acquired  MRSA. CA-MRSA is usually susceptible to a variety of oral non—beta-lactam  antibiotics, including trimethoprim-sulfamethoxazole, clindamycin, tetracyclines,  and linezolid. Parenteral therapy with vancomycin or daptomycin also can be  considered. Ceftaroline has been effective for both skin and systemic infections.  Mupirocin may be used to clear MRSA from nasal secretions if cultures show  contamination in the nose. New drugs are under investigation. Preventive mea-  sures include practicing good hand hygiene, applying antiseptics and covering  cuts and abrasions, using antibacterial soaps for showers after contact sports,    Data from Casapao AM et al: Expert Opin Pharmacother 13(8):1177-1186, 2010; Nimmo GR: Clin Microbiol Infect 18(8):725-734, 2012; Tattevin P  et al: Clin Infect Dis 55(6):781-788, 2012; Tonn K, Ryan TJ: J Environ Health 75(6):44-49, 2013; Watkins RR, David MZ, Salata RA: J Med Microbiol    FIGURE 46-16 Furuncle on the Forearm. (Courtesy Department of Dermatol-  ogy, School of Medicine, University of Utah.)    usually S. aureus, including community-associated methicillin-  resistant S. aureus (CA-MSRA). The infecting strain may spread  to the skin from the anterior nares. Any skin area with hair can  be infected, and one or several lesions may be present. The  precipitating events are similar to those for folliculitis. The initial  lesion is a deep, firm, red, painful nodule 1 to 5 cm in diameter  (Figure 46-16). Within a few days the initial erythematous  nodule changes to a large fluctuant and tender cystic nodule  that may be accompanied by cellulitis. No systemic symptoms  are present, and the lesion may drain large amounts of pus and  necrotic tissue.”°   A carbuncle is a collection of infected hair follicles occur-  ring most often on the back of the neck, the upper back, and  the lateral thighs. The lesion begins in the subcutaneous tissue  and lower dermis as a firm mass that evolves into an erythema-  tous, painful, swollen mass that drains through many openings.  Abscesses may develop. Chills, fever, and malaise are systemic  symptoms that can occur during the early stages of lesion  development.   Furuncles and carbuncles are treated with warm compresses  to provide comfort and promote localization and spontane-  ous drainage. Abscess formation requires incision and drainage  and recurrent infections, extensive lesions, or those associated   Cellulitis. Cellulitis is an infection of the dermis and  subcutaneous tissue usually caused by Staphylococcus,  CA-MRSA, or group B streptococci. Cellulitis can occur as  an extension of a skin wound, of an ulcer, or from furuncles  or carbuncles. It can be associated with chronic venous  insufficiency and stasis dermatitis. Risk factors include diabetes  mellitus, edema, peripheral vascular disease, tinea pedis,  insect bites, and immune suppression. The infected area is  erythematous, warm, swollen, and painful and can extend to  lymph nodes and the blood. Initial systemic treatment with  antibiotics should cover both Staphylococci and Streptococci,  and Burrow soaks can be used to relieve pain. Corticosteroids  are used for adjuvant therapy.””   Cellulitis must be differentiated from necrotizing fasciitis.  Necrotizing fasciitis is a rare, rapidly spreading inflammation  starting in the fascia, muscles, and subcutaneous fat with subse-  quent necrosis of the overlying skin; it is treated with antibiotics  and often requires surgical débridement.”®   Erysipelas. Erysipelas is an acute superficial infection  of the upper dermis (a superficial form of cellulitis) most  often caused by Streptococcus pyogenes, beta-hemolytic  streptococci, and Staphylococcus aureus. The face, ears, and  lower legs are common sites of involvement, and the site  of initial infection may not be identified. Chills, fever, and  malaise precede the onset of lesions by 4 hours to 20 days.  The initial lesions appear as firm, red spots that enlarge  and coalesce to form a clearly circumscribed, advancing  edge, bright red, hot lesion with a raised border. Vesicles  may appear over the lesion and at the border, producing a  bullous form of the disease. Itching, burning, and tenderness  accompany the development of the lesion. Cold compresses  provide symptomatic relief, and systemic antibiotics are  required to arrest the infection.”   Impetigo. Impetigo, most common in children, is a  superficial lesion of the skin caused by coagulase-positive  Staphylococcus aureus or alpha-hemolytic streptococci! (see  Chapter 47).    FIGURE 46-17 Herpes Simplex. Typical presentation with tense vesicles  involving the nasal mucosa and extending onto the skin. (From Habif TP: Clinical  dermatology: a color guide to diagnosis and therapy, ed 4, Philadelphia, 2004,  Mosby.)   Herpes Simplex Virus. Skin infections with herpes simplex  virus (HSV) are commonly caused by two types: HSV-1 and  HSV-2. Either type can occur in different parts of the body,  including oral and genital locations. Their differences are  distinguished by laboratory tests. HSV-1 is generally associated  with oral infections (cold sore or fever blister) or infection of the  cornea (herpes keratitis) but it also can cause genital herpes.!°!  HSV-1 is usually transmitted by contact with infected saliva.  With primary infection, the virus infects epithelial cells and  moves by retrograde axonal transport to the dorsal root ganglion,  where the virus develops lifelong latency. The incubation  period ranges from 2 to 14 days. During the secondary phase,  the lesions occur at the same site from reactivation of the virus.  The virus travels down the peripheral nerve to the site of the  original infection, where it is shed. Exposure to ultraviolet light,  skin irritation, fever, fatigue, or stress may cause reactivation.   The lesions for HSV-1 appear as a rash or clusters of inflamed  and painful vesicles (e.g., within the mouth, over the tongue,  on the lips, within and/or around the nose) (Figure 46-17).  Increased sensitivity, paresthesias, and mild burning often  occur before onset of the lesions. The vesicles rupture, form-  ing a crust. Lesions may last from 2 to 6 weeks. Treatment is  symptomatic and includes topical antiviral agents; lesions usu-  ally resolve within 2 weeks. Oral antivirals may be indicated at  the time of acute infection or through daily suppressive dosing  to prevent acute infections. !"   Genital infections are more commonly caused by HSV-2.  The virus is spread by skin-to-skin mucous membrane con-  tact during viral shedding. Risk of infection is high after sexual    FIGURE 46-18 Herpes Zoster. Diffuse involvement of a dermatome. (Cour-  tesy Department of Dermatology, School of Medicine, University of Utah.)    contact with infected individuals and for those who are immu-  nosuppressed and there is increased risk for human immuno-  deficiency virus (HIV) infection. Vertical transmission from  mother to neonate is associated with significant neonatal neu-  rologic morbidity and mortality.!°° The primary infection is  asymptomatic. With recurrent exposure, the lesions begin as  small vesicles that progress to ulceration within 3 to 4 days  with pain, itching, and weeping. Treatment is symptomatic and  includes topical or oral antiviral agents. Efforts are in progress  to develop prophylactic vaccines.!%   Herpes Zoster and Varicella. Herpes zoster (shingles) and  herpes varicella (chickenpox, see Chapter 47) are caused by  the same herpes virus—varicella-zoster virus (VZV). VZV  is the primary infection followed years later by herpes zoster  (shingles) from reactivation of the virus, particularly among  those who are immunosuppressed.!°° It can cause severe disease  in nonimmune pregnant women. Following the primary  infection the virus remains latent in trigeminal and dorsal root  ganglia.   Herpes zoster has initial symptoms of pain and paresthe-  sia localized to the affected dermatome (the cutaneous area  innervated by a single spinal nerve; see Chapter 15), followed  by vesicular eruptions along a facial, cervical, or thoracic lum-  bar dermatome (Figure 46-18). Some individuals have vesicles  scattered outside the area of the dermatome but lesions do not  usually cross the midline. Local symptoms are alleviated with  compresses, calamine lotion, or baking soda. Persistent pain  may last for weeks or months and is a debilitating complication,  particularly in older adults, and requires treatment. Approxi-  mately 15% to 20% of individuals experience postherpetic neu-  ralgias.'°° There is no cure for herpes zoster. Antiviral drugs are  useful if used within the first 72 hours.!°” Treatment includes a  topical lidocaine patch, anticonvulsant medication, controlled-  release narcotics, tricyclic antidepressants, and topical capsa-  icin.!°° Because older adults are at increased risk due to declining  immunocompetence, the live-attenuated varicella vaccine is rec-  ommended for those older than age 60 as it is well tolerated and  effective and may boost humoral and cellular immunity.!0%!!°   Warts. Warts (verrucae) are benign lesions of the skin  caused by the many different types of human papillomavirus  (HPV) that infect the stratified epithelium of skin and mucous    FIGURE 46-19 Verruca Vulgaris. (Courtesy Department of Dermatology,  School of Medicine, University of Utah.)    membranes. Specific viruses are associated with specific kinds  and locations of lesions.'!! The lesions are round and elevated  with a rough, grayish surface; can occur anywhere on the skin;  and are transmitted by touch. Common warts (verrucae vulgaris)  occur most often in children and are usually on the fingers,  although they may be located on any skin surface or mucous  membrane. Warts vary in shape, size (flat, round, or fusiform),  and location (Figure 46-19). Plantar warts are usually located at  pressure points on the bottom of the feet.   Diagnosis of warts is by visualization. Treatment considers  age of the individual and size and location of the lesion. Warts  can be removed by freezing with liquid nitrogen, electrocau-  terization, vaporization with lasers, application of keratolytics,  or application of irritants and corrosives such as salicylic acid,  formaldehyde, interferons, or podophyllum.'!* Recalcitrant  warts may benefit from application of topicals such as imiqui-  mod 5% cream (immunomodulatory) or 5-fluorouracil, by  intralesional injections of bleomycin or Candida (immunotre-  active antigen), or by more aggressive surgical procedures.!!°  Many warts resolve spontaneously but often recur.   Condylomata acuminata (venereal warts) are highly con-  tagious and sexually transmitted. The cauliflower-like lesions  occur in moist areas along the glans of the penis, vulva, and  anus (see Chapter 26). Oncogenic HPV (e.g., types 16 and 18) is  a primary cause of cervical cancer (see Chapter 24).    The fungi causing superficial skin infections are called derma-  tophytes, and they thrive on keratin (stratum corneum, hair,  nails). Fungal disorders are known as mycoses; when caused by  dermatophytes, the mycoses are termed tinea (dermatophytosis  or ringworm).   Tinea Infections. Tinea infections are fungal infections of  the skin and are classified according to their location on the  body.!!4 The most common sites are summarized in Table 46-7.  These infections are common in children (see Chapter 47).  Tinea unguium (onychomycosis) is a fungal infection of the  nails and is discussed on p. 1647. Tinea pedis is a chronic,  superficial fungal infection of the skin of the foot common in  adults (Figure 46-20). In prepubertal children, most scaling  disorders of the toes and feet are eczema. Tinea corporis   Circular, clearly circumscribed, mildly  erythematous scaly patches with a slightly  elevated ringlike border; some forms are dry  and macular, and other forms are moist and  vesicular   Small erythematous and scaling vesicular  patches with a well-defined border that  spreads over the inner and upper surfaces of  the thighs; occurs with heat and high humidity   Tinea pedis (foot, also Occurs between the toes and may spread to the  known as “athlete's soles of the feet, nails, and skin of toes; slight  foot’) scaling, macerated painful skin, occasionally  with fissures and vesiculation   Dry, scaly, erythematous lesions, or moist  vesicular lesions that begin with clusters  of intensely itching, clear vesicles; often  associated with fungal infection of the feet   A superficial or deep inflammation of the nail  that develops yellow-brown accumulations  of brittle keratin over all or portions of the nail    FIGURE 46-20 Tinea Pedis. Inflammation has extended from the web area  onto the dorsum of the foot. (Courtesy Department of Dermatology, School of Medi-  cine, University of Utah.)    (ringworm) and tinea capitis (a fungal infection of the scalp)  are much more common in children than adults. (See Chapter  47 for a discussion of fungal infections in children.)   Tinea is diagnosed by culture, microscopic examination of  skin scrapings prepared with potassium hydroxide wet mount,  or observation of the skin with a UV light (Wood lamp).    Cultures establish the particular type of fungus and are neces-  sary for hair and nail infections. Fungi have characteristic spores  and filaments known as hyphae that are more prominent when  prepared in potassium hydroxide. The spores fluoresce blue-  green when exposed to UV light. Treatment is related to the  type of fungi and includes both topical and systemic antifungal  medications.   Candidiasis. Candidiasis is caused by the yeastlike fungus  Candida albicans and normally can be found on mucous  membranes, on the skin, in the gastrointestinal tract, and in the  vagina. C. albicans can, under certain circumstances, change  from a commensal microorganism to a pathogen, particularly  in the critically ill and those who are immunosuppressed.'!°  Factors that predispose to infection include: (1) a local  environment of moisture, warmth, maceration, or occlusion;  (2) the systemic administration of antibiotics; (3) pregnancy;  (4) diabetes mellitus; (5) Cushing disease; (6) debilitated  states; (7) age younger than 6 months (more likely to get  an infection because of decreased immune reactivity);  (8) immunosuppression; and (9) certain neoplastic diseases  of the blood and monocyte-macrophage system. The resident  bacteria on the skin, mainly cocci, inhibit proliferation of C.  albicans. Cell-mediated immunity plays a major role in the  defense against monilial infections. C. albicans can activate the  complement system by the alternative pathway and can include  small abscesses. Candidiasis affects only the outer layers of  mucous membranes and skin and occurs in the mouth, vagina,  uncircumcised penis, nail folds, interdigital areas, and large  skinfolds (inframammary area, intertriginous area, perianal  region, and abdominal creases). Table 46-8 lists selected sites  of candidiasis. Innate and adaptive immune responses are  required for elimination of C. albicans.''°   The initial lesion is a thin-walled pustule that extends under  the stratum corneum with an inflammatory base that may burn  or itch. The accumulation of inflammatory cells and scale pro-  duces a whitish yellow curdlike substance over the infected area.  The lesion ceases to spread when it reaches dry skin.!!” Topical  antifungal medication is most commonly used for treatment.   Pinpoint, red, tender papules and pustules on  glans and shaft of penis   Pruritic red rash progressing to vesicles and  papules that enlarge and rupture    Vascular abnormalities are commonly associated with skin  diseases, or they may be present as congenital vascular mal-  formations (see Chapter 47) or as vascular responses to local  or systemic vasoactive substances. Blood vessels may increase  in number, dilate, constrict, or become obliterated by disease  processes.    Cutaneous vasculitis (angiitis) is an inflammation of the blood  vessels of the skin. The vasculitis is often idiopathic or can be  triggered by infection, decreased blood flow (i.e., venous stasis),  drugs, or autoimmune disorders. The initiating site of inflam-  mation may be the blood, the vessel wall, or the adjacent tissue.  Small vessels are usually affected. Immune complexes, which  initiate an uncontrolled inflammatory response, are often the  cause of damage, and the lesions are often polymorphic.   Cutaneous vasculitis develops from the deposit of immune  complexes in small blood vessels as a toxic response to drugs  (phenothiazines, barbiturates, sulfonamides) or allergens, as a  response to streptococcal or viral infection, or as a component  of systemic vasculitic syndromes. The precise mechanism is not  known, but the deposit of immune complex activates comple-  ment, which is chemotactic for polymorphonuclear leukocytes  and other mediators of inflammation that disrupt adhesion  molecules and the vessel wall. The cutaneous form usually  resolves in a few weeks and is treated with steroids.   A systemic form (cutaneous systemic vasculitis) can involve  other organs, including the kidneys, lungs, and gastrointesti-  nal tract (e.g., Wegener granulomatosis). The extremities are  the chief sites affected, primarily the lower legs and feet. The  lesions appear as palpable purpuras (from the leakage of blood  from damaged vessels) and progress to hemorrhagic bullae with  necrosis and ulceration from occlusion of the vessel (Figure  46-21). Lesions appear in clusters and remain from 1 to 4 weeks.  Recurrences are common.   Serum analysis and biopsy provide the most accurate dif-  ferential diagnosis. Identifying the primary disease or removing    FIGURE 46-21 Vasculitis of the Leg. (Courtesy Department of Dermatology,  School of Medicine, University of Utah.)    FIGURE 46-22 Urticaria. (Courtesy Department of Dermatology, School of  Medicine, University of Utah.)    the antigen (chemical, drug, or source of infection) is the first  step of treatment. Corticosteroids and immunosuppressants  are used when symptoms are severe.!!°:!!°    Urticaria (hives) is a pruritic circumscribed area of raised  erythema with central pallor occurring in the superficial der-  mis; they are often generalized in distribution. The erythema  blanches with pressure. Urticarial lesions are most commonly  associated with type I hypersensitivity reactions to drugs (e.g.,  penicillin, aspirin), certain foods (e.g., strawberries, shellfish),  systemic diseases (e.g., intestinal parasites, lupus erythemato-  sus), physical agents (e.g., heat, cold), or complement-mediated  reactions (see Chapter 9). They may occur with angioedema  (edema of the dermis and subcutaneous tissue). The lesions are  usually mediated by IgE-stimulated release of histamine, brady-  kinin, or kallikrein from mast cells or basophils, or both, which  causes the endothelial cells of skin blood vessels to contract,  increasing permeability. IgG antibody directed against the IgE  receptor and other inflammatory mediators, such as serotonin,  leukotrienes, prostaglandins, and kinins, also may be media-  tors of urticaria. Fluid leakage from vessels appears as wheals,  welts, or hives; there may be a few leaks or many leaks distrib-  uted over the entire body (Figure 46-22). Most lesions resolve  spontaneously within 24 hours, but new lesions may appear. All  possible causes should be removed. Nonsedating, second-gen-  eration antihistamines (H1 antagonists) usually reduce hives  and itching but may be combined with histamine H2 blockers,    FIGURE 46-23 Scleroderma. Note inflammation and shiny skin. (Courtesy  Department of Dermatology, School of Medicine, University of Utah.)    first-generation antihistamines, or leukotriene receptor ago-  nists to improve outcomes.!”° Epinephrine or corticosteroids  and a-adrenergic agonists may be required for treatment of  severe attacks (i.e., angioedema). Chronic urticaria (recurrent  wheals for more than 6 weeks) is either an autoimmune or an  idiopathic disease.!?!    Localized scleroderma (morphea) means sclerosis of the  skin. The disease is rare and the cause is unknown. It is more  prominent in white females, usually with childhood onset.  Genetic predisposition, autoimmunity, and an immune reac-  tion to a toxic substance are possible initiating mechanisms of  the disease. T helper cells (Th1 and Th17) and their cytokines  are associated with fibroblast proliferation and fibrosis. Several  autoantibodies also have been identified, including antinuclear  antibody (ANA), antihistone antibody (AHA), and single-  stranded DNA antibody (ss-DNA Ab).!”? The cutaneous lesions  are most often on the face and hands, neck, and upper chest,  but the entire skin can be involved.   There are massive deposits of collagen with fibrosis, accom-  panied by inflammatory reactions, vascular changes in the capil-  lary network with a decrease in the number of capillary loops,  dilation of the remaining capillaries, enhanced expression of  adhesion molecules, endothelial injury and dysfunction, peri-  vascular infiltrates, and ischemia. Fibrosis occurs in the papil-  lary and reticular dermis and in the subcutaneous tissue and  deep fascia. The skin is hard, hypopigmented, taut, shiny, and  tightly attached to the underlying tissue. The tightness of the  facial skin projects an immobile masklike appearance, and the  oral aperture is limited. The nose may assume a beaklike appear-  ance. The hands are shiny and sometimes red and edematous  (Figure 46-23). The fingers become tapered and flexed, often  with contractures, depressed scars, and loss of fingertips from  atrophy. Raynaud phenomenon with episodic arteriolar vaso-  constriction of the fingers contributes to pain, ulcer formation,  and gangrene. The nails may be shed. Calcium deposits develop  in the subcutaneous tissue and erupt through the skin. There  may be progression to underlying muscle and bone and other  body organs with esophageal involvement being most common.    Suitable clothing and a warm environment are essential to  protecting the hands. Trauma and smoking should be avoided.!?°  Treatment is individualized and based on severity and progres-  sion of the disease. Immunosuppressive medications, ultraviolet  light treatment, and other therapies are prescribed.!*4!75    Ticks are significant vectors of transmitted diseases, including  Rocky Mountain spotted fever and other rickettsial diseases,  tularemia, Congo-Crimean hemorrhagic fever, and Lyme dis-  ease.!*° Ticks vary from 1 cm to about the size of a comma on  this printed page. They embed their heads in the skin to obtain  blood. As they gorge themselves on blood, they enlarge to  many times their normal size and may release toxins or trans-  mit microorganisms during feeding. In most instances, there is  no consequence from a tick bite, with the exception of papu-  lar urticaria at the site of the bite. If mouthparts remain in the  skin when the tick is removed, a persistent nodule remains that  may require excision; ideally the tick should be removed com-  pletely intact. Irritant substances, such as camphor, soft wax, or  heat from a match, may stimulate the tick to withdraw its head.  Wearing protective clothing and applying tick repellant, such as  diethyltoluamide (DEET), butopyronoxyl (Indalone), or ben-  zylbenzoate, help prevent tick bites.   Lyme disease is a multisystem inflammatory disease caused  by the spirochete Borrelia burgdorferi transmitted by tick bites  and is the most frequently reported vector-borne illness. The  highest incidence is among children (50% of infected individu-  als are symptom free). An immune response to B. burgdorferi  contributes to the pathogenesis of the disease. The microor-  ganism is difficult to culture and it escapes immunodefenses  through antigenetic diversity; blocks complement-mediated  killing; impedes release of antimicrobial peptides, leukocyte  chemotaxis, and antimicrobial killing; and hides in tissue. It  spreads to other tissues by entering capillary beds.'7’   Symptoms of the disease occur in three stages.!*° Localized  infection occurs soon after the bite (3 to 32 days, the incubation  period) with erythema migrans (bull’s-eye rash) with or with-  out fever, fatigue, malaise, myalgias, and arthralgias. Erythema  migrans is a T-cell-mediated response. Within days to weeks  after the onset of the illness, there is disseminated infection with  secondary erythema migrans, usually with arthralgias, meningi-  tis, neuritis, or carditis. Late persistent infection (more common  in Europe) can continue for years with arthritis, encephalopa-  thy, polyneuropathy, or heart failure. The diagnosis of Lyme  disease is based on the clinical presentation and history of tick  bite, if known. Serologic tests may be used to confirm the diag-  nosis.!*? Antibiotics (e.g., doxycycline [not used in children  younger than 8 years or in pregnant or breast-feeding women]  or amoxicillin) are used for treatment.!*° Reinfection can occur.  There is currently not a vaccine for Lyme disease.!*!   Borrelia miyamotoi also is carried by ticks. The first report of  infection was in Russia in 2011 and cases have been confirmed  in the United States in areas where Lyme disease is endemic.  Serum assays confirm diagnosis. Infected individuals have flu-  like symptoms and respond to antibiotic therapy (doxycline or  amoxicillin).!*?    FIGURE 46-24 Seborrheic Keratosis. Typical lesion that is broad, flat, and  comparatively smooth surfaced. (Courtesy Department of Dermatology, School of  Medicine, University of Utah.)    FIGURE 46-25 Keratoacanthoma. Classic presentation of a fully developed  tumor. Round, smooth, dome-shaped mass with a central keratin-filled crater.  (Courtesy Department of Dermatology, School of Medicine, University of Utah.)    Most benign tumors of the skin are associated with aging.  Benign tumors include seborrheic keratosis, keratoacanthoma,  actinic keratosis, and nevi (moles).    Seborrheic keratosis is a benign proliferation of cutaneous  basal cells that produces smooth or warty elevated lesions. The  pathogenesis is unknown. These tumors are usually seen in  older people and occur as multiple lesions on the chest, back,  and face. The color varies from tan to waxy yellow, flesh col-  ored, or dark brown-black. Lesion size varies from a few mil-  limeters to several centimeters, and they are often oval and  greasy appearing with a hyperkeratotic stuck-on scaly appear-  ance (Figure 46-24). Both cryotherapy with liquid nitrogen and  electrocautery are effective treatments, and the lesions usually  slough 2 to 3 weeks after treatment.    A keratoacanthoma is a benign self-limiting tumor of squa-  mous cell differentiation arising from hair follicles. It usually  occurs on sun-damaged skin of older adults and smokers; the  incidence is high in males. The most commonly affected sites  are the face, back of the hands, forearms, neck, and legs (Figure  46-25). The lesion develops over a period of 1 to 2 months and    FIGURE 46-26 Actinic Keratosis. (Courtesy Department of Dermatology,  School of Medicine, University of Utah.)    has a histologic course resembling a well-differentiated squa-  mous cell carcinoma as follows:   Although the lesions resolve spontaneously, they can be  removed by curettage or excision to improve cosmetic appear-  ance and reduce risk of destructive growth or a missed diagno-  sis of squamous cell carcinoma. Intralesional 5-FU, bleomycin,  interferon, or methotrexate also have been effective.!°?-!°°    Actinic keratosis is a premalignant lesion composed of aberrant  proliferations of epidermal keratinocytes caused by prolonged  exposure to UV radiation. The prevalence is highest in indi-  viduals with unprotected light-colored skin. Actinic keratosis is  rare in black skin. The lesions appear as rough or scaly, poorly  defined pink to reddish or reddish brown papules that are felt  more than seen (Figure 46-26) and are considered an early in  situ squamous cell carcinoma. Surrounding areas may have tel-  angiectasia. Dermoscopy and biopsy aid evaluation. Treatment  options include ablative and topical therapies, such as 5-FU and  imiquimod. The lesions should continue to be evaluated for  progressive squamous cell carcinoma. Protection from the sun  with clothing or a sunblock to prevent lesions from developing  elsewhere is advised.!°°    Nevi (moles) are benign pigmented or nonpigmented lesions  (Figure 46-27) that form from melanocytes beginning at ages 3  to 5 years. Melanocytic nevus, formed from melanocytes, may  be congenital or acquired. During the early stages of develop-  ment, the cells accumulate at the junction of the dermis and  epidermis and are macular lesions. Over time the cells move  deeper into the dermis and the nevi become nodular and sym-  metric without irregular borders. Nevi may appear on any part  of the skin, and vary in size. They occur singly or in groups and    LGB Zs  FIGURE 46-27 Nevi. A, Junction nevus: slightly raised, dark, and uniform.  B, Dermal nevus: pedunculated with a soft, flabby, wrinkled surface. (From Habif  TP: Clinical dermatology: a color guide to diagnosis and therapy, ed 5, Philadelphia,  2010, Mosby.)    are not considered disfiguring. Nevi may undergo transition to  malignant melanomas (see p. 1643).!°7 Nevi repeatedly trau-  matized, irritated by clothing, or considered too large can be  excised.    Basal cell carcinoma and squamous cell carcinoma are the most  prevalent forms of cancer. Malignant melanoma is the most  serious and the most common cause of death from skin can-  cer.'°* Important trends related to skin cancer are presented in  Box 46-4.   Chronic ultraviolet (UV) radiation causes most skin can-  cers. Protection from UV radiation from the sun and artificial  sources (e.g., tanning beds), particularly during the childhood  years, significantly reduces the risk of skin cancer in later years.  Areas commonly exposed to the sun’s rays—face, neck, and  hands—are highly vulnerable for such lesions. Dark-skinned  persons and those avoiding sunlight are significantly less likely  to develop these malignant tumors. In dark-skinned persons,  basal cells contain the pigment melanin, a protective factor  against sun exposure.   Basal cell carcinoma is a surface epithelial tumor of the skin  originating from undifferentiated basal or germinative cells.  The tumors grow upward and laterally or downward to the   More than 3.5 million cases per year with likely underreporting because of lack  of anon—melanoma skin cancer registry   Greater in women younger than age 40 years; greater in men after age 40 years;  40 times more prevalent in whites than in blacks; increases steadily with  age; increasing among young individuals with chronic exposure to artificial  UV radiation   Majority of cases are highly curable basal or squamous cell cancers and the  most serious is malignant melanoma with an estimated 76,690 new cases    in 2013; it represents 4% of all skin cancer cases but causes about 79% of  all skin cancer deaths    Mortality  Total estimated deaths in 2013 were 9480 from melanoma and approximately  3170 from other nonepithelial types of skin cancer   Exposure to artificial UV radiation, particularly in ages less than 25 years  Fair complexion, blue eyes, blonde hair    Data from American Cancer Society: Cancer facts and figures 2013, Atlanta,    dermal-epidermal junction. They usually have depressed cen-  ters and rolled borders. Early tumors are so small that they are  not clinically apparent.   Basal cell carcinoma is the most common type of skin cancer  in whites and is thought to be caused by UV radiation exposure.  It also is associated with arsenic from groundwater wells'*? and  autosomal dominant nevoid basal cell carcinoma syndrome.  Basal cell carcinoma arises from mutation in the TP53 tumor-  suppressor gene, leading to loss of keratinocyte repair functions  and apoptosis resistance of DNA-damaged cells. Other onco-  genic pathways include mutation in the PTCH1 gene that has  tumor-suppressor activity, and alteration in the Sonic Hedge-  hog signaling pathway genes (codes for a protein important for  cell growth and differentiation).'*°   Lesion subtypes include superficial, nodular, and scleros-  ing/morpheaform, which can be pigmented or nonpigmented  (Figure 46-28). Early tumors are so small that they are not clini-  cally apparent. The lesion often begins as a nodule (greater than 5  mm across) that is pearly or ivory in appearance and slightly ele-  vated above the skin surface with small blood vessels on the sur-  face (telangiectasias). The tumors grow upward and laterally or  downward to the dermal-epidermal junction. They usually have  depressed centers and rolled borders. As the lesion grows, it often  ulcerates, develops crusting, and becomes firm to the touch. Ifleft  untreated basal cell lesions invade surrounding tissues and, over  months or years, can destroy a nose, an eyelid, or an ear. Meta-  static spread is rare because these tumors do not invade blood  or lymph vessels. Treatment includes complete surgical excision,  radiotherapy, curettage, cryotherapy, photodynamic therapy,  and topical applications of imiquimod or 5-fluorouracil.!“°    Squamous cell carcinoma (SCC) is a tumor of the epidermis  and the second most common human cancer. Two types are    Occupational exposure to coal tar, pitch, creosote, arsenic compounds, and radium  Exposure to human papillomavirus and human immunodeficiency virus  Immunosuppression   Skin cancer is negligible in blacks because of heavy skin pigmentation    Warning Signals  Any change on the skin, especially a change in the size or color of a mole or other  darkly pigmented growth or spot   Avoidance of artificial UV radiation and sun when ultraviolet light is strongest  (e.g., 10 am to 3 pm); use of protective clothing and sunscreen preparations,  especially those containing ingredients such as para-aminobenzoic acid  (PABA); prevention for all types of skin cancer should begin in childhood   For basal cell and squamous cell cancers, cure is highly likely with early detec-  tion and treatment; malignant melanoma metastasizes quickly, accounting for  a lower 5-year survival rate    FIGURE 46-28 Types of Basal Cell Carcinoma. A, Superficial. B, Nodular.  C, Pigmented. D, Morpheaform—recurrent tumor. (A and D from Bolognia JL,  Jorizzo JL, Schaffer JV: Dermatology, ed 3, Philadelphia, 2012, Saunders; B and  C from James WD, Berger TG, Elston DM: Andrews’ diseases of the skin: clinical  dermatology, ed 11, Philadelphia, 2011, Saunders.)    characterized: in situ (Bowen disease [BD]) and invasive. Areas  affected are the head and neck (75%) and the hands (15%),  with 10% of squamous cell carcinomas occurring elsewhere  on the body. These tumors are more predominant in countries  where arsenic is found in higher rates in drinking water. UV  light exposure from sun and the use of tanning beds are the  primary risk factors. Gamma rays and x-rays are also associated    FIGURE 46-29 Squamous Cell Carcinoma. The sun-exposed ear is a com-  mon site for squamous cell carcinoma. (Courtesy Department of Dermatology,  School of Medicine, University of Utah.)    with squamous cell carcinoma. In addition, patients who are  immunosuppressed experience a greater occurrence of this  carcinoma.   UV exposure causes SCC, particularly mutation of the TP53  gene and other oncogenic signals.'*! It is unclear how UV light  produces alterations in DNA, and DNA repair. Invasive SCC  can arise from premalignant lesions of the skin. It rarely arises  from normal-appearing skin or de novo. The premalignant  lesions include sun-damaged skin or dysplasias (actinic kerato-  sis); leukoplakia, or whitish, discolored areas; scars; radiation-  induced keratosis; tar and oil keratosis; and chronic ulcers and  sinuses.   In situ SCC is usually confined to the epidermis (intraepider-  mal) but may extend into the dermis. Common premalignant  skin lesions associated with in situ squamous cell carcinomas  are actinic (solar) keratosis and BD. Actinic keratosis is a white,  scaly, keratotic (horny) lesion on the exposed areas of the body  (see Figure 46-26). BD is a dysplasia of the basal layer of the der-  mis or carcinoma in situ. It often is found on unexposed areas  of the body and is demonstrated by flat, reddish, scaly patches.  These lesions may enlarge to more than 1 cm in diameter,  rarely invading surrounding tissue and very rarely metastasiz-  ing. Other cellular components in the skin (e.g., sweat glands,  hair follicles) can give rise to SCC but these cancers are rela-  tively uncommon. Invasive SCC grows more rapidly than basal  cell carcinomas and can spread to regional lymph nodes with  metastasis. These tumors are firm and increase in elevation and  diameter. The surface may be granular and bleed easily (Figure  46-29). Treatment includes surgical excision and radiotherapy  with consideration of adjuvant chemotherapy for advanced dis-  ease.'“? Mohs micrographic surgery (MMS), a tissue-sparing  surgical technique, is indicated for non-melanoma skin cancers  (NMSCs) with a high risk of recurrence, lesions involving the  face, ears, genitalia, or when wider excision may risk functional  impairment. !472    Cutaneous melanoma is a malignant tumor of the skin origi-  nating from melanocytes, or cells that synthesize the pigment  melanin. The incidence of melanoma is increasing, and young to  middle-age adults are at highest risk. Risk factors implicated in  melanoma induction include genetic predisposition, exposure    Junctional nevus Flat, well circumscribed, vary in size up to 2 cm,  dark color, hairs may be present; originate in  basal layer of epidermis and can eventually reach  the cutaneous surface; rarely develop into a  melanoma   Most common in adolescents; the majority of  pigmented lesions are in children; rarely develops  into melanoma; usually 1 cm in size; hairs may be  present; surface is elevated and smooth   Small (less than 1 cm) with regular edges and  bristle-like hairs; color ranges from skin tone to  light brown; has a slight likelihood of developing  into a melanoma    to ultraviolet light (solar and artificial), acquired melanocytic  nevi, family history of melanoma, fair hair, light skin with a  propensity to sunburn, and the presence of susceptibility genes  (e.g., BRAF and RAS mutations).'**!“* Specific genetic altera-  tions are associated with particular clinical and histopathologic  features of the disease. '*°   The relationship between nevi (see Figure 46-27) and mela-  noma makes it important for the clinician to understand the  various neval forms (Table 46-9). Most nevi never become  suspicious; however, suspicious nevi should be evaluated and  removed. Indications for biopsy include changes in color and  size, irregular notched margin, itching, bleeding or oozing,  nodularity, scab formation, ulceration, or an unusual pattern  of presentation. The ABCDE rule is used as a guide: Asymme-  try, Border irregularity, Color variation, Diameter larger than  6 mm, and Elevation, which includes raised appearance or  rapid enlargement.!“° Clinical characteristics are summarized  in Table 46-10.   Melanomas arise as a result of malignant degeneration of  melanocytes located either along the basal layer of the epider-  mis or in a benign melanocytic nevus. The clinical types of cuta-  neous melanoma are based on their growth pattern and include  lentigo malignant melanoma (LMM) (Figure 46-30), superfi-  cial spreading melanoma (SSM) (the most common), primary  nodular melanoma (PNM), and acral-lentiginous melanoma.  Rare and difficult to diagnose subtypes include desmoplastic  melanoma, which resembles a scar, and amelanotic (nonpig-  mented) melanoma.'*” The pathogenesis of malignant mela-  noma is complex and a number of proto-oncogenes have been  identified. !**   Surveillance strategies include clinician-based total body  skin examination, total body photography, dermoscopy, and  individual-based_ self-skin examination. Detection of vola-  tile biomarkers are in development.'*** Staging of melanoma  is determined using tumor, node, metastasis (TMN) criteria  established by the American Joint Committee on Cancer and is  summarized in Box 46-5.   Prognostic factors include the thickness of the lesion, mitotic  index, immunohistochemical assessment, ulceration and me-  tastasis (e.g., number of lymph nodes or viscera involved).!“”    Lentigo Malignant Melanoma  Frequency 4% to 15% of cutaneous melanomas  Age at diagnosis 50 to 80 years old, mean age 65 years  Primary location Head, neck, dorsum of hands (sun-  exposed areas)  Pigmentation according to  thickness  <1.5 mm (levels | and I!)  >1.5 mm (level III)  >1.5 mm (levels IV and V)    Superficial Spreading Melanomas  Frequency 57% to 70% of cutaneous melanomas  Age at diagnosis 20 to 60 years old  Primary location Legs of females; upper back of both  genders  Pigmentation according to  thickness  <1.5 mm (levels | and I!)  >1.5 mm (level III)  >1.5 mm (levels IV and V)    Primary Nodular Melanoma  Frequency 12% to 21% of cutaneous melanomas  Age at diagnosis 20 to 60 years old, mean age 53 years  Primary location Trunk, head, or neck  Pigmentation according to  thickness  >1.5 mm (level III)  >1.5 mm (levels IV and V)    2% to 8% in whites; 30% to 75% in  blacks, Hispanics, Asians  20 to 60 years old  Palms, soles of feet, mucous membranes  Blue-black irregular macules, papules,  or nodules    Data from Bolognia JL, Jorizzo JL, Schaffer JV: Dermatology, ed 3,  Philadelphia, 2012, Saunders; Greenwald HS, Friedman EB, Osman |:  Melanoma Res 22(1):1-8, 2012; Habif TP, editor: Clinical dermatology,  ed 5, St Louis, 2010, Mosby; Scolyer RA, Long GV, Thompson JF:  Mol! Oncol 5(2):124-136, 2011; Situm M, Buljan M: G /ta! Dermatol  Venereol 147(1):21-27, 2012.    Figure 46-31 illustrates a nodular melanoma. Efforts are in  progress to refine the morphologic classifications by adding  subgroups that include molecular markers for proto-oncogene  mutations and specific signaling pathways.'°° Early recognition  of cutaneous melanomas can have a major effect on achieving  a surgical cure.   Prevention of melanoma includes avoidance of UV radiation  exposure through use of protective clothing and sunscreens,  and avoidance of artificial UV radiation exposure. Treatment  of melanoma with no evidence of metastatic disease involves    Stage 0: carcinoma in situ (TisNOMO)  Stage | A/B: includes lesions up to 2 mm with no nodal or distant metastases  (T1aNOMO, T1bNOMO, T2aNOMO).    Stage II A/B/C: includes larger lesions, greater than 2 mm without positive  nodes or distant metastases (T2bNOMO, T3aNOMO, T3bNOMO, T4aNOMO,  T4bNOMO).   Stage Ill: includes lesions of any size with positive lymph nodes (TxN1MO,  TxN2M0, TxN3M0).   Stage IV: includes lesions of any size with distant metastases (TxNx!V1).    Data from Piris A, Lobo AC, Duncan LM: Melanoma staging: where are  we now?, Dermatol Clin 30(4):581-592, v, 2012.    FIGURE 46-30 Lentigo Malignant Melanoma. (Courtesy Department of Der-  matology, School of Medicine, University of Utah.)    FIGURE 46-31 Nodular Melanoma. (Courtesy Department of Dermatology,  School of Medicine, University of Utah.)    surgical excision to the primary site and regional lymph nodes.  The extent of surgery is determined by the staging of disease.  Lesions of the extremities have the best prognosis; head and  neck lesions and trunk lesions have the poorest prognosis. Sur-  vival rate for advanced disease is very low. Immunotherapy is  advancing. Ipilimumab blocks cytotoxic T-lymphocyte antigen  4 and vemurafenib has prolonged survival with BRAF-mutated  melanoma, and new drugs are in clinical trials. Improving  response and survival rates with novel cellular targets and com-  bination therapies to overcome tumor resistance is an ongoing  need.!°!!52 Vaccines, biomarkers, and genetically-modified  T cells are under investigation.!**)!>4    FIGURE 46-32 Kaposi Sarcoma. The purple lesion commonly seen on the  skin. (Courtesy Department of Dermatology, School of Medicine, University of  Utah.)   Kaposi sarcoma (KS) is a vascular malignancy associated with  different presentations: (1) drug-induced immunosuppres-  sions, for example, after kidney transplantation; (2) an endemic  form in equatorial Africa; (3) classic form presenting on the  lower legs of older men; (4) epidemic and nonepidemic forms  related to acquired immunodeficiency syndrome (AIDS), and  (5) iatrogenic.!°°   Kaposi-associated herpesvirus 8 (HHV-8) is found in all  forms of KS and may be a common etiology for all types of KS  in combination with host immune dysfunction and the local  inflammatory state.'°? Immunosuppression allows for oppor-  tunistic infections and malignancy. Proliferation of the tumor  depends on the presence of platelet-derived and other growth  factors.!°°   The endothelial cell is thought to be the progenitor of KS  but the specific origin is elusive. The lesions emerge as purplish  brown macules and develop into plaques and nodules. They  tend to be multifocal rather than spreading by metastasis. The  lesions initially appear over the lower extremities in the classic  form (Figure 46-32). The rapidly progressive form associated  with AIDS tends to spread symmetrically over the upper body,  particularly the face and oral mucosa. The lesions are often  pruritic and painful. About 75% of individuals with epidemic  KS have involvement of lymph nodes, particularly in the gas-  trointestinal tract and lungs. Organ involvement is much less  common in the classic form. The rapidly progressive form has a  poor prognosis and shorter survival rates than the classic form.  (See Chapter 10 for a further discussion on AIDS.)   Diagnosis is by skin biopsy, with a high index of suspicion  for those with immunodeficiency. The disease is incurable.  Local lesions can be excised. Multiple disseminated lesions may  be treated with a combination of immunomodulatory, cyto-  toxic, and antiviral drugs. The new, highly active antiretroviral  therapy (HAART) for AIDS treatment is decreasing the inci-  dence of KS in resource rich countries, but new treatments are  needed.!°7    Primary cutaneous lymphomas are cutaneous T-cell and  B-cell lymphomas that are present in the skin without    FIGURE 46-33 Mycosis Fungoides. A, Hypopigmented patches of mycosis  fungoides. B, Plaques of mycosis fungoides. C, Tumors of mycosis fungoides com-  bined with patches. (Courtesy of Ellen Korn, M.D. In James WD, Berger TG, Elston  DM: Andrews’ diseases of the skin: clinical dermatology, ed 11, Philadelphia, 2011,  Saunders.)    evidence of extracutaneous disease at the time of diagnosis  (see Chapter 29 for classification and general pathophysiology  of lymphomas). Cutaneous lymphomas are rare but are the  second most common site of extranodal non-Hodgkin lym-  phoma. The incidence rate is about 14/100,000 and their cause  is unknown.!°* Cutaneous lymphomas are more common in  men and generally present after age 50 years; 75% of cases  are T-cell lymphomas and 25% are B-cell lymphomas. The  most common cutaneous T-cell lymphoma is mycosis fun-  goides (50% of cases), which is more common among blacks.  Sézary syndrome (a leukemic variant of T-cell lymphoma)  and primary cutaneous CD30-positive lymphoproliferations  (less than 10% of cases) are the most aggressive. Cutane-  ous lymphomas develop from clonal expansion of B cells, T  helper cells, and rarely T suppressor cells. Mycosis fungoides  can present as focal or widespread erythematous patches or  plaques, follicular papules, comedone-like lesions, and tumors  (Figure 46-33). There may be patches of alopecia. The lesions  progress over a period of months or years. Mycosis fungoides  lesions are pruritic and cause considerable distress and debili-  tation.'°? Involvement of other organs can occur in advanced  stages of the disease.   The differential diagnosis of the different types of cutane-  ous lymphomas is based on clinical manifestations, histo-  logic appearance, immunologic and cytogenetic features, and  response to appropriate treatment.!©!°* Lesions also must be  distinguished from psoriasis, eczema, generalized dermatitis,  and drug reactions. Treatment is based on staging of the dis-  ease following consensus-based guidelines that include a range  of topical and systemic therapies, such as anti-inflammatory,  immunomodulatory, and biologic agents; histone deacetylase  inhibitors; rexinoids; and chemotherapeutics.!°!!° Radio-  therapy has historically been the most common successful  therapy.!°°   color with plaques or nodules, pain, and pruritus but  without ice crystal formation; a chronic vasculitis can  develop and is usually located on the face, anterior lower  leg, hands, and feet   peratures below —2° C (28° F), progressing from distal to  proximal; is potentially reversible   Areas most commonly affected are fingers, toes, ears, nose,  and cheeks. Initially the body responds with alternating cycles  of vasoconstriction and vasodilation—the “hunting reflex.”  The mechanism of injury is complex but is related to direct cold  injury to cells, indirect injury, cell death from extracellular and  intracellular ice crystal formation, impaired circulation with  anoxia because of thrombosis in the exposed area, and reper-  fusion injury. With tissue reperfusion there is infiltration of  neutrophils and mast cells and these cells and the damaged epi-  thelium release inflammatory mediators (e.g., prostaglandins,  thromboxanes, bradykinin, and histamine). Edema can cause  capillary compression and vascular stasis. Frozen skin becomes  white or yellowish, waxy, and firm to the touch. There is numb-  ness and no sensation of pain.   Skin damage can range from mild to severe. With mild frost-  bite, redness and discomfort occur during rewarming, followed  by a return to normal in a few hours. In more severe cases, cya-  nosis and mottling develop, followed by redness, swelling, throb-  bing, and burning pain on rewarming. Within 24 to 48 hours,  vesicles and bullae appear and resolve into crusts that eventu-  ally slough off, leaving thin, newly formed skin. The most severe  cases result in gangrene with loss of the affected part. Frostbite  may be classified by depth of injury after rewarming as follows:   white area surrounded by erythema and edema and  including partial skin freezing without blistering   subcutaneous freezing with tissue necrosis and hemor-  rhagic vesicles and blisters   Immediate treatment of frostbite is to cover affected areas  with other body surfaces and warm clothing. The area should  not be rubbed or massaged. Local, dry heat should be avoided.  Immersion in a warm water bath (40° to 42° C [104° to 107.6°  F}) until frozen tissue is thawed is the best treatment. Ibupro-  fen is used to inhibit prostaglandins, and aloe vera is a topical  inhibitor of thromboxane. Thrombolytic therapy reduces the  incidence of amputation when administered within 24 hours  of injury.!°°    Pain during the thawing period is severe and should be  treated with potent analgesics. Gentle cleansing and no pressure  on the skin should be maintained during healing. Amputation  of necrotic tissue is delayed until a clear line of demarcation is  established.!°°   Alopecia means loss of hair. Localized hair loss in men is not  a disease but rather a variation in the androgen receptor (AR)  gene that clusters in families. The mechanism of inheritance is  unknown. Within the distribution of hair over the scalp, andro-  gen-sensitive hair follicles are on top and androgen-insensitive  follicles are on the sides and back. In genetically predisposed  men, the androgen-sensitive follicles are transformed into vel-  lus follicles. The normal hair is shed and replaced by fine, light,  short hair. Male-pattern baldness begins with frontotemporal  recession and progresses to loss of hair over the top of the scalp.  Minoxidil may be used to stimulate hair growth and finaste-  ride may decrease the effect of androgens on hair follicles. New  treatments are being evaluated.'°” Affected men may choose to  wear wigs or have hair transplants.   Women in their twenties and thirties (6% to 12%) and women  older than 70 years (55%) experience progressive thinning  and loss of hair over the central part of the scalp. Contrary to  male-pattern baldness, no loss of hair occurs along the frontal  hairline but follicles are smaller and less functional. Many of  these women have elevated levels of serum adrenal androgen  dehydroepiandrosterone sulfate (DHEAS), and treatment with  antiandrogens can be effective. Lower levels of estrogen can also  decrease hair growth after menopause. Finasteride, minoxidil,  light therapy or combinations of therapy may be used and work  best when started early.!®*:!°? In rare instances a male-pattern  baldness develops. Laboratory evaluation of serum androgenic  hormones shows elevations, and some women have decreased  hair loss when treated with daily doses of spironolactone.   Alopecia areata is an autoimmune T-cell—mediated chronic  inflammatory disease directed at hair follicles that results in  baldness. Hair loss occurs in multiple areas of the scalp, usu-  ally in round patches. The eyebrows, eyelashes, beard, and other  areas of the body are rarely involved. The cause is unknown, but  stressful events, cell-mediated immune factors, and genetic sus-  ceptibility are linked to hair loss.'”° Metabolic disorders, such as  Addison disease, thyroid disease, and lupus erythematosus, also  are associated with alopecia areata.!”!   The affected areas of skin are smooth or may have short shafts  of poorly developed hair that breaks at the surface. Regrowth  occurs within 1 to 3 months, but hair loss may recur at the same  site. Permanent regrowth of hair usually occurs. Total loss of  hair (alopecia totalis) occurs in some young people; the long-  term prognosis for total hair regrowth is poor.    Diagnosis is made by observation of the pattern of hair  loss. Biopsy may show a lymphocytic infiltrate around the fol-  licle. There are several treatments for alopecia areata includ-  ing watchful waiting, corticosteroids, minoxidil, and topical  immunotherapy.!”   Hirsutism is the abnormal growth and distribution of hair on  the face, body, and pubic area in a male pattern that occurs in  women. There is also frontotemporal hair recession. These areas  of hair growth are androgen sensitive. Variations of hair growth  in women are great, and a male pattern can be normal. Women  who develop hirsutism may be secreting hormones associated  with ovarian or adrenal disease, and such women should be  evaluated for polycystic ovaries, adrenal hyperplasia, or adrenal  tumors.!”° Ifno hormonal pathologic conditions exist, undesir-  able hair can be mechanically removed. Endocrine therapy to  suppress androgens may be considered.!”*   Paronychia is an acute or chronic infection of the cuticle.  Acute paronychia is manifested by the rapid onset of painful  inflammation of the cuticle, usually after minor trauma. An  abscess may develop, requiring incision and drainage (I&D) for  relief of pain. The most common causative microorganisms are  Staphylococci, Streptococci, and occasionally Candida.    Chronic paronychia develops slowly, with tenderness and  swelling around the proximal or lateral nail folds. One or more  fingers or toes may be involved. Individuals whose hands are  frequently exposed to moisture are at greatest risk. Manipula-  tion or chronic wetting of the cuticle increases risk because it  disrupts the natural protective barrier provided by the cuticle,  leaving a moist, warm medium for pathogenic microorganisms  to incubate. The skin around the nail becomes more edematous  and painful with progressive infection. Pus may be expressed  from the proximal nail fold. The nail plate is usually not  affected, although it can become discolored and develop ridges  with chronic infections.   Treatment includes keeping the hands dry. Abscesses are  treated with incision and drainage; severe bacterial cases may  require systemic antibiotics. Oral antifungals are not very effec-  tive because they do not penetrate the affected tissues but effi-  cacy is increased with topical application of steroid creams.!”°   Onychomycosis is a fungal or dermatophyte infection of the nail  plate that occurs in 2% to 18% of the population.'”° The most  common pattern is a nail plate that turns yellow or white (infec-  tion develops from the dorsal surface) and becomes elevated  as a result of the accumulation of hyperkeratotic debris within  the plate. Fungal infections of the nail may require culture and  microscopy. Treatment includes débridement and systemic  antifungal therapy. Surgical excision of the nail may be required.  New systemic and topical antifungals are being investigated.!””   1. The skin is the largest organ of the body and equals about  20% of body weight.   2. The skin has three layers: the dermis, epidermis, and subcu-  taneous layer.   3. Keratinocytes produce keratin to form the superficial layer  of the epidermis. The underlying epidermis contains a basal  and a spinous layer with melanocytes, Langerhans cells, and  Merkel cells.   nerves, and lymphatic vessels.  . The subcutaneous layer contains fat cells and connective tissue.   6. The dermal appendages include the nails, hair, sebaceous  glands, and the eccrine and apocrine sweat glands.   7. The papillary capillaries provide the major blood supply to  the skin, arising from deeper arterial plexuses. The sympa-  thetic nervous system regulates skin blood flow.   8. Heat loss and heat conservation are regulated by arteriove-  nous anastomoses that lead to the papillary capillaries.   9. Older skin is thinner and drier with less collagen; it has  fewer capillary loops and fewer changes in pigmentation.   10. Loss of melanocytes and hair follicles leads to gray and  thinner hair.    11. The skin of older adults is more permeable; there is  decreased sweating and loss of thermal regulation and  decreased protective functions.   12. Pressure ulcers develop from continuous pressure and  shearing forces that occlude capillary blood flow with  resulting ischemia and necrosis. Areas at greatest risk are  pressure points over bony prominences, such as the greater  trochanter, sacrum, ischia, and heels. Immobilized individ-  uals with fractures and neurologic deficits are most likely to  develop pressure ulcers.   13. Keloids are scars that extend beyond the border of injury  and result from abnormal fibroblast activity and excess col-  lagen formation. Hypertrophic scars are elevated erythema-  tous fibrous lesions that do not expand beyond the border  of injury.   14. Pruritus (itching) is associated with many skin disorders.  Itch mediators, peripheral polymodal C nerve fibers, and  central processes contribute to itching. Scratching can  cause skin trauma, infection, and scarring.    Disorders of the Skin  1. Allergic contact dermatitis is a form of delayed hypersensi-  tivity that develops with sensitization to allergens, such as  metals, chemicals, or poison ivy.    Irritant contact dermatitis develops as an inflammatory  response to prolonged exposure to chemicals, such as acids  or soaps.    . Atopic or allergic dermatitis is associated with a family his-    tory of allergies, hay fever, elevated IgE levels, and increased  histamine sensitivity; it is more common in children.    . Stasis dermatitis occurs on the legs and results from venous    matory plaques of the scalp, eyebrows, eyelids, ear canals,  chest, axillae, and back. The cause is unknown.    matory skin disease with thickening of the epidermis  and dermis characterized by scaly, erythematous pruritic  plaques. The forms of psoriasis are plaque, inverse, guttate,  pustular, and erythrodermic. Systemic complications can  accompany the disease including arthritis and cardiovascu-  lar disease.    oval lesions with scales around the edges located along skin  lines of the trunk.    inflammatory lesion involving T cells and inflammatory  cytokines manifested by severe pruritus and can involve  both skin and mucous membrane lesions.   Acne vulgaris is a facial inflammation of the pilosebaceous  follicles with hypertrophy of sebaceous glands and telangi-  ectasia, particularly of the nose.   Acne rosacea develops on the middle third of the face with  hypertrophy and inflammation of the sebaceous glands  that may be the result of infection or immune-mediated  inflammation.   Lupus erythematosus is an inflammatory autoimmune dis-  ease that can affect only the skin (discoid) or have a sys-  temic presentation. The inflammatory lesions usually occur  in sun-exposed areas with a butterfly distribution over the  nose and cheeks.   Pemphigus is a chronic, autoimmune, blistering disease that  begins in the mouth or on the scalp and spreads to other  parts of the body, often with a fatal outcome. The forms  of pemphigus include pemphigus vulgaris (most common),  pemphigus foliaceus, paraneoplastic pemphigus, and IgA  pemphigus.   Bullous pemphigoid is a benign autoimmune blistering dis-  ease that resolves rapidly.   Erythema multiforme is an acute inflammation of the skin  and mucous membranes with lesions that appear target-  like with alternating rings of edema and inflammation; it is  often associated with allergic reactions to drugs.   A furuncle is an infection of the hair follicle that extends to  the surrounding tissue.    . A carbuncle is a collection of infected hair follicles that  forms a draining abscess.   . Cellulitis is a diffuse infection of the dermis and subcutane-   where on the body and are classified by location (i.e., tinea   the skin that also may affect muscle, bone, and other body   Ticks cause a local reaction on the skin of humans and can   areas. There are three stages of development that result in a   or fleshy pink. They occur singly or in groups and may    ciated with sun exposure and can be localized (in situ) or    38. Cutaneous melanoma arises from melanocytes; if it is not  excised early, metastasis occurs through the lymph nodes.   39. KS is a vascular malignancy associated with immunodefi- 4  ciency states and is associated with herpesvirus 8.    37. Squamous cell carcinoma is a tumor of the epidermis asso- —-2.. Female-pattern alopecia is a thinning of the central hair of    the scalp beginning in women at 20 to 30 years of age.    3. Alopecia areata is patchy loss of hair associated with an auto-    extracutaneous disease at the time of diagnosis.  41. Frostbite usually occurs on cheeks and digits, causing direct  injury to cells and impaired circulation.    Disorders of the Nail  1. Paronychia is an inflammation of the cuticle that can be    immune process and triggered by stress or metabolic dis-  eases; it is usually reversible.  Hirsutism is a male pattern of hair growth in women that  may be normal or the result of excessive secretion of andro-  genic hormones.    1. Male-pattern alopecia is an inherited form of irreversible  baldness with hair loss in the central scalp and recession of    Hair follicle, 1618  Herald patch, 1630  Herpes simplex virus (HSV), 1636  Herpes varicella, 1636   Nevi (sing., nevus; also known as a mole), 1641  Onychomycosis, 1647    Papillary capillary, 1619  Papulosquamous disorder, 1629  Paraneoplastic pemphigus, 1633  Paronychia, 1647   Spinous layer (stratum spinosum), 1617  Squamous cell carcinoma (SCC), 1642  Stasis dermatitis, 1628    Gros E, Novak N: Cutaneous dendritic cells in allergic inflammation,  Clin Exp Allergy 42(8):1161-1175, 2012.   Myung P, Ito M: Dissecting the bulge in hair regeneration, J Clin Invest  122(2):448—454, 2012.   Naylor EC, Watson RE, Sherratt MJ: Molecular aspects of skin ageing,  Maturitas 69(3):249-256, 2011.   Ortiz A, Grando SA: Smoking and the skin, Int J Dermatol 51(3):  250-262, 2012.    . Kohl Eet al: Skin ageing, J Eur Acad Dermatol Venereol 25(8):873-884,    . 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Singal A, Khanna D: Onychomycosis: diagnosis and management,  Indian J Dermatol Venereol Leprol 77(6):659-672, 2011.    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Acne Vulgaris, 1653  Dermatitis, 1654  Atopic Dermatitis, 1654  Diaper Dermatitis, 1655  Infections of the Skin, 1656  Bacterial Infections, 1656  Fungal Infections, 1657  Viral Infections, 1658  Insect Bites and Parasites, 1661  Scabies, 1661  Pediculosis (Lice Infestation), 1661    Children often develop alterations in the skin that may be minor  or severe and localized or generalized. Skin diseases in children  may have a different causative mechanism of expression than  those found in adults, although there may be similarities. Diag-  nosis is commonly made from the history, appearance, and  distribution of the lesion or lesions. Common skin diseases of  childhood are presented here.    Acne vulgaris is the most common skin disease and affects 85%  of the population between the ages of 12 and 25 years. Onset  is occurring at a younger age and may be associated with ear-  lier onset of puberty in the United States. Genetic influences  may determine an individual’s susceptibility and severity of dis-  ease. Severe acne tends to have a genetic predisposition.! The    Fleas, 1662  Bedbugs, 1662  Hemangiomas and Cutaneous  Vascular Malformations, 1662  Hemangiomas, 1662  Vascular Malformations, 1663  Other Skin Disorders, 1664  Miliaria, 1664  Erythema Toxicum Neonatorum, 1664  Stevens-Johnson Syndrome and Toxic  Epidermal Necrolysis, 1664    incidence of acne is the same in both genders, although severe  disease affects males more often.   Acne develops at distinctive pilosebaceous units, known as  sebaceous follicles. Located primarily on the face and upper parts  of the chest and back, these follicles have many large sebaceous  glands, a small vellus hair (very short, nonpigmented, and very  thin hair), and a dilated follicular canal that is visible as a pore  on the skin surface. Acne lesions may be inflammatory (pus-  tules, papules, nodules) or noninflammatory. In noninflam-  matory acne the comedones are open (blackheads) and closed  (whiteheads), with the accumulated material causing distention  of the follicle and thinning of follicular canal walls. Inflamma-  tory acne develops in closed comedones when the follicular wall  ruptures, expelling sebum into the surrounding dermis and ini-  tiating inflammation. Pustules form when the inflammation  is close to the surface; papules and cystic nodules can develop    FIGURE 47-1 Cystic Acne. Multiple pustules (erythematous papules and pus-  tules) are present, and several have become confluent. Note areas of scarring.  (Courtesy Department of Dermatology, School of Medicine, University of Utah.)    when the inflammation is deeper, causing mild to severe scar-  ring (Figure 47-1). Many types of lesions may exist in the same  individual.   The exact cause of acne is unknown and various pathophysi-  ologic factors contribute to the development of acne. The prin-  cipal factors are follicular hyperkeratinization, excessive sebum  production, follicular proliferation of Propionibacterium acnes,  and inflammation and rupture of a follicle from accumulated  debris and bacteria within the follicle. Androgens (dihydrotes-  tosterone and testosterone) synthesized in increasing amounts  during puberty boost the size and productivity of the sebaceous  glands and promote P. acnes. Acne also is associated with poly-  cystic ovarian syndrome, congenital adrenal hyperplasia, and  various endocrine tumors as a result of higher circulating levels  of androgens. The P. acnes anaerobic bacteria produce extra-  cellular porphyrins and proinflammatory molecules, including  chemotactic factors and lipolytic and proteolytic enzymes. The  hydrolytic action of the enzymes converts triglycerides into free  fatty acids that stimulate inflammation and edema and result in  breakdown of the follicle wall. Chemotactic substances also may  be released that involve mediation of inflammation by attrac-  tion of polymorphonuclear leukocytes.”   Treatment of acne should address the causative factors and  be individualized according to severity. The combination of a  topical retinoid, benzoyl peroxide, and antimicrobial agents  is preferred. Retinoids are anticomedogenic and comedolytic  and have some anti-inflammatory effects. Benzoyl peroxide is  antimicrobial with some keratolytic effects. Topical antibiotics  (e.g., erythromycin and clindamycin) have anti-inflammatory  and antimicrobial effects. Combined oral contraceptives may  be effective for acne in women.’ Use of systemic therapies,  including oral antibiotics, corticosteroids, and isotretinoin, is  encouraged in more severe cases but may be limited by side  effects. Dietary based guidelines need further investigation.*  Acne surgery, including comedo extraction, intralesional ste-  roids, and cryosurgery, may be useful in selected individuals.  Severe scarring may be treated with dermabrasion, lasers, and  resurfacing techniques. Special consideration must be given to  treatment for those with darker skin because they have greater    risk for hyperpigmentation and keloidal scarring.° Psychosocial  morbidity is significant, particularly in adolescents.*7   Acne conglobata is a highly inflammatory form of severe  acne with communicating cysts and abscesses beneath the skin  that can cause scarring. Remissions tend to occur during the  summer, perhaps from more exposure to sunlight. This type of  acne requires the use of systemic and combination therapies to  prevent drug resistance.    Atopic dermatitis (AD), also known as atopic eczema, occurs  with a prevalence rate up to 20% in children. AD is increas-  ing throughout the world.* Onset is usually from 2 to 6 months  of age, and 85% of cases occur within the first 5 years of life;  75% to 80% of individuals with AD have a personal or family  history of asthma, allergic rhinitis (hay fever), or food allergy.  The cause of this chronic relapsing form of pruritic eczema  involves an interplay of genetic predisposition, altered skin bar-  rier function associated with filaggrin gene missense mutations  (proteins that bind keratin in the epidermis), reduced ceramide  (a stratum corneum lipid) levels, altered innate immunity, and  altered immune responses to allergens, irritants, and microbes.”   There is debate as to whether the pathophysiology favors  an “inside-out” explanation with immunologic dysregulation  leading to epidermal barrier abnormality or an “outside-in”  explanation with primary barrier dysfunction as the cause of  the immunologic perturbations.'? Regardless of the debate,  both are involved in the disease. Positive skin tests to a variety of  common food and inhalant allergens are seen in approximately  80% of individuals. Children with atopic dermatitis are more  likely to have asthma.'!   In AD, memory T cells in the blood express cutaneous lym-  phocyte antigen (CLA), which leads to the homing of lympho-  cytes to the skin. Inflammation is associated with activation of  Th2 and Th1 cells with release of numerous cytokines, chemo-  kines, interferon-gamma (IFN-y), and granulocyte-macrophage  colony-stimulating factor (GM-CSF). Activation of mast cells,  eosinophils, and macrophages and expression of IgE contribute  to the inflammation.”   Alterations in filaggrin protein lead to a defect of the epi-  dermal barrier that causes transepidermal water loss and allows  easy penetration of pathogens and allergens through the skin  and a systemic hyperactive immune response. Filaggrin gene  mutations also are associated with increased risk for asthma  in AD and ichthyosis vulgaris (dry, scaly skin). In AD kerati-  nocytes are deficient in their ability to express Toll-like anti-  microbial peptides (see Chapter 7), and may predispose such  individuals to skin colonization and infection with Staphylococ-  cus aureus, viruses, and fungi.!°   AD has a long-term course with frequent exacerbations,  severe pruritus, and characteristic eczematoid appearance with  redness, edema, and scaling (Figure 47-2). The skin becomes  increasingly dry, sensitive, itchy, and easily irritated because the  barrier function is impaired. Microscopic epidermal cracks that  allow water to be expelled and irritants, allergens, and microbes    _ i  FIGURE 47-2 Atopic Dermatitis. Characteristic lesions with crusting from  irritation and scratching over knees and around ankles. (Courtesy Department of    to enter further inflammation, drying, and cracking. Itching is  the hallmark of atopic dermatitis, and rubbing and scratching  to relieve the itch are responsible for many of the clinical skin  changes of AD. Histamine level is elevated in AD lesions but is  not considered a major pruritogen because blockage of H1 and  H2 receptors alone is ineffective at relieving itch. However, H4  receptor blockers are being evaluated.'* Pruritus is a complex  process with immune and neurologic pathways.!*!°   In infants, the rash appears primarily on the face, scalp,  trunk, and extensor surfaces of the arms and legs. In older chil-  dren and adults, the rash tends to be found on the neck, ante-  cubital and popliteal fossae, and hands and feet. Lichenification  (thickening of the epidermis from constant scratching) is more  common in adults with chronic eczema. Individuals with AD  tend to develop viral, bacterial, and fungal skin infections in  the areas with eczema. The irritation and itching interfere with  sleep and cause irritability.   There are no specific laboratory features of AD that can be  used for diagnostic purposes, and diagnosis is based on clini-  cal history and presentation of symptoms. Management of  AD requires a systematic, multidimensional, individualized  approach that considers the individual’s skin reaction pattern  and acuity of the rash.'’ Treatment guidelines establish the foun-  dation of AD management, addressing the skin barrier defect  with regular use of emollients and skin hydration along with  the identification and avoidance of specific and nonspecific trig-  ger factors. Various topical agents are mainstays of treatment.  Topical corticosteroids and calcineurin inhibitors continue to  dominate therapy and, to date, their safety record seems good    FIGURE 47-3 Diaper Dermatitis. A, Diaper dermatitis with erosions. B, Dia-  per dermatitis with Candida albicans secondary infection. (Courtesy Department of  Dermatology, School of Medicine, University of Utah.)    (despite the Black Box warning issued in the United States). In  severe cases that cannot be controlled, guidelines suggest sys-  temic treatment options including systemic corticosteroids,  cyclosporine A, ultraviolet light therapy, and wet wrap therapy  being added to the topical treatment regimen. Systemic cortico-  steroids are known to be effective in short-term treatment of AD,  but evidence is limited to support their use because of long-term  side effects and rebound flaring.!*° Research is in progress to  develop targeted molecular therapy that is safe and cost-effective.   Diaper dermatitis is a form of irritant contact dermatitis initi-  ated by a combination of factors that include prolonged expo-  sure to and irritation by urine and feces, maceration by wet  diapers, complications from use of airtight plastic diaper covers,  and possibly increased association with intercurrent illnesses  and early introduction of cereals. Disposable diaper designs  have decreased diaper dermatitis in infants.”! Diaper dermatitis  is frequently secondarily infected with Candida albicans.   The lesions vary from mild erythema to erythematous papu-  lar lesions. Candidal (monilial) diaper dermatitis is usually very  erythematous, with sharp margination and pustulovesicular  satellite lesions (Figure 47-3).   Treatment includes changing the diaper frequently to keep  the area clean and dry or frequently exposing the perineal area  to air, using super-absorbent diapers, and applying topical pro-  tection with a product containing petrolatum or zinc oxide, or  both. Topical antifungal medication is used to treat C. albicans  when present.”    FIGURE 47-4 Impetigo. Multiple crusted and oozing lesions of impetigo.  (From Kliegman RM et al: Nelson textbook of pediatrics, ed 19, Philadelphia, 2011,  Saunders.)    Infectious diseases caused by bacteria, viruses, and fungi con-  stitute the major forms of skin disease. Breaks in the skin integ-  rity, particularly those that inoculate pathogens into the dermis  and epidermis, may cause or exacerbate infections. Most infec-  tions tend to occur superficially; however, systemic signs and  symptoms do develop occasionally and can be life threatening  in immunosuppressed children.   Impetigo is a common bacterial skin infection in infants and  children. The mode of transmission is by both direct and indi-  rect contact. The disease is more common in midsummer to  late summer, with a higher incidence in hot, humid climates.  Impetigo is particularly infectious among people living in  crowded conditions with poor sanitary facilities or in settings  such as daycare facilities. It affects children in good health, but  conditions such as anemia and malnutrition are predisposing  factors. There are two common types of impetigo: nonbullous  and bullous. Both start as vesicles with a very thin vesicular roof  composed of stratum corneum.   Nonbullous impetigo is a contagious, acute, superficial, vesic-  ulopustular form of impetigo caused by Staphylococcus aureus or  group A Streptococcus pyogenes (alone or in combination with  S. aureus). The microorganisms are disseminated by direct phys-  ical contact from other infected individuals or through insect  bites. The lesions begin as small vesicles with a honey-colored  serum. Yellow to white-brown crusts form as the vesicles rup-  ture (Figure 47-4). The lesions must be differentiated from her-  pes simplex lesions (see Figure 46-17, p. 1636). Untreated lesions  may last for weeks and extend to cover a large area. In contrast to  bullous impetigo, regional lymphadenitis is common.   Bullous impetigo is a rarer variant of impetigo caused by  S. aureus.” The pathogen is often carried in the anterior nares,  perineal region, or fingernails and is transmitted by contact  with the individual or contaminated equipment.” The staphy-  lococci produce bacterial toxins called exfoliative toxins (ETs)  that cause a disruption in desmosomal adhesion molecules with    blister formation.”? The blisters enlarge or coalesce to form  superficial bullae. There may be a few localized lesions or many  lesions scattered over the skin. As the bullae rupture, a thin, flat,  honey-colored crust appears.   The crust is the hallmark of impetigo. A moist, inflamed  serum-weeping base is revealed when the crust is removed. The  lesions are often located on the face around the nose and mouth,  but the hands and other exposed areas are also involved. Regional  lymphadenitis is uncommon. Treatment of choice for both  types of impetigo is topical mupirocin and topical fusidic acid  or oral antibiotics. Antibiotic therapy should be determined by  bacterial culture and drug sensitivity because the prevalence of  community-acquired methicillin-resistant S. aureus—associated  impetigo is increasing. For extensive or complicated impetigo,  systemic antibiotics may be warranted but beta-lactam antibiot-  ics should be avoided if methicillin-resistant S. aureus (MRSA)  is suspected.*>° Prompt treatment avoids complications, such  as glomerulonephritis, necrotizing fasciitis, and septic shock  syndrome. Handwashing and isolation of the infected child’s  washcloth, towels, drinking glass, and linen are important prac-  tices to control this highly contagious disease.    Staphylococcal scalded-skin syndrome (SSSS) is the most seri-  ous staphylococcal infection that affects the skin and usually  is seen in infants and children younger than 5 years.’ SSSS is  caused by virulent group II staphylococci, which produce an  exfoliative toxin that attacks desmoglein and adhesion molecules  and causes a separation of the skin just below the granular layer  of the epidermis.”* The toxins are usually produced at body sites  other than the skin and arrive at the epidermis through the cir-  culatory system. Staphylococci typically are not found in the skin  lesions themselves. Adults have circulating antistaphylococcal  antibodies and are better able to metabolize and excrete the toxin.  Newborns and premature infants are at the highest risk because  of immature immunity (absence of prior exposure to the toxin).   The clinical symptoms begin with fever, malaise, rhinorrhea,  and irritability followed by generalized erythema with exqui-  site tenderness of the skin. There may be an associated impe-  tigo, but the infection often begins in the throat or chest. The  erythema spreads from the face and trunk to cover the entire  body except the palms, soles, and mucous membranes. Within  48 hours, blisters and bullae may develop, giving the child the  appearance of being scalded (Figure 47-5). The pain is severe.  Fluid loss from ruptured blisters and water evaporation from  denuded areas may cause dehydration and loss of body heat.  Perioral and nasolabial crusting and fissures develop. In severe  cases the skin of the entire body may slough. When secondary  infection can be prevented, healing of the involved skin occurs  in 10 to 14 days, usually without scarring.   Before medical intervention is begun, culture, histology, or  exfoliative cytology must be done to differentiate SSSS from  toxic epidermal necrolysis (TEN) (see p. 1664). When the infec-  tion is confirmed, treatment with oral or intravenous antibiot-  ics is begun. Topical antibiotics are ineffective. The skin should  be treated the same as that with a severe burn—with meticulous  aseptic technique. Skin substitutes may be used for adjuvant    FIGURE 47-5 Staphylococcal Scalded-Skin Syndrome (SSSS). The skin  lesions, showing desquamation and wrinkling of the skin margins, appeared 1 day  after drainage of a staphylococcal abscess. (From Habif TP: Clinical dermatology: a  color guide to diagnosis and therapy, ed 5, St Louis, 2010, Mosby.)    Fungal disorders are known as mycoses and, when caused by  dermatophytes (fungi that thrive on keratin), the mycoses are  termed tinea (dermatophytosis or ringworm). The different  types of tinea are classified according to their location on the  body. Tinea pedis (a chronic, superficial fungal infection of  the skin of the foot) occurs in children but is rare. Scaling dis-  orders of the toes and feet in prepubertal children are usually  eczema. Tinea capitis (infection of the scalp) and tinea corpo-  ris (infection of the body) are much more common in children  than in adults. Dermatophytes of the genus Epidermophyton  are the major cause of superficial fungal infections in chil-  dren.*” These dermatophytes invade the stratum corneum and  not the remainder of the epidermis or dermis. The inflamma-  tory response is thought, in part, to be secondary to the toxins  released by the dermatophyte. It is important to confirm by cul-  ture the exact microorganism that is causing the fungal infec-  tion before commencing therapy.    FIGURE 47-6 Tinea Capitis. (Courtesy Department of Dermatology, School of  Medicine, University of Utah.)   Tinea capitis, a fungal infection of the scalp, is the most com-  mon fungal infection of childhood. It rarely affects infants and  is seen in children younger than age 12. Primary microorgan-  isms responsible for the disease are Trichophyton tonsurans  and Microsporum canis. T. tonsurans is transmitted by human-  to-human contact. Areas of crowding are the most prevalent  environments for this microorganism, which frequently affects  inner-city children. T. tonsurans is often the predominant der-  matophyte found in North America; many of these infections  are not symptomatic.*! The prevalence of asymptomatic carri-  ers among household contacts of a child with active T. tonsurans  disease is high. M. canis is found on cats, dogs, and certain  rodents. Humans appear to be a terminal host for M. canis, and  children who handle such animals are possible hosts. Human-  to-human transmission does not occur with M. canis.   When symptoms are present, the clinical presentations vary,  depending on the microorganism. Often the lesions are circular  and manifest by broken hairs 1 to 3 mm above the scalp, leaving  a partial alopecia 1 to 5 cm in diameter* (Figure 47-6). Slight  erythema and scaling with raised borders can be observed.   Diagnosis is best confirmed by performing Wood light  examination, potassium hydroxide (KOH) examination, and  fungal culture, in that order. T. tonsurans does not fluoresce  with Wood light examination. Oral griseofulvin is the treat-  ment of choice because topical fungicides do not penetrate to  the hair bulb. Terbinafine, itraconazole, and fluconazole are  effective alternatives.°! Adjunct therapy includes 2% ketocon-  azole and 1% selenium sulfide shampoos. Treatment of house-  hold contacts with a sporicidal shampoo should be considered  and co-sleeping and comb-sharing must be discouraged.   Tinea corporis (ringworm) is a common superficial der-  matophyte infection in children. The microorganisms most  commonly responsible for this disease are M. canis and Tricho-  phyton mentagrophytes. As in tinea capitis, contact with kittens  and puppies is a common source of the disorder. Tinea corpo-  ris preferentially affects the nonhairy parts of the face, trunk,  and limbs. Lesions are often erythematous, round or oval scal-  ing patches that spread peripherally with clearing in the center,    creating the ring appearance, which is why this disease is com-  monly referred to as ringworm. The lesions are distributed  asymmetrically, and multiple lesions (when present) overlap.  Transmission occurs by direct contact with an infected lesion  and through indirect contact with personal items used by the  infected person. Potassium hydroxide examination of the scale  from the border of the lesions confirms the diagnosis for most  lesions. Most lesions respond well to applications of appropri-  ate topical antifungal medications.*°    Thrush is the term used to describe the presence of Candida  albicans in the mucous membranes of the mouth of infants and  less commonly in adults, and both may be immune compro-  mised. C. albicans penetrates the epidermal barrier more easily  than other microorganisms because of its keratolytic proteases  and other enzymes. C. albicans attracts neutrophils to skin sites  of invasion but evades neutrophil killing.°* Thrush is character-  ized by the formation of white plaques or spots in the mouth  that lead to shallow ulcers. The tongue may have a dense, white  covering. The underlying mucous membrane is red and tender  and may bleed when the plaques are removed. The disease is  often accompanied by fever and gastrointestinal irritation. The  infection commonly spreads to the groin, buttocks, and other  parts of the body. Treatment may be difficult and may include  oral antifungal washes, such as nystatin oral suspension. Gen-  tian violet can also be effective but is messy.** Simultaneous  treatment of a Candida nipple infection or vaginitis in the  mother is helpful in reducing the C. albicans surface coloniza-  tion of the infant. Feeding bottles and nipples should be steril-  ized to prevent reinfection. The diaper area should be kept clean  and dry.    Viral infections of the skin in children are caused by poxvirus,  papovavirus, and herpesvirus. The most common infections are  described here.    Molluscum contagiosum is a common highly contagious pox-  virus infection of the skin and occasionally conjunctiva that  affects school-aged children and sexually active young adults.  The disease can be more severe or prolonged in individuals  with atopic dermatitis and a variety of immunodeficient states,  including acquired immunodeficiency syndrome (AIDS). It is  transmitted by skin-to-skin contact (e.g., contact sports), auto-  inoculation, and fomites, such as clothing, wash devices, and  towels. The poxvirus induces epidermal cell proliferation and  blocks immune responses that would control the virus. The  epidermis grows down into the dermis to form saccules con-  taining clusters of virus. The characteristic molluscum body is  composed of mature, immature, and incomplete viruses and  cellular debris.°°   The lesions of molluscum are discrete, slightly umbilicated,  dome-shaped papules 1 to 5 mm in diameter that appear any-  where on the skin or conjunctiva. The skin distribution in chil-  dren is mainly on the trunk, face, and extremities (Figure 47-7).    The pubic, genital, and perineal areas are favored in adults.  Usually no inflammation surrounds molluscum lesions unless  they are traumatized or secondary infection occurs. Scarring  may occur with healing.   The best three diagnostic procedures are: (1) staining  smears of the expressed molluscum body, (2) examining a  biopsy, and (3) inoculating a molluscum suspension into cell  cultures to demonstrate the cytotoxic reactions. Most lesions  are self-limiting and clear in 6 to 9 months if not manipulated.  However, because children often do manipulate these lesions,  spontaneous involution may take 2 to 4 years without therapy.   Treatment options include immunomodulatory and antivi-  ral therapy and destructive procedures (cryotherapy, curettage,  or laser ablation); however, no treatment is universally effective.  Treatment is recommended for genital molluscum to prevent  sexual transmission and autoinoculation.*° Destructive therapy  is poorly tolerated by children. Measures to prevent spread of  infection must be taken and recurrences are common.    Rubella is a common communicable disease of children and  young adults caused by a ribonucleic acid (RNA) virus that  enters the bloodstream through the respiratory route. This  disease is mild in most children. The incubation period ranges  from 14 to 21 days. Prodromal symptoms are few but may  include enlarged cervical and postauricular lymph nodes, low-  grade fever, headache, sore throat, runny nose, and cough. A  faint-pink to red, coalescing maculopapular rash develops on  the face, with spread to the trunk and extremities, sparing the  palms of the hands and soles of the feet, 1 to 4 days after the  onset of initial symptoms (Figure 47-8). The rash is thought to  be the result of virus dissemination to the skin. The rash sub-  sides after 2 to 3 days, usually without complications. Children  are generally not contagious after development of the rash.  There is lifelong immunity to rubella—as there is for measles,  chickenpox, and roseola—after contracting the disease. Differ-  ential presentations of viral diseases producing rashes are given  in Table 47-1.    FIGURE 47-7 Molluscum Contagiosum. Waxy pink globules with umbili-  cated centers. (From Habif TP: Clinical dermatology: a color guide to diagnosis and  therapy, ed 5, St Louis, 2010, Mosby.)    Vaccination for rubella is usually combined with vaccines for  mumps and measles (rubeola) (MMR). Vaccine recommenda-  tions are presented in Chapter 10. Measles are known to occur in  previously immunized children.*” Rubella has almost been elim-  inated in the United States because of vaccination campaigns.  However, challenges to maintain elimination include large out-  breaks of measles in highly traveled developed countries, fre-  quent international travel, and clusters of U.S. residents who  remain unvaccinated because of personal belief exemptions.°*    FIGURE 47-8 Rubella (Measles). Maculopapular rash with tendency to  coalesce. The rash is similar to rubeola (red measles) but less intense. (From  Marx JA et al: Rosen's emergency medicine: concepts and clinical practice, ed 7,  Philadelphia, 2010, Mosby.)    Although the MMR vaccine may rarely be associated with  adverse neurologic events (e.g., seizures because of fever, deaf-  ness), studies conclude that MMR immunization does not  cause autism.°”*? Lack of vaccination, however, leads to sig-  nificant morbidity and mortality, with pneumonia, croup, and  encephalitis being causes of death worldwide.*!   Women of childbearing age are immunized if their rubella  hemagglutination-inhibition titer is low. Pregnancy should  be avoided for 3 months after vaccination because the attenu-  ated virus in the vaccine may remain for this period. However,  accidental receipt of MMR vaccination is not known to cause  maternal or fetal complications, or both.*? Pregnant women  who have rubella early in the first trimester may have a fetal  death or a fetus that develops congenital defects.“4   There is no specific treatment for rubella. Recovery is spon-  taneous, although lymph nodes may remain enlarged for weeks.  Supportive therapy includes rest, fluids, and use of a vaporizer.  In rare cases a mild encephalitis or peripheral neuritis may fol-  low rubella.    Rubeola is a highly contagious, acute viral disease of children.  It is transmitted by direct contact with droplets from infected  persons and is caused by an RNA-containing paramyxovirus  with an incubation period of 7 to 12 days, during which time no  symptoms manifest. The virus enters the respiratory tract and  attaches to dendritic cells and alveolar macrophages, amplifies  in local lymphatic tissue, and progresses to systemic disease.*°  Prodromal symptoms include high fever (up to 40.5° C [104.9°  F]), malaise, enlarged lymph nodes, runny nose, conjunctivi-  tis, and “barking” cough. Within 3 to 4 days, an erythematous  maculopapular rash develops over the head and spreads dis-  tally over the trunk, extremities, hands, and feet. Early lesions  blanch with pressure, followed by a brownish hue that does not  blanch as the rash fades. Characteristic pinpoint white spots  surrounded by an erythematous ring develop over the buccal  mucosa and are known as Koplik spots. These spots precede the    Koplik spots 1-3 days before rash  Rash develops when fever subsides    Eruption of new lesions for 4-5 days  Occasional ulcerative lesion in the  mouth    rash by 1 to 2 days and are usually missed because they appear  so early. The rash then subsides within 3 to 5 days.  Complications associated with measles may be caused by the  primary infection or a secondary bacterial infection. Measles  encephalitis occurs in about 1 of 800 cases, and most children  recover completely. Only a small minority develop permanent  brain damage or die. Bacterial complications include otitis  media and pneumonia, usually caused by group A hemolytic  streptococcus, Haemophilus influenzae, or S. aureus infection.  Measles is prevented by a single vaccination of live attenu-  ated measles virus. There is no specific treatment for measles,  and supportive therapy is the same as for rubella. Antibiotic  therapy is initiated if secondary bacterial infections develop.    Roseola is a presumed viral infection of infants between 6 months  and 2 years of age, but it can be seen in children as old as 4 years.  The incubation period is 5 to 15 days, followed by the sudden  onset of fever (38.9° to 40.5° C [102° to 104.5° F]) that lasts 3  to 5 days. After the fever an erythematous, nonpruritic macular  rash that lasts about 24 to 48 hours develops primarily over the  trunk, neck, and arms. Children usually feel well, eat normally,  and have few other symptoms. Usually no treatment is required  and there are no complications.    Chickenpox and Herpes Zoster  Chickenpox (varicella) and herpes zoster (shingles) are pro-  duced by the varicella-zoster virus (VZV). VZV is a complex  herpes group deoxyribonucleic acid (DNA) virus. The incuba-  tion period is 10 to 27 days, averaging 14 days. Productive infec-  tion occurs within keratinocytes such that the vesicular lesions  occur in the epidermis, and an inflammatory infiltrate is often  present. Histologically, VZV lesions form intraepidermal vesi-  cles. Infected keratinocytes degenerate, swell, detach from each  other, and often contain inclusions surrounded by a clear halo  and a circle of darkly staining chromatin. As the vesicle evolves,  polymorphonuclear cells enter the vesicle and can lead to a pus-  tular appearance. The vesicle eventually ruptures and is followed  by crust formation. On mucous membranes the vesicles rupture  and leave superficial, transient ulcers. Varicella occurs in people  not previously exposed to VZV, whereas herpes zoster occurs in  partially immune individuals who have had varicella.*°  Chickenpox (Varicella). Chickenpox is a disease of early  childhood, with 90% of children contracting the disease during  the first decade of life. It is a highly contagious virus that is  spread by person-to-person contact and airborne droplets.  Introduction of an infected person into a household results  in a 90% possibility of susceptible persons in the household  developing the disease within the incubation period—usually  14 days. Children are contagious for at least 1 day before  development of the rash. Transmission of the virus may occur  until approximately 5 to 6 days after the onset of the first skin  lesions in healthy children. In inmunocompromised children  the virus is recoverable for a longer period, but these children  must be considered contagious for at least 7 to 10 days.  Healthy children who develop chickenpox have no prodromal  symptoms. The first sign of illness may be itching or the    FIGURE 47-9 Chickenpox. A, Early stage lesions; B, late stage lesions. (A from  Long SS et al: Principles and practice of pediatric infectious diseases, ed 4, Philadel-  phia, 2012, Saunders. B courtesy of David Effron, MD. From Marx J et al: Rosen's  emergency medicine: concepts and clinical practice, ed 7, Philadelphia, 2010, Mosby.)    appearance of vesicles, usually on the trunk, scalp, or face. The  rash later spreads to the extremities. Characteristically, lesions  can be seen in various stages of maturation with macules,  papules, and vesicles present in a particular area at the same  time (Figure 47-9). The vesicular lesions are superficial and  can be easily ruptured. New lesions will erupt for 4 to 5 days,  until there are approximately 100 to 300 in different stages of  development. The vesicles become crusted, with only the crust  remaining. Occasionally a vesicle may appear on the palm  later in the disease. Although uncommon, ulcerative lesions  are sometimes seen in the mouth and, less commonly, on the  conjunctiva and pharynx. Fever usually lasts 2 to 3 days and  ranges from 38.5° to 40° C [101.3° to 104° F]).   Complications are rare in children but more common in  adults. They can include transient hematuria (from rupture of  vesicles in the bladder), epistaxis, laryngeal edema, and varicella  pneumonia. One case of chickenpox produces almost complete  immunity against a second attack. Rarely, the fetus may be mal-  formed (congenital varicella syndrome) if chickenpox develops  in the mother in the first trimester of pregnancy.*”   Infants whose mothers have chickenpox at any stage of  pregnancy have a higher risk of developing herpes zoster  during the first few years of life. Administration of maternal  varicella-zoster immunoglobulin before rash development,  with or without antiviral medication, can modify the pro-  gression of the disease.*®   Uncomplicated chickenpox requires no specific therapy.  Baths, wet dressings, and oral antihistamines are occasionally  helpful to relieve itching and to prevent secondary infection as  a result of scratching. Oral antistaphylococcal drugs should be  given if secondary bacterial infection is present. Zoster immune  globulin may be administered to immunodeficient individuals    if given within 72 hours after exposure to chickenpox. Oral  antiviral drugs may be valuable in reducing symptoms in other-  wise healthy children as well as in immunosuppressed or other  select groups of children.*? Chickenpox can be prevented with a  safe and effective vaccine (see Chapter 10).   Herpes Zoster. Although herpes zoster (shingles) occurs  mainly in adults, approximately 5% of cases are in children  younger than 15 years.°? The pathophysiology and treatment  are reviewed in Chapter 46.   Smallpox (variola) is a highly contagious and deadly but pre-  ventable disease. It is caused by poxvirus variolae. Because of  worldwide mass immunization, the world is now virtually free  of smallpox. Concerns regarding smallpox as a weapon of bio-  terrorism have led to vaccination programs for the military and  for selected civilian populations. The U.S. government has an  adequate supply of smallpox vaccine to vaccinate the popula-  tion in the event of an emergency.”!    Insect bites and infestations are common causes of skin dis-  orders in children and adults. Skin damage occurs by various  mechanisms, including trauma of bites and stings, allergic reac-  tions, transmission of disease, injection of substances that cause  local or systemic reactions, and inflammatory reactions from  retained mouthparts.    Scabies is a contagious disease caused by the itch mite, Sarcoptes  scabiei (Figure 47-10, A), that can colonize the human epider-  mis. Scabies is a common skin infection in tropical settings  and affects large numbers of people, particularly children. It is  transmitted by personal contact and by infected clothing and  bedding. Scabies is often epidemic in areas of overcrowded  housing, in areas with poor sanitation, or in long-term care  institutions. Scabies is often associated with immunocompro-  mised individuals, such as those with human T-cell leukemia/  lymphoma virus I (HTLV-1) and human immunodeficiency  virus (HIV), and can facilitate Streptococcus pyogenes and  Staphylococcus aureus skin infection.» Infestation is initiated by  a female mite that tunnels into the stratum corneum, deposit-  ing eggs and creating a burrow several millimeters to 1 cm long.  Over a 3-week period, the eggs mature into adult mites, which  sometimes can be recognized as tiny dots at the end of intact  burrows.   Symptoms appear 3 to 5 weeks after infestation. The primary  lesions are burrows, papules, and vesicular lesions, with severe  itching that worsens at night. Two or three bites (commonly  referred to as “breakfast, lunch, and dinner”) usually appear ina  line on exposed areas of the skin. Itching is thought to be related  to sensitization to the larval stages of the parasite. In older chil-  dren and adults the lesions occur in the webs of fingers, axil-  lae, and creases of the arms and wrists; along the belt line; and  around the nipples, genitalia, and lower buttocks. Infants and  young children have a different pattern of distribution, with    from its burrow. B, Characteristic scabies bites. (Courtesy Department of Derma-  tology, School of Medicine, University of Utah.)    involvement of the palms, soles, head, back, neck, and face (see  Figure 47-10, B). Secondary infections and crusting develop  from scratching and eczematous changes.   Diagnosis of scabies is made by observation of the tunnels  and burrows and by scraping of the skin with microscopic  examination of the mite or its eggs or feces. Treatment is the  application of permethrin cream, a scabicide. Generalized sca-  bies is treated with oral ivermectin.°* Even with elimination of  all viable scabies microorganisms, itching may persist for 10 days  or longer. All clothing and linens should be washed and dried in  hot cycles or dry-cleaned.   The three known types of human lice are: (1) the head louse  (Pediculus capitis), (2) the body louse (Pediculus corporis), and  (3) the crab or pubic louse (Phthirus pubis). They are highly  contagious parasites that survive by sucking blood. The female  louse reproduces every 2 weeks, producing hundreds of nits  as newly hatched lice mate with old lice. The mouthparts are  shaped for piercing and sucking and attach to the skin while  feeding. When piercing the skin, the louse secretes a toxic saliva;  the mechanical trauma and toxin produce a pruritic dermatitis.  Head and body lice are acquired by personal contact, combs,  or brushes. Crab lice are spread by body contact, such as con-  tact with an infected adult. Sharing clothing is also a common  source of transmission.>*    FIGURE 47-11 Flea Bites. Flea bite producing an urticarial wheal with central    puncture. (Courtesy Department of Pediatrics, Division of Allergy and Immunology,  National Jewish Health.)    Itching is the major symptom of lice infestation. In head  lice infestation the ova attach to hairs above the ears and in  the occipital region. The primary lesion of the body louse is  a pinpoint red macule, papule, or wheal with a hemorrhagic  puncture site. The primary lesion often is not seen because it  is masked by excoriations, wheals, and crusts. The crab louse is  found on pubic hairs but also may involve other body hair such  as eyelashes, mustache, beard, and axillae. Young children par-  ticularly may become infected with crab lice on their eyebrows  or eyelashes.   The live louse, 2 to 3 mm long, is rarely observed, although the  ova, or nits, can be observed as oval, yellowish pinpoint specks  fastened to a hair shaft. The ova fluoresce under an ultraviolet  light (Wood lamp) and can be best observed with a microscope.  Infestations can be treated with a topical pediculicide (i.e., per-  methrin) or oral ivermectin.°° Head lice are effectively treated  with topical ivermectin.*° All clothes, towels, bedding, combs,  and brushes should be washed and dried in hot air or boiled,  or the clothes should be ironed. Individuals who have personal  contact also should be treated.    Young children are very susceptible to flea bites, and the most  common are the bites of cat, dog, and human fleas.°” Bites  occur in clusters along the arms and legs or where clothing  fits tightly. The bite produces an urticarial wheal with a cen-  tral hemorrhagic puncture (Figure 47-11). Treatment includes  spraying carpets, crevices, and furniture with malathion or lin-  dane powder. Infected animals should be treated, and clothes  and bedding should be washed in hot water.    FIGURE 47-12 Bullous Bedbug Bites. (Courtesy Department of Dermatology,  School of Medicine, University of Utah.)    The common bedbug, Cimex lectularius, is a blood-sucking  nocturnal parasite of man. Chickens, bats, and some domestic  animals are the other hosts for this bug.°* Bedbugs live in the  crevices and cracks of floors, walls, and furniture and in bed-  ding or furniture stuffing. They are 3 to 5 mm long and reddish  brown. Bedbugs are nocturnal, emerging to feed in darkness,  are attracted by warmth and carbon dioxide, and attach to the  skin to suck blood. Feeding occurs for 5 to 15 minutes; then the  bedbug leaves. It will move long distances to search for food and  can travel from house to house.   Immunologic reactions to bedbug saliva vary, but bites typi-  cally yield erythematous and pruritic papules. The face and dis-  tal extremities, areas uncovered by sleeping clothes or blankets,  are preferentially involved. If the host has not been previously  sensitized, the only symptom is a red macule that develops into  a nodule, lasting up to 14 days. In sensitized children and adults,  pruritic wheals, papules, and vesicles may form (Figure 47-12)  and, rarely, anemia and angioedema. Most lesions respond to  antihistamines or corticosteroids. Secondary infections require  antibiotic treatment. Bedbugs are eliminated by inspecting  and cleaning or disposing of bedding, mattresses, furniture,  and other contaminated items, and by using applications of  approved insecticides, usually by a professional.°?    Cutaneous vascular anomalies are frequent tumors of early  infancy and can be categorized as either hemangiomas or vas-  cular malformations.   Hemangiomas are benign tumors that form from the rapid  growth of vascular endothelial cells, which results in forma-  tion of extra blood vessels. Hemangiomas can be superficial  or deep. Superficial hemangiomas are known as strawberry  hemangiomas, and deep lesions are known as cavernous hem-  angiomas. The etiology may be related to embolization of fetal  placental endothelial cells in association with placental trauma  or loss of placental angiogenic inhibitor of placental and mater-  nal origin.°! There is proliferation of mast cells that are thought    to promote the angiogenesis. Infiltration of fat cells, fibrosis,  and the rich vascular network give the lesions a firm, rubbery  feel. Females are affected more often than males. About 30%  of hemangiomas are apparent at birth, with most emerging  during the first few weeks of life; they grow rapidly during the  first few years, and then shrink or involute during childhood  years. With involution the lesions become darker in color and  then gradually turn to a flesh color. There may be some residual  telangiectasia. Most require no treatment depending on loca-  tion. Hemangiomas located over the eye, ear, nose, mouth, ure-  thra, or anus may require treatment because they interfere with  function and have a higher risk for infection or injury. Rapidly  progressing hemangiomas are treated with propranolol with  regression occurring within 2 weeks; propranolol should be  considered a first-line agent.©* Other therapies include systemic  or intralesional steroids, cryosurgery, laser surgery, sclerother-  apy, and embolization. Interferons, vincristine, cyclophospha-  mide, and radiotherapy can suppress angiogenesis.   Strawberry hemangiomas are distinct superficial hemangio-  mas that may be present at birth but usually emerge 3 to 5 weeks  after birth. They proliferate and become bright red and elevated  with minute capillary projections that give them a strawberry  appearance. Only one lesion is usually present, and it is located  on the head and neck area or trunk (Figure 47-13). After the  initial growth, the lesion grows at the same rate as the child and  then starts to involute at 12 to 16 months of age. Approximately  90% of strawberry hemangiomas involute by 5 to 6 years of age,  usually without scarring.   Cavernous (congenital) hemangiomas are present at birth  and have larger and more mature vessels within the lesion than  strawberry hemangiomas. Some lesions, however, are com-  posed of a mixture of strawberry and cavernous hemangiomas.  They appear primarily on the head and neck, are bluish red,  and have less distinct borders (Figure 47-14). Cavernous hem-  angiomas grow rapidly up to 6 months of age and mature by  1 year of age. A period of involution begins and proceeds for    Pi Bde. 72  FIGURE 47-14 Cavernous Hemangioma. (Courtesy Department of Dermatol-  ogy, School of Medicine, University of Utah.)    6 to 12 months, with complete involution by 2 to 3 years in 30%  of children and by 9 years of age in 90% of children.    Vascular malformations are congenital anomalies of blood ves-  sels present at birth but may not be apparent for several years.  They grow proportionately with the child and never regress.°°  The malformations occur equally among males and females.  Occasionally they expand rapidly, particularly during the hor-  monal changes of puberty or pregnancy and in association with  trauma. Vascular malformations are classified as low flow or high  flow. Low-flow malformations involve capillaries, veins, and lym-  phatics. High-flow malformations involve arteries. In addition to  locations within the skin they may involve the gastrointestinal  tract, bone (Maffucci syndrome), facial capillary malformation,  skin, vascular malformation of the eye, and vascular malforma-  tion of the brain (leptomeningeal hemangioma—Sturge-Weber  syndrome).°! Overgrowth syndromes can occur with either high-  or low-flow malformations, with overgrowth of the underlying  structures (i.e., legs, arms, facial bones). The most common  vascular malformation is nevus flammeus (port-wine stain) and  salmon patches (stork bite, angel kiss).   Port-wine (nevus flammeus) stains are congenital malfor-  mations of the dermal capillaries. Sturge-Weber syndrome is  a port-wine stain distributed along the ophthalmic branch of  the trigeminal nerve and is associated with the leptomenin-  ges of the brain and choroid, glaucoma, seizures, stroke, and  intellectual disability. These capillary malformation are associ-  ated with a mutation in the GNAQ gene (Guanine nucleotide-  binding protein G, q polypeptide).°* The lesions are flat, and  their color ranges from pink to dark reddish purple. They are  present at birth or within a few days after birth and do not fade  with age. Involvement of the face and other body surfaces is  common, and the lesions may be large (Figure 47-15). Dur-  ing adolescence and later adult years, the port-wine stain may  become papular and cavernous. The flashlamp pulsed dye laser    FIGURE 47-15 Capillary Malformation in a Child. (Courtesy Department of  Dermatology, School of Medicine, University of Utah.)    is the treatment of choice to successfully lighten the color and  flatten the more nodular and cavernous lesions.°! Waterproof  cosmetics may be used to cover the lesions.   Salmon patches (nevus simplex) are macular pink lesions  present at birth and located on the nape of the neck, forehead,  upper eyelids, or nasolabial fold. They are a more superficial  variant of nevus flammeus and one of the most common con-  genital malformations in the skin. The pink color results from  distended dermal capillaries, and 95% fade by 1 and 3 years of  age. Those located at the nape of the neck may persist for a life-  time, but generally do not present a cosmetic problem.   Miliaria is a dermatosis commonly seen in infants. It is char-  acterized by a vesicular eruption after prolonged exposure to  perspiration, with subsequent obstruction of the eccrine ducts.  There are two forms of miliaria: miliaria crystallina and miliaria  rubra. In miliaria crystallina, ductal rupture occurs within the  stratum corneum and appears as 1- to 2-mm clear vesicles with-  out erythema. They rupture within 24 to 48 hours and leave a  white scale. In miliaria rubra the ductal rupture occurs in the  lower epidermis, with inflammatory cells attracted to the site  of the rupture. Miliaria rubra (prickly heat) is characterized  by 2- to 4-mm discrete erythematous papules or papulovesicles  (Figure 47-16). Both forms may become secondarily infected,  requiring treatment with systemic antibiotics. The key to man-  agement is avoidance of excessive heat and humidity, which  cause sweating. Light clothing, cool baths, and air conditioning  assist in keeping the skin surface dry and cool.    FIGURE 47-16 Miliaria Rubra. Note discrete erythematous papules or papu-  lovesicles. (Courtesy Department of Dermatology, School of Medicine, University  of Utah.)   Erythema toxicum neonatorum (toxic erythema of the new-  born) is a benign, erythematous accumulation of macules, pap-  ules, or pustules that appear at birth or 3 to 4 days after birth.  The lesions first appear as a blotchy, macular erythematous  rash. The macules vary from 1 mm to 1 cm. When papules or  pustules develop, they are light yellow or white and 1 to 3 mm  in diameter. There may be few or several hundred lesions and  any surface of the body can be affected, with the exception of  the palms and soles, where there are no pilosebaceous follicles.  The cause of the lesion is unknown but it may be related to an  innate immune response to the first commensal microflora with  release of mast cell mediators. Eosinophils are abundant in the  lesions. It is self-limiting and resolves spontaneously within a  few weeks of birth. No treatment is required.    Stevens-Johnson Syndrome and Toxic  Epidermal Necrolysis  Stevens-Johnson syndrome (SJS) and toxic epidermal necrol-  ysis (TEN) are rare, severe, immune drug reactions that are  considered to be the same pathologic process but with TEN  being more extensive. The mortality is between 5% and 35%.  Hypersensitivity to drugs includes allopurinol, sulfonamides,  nonsteroidal anti-inflammatory agents, anticonvulsants (i.e.,  phenytoin), and others. There is widespread epidermal (kerati-  nocyte) apoptosis and detachment with drug-specific cytotoxic  T cells and macrophages involved in the immunopathology.°°”  Bursts of nitric oxide formation have been proposed as the  cause of epidermal apoptosis and necrosis. There is destruction  of the epidermis in toxic epidermal necrolysis.°°   The onset of skin eruptions is preceded by malaise, anorexia,  fever, and mild inflammation of the eyelids, conjunctiva,  mouth, or genitalia. Erythema with tenderness is first described  in the trunk, face, and palms, extending to the groin and  mucous membranes. Blisters and bullae form and large areas of  necrotic epidermis may be shed, leaving open, weeping, pain-  ful areas of underlying skin. Complications can include dehy-  dration, protein loss, altered temperature regulation, ocular  complications leading to blindness, and organ failure. About  one third of children have pulmonary complications.” A sever-  ity of illness score for toxic epidermal necrolysis (SCORTEN)    cal scalded-skin syndrome (SSSS) and acute graft-versus-host  disease. Skin biopsy shows full-thickness epidermal necro-    prompt withdrawal of causative drugs and intensive burn  equivalent management, preferably in a burn unit. Treatment  with corticosteroids and intravenous immunoglobulin is con-  troversial and needs further study, which is difficult because the  disease is so rare.’!)7    Acne vulgaris is the most common skin disease, affecting  85% of the population between the ages of 12 and 25 years.    tory lesions related to follicular hyperkeratinization, exces-  sive sebum production, plugging of sebaceous glands, and  P. acnes colonization. Acne conglobata is a severe form of  acne with communicating cysts and abcesses.    family history of asthma and hay fever, and altered skin bar-  rier function. Red, scaly lesions commonly occur on the face,  cheeks, and flexor surfaces of the extremities in infants and  young children.    . Diaper dermatitis is a type of irritant contact dermatitis ini-    tiated by a combination of factors that include prolonged  exposure to urine and feces; frequently the infant becomes  infected secondarily with C. albicans.    Impetigo is a contagious bacterial disease that occurs in two  forms: bullous and vesicular (contagious). The toxins from  the bacteria produce a weeping lesion with a honey-colored  crust.    commonly in young children with low titers of antistaphy-  lococcal antibody. Painful blisters and bullae form over  large areas of the skin, requiring systemic antibiotics for  treatment.    ris (infection of the body) are fungal infections caused by  dermatophytes.    . C. albicans infection is a superficial fungal infection of the    . Rubella (also known as German or 3-day measles) is a    communicable disease characterized by fever, sore throat,  enlarged cervical and postauricular nodes, and a general-  ized maculopapular rash that lasts 1 to 4 days.    toms include high fever, enlarged lymph nodes, conjuncti-  vitis, and a red rash that begins on the head and spreads to  the trunk and extremities and lasts 3 to 5 days. Bacterial and  viral complications may accompany rubeola.    . Roseola is a benign disease of infants with a sudden onset    of fever that lasts 3 to 5 days, followed by a rash that lasts 24  hours.    Chickenpox (varicella) is a highly contagious disease caused  by the VZV. Vesicular lesions occur on the skin and mucous  membranes. Individuals are contagious from 1 day before  the development of the rash until about 6 days after the rash  develops.   Herpes zoster (shingles) is a viral eruption of vesicles on  the skin along the distribution of a sensory nerve caused by  latent activation of the VZV. Children with immune sup-  pression develop more serious complications.   Smallpox (variola) is a highly contagious, deadly disease  that has been eradicated worldwide by vaccination.    Scabies is an itching lesion caused by the itch mite that bur-  rows into the skin, forming papules and vesicles. The mite  is very contagious and is transmitted by direct contact.    parasites that secrete a toxic saliva and damage the skin to  produce a pruritic dermatitis. Lice are spread by direct con-  tact and are recognized by the ova, or nits, that attach to the  shaft of body hairs.    . Flea bites produce a pruritic wheal with a central puncture    floors, furniture, or bedding and feed at night. They pro-  duce pruritic wheals and nodules.    Hemangiomas are benign vascular tumors that emerge at  birth and resolve spontaneously through the childhood  years. Strawberry hemangiomas (distinct, raised vascular  lesions) are more superficial, and cavernous hemangiomas,  with larger and more mature vessels, are deeper lesions.    vessels. Low-flow malformations involve capillaries, veins,  and lymphatics; high-flow malformations involve arteries.    malformation of the dermal capillaries, and salmon patches  are more superficial vascular malformations.    Miliaria is characterized by small pruritic papules or ves-  icles that result from prolonged exposure to perspiration  and subsequent obstruction of the eccrine ducts in infants.    accumulation of macules, papules, and pustules that appear  at birth or 3 to 4 days after birth and then spontaneously  resolve within a few weeks.    . 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As part of your Pageburst Digital Book, you can access the following Integrated Resources:    http://evolve.elsevier.com/McCance/  * Review Questions and Answers  * Online Course: Module 19    Shock, 1668  Cellular Alterations and Impairment  of Cellular Metabolism, 1669  Types of Shock, Clinical Manifestations,  and Treatment, 1671    Shock occurs when the cardiovascular system fails to perfuse  tissues, cells, and organs adequately, resulting in widespread  impairment of cellular metabolism and tissue function. Tissue  perfusion is defined as the adequacy of blood flow through the  small vessels of the extremities to maintain tissue function.! Tis-  sue perfusion can be disrupted by any factor that alters delivery  of blood to cells and tissues and increases oxygen consumption,  such as decreased cardiac output, blood volume, or blood pres-  sure. Shock has many causes and clinical manifestations related  to the type of shock. Ultimately, shock from any cause will  progress to organ failure and death, unless physiologic mecha-  nisms reverse the process or clinical intervention succeeds in  stopping the progression. Untreated, severe shock overwhelms  the body’s compensatory mechanisms that may result in multi-  system organ failure.   Multiple organ dysfunction syndrome (MODS) is progres-  sive and often involves the ultimate failure of two or more organ  systems after a severe illness or injury. The disease process is ini-  tiated and perpetuated by uncontrolled systemic inflammatory  and stress responses and is characterized by a hypermetabolic and  hyperdynamic state that persists as organ dysfunction develops.  For many years the syndrome was referred to as multiple organ    failure or multiple systems organ failure. Gradually it was recog-  nized that the term organ dysfunction more accurately describes  the syndrome as a process of physiologic deterioration.   Major burns result in extensive immediate tissue injury and  thus are a form of trauma with wide-reaching effects on all organ  systems. The cause of injury may be thermal contact, flame,  chemical agents, or electrical agents; each cause requires a dif-  ferent approach in diagnosis and treatment. Closely associated  with thermal burns is smoke inhalation injury, which accounts  for about 25% of all burn unit admissions. As a multiorgan  problem, thermal injuries can have an overwhelming effect  on survival of the burned individual. Regardless of the cause  of burns, the result is a final common pathway of physiologic  response dependent on the extent of burn surface involvement  and the depth of tissue destruction.    Shock can be classified by type, principal pathophysiologic pro-  cess, or clinical manifestations. Classification by type is perhaps  the most useful because it suggests the cause and pathophysio-  logic process of the underlying disorder, which must be treated    CHAPTER 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults    4 Serum albumin T Serum branched-chain  amino acids  T Urea, NH, formation  and synthesis    to prevent the irreversible cellular alterations and impairment of  cellular metabolism. Shock is classified as cardiogenic (caused  by heart failure); neurogenic or vasogenic (caused by altera-  tions in vascular smooth muscle tone); anaphylactic (caused by  hypersensitivity); septic (caused by infection); or hypovolemic  (caused by insufficient intravascular fluid volume).   The body consists of many organs, tissues, and cells that may  function or malfunction at different stages of metabolic impair-  ment. The common pathway in all types of shock is impairment  of cellular metabolism, attributable to decreased delivery of oxy-  gen and nutrients, frequently coupled with an increased demand  and consumption of oxygen and nutrients and a decreased  removal of cellular waste products.’ Figure 48-1 illustrates the  pathophysiology of shock at the cellular level.   In all types of shock, the cells do not receive adequate amounts  of oxygen because of decreased delivery or increased cellular  consumption, or both, and are therefore unable to use oxygen  normally (see Figure 48-1). In cardiogenic shock cardiac output  is too low to deliver adequate oxygen to the cell. In hypovole-  mic shock, oxygen delivery is impaired by inadequate numbers    of red cells that carry oxygen and inadequate blood volume.  In neurogenic, anaphylactic, and septic shock, systemic vascu-  lar resistance (SVR) becomes very low because of vasodilation,  resulting in inadequate perfusion pressure in the capillaries.  Thus, the pressure needed to drive oxygen and nutrients across  cell membranes is inadequate. In septic shock, hypoxia is wors-  ened by increased inflammatory responses, such as fever, that  increase the cell’s oxygen demand and consumption rate, and  by direct toxic and inflammatory chemical disruption of cellular  metabolism, that impairs the cells’ ability to use oxygen.   Both positive and negative compensatory mechanisms, such  as anaerobic metabolism, lysosomal enzyme release, decreased  intravascular volume, and activation of the clotting cascade, may  further impair oxygen delivery and use. Anaerobic metabolism  results in disruption of electrolyte and lysosomal enzymatic  processes, thus changing the normal ionic and osmotic levels  in cells governed by the physical law of diffusion. Diffusion of  nutrients and wastes into and out of the cell takes longer, and  cellular metabolism is further altered. Without oxygen, the cell  shifts from aerobic to anaerobic metabolism. Anaerobic metab-  olism is a less efficient method of extracting energy from carbon  bonds, and the cell begins to use adenosine triphosphate (ATP)  faster than it can be replaced. Without ATP the cell loses its abil-  ity to maintain an electrochemical gradient across its selectively  permeable membrane. Specifically, the cell cannot operate the    sodium-potassium pump. Sodium and chloride accumulate  inside the cell and potassium exits the cell. Cells of the ner-  vous system and myocardium are profoundly and immediately  affected. The resting potentials of these cells are reduced, and the  action potentials decrease in amplitude (see Chapter 1). Myo-  cardial depressant factor also decreases the contractility of the  heart. A variety of clinical manifestations of impaired central  nervous system and myocardial function result.   As sodium moves into the cell, water follows. Throughout  the body, the water drawn from the interstitium into the cells  is “replaced” by water that is in turn drawn out of the vascular  space, often called “third spacing” of fluid. This decreases circu-  latory volume. Within the cells, water causes cellular edema that  disrupts cellular membranes, releasing lysosomal enzymes that  injure the cells internally and leak into the interstitium.   In addition to decreasing ATP stores, anaerobic metabolism  affects the pH of the cell, and metabolic acidosis develops. A  compensatory mechanism is initiated that enables cardiac and  skeletal muscles to use lactic acid as a fuel source, but only for  a limited time. The decreasing pH of the cell that is functioning  under anaerobic conditions has serious consequences. Enzymes  necessary for cellular function dissociate under acidic condi-  tions. Enzyme dissociation stops cell function, repair, and divi-  sion. As lactic acid is released systemically, blood pH drops,  reducing the oxygen-carrying capacity of the blood (see Chap-  ter 2), and the heart’s ability to pump. Therefore, less oxygen  is delivered to the cells and further hypoxia results in acidosis,  which triggers more lysosomal enzyme release caused by dis-  ruption of lysosomal membrane integrity. Lysosomal enzymes  released during shock injure the cell that released them and  injure adjacent cells. By damaging the mechanisms of sur-  rounding cells, lysosomal enzymes extend areas of impaired  metabolism and cellular injury.   Intravascular fluid loss into the intracellular and interstitial  spaces, described as “third spacing” earlier, is amplified when  serum albumin and other plasma proteins are consumed for  fuel, which results in decreased intravascular osmotic pres-  sure, shift of fluid to the interstitial or extracellular spaces,  and decreased circulatory volume. Decreased circulatory vol-  ume magnifies decreased tissue perfusion in all types of shock.  Decreased intravascular volume causes decreased cardiac out-  put in septic shock and further reduces cardiac output in car-  diogenic shock. In individuals with anaphylactic, neurogenic,  or septic shock and an already dilated vasculature, hypotension  worsens as a result of decreased circulatory volume. New data  on additional mechanisms for hypotension (vasodilation) are  illustrated in Figure 48-7 (p. 1678).   Concurrently, diffusion across capillary membranes occurs  more slowly, as blood flow in the capillary beds becomes slug-  gish, caused by decreased fluid volume with increased viscosity of  blood. Sluggish capillary flow decreases tissue perfusion further,  microvascular clots form, and activation of the clotting cascade  may begin (see Chapter 27). Microemboli formation and platelet  aggregation account for common complications of shock, such  as acute tubular necrosis, acute respiratory distress syndrome  (ARDS), and disseminated intravascular coagulation (DIC). It  also may activate or be activated by the inflammatory response.”    Impaired glucose use can be caused by either impaired glucose  delivery or impaired glucose uptake by the cells (see Figure  48-1). The reasons for inadequate glucose delivery are the same  as those enumerated for inadequate oxygen delivery. In addi-  tion, in septic and anaphylactic shock, glucose metabolism may  be increased or disrupted because of fever or bacteria, and  glucose uptake can be prevented by the presence of vasoactive  toxins, endotoxins, histamine, and kinins.   Some of the compensatory mechanisms activated by shock  contribute to decreased glucose uptake and use by the cells.  High serum levels of cortisol, growth hormone, and catechol-  amines account for hyperglycemia and insulin resistance, tachy-  cardia, increased SVR, and increased cardiac contractility. Cells  shift to glycogenolysis, gluconeogenesis, and lipolysis to gener-  ate fuel for survival (see Chapter 1). Except in the liver, kidneys,  and muscles, the body’s cells have extremely limited stores of  glycogen. In fact, total body stores can fuel the metabolism for  only about 10 hours. The depletion of fat and glycogen stores  is not itself a cause of organ failure, but the energy costs of gly-  cogenolysis and lipolysis are considerable and contribute to the  cellular failure.   The depletion of protein is, however, a cause of organ failure.  When gluconeogenesis causes proteins to be used for fuel, these  proteins are no longer available to maintain cellular structure,  function, repair, and replication. The breakdown of protein  occurs in starvation states, hyperdynamic metabolic states, and  septic shock. Under anaerobic metabolism, protein breakdown  liberates alanine, which is converted to pyruvate. Pyruvic acid  is changed into lactic acid, leading to an increased affinity for  oxygen to bind to hemoglobin with resultant hypoxia and  metabolic acidosis.   As proteins are metabolized anaerobically, ammonia and  urea are produced. Ammonia is toxic to living cells. Uremia  develops, and uric acid further disrupts cellular metabolism.  Proteins are broken down preferentially. Serum albumin and  other plasma proteins are consumed for fuel first. Serum pro-  tein consumption decreases capillary osmotic pressure and  contributes to the development of interstitial edema, creating  another negative compensatory outcome that decreases cir-  culatory volume. In septic shock, plasma protein breakdown  includes breakdown of immunoglobulins, thereby impairing  immune system function when it is most needed.   Muscle wasting caused by protein breakdown weakens skel-  etal and cardiac muscle. Skeletal muscle wasting impairs the  muscles that facilitate breathing. Muscle wasting therefore alters  the actions of both heart and lungs. The delivery of oxygen and  glucose to the cells is directly reduced, as is the removal of meta-  bolic waste products, such as the formation of carbon dioxide  and lactic acid, causing metabolic acidosis with resultant inabil-  ity of muscles, organs, and tissues to function mechanically and  electrically.   The metabolic wastes that accumulate in the cell and inter-  stitial spaces are toxic to the cells and further disrupt cellular  function and membrane integrity. In septic shock, for example,  a deficiency in cellular metabolism and the buildup of toxins  may precede and cause decreased tissue perfusion.    CHAPTER 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults    Each type of shock (cardiogenic, hypovolemic, neurogenic, ana-  phylactic, septic) involves numerous clinical manifestations,  signs, and symptoms that also may characterize other conditions,  making diagnosis difficult. An individual’s history and situation  are correlated with the specificity of the shock state suspected  or anticipated. Clinical manifestations common in septic shock  are fever, high heart rate, high respiratory rate, or elevations in  immune responses, such as increased levels of white blood cells  and circulating blood glucose. Subjective complaints often are  nonspecific and general. The individual may report feeling sick,  weak, cold, hot, nauseated, dizzy, confused, afraid, thirsty, and  short of breath.   The initial management for shock is to discover, diagnose,  and correct or remove the underlying cause. Although this  seems a simple tenet, it is one that is not always remembered.  Thus treatment for cardiogenic shock begins with diagnosis and  treatment of heart failure or at least enhancement of cardiac  output. If hypovolemia is the cause of shock, hemorrhage and  other causes of fluid loss must be stopped. In neurogenic shock,  as a result of spinal cord trauma, stabilization of the spine and  surrounding tissue is an initial approach and pain usually can  be decreased to a level at which neutrally-mediated decreases  of SVR cease. The initial treatment for anaphylactic shock is to  remove or neutralize the antigen. Treatment for septic shock  begins with eradication of the infective agent, usually with  antimicrobials.   Simultaneous to correcting the underlying cause or condi-  tion, treatment is directed at targeting improvement of micro-  circulatory tissue perfusion. Optimizing oxygenation is an  absolute necessity in all shock states. The goal has a dual purpose  to both optimize oxygen delivery and reduce oxygen consump-  tion. Intravenous fluid is administered to expand intravascular  volume and thereby improve tissue perfusion by increasing  blood pressure and cardiac output, except in cases of cardio-  genic shock, which require diuresis to reduce preload.   Effective glucose level control in various shock states has  been shown to improve outcomes. Hyperglycemia, caused by  insulin resistance in the liver and muscle, is a common finding  in the critically ill. This is most likely an adaptive response pro-  viding glucose for the brain, red blood cells, and wound heal-  ing. The extent of appropriate glucose level control has been  evaluated in recent years, leading to more aggressive treatment  with continuous, titrating insulin infusions to maintain blood  glucose levels closer to normal, thus promoting normal cellular  function and healing.°   Once cellular and organ dysfunction and physiologic derange-  ment are established, risk of morbidity and mortality increases.  Prevention and early treatment offer the best prognosis.   Cardiogenic shock results from the inability of the heart to  pump adequate blood to tissues and end organs from any cause,  the most common being the short-term consequences of an  acute myocardial infarction or a severe episode of myocardial    ischemia. Cardiogenic shock is defined as persistent hypotension  and tissue hypoperfusion caused by cardiac dysfunction in the  presence of adequate intravascular volume and left ventricular  filling pressure.° Pathologic conditions that reduce contractility,  cause pump failure, impair diastolic filling, or cause obstruction  can lead to cardiogenic shock. Decreased contractility and pump  failure can result from (1) acute myocardial infarction (AMD),  cardiomyopathy, sepsis, myocarditis, pericarditis, aneurysm,  dysrhythmias, contusion, metabolic abnormalities, papillary  muscle rupture; (2) impaired diastolic filling related to dysrhyth-  mias; and (3) obstruction attributable to pulmonary embolism,  cardiac tamponade, valvular disorders, tumors, and wall rupture  or defects.’   Overall hospital mortality because of cardiogenic shock has  decreased from approximately 90% in the 1970s to a recent esti-  mate of 50%.°   As cardiac output decreases, compensatory adaptive  responses are activated, such as the renin-angiotensin, neuro-  hormonal, and sympathetic nervous systems, that lead to fluid  retention, systemic vasoconstriction, and tachycardia.’ Activa-  tion of the inflammatory response (resulting in expression of  inducible nitric oxide synthase), activation of inflammatory  cytokines, and activation of the complement system appear  to play an important role in the pathogenesis and outcome of  cardiogenic shock.!° Increases in contractility, heart rate, and  blood pressure are maintained in mild shock states through  vasoconstriction in response to catecholamine release from  the adrenals. Vasoconstriction increases vascular resistance to  normalize blood pressure and increases cardiac performance  by returning more blood volume and increasing perfusion  to the heart; however, this increases myocardial demand and  consumption of oxygen and nutrients by the heart. Increas-  ing myocardial requirements burden the already failing heart,  which can no longer pump an adequate volume of blood with  sufficient force to perfuse the tissues. Thus increased coronary,  tissue, and cellular ischemia further deteriorates myocardial  function and shock.   Mortality in cardiogenic shock is reduced by use of intra-  aortic balloon counterpulsation (IABP); cardiosupportive drug  regimens and early coronary interventions have also improved  outcomes.!”!?_ Following myocardial infarction, reperfu-  sion and revascularization can be achieved with treatment  modalities that include fibrinolytic therapies (medications that  disintegrate the coronary thrombus) and percutaneous inter-  ventions (balloon angioplasty, stent placement, and thrombec-  tomies). Surgery (coronary artery bypass, ventriculoplasty, or  heart transplant) is also utilized to open the coronary vessels  during an acute myocardial infarction or to replace irreparable  heart muscle. Cardio-supportive drug and fluid regimens are  initiated to maintain adequate blood pressure and essential  fluid and electrolyte balance, and to optimize coronary perfu-  sion to the myocardium. Mechanical assist devices, specifically  intra-aortic balloon pumps and percutaneous or ventricu-  lar assist devices (VADs), are used to support cardiac output  temporarily until the individual improves or transplantation  is possible.'! Implantable VADs, pacemakers, or internal defi-  brillator devices are sometimes used as permanent treatment    FIGURE 48-2 Cardiogenic Shock. Shock becomes life threatening when compensatory mechanisms (orange boxes)  cause increased myocardial oxygen requirements. ADH, Antidiuretic hormone; SVA, systemic vascular resistance.    for those who survive cardiogenic shock. Continuous hemo-  dynamic monitoring should be employed to evaluate vascular  volume and pressures, optimize fluid levels, and monitor drug  administration with the goal of improving cardiac output and  tissue perfusion.!°   The clinical manifestations of cardiogenic shock are  caused by inadequate perfusion to the heart and end organs  (Figure 48-2). Subjective complaints of chest pain, dyspnea,  and faintness, along with feelings of impending doom, are often  revealed. Classic observable signs and symptoms of tachycardia,  tachypnea, hypotension, jugular venous distention, dysrhyth-  mia, and low measured cardiac output are hallmarks. Cyano-  sis; skin mottling; rapid, faint, or irregular pulses; low urine  output; and occasional peripheral edema are additional signs  and symptoms of end-organ hypoperfusion. Myocardial dys-  function from fluid overload may result in extra heart sounds,  pulmonary edema, hypoxemia, and elevated end-organ labora-  tory values. The amount of brain natriuretic peptide, produced  when the heart stretches in relation to increased volume with  decreased cardiac output, is increased to help diurese the fluid  volume excess.’ Pulmonary edema increases as volume accu-  mulates and expands from the heart into the lungs as evidenced  by audible crackles and wheezes as well as abnormal vascular  congestion on chest radiography. Metabolic abnormalities  involving electrolyte imbalances and elevated levels of inflam-  matory markers may result from or concur with the cardiac  cascade of shock.    Hypovolemic Shock  Hypovolemic shock is caused by loss of whole blood (hemor-  rhage), plasma (burns), or interstitial fluid (diaphoresis, diabetes  mellitus, diabetes insipidus, emesis, or diuresis) in large amounts.  Loss of whole blood or plasma causes hypovolemia directly. Loss  of interstitial fluid causes an indirect “relative” hypovolemia by  promoting diffusion of plasma from the intravascular to the  extravascular space. Hypovolemic shock begins to develop when  intravascular volume has decreased by about 15%.   Hypovolemia is offset initially by compensatory mecha-  nisms (Figure 48-3). Heart rate and SVR increase as a result  of catecholamine release by the adrenals. This boosts cardiac  output and tissue perfusion pressures. Compelled by a decrease  in capillary hydrostatic pressures, interstitial fluid moves into  the vascular compartment. The liver and spleen add to blood  volume by disgorging stored red blood cells and plasma. In the  kidneys, renin (through several intermediaries) stimulates aldo-  sterone release and the retention of sodium (and hence water),  whereas antidiuretic hormone (ADH, or vasopressin) from the  posterior pituitary gland increases water retention. Data on the  compensation of ADH, however, show that as shock worsens,  ADH in plasma decreases. Hypovolemic shock results in com-  pensatory vasoconstriction and increased SVR and afterload in  order to improve blood pressure and perfusion to core organs  of the body.   These compensatory mechanisms are, however, finite.  If the initial fluid or blood loss is great or if loss continues,    CHAPTER 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults    FIGURE 48-3 Hypovolemic Shock. This type of shock becomes life threatening when compensatory mechanisms (orange  boxes) are overwhelmed by continued loss of intravascular volume. ADH, Antidiuretic hormone; SVR, systemic vascular    compensation fails, resulting in decreased tissue perfusion.  Nutrient delivery to the cells is impaired, and cellular metab-  olism fails. Mortality from traumatic hemorrhagic shock  ranges from 10% to 31%. Prompt control of hemorrhage is  the treatment of choice. Fluid replacement is also important,  but the type of fluid to be used and the rate of replacement are  controversial.!*!> The clinical manifestations of hypovolemic  shock include high SVR, poor skin turgor, increased thirst,  oliguria, low systemic and pulmonary preloads, and rapid  heart rates.   Neurogenic shock also is called vasogenic shock. Both terms  refer to a widespread and massive vasodilation that results  from an imbalance between parasympathetic and sympathetic  stimulation of vascular smooth muscle (see Chapter 31). Occa-  sionally, parasympathetic overstimulation or sympathetic  understimulation persists, causing vasodilation for an extended  period. Extreme, persistent vasodilation leads to neurogenic  shock (Figure 48-4). Neurogenic shock creates “relative hypo-  volemia.” Blood volume has not changed, but the amount of  space containing the blood has increased, so that SVR decreases  drastically; thus pressure in the vessels is inadequate to drive  nutrients across capillary membranes, and nutrient delivery to  the cells is impaired. As with other types of shock, this leads to  impaired cellular metabolism.    FIGURE 48-5 Anaphylactic Shock. DIC, Disseminated intravascular coagulation; ECF-A, eosinophil chemotactic factor  anaphylaxis; /g£, immunoglobulin E; SVA, systemic vascular resistance.    Neurogenic shock can be caused by any factor that stimulates  parasympathetic activity or inhibits sympathetic activity of vas-  cular smooth muscle. (Parasympathetic stimulation automati-  cally inhibits sympathetic activity and vice versa; see Chapter 31.)  Normally, sympathetic stimulation maintains muscle tone. If  sympathetic stimulation is interrupted or inhibited, vasodilation  occurs. Therefore, trauma to the spinal cord or medulla, condi-  tions that interrupt the supply of oxygen to the medulla, or condi-  tions that deprive the medulla of glucose (e.g., insulin reactions)  can cause neurogenic shock by interrupting sympathetic activity.  Depressive drugs, anesthetic agents, and severe emotional stress  and pain are other causes of neurogenic shock.   The clinical hallmark of neurogenic shock is a very low SVR,  along with other indicators of excessive parasympathetic activity.  Bradycardia is the most obvious manifestation, especially in the  early stages. Bradycardia may cease when compensatory mecha-  nisms, particularly an increase in sympathetic system activity,  have been initiated. The ejection fraction remains high, indicating  a healthy myocardium, whereas central venous pressure decreases  as the veins dilate. Neurogenic shock causes fainting if blood pres-  sure decreases to the point that cerebral metabolism is not suffi-  cient to support consciousness. Most episodes of fainting are not    shock, however; for such episodes to progress to shock is rare. By  allowing the blood pressure to equalize from head to toe as the  individual becomes prone, fainting can actually prevent shock.    Anaphylactic shock is the outcome of a widespread hyper-  sensitivity to an allergen that triggers a reaction known as  anaphylaxis. (An allergen is an antigen to which an individual  is hypersensitive; see Chapters 7, 8, and 9 for discussions of  immunity, inflammation, and hypersensitivity.) Immunologic  causes are related to the inflammatory and vasodilatory effects  triggered by a pathologic allergic reaction to an antigen. Pro-  duction of mast cells, IgE, and low-affinity IgE receptor (FceRI)  is induced by cellular response to the antigen. Anaphylactoid  type reactions, which are nonimmunologic in origin, can be  related to cold weather, exercise, and contaminants in medica-  tions.'° Physiologic alterations related to the inflammatory and  immune response, similar to neurogenic shock, are massive—  vasodilation, peripheral pooling, and relative hypovolemia lead  to decreased tissue perfusion and impaired cellular metabo-  lism (Figure 48-5). Anaphylactic shock is often severe and has  immediate symptoms, including an itchy rash, throat swelling,    CHAPTER 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults    and low blood pressure, related to the massive vasodilation and  systemic inflammation that may progress to death in minutes if  emergency treatment is not rendered.   Some allergens known to cause hypersensitivity reactions are  foods, insect and snake venoms, pollens, medications, and latex.  Once in the body, the allergen causes the extensive immune and  inflammatory response. The vascular effects of this response  include vasodilation and increased vascular permeability,  resulting in peripheral pooling and tissue edema. The extra-  vascular effects include constriction of extravascular smooth  muscle. Constriction often causes respiratory difficulty because  it tends to affect smooth muscle layers in the airway walls (e.g.,  the larynx and bronchioles; see Chapter 34).   Clinical manifestations of anaphylactic and anaphylactoid  shock may be anxiety, difficulty in breathing, gastrointestinal  cramps, edema, hives (urticaria), sensations of burning or itch-  ing of the skin, fever, and hemolysis. A precipitous decrease in  blood pressure occurs and is followed by impaired mentation.  Other signs include decreased SVR (with high or normal cardiac  output) and oliguria. Treatment begins with removal of the anti-  gen (if possible). Epinephrine is administered to decrease mast  cell and basophil degranulation, cause vasoconstriction, and  reverse airway constriction.!’ Volume expanders (e.g., lactated  Ringer solution) are given intravenously to reverse the relative  hypovolemia, and antihistamines and corticosteroids are given  to stop the inflammatory reaction.   In response to the need for improved anaphylaxis diagnosis  and treatment, the World Allergy Organization (WAO) formu-  lated global guidelines in 2011 for assessment and management  of anaphylaxis.'’ These guidelines were further updated in 2012  to include recommendations for validation of the clinical cri-  teria for diagnosis, use of epinephrine, development of in vitro  tests to distinguish clinical risk from asymptomatic sensitiza-  tion, and immune modulation to prevent anaphylaxis!® (see  What’s New? Anaphylactic Shock).    Septic shock is the endpoint of a continuum of progressive  dysfunction.'® The syndrome begins with systemic inflamma-  tory response syndrome (SIRS), then sepsis, then severe sepsis,  and then septic shock. Consensus on definitions of each com-  ponent was updated at an international sepsis conference in  2003 (Table 48-1).!®° The International Sepsis Forum reviewed  research for sepsis to identify and define the six most common  infection sites (pneumonia, bloodstream, intravascular cath-  eter, intra-abdominal, urosepsis, and surgical wound infection)  associated with sepsis in the intensive care setting.’   Severe sepsis is the tenth most common cause of death in  the United States.’° Mortality ranges from 28% to 60%.*! Sep-  tic shock is caused by gram-negative bacteria, gram-positive  bacteria, and fungi. Advances in antibiotic therapy for gram-  negative sepsis have made gram-positive bacteria the leading  cause of sepsis.?? Even when properly treated with available  therapies, it carries a high mortality rate. Prognosis is signifi-  cantly affected by the source and virulence of the infectious  microorganism.    WHAT’S NEW?  Anaphylactic Shock  In response to the need for improved anaphylaxis diagnosis and treatment,    the World Allergy Organization (WAO) formulated global guidelines in 2011  for assessment and management of anaphylaxis. These guidelines were fur-    ther updated in 2012 to include recommendations for validation of the clinical  criteria for diagnosis, use of epinephrine, development of in-vitro tests to dis-  tinguish clinical risk form asymptomatic sensitization, and immune modulation  to prevent anaphylaxis.    Data from Simons FE et al: Curr Opin Allergy Clin Immunol 12(4):  389-399, 2012.    Septic shock begins with a nidus of infection that may be  readily discernible or extremely difficult to locate (Figure 48-6).  Bacteria and fungi enter the bloodstream to produce bacteremia  in one of two ways: (1) directly from the site of infection, or  (2) indirectly from toxic substances released by the bacteria  directly into the bloodstream. These toxic substances, which act  as triggering molecules in the septic syndrome, include endotox-  ins released by gram-negative microorganisms, lipoteichoic acids  and peptidoglycan released by gram-positive microorganisms,  and superantigens.”   The triggering molecules cause the host to initiate a proin-  flammatory response. Proinflammatory cells released include  polymorphonuclear leukocytes, macrophages, monocytes, and  platelets. Proinflammatory mediators released include cytokines  (interleukins [IL]-1, IL-2, IL-6, IL-8, and IL-15; tumor necrosis  factor-alpha [TNF-a]; and granulocyte cell—-stimulating factor),  complement and complement cascade activation, kinins, arachi-  donic acid metabolites (prostaglandins, prostacyclin, leukotrienes,  and thromboxane), soluble adhesion molecules, platelet-activat-  ing factor, endorphins, vasoactive neuropeptides, histamine, sero-  tonin, monocyte chemoattractant proteins 1 and 2, proteolytic  enzymes (e.g., elastase and lysosomal enzymes), protein kinase,  tyrosine kinase, CD14, toxic oxygen metabolites (e.g., superoxide,  hydroxyl radical, hydrogen peroxide, peroxynitrite), neopterin,  and clotting cascade activation.*** Proinflammatory cytokines  enhance tissue factors, which initiates coagulation. Diminished  thrombomodulin (cell surface glycoprotein of endothelial cells)  inhibits the conversion of protein C and activated protein C. A  compensatory anti-inflammatory response syndrome is pre-  sumed to follow this response.*”** Anti-inflammatory media-  tors released include lipopolysaccharide-binding protein; IL-1  receptor antagonist; soluble CD-14; type 2 IL-1 receptor; leu-  kotriene B, receptor antagonist; IL-4, IL-10, and IL-13; soluble  tumor necrosis factor receptor; transforming growth factor-beta  (TGF-B); epinephrine; and nitric oxide.>>+ Presumably the end  result is a mixed antagonistic response syndrome as proinflam-  matory and anti-inflammatory mediators respond, intensify, and  lead the host into MODS.   Clinical manifestations of septic shock are persistent low  arterial pressure, low SVR from vasodilation, and an altera-  tion in oxygen extraction by all cells. Septic shock and states  of prolonged shock causing tissue hypoxia with lactic acido-  sis increase nitric oxide synthesis, activate ATP-sensitive and    Still viewed as an imperfect definition  Infection can be strongly suspected without microbiologic confirmation    Infection A pathologic process that results from an invasion  of a normal part of the body by pathogenic or  potentially pathogenic microorganisms   Presence of viable bacteria in the blood Neither necessary nor sufficient to make a diagnosis of sepsis   Systemic inflammatory response syndrome is Diagnostic criteria:  manifested by two or more of general variables: 1. General variables  1a through 1d or 2a through 2c a. Fever—core temperature >38.3° C (100.9° F)   Systemic response to infection, which is manifested b. Hypothermia—core temperature <36° C (96.8° F)  by two or more of the SIRS criteria c. Heart rate >90 beats/minute   d. Tachypnea  e. Altered mental status  Significant edema or positive fluid balance (>20 ml/kg over 24 hr)  g. Hyperglycemia (blood sugar >140 mg/dl) in the absence of diabetes    Leukocytosis (WBC count >12,000)  . Leukopenia (WBC count <4000)  c. Normal WBC with >10% immature forms  . Plasma C-reactive protein >2 SD above the normal value  . Plasma procalcitonin >2 SD above the normal value  . Hemodynamic variables  a. Arterial hypotension (SBP <90 mmHg; MAP <70, or an SBP decrease >40 mmHg)  b. SVQ, >70%  c. Cardiac index >3.5 L/min  . Organ dysfunction variables  . Arterial hypoxemia (PaO2/Fi0, <300)  . Acute oliguria (urine output <0.5 ml/kg/hr or 45 ml for at least 2 hr)  . Creatinine increase >0.5 mg/dl  . Coagulation abnormalities (INR >1.5 or a PTT >60)  . lleus  . Thrombocytopenia (platelet count <100,000)  . Hyperbilirubinemia (plasma total bilirubin >4 mg/dl or 70 mmol/L)  . Tissue perfusion variables  a. Hyperlactatemia (>1 mmol/L)  b. Decreased capillary refill or mottling  May be difficult to differentiate underlying organ dysfunction from sepsis-related organ  dysfunction  Persistent systolic blood pressure <90 mmHg   Severe sepsis complicated by persistent hypotension  refractory to early fluid therapy    Data from Dellinger RP et al: Crit Care Med 41(2):580-637, 2013; Levy MM et al: Crit Care Med 312:1250, 2003; Opal SM, Scand J Infect Dis  35:529, 2003.   INR, International normalized ratio; MAP mean arterial pressure; Pa02/FiO>, partial pressure of oxygen in arterial blood/fraction of inspired oxygen; PTT,  partial thromboplastin time; SD, standard deviation; SBP systolic blood pressure; SVO,, saturation of hemoglobin with oxygen; WBC, white blood cell.    calcium-regulated potassium channels (Karp and Kc,, respec-  tively) in vascular smooth muscle (see Chapter 31), and lead    are determined; obtaining blood cultures; starting administra-  tion of antibiotics and antifungals; implementing a fluid chal-    to depletion of ADH (vasopressin) (Figure 48-7). Tachycardia  causes cardiac output to remain normal or become elevated,  although myocardial contractility is reduced. Temperature  instability is present, ranging from hyperthermia to hypother-  mia. Effects on other organ systems may result in deranged  renal function, gastrointestinal mucosa changes that result in  release of bacteria from the gut, jaundice, clotting abnormali-  ties, deterioration of mental status, and tachypnea that often  progresses to ARDS.   Early detection of high-risk illness and rapid implementation  of the following standard protocols are increasingly being used  by hospitals worldwide: decreasing the time before lactate levels    lenge; achieving goals for blood pressure, central venous pressure  (CVP), and central venous oxygen saturation.”?° Promptly ini-  tiated treatment helps reduce mortality and morbidity related to  multiple organ dysfunction. Infection and sepsis identified in the  early stages and treated with antibiotics and fluid resuscitation  may prevent evolution to severe sepsis and shock; however, once  these are identified, more stringent treatment is recommended.  The current guidelines for severe sepsis and septic shock?’ rec-  ommend immediate resuscitation in patients with lactate levels  >4 mmol/L. Elevated lactate levels indicate tissue hypoperfu-  sion and patients should begin early goal-directed therapy or  fluid resuscitation within 6 hours, regardless of blood pressure    CHAPTER 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults   *| e Interleukin 1 alpha and beta (IL-1a and 8), IL-6  ¢ Other proinflammatory cytokines    Altered p/f ratio <300 Urine Hypotension Thrombocytopenia Metabolic acidosis Poor capillary  mental status Tachypnea <0.5 mi/kg/hr || Tachycardia T p-dimer T Lactate refill  Death  FIGURE 48-6 Summary of Sepsis Pathology. p/f (Pa0,/Fi0,), Oxygenation ratio. (A from Lazaron V, Barke RA: Urol Clin  North Am 26[4]:687, 1999. B © 2003, Eli Lilly and Company. All rights reserved. Reprinted with permission from Eli Lilly and    FIGURE 48-7 Mechanisms of Vasodilation in Shock. Vasodilatory shock is caused by the inappropriate activation of  vasodilatory mechanisms and the failure of constrictor mechanisms. Unregulated nitric oxide, by regulating guanylate cyclase  and generating cyclic guanosine monophosphate (cGMP), causes dephosphorylation of myosin and, thus, vasodilation. Nitric  oxide synthesis and metabolic acidosis activate the potassium channels (Kap and K,q) in the plasma membrane of vascular  smooth muscle. The resulting hyperpolarization (see Chapter 3) of the membrane presents the calcium that mediates norepi-  nephrine and angiotensin II-induced vasoconstriction from entering the cell. Therefore, hypotension and vasodilation stub-  bornly persist despite high plasma levels of these hormones. In contrast, and unexpectedly, the plasma level of antidiuretic  hormone (ADH) (vasopressin) is low despite the presence of hypotension. The early, massive release of ADH may result in    level.?>° Specifically, fluid resuscitation with either crystalloid  or colloid fluids should be goal-directed to maintain the fol-  lowing values: central venous pressure, 8 to 12 mmHg (or 12 to  15 mmHg when the patient is being mechanically ventilated);  mean arterial pressure, 65 mmHg; urine output, 0.5 ml/kg/hr;  mixed venous saturation (S¥0), 65%. In addition, specific ana-  tomic sites of infection with source identification should be  determined so that appropriate antibiotics can be prescribed  and control measures can be implemented that eliminate or  reduce the spread of infection.’”** Fungal assays, including  1,3-B-p-glucan assay and mannan and anti-mannan antibody  assays, are recommended to identify suspected fungal infec-  tion.’? Normal saline, at least 1 L or 30 ml/kg body weight, is the  initial fluid of choice and hetastarches with molecular weights  >200 daltons are not recommended. Adequate and incremental  fluid resuscitation is a prerequisite and should be continued to  achieve perfusion; supplementation with vasopressors is recom-  mended if the endpoints of tissue perfusion (CVP and normal-  ized lactate levels) are not met.”?   Pharmacologic hemodynamic support and adjunctive ther-  apy to maintain tissue perfusion include vasoactive agents.  Norepinephrine is now considered the initial vasopressor of    choice.”” Dopamine, epinephrine, phenylephrine, and vaso-  pressin are alternatives; however, these are less preferred  because of potential tachycardia, dysrhythmias, or reduction  in splanchnic blood flow. Dobutamine, an inotropic agent,  should be used if myocardial dysfunction is present or hypoten-  sion remains after intravascular volume and blood pressure are  achieved. Similarly, intravenous corticosteroids are suggested  in septic shock to help replace intrinsic loss of cortisol, but  only when blood pressure remains unresponsive to volume.”  Other supportive therapies in the treatment of severe sepsis  include blood product administration to maintain hemoglo-  bin levels between 7 and 9 g/dl, targeted tidal volume (6 ml/kg)  when mechanically ventilated with plateau pressure less than  30 cm H,O, utilization of sedation and analgesic protocols  when needed, and avoidance of neuromuscular blockers if pos-  sible. Glucose concentration is to be maintained at less than  180 mg/dl. If renal dialysis is required, intermittent hemodialy-  sis and continuous venovenous hemofiltration are considered  equivalent. Bicarbonate therapy is contraindicated for the pur-  pose of treating hypoperfusion lactic acidemia, unless the pH is  <7.15. Use of deep vein thrombosis prophylaxis, such as low-  dose unfractionated heparin or low-molecular-weight heparin,    CHAPTER 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults    or mechanical compression prophylaxis of heparin, is contrain-  dicated. Stress ulcer prophylaxis with H2-receptor antagonists  or proton pump inhibitors is indicated. Digestive tract decon-  tamination and selective oropharyngeal decontamination are  recommended in the prevention of ventilator-acquired pneu-  monia.”’ It is important to discuss advance directives with the  individual and family.”’ Seeking to decrease use of antibiotics  in the critically ill and, thus, prevent resistance to antibiotics is  an important strategy in treating infection (see What’s New?  Procalcitonin Levels). Recent research suggests that monitoring  serial procalcitonin (PCT) levels, a precursor hormone to cal-  citonin, may be used to shorten antibiotic use in the treatment  of respiratory tract infections.*? PCT, normally not discern-  ible on assay, when elevated may indicate specific proinflam-  matory response during bacterial infection. PCT levels should  not be used as an indicator to start antibiotics, but if monitored  sequentially at the start of empiric antibiotics and then dropping  to low levels, discontinuation may be clinically indicated.°°?!    Seeking to decrease use of antibiotics in the critically ill and thus prevent  resistance to antibiotics is an important strategy in treating infection. Recent  research suggests that monitoring serial procalcitonin (PCT) levels, a precur-  sor hormone to calcitonin, may be used to shorten antibiotic use in the treat-    ment of respiratory infections. PCT, normally not discernible on assay, when  elevated may indicate specific proinflammatory response during bacterial  infection. PCT levels should not be used as an indicator to start antibiotics but  if monitored sequentially at the start of empiric antibiotics, then dropping to  low levels, discontinuation may be clinically indicated    Data from Kopterides P et al: Crit Care Med 38(11):2229-2241, 2010;  Layios N et al: Crit Care Med 40(8):2304-—2309, 2012.    Multiple organ dysfunction syndrome (MODS) is the progres-  sive dysfunction of two or more organ systems resulting from an  uncontrolled inflammatory response to a severe illness or injury.  The organ dysfunction can progress to organ failure and death.  MODS occurs during severe sepsis. In 2001, an international  consensus conference developed a set of definitions for sepsis  and related disorders (see Table 48-1), and a predisposition-  infection-response-organ (PIRO) dysfunction staging system  was proposed as a template for staging sepsis (Table 48-2).  MODS is the end stage of a variety of injuries that terminate in  severe, generalized inflammatory response.   MODS was first recognized as a distinct clinical syndrome in  the mid-1970s*** when advances in resuscitation and support  technologies allowed many individuals to survive life-threatening  illness or trauma only to die of complications of their disease.  Today MODS is a leading cause of mortality in surgical intensive  care units (ICUs). Mortality for individuals with MODS increases  progressively from 54% with two failing organ systems to 100%  with five failing organ systems. Moreover, mortality has not  improved much over the past 15 to 20 years.*4*°   Although sepsis and septic shock are the most common  causes, MODS can be initiated by any severe injury or disease  process that activates a massive systemic inflammatory response  by the host. Documented clinical infection is not necessary for  its development. Other common triggers are severe trauma,  major surgery, burns, circulatory shock, acute pancreatitis, acute  renal failure, ARDS, blood transfusion, heat stroke, liver failure,  mesenteric ischemia, propofol infusion syndrome, persistent  inflammatory foci, DIC, and necrotic tissue (Box 48-1). MODS  is the major cause of death following septic shock, trauma,  burn injuries, and ARDS. People at greatest risk for developing    Premorbid illness with reduced  probability of short term survival  Cultural or religious beliefs    Premorbid factors affect the potential  attributable morbidity and mortality of an  acute insult    Specific therapies directed against  inciting insult require demonstration of  characterization of that insult    Mortality risk and potential to respond to  therapy vary with nonspecific measures of   Specific mediator-targeted therapy is predicated  on presence and activity of mediator   Therapies targeting the injurious cellular  process require that it be present    From Levy MM et al: 2007 Intensive Care Med 29:530, 2003. Reproduced with kind permission of Springer Science + Business Media.  SIRS, Systemic inflammatory response syndrome.    Data from Abboud B, Daher R, Boujaoude J: World J Gastroenterol  14(35):5361-5370, 2008; Adukauskiené D et al: Medicina (Kaunas)  44(7):536-540, 2008; Beger HG, Rau BM: World J Gastroenterol  13(38):5043-5051, 2007; Bouchama A, Knochel JP: N Engl J Med  346:1978-1988, 2002; Broessner G et al: Crit Care 9(5):R498-R501,  2006; Carnovale A et al: J Pancreas (Online) 6(5):438-444, 2005; Ciesla  DJ et al: Arch Surg 140(5):432-440, 2005; Gando S: Crit Care Med  38(2)S35-S42, 2010; Kam PCA, Cardone D: Anesthesia 62(1):690-701,  2007; Oeckler RA, Hubmayr RD: Eur Respir J 30(6):1216-1226, 2007;  Shaheen MA, Akhtar AJ: J Nat Med Assoc 99(12):1402-1406, 2007;  Varghese GM et al: Emerg Med J 22:185-187, 2005; Vincent JL,  Nelson DR, Williams MD: Crit Care Med 39(5):1050-1055, 2011;  Zaccheo MM, Bucher DH: Crit Care Nurse 28(3):18-26, 2008.    MODS are older adults and persons with significant tissue injury  or pre-existing disease.'®   The PIRO system (see Table 48-2), a clinically useful sep-  sis staging system, stratifies individuals with disease by baseline  risk of adverse outcomes and potential to respond to therapy.'®   PATHOPHYSIOLOGY. In primary MODS the organ injury is  directly associated with a specific insult, most often ischemia  or impaired perfusion from an episode of shock or trauma,  thermal injury, soft tissue necrosis, or invasive infection.*° This  decreased perfusion is local (in the injured organs themselves)  and generalized. The generalized hypoperfusion in primary  MODS usually cannot be detected clinically. As a result of the  insult, a stress response is initiated and stress hormones—in  particular, catecholamines—are released. The inflammatory  and stress responses are not as evident as they are in secondary  MODS. In primary MODS during the inflammatory response,  presumably neutrophils and macrophages are “primed” by  cytokines.*° Any second insult, such as additional tissue injury,  infection, or organ ischemia, may then activate the primed cells  to produce an exaggerated response of secondary MODS*°*”  (Figure 48-8).   The progressive organ dysfunction of secondary MODS is  the result of an excessive inflammatory reaction, after a latent  period following the initial injury, in organs distant from the  site of the original injury. It is postulated that the resulting  organ trauma is caused by the host response to a second insult  rather than being a direct result of the primary injury. Often the    second insult is mild but produces an immense disproportion-  ate response because of the previous priming of leukocytes. The  interaction of injured organs then leads to a self-perpetuating  inflammation.   Secondary MODS is initiated by the delayed postinjury insult  as primed macrophages release a barrage of mediators, particu-  larly the cytokines TNF and IL-1. These mediators damage the  endothelium throughout the body. Ifa gram-negative bacterial  infection is present, endotoxin released from the bacteria also  causes severe damage to endothelial cells. Normal endothelial  cells have little interaction with leukocytes, but when stimu-  lated by TNF, IL-1, IL-6, or endotoxin, they change to a proin-  flammatory state and express adhesion molecules that mediate  adhesion of neutrophils. The adhered neutrophils then migrate  through the endothelium, aggregate in the area of damaged tis-  sue, and amplify the inflammation.’ The activated endothelial  cells increase production and release of nitric oxide (endothe-  lium), a potent vasodilator that is considered an important fac-  tor in the blood flow changes and loss of vascular tone noted  in systemic inflammation.** The injured endothelium also  becomes much more permeable, allowing fluid and protein  to leak into the interstitial spaces. An important function of  normal endothelium is anticoagulation. When damaged, the  endothelium loses much of its ability to prevent blood clotting,  allowing microvascular thrombi to develop.   The postinjury insult also activates the neuroendocrine sys-  tem, resulting in a second, more extensive stress response. The  normal function of the stress response is to maintain basal and  stress-related homeostasis*’; however, homeostasis cannot be  maintained in MODS. In fact, the endocrine response becomes  excessive and injurious. There is an early increase in the levels of  circulating catecholamines that contributes to many of the clini-  cal manifestations of MODS, such as tachycardia, hypermetab-  olism, and increased oxygen consumption. Cortisol, glucagon,  insulin, human growth hormone, ADH (which may become  depleted), and endorphin levels also are increased. Many of these  hormones contribute to the extreme catabolic state of MODS,  and endorphins, which are vasodilators, decrease SVR. The  sympathetic nervous system, to compensate for complications  resulting from the injury (e.g., fluid loss, hypotension), also is  stimulated. The stimulation persists throughout the period of  critical illness.°’ The stress response can be amplified by a num-  ber of factors, including pain, anxiety, psychosis, and hyperther-  mia. (The stress response is discussed in detail in Chapter 11.)   Because of endothelial cell dysfunction and the release of  mediators, four major plasma cascades are activated: comple-  ment, kallikrein-kinin, coagulation, and fibrinolytic.*° Comple-  ment components, particularly the anaphylatoxins C3a and  C5a, cause vasodilation by stimulating release of histamine  from mast cells. They also have strong chemotactic proper-  ties. C5a, especially, causes adhesion and the activation and  degranulation of neutrophils. Complement is thought to be a  powerful trigger for the exaggerated inflammatory response.  Activation of the kinin system results in the production of  bradykinin, a very potent vasodilator known to decrease SVR.  Coagulation mechanisms also are activated, and because tissue  injury and endothelial dysfunction are extensive, microvascular    CHAPTER 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults    thrombosis occurs throughout the body, resulting in impaired  microvascular circulation and organ ischemia. Concurrently,  fibrinolytic mechanisms are activated. The tendency toward  clotting, however, is greater, resulting in a net procoagulant  state that can lead to the development of DIC. The overall effect  of the activation of the plasma cascades is a hyperinflamma-  tory and hypercoagulant state that contributes to vasodilation,  vasopermeability, cardiovascular instability, endothelial dys-  function, and clotting abnormalities.*!   Once cytokines and other mediators have been released and  the plasma enzyme cascades have been activated, a massive  systemic inflammatory response develops. It involves several  types of inflammatory cells, particularly neutrophils, macro-  phages, and mast cells. These cells, having been primed by their  response to the initial organ injury, now pour large amounts  of chemical mediators into tissues and into the systemic circu-  lation. Neutrophils have tremendous inflammatory potential.  The accumulation of activated neutrophils in organs is thought  to play a key role in the pathogenesis of MODS.** When neu-  trophils adhere to the endothelium, they undergo a “respiratory  burst” (oxidative burst) and release oxygen-free radicals. The  respiratory burst occurs as the activated neutrophil experiences  a sudden increase in oxidative metabolism, producing large  quantities of highly toxic oxygen-free radicals. These reactive  oxygen species (ROS) cause oxidative stress. The primary ROS  produced are superoxide, hydrogen peroxide (HO ), hydroxyl  radical (OH~), and singlet oxygen (O). Oxygen-free radicals  are extremely damaging to vascular endothelium and tissue  cells, attacking deoxyribonucleic acid (DNA), cross-linking  membrane structures, and inducing membrane peroxidation—  reactions that disorganize cell membranes and lead to tissue  necrosis** (also see Chapter 2).   Other important mediators released by neutrophils are  proteases, particularly collagenase and elastase. Proteases  directly damage endothelium and neighboring cells, resulting in  increased capillary permeability and organ damage. When acti-  vated, neutrophils also release platelet-activating factor (PAF), a  mediator that damages endothelium, stimulates clot formation,  and activates increasing numbers of phagocytes. Finally, neu-  trophils release arachidonic acid metabolites (eicosanoids) as a  result of lipid peroxidation of their cell membranes. Of the ara-  chidonic acid metabolites (prostaglandins, thromboxanes, leu-  kotrienes), two are particularly important in the pathogenesis  of organ hypoperfusion: prostacyclin (PGI,) and thromboxane  A, (TXA,). TXA, is a powerful vasoconstrictor, and PGI, is a  potent vasodilator. When released in varying amounts in differ-  ent organ beds, they are largely responsible for the maldistribu-  tion of blood flow characteristic of MODS. In total, neutrophils  produce at least 50 to 60 toxins.**** Collectively, products  released by neutrophils cause endothelial dysfunction, systemic  vasodilation, selective vasoconstriction (vasoconstriction of cer-  tain organ beds or parts of organ beds), increased vascular per-  meability, and microvascular coagulation.   Macrophages, present in most tissues, are activated by endo-  toxin, complement, and monocyte chemotactic substances.’  Macrophages share a key role in the development of the unreg-  ulated inflammation of secondary MODS with the neutrophils.    Like neutrophils, they produce oxygen-free radicals, proteases,  cytokines, nitric oxide, and arachidonic acid metabolites. It has  been reported that excessive or prolonged stimulation of mac-  rophages leads to the overproduction of cytokines and nitric  oxide that initiate the cycle of harmful effects in MODS.*7445  TNE and IL-1, which share many of the same functions and  act synergistically, are the major cytokines that mediate inflam-  mation.*>*° TNF has potent metabolic effects, including fever,  anorexia, hyperglycemia, hypermetabolism, and weight loss. It  activates neutrophils, damages endothelial cells, and potentiates  hypotension and shock. IL-1 also has metabolic effects, induc-  ing fever, hypermetabolism, and muscle wasting. Normally,  TNE activates cytokines, the coagulation system, fibrinolysis,  and neutrophils. With the exception of neutrophil activation,  IL-1 causes similar activation in individuals with cancer.*’ In  the pathogenesis of MODS, the cytokines are linked to all cel-  lular, hemodynamic, and metabolic alterations.   The gastrointestinal mucosa is particularly vulnerable to  inflammatory mediators released by macrophages and neu-  trophils. Under normal circumstances the gut mucosa serves  as a barrier to prevent bacteria from the gastrointestinal tract  from entering the systemic circulation. Damage to the mucosa  results in microcirculatory failure of the gut and consequent  loss of the gut barrier function. The loss of intestinal barrier  function leads to the systemic spread of bacteria and/or endo-  toxin from the gut (systemic endotoxemia). This phenomenon  is called translocation of bacteria. The idea that the gut acts as a  reservoir of bacteria and endotoxin that can initiate or perpetu-  ate the development of MODS is known as the gut hypothesis.  The gut hypothesis provides a possible explanation for the fact  that an infectious focus is not always found in individuals with  MODS. Although this hypothesis has been substantiated by ani-  mal studies and has much support, the evidence from human  studies is inconclusive.**?   The numerous inflammatory processes operating in MODS  cause maldistribution of blood flow and hypermetabolism.  Maldistribution of blood flow refers to the uneven distribution  of flow to various organs and between the large vessels and cap-  illary beds of the body. It is caused by generalized vasodilation,  increased capillary permeability, selective vasoconstriction,  endothelial dysfunction, and impaired microvascular circula-  tion. It is a major factor in the pathophysiology of MODS.*°  The alterations in blood flow—which can occur at the cellu-  lar, organ, or regional level—lead to impaired tissue perfusion  and a decreased supply of oxygen to the cells. The organs most  severely affected by hypoperfusion are the lungs, splanchnic  bed, liver, and kidneys. Despite supernormal systemic blood  flow, oxygen delivery to the tissues decreases. Several factors  contribute to the problem. First, blood is shunted past selected  regional capillary beds. Shunting, caused by loss of autoregula-  tion in some organs, may be an early indicator of progression of  sepsis into MODS.* This occurs because inflammatory media-  tors, particularly TXA,, override the normal vascular control  mechanisms to cause selective vasoconstriction and because  injured endothelial cells are unable to respond to normal vaso-  dilator mediators. Second, interstitial edema, resulting from  microvascular permeability, contributes to decreased oxygen    CHAPTER 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults    delivery to cells by increasing the distance oxygen must travel  to reach the cells. Third, capillary obstruction occurs because of  the formation of microvascular thrombi and the aggregation of  leukocytes.*7*°   Hypermetabolism, with accompanying alterations in car-  bohydrate, fat, and lipid metabolism, is initially a compensa-  tory measure to meet the body’s increased demands for energy.  Eventually, however, hypermetabolism becomes detrimental,  placing enormous demands on the heart. Hypermetabolism  is the result of: (1) the neuroendocrine response to stress with  the release of catecholamines and cortisol, and (2) the action  of TNF and IL-1. With increased metabolism the calorie  requirements are markedly increased,** and the cardiac output  increases 1.5 to 2 times normal.*! The alterations in metabo-  lism affect all aspects of substrate use. Most important is the  catabolism of protein, primarily of skeletal muscle and visceral  organs. The extreme catabolism of protein can rapidly deplete  lean body mass. Hyperglycemia occurs as gluconeogenesis by  the liver increases and glucose use by the cells decreases. Fatty  acids are mobilized from adipose tissue. The net result of the  hypermetabolism is depletion of oxygen and fuel supplies.   Myocardial depression also accompanies MODS. The cause  remains unclear, but possible explanations are the effects of  myocardial depressant factor (MDF), TNF, and IL-1 on cardiac  contractility; alterations in a-adrenergic receptors in the heart;  and hypoxia of the myocardium.°*”*   The decreased oxygen delivery to the cells (resulting from  the maldistribution of blood flow) and the increased oxygen  needs of the cells (resulting from hypermetabolism) combine to  create an imbalance in oxygen supply and demand. This imbal-  ance is critical in the pathogenesis of MODS because it results  in a pathologic condition known as supply-dependent oxygen  consumption. Ordinarily the amount of oxygen consumed by  the cells depends only on the needs of the cells because there is  an adequate reserve of oxygen that can be delivered if required.  In MODS, however, the reserve has been exhausted and the  amount of oxygen consumed becomes dependent on the  amount the circulation is able to deliver. Because the amount  is inadequate in MODS, the tissues become hypoxic. Com-  pounding the hypoxic damage to cells is a phenomenon called  reperfusion injury (see Chapter 2). Much of the organ damage  in MODS occurs with the reestablishment of blood flow after a  period of ischemia. During the ischemic episode, energy stores  and ATP are depleted and the enzyme xanthine dehydrogenase  is converted to xanthine oxidase. With reperfusion of the ische-  mic tissue, oxygen-free radicals are formed from oxygen by the  action of xanthine oxidase, and they attack the already dam-  aged tissues. Consequently, although reperfusion is necessary  to restore oxygen supply to ischemic organs, it can increase  the extent of injury. Therefore, because of supply-dependent  oxygen consumption and reperfusion injury, tissues become  increasingly hypoxic. The result is cellular acidosis, impaired  cellular function, and ultimately multiple organ failure.   CLINICAL MANIFESTATIONS. In MODS the organs that show clini-  cal manifestations of failure are not always the organs involved as  part of the initial injury, and there is usually a lag time between  the initial insult and the development of systemic organ failure.    The development of primary MODS is difficult to monitor, but  there is a well-established general pattern in the clinical devel-  opment of secondary MODS.*°** Following the inciting event  and aggressive resuscitation of the individual for approximately  24 hours, the individual develops low-grade fever, tachycardia,  tachypnea, dyspnea, altered mental status, and a general hyper-  dynamic and hypermetabolic state (Box 48-2). Following this, the  lungs begin to fail and ARDS may appear within 24 to 72 hours  (see discussion of ARDS, Chapter 35). Between days 7 and 10, the  hypermetabolic and hyperdynamic state intensifies; bacteremia  with enteric organisms is common; and signs of hepatic, intes-  tinal, and renal failure develop. During days 14 to 21, the renal  failure and liver failure become more severe. Hematologic failure  and myocardial failure are usually later manifestations. Encepha-  lopathy, characterized by mental status changes ranging from  confusion to deep coma, may occur at any time. This sequence  can evolve rapidly, with death occurring between 14 and 21 days  later, or it can evolve over weeks. Individuals can recover from  either the slowly or the rapidly evolving course.   The clinical manifestations of failure of individual organs in  MODS are caused by inflammatory mediator damage, tissue  hypoxia, and hypermetabolism. Respiratory failure progresses  early to ARDS and is characterized by tachypnea, pulmonary  edema with crackles and diminished breath sounds, use of acces-  sory muscles, and hypoxemia. Liver failure, although early in its  development, is not clinically detectable until the later stages  of MODS, when jaundice, abdominal distention, liver tender-  ness, muscle wasting, and hepatic encephalopathy appear. All  aspects of metabolism, substance detoxification, and immune  response are impaired. Albumin and clotting factor synthesis  decreases, protein wastes accumulate, and liver tissue macro-  phages (Kupffer cells) no longer function effectively.   The gastrointestinal system is very sensitive to ischemic and  inflammatory injury. Clinical manifestations of bowel involve-  ment are hemorrhage, ileus, stress ulcers, malabsorption, diar-  rhea or constipation, vomiting, anorexia, abdominal pain, and  pancreatitis. Intolerance to enteral feeding may develop. Add-  ing to damage caused by injury to the bowel is bacterial trans-  location into the bloodstream resulting from the loss of the  gut barrier function. The overwhelmed liver is unable to clear  the bacteria from the systemic circulation. Thus, regardless of  whether infection or some other injury was the precipitating  cause of MODS, once intestinal bacteria enter the systemic cir-  culation, it is likely that sepsis will be a problem. Renal failure  develops at about the same time and is marked by progressive  oliguria, azotemia, and edema. If renal shutdown is severe,  anuria, hyperkalemia, and metabolic acidosis occur.   The first manifestations of cardiac failure are similar to those of  septic shock: tachycardia, bounding pulse, increased cardiac out-  put, fall in SVR, hypotension, warm skin, and supraventricular  dysrhythmias. In the terminal stages, profound hypotension and  ventricular dysrhythmias may develop. Changes in central ner-  vous system function may be noted. Ischemia and inflammation  are responsible for the changes, which include apprehension, con-  fusion, disorientation, restlessness, agitation, headache, decreased  cognitive ability and memory, and decreased level of conscious-  ness. When ischemia is severe, seizures and coma can occur.   e Acute respiratory distress syndrome (ARDS) pattern of respiratory failure (dys-  pnea, patchy infiltrates, refractory hypoxemia, respiratory acidosis, abnormal  O, indices)    Gastrointestinal  Abdominal distention and ascites  Intolerance to enteral feedings  Paralytic ileus  Upper and lower gastrointestinal bleeding (guaiac-positive stools)  Diarrhea  Ischemic colitis  Mucosal ulceration  Decreased bowel sounds  Bacterial overgrowth in stool    Liver  Increased serum bilirubin level (hyperbilirubinemia)  Increased liver enzyme levels (serum aspartate transaminase [SAST], serum  alanine aminotransferase [SALT], lactic dehydrogenase [LDH], alkaline  phosphatase)  Increased serum ammonia level  Decreased serum transferrin level  Jaundice  Hepatomegaly    Gallbladder  Right upper quadrant tenderness or pain  Abdominal distention  Unexplained fever  Decreased bowel sounds    Hypertriglyceridemia  ncreased serum lactate levels  Decreased serum albumin, serum transferrin, prealbumin, retinol-binding protein   e Oliguria, anuria, or polyuria consistent with prerenal azotemia or acute tubular  necrosis   Decreased pulmonary capillary wedge pressure  Decreased systemic vascular resistance  Decreased right atrial pressure   ncreased left ventricular stroke work index  Decreased oxygen delivery and consumption  Decreased cardiac output and cardiac index    Modified from Thelan LA et al: Critical care nursing: diagnosis and management, ed 6, St Louis, 2010, Mosby.    EVALUATION AND TREATMENT. Because there is no specific  therapy for MODS, early detection or prevention is extremely  important so that supportive measures are initiated instantly.**  Frequent assessment of the clinical status of individuals at  known risk is essential. Unfortunately, there is no way to deter-  mine with certainty when an organ is failing. Indicators of  organ dysfunction are presented in Table 48-1.   Several systems for scoring severity of illness also have been  developed. Commonly used systems are the Acute Physiology  and Chronic Health Evaluation II and III (APACHE II and  APACHE IID), the logistic organ dysfunction score (LODS), the  sequential organ failure assessment (SOFA), the MODS score,  and the PIRO staging system.*° Once organ failure develops,  monitoring of laboratory values and hemodynamic parameters  is necessary to assess the degree of clinical impairment.    The therapeutic management of MODS consists of preven-  tion and support. Prevention of the syndrome is essential! First,  if possible, the initial source of inflammation must be elimi-  nated or controlled. Next, a second insult must be avoided. It is  paramount to remove any potential site of infection by débrid-  ing necrotic tissue, draining abscesses, reducing the numbers  of invasive procedures performed, and removing hematomas.  Nosocomial infections from contaminated lines and catheters  are of concern and must be prevented. Nosocomial infection  rates of 15% to 25% have been reported in critically ill individu-  als.°° Early reduction of long-bone fractures and surgical repair  of injured tissues are also important preventive measures.   The goals of therapy are to control infection, provide ade-  quate tissue oxygenation, restore intravascular volume, and  support the function of individual organs.*° After the initial    CHAPTER 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults    injury has been aggressively treated and sources of infection  have been removed, antibiotics generally are administered. The  choice of agents is based on the individual’s disease process, but  the regimen is usually a combination of antibiotics that covers  both gram-negative and gram-positive organisms.   Because oxygen is not stored in the tissues, it must be contin-  uously delivered. Maintaining an arterial oxygen saturation of  88% to 92% is recommended,”° and hemoglobin levels should  be kept greater than 9 g/dl.° Mixed venous oxygen saturation  greater than or equal to 70% is recommended. Blood transfu-  sions may be necessary to ensure an adequate hemoglobin level.  To deliver oxygen to the organs in the face of profound sys-  temic vasodilation, fluid volume must be restored. Therefore,  aggressive fluid therapy is initiated early. Usually large volumes  of isotonic crystalloid solutions are administered, although col-  loids (often albumin) also may be added to maintain adequate  preload and circulation volume.”°   Finally, support for individual organ systems must be pro-  vided. Respiratory failure is treated with mechanical ventilation  with low tidal volumes, high oxygen concentrations, and posi-  tive end-expiratory pressures (PEEP).°’ To provide adequate  nutrition and metabolic support, the failing gastrointestinal  system is supported with enteral feedings. It is now well recog-  nized that enteral feedings help preserve gut microbial barrier  function, and thus are preferred to parenteral feedings.°* How-  ever, if the individual is unable to tolerate the amount of enteral  feeding required to meet the enormous metabolic demands,  hyperalimentation may be added. Ideally the feeding formula  is carefully calculated to meet the individual’s nutritional  requirements. Tight glucose level control (80 to 110 mg/dl)  is recommended.*? Once renal failure is established, dialysis or  continuous hemofiltration may be required to maintain fluid  and electrolyte balance. To support the failing cardiovascu-  lar system, inotropic drugs, such as low-dose dopamine and  dobutamine, or vasopressors, such as norepinephrine, may be  required to maximize cardiac contractility and maintain cardiac  output. Although steroids have anti-inflammatory effects, their  use is controversial because they have been shown to be effec-  tive in adults with septic shock. Obtaining an adrenocortico-  tropic hormone (ACTH) level is not recommended. Deep vein  thrombosis prophylaxis is also important.°   Scientific knowledge gained about MODS and inflamma-  tory mediators has led to many investigational therapies. Novel  molecular approaches targeting a variety of interdependent  mediators of MODS are being investigated.”    Major thermal injury is a source of massive tissue injury and  destruction that has wide-reaching effects on virtually all organ  systems. Burn is a generic term used to describe cutaneous  injury resulting from thermal, chemical, or electrical envi-  ronmental causes. In addition to cutaneous injury, burns are  often associated with smoke inhalation injury or other trau-  matic injuries that aggravate the local and systemic problems  of burns. Pulmonary injury, both primary and secondary, is  common and often necessitates ventilator support. The use of    tracheostomy also has been examined and is controversial.°°!  This model of multisystem injury provides an opportunity to  examine the interaction of shock, inflammation, and immuno-  compromise in a clinical setting.    The annual number of burns and fire-related injuries that occur  in the United States is now estimated to be about 450,000.°  Deaths consequent to these injuries have decreased more than  50%—from 9000 in 1971°° to 4000 in 2005. This remark-  able progress is the result of several factors, including ongo-  ing research in burn physiology and burn care,™ an increased  national focus on fire safety and burn prevention, the estab-  lishment of regional burn centers, the use of smoke detectors,  regulation of consumer product safety, and the implementation  of occupational safety mandates. A decrease in hospitalization  reflects a shift to outpatient care and improved prehospital  and emergency treatment, but burn assessment and delivery of  care can be improved® to reduce medical transport and treat-  ment costs. International interest in telemedicine has increased  over the past decade.*°” These advances in care are changing  emphasis from survival to outcomes in burn survivors.°*?   The causes of burn injury may be thermal or nonthermal,  such as chemical, electrical, or radioactive. Thermal burns may  result from thermal contact, flame, or scald. Adherent materi-  als (e.g., asphalt, tar, or plastic) may likewise produce a serious  contact burn. Chemical injuries are a result of contact with sub-  stances that are directly toxic to skin or the lining of the respira-  tory or alimentary tract. Such chemicals are often acid, alkali,  or organic agents, termed vesicants, that cause blistering of  the epithelial surfaces. Electrical burns may be the result of the  conduction of electrical current through the body with heat-  ing of tissue or flash over the body surface associated with an  electrical discharge. Quality of life can be affected but, by self-  reports, may exceed normal population averages with proper  intervention.”    The classification of burn wound depth is usually based on  the physical appearance and the symptoms associated with the  affected skin. The definitive diagnosis is determined by the his-  tologic depth of tissue necrosis. Such evaluation, unfortunately,  necessitates a skin biopsy. Because of the invasive nature of  biopsy, clinical depth assessment is used and the ultimate fate of  the wound determines final diagnosis. Recent advances in laser  Doppler technology have resulted in extensive exploration of a  noninvasive means for burn wound depth assessment.’!"*  First-degree burns are a partial-thickness injury involv-  ing only the epidermis without injury to the underlying dermal  or subcutaneous tissue (Table 48-3). The skin maintains water  vapor and bacterial barrier functions. Many sunburns are first-  degree injuries caused by exposure of skin to ultraviolet radia-  tion from the sun. Initially there is local pain and erythema, but  no blisters appear until after about 24 hours. An extensive first-  degree burn may cause systemic responses such as chills, head-  ache, localized edema, and nausea or vomiting. No treatment  of extensive first-degree burns is required unless the person is    elderly or an infant, in which case severe nausea and vomiting  may lead to inadequate fluid intake and dehydration. Therapy  consists of intravenous hydration until the nausea and vomit-  ing subside 24 to 72 hours after burn injury. Comfort measures  for previously healthy children or adults with extensive first-  degree burns consist of aspirin for adults or acetaminophen for  children every 4 hours in age-appropriate doses and frequent  application of a water-soluble lotion. First-degree burns heal in  3 to 5 days without scarring.   Second-degree burns describe two categories of burn depth  with markedly different characteristics. Both of these are partial-  thickness injuries, but they evoke vastly different responses. The  hallmark of superficial partial-thickness injury is the appear-  ance of thin-walled, fluid-filled blisters that develop within just  a few minutes after injury. Another dominant characteristic  of superficial injury is pain. As blisters break or are removed,  nerve endings are exposed to air (Figure 48-9). Tactile and pain  sensors remain intact throughout healing, with each wound  care procedure causing substantial pain. Wounds heal in 3 to  4 weeks if the individual is adequately nourished and no compli-  cations develop (Figure 48-10). Scar formation is unusual with  this injury. The amount of scarring that develops is a genetically  determined trait and is not predictable during the early course  of treatment.   Deep partial-thickness burns involve the entire dermis,  sparing skin appendages such as hair follicles and sweat glands  (see Table 48-3). The burn often looks waxy white and is sur-  rounded by margins of superficial partial-thickness injury. The  injury is often clinically indistinguishable from a full-thickness  injury (Figure 48-11), but by 7 to 10 days after burn injury,  skin buds and hair will appear from hair follicles, indicating  that skin appendages remain. These wounds take weeks to heal,   White, cherry red, or black; may  contain visible thrombosed veins;  dry, hard leathery surface   Skin graft; scarring minimized  by early excision and grafting;  influenced by genetic  predisposition    Highest incidence because of slow  healing rate promoting scar tissue  development; also influenced by  genetic predisposition    FIGURE 48-9 Superficial Partial-Thickness Injury. Scald injury following  débridement of overlying blister and nonadherent epithelium. (Courtesy Intermountain  Burn Center, University of Utah.)    and current therapy consists of surgical removal of the burn  wound (excision) followed by application of the person’s own  unburned skin from another body area (autograft). Wounds  that heal slowly produce more scar tissue and continue to be a  potential source of infection until closed. In the presence of rel-  ative surgical contraindications, such as cardiopulmonary fail-  ure, deep partial-thickness wounds are not surgically treated but  are allowed to heal primarily. The fate of partial-thickness burns  can be affected by treatment, such as topical antibiotics, or by  the condition of biologic membranes." The ultimate healing of  deep partial-thickness burns commonly results in hypertrophic  scarring with poor functional and cosmetic results.  Third-degree burns, or full-thickness injuries, involve  destruction of the entire epidermis, dermis, and often the under-  lying subcutaneous tissue (see Table 48-3). On occasion, all    CHAPTER 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults    FIGURE 48-10 Axillary Burn Scar Contracture. Note the blanching of the  anterior axillary fold and small ulceration, both indicating the diminished range of  motion. (Courtesy Intermountain Burn Center, University of Utah.)    FIGURE 48-11 Deep Partial-Thickness Wound. Note pale appearance and  minimal exudate. (Courtesy Intermountain Burn Center, University of Utah.)    underlying subcutaneous tissue is destroyed and muscle or bone  may be involved. Full-thickness wounds often appear relatively  innocuous when their color is white and the delineation between  normal and burned skin is not accompanied by a marked color  change. Elasticity of the dermis is absent, leaving the wound  dry and leathery in appearance and texture (Figure 48-12). As  marked edema develops, distal circulation may be compro-  mised in areas of circumferential burns. Escharotomies (cutting  through burned skin) are performed to release underlying pres-  sure. Full-thickness burns are painless because all nerve endings  have been destroyed by the injury.   The extent of the total body surface area (TBSA) burn is  estimated using either the “rule of nines” (Figure 48-13) or  the Lund and Browder chart (Figure 48-14). Areas of partial-  thickness and full-thickness injury are marked on the diagram  in Figure 48-14. First-degree burns are not included in the TBSA  estimate. The surface area of the palm, including palmar finger  surface, averages 1% of the body surface area over a wide range  of ages; thus it can be used to estimate burn areas of irregular  size and shape.*?   Severity of burn injury is a combination of many factors,  including age, medical history, extent and depth of injury, and  body area involved. The American Burn Association has defined  criteria to assist healthcare professionals in identifying individ-  uals who require care at a specialized burn center (Box 48-3).  The multidisciplinary burn center is recommended for those    FIGURE 48-12 Full-Thickness Thermal Injury. The wound is dry and insen-  sate. (Courtesy Intermountain Burn Center, University of Utah.)    FIGURE 48-13 Rule of Nines. A commonly used assessment tool with esti-  mates of the percentages (in multiples of 9) of the total body surface area burned.  A, Adults (anterior view). B, Adults (posterior view).    persons who are at high risk for morbidity, mortality, or perma-  nent functional loss.   PATHOPHYSIOLOGY AND CLINICAL MANIFESTATIONS. Burn injury  results in dramatic changes in many physiologic functions of  the body within the first few hours after the event. The effect  of burn depends on two factors: first, the extent of body sur-  face involved and, second, the depth of cutaneous injury. Body  surface burn extent is described by the percentage of TBSA  injured. Burns exceeding 20% of TBSA in most adults are  considered to be major burn injuries and are associated with  massive evaporative water losses and flux of large amounts of  fluid and electrolytes in the tissues, manifested as generalized  edema and circulatory hypovolemia. Depth of cutaneous injury  has been categorized in many ways but always depends on the  severity of injury of epidermal and dermal elements of the skin  and whether the alteration is a permanent or reversible injury.   With a major burn injury, a systemic pathophysiology ensues  that requires therapeutic intervention to sustain life. The imme-  diate (acute) physiologic consequences of a major burn injury    Post. Trunk 13  2/2 24/2  21/2  | Genitalia | 1  3  21/2  21/2  si  61/2  5  31/2  31/2    FIGURE 48-14 Lund and Browder Chart. Regional differences in body surface are calculated based on age. (Courtesy  Intermountain Burn Center, University of Utah.)    CHAPTER 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults    A burn unit may treat adults or children or both.  Burn injuries that should be referred to a burn unit include the following:   . Partial-thickness burns greater than 10% total body surface area (TBSA)   . Burns that involve the face, hands, feet, genitalia, perineum, or major joints   . Burn injury in individuals with pre-existing medical disorders that could   complicate management, prolong recovery, or affect mortality  . Any patients with burns and concomitant trauma (such as fractures) in  which the burn injury poses the greatest risk of morbidity or mortal-   ity. In such cases, if the trauma poses the greater immediate risk, the  patient's condition may be initially stabilized in a trauma center before  being transferred to a burn center; physician judgment will be necessary  in such situations and should be in concert with the regional medical  control plan and triage protocols.  . Burned children in hospitals without qualified personnel or equipment  or the care of children  . Burn injury in patients who will require special social, emotional, or  ong-term rehabilitative intervention    From Resources for Optimal Care of the Injured Patient: “Guidelines  for the Operation of Burn Centers,” Chicago, IL, 2006, Committee on  Trauma, American College of Surgeons.    center around the profound, life-threatening hypovolemic  shock that occurs in conjunction with cellular and immuno-  logic disruption within a few hours of injury (Figure 48-15).  Burn shock is a phenomenon consisting of both a hypovolemic  cardiovascular component and a cellular component.   Hypovolemia associated with burn shock results from mas-  sive fluid losses from the circulating blood volume. The losses  are caused by an increase in capillary permeability that persists  for approximately 24 hours after burn injury. Fluid resuscita-  tion is the administration of intravenous fluids, such as lactated  Ringer solution, in an effort to restore the circulating blood  volume during the period of increasing capillary permeabil-  ity. In addition to hypovolemia, most other organ systems are  affected. Cardiac contractility is diminished during the initial  24-hour resuscitation period with shunting of blood away from  the liver, kidney, and gut. This is often termed the ebb phase  of the response to trauma and can be seen with other severe  injuries. Normal blood volume does not result in restoration  of normal cardiac output because of a phenomenon known  as myocardial depression. The decrease in perfusion of viscera  results in a decrease in their function. This may be an explana-  tion for decreased gut barrier function seen in thermal injury.*°  Other mechanisms include hypoxia and inflammation with his-  tologic damage of intestinal mucosa.*”   There also is evidence that cellular metabolism is disrupted  when the burn wound is created, resulting in altered cell mem-  brane permeability and loss of normal electrolyte homeosta-  sis. This cellular defect may be the pathophysiologic process  responsible for the genesis of burn shock. There are numerous  circulating factors in burn serum that may play a role in these  cellular processes. Although the cardiovascular and systemic    responses are intricately interwoven into the cellular response,  these responses are presented here as discrete entities for pur-  poses of description.    The clinical manifestations of burn shock are the result of  more than simple loss of extracellular fluid at the burn wound  site. Hypovolemia and numerous local mediators in the burn  wound,*® as well as systemic signals, result in alteration of cel-  lular function throughout the body. The restoration of normal  intravascular volume with either saline solutions or colloid  materials (e.g., albumin, blood, or dextrans) does not reverse  changes such as increases in pulmonary vascular resistance or  myocardial contractility.°° This is reflected in cardiac output  with precipitous decreases that often result in inadequate perfu-  sion of most tissues at the capillary level, which is the hallmark  of burn shock. Fluid infusion, likewise, does not return cardiac  output to preburn levels.”®”! These findings led to the postu-  lation of a specific myocardial depressant factor (MDF).??-*  Other causes also have been suggested, such as reactive oxygen-  free radicals that attack cell membranes and other subcellular  organelles as a result of first ischemia and then reperfusion of  tissues during burn shock and resuscitation.”? A third factor  may be the level of nitric oxide after burn injury, which could  have a direct myocardial depressant effect.»°°’ The relation-  ship of nitric oxide and myocardial function is not yet totally  clear. Gamelli and colleagues”® found nitric oxide production  to be significantly depressed in burned individuals who did  not survive their injuries. They postulate that nitric oxide may  scavenge reactive oxygen-free radicals and protect tissues from  oxidative injury.    TABLE 48-4 ELECTROLYTE CONTENT OF  RINGER LACTATE SOLUTION  AND EXTRACELLULAR FLUID    *Normal values may vary slightly between laboratories.  tPlus 80-100 ml free water per liter.    aif 2  FIGURE 48-16 Edema Related to Burn Injury. Superficial facial burns can  result in marked swelling, requiring prompt endotracheal intubation to maintain  the airway. (Courtesy Intermountain Burn Center, University of Utah.)    Regardless of the contribution of these mechanisms, fluid  resuscitation eventually results in improved outcome of the  massively burned person. This resuscitation involves infusion  of intravenous fluid at a rate faster than the loss of circulatory  vascular volume for a period of about 24 hours from the time of  burn injury, and may require up to 30 Lina major burn. Resus-  citation from burn shock can be accomplished using any of a  number of infusion protocols. The most frequently used proto-  col is the Parkland formula.”’ Lactated Ringer solution is used  because it closely approximates extracellular fluid, the reposi-  tory of fluid leaving the circulatory system during this phase  of extensive edema formation (Table 48-4). The use of electro-  lyte-free fluids, such as D;W (dextrose 5% in water), results in  life-threatening hypovolemia and hyponatremia. Resuscitation  with hypertonic saline has been used in some medical centers  but is reserved for special circumstances; its use can result in  adverse outcomes.!°   The massive edema associated with burn shock is inevitable  with fluid resuscitation, and failure to administer resuscitation  fluid results in irreversible hypovolemic shock and death. The  edema occurs in unburned as well as burned areas (Figure 48-16).  This often leads to mechanical airway obstruction, necessitation  of tracheal intubation, and increased severity of the interstitial  pulmonary edema associated with inhalation injury.   The most reliable criterion for adequate resuscitation of  burn shock is urine output. The individual is in hypovolemic    1. Basal fluid replacements per day  1500 ml/day/m? body surface area = 24-hour requirements  2. Evaporative water loss from burn wound  a. Adults: 25 + % total body surface area burn ((m2 body surface area) = ml/hr  b. Children: 35 + % total body surface area burn (m2 body surface area) = ml/hr  3. Total hourly maintenance fluids  Basal fluid requirements per day + 24 hours + evaporative water loss per  hour = ml/hr maintenance fluids  Example: A 70-kg adult with a 50% total body surface area burn and a body  surface area of 2 m requires the following:  e Basal = (1500 ml/day) (2m2 body surface area) = 3000 ml/24 hr,  or 125 ml/hr  e Evaporative = (25 + 50% total body surface burn)  e (2m? total body surface area) = (75) (2) = 150 ml/hr  e Total maintenance fluids = 125 ml + 150 ml = 275 ml/hr    shock and will, as a compensatory mechanism, decrease or stop  urine output in an effort to preserve circulation volume. The  adult receiving sufficient intravenous fluids will excrete urine  amounting to 30 to 50 ml/hr; children will produce 1 ml/kg/hr.  If the individual does not have adequate urine output, it often  indicates inadequate fluid resuscitation. The massive amount  of intravenous fluid required by burned individuals during the  shock phase is often intimidating to the person unfamiliar with  burns. One common concern is that massive fluid administra-  tion will result in pulmonary edema. It should be remembered  that the individual is in hypovolemic shock and that fluid is  lost dramatically during the resuscitation period through third  spacing, exudation, and evaporation.   The endpoint of burn shock is defined as the state in which the  individual is able to maintain adequate urine output for 2 hours  with the intravenous fluid administration rate equal to the indi-  vidual’s calculated maintenance rate (Box 48-4). As burn shock  ends, fluid administered remains in the circulating volume  and is reflected as an increase in urine output. The mechanism  whereby capillary integrity is restored is unknown but usually  occurs about 24 hours after burn injury (Figure 48-17). After  the individual has reached the endpoint of burn shock, the term  used to describe the vascular status of the individual is capil-  lary seal. In individuals with large burns, colloid-containing  fluids may be given to help maintain oncotic pressure during  the resuscitation phase and afterward to enhance the mobiliza-  tion of interstitial fluid and diuresis.!°' Efforts to decrease burn  edema and fluid resuscitation volumes can involve the use of  hypertonic fluid resuscitation as well.!°   In addition to capillary endothelial permeability changes result-  ing in vascular fluid losses, transmembrane potential changes  occur in cells not directly damaged by heat. The normal poten-  tial of -90 mV decreases to nearly —70 mV, with an increase  in intracellular sodium and water. Such membrane potential    CHAPTER 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults    FIGURE 48-17 Direction of Fluid and Electrolyte Shifts Associated with Burn Shock. (Courtesy Intermountain Burn    changes may be caused by a circulating shock factor.!°° Apop-  tosis is central to the cellular responses to burn injury.!°* Other  changes can be categorized as: (1) a metabolic response to the  burn injury or (2) an immunologic response to the burn injury.  Metabolic Response. The metabolic changes after a burn  injury were described in 1967 by Welt and associates as “sick  cell syndrome.”!°° This was considered to be a cell membrane  transport defect related to an alteration in the steady-state  composition characterized by high intracellular concentrations  of sodium. Trunkey and colleagues!”° found a marked decrease  in primate muscle extracellular water and an increase in  intracellular sodium and water during hypovolemic shock. In  addition, other researchers demonstrated an associated decrease  in resting membrane potential, a decrease in amplitude of the  action potential, and a prolongation of the repolarization and  depolarization times in association with a decreased intracellular  potassium concentration.!°”!°° The cellular dysfunction of burn  injury extends beyond the transmembrane potential disruption  and the sodium-potassium pump impairment to include a loss  of intracellular magnesium and phosphate!” and elevated serum  lactic acid dehydrogenase (LDH) levels.''!° Thus impairment  of basic cellular function may be the underlying cause of the  diminished membrane potentials. The data suggest a decrease  in the efficiency of the pump. The failure of rapid intravascular  volume repletion to restore membrane potential completely  suggests other pathways for cellular metabolic derangement.'!!  Metabolic reactions to the stress of a major burn injury  involve the response of the sympathetic nervous system and  other homeostatic regulators. Catecholamines are found in  elevated amounts in both the serum and urine of burned indi-  viduals. Cortisol, glucagon, and insulin levels are elevated, with  a corresponding increase in gluconeogenesis, lipolysis, and pro-  teolysis. Changes in lipid metabolism are reflected as an eleva-  tion in the levels of plasma free fatty acids (FFAs) and a decrease  in the levels of plasma cholesterol and phospholipids.!!* Hern-  don and colleagues found that the use of propranolol, a non-  selective beta,- and beta-blocker, could decrease symptoms of  the hypermetabolic, hypercatabolic, and osteopenic responses  in pediatric patients, including a decrease in heart rate and    lipolysis.'!?* Glucose and lactate kinetics are altered after burn  injury. Although tissue hypoxia produces lactic acidosis, its per-  sistence in the presence of adequate tissue perfusion suggests an  increased rate of glycogenolysis.!!°   Burn injury induces a hypermetabolic state that persists  until wound closure. Wilmore and colleagues!'* described the  hypermetabolic state of 20 burned individuals as unrelated to  ambient temperatures, with persistent elevation of core body  temperatures. The metabolic rate increased with burn size in  a curvilinear relationship, with oxygen consumption rarely  exceeding two times basal levels. Evaporative water loss and  surface cooling are not the primary stimulus for the hypermeta-  bolic state; rather, the hypermetabolism is related to an increase  and resetting of the thermal regulatory set point. A core body  temperature of 38.5° C (101.3° F) is typical. A reflex arc mobi-  lizes neural or hormonal afferent stimuli to the hypothalamus,  producing a catecholamine response clinically manifested as  hypermetabolism, hyperthermia, and hyperglycemia.   Evidence also exists that the burn wound itself directly medi-  ates the response to injury at both the local and system levels.  Cytokines, oxygen-free radicals, chemotactic substances, and  eicosanoids contribute to the systemic inflammatory response  and hypermetabolic state. The inflammatory response to the  wound level is magnified into a generalized systemic inflam-  matory response that is often deleterious.'!*!!” Vasodilation,  increased capillary permeability, and edema occur to facilitate  healing of the local area. The distribution of the peripheral cir-  culation after burn injury transports heat and glucose prefer-  entially to the wound. The energy cost of these reparative and  transport processes is reflected in the increased metabolism and  hyperdynamic circulation.   The extensive evaporative water loss that occurs in burn tis-  sue is a heat-consuming process, and the energy of evaporation  is provided by increased visceral heat production. The signal  for the response is unknown because individuals whose wounds  have been denervated continue to have a posttraumatic hyper-  metabolic response. Hypothalamic function alterations result  in the elevation of human growth hormone (hGH) serum lev-  els in the presence of hyperglycemia, a finding opposite that    in normal states.!'* Further, the hypermetabolic rate is not  decreased during rest, sleep, or warmth.   Evidence of hepatic response to burn injury is characterized  by alterations in the clotting factors.''® A hypercoagulable state  develops as manifested by an elevated plasma fibrinogen con-  centration in the presence of shortened prothrombin time (PT)  and activated partial thromboplastin time (PTT).!””   In summary, extensive burn injury initiates the most marked  alterations in body metabolism associated with any illness  (Figure 48-18). Much of the work explaining this response has  been conducted by Wilmore,!*°'?! who reported that the per-  sistent tachycardia, hyperpnea, hyperpyrexia, and marked body  wasting seen in burn injury reflect heightened metabolic activity  and accelerated body catabolism. The development of decreased  bone density can last long after discharge from the hospital.!  These system alterations occur as a result of the cutaneous  inflammatory process and are thought to facilitate wound repair.  The neural component of this alteration is in response to a sym-  pathetic reaction that releases catecholamines in large amounts.   Immunologic Response. The immunologic response to  burn injury is immediate, prolonged, and severe. The result  in individuals surviving burn shock is immunosuppression  with increased susceptibility to potentially fatal systemic burn  wound sepsis.   Several cytokines have been identified in the immediate  postburn period. IL-1 (interkeukin-1) is detected in the serum    of burned individuals. The level of IL-1 correlates inversely with  burn survival; low levels may be associated with a higher mor-  tality.!°? Fatal burn injury has often shown decreased levels of  IL-2, which may result in decreased T helper 1 (Th-1) lympho-  cytes. Th-1 cells produce IL-2, interferon-gamma, and TNF,  which help to initiate cellular immunity and immunoglobulin  G (IgG) production. IL-4 is elevated after burn injuries and  causes a shift in the T helper cell production from Th-1 to Th-2  lymphocytes. Th-2 cells secrete IL-4 which promotes further  conversion of nonspecific Th cells to Th-2 cells. Th-2 cells also  produce other cytokines and antibodies.'** IL-6 levels increase  quickly after burn injury and remain elevated for several weeks.  The level of IL-6 correlates with the extent of burn injury.!”°  IL-6 and platelet-activating factor (PAF) activates polymorpho-  nuclear neutrophils (PMNs) causing infiltration of neutrophils  into burned tissue and adhesion to vascular endothelial sur-  faces.!*°!?7 IL-8 levels are elevated after burn injury, with sig-  nificantly greater elevations in individuals with a TBSA burn of  40% or higher. IL-8 activity may play a role in the strong and  persistent activation of neutrophils noted in people with large  burns.!?° Burn blister fluid contains large amounts of IL-6 and  IL-8 in addition to substances such as epidermal growth factor,  platelet-derived growth factor, and TGF.!”?   Macrophages, platelets, neutrophils, and vascular endothe-  lial cells release prostaglandins and leukotrienes, which are the  byproducts of arachidonic acid metabolism. These chemical    CHAPTER 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults    mediators cause peripheral vasodilation, pulmonary vasocon-  striction, increased capillary permeability, and local tissue ische-  mia in the burn wound.   A host of chemicals found in burn plasma in altered concentra-  tions also may play a role in burn shock. These include vasoactive  amines (histamine, serotonin), products of complement activa-  tion (C3a, C5a), prostaglandins, kinins, endotoxin, and meta-  bolic hormones (catecholamines, glucocorticoids). A decrease in  complement components C3a and C5a in the circulation after  burn injury suggests a nonspecific activation of the complement  system.!°° Activation of the complement system in injured tissue  results in an inflammatory response caused by release of histamine  and serotonin by C3a and C5a, because histamine and serotonin  alter capillary permeability and participate in the mechanism of  burn shock along with kinin polypeptides and other chemical  mediators. Prostaglandins function in the inflammatory process  by regulating metabolism of cells of inflammation (see Chapter 7).   Burn shock can induce changes in the integrity of the intesti-  nal wall, facilitating bacterial translocation and endotoxemia.!*!  Bacterial translocation from the gut may be a mechanism of  infection leading to septic shock after burn injury and other  major trauma.!*? Circulating endotoxin is correlated with the  development of MODS and death after major burn injury.!°*   White blood cells are also altered at this time, when their need  to inhibit sepsis is vital. Natural resistance to infection in burn  wounds is a function of the nonspecific immune system; that is,  resistance to microorganisms that infect wounds rests almost  solely on the ability of phagocytic cells (i-e., granulocytes, mac-  rophages) to leave the bloodstream, migrate to the site of infec-  tion, and ingest and kill microorganisms.'** Opsonins normally  render bacteria susceptible to phagocytosis but the burn injury  triggers a consumptive opsoninopathy. Burn serum contains an  inhibitor of C3 conversion that leads to decreased opsonization  and polymorphonuclear (PMN) dysfunction.!*>!°°   Individuals with altered immunocompetence before burn  injury are at additional risk for complications. Opportunistic  infections, such as fungal sepsis, can increase a hospital stay  and ICU costs.!*” Included in this group are individuals at the  extremes of age and those with cardiac disease, malnutrition,  immunodeficiency disease, and a history of alcohol or drug  abuse.!**!°° Additional risk factors include diabetes mellitus  and pulmonary or renal dysfunction.    One of the major purposes of intact skin is to serve as a barrier to  evaporative water loss (EWL) from the body. With major burn  injury, this ability of the skin to regulate evaporative water loss is  totally disrupted. In a classic 1962 study, Moncrief and Mason'*°  attempted to determine the magnitude of such a loss and deter-  mined that daily evaporative water loss was in the range of 20  times normal in the early phase of injury, with gradual decreases  as wound closure is achieved. Further studies indicated that  insensible water loss through burned skin is not from evapo-  ration of water from sweat glands but rather from water vapor  formed within the body and lost through the skin.!4!)!7  Calculation of the amount of fluid lost by evaporative water  loss includes losses from all sources. Normally the skin is the    FIGURE 48-19 Hypertrophic Scarring. Deep partial-thickness thermal injury  can result in extensive hypertrophic scarring. (Courtesy Intermountain Burn Center,  University of Utah.)    major source of insensible loss (75%) and the lungs are minor  sources (25%), with a total loss of only approximately 600 to  800 ml/day. This changes dramatically with burns, because  not only does skin loss increase but also lung loss increases by  hypermetabolism and hyperventilation, especially in an intu-  bated individual. Total evaporative losses exceed many liters  per day in an adult with large burn wounds. Replacement of the  loss is mandatory to prevent volume deficit.   EVALUATION AND TREATMENT. Burn recovery can be long and  difficult, with complications often the rule rather than the  exception. The goal of burn management is wound closure in  a manner that promotes survival. Scar formation with contrac-  tures is often a consequence of healing in deep partial-thickness  and full-thickness burns (Figure 48-19; see also Figure 48-10).  Assessment of tissue viability can be difficult in complex extrem-  ity injury; pyrophosphate nuclear scanning can assist in evalu-  ation.'*? Early intervention may have effects on tissue survival  as is evident in the zone of stasis and application of cerium  nitrate.!“4 The advancement in survival and outcome can be as  simple as using antibiotic catheters to reduce catheter-associated  bloodstream infections'* or better glycemic management dur-  ing ICU treatment.'*° Advances in care systems have shown the  value of advanced practice nurses in a collaborative role in the  burn ICU and emergency departments. !“”   The three essential elements of survival of major burn injury  are: (1) meticulous wound management, (2) adequate fluids  and nutrition, and (3) early surgical excision and grafting. Cur-  rent therapy for deep partial- and full-thickness burn injury  includes surgical removal of the burn tissue (excision) followed  by grafting of the person’s unburned skin (autograft) onto the  excised wound. Techniques of early wound care, such as the use  of amniotic membrane,'** may well affect the nature of burn  scarring. Satisfactory wound closure with cultured epithelial  autograft (Figure 48-20) has been inconsistent and costly.!4%!°°  Early enthusiasm for synthetic dermal replacement has been  tempered by a high rate of dermal graft loss and slow epider-  mal engraftment.!°!)'°* Such advancements in skin replacement  technology include sheets of acellular dermal matrix that can be  used with thin, meshed autografts or cultured epithelial auto-  grafts.'°°!>4 This concept also is being used on the donor site;  glycosaminoglycan hydrogels, and even topical gene therapy or  stem-cell applications,'°°"!°’ may supplement donor site wound    FIGURE 48-20 Application of Cultured Epithelial Autografts. The thin  sheets of keratinocytes are attached to gauze backing to allow application  onto the clean, excised thigh. (Courtesy Intermountain Burn Center, University  of Utah.)    dressings. !°* Scar reduction or prevention is a challenging prob-  lem that is being addressed with pulsed-dye laser treatment.'°”  Current research also is directed toward therapies to modulate  hypermetabolic and inflammatory responses. Nutritional ther-  apy is focused on early enteral feeding to reduce the potential  of gut-mediated sepsis. Ongoing clinical trials using anabolic  agents (e.g., recombinant human growth hormone) and phar-  macologic agents that modulate inflammatory and endocrine  mediators (e.g., ibuprofen, propranolol) show promise in the  treatment of severe burn injuries.” Altered body image is a sig-  nificant hurdle to those with facial burns. A supportive frame-  work to aid individuals is essential to integrate them back into  the community.'° Burn pain is almost always acute and treat-  ment strategies usually differ from strategies for chronic pain.  The understanding and management of burn pain is key to  recovery.!°!!© In addition to opioid-based agents, newer treat-  ment approaches may include antianxiety agents, hypnosis, and  relaxation techniques,'® as well as virtual reality systems.°!4   1. Shock occurs when the cardiovascular system fails to perfuse  tissue, cells, and organs adequately, causing a widespread  impairment of cellular metabolism and tissue function. It is  a downward physiologic spiral that, if not reversed, can lead  to MODS.   2. Types of shock are cardiogenic, hypovolemic, neurogenic  or vasogenic, anaphylactic, and septic.   3. The final common pathway in all types of shock is impaired  cellular metabolism and cells switch from aerobic to anaer-  obic metabolism. Energy stores drop, and cellular mecha-  nisms relative to membrane permeability, action potentials,  and lysozyme release fail.   4, Anaerobic metabolism results in activation of the inflam-  matory response, decreased circulatory volume, and  decreasing pH.   5. Impaired cellular metabolism results in cellular inabil-  ity to use glucose because of impaired glucose delivery or  impaired glucose intake, resulting in a shift of glycogenoly-  sis, gluconeogenesis, and lipolysis for fuel generation.   6. Glycogenolysis is affected for up to 10 hours. Gluconeogen-  esis results in the use of proteins necessary for structure,  function, repair, and replication that leads to more impaired  cellular metabolism. Lipolysis is ineffective because of a lack  of transport serum proteins.   7. Gluconeogenesis contributes to lactic acid, uric acid, and  ammonia buildup; interstitial edema; and impairment  of the immune system, as well as general muscle weak-  ness leading to decreased respiratory function and cardiac  output.   8. Cardiogenic shock results from persistent hypotension and  tissue hypoperfusion caused by cardiac dysfunction in the  presence of adequate intravascular volume and left ventric-  ular filling pressure.    9. Hypovolemic shock is caused by loss of whole blood,  plasma, or interstitial fluid in large amounts. The use of  compensatory mechanisms may be vigorous, but tissue per-  fusion ultimately decreases and results in impaired cellular  metabolism.   10. Neurogenic (vasogenic) shock results from massive vaso-  dilation that results from an imbalance between parasym-  pathetic and sympathetic stimulation of vascular smooth  muscle. It causes a relative hypovolemia (even though car-  diac output may be high), and results in impaired cellular  metabolism.   11. Anaphylactic shock is the outcome of a widespread hyper-  sensitivity to an allergen that triggers anaphylaxis. The  inflammatory response is triggered, and a massive vasodila-  tion with fluid shift into the interstitium follows. The rela-  tive hypovolemia leads to impaired cellular metabolism.   12. Septic shock begins with impaired cellular metabolism  caused by uncontrolled septicemia. The infecting agent  triggers the inflammatory and immune responses. It is part  of a continuum known as SIRS. Mortality for septic shock  is very high.   1. MODS is the progressive dysfunction of two or more organ  systems resulting from a systemic inflammatory response  after a severe illness or injury. The inflammatory response  can be triggered by sepsis, necrotic tissue, trauma, burns,  ARDS, acute pancreatitis, major surgery, circulatory shock,  DIC, acute renal failure, blood transfusion, heat stroke, liver  failure, mesenteric ischemia, propofol infusion syndrome,  persistent inflammatory foci, and other severe injuries.   2. Primary MODS is the immediate local or mild systemic  response to the triggering event or illness. It primes the  inflammatory system.    CHAPTER 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults    Secondary MODS is the uncontrollable, excessive systemic  inflammatory response that develops after a latent period  and results in organ dysfunction.    adults, those with significant tissue injury or preexisting  disease, and those in whom resuscitation from the initiat-  ing illness or injury has been delayed or inadequate.    . MODS is a leading cause of mortality in surgical intensive    care units (ICUs). Mortality for individuals with MODS  increases progressively from 54% with two failing organ  systems to 100% with five failing organ systems.    release of complement, coagulation, and kinin proteins;  changes in the vascular endothelium; and numerous  inflammatory processes mediated by substances released  by activated neutrophils and macrophages. The accumu-  lation of activated neutrophils in organs is thought to  play a key role in the pathogenesis of MODS, as well as  macrophages.    in MODS are vasodilation, increased vasopermeability,  and selective vasoconstriction resulting in maldistribu-  tion of blood flow; hypermetabolism; myocardial depres-  sion; and hypoxic injury to cells. Cellular hypoxia and  acidosis impair cellular metabolism, leading to organ  dysfunction.    general during the first 24 hours: low-grade fever, tachy-  cardia, tachypnea, dyspnea, and altered mental status. Over  the next several days, beginning with the lungs, individual  organ systems show signs of failure.    . Because there is no specific therapy for MODS, early detec-    tion is extremely important so that supportive measures  can be initiated as soon as possible.   At present the therapeutic management of MODS consists  of prevention or removal of triggering mechanisms and  support of individual organs. Recent scientific knowledge  about inflammatory mediators has led to many promising  future therapies for MODS.    Burns are classified according to depth and extent of injury.  First-degree burns involve the superficial skin without loss  of protective function.   Second-degree burns are superficial (blister formation) or  superficial involving partial skin thickness with a waxy white  appearance and no involvement of dermal appendages.    underlying tissues. They are painless and can be life threat-  ening as a result of hypovolemic shock and metabolic and  immunologic responses.    The TBSA burned is estimated using either the rule of nines  or the Lund and Browder chart.   Hypovolemia associated with burn shock is caused by  increased capillary permeability with massive fluid losses  from blood volume.    with shunting of blood away from the liver, kidney, and gut.    involves infusion of fluid at a rate faster than the loss of  circulating volume.    . Capillary seal is the term used to indicate the end of burn    damaged by heat, with impairment of the sodium-potassium  pump and loss of magnesium and phosphate.   The stress of a major burn activates the sympathetic ner-  vous system with release of catecholamines, cortisol, gluca-  gon, and insulin.   Burn injury produces a hypermetabolic state that persists  until wound closure and is related to a higher thermal regu-  latory set point.   The local inflammatory response at the burn site releases  cytokines, oxygen-free radicals, chemotactic factors, and  eicosanoids, which lead to a systemic inflammatory response  and contributes to hypermetabolism.   A posttraumatic hypermetabolic response is associated with  increased visceral heat production.   Alterations in clotting factors produce a hypercoagulable  state following major burns.   The immune response following a burn is immediate, pro-  longed, and severe.   Numerous alterations in inflammatory cytokines are evi-  dent in the immediate burn period, affecting cellular immu-  nity, antibody production, and attraction of neutrophils  and contributing to the vasodilation and increased capillary  permeability associated with burn shock.   White blood cells are altered, and there is decreased opso-  nization and phagocytosis, contributing to the develop-  ment of sepsis.   Changes in intestinal wall integrity lead to translocation of  bacteria, endotoxemia, and septic shock.   Loss of intact skin with a major burn results in significant  evaporative water loss contributing to hypovolemia.  Treatment of major burns involves meticulous wound  management, adequate fluids and nutrition, early surgical  excision and grafting, modulation of the hypermetabolic  state, and pain management.    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Duan H et al: Effect of burn injury on apoptosis and expression of  apoptosis-related genes/proteins in skeletal muscles of rats, Apoptosis  14(1):52-65, 2009.   Trunkey DD et al: The effect of hemorrhagic shock on intracellular  muscle action potentials in the primate, Surgery 74(2):241-250, 1973.  Cunningham JN Jr, Shires GT, Wagner Y: Changes in intracellular  sodium and potassium content of red blood cells in trauma and shock,  Am J Surg 122(5):650-654, 1971.   Rosenthal SR, Tabor H: Electrolyte changes and chemotherapy in  experimental burn and traumatic shock and hemorrhage, Arch Surg  51:244, 1945.    Turinsky J, Gonnerman WA, Loose LD: Impaired mineral metabolism  in postburn muscle, J Trauma 21(6):417—423, 1981.   Deets DK, Glaviano VV: Plasma and cardiac lactic dehydrogenase activ-  ity in burn shock, Proc Soc Exp Biol Med 142(2):412-416, 1973.   Button B: Evidence of circulating membrane depolarization factor(s) in  hemorrhagic shock, Shock 1(Suppl):15, 1994.   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Holder IA, Neely AN: Hageman factor dependent activation and its  relationship to lethal Pseudomonas aeruginosa burn wound infections,  Agents Actions Suppl 38(Pt 3):329-342, 1992.   McManus WF, Eurenius K, Pruitt BA Jr: Disseminated intravascular  coagulation in burned patients, J Trauma 13(5):416—422, 1973.  Wilmore DW, editor: The metabolic management of the critically ill, ed 2,  New York, 1990, Plenum.   Wilmore DW, Aulick LH: Metabolic changes in burned patients, Surg  Clin North Am 58(6):1173-1187, 1978.   Edelman LS et al: Sustained bone mineral density changes after burn  injury, J Surg Res 114(2):172-178, 2003.   Wright K et al: Burn-activated neutrophils and tumor necrosis factor-  alpha alter endothelial cell actin cytoskeleton and enhance monolayer  permeability, Surgery 128(2):259-265, 2000.   Goebel A et al: Injury induces deficient interleukin-12 production, but  interleukin-12 therapy after injury restores resistance to infection, Ann  Surg 231(2):253-261, 2000.   Nishiura T et al: Gene expression and cytokine and enzyme activation in  the liver after a burn injury, J Burn Care Rehabil 21(2):135-141, 2000.  Biffl WL et al: Interleukin-6 delays neutrophil apoptosis via a mecha-  nism involving platelet-activating factor, J Trauma 40(4):575-578, 1996.  Choi M et al: Preventing the infiltration of leukocytes by monoclonal  antibody blocks the development of progressive ischemia in rat burns,  Plast Reconstr Surg 96(5):1177—1185, 1995.   Iocono JA et al: Interleukin-8 levels and activity in delayed-healing  human thermal wounds, Wound Repair Regen 8(3):216-225, 2000.  Ortega MR, Ganz T, Milner SM: Human beta defensin is absent in burn  blister fluid, Burns 26(8):724—726, 2000.   Heideman M, Kaijser B, Gelin LE: Complement activation and hema-  tologic, hemodynamic, and respiratory reactions early after soft-tissue  injury, J Trauma 18(10):696—700, 1978.   Grzybowski J et al: Antidietary antigen antibodies in the sera of patients  with burns as a potential marker of gut mucosa integrity failure, J Burn  Care Rehabil 13(2 Pt 1):194-197, 1992.   Deitch EA, Berg R: Bacterial translocation from the gut: a mechanism of  infection, J Burn Care Rehabil 8(6):475—482, 1987.   Yao YM et al: The association of circulating endotoxaemia with the  development of multiple organ failure in burned patients, Burns  21(4):255—-258, 1995.   Benhaim P, Hunt TK: Natural resistance to infection: leukocyte func-  tions, J Burn Care Rehabil 13(2 Pt 2):287—292, 1992.   Alexander JW et al: Consumptive opsoninopathy: possible pathogenesis  in lethal and opportunistic infections, Ann Surg 184(6):672-678, 1976.  Bjornson AB, Altemeier WA, Bjornson HS: Changes in humoral com-  ponents of host defense following burn trauma, Ann Surg 186(1):88-96,  77.   Cochran A et al: Systemic Candida infection in burn patients: a case-  control study of management patterns and outcomes, Surg Infect  (Larchmt) 3(4):367—374, 2002.    Goff DR et al: Cardiac disease and the patient with burns, J Burn Care  Rehabil 11(4):305-307, 1990.   McGill V et al: The impact of substance use on mortality and morbidity  from thermal injury, J Trauma 38(6):931-934, 1995.   Moncrief JA, Mason AD Jr: Water vapor loss in the burned patient, Surg  Forum 13:38-41, 1962.   Moncrief JA: Burns. In Schwartz SI, editor: Principles of surgery, ed 2,  New York, 1974, McGraw-Hill.   Roe CF, Kinney JM: Water and heat exchange on third-degree burns,  Surgery 56:212-220, 1964.   Affleck DG et al: Assessment of tissue viability in complex extremity  injuries: utility of the pyrophosphate nuclear scan, J Trauma 50(2):  263-269, 2001.   Eski M et al: Cerium nitrate treatment prevents progressive tissue necro-  sis in the zone of stasis following burns, Burn 38(2):283-289, 2012.  Weber JM et al: Incidence of catheter-associated bloodstream infection  after introduction of minocycline and rifampin antimicrobial-coated  catheters in a pediatric burn population, J Burn Care Res 33(4):539-543,  2012,   Lee J et al: Computerized insulin infusion programs are safe and effec-  tive in the burn intensive care unit, J Burn Care Res 33(3):e114-e119,  2012.   Zaletel CL: Factors affecting fluid resuscitation in the burn patient: the  collaborative role of the APN, Adv Emerg Nurs J 31(4):309-320, 2009.  Fraser JF et al: A randomized controlled trial of amniotic membrane in  the treatment of a standardized burn injury in the merino lamb, Burns  35(7):998-1003, 2009.   Ronfard V et al: Long-term regeneration of human epidermis on third  degree burns transplanted with autologous cultured epithelium grown  ona fibrin matrix, Transplantation 70(11):1588—1598, 2000.  Williamson JS et al: Cultured epithelial autograft: five years of clinical  experience with twenty-eight patients, J Trauma 39(2):309-319, 1995.  Fitton AR, Drew P, Dickson WA: The use of a bilaminate artificial skin  substitute (Integra) in acute resurfacing of burns: an early experience,  Br J Plast Surg 54(3):208-212, 2001.   Peck MD et al: A trial of the effectiveness of artificial dermis in the treat-  ment of patients with burns greater than 45% total body surface area,   Carsin H et al: Cultured epithelial autografts in extensive burn coverage  of severely traumatized patients: a five year single-center experience with  30 patients, Burns 26(4):379-387, 2000.   Wainwright D et al: Clinical evaluation of an acellular allograft dermal  matrix in full-thickness burns, J Burn Care Rehabil 17(2):124—136, 1996.  Branski LK et al: A review of gene and stem cell therapy in cutaneous  wound healing, Burns 35(2):171-180, 2009.   Curinga G et al: Comments on “platelet-rich plasma in burns, ” Burns  36(6):944—945, 2010.   Pullua N, Wolter T, Markowicz M: Platelet-rich plasma in burns, Burns  36(1):4-8, 2010.   Kirker KR et al: Glycosaminoglycan hydrogels as supplemental wound  dressings for donor sites, J Burn Care Rehabil 25(3):276-286, 2004.  Liew SH, Murison M, Dickson WA: Prophylactic treatment of deep  dermal burn scar to prevent hypertrophic scarring using the pulsed dye  laser: a preliminary study, Ann Plast Surg 49(5):472-475, 2002.  Sainsbury DC: Body image and facial burns, Adv Skin Wound Care  22(1):39-44, 2009.   Connor-Ballard PA: Understanding and managing burn pain: part 1,  Am J Nurs 109(4):48—56, 2009.   Connor-Ballard PA: Understanding and managing burn pain: part 2,  Am J Nurs 109(5):54-62, 2009.   Jellish WS et al: Effect of topical local anesthetic application to skin  harvest sites for pain management in burn patients undergoing skin-  grafting procedures, Ann Surg 229(1):115—-120, 1999.   ity relaxation on pain and anxiety when added to PCA morphine in  patients having burn dressings changes, Burns 35(4):491—499, 2009.    CHAPTER 48 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Adults    As part of your Pageburst Digital Book, you can access the following Integrated Resources:  Case Study    Mary Fran Hazinski, Mary A. Mondozzi, and Rose A. Urdiales Baker    Shock and Multiple Organ Dysfunction Syndrome, 1699  Types of Shock, 1700  Clinical Manifestations of Shock, 1700  Reperfusion and Inflammatory Injury, 1710  Evaluation and Treatment of Shock, 1710    This chapter reviews shock, multiple organ dysfunction syn-  drome, and burns in children. It focuses on the assessment and  care of children but also notes many of the differences between  these conditions in children and adults.    Shock is a condition of acute and progressive circulatory dysfunc-  tion that results in inadequate delivery of oxygen and nutrients  to the tissues. Shock in children most often results from hemor-  rhage, severe dehydration, progressive heart failure, or sepsis. It  may also complicate the care of the child with congenital heart  disease, pulmonary hypertension (cor pulmonale), drug toxic-  ity, electrolyte or acid-base imbalance, dysrhythmias, or multiple  organ failure.   Shock in children is present when there are signs of poor  systemic perfusion, regardless of the blood pressure—shock  may be present with normal, high, or low blood pressure.    When the systolic blood pressure is adequate for age, but there  are signs of inadequate tissue perfusion, the child is in com-  pensated shock. In this child, although the systolic blood pres-  sure may be normal, the diastolic or mean blood pressure is  typically low. If systolic hypotension is associated with inad-  equate tissue perfusion, the child is in hypotensive (formerly  called decompensated) shock.'!*   Shock causes tissue ischemia (inadequate blood flow) and  hypoxia (inadequate oxygen delivery) that leads to acidosis and  cell dysfunction. Oxygen delivery may be inadequate because  arterial oxygen content or cardiac output is low, or because  there are increased metabolic requirements or impaired cellular  use of oxygen. Ischemia and hypoxia are primary insults to cells.  Restoration of adequate blood flow and oxygen delivery may  trigger the development of reperfusion injury, a secondary prob-  lem characterized by an exaggerated inflammatory response  that may produce cellular death and organ failure.   Multiple organ dysfunction syndrome (MODS) is the simul-  taneous failure of at least two organs resulting from a single cause.    MODS may be either primary or secondary. Primary MODS is  directly attributable to the insult and typically occurs soon (3 to  7 days) after an insult. Secondary MODS typically occurs later  and may be associated with more sequential development of  organ dysfunction. Risk factors for MODS include severe or pro-  longed shock, sepsis, trauma, cardiopulmonary arrest, congeni-  tal heart disease, and liver and bone marrow transplantation.*°  Children with chronic diseases have an increased risk for MODS  and increased mortality.°   rogenic): results from inappropriate distribution of blood  flow, increased capillary permeability, and myocardial  dysfunction (e.g., septic or anaphylactic shock) or central  nervous system injury (e.g., neurogenic or spinal shock)   blood flow into and through the heart and great vessels  (e.g., cardiac tamponade, pulmonary embolus, obstruc-  tive congenital heart lesions such as critical aortic steno-  sis) resulting in low cardiac output   With hypovolemic or cardiogenic shock blood flow distri-  bution is reduced to skin, gut, and kidney to maintain blood flow  to the heart and brain. With distributive (septic, anaphylactic,  and neurogenic) shock, blood flow is unregulated throughout  the skin and organ systems and vasodilation and increased capil-  lary permeability are typically present, so a normal cardiac out-  put is likely to be inadequate to maintain sufficient perfusion  of all tissue beds. Volume administration is necessary to ensure  that the intravascular volume is adequate relative to the vascu-  lar space, and vasoactive drugs are needed to support adequate  cardiac output and oxygen delivery. Neurogenic shock is a form  of hypovolemic and vasogenic (maldistributive) shock. It is  caused by a loss of vasomotor tone after severe head or spinal  cord injury. Massive vasodilation and loss of sympathomimetic  tone result in a relative hypovolemia and hypotension. The loss  of sympathetic tone prevents compensatory tachycardia.   In obstructive shock, low cardiac output is caused by  mechanical obstruction to blood flow, such as cardiac tampon-  ade, tension pneumothorax, critical left heart or aortic obstruc-  tion, or pulmonary embolus.” Obstructive shock is difficult to  distinguish from cardiogenic shock because both may present  with signs of low cardiac output and evidence of systemic or  pulmonary venous congestion. Prompt detection and treat-  ment are critical to survival.*”   An etiologic classification of shock is helpful because it  indicates the initial therapy required. However, any child with  late or progressive shock is likely to demonstrate widespread  cardiovascular dysfunction that may include inappropriate  intravascular volume relative to the vascular space, poor myo-  cardial function, and maldistribution of blood flow so the etio-  logic classification of shock is oversimplified for such children.    Signs of Shock in Infants and Children  Change in responsiveness (initial irritability followed by lethargy)  Tachypnea  Mottled color, pallor (distributive shock may be associated with flushed skin)  Tachycardia  Cool skin, prolonged capillary refill (distributive shock may cause “flash”  [instantaneous] refill)  Diminished intensity of peripheral pulses (may also vary in intensity)  Metabolic (lactic) acidosis (serum lactate >4 mmol/L is typically well above  normal for arterial or venous blood)  Decreased central venous oxygen saturation (more than 25% to 30% below  arterial oxygen saturation)  LATE: Hypotension, bradycardia    Nonspecific Signs of Distress in Newborns  Jitteriness or lethargy with decreased tone  Change in oxygen requirements  Apnea  Bradycardia or decreased heart rate variability  Temperature instability, hypothermia  Glucose instability, hypoglycemia  Feeding intolerance (e.g., increased residual volume)    Severe shock of any kind may be followed by complications  such as reperfusion injury or MODS. An etiologic classification  is also incomplete for children with septic shock, because sep-  sis produces elements of hypovolemic and cardiogenic shock in  addition to the complications of infection and maldistribution  of blood flow. Thus, healthcare providers must assess and sup-  port all aspects of cardiovascular function and oxygen delivery  during the treatment of any form of shock.    The child with inadequate cardiac output demonstrates signs of  inadequate blood flow to some tissue beds and evidence of organ  system dysfunction (Box 49-1). Critical parameters to evaluate  when approaching the child include assessment of conscious-  ness, breathing, and color. This initial assessment is described  in the Pediatric Advanced Life Support course.* Through this  assessment the provider determines if the child “looks good”  (appears stable, in no acute distress) or “looks bad” (in need of  immediate intervention).° More detailed assessment of organ  function and acid-base status will detect evidence of inadequate  organ perfusion.   The child’s level of consciousness and responsiveness often  provides valuable information about the severity of illness.  The healthy infant should orient to faces, make eye contact,  and track bright objects across a visual field. The healthy tod-  dler is reluctant to be separated from parents or examined by  strangers, and the healthy child is alert and responds to ques-  tions. By comparison, the critically ill infant or child is often  extremely irritable; lethargy indicates severe deterioration in the  child’s level of consciousness. A decreased response to painful    CHAPTER 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children   The infant or child normally breathes without evidence of  distress or increased effort, such as retractions or nasal flar-  ing. An extremely rapid respiratory rate (tachypnea), increased  depth of respirations (hyperpnea), or evidence of increased  respiratory effort (e.g., retractions, grunting) may indicate the  presence of heart failure or shock. The development of apnea or  inadequate respiratory rate or effort may indicate deterioration  and need for immediate support of airway, oxygenation, and  ventilation.   If perfusion is adequate and the ambient temperature is  warm, the child’s color will be consistent over the surface of the  skin, with pink lips and mucous membranes. Children who are  in a cold environment, those who have undergone hypothermic  surgery or a procedure in a cold room, and children in shock  often demonstrate mottling (a marbled or “blotchy” appear-  ance to the skin).”*° Pallor also may be observed when per-  fusion is poor (Figure 49-1). Children with sepsis occasionally  demonstrate flushed, bright red skin.?*°    : /% 2, x  FIGURE 49-1 Mottling of Skin Caused by Poor Systemic Perfusion. A, Mot-  tling of skin color often indicates inadequate tissue oxygenation; this may result  from hypoxemia or poor systemic perfusion. This child developed myocardial dys-  function and signs of cardiogenic shock. B, Mottled skin color is often associated  with other signs of compromise of skin perfusion, including delayed capillary refill.  The skin over this infant's right ankle was blanched using three fingers (arrows),  and the skin failed to perfuse for more than 5 seconds. This infant suffered from  septic shock. (From Hazinski MF: Cardiovascular disorders. In Hazinski MF, editor:  Nursing care of the critically ill child, ed 2, St Louis, 1992, Mosby.)    If perfusion is adequate and the ambient temperature is  warm, the child’s capillary refill is normally brisk (<2 seconds).  A prolonged capillary refill time (>2 seconds ) may indicate  a compromise in systemic perfusion (see Figure 49-1, B) and  the development of shock.**° However, evaluation of capillary  refill time is subjective and gradual changes may be difficult to  detect.’   The child’s vital signs must be evaluated in light of the child’s  clinical condition. Normal vital signs are not always appropriate  in the seriously ill or injured child® (Box 49-2 and Table 49-1).   The child’s heart rate should be appropriate for age and  clinical condition. The child in shock is often tachycardic. The  tachycardia may be primary (i.e., associated with a tachydys-  rhythmia) or secondary to stress (i.e., sinus tachycardia). If the  heart rate is extremely rapid or if it is present in the child with  decreased myocardial function, tachycardia may be the cause  rather than the symptom of shock. In general, if the ventricu-  lar rate exceeds 200 to 220/min in the infant or 160 to 180/min  in the child, ventricular diastolic filling time and coronary  artery perfusion time are significantly reduced and stroke vol-  ume falls. As a result, cardiac output falls and signs of heart  failure or shock develop. Once supraventricular or ventricu-  lar tachycardia produces signs of shock, urgent treatment is  required.®   Bradycardia, an abnormally low heart rate, can cause a  fall in cardiac output or it can be a symptom of deterioration.  In young animal models, a fall in heart rate produces a com-  mensurate fall in cardiac output.” The most common cause of  bradycardia in young children is hypoxia.*!° Therefore, if the  infant or child develops bradycardia with poor perfusion, the  provider must immediately assess and support the child’s air-  way, oxygenation, and ventilation, and be prepared to initiate  chest compressions if the heart rate and systemic perfusion do  not improve.?!0    BOX 49-2 ESTIMATING BLOOD PRESSURE  IN CHILDREN 1 TO 10 YEARS  OF AGE    Typical systolic BP for 1-10 years of age: The typical “normal” (i.e., median,  or 50th percentile) systolic blood pressure for a child 1 to 10 years of age of  normal height may be estimated by adding 90 mmHg to twice the child's age  in years (90 mmHg + [2 x age in years]); this corresponds to the 50th percentile  systolic blood pressure for the child's age.   Hypotensive systolic BP for 1-10 years of age: A systolic pressure less than  70 mmHg plus twice the child's age in years (<70 mmHg + [2 x age in years])  is considered hypotensive for children 1 to 10 years of age because this blood  pressure corresponds to the 5th percentile systolic blood pressure for age (ie.,  only 5% of normal, healthy children of average height demonstrate a systolic  blood pressure lower than that number).   Hypotensive mean arterial pressure for 1-10 years of age: A mean arterial  pressure less than 40 mmHg + (1.5 x age in years) is consistent with hypoten-  sion because this mean arterial pressure corresponds to the 5th percentile  mean arterial pressure in children of average height.    Data from Chameides L et al, editors: Systematic approach to the seri-  ously ill or injured child. In Textbook of pediatric advanced life support,  Dallas, 2011, American Heart Association; Hacque IU, Zaritsky AL:  Pediatr Crit Care 8:138-144; 2007.    AWAKE HEART RATE SLEEPING HEART RATE RESPIRATORY RATE*  (Per min) (Per min)   100-180 90-160 30-53  98-140 80-120 27-37  80-120 65-100 20-28  75-118 98-90 18-25  60-100 50-90 12-20    SYSTOLIC BLOOD DIASTOLIC BLOOD MEAN ARTERIAL  AGE PRESSURE (mmHg)* PRESSURE (mmHg)* PRESSURE (mmHg)*   Toddler (1-2 yr) 86-106 42-63 49-62 </0 + (2 x age in years)  Preschool (3-5 yr) 89-112 46-72 58-69 </0 + (2 x age in years)  School-age child (6-7 yr) 97-115 57-76 66-72 </0 + (2 x age in years)  Preadolescent (10-12 yr) 102-120 61-80 71-79 <90    Note: Always consider patient's normal range and clinical condition. Heart and respiratory rates normally increase with fever or stress.   From Hazinski MF: Children are different. In Hazinski MF, editor: Nursing care of the critically ill child, ed 3, St Louis, 2013, Mosby.   *Respiratory rates from Fleming S et al: Normal ranges of heart rate and respiratory rate in children from birth to 18 years of age: a systematic  review of observational studies, Lancet 377:1011-1018, 2011.   tSystolic and diastolic blood pressure ranges assume 50th percentile for height for children 1 year and older, and are consistent with the Pediatric  Advanced Life Support course (Chameides L et al: Pediatric advanced life support provider manual, Dallas, 2011, American Heart Association).  *Mean arterial pressures (Diastolic pressure + [Difference between systolic and diastolic pressures + 3]) for 1 year and older, assuming 50th percentile  for height.   SThreshold for hypotension in children 1 to 10 years old from Pediatric Advanced Life Support course (Chameides L et al: Pediatric advanced life  support provider manual, Dallas, 2011, American Heart Association).   Blood pressure ranges from the following sources: Gemelli M et al: Eur J Pediatr 149:318-320, 1990; Versmold H et al: Pediatrics 67:107, 1981;  Haque IU, Zaritsky AL: Pediatr Crit Care 8:138-144, 2007; National Heart, Lung and Blood Institute: Fourth report on the diagnosis, evaluation, and  treatment of high blood pressure in children and adolescents, Bethesda, MD, 2004, National Heart, Lung and Blood Institute. Available at www.nhlbi.  nih.gov/guidelines/hypertension/child.tbl.htm. Accessed July 10, 2013.    Bradycardia often indicates impending cardiovascular col-  lapse and is the most common terminal cardiac rhythm observed  in children.*?°!° The child’s stroke volume may be altered by  conditions affecting ventricular preload, compliance, contrac-  tility, and afterload (Table 49-2). Evaluate and optimize each of  these variables in the treatment of shock (see Chapter 48).   Evaluate the child’s blood pressure in light of age and clini-  cal condition; note that shock may be present despite a systolic  blood pressure within the normal range for age. When hypo-  volemic or cardiogenic shock is present, compensatory vaso-  constriction may initially maintain the systolic blood pressure,  although the mean and diastolic arterial pressures may fall. The  development of systolic hypotension in the child with hypovo-  lemic or cardiogenic shock indicates severe shock, and rapid  deterioration may follow. In septic shock, by comparison, mild  systolic hypotension may develop early in the clinical course.  However, in all children, the development of systolic hypoten-  sion or a fall in mean arterial pressure indicates hypotensive  shock, and urgent treatment is needed.**°    The central venous pressure (CVP) is normally 0 to 5 mmHg  and the pulmonary artery wedge pressure (PAWP, also called  pulmonary artery occlusion pressure [PAOP]) is normally 5 to  8 mmHg or less. Inadequate CVP or PAWP may indicate hypo-  volemia, whereas high measurements typically result from heart  failure or cardiogenic shock. Note that in the absence of tri-  cuspid valve disease, tension pneumothorax, or influence from  positive pressure ventilation, the CVP reflects the right ventric-  ular end-diastolic pressure, whereas the PAWP should, in the  absence of mitral valve disease, reflect the left ventricular end-  diastolic pressure (if the catheter is appropriately placed and  calibrated). The cardiac silhouette is normally less than 50% of  the width of the chest on chest radiograph.   If a central venous catheter is in place, the superior vena cava  (SVC) oxygen saturation is monitored to evaluate the balance  of oxygen delivery versus consumption. The SVC saturation is  central venous oxygen saturation (ScyO>) that is used as a sur-  rogate for mixed venous oxygen saturation that would require  a sampling of blood from the pulmonary artery. Normally, the    CHAPTER 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children    Major factor affecting cardiac output in children. Normally more rapid in children than in adults. Because the stroke    volume is smaller than in adults, the cardiac output of the child is more closely related to heart rate than stroke  volume. /achycardia is expected in the seriously ill or injured child. The most common cause of bradycardia in  young children is hypoxia; bradycardia is an ominous sign if present in association with poor perfusion. Urgent  treatment is required once bradycardia or supraventricular or ventricular tachycardia produces signs of shock.    Averages 1.5 ml/kg; affected by conditions altering ventricular preload, compliance, contractility, and afterload  Optimal pressure for children in shock is unknown. Aggressive fluid administration is linked to improved survival in    Can be affected by congenital heart defects such as atrial septal defects (ASDs) and complex congenital heart    defects. If compliance is low, such as in newborns and infants, volume administration may increase VEDP.  Hypoplastic ventricles are often noncompliant. Hypertrophied ventricles, present in children with severe  pulmonary stenosis or aortic stenosis, may become fibrotic and noncompliant. Increased compliance may be    Contractility probably similar in normal newborns, infants, children, and adults. Newborn myocardium does have    fewer contractile proteins and higher water content than adult myocardium, but the clinical significance of this is    Newborn myocardium can adapt to mild, nonacute increases in afterload. Afterload may be increased in children    with systemic vasoconstriction or pulmonary hypertension (constrictors include alveolar hypoxia, acidosis,  hypothermia, and alveolar distention). Some uncorrected congenital heart defects may increase afterload.  Coarctation of the aorta and aortic stenosis increase left ventricular afterload. Pulmonary stenosis increases right  ventricular afterload. Afterload may be decreased in septic shock.    Highest per kilogram body weight during the neonatal period and infancy. The young child requires a higher cardiac    output and oxygen delivery per kilogram than the adult. Increased oxygen consumption occurs in critically ill  newborns exposed to cold because they cannot shiver to generate heat. Other causes of increased oxygen  consumption in children and infants include fever, sepsis, trauma, pain, and seizures.    ScyO2 is 25% to 30% below the arterial oxygen saturation. A  fall in ScyO, can indicate a fall in oxygen delivery (caused by  decreased arterial oxygen content or decreased cardiac output),  an uncompensated rise in oxygen consumption, or both.’   Shock compromises renal perfusion, so urine volume  decreases, typically to less than 2 ml/kg/hr in infants, less than  1 ml/kg/hr in children, and less than 0.5 ml/kg/hr in adoles-  cents, despite adequate fluid intake. Liver enzymes may be  elevated if hepatic perfusion is reduced. The development of  metabolic acidosis and a rise in serum lactate to greater than  4 mg/dl indicate that blood flow to some tissues is inadequate to  support aerobic metabolism.   Infants have high glucose needs and low glycogen stores that  may be rapidly depleted during stress. For this reason, hypo-  glycemia (glucose <60 mg/dl) may be observed in seriously ill  or injured infants and may be associated with cardiovascular  or neurologic deterioration.”!! Hyperglycemia (>150 mg/dl)  may develop in critically ill or injured children as the result of  a relative insulin-resistant state associated with high levels of  endogenous catecholamines and hydrocortisone secretion.*!!  Such hyperglycemia in children is often observed in the first 12  to 18 hours after initial injury or development of shock, then  falls to normal levels; persistent hyperglycemia (>180 mg/dl  or 10 mmol/L) has been linked with poor survival in criti-  cally ill children,'*! and hypo-, hyperglycemia, and glucose  instability (episodes of both hypo- and hyperglycemia in same  child) have been linked with development of multiple organ  dysfunction.!°   Hypovolemic shock, the most common type of shock in chil-  dren, is associated with a reduction in the intravascular volume  relative to the vascular space. Dehydration and trauma are the  most common causes of hypovolemic shock in children. A  relative hypovolemia also may result from vasodilation and a  redistribution of blood volume or from increased capillary per-  meability, such as may develop following burns or with sepsis.   When hypovolemia is mild or moderate, such as with 5%  to 10% dehydration or mild hemorrhage, compensatory adren-  ergic vasoconstriction redistributes blood from the skin, the  mesenteric (gut), and renal circulations to maintain blood  flow to the heart and brain. The child with mild hypovole-  mic shock typically maintains systolic blood pressure with this  vasoconstriction.   Hypotension is a sign of severe, decompensated hypovole-  mic shock and may not develop unless intravascular volume  loss is rapid or severe.*’ Hypotension typically develops with  greater than 10% isotonic or hypotonic dehydration in the  infant or child (or greater than 6% to 7% dehydration in the  adolescent).'' Hypotension may not be observed in the child  with trauma unless hemorrhage totals about 20% to 25% of cir-  culating blood volume.!*!®   Relative hypovolemia may be caused by a decrease in the  intravascular volume relative to the vascular space. This may  be associated with the vasodilation of sepsis, anaphylaxis, or  neurogenic shock (see following text) or with B,-adrenergic  drug toxicity. A relative hypovolemia also may be caused by    increased capillary permeability with a redistribution of intra-  vascular volume, such as with burns, anaphylaxis, or sepsis. The  translocation of extravascular fluid to a location that is neither  intravascular nor intracellular, as in edema, is termed “third  spacing” of fluids.'!   Compensatory Responses. Significant dehydration, hypovo-  lemia, and low cardiac output stimulate adrenergic and renal  compensatory mechanisms characterized by the “fight-or-flight”  response. These include tachycardia and redistribution of blood  from the skin, gut, and kidney to the brain and heart. Reduced  renal perfusion stimulates the renin-angiotensin-aldosterone  system, resulting in renal sodium and water retention.  Decreased atrial stretch stimulates the secretion of antidiuretic  hormone (ADH, also known as arginine vasopressin [AVP])  and produces free water retention by the kidneys.’ These  mechanisms are similar in adults and children and may help  restore or maintain intravascular volume over time. Neonatal  and young infant kidneys, however, are incapable of excreting  concentrated urine, so these compensatory mechanisms are  relatively ineffective during the first weeks of life.!!   Compensatory mechanisms cannot be maintained indefinitely.  Systemic vasoconstriction increases left ventricular afterload and  myocardial oxygen consumption and may produce tissue ischemia.  Prolonged tachycardia may impair subendocardial blood flow and  increase myocardial oxygen consumption; both may ultimately  contribute to myocardial ischemia.* Extreme tachypnea increases  oxygen demand and reduces effective ventilation. A severe com-  promise in blood flow and systemic perfusion contributes to cere-  bral, renal, or hepatic ischemia and possible organ failure.    CLINICAL MANIFESTATIONS. The child with hypovolemic shock  demonstrates signs of inadequate blood flow to some tissue beds  and some evidence of organ system dysfunction (see Box 49-1).  The infant or child may be irritable or lethargic. Respirations will  be rapid and may be labored if shock is severe or associated with  myocardial failure. The skin will be mottled, although pallor also  may be observed. A prolonged capillary refill time (>2 seconds)  is consistent with the development of shock.?*!°   The child in hypovolemic shock is often tachycardic. Bradycar-  dia often indicates impending cardiovascular collapse or cardiac  arrest and is the most common terminal cardiac rhythm observed  in children.2?!° When hypovolemic shock is present, compen-  satory vasoconstriction may initially maintain the systolic blood  pressure, although the mean arterial pressure may fall. The devel-  opment of systolic hypotension often indicates severe shock, and  rapid deterioration may follow. The CVP is less than 5 to 8 mmHg,  unless heart failure or pulmonary hypertension is present.   Hypovolemic shock compromises renal perfusion so urine vol-  ume decreases despite adequate fluid intake. Liver enzymes may  be elevated if hepatic perfusion is reduced. The development of  metabolic acidosis and a rise in serum lactate indicate that blood  flow to some tissues is inadequate to support aerobic metabolism.   Hypoglycemia (glucose <60 mg/dl) may be observed in seri-  ously ill or injured infants, especially if intake has been compro-  mised, and may be associated with cardiovascular or neurologic  deterioration. Hyperglycemia (>150 mg/dl) may develop in  critically ill or injured children.   Clinically significant dehydration is associated with weight  loss (Table 49-3). Fluid intake and output records (or reports    Fluid output exceeds intake. Loss of free water is proportional to loss of sodium, so serum sodium concentration remains    normal. Fluid loss is from intravascular and extravascular compartments. Compromises peripheral perfusion when the young  child has lost approximately 10% (100 ml/kg) of body weight. Compromises systemic perfusion in the adolescent with acute  fluid loss equivalent to 5% to 6% of body weight.   Produces hypotension (decompensated shock) when the young child has lost 15% (150 ml/kg) of body weight. Produces  hypotension in the adolescent with a fluid loss equivalent to 7% to 9% of body weight because body water constitutes a    smaller percentage of body weight in older children and adults than in young children.   Associated with a proportionately greater loss of sodium than free water; thus the serum sodium falls. Resultant acute fall in  serum osmolality produces an acute extravascular fluid shift and further loss of extravascular volume. Fluid loss in hypotonic  dehydration is primarily from the intravascular compartment; thus a compromise in systemic perfusion will be observed after  even small quantities of fluid loss.   Poor peripheral perfusion occurs in a child with a fluid loss equivalent to 5% (50 ml/kg) of body weight. Adolescents  with hyponatremic dehydration may demonstrate a compromise in peripheral perfusion with a fluid loss equivalent to  approximately 3% of body weight.   Hypotension often is observed when fluid loss is equal to approximately 10% (100 ml/kg) of body weight. Hypotension in an  adolescent is observed when the fluid loss equals approximately 5% to 6% of body weight.   Free water deficit is proportionately greater than the deficit of sodium, so serum sodium concentration rises, increasing serum  osmolality and producing an intravascular shift of free water. For this reason the child with hypernatremic dehydration is  likely to maintain intravascular volume and systemic perfusion until relatively large quantities of fluid are lost.   Compromise in systemic perfusion is not likely to be observed in the chi/d with hypernatremic dehydration until severe dehydration  is present with a fluid loss equivalent to 10% of body weight (or 5% to 6% of body weight in the adolescent).   Hypotension may not be observed until the fluid loss approximates 15% or more of body weight (7% to 9% or more of body  weight in the adolescent).   Hypotension in the child with hypertonic/hypernatremic dehydration indicates a substantial fluid deficit. However, the deficit  must be replaced carefully to correct shock and avoid rapid lowering of serum sodium concentrations.    Data in part from Roberts KE: Pediatr Rev 22:380-386, 2001; Roberts KE: Fluid, electrolyte and endocrine problems. In Hazinski MF, editor: Nursing  care of the critically ill child, ed 3, St Louis, 2013, Mosby.    CHAPTER 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children   Alert, restless, thirsty  Full  Norma  Pinch retracts immediately  Norma  Present  Moist  Norma  <2 seconds  Varies with age  Norma    Modified from Perkin RM et al: Shock, cardiac arrest and resuscitation. In Hazinski MF, editor: Nursing care of the critically ill child, ed 3, St Louis,    *The interpretation of the assessments must be appropriately modified for age and type of dehydration (hypotonic or hypertonic).    From Hazinski MF: Children are different. In Hazinski MF, editor: Nursing  care of the critically ill child, ed 3, St Louis, 2013, Mosby.    from parents or primary caretakers) reveal a history of inad-  equate fluid intake or excessive fluid losses. The child with  significant dehydration demonstrates dry mucous mem-  branes, a sunken fontanel (in infants), and poor skin turgor!!  (Table 49-4). Moderate isotonic dehydration produces signs  of peripheral circulatory compromise, and severe isotonic  dehydration will produce hypotension. The blood urea nitro-  gen (BUN) and urine specific gravity are usually elevated. The  serum sodium concentration and osmolality are affected by the  type and severity of dehydration present.   Hemorrhage is another potential cause of hypovolemic  shock. To appreciate the significance of any blood lost or drawn  for laboratory analysis, the total blood loss should be consid-  ered as a percentage of the child’s circulating blood volume  (Table 49-5).   Tachycardia, peripheral vasoconstriction, and altered level  of consciousness may be the only early evidence of hemor-  rhage in the child with trauma (Table 49-6). Acute blood loss  (hemorrhage) may not compromise a child’s peripheral per-  fusion until an estimated 25% to 30% of intravascular vol-  ume is lost (i.e., an acute intravascular or blood loss of 16  to 24 ml/kg).!*'!° Once hypotension develops, cardiovascular  collapse is imminent and immediate, rapid intravascular vol-  ume expansion is required and surgical intervention may be  needed.    Redistribution of blood volume associated with systemic  vasodilation, high capillary pressure or transudative fluid  losses, or capillary leak may produce a relative hypovolemia  and signs of poor systemic perfusion in the absence of evi-  dence of absolute volume loss. For example, children with  end-stage hepatic failure may demonstrate a relative hypovo-  lemia associated with ascites and hepatorenal syndrome. Chil-  dren demonstrate increased capillary permeability and loss  of intravascular volume immediately after a burn. The septic  child also may demonstrate systemic edema associated with  capillary leak and intravascular volume loss. In these children  some evidence of extravascular fluid movement (ascites, sys-  temic edema, or fluid loss to dressings over burns) is usually  observed.   Signs of neurogenic shock in the child with a recent, severe  spinal cord injury include warm skin and hypotension with a  low diastolic blood pressure. Signs of poor systemic perfusion  also are observed (see Clinical Manifestations of Shock, previ-  ously), although loss of sympathetic nervous system tone pre-  vents the typical tachycardic response.   Cardiogenic shock is present when impaired myocardial  function compromises cardiac output. This form of shock is  observed:   1. Following cardiovascular surgery or with inflamma-  tory disease of the heart, such as cardiomyopathy and  myocarditis   3. Asa complication of any form of shock and early in septic  shock   shock, adrenergic compensatory mechanisms produce  tachycardia, peripheral vasoconstriction, and constriction of  the splanchnic arteries to divert blood flow from the skin, gut,  and kidneys to maintain flow to the heart and brain.**'° These  compensatory mechanisms may be sufficient to maintain the    TABLE 49-6 CLASSIFICATION OF PEDIATRIC HEMORRHAGIC SHOCK IN TRAUMA PATIENTS  BASED ON CLINICAL EVALUATION    Low to normal blood pressure (systolic  BP >70 mmHg + [2 x (age in years)])    Moderate tachycardia  Thready peripheral pulses, weak central pulses  Frank hypotension (systolic BP <70 mmHg +  [2 x (age in years)))  Moderate acidosis    From Soud T, Pieper P, Hazinski MF: Pediatric trauma. In Hazinski MF, editor: Nursing care of the critically ill child, ed 2, St Louis, 1992, Mosby.    child’s systolic blood pressure and effective coronary artery and  cerebral blood flow. However, tachycardia and systemic arterial  constriction increase myocardial oxygen consumption. In  addition, reduction in gut and kidney blood flow may produce  hepatic, mesenteric, or renal ischemia or failure. Decreased  renal perfusion stimulates the renin-angiotensin-aldosterone  system, as described for hypovolemic shock.   If the mean arterial pressure or pulse pressure falls, stimula-  tion of the baroreceptors in the carotid sinuses and aortic arch  is reduced. This reduced baroreceptor activity removes inhi-  bition from the vasomotor center in the medulla, resulting in  increased adrenergic stimulation.’ If myocardial dysfunction  progresses, cardiac output and systemic blood pressure ulti-  mately fall. Myocardial ischemia then exacerbates myocardial  dysfunction, and multisystem organ failure may result from  persistent or severe organ ischemia.   CLINICAL MANIFESTATIONS. The child with cardiogenic shock  demonstrates signs of inadequate systemic perfusion despite ade-  quate intravascular volume or even relative hypervolemia. This  form of shock is generally associated with low cardiac output.  The child’s extremities are cool to touch (will cool peripherally to  proximally), with delayed capillary refill despite a warm, ambient  temperature.» !° The skin may be mottled (see Figure 49-1).   Evidence of an adequate or high central venous pressure,  including hepatomegaly and periorbital edema, is typically  present in uncomplicated cardiogenic shock, particularly if  right ventricular failure is involved. Evidence of pulmonary  edema may be noted on a chest radiograph or clinical assess-  ment (including signs of respiratory distress, reduced lung  compliance during hand ventilation, or frothy pink sputum  suctioned from the endotracheal tube) if left ventricular fail-  ure is present. The cardiac silhouette is usually enlarged on the  chest radiograph, unless concurrent hypovolemia is present. If  myocardial function is severely compromised, peripheral pulses  may be diminished in intensity (dampened) or they may vary in  intensity (pulsus alternans).    A low cardiac output may be documented by invasive or  noninvasive devices. If a pulmonary artery catheter is in place,  the cardiac output may be calculated through a thermodilution  technique or continuous monitoring of the mixed venous oxy-  gen saturation.   Signs of low cardiac output and cardiogenic shock may be  identical to signs of cardiac tamponade. Although some clas-  sic signs of tamponade, including muffled heart tones or pul-  sus paradoxus may be observed, these signs may be difficult  to appreciate if cardiac output and blood pressure are severely  compromised. Therefore, if cardiogenic shock is suspected in  a child after cardiovascular surgery or in any child at risk for  the development of pericardial effusion, tamponade should be  ruled out through an echocardiogram.   Sepsis and its complications result from activation of bio-  chemical and physiologic cascades that lead to the formation  or activation of cytokines and other mediators that produce  vasodilation, increased capillary permeability, maldistribution  of blood flow, and cardiovascular dysfunction.’ Sepsis and its  complications may result in organ system dysfunction and are  leading causes of death in noncoronary intensive care units. An  estimated 42,000 pediatric cases of sepsis are reported annually  in the United States and result in approximately 4400 deaths  per year.!”   Much information about the pathophysiology and clinical  signs of sepsis has been extrapolated from adult studies and  adult animal models of sepsis. Some information gleaned from  adult experience is applicable to children, whereas other infor-  mation is not. More research is needed to better understand  pediatric sepsis and septic shock.   Watson’s 2003 hospital data from seven states!” still provides  the most detailed information regarding causes of pediatric  sepsis in the United States. The most common sites of infec-  tion from these data were primary bloodstream (25%) and    CHAPTER 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children    respiratory tract (37%) infections;!” about half of children with  sepsis had an underlying disease and more than one fifth were  low-birth-weight neonates.!”!®   Many bloodstream and respiratory infections may be pre-  vented with proper handwashing by healthcare providers  before and after contact with children, appropriate sterile and  aseptic technique during catheter insertion and tubing changes,  and use of protocols to reduce central venous catheter infec-  tions and ventilator-associated pneumonias.'?° More pediatric  data are needed to develop evidence-based recommendations  to reduce hospital-acquired infections and sepsis.   The microorganisms that cause sepsis vary according to age,  immune function, and location (e.g., in the hospital versus in  the community).”! Approximately 40% of all hospital-acquired  infections in adults and children are linked to gram-negative  infections; 40% to gram-positive infections; and 20% to viruses,  fungi, or rickettsial microorganisms.'® Prevention of hospital-  acquired infections can substantially reduce the risk of sepsis  and its complications.!°° Clinicians must be aware of the com-  mon pathogens in various populations.   Factors associated with risk for the development of sep-  sis include extremes of age (infants, young children and older  adults)*!’; invasive catheters, surgical incisions, or wounds or  burns; immunocompromise; and long-term antibiotic ther-  apy.'”!8 Many of these risk factors are present in seriously ill or  injured children and children with a chronic disease.   It is now clear that genetic variations among children and  among invading microorganisms can alter the outcome of  infections, sepsis, and septic shock.*! Genetic variation in any of  several genes that affect host responses to invading microorgan-  isms can influence outcomes of infections.’? Certainly, infec-  tious diseases, such as meningococcal disease, can vary widely  in their invasiveness and in the severity of effects on the host.?*  It is anticipated that genetic information will ultimately influ-  ence identification of a child’s susceptibility to infection and  sepsis, risk modification, early detection of sepsis, tailoring of  therapy, and prognostication.””   Both proinflammatory and anti-inflammatory cytokines  serve essential protective functions in fighting infection and  modulating the immune response. Sepsis is caused by the effects  of the invading microorganism and its toxins, but most effects  that contribute to shock result from a disruption in the bal-  ance between proinflammatory mediators (including tumor  necrosis factor-alpha [TNF-a], interleukin [IL]-1, IL-6, and  IL-8; platelet-activating factor; arachidonic acid metabolites;  nitric oxide; and many kinins) and anti-inflammatory mediators  (IL-4, IL-10, IL-11, and IL-13; transforming growth factor-beta;  colony-stimulating factors; soluble tumor necrosis factor recep-  tor; IL-1 receptor antagonist; and activated protein C).° Extremely  high levels of proinflammatory mediators, such as TNF, nitric  oxide, and platelet-activating factor can become destructive,  even after the triggering microorganism is eradicated.>”!   High proinflammatory cytokine levels have been implicated  in the development of sepsis-induced disseminated intravascu-  lar coagulation, pulmonary injury, and microcirculatory dis-  ruptions, such as are observed in burns, severe trauma, shock  reperfusion syndromes, and MODS.?! Tumor necrosis factor    levels have been directly related to mortality in newborns and  children with meningitis and sepsis,** and interleukin-8 levels  have been shown to be reliable predictors of pediatric sepsis  mortality.”   Increased nitric oxide concentrations are thought to con-  tribute to vasodilation, hypotension, and decreased myocar-  dial function that develop during adult sepsis. In comparison,  infants with sepsis often demonstrate pulmonary vasoconstric-  tion resulting from shock-induced acidosis and hypoxia, and  may benefit from administration of inhaled nitric oxide or  other vasodilators.”   During sepsis, endotoxin stimulates the endothelium to  become a secretory organ. The endothelium changes from the  normal profibrinolytic and anticoagulant state to an antifibri-  nolytic and precoagulant one.’? This change can lead to the  development of microthrombin in some areas of the micro-  circulation, further contributing to maldistribution of blood  flow. Mediators (e.g., activated protein C) that regulate coagu-  lation pathways have been implicated in the sepsis process.”>"7’  Activated protein C also regulates inflammation and activated  protein C deficiency is a marker for severe sepsis in all ages.”  Although administration of activated protein C improved sur-  vival in adults with severe sepsis,** it has not been shown to  improve outcome in children and may produce excessive bleed-  ing complications.”°   There is clear interaction among catecholamines, adreno-  receptors, and glucocorticoids. Endogenous glucocorticoids  have an anti-inflammatory effect (they decrease activation of  proinflammatory mediators), and they modulate vasomotor  tone by enhancing cardiovascular and vasomotor response to  catecholamines.”?   Critically ill children may have adrenal insufficiency (caused  by adrenal hemorrhage, decreased renal perfusion, inhibition  of corticosteroid production by TNF, or actual adrenal disease)  or a relative adrenal insufficiency, with inadequate adrenal  stress response or decreased response to circulating glucocorti-  coids.°°°! When sepsis is present and the child fails to respond  to initial fluid therapy and vasoactive support, providers should  rule out adrenal insufficiency and consider hydrocortisone  administration, especially if risk of adrenal insufficiency is  present.*?   CLINICAL MANIFESTATIONS. Sepsis and its complications produce  a cascade of physiologic and biochemical changes. The clinical  progression of sepsis in children has been described and defined  by a consensus panel of international physicians‘ (Box 49-3).   Systemic inflammatory response syndrome (SIRS) repre-  sents a nonspecific response to a variety of insults, including  trauma, burns, pancreatitis, or infection. SIRS is present when  the child demonstrates two or more of the following as an acute  change from baseline: change in temperature, specifically fever  (greater than 38.5° C [101.3° F]) or hypothermia (less than 36° C  [96.8° F]), change in heart rate (tachypnea or, in infants, brady-  cardia), change in respiratory rate (or need for mechanical ven-  tilation), or change in white blood cell (WBC) count (including  leukocytes, leukopenia, or an increase in the percentage of  immature or band forms of WBCs).* These clinical signs must  be interpreted in light of the child’s baseline function.    Systemic Inflammatory Response Syndrome (SIRS)  The presence of at least two of the following four large bulleted criteria, one of  which must be abnormal temperature or leukocyte count:  e ALTERATION IN TEMPERATURE: Core body temperature of >38.5° or <36°C  e ALTERATION IN HEART RATE (characterized by any of the three open bullets,  below):  o Tachycardia in the absence of external stimulus, chronic drugs, or painful  stimuli, defined as follows:  — Newborn to 1 year: HR >180/min  — 2-5 years: >140/min  — 6-12 years: >130/min  — 13 to <18 years: >110/min  o Otherwise unexplained persistent elevation over a 0.5 to 4-hour time  period  o For children younger than 1 yr: bradycardia, in the absence of external  vagal stimulus, B-blocker drugs, or congenital heart disease, defined by  one of the three dashes below:  — Newborn to 1 month: <100/min  — 1 month to 1 year: <90/min  — Otherwise unexplained persistent depression over a 30-minute time  period  e ALTERATION IN RESPIRATORY RATE (characterized by either of the open  bullets, below):  o Mean respiratory rate >95th percentile normal for age, defined as follows:  Newborn to 1 week: >50/min  1 week to 1 month: >40/min  1 month to 1 year: >34/min  2-5 years: >22/min  6-12 years: >18/min  13 to <18 years: >14/min    o Mechanical ventilation for an acute process not related to underlying  neuromuscular disease or the receipt of general anesthesia  e ALTERATION IN WHITE BLOOD CELL COUNT:  o Leukocyte count elevated or depressed for age (not secondary to chemotherapy-  induced leukopenia) or >10% immature neutrophils   e A suspected or proven (by positive culture, tissue stain, or polymerase chain  reaction test) infection caused by any pathogen   imaging, or laboratory tests (e.g., white blood cells in a normally sterile body    Sepsis  e SIRS in the presence of or as a result of suspected or proven infection    Severe Sepsis  e Sepsis plus one of the following:  o Cardiovascular organ dysfunction  o Acute respiratory distress syndrome  o Two or more other organ dysfunctions (organ dysfunctions are defined in  Box 49-4)    From Perkin RM et al: Shock, cardiac arrest and resuscitation. In Hazinski MF, editor: Nursing care of the critically ill child, ed 3, St Louis, 2013,    Mosby; Modified from Goldstein B et al: Pediatr Crit Care Med 6:2-8, 2005.    Sepsis is a systemic response to infection. It is present when  manifestations of SIRS are observed in conjunction with sus-  pected infection. Positive blood or other cultures are not neces-  sary for the diagnosis, but suspicion of infection is required.*  For example, if the child with trauma develops a high fever  or pulmonary congestion several days after injury, it is highly  likely that an infection is present.   Severe sepsis is present when the child demonstrates evidence  of sepsis (SIRS with suspected infection) and signs of cardiovas-  cular or pulmonary dysfunction, or if the child has sepsis and  evidence of two or more other organ dysfunctions (Box 49-4).*  Altered organ perfusion is signaled by signs of organ system dys-  function. The dysfunctional organ system should be separate  from the site of suspected infection and not explained by effects  of drug therapy or other acute effects.‘ This important distinc-  tion will enable separation of signs of severe sepsis from signs of  simple pneumonia and associated respiratory failure.   Septic shock is heralded in the child with sepsis by the devel-  opment of cardiovascular dysfunction. This may be character-  ized by hypotension despite adequate fluid resuscitation or by  the need for vasopressors to maintain blood pressure.’ Because  children tend to develop hypotension only late in the course  of any shock, septic shock should be identified when the child    develops more subtle signs of poor perfusion despite adequate  fluid resuscitation. When the child with sepsis does develop  hypotension plus signs of poor perfusion, hypotensive/decom-  pensated septic shock is present, and mortality may be as high  as 30%.*?   Kissoon, Orr, and Carcillo** have proposed simplified diag-  nostic criteria for pediatric septic shock. They note that fever,  tachycardia, and vasodilation are signs of inflammation. They  propose that if the child with this triad of inflammatory signs  also develops altered level of consciousness, the diagnosis of  septic shock should be considered. Carcillo*>** has distilled  the international consensus definitions of septic shock to  include suspected infection with hypo- or hyperthermia and  clinical signs of inadequate perfusion. Carcillo defines signs  of inadequate perfusion as including any one of the following:  decreased level of conscious or change in mental status; pro-  longed (>2 seconds) capillary refill; abnormal pulses (either  diminished or bounding with wide pulse pressure); mottled,  cool extremities; or decreased urine output. Carcillo also notes  that hypotension is not required for the diagnosis but, if pres-  ent, is confirmatory.>**   Children with septic shock may have a high, normal, or  low cardiac output. Unlike adults, who typically present with    CHAPTER 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children    BOX 49-4 CRITERIA FOR ORGAN DYSFUNCTION IN CHILDREN WITH SEVERE SEPSIS  OR SEPTIC SHOCK    Cardiovascular  Despite administration of isotonic intravenous fluid boluses of more than  40 ml/kg in 1 hour, is described by the characteristics in one or more of the three  bullets below:  e Decrease in blood pressure (BP) (hypotension) to <5th percentile for age, esti-  mated for children 1-10 years of age as follows:  — Mean arterial pressure: <40 mmHg + (1.5 x age in years)  — Systolic BP <70 mmHg + (2 x age in years)  Need for vasoactive drug to maintain BP in normal range (dopamine >5 mcg/  kg/min; or dobutamine, epinephrine, or norepinephrine at any dose)  Two of the following:  Unexplained metabolic acidosis: base deficit more severe than —5 mEq/L  Increased arterial lactate >2 times upper limit of normal  Oliguria: urine output <0.5 ml/kg/hr  Prolonged capillary refill: >5 seconds  Core to peripheral temperature gap >3°C   e PaCO,/Fi0, <300 in absence of cyanotic heart disease or pre-existing lung  disease    © Proven need! or >50% inspired oxygen to maintain saturation >92%  e Need for nonelective invasive or noninvasive mechanical ventilation*   e Acute change in mental status with a decrease in Glasgow score =3 points  from abnormal baseline   e A decline of 50% in platelet count from highest value recorded over the past  3 days (for chronic hematology/oncology)    Renal  e Serum creatinine >twofold upper limit of normal for age or twofold increase  in baseline creatinine    Hepatic (either of the following)  e Total bilirubin =>4 mg/dl (not applicable for newborn)  e ALT twofold upper limit of normal for age    From Perkin RM et al: Shock, cardiac arrest and resuscitation. In Hazinski MF, editor: Nursing care of the critically ill child, ed 3, St Louis, 2013,    Mosby. Modified from Goldstein B et al: Pediatr Crit Care Med 6:2-8, 2005.    *Acute respiratory distress syndrome must include a Pao2/FiO, ratio <200 mm Hg, bilateral infiltrates, acute onset, and no evidence of left heart  failure. Acute lung injury is defined identically except the Pao./FiO, ratio must be <300 mmHg.   *In postoperative patients this requirement can be met if the patient has developed an acute inflammatory or infectious process in the lungs that    vasodilation, hypotension, and normal or high cardiac output,  approximately half of children with septic shock present with  severe peripheral vasoconstriction, high systemic vascular resis-  tance, and low cardiac output.?>**   The child with septic shock has significant hypovolemia  and maldistribution of blood flow that typically respond to  aggressive fluid administration, antibiotics and titration of  inotropes, vasopressors, and vasodilators. Therapeutic goals  include restoring blood pressure, normalizing heart rate and  capillary refill, and maintaining high cardiac index (3.3 to  6 L/min/m? body surface area [BSA]) and high oxygen delivery  (more than 200 ml/min/m?) BSA.*?~°” In fact, in a small but  seminal report of outcomes of septic shock in children,*° Car-  cillo, Davis, and Zaritsky showed that aggressive fluid resus-  citation (more than 40 ml/kg administered within the first  hour of therapy and more than 200 ml/kg administered during  the first 8 hours of therapy) was associated with significantly  higher survival than less aggressive fluid resuscitation. In the  most recent consensus recommendations for hemodynamic  support of children with septic shock,** the experts noted the  reduction in mortality (from initial 35% to 40% mortality to  about 2% to 8% mortality) associated with the implementation  of their consensus therapy recommendations.°*** In fact, for  every hour delay in the restoration of normal blood pressure  for age and restoration of capillary refill less than 3 seconds, the  child’s mortality doubled.”>~?"*4    The ultimate goal of treatment of septic shock is to support  adequate systemic oxygen delivery and organ perfusion and  function. This requires careful titration of fluid administra-  tion, inotropic support, and vasoconstrictors or vasodilators  to maximize systemic oxygen delivery and organ perfusion and  function.   The terms warm and cold septic shock are imprecise terms and  should be used only in conjunction with other descriptions of  systemic perfusion and cardiovascular function. Warm shock  is characterized by peripheral vasodilation, warm skin with  flash capillary refill, bounding pulses, and wide pulse pressure.  Warm shock was thought to be associated with hyperdynamic  cardiovascular function and high cardiac output. These charac-  teristics are most commonly seen in adults with septic shock.”°  Cold shock is characterized by peripheral vasoconstriction,  cold skin with prolonged capillary refill, and decreased periph-  eral pulses. Cold shock is often associated with low cardiac out-  put; these characteristics are present in almost half of children  who present with septic shock.”> However, cardiac output may  be low, normal, or high regardless of skin temperature, perfu-  sion, and pulses; these characteristics alone will not identify the  cardiovascular support required. When inadequate systemic  perfusion persists, the child likely needs more aggressive fluid  administration and titration of vasoactive drug therapy.   Many adults and some children with sepsis generate a cardiac  output that is higher than normal despite a fall in ventricular    ejection fraction. This high cardiac output may be associated  with temporary adaptive ventricular dilation and an increase in  ventricular end-diastolic volume, an increase in heart rate, and  a fall in systemic vascular resistance. This low ejection fraction  and ventricular dilation has not been documented in most chil-  dren with septic shock. Most demonstrate severe hypovolemia,  and cardiac function may be maintained or restored if fluid  resuscitation is adequate.”   Kissoon, Orr, and Carcillo** describe the calculation of a  shock index for children with septic shock. This shock index  (heart rate + systolic blood pressure) is high (2.4 or higher)  with untreated or inadequately treated septic shock but falls  with effective treatment of septic shock.    Obstructive shock is inadequate cardiac output caused by an  impediment to blood flow to or from the heart into the pul-  monary or systemic circulation. Causes of obstructive shock  in children include congenital heart defects (such as critical  aortic stenosis and those with ductal-dependent pulmonary or  systemic blood flow), tension pneumothorax, and pulmonary  embolus. Obstruction to blood flow results in low cardiac out-  put and circulatory collapse, typically with signs of peripheral  vasoconstriction as adrenergic stimulation attempts to reduce  blood flow to the skin, gut, and kidney and maintain adequate  blood flow to the heart and brain. Signs of systemic or pulmo-  nary venous obstruction are observed.   Additional clinical manifestations of obstructive shock are  based on the cause of the obstruction. For example, the new-  born with ductal-dependent pulmonary blood flow develops  profound hypoxemia when the ductus arteriosus begins to con-  strict. If a newborn has ductal-dependent systemic blood flow,  systemic pulses become faint or absent, extremities become cold  and pale, and signs of pulmonary venous congestion develop  when the ductus arteriosus begins to close. Tension pneumo-  thorax produces signs of systemic venous obstruction and con-  gestion, decreased breath sounds and chest expansion on the  side of the pneumothorax, and shift of the mediastinum to the  contralateral chest. Significant hypoxemia is present. When  cardiac tamponade is the cause of the obstruction, signs of sys-  temic or pulmonary edema, or both, develop with low cardiac  output. When pulmonary embolus is the cause of the obstruc-  tion, hypoxemia, severe respiratory distress (or shortness of  breath), and signs of right ventricular failure are observed.*:!°   Treatment of obstructive shock focuses on restoration of  systemic oxygenation and perfusion, and elimination of the  obstruction to flow. To support systemic oxygenation and  perfusion, providers must establish and maintain an adequate  airway and support oxygenation and ventilation. Following  establishment of vascular access, administration of a fluid bolus  of 10 to 20 ml/kg of isotonic crystalloid may improve systemic  perfusion; repeat if it is effective.*°’ Diagnostic studies are lim-  ited to those essential to establishment of the diagnosis. Elimi-  nation of the cause of obstruction may require administration  of prostaglandin E, (to reopen a constricted ductus arteriosus  in newborns with ductal-dependent congenital heart disease),  interventional cardiac catheterization for treatment of other    defects causing obstruction, needle decompression of a tension  pneumothorax or cardiac tamponade, and fibrinolytic therapy  and anticoagulation (and possible embolectomy) for treatment  of massive pulmonary embolus.°””    Reperfusion (reoxygenation) injury is cell damage caused by  the restoration of blood flow and physiologic concentrations of  oxygen to cells that have been exposed to injurious but non-  lethal hypoxic conditions.** Ischemia causes changes in trans-  membrane permeability to sodium and calcium, and damage to  intracellular organelles.*? This damage triggers a proinflamma-  tory and procoagulant response that can be very similar to that  described for septic shock (described previously).   Restoration of oxygen delivery to extremely ischemic tis-  sues produces highly reactive oxygen intermediates (e.g., free  oxygen radicals and superoxide) that damage cell membranes,  denature proteins, and disrupt chromosomes (see Chapter 2).°”  The amount of free oxygen radical produced is directly related  to the severity and duration of the ischemic period. The reper-  fusion process is most likely to affect endothelial cells of the  microvasculature, compromising organ perfusion after shock  resuscitation.°>°?   An ischemic insult activates white blood cells, priming  monocytes and macrophages and contributing to the release  of inflammatory mediators or cytokines, including TNF, IL-1,  IL-6, IL-8, and platelet-activating factor. These cytokines in turn  contribute to vasodilation, increased capillary permeability, and  altered platelet function. The ultimate result is a maldistribution  of blood flow and a compromise in organ perfusion.**°? The  role of these mediators is summarized in Table 7-5. Chapter 48  includes a more comprehensive discussion of MODS.   Signs of organ dysfunction include but are not limited  to lactic acidosis, oliguria, and an acute alteration in level of  consciousness (e.g., decrease in Glasgow Coma Scale score  of 1 point or more); hypoxemia, hypotension, poor capillary  refill, or shock plus signs of coagulopathy, respiratory, renal, or  hepatic dysfunction, or neurologic dysfunction. Gut injury and  inflammation may enable translocation of gram-negative bac-  teria or endotoxin into the bloodstream, and may contribute  to gastrointestinal bleeding.” Box 49-4 contains information on  other potential signs of organ system failure in children.   Several scoring systems are available to characterize the  severity of illness in critically ill children with organ dysfunc-  tion. These include the Pediatric Logistic Organ Dysfunction  (PELOD) scoring system*? and the Pediatric Multiple Organ  Dysfunction Score (P-MODS).*°? These scoring systems may  be useful as prognostic indicators when they are used for several  days. Important differences exist between neonates and chil-  dren in terms of mortality associated with specific organ failures  and with specific PELOD scores.*!    The goals of treatment of shock are maximization of oxygen  delivery and minimization of oxygen demand. The airway, oxy-  genation, ventilation, and perfusion must be supported. Reduc-  tion of oxygen demand requires treatment of fever and pain. In    CHAPTER 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children    addition, the child should be kept warm and shivering should be  prevented. Blood components and, perhaps, intravenous fluids  should be warmed before administration to young infants and  children with hypothermia. Fear and pain increase oxygen con-  sumption, so care must be taken to reassure the child and treat  pain as indicated.   As noted, all children in shock require support of airway,  oxygenation, and ventilation. Specific treatment of hypovolemic  shock is volume resuscitation. Treatment targeting cardiogenic  shock requires titration of fluid administration to optimize car-  diac preload, but vasoactive drugs are needed to improve myo-  cardial function and vasodilators or vasoconstrictors may be  needed to support systemic perfusion. Specific management of  septic shock includes administration of antimicrobial therapy,  fluid resuscitation, and initiation of vasoactive support within  the first hour of care following initial medical contact. Treat-  ment specific to obstructive shock includes elimination of the  cause of the obstruction to blood flow.   To evaluate and support airway patency and ventilation the  child is positioned in a manner that supports maximal airway  patency, and the provider then assesses airway and ventilation.  Humidified supplementary oxygen is given as needed at up to  10 to 15 L/min by nonrebreathing mask or bag-mask ventila-  tion. An advanced airway is placed in children before respiratory  deterioration or arrest complicates shock management. Oxy-  genation is monitored continuously through pulse oximetry.   The child’s heart rate must be adequate to support effective  cardiac output and systemic perfusion. The most common pedi-  atric dysrhythmias are listed in Box 49-5. Treat bradydysrhyth-  mias and extreme tachydysrhythmias promptly. Pharmacologic    therapy, pacing, or synchronized direct current (DC) cardio-  version may be required.   The rhythms associated with loss of pulses (“arrest” rhythms)  include asystole, electromechanical dissociation (EMD), pulseless  ventricular tachycardia, and ventricular fibrillation. Regardless of  electrocardiogram (ECG) findings, provide cardiopulmonary  resuscitation—including cardiac compression—when pulses are  lost or if, despite support of oxygenation and ventilation, the child  demonstrates a heart rate less than 60/min with poor perfusion.   Adequate vascular access is needed to establish hemody-  namic monitoring and to provide volume and inotropic sup-  port as needed. Once systemic perfusion is restored, transfer to  a pediatric intensive care unit is advised.   Volume resuscitation is designed to restore intravascular  volume relative to the vascular space and to optimize ventricu-  lar preload. The specific fluid selected and route of administra-  tion are determined by the child’s clinical condition. In general,  isotonic crystalloids (isotonic salt-containing solutions, such as  normal saline or lactated Ringer’s solution) or colloids (protein-  containing fluids, such as albumin or blood) are administered  in boluses of 20 ml/kg (or 10 ml/kg of packed red blood cells)  given over 5 to 20 minutes for hypovolemic and septic shock. If  cardiogenic shock (myocardial dysfunction) is present, smaller  fluid boluses (5 to 10 ml/kg) are administered over about 10 to  20 minutes. Hypotonic fluids should not be administered.**”  After each bolus, reassess systemic perfusion and administer  additional fluids if indicated.   Children in septic shock require a large volume of intrave-  nous fluid to restore and maintain systemic perfusion. More than  40 ml/kg in fluid boluses will likely be required during the  first hour of volume resuscitation, and a total of 200 ml/kg or  more may be required during the first several hours of ther-  apy.°°?49>37 Tn fact, rapid volume administration, particularly  during the first hour of therapy, has been linked with improved  survival in hypotensive children in septic shock.** An algorithm  for the treatment of septic shock, based on the recommendations  of the American College of Critical Care Medicine and the Pedi-  atric Advanced Life Support course, is presented in Figure 49-2.   Unless shock is mild or responds immediately to volume  therapy, insertion of a central venous (monitoring) catheter is  advisable. Several multilumen catheters are available in pediat-  ric sizes that enable simultaneous monitoring of central venous  pressure and administration of fluids. Continuous or intermit-  tent monitoring of the superior vena cava ScyO, will enable  evaluation of the balance between the child’s oxygen delivery  and oxygen consumption. If cardiac output is adequate, oxygen  saturation in the SVC will be approximately 25% to 30% lower  than the arterial oxygen saturation. A larger arterial venous oxy-  gen saturation difference suggests inadequate oxygen delivery  (caused by inadequate arterial oxygen content or inadequate  cardiac output or both) or excessive oxygen demand.°   Monitoring of the volume of urine output and specific grav-  ity is useful in determining the child’s response to fluid therapy.  A urinary catheter should be inserted if shock is present unless  the child has sustained pelvic trauma or a urethral tear is sus-  pected. All sources of fluid intake and output should be moni-  tored and recorded hourly or more frequently if needed.    IDENTIFY SIGNS OF SEVERE SEPSIS/SEPTIC SHOCK  ¢ Poor systemic perfusion  ¢ Change in mental status, responsiveness  ¢ Possible hypotension    Give oxygen; monitor and support airway and ventilation  Begin resuscitation and treat infection  Immediate:  ¢ Establish IV/IO access  ¢ Give 20 ml/kg isotonic crystalloid bolus; reassess, repeat as needed    ¢ Repeat fluid boluses as needed, monitor for evidence of myocardial failure  (respiratory distress, rales, hepatomegaly)  - Give up to 3-4 boluses (or more) as needed to treat shock  - Give isotonic crystalloid, colloid, or combination  ¢ Begin vasoactive therapy (via peripheral catheter, if necessary) if shock    ¢ Transfer to pediatric critical care unit as soon as possible    - Establish central venous access  - Monitor central venous (superior vena caval) oxygen    * Give vasopressors, inotropes, inodilators, vasodilators as  needed (target: normotension, S,,O. =70%, and cardiac  index: 3.3-6 L/min per m? BSA)    ¢ Rule out reversible causes of shock (e.g., pericardial effusion,  tension pneumothorax)    FIGURE 49-2 Hemodynamic Support in Pediatric Septic Shock. BSA, body surface area; /O, intake/output; /V, intra-  venous. (From Perkin RM et al: Shock, cardiac arrest and resuscitation. In Hazinski MF, editor: Nursing care of the critically ill  child, ed 3, p 126, St Louis, 2013, Mosby; data from Brierley J et al: Crit Care Med 37:666-688, 2009.)    An intra-arterial line should be inserted if shock persists.  This enables reliable, continuous evaluation of arterial pressure.  Noninvasive oscillometric blood pressure—monitoring devices  may not accurately measure low or rapidly falling blood pres-  sures and may overestimate the blood pressure, particularly in  trauma patients.“*   Insertion of a pulmonary artery catheter may be considered  if the child demonstrates shock that is unresponsive to volume  and vasoactive drug support. A pulmonary artery catheter with  thermodilution cardiac output thermistor, a fiberoptic pulmo-  nary artery catheter, or both can enable continuous monitoring    of mixed venous oxygen saturation or continuous monitoring  of cardiac output. Quantification of these variables can be par-  ticularly helpful if precise tracking of hemodynamic measure-  ments is desired. This may be necessary in the care of the child  with septic shock or MODS.   The optimal hemoglobin threshold for transfusion in criti-  cally ill children is unknown. In a multicenter trial of critically  ill children, a hemoglobin red-cell transfusion threshold of  7 g/dl decreased transfusion requirements without increasing  adverse outcomes.*° However, that study excluded premature  infants and children with severe hypoxemia, hemodynamic    CHAPTER 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children    instability, active blood loss, and cyanotic heart disease. A more  recent publication from the same researchers*® recommends  higher transfusion thresholds (9 to 12 g/dl) for children with  cardiac or respiratory disease, with the highest thresholds for  children with cyanotic congenital heart disease and those with  hemodynamic instability.   Administration of blood or blood component therapy is  needed to treat hemorrhage or severe coagulopathies. A “nor-  mal” hematocrit does not rule out the possibility of hem-  orrhage; the hematocrit typically falls in a person who has  sustained whole blood loss after the blood loss is replaced with  crystalloids or colloids. In general, 10 ml/kg boluses of packed  red blood cells are used for every second or third fluid bolus  needed to treat significant blood loss.!4!>*7   Transfusion for the child with chronic anemia and shock  must be accomplished slowly to prevent hypervolemia and fur-  ther deterioration in myocardial function. Administration of  packed red blood cells at a rate averaging 3 to 5 ml/kg/hr over  several hours may be well tolerated, particularly if it is preceded  and followed by administration of diuretics.” If severe anemia  is associated with severe hypervolemia and myocardial dysfunc-  tion, an exchange transfusion may be required. If a coagulopa-  thy is present, administer specific blood component therapy  necessary to prevent or treat hemorrhage.   Hypoxemia, metabolic acidosis, and electrolyte imbalances  depress myocardial function and must be corrected when shock  is present. Administer oxygen during resuscitation of the child  in shock and be prepared to institute noninvasive pressure sup-  port ventilation or mechanical ventilation when needed.   The child’s serum glucose concentration should be moni-  tored using rapid bedside testing. Hypoglycemia requires glucose  administration; continuous infusion is preferred to repeated  intermittent bolus therapy. If severe hyperglycemia develops,  insulin administration may be indicated to reduce the serum  glucose concentration to less than 150 to 180 mg/dl. Although  tight glycemic control has been linked with improved survival  in critically ill children,** it also caused frequent episodes of  hypoglycemia. The relative risks of severe hyperglycemia ver-  sus unintentional hypoglycemia have not been established.*” In  a recent survey, pediatric intensivists reported management of  hyperglycemia with insulin therapy; the preferred blood glucose  target range was 90 to 140 mg/dl.°° A randomized clinical trial  of pediatric glycemic control is needed.   During resuscitation, providers must avoid acute or severe  alterations in the serum sodium concentration.*'!*” Acute  changes in serum sodium alter the serum osmolality and result  in fluid shifts into and out of the vascular spaces. Such fluid  shifts can be associated with neurologic complications includ-  ing seizures, cerebral edema, and intracranial hemorrhage.!!   Alterations in serum potassium concentration may affect  myocardial contractility and conduction. However, children are  far less sensitive than adults to minor changes in serum potas-  sium concentration. Hypokalemia may result from inadequate  potassium administration during volume therapy or from exces-  sive potassium losses caused by drug therapy (e.g., furosemide).  The serum potassium concentration falls in the presence of alka-  losis; this represents an intracellular shift of potassium and is    corrected when the pH is normalized. Treat true hypokalemia  with an infusion of potassium chloride at a dose equivalent to  0.5 to 1 mEq/kg administered over several hours.!!   Hyperkalemia may result from excessive potassium admin-  istration, reduced potassium excretion (e.g., in renal failure),  or massive cell lysis (e.g., tumor lysis syndrome). Serum potas-  sium concentration also rises when acidosis develops; the rise  in serum potassium is caused by a shift of potassium from the  intracellular to the vascular space (ie., exchanged for vascular  H*) and falls when the serum pH is corrected."   Both ionized and total calcium concentration should be  monitored, and documented hypocalcemia must be treated.  Note that the ionized serum calcium falls with alkalosis and  rises with acidosis. Serum ionized calcium concentration is  often low (less than 4.5 mEq/L) in children with septic shock.!"   Hypercalcemia may be observed in children with some  malignancies, including acute lymphocytic leukemia, lympho-  mas, and soft tissue sarcomas. Malignant cells often secrete a  parathormone-like substance that stimulates bone reabsorp-  tion, release of calcium, and rapid cell turnover. Although mild  hypercalcemia is not life threatening, extreme hypercalcemia  (total serum calcium approaching 19 to 20 mEq/L) may pro-  duce renal and cardiovascular complications.*”   Table 49-7 summarizes drug therapy for children in shock.  If oxygenation, ventilation, heart rate, and intravascular volume  are appropriate and myocardial function and systemic perfu-  sion remain poor, vasoactive drug therapy with inotropes is  indicated.    Prevention of shock is important. Prevention of trauma (injury  prevention) and treatment of dehydration can eliminate the two  leading causes of hypovolemic shock in children. Haemophilus  influenzae sepsis and meningitis have been nearly eradicated  in the United States since the introduction and widespread  use of H. influenzae vaccine for infants, and immunization  against Neisseria meningitidis (the causative microorganism of  meningococcal sepsis and meningitis); pneumococcus vaccine  may similarly reduce the incidence of pneumococcal infec-  tion and sepsis. The incidence of septic shock from hospital-  acquired infections, such as ventilator-associated pneumonia or  catheter-related bloodstream infections, is decreasing with the  use of quality improvement approaches.”°   Advances in shock therapy have been made in recent years,  and several show promise for continued improvement in treat-  ment. First, there is a better understanding of resuscitation goals  with an appreciation of the need to target high, rather than nor-  mal, cardiac output and oxygen delivery during resuscitation.   Trauma resuscitation has become more targeted in adults  and children. In the prehospital setting, prehospital fluid resus-  citation is reserved for children with signs of shock. If pene-  trating trauma is associated with hypovolemic shock, the child  requires urgent surgical intervention, so delays during trans-  port are minimized.   Because massive transfusions can produce immunologic and  coagulation complications, the surgical approach to trauma  has changed to include staged surgical repair of significant    Selective B-adrenergic effects, increases cardiac  contractility and also increases heart rate (this latter  effect is variable); Bz effects produce peripheral  vasodilation; no dopaminergic or a-adrenergic  effects   Dopaminergic effects predominate, including increase  in glomerular filtration rate and urine volume    Dopaminergic effects persist and B, effects are seen,  especially an increase in heart rate   Endogenous catecholamine, which produces a, By,  and B» adrenergic effects; at low doses, B, effects  dominate   B-Adrenergic effects; B, effects may result in rapid  increase in heart rate; B effects may produce  peripheral vasodilation and also may effectively treat  bronchoconstriction   Endogenous catecholamine with a- and B-adrenergic  effects; produces potent peripheral and renal  vasoconstriction; can increase blood pressure    Antidiuretic hormone analog that acts on vasopressin  receptors; produces peripheral and splanchnic  vasoconstriction; also used to treat Gl hemorrhage  for this reason    Inamrinone:  Loading dose 0.075 to 0.1 mg/kg  (75 to 100 mcg/kg) slowly  Infusion: 5-10 meg/kg/min    Milrinone:  Loading dose: 0.05 mg/kg (50 mcg/kg)  over 10-60 min  Infusion: 0.25-0.75 meg/kg/min    Vasodilators  Nitroglycerin: 0.25-0.5 mcg/kg/min;  increase as tolerated to maximum  10 meg/kg/min (adolescents,  5 mcg/min; note not per kg per min)  Nitroprusside: 0.3-0.5 meg/kg/min; titrate    Nonadrenergic inotropic agent that produces  phosphodiesterase inhibition and increase in  intracellular cyclic adenosine monophosphate  (cAMP); intracellular calcium uptake also is delayed;  these effects result in improved cardiac contractility  and vasodilation    Extreme tachyarrhythmias have been reported,  particularly in infants; hypotension may develop; may  produce pulmonary vasoconstriction    Can produce extreme tachyarrhythmias; can result in  increase in pulmonary artery pressure; inhibits thyroid-  stimulating hormone and aldosterone secretion   Will increase myocardial work and oxygen consumption  at any dose; splanchnic constriction will occur at even  low doses    May cause tachyarrhythmias, increased myocardial  work, and increased oxygen consumption; may result  in hepatic and mesenteric ischemia    Monitor for arrhythmias (especially accelerated  junctional rhythm, junctional tachycardia, and  ventricular ectopy); may produce hypotension  (especially if patient is hypovolemic), liver and Gl  dysfunction, thrombocytopenia, and abdominal pain;  experience in children is limited and recent    Light sensitive; use special infusion set or cover tubing  when infusion slow; may produce thiocyanate and  cyanide toxicity, particularly for higher doses or  prolonged infusion    Modified from Perkin RM et al: Shock, cardiac arrest and resuscitation. In Hazinski MF, editor: Nursing care of the critically ill child, ed 3, p 120,    *Infusion rate = ml/hr = Weight (kg) x Dose (mcg/kg per min) x 60 min/hr + concentration (mcg/ml).    CHAPTER 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children    injuries (e.g., liver and bowel injuries). The initial surgery is  performed to stabilize the child, and, if needed, subsequent pro-  cedures repair the injury. This multistage approach, based on  battlefield experiences, reduces the volume of blood products  administered and has been linked with reduced morbidity and  mortality.!°   We now have a better understanding of the pathophysiology  of septic shock in children,** appreciating the critical role that  immediate antibiotics, early and aggressive fluid resuscitation,  and vasoactive therapy play in the outcome of pediatric sep-  sis.°*°° Such resuscitation should be provided during the first  hour of therapy; every hour of delay has been reported to result  in a 40% increase in mortality.**   Goals for management of pediatric septic shock are to  restore the child’s heart rate and blood pressure to normal for  age, to achieve targeted perfusion pressure (mean arterial pres-  sure — CVP) of about 55 to 65 mmHg, to reduce capillary refill  to less than 2 seconds, and to support a cardiac index of 3.3  to 6 L/min/m? body surface area, and to maintain the SVC’s  ScyO, at 70% or higher.**?-°” This goal-directed therapy, tar-  geting an ScyO of 70% or higher in children, has been shown  to substantially reduce mortality (by two thirds in one study)  and organ failure.*°   In an excellent and very concise summary of the manage-  ment of the child in septic shock, Kissoon, Ort, and Carcillo  suggest calculation of a shock index, dividing the child’s heart  rate by the child’s systolic blood pressure (heart rate [HR] +  systolic BP). This shock index can serve as an indicator of left  ventricular ejection, and should fall (e.g., from 2.25 to 1.75) in  the first hour of effective management.**   Therapeutic hypothermia suppresses proinflammatory  mediators and may enhance anti-inflammatory mediators.°!°?  Mild to moderate induced hypothermia (to 32° to 34° C [89.6°  to 93.2° F]) has been shown to increase survival in neurologic  outcome in neonates with hypoxic-ischemic encephalopa-  thy°’ and in comatose, hemodynamically stable adults follow-  ing resuscitation from cardiac arrest.** It is possible that such  therapy may be helpful for victims of shock, particularly those  with MODS. However, it is important to note that the control  groups in these neonatal and adult hypothermia studies were  all febrile. We know that fever develops following resuscitation  from cardiac arrest and that fever is associated with unfavor-  able neurologic outcome.*° While we await the results of multi-  centered clinical trials of therapeutic hypothermia in children,  it is important to treat fever following resuscitation.   It soon may be possible to tailor sepsis and other critical  therapies through the use of genetic profiling of the microor-  ganism~ and of the child.”” Prospective identification of genetic  markers for risk of sepsis and responsiveness to therapy may  enable individual tailoring of surveillance and interventions to  maximize survival and minimize risks from those therapies that  are unlikely to be effective.   Finally, several devices are available that enable noninvasive  or minimally invasive calculation of cardiac output and index,  stroke volume, and circulating blood volume in children.’ As  providers gain experience with the use of such devices and  more published data are available about their reliability, we    will have more tools to confirm clinical assessment and moni-  tor response to therapy.    Management of pediatric burn injuries requires an understand-  ing of the differences that exist in this population related to etiol-  ogy of injury, growth and development, physiology, and clinical  course. In 1988 the American Burn Association established cri-  teria to guide transfer of a patient to a specialized burn center.  These criteria remain a standard in burn care and are based on  complex management issues related to treatment of acute burns  and the long-term rehabilitation needs of children.°°   Burn injuries in children often are preventable and often  are the result of inadequate supervision, curiosity, inability to  escape the burning agent, or intentional abuse. Scald injuries  (ie., hot water, grease, other) are most common among young  children, whereas flame burns are more prevalent among older  children.*’ A child exposed to hot tap water at 60° C (140° F) for  3 seconds will sustain a third-degree burn.°*   A child’s skin is thinner and thus more susceptible to injury  than an adult’s. The extent of injury is determined by the tem-  perature of the burning agent and the duration of exposure.  Because very young children may be unable to escape the heat  source, the depth of the injury is likely to be greater. The kitchen  also is a common site for burn injury and often involves pull-  ing over dishes or appliances containing hot liquids. These are  common burn injury sources for children 2 years of age and  younger.   Although child abuse can occur at any age, young children  are particularly vulnerable to serious injury. Approximately  10% of all forms of abuse cases in the United States are caused  by burning.°’ Burns that may suggest physical maltreatment  include: (1) patterned burns, (2) classic forced immersion burn  pattern with sharp stocking or glove demarcation and sparing  of flexed protected areas, (3) splash/spill burn patterns not con-  sistent with history or developmental level, and (4) cigarette  burns. Abuse is suggested with: (1) incompatible history and  physical examination; (2) incompatible burn and developmen-  tal level; (3) bilateral or mirror image burns; (4) localized burns  to genitals, buttocks, and perineum (especially at toilet-training  stage); (5) evidence of excessive delay in seeking treatment; and  (6) presence of other forms of injury.©° Forced immersion in  hot water typically presents with deep symmetric injuries lack-  ing any evidence of splash wounds (Figure 49-3). By contrast,  a pull-down splash burn usually has a triangular pattern with  immediate skin contact reflected as the area of greatest burn  injury. The burn injury then forms an arrow pointing down-  ward. Contact burns also may be intentionally inflicted by con-  tact with cigarettes or other hot objects such as curling irons.  Young children may inadvertently grasp a hot object. However,  the pattern of injury will be confined to the palm. Burns to the  dorsum of the hand are viewed with suspicion.”   Children 3 to 8 years of age are most often injured by flame  during fire play. Lighters and matches ignite clothing and cause  house fires. Young children may run when clothing ignites and  increase the severity of injury. Approximately 50% of all deaths    FIGURE 49-3 Burn Pattern Typically Seen After Forced Emersion in Hot  Water.    in burn children are caused by inhalation injury.°! Escape from  a burning residence or motor vehicle is often delayed because  young children cannot cognitively comprehend the circum-  stances or physically remove themselves from the danger.  Flame burns involving flammable liquids, especially gasoline,  are more common in older children.   Although flame and scald burns account for the majority of  thermal injuries in children, electrical burns result from direct  contact with high- or low-voltage current. Most commonly  these injuries occur as a result of risk-taking behavior on the  part of young males. Trauma from contact with electrical energy  results from the passage of current through vital organs, muscle  compartments, and nerve or vascular pathways. Very young  children are at risk for injury from chewing on electrical cords  or inserting objects into electrical outlets (Figure 49-4). Light-  ning strikes also account for some electrical burns. Chemical  burns occur most often in an industrial setting for the adult. At  home, children may be burned by swallowing corrosive agents.  The type of causative agent has important implications for the  evaluation, treatment, and prognosis of the child.    The severity of burn injury is assessed based on the percentage of  the total body surface area (TBSA) involved. Use of the standard    FIGURE 49-5 Areas of Indeterminate Depth of Injury in a Young Child.    Rule of Nines results in inaccurate calculation of the percent-  age of TBSA involved in children. Although the infant’s trunk  and arms are of roughly the same proportion as the adult’s, the  head and neck make up 18% of TBSA and each lower extremity  is 14% of TBSA. A modified Rule of Nines deducts 1% from  the head and adds 0.5% to each leg for each year of life after  2 years.°® Various charts are available that assign body propor-  tions to children of different ages. These are generally used in  pediatric burn facilities and do accurately compute the extent  of burn injury.   Because burn trauma represents a_three-dimensional  wound, the severity of injury is assessed also in relation to the  depth of injury. The etiology of the burn and the duration of  contact with the burning agent are important considerations in  determining the depth of injury. In general, the more intense  the heat source and longer the contact, the deeper the result-  ing injury; however, infant skin is extremely fragile and more  likely to sustain a deeper burn. This makes the estimation of the  depth of burn difficult in very young children, especially fol-  lowing scald injuries (Figure 49-5). Intentionally inflicted burns  tend to be more severe because contact with the burning agent  is prolonged. Electrical injuries also may mask the extent of  damage on initial assessment. Visible tissue damage may appear  minimal despite severe injury to underlying structures.   Another important factor in assessing the severity of injury  is the victim’s age. Children younger than 2 years have a signifi-  cantly higher risk for associated morbidity and mortality after  sustaining a burn injury. They have not achieved maturity of the  immune system and are at increased risk for infection and sep-  sis. In addition, very young children are intolerant of rapid fluid  shifts and demonstrate immature renal function, which nega-  tively affects their ability to retain sodium and water (see Shock).   The areas of the body injured are another consideration  when assessing the severity of the burn. Burns of the hands, feet,  and perineum and across joints carry the potential for scar for-  mation and contracture that may interfere with function as well  as growth and development. Specialized care is required to pre-  serve maximal function. In addition, burns to the face and neck  may result in airway compromise as well as deformity caused by  damage to delicate cartilage of the nose and ears.    CHAPTER 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children    Concomitant injuries may be suggested by the circumstances  of the burn and should always be investigated; for example,  initially burns do not bleed. Bloody drainage suggests another  source of trauma. Fractures may result from jumping from a  window to escape a house fire. Electrical injuries and motor  vehicle accidents often result in associated trauma. Any suspi-  cion of intentionally inflicted burns should alert the burn team  to assess for other injuries.   PATHOPHYSIOLOGY, CLINICAL MANIFESTATIONS, AND TREATMENT.  Major burn trauma involves all body systems, and the conse-  quences of injury include shock, infection, hypermetabolism,  organ failure, and functional limitations. These effects can be  magnified in the pediatric population as a result of physiologic  immaturity and age-related variation in treatment modalities.  Along with recognition of changes in the pathophysiology with a  burn injury, clinical manifestations are apparent in all organ sys-  tems. Although the cutaneous trauma is the initiator of the chain  of responses, it is important to consider all of the likely conse-  quences of the injury. An awareness of the changing patterns of  convalescence and the development of complications assists in  the identification and early treatment of potential sequelae.    The local response manifested in the area of trauma includes cellu-  lar destruction and damage. Progressive injury caused by dermal  ischemia may result from ineffective initial management, espe-  cially inadequate or delayed resuscitation. An increase in the per-  meability and hydrostatic pressure of the capillaries results in the  loss of fluid, proteins, and electrolytes into the interstitial spaces.  A diminishing intravascular oncotic pressure further enhances  these losses and results in edema formation. Marked edema can  result not only in the area of injury but also in unburned areas.  Loss of substantial areas of skin has immediate and profound  physiologic effects. Direct and evaporative fluid losses are seen  immediately.” Although these losses are maximal in the immedi-  ate postburn period, they persist until wound closure.   Circulatory alterations also occur in the area of injury.  Reduced blood flow and capillary stasis result from hemocon-  centration, the release of thromboplastin and clot-activating  factors from heat-damaged cells, reduced cardiac output, and  edema formation. Circulation in the area of partial-thickness  wounds ceases for 24 to 48 hours after injury, after which it is  usually restored. Vascular supply in the area of full-thickness  injuries is completely occluded and is not restored until gran-  ulation tissue forms or the wound is surgically repaired. The  dry, leathery eschar provides an ideal environment for bacterial  growth. Infection, trauma, or applying ice to the burn area may  convert a partial-thickness injury to a full-thickness one, espe-  cially in young children, who have thinner, more delicate skin.   Vitamin D, an essential factor for proper formation of bone  during growth and development, is an important nutrient in  children to facilitate intestinal absorption of calcium. Vita-  min D deficiency has been associated with adverse effects on  the skeletal system, as well as the immune system. Vitamin D  production may be compromised in burned children demon-  strated by a high incidence of low-serum vitamin D levels. Burn  wound scarring and lack of sunlight may limit cutaneous vita-  min D biosynthesis.”    The marked reduction in cardiac output immediately following  injury is accompanied by an initial increase in systemic vascular  resistance. As fluid is lost into the interstitial spaces, a further  reduction in cardiac output occurs, accompanied by vasodila-  tion. Because the infant maintains cardiac output by increasing  heart rate preferentially to stroke volume, extremely elevated  heart rates result in a decreased filling time and a further reduc-  tion in cardiac output.°* Adequate resuscitation returns cardiac  output to normal levels in approximately 24 to 36 hours. With-  out fluid replacement, cardiac output continues to decrease and  results in organ failure and death.   The inefficient and labile peripheral circulation of the infant  further complicates management of the burn shock phase of  treatment. The rapid fluid shift to the interstitial space and  drying of the eschar results in compromised circulation and a  resultant tourniquet effect in the extremities. Blood vessels and  nerves become entrapped because the fascia cannot expand to  accommodate the massive edema. Release of pressure is required  to restore blood flow and preserve nerve function (Figure 49-6).   Constriction of the chest and impairment of respiratory excur-  sion also may result, especially in the very young child, because of  the increased pliability of the rib cage. Excessive fluid volume can  contribute to a serious complication (increased intra-abdominal  pressure) that may have an underestimated incidence in burned  individuals. Although children with increased intra-abdominal  pressure readings tended to be younger, larger TBSA injuries  and full-thickness components were significantly associated with  elevated pressures. Increased intra-abdominal pressure has  the potential to impair hemodynamics, renal function, hepatic  malperfusion, and pulmonary dysfunction. Despite maintaining  cardiac output with fluid replacement, renal function remains  impaired in the presence of increased intra-abdominal pressure.  Intra-abdominal pressure, as a stressor, can stimulate the neuro-  endrocrine system and elicit stress reactions directed at neutraliz-  ing the initial insult of the burn. Increases in the production and  release of catecholamines, glucocorticoids, and beta-endorphins  support the clinical finding of profoundly altered cardiovascular,  pulmonary, and renal function.°°    The clinical manifestations of burn injury related to the pul-  monary system include a variety of complications ranging from  inhalation injury, pulmonary edema, and respiratory failure to  aspiration of gastric contents and pneumonia. Inhalation injury  has a negative, prolonged effect on pulmonary function that is  associated with and remains a major determinant of increased  morbidity and mortality.”   Anatomic differences in the pediatric airway affect the  response to pulmonary complications, as well as therapeutic  interventions. The infant airway is positioned anteriorly, mak-  ing visualization of the cords more difficult. The difficult visual-  ization is further compounded by the relatively large tongue and  slanting vocal cords. A small degree of edema results in greatly  increased work of breathing in the child (Figure 49-7). These  considerations are particularly important during the resuscita-  tion phase when progressive edema threatens to obstruct the  airway. Significant edema results in impairment of respiratory  function unless an artificial airway is inserted (Figure 49-8).  Malposition of an endotracheal tube may result in inadvertent  extubation, intubation of the bronchi, and atelectasis. Because  of the relatively short length of the infant trachea, alterations  of the position of the head and neck can affect tube position  despite maintenance of the tube position at the teeth.°*-”°   Infants compensate for pulmonary compromise by increas-  ing the respiratory rate. However, because the child possesses  fewer type I muscle fibers, fatigue related to the increased work  of breathing results in more rapid desaturation than in adults.  The soft cartilage of the pediatric airway is prone to collapse in  the presence of partial obstruction. Children with burns are at  increased risk for these events because of underlying respiratory  disease or injury.   Mechanical ventilation of severe inhalation injury is a  dynamic and complex task.’' Therapeutic interventions  required for maintenance of pulmonary function have been  implicated in postextubation stridor and barotrauma. Evidence  suggests that barotrauma from mechanical ventilation may  be minimized by protocols based on permissive hypercapnia.  Moderate respiratory acidosis was well tolerated and ventilat-  ing pressures maintained below 40 cm.”* The low incidence of  mortality associated with this strategy suggests a reduction in  ventilator-induced lung injury. In addition, high-frequency  oscillatory ventilation (HFOV) in severe pediatric burn patients  has significant, early, and sustained improvement in oxygen-  ation. When HFOV is begun early in burn care, barotrauma is  significantly reduced.’°    The consequences of metabolic and physiologic changes  occurring during the acute phase of injury remain apparent  during convalescence. Severe burns result in a decrease in pul-  monary function from restrictive and obstructive pulmonary  disease evidenced by a reduction in pulmonary volumes and  maximum voluntary ventilation lasting up to 8 years. At times,  chest wall scarring in children caused by burns severely limits  thoracic cage excursion.    The pathophysiologic responses of burn injury result in hypo-  volemia and extracellular sodium depletion in the burn-injured  individual. Manifestations for adults are discussed in Chapter 48.  Hypotension is a late sign of shock in the child. A complete cir-  culatory assessment, including heart rate and peripheral param-  eters, is a more reliable measure. Urine output is a reflection of  end-organ perfusion and is therefore the most accurate moni-  tor of the adequacy of fluid resuscitation. A urine output of 30  to 50 ml/hr in adults and 1 ml/kg/hr in children weighing less  than 30 kg are the suggested endpoints associated with many  resuscitation formulas. Fluid is titrated to maintain the output  within the parameters.°*   The fluid of choice for burn shock resuscitation should  approximate the fluid lost from the circulating volume, for  example, lactated Ringer’s solution. Children require fluid  resuscitation for smaller burns than do adults as a result of their  limited physiologic reserves. The child’s relatively greater ratio  of body surface area to weight results in increased evapora-  tive water losses and proportionately more fluid during resus-  citation. Although colloid replacement during burn shock    CHAPTER 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children    resuscitation remains controversial, colloids may be required  in the very young child who fails to respond to fluid replace-  ment.’”* A component for maintenance fluid must be included  in the calculation of fluid needs during resuscitation. Mainte-  nance fluids represent the body requirements in the absence of  burn injury.   Successful resuscitation depends on establishment of  intravenous access. Although this is usually accomplished by  peripheral or central venous cannulation, circulatory collapse  may preclude timely administration of fluid replacement.  Cannulation of veins in the pediatric population is further  complicated by small vessels and increased subcutaneous fat.  Children are good candidates for intraosseous cannulation  when traditional venous access techniques fail. Blood, drugs,  and fluid are readily absorbed by red marrow that drains into  medullary venous channels and thus to the systemic circu-  lation. This technique is most effective in children younger  than 5 years, because red marrow is steadily replaced by yel-  low marrow in the limbs, making infusion more difficult,  hence decreasing the infusion rate.’? With proper care and  removal as soon as other access is available, complications are  minimal.   Fluid resuscitation is generally required for children after  thermal injuries in excess of 10% to 15% of the TBSA. Fluid is  administered to compensate for fluid and electrolytes extrava-  sating into the interstitial spaces. This replacement restores  circulating volume, improves perfusion, and alleviates organ  dysfunction associated with impaired circulation.   Various protocols have been proposed as guidelines for fluid  administration. It is important to remember that any regimen  serves merely as a guideline and will require adjustment based  on the individual response of each child. Because the linear  relationship between weight and surface area does not exist in  children (surface area varies to weight as a two-thirds function),  use of adult formulas result in under- or over-resuscitation.”° A  commonly used protocol is a modification of the Parkland for-  mula. Children also tend to require relatively more fluids than  adults because they have higher evaporative losses because of  their body surface area-to-weight ratio. Evaporative fluid loss  can be a significant contributor to hypovolemia in the burned  child. This evaporative fluid loss continues until the burn  wounds are closed. As in adults, inhalation injury also contin-  ues until burn wounds are closed. And as in adults, inhalation  injury increases the magnitude of total body surface area injury;  therefore, children with burn injuries require more fluids.”   Research suggests that in the acute phase of the burn injury  children receive far more fluid resuscitation than calculated by  the modified Parkland (Baxter) formula guidelines. This syn-  drome has been termed “fluid creep.”’” Onset maybe caused  by higher fluid limits and increased use of opiates resulting in  an increased abdominal pressure. The method to control fluid  creep includes strict adherence to the modified Parkland for-  mula. In children who have developed increased abdominal  pressure, decompressive laparotomy may resolve the increased  intra-abdominal pressure.”    Renal System  Loss of circulating volume into the interstitial spaces results in  reduced renal blood flow and decreased glomerular filtration.  An important measure of the adequacy of volume replacement  is urine excretion. Sufficient volume replacement maintains  urine output during resuscitation. Approximately 36 hours after  injury, edema fluid begins to mobilize and output increases.   Children younger than 2 years of age lack the ability to con-  centrate urine because of the immaturity of the renal system  and are, therefore, at increased risk for dehydration. In addi-  tion, the child has a relatively larger TBSA in relation to weight  than the adult. Combined with limited physiologic reserves,  increased fluid requirements are necessary for children during  burn shock resuscitation and to compensate for evaporative  water losses.”°   Evidence of pigment in the urine results from the hemolysis  of red blood cells. This is especially common after extensive elec-  trical injuries and destroyed muscle from deep thermal injury.  The release of myoglobin may occlude the kidney tubules and  result in renal failure.    Gastrointestinal System  The gastrointestinal (GI) system plays an important role in the  pathophysiology of burns. Alterations in blood flow result in  decreased perfusion to the GI tract. Ischemia may cause erosion  and necrosis of GI tissue. The GI response to a burn injury often  includes mucosal atrophy, changes in digestive absorption, and  increased intestinal permeability. Depending on the proportion  of burn size, atrophy of the GI tract mucosa can occur imme-  diately after injury. The atrophy results in gut barrier dysfunc-  tion leading to increased bacterial translocation and ultimately  sepsis.’®   Paralytic ileus occurs often after major burn injuries.  Although digestion ceases in the stomach and the large bowel,  the small intestine maintains motility and absorptive capacity.  Intestinal motility returns as fluid losses are replaced unless  irreversible necrosis of the bowel has occurred as a result of  insufficient perfusion.    Burn trauma—induced immunosuppression results in increased  susceptibility to infection and sepsis. Although the exact  mechanisms responsible for this immunosuppression remain  obscure, it is clear that complex interactions of the hypermeta-  bolic response, nutritional support, bacterial translocation,  and defects in both innate and acquired immune function  are involved (Figure 49-9). In addition, young children are at  increased risk for microbial invasion caused by an immature  immune system and limited antibody production.   Deitch reported that wound- or gut-derived endotoxemia  may be one of the mediators of the hypermetabolic response  observed after thermal injury, and this finding remains undis-  puted.”? When bacteria translocate from the gut or from the  burn wound, endotoxin may affect immunologic response as  inflammatory mediators are released. A further complication in  the activation of inflammatory mediators is the release of toxic  metabolites, such as oxygen free radicals.*°    FIGURE 49-9 Altered Immune Function After Thermal Injury. Cell-mediated  immunity, antibody production, humoral response. PMN, Polymorphonuclear leukocyte.    Circulating immunoglobulins may be affected by several  factors, including age and the severity of injury.®! Therapeu-  tic interventions such as multiple transfusions, surgical pro-  cedures, and antibiotic and anesthetic administration also  introduce elements that confound the evaluation of immuno-  suppressive effects. The immune system is activated systemi-  cally after a large burn injury with extensive tissue necrosis and  may become ineffective or even self-destructive. Infections in  burns may result in the loss of some components of innate  immune function.**   An additional aspect of the immunopathologic consequence  of a burn is the role of immunomodulatory cytokines that are  suggested to regulate innate regulatory lymphocytes. Research  regarding four cell types—NK (natural killer), natural killer  T (NKT), gamma-delta T (v8), and regulatory T (Treg)—  indicates their central role in protective immunity.** In chil-  dren with moderate to severe burn injury, cytokines have been  found to increase inflammation by enhancing catabolism and  hypermetabolism. In this immunomodulatory process the pro-  inflammatory function of cytokines enhances protection from  sepsis, and the anti-inflammatory function supports anabolism  (i.e., tissue repair).°*    Whereas shock and pulmonary compromise present the  most immediate threat after burn trauma, local and systemic    infections become the primary complication during healing.  The burn wound initially is relatively free of pathogens; how-  ever, dead, avascular tissue and wound exudate provide a fertile  environment for bacterial growth. Colonization of the wound  is apparent by the fifth postburn day. Gram-positive microor-  ganisms are usually recovered from cultures first, followed by  opportunistic gram-negative bacteria. The impaired vascular  supply to burned tissue enhances the proliferation of patho-  genic microorganisms. Bacterial invasion results in thrombosis  and a further impairment of circulation sufficient to convert a  partial-thickness injury to a full-thickness wound.   Improvements in treatment have resulted in a reduction  in wound infection. Aggressive excision and grafting of the  wounds, improved nutritional support, and the development  of microorganism-specific topical antimicrobials have con-  tributed to this trend. However, the incidence of septicemia  remains relatively constant. This is perhaps explained by the  survival of children with burns of increasingly large body sur-  face area. The burn wound serves as the site of primary invasion  for the majority of instances of local or generalized infection.  Because the burned child is immunosuppressed for many weeks  after injury, maintaining wounds at low contamination levels  by meticulous wound care decreases the frequency and dura-  tion of septic episodes caused by wound flora.*°    Complex metabolic alterations are observed after burn injury.  The extent of metabolic derangement is proportional to the  magnitude of TBSA burn sustained. Wilmore demonstrated the  linear increase in metabolic rate up to 2% times normal resting  energy expenditure.®° As burn injury approaches 50% of TBSA,  a plateau is reached, limiting further physiologic response to the  trauma or other challenges such as infection.   A biphasic pattern of physiologic response is evident in ther-  mally injured children. The initial ebb phase occurs during  the immediate postburn period and continues for 3 to 5 days.  This phase is characterized by reduced oxygen consumption,  impaired circulation, and cellular shock. After the resolution of  the shock and the restoration of circulating volume, the meta-  bolic response shifts to a catabolic (flow) phase (Table 49-8).  A state of hypermetabolism ensues, characterized by increased  oxygen consumption and elevation of catecholamines, gluco-  corticoids, and glucagon.   Increased blood flow to the wound supplies additional glu-  cose necessary for tissue repair. Insulin levels are usually normal  or even elevated but are inappropriately low in relation to glu-  cagon. Catecholamines and glucocorticoids act as antagonists to  insulin. This effect combined with a tissue resistance to insulin  stimulates glycogenolysis and gluconeogenesis, thus increasing  glucose flow from the liver.°° In the child, glycogen stores for  meeting the increased energy demands of the burn are limited.  The initiation of protein and lipid catabolism for glycogenesis is  accelerated. This prolonged metabolic dysfunction may lead to  loss of lean body mass and increased morbidity.*”   Metabolic rates slowly return to normal with wound closure.  However, a reactivation of the hypermetabolic response may  occur with sepsis or organ failure.    CHAPTER 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children    From Gottschlich M, Alexander JW, Bower RH. In Rombeau JL, Caldwell MD, editors: Enteral and tube feeding, Philadelphia, 1990, Saunders.    The hypermetabolic response after burn injury profoundly  alters the production and use of nutrients. As a consequence of  these phenomena, caloric requirements increase dramatically.  Advances in burn care have allowed the performance of indirect  calorimetry and assessment of metabolic rate at the bedside.  Nutritional support must have an increased metabolic rate fac-  tored in (increased by 10% to 20%) because of fluctuations in  energy use associated with activity. Current recommendations  suggest 1.5 to 2 g protein/kg/day for adults and up to 2.5 to 4g  protein/kg/day for children.*’   In addition to age, body composition has been found to  significantly affect the postburn course. Preexisting obesity in  burn children has been associated with longer hospital stay  and associated morbidity.** However, the heightened nutrient  requirements of the burned child preclude a reduction in nutri-  tional support during the acute phase of recovery. Aggressive  nutritional therapy is critical to the recovery of these children,  and programs designed to achieve ideal body weight should not  be instituted until wound healing is achieved.   Metabolism of many micronutrients is greatly affected  by burn injury. Micronutrient supplementation is necessary  because vitamin and mineral requirements increase with the  severity of the burn related to heightened protein synthesis,  enhanced caloric expenditure, and increased micronutrient  losses. Pre-burn status also indicates individual vitamin and  mineral needs.°? Hypermetabolism results in a rapid turnover  in vitamins and trace minerals important in the wound healing  and immune response. A deficiency of specific nutrients inter-  feres with carbohydrate and nucleic acid metabolism, collagen  formation, and immune function.    The thermoregulatory response after burn injury results  in an elevation in core body temperature. Burned individuals  strive for temperatures of about 38° C (100.4° F). Depressed  or “normal” temperature may be indicative of overwhelming  sepsis, or an exhausted physiologic capability to maintain tem-  perature, and should be viewed as an ominous sign. Routine  methods of heat conservation after a major burn injury are  inadequate because of excessive heat loss through convection  and evaporation.** Therapeutic intervention, such as operative  procedures and dressing changes, and transport present situa-  tions requiring increased diligence to prevent inadvertent cool-  ing. Infants are at increased risk for a precipitous drop in core  body temperature caused by an inability to regulate heat loss  by shivering. Heat is also lost because of evaporation of water  from damaged skin surfaces. Infants and children are especially  vulnerable because of the large surface area relative to metaboli-  cally active tissue.’”    The heightened metabolic demands after burn injury combined  with a poor appetite often necessitate supplementation of oral  intake. Children with burns in excess of 20% of TBSA often  require supplementation with tube feeding. Feeding does not  need to be delayed pending resolution of paralytic ileus and the  resumption of bowel sounds because the small bowel maintains  motility and absorptive capability. A small-bore feeding tube  placed in the duodenum provides a safe route for the delivery  of essential nutrients. Parenteral hyperalimentation is reserved  for those children who are unable to tolerate enteral support  because of attendant risks of catheter sepsis and loss of intes-  tinal integrity. Early enteral supplementation preserves gut    Ongoing research and development continues to focus on the burn wound  dressing, providing more therapeutic options with major wounds. Impregnated  silver dressings kill bacteria but because most are processed with a special  layer, they are less painful to remove. Some of these products can be left on  the wound for up to 2 weeks allowing less frequent dressing changes and more  comfort for the individual. A new extracellular matrix (ECM) product is being  researched for repair and remodeling of damaged tissues in a burn injury and    other therapeutic wound care situations. Derived from porcine urinary blad-  der, this ECM technology contains a bimodal surface technology with naturally  occurring collagens and proteins and maintains an epithelial basement mem-  brane surface. An in vitro study demonstrated that urinary bladder ECM is the  best basement membrane as compared to small intestine or liver ECM. Another  study suggested that antibacterial activity exists within ECM and these low-  molecular-weight peptides may help explain resistance to bacterial infection.    Data from Brennan A et al: Tissue Eng 12(10):2949-2955, 2006; Brown  B et al: Tissue Eng 12(3):519-526, 2006.    mucosal integrity and improves intestinal blood flow, as well  as motility.® Early initiation of enteral supplementation along  with aggressive management of complications permits success-  ful enteral alimentation in most burned children.   Severe burn injury causes exaggerated muscle protein catab-  olism, contributing to weakness and delayed healing. Many  therapeutic strategies have been used to avert the hypermeta-  bolic response and improve clinical outcomes. Pharmaco-  logic agents, such as recombinant growth hormone, low-dose  insulin, and testosterone, have been shown to improve muscle  kinetics and wound healing. However, these can cause seri-  ous side effects. Investigators have found that anabolic steroid  agents, along with nutritional support, improve muscle protein  metabolism through enhanced protein synthesis efficiency in  children and adults.*? Outpatient follow-up should include reg-  ular weighing of the child and nutritional assessment to identify  children at risk for further weight loss.    The goals of wound management include prevention of infec-  tion, removal of devitalized tissue, and closure of the wound  (see What’s New? Advances in Burn Wound Care). Burns that  are clearly deep dermal or full-thickness injuries are surgically  excised as soon as the child is hemodynamically stable after  resuscitation. Early excision reduces the incidence of wound  infection and systemic sepsis.””"°* Coverage of the excised wound  is necessary to achieve wound closure. The choice of a coverage  technique depends on the availability of donor skin.  Split-thickness sheet grafts are selected for areas of maximal  functional and cosmetic results (Figure 49-10). Children with  very large burn injuries often do not have sufficient unburned  skin available to facilitate use of the sheet graft. In these cases  the surgeon uses a meshing technique to expand the available  skin and increase the size of the graft. The pattern created heals  by migration of epithelium from the meshed edges. Scar forma-  tion is increased, and the mesh pattern remains clearly visible  (Figure 49-11). The color, texture, vascularity, thickness, and    hair-bearing nature of the skin vary from one area to another.  Site selection and depth of donor sites require careful consider-  ation. Skin grafts for the face should be taken, if possible, from  above the nipple line for best color match and “blush” ability.”    In normal epidermal healing, minimal disruption in skin  color, texture, and thickness occurs. However, burn wounds  that extend into the dermis are repaired through scar forma-  tion and may result in an overgrowth of dermal constituents  (Figure 49-12, A). Accelerated collagen synthesis most likely  begins with high levels of activity in granulation tissue. The  hypertrophic scar consists of hypercellular and disorganized  connective tissue that is erythematous, raised, and pruritic.  Normal dermis contains thick fibers and fiber bundles running  parallel to the surface. In the hypertrophic scar, the collagen is  arranged in whorls and nodules that account for its inelasticity  and increased turgor.”* As the hypertrophic scar matures, col-  lagen begins to orient in a more parallel fashion, and vascular-  ity decreases (see Figure 49-12, B). Collagen synthesis is very  active soon after wound closure, and alteration of the scar can  be accomplished before strong cross-linking of the collagen is  established.    CHAPTER 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children    FIGURE 49-12 Scar Maturation. A, Immature hypertrophic scar. B, Flat,  mature scar after pressure therapy.    Although duration of wound healing varies among indi-  viduals, the length of time required to achieve wound closure  is the most reliable predictor of hypertrophic scarring. Deeper  burns demonstrate increased scarring caused by the formation  of granulation tissue and prolonged healing time. Generally,  darker-pigmented races are more susceptible to hypertrophic  scarring.’”> Although age has not been found to be a predictor  of hypertrophic scar formation, younger individuals are more  susceptible to trauma and have greater skin tension and an  accelerated rate of collagen synthesis. Increased tension with  resultant trauma stimulates inflammation, which in turn results  in the formation of additional collagen.   Scar tissue is metabolically active and highly vascular. Colla-  gen is deposited in random patterns, and contraction of the scar  can result in disabling deformities. The scar is active as long as  it is raised, red, and firm. Scar maturation requires 1 to 2 years  and depends on individual differences and compliance with  the rehabilitation program. The mature scar is characterized by  increased suppleness, flattening, and pigmented color.   Scar tissue does not grow and expand like normal tissue.  Although massage therapy offers some benefit in stretching,  functional limitation may develop as the child grows. This is  particularly evident over joints. Reconstructive surgery is often  necessary to restore anatomic integrity and to promote inde-  pendent function.    Itching may occur at any time during burn wound healing.  As a complication, healed skin may be scratched away in an  effort to obtain relief. The combination of H, and H, antago-  nists may be used to control itching.”*    Pain management presents a significant challenge in the  pediatric population. In addition to procedural pain, there  is a component of background pain that is present without  activity. Pain perception is also affected by the degree of emo-  tional overlay or affective experience.”? The measurement of  pain is particularly challenging in young infants, who lack the  language skills to express pain. A variety of tools, from physi-  ologic monitors to behavioral analyses and analog scales,  have been developed to measure pediatric pain. The qual-  ity of pain control in burn centers has improved along with  the ability to assess pain in the pediatric population. Stud-  ies have documented pharmacologic as well as nonpharma-  cologic interventions that have improved the quality of pain  control.”    Rehabilitation becomes the major focus of care once wound  coverage has been achieved and continues until all reconstruc-  tive procedures have been completed. This phase may extend  over many years in the pediatric population. Children require  specialized management to ensure optimal functional and  cosmetic results. Scar and contracture management is neces-  sary for prolonged periods because of changes in body com-  position as the child grows and matures. Very young children  present unique challenges because the small body size can be  difficult to fit with pressure garments and splints, growth is  rapid, and cooperation with the rehabilitation program is  limited.   Infant skin is thinner, and the epidermis is more loosely con-  nected to the dermis. This increases the risk of blistering, chaf-  ing, and rash formation. The infant also produces less sebum  and sweat, which further exacerbates the propensity to skin  irritation. Because scar tissue contains no sweat glands, these  characteristics of the skin in growing children compound the  difficulty in maintaining pressure on maturing scars while cool-  ing the body.   Positioning and splinting to prevent contracture forma-  tion, as well as rehabilitative aspects of therapy, are instituted  on admission and continue throughout the hospitalization.  Physical therapy and occupational therapy provide exercise to  maintain range of motion and function. Psychosocial support  is very important for the child and the family. The information  provided should be consistent and honest to allow clarification  of concerns. In addition to the functional aspects of rehabilita-  tion, attention must be directed to psychosocial needs and com-  munity reintegration.   A method to facilitate the transition from the hospital to  the community is the school reentry program offered by many  burn centers. These programs provide education for teachers  and peers about the injury, appearance, and abilities of the  returning child.    Shock in children is present when there are signs of poor  systemic perfusion, regardless of blood pressure.    . Hypovolemic shock is the most common type of shock in    children and it most frequently results from dehydration  and trauma. Hypovolemic shock also may result from  expansion of the vascular space, producing inadequate  intravascular volume relative to the vascular space.    equate systemic perfusion associated with intravascular fluid  loss. Adrenergic compensatory mechanisms can produce  tachycardia, redistribution of blood flow, peripheral vasocon-  striction, cool extremities, delayed capillary refill, and oliguria.    . Neurogenic shock is caused by a loss of vasomotor tone    skin, hypotension with a low diastolic blood pressure, and  poor systemic perfusion. Tachycardia is not present.    observed most commonly after cardiovascular surgery or  with inflammatory diseases of the heart, such as cardiomy-  opathy and myocarditis. It is also found in children with  obstructive congenital heart disease and those with drug  toxicity or severe electrolyte or acid-base imbalances.    equate systemic perfusion despite adequate intravascular  volume. Cardiac output is typically low. Adrenergic com-  pensatory mechanisms, including peripheral vasoconstric-  tion and decreased urine volume, are similar to those found  in hypovolemic shock.    urgently needed. Therapy in the first hour includes aggres-  sive fluid resuscitation (typically 60 to 80 ml/kg adminis-  tered in first hour of therapy, and approximately 200 to 240  ml/kg in the first 8 hours of therapy). If the child does not  respond to volume administration alone, vasoactive sup-  port must be initiated within the first hour of treatment.  Antibiotics also must be administered within the first hour.  Goals of therapy are to rapidly normalize the heart rate and  blood pressure for age and to normalize capillary refill to  less than 2 seconds. The child’s shock index (heart rate/  systolic blood pressure) should fall during the first hour  of management if therapy is effective. Fluid and vasoactive  therapy should support high cardiac output and oxygen  delivery, maintaining the Svo) at approximately 70%.  Sepsis is a systemic response to infection. It is present when  manifestations of SIRS are observed. SIRS is present when  the child demonstrates two or more of the following as an  acute change from baseline values: altered temperature,  altered heart rate, altered respiratory rate, and alteration in  the WBC count. The newborn often develops hypothermia  rather than fever as a sign of infection and may develop bra-  dycardia instead of tachycardia.    Severe sepsis is present when there is evidence of SIRS and  signs of organ dysfunction, hypoperfusion, or hypotension.  The development of septic shock is heralded when the child  with severe sepsis develops signs of cardiovascular dysfunc-  tion. The child may become hypotensive despite adequate  fluid resuscitation or require vasopressors to maintain  blood pressure.   Reperfusion and inflammatory injury stimulate free oxy-  gen radicals that can damage cell membranes, denature  proteins, and disrupt chromosomes. This process likely  affects endothelial cells and the microvasculature, causing  MODS.   Lactic acidosis (1.e., rise in serum lactate) may be the most  sensitive indicator of inadequate systemic perfusion in  children; effective shock therapy should eliminate lactic  acidosis.   The general goals of treatment for shock are maximization  of oxygen delivery and minimization of oxygen demand.  This requires support of airway, oxygenation, and ventila-  tion. Support of cardiovascular function requires support  of appropriate heart rate and rhythm, adequate intravas-  cular volume, good myocardial function, and appropri-  ate vascular resistance and distribution of blood flow.  The child should be kept warm but fever must be treated  promptly.   The signs of shock should lessen or disappear if man-  agement of shock is effective. The warmth of the child’s  extremities, briskness of capillary refill, quality of peripheral  pulses, level of consciousness and responsiveness, urine vol-  ume, oxygenation, ventilation, and acid-base status should  improve throughout shock therapy.    Burns in children are often the result of inadequate super-  vision, curiosity, inability to escape the burning agent, or  intentional abuse.    result from exposure to hot water, grease, or other hot liq-  uids, whereas flame burns are more prevalent among older  children.    than adult skin. The kitchen and bathroom are common  sites of burn injury.    . Approximately 10% of all forms of child abuse cases in the    gasoline, are more common in older children. Risk-taking  behaviors in young males can lead to electrical burns.  Children may be exposed to chemical injury by swallowing  caustic agents at home.    . Use of the standard Rule of Nines results in inaccurate    calculation of the percentage of TBSA in children. A  modified Rule of Nines deducts 1% from the head and  adds 0.5% to each leg for each year of life after 2 years  of age.    CHAPTER 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children    7. Major burn trauma involves all body systems, and the con-    sequences of injury include shock, infection, hypermetabo-  lism, organ failure, and functional limitations. These effects  can be magnified in the pediatric population as a result of  physiologic immaturity and age-related variation in treat-  ment modalities.   Infection, trauma, or applying ice to the burn area may con-  vert a partial-thickness injury to a full-thickness one, espe-  cially in young children, who have thinner, more delicate skin.  Marked reduction in cardiac output occurs immediately  after injury and is accompanied by an initial increase in sys-  temic vascular resistance. The inefficient and labile periph-  eral circulation of the infant complicates management of  the burn shock phase of treatment. Constriction of the  chest and impairment of respiratory excursion may occur  in the very young child because of the increased pliability of  the rib cage. Younger children are also more susceptible to  increased intra-abdominal pressure.   The leading cause of death in children after burn injury, as  in adults, is inhalation injury.   Children require fluid resuscitation for smaller burns than  does the adult population as a result of limited physiologic  reserves. Colloid replacement may be required in the very  young child who fails to respond to fluid replacement.  Children younger than 2 years lack the ability to concen-  trate urine because of the immaturity of the renal system  and are therefore at increased risk for dehydration. Because    children have a relatively larger body surface area in rela-  tion to weight than adults, they require proportionately  increased fluid during burn shock resuscitation to compen-  sate for evaporative water losses.   Some children exhibit immunosuppression for a prolonged  period after wound closure.    the burn-injured child. The initial ebb phase occurs dur-  ing the immediate postburn period and continues for 3 to  5 days. This phase is characterized by reduced oxygen con-  sumption, impaired circulation, and cellular shock. After  this phase and the restoration of volume, the metabolic  response shifts to a catabolic, or flow, phase. This phase is  characterized by hypermetabolism with an increased oxy-  gen consumption and elevation of catecholamines, gluco-  corticoids, and glucagon.   Glycogen stores are limited in children, making it hard for  them to meet the increased energy demands of the burn.  This prolonged metabolic dysfunction may lead to loss of  lean body mass and increased morbidity.   Although age was not found to be a predictor of hypertro-  phic scarring, children have greater skin tension and an  accelerated rate of collagen synthesis.   Children require specialized management to ensure opti-  mal functional and cosmetic results. Long-term scar and  contracture management is necessary because of changes in  body composition as the child grows and matures.    Haque IU, Zaritsky AL: Analysis of the evidence for the lower limit of  systolic and mean arterial blood pressure in children, Pediatr Crit Care  8:138—144, 2007.   Chameides L et al, editors: Pediatric advanced life support provider  manual, Dallas, 2011, American Heart Association.   Perkin RM et al: Shock, cardiac arrest and resuscitation. In Hazinski MF,  editor: Nursing care of the critically ill child, ed 3, St Louis, 2013, Mosby.  Goldstein B, Giroir B, Randolph A: International Pediatric Sepsis  Consensus Conference: definitions for sepsis and organ dysfunction in  pediatrics, Pediatr Crit Care Med 6:2-8, 2005.    Proulx F et al: The pediatric multiple organ dysfunction syndrome, Pedi-  atr Crit Care Med 10:12—22, 2009.   Hazinski MF: Children are different. In Hazinski MF, editor: Nursing care  of the critically ill child, ed 3, St Louis, 2013, Mosby.   Otieno H et al: Are bedside features of shock reproducible between dif-  ferent observers? Arch Dis Child 89(10):977-979, 2004.   Chameides L et al: Recognition and management of tachycardia. In  Chamiedes L et al, editors: Pediatric advanced life support provider  manual, Dallas, 2011, American Heart Association.   Rudolph AM: Congenital diseases of the heart, Chicago, 1974, Year Book  Medical.    Chameides L et al: Recognition and management of bradycardia. In  Chamiedes L et al, editors: Pediatric advanced life support provider  manual, Dallas, 2011, American Heart Association.   Roberts KE: Fluid, electrolyte and endocrine problems. In Hazinski MF,  editor: Nursing care of the critically ill child, ed 3, St Louis, 2013,   Nayak PP et al: Early change in blood glucose concentration is an indica-  tor of mortality in critically ill children, Intensive Care Med 39(1):123-128,  2012.   Bhutia TD, Lodha R, Kabra SK: Abnormalities in glucose homeostasis in  critically ill children, Pediatr Crit Care Med 14(1):e16—-e25, 2013.  American College of Surgeons: Extremes of age: pediatric trauma. In  Advanced trauma life support program for doctors, ed 7, Chicago, 2004,  American College of Surgeons.   Armstrong A, Unni P, Pietsch JB: Pediatric trauma. In Hazinski MF, edi-  tor: Nursing care of the critically ill child, ed 3, St Louis, 2013, Mosby.  Chameides L et al: Recognition of shock. In Chamiedes L et al: Pediatric  advanced life support provider manual, Dallas, 2011, American Heart  Association.   Watson RS et al: The epidemiology of severe sepsis in children in the  United States, Am J Respir Crit Care Med 167(5):695—701, 2003.  Singh-Naz N et al: Risk factors for nosocomial infections in critically ill  children: a prospective cohort study, Crit Care Med 24(5):875-878, 1996.  Foglia E, Meier MD, Elward A: Ventilator-associated pneumonia in  neonatal and pediatric intensive care unit patients, Clin Microbiol Rev  20(3):409-425, 2007.   Trimarchi T: Fundamentals of patient safety and quality improvement.  In Hazinski MF, editor: Nursing care of the critically ill child, ed 3, St  Louis, 2013, Mosby.   Nadel S: Severe pediatric sepsis, Expert Rev Anti Infect Ther 10(2):  111-114, 2012.   Wong HR: Genetics and genomics in pediatric septic shock, Crit Care  Med 40:1618-1626, 2012.   Brandtzaeg P, van Deuren M: Classification and pathogenesis of menin-  gococcal infections, Methods Molec Biol 799:21-35, 2012.   Sullivan JS et al: Correlation of plasma cytokine elevation with mortality  rate in children with sepsis, J Pediatr 120(4 Pt 1):510-515, 1992.   Aneja RK, Carcillo JA: Differences between adult and pediatric septic  shock, Minerva Anesthesiol 77:986—992, 2011.   Decker T: Sepsis: avoiding its deadly toll, J Clin Invest 113(10):1387-1389,  2004,   Haley M et al: Activated protein C in sepsis: emerging insights regarding  its mechanism of action and clinical effectiveness, Curr Opin Infect Dis  17(3):205-211, 2004.   Bernard GR et al: Efficacy and safety of recombinant human activated  protein C for severe sepsis, N Engl J Med 344(10):699-709, 2001.  Batzofin BM, Sprung CL, Weiss YG: The use of steroids in the treatment  of severe sepsis and septic shock, Best Pract Res Clin Endocrinol Metab  25(5):735—-743, 2011.   Karaguzel G et al: The effects of three specific conditions related to   the critical care on adrenal function in children, Intensive Care Med  38(10):1689-1696, 2012.   Hebbar KB, Petrillo T, Fortenberry JD: Adrenal insufficiency and  response to corticosteroids in hypotensive critically ill children with  cancer, J Crit Care 27(5):480—487, 2012.   Brierley J et al: Clinical practice parameters for hemodynamic support of  pediatric and neonatal septic shock: 2007 update from American College  of Critical Care Medicine, Crit Care Med 37:666—688, 2009.   Carcillo JA et al: Mortality and functional morbidity after use of PALS/  APLS by community physicians, Pediatrics 124:500-508, 2009.   Kissoon N, Orr RA, Carcillo JA: Updated American College of Critical  Care Medicine—Pediatric advanced life support guidelines for manage-  ment of pediatric and neonatal septic shock: relevance to the emergency  care clinician, Pediatr Emerg Care 26(11):867—-869, 2010.   Carcillo JA, Davis AL, Zaritsky A: Role of early fluid resuscitation in  pediatric septic shock, JAMA 266(9):1242-1245, 1991.   de Oliveira CE et al: ACCM/PALS haemodynamic support guidelines  for paediatric septic shock: an outcomes comparison with and with-   out monitoring central venous oxygen saturation, Intensive Care Med  34:1065-1075, 2008.   :Chamiedes L et al, Management of shock Chameides L et al: Pediatric  advanced life support provider manual, Dallas, 2011, American Heart  Association.   Banz Y, Rieben R: Role of complement and perspectives for intervention  in ischemia-reperfusion damage, Ann Med 44:205—217, 2012.    Francischetti I et al: Leukocytes and the inflammatory response in  ischemia-reperfusion injury, Rev Bras Cir Cardiovasc 25(4):575—584, 2010.  Lacroix J, Cotting J, for the Pediatric Acute Lung Injury and Sepsis  Investigators (PALISI) Network: Severity of illness and organ dysfunction  scoring in children, Pediatr Crit Care Med 6(Suppl 3):S126-S134, 2005.  Bestati N et al: Differences in organ dysfunctions between neonates and  older children: a prospective, observational, multicenter study, Crit Care  14:R202, 2010.   Leteurtre S et al: Daily estimation of the severity of multiple organ  dysfunction syndrome in critically children, CMAJ 182(11):1181-1187,  2010.   Hutton P et al: An assessment of the Dinamap 845, Anesthesiology 39:261,  1984.   Davis JW et al: Are automated blood pressure measurements accurate in  trauma patients? J Trauma 55(5):860-863, 2003.   Lacroix J et al: Transfusion strategies for patients in pediatric intensive  care units, N Engl J Med 356:1609-1619, 2007.   Lacroix J, Demaret P, Tucci M: Red blood cell transfusion: decision mak-  ing in pediatric intensive care units, Semin Perinatol 36:225—231, 2012.  Burke ML, Salani D: Hematologic and oncologic emergencies requiring  critical care. In Hazinski MF, editor: Nursing care of the critically ill child,  ed 3, St Louis, 2013, Mosby.   Vlasselaers D et al: Intensive insulin therapy for patients in paediat-   ric intensive care: a prospective, randomised controlled study, Lancet  373:547-556, 2009.   Ulate KP: A critical appraisal of Vlasselaers D et al: Intensive insulin ther-  apy for patients in paediatric intensive care: a prospective, randomised  controlled study, Lancet 2009; 373:547—-556, 2009, Pediatr Crit Care Med  12:455—458, 2011.   Hirshberg E et al: Clinical equipoise regarding glycemic control: a survey  of pediatric intensivist perceptions, Pediatr Crit Care Med 14(2):123-129,  2013:   Polderman KH: Mechanisms of action, physiological effects, and compli-  cations of hypothermia, Crit Care Med 37(Suppl):S186—S202, 2009.  Pietrini D et al: Neuroprotection and hypothermia in infants and chil-  dren, Curr Drug Targets 13(7):925—935, 2012.   Shankaran S et al: Whole body hypothermia for neonates with hypoxic-  ischemic encephalopathy, N Engl J Med 353:1574-1584, 2005.  Hypothermia After Cardiac Arrest Study Group: Mild therapeutic hypo-  thermia to improve the neurologic outcome after cardiac arrest, N Engl J  Med 346(8):549-556, 2002.   Bembea MM et al: Temperature patterns in the early postresuscitation  period after pediatric inhospital arrest, Pediatr Crit Care Med 11(6):  723-730, 2010.   Committee on Trauma: Resource for optimal care of the injured patient  [pamphlet], 1999, American College of Surgeons.   Safe Kids Worldwide (SKW): Burn and scalds safety 2011. Available at  www.safekids.org/assests/docs/ourwork/research/2011-burns-and-  scalds.pdf. Accessed May 29, 2012.   American Burn Association: Pediatric burn injuries. 2011 Advanced burn  life support provider manual, Chicago, 2011, American Burn Association.  Greenhalgh DG: Burn-related child abuse. In Phillips BJ, editor: Pediatric  burns, Amherst, 2012, Cambria.   Knox BL, Starling SP: Medical evaluation of burn injuries, National Center  for Prosecution of Child Abuse Update 22 (Number 2&3) 2009. Available at  www.ndaa.org/pdf/update_22_2and3.pdf. Accessed May 29, 2012.   Fujii TK, Schwartz SJ, Phillips BJ: Inhalation injury. In Phillips BJ, editor:  Pediatric burns, Amherst, 2012, Cambria.   Sheridan RL, Tompkins RG: Alternative wound coverings. In Herndon  DN, editor: Total burn care, Philadelphia, 2012, Saunders.   In Samour PQ, King K, editors: Pediatric nutrition, Sudbury, MA, 2012,  Jones & Bartlett.   Helvig E: Pediatric burn injuries, AACN Clin Issues Crit Care Nurs  4(2):433—442, 1993.   Jensen AR, Hughes WB, Grewal H: Secondary abdominal compartment  syndrome in children with burns and trauma: a potentially lethal compli-  cation, J Burn Care Res 27(2):242-246, 2006.   Peng D, Huang W: Etiology of immune dysfunction in thermal injuries.  In Phillips BJ, editor: Pediatric burns, Amherst, 2012, Cambria.  Serebrisky D: Inhalation injury. In Bye MR et al: Medscape Reference,  2012. Available at http://emedicine.medscape.com/article/1002413-  overview. Accessed June 12, 2012.   Conrardy PA et al: Alteration of endotracheal tube position, Crit Care  Med 4(2):8, 1976.    CHAPTER 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children    Sharar SR: Endotracheal tube tip position in an infant with severe burns,  J Burn Care Rehabil 16(6):654, 1995.   Trout S et al: Influence of head and neck position on endotracheal tube  tip position on chest x-ray examination: a potential problem in the infant  undergoing intubation, J Burn Care Rehabil 15(5):405—407, 1994.  Palmieri TL: What’s new in critical care of the burn-injured patient? Clin  Plast Surg 36(4):607—615, 2009.   Sheridan RL et al: Permissive hypercapnia as a ventilatory strategy in  burned children: effect on barotrauma, pneumonia, and mortality,   Greathouse ST et al: High-frequency oscillatory ventilators in burn  patients: experience of Riley Hospital for Children, J Burn Care Res  33(3):425—435, 2012.   Phillips BJ: Pediatric burn resuscitation. In Phillips BJ, editor: Pediatric  burns, Amherst, 2012, Cambria.   Tintinalli JE et al: Emergency medicine: a comprehensive study guide, New  York, 2004, McGraw-Hill.   Lee JO, Herndon DH, Norbury WB: Special considerations of age: the  pediatric burn patient. In Herndon DH, editor: Total burn care, Philadel-  phia, 2012, Saunders.   Colon NC, Schlegel C, Chung DH: Surgical management of complica-  tions of burn injury. In Herndon DH, editor: Total burn care, Philadel-  phia, 2012, Saunders.   Deitch EA: Nutritional support of the burn patient, Crit Care Med  11(3):735, 1995.   Supple KG: Physiologic response to burn injury, Crit Care Nurs Clin  North Am 16(1):119, 2004.   Stratta RJ et al: Immunologic parameters in burned patients: effect of  therapeutic interventions, J] Trauma 26(1):7, 1986.   Murphey ED, Sherwood ER, Tolliver-Kinsky T: The immunological  response and strategies for intervention. In Herndon DN, editor: Total  burn care, Philadelphia, 2012, Saunders.    Schneider DF, Glenn CH, Fauce DE: Innate lymphocyte subsets and  their immunoregulatory roles in burn injury and sepsis, J Burn Care Res  28(3):365—379, 2007.   Phillips BJ, Carter MJ: Changes to the hypothalamic-pituitary-adrenal  axis in burns and the use of steroids. In Phillips BJ, editor: Pediatric  burns, Amherst, 2012, Cambria.   Gallagher JJ et al: Treatment of infection in burns. In Herndon DN,  editor: Total burn care, Philadelphia, 2012, Saunders.    Clin Plast Surg 1(4):603-619, 1974.  Rodriguez NA et al: Nutrition in burns: Galveston contributions, J Parenter  Enteral Nutr 35(6):704—714, 2011.    . Saffle JR, Graves C, Cochran A: Nutritional support of the burned    patient. In Herndon DN, editor: Total burn care, Philadelphia, 2012,  Saunders.   Wolf SE et al: Effects of oxandrolone on outcome measures in the  severely burned: a multicenter prospective randomized double-blind  trial, J Burn Care Res 25(2):131-139, 2006.   Petersen SR, Umphred E, Warden GD: The incidence of bacteremia  following burn wound excision, J Trauma 22(4):274-279, 1982.   Lee JO et al: Operative wound management. In Herndon DN, editor:  Total burn care, Philadelphia, 2012, Saunders.   Kwan P, Desmouliére A, Tredget EE: Molecular and cellular basis of  hypertrophic scarring. In Herndon DN, editor: Total burn care, Philadel-  phia, 2012, Saunders.   Hawkins HK, Finnerty CC: Pathophysiology of the burn scar. In Hern-  don DN, editor: Total burn care, Philadelphia, 2012, Saunders.   Baker RU et al: Burn wound itch control using H1 and H2 antagonists,   Bayat A, Ramaiah R, Bhananker SM: Analgesia and sedation for children  undergoing burn wound care, Expert Rev Neurother 10(11):1747-1759,  2010.    CHAPTER 49 Shock, Multiple Organ Dysfunction Syndrome, and Burns in Children    Pageburst Integrated Resources  As part of your Pageburst Digital Book, you can access the following Integrated Resources:    Absolute polycythemia excessive red blood  cell production; a physiologic response result-  ing from increased erythropoietin secretion in  response to chronic hypoxia or as a symptom of  polycythemia vera.   Acid maltase deficiency (glycogen storage  disease type Il or Pompe disease) an auto-  somal recessive metabolic disorder that dam-  ages muscle and nerve cells throughout the body  by an accumulation of glycogen in the lysosome  attributable to deficiency of the lysosomal acid  a-glucosidase enzyme. The buildup of glycogen  causes progressive muscle weakness (myopathy)  throughout the body and affects various body  tissues, particularly in the heart, skeletal mus-  cles, liver, and nervous system.   Acne a common skin disease characterized by  pimples on the face, chest, and back. It occurs  when the pores of the skin become clogged with  oil, dead skin cells, and bacteria.   Acne conglobata severe cystic acne charac-  terized by cystic lesions, abscesses, communi-  cating sinuses, and thickened, nodular scars;  usually does not affect the face.   Acne rosacea a chronic form of dermatitis of  the face in which the middle portion of the  face appears red with small red lines caused  by dilation of capillaries.   Acne vulgaris an inflammatory eruption of  the sebaceous follicles usually occurring on  the face, upper back, and chest that consists  of blackheads, cysts, papules, and pustules.   Noninflammatory acne open comedones  caused by the enlargement and dilation of a  plug resulting from the accumulation of oil  and dead skin cells inside the hair follicle and  by closed comedones that form if the hair  follicle pore remains closed; they appear as a  tiny, sometimes pink bump in the skin.   ACTH deficiency a condition characterized by  decreased or absent production of adrenocor-  ticotropic hormone (ACTH) by the pituitary  gland, resulting in a reduction in the secretion  of adrenal hormones and subsequent weight  loss, lack of appetite, weakness, nausea, vomit-  ing, and low blood pressure.   Actinic keratosis a condition in which a pre-  malignant small, reddish, rough spot appears on  skin chronically exposed to the sun.   Acute chest syndrome a syndrome occurring  in association with sickle cell disease defined by  a new infiltrate on chest radiograph; associated  with one or more new symptoms: fever, cough,  sputum production, dyspnea, or hypoxia. It  occurs most commonly in the 2- to 4-year-old  age group and declines in incidence with age.   Acute colonic pseudo-obstruction (Ogil-  vie syndrome) a massive dilation of the large  bowel that occurs in critically ill patients and  immobilized older adults. It is characterized by    significant dilation of the cecum and absence of  mechanical obstruction, and is related to exces-  sive sympathetic motor input or decreased para-  sympathetic motor input.   Acute confusional state (ACS) a form of delir-  ium caused by interference with the metabolic or  other biochemical processes essential for normal  brain functioning. Symptoms may include distur-  bances in cognition and levels of awareness, short-  term memory deficit, retrograde and anterograde  amnesia, and disturbances in orientation, accom-  panied by restlessness, apprehension, irritability,  and apathy. The condition may be associated with  an acute physiologic state, delirium, toxic psycho-  sis, or acute brain syndrome.   Acute coronary syndrome a _ classification  encompassing clinical presentations ranging  from unstable angina through infarction.   Acute cystitis an inflammation of the bladder,  which is the most common site of urinary tract  infection.   Acute epiglottitis an infection that causes  inflammation of the epiglottis and surrounding  tissues and may lead to upper airway blockage.   Acute gastritis an inflammatory disorder of the  gastric mucosa, usually caused by injury of the  protective mucosal barrier by drugs, chemicals,  or Helicobacter pylori infection.   Acute gouty arthritis an abrupt pain of a joint,  most often the great toe, which is swollen, hot,  and shiny secondary to an attack of gout.   Acute liver failure (fulminant liver failure) a  rare clinical syndrome resulting from severe  impairment or necrosis of liver cells without  pre-existing liver disease or cirrhosis. Acetamin-  ophen overdose is the leading cause.   Acute lung injury (ALI)/acute respiratory dis-  tress syndrome (ARDS) a spectrum of acute  lung inflammations and diffuse alveolocapillary  injury.   Acute mesenteric ischemia caused by acute  occlusion of the mesenteric artery that results in  a significant reduction in mucosal blood flow to  the large and small intestines. Aortic aneurysms,  arterial thrombi, or emboli can be causes.   Acute mountain sickness (AMS) the pres-  ence of a combination of nonspecific symp-  toms that appear within a few hours after ascent  to altitude, and may include headache, loss of  appetite, nausea, vomiting, weakness, lassitude,  dizziness, and difficulty sleeping.   Acute otitis media (AOM) an infection of the  middle ear space, behind the eardrum (tym-  panic membrane); characterized by pain, dizzi-  ness, and partial loss of hearing.    Acute orthostatic hypotension an abnor-  mal decrease in blood pressure when a person  stands. This may lead to fainting.   Acute pancreatitis inflammation of the pan-  creas resulting from obstruction to the outflow  of pancreatic digestive enzymes caused by bile  duct or pancreatic duct obstruction (e.g., gall-  stones). Usually a mild disease and resolves  spontaneously.   Acute pyelonephritis acute inflammation of  the renal parenchyma and pelvis characterized  by small cortical abscesses and yellowish streaks  in the medulla resulting from the accumulation  of pus in the collecting tubules and interstitial  tissue.   Acute renal failure (acute renal injury)  a sudden decline in kidney function with a  decrease in glomerular filtration and accumula-  tion of nitrogenous waste products in the blood  as demonstrated by an elevation in plasma cre-  atinine and blood urea nitrogen levels.   Acute respiratory distress syndrome (ARDS)  capillaries or alveoli of the lungs are damaged  as a result of infection, injury, blood loss, or  inhalation injury causing fluid to leak from the  capillaries into the alveoli, resulting in pulmo-  nary edema and collapse of some alveoli.   Acute tubular necrosis (ATN) the kidney  undergoes ischemic or nephrotoxic injury  because of severe hypotension, aminoglyco-  sides, or radiocontrast agents and produces  granular and epithelial cell casts in urine.   Acute urethral syndrome the bladder is irri-  tated and the typical symptoms of a urinary  tract infection are present in the absence of an  infection.   Adenocarcinoma tumor arising from epithelial  cells with a glandular or glandlike pattern.   Adenocystic tumor (cylindroma) rare bron-  chial gland tumors that arise predominantly  in the trachea or large airways and cause  obstruction.   Adenomyosis the presence of islands of endo-  metrial glands surrounded by benign endome-  trial stroma within the uterine myometrium.   Adrenarche growth of axillary and pubic hair  and other physiologic changes induced by  hyperactivity of the suprarenal cortex and adre-  nocortical secretion of androgenic hormones in  early puberty.   Agoraphobia a mental disorder characterized  by an irrational fear of leaving the familiar  setting of home, or venturing into the open,  so pervasive that a large number of external  life situations are entered into reluctantly  or are avoided; often associated with panic  attacks.    Akinesia _ slowness or loss of normal motor func-  tion resulting in impaired muscle movement.  Akinetic mutism (AM) a syndrome character-  ized by the inability to speak, loss of voluntary  movement, and apparent loss of emotional  feeling. It is related to lesions of the upper   Albright syndrome (Albright-McCune-Stern-  berg syndrome) polyostotic fibrous dyspla-  sia, patchy dermal pigmentation, and endocrine  dysfunction.   Alcoholic fatty liver (steatosis) the mildest  form of alcoholic liver disease; can be caused by  chronic ingestion of relatively small amounts of  alcohol, may be asymptomatic, and is reversible  with cessation of drinking.   Alcoholic hepatitis (steatohepatitis) a pre-  cursor of cirrhosis characterized by inflamma-  tion; degeneration and necrosis of hepatocytes;  infiltration of neutrophils, macrophages, and  lymphocytes; immunologic alterations; and  lipid peroxidation.   Alkaline reflux gastritis inflammation of the  stomach caused by reflux of bile and alkaline  pancreatic secretions that contain proteolytic  enzymes and disrupt the mucosal barrier in the  remnant stomach.   Allodynia a condition in which pain arises from  a stimulus that would not normally be experi-  enced as painful.   Alogia inability to speak because of mental defi-  ciency, mental confusion, or aphasia.   Alopecia areata an autoimmune T-cell—medi-  ated chronic inflammatory disease directed at  hair follicles that results in baldness, usually in  round patches.   Alzheimer disease (dementia of Alzheimer  type [DAT], senile disease complex) a  degenerative disease characterized by amyloid  plaques and fibrillary tangles in the cortex and  atrophy and widened sulci in the frontal and  temporal lobes.   Amblyopia poor vision caused by abnormal  development of visual areas of the brain in  response to abnormal visual stimulation during  early development.   Amyotrophic lateral sclerosis (ALS) (spo-  radic motor system disease, sporadic  motor neuron disease, motor neuron dis-  ease, Lou Gehrig disease) a disease that  breaks down tissues in the nervous system (a  neurodegenerative disease); it is of unknown  cause and affects the nerves responsible for  movement.   Anaphylactic shock a state of shock caused by  a severe allergic reaction that lowers blood pres-  sure and results in urticaria, breathing difficul-  ties, and possibly death.    Anaphylactoid purpura (allergic purpura,  Henoch-Schonlein purpura) nonthrom-  bocytopenic purpura attributable to immune  hypersensitivity to foods, drugs, and insect bites.   Anemia hemoglobin concentration is less than  normal because of a deficiency in red blood  cells, a low level of hemoglobin in cells, or both;  it manifests as pallor of the skin and mucous  membranes, weakness, dizziness, easy fatigabil-  ity, and drowsiness caused by oxygen deficiency.  Congenital hemolytic anemias   Alpha-thalassemia major thalassemia in  which all four a-chains of hemoglobin  are defective, resulting in a fatal condition  because oxygen cannot be released to the  tissues.   Alpha-thalassemia minor thalassemia in  which two a-chains of hemoglobin are  defective.   Beta-thalassemia major (Cooley ane-  mia) thalassemia in which a-chain  synthesis and f-chain synthesis are uncou-  pled; f-chain production is depressed  moderately in the heterozygous form,  beta-thalassemia minor, and severely in  the homozygous form, beta-thalassemia  major, resulting in erythrocytes that have  a reduced amount of hemoglobin and  accumulations of free a-chains.   Glucose-6-phosphate dehydrogenase  (G6PD) deficiency an inherited condi-  tion that is asymptomatic in the absence  of exposure to particular substances such  as certain medicines, mothballs, or severe  infections; with exposure the red blood  cells undergo destruction, producing  excessive bilirubin that overloads the liver  and causes jaundice.   Hemoglobin H disease a form of alpha-  thalassemia in which a hemoglobin H gene  is expressed but cannot bind oxygen.   Hereditary spherocytosis (congenital  hemolytic anemia, congenital achol-  uric jaundice) a defect in the cell  membrane of red blood cells that causes  thickened, fragile red blood cells that are  susceptible to spontaneous hemolysis and  results in chronic anemia, jaundice, fever,  and abdominal pain.   Sickle cell anemia (sickle cell disease  [SCD]) an inherited autosomal recessive  disorder of the blood caused by abnor-  mal hemoglobin that distorts red blood  cells and makes them fragile and prone to  rupture and can cause anemia, joint pain,  fever, leg ulcers, and jaundice.   Sickle cell-Hb C disease a heterozy-  gous form in which the child simultane-  ously inherits a hemoglobin C gene from  another parent.   Sickle cell-thalassemia disease a_ het-  erozygous form in which the child simul-  taneously inherits a thalassemia gene from  another parent.   Sickle cell trait an inherited condition in  which an individual carries only one gene for  sickle cell disease and is without symptoms.    Thalassemia a potentially fatal genetic  disorder in which hemoglobin molecules  are abnormal, resulting in severe anemia;  enlarged heart, liver, and spleen; and skel-  etal deformation.   Macrocytic anemia (megaloblastic anemia)  a condition characterized by erythrocytes  that are larger than normal; associated  with deficiency of vitamin B, or folic acid  caused by inadequate intake or insufficient  absorption secondary to alcoholism or drugs  that inhibit DNA replication.   Pernicious anemia an autoimmune dis-  order that causes a deficiency in intrinsic  factor, resulting in the inability to absorb  vitamin B,, and a subsequent increase in  the production of abnormal erythrocytes.   Microcytic-hypochromic anemia a condi-  tion in which red blood cells are smaller than  normal as a result of iron deficiency.  Acquired sideroblastic anemia a hetero-   geneous group of disorders characterized  by anemia of varying severity caused by  a defect in mitochondrial heme synthe-  sis; occurs as a primary disorder with no  known cause (idiopathic) or is associated  with other myeloproliferative or myelo-  plastic disorders.   Hereditary sideroblastic anemia _het-  erogeneous group of rare disorders char-  acterized by anemia of varying severity  caused by a defect in mitochondrial heme  synthesis; occurs almost exclusively in  males, suggesting a predominant recessive  X-linked transmission.   Hypoplastic anemia a condition in which  anemia results from greatly depressed,  inadequately functioning bone marrow  and smaller-than-normal erythrocytes.   lron deficiency anemia (IDA) an insuffi-  cient dietary intake or absorption of iron,  resulting in decreased incorporation of  hemoglobin into red blood cells and sub-  sequent feelings of fatigue, weakness, and  shortness of breath as well as pale earlobes,  palms, and conjunctivae.   Reversible sideroblastic anemia associ-  ated with alcoholism; results from nutri-  tional deficiencies of folate.   Sideroblastic anemia (SA) refractory  anemia of varying severity that is caused  by altered mitochondrial metabolism  and is marked by sideroblasts in the bone  marrow.   Normocytic-normochromic anemia (NNA)  erythrocytes are of normal size and  hemoglobin content but of insufficient  number; usually caused by hereditary  spherocytosis, drug-induced anemia, and  anemia secondary to malignancies.   Anemia of chronic disease (ACD) a  mild to moderate anemia resulting from  decreased erythropoiesis in individuals  with conditions of chronic systemic dis-  ease or inflammation.   Aplastic anemia decreased bone mar-  row production of adequate amounts  of new red blood cells; results from an    autoimmune disorder or exposure to  radiation or substances such as benzene or  certain drugs.    marrow causes erythropoiesis, resulting  in an acute fall in hemoglobin levels and  subsequent anemia.    a form of hemolytic anemia involving auto-  antibodies against red blood cell antigens.    anemia acquired disorder caused by  autoantibodies against antigens normally  on the surface of erythrocytes; mediated  by immunoglobulin M (IgM) antibod-  ies that optimally bind to and agglutinate  erythrocytes in colder portions of the body  (e.g., fingers, toes), and occurs less often  than warm antibody hemolysis, affecting  mostly middle-aged and older adults.    anemia (paroxysmal cold hemoglo-  binuria) a disorder in which exposure to  cold initiates acute and severe intravascu-  lar hemolysis that, unlike cold agglutinin  anemia, results in hemoglobinuria. The  chronic form of this anemia is extremely  rare, but an acute form of paroxysmal cold  hemoglobinuria is frequently observed    of immune hemolytic anemia usually  resulting from an allergic reaction against  foreign antigens (e.g., antibiotics) that  have attached to the surface of red blood  cells.   a genetic disease affect-  ing bone marrow that is characterized  by pancytopenia, hypoplasia of the bone  marrow, congenital anomalies, and  pigment changes of the skin and that  predisposes the individual to myelodys-  plasia and to acute myeloid leukemia or  cancers of the mouth, esophagus, intesti-  nal and urinary tracts, and reproductive  organs.    red blood cells are destroyed in response  to certain toxic or infectious agents or in  certain inherited blood disorders and the  rate of breakdown exceeds the body’s abil-  ity to compensate.    (erythroblastosis fetalis) a condition  that affects a fetus or newborn in which  red blood cells break down because of  antibodies made by the mother that are  directed against the infant’s red cells,  potentially resulting in anemia, heart fail-  ure, jaundice, and brain damage.    mocytic-normochromic anemia that is  caused by sudden blood loss in an indi-  vidual with normal iron stores and triggers  a compensatory response in which water  and electrolytes from tissues and inter-  stitial spaces are used to expand plasma   Warm autoimmune hemolytic anemia  the most common form of autoimmune  hemolytic anemia; caused by IgG that  binds to erythrocytes at normal body  temperature; often secondary to other  diseases, especially lymphomas, chronic  lymphocytic leukemia, other neoplastic  disorders, or systemic lupus erythemato-  sus (SLE).   Anencephaly anomaly in which the soft, bony  component of the skull and much of the brain  are missing.   Angelman syndrome (happy puppet syn-  drome) an inherited syndrome of jerky pup-  petlike movements, frequent laughter, mental  and motor retardation, peculiar open-mouthed  facies, and seizures.   Angina pectoris chest pain caused by reduced  cardiac blood flow and myocardial ischemia.  Anhedonia absence of pleasure from the per-  formance of acts that would ordinarily be   Ankylosing spondylitis (AS, spondyloarthri-  tis) chronic inflammation of the spine and  sacroiliac joints with gradual fusion of the ver-  tebrae that immobilizes the spine.   Anorexia nervosa (AN) a disorder with both  psychologic and physiologic components that  begins with dieting to lose weight and manifests  into an inappropriate self-control behavior;  continued restrictive eating may lead to starva-  tion and eventually death.   Anorgasmia_ (orgasmic dysfunction) the  inability of the woman to reach or achieve  orgasm.   Anxiety disorder a group of disorders involv-  ing various manifestations of anxiety that are  grouped together and include panic disorder,  specific phobia, social phobia, obsessive-com-  pulsive disorder (OCD), posttraumatic stress  disorder (PTSD), acute stress disorder, gen-  eralized anxiety disorder (GAD), and anxiety  disorders secondary to medical conditions or  substance-induced or not otherwise specified.   Appendicitis inflammation of the appendix as  a result of blockage of the opening from the  appendix into the cecum; the appendix wall  becomes infected and ruptures, allowing the  infection to spread throughout the abdomen  and cause pain, anorexia, fever, nausea, vomit-  ing, and diarrhea.   Apraxia a disorder of voluntary movement con-  sisting of impairment of the performance of  skilled or purposeful movements; results from  acquired cerebral disease.   Arcus senilis a gray to white ring at the periph-  ery of the cornea; caused by deposits of choles-  terol in the cornea or hyaline degeneration and  occurs primarily in older persons.   Arterial ischemic stroke (pediatric arterial  ischemic stroke) a rare disorder in children  resulting from embolism, arteriopathy, or,    rarely, sinovenous thrombosis and leading to a  decreased flow of blood and oxygen to areas of  the brain.   Asbestosis pulmonary inflammation and fibro-  sis resulting from inhalation of hydrous silicates  of various metals in fibrous form.   Aseptic meningitis a form of inflammation  of the meninges and subarachnoid space sur-  rounding the brain and spinal cord without  evidence of bacterial infection; may be associ-  ated with viral infection, systemic disease, or  drugs.   Aspiration pneumonitis a condition caused by  the abnormal entry of fluids, particulate mat-  ter, or secretions into the lower airways that  can lead to chemical pneumonitis from entry of  toxic material such as gastric acid, from bacte-  rial infection, or by mechanical obstruction of  the lower airways.   Asthma _ a chronic inflammatory disorder of the  airways involving bronchial hyperresponsive-  ness and airway obstruction marked by periodic  attacks of wheezing, shortness of breath, a tight  feeling in the chest, and a cough that produces  mucus because of an allergic reaction triggered  by certain drugs, irritants, viral infection, exer-  cise, or emotional stress.   Asymptomatic bacteriuria the presence of bac-  teria in the urine without evidence of infection.   Ataxic cerebral palsy a form of cerebral palsy  associated with damage to the cerebellum and  resulting in gait disturbances and instability;  at birth the infant may have hypotonia, but  develops stiffness of the trunk muscles later in  infancy.   Atelectasis a part of or an entire lung collapses  and the alveoli deflate as a result of surgery,  smoking, or blockage of a bronchiole.  Absorption atelectasis collapse of lung   tissue resulting from gradual absorption of  air from obstructed or hypoventilated alveoli  or from inhalation of concentrated oxygen or  anesthetic agents.   Compression atelectasis air pressure in  the pleural space pushes against the already  recoiled lung, causing compression atelectasis,  and against the mediastinum, compressing  and displacing the heart and great vessels.   Surfactant impairment decreased produc-  tion or inactivation of surfactant, which is  necessary to reduce surface tension in the  alveoli and causes lung collapse during expi-  ration; can occur because of premature birth,  acute respiratory distress syndrome, anesthe-  sia, or mechanical ventilation.   Atherosclerosis a type of arteriosclerosis in  which the inflammatory changes of thicken-  ing and hardening of the walls of large- and  medium-sized arteries are caused by an ath-  eroma or plaque of lipids, cells, and connective  tissue in the tunica intima.   Atopic dermatitis (AD) (allergic dermatitis) a  chronic hereditary skin disease character-  ized by intense itching and inflamed skin that  causes redness, swelling, cracking, crusting, and  scaling.    Atrial septal defect (ASD) a congenital heart  disease involving the interatrial septum of the  heart that separates the right and left atria,  which results in misdirected blood flow between  the two sides of the heart.   Atrioventricular canal (AVC) defect a large  hole is present in the center of the heart where  the wall between the atria joins the wall between  the ventricles, and the tricuspid and mitral  valves are formed into a single large valve that  crosses the defect.   Atypical hyperplasia increased number of cells  with some variation in cellular structure but  without sufficient qualitative or quantitative  features of carcinoma.   Autoimmune vascular purpura (allergic pur-  pura) purpura caused by antibody-mediated  injury of blood vessel walls, typically arterioles  and capillaries. The reaction is directed to for-  eign proteins or chemicals in the blood (micro-  organisms, drugs, or other chemicals) that  deposit on the vessel walls.   Autonomic hyperreflexia (dysreflexia) a syn-  drome resulting from afferent stimuli that cause  intense sympathetic discharge originating with  spinal cord injury above the major splanch-  nic outflow; characterized by hypertension,  bradycardia, sweating of the forehead, severe  headache, and piloerection on distention of the  bladder and rectum.   Autosomal dominant polycystic kidney disease  (ADPKD) a progressive disease characterized by  formation of multiple cysts of varying size scat-  tered diffusely throughout both kidneys, resulting  in compression and destruction of renal paren-  chyma, usually with hypertension, gross hematu-  ria, and uremia leading to progressive renal failure.   Azotemia kidney dysfunction characterized by  increased serum urea levels and frequently asso-  ciated with increased creatinine levels.   Bacterial pneumonia an acute or chronic  disease marked by inflammation of the lungs  caused by bacterial infection.   Bacterial tracheitis a condition in which the  larynx, trachea, and bronchi are inflamed and  present with signs similar to those of epiglotti-  tis and croup; may result in airway obstruction  secondary to subglottic edema or sloughing of  the epithelial lining or the mucopurulent mem-  brane within the trachea. 
PathophsysiologyTheBiologicBasisForDiseaseInAdultsAndChildrenSeventhEdition Pathophsysiology ,The Biologic Basis for Disease in Adults and Children, Seventh Edition_djvu.txt