• pathological — when cellular damage has occurred,  often at the nuclear level (i.e. DNA damage). Apo-  ptosis can, therefore, prevent the perpetuation of a  genetically abnormal cell.   A key point: apoptosis is an energy-dependent process  that does not result in an inflammatory response. This is  in contrast to necrosis, an energy-independent process  that can cause inflammation.   The execution of apoptosis is achieved by the activation  of a cascade of proteases known as caspases. Caspase-3  is thought to be a crucial final enzyme in this caspase  cascade, which can be initiated by two pathways  (Fig. 2.14):   1. The extrinsic pathway — external 'death receptors'  (e.g. TNF receptors) are activated by an appropriate  ligand.   2. The intrinsic pathway — proapoptotic molecules  are released from mitochondria after the breakdown  of normal anti-apoptotic signalling (e.g. Bcl-2).   Fig. 2.14 Initiation of apoptosis. The common caspase  cascade may be triggered by the extrinsic ('death receptor')  pathway or intrinsic (mitochondrial) pathway.    Examples of where this occurs include the loss of cel-  lular signalling and exposure to radiation or toxins.   The caspase cascade is the common result of both  pathways. Morphologically, an apoptotic cell is charac-  terized by:   • formation of apoptotic bodies with intact plasma  membrane and organelles. These are eventually  phagocytosed by adjacent cells.   A comparison of cell death by apoptosis and necrosis  is given in Fig. 2.15.   • Briefly describe the epidemiology of cancer in the UK and worldwide.   • Describe the role of protooncogenes and tumour suppressor genes in the development of cancers.   • Describe the process of tumour growth and angiogenesis, invasion and metastasis.   • Describe the role of chemicals, radiation and viruses as carcinogenic agents.   • Understand the importance of tumour markers, grading and staging in clinical cancer pathology.   A tumour can be defined as an abnormal mass of tissue  resulting from autonomous disordered growth that per-  sists after the initiating stimulus has been removed. A  tumour results from genetic alteration and deregulated  growth control mechanisms. There may be an inherited  predisposition to tumour development (e.g. breast and  ovarian cancer families), although this accounts for  only a small proportion of total tumours. Tumours are:   • progressive — they are independent of normal growth  control and continue to grow regardless of require-  ments and in the absence of any external stimuli   All tumours have the suffix ' — oma', which means a  swelling.   • anaplastic neoplasm — a very poorly differentiated  neoplasm. Anaplastic specimens highlight the typical  changes of a malignant neoplasm: pleomorphism    (variation in shape and size) of cells and nuclei, nu-  merous mitoses, abnormal nuclear morphology and  cellular disorganization (i.e. loss of cellular polarity).   Dysplasia is the disordered development of cells result-  ing in an alteration in their size, shape and organization.  It may be reversible but is also known to precede neo-  plasia. It is, therefore, referred to as a premalignant state  in certain circumstances.   Metaplasia is the change from one type of differentiated  tissue to another, usually in response to an irritating  stimulus, e.g. a change from mucus-secreting epithe-  lium to stratified squamous epithelium in the bronchial  irritation associated with cigarette smoking. Metaplasia  is reversible and often represents an adaptive response  to environmental stress.   This refers to an increase in the number of cells in a tis-  sue or organ, which may result in an increase in the  overall size. An example is the hyperplasia of breast tis-  sue during pregnancy.   Hypertrophy is an increase in tissue or organ size due to  an increase in the size of cells. Crucially, there is no in-  crease in the number of cells in the tissue. Cells that are    permanent (e.g. myocardial fibres) cannot divide and so  undergo hypertrophy to increase tissue size (e.g. left  ventricular hypertrophy as a response to hypertension).   In general, tissues capable of division can undergo  both hyperplasia and hypertrophy to increase tissue size.   Tumours are classified as either benign or malignant,  according to their appearance and behaviour (Fig. 3.1).  Benign tumours are usually well differentiated, localized  cancers that do not invade the surrounding tissues or  metastasize to other organs. Metastasis is the process  whereby malignant cells spread from their site of origin  (a primary tumour) to distant sites and grow into second-  ary tumours.   Malignant tumours are capable of invasion and spread  to distant organs. This distinction is crucial in the clinic  because metastatic disease is associated with significant  morbidity and mortality. Malignant neoplasms can show  a range of differentiations.   Tumour nomenclature (Fig. 3.2) is based on histologi-  cal and behaviour patterns. Histology provides informa-  tion about the type of cell from which the tumour has  arisen, whereas behaviour provides information as to  whether the cell is benign or malignant.   Note that invasion is the only absolute distinguishing  feature between benign and malignant neoplasms.   * Those tumours that are always malignant and do not  have benign counterparts.   Carcinomas are malignant tumours of epithelial tissue.  Carcinomas of non-glandular epithelium are prefixed  by the name of the epithelial cell type. Malignant tu-  mours of glandular epithelium are termed adeno-  carcinomas. Carcinomas can be further subclassified  according to their ability to invade or not, and    behavioural information can be gained from histologi-  cal grading of cellular differentiation.   Cervical intraepithelial neoplasia (CIN) is a  premalignant state that may exist for many years  before cervical cancer develops. CIN is categorized  according to the level of dysplasia seen in the  squamous epithelium of the cervical transformation  zone (the area examined on routine 'smear' screening).  Three grades are observed:   • CIN III — severely dysplasic (carcinoma in situ at high  risk of invasion).   This is an epithelial neoplasm with all the cellular fea-  tures associated with malignancy but which has not yet  invaded through the epithelial basement membrane.    The in-situ phase may not progress, or it may last for sev-  eral years before invasion commences.   This is an epithelial neoplasm that invades through the  basement membrane. The tumour gains access to the  vascular supply and lymphatics, and will often metasta-  size to distant tissues.   As a cause of mortality in the UK, cancer is the second  biggest killer (after cardiovascular disease). Its incidence  (Fig. 3.3) is as follows:   • Almost 1 in 3 of the population will develop cancer  during their lifetime.   • Almost 1 in 4 of the population will die of cancer.   The incidence of different cancers varies from country to  country. This variation provides clues to the causes of  the cancers. For example, in Japan, gastric carcinoma  is 30 times more common than in the UK, whereas pan-  creatic cancer is much rarer. I lowever, migration of a    Fig. 3.3 Incidence of the ten most common cancers of (A) men and (B) women in the UK. The data exclude non-melanoma skin  cancers (e.g. basal cell carcinoma) because, although common, they are rarely fatal. Data from Cancer Research UK, 2003.  (Adapted from Underwood, 2009.)    subset of the Japanese population to different geograph-  ical areas (e.g. USA, UK) alters the incidences of these  diseases within that population. These findings suggest  that environmental factors (such as diet and occupa-  tional, social and geographic effects) rather than genetic  causes account for most of the observed differences  between countries.   Cell proliferation and division is usually tightly regu-  lated by two sets of opposing functioning genes:   Abnormal activation of proto-oncogenes and loss of  function of TSGs lead to the transformation of a normal  cell into a cancer cell.   Proto-oncogenes are genes that are expressed in normal  cells. They code for oncoproteins, which positively  regulate cell growth and differentiation (growth factors,  transcription factors and receptor molecules). In  healthy cells, the transcription of these genes is tightly  controlled. Inappropriate expression of oncoproteins  leads to abnormal cell growth and survival. Normally  functioning proto-oncogenes can be activated into  cancer-causing oncogenes in two ways:   • A mutation can produce an oncoprotein that is  functionally altered and abnormally active. For  example, intracellular signalling is affected by the  hyperactive mutant ras protein.   • A normal oncoprotein can be produced in abnor-  mally large quantities because of enhanced gene  amplification (e.g. the myc oncogene in neuroblasto-  mas) or enhanced transcription (formation of the  Philadelphia chromosome from a translocation  between chromosomes 9 and 22).   Oncogenes can be classified according to the func-  tion of their product. Oncogenes include genes that  express:   • receptors for growth factors, e.g. c-erb B-2/HER-2,  which is related to epidermal growth factor receptor    Expression of abnormal oncogene products corre-  sponds to the behaviour and appearance of transformed  cells. These include:   Tumour suppressor genes (TSGs) (e.g. p53 and RBI) en-  code proteins that prevent or suppress the growth of  tumours. Inactivation of TSGs results in increased suscep-  tibility to cancer formation. Genetically increased suscepti-  bility to cancer formation was first proposed by Knudson,  who studied the childhood retinal cancer retinoblastoma.   Retinoblastoma is a rare malignant tumour of the  retina. In familial cases (bilateral), a germline mutation  in the RBI gene is present, meaning that only one  further somatic mutation is required for tumour  formation. Other cases of retinoblastoma are unilateral  and sporadic, needing two somatic mutations on an  initially fully functioning RBI gene. This requirement  for separate mutations in both alleles of a TSG has been  termed the 'two-hit' hypothesis of oncogenesis.   • BRCA1 — implicated in breast and ovarian cancer  and located on chromosome 17q   • Binding of normal TSG protein to proteins encoded by  viral genes, e.g. human papillomavirus proteins E6/E7   • Complexing of normal TSG protein to mutant TSG  protein in heterozygous cells.    TSGs function by maintaining the integrity of the  genome through cell-cycle arrest in abnormally dividing  cells and repair of DNA damage. They also function to  promote cell suicide or apoptosis (see Chapter 2) in  cells with sustained DNA damage.   One of the most studied TSGs is the p53 gene, which  is located at 17p; it is called 'the guardian of the ge-  nome'. p53 is mutated or functionally altered in over  50% of all human cancers. In addition, a familial inher-  ited mutation is found in Li-Fraumeni's syndrome, in  which there is an increased predisposition to several  tumour types.   p53 can recognize damaged DNA and responds  either through cell-cycle growth arrest at the Gi check  point or through the initiation of apoptosis. For exam-  ple, the p53 protein product recognizes DNA damage  caused by ultraviolet (UV) irradiation and activates  apoptotic cell death pathways before the cell can div-  ide and proliferate (Fig. 3.4).   Genes and proteins involved in the process of apo-  ptosis include the death receptor and ligand families,  cell-cycle-related genes, the Bcl-2 family, the caspase  family and the caspase substrates.   Cellular proliferation is tightly regulated by two sets of  opposing functioning genes. Proto-oncogenes are    Fig. 3.4 Role of p53 in cells with damaged DNA. Cells either  undergo G-, arrest and DNA repair, or cell death by apoptosis.  (Adapted from Underwood, 2009.)    growth-promoting genes whereas tumour suppressor  genes are growth-suppressing genes. Deregulated  function of proto-oncogenes and tumour suppressor  genes leads to cell transformation and tumourigenesis.   Tumourigenesis is a multistage process that results from  accumulated mutation. Tumours arise from single cells,  which proliferate to form a clone of cells with identical  abnormalities. As tumours develop, they undergo fur-  ther somatic mutations, which cause abnormalities in  other oncogenes and/or tumour suppressor genes.  These additional mutations result in cells that are genet-  ically different from each other but which are part of the  same tumour: this is heterogeneity.   Fast-growing, less-differentiated cells take over and  eliminate the slower-growing, better-differentiated cells.   Chemotherapy will kill the majority of tumour cells.  However, tumour cells that are resistant to chemother-  apy will survive and be selected for (because of ablation  of competing, non-resistant cells), resulting in the  regrowth of a tumour that is resistant to chemotherapy  (Fig. 3.5). This highlights the concept of 'minimal resid-  ual disease', i.e. the small number of tumour cells that  survive an intervention such as chemotherapy.   The progressive nature of tumourigenesis is clearly  illustrated in Vogelstein's model of the development of  colonic cancer. The accumulation over time of mutations  in oncogenes such as Ki-ras, and loss of function muta-  tions in tumour suppressor genes such as APC, results  in the eventual formation of colon carcinoma (Fig. 3.6).   Angiogenesis is the formation of new blood vessels and  is an important physiological process in normal em-  bryogenesis, the female reproductive cycle and wound  healing. However, pathological angiogenesis is a key  player in many disorders, including cancer. This is  because a solid tumour cannot grow beyond a few  millimeters in diameter without a blood supply to  maintain nutrient and oxygen provision and remove  metabolic waste.   In normal cells, angiogenesis is a highly regulated  mechanism. In contrast, tumour cells can release pro-  angiogenic factors, which induce vascular proliferation.   tumour arises from single cell  which proliferates to form a clone  of cells with identical abnormalities    cells are genetically  different from each other, but are  part of the same tumour —  this is heterogeneity   fast-growing, less  differentiated cells  take over and  eliminate the slower-  growing, better  differentiated cells   however, tumour cells  resistant to  chemotherapy  will survive and are  selected for, resulting  in re -growth of a  tumour resistant to  chemotherapy   Fig. 3.6 Multistep development of colonic cancer. The accumulation of genetic mutations corresponds to the altered behaviour of  the tumour cells. (APC, adenomatous polyposis coli; MCC, mutated in colorectal cancer.) (Adapted from Underwood, 2009.)    This is sometimes called the angiogenic switch. The  angiogenic switch results in the production of pro-  angiogenic molecules such as vascular endothelial  growth factor.   Eventually, the tumour outgrows its blood supply  and areas of necrosis may appear, resulting in slower  growth but a more malignant phenotype (Fig. 3.7). This  is because only the strongest cells survive the hypoxic  conditions.   The ability to invade is the only absolute criterion for  malignancy. Invading malignant cells have the follow-  ing properties:    Fig. 3.7 Kinetics of tumour growth and angiogenesis. (A)  Transformed cell. (B) Avascular tumour nodule. (C) Vascularized  tumour. (D) Vascularized tumour with central necrosis. (TAF,  tumour angiogenic factors.) (Adapted from Underwood, 2009.)   Metalloproteinases, such as collagenases and gelati-  nases, are the most important enzymes in neoplastic  invasion. They digest the surrounding connective tissue,  thus aiding invasion.   In metastatic cancer, the total mass of secondary tu-  mours usually exceeds that of the primary lesion. How-  ever, only a proportion of neoplastic cells in a malignant  tumour are able to metastasize.   It can be impossible to find the primary lesion in  some cancer patients who present with extensive sec-  ondary metastases.   To metastasize through vessels, neoplastic cells un-  dergo the following sequence of events:   • Invasion of the tissue basement membrane and then  surrounding connective tissue   • Evasion of the host's defence mechanisms, often by  forming a tumour cell embolus with platelets or host  lymphoid cells    • Extravasation of cells from vessel lumen into sur-  rounding tissue.   Following extravasation, the malignant cells prolifer-  ate and secrete more angiogenic growth factors for vas-  cularization. Hence a new tumour is formed. However,  not all cancer cells will grow at all distant sites. This is  the seed and soil effect: conditions must be appropriate  for cell proliferation.   1. Local invasion — most common pattern of spread of  malignant tumours is by direct growth into adjacent  tissues.   3. Blood-borne (haematogenous) spread — cells enter  the bloodstream and form secondary tumours in  organs perfused by blood that has drained from a  tumour.   It is clinically important to know the major tumours that  spread to bone via the blood. These are cancers of the  bronchus, breast, thyroid, kidney and prostate. Bone  metastases can be evaluated using radionucleotide  bone scanning, except in myeloma, where a skeletal  survey is needed.   Fig. 3.8 Routes of metastasis exemplified by a carcinoma of  the bowel, i.e. via the bloodstream, via the lymphatic spread,  through peritoneal cavities and via local invasion.    Carcinogens are substances known to cause an in-  creased incidence of cancer.   Carcinogens can exert their effect either by genetic  mechanisms (i.e. causing DNA alteration; this is the  majority of carcinogens) or epigenetic mechanisms  (i.e. acting on the protein product of growth-regulating  genes).   Most chemical carcinogens are procarcinogens and re-  quire metabolic conversion into an active form (ulti-  mate carcinogens), usually by the cytochrome P450  system, which shows significant variability in activity  (gene polymorphisms) between individuals. Some peo-  ple are therefore inherently more susceptible to produc-  ing ultimate carcinogens.   Some carcinogens act directly to induce cellular dam-  age. Examples of chemical carcinogens are given in  Fig. 3.9.   based on observations of the effects of chemical carcin-  ogens on laboratory animals. This model proposes three   2. Promotion — a stimulus for proliferation of the ini-  tiated cell; this may be an external agent or a further  random mutational genetic abnormality.   3. Persistence — when proliferation of tumour cells be-  comes autonomous, i.e. it no longer requires the  presence of initiators or promoters.   The stages of chemical carcinogenesis are: initiation,  promotion and persistence. The classic examples of  initiation and promotion are the effects of  methylcholanthrene and croton oil, discovered from  experiments in mice. Remember that as humans are  likely to be simultaneously exposed to initiators and  promoters, chemical carcinogenesis is probably very  complex.   1. Directly — causing strand breaks, base alterations  and cross-linking of DNA.   2. Indirectly — ionization of FI 2 0 with formation of  reactive oxygen free radicals, which interact with  and damage DNA.   UV radiation is associated with many different kinds of  skin cancer, particularly:   Skin cancer is the most common type of cancer in the  UK and USA. It is more common in fair-skinned  individuals.   UV light is thought to induce the formation of link-  ages between pyrimidine bases on the DNA molecule.    Fig. 3.10 Stages of chemical carcinogenesis. (A) Initiation: induction of genetic changes in cells that result in neoplastic potential.  (B) Promotion: induction of cellular proliferation in the initiated cell. (C) Persistence: proliferating tumour cells no longer require the  presence of initiators or promoters. Tumour cells exhibit autonomous growth.    The risk is greatly increased in patients with xeroderma  pigmentosum, a rare, autosomal recessive disease char-  acterized by deficiency of DNA repair enzymes.   Radiotherapy can cause cancer as well as curing it! It is  associated with radiation-induced malignant neo-  plasms, often sarcomas. These tumours may occur  months or years after radiation therapy, in the lungs,  CNS, bones, kidneys and liver.   Radioactive iodine, which is used to treat thyroid dis-  ease, is associated with an increased risk of cancer devel-  opment as much as 15-25 years after treatment.   Survivors of the Hiroshima and Nagasaki atomic  bombs, and of the accident at the Chernobyl nuclear  power plant, have shown a greatly increased incidence  of cancer, including leukaemia and carcinoma of the  breast, lung and thyroid.   DNA is the cellular constituent most sensitive to radia-  tion. Fortunately, cells have DNA repair genes (e.g.  MSH2 ) that deal with DNA damage. Repair occurs  rapidly in the vast majority of cases but damage is some-  times irreparable and major chromosomal and chroma-  tid alterations occur. If such cells also evade cell-cycle  arrest and apoptosis, a tumour may develop.   Repair of single-stranded breaks, particularly in rap-  idly dividing cells, is error prone and introduces single-  base mutations.    Double-stranded cleavage leads to chromosome  breakage. Attempts to repair multiple breaks result in  inappropriate recombination events, e.g. translocation  or interstitial deletion.   An excellent example of failed DNA repair mechanisms  is the autosomal dominant condition hereditary non-  polyposis colon cancer (HNPCC; discussed in  Chapter 8). A DNA repair gene (e.g. MSH2, MLH1) is  inactivated, resulting in failed mismatch repair and  predisposition to multiple somatic mutations.   Certain DNA viruses and retroviruses (Fig. 3.11) can  cause neoplasia, as follows:   • Retroviruses have reverse transcriptase enzyme to  produce a DNA copy of viral RNA. The DNA copy  is then inserted into the host genome.   Inserted viral genes may be viral oncogenes themselves  (v-onc), expression of which may lead to uncontrolled  proliferation, or they may be activators or repressors  of important cell-cycle regulating genes.   The mechanism of viral carcinogenesis is understood  best in one of the most studied tumour viruses, the hu-  man papilloma virus. This double-stranded DNA virus  has a tropism for squamous epithelium and subtypes    1 6 and 1 8 are implicated in cervical carcinoma. The viral  genome incorporates into the host DNA and expresses  the E6 oncoprotein, which inactivates the tumour sup-  pressor protein p53. In addition expression of the E7  oncoprotein inactivates the tumour suppressor protein  RBI. These oncoproteins, together with other factors,  result in cervical intraepithelial neoplasia (CIN).    Some tumours are known to stimulate both innate (pas-  sive) and adaptive (active) immunological reactions in  the host.   Activation of macrophages and natural killer cells can  prevent growth of some tumours in vitro. Some tu-  mours activate complement via the alternative pathway.   Antibodies may have a protective role, through com-  plement activation or opsonization of tumour cells  for cell-mediated destruction. They are more likely to be  effective against free cells (e.g. leukaemia or metasta-  sizing tumours) than those in solid lumps.   Cell-mediated immunity is involved in recognition and  monitoring of cells progressing towards malignancy.  Therefore, cells that become significantly different to    be recognized as 'foreign' may be eliminated by the im-  mune system. This is particularly true of those tumours  with a suspected viral aetiology.   The importance of immune surveillance in the  prevention of cancer is clearly illustrated in immuno-  compromized patients. For example, lymphomas asso-  ciated with Epstein-Barr virus can present 4-7 years  post-immunosuppressive therapy following organ  transplant.   Cytotoxic T cells are thought to play a role in tumour  regression, particularly in virus-associated neoplasms.  Infiltration of some tumours by lymphocytes and mac-  rophages is associated with better prognosis.   Although many immune mechanisms are known to  be active against tumour cells, most tumours are not dis-  tinguishable from normal host cells and so are not easily  detected by the immune system. Additionally, tumour  cells develop mechanisms to evade the immune system.  These are thought to include reducing the expression of  the surface major histocompatibility complex (MHC),  antigen masking and actually suppressing the host im-  mune system through cytokine release or apoptosis  stimulation.    Tumour markers are increasingly being used for prognostic  and management decision processes. These are products  derived from the tumour that can be found in the blood  and used for diagnosis, assessing response to treatment  and detecting recurrence. Examples include the CA125  ovarian tumour marker, the prostate-specific antigen  (PSA) marker in prostate carcinoma and the a-fetoprotein  in hepatocellular carcinoma and testicular teratoma.   Pathology reports of resected tumours contain  macroscopic and microscopic descriptions that give  information about the size and type of a cancer, local  invasion and lymph node metastasis.   The grade of a tumour is based on morphological study  (proliferation, differentiation, pleomorphism) and indi-  cates tumour differentiation. Staging is used to determine  how advanced a tumour is. For example, colorectal  tumours can be staged by the Dukes classification  (A-C/D). The TNM (tumour size, lymph node spread,  metastasis formation) system is used to stage many  tumours.   • Outline the categories of infectious agents, their key features and main differences.   • Describe host defences against infection and how microorganisms attempt to evade them.   • Describe the mechanisms of viral and bacterial pathogenicity, and the immune responses of the host.   • Understand the importance of hospital-acquired infection and the pathogens responsible.   Infectious diseases are a common cause of morbidity  and mortality. The prevalence of infectious diseases  varies considerably between developed and develop-  ing nations. The burden of specific diseases depends  on the quality of the drinking water, sanitation, health-  care system and the prevailing social and climatic  conditions.   Infection is the invasion and proliferation of micro-  organisms in the tissues of the body. This usually fol-  lows the successful breach of host barriers and  immune defence mechanisms.   Following invasion, infective organisms can spread  to distant tissue sites by:   Colonization is the inhabitation of the external body  surfaces — the skin, gastrointestinal (GI) tract, external  genitalia and vagina — usually by harmless microorgan-  isms. This generally occurs soon after birth.   Pathogens are microorganisms that are normally absent  from the body but which have mechanisms to invade  and cause infection. Commensals are those micro-  organisms that constitute the normal flora of a healthy  body. They do not normally cause disease and they are  often advantageous to the host by the production of nu-  trients, such as vitamin B 12 , and by the exclusion of  harmful bacteria. For example, the normal commensal  flora of the skin prevents colonization by pathogenic  bacteria.   The distinction between commensals and pathogens is  not absolute. Many commensals are potential  pathogens, i.e. they are harmless only so long as they  are kept at bay by the host's defence mechanisms.   Pathogenicity is the capacity of a particular micro-  organism to cause disease.   Virulence is a measure of the pathogenicity of a micro-  organism, which can be said to be highly virulent if a  small number of microbes can cause severe disease.   Opportunistic infection is an infection by organisms of  low pathogenicity, usually due to impaired immune re-  sponses. Opportunistic infections are common in immu-  nocompromized patients, such as those with a primary  or second immunodeficiency. Examples include:   • children with severe combined immunodeficiency  (SCID), a rare group of inherited syndromes (often  X-linked) that require bone marrow transplantation  to prevent death in early infancy   • patients infected with human immunodeficiency  virus (HIV), which results in the destruction of  CD4+T cells   Deficiency of specific immune defences predisposes  individuals to characteristic patterns of infection. For  example the T -cell-deficient disease, DiGeorge  syndrome, results in chronic viral, fungal and  intracellular bacterial infections. This syndrome occurs  due to the lack of development of the thymus and  parathyroid glands.    There are numerous different categories of infectious  agent. The classification of the major pathogens is  shown in Fig. 4. 1 .   derived from host cell membrane  (surface, internal, nuclear)  with inserted glycoproteins   Viruses carry nucleic acids but lack synthetic machin-  ery. They can therefore replicate only within the  host cell, i.e. they are obligate intracellular parasites  (Fig. 4.2).   • They consist of a nucleic acid core and protein coat  (capsid), which together constitute the nucleocapsid.   • Some, but not all, viruses are enveloped by a mem-  brane of host-cell origin.   • Classification is usually based on type of nucleic acid  (Fig. 4.3).   Utilize host cell polymerases for mRNA synthesis  Can remain in infected cell and establish  persistent infections (latent, immortalizing viruses)   Encode their own replicative enzymes for formation of more mRNA  (Host enzymes cannot replicate RNA)   Contain 'reverse transcriptase' enzyme for production of viral mRNA  Viral DNA is inserted into host genome   • direct cytopathic effect — viral replication within  cells leads to degenerative changes, including cell  lysis, e.g. respiratory epithelial cells infected with  influenza virus   • induction of an immune response — stimulated by  viral proteins on the surface of host cells   • incorporation of viral genes into the host genome —  often inducing cellular death by apoptosis, e.g. HIV   • cellular transformation — some viruses can cause cel-  lular proliferation and transformation to produce  cancers, e.g. Epstein-Barr virus, human papilloma-  virus (see Chapter 3).   Therefore, the harmful effects of viral infections in-  clude cell death, acute and chronic tissue damage, trig-  gering of an autoimmune response and transformation  of cells to form tumours.   • Detection of host-produced antiviral antibodies by  enzyme-linked immunosorbent assay (ELISA)   • Detection of viral nucleic acid by polymerase chain  reaction (PCR).   Bacteria are prokaryotes with a single circular DNA  chromosome. Bacteria are divided into two broad  groups — Gram-positive and Gram-negative — based on    their reaction to the Gram stain (a staining procedure  used with light microscopy).   Gram staining is a key microbiological test. Crystal  violet and iodine are used to stain the bacterial cell wall.  Gram-positive bacteria (lots of cell wall peptidoglycan)  retain these components on challenge with acetone,  and so stain purple. Gram-negative bacteria (little  peptidoglycan) lose the iodine and crystal violet  colouring with the addition of acetone, instead staining  pink from the use of safranin counterstain.   Not all bacteria stain using the Gram method, e.g.  Mycobacterium tuberculosis requires a special staining  technique known as Ziehl-Neelsen.   Further classification is based on practical character-  istics, i.e. size, shape, respiration and reproduction. Bio-  chemical and immunological measures can provide  further information. For example, Gram-positive cocci  can be distinguished by testing for the production of  the catalase enzyme; Staphylococcus species produce cat-  alase whereas Streptococcus species do not.   A generalized structure of a bacterium is shown in  Figure 4.4 and an example of the characteristics used  to classify bacteria is shown in Figure 4.5.   The pathogenic effects of bacteria are the results of  the release of endotoxins and exo toxins. These produce  acute and chronic inflammation and tissue damage.   Bacterial infections can be diagnosed from a number  of different samples obtained from the patient. These  include blood, faeces, urine, cerebral spinal fluid and  swabs taken from infected wounds. Samples will    generally be cultured to determine the species of bacte-  ria and their sensitivity to different antibiotics.   Fungi are unicellular, multicellular or multinucleate or-  ganisms (Fig. 4.6). They are eukaryotes and contain  ergosterol instead of cholesterol in their plasma  membranes.   Fungi have a well-defined cell wall composed of  polysaccharides and chitin; they can be moulds, yeasts  or dimorphic.   Fungal infections are either superficial (e.g. involving  the skin, hair, nails and mucous membranes) or sys-  temic (e.g. involving the lungs, brain or heart); the latter  are usually found only in the immunocompromized.  Such opportunistic fungi include Aspergillus, Candida  and Cryptococcus.   Some fungi produce toxins termed mycotoxins. For  example, Aspergillus flavus proliferates on food stored  in humid conditions and produces aflatoxins, which are  highly carcinogenic mycotoxins. Ingestion of food  contaminated with aflatoxins causes an increased risk  of hepatocellular carcinoma in humans, particularly  where there is underlying hepatitis B infection.   Protozoa are unicellular eukaryotes that may develop  into cysts in harsh environmental conditions. The main  divisions of protozoa are shown in Figure 4.7. Protozoa  species may be capable of replicating intracellularly or  extracellularly. The most important protozoal disease  worldwide is malaria, which is caused by the Plasmo-  dium species.   Identification of protozoa often occurs by micros-  copy of patient specimens. Specimens include faeces,  blood and tissue. Culture methods are not routinely  applied for identification purposes.   Helminths are a group of parasitic worms, as shown in  Figure 4.8. Ectoparasites (e.g. bed bugs, crab louse, fleas,  etc.) are parasites that live on the outer surfaces of the  host.   Microscopy of patient specimens (faeces, blood,  tissue) allows the identification of most helminths  and ectoparasites.   Fig. 4.5 The characteristics used to classify bacteria, using Gram-positive bacteria as an example.   Chlamydiae and Rickettsiae are obligate intracellular or-  ganisms. Chlamydia replicates within vacuoles formed  inside epithelial cells. Chlamydia trachomatis is an im-  portant cause of female infertility (scarring of fallopian  tubes) and preventable blindness (corneal scarring and  opacification) .    Rickettsiae are transmitted by arthropod vectors (e.g.  lice, ticks, mites) and replicate in the cytoplasm of epi-  thelial cells to produce injury (usually a haemorrhagic  vasculitis).   Mycoplasma lack cell walls and are the smallest free-  living organisms known to man (typically 125-  300 nm). They can be transmitted between people by  aerosol to produce an atypical pneumonia.   resistant cuticle;  longitudinal muscles;  complete digestive system;  separate sexed reproductive  system,   cellular epithelium;  no digestive system;  all hermaphrodites,  e.g. Taenia solium,  Echinococcus granulosus   cellular epithelium;  circular and longitudinal  muscles; incomplete  digestive system;  mostly hermaphrodites,  e.g. Schistosoma   Prions are an abnormal isoform of a normal host protein  (the prion protein; PrP). Prions are not microorganisms  but are infectious proteins that are highly resistant to de-  contamination methods, such as standard autoclaving or  disinfectants. Humans express normal prion proteins but  their function is unknown. Inoculation of an abnormal  prion protein into a normal host induces conformational  changes in the normal host prions, resulting in their con-  version to abnormal host prions. Disease occurs when  the abnormal prion protein is resistant to protease break-  down where the original protein was protease sensitive.   Thus, the original inoculated prion protein is able to  catalyse a chain reaction in which host proteins become  conformationally abnormal.   The net result is the formation of amyloid plaques of  prion protein in the CNS. These plaques result in vacu-  olar spongiform degeneration of neuronal processes  with neuronal loss and glial proliferation.   In humans, several forms of prion protein disease  exist — including kuru and Creutzfeldt- Jakob disease  (CJD), both of which are always fatal, usually within  6 months. Since the 1990s, an emerging variant (vCJD)  has occured in people under the age of 50. The consum-  ption of offal contaminated with bovine spongiform en-  cephalopathy (BSE) prions has been proven in its aetiology.   Infective agents include bacteria, viruses, fungi,  parasites and prions. Remember, prions are not  infective organisms.   The majority of infectious agents encountered by an in-  dividual are prevented from entering the body by a  variety of biochemical and physical barriers (Fig. 4.9).  For example, anatomical barriers such as the skin,  mucous membranes, GI tract and genitourinary tract  provide a physical environment of unfavourable growth  conditions for bacteria.   Further host defence is provided by the innate and  adaptive immune mechanisms. Innate immunity con-  sists of non-specific mechanisms that contribute to  resistance and recovery from infection. Innate immunity  includes soluble proteins (complement, acute-phase pro-  teins), immune cells [macrophages, neutrophils, natural  killer (NK) cells] and receptors (Toll-like receptors).  Adaptive immunity is specific and includes cellular im-  munity (cytotoxic and helper T cells) and humoral im-  munity (B cells). Adaptive immunity is characterized  by antigen specificity and clonal proliferation. In addi-  tion, the generation of immunological memory initiates  a heightened response to subsequent antigen exposure.   However, despite these defences, pathogenic micro-  organisms possess efficient mechanisms for attaching  to, and often penetrating, the body surfaces where they  proliferate and disseminate. If they are to be transmitted  to a fresh host, the microorganisms must also exit from  the body.   The different routes of entry and exit of micro-  organisms are outlined in Figure 4.10.   1 . DNA viruses have their own DNA and use the host's  cellular machinery to make more DNA, protein and  glycoprotein. These are then reassembled into new  virus particles prior to release from the cell.   2 . RNA retroviruses first make viral DNA using the viral  reverse transcriptase enzyme. Viral DNA is then  inserted into the host genome prior to its transcrip-  tion to form messenger RNA (mRNA). Viral RNA is  in turn translated into viral protein, which is    packaged together with the RNA into new virus par-  ticles and released.   Non-enveloped viruses (e.g. adenoviruses) are released  directly into the extracellular environment by lysis of  the host cell; their mode of release results in the death  of the cell.   Enveloped viruses (e.g. HIV and herpesvirus) are re-  leased by 'budding' from the host cell membrane:   • A modified area of host cell membrane extends out  from the cell surface and is pinched off (i.e. budded)  from the host cell enclosing the new viral particle.   This mechanism does not cause the death of the cell,  and so viral replication can continue.   • Virally infected cells express viral peptides bound to  major histocompatibility complex (MHC) class I on  their cell surfaces.   • Cytotoxic T cells (T c ) recognize viral antigen via the  T-cell receptor.   • T c cells secrete cytolysins, which results in the lysis of  the virally infected cells.   NK cells can do the same, but less effectively. The  activity of these cells is enhanced by interferons produced  byT c and helperT cells (T H ). Interferons also prevent ad-  jacent cells from becoming infected by intercellular viral  transport.   It is worth noting that as well as spreading infection,  immune responses can lead to tissue injury. For exam-  ple, the liver damage following hepatitis B infection is  largely mediated by the strong immune response of  T c cells towards infected hepatocytes.   Certain bacteria are able to adhere specifically to epithe-  lial cells by means of pili (also called fimbriae), which are  slender filamentous processes on the surfaces of some  bacteria. Pili are coated with recognition molecules  called adhesins. Specific interactions between adhesins  of pili and molecules on the surface epithelial cells en-  able the bacterium to adhere to the host cell membranes.  Polymorphisms in host cell-surface glycoproteins may   Fig. 4.11 Viral replication cycles. (A) DNA virus: DNA viruses have their own DNA. The viruses use the host's cellular machinery to  make more DNA, protein and glycoprotein. These are then reassembled into new virus particles prior to release from the cell.   (B) RNA retrovirus: RNA retroviruses first make viral DNA using viral ‘reverse transcriptase'. Viral DNA is then inserted into the host  genome prior to its transcription to form mRNA. Viral RNA is in turn translated into viral protein, which is packaged together  with the RNA into new virus particles and released.    make an individual more susceptible to binding by cer-  tain types of bacterial adhesins.   Pili are more common in Gram-negative bacteria, al-  though a few Gram-positive bacteria also possess them.  Lipoteichoic acids (Gram-positive bacteria only) can  function in a similar manner to pili by binding to fibro-  nectin and epithelial cells.   Toxins are responsible for many of the local and distant  effects of bacterial infection.   Exotoxins are proteins secreted by bacteria which are  highly toxic to the host. The modes of action of some  exotoxins are considered below:   • Pore forming — a-toxin of Staphylococcus aureus  disrupts host cell membrane by pore formation   • Affecting synaptic transmission at neuromuscular  junctions, e.g. tetanus and botulinum toxins.  Treating exotoxin with formaldehyde or high tem-  peratures can denature the toxin to form toxoids, which  can be useful for vaccination.   Endotoxins are integral parts of bacterial cell walls, nor-  mally released only when the bacterium dies. They are  typically lipopolysaccharides contained within the cell  walls of Gram-negative bacteria. (But note that an ex-  ception is the 'superantigen' endotoxin TSST1, which  is produced by the Gram-positive Staphylococcus aureus  and causes toxic shock syndrome.)   These endotoxins are not in themselves toxic but can  induce toxic effects by their potent activation of:   • cytokines, notably tumour necrosis factor and  interleukin- 1 released from leucocytes, causing  fever.   In overwhelming infections, the patient is said to suf-  fer from endotoxic shock with fever, hypotension and  cardiac and renal failure.   Aggressins are bacterially produced enzymes that act pre-  dominantly in the local tissue environment. They include  enzymes such as coagulase, streptokinase and collage-  nases. Aggressins facilitate the growth and proliferation  of the bacteria.   • Preventing phagocyte contact — some bacteria have  an external capsule of polysaccharide, which gives  a slimy surface and provides protection against  phagocytosis, e.g. Streptococcus pneumoniae.   • Protection against intracellular death — this allows  the microorganism to survive within the phagocyte  by, for example, inhibition of phagosome and lyso-  some fusion (Mycobacterium tuberculosis) or escaping  from the phagolysosome into cytoplasm (Listeria  monocytogenes).   Many bacteria are resistant to antibiotics. Resistance is  conferred by genes that encode bacterial enzymes that  block the effect of an antibiotic. These genes are not usu-  ally contained within the bacterial genome, but rather  within extrachromosomal DNA termed 'plasmids'.  These plasmids are capable of self-replication and can  be transferred from bacterium to bacterium.   Antibiotic-susceptible bacteria (those lacking plas-  mids conferring antibiotic resistance) can acquire plas-  mids from resistant bacteria and so gain antibiotic  resistance. These newly resistant forms are then differen-  tially selected under antibiotic treatment, with the non-  resistant bacteria being deleted from the population.   Resistance to antibiotics can be transferred between  bacteria by any of the methods of bacterial genetic  recombination i.e. conjugation, transduction and  transformation.   Hospital-acquired infection (nosocomial infection)  occurs in up to 10% of uninfected admitted patients.  It is thought to be the direct cause of 5000 deaths per  year in the UK and it contributes to a further 15 000  deaths. Common pathogens include Streptococcus pyo-  genes, Staphylococcus aureus, Escherichia coli and Pseudo-  monas aeruginosa. Common sites of nosocomial  infections include the:   • blood (bacteraemia) — either by direct introduction  such as through a venous catheter (primary), or by  spread from another site such as a urinary tract infec-  tion (secondary).   Such infections can delay recovery, increase complica-  tion rates and ultimately result in the death of a patient.  Of particular concern is the emergence of multi-drug-  resistant infections that do not respond to traditional  broad-spectrum antibiotics. Important examples in-  clude methicillin-resistant Staphylococcus aureus (MRSA)  and vancomycin-resistant enterococci (VRE).   Although measures should be put in place to reduce  levels of nosocomial infection, it is important to re-  member that many hospital patients are at inherently  high risk of developing an infection in hospital regard-  less of these measures.   Important measures to reduce levels of hospital  acquired infection include hand-washing (staff and  visitors), minimizing the length of preoperative hospital  stays, careful use of prophylactic antibodies before  certain procedures, isolating infected patients in  side-rooms and using barrier-nursing techniques.    Sepsis is defined as the association of systemic inflam-  matory responses with evidence of a microbial origin.  In the absence of infection this is known as systemic  inflammatory response syndrome (SIRS). There are  abnormal clinical physiological variables such as pulse  rate, body temperature, hypotension, abnormal leuco-  cyte count, and - critically - response to restorative  measures and fluid administration. The source of the in-  fection may be organ-specific (e.g. lung in pneumonia, or  abdomen in peritonitis), but often there is only blood  stream infection - bacteraemia. The diagnosis is often  presumptive because blood and other site microbiologi-  cal cultures may be negative, partly from previous anti-  biotic administration.   A key concept in sepsis is the host response with pro-  duction of cytokines (see Chapter 2). Some patients  over-react to a standard infection stress and may suffer  severe sepsis.   Early antibiotic treatment and supportive care are  the mainstays of management. In the example of me-  ningococcal sepsis ( Neisseeria meningitidis), the mo-  ment it is suspected from the clinical status of the  patient and the haemorrhagic skin rash, antibiotics  are given and the microbiological investigations  follow later.   This is characterized by the production of pus, such as in  a boil or abscess, which is usually caused by infection  with pyogenic bacteria (e.g. Staphylococcus aureus,  Streptococcus pyogenes).   This is caused by persisting reactions of tissue to injury  and it occurs over weeks, months or even years. The cell-  mediated immune response is characterized by lympho-  cytes, plasma cells and macrophages.   Examples include hepatitis B viral infection, which  may lead to liver cirrhosis.   This is a form of chronic inflammation in which mod-  ified macrophages — epithelioid cells — aggregate to  form small clusters or granulomas surrounded by lym-  phoid cells. It occurs in response to the presence of  microorganisms within macrophages that are resistant  to intracellular cell killing (e.g. Mycobacterium  tuberculosis ).   In gangrene, necrotic tissue is invaded by putrefactive  organisms, notably clostridia. Tissue appears green or  black because of the breakdown of haemoglobin.   • Describe common pathological presentations in the central nervous system (CNS).   • Describe congenital malformations, developmental diseases and perinatal injury of the CNS.   • Recall traumatic injuries to the CNS and describe their effects.   • Briefly describe the effect of metabolic disorders and toxins on the CNS.   • Recall the neoplasms that affect the central and peripheral nervous systems, briefly describing them.   • Give examples of peripheral neuropathies of hereditary, traumatic, inflammatory, infectious, metabolic  and toxic origin.   Intracranial herniation is the movement of part of the  brain from one space to another with resultant damage.  It usually occurs following a critical increase in intra-  cranial pressure caused by an expanding lesion, e.g.  tumour or haematoma. However, it may be inadvertently  precipitated by withdrawing cerebrospinal fluid (CSF)  at lumbar puncture.   Figure 5.1 shows a diagrammatical representation of  the sites of intracranial herniation.   This is an abnormal accumulation of fluid in the cere-  bral parenchyma. It may be the result of breakdown  of the blood-brain barrier (vasogenic oedema), paren-  chymal cell membrane injury (cytotoxic oedema) or a  combination of the two. Possible causes include:   The condition is associated with raised intracranial  pressure and may result in herniation.   Hydrocephalus is an increase in the volume of CSF  within the brain resulting in the expansion of the cere-  bral ventricles and eventual increase in intracranial pres-  sure. It can occur by one of three mechanisms:   3. Overproduction of CSF by choroid plexus neo-  plasms (very rare).   Congenital hydrocephalus occurs in 1 per 1000  births, due to Arnold-Chiari and Dandy-Walker malfor-  mations (see page 39) and cerebral aquaduct stenosis.   Acquired obstructive hydrocephalus can result  from any lesion that obstructs the CSF within the ven-  tricles preventing flow into the subarachnoid space,  such as:   Caused by an impairment outside the ventricular system  in the absence of any CSF flow obstruction, e.g. menin-  gitis or subarachnoid haemhorrage. Normal pressure    Fig. 5.1 Sites of intracranial  herniation. (A) Subfalcine herniation.  (B) Transtentorial herniation. (C)  Tonsillar herniation. (D) Herniation of  swollen brain through any defect in  the dura and skull.   hydrocephalus (intermittent pressure hydrocephalus) is  a particular form of communicating hydrocephalus.  This is a rare condition of progressive dementia associ-  ated with ventricular dilatation. Random sampling  shows normal CSF pressure, but continuous monitoring  reveals intermittent increases.   In this special type of hydrocephalus, an increase in CSF  occurs as a compensatory measure following loss of  brain tissue, e.g. due to infarction or atrophy. There is  no associated increase in CSF pressure.   Congenital hydrocephalus may be diagnosed  antenatally via ultrasound (if severe) or present as a  considerably enlarged head at birth. In acquired  hydrocephalus, enlargement of the head is  prevented by the inability of skull expansion (sutures  are fused), resulting in increased intracranial  pressure. Associated features include dementia, gait  disturbances and incontinence. Treatment involves  insertion of a ventricular shunt to drain CSF into the  peritoneum, attempting to prevent irreversible brain  damage.   The aetiology of central nervous system (CNS) malfor-  mations includes genetic factors, maternal infections,  toxicity, metabolic factors and irradiation in utero.   Neural tube defects are the most common congenital  abnormalities of the CNS and are caused by defective  closure of the midline structures over the neural tube.  The most common forms in the newborn affect the spi-  nal cord (e.g. spina bifida). Screening for neural tube  defects can be performed with ultrasound or by mea-  surement of a-fetoprotein in the maternal serum or am-  niotic fluid (raised in 90% of cases).   Posterior fossa abnormalities are the second most com-  mon development abnormality of the CNS. Figure 5.2  illustrates the types of congenital abnormalities.   Syringomyelia is a rare condition in which a cyst  (syrinx) develops within the spinal cord, usually post-  erior to the central canal (Fig. 5.3). The cavity is lined  with astrocytes by the process of gliosis. It is most com-  mon in the cervical spinal cord, but it may extend into  the medulla (syringobulbia).   Absence of the cranial vault and failure in the development of the  cerebral hemispheres   Ossification defects in the bones of the skull result in herniation of the  brain and meninges. Most common form is occipital   Abnormal development of the vertebral arches but the cord and  meninges are normal. Usually asymptomatic   Abnormal development of the vertebral arches results in cystic  outpouching. Presents either with protrusion of CNS tissue through a  vertebral column defect (meningomyelocele: 90% of cases) or  protrusion of only the meninges (meningocele: 10% of cases)   Prolongation of the cerebellum downwards through the foramen  magnum often resulting in obstructive hydrocephalus   Obstruction of the foramina of Luschka and Magendie (exit of the  fourth ventricle) results in the formation of a cyst-like structure between  the cerebellar hemispheres    Fig. 5.3 Syringomyelia. (A) Early effects: damage to the  decussating sensory fibres, with loss of temperature and touch  in local segments. (B) Late effects: destruction of grey matter  and gradual affection of long tracts with loss of local reflexes,  severe sensory loss and spastic paralysis.   Hydromyelia is the term used when the ependyma-  lined central canal of the spinal cord (containing  CSF) is dilatated.   These conditions are usually acquired due to trauma,  ischaemia or associated spinal cord tumours. Rarely,  they occur because of congenital abnormalities such  as the Arnold-Chiari malformation.   Syringomyelia may produce muscle weakness and at-  rophy in the upper limbs due to compression of the an-  terior horn cells. There is loss of the sensations of pain    and temperature, but preservation of those of position  and vibration, due to damage of nerve fibres crossing  the cord in the lateral spinothalamic tracts.   This term refers to any brain injury sustained in the  period shortly before and after birth. It is an important  cause of childhood disability.   Cerebral palsy describes brain malformation or damage  affecting motor areas of the brain. It is the leading cause  of handicap in children, affecting 2 per 1000 live births.  The different presentations of cerebral palsy are out-  lined in Figure 5.4.   Note that cerebral palsy is a general term covering any  non-progressive motor deficit caused by perinatal  injury. Possible presentations include spasticity  (increased muscle tone), dystonia (disordered muscle  tone), ataxia (disordered muscle coordination) and  paresis (incomplete paralysis).   Ischaemia and hypoxia are major causes of severe peri-  natal brain damage. Perinatal hypoxia is usually due to  asphyxiation associated with the trauma of birth,  whereas perinatal ischaemia is commonly caused by  intracranial haemorrhages.   Premature infants are highly susceptible to develop-  ing intracranial haemorrhages because of disturbances  in the cerebral circulation, possibly caused by in-utero  hypoxia/ischaemia. Mortality is high; one-third of  survivors develop cerebral palsy, epilepsy or mental  retardation.   In full-term infants, intracranial haemorrhages with  the formation of small haematomas may occur during  difficult deliveries, although this is less common with  modern obstetric care.   The common types of CNS trauma are summarized in  Figure 5.5 and discussed in more detail below.   Skull fractures occur in approximately 80% of fatal cases  of head injuries. The most common are linear fractures  of the vault of the skull; such fractures may extend into  the base of the skull causing cranial nerve laceration.  The other types of skull fracture are:   • compound — increased risk of infection due to lacer-  ation of the scalp and tearing of the dura   This is an abrupt transient loss of consciousness due to  temporal neuronal dysfunction following a relatively  slight impact. It is caused by an enormous, but short-  lived, increase in pressure within the cranium at time  of impact. Full recovery usually ensues, although  amnesia for the event often persists.   A contusion is a bruise with extravasation of blood but  with the pia-arachnoid intact. A laceration is where the  pia-arachnoid is tom. Both are focal types of brain dam-  age occurring at the moment of injury, caused by strik-  ing the brain against adjacent bone. They are most  common at the frontal and occipital poles and mainly  affect the crests of gyri. Both lesions are characteristically  haemorrhagic.   • Contrecoup contusion — occurs diametrically oppo-  site to the site of impact.   • Gliding contusion — occurs at the superior margins  of the cerebral hemispheres; usually caused by inter-  ference of the dura with a rotational movement of  the brain.   This condition is produced as a result of rotational  movements of the brain within the skull during angular  acceleration or deceleration. It often occurs in the ab-  sence of any skull fracture or cerebral contusions. There  are two main features:    1 . Small haemorrhagic lesions in the corpus callosum  and the dorsolateral quadrant of the brainstem  (macroscopic)   2. Widespread tearing of axons, usually at the nodes of  Ranvier (microscopic).   Diffuse axonal injuries occur in up to 50% of patients  who develop coma shortly after trauma. It is associated  with head injuries involving vehicular accidents.   Bleeding from craniocerebral trauma is often associated  with high mortality. It can occur in one or more of the  potential spaces surrounding the brain, e.g. extradural  and subdural.   This type occurs in 2% of all head injuries and in 1 5% of  fatal cases. Haemorrhage occurs into the potential space  between the skull and dura, gradually stripping dura  from bone to form a large, saucer-shaped haematoma.   This injury is almost always the result of skull frac-  ture, usually of the temporal bone, with laceration of  the middle meningeal artery that runs through it (a  branch of the maxillary artery).   It is associated with a post-traumatic lucid interval of  several hours followed by a rapid increase in intra-  cranial pressure.   Haemorrhage occurs into the potential space between  the dura and the outer surface of the arachnoid mem-  brane. Usually caused by a rupture of the small bridging  veins or the venous sinuses within the subdural space.  The resulting haematoma is often extensive because of  the loose attachment of the dura and arachnoid  membranes.   Subdural haemorrhage can occur following acute se-  vere head injury or chronically, over days and weeks.  Chronic subdural haemorrhage is more common in:   • the elderly — even with minimal trauma, due to  brain atrophy and the subsequent stretching of  bridging veins   Arterial rupture into the subarachnoid space is usually  secondary to superficial contusions or lacerations of  the brain. Small amounts of blood can be disposed  of by arachnoid granulations. Larger haemorrhages  cause arachnoid fibrosis leading to meningeal irrita-  tion and raised intracranial pressure. It can also occur   This is caused by direct rupture of the intrinsic cerebral  vessels at the time of injury.   3. Burst lobe — intracerebral or intracerebellar haema-  toma in continuity with subdural haematoma; most  common in temporal and frontal lobes; rapidly  fatal.   Most spinal injuries occur in males aged under 40 years.  Road traffic accidents account for more than 80% of  such injuries.   There are two types of spinal cord injury: open and  closed.   These are rare. They are a result of direct trauma to the  spinal cord and nerve roots and can be either perforat-  ing (i.e. with extensive disruption and haemorrhage) or  penetrating (i.e. with incomplete cord transection —  Brown-Sequard syndrome).   These are in the majority and are associated with  fracture or dislocation of the spinal column causing  compression of the cord by distortion of the spinal  canal.   The consequences depend mainly on the site and  severity of the lesion. Cervical lesions may result in tet-  raplegia; lower thoracic lesions may result in  paraplegia.   Remember that with limited CNS repair mechanisms,  the site of trauma is more important than the size of  lesion. For example, a small lesion of the frontal lobe  may be clinically silent, but would cause tetraplegia if  located in the cervical spinal cord, and death if in the  brainstem.   Cerebrovascular disease is the third leading cause of  death in the UK.    Stroke is a common outcome of cerebrovascular dis-  ease and it is defined as a sudden event in which neuro-  logical deficit develops over minutes or hours and lasts  for longer than 24 hours.   If CNS disturbance lasts for less than 24 hours the  condition is termed a transient ischaemic attack (TIA).   The incidence of stroke is 2 or 3 per 1000 per year,  but is much higher than this in the elderly, affecting  males more than females. Causes are:   Pathological effects occur because of extensive hyp-  oxic neuronal damage. The area of brain affected can  be readily localized since the blood supply of the brain  has a fairly constant anatomic distribution. Figure 5.6  shows the territories of the major arteries.   Clinical features of stroke depend on localization  and the nature of the lesion. Risk factors are athero-  sclerosis, ischaemic heart disease, hypertension and  diabetes mellitus.   Cerebral infarction is the process whereby a focal area of  necrosis is produced in the brain in response to a de-  creased supply of oxygen (and glucose) in the territory  of a cerebral arterial branch. There are two main causes  of infarction:   1 . Hypoxia — the reduction of oxygen supply to tissues  despite an adequate blood supply, e.g. following  respiratory arrest.   2. Ischaemia — blood supply to tissues is absent, or  severely reduced, usually as a result of constriction  or obstruction of a blood vessel.   Ischaemia accounts for the majority of cases of cere-  bral infarction.    Fig. 5.6 Territories of the major  arteries. (1) Main cerebral arteries  forming circle of Willis. (2) Their  territories: (A) Lateral view.   (B) Inferior view. (C) Medial view.  (Reproduced with permission from  Anderson's Pathology, Damjanou,  ed., Mosby.)    • cardiac disease, e.g. prolonged hypotension (pro-  ducing global cerebral ischaemia) or cardiac  embolism   Infarcted tissue becomes swollen and soft with the  loss of definition between grey and white matter. It  undergoes liquefactive (colliquative) necrosis and  shows microglial macrophage infiltration. Eventually,  the necrotic tissue is completely phagocytosed to  leave a fluid-filled cystic cavity with a gliotic wall.   In global cerebral ischaemia, the peripheral cortical  ribbon of brain undergoes infarction, starting at the  watershed areas where cerebral artery territories appose.   Figure 5.7 shows the macroscopic and microscopic  pathological features of cerebral infarction.   The majority of intracerebral haemorrhages are thought  to arise from Charcot-Bouchard microaneurysms asso-  ciated with hypertension and diabetic vascular disease.  These haemorrhages occur most frequently in the basal  ganglia.   The resulting haematoma acts as a space-occupying  lesion leading to increased intracranial pressure and  herniation.   This can occur at any age, but it is an important cause of  death and disability in the 20-40-year age group. The  majority of subarachnoid haemorrhages are caused by  saccular (berry) aneurysms, which develop at proximal  branch points in the major cerebral vessels on the circle  of Willis (Fig. 5.8).   These aneurysms occur in 1-2% of the population,  but they are more common in the elderly and those with  hypertension.   Fig. 5.8 Berry aneurysms: approximate frequency and  distribution. The dotted line separates anterior from posterior  circulation. (Redrawn with permission from Anderson's  Pathology, Damjanou, ed., Mosby.)   • Atheroma of the larger cerebral vessels leads to a loss  of autoregulation of cerebral blood flow. It may also  allow small cavitary (lacunar) infarcts to develop,  particularly in the lenticular nucleus and thalamus.   • Encephalopathy — pathogenesis is uncertain but  damage to the blood-brain barrier leads to forced  cerebral hyperperfusion.   Line of demarcation between normal and  abnormal myelin in white matter    Chronic hypertension may lead to multiple infarct  events, often producing a syndrome of dementia and  neurological deficit (multi-infarct dementia).   Strokes caused by cerebral infarction clinically present  with slowly evolving signs and symptoms depending  on the area of the brain affected. Intracerebral  haemorrhage commonly gives rise to sudden  headache, vomiting, and impairment of consciousness.  Mortality is about 80%. Subarachnoid haemorrhage  presents with a sudden onset intensely severe  headache accompanied by neck pain/stiffness and  vomiting. Only 30-40% survive the first few hours and  their prognosis remains poor.   Meningitis refers to inflammation of the meninges; specif-  ically, the leptomeninges and CSF within the sub-  arachnoid space. Pachymeningitis refers to inflammation  centred on the dura, whereas meningoencephalitis is  inflammation of the meninges and brain parenchyma.   This is the most common cause of meningitis, usually  caused by viral infection. The term 'aseptic' is confusing,  referring to an absence of recognizable (bacterial) or-  ganisms. It is a benign and self-limiting illness, usually  less severe than bacterial meningitis.   The common causative organisms are enteroviruses  (e.g. echoviruses, Coxsackie viruses, polioviruses) and  mumps virus. It may occur as a complication of viral in-  fection, e.g. mumps or measles.   Affected individuals present with headache, irritabil-  ity and rapid development of meningeal irritation.   Organisms that typically cause this condition vary be-  tween age groups (Fig. 5.9).    The clinical features are headache, photophobia,  drowsiness and neck stiffness. These indicators of men-  ingeal irritation usually occur with systemic signs of  infection (e.g. fever) and the development of a petechial  rash.   • cerebral infarction due to an obliterative endarteritis  of local arteries   Mortality varies by bacteria, but may be as high as  60% with Streptococcus pneumoniae, particularly affect-  ing the very young and the elderly (see Figure 5.5).   A brain abscess is a severe focal infection of the brain  and is typically 1-2 cm across. It starts as an area of  cerebritis — inflammation of the brain parenchyma —  and develops into a pus-filled cavity walled off by gliosis  and surrounded by cerebral oedema. Multiple abscesses  may develop, particularly with haematogenous spread  of the causative organism. It often results in raised intra-  cranial pressure.   Common causative organisms are Streptococcus vivi-  dans, Staphylococcus aureus and Klebsiella species, but it  can also be caused by fungal infection.   Treatment involves antibiotic therapy at an early  stage, with surgical aspiration or excision of the capsule.   Overall mortality is between 10 and 20%, often be-  cause of a delay in diagnosis.   This is a collection of pus in the subdural space and it is  relatively uncommon. In adults, it usually results from  frontal sinusitis, whereas in infants it is usually second-  ary to meningitis.   Clinically, patients with subdural empyema are usu-  ally very ill. The pus spreads rapidly on the surface of a  hemisphere, producing hemiparesis, raised intracranial  pressure, fits and meningism.   This is meningitis due to infection by Mycobacterium  tuberculosis. It is rare in the UK but a major problem  in developing countries.   The disorder is almost always secondary to tubercu-  losis elsewhere in the body; infection usually reaches  the CNS via the bloodstream.   Pathogenesis — granulomatous inflammation affects  the basal meninges, large arteries and cranial nerves,  covering the brain in a gelatinous, greenish exudate.   It presents clinically with slow-onset, subacute meningi-  tis. It maybe accompanied by isolated cranial nerve palsies.   Hydrocephalus may result from impaired reabsorp-  tion of CSF or obstruction of CSF outflow from arach-  noid fibrosis.   CSF shows an initial increase in mononuclear cells  and polymorphs (Fig. 5.10). Untreated, the disease is  usually fatal. Intensive treatment with antituberculous  drugs lowers mortality to 15-20%.   This is caused by invasion of the CNS by the micro-  organism Treponema pallidum. It can occur weeks, months  or years after initial infection (tertiary-stage syphilis).    Meningitic illness occurs in only approximately 10%  of cases of untreated syphilis. It is usually mild or even  asymptomatic, but it may be severe with transient  cranial nerve palsies and convulsions.   This disorder is caused by the tick-borne spirochete  Borrelia burgdorferi. It is a systemic illness characterized  by skin lesions and neurological features.   This is a virally induced diffuse inflammation of the  brain, which is usually concomitant with meningo-  encephalitis. It is a common complication of many  viral illnesses. Common causative viruses are:   Most cases are mild and self-limiting. However, some  cases (e.g. those involving herpes simplex virus type I  and rabies) result in extensive tissue destruction and  may be fatal.   Mortality for the more severe type is 50%, and the  majority of survivors have severe, permanent brain  damage.   These are relatively rare and occur mainly in the im-  munosuppressed (e.g. associated with chemotherapy,  steroid treatment, acquired immune deficiency syn-  drome; AIDS), but some organisms, e.g. Cryptococcus  neoformans, can produce disease in the absence of  immunosuppression.    The spread can be haematogenous (e.g. from the  lungs, which is the most common) or direct (e.g. from  the nose and paranasal sinuses, which is rare).   The most common causative organisms are  Cryptococcus neoforrnans and Candida albicans (causes  fungal abscesses).   This is caused by infection with Toxoplasma gondii. It  may be acquired by eating poorly cooked infected meat  or food contaminated with feline faeces. It has two  forms: congenital and acquired.   In the congenital form, the organism is transmitted  to the fetus through the placenta during maternal infec-  tion, potentially leading to:   • moderate brain damage and chorioretinitis, compat-  ible with life but with permanent disability.  Acquired toxoplasmosis is the most common oppor-  tunistic infection of the CNS in adults with AIDS. It re-  sults in:   Other protozoan organisms that may cause infection  of the CNS are:   Multifocal destruction of oligodendrocytes results in  demyelination with minimal inflammation and dam-  age to axons. It is caused by the DNA JC polyomavirus,  and it occurs in association with underlying diseases  such as AIDS, chronic lymphocytic leucaemia, carci-  noma and systemic lupus erythematosus (SLE).   Patients present with progressive dementia. The dis-  ease is progressive and death usually occurs within a few  months.   This subacute encephalitis occurring in children is due  to persistent measles infection. It presents with progres-  sive neurological dementia, and death usually occurs  within 2 years of onset. It is now rare due to immuniza-  tion with the MMR vaccine.   This presents as rapidly progressive dementia, ataxia and  myoclonus; it is rare in the UK ( 1 per million people per  year). Spongiform changes include the formation of in-  tracellular vacuoles in neurons and glia. The infectious  agent is a prion protein (PrP; see page 32) . The condition  has an incubation period of up to 30 years, but it is al-  ways fatal, usually within 6 months. The disease typically  affects people over 70 years old.   Variant Creutzfeldt-Jakob disease (vCJD) is a human  disease associated with bovine spongiform encepha-  lopathy that shows the potential for prion transmission  between species. Descriptions of the disease are rela-  tively recent but it appears to affect younger individuals  than does classic CJD. Neurological decline seems to  be slower, but fatal progression is — so far — universal.  A genetic predisposition may increase susceptibility to  vCJD from eating infected beef. Recent estimates have  suggested that the disease might be responsible for hun-  dreds or thousands of cases.   This group of diseases has a common factor of primary  damage to myelin of nerves while the axons and nerve  cells remain relatively intact.   Multiple sclerosis (MS) is the most common demyelin-  ating disorder of the CNS, affecting 50 per 100 000 in  the UK. Peak incidence is between 20 and 40 years, with  a slight female predominance.   MS is characterized by relapsing and remitting  episodes of immunologically mediated demyelination  within the CNS. Recovery from each episode of demye-  lination is usually incomplete, leading to progressive  deterioration. There is an association between the dis-  ease and certain human leucocyte antigens (HLA, e.g.  A3, B7, DR2 and DQ1). The incidence also increases  with distance from the equator, suggesting a possible  environmental trigger.   Pathogenesis — activated T lymphocytes cross the  blood-brain barrier, reacting to self-antigens against  myelin that are presented by microglia. A strong inflam-  matory reaction follows, enhanced by the release of  proinflammatory cytokines. Acute demyelination oc-  curs in the central white matter in discrete areas known  as plaques.   Abnormalities are confined to the CNS; the periph-  eral nervous system (PNS) is usually spared. Common  sites are the optic nerve, brainstem, cerebellum, peri-  ventricular regions and cervical spinal cord.    Figure 5.11 lists the clinical manifestations of MS and  their causes.   MS diagnosis involves identification of abnormal CNS  areas (e.g. by MRI scanning) in the absence of another  explanation. The CSF may show increased lymphoid  cells and oligoclonal bands of IgG. There is no specific  treatment, but high-dose intravenous corticosteroids  may accelerate remission in relapse. Beta-interferon  has also been used to some success. Most follow a  relapsing-remitting course with variable disability, but a  minority (5%) suffer rapidly progressive (fulminant)  disease, which is fatal within 5 years.   These diseases primarily affect the grey matter, with pro-  gressive neuronal loss. A common feature of this group  is the development of protein aggregates (cellular inclu-  sions) that are resistant to degradation.   This is the most common cause of dementia in Western  countries.   Dementia is defined as the progressive loss of cogni-  tive function, independent of the state of attention, and  occurs due to degeneration of the cerebral cortex.  Alzheimer's disease affects 5% of people over 65 years,  and 15% of people over 80 years in the UK; females  more than males. Also of significance is the subgroup  of early-onset patients (40-60 years).    Genetic studies have shown that there is an increase  in incidence of sporadic cases in individuals with  ApoEe4 genotype on chromosome 19. The amyloid pre-  cursor protein (APP) gene on chromosome 21 has been  implicated in the familial cases.   The aetiology and pathogenesis are unknown; some  cases (5%) are familial, but most (95%) are sporadic.   Macroscopically, there is marked cortical atrophy, es-  pecially of the frontal lobes; the brain is reduced in  weight to 1000 g or less (normal average 1400 g). There  is a loss of cortical grey and white matter.   • Senile (neuritic) plaques — composed of an extracel-  lular core of amyloid protein (10-150 nm diameter)  surrounded by dystrophic neurites; occur most fre-  quently in the hippocampus, cerebral cortex and  deep grey matter. The main component of the core  is A, a readily aggregating peptide that is thought  to be central in the pathogenesis of dementia.   • Neurofibrillary tangles — abnormal tangles of insol-  uble cytoskeletal-like proteins (tau proteins - paired  helical filaments) that form within the cytoplasm of  neurons.   • Neuropil threads — distorted, twisted and dilated  dendritic processes and axons of cerebral cortex  found around amyloid plaques.   Clinically, there is failure of memory and disturbance  of emotions. There tends to be progressive physical  decline with poor food intake and inability to walk.  Death is commonly due to the development of  pneumonia.   This term is used to refer to patients whose clinical pre-  sentation typically consists of:   This is characterized by rest tremor, slowness of volun-  tary movement and rigidity. It occurs in 1 per 1000  adults, but 1 per 200 over the age of 65. The aetiology  is unknown.   • The disorder shows degeneration of pigmented  dopaminergic neurons of the substantia nigra, the  locus caeruleus and several other brainstem nuclei.   • Degeneration of these cells causes disease by reduc-  ing the amount of dopamine in the corpus striatum.   • Surviving cells in the substantia nigra contain eosin-  ophilic spherical inclusions (Fewy bodies), which  contain cytoskeletal filaments.   The disease can be symptomatically treated with drugs,  such as L-Dopa, that correct neurotransmitter imbalance.  Eventually, there is failure of response to treatment and  patients die from wasting and poor nutritional intake.  Several genes have been implicated in the development  of Parkinson's disease, including those encoding the pro-  teins a-synuclein and parkin.   This progressive, neurodegenerative disease is character-  ized by the selective loss of both upper and lower motor  neurons from the spinal cord, brainstem and motor cor-  tex. Its prevalence is 5 per 100 000 of the population,  with male incidence greater than female.   The majority of cases are sporadic but 5% of cases are  familial — due to mutation of the superoxide dismutase  gene.   It eventually progresses to severe paralysis with loss of  swallowing and respiration, leading to death in 2-3 years.    • Wernicke's encephalopathy — memory impairment,  ataxia, visual disturbances and peripheral  neuropathy   • Korsakoff s psychosis — confused state, memory loss  and confabulation.   This produces weakness and paraesthesia in the lower  limbs with loss of vibration and proprioception result-  ing from subacute combined degeneration of the spinal  cord (Fig. 5.13). Replacement therapy at an early stage  reverses the degenerative process, but long-standing  cases show irreversible axonal damage with reactive  gliosis.   Severe iodine deficiency causes hypothyroidism; it is the  most important endocrine disorder to affect the CNS in  children. In the fetus, severe iodine deficiency causes  cretinism characterized by dwarfism, mental defect  and spastic diplegia. This can be prevented by iodine  supplements during pregnancy.   Carbon monoxide (CO) binds irreversibly to haemo-  globin, rendering erythrocytes incapable of oxygen  transport. CO poisoning therefore results in brain dam-  age due to hypoxia. This poisoning may be accidental or  associated with attempted suicide.   The amounts of carbon-monoxide-bound haemo-  globin (HbCO) with corresponding clinical symptoms  are as follows:   Progressive dementia with severe memory and speech loss. Atrophy of cortex in areas  of the frontal and temporal lobes. Surviving neurons contain Pick's bodies   Autosomal dominant disorder (trinucleotide repeat, chromosome 4) characterized by  chorea and progressive dementia. Cerebral atrophy in the caudate nucleus and  putamen    Fig. 5.13 Subacute combined degeneration of the spinal cord.  Degeneration of posterior columns leads to sensory loss  (vibration and proprioception) causing ataxia. Degeneration of  corticospinal tracts leads to upper motor neuron damage  causing spastic paralysis.   Hypoxia results in neuronal necrosis with a predilec-  tion for globus pallidus. Other selectively vulnerable re-  gions are the hippocampus and the cerebral and  cerebellar cortices.   Methanol is highly toxic to the CNS, particularly to the  retina. It is lipid soluble, so readily diffuses into the CSF  and aqueous humour in concentrations higher than in  plasma.   Methanol is metabolized into formic acid and form-  aldehyde. It is the formaldehyde that is thought to be  the mediator of toxic effects. There are two types of  methanol poisoning:   2. Chronic — atrophy of retinal ganglion cells with sec-  ondary degeneration of the optic nerve.   The consequences of excessive ethanol intake on the  CNS are manifold (Fig. 5.14).   Gliomas are tumours that arise from glial supportive tis-  sue of brain. They are the most common primary brain  tumours, accounting for 50% of all CNS tumours.   Note that glial cells are the support cells of the CNS. The  group includes astrocytes (throughout the CNS),  oligodendrocytes (form myelin sheaths), ependymal  cells (line the ventricular system) and microglia (act as  CNS macrophages).   This is a glioma derived from astrocytes. It is more com-  mon in children, usually occurring in the cerebellum. It  accounts for 10% of all primary tumours in adults, usu-  ally in the cerebral hemispheres. Common types of  astrocytomas and their corresponding tumour grading  include:   • well-differentiated fibrillary astrocytoma (grade  II) — small increase in glial cell nuclei   • anaplastic astrocytoma (grade III) — densely cellular  with nuclear pleomorphism    Fig. 5.14 Consequences of excess ethanol intake on the central nervous system    • glioblastoma (grade IV) — the most common and  most malignant of primary brain tumours, relatively  poorly differentiated. Areas of necrosis and haem-  horrage surrounded by a 'pseudopalisade' arrange-  ment of tumour cells.   These ill-defined, slow-growing tumours arise from  oligodendrocytes in the white matter of the cerebral  hemispheres, especially the temporal lobe. They account  for 5% of all primary CNS neoplasms in adults. They are  characterized by large nuclei cells with perinuclear  halo, the so-called 'fried egg' appearance.   These tumours arise from the ependymal cells lining the  ventricle and central canal of the spinal cord. Ependy-  moma is the most common tumour of the spinal cord,  accounting for 5% of all primary CNS neoplasms. It is  common in children and young adults.   This highly malignant tumour of primitive neuro-  epithelial cells arises in the cerebellum of children. It  is the most common tumours of childhood CNS. The  tumour is highly radiosensitive, but without treatment  it is rapidly fatal.   These tumours are more common than any primary  intracranial neoplasms. The cerebellum is the preferred  site but they can affect any part of the brain as well as  other intracranial structures, especially meninges (ma-  lignant meningitis). Metastases often occur at the  boundary between grey and white matter, surrounded  by oedema.   These account for approximately 15% of adult intracra-  nial tumours and are the second most common primary  intrancranial neoplasms. Tumours arise from the arach-  noid mater. They are usually benign and external to the  brain. They are characterized by laminated calcified  psammoma bodies.    Disorders of peripheral nerves are termed neuropathies.  They can be predominantly sensory, predominantly  motor or mixed, depending on which nerves are af-  fected.   • Disorders affecting many peripheral nerves are  termed polyneuropathies, and they usually cause  symmetrical deficits.   • Disorders affecting only one (mononeuropathy) or a  few (multiple mononeuropathies) peripheral nerves  typically cause asymmetrical deficits.   This disorder is characterized by pronounced atrophy of  the calf muscles with associated sensory deficits as a re-  sult of slowly progressive symmetric neuropathy. It is  the commonest of the hereditary neuropathies, and it  is usually autosomal dominant. It impedes ambulation  and causes foot deformities (pes cavus), but it does not  shorten the lifespan.   Figure 5.15 provides a table of the different types of  peroneal muscular atrophy and their characteristics.   This group of autosomal inherited diseases produces  mainly sensory and autonomic neuropathies. There  are three major types, as described in Figure 5.16.   This is a jagged tear of the peripheral nerve in which  there is partial or complete loss of continuity of the  nerve. It occurs most commonly from cutting injuries,  misplaced intramuscular injections or fragments of frac-  tured bone.    Fig. 5.15 Different types of peroneal muscular atrophy and their characteristics   Degeneration of large  myelinated fibres of  both peripheral nerves  and posterior columns  of spinal cord   This is the tearing of nerve fibres from the surface of the  spinal cord or from a muscle. It may be partial or com-  plete depending on whether all or only some of the  nerve rootlets are involved.   Nerve roots may be avulsed from the spinal cord in  two ways:   1. Tensile stresses from cervical plexus transmitted  centrally can stretch and finally avulse the nerve  roots.   2. A spinal cord injury, such that displacement of the  cord acts directly on the nerve roots between their  attachment to the cord and their entry into the intra-  vertebral foramen.   Both laceration and avulsion injuries cause the sev-  ered ends of the damaged nerve to retract and then to  undergo Wallerian degeneration to form a traumatic  neuroma (a type of benign tumour). Subsequently,  the proximal portion of the nerve develops neuritic  sprouts which, if sited in proximity to the severed distal  nerve, may reinnervate by slow regrowth along the  nerve sheath.    If continuity of the nerve is completely interrupted,  basal laminae sheaths no longer form continuous tubes  to guide regeneration sprouts and so the potential for  recovery is limited.   Compressed nerves undergo segmental demyelination  with decreased nerve conduction velocity. If compres-  sion is prolonged or severe, axonal degeneration may  occur. Symptoms of nerve compression are paraesthe-  sia, anaesthesia and loss of muscle strength.   • nerve roots in the intervertebral foramina by  prolapsed intervertebral discs or osteophytes due to  osteoarthritis of the spine   • ulnar nerve in flexor carpal tunnel at the medial  epicondyle of humerus   This is a disorder in which the size of the carpal tunnel is  significantly reduced, causing compression of the me-  dian nerve. Causes include inflammation of the flexor  retinaculum and arthritic changes.   This is the most common form of acute neuropathy caused  by immune-mediated demyelination of peripheral nerves,  usually occurring 2-4 weeks after viral illnesses such as Ep-  stein-Barr infection. The pathogenesis is unclear, but  it appears that vims infection niggers a T-cell-mediated  autoimmune-like response against peripheral nerves.   Affected patients develop motor neuropathy that rises  from the peripheral limbs ('ascending paralysis'), with  lesser sensory changes due to widespread demyelination  of the peripheral nerves. Recovery (i.e. remyelination)  occurs over 3-4 months and is usually complete.   A chronic granulomatous disease caused by Mycobacterium  leprae. It is the most common cause of peripheral neuritis  worldwide, affecting about 10 million patients in total.   The clinicopathological features of leprosy are depen-  dent on the host's response to infection, with a spectrum  of disease ranging from tuberculoid to lepromatous form  (see Fig. 5.17).   An invasion of cutaneous sensory nerves during primary  infection with varicella-zoster virus (VZV, the virus that  causes chickenpox) leads to infection of the dorsal root  ganglia where the vims enters a latent state. Reactivation  of VZV may occur years later causing shingles — painful,  vesicular skin emptions in the distribution of sensory  dermatomes, usually thoracic or trigeminal. The reason  for reactivation is unknown but there is increased inci-  dence in immunocompromised individuals.   This occurs in both type I and II diabetes mellitus with  a prevalence of 10-60% clinically, but up to 100%  when evaluated by nerve conduction studies. There is  increased prevalence with increased duration of the  disease.   Vascular occlusion of the blood vessels supplying  the nerves results in neuronal atrophy. There are four  types:    Fig. 5.17 Comparison of peripheral nerve damage by lepromatous and tuberculoid forms of leprosy   Sensory, motor and autonomic involvement  Peripheral nerve palsies  Anaesthetic areas prone to injury and  secondary infection   Progression slow, but immune response  produces extensive destruction of tissue  resulting in severe disfigurement  Eventually heals spontaneously   Approximately 60% of patients with chronic renal fail-  ure have symptoms of uraemic neuropathy at onset of  dialysis. It is typically distal and symmetrical, producing  pain and paraesthesia with the lower extremities prefer-  entially involved. Dialysis usually improves symptoms.   Many toxins cause damage to peripheral nerves. The  most common toxins are:   • drugs — e.g. isoniazides, sulphonamides, vinca alka-  loids, dapsone and chloroquine   Most toxins produce a 'dying back' pattern of axonal  damage resulting in a distal symmetric pattern of senso-  rimotor involvement. There is a 'stocking glove' distri-  bution at onset but continued exposure to the toxin  extends the deficit to the lower calves and forearms.   Cancer patients frequently have mononeuropathies  caused by direct infiltration of individual nerves or plex-  uses, e.g. brachial plexopathy due to apical lung cancer.   An uncommon condition caused by loss of sympathetic  innervation to the eye. It is characterized by:    • pupillary constriction (miosis) due to unopposed  action of the pupillary constrictor   • partial ptosis (drooping) of the upper eyelid due to  paralysis of smooth muscle fibres contained in the  levator muscle of the upper eyelid   • anhidrosis (loss of sweating) on affected side of  the face.   Lesions affecting any part of the sympathetic  pathway (Fig. 5.19) may produce Horner's  syndrome:   • cervical sympathetic chain — pancoast tumours (apical  tumours of the lung) frequently invade adjacent sites;  invasion of the superior cervical sympathetic ganglion  often results in Horner's syndrome.   Fig. 5.19 Sympathetic innervation to the eye and face showing  the relationship of the sympathetic trunk to the apex of the lungs.   Benign tumour of schwann cells of the nerve sheaths.  Most common site is the vestibular branch of CN VIII   A tumour of the neural crest cells derived from the epineurium and endoneurium   Surgical sympathectomies are sometimes performed for  the relief of such conditions as:   • Raynaud's phenomenon — pallor, pain and numb-  ness of the fingers caused by vasospastic constriction  of the digital arteries; sympathectomy is occasionally  performed to improve limb perfusion   • causalgia — severe burning pain that occurs follow-  ing injury to the major peripheral nerves of the limbs  (e.g. median, ulnar, sciatic) presumed to be due to  disturbances of sympathetic reflexes   The consequences of either traumatic or surgical sec-  tion of the sympathetic chain depend on the level of the  section, but may cause:   This is a rare tumour arising from chromaffin cells of the  adrenal medulla, occurring in 1 in 1000 cases of hyper-  tension. The majority are sporadic but about 10% are  familial. Most are benign but about 5% are malignant.    The effects are those of hypersecretion of cate-  cholamines, i.e. hypertension, hypermetabolism and  hyperglycaemia. There is also pallor, headaches, sweat-  ing and nervousness.   • von Hippel-Lindau syndrome — associated with re-  nal cell carcinomas and multiple hemangiomas.   It is diagnosed by increased amounts of urinary ex-  cretion of catecholamines and their metabolites, such  as vanillylmandelic acid (VMA).   The most common site of parasympathetic ablation is  the vagus nerve (vagotomy) for treatment of duodenal  ulcers. This is less common now because of increasing  awareness of the bacterial aetiology (Helicobacter pylori)  of intestinal ulcers.   • Understand the fetal circulation and how alterations produce congenital abnormalities of the heart.   • Describe the key processes of atherosclerosis, hypertension and thrombosis (arterial and venous).   • Describe the spectrum of ischaemic heart disease and the commonly resulting heart failure.   • Briefly describe the inflammatory and neoplastic diseases of the vasculature.   Congenital heart abnormalities are relatively common,  affecting nearly 1% of live births. The incidence is higher  in premature babies.   These are the majority of cases and no teratogenic fac-  tors can be identified.   There is an increased incidence associated with certain  maternal factors including:   These factors are of greatest importance between the  fourth and ninth week after conception.   These are associated with an increased incidence  of congenital heart malformations (e.g. Down's  syndrome).   Most cardiac abnormalities become apparent at or  shortly after birth, usually by some manifestation of  heart failure such as cyanosis, breathlessness, feeding  difficulties, or a failure to thrive. However, it is possible  for some conditions to be undetected until adulthood.   Congenital heart defects may be divided into two main  groups depending on whether the lesions cause:   1. abnormal shunting of blood between the two sides  of the heart. A shunt is defined as an abnormal  communication between heart chambers or blood  vessels. In congenital heart disease there may be either  left-to-right (more common) or right-to-left shunts   2. obstruction to blood flow by narrowing of cham-  bers, valves or blood vessels. Complete obstruction  is termed an atresia.   As the fetus does not breathe in the uterus, blood flow is  controlled by three unique mechanisms (Fig. 6.1):   • Foramen ovale — connection from the right atrium  to the left atrium allows oxygenated maternal blood  from the umbilical vein to bypass the lungs and di-  rectly enter the left side of the heart.   • Ductus arteriosus — connection between the pulmo-  nary artery and aorta allows blood entering the pul-  monary circulation to be diverted away from the  lungs and to the body. This blood is generally less  oxygenated, having entered the heart from the   Fig. 6.1 Schematic representation of the fetal circulation. Note  the role of the foramen ovale and ductus arteriosus in diverting  blood away from the immature lungs. The aortic isthmus  ensures that highly oxygenated blood is delivered to the crucial  head and neck structures, with less oxygenated blood supplying  the immature organ systems. (IVC, inferior vena cava; SVC,  superior vena cava.)   superior vena cava, so avoiding diversion through  the foramen ovale. The high resistance of the imma-  ture lungs aids flow through this low-resistance  pathway.   • Aortic isthmus — this constriction in the fetal aorta  after the origin of the head and neck arteries ensures  that relatively low oxygenated blood from the ductus  arteriosus supplies the immature organ systems of  the body, rather than crucial head and neck  structures.   After birth, pulmonary vascular resistance drops,  allowing the foramen ovale and ductus arteriosus to  close. The aortic isthmus also expands shortly after  birth.   These are malformations that result in the shunting of  blood from the left side of the heart to the right because  of the higher pressures in the left side of the heart; they  are the most common group of congenital heart abnor-  malities. These defects clinically are acyanotic as the  blood does not bypass the lungs.   This defect of the interventricular septum is the most  common cardiac abnormality, accounting for 25-30%  of all cases of congenital heart disease (Fig. 6.3). The  interventricular septum can be divided into a membra-  nous (fibrous) portion and a muscular portion.   Most congenital defects are perimembranous, i.e.  occurring at the junction of the membranous and  muscular portions.   Fig. 6.3 Ventricular septal defect. Larger defects involve the  septal muscle but smaller defects may be confined to the  maladie de Roger (tiny membranous region). (LA, left atrium;  LV, left ventricle; PA, pulmonary artery; RA, right atrium;    The size and site of the defect determines the extent  of shunting of the blood from left to right. Defects may  present as cardiac failure in infants, or as a murmur in  older children or adults.   • pansystolic murmur, caused by flow from the high-  pressure left ventricle to the low-pressure right  ventricle during systole. The smallest defects  generally produce the loudest murmurs   Small defects need no treatment; larger ones require  surgical repair to prevent cardiac failure.   This is a common congenital heart defect, affecting fe-  males more than males by 2:1. Blood flows from left  to right due to the high compliance of the right ventri-  cle. The defect may be of two types (Fig. 6.4):   1. Ostium primum — defect is at the level of the atrio-  ventricular septum and is associated with an abnor-  mal mitral valve (split anterior leaflet).   Fig. 6.4 Atrial septal defect. The defect is usually located at the  level of the fossa ovalis. (LA, left atrium; LV, left ventricle;    2. Ostium secundum — the foramen ovale fails to close,  remaining patent as the fossa ovalis. This is the most  common form of atrial septal defect.   Most children are asymptomatic, however some  children present with dyspnoea, chest infections, car-  diac failure or arrhythmias (e.g. atrial fibrillation).   The characteristic physical signs are a systolic flow  murmur over the pulmonary valve and wide splitting  of the second heart sound.   Atrial septal defects should be closed surgically to  prevent shunt reversal (see below). If performed  before this develops, the prognosis after surgery is  excellent.   This persistence of the embryological connection be-  tween the aorta and the pulmonary is shown in  Figure 6.5. Patent (open) ductus arteriosus occurs in  about 1 0% of all cases of congenital heart disease, affect-  ing females more than males. There is a recognized  association with maternal rubella.   A continuous 'machinery-like' murmur is classically  detected, as high volumes of oxygenated blood are  shunted from the high-pressure aorta back into the lungs.  This can dramatically increase the work of the heart in a  large defect, leading to eventual cardiac failure without  early surgical correction.   Fig. 6.5 Patent ductus arteriosus. Persistence of the duct  is more common in females, and it is associated with maternal  rubella.   All the left-to-right shunts described above have the po-  tential to result in pulmonary hypertension, partly due  to the obliteration of small vessels in the lungs and the  increase in flow. Eventually, this increase in pulmonary  resistance can be so great that reversal to a right-to-left  shunt occurs, producing marked cyanosis as deoxygen-  ated blood is pumped around the body (Eisenmenger's  syndrome).   The condition is irreversible and usually prevents  surgery to correct the original congenital defect.   These are less common than left-to-right shunts. The re-  sult of a right-to-left shunt is that deoxygenated blood  bypasses the lungs to enter the systemic circulation.  Cyanosis may, therefore, develop in the early postnatal  period with any of these conditions.   Understanding the embryonic development of the  heart assists in the understanding of congenital  abnormalities, for example, the involvement of the  embryonic foramen ovale in the development of atrial  septal defects, and the congenital abnormality created  by a persistent ductus arteriosus.   This is the most common cause of cyanotic congenital  heart disease, occurring in about 1 in 2000 live births.  The abnormality consists of four defects (Fig. 6.6):   Aetiopathogenesis — defects are caused by the abnor-  mal embryological development of the bulbar septum,  which normally separates the ascending aorta from the  pulmonary artery (and should fuse with the interventri-  cular septum).   Pulmonary stenosis leads to inadequate perfusion of  the lungs and the over-riding aorta receives blood from  both the right and left ventricles. The net result is that  the systemic circulation contains deoxygenated blood,  causing cyanosis in affected individuals.   • cyanosis — especially after a crying attack. This is  termed a 'Fallot's spell', as adrenergic stimulation ex-  acerbates the right ventricular outflow obstruction,   Fig. 6.6 Fallot's tetralogy is an important cause of right-to-left  shunting.   so increasing the amount of blood shunted. Squat-  ting after exertion can relieve these symptoms by  increasing the afterload of the left heart   • loud ejection systolic murmur — either from the  ventricular septal defect or pulmonary stenosis.  Most cases are now surgically corrected, with a good   prognosis if performed in early childhood. Complica-  tions include endocarditis and consequent cerebral  infarction or brain abscess.   Connections between the right and left ventricle, aorta,  and pulmonary artery are disordered — the aorta ema-  nating from the right ventricle and the pulmonary artery  arising from the left (Fig. 6.7).   Postnatal survival is possible only if one or more of  the following shunts exists:   • atrial septal defect — this is often surgically enlarged  in early life to ensure adequate oxygenated blood  mixes into the systemic circulation   Surgical correction is possible, at which point all  shunts are closed.   Both the aorta and pulmonary artery develop from  a single tube: the truncus arteriosus. Persistence of  the truncus results in a single great artery that receives   Fig. 6.7 Transposition of the great vessels. Survival is possible  only if other shunts are present at either the atrial (A), ventricular  (B) or ductus (C) level.   blood from both ventricles. A ventricular septal defect  is also present.   Cyanosis occurs due to the mixing of blood from the  right and left ventricles.   This is a stenotic narrowing of the aorta, usually located  in the region where the ductus arteriosus joins the aorta,  i.e. the fetal aortic isthmus (Fig. 6.8). About 50% of  affected individuals have an associated bicuspid aortic  valve. 'Berry' aneurysms of the cerebral circulation are  also more common in these individuals.   This defect accounts for up to 5% of all forms of con-  genital heart disease, and it affects 1 in 4000 live births,  male incidence being greater than female by 2:1.  Clinical features — stricture produces:   • hypertension proximal to the stenosis, leading to  symptoms such as headache and dizziness   • hypotension distal to the stenosis, leading to gener-  alized weakness and poor peripheral circulation.  Characteristically, the blood pressure is raised in the   • Upper body — abnormally large arterial pulsations  may be seen in the neck, and severe hypertension  leads to the development of collateral circulations,  which may be visible or present on imaging in older  children and adults, e.g. pericapsular and intercostal  arteries.   Fig. 6.8 Coarctation of the aorta. Signs and symptoms depend  largely on the size of the narrowing.    • Lower body — femoral pulses are weak and delayed  when compared to the radial pulse.   A systolic murmur may sometimes be heard posteri-  orly over the coarctation.   • Dissection of the aorta, particularly in patients with  associated bicuspid aortic valves   This presents as a narrowing (stenosis) or fusion (atre-  sia) of the trunk of the pulmonary artery. In atretic cases,  the patent foramen ovale forms the only outlet for  blood from the right side of the heart. The ductus arter-  iosus is always patent and represents the only access  route to the pulmonary circulation.   Semilunar aortic valves may be stenosed or atretic.  If fusion is complete, the aorta, left ventricle and left  atrium are markedly underdeveloped. This is usually    accompanied by an open ductus arteriosus which de-  livers blood into the aorta. The condition is associated  with severe cyanosis.   1 . Atherosclerosis — the most common form. A degen-  erative disease involving the intima of large- and  medium-sized arteries. Atherosclerotic lesions are  termed atheromas. This is discussed in greater detail  below.   2. Monckeberg's medial calcific sclerosis — this degen-  erative disease of older individuals involves the de-  position of calcium in the media of medium-sized  muscular arteries. These deposits do not reduce  the size of the vessel lumen.   3. Arteriolosclerosis — the thickening of small artery  and arteriole vessel walls, with subsequent reduc-  tion in lumen size. This is associated with systemic  hypertension and diabetes mellitus, and particularly  affects vessels in the kidney, pancreas, gall bladder,  small intestine, adrenals and retina.   The terms ‘arteriosclerosis' and ‘atherosclerosis' are  often confused. They are not synonymous and they  should not be used interchangeably. Arteriosclerosis is  hardening or loss of elasticity of the arteries from any  cause, whereas atherosclerosis implies hardening or  loss of elasticity due to atheroma.   Arteriosclerosis contributes to the high frequency  of cardiac (myocardial infarction, angina pectoris),  cerebral (stroke, transient ischaemic attack), colonic  (malabsorption, ischaemic colitis) and peripheral (in-  termittent claudication, rest pain) diseases in the elderly  population.   Certain diseases are known to accelerate and aggra-  vate arteriosclerosis, e.g. hypertension and diabetes.   A degenerative, progressive and inflammatory disease of  large- and medium-sized arteries (but not veins), this is  characterized by the focal accumulation of lipid-rich  material in the intima of arteries and associated cellular  reactions. Although essentially a disease of the vessel in-  tima, atherosclerosis also has an impact on the structure  and function of the underlying media.   Atherosclerotic lesions are found to some extent in  virtually every adult over the age of 40 as well as in many  younger individuals. The consequences of atherosclero-  sis account for half of all deaths in the Western world.  Commonly affected arteries are:   Atherosclerosis is rare in the arteries of the upper  limb and in the pulmonary arteries.   Epidemiological studies have identified risk factors  associated with atheroma development. These can be  broadly classified into:    • modifiable risk factors, i.e. those that may be con-  trolled (although often to a very limited extent).  Fixed risk factors are:   • gender — females have half the incidence of males up  to the age of 55, due to the protective effect of oestro-  gens; over 55 years, the male to female ratio is equal   • race — wide interracial variations exist in the inci-  dence of atheroma, but this may be due to dietary  differences. The condition is relatively uncommon  in China, Japan and Africa.   Modifiable risk factors lead to an increased severity  of atherosclerosis. Such factors are multiplicative rather  than additive — this means that combinations of risk  factors massively increase the risk of atherosclerosis.  Examples are:   • hypercholesterolaemia [increased serum levels of cho-  lesterol or low-density lipoprotein (LDL)] — usually  dependent on diet, but may also occur as a result of  some forms of familial hypercholesterolaemia   • hypertension — increased blood pressure, both the  systolic and diastolic levels   • cigarette smoking — there is a strong link between  smoking and deaths from coronary artery disease;  the mechanism is unclear   • sedentary lifestyle — exercise decreases the incidence  of sudden death from ischaemic heart disease but it  is not clear whether it directly reduces atherosclero-  sis formation   • obesity — particularly central or truncal obesity,  probably a reflection of poor diet and resultant  hyperlipidaemia.   Following development of atherosclerosis, factors  such as stress, personality traits and coagulation disor-  ders may alter the risk of a related event (e.g. stroke  or ischaemic heart disease) .   • HMG CoA reductase inhibitors (statins) — lower  cholesterol by inhibiting hepatic synthesis   • anticoagulants — 75 mg aspirin (low-dose aspirin)  daily to minimize thrombotic risk   • lifestyle advice, e.g. stopping smoking, healthier diet  and increased exercise.   The pathogenesis of the characteristic lipid plaques of  atherosclerosis is described by the response to injury hy-  pothesis. This states that atherosclerosis is a chronic in-  flammatory response of the arterial wall to endothelial  injury.   Atherosclerosis begins early in life; the first signs of  the disorder are termed fatty streaks, which usually oc-  cur in areas of altered arterial stress (e.g. bifurcations  and sites of endothelial injury). Endothelial dysfunc-  tion may also have a role in the early pathogenesis of  plaque formation.   • altered haemodynamics — the damaging effect of tur-  bulent blood flow (e.g. at major arterial bifurca-  tions) may be further worsened by hypertension   • homocysteine — this amino acid may directly dam-  age the arterial wall. Individuals with the rare genetic  disorder homocystinuria, which results in raised  blood homocysteine levels, develop premature vas-  cular disease   • others — viruses, other infectious agents and inflam-  matory cytokines have all been suggested as poten-  tial inducers of endothelial injury.   The key stages in the development of atherosclerotic  plaques (atheromas) are as follows:   1. Chronic endothelial injury results in endothelial  dysfunction, causing an increased permeability of  the vessel wall, and the expression of receptors for  leucocyte adhesion.   2. Plasma proteins (including LDL) diffuse into the ar-  terial intima.   3. Monocytes bind newly expressed receptors and mi-  grate into the intima, differentiating into macro-  phages. These macrophages take up oxidized LDL to  form foam cells. When they die, release of the cellular  contents of these cells forms extracellular lipid pools.   5. Release of cytokines and growth factors (e.g.  platelet-derived growth factor) by platelets and acti-  vated macrophages results in the migration of  smooth muscle cells from the media to the intima  (myointimal cells). These muscle cells change from  a contractile to repair phenotype, producing colla-  gens in an attempt to stabilize the growing lesion.   The above scheme outlines the formation of a stable  atherosclerotic plaque (see Fig. 6.10, parts A-C). Such a  plaque can remain asymptomatic for many years, slowly  growing to the point where it may significantly obstruct  blood flow.    The maintenance of a stable atherosclerotic plaque  depends on the balance between inflammation (macro-  phage mediated) and repair (smooth muscle mediated).  If activated macrophages start producing additional cy-  tokines (e.g. interleukin- 1, matrix metalloproteinases),  the muscle cells forming the protective fibrous cap  may become senescent, resulting in an unstable plaque.  Thinning of the cap follows, with potential for erosion,  rupture (releasing prothrombotic material) or ulcera-  tion (see Fig. 6.8, part D).   Figure 6.11 provides a summary of the events  involved in the pathogenesis of atherosclerosis.    Fig. 6.10 Atheroma formation. (A) Endothelial injury: allows  entry of cholesterol-rich, low-density lipoproteins (LDLs) into  the intima. (B) 'Fatty streaks': barely visible pale bulges form as a  result of phagocytosis and accumulation of lipid by intimal  macrophages. (C) Stable plaques: raised, yellow lesions within  the intima consisting of free lipid released by macrophages and  collagen deposited by myointimal cells (repair phenotype).   (D) Unstable plaque with ulceration: allowing platelet  aggregation and thrombosis with the potential for embolism to  a distant site. Note that pressure atrophy of the underlying  media and elastic lamina results in weakening of the arterial  wall.   The migration of smooth muscle cells away from the  arterial media produces the complex effect of remodel-  ling. Two types have been proposed:   1. Negative remodelling — some arterial segments  affected by atherosclerosis constrict, increasing the  likelihood of occluding the lumen.   2. Positive remodelling — affected arterial segments  dilate, potentially compensating for the plaque  and maintaining the size of the lumen.   Thinning of the muscular arterial media predisposes  an artery to aneurysm.   Elevated blood pressure is an important and treatable  cause of cardiac failure. It is a major risk factor for ath-  erosclerosis and cerebral haemorrhage. Any increase in  blood pressure is associated with an increased risk of  disease.   Hypertension is increasingly being defined by the level  at which intervention (e.g. antihypertensive medica-  tion) is of proven benefit. Sustained systemic blood  pressure above 140 mml-Ig systolic and/or above  85 mmHg diastolic should be treated to reduce cardio-  vascular events such as strokes. Target levels for those  with diabetes and renal disease are lower.   Hypertension can be classified into two main types  according to its aetiology (Fig. 6.12):   1. Primary (essential or idiopathic) hypertension — a  complex, multifactorial disease in which blood    pressure is elevated with age, but with no apparent  cause. This accounts for 90% of all cases and prob-  ably has a strong genetic determinant.   2. Secondary hypertension — elevated blood pressure  due to an identifiable cause. It accounts for 10%  of hypertension. Examples include renal hyperten-  sion, endocrine causes and coarctation of the aorta.   • Malignant (accelerated) hypertension — a rare condi-  tion characterized by a dramatic elevation of blood  pressure over a short period of time.   e.g. Oral contraceptives, anabolic steroids, corticosteroids, epinephrine  (adrenaline) and related sympathomimetic drugs   • increased fragility of vessels leads to an increased risk  of haemorrhage (especially cerebral).   After many years of benign progression, 5%  of such patients enter an accelerated malignant  phase.   Acute, destructive changes occur in the walls of small ar-  teries when blood pressure rises suddenly and mark-  edly. This results in necrosis of the vessel wall and  infiltration of the necrotic media by fibrin (i.e. fibrinoid  necrosis of vessels).   The destructive changes result in a cessation of  blood flow through small vessels with multiple  foci of tissue necrosis, often with intravascular throm-  bosis. Areas typically affected include the retina (high-  grade retinopathy) and the kidneys (glomerular  disease).   Hypertension accelerates atherosclerosis, which causes  thickening of the media of muscular arteries, particu-  larly the smaller arteries and arterioles. Structural  changes perpetuate further rises in blood pressure, caus-  ing a progressively worsening clinical picture.   The normal flow of protein into the vessel wall is in-  creased resulting in intramural protein deposition  termed hyaline in benign hypertension, and fibrinoid  in malignant hypertension:   • Hyaline deposition — a common feature of ageing  small arteries (< 1 mm diameter); refers to the  homogeneous appearance of vessel walls due to  infiltration by plasma proteins   • Fibrinoid deposition — a combination of fibrin  infiltration with necrosis of the vessel wall.   The left ventricle undergoes hypertrophy resulting from  the increased workload, causing increased susceptibility  to spontaneous arrhythmias. Ischaemic heart disease  due to accelerated atherosclerosis is a common compli-  cation of hypertension.   Intracerebral haemorrhage is a frequent cause of  death in hypertension. Small-vessel damage within  the cerebral hemispheres results in the development   Begins at < 45 years but prolonged  into 6th and 7th decades    of micro-infarcts, which form hypertensive lacunae, i.e.  small areas of destroyed brain filled with fluid.   Arteriolosclerosis leads to progressive ischaemia of the  nephrons and chronic renal failure. This is termed be-  nign hypertensive nephrosclerosis, and it is a common  cause of chronic renal failure in the middle-aged and  elderly population.   Hypertension may produce retinal ischaemia and  infarction, visible on fundoscopic examination.   This is defined as pulmonary arterial pressure in excess  of 30 mmHg. Figure 6.15 lists the causes of pulmonary  hypertension.   With acute onset, there is a massive transudation of  fluid from the pulmonary capillaries into the alveoli  (pulmonary oedema), leading to shortness of breath  and expectoration of bloodstained, watery fluid.  Chronic onset has three effects:   2. Necrotizing arteriolitis — increased pressure within  the pulmonary arteries causes weakening of the ves-  sel wall with repeated episodes of haemorrhage into  the alveolar spaces, which contain haemosiderin-  laden macrophages   3. Cor pulmonale — right ventricular hypertrophy  and dysfunction as a result of increased workload.   Individuals with diabetes suffer from an increased sever-  ity of atherosclerosis and capillary microangiopathy in  which thickening of the small-vessel walls is attributed  to hyaline arteriolosclerosis and marked expansion of  the basement membrane.   Vessel damage is complex and is probably due  to the increased plasma levels of cholesterol and  triglycerides. Biochemically there is abnormal glyco-  sylation of protein within the vessel wall. Clinical se-  quelae of diabetic vessel damage are described  in detail in Chapter 10; they include diabetic  retinopathy, diabetic nephropathy and peripheral  neuropathy.   Fibrinoid deposition due to combination of fibrin  deposition and necrosis of vessel wall   T susceptibility to spontaneous arrhythmias  Heart failure in 60% of cases  Ischaemic heart disease   T susceptibility to spontaneous arrhythmias  Focal myocardial necrosis  Acute heart failure  Ischaemic heart disease   Encephalopathy (fits and loss of consciousness)  due to cerebral oedema  Cerebral haemorrhage   Ischaemia and infarction ('cotton wool' exudates)  Association with central retinal vein thrombosis   Thrombosis is the formation of a solid mass of blood  constituents — thrombus — within the vascular system.  It is not to be confused with a clot, which occurs in  non-flowing blood.   A thrombus is different from a clot! A clot is defined as  blood coagulated outside the vascular system or within  the vascular system after death.   This is most commonly superimposed on an atheroma.  As the plaque enlarges, it causes turbulent blood flow,  which results in the loss of intimal cells. The exposure  of vessel collagen predisposes to platelet activation. Tur-  bulence itself will predispose to fibrin deposition and  platelet clumping.   The greatest degree of turbulence occurs at the down-  stream side of the forming thrombus; thrombi, there-  fore, grow in the direction of the blood flow  (propagation). An arterial thrombosis may result in   Many venous thrombi begin at damaged valves that  produce turbulence. Furthermore, blood stasis during  surgery or due to immobilization may result in the for-  mation of a deep vein thrombosis (risking pulmonary  embolism). However, some thrombi form at sites with  no known predisposing factors. Often thrombi grow by  successive deposition of alternating bands of platelets  and red blood cells. These patterns are known as the  lines of Zahn.   A thrombosed vein may cause an inflammatory re-  sponse (thrombophlebitis) or a vein that is inflamed  may thrombose (phlebothrombosis). A histological dif-  ferentiation between the two types is in most cases  impossible.   • deep leg veins (90% of cases), particularly the lower  leg   The most serious acute complication is embolism of the  thrombus to the pulmonary arteries, causing a pulmo-  nary embolism (PE). These are divided into massive,  major and minor events and are discussed in detail  on page 109.   Chronic complications are aching pains due to vari-  cose veins, venous congestion, oedema, venous eczema  and ulceration.   Deep vein thrombosis (DVT) is a key clinical topic, as a  resulting pulmonary embolus may be life-threatening.  High-risk patients should be identified and offered  prophylaxis. DVTs typically present as a painful  unilaterally swollen calf, which is warm to the touch.  Diagnosis is aided by radiographic venograms and non-  invasive ultrasound (large veins only). Immediate  treatment involves heparin and prolonged warfarin,  the latter being used continuously in those with  repeated DVTs.   Factors that predispose any blood vessel to thrombosis  can be classified into three main groups, collectively  known as Virchow's triad (Fig. 6.16):   • Changes in the blood constituents — forming a  hypercoaguable state   • Changes in the blood vessel endothelium — usually  at the point of injury   • Changes in the pattern of blood flow — stasis or  turbulence.   Hereditary defects of hypercoagulability lead to a life-  long tendency to thrombosis (thrombophilia). They  usually affect the venous system:   Fig. 6.16 Virchow's triad in thrombosis. Endothelial integrity is  the single most important factor: injury can affect local blood  flow and/or coagulability. Abnormal blood flow (turbulence or  stasis) can, in turn, cause endothelial injury. The elements of the  triad may act independently or combine to cause thrombus  formation. (Redrawn with permission from Robbins and Cotran,  Pathologic Basis of Disease, 7th edition, V Kumar, A Abbas, and  N Fausto, Elsevier Saunders, 2005).   • Anfithrombin III deficiency — autosomal dominant  condition characterized by recurrentvenous thrombo-  ses usually starting in early adult life. Primary defect is a  deficiency of antithrombin III, which usually neutral-  izes thrombin and other activated clotting factors.   • Protein C deficiency — autosomal dominant condi-  tion resulting in failure of neutralization of activated  factors V and VIII. Protein S is a cofactor for protein  C. Therefore, protein S deficiencies produce a similar  pathology.   • Factor V Feiden — point mutation in the factor V  gene, which results in factor V protein that is resis-  tant to neutralization by protein C. This is very  common, affecting up to 5% of Caucasians.   • Prothrombin G20210A — this prothrombin gene  polymorphism occurs in 2% of the population  and is associated with increased levels of prothrom-  bin and venous thromboembolism.   • Malignancy — patients with carcinoma of the breast,  lung, prostate, pancreas or bowel have an increased  risk of venous thrombosis.   • Blood disorders, e.g. increased viscosity (especially  polycythaemia rubra vera) and thrombocytosis lead  to an increased risk of venous thrombosis.   • Oestrogens — associated with raised plasma levels of  various clotting factors leading to an increased risk  of venous thrombosis.    • Antiphospholipid antibody syndrome — leads to  the interaction of antibodies (lupus anticoagulant  and anticardiolipin antibodies) with phospholipid-  bound proteins involved in coagulation. This causes  prolongation of clotting times in vitro, with a paradox-  ical increased risk of venous and arterial thrombosis.  Often found in patients with autoimmune disease, es-  pecially systemic lupus erythematosus (SLE).   • Cholesterol — partly genetic, partly acquired (diet/  lifestyle), leads to an increased risk of arterial  thrombosis.   • Smoking — has been implicated as a predisposing  risk factor for thrombosis, possibly by causing a  hypercoagulable state.   Direct injury to the endothelium as seen in trauma (in-  cluding intravenous cannulation) and inflammation   • turbulence — may cause physical trauma to endothe-  lial cells. Loss of laminar flow may bring platelets  into contact with endothelium.    Ischaemic heart disease (II ID) is a condition caused by a  reduction or cessation of the blood supply to the myo-  cardium (myocardial ischaemia). This is usually as a re-  sult of atherosclerosis, although in rare cases it may be  caused by coronary embolism, arteritis or ostial obstruc-  tion. The left ventricle is more prone to ischaemia be-  cause of its greater bulk and work requirement, and  its higher oxygen demand.   II ID is the most common type of cardiac disease and  a leading cause of death in the Western world, account-  ing for about one-third of all male deaths and  one-quarter of all female deaths. Risk factors for the de-  velopment of ischaemic heart disease are the same as  those for the development of atherosclerosis.   4. Congestive cardiac failure (chronic manifestation).  The acute manifestations of cardiac ischaemia form   the continuous spectrum of disease termed the acute  coronary syndromes (ACS).   Angina pectoris is episodic chest pain caused by ischae-  mia of the myocardium following exercise. Ischaemia is  usually the result of stenosis of one or more of the cor-  onary arteries resulting in reduced blood flow to the  myocardium.   Stenosis of the coronary arteries is typically the result  of atherosclerosis. Atheromatous plaques may lie in two  possible positions:   1 . Eccentric — fibrolipid plaques affecting only one side  of the wall of a coronary artery. Improvement of  flow at the site of such plaques may be achieved  by the use of vasodilator drugs. These drugs, such  as glyceryl trinitrate, produce relaxation of the un-  affected part of the vessel wall.   2. Concentric — collagenous plaques affecting the  whole of the arterial wall circumference. As the  whole wall is abnormal, drug therapy cannot im-  prove flow over a narrowed segment.   Pain of angina (and myocardial infarction) commonly  radiates from the substernal and left pectoral regions to  the left shoulder and the medial aspect of the left arm;  this is known as cardiac referred pain.   Afferent fibres of the heart, and sensory fibres of af-  fected cutaneous zones, enter the same spinal cord seg-  ments (T1 to T4/T5 on the left side) and ascend in the  CNS along a common pathway. The brain is unable to  discern the origin of the pain, hence the phenomenon  of cardiac referred pain.   Less commonly, pain radiates to the right shoulder and  arm, with or without concomitant pain on the left side.   This is a predictable angina that occurs at a fixed level of  exercise, as a result of an increased demand in myocar-  dial work, usually in the presence of impaired perfusion  by blood. It is caused by a fixed obstruction of one or  more of the coronary arteries, therefore limiting any in-  crease in coronary blood flow. Pain can usually be re-  lieved by 1 or 2 minutes of rest. A stenosis of at least  75% of the lumen of the arteries is required to produce  angina on exercise.   Unstable anginal pain is unpredictable and not related  to exercise. It reflects reversible ischaemia due to vari-  able luminal stenosis of some segments of the coronary  arteries: so-called dynamic obstruction.   The condition is usually the result of active Assuring  and/or rupture of plaques with intimal surface throm-  bus deposition, microembolization and occlusion. Un-  stable angina is an acute event, often preceding the  development of acute myocardial infarction.   This is angina at rest caused by an increase in the coro-  nary vasomotor tone. The mechanism for coronary  spasm is unknown. Prinzmetal's angina is particularly  common in the early morning. Attacks are usually self-  limiting and, although pain may be severe, they rarely  lead on to myocardial infarction.   • Stable angina is predictable (i.e. it occurs at a fixed  level of exercise), and it is caused by a fixed arterial  obstruction.   • Unstable angina is unpredictable (i.e. it is unrelated to  exercise), and it is caused by a variable luminal  stenosis of the coronary arteries.   • Prinzmetal's angina is also unpredictable, and this is  caused by coronary artery spasm.   • Combination drug therapy with low-dose aspirin  and — potentially — nitrates, (1-blockers and Ca 2+  channel blockers.   • Invasive — percutaneous coronary intervention (PCI),  using balloon angioplasty to dilate a coronary artery  stenosis. If the stenosis is highly progressive or disease  is very severe (e.g. involving all three key coronary  arteries), coronary artery bypass grafting (CABG)  may be indicated.   Patients with unstable angina should be admitted to  hospital for ECG analysis and potential thrombolyis or  invasive correction of their occlusion. Such active man-  agement reduces progression to infarction. Unstable an-  ginas are included in the NSTEMI category of acute  coronary syndrome.   Myocardial infarction (MI) is necrosis of the myocar-  dium as a result of severe ischaemia. MI is extremely  common, accounting for 10-15% of all deaths and    about 60% of sudden unexpected deaths. It typically af-  fects middle-aged individuals, between 50 and 60 years,  but 10% occur in 35- to 50-year-olds. MI affects males  more than premenopausal women (by 5:1), but there  is an increasing incidence in women postmenopausally.   Clinical features are chest pain accompanied by  breathlessness, vomiting and collapse or syncope. Pain  occurs in the same sites as angina, but it is usually more  severe and lasts for longer.   Infarcts occurs in the territory supplied by one maj or com-  mon artery, involving only one segment of the ventricular  wall. The cause of infarction is nearly always thrombus  formation on a ruptured or eroded unstable athero-  matous plaque. Patterns of regional MI and sites of MI  are shown in Figures 6.17 and 6.18   An acute MI should be classified as STEMI when there is:   • ST elevation (2 mm in two or more chest leads, or  1 mm in two or more limb leads)   Other Mis that do not meet these criteria should be  classified as NSTEMI. The main difference between the  two classification are their emergency mangement  protocols.   Fig. 6.17 Patterns of regional myocardial infarction (Ml).  (A) Transmural or full thickness infarct. (B) Regional  subendocardial infarct.   RCA: right coronary artery LCA: left coronary artery  LAD: left anterior descending LCX: circumflex coronary artery   MI comprises necrosis and acute inflammation. The ne-  crotic tissue is gradually replaced by a collagenous scar.  The entire process from coagulative necrosis to scar for-  mation takes 6-8 weeks, the macroscopic and micro-  scopic appearances of the infarct changing with time  (Fig. 6.19). The extensive necrosis of cardiac muscle is  associated with the release of cardiac enzymes and pro-  teins that can be used as clinical markers for a MI event.  Examples include troponin T creatinine kinase (CK-MB  cardiac isoform) and lactate dehydrogenase.   The effects and sequelae of MI are variable, and they can  be classified into:   infarcted muscle appears  uncolored on staining with  nitroblue tetrazolium due to  loss of oxidative enzymes;  non-infarcted muscle stains  blue   1. Arrhythmias — due to the involvement of conduc-  tion tissue, leading to ventricular fibrillation, atrial  fibrillation, heart block and sinus bradycardia.  Nearly all MI patients have some form of arrhyth-  mia, usually resolving spontaneously.   2. Left ventricular failure — this is common with large  areas of infarction; the necrotic wall softens in organi-  zation leading to cardiac dilatation. Ventricular remo-  delling is the process of thinning and stretching of the  infarcted segment, with progressive dilatation and hy-  pertrophy of the remaining ventricle.   I. external (majority) — blood bursts through the  external wall into the pericardial cavity (haemo-  pericardium); the sudden rise in intrapericardial  cavity pressure prevents cardiac filling (cardiac  tamponade), leading to rapid death   II. internal (rarely) — intracardiac rupture through  the septum leads to an acquired septal defect,  causing a left-to-right shunt and the develop-  ment of left ventricular failure.   4. Papillary muscle dysfunction — when one or more  valve leaflets are unable to close during systole there  is mitral valve incompetence.   5. Mural thrombosis — on the inflamed endocardium  over the area of infarction; there is a high risk of embo-  lization producing infarction of various organs, e.g.  cerebral, renal, splenic, mesenteric and lower limbs.   1 . Chronic intractable left-heart failure — the long-term  effects of ventricular remodelling result in inade-  quate left ventricular pumping action; common  when the infarct is extensive and full thickness.   2. Ventricular aneurysm (in 10% of long-term survi-  vors) — gradual distension of the weakened fibrotic  part of the left ventricular wall with thrombus for-  mation, embolism or severe functional deficit.   4. Dressler's syndrome — a form of autoimmune-  mediated pericarditis associated with a high erythro-  cyte sedimentation ratio (ESR) and persistent fever;  develops in a very small number of cases after  infarction.   • anticoagulation to prevent reinfarction and reduce  thromboembolic risk (e.g. heparin)   • bed rest for the first 24-48 hours on the coronary care  unit.   Sudden cardiac death is the most important imme-  diate consequence of myocardial ischaemia. It is usu-  ally due to ventricular fibrillation. This may be the  result of:   • previous ischaemic heart disease, e.g. angina or pre-  vious infarction; cardiac arrhythmias can arise from  muscle adjacent to an area of old scarring   • acute myocardial ischaemia, which, due to a new  thrombotic event, may precipitate arrhythmia.   Other causes of sudden death include ruptured or  dissecting aneurysms of the aorta and pulmonary  emboli.   Heart failure can result from many different types of  heart disease. It develops when the heart is no longer  able to maintain an adequate cardiac output, or can  only do so by increasing the filling pressure. The prog-  nosis of heart failure is worse than many cancers; half of  those with severe left-ventricular impairment die within  2 years.   Heart failure may develop acutely (e.g. following  myocardial infarction) or chronically (e.g. gradually  progressing ischaemic heart disease).   This occurs due to either reduced output from the left  ventricle or increased input pressure from the left  atrium. Common causes include:   • hypertension — pressure overload produces initial  ventricular hypertrophy, but this compensatory  change cannot be maintained indefinitely and the  ventricle eventually dilates   works back through the vasculature resulting in pulmo-  nary hypertension. Pulmonary oedema (also termed  pulmonary congestion) and eventual right-sided heart  failure may follow, resulting in symnptoms of dyspnoea  (breathlessness), orthopnoea (breathlessness on lying  flat) and paroxysmal nocturnal dyspnoea (attacks of  extreme breathlessness, usually at night).   The most common cause is progression of left-sided  failure, so-called biventricular heart failure. In these  cases, the right ventricle has to pump against increased  resistance in the pulmonary circulation.   This many result in clinical symptoms of peripheral  oedema, congestive hepatomegaly, and congestive  splenomegaly.   Both types may coexist in one valve but one type is  usually dominant.   The mitral and aortic valves are the most frequently  affected; the tricuspid and pulmonary valves only  infrequently.   Diseased valves often cause regurgitant jets of blood,  with concomitant development of endocardial lesions  opposite the jet's origin. These lesions (jet lesions) are  typically seen on the septum opposite the aortic valve.   1 . Degenerative calcific aortic valve stenosis — calcifica-  tion of the aortic valve associated with increasing  age; typically affects the elderly    2. Bicuspid calcific aortic valve stenosis — calcification  of the congenital bicuspid aortic valve (present in  1% of people); quite common, usually manifesting  by 40-50 years of age.   In both types, the valves become thick and fibrotic  with a fusion of the commissures. Large nodular masses  of calcium may be found subendothelially within the  sinuses of Valsalva, so restricting the opening of the  aortic cusps.   Stenosis and regurgitation result in left ventricular  hypertrophy, coronary insufficiency (often angina),  and syncope or sudden death due to acute left-sided  heart failure.   This is 'wear and tear' of the mitral valve with calcifica-  tion of the valve leaflets. Massive calcification can im-  mobilize the valve and predispose to the development  of either thrombosis or bacterial endocarditis.   The changes here are due to myxomatous degeneration.  The leaflets are thickened and redundant, containing  large amounts of mucopolysaccharides and abnormal  collagen. It most commonly involves the posterior mi-  tral leaflet, which is soft and bulges upwards into the  atrium during systole. The net result is mild valvular in-  competence and an increased risk of rupture of one of  the chordae, which may lead to sudden, severe valvular  incompetence.   Mitral valve prolapse can also be a feature of connec-  tive tissue disorders such as Marfan's syndrome.   Rheumatic fever is an immune disorder that follows  2-3 weeks after a streptococcal infection, usually tonsil-  litis or pharyngitis.   This disease occurs mainly in children aged 5-15 years.  It was once prevalent in Europe, including the UK, and  in the USA. Its incidence has now decreased in the   Left-sided cardiac failure with  predisposition to atrial thrombosis  Left atrial hypertrophy and dilation  leads to:    developed world and it is now most frequently seen in  parts of central Africa, the Middle East and India.   Susceptible individuals develop antibodies to antigens  produced by specific strains of group A streptococci;  these antibodies then cross-react with host antigens.  The disease is a systemic disorder affecting:   The most important target organ is the heart. Re-  peated attacks of rheumatic fever lead to progressive    fibrosis of the endocardium and valves, which is the  main cause of chronic scarring of the valves.   These pathognomonic heart lesions consist of multi-  nucleate giant cells surrounded by activated macro-  phages and lymphoid cells (predominantly T cells).  Lesions stimulate fibroblast proliferation and lead to  scarring.   In the acute phase, rheumatic fever causes a pancarditis,  the components of which are:   • rheumatic endocarditis — mitral valves are most  prone to the development of severe lesions.   The main morbidity of rheumatic fever is the long-term  effects of the immune damage causing chronic scarring  of valves, particularly the mitral valve. Chronic valvular  heart disease develops in about 50% of those affected by  rheumatic fever with carditis. Lesions may develop after  10-20 years in Western countries, but much earlier in  developing countries.   Endocardial valvular damage from the acute phase heals  by progressive fibrosis. Valve leaflets and chordae tendi-  neae become thickened, fibrotic and shrunken, often  with fusion to their partners; there is frequent secondary  deposition of calcium.   Once damage has developed, the altered haemody-  namic stresses extend the damage even in the absence  of continued autoimmune processes.   This is an acute or subacute disease resulting from infec-  tion of a focal area of the endocardium, which usually  has pre-existing damage. It can affect almost any age  group, but it is increasing in incidence in the elderly  population. Predisposing factors in susceptible individ-  uals include genitourinary infection, diabetes, tooth ex-  traction, pressure ulcers and surgical procedures. It is  more common in males than females (3:1).   The characteristic lesions of endocarditis are termed  vegetations. These are formed from deposits of platelets,  fibrin and bacteria. The mechanism of formation is out-  lined in Figure 6.21. Vegetations may form in areas of  high-pressure gradients, for example at an incompetent  valve.   Almost all vegetation occurs on valve leaflets or chor-  dae tendinae. The size varies from a small nodule to a  large mass that may occlude the valve orifice. The mitral  and aortic valves are the most commonly affected.   Pathogens such as Staphylococcus aureus, alphahaemoly-  tic streptococci, pneumococci, meningococci and  Escherichia coli are commonly responsible.   Fig. 6.21 Pathogenesis of vegetation formation in infective  endocarditis. (A) Abnormality on endocardium of valve leaflet is  coated with small deposits of platelets and fibrin (thrombus).   (B) Circulating bacteria or fungi colonize the platelet thrombus.  (C, D) Further layers of platelets and fibrin are deposited, and the  microorganisms proliferate in the superficial layer of the vegeta-  tion. They are separated from blood by a thin layer of fibrinous  material, which protects against immune destruction but allows  diffusion of nutrients. (Adapted from Underwood, 2009.)   Fungi such as Candida and Aspergillus can occasionally  cause endocarditis, particularly in drug addicts, the  immunosuppressed or those with valve prostheses.   The type of causative organism responsible depends  on whether the affected valve is structurally normal or  abnormal.   Infective organisms are pathogenic and directly invade  the valve causing rapid destruction. This is commonly  seen in intravenous drug addicts (often affecting the tri-  cuspid valve), after open heart surgery and following  septicaemia from other causes. Highly virulent forms  of Staphylococcus aureus are often responsible for such  infections.   Infective organisms are of low pathogenicity and are de-  rived from normal commensal organisms of the skin,  mouth, urinary tract and gut. Following trivial episodes  of bacteraemia, organisms become enmeshed in platelet  aggregates on the surface of the abnormal endocardium,  growing to cause persistent infection. The main under-  lying abnormalities in this group are:   The incidence has increased in Western countries  in recent years, mainly as a result of patients surviving  with structurally abnormal hearts and heart valves.   The cause is usually a virulent organism, such as  Staphylococcus aureus. It can affect either normal or ab-  normal heart valves.   The bacteria proliferate in the valve, causing necrosis  and the generation of thrombotic vegetations. Conse-  quently, there is destmction of valve leaflets with perfo-  ration and acute disturbance of valve function leading  to acute heart failure.   Prognosis — disease is rapidly progressive and often fa-  tal due to the incidence of embolic events, renal failure  and heart failure.   The typical cause here is when less virulent organisms,  such as Streptococcus viridans are involved.   The bacteria proliferate slowly in the thrombotic  vegetation on damaged valve surfaces. Gradual  valve destruction occurs, stimulating further throm-  bus formation with the potential for systemic  embolization.   • systemic symptoms — fever, weight loss and malaise  due to cytokines (low-grade infection)   • skin petechiae and microhaemorrhages in the retina  and skin, particularly around the fingernails (splinter  haemorrhages), caused by the deposition of immune  complexes in small vessels — they also cause  glomerulonephritis   • finger clubbing (cause unknown), occasionally  with characteristic Janeway lesions and/or Osier 's  nodes   • Valvular regurgitation due to gradual destruction of  valves leading to cardiac failure.   • Perivalvular abscesses following extension of the in-  fection into the valve ring and myocardium,   • Mycotic aneurysms — infection of the muscular wall  of a medium-sized artery caused by emboli to the  vasa vasorum.   • Multi-organ infarction — small emboli of infected  thrombotic material enter the systemic circulation  producing infarction of many organs especially the  brain, spleen and kidneys. Infarcted organs may in  turn become infected by organisms within the  occluding thrombus.   Non-bacterial thrombotic endocarditis is inflamma-  tion of the valves with the formation of sterile throm-  botic vegetations (marantic vegetations) on the closure  lines of valve cusps. It occurs in severely debilitated pa-  tients with serious systemic disease, particularly  malignancy.   Thrombotic vegetations complicate SLE in 50% or more  of fatal cases. The vegetations are small, meaning that  valvular changes rarely give rise to any appreciable func-  tional deficiency, but thrombotic material can fragment  and cause embolic infarction.   Carcinoid syndrome is caused by excess 5-hydroxy-  tryptamine secretion by a carcinoid tumour (usually  of the small intestine, which has metastasized to the  liver) and can result in endocardial fibrosis of the tricus-  pid and pulmonary valves, in turn resulting in stenosis  or incompetence.   • valve failure due to breakage of a mechanical pros-  thesis, or tissue calcification and cusp rupture of  bioprosthesis   • infective endocarditis from turbulence and pros-  thetic material; its incidence is 1-2% per year   • obstructive gradients — the valve may be too small or  there may be tissue ingrowth of the pannus onto the  valve ring   • haemolysis of red blood cells passing through a me-  chanical valve, occasionally leading to jaundice.   The precautions are lifelong anticoagulation (with war-  farin) and appropriate prophylactic antibiotic therapy  to protect against infective endocarditis, e.g. before den-  tal procedures.   This is a group of disorders in which the structural or  functional abnormality primarily affects the myocar-  dium. It should only be considered if all other potential  causes of myocardial impairment have been excluded.   Cardiomyopathies usually cause progressive develop-  ment of cardiac failure. The time scale varies from weeks  to years depending on the specific pathology. In some  instances, sudden cardiac death is the first manifesta-  tion of disease.   2. Secondary cardiomyopathies — diseases of the heart  muscle associated with/caused by a systemic disease.   The terms ‘cardiomyopathy’ and 'myocarditis' are  frequently confused: myocarditis refers to  inflammation of the myocardium and it is a form of  secondary cardiomyopathy, but it is not synonymous  with cardiomyopathy.   Primary cardiomyopathies follow three main patterns  according to the dysfunction of the myocardium —  dilated, hypertrophic obstructive or restrictive.   These are abnormalities of the myocardium causing  poor systolic contraction. They are characterized by:   Aetiology is often unidentifiable but the condition  may represent end-stage myocardial damage for known  causes, including viral myocarditis, alcohol and other  forms of secondary cardiomyopathies.   A familial condition (usually autosomal dominant)  resulting in systolic function with marked reduction  in systolic volume and difficulty in diastolic filling. This  is characterized by:   • gross hypertrophy of the heart walls, particularly  affecting the interventricular septum    The genetic mutations identified tend to affect the  production of proteins making up the myocardial mus-  cle unit (sarcomere). This condition may present in  young adults and juveniles with sudden unexplained  death on exertion (hypertrophic obstructive cardiomy-  opathy, HOCM). Less dramatic presentations include  angina and breathlessness on exertion in a young per-  son or repeated fainting attacks.   Abnormal stiffness of the myocardium results in im-  paired ventricular filling during diastole. The stiffness is  caused by infiltration of the myocardium, for example:   • fibrosis in endomyocardial fibrosis (fibrosis of  thrombotic material deposited on the endocardial  surfaces).   The condition causes high atrial pressures resulting  in atrial hypertrophy — > atrial dilatation — > atrial  fibrillation.   This rare disease is characterized by the presence of in-  flammatory cells in the myocardium. The clinical pic-  ture is highly variable, from an asymptomatic disorder  with minor ECG changes, to rapidly progressing heart  failure.   The vast majority of cases of myocarditis are either infec-  tious or immune-mediated. The infectious causes are:   • viruses — viral infection is the commonest cause of  myocarditis in the UK. Coxsackie virus is the com-  monest. Other agents include influenza, echovirus,  HIV, CMV, poliomyelitis or mumps virus   Other less common causes include sarcoidosis (see  Chapter 7) and giant cell myocarditis, an acute fulmi-  nating form of fatal acute myocarditis.   • myxoma — a benign tumour of stellate cells, typically  arising from the endocardium (usually of the left  atrium)   • connective tissue tumours, such as lipomas, fibro-  mas and fibroelastomas   • serous — transudate has a low protein content  (<2g/100mL) and usually contains only very  scanty mesothelial cells. Caused by heart failure,  hypoalbuminaemia or myxoedema   • serosanguinous — exudate with high protein content  (>3 g/100 mL). Occurring with infection, uraemia,  neoplasia or connective tissue disorders   • chylous — accumulation of lymphatic fluid occur-  ring in the presence of lymphatic obstruction of peri-  cardial drainage, most commonly due to neoplasms  and tuberculosis.    The aetiology is of two types: inflammatory (e.g. acute  pericarditis) and non-inflammatory. If non-inflammatory,  at least one of the following effects must have occurred:   • l plasma oncotic pressure, e.g. cirrhosis and the  nephrotic syndrome.   Clinical effects depend on the increase in pressure  within the pericardium which, in turn, depends on:   • volume of effusion — the greater the volume the  greater the interference with cardiac function   • compliance characteristics of the pericardium — even  small effusions may cause marked elevation of pres-  sure if there is stiffness of the pericardium, e.g.  chronic constrictive pericarditis.   The condition is often asymptomatic, but it may pre-  sent with a dull constant ache in the left side of the chest.  Unlike ischaemic cardiac pain, it is accentuated by inspi-  ration, by movement, and by lying flat.   This is the accumulation of blood in the pericardial sac.  The causes of haemopericardium are outlined in  Figure 6.24. In most cases, death occurs rapidly due to  the sudden rise in intrapericardial cavity pressure, which  prevents cardiac filling (cardiac tamponade): as little as  200-300 mL usually being sufficient.   Fluid (of any kind) accumulates under high pressure,  compressing the cardiac chambers to such an extent that  filling of the heart is severely limited, resulting in acute    heart failure. The condition is often associated with ma-  lignant disease.   • increased jugular venous pulse (often with a further  rise on inspiration — Kussmaul's sign)   shows the presence of pericardial effusion with right  ventricular diastolic collapse) and cardiac catheteriza-  tion combined with pericardiocentesis.   The management of cardiac tamponade depends on  the extent of haemodynamic compromise. Severe cases  may be rapidly fatal and require relief by emergency para-  centesis; less critical cases require formal surgical drainage.   Pericarditis, i.e. inflammation of the pericardium, is the  main disorder of the pericardium. The condition is of-  ten complicated by the development of an effusion.   In acute pericarditis both pericardial surfaces (visceral  and parietal layers) are coated with a fibrin-rich acute  inflammatory exudate. The loss of smoothness leads  to the clinical sign of a friction rub. The causes of acute  pericarditis are listed in Figure 6.25.   • serous, non-bacterial inflammation — the exudate is  a clear, straw-coloured and protein-rich fluid   • serofibrinous or fibrinous — occurs with MI. The ex-  udate contains plasma protein including fibrinogen.  This is the most common form of acute pericarditis   • caseous — fibrinous exudate with granulation tissue  and areas of caseation caused by tuberculosis.   • pleuritic chest pain — typically retrosternal pain radi-  ating to the shoulders and neck   Myocardial infarction: local pericarditis over infarct is the commonest cause of pericarditis   Viral infections: second most common cause, usually clinically mild, rarely requiring hospital treatment  Pyogenic: e.g.staphylococci, streptococci, haemophilus septicaemia or pneumonia  Tuberculosis: spread to pericardium from tuberculous lymph nodes in mediastinum; now rare   Malignant pericaritis: usually due to infiltration of pericardium by local spread from a primary bronchial  tumour; less commonly the cause is blood-borne metastases from a distant site,  e.g. malignant melanoma   Immune pericarditis: associated with rheumatic fever or may present in patient with systemic   Although fibrinous pericarditis may resolve completely,  it occasionally results in fibrinous adhesions or even in  complete obliteration of the pericardial sac.   Progressive fibrosis and calcification of the pericardium  cause restriction of ventricular filling and interference  with ventricular systole. The heart is effectively encased  in a solid shell and filling is impaired. Calcification may  extend into the myocardium, producing impaired myo-  cardial contraction.   This condition often follows tuberculous pericarditis,  but it can also complicate haemopericardium, viral peri-  carditis, rheumatoid arthritis and purulent pericarditis.   In chronic pericarditis, the fibrous tissue impairs venous  return resulting in symptoms and signs of systemic ve-  nous congestion, namely raised jugular venous pres-  sure, enlarged liver and ascites. Atrial fibrillation is  also common.   Rheumatic disease of the pericardium is an acute form  of pericarditis occurring with generalized pancarditis  following streptococcal infection.   An aneurysm is an abnormal localized, permanent, dila-  tation of an artery. The term can also be applied to the wall  of the heart. Types of aneurysm are shown in Figure 6.26:   • True aneurysms — the wall is formed by one or more  layers of the affected vessel. These can be saccular or  fusiform   • False aneurysms (pseudoaneurysms) — the vascular  wall is breached (usually following trauma or infec-  tion), allowing communication with an extra-  vascular space that is limited by surrounding tissue  (usually an organized haematoma).   Saccular aneurysms take the form of globular sacs,  whereas fusiform aneurysms are spindle-shaped due  to long segments of the vessel wall being affected  around the whole circumference.   • Atherosclerosis — the most common cause, typically  affecting the abdominal aorta causing thinning and  fibrous replacement of media.   • Cystic medial degeneration — focal degeneration of  media with the formation of small cyst-like spaces  filled with mucopolysaccharide. Aetiology may be id-  iopathic or associated with connective tissue diseases,  e.g. Marfan's syndrome and Ehlers-Danlos syndrome.   • infectious aortitis, e.g. syphilitic aortitis (rare, typically  affecting the ascending and transverse portions of the  aortic arch causing inflammatory destruction of the  media with fibrous replacement) and mycotic aneu-  rysms (small saccular dilatations with destruction of  the wall caused by bacteria in infected thrombus)   • vasculitic syndromes (see pages 82) — inflammation  of the vessels caused by immune complex deposi-  tion or cell-mediated immune reactions of the arte-  rial wall leading to a weakening of the vessel wall  then aneurysmal dilatations   The majority of aneurysms occur because of a weaken-  ing of the arterial wall with loss of elasticity and contrac-  tility. Stretching of the weakened wall is gradually  progressive due to haemodynamic pressure forces pro-  ducing an increased thinning of the wall until eventual  rupture occurs.   The build-up of layers of thrombus within the lumen  of the aneurysmal sac is protective, but not usually suf-  ficient to repair the defect and reconstitute a normal lu-  men to the artery.   The most frequent cause of an aneurysm is an  atheroma. However, any abnormality that weakens  the media may predispose a patient.   The main complications of aneurysms are rupture with  critical haemorrhage and predisposition to thrombosis.  The risk of rupture is usually greater with an increased  size of aneurysm; high blood pressure is the most im-  portant factor in increasing the rate of growth.   Abdominal aortic aneurysms (AAAs) are more common  in men, especially over 60 years of age.   Aetiology — Atherosclerosis is the most common  cause of abdominal aneurysms. However, they may also  arise as a result of inflammation (vasculitis) or infection  (mycotic aneurysms).   Site — 80% of AAAs are situated below the origin of  the renal arteries and are thus amenable to resection  and replacement by graft.   The majority of AAAs are asymptomatic, but occasion-  ally patients are aware of a pulsatile mass. It is often first  suspected because of aortic dilatation observed on radio-  graphs, especially if the walls of the aneurysm are  calcified. It may also come to attention by careful palpa-  tion during physical examination.   Symptoms may occur because of compression of  neighbouring structures by the expanding aneurysm,  e.g. back pain from vertebral compression, or vomiting  following duodenal obstruction.   Confirmation of an AAA is achieved by ultra-  sonography CT, MRI or arteriography.   Rupture is the most devastating consequence and is of-  ten fatal. This may occur suddenly without warning or,  alternatively, blood may slowly leak into the vessel wall  resulting in pain and local tenderness.   Haemorrhage can occur into the retroperitoneal  space, abdominal cavity or erode into the intestines  resulting in massive gastrointestinal (GI) bleeding.   Thrombus formation on large atheromatous plaques  is favoured, increasing the risk of embolic events, e.g.  stroke.   Fifty per cent of all abdominal aortic aneurysms that are  more than 6 cm in transverse diameter rupture within  2 years if not surgically resected. Aneurysms less than  6 cm across may also rupture, albeit less frequently.   Elective surgical repair has a much lower mortality than  emergency surgery for rupture and it is, therefore, recom-  mended for most AAAs greater than 5.5 cm in diameter,  or those which are rapidly progressing or symptomatic.  Mortality for surgical repair of abdominal aneurysms is  also lower than that of thoracic aneurysms.   An aortic dissection is a tear in the intima of the aorta  allowing the entry of blood into media with separation  of a 'flap' of intima from the rest of the aortic wall.  A false lumen is created, usually between the inner  two-thirds and outer third of the medial thickness  giving the appearance of a doublebarrelled aorta.   1 . Type A (67% of dissecting aneurysms) — arise in the  ascending aorta with or without extension into the  descending aorta.   2. Type B (33% of dissecting aneurysms) — are con-  fined to the descending aorta, distal to the origin  of the left subclavian artery.   Epidemiology — there are approximately 600 cases per  year in the UK, occurring most commonly in people be-  tween 50 and 70 years old and affecting males more  than females by 2:1.   • externally — external rupture leads to massive fatal  bleed into the thoracic cavity or, less commonly,  the pericardial sac, pleural cavity or abdomen   • sudden onset severe chest pain, radiating back  between the shoulder blades   • Type B — hypertension control with bed rest; surgical  intervention may be needed if there is leakage or  organ ischaemia.   Prognosis — this condition is fatal without treatment:  25% die within 24 hours, 50% within the week, and al-  most all by 1 year.   This is a group of disorders characterized by inflamma-  tion of the blood vessel walls (vasculitis). Vasculitis can  affect capillaries, venules, arterioles, arteries and, occa-  sionally, large veins.   • mild cases — transient damage to the vessel wall,  which produces leakage of red blood cells   • severe cases — irreversible vessel wall destruction  resulting in ischaemia and organ damage with asso-  ciated systemic disturbances, commonly fevers, my-  algias, arthralgias and malaise.   the vessel affected (Fig. 6.27) or according to the path-  ogenesis of the inflammation (Fig. 6.28).    Fig. 6.27 Classification of vasculitis according to  size of affected vessel   Syphilitic aortitis  Takayasu's disease  Giant cell arteritis  Kawasaki's disease  Rheumatoid disease   Giant cell arteritis  Scleroderma (systemic sclerosis)  Takayasu's (pulseless) disease  Kawasaki's disease  Buerger's disease    • Scleroderma (systemic sclerosis) — vascular changes  are similar to those of benign or malignant hyperten-  sion, but only about 25% of patients are hyperten-  sive. The condition is associated with progressive  subcutaneous fibrosis leading to a marked tighten-  ing of the skin of the arms and hands; there are no  effective treatments.   • Takayasu's (pulseless) disease — a rare chronic in-  flammatory and granulomatous disorder of the  aorta and its proximal branches, typically affect-  ing young or middle-aged females. The condition  is characterized by severe necrotizing inflamma-  tion of all layers of affected vessel walls with  fibrous replacement of muscle and a reduction  of lumen. It presents clinically with hypertension  or ischaemic symptoms of the arms, with loss of  arm pulses.   • Kawasaki's disease — a disease of infants, primarily in  Japan, affecting the main aortic branch arteries par-  ticularly the coronary arteries. It is characterized by  medial fibroblastic thickening and, sometimes,  aneurysm formation.   • Buerger's disease (thromboangitis obliterans) — a  rare disease with a strong association with smoking,  usually in young males. The condition mainly affects  the small arteries of the arms and lower leg which  show intimal fibrosis, thrombus formation and ad-  ventitial tissue changes affecting adjacent veins and  nerves. Clinically, peripheral gangrene develops in  the fingers and toes; the disease is progressive and  amputations are often required.   Pathogenesis is due to immune complex formation be-  tween antigens and antibodies, which become trapped  in venule walls and stimulate an acute inflammatory re-  sponse with neutrophil chemotaxis. Neutrophils release  enzymes that destroy the vessel wall. There are two main  types:   1. Hypersensitivity (neutrophilic) vasculitis — most  common pattern affecting capillaries and venules;  usually manifests as a skin rash, often as a result  of an allergy to a drug or occasionally arising as an  allergic rash in viraemia or bacteraemia. It also oc-  curs in Henoch-Schonlein purpura, serum sickness  and cryoglobulinaemia.   2. Multi-organ autoimmune diseases, e.g. SLE and  rheumatoid disease (mainly affects the aorta).   Autoantibodies that react against neutrophils  (antineutrophil cytoplasmic antibodies; ANCA) can  be detected in 90% of patients with Wegener's granulo-  matosis and in other types of immune-mediated vascu-  litis. Identification of these antibodies in serum is used  in diagnostic evaluation of patients with possible  vasculitis.   • syphilitic aortitis — tertiary manifestation of syphilis  typically affecting the ascending and transverse por-  tions of the aortic arch causing inflammatory de-  struction of media with fibrous replacement   • other infections — bacteria in infected thrombi can  cause destruction of vessel walls with the develop-  ment of small saccular dilatations and mycotic  aneurysms.   Giant cell arteritis is a systemic disease that mainly in-  volves arteries in the head and neck region, particularly  the temporal arteries (hence the alternative name of  temporal arteritis).   Epidemiology — the disease is relatively common, af-  fecting 10 per 100 000 per year in the general popula-  tion in Europe. Incidence increases with age, and it is  rare in people under 50 years; it affects females more  than males by 2:1.   Aetiology — an idiopathic disease with associations  with certain types of human leucocyte antigen (TILA)  DR (HLA-DR).   • inflammatory cell infiltration — mainly T lymphocytes  but also histiocytes and giant cells (hence the name)   • visual disturbance from involvement of the ophthal-  mic arteries. This is a medical emergency requiring  prompt treatment to prevent blindness   • an association with polymyalgia rheumatica, a mus-  culoskeletal condition causing muscle pain and stiff-  ness classically in the upper body.   or C-reactive protein (CRP). Diagnosis is made by bi-  opsy of the temporal artery with histological investiga-  tion. Management is with high-dose corticosteroid  therapy to control the disease.   This systemic disease is characterized by inflammatory  necrosis of the walls of small and medium-sized arteries.  Although the disease is systemic, it causes patchy and    focal inflammation with only parts of some arteries be-  ing involved.   Epidemiology — a rare disease (about 5-10 per mil-  lion per year in most populations), but it can occur in  all age groups; males more than females by 2 : 1.   Aetiology — the cause is unknown but the presence  of antineutrophil cytoplasmic antibodies (i.e. ANCA  positive) suggests an autoimmune pathogenesis.  There is also an association with chronic hepatitis B  infection.   Pathogenesis — inflammatory destruction of the ves-  sel wall with necrosis of muscle cells and destruction  of the elastic lamina. Healing occurs with fibrous re-  placement of the muscular media. Extensive damage  to the intima predisposes to thrombosis, which is  often followed by vessel occlusion and downstream  infarction.   Clinical features include systemic features of inflam-  mation (fever, weight loss, myalgia and muscle wasting)  and the effects of vessel occlusion producing small areas  of infarction. Tissues most seriously affected are the kid-  neys, GI tract and liver.   Management is by cyclophosphamide with cortico-  steroids, which has significantly improved the outcome.  Antihypertensive drugs reduce morbidity from hyper-  tensive complications.   Haemangiomas are common developmental malfor-  mations composed of dilated vascular spaces derived  from blood vessels.   1. Capillary haemangiomas (strawberry naevi), which  are composed of small, capillary-like vessels.   2. Cavernous haemangiomas, which are composed of  cavernous, endothelial-lined spaces (vein-like vessels).   3. Sclerosing haemangiomas, which are fibrous nod-  ules containing iron pigment produced as a result  of fibrosis or sclerosis of a capillary haemangioma.   Haemangiomas are not 'true' tumours, but they are  often grouped with neoplasms because they appear as  localized tissue masses. They are more accurately  described as hamartomas, i.e. non-neoplastic  overgrowths of tissue.   Dilatations of capillaries are often seen in the elderly  and those with irradiated skin or liver failure (spider  naevi). Vessels are dilated but histologically normal.   A malignant tumour of blood vessel endothelium. This  most commonly occurs as a raised bluish-red patch on  the face or scalp of elderly people, which is often con-  fused with a benign haemangioma.   Progressive enlargement of the tumour is accompa-  nied by ulceration and, later, metastasis to regional  lymph nodes.   Varicose veins are persistently distended superficial  veins in the lower limbs (long and short saphenous  veins). They result from incompetent valves that allow  the veins to become engorged with blood under the in-  fluence of gravity.   Epidemiology — the condition affects 10-20% of the  general population at some age. There is an increasing  incidence with age, and it is most common above 50.  It affects females more than males by 4:1.   Anatomy of varicose veins — the superficial and deep  venous plexuses of the lower limb are connected by per-  forating veins (Fig. 6.30).   Pathogenesis — the return of blood from the deep  veins is aided by normal contraction of the calf and  thigh muscles. If the valves in the perforating veins be-  come incompetent, blood is forced from deep venous  plexuses to superficial venous plexuses resulting in in-  creased pressure in the superficial veins. Combined    with prolonged blood stasis, there is a tendency towards  the development of varicosities.   Varicose leg ulcers are a common clinical condition, and  they are associated with chronic venous insufficiency.   • increased pressure produces a dilatation of the lu-  men and an increased tension on vessel walls with  compensatory hypertrophy of the muscle and elastic  tissues   • prolonged increased pressure produces irregular at-  rophy of muscle and elastic lamina with fibrous re-  placement leading to stretched, tortuous veins with  localized bulging.   • oedema (of lower limbs) due to increased hydro-  static pressure   • varicose ulcers — dermatitis may proceed to ulcera-  tion, which is very slow to heal. Usually on the me-  dial aspect of the ankle or lower leg   Fig. 6.30 Superficial veins of the  right lower limb. (A) Long saphenous  vein. (B) Short saphenous vein. (C)  'Venous pump’ showing valved  perforating veins, which link deep and  superficial veins.    • thrombosis and embolism are very rare sequelae;  these tend to affect deep veins.   Lymphangitis is inflammation of lymphatic channels  draining any focus of infection. The channels are dilated  and contain inflammatory cells. The condition may re-  sult in the spread of the infection in some cases, e.g. in  tuberculosis.   Lymphoedema is oedema of the tissues caused by ob-  struction of the lymphatics.   • filariasis (elephantiasis) — nematode infection of  lymph nodes (most common organism is Wucher-  eria bancrofti); transmitted by the bite of an infected  mosquito   • severe cases result in thickening of skin and overgrowth  of dermal connective tissues leading to elephantiasis.   • Describe common disorders of the upper respiratory tract affecting the nose, nasopharynx and  larynx.   • Describe the pathological processes in chronic obstructive pulmonary disease, including emphysema  and chronic bronchitis.   • Recognize asthma as a common cause of obstructive lung disease and describe the differences between  intrinsic and extrinsic forms.   • Understand the effect of interstitial lung diseases on producing a restrictive pattern of lung function.   • Describe infections of the lung, most notably the pneumonias and tuberculosis.   • Recall the neoplastic diseases of the lung, particularly the four most common pathological patterns.   • Understand disorders of the pleura, notably effusions, pneumothorax and neoplasms.   Rhinitis, inflammation of the nasal mucosa, is the most  common nasal disorder seen in family practice. The  condition may be either acute or chronic.   Infectious rhinitis is usually of viral origin, e.g. the  common cold (rhinoviruses, adenoviruses). Virally in-  duced inflammation of surface epithelial cells is fol-  lowed by exudation of fluid and mucus from the  damaged surface ('runny nose'). Later, submucosal oe-  dema produces swelling, which may lead to a partial  blockage of the nasal airways.   Allergic rhinitis ('hay fever') is a type I (IgE-medi-  ated) hypersensitivity reaction to inhaled materials such  as grass and pollens, producing a mixed serous-mucous  exudate and submucosal oedema leading to nasal  blockage. Eosinophils are prominent in the inflamma-  tory infiltrate.   Chronic rhinitis can be caused by repeated attacks of acute  rhinitis, which often develop a secondary bacterial infec-  tion. It may result in the development of nasal polyps.   Macroscopically, nasal polyps are typically smooth-  surfaced, creamy, semi-translucent, ovoid masses.   Microscopically, they have oedematous tissue with  scattered infiltrate of chronic inflammatory cells includ-  ing plasma cells. Eosinophils are often very numerous in  allergic polyps.   Sinusitis, is inflammation of the paranasal sinuses  (maxillary, ethmoidal, frontal, etc.), usually secondary  to acute or chronic rhinitis. Rhinitis usually results in  the inflammation of the sinus linings; swelling of the  mucosa around the drainage foramen of the maxillary  sinus in the nasal cavity and may cause stasis of maxil-  lary sinus secretions. Stasis predisposes to secondary  bacterial infection with alteration of the static maxillary  fluid from seromucous to purulent.   In severe cases, the infection may spread into the eth-  moid and frontal sinuses with a risk of spread of infec-  tion to the meninges. Orbital cellulitis may also  complicate acute sinusitis.   Chronic sinusitis is charactierized by chronically  thickened and inflamed mucosa of the sinuses and by  persistent fluid accumulation.   This is a syndrome of bronchiectasis, sinusitis and situs  inversus (transposition of viscera). Sinusitis is caused by  abnormal ciliary function resulting in a failure to clear  mucus and bacteria.   This is a condition presenting with progressive granulo-  matous inflammation, ulceration and destruction of  the structures in the upper respiratory tract, i.e. the nose,  nasopharynx, palate and sinuses. It is thought to be a  form of lymphoma affecting natural killer cells, and  may occur alongside lymphomatous disease elsewhere  in the body.   Untreated, death occurs from systemic disease  caused by erosion of blood vessels, local infection or  the development of pneumonia.   This is a squamous or anaplastic carcinoma of the naso-  pharynx (part of the pharynx that lies immediately  behind the nasal cavities) with characteristic abundant  lymphoid tissue in the stroma.   It is strongly associated with Epstein-Barr virus infec-  tion, the virus being demonstrable in tumour cells in  most cases. The carcinoma is most commonly found  in East Africa and South East Asia, but is rare elsewhere  in the world.   The tumours often remain small and undetected un-  til metastasis to the lymph nodes in the neck has  occurred.   The prognosis is good with radiation therapy: the  5-year survival rate is 80% for localized disease and  50% for advanced disease.   This malignant tumour is composed of monoclonal  plasma cells. It presents as a soft, haemorrhagic nasal/  nasopharyngeal mass.   This is a rare tumour presenting in the upper part of the  nasal cavity, often as a haemorrhagic mass with evi-  dence of bone destruction. The tumours usually develop  from neuroendocrine cells found in the olfactory mu-  cosa. They are highly malignant and may metastasize  widely.   This rare benign tumour (also known as juvenile angio-  fibroma) occurs almost exclusively in males between 10  and 25 years old. The lesions are typically located in the  nasopharynx rather than the nose, and may mimic a  malignant tumour due to their rapid growth and ten-  dency to erode bone. Ulceration and bleeding are  common.   This acute inflammation of the larynx may be as a result  of viruses, bacteria, irritants (cigarette smoke), mechan-  ical factors (endotracheal intubation), or overuse of the  voice.   • Spread of infection may occur throughout the  respiratory tract with the development of tracheo-  bronchitis, bronchopneumonia or lung abscesses;  this is more common in the elderly or debilitated  due to a poor cough reflex   • Airway, obstruction — laryngeal oedema can result in  a life-threatening narrowing of the airway especially  in children (whose airways are narrower) suffering  from Haemophilus influenzae epiglottitis or in cases  of corrosive chemical ingestion.   Chronic inflammation of the larynx is most commonly  seen in heavy cigarette smokers. It may lead to a perma-  nent thickening of the laryngeal mucosa and sub-  mucosa, particularly where there is associated excess  production of keratin ('smoker's keratosis').   Overlying epidermis may also undergo keratotic  thickening with dysplastic change in the basal layer; this  is a predisposing factor in the development of squa-  mous carcinoma of the larynx.   Croup is life-threatening acute inflammation and ob-  struction of the respiratory tract involving the larynx,  trachea and epiglottis. It usually affects young children  aged 6 months to 3 years and is typically caused by viral  infection.   Characteristics include symptoms of laryngitis  accompanied by signs of obstruction: inspiratory stri-  dor, a rising pulse rate, restlessness and cyanosis.   Treatment is by reassurance and humidification of  inspired air, which usually reverses the symptoms. In se-  vere cases, the obstruction may require emergency intu-  bation or tracheostomy.   This common benign lesion is associated with upper re-  spiratory tract infection or occurs after vocal abuse, e.g.  shouting. Presentation is with hoarseness that will not  resolve until the polyp is removed.   These are small, benign bilateral laryngeal nodules lo-  cated at the nodal point (junction between the anterior  third and posterior two-thirds of the vocal cords). Nod-  ules are especially common in singers and professional  voice users, and they can alter the character of the voice  even when only a few millimeters in diameter. They  consist of oedematous connective tissue with submuco-  sal fibrosis covered by squamous epithelium.   Reactive nodules of the larynx affect men more than  women. Remember that polyps are unilateral lesions  whereas singer's nodules are bilateral.   Warty papillomas on the larynx are usually due to infec-  tion by the human papillomavirus (HPV 11 and 16).  The lesions are usually solitary and confined to the true  vocal cords.   Juvenile laryngeal papillomatosis  These multiple, soft, pink papillomas on the vocal cords  are largely confined to children. Lesions often extend  into other parts of the larynx, sometimes even down  the trachea, and they have the histological features of  florid viral warts. Spontaneous regression often occurs  at puberty, although the lesions are typically difficult  to eradicate if this does not happen.   This is the most common malignant tumour of the  larynx and accounts for 1-2% of cancers with an inci-  dence of 1 -2 per 1 00 000 per year worldwide. It typically  presents after 40 years of age, affecting males more than  females (but the incidence is rising in females). The  risk factors are smoking, radiation to the head and neck,  carcinoma in situ and keratosis (see above). The  affected sites are:   • glottic region (60%) — arises from true vocal cords.  The best prognosis follows early detection because  this area is alymphatic, which restricts the routes  for metastasis. The earliest symptom is hoarseness,  which should always be investigated if persisting  for more than 4 weeks.    • supraglottic region (30%), i.e. the lower epiglottis,  false cords, ventricles and arytenoids. Less common  laryngeal carcinoma and has a worse prognosis.   • subglottic region (10%) — arising below the true  vocal cords and above the first tracheal ring; poor  prognosis as late presentation is common (rich lym-  phatic supply to this area).   Microscopically, the majority are well-differentiated,  keratinizing squamous carcinomas; a minority are  poorly differentiated with spindle cells.   • local — to adjacent laryngeal structures but often  confined by laryngeal cartilages for a considerable  time. The presence of a palpable neck lump usually  indicates metastatic disease.   • haematogenous — occurs late if at all; lungs are the  most common site.   The prognosis depends on location, extent of spread  and the presence of lymph node metastasis. The overall  5-year survival is as follows:   This is a defective expansion and collapse of the lung. It  may occur as a result of:   Obstruction of the larger bronchial tubes leads to re-  sorption of air from the lung distal to the obstruction.  Causes of obstruction can be within the lung (e.g. mu-  cus plugs in bronchiectasis, inhaled foreign bodies) or  outside the lung (enlarged lymph nodes as in tubercu-  losis or lung cancer).   Patchy atelectasis describes the pattern of atelectasis  associated with chronic obstructive airway diseases.   Compressive atelectasis is the compression of the lung  caused by the accumulation of fluid or air in the pleural  cavity, e.g. following a pneumothorax.   Scarring of the lung may cause contraction of the paren-  chyma and lung collapse.   Surfactant is a surface active agent produced by  type 2 pneumocytes (alveolar cells). It reduces surface  tension and gives the lung sufficient compliance  to expand without collapse. Surfactant loss can be  either developmental or acquired and leads to a  generalized failure of lung expansion, termed  microatelectasis.   Lack of surfactant causes respiratory distress in pre-  mature infants; steroids may be administered to the  mother to aid fetal lung development (and surfactant  production) if premature labour is inevitable.   The collapse of a lung has important clinical con-  sequences as respiratory function will be disturbed  and there is a predisposition to infection. Expansion  can be aided by physiotherapy and bronchoscopy-  mediated removal of the obstructive/compressive  cause. However, prolonged atelectasis becomes  irreversible.   Obstructive lung diseases are those in which there is ob-  struction to the flow of air within the lungs, although  the lungs themselves may be hyperinflated. Disorders  include emphysema, chronic bronchitis, bronchiectasis  and asthma.   Chronic obstructive pulmonary disease (COPD) is  used clinically where emphysema and chronic bronchi-  tis occur together, almost always as the result of long-  term cigarette smoking.   Restrictive lung diseases are those in which there is  obstruction to the expansion of the lungs (e.g. due to fi-  brosis or oedema) such that they can only take in a lim-  ited amount of air. In these diseases, although the lungs  are often underinflated, the rate of air flow is unaffected.  Causes of this restrictive pattern are covered in more  detail later under 'Diffuse interstitial diseases' (see  page 96).   Both obstructive and restrictive lung diseases can  cause significant respiratory impairment with a charac-  teristic pattern of pulmonary function tests (Fig. 7. 1 and  Fig. 7.2).   Chronic obstructive pulmonary disease (COPD) is a  chronic, slowly progressive disease of airflow limitation  caused by an abnormal inflammatory response of the  lungs to noxious substances (usually from cigarette  smoking).   1 . Chronic bronchitis — this causes hyperpalsia of the  bronchial submucosal glands, leading to an in-  creased Reid index.   2. Emphysema — abnormal diltation of air spaces with  destruction of alveolar walls.   3. Bronchiolitis — this describes inflammation of the  small airways (bronchioles).   Chronic bronchitis and emphysema are considered  in more detail in separate sections below.   Common symptoms of COPD are persistent cough,  sputum production and breathlessness. If combined  with a strong history of tobacco or pollutant exposure,  lung function tests are performed (see Figs 7. 1 and 7.2).  These are suggestive of COPD if:    Fig. 7.1 Characteristic patterns of lung function tests in obstructive and restrictive lung diseases    Fig. 7.2 Illustration of a normal, obstructive deficit and  restrictive deficit vitalography.    • forced expired volume in one second (FEV | ) is less  than 80% predicted   • FEVl/forced vital capacity (FVC) ratio is less than  70% predicted   • the limitation is incompletely reversible with broncho-  dilators (e.g. inhaled salbutamol). This distinguishes  the result from asthma, which is fully reversible.   A chest X-ray may show hyperinflation, flat hemi-  diaphragms, reduced peripheral vascular markings  and bullae.   • bronchodilators — often combinations of inhaled f) 2 -  agonists (e.g. salbutamol), anticholinergics (e.g.  tiotropium) and oral theophyllines   The frequency of complications increases with progres-  sion of the disease:   • pneumothorax — bullae are thin-walled airspaces  created by alveolar collapse. Rupture of subpleural  bullae may produce a pneumothorax   Note that in COPD, the respiratory centre may be-  come relatively insensitive to C0 2 , relying on hypoxic  drive to maintain respiratory effort. It is, therefore, poten-  tially dangerous to give these patients high-concentration  oxygen without careful observation, as hypoventilation  or apnoea may result.   Emphysema is a permanent dilatation of any part of the  air spaces distal to the terminal bronchiole, occurring  with tissue destruction but without fibrosis. It is a com-  mon condition, which usually forms part of COPD, but  may occasionally present alone.   The aetiology is unclear, but risk factors are the same  as for COPD, including cigarette smoking, occupational  dusts or chemicals and atmospheric pollution. The  inherited disorder a ! -antitrypsin deficiency predisposes  to early emphysema.   In normal individuals, extracellular elastases secreted  into the lung by inflammatory cells are inhibited by pro-  tease inhibitors (particularly a j -antitrypsin). In emphy-  sema, these inhibitors are either inactivated (e.g. by  cigarette smoke) or absent (inherited disorder), result-  ing in continued activity of the elastases with destruc-  tion of lung parenchyma. Destruction of respiratory  tissue leads to a loss of elastic recoil in the lungs and  a decreased area available for gaseous exchange. About  one-third of lung capacity must be destroyed before  clinical symptoms of emphysema appear.   There are several forms of emphysema, defined by  the location of damage in the respiratory acinus  (Fig. 7.3):   • Centrilobular — dilatation of the respiratory bron-  chioles at the centre of acinus. It is most common  in men and is closely associated with cigarette   • Panacinar — dilatation of the terminal acinus, which  later affects the respiratory bronchioles, thereby af-  fecting the whole acinus. Typically affects the lower  lobes. This pattern is typically seen in inherited ax-  antitrypsin deficiency (caused by variants of the pi  gene with the homozygous piZZ state resulting in  hepatic cirrhosis as well).   • Paraseptal — involves air spaces at the periphery of  lobules, typically adjacent to the pleura. Usually af-  fects the upper lobes adjacent to areas of scarring or  atelectasis.   • Irregular — irregular involvement of the respiratory  acinus and almost always associated with scarring.  It is thought to be caused by the trapping of air fol-  lowing lung fibrosis and it is, therefore, commonly  present around old healed tuberculous scars at the  lung apices.   In the early stages of emphysema, a rapid respira-  tory rate enables individuals to maintain blood  oxygenation, such that levels of PaC0 2 and Pa0 2  are near normal. Patients are breathless but not cya-  nosed (so-called 'pink puffers'). However, on the  slightest exertion patients become increasingly  breathless and ultimately hypoxic (type 1 respiratory  failure). Complications are the same as described for  COPD.   The lungs are hyperinflated, the trachea is often des-  cended (i.e. there is decreased cricosternal distance be-  tween the cricoid cartilage and the sternal notch) and  the accessory muscles may be hypertrophied. Associated  chronic bronchitis may produce cough and sputum.  Breath sounds are quiet, especially over bullae, often  with crepitations or wheezes.   Chronic bronchitis is defined as a cough productive of  sputum on most days for 3 months of the year for at  least 2 successive years. It typically affects middle-aged  men and normally forms part of COPD; most cases  are due to cigarette smoking.   Constant irritation by cigarette smoke causes chronic in-  flammation of the respiratory bronchioles (bronchio-  litis) and increased mucous secretion.   Hypersecretion of mucus is associated with hyper-  plasia of the submucosal mucus-secreting glands.  Proteases stimulate this hypersecretion following  their release by neutrophils recruited as part of the    inflammatory response. The Reid index gives the ratio  of gland to wall thickness in the bronchus, and it is  significantly increased in cases of chronic bronchitis.   Bronchiolar obstruction must be extensive and wide-  spread to give clinical symptoms. Eventually, extensive  mucus plugging leads to the clinical obstructive fea-  tures of the disease with typical cough and sputum  production.   In later stages of the disease, progressive obstruction  may result in patients with hypercapnia, hypoxaemia  and cyanosis (so-called 'blue bloaters'). Other compli-  cations include:   • recurrent low-grade bronchial infections caused by  bacteria such as Haemophilus influenzae and Strepto-  coccus pneumoniae, or viruses such as respiratory syn-  cytial virus and adenovirus   • squamous metaplasia — loss of ciliated cells as a re-  sult of squamous metaplasia can further exacerbate  the problem   • malignancy — persistent injury by smoking may in-  voke dysplastic changes in metaplastic squamous ep-  ithelium, which may ultimately become malignant  (squamous cell carcinoma of the bronchus).   The late complications of COPD discussed previ-  ously may also occur.   Asthma is an increased irritability of the bronchial tree  with paroxysmal narrowing of the airways, which may  reverse either spontaneously or after treatment with  bronchodilators.   This is a common disorder, affecting around 15% of  children and 7% of adults. Its incidence is thought to be  rising, possibly due to environmental atmospheric  pollution.   Asthma can be classified into two categories, depending  on whether there is an allergic basis to the disease:   1. Extrinsic asthma (atopic) — early-onset asthma  triggered by environmental allergens. Individuals  often have a family history of allergic disorders.  IgE levels are raised and an immediate type 1 hy-  persensitivity to the allergen is produced on skin  challenge. This is the most common type of  asthma.   2. Intrinsic asthma (non-atopic) — adult-onset asthma  often associated with chronic bronchitis, as well as  other asthma triggers such as cold or exercise. IgE  levels are normal, there is no family history of aller-  gic disorders and skin testing is negative.   1. Airflow limitation — obstruction is caused by a com-  bination of bronchospasm, oedema and mucous  plugging. This may be spontaneously reversible, or  reversible with bronchodilator treatment.   3. Airway inflammation — it appears that the allergic  inflammation process of extrinsic asthma is driven  by type 2 helper T cells (Th2). With time, airway  remodelling occurs so that the smooth muscles of  the bronchial wall become hypertrophied, increas-  ing airflow limitation.   Remember that both asthma and COPD are obstructive  lung diseases, but there are key differences between  them:   • Asthma is due to a sensitizing agent; COPD is due to a  noxious agent.   • Asthmatic airway inflammation is predominated by  CD4+ T cells and eosinophils; COPD occurs with  predominantly CD8+ T cells, macrophages and  neutrophils.   • Asthma airflow limitation is completely reversible  with bronchodilator medication; COPD is only  partially reversible.   • Early (15-20 minutes) — a rapid onset of broncho-  constriction caused by histamine release from mast  cells. The allergen binds to IgE antibodies on the sur-  face of mast cells causing cross-linking and degranu-  lation (Fig. 7.4).   • Late (4-6 hours) — following recovery from the early  phase, inflammatory mediators released by mast cells  cause activation of macrophages and chemotaxis of  polymorphs and eosinophils into the bronchial  mucosa. These cells release inflammatory mediators  causing a secondary wave of bronchoconstriction  unrelated to exposure to the original antigen (Fig. 7.4).   • Prolonged hyper-reactivity (over days) — an exagger-  ated response of the airway on further re-exposure to  the allergen or other bronchoconstrictor trigger fac-  tors over ensuing days. Persistence of inflammatory  cells within the bronchial wall leads to damage and  loss of epithelial cells.    Fig. 7.4 Pathogenesis of the early and late stages of asthma. (Cl, cellular infiltration; M, mucus; SM, smooth muscle.)   The main structural changes that take place in asth-  matic airways are listed below and illustrated in  Figure 7.5:   • Immune cell infiltration — the bronchial mucosa is  infiltrated by eosinophils, mast cells, lymphoid cells  and macrophages   • Hypertrophy of bronchial smooth muscle due to re-  current bronchoconstriction   • Focal necrosis of the airway epithelium, caused by  prolonged inflammation    • Deposition of collagen beneath the bronchial epi-  thelium in long-standing cases   • Sputum contains Charcot-Leyden crystals (derived  from eosinophil granules) and Curschmann's spirals  (composed of mucus plugs from small airways).   • Mild disease (majority of cases) — acute, intermittent  episodes of bronchospasm (wheezing, dyspnoea  or coughing) are triggered by well-recognized  causes.   • Moderate to severe disease (small percentage) —  increasingly severe and irreversible asthma in mid-  dle or old age (chronic asthma); patients may pre-  sent with signs of respiratory distress.   • Acute severe asthma (formerly status asthmaticus) —  severe, acute disease usually presenting with tachyp-  noeic distress, tachycardia and pulsus paradoxus. Air  entry may be inadequate to generate any wheeze (the  silent chest is an ominous sign) and death may result  from acute respiratory insufficiency.   The main complication is cor pulmonale. Pulmo-  nary vasoconstriction caused by chronic alveolar hypo-  ventilation results in pulmonary hypertension leading   The clinical signs of asthma include widespread,  polyphonic, high-pitched wheezes. In severe chronic  asthma, a barrel chest may develop.   The disease can usually be controlled by treatment  including p 2 -agonists, corticosteroids, theophyllines  and leukotriene receptor antagonists.   Acute severe asthma can be life-threatening. It  requires immediate oxygen, nebulized (l 2 -agonists and  anticholinergics and systemic corticosteroids. Arterial  blood gases should be taken to determine severity; if  life-threatening, intravenous aminophylline or  magnesium sulphate may be of use.   • Remission — approximately 50% of cases of child-  hood asthma resolve spontaneously but may recur  later in life; remission in adult-onset asthma is less  likely.   • Mortality — death occurs in approximately 0.2% of  asthmatics accounting for about 2000 deaths per  year in the UK. Mortality is usually (but not always)  preceded by an acute attack and about 50% are more  than 65 years old.   This is an irreversible dilatation of the bronchi or their  branches. Its causes are:   • congenital — cystic fibrosis, primary ciliary dyskine-  sia and Kartagener's syndrome (bronchiectasis, situs  inversus and sinusitis)   • acquired — infection (especially whooping cough,  necrotising pneumonia or measles in childhood)  and obstruction (either by an inhaled foreign body  or by tumour).   Widened bronchi are more prone to infections, Hae-  mophilus influenzae and Pseudomonas aeruginosa being  the most common pathogens. Patients often cough up  purulent sputum, which may contain blood.   Treatment consists of antibiotics (often long-term)  for infections and postural drainage physiotherapy to  drain sputum.   Cystic fibrosis (CF) is a hereditary multisystem disease  characterized by the production of abnormally  thick mucus, and primarily affects the lung and the  pancreas. It is the most common autosomal recessive  disorder affecting 1 in 2000 newborns. Approximately  1 in 25 Caucasians are heterozygous carriers of the  CF gene.   The mutated gene is found on chromosome 7 and en-  codes for a protein termed the cystic fibrosis transmem-  brane regulator (CFTR). The most common mutation is  deletion of the phenylalanine residue at position 508,  which is found in 70% of cases. This protein normally  enables the transport of chloride ions across cell mem-  branes. In cystic fibrosis, defective CFTR results in im-  paired chloride transport, which prevents the release  of sodium and water to liquefy mucus. The net result  is the production of extremely thick and viscous mucus  by the exocrine glands.   • Intestine — causing meconium ileus in newborn  babies and distal intestinal obstruction syndrome  later in life   • Pancreas — causing deficiency of the pancreatic en-  zymes, resulting in malabsorption and failure to  thrive    In the respiratory tract, the bronchi and bronchioles  become obstructed by abnormally viscid mucus, which  leads to four main problems:   1. Infections — obstruction and stagnation of secre-  tions leads to repeated bouts of infection, particu-  larly with Staphylococcus aureus and Pseudomonas  aeruginosa. Burkholderia cepacia infection is often in-  trinsically resistant to multiple antibiotics and some  forms are transmissible between patients. This has  resulted in the segregation of CF patients in hospi-  tals and the community.   3. Hyperinflation of the lungs due to air trapping be-  hind mucin plugs; increased risk of developing  spontaneous pneumothorax.   4. Hypoxia, scarring and destruction of the pulmonary  vascular bed, leading to pulmonary hypertension  and cor pulmonale.   The median age of survival is just over 30 years, but  newly born CF sufferers are now expected to live beyond  40 years. Newer drugs, such as DNAase mucolytics and  nebulized tobramycin (an antibiotic), appear to reduce  the rate of decline. Future treatment goals include the  replacement of the defective gene using gene therapy  strategies.   Interstitial lung diseases are a group of non-infectious,  non-malignant disorders in which there is inflamma-  tion of the alveolar walls with a thickening of the inter-  stitium between the alveoli, usually with fibrosis. This  large group of diseases occurs with a mainly restrictive  pattern (see Fig. 7.1).   Disorders can be classified into broad groups, as  shown in Figure 7.6. There are thought to be over 200  distinct diffuse interstitial conditions. The most impor-  tant of these are discussed below.   This disease, of unknown aetiology, is rare but increas-  ing in incidence. It mainly affects the elderly, and males  more than females. Fibrosis occurs at the lung bases,  resulting in peripheral 'honeycombing'. This describes  the appearance of the cut surface of the lung (and can  be seen using high-resolution CT scanning).   As with all diseases causing interstitial fibrosis, there  is some inflammation involving neutrophil and lym-  phocyte infiltration. Even the earliest lesions show focal  accumulation of fibroblasts; such foci become more col-  lagenous as the disease progresses. Fibrosis results in al-  veolar wall collapse and the production of cystic spaces.   Macroscopically, the lung is converted into a mass of  cystic airspaces separated by areas of dense collagenous  scarring.   Connective tissue disease, e.g. rheumatoid disease, scleroderma  Drug- or toxin-induced disease, e.g. nitrofurantoin, amiodarone,  methotrexate   Pneumoconiosis, e.g. coal-worker's pneumoconiosis, silicosis orasbestosis  Extrinsic allergic alveolitis, e.g. farmer's lung, bird fancier's lung   Part of a systemic inflammatory disease, e.g. acute respiratory distress  syndrome (ARDS)   Diffuse intrapulmonary haemorrhage, e.g. Goodpasture's syndrome  Rare disorders, e.g. alveolar proteinosis, histiocytosis    The clinical feature of the early-stage disease is a  slowly increasing respiratory insufficiency due to re-  duced lung capacity and residual volume, reduced com-  pliance and reduced diffusion capacity.   The characteristic signs are dyspnoea, cough and fin-  ger clubbing. There is a restrictive pattern of lung func-  tion tests. Median survival is 4 years, although the  response to traditional end-stage drug regimens is very  variable (usually corticosteroids and azathioprine).   This is a group of interstitial lung diseases resulting from  chronic exposure to inorganic dust. The three most  common types of pneumoconioses are coal-worker's  pneumoconiosis (CWP), silicosis and asbestosis.   In the normal lung, inhaled dust is coughed out, or  ingested by macrophages. However, if the dust is toxic  to macrophages there is local inflammation, secretion  of cytokines and stimulation of fibrosis. The end result  is a restrictive pattern of respiratory dysfunction.   CWP is an interstitial lung disease caused by inhaling  coal dust. It has three types of pathology:   1 . Simple coal-worker's pneumoconiosis — not usually as-  sociated with any clinically significant impairment of  respiratory function, despite focal aggregates of dust-  laden macrophages. The condition does not progress  if the affected individual leaves the mining industry.   2. Progressively massive fibrosis — large nodules and  scarring results in severe respiratory impairment.  The upper lobes are predominantly affected and there  may be cavitation of the nodules. This condition may  progress even after leaving the mining industry.   This is caused by the inhalation of quartz-containing  dust (quartz being silicon dioxide), which is abundant  in stone and sand.   It is associated with occupations such as slate mining,  quarrying and stone masonry.   Tuberculosis is a common complication of silicosis  (silicotuberculosis). This is thought to be due to im-  paired local defences as a consequence of accumulated  silica in macrophages.   This interstitial lung disease is caused by the inhalation  of asbestos, a fibrous silicate mineral that was widely  used between 1890 and 1970. It is associated with    occupations involving asbestos mining/processing, the  building industry, insulating and fire-resistant material  and shipyard and ship's engine-room work. There are  two main forms of asbestos:   1. Serpentine asbestos (white asbestos) — this is the  most common form; fibres persist in the lung for  a limited time.   2. Amphibole asbestos (blue and brown asbestos) —  fibres persist in the lung for many years and are  the main cause of malignant mesothelioma.   Risk of disease depends on the duration and intensity  of exposure, and the type of asbestos (short fibres are  less pathogenic).   • there is usually a latent period of 25 years before  clinical symptoms become evident   • interstitial fibrosis is maximal at lung bases and as-  bestos bodies may be seen histologically. Asbestos  bodies are fibres coated in acid mucopolysaccha-  rides and haemosiderin   • the disease progresses with an increasing restrictive  defect associated with interstitial fibrosis   • pulmonary hypertension and cor pulmonale de-  velop in the late stages.   Sarcoidosis is a multisystem disease of unknown  aetiology characterized by the presence of non-  caseating granulomas primarily affecting the lymph  nodes and lungs.   Maximum incidence is in people between 30 and  40 years of age, affecting slightly more females than males.   Other affected sites are the skin, eyes, liver, spleen,  nervous system, phalanges, parotid glands and (rarely)  the heart.   The aetiopathogenesis is unknown but thought to in-  volve the type IV hypersensitivity reaction. The disease  seems to be less common in smokers and more com-  mon with increasing geographical distance from the  equator.   Histology shows non-caseating histiocytic granulo-  mas in the lung interstitium. Patients with lung in-  volvement present with slowly progressive dyspnoea  and cough and are found to have lung shadowing on  chest radiograph with enlargement of the hilar lymph  nodes.   Diagnosis — there are no diagnostic blood tests for  sarcoidosis, but there is often hypercalcaemia, raised se-  rum angiotensin converting enzyme and a reduced tu-  berculin skin test. The definitive diagnosis is  histological, requiring a tissue sample, e.g. skin lesion  biopsy, transbronchial biopsy.   • Goodpasture's syndrome — a diffuse pulmonary  haemorrhagic syndrome caused by complement  activation following autoantibody binding to the  basement membrane.   • Idiopathic pulmonary haemosiderosis — a rare con-  dition with type II pneumocyte hyperplasia.   • Rheumatoid disease — the lung and pleura are af-  fected in 10-15% of patients.   • Extrinsic allergic alveolitis — immune mediated in-  terstitial granulomatous inflammation caused by in-  halation of organic agents (type III and type IV  hypersensitivity). Examples include farmer's lung  and pigeon-fancier's lung. See figures 7.6, 7.7.   Pneumonia is defined as the infection of alveolar tissue  resulting in the consolidation of lung tissue with an  intra-alveolar inflammatory exudate.   Pneumonia is the fifth most common cause of death  in the USA. It is most common in the very young and the  elderly.   Although pneumonia frequently occurs in previously  healthy individuals, it is also predisposed by the pres-  ence of debility and immobility:   • Suppressed cough reflex, e.g. in coma, anaesthesia  and neuromuscular junction disorders   • Impaired mucociliary clearance, e.g. through ciga-  rette smoke, irritant gases, viral diseases (e.g. influ-  enza) and genetic conditions (e.g. immotile cilia  syndrome)   • Immunosuppression, e.g. drugs (cytotoxics and im-  munosuppressives), AIDS, congenital immunodefi-  ciencies and leukaemias   • microbiology — causative organism may be bacterial,  viral, fungal or protozoal   • clinical classification — according to circumstances  surrounding the development of disease, e.g. com-  munity acquired, hospital acquired, disease of im-  munosuppression or aspiration pneumonia.   Bacterial infection is the most common type of pneu-  monia, accounting for 80-90% of cases. Knowledge  of the circumstances in which a person develops pneu-  monia is a strong clue as to the likely organism causing  the infection (Fig. 7.8).   The clinical features are fever, shortness of breath,  cough, pleuritic pain and sputum (occasionally with  haemoptysis). There are signs of consolidation with  bronchial breathing and/or coarse crackles. Confusion,  uraemia, tachypnoea (raised respiratory rate) and hypo-  tension are signs suggestive of severe infection requiring  hospital admission.   As a general rule of thumb, community-acquired  pneumonia is usually caused by Gram-positive bacteria  whereas hospital-acquired pneumonias are mainly due  to Gram-negative bacteria.   Infection is centred on the bronchi but with the extension  of the inflammatory exudate into the alveoli, causing a  patchy consolidation of the lung (lobular distribution).  Bronchopneumonia is illustrated in Figure 7.9.   The condition primarily affects the very young, very  old or debilitated patients.   The infecting organism depends on whether the in-  fection is hospital or community acquired, but it is quite  often of the hospital-acquired variety due to underlying  disease.   Patients develop retention of secretions, which gravitate  to dependent parts of the lungs and become infected,  hence bronchopneumonia most commonly involves  the lower lobes.   Macroscopically, multiple areas of consolidation  usually occur distributed bilaterally around bronchi/  bronchioles in dependent parts of the lung. Affected  areas are firm and airless and have a dark red or grey   appearance. Bronchial mucosa is inflamed and pus may  be present in the more peripheral bronchi. Patchy col-  lapse is associated with bronchial obstruction. Involve-  ment of the pleura is common with purulent pleuritis.   Microscopically, there is acute inflammation of the  bronchi and bronchioles with an acute inflammatory  neutrophil-rich exudate present in the lumina and  extending into the peribronchial alveoli.   • resolution — complete resolution occurs only if treat-  ment is instituted early, before the onset of structural  damage   • bronchial damage — imperfect repair of the bron-  chial mucosa results in scarring of the bronchial  wall, with increased predisposition to further infec-  tion and to bronchiectasis   As well as organisms responsible for community-acquired  pneumonia (but much less frequently)   • empyema — pus in the pleural cavity as a result of ex-  tension of infection into the pleural cavity   • death — very common cause of death, particularly as  a terminal manifestation of debilitating diseases.   This is a uniform or homogenous consolidation of part  of a lobe or of the whole lobe caused by infection  (Fig. 7.10). The condition often affects otherwise  healthy adults, primarily between the ages of 20 and  50 years old. Individuals living in poor social condi-  tions, and alcoholics who have reduced access to good  medical care, are particularly prone to this pattern of  pneumonia, which is often caused by Streptococcus  pneumoniae.   Organisms gain entry to distal air spaces without colo-  nization of bronchi. Infection spreads rapidly through  the alveolar spaces and bronchioles, causing acute in-  flammatory exudation into air spaces.    Microscopically, the alveoli are filled with an acute  inflammatory exudate, which is limited by the pulmo-  nary fissures.   2. Red hepatization — massive accumulation of red  cells and polymorphs in the alveolar spaces, giving  a liver-like consistency (hence 'hepatization')   4. Resolution — most patients recover with their lungs  returning to normal structure and function.  Complications and sequelae are as follows:   • Lung fibrosis — inflammatory exudate is often not  completely absorbed but is organized with residual  fibrous scarring and permanent lung dysfunction.   • Bacteraemia — bacterial dissemination of organisms  can lead to septicaemia with meningitis, arthritis,  endocarditis or pyemic abscesses.   • Empyema — pus in the pleural cavity as a result of ex-  tension of infection into the pleural cavity.   This is an inflammation of the alveolar septa by inflam-  matory cells (acute interstitial pneumonitis) in the ab-  sence of any consolidation. Patients develop fever, dry  cough and dyspnoea, but there is little sputum and  few signs of consolidation, hence the term 'atypical'  pneumonia. It may be caused by several factors includ-  ing infection by viruses, Mycoplasma, Chlamydia and  Rickettsia species.   This is a common cause of pneumonia in early child-  hood but is much less frequent in healthy adults. The  majority of viral lung infections cause an atypical pneu-  monia, which is typically self-limiting (e.g. cytomegalo-  virus, measles or varicella). Llowever, these infections  can prove fatal in an immunocompromised host.   A minority of viruses cause a much more severe pat-  tern of infection. The influenza viruses can cause an  acute fulminating pneumonia with pulmonary haemor-  rhage; the clinical course may be rapidly fatal.   A common complication is secondary infection with  pyogenic bacteria, due to the stripping of the respiratory  epithelium by the initial viral infection. This can trans-  form a mild viral lung infection into a severe suppura-  tive bronchopneumonia, particularly after influenza  infection.   Mycoplasma species account for 15-20% of community-  acquired pneumonia. It is more common in children  between 5 and 15 years old, but more serious in adults.  The organisms cause a low-grade, chronic, atypical  pneumonia that can result in pulmonary fibrosis. It  may occur in epidemics.   A number of chlamydial and rickettsial infections are  complicated by the development of pneumonia. Such  infections include typhus, psittacosis and Q fever. Fatal  cases are rare, except in psittacosis.   The lungs of immunocompromised patients are ex-  tremely prone to disease by opportunistic infections,  i.e. infections caused by microorganisms that are non-  pathogenic to healthy, immunocompetent individuals.  Common opportunistic agents include:   • viruses — cytomegalovirus, respiratory syncytial vi-  rus, varicella-zoster virus, measles (see primary  atypical pneumonia, above). Cytomegalovirus  pneumonitis is particularly common after bone mar-  row transplantation   • fungi — both Candida and Aspergillus can cause  widespread areas of necrosis with the formation  of microabscesses containing characteristic hyphae,  e.g. invasive pulmonary aspergillosis. Mortality  is high   • protozoa — Pneumocystis carinii pneumonia (PCP) is  common in AIDS patients, affecting 30-50% of  cases. Alveoli are filled with a fine, honeycomb-  like material in which the small fungal yeasts of  the infection can be seen. This disease has a very  high mortality rate in patients with AIDS if not  treated.   Pulmonary tuberculosis (TB) is a chronic granuloma-  tous infection of the lung caused by Mycobacterium tuber-  culosis. It is overall uncommon in the UK and other  developed countries (at about 10 per 100 000, although  over 40 per 100 000 in London), but extremely com-  mon worldwide (up to 500 per 100 000 in parts of  Africa) where it is a leading cause of death.   Rates in the UK are increasing as a result of HIV in-  fection, the increasingly elderly population, overcrowd-  ing and social deprivation, immigrant populations and  a reduced priority for control. The development of  multi-drug-resistant (MDR) tuberculosis has exacer-  bated this problem.   • Inhalation of Mycobacterium tuberculosis in the form  of droplets (by far the most common mode)   The main form of definitive diagnosis is a positive  Ziehl-Neelsen stain of a patient sample (e.g. sputum).  Such samples should be cultured and tested to assess  drug sensitivity.   • close contact with infected individuals — increased  risk for those living/working in crowded or un-  hygienic conditions and for healthcare workers   • immunosuppression — the very young, very old, im-  munosuppressive therapy and other diseases of im-  munodeficiency, particularly AIDS   • other diseases — pre-existing chronic lung disease  (especially silicosis), diabetes mellitus and  alcoholism.   The destructive effects of infection are entirely due to the  hypersensitivity reaction of the host directed against  bacterial cell-wall constituents. The following sequence  of events occurs:   1. 0-10 days — mycobacteria excite a transient but  marked acute inflammatory response. Neutrophils  phagocytose the organisms but are unable to destroy  them, as the cell walls are resistant to degradation.  Instead, engulfed bacteria are drained into local  lymph nodes.   2. After 10 days — development of a T-cell-mediated  immune response (type IV hypersensitivity reac-  tion) to the bacillary cell-wall constituents results  in cytokine release and macrophage activation.  Gradually a chronic inflammatory pattern develops,  which is dominated by aggregates of macrophages  called epithelioid cells, which form variable num-  bers of granulomas (see Chapter 2) with a central  core of necrotic caseous tissue containing viable  mycobacteria. Tuberculous granulomas are termed  tubercles.   Macroscopically, the granulomas appear as pinhead-  sized white or greyish foci (tubercles) in the tissues.    Microscopically, granulomas are the histological  hallmark of TB infection. A granuloma consists of a cen-  tral area of amorphous caseous necrosis, surrounded by  three cellular layers:   1 . An inner layer of activated macrophages (epithelioid  cells) with Langhans' giant cells   3. An outer layer of fibroblastic tissue, which merges  with surrounding structures and increases with the  age of the lesion.   The healing of a granuloma occurs slowly, with  progressive fibrosis and later calcification. The central  necrotic area remains caseous for some time and myco-  bacteria may remain viable indefinitely within a  healed lesion. This is partly due to the ability of the  Mycobacterium tuberculosis to remain latent within mac-  rophages (inside phagosomes), inhibiting the fusion of  lysosomes. Reactivation results in secondary (or post  primary) tuberculosis.   TB can be classified into two types, according to the  pattern of infection:   1 . Primary infection — the first encounter with the or-  ganism, resulting in the development of a small pa-  renchymal peripheral focus with a large response in  the draining lymph nodes.   2. Secondary infection — reactivation or reinfection  of a previously infected individual, resulting  in the development of a large, localized, parenchy-  mal reaction but with minimal lymph-node  involvement.   The lung is by far the most common site of primary in-  fection, usually occurring in a child or young adult with  no specific immunity. Other sites include the pharynx,  larynx, skin and intestine.   Inhaled organisms proliferate in the alveoli at the pe-  riphery of the lung, often just beneath the pleura. This  primary parenchymal tubercle is termed the Ghon fo-  cus. It is often associated with enlarged caseous hilar  lymph nodes. The combination of lung and lymph  node lesions together constitutes the primary complex  or Ghon complex.   This occurs in the majority of cases (85-90%) and the  episode is often entirely asymptomatic. The Ghon focus  and caseating granulomas in the lymph nodes heal with  fibrosis. The disease does not progress due to the con-  finement of organisms within a fibrotic shell. However,  walled-off bacteria may remain viable within the healed  primary complex (latent tuberculosis). A tuberculin    skin test becomes positive 1-2 months after the onset  of infection.   In patients with poor immunity, the disease is progres-  sive. There is a further spread of mycobacteria with con-  tinuing enlargement of the caseating granulomas in the  lymph nodes (progressive primary TB). Enlarging nodes  spread the infection by eroding into adjacent structures  in two ways:   1 . Bronchus — erosion of an infected lymph node into  a bronchus results in tuberculous broncho-  pneumonia (Fig. 7.11A). The bacilli pass down into  the bronchi of one lung where infection can then  spread into the opposite lung. There is further  spread of infection into the bronchioles and alveoli  with the development of extensive, confluent, case-  ating, granulomatous lesions. This condition is  known as 'galloping consumption' and it is usually  rapidly fatal.   2. Blood vessel — erosion of an infected lymph node  into a blood vessel results in haematogenous spread  of mycobacteria to many parts of the body, includ-  ing the remainder of the lung, causing miliary tuber-  culosis (Fig. 7.11B).   Direct lymphatic spread (i.e. without erosion) may  allow spread to the pleura and pericardium.   This occurs as a result of the reactivation of quiescent  but viable mycobacteria in hosts with weakened im-  mune responses, or as a result of reinfection by addi-  tional organisms. Reactivation occurs in 5-10% of  those with latent infection, usually in the lungs.   Caseous granulomas typically develop in the apical  segments of the lungs, spreading directly and locally  but without lymph node lesions. The initiating apical  lesion is often called an Assmann focus, and it is histo-  logically similar to the Ghon focus.   Spontaneous healing with fibrosis and calcification oc-  curs, though viable organisms may remain without pro-  ducing any clinical symptoms.   In adults with poor immune responses, secondary tu-  berculosis progresses locally with direct extension and  continuing caseation. Further spread of mycobacteria  produces various types of progressive tuberculosis:   • Apical cavitation fibrocaseous tuberculosis — a direct  extension of the infection. Continuing caseation re-  sults in the formation of a large caseous mass   Fig. 7.11 Patterns of progressive  pulmonary tuberculosis. (A)  Tuberculous bronchopneumonia.  (B) Miliary tuberculosis of the lung.   surrounded by a thin cellular wall. If caseous mate-  rial is expectorated, a cavity results. The lesion can  heal at this stage but it may spread further into the  bronchi, bloodstream or directly into the pleura.  Tuberculous pneumonia (see above).    Miliary tuberculosis — the disease becomes widely  disseminated with numerous small granulomas in  many organs. Common target tissues are the kid-  neys, liver, bone marrow and meninges; disease  can, therefore, occur in any of these tissues.    Complications are usually the result of extensive fi-  brosis involved in the healing process:   • Pulmonary fibrosis — lung lesions typically heal with  fibrosis, which may be extensive, producing local-  ized honeycombing. This is common in relapsing  and progressive untreated disease.   • Bronchiectasis — scarring of the bronchial walls can  cause distal pulmonary collapse, secondary infection  and bronchiectasis.   Immunization with the BCG vaccine is common  practice in the UK, with a protective efficacy of 80%.  Treatment of infected individuals involves initial ther-  apy with three drugs (rifampicin, isoniazid and pyrazi-  namide), followed by continued therapy with  rifampicin and isoniazid only. Total treatment lasts  6 months. Ethambutol is added to the regimen where  drug resistance is likely (e.g. in HIV-positive patients)  and the total treatment time may be extended.   Tuberculosis is a good example of a chronic  inflammatory disease. Remember that primary  pulmonary tuberculosis has a small granulomatous  focus but large lymph node response. By contrast,  secondary disease presents with large granulomatous  disease (potentially in a number of different tissues)  and minimal lymph node involvement.   Bronchogenic carcinoma is the most common cause of  death from neoplasia in the UK, affecting 30 000 people  per year. Males are affected more than females, but there  is an increasing incidence in women. The peak inci-  dence is between the ages of 40 and 70 years, reflecting  the cumulative exposure to several potential causative  carcinogens. The risk factors include:   • cigarette smoking — the earlier the age at which smok-  ing starts and the more cigarettes smoked result in an  increased risk. Cigarette smoke contains a large num-  ber of carcinogens, e.g. polycyclic hydrocarbons.  There is a steady decline in risk if smoking stops   • occupational factors, such as exposure to radioactive  material, asbestos, nickel, chromium, iron oxides  and coal gas plants   • environmental factors, such as radon (a natural ra-  dioactive gas in certain geographic areas)    • pulmonary fibrosis — somewhat controversial, but it  appears that there is an increased risk of carcinoma  development in areas of lung affected by fibrosis.  There are four main histological types of lung carci-  noma (Fig. 7.12):   Central or hilar tumours (70%) arise in relation to  the main bronchi extending into the bronchial lumen  and invading the adjacent lung.   Peripheral tumours (30%) arise in peripheral air-  ways or alveoli, often occurring in relation to scars  and frequently extending to the pleural surface.   • Local — central tumours invade locally either  through the bronchial wall into the surrounding  lung or along the outside of the bronchi (peri-  bronchial spread) to distant parts of the lung. Direct  extension into pleura and adjacent mediastinal  structures is a feature of advanced disease. Apical  lung tumours (Pancoast tumours) may invade local  sympathetic ganglia and produce Homer's syn-  drome (ptosis, miosis and anhidrosis).   • Lymphatic spread — carcinomas spread to the ipsilat-  eral and contralateral peribronchial and hilar lymph  nodes. Compression of adjacent tissues by infil-  trated nodes may then cause symptoms.   • Transcoelomic spread — tumour cells may seed  within the pleural cavity, causing a malignant pleu-  ral effusion.   • Haematogenous spread — most commonly to the  brain, bone, liver, adrenal glands and skin.   This is the most common type of lung cancer. It  is thought to be derived from metaplastic squamous  epithelium, which develops to line the main bronchi  as a result of exposure to agents such as cigarette  smoke.   Tumours are typically central and close to the carina,  frequently presenting with features related to bronchial  obstruction. Compared with other types, they are rela-  tively slow growing and metastasize outside the thorax  late; they may be resectable.   Histologically, the tumours show a range of differen-  tiation, from well-differentiated lesions producing lots   Note: ACTH, adrenocorticotrophic hormone; ADH, antidiuretic hormone; HPOA, hypertrophic pulmonary  osteoarthropathy    of keratin through to poorly differentiated lesions with  only a few keratin-producing cells.   These highly malignant tumours arise from the bron-  chial endocrine or APUD cells. They contain a few dense  secretory granules that are also seen in greater numbers  in bronchial carcinoid tumours. Therefore, small cell  carcinoma is thought to represent a type of neuroendo-  crine tumour.   Due to their endocrine nature, this form of cancer  can be associated with paraneoplastic syndrome, the  most frequent of which is adrenocorticotropic hormone  (ACTH); also of note is the syndrome of inappriopriate  ADH secretion (SIADII). Squamous cell carcinoma is  associated with parathyroid hormone-like activity.   Macroscopically, these tumours are usually centrally  located and they are associated with a rapid rate of  growth. Metastases are usually present at the time of  diagnosis.   Microscopically, the cells are round to oval and have  little cytoplasm. All small cell carcinomas are consid-  ered high grade.   This poorly differentiated tumour is thought to be of  either squamous or adenocarcinoma origin. Lesions  may be central or peripheral and they are composed  of large cells with nuclear pleomorphism and frequent    giant cell forms. They have a poor prognosis and are fre-  quently widely disseminated at the time of diagnosis.   This tumour is derived from glandular cells, such as mu-  cous goblet cells, Clara cells, or type II pneumocytes. A  proportion of adenocarcinomas are thought to origi-  nate in areas of pre-existing lung scarring or fibrosis  (scar cancers). Adenocarcinoma has the slowest rate  of growth and is the most common form of lung cancer  in women. It can be linked to passive cigarette smoking  and characteristically develops peripherally. There are  four main histological patterns:   Cigarette smoking is the major risk factor for the  development of neoplastic diseases of the lung. It is  thought to be responsible for over 90% of all lung  carcinomas. Passive smoking has been linked to  approximately 5% of all lung cancers.   There are no early symptoms of lung cancer; it is usual  for a lesion to have been growing for many years before  clinical presentation. The presentations of lung cancer  are outlined in Figure 7.13 and they can be classified  into:   • pulmonary symptoms — most common types of pre-  senting symptom including cough, dyspnoea, chest  pain and haemoptysis   • metastatic symptoms — metastatic spread is present  in 70% of patients at presentation; 30% present with  symptoms caused by metastatic disease   • local symptoms — local spread within the thorax can  cause superior vena cava syndrome (compression of   • non-metastatic extrapulmonary syndromes (para-  neoplastic syndromes) — lung cancer frequently  causes systemic syndromes that are not associated  with metastatic effects and these may rarely be a pre-  senting feature of disease   • asymptomatic: finding a lesion on chest X-ray or  CT scan.   Diagnosis is through clinical features (see above),  imaging (chest X-ray and CT scans) and histological  confirmation techniques:   Horner's syndrome: local invasion of cervical sympathetic ganglion  Hoarseness: spread to the left hilar region may cause recurrent laryngeal nerve palsy  Pain in T1 dermatome and wasting of intrinsic hand muscles: caused by  brachial neuritis as a result of direct invasion of plexus by apical tumours  Pericarditis: due to direct tumour invasion   by low sodium and plasma osmolality with high urine osmolality  Ectopic ACTH secretion: caused by small cell carcinoma and associated  with Cushing's syndrome   Hypercalcaemia: caused by secretion of parathyroid hormone-related  peptide by a squamous cell carcinoma   Lambert-Eaton myasthenic syndrome: associated with small cell tumours  Hypertrophic pulmonary Finger clubbing   osteoarthropathy (HPOA) Swelling of wrists and ankles with periosteal new bone formation (seen   Histological types and the stage of lung cancer deter-  mine the outcome and its likely response to treatment.  Survival is better for early stage disease, except for small  cell carcinoma (very early metastases).   The staging system used for lung cancer is shown in  Figures 7.14 and 7.15.   Tumours are classified as either operable or inoperable,  according to the stage of the disease. For example, dis-  tant metastases and advanced local spread are contra-  indications for surgical resection.   Only 10% of all lung tumours are considered opera-  ble at diagnosis. Many patients are unsuitable for sur-  gery due to comorbidities (e.g. poor cardiac status).  However, 5-year survival rates are as high as 75% in  carefully selected patients with early disease (stage 1).   Tumours are grouped into two categories according to  differences in prognosis and response to radiotherapy  and chemotherapy:   1. Small cell lung carcinoma — very sensitive to radio-  therapy and chemotherapy. However, the disease  is usually extensive at diagnosis such that survival  is still poor despite local control of tumour growth.  Treatment offers good palliation of pain, cough and  dyspnoea. Therapy produces a median survival of  1 1 months (compared with 3 months if untreated)  and a 1-year survival of 45%.   2. Non-small cell lung carcinoma (squamous, large-  cell and adenocarcinoma); inoperable cases may  be treated with radiotherapy depending on clinical  circumstances. The role of chemotherapy is limited.  Overall prognosis is poor with only a 50% 2-year  survival without spread, 10% with spread.   Combination chemotherapy for small cell lung  cancer often involves intravenous cyclophosphamide,  doxorubicin and vincristine given in cycles lasting  3 weeks each. Although small cell cancer is very  sensitive to this therapy, it has almost always  metastasized by the time of treatment. Radiotherapy  alone is rarely radical (curative) in lung cancer but is of  great use in the palliation of symptoms such as superior  vena cava obstruction and pain caused by invasion  of the chest wall.   Tumour < 3 cm; distal to origin of lobar bronchus (Tl)   With (N1) or without (NO) spread to ipsilateral hilar nodes  No metastases (MO)   Tumour > 3 cm, 2 cm distal to the carina, which invades  visceral pleural (T2)   With (N1) or without (NO) spread to ipsilateral hilar nodes  No metastases (MO)   This is a special type of adenocarcinoma derived from  alveolar or bronchial epithelial cells (Clara cells and  type II pneumocytes). There are two types:   1 . Multifocal diffuse infiltrative tumours — replace  areas of lung in a manner resembling pneumonic  consolidation. Cells are tall, columnar, have few mi-  toses and secrete mucin.   2. Single, grey masses of tumour up to 10 cm in  diameter — cells are cuboidal with hyperchromatic  nuclei and mitoses. Cells form papillary structures;  there is often no mucin secretion. In the absence  of metastases, this subtype has a better prognosis  than other forms of lung cancer.   Metastatic deposits may spread to the lungs from distant  primary sites, most often from carcinomas of the breast,  kidney, uterus, ovary, testes and thyroid. Spread is usu-  ally via the blood, most commonly resulting in bilateral  deposits.   These are neuroendocrine tumours of the lungs, repre-  senting about 5% of all pulmonary neoplasms. The ma-  jority are benign, although a minority has the potential  for local recurrence or metastasis (atypical pulmonary  neuroendocrine tumours).   In contrast to intestinal carcinoid tumours, most pul-  monary lesions do not secrete 5-hydroxytryptamine  (serotonin).   These are common but benign lesions of the lung, usu-  ally 1-3 cm in diameter and consisting largely of carti-  lage. They are firm and glistening white in appearance  (often termed chondromas). Other elements are bron-  chial epithelium, fat and muscle. Bronchial hamarto-  mas are asymptomatic and are mainly discovered at  post-mortem examination.   These tumours can be either benign (e.g. neuro-  fibromas, lipomas) or malignant (sarcomas are ex-  tremely rare in the lung).   Pulmonary oedema is defined as an increase in extra-  vascular fluid in the alveolar walls (pulmonary intersti-  tium), which, if severe, subsequently affects the alveolar  spaces.   Normally, a balance exists between hydrostatic pressure  and colloid osmotic (oncotic) pressure such that only  a small amount of fluid passes into the interstitium.  This fluid is drained from the lung via lymphatic  channels.   Pulmonary oedema can result from increased hydro-  static pressure (left ventricular failure) or increased alve-  olar capillary permeability (inflammatory aloveolar  reactions) where the lymphatic drainage capacity is  exceeded, resulting in a net accumulation of fluid within  the interstitium.   Macroscopically, the lungs are heavy and congested.  In fatal cases, fluid flows from the cut surfaces and it can  often be seen in the large airways.   Microscopically, the interstitium is widened, the  capillaries are congested and the alveoli are filled with  proteinaceous fluid.   Acute respiratory distress syndrome (ARDS) is a clinical  syndrome of diffuse alveolar capillary damage, charac-  terized by pulmonary exudation and oedema with  widespread systemic metabolic derangements.   Many conditions predispose to ARDS, most com-  monly systemic sepsis and severe trauma. The causes  are listed in Figure 7.16.   The exact pathogenesis is unknown in many cases, but  events are thought to occur in two phases: an acute exu-  dative phase (with capillary and alveolar endothelium  injury) and a late organization phase (cell proliferation  and fibrosis). This forms a characteristic intra-alveolar  hyaline membrane composed of fibrin and cellular de-  bris, resulting in severe hypoxia.   In severe cases of ARDS, cytokines liberated from the  lung vascular bed can enter the systemic circulation and  these may cause systemic endothelial activation with  massive neutrophil recruitment leading to multiorgan  failure.   Major trauma, especially associated with  raised intracranial pressure  Septicaemia  Major burns   Pulmonary aspiration of gastric contents  Inhalation of toxic fumes or smoke  Near drowning   Pulmonary embolism (PE) is the occlusion of a pulmo-  nary artery, most commonly by thromboemboli origi-  nating in the systemic veins (Fig. 7.18). The condition  accounts for 1% of all hospital deaths, but this rises  to 30% in patients with severe burns or trauma.   The vast majority of cases are caused by emboli aris-  ing from thrombosis of the deep leg veins (calf, popli-  teal, femoral and iliac veins). Venous thrombosis is  considered in more detail in Chapter 6.   The consequences of PE are pulmonary hypertension  (which puts a strain on the right side of the heart) and  infarction of the lung (which occurs in only about 10%  of cases of PE, as dual circulation protects against ischae-  mic necrosis).   The effect of PE depends on the extent of the pulmonary  vasculature blockage and the time scale involved:   • Massive PE (5% of cases) is a sudden blockage of  more than 60% of the pulmonary vasculature, result-  ing in electromechanical dissociation of the heart, i.e.  the heart continues to beat but there is no output as  pulmonary vascular resistance is too high. This results  in cardiovascular collapse and rapid death. One ex-  ample is a saddle embolus at the bifurcation of the left  and right pulmonary arteries.   • Major PE (10% of cases) is a blockage of the middle-  sized pulmonary arteries. These patients commonly   Fig. 7.17 Main events and outcomes in adult respiratory  distress syndrome.   experience breathlessness. Lung infarction develops  in about 10% of such cases, which may lead to  haemoptysis and pleuritic chest pain, if adjacent to  the pleura. If untreated, patients may develop a sub-  sequent massive thromboembolism.   • Minor PE (85% of cases) is a blockage of the small  peripheral vessels by small emboli. Patients may  be asymptomatic or may experience breathlessness  and pleuritic chest pain as a result of small infarcts.  As with major pulmonary embolism, patients may  develop a subsequent massive thromboembolism  if untreated.   • Recurrent minor PE (minority) is a blockage of the  many small peripheral arteries over a period of many  months by recurrent small emboli. The condition    can lead to the obliteration of the vascular bed with  the development of pulmonary hypertension and  right heart strain.   Pulmonary thromboembolism is the most common  preventable cause of death in hospital patients. Preven-  tion involves:   Treatment is with oxygen, analgesia and anticoagula-  tion therapy (heparin, warfarin).   • decompression sickness, e.g. in deep sea divers ('the  bends' or Caisson disease). Rapid decompression  releases nitrogen bubbles, which cause problems  in the CNS and bones and can produce functional  obstruction of the pulmonary vessels    The lower lobes are involved in 75% of cases.  Macroscopically, pulmonary infarcts are typically  haemorrhagic (because of blood entering from the  bronchial circulation) and wedge shaped, and there is  often an associated pleural reaction, which causes chest  pain. With time, the infarct becomes organized to form  a fibrous scar.   • pulmonary vascular obstruction leading to right  heart failure (cor pulmonale)   • septic infarction due to either a primary septic em-  bolism or secondary infection leading to abscess  formation.   This is increased pressure of the lung vasculature, the  most important being:   • pulmonary vasculature — medial hypertrophy of the  muscular arteries (increased smooth muscle) and  pulmonary veins (arterialization); occlusion of the  pulmonary arteries caused by intimal proliferation   • right side of the heart — increased workload of the  right side of the heart causes ultimate development  of right heart failure (cor pulmonale).   The clinical effects are breathlessness and the symp-  toms and signs of right-sided cardiac failure.   A few interstitial lung disorders may produce diffuse  haemorrhage, often with rapid patient deterioration.  Important examples include:   • Goodpasture's syndrome — an autoimmune disease  resulting in the breakdown of collagen in both lung  alveoli and kidney glomeruli   • Wegener's granulomatosis — an autoimmune granu-  lomatous vasculitis affecting blood vessels of the up-  per respiratory tract and lung   • idiopathic pulmonary haemosiderosis — a rare disor-  der, probably of immunological origin, that can  produce repeated diffuse alveolar haemorrhage,  particularly in children.   Many drugs have pulmonary side effects, such as some  anticancer agents that produce chronic pulmonary  fibrosis. The calcium channel blocker and anti-  arrhythmic drug amiodarone can have similar effects.   Asthma can by induced by aspirin (the mechanism for  this is unknown) and certain (3-blockers (by broncho-  constriction caused by an antagonistic effect on (32-  receptors of bronchial smooth muscle).   Excessive exposure to radiation causes diffuse alveolar  damage and is an established cause of ARDS.   Less severe exposure occurring over a longer period of  time results in progressive pulmonary fibrosis with  the typical restrictive defect of pulmonary function.   This acute inflammation of the pleura is accompanied  by an accumulation of high-protein fluid (>30 g pro-  tein/L; exudate) containing fibrinogen/ fibrin between  the pleural surfaces.   The condition is commonly due to infection, infarc-  tion or tumour.   Effusion is the result of movement of fluid through  damaged vessel walls.   In serofibrinous pleuritis, the effusion is typically  unilateral, with the pleural surface covered by a fibri-  nous exudate. The fluid consists of a straw-coloured fi-  brinous fluid containing mesothelial cells, lymphocytes  and polymorphs. In neoplastic diseases, malignant cells  can also be identified within the pleural fluid.   • adhesions — formation of fibrous adhesions be-  tween the visceral and parietal pleura   • fibrosis — obliteration of the pleural space by fibro-  sis, which is common in long-standing effusions   This is an acute inflammation of the pleura with accu-  mulation of pus in the pleural cavity. Typically caused  by pulmonary infection (e.g. pneumonia, tuberculosis,  lung abscess), it can also complicate thoracic surgery or  penetrating chest wall injury.   Common sequelae include septicaemia (haemato-  genous spread of infection to other organs) and atelec-  tasis (lung collapse as a result of compression).   This acute inflammation of the pleura occurs with the  accumulation of a blood-stained exudate and is often  caused by tumour or pulmonary infarcts.   This collection of low-protein fluid (<30 g protein/L;  transudate) is due to the movement of excess fluid  through normal vessel walls. Common causes are:   surface appears normal. Fluid is straw coloured and con-  tains occasional lymphocytes and mesothelial cells.   The condition can cause pulmonary collapse (com-  pression of the lungs causing respiratory impairment)  or it may resolve completely (resorption of fluid on  correction of the cause with no structural alterations).   The difference between 'transudate' and ‘exudate’  is important. Transudates are characterized by low-  protein content (e.g. hydrothorax) in contrast to  exudates, which have high-protein content (e.g.  serofibrinous pleuritis).   Bleeding into the chest is called haemothorax. It is most  commonly the result of:   • spontaneous rupture of diseased arteries, e.g. ather-  omatous and dissecting aortic aneurysm.    If blood remains within the pleural cavity, the result  is organization and pleural fibrosis.   The accumulation of chyle (milky white emulsified fat)  within the pleural cavity, caused by a leakage from the  thoracic duct, is typically the result of malignant infiltra-  tion, surgery or trauma.   This is the presence of air in the pleural cavity, the causes  of which are described in Figure 7.19.   Spontaneous pneumothorax can be either primary  (of unknown cause occurring in otherwise healthy  individuals) or secondary (i.e. secondary to lung  disease).   Traumatic pneumothorax is a result of chest injury or  is iatrogenic.   • Atelectasis — lung collapse due to compression of the  underlying lung.   in air pressure within the pleural cavity, causing  massive collapse of the affected lung, mediastinal  shift and compression of the contralateral lung  producing life-threatening respiratory insuffi-  ciency. The condition occurs as a result of a  one-way valve-like mechanism at the point at   Idiopathic rupture of pulmonary 'bleb'; most  common in thin young males    which air enters the pleural cavity. Air that enters  the cavity in inspiration is unable to escape during  expiration.   This is a benign tumour of submesothelial connective  tissue. The causes are unknown but there is no associa-  tion with asbestos. The tumour is well circumscribed,  localized and attached to the pleural surface by a pedi-  cle. Histologically, it is composed of fibroblast-like cells  with abundant collagen fibres.   These are the most common pleural tumours, most fre-  quently arising from the lungs, breast or ovary, but  they can arise from any malignant tumour. They are  usually associated with a high-protein exudate (see  above).   This primary neoplasm of the pleura is rare, but is an  important cause of death in people previously exposed  to asbestos, such as those from the ship building indus-  try. There is a latent interval between asbestos exposure    and disease presentation of between 25 and 45 years.  Fibres of crocidolite (blue asbestos) are thought to be  most important in the development of mesothelioma.  These asbestos fibres become trapped in the lung fol-  lowing inhalation and they are particularly resistant to  macrophage and neutrophil destruction.   Macroscopically, the tumours are highly malignant  and they spread locally around the pleural cavity and  pericardium. However, haematogenous/lymphatic me-  tastasis is rare.   Clinical features include chest pain and breathless-  ness and there are commonly recurrent or persistent  pleural effusions, which may be bloodstained.   Asbestos exposure also increases risk of lung cancer.  Indeed, an individual exposed to asbestos has a far greater  risk of dying from lung cancer than mesothelioma,  particularly if they also smoke. However, the number of  mesothelioma cases has rapidly risen in the UK over the  last 20 years and it is estimated that this trend will continue  until at least 201 0. No curative treatment is possible and  death usually occurs within 10 months of diagnosis.   • Describe disorders of the upper gastrointestinal tract, most notably those of the oesophagus.   • Understand congenital abnormalities, inflammation, ulceration and neoplasia of the stomach.   • Describe patterns of liver injury, including cirrhosis, and reflect on the resulting complications.   • Recall the causes and mechanisms of liver injury, including infection, alcohol and cancer.   • Recognize congenital abnormalities, infection and inflammation as potential disorders of the  intestine.   • Describe the causes of intestinal malabsorption, obstruction and vascular compromise.   • Discuss neoplastic disease of the intestine and how it develops.   • Understand common pathology of the peritoneum, namely inflammation and tumours.   These are the most common major congenital malfor-  mations of the mouth. They frequently occur together  as a result of the same process, namely a failure of fusion  during the embryonic period.   Aetiology — a few cases are associated with a chromo-  somal abnormality (e.g. trisomy 13 or 18), but the ma-  jority have no identified cause. Retinoic acid (vitamin  A) has recently been proposed as having teratogenic ac-  tivity in the developing palate.   • Cleft lip — may be unilateral or bilateral, involving  the lip only or extending upwards and backwards  to include the floor of the nose and the alveolar ridge  (Fig. 8.1).   • Cleft palate — considerable variation, from a small  defect in the soft palate (bifid uvula) that causes lit-  tle disability, to a complete separation of the hard  palate combined with a cleft lip (Fig. 8.2).   The effects are an abnormal facial appearance, defec-  tive speech and feeding difficulty with extensive lesions  (child is unable to suck).   Management is by artificial feeding, with plastic  surgery recommended between 1 and 2 years of age.   This describes inflammation of the oral cavity, which  can be non-infective or infective.   Aphthous ulcers are tiny, painful and shallow, occurring  on a background of red mucosa typically on the lips,  tongue or buccal mucosa. The ulcer crater is covered  by a creamy exudate composed of fibrin and inflamma-  tory cells, mainly neutrophils.   Aetiology and pathogenesis are unknown. These ul-  cers may be associated with Crohn's disease, coeliac dis-  ease and Behfet's syndrome; they also occur in 20% of  the normal population.   Most aphthous ulcers spontaneously heal within a  week, although they often recur. Occasionally, large  ulcers may persist for several weeks before healing by  fibrosis.   The majority of infections of the lips and buccal cavity  are due to either viruses or fungi:   • Herpes simplex vims (herpetic stomatitis) — viral  infections of the lips and mouth. Usually manifest  as large blisters or crops of small painful vesicles,  which eventually erode to form shallow tender  ulcers. Severe herpetic stomatitis is important in  the immunosuppressed (e.g. HIV-positive patients).   • Oral candidiasis — Candida albicans infection of the  mouth (also known as 'oral thrush'). Common in   This inflammation of the tongue arises either as a result  of infective stomatitis (see above) or is due to a defi-  ciency of nutritional factors, especially niacin, ribo-  flavin, folic acid and vitamin B 12 :    Fig. 8.1 Different types of cleft lip. (A) Median cleft upper lip.  (B) Median cleft lower lip. (C) Unilateral cleft lip. (D) Bilateral  cleft lip. (E) Oblique facial cleft.   (B) Cleft soft and hard palate. (C) Total unilateral cleft palate  and cleft lip. (D) Total bilateral cleft palate and cleft lip.    infants but less so in adults without diabetes mellitus  or immunosuppression. The condition develops as  white patches on palatal, buccal and tongue surfaces.  Lesions are composed of tangled fungal hyphae  mixed with acute inflammatory cells and some des-  quamated epithelium. Underlying epithelium is  acutely inflamed and red.   This premalignant epithelial dysplasia may precede the  development of carcinoma. The condition is character-  ized by a white patch or plaque (hyperkeratosis) of the  oral cavity that cannot be scraped away. The condition  usually affects the tongue. All lesions are considered  precancerous unless proven otherwise by histological  evaluation.   Less common than leucoplakia, this is characterized  by the presence of red velvety patches of epithelial atro-  phy and pronounced dysplasia. It is seen mainly in  elderly males on the buccal mucosa or the palate.   Malignant transformation is far more common than  with leucoplakia. The development of erythroplakia is  associated with heavy tobacco use.   This is the most common tumour of the mouth, and it is  derived from lining epithelium. It may arise from pre-  existing dysplasia such as described above. Carcinoma  affects 2 per 100 000 in the UK, occurring in men more  than women by about 2:1. The risk factors are:   • smoking — direct relationship between number of  cigarettes smoked per day and the risk of developing  oral cancer   Macroscopically, there are raised nodular lesions and  central ulceration with hard raised edges.   • tongue — typically occurring on the lateral border of  the anterior two-thirds    • cheek or floor of the mouth (less common in the  UK) — generally asymptomatic, resulting in extensive  local invasion making surgical removal difficult.  Prognosis — may infiltrate locally and metastasize to  regional lymph nodes in the neck. Five-year survival is  about 50%.   Remember that 95% of all cancers arising in the head  and neck are squamous cell carcinomas, most  commonly occurring in the oral cavity. These cancers  are classically seen in men who are heavy tobacco  smokers and alcohol drinkers.   In oesophageal atresia, the upper end of the oesophagus  is intact, but it ends in a blind pouch. Oesophageal atre-  sia affects 1 per 4000 live births, and more than 85%  of cases are associated with the tracheo-oesophageal  fistula — an abnormal communication between the  lower oesophagus and trachea (Fig. 8.3).   • Fetus — inability to swallow amniotic fluid results in  polyhydramnios, the accumulation of an excessive  amount of amniotic fluid.   • Neonate — appears healthy initially but swallowed  fluid returns through the nose and mouth and respi-  ratory distress occurs. The condition must be surgi-  cally corrected in early life, but is also associated  with other congenital abnormalities such as those  of the heart.   These localized constrictions of the oesophagus are  caused by mucosal folds or muscular contractions.   In Plummer- Vinson or Paterson-Brown-Kelly syn-  drome, upper oesophageal webs are associated with  dysphagia in patients with iron-deficiency anaemia,  cheilosis and glossitis. This is a rare but important con-  dition because of an association with the development  of postcricoid oesophageal carcinoma.   Inflammation of the oesophagus caused by gastro-  oesophageal reflux disease (GORD) is the most com-  mon oesophageal abnormality and is caused by reflux   Fig. 8.3 Oesophageal atresia. (A) Blind ending of  oesophagus with fistula formed between lower part and  trachea. (B) Oesophageal atresia with no fistulous  communication: very rare.    of gastric acid through the lower oesophageal sphincter.  The condition affects about 5% of adults; it can occur  at any age (but with increased incidence over the age  of 55 years), and it affects males more than females.   Symptoms are a burning pain in the centre of the  lower chest commonly known as 'heartburn'.   • Barrett's oesophagus — metaplasia of lower oesopha-  geal mucosa, with normal squamous epithelium  replaced by glandular columnar epithelium com-  posed of tall columnar cells. This increases the risk  of oesophageal adenocarcinoma (see below).  Relevant investigations include endoscopy and   • lifestyle alterations — weight loss, stopping smoking,  avoiding late meals and decreasing alcohol intake    • drug therapy — antacids, alginates, H 2 -receptor  antagonists and proton pump inhibitors (severe  symptoms)   • surgery — for those not responding to medical  therapy, repair of hiatal defects or fundoplication  may be appropriate.   • infective agents — Candida albicans, herpes simplex  and cytomegalovirus may cause acute oesophagitis  in the immunosuppressed   • desquamative skin diseases, e.g. pemphigoid and  epidermolysis bullosa may cause oesophageal ulcer-  ation, blistering and eventual erosion.   Achalasia is a condition in which peristalsis is abnormal  and lack of relaxation of the lower oesophageal sphinc-  ter. This may occur at any age but it is mainly seen in  middle-aged individuals. The cause is unknown but re-  duced numbers of ganglion cells in the muscle plexus  have been noted in long-standing cases.   • increased predisposition to development of squa-  mous cell carcinoma of the oesophagus.   Infection by Trypanosoma cruzi is a cause of secondary  achalasia due to destruction of the myenteric plexus.  It is common in South America.   This is a common condition in which the upper  part of the stomach herniates through the dia-  phragmatic oesophageal opening (hiatus) into the  thoracic cavity.   The incidence is 5 per 1 000 in the UK but it is 50- 1 00  times less common in Asia and Africa. It may rarely be  caused by a congenitally short oesophagus but is mainly  thought to arise from increased abdominal pressure and  loss of diaphragmatic muscular tone.   1. Sliding hiatus hernia (90%) — stomach herniates  through oesophageal diaphragmatic hiatus.   Fig. 8.5 Types of hiatus hernia. (A) Sliding hiatus hernia.  (B) Rolling hiatus hernia.    resulting in the gastro-oesophageal junction moving  into the thorax (associated with reflux oesophagitis  and peptic ulceration).   2. Rolling (para-oesophageal) hiatus hernia (10%) —  the fundus of the stomach protrudes through  the hiatus, but the gastro-oesophageal junction re-  mains below the diaphragm (less associated with  reflux).   'Mallory-Weiss tear' is a longitudinal oesophageal  laceration as a result of severe retching or vomiting. This  is most commonly seen in alcoholics, and classically oc-  curs with vomiting of clear fluid (pretearing), followed  by vomiting of blood (post-tearing).   The condition is caused by portal hypertension  (most commonly associated with cirrhosis of the liver).   Oesophageal veins normally drain into both systemic  and portal venous systems.   Increased pressure in the portal venous system (e.g.  as a result of severe diffuse long-standing liver disease)  causes dilatation of the oesophageal veins, which often  protrude into the lumen.   Rupture of these varices, or ulceration of overlying  mucosa, can produce a massive haemorrhage into the  oesophagus and stomach, often precipitating vomiting  of blood (haematemesis).   1. Local measures to control bleeding — sclerotherapy,  balloon tamponade and transjugular intrahepatic  portosystemic stent shunting (TIPSS). TIPSS creates  a shunt directly connecting the portal and hepatic  veins of the liver, so reducing portal hypertension   2. Reduction of portal venous pressure — drug therapy  with terlipressin and somatostatin   Definition — metaplastic replacement of normal squa-  mous oesophageal epithelium with glandular columnar  epithelium. Caused by persistent oesophageal reflux; ap-  proximately 10% of these patients will develop Barrett's  oesophagus.   Barrett's oesophagus predisposes to the development  of adenocarcinoma. Metaplastic glandular epithelium  can progress to epithelial dysplasia and then to frank  adenocarcinoma.   Barrett's oesophagus is a classic example of metaplasia,  and is a good example to quote in an examination.   Benign tumours of the oesophagus are rare. The major-  ity are leiomyomas derived from the smooth muscle of  muscularis propria; the minority are derived from  nerves, i.e. schwannomas and neurofibromas.   The most common malignant tumours of the oesopha-  gus are squamous carcinomas and adenocarcinomas.  Incidence is 5-10 per 100 000 per year in the UK. Risk  factors are:   • Barrett's oesophagus — 10% of these cases will  develop adenocarcinoma in their lifetime   • ITPV infection — this may have a role in the develop-  ment of some squamous cell carcinomas.  Squamous cell carcinomas are more common than   adenocarcinomas. They mostly develop in men who  are heavy alcohol drinkers or heavy smokers, and may  be preceded by an epithelial dysplastic change. They  usually present late, located in the middle and lower  oesophagus, and often causing dysphagia.   Adenocarcinomas mainly occur in the lower  oesophagus in areas of metaplasia (Barrett's oesopha-  gus). However, some adenocarcinomas are primary car-  cinomas of the stomach that have infiltrated the lower  oesophagus.   • Common — progressively worsening painless dyspha-  gia, anorexia, weight loss, anaemia (acute or chronic)   • Rare — hoarse voice (involvement of larynx or left  recurrent laryngeal nerve palsy), supraclavicular  lymphadenopathy tracheo-oesophageal fistula.  Investigations of choice are:   • CT of chest and abdomen — stage the tumour and so  determine operability   Management is often palliative to relieve pain and dys-  phagia (intubation, dilatation, bypass). Combinations  of surgery, radiotherapy and chemotherapy (often neo-  adjuvant) may be attempted in early disease. Squamous  carcinoma has a slightly better prognosis due to its radio-  sensitivity, but overall 5-year survival from oesophageal  cancer is just 6-9%.   Gastritis is the term used to describe inflammation of  the gastric mucosa.   This superficial acute inflammation is typically caused  by ingested chemicals, the most common being alcohol,  aspirin and other non-steroidal anti-inflammatory  drugs (NSAIDs).   Focal loss of the superficial gastric epithelium causes  dyspepsia with vomiting and possibly haematemesis,  if the erosions are numerous.   • severe stress or shock (e.g. after major trauma or  burns)   Chronic inflammation of the gastric mucosa is a com-  mon condition. It increases with age and is more com-  mon in developed countries. Mucosal atrophy occurs  with intestinal metaplasia, increasing the likelihood of  gastric carcinoma.   The condition is present in over 90% of patients with  duodenal ulceration, in about 70% of those with gastric  ulceration, and it is also common in those with gastric  cancer.   • Immune — pernicious anaemia and atrophic gastritis  without pernicious anaemia   This is the most common form of chronic gastritis,  accounting for more than 90% of cases, and it  may arise at any age. The pyloric antrum is the most  severely affected area, but damage is also seen in the  fundus.   • Colonization — Helicobacter pylori colonizes epithe-  lial surface beneath thin layer of mucus. This causes  an initial acute neutrophilic gastritis, which gives  way to chronic gastritis.   • Urease production — the bacterium produces the en-  zyme urease, which breaks down urea to give C0 2  and ammonia.   • Persistence of infection — once established, infection  may persist for years.   • mixed acute and chronic inflammatory cell reaction  in lamina propria and superficial epithelium   • intestinal metaplasia — normal gastric epithelium  is replaced by a type similar to that of the small  intestine.   The tests available for diagnosis of Helicobacter pylori  infection are listed in Figure 8.6.   This organ-specific autoimmune disease associated with  pernicious anaemia is generally seen in elderly patients  with the development of severe atrophy of the mucosa  (atrophic gastritis). It particularly affects the body of the  stomach.   Radiolabelled urea is administered; urease produced by  Helicobacter pylori — > radioactive C0 2 , which can be detected  on the breath   1. Antibodies against gastric parietal cells (90%) —  associated with decreased hydrochloric acid produc-  tion (hypochlorhydria)   2. Antibodies against intrinsic factor (60%) — > failure of  absorption of dietary vitamin B j 2 — > interference with  normal erythropoiesis in bone marrow — > megalo-  blastic, macrocytic anaemia (pernicious anaemia).  The most common form occurs without pernicious   anaemia, even though antibodies of both types are often  present. This is due to a residual ability to absorb vita-  min B 12 , which may be lost with time producing perni-  cious anaemia.   In this pattern of mucosal injury the dominant feature is  epithelial change with minimal inflammatory cell infil-  trates. The causes are threefold:   2. Reflux of alkaline bile-containing duodenal fluid  into the lower part of the stomach. This may be  caused by motility disturbances (e.g. due to gall-  stones or cholecystectomy) or pyloric incom-  petence (as a result of previous surgery to the  pyloric area)   • Peptic ulcerations — caused by damage to the gastric  lining by acidic gastric secretions.   Peptic ulcers are ulcers of the oesophagus, stomach or  duodenum caused by damage to the epithelial lining  by gastric secretions, particularly acid.    It is estimated that about 10% of the Western  population experience peptic ulceration at some time.  Ulcers usually develop in adulthood and have a natural  history of repeated healing and relapse over many  years.   • stomach — usually at the antrum due to regurgitated  bile in pyloric incompetence, or surface epithelial  damage by Helicobacter pylori infection or NSAIDs   Aetiology is probably multifactorial but damaging  influences include Helicobacter pylori infection, NSAIDs  and stress. Less commonly, peptic ulcers may be  associated with acid hypersecretion (e.g. gastrinoma),  infection, duodenal obstruction/disruption, vascular  insufficiency or radiation.   Other factors, such as chronic gastritis, smoking and  genetic predisposition, are also believed to play a role in  the pathogenesis.   Upper GI mucosa is normally protected by either squa-  mous epithelium (oesophagus) or an acid-resisting  mucous barrier containing neutralizing bicarbonate  ions. Peptic ulceration occurs when the aggressive ac-  tion of acid and pepsin is not opposed by adequate mu-  cosal protective mechanisms.   Macroscopically, peptic ulcers are typically 1 -2 cm in  diameter (but they can be much larger) with sharply  defined borders surrounding the ulcer crater.   Microscopically, the ulcer crater usually penetrates  into the muscularis propria of the stomach and it has  four histological zones, namely:   Complete healing of the ulcer leads to fibrous re-  placement of muscle with regrowth of epithelium over  the scar. Clinical features include episodic epigastric  pain (alleviated by antacids) which is worsened by eat-  ing and may occur with nausea and heartburn (oeso-  phageal ulcers).   • Healing — slow process hastened by acid-inhibiting  agents or mucosal protectants.    • Haemorrhage — may be small and undetected (caus-  ing chronic anaemia) or occur as an acute episode of  haematemesis.   • Adherence and erosion — ulcer penetrates full thick-  ness of the stomach or duodenal wall, adhering to  and eroding into underlying tissue, particularly the  pancreas or liver.   • Fibrous strictures — caused by the healing of peptic  ulcers, which may obstruct the oesophagus or stom-  ach (acquired pyloric stenosis).   • Medical — eradication of Helicobacter pylori [triple  therapy with a proton pump inhibitor (e.g.  omeprazole), plus two antibiotics, e.g. clarithromycin  and metronidazole]. If no infection is present, acid  suppression medications include antacids, PPI and  H 2 -receptor antagonists.   • Surgical — rarely in acute ulcer haemorrhage or where  medical control is impossible. A partial gastrectomy is  used for gastric ulcers but complications are common.   Acute peptic ulcers usually develop in areas of erosive  gastritis, and they are predisposed by the same factors  that promoted erosion (e.g. NSAIDs). In contrast to  chronic ulcers, they are generally multiple and shallow  with minimal surrounding inflammation or fibrosis.   Acute ulcers may heal without scarring or they may  progress to chronicity.   This rare disease of unknown cause is characterized by  gross hyperplasia of gastric pits, atrophy of glands and  a marked overall increase in mucosal thickness. It is as-  sociated with hypoalbuminaemia as a result of gastric  protein loss via superficial ulcerations (a form of  'protein-losing gastroenteropathy') .   An extremely rare condition, this is characterized by acid  hypersecretion and gastric protein loss.   A gastrin-secreting tumour (gastrinoma) of the pancre-  atic G cells results in gastric gland hyperplasia and gas-  tric hypersecretion (see Chapter 10). Multiple peptic  ulcers and diarrhoea also occur.   Benign gastric polyps are rare compared with the  incidence of malignant tumours of the stomach. The  types are:   • hyperplastic polyps — most common polyp of the  stomach, formed by regeneration of mucosa, often  at the edge of an ulcer in the stomach antrum   • adenomatous polyps — true benign tumours of the  surface epithelium ranging up to 5 cm in size. Very  rare, but dysplasia indicates that malignant change  is possible   • hamartomatous polyps — occur in Peutz-Jeghers  syndrome (hereditary condition of multiple polyps  in the small intestine associated with pigmented  areas around the lips, inside mouth, and on palms  and soles).   Other benign tumours of the stomach are derived  from mesenchymal tissues, the most common being  leiomyomas. These appear as mucosal or intramural  nodules and are usually asymptomatic.   The vast majority of malignant tumours of the stomach  are adenocarcinomas derived from mucus-secreting  epithelial cells. Incidence has been falling worldwide,  with 17 per 100 000 males and 7 per 100 000 females  affected per year in the UK. Males are affected more than  females by 3:2.   Gastric adenocarcinoma is common in the Far East  and certain parts of South America, but less so in  Western Europe and North America.   • pylorus (60%) — often produce symptoms of  obstruction to the gastric outlet   Aetiology is unknown but dietary factors are sug-  gested to account for geographical variation, e.g. inges-  tion of smoked and salted-preserved foods. Other risk  factors include:    • Helicobacter pylori infection — chronic Helicobacter  pylori infection increases gastric carcinoma risk 5- to  6-fold. This is thought to be the result of chronic gas-  tritis producing intestinal metaplasia, with eventual  dysplasia and carcinoma. Chronic inflammation  creates reactive oxygen species capable of damaging  DNA, along with gland atrophy and hypochlor-  hydria, which favour further bacterial growth. How-  ever, the vast majority of those with Helicobacter  pylori infection do not develop cancer   • Chronic gastritis and intestinal metaplasia of other  cause, e.g. autoimmune gastritis   The sequence of events in the development of gastric  carcinomas is as follows:   Normal mucosa — > chronic gastritis — > intestinal  metaplasia — > dysplasia — > intramucosal carcinoma  (early gastric cancer) — > invasive carcinoma.   Several genetic changes have been reported in gastric  cancer, including alterations of p53 and E-cadherin  expression, along with overexpression of oncogenes  such as c-myc. E-cadherin changes appear unique to  diffuse gastric cancer.   Gastric cancers are classified as either early or ad-  vanced according to the extent of their spread through  the stomach wall.   This is confined to the mucosa and/or submucosa re-  gardless of whether spread has occurred to regional  lymph nodes. It is associated with a good prognosis.  The cancer is further divided into three types according  to macroscopic appearance (Fig. 8.7).   These extend beyond the submucosa, and are associated  with a poor prognosis. They are further divided into  three types macroscopically (Fig. 8.8):    Fig. 8.7 Macroscopic classification of early gastric cancers:  type 1 polypoid; type II is further divided into: (A) elevated,   1. Polypoid — protrudes into stomach lumen and pre-  sents early due to gastric discomfort and bleeding  when traumatized. Usually amenable to surgical  excision and has the best prognosis.   2. Ulcerating (most common type) — similar to benign  peptic ulcers but with a raised edge, necrotic shaggy  base and an absence of the radiation folds seen in  benign peptic ulcers.   3. Diffuse infiltrative pattern (linitis plastica) — presents  late and has the worst prognosis. Tumour spreads  extensively within mucosa and submucosa produc-  ing a shrunken, inexpansible, rigid stomach. Symp-  toms are usually non-specific (e.g. vomiting due to  small stomach capacity) and metastatic spread is  common at the time of diagnosis. Surface ulceration  is not a prominent feature and so haematemesis is  not common until the later stages.   • lymphomas (see Chapter 13) — a common site for  extranodal non-Hodgkin's lymphoma. Helicobacter  pylori infection is associated with a low-grade lym-  phoma (so-called 'MALToma')   • gastrointestinal stromal tumours (GISTs) — relatively  rare tumours that are thought to arise from interstitial  cells that control gastrointestinal peristalsis. GISTs  may be benign or malignant; it appears that 85% of  cases display c-KIT mutations.   Following hepatic injury, the liver has a limited set of  responses:   All pathological processes of the liver result in one or  more of the above reactions.   Acute hepatocellular injury can result in variable forms  of necrosis. The underlying type of necrosis depends on  aetiology.   This is the ballooning of individual hepatocytes, gener-  ally as a result of viral hepatitis. Mild swelling is revers-  ible, but more advanced changes may progress to  necrosis.   Necrosis of small groups of hepatocytes occurs in acute  viral- or drug-induced hepatitis.   Necrosis confined to certain zones is seen with particu-  lar conditions, e.g. centrilobular area (zone 3) is affected  in acetaminophen (paracetamol) toxicity (Fig. 8.9).   Necrosis of the majority of hepatocytes occurs with  fulminant hepatic damage and is seen in some cases  of viral- and toxin-induced damage.   Fig. 8.9 Centrilobular (zone 3) zonal necrosis. Zone 1 is  perivenous (near portal vein) with a good oxygen supply,  whereas zone 3 is pericentral (near central vein) with a poorer  oxygen supply.   Liver cells at the interface between the periportal paren-  chyma and inflamed portal tracts are destroyed.   Inflammation of the liver is known as hepatitis, and it is  a common response to a wide array of damage, e.g. viral  infection, autoimmune disorders, drugs and toxins.   Under normal circumstances there is very little liver cell  proliferation. However, following hepatic injury, liver  cell regeneration occurs to restore liver function, even  if the architectural structure of the liver cannot be re-  stored. This is a crucial phenomenon for recovery for  patients with fulminant or subfulminant liver failure.   Repeated chronic damage to the liver can result in fibro-  sis, which is usually considered an irreversible change.  Growth factors produced as part of an inflammatory  response are thought to stimulate proliferation and dif-  ferentiation of mesenchymal cells (the normally incon-  spicuous fat-storing cells of Ito located in the space of  Disse) into collagen-secreting fibroblasts.   Development of fibrosis is an important complica-  tion of several liver diseases, and it is one of the charac-  teristic features of cirrhosis.   Cirrhosis is an irreversible condition in which the liver's  normal architecture is diffusely replaced by nodules of  proliferating hepatocytes separated by bands of scar  tissue. Cirrhosis represents the end-stage of many  processes — it is not a specific disease in itself. It involves:   • regeneration of hepatocytes to cause nodules.  Macroscopically, the liver is tawny and characteristi-  cally knobbly (due to nodules). On a cut surface,  parenchyma is replaced by nodules of regenerated hepa-  tocytes separated by fine fibrosis.   Microscopically, the nodules of hepatocytes are sep-  arated by bands of collagenous tissue. Bile ducts and  portal vessels run in the fibrous septa.   Cirrhosis can be classified either according to the size  of regenerative nodules (Fig. 8.10) or according to its  aetiology (Fig. 8.11). The aetiological classification is  most useful in determining prognosis and treatment.  The clinical features of cirrhosis are illustrated in  Figure 8.12.    Fig. 8.11 Classification of cirrhosis according to incidence  in the Western world   Alcoholic liver disease  Cryptogenic (no cause found)  Chronic hepatitis caused by  hepatitis B and C viruses   Autoimmune chronic hepatitis  Primary biliary cirrhosis  Chronic biliary obstruction  (biliary cirrhosis)   • portal hypertension and its complications (see  below) — a result of impeded blood flow through  liver   This is a continued elevation in portal venous pre-  ssure, normal portal venous pressure being less than  2-5 mmflg. Causes of portal hypertension can be  classified according to whether the site of obstruction  to flow is:   • posthepatic — blockage in the central veins, hepatic  veins or vena cava.   Figure 8.13 lists the causes of portal hypertension.  Complications — portal hypertension causes back-  pressure in the portal vascular bed leading to spleno-  megaly, ascites and varicose venous channels.   The causes and effects of portal hypertension are  shown in Figure 8.14.   Portal hypertension can be controlled with (3-blocker  drugs (usually propranolol) to reduce the risk of oeso-  phageal variceal haemorrhage.   Venous communications that link portal and systemic  venous systems become enlarged in portal hyperten-  sion. The four sites of portal-systemic anastomosis are:   1. Lower third of the oesophagus — left gastric vein  (portal tributary) anastomoses with oesophageal  veins (systemic tributary)   2. Halfway down the anal canal — superior rectal veins  (portal tributary) draining upper half of anal canal  anastomose with middle and inferior rectal veins  (systemic tributaries)   3. Paraumbilical veins — connect left branch of the por-  tal vein with superficial veins of anterior abdominal  wall (systemic tributaries)   4. Veins of ascending colon, descending colon, duode-  num, pancreas and liver (portal tributaries) anasto-  mose with renal, lumbar and phrenic veins (systemic  tributaries).   • Alkaline phosphatase: may be greatly elevated  if the cause is biliary obstruction.   • AST and ALT: transaminase levels are  elevated, proportional to the activity of  liver cell destruction.   • Bilirubin: elevated levels, which may be very  high in cases caused by biliary obstruction.   • Serum albumin: low, as a result of failure of  synthesis.   • Prothrombin time: prolonged because of  failure of synthesis of coagulation factors.   Idiopathic portal hypertension  Hepatic fibrosis: caused by schistosomiasis  (important cause in endemic areas)  Polycystic disease of the liver   Disease of hepatic veins and branches, e.g.  Budd-Chiari syndrome  Severe right-sided heart failure  Constrictive pericarditis    Pathogenesis — under normal conditions, portal  venous blood traverses the liver and drains into the  inferior vena cava of the systemic venous circulation  by way of the hepatic veins. In portal hypertension,  flow through this direct route is reduced and the portal  venous blood is forced through smaller communica-  tions that exist between the portal and systemic  systems.    Anastomotic channels become dilated resulting in  the development of varicose venous channels, namely:   Ascites is the accumulation of free fluid in the peritoneal  cavity. Common causes are:   Pathogenesis of ascites in cirrhosis — increased transu-  dation of fluid in ascites occurs as a result of:   • t plasma oncotic pressure (due to lowered albumin  synthesis by damaged liver cells).   Clinical features are abdominal distension with full-  ness in the flanks, shifting dullness on percussion and  fluid thrill.   Increased pressure in the portal vein is transmitted to  the splenic vein resulting in splenomegaly. A variety  of haematological abnormalities are associated with  hypersplenism (see Chapter 13).   • Paracentesis — drain 3-5 L over 1-2 hours for  immediate relief. Drainage to dryness may be  supported by colloid (e.g. albumin).    • LeVeen shunt — a subcutaneous draining tube  connecting peritoneum to internal jugular vein via  a one-way valve. Complications of infection,  thrombosis and pulmonary oedema limit use.   This presents as a yellowing of the skin, sclerae or mu-  cous membranes, indicating excess bilirubin in the  blood. It is clinically detectable when plasma bilirubin  exceeds 50 pmol/L (3 mg/dL), although the biochemi-  cal definition refers to any reading above normal levels  (approximately 18-24 pmol/L).   The easiest way to classify jaundice is by aetiology  (Fig. 8.17):   • Prehepatic — the most common cause is haemolysis-  associated jaundice, a mild form of which occurs in  many neonates due to immature liver function in the  first weeks of life.   • Intrahepatic — any cause of hepatocellular damage  or intrahepatic cholestasis may be responsible.  Hereditary enzyme defects may reduce the ability  to conjugate bilirubin, so producing jaundice.  Gilbert's syndrome is the most common of these  conditions; it is not serious and requires no  treatment.   An alternative classification system is based on chemical  analysis of bilirubin in the blood (Fig. 8.18).   Failure of bile flow caused by the obstruction of  either small (intrahepatic) or large (extrahepatic) bile  ducts is termed cholestasis. It results in jaundice due  to conjugated hyperbilirubinaemia. The high levels of  conjugated bilirubin pushed back into the blood result  in dark urine (high urobilinogen content), while the  kidney lack of bilirubin passing through the liver produces pale   faeces. Conjugated bilirubin may be deposited in the  skin causing itching (pruritus).   Unconjugated hyperbilirubinaemia is caused by states  such as haemolysis, where the excessive release of biliru-  bin overwhelms the ability of the liver to conjugate it into  a water-soluble form (bilirubin-glucuronate). Insoluble  bilirubin does not enter the urine and so this remains  a normal colour, but faeces are darkened by the increased  amount of bilirubin excreted through the liver. Pmritus  urobilinogen does not usua )ly occur.   1. Liver disease is not the only cause of jaundice; there  are other causes, e.g. haemolysis.   This is usually the end point of long-standing chronic  liver disease, when up to 90% of hepatic function has  been lost.   • Compression by extrinsic masses, e.g. carcinoma of the pancreas,  enlarged lymph nodes    Fig. 8.18 Classification of jaundice according to chemical composition of bilirubin   This is a neuropsychiatric syndrome caused by severe liver  disease, occurring most often with cirrhosis but occasion-  ally in a more acute form in fulminant hepatic failure.  Pathogenesis is:   • Liver failure — the liver is unable to remove exogenous/  endogenous compounds from the circulation.  Neurotoxins (e.g. ammonia) accumulate and  impair neuronal transmission.   • Shunting — in portal hypertension, there is shunting  of portal blood past the liver directly into the  systemic circulation.   The overall effect is a biochemical disturbance of  brain function. The condition is reversible and rarely  shows marked pathological changes in the brain.   Renal failure secondary to liver failure occurs in  advanced cirrhosis, and almost always in conjunction  with ascites.   The kidneys themselves are normal. Renal failure is  thought to result from altered systemic blood flow  including diminished renal flow.   Prognosis — recovery depends on improvement of  liver function, but in chronic liver disease this seldom  occurs.   This condition is caused by excessive deposition of  iron in the tissues, including the liver. There are two  types:   1. Primary (hereditary) — an autosomal recessive trait  that leads to the production of abnormal HFE pro-  tein, which is linked to excessive absorption of iron  from the gut. Ninety per cent of those affected are  male.   2. Secondary — results from excessive iron accumula-  tion caused by other primary diseases (such as  sideroblastic anaemia and chronic haemolytic  disorders).   Iron accumulates as haemosiderin in many tissues in-  cluding the liver, pancreas, pituitary, heart and skin.  Affected tissues appear rusty brown due to haemosi-  derin within cells, as follows:   • In the liver — hepatocyte necrosis begins in the peri-  portal region and spreads to affect the whole liver.    Free radical generation may play a key role in this re-  action. Cirrhosis ultimately develops, often with  hepatomegaly.   • In the heart — infiltration of cardiac muscle can cause  cardiomyopathy with heart failure.   • In the pancreas — damage to pancreatic islets may re-  sult in diabetes mellitus.   • In the skin — leaden grey pigmentation of skin due to  excess melanin, especially in exposed parts, i.e. the  axillae, groin and genitalia.   Diagnosis — there is a high saturation of transferrin in  the blood, and high serum iron and ferritin levels. Diag-  nosis is confirmed by a liver biopsy showing heavy iron  deposition and hepatic fibrosis, which may have pro-  gressed to cirrhosis.   • Weekly venesection (bleedings) of 500 mL until  serum iron is normal followed by venesection as  required to maintain normal serum ferritin.   • Investigation of first-degree relatives by blood testing  and possible genetic screening.   The term 'bronzed diabetes' is often used to describe  haemochromatosis due to the combination of diabetes  and hyperpigmentation.   This autosomal recessive disorder of copper metabolism  results in chronic destructive liver disease.   Normally, dietary copper is taken up by the liver,  complexed to ceruloplasmin (a copper-binding pro-  tein) and then the whole complex is secreted into the  plasma. Circulating ceruloplasmin is subsequently  recycled by the liver, with any remaining excess copper  being re-excreted into the bile.   In Wilson disease, a mutation in a copper transport  ATPase gene results in failure of the liver to secrete the  copper-ceruloplasmin complex into the plasma. The  copper complex accumulates within the hepatocytes,  saturating the available ceruloplasmin and leaving free  copper to overspill into the blood, where it can cause  haemolysis or be deposited in various tissues:   • eye — development of greenish-brown discoloura-  tion around cornea (Kayser-Fleischer rings).    Diagnosis — low levels of serum ceruloplasmin and  high free copper in the blood; liver effects confirmed  by biopsy.   Affected individuals with this inherited condition fail to  produce the normal active extracellular protease inhib-  itor o'! -antitrypsin.   Pathogenesis — oq-antitrypsin is normally produced  and secreted by the liver to inhibit the activity of prote-  ase enzymes. Mutations in the genes encoding the in-  hibitor prevent their secretion such that protease  enzymes are not inhibited. The PiZ gene is most com-  monly affected.   In heterozygotes, there is an increased risk of lung  damage, especially emphysema in smokers. ITomozy-  gotes develop emphysema and liver disease (cholestatic  jaundice in the neonate; chronic hepatitis and cirrhosis  in adults). This actually occurs due to the accumulation  of abnormal sq-antitrypsin globules in the liver, which  cannot be secreted into the bloodstream.   This rare syndrome is characterized by acute encepha-  lopathy with cerebral oedema as a result of sudden se-  vere impairment of hepatic function (associated with  microvesicular fatty degeneration). It occurs with  high-dose aspirin use in children and adolescents, often  following an upper respiratory tract infection.   Viral infection is a common cause of acute hepatitis.  The main so-called hepatitis viruses are a group of hepa-  totrophic viruses. Although all cause a primary hepati-  tis, they are unrelated and they belong to different  viral types.   Clinical features are similar in all forms of acute hep-  atitis regardless of aetiology.   Symptoms are nausea, anorexia, low-grade pyrexia  and general malaise. Signs are hepatomegaly with ten-  derness, and jaundice 1 week after onset of symptoms,  peaking at about 10 days.   Investigations — raised serum levels of conjugated bil-  irubin and liver aminotransferases (both aspartate and  alanine).   This RNA enterovirus is prevalent in tropical countries,  but uncommon in developed countries.   It is the most common travel related illness in  the UK.   • nurseries or institutions where hygiene levels are  inadequate (person-to-person via hand-to-hand  contact)   Prognosis — the majority of patients recover fully with  restoration of normal liver function tests. However, a  small minority (1-3 per 1000) develop fulminant he-  patic failure with a mortality rate of 85%.   The disease never causes chronic hepatitis and infec-  tion confers subsequent immunity. A vaccine is avail-  able for long-term immunity.   This is a DNA virus of the Hepadna group. It can inte-  grate into host DNA. Transmission can be:   • vertical — transmission from mother to child; either  perinatally (transplacental) or postnatally (breast  milk).    Fig. 8.19 Course of infection in hepatitis A. HAV-hepatitis A  virus.    2. Acute self-limiting hepatitis (25%) — symptoms in-  clude jaundice, malaise and anorexia, but the major-  ity recover and develop lifelong immunity. There is a  1% mortality associated with fulminant acute hepa-  titis (massive hepatocyte necrosis)   3. Chronic hepatitis B infection (10%) — the majority  enter an asymptomatic carrier state, which carries  a future risk of chronic hepatitis. A minority progress  to chronic hepatitis after initial infection; chronic  hepatitis is a strong risk factor for cirrhosis.   Time course — illustrated in Figure 8.21.  Complications are cirrhosis (as a result of chronic  hepatitis) and hepatocellular carcinoma. Carriers of  hepatitis B are 200 times more likely to get liver cancer  than non-carriers. However, there is typically a latency  period of 20-30 years between infection and cancer.   Treatment — large doses of interferon-a/p for carriers.  The role of the antiviral nucleoside drug lamivudine is  currently being evaluated. Prophylactic vaccination  based on the hepatitis B surface antigen (HBsAg) is  available but up to 10% of normal individuals fail to  produce protective antibodies.   Transmission — predominantly blood-borne spread,  although sexual and vertical transmissions do occur.  I-Iepatitis C is widespread among intravenous drug    Fig. 8.20 Summary of the possible courses of infection. (HBV,  hepatitis B virus; HBsAg, hepatitis B surface antigen.) (Adapted  with permission from Clinical Medicine, 7th edn, by P Kumar  and M Clarke, Bailliere Tindall, 2009.)    Fig. 8.21 Course of infection in hepatitis B. (A) Acute hepatitis.  (B) Chronic hepatitis. (HBsAg, hepatitis B surface antigen; HBeAg,  hepatitis Be antigen; anti-HBs, antibody to HBsAg; anti-HBc,  antibody to hepatitis B core antigen; anti-HBe, antibody to  HBeAg.) HBsAg window is time point where neither HBsAg nor  anti-HBs can be detected because of immune complex formation.   abusers and was previously spread by blood transfusions  before serological screening of donated samples was  introduced.   Infection is asymptomatic in 10-35% of cases,  although it may progress to the carrier state. However,  the majority of patients develop acute hepatitis (in  65-90% of cases).   Chronic hepatitis develops in 70-80% of those  infected, increasing lifelong risk of cirrhosis and hepato-  cellular carcinoma.   Treatment is with interferon-cc and ribavirin, al-  though only half of patients will respond.   This RNA virus is incomplete and can only cause infec-  tion in the presence of hepatitis B virus; transmission is  as for hepatitis B virus. Both viruses may be acquired si-  multaneously or hepatitis D may be acquired later as a  superinfection.   The virus increases the severity of chronic hepatitis,  and it may predispose to the development of fulminant  hepatitis.   This RNA virus has the same transmission pattern as  hepatitis A. Infection by hepatitis E is clinically similar  to hepatitis A infection.   Non-hepato trophic viruses may also cause hepatitis.  Examples include group B arbovirus (yellow fever),  Epstein-Barr virus and cytomegalovirus.   It has a prevalence of about 4 per 10 000, and it typically  occurs in women (70% of cases) between the ages of 20  and 40 years.   The condition is associated with hyperglobulinaemia  and autoantibodies in the serum (antismooth muscle  and antinuclear antibodies in type I disease; antiliver-  kidney microsomal antibodies in type II). Type I disease  (most common) is associated with other autoimm-  une disorders such as Graves disease and Sjogren's  syndrome (dry eyes and mouth).   Clinically, there is insidious onset of anorexia, mal-  aise and fatigue accompanied by abdominal distension  and mild jaundice (with dark urine and itching).   • Hyperglobulinaemia (mainly IgG increases), often  with a raised erythrocyte sedimentation ratio (ESR)   • Serology — autoantibodies are useful if titres are high,  but low levels may be found in healthy people.   The disease may run a relapsing and remitting course  but it progresses inexorably to cirrhosis.   Treatment is with corticosteroids; azathioprine may  help to reduce steroid dosage.   Prognosis — patients who do not respond to treat-  ment will almost always progress to cirrhosis. Also,  many patients develop cirrhosis despite having a re-  sponse to treatment. If end-stage liver disease develops,  liver transplantation is an effective procedure.   This rare syndrome of hepatic encephalopathy results  from sudden severe impairment of hepatic function. It  is caused by acute, severe liver damage such as:   • drugs and poisons, e.g. acetaminophen (paraceta-  mol) overdose, carbon tetrachloride   The pathogenesis of hepatic encephalopathy has  already been described (see page 129).   Fulminant hepatitis is distinguished from hepatic  encephalopathy occurring as a result of  deteriorating chronic liver disease by its occurrence  within 8 weeks of onset of the precipitating  illness, and in the absence of evidence of pre-existing  liver disease.   • cerebral disturbance (mental changes progressing  from confusion to stupor and coma)   The liver may enlarge initially, but later it becomes  impalpable; disappearance of hepatic dullness on  percussion indicates shrinkage and is a bad progno-  stic sign.   • Oedema — this may be cerebral (causing raised in-  tracranial pressure) or pulmonary (contributing  to respiratory failure)   There is no specific treatment. Management is by  close observation, treating complications as necessary.  Prognosis:   • those who recover from fulminant hepatic failure  usually regain normal hepatic structure and function.   This localized collection of pus within the liver is walled  off and surrounded by damaged and inflamed liver tis-  sue. Liver abscesses are rare but important, as they are  inevitably fatal if untreated.   The most common causative organisms are Escherichia  coli, various streptococci and other enterobacteria.  Mode of infection:   • Ascending spread from colonization of biliary tract  (most common) — almost always predisposed by  biliary obstruction and usually resulting in multiple  small abscesses   Symptoms of infection and right upper quadrant  pain (may radiate to the right shoulder) are common,  along with hepatomegaly and a mild jaundice.   Investigations include ultrasound imaging. Needle  aspiration at this time can confirm the diagnosis in  addition to providing pus for culture.   Management is by prolonged antibiotics and drain-  age of the abscess.   Prognosis — the mortality of liver abscesses is 20-  40%, usually through failure to make the diagnosis.   The most common causative organism is Entamoeba his-  tolytica, which is transmitted from the bowel to the liver  via the blood. The disease is rare in the UK but common  worldwide, and it must be considered in patients travel-  ling from endemic areas such as Africa, Asia and South  America.   Alcohol abuse is the most common cause of liver disease  in Western countries. Women are more prone to alco-  hol-induced liver damage than men.   Alcohol is metabolized almost exclusively in the liver  and liver damage is related to daily alcohol intake. Tox-  icity of ethanol is probably caused by the generation  of its metabolic breakdown product, acetaldehyde,  which binds to liver proteins and damages hepatocytes.  Alcohol also stimulates collagen synthesis in the liver  leading to fibrosis.   This is the most common lesion of alcoholic liver  disease. The condition is characterized by the accumula-  tion of fat globules within the cytoplasm of hepatocytes.  It is reversible on cessation of alcohol ingestion.   It is thought that alcohol stimulates hepatocyte  triacylglycerol production, while impairing its excretion  from the liver. The condition reflects severe metabolic  derangement and it may affect a few or almost all  hepatocytes.   This is acute hepatitis with focal necrosis of liver cells. At  high concentrations, alcohol causes toxic injury to  hepatocytes, evoking a neutrophil-dominant inflamma-  tory reaction, which is reversible on abstinence. Eosin-  ophilic accumulations called Mallory bodies may be  seen on liver biopsy. Continued alcohol consumption  causes the development of fibrosis around central veins.  The result is hepatic fibrosis that may progress to  cirrhosis.   The illness resembles acute viral hepatitis and liver  function tests show raised levels of aminotransferases  and y-glutamyltransferase (GGT).   Irreversible architectural disturbance occurs as a result  of sustained alcoholic liver injury.   Normal liver architecture is diffusely replaced by  nodules of regenerated liver cells separated by bands  of collagenous fibrosis. This may develop after episodes  of acute alcoholic hepatitis or may be insidious in its on-  set presenting only as end-stage liver disease.   It affects fewer than 10% of patients suffering from  chronic alcoholism.   Fatty change can occur without excessive alcohol  intake; it is commonly seen amongst the obese and  type 2 diabetic populations. There is predominantly  macrovesicular change (large fat globules), although  conditions such as pregnancy may be microvesicular  (small fat globules). In a minority of individuals, there  may be an accompanying inflammatory infiltrate,  producing a non-alcoholic steatohepatitis (NASH) . This  is associated with the same risks of progression to  cirrhosis as alcoholic hepatitis.   The liver is the main organ of drug metabolism and,  consequently, drugs are a common cause of liver dis-  ease. Hepatotoxic drugs may be divided into two main   These have dose-dependent, predictable toxic effects.  They are responsible for a high incidence of toxic dam-  age to the liver via either direct toxicity of an unmetabo-  lized drug or normal hepatic conversion to a toxic  metabolite.   These have non-dose-dependent, unpredictable toxic ef-  fects. They cause liver disease in a small percentage of ex-  posed individuals as a result of hypersensitivity (drug-  mediated autoimmunity) or abnormal drug metabolism.   Vascular disorders of the liver (Fig. 8.22) can be classi-  fied into one of three categories depending on their  pathogenic mechanisms:   3 . Obstruction to inflow — obstruction of portal vein or  hepatic artery occlusion.   • Budd-Chiari syndrome — obstruction occurs in the  larger hepatic veins   • Cardiac disease — right-sided cardiac failure causes  congestion of the inferior vena cava.   Clinical manifestations depend on the cause and  speed with which obstruction develops, but congestive  hepatomegaly and ascites are features in all patients.   This rare condition is caused by occlusion of the main  hepatic vein or (more rarely) the intrahepatic vena cava  (Fig. 8.23).   Obstruction of the hepatic vein causes severe hepatic  congestion with atrophy and/or necrosis of liver cells in  the affected areas. Fibrous scarring eventually occurs in  areas of hepatocyte necrosis. True cirrhosis supervenes  in a minority of cases.   Underlying cause cannot be found in more  than half of cases   • Deficiencies of antithrombin III, proteins C and S  Pregnancy/oral contraceptives   Obstruction due to tumours, e.g. liver, kidneys or adrenals  Congenital venous webs  Inferior vena cava stenosis   Congestive cardiac failure causes venous outflow ob-  struction in the liver due to back pressure transmitted  as described below:   Inferior vena cava — > hepatic vein — > central veins  — > centrilobular congestion   Centrilobular sinusoids are dilated by blood and the  centrilobular hepatocytes undergo atrophy and necrosis  (centrilobular necrosis), giving rise to the appearance of  what is described as a 'nutmeg liver' (chronic passive  venous congestion).    The condition is common in tricuspid valve incom-  petence when the liver is pulsatile.   Arterial hypotension may increase the congestive  effect of right-sided cardiac failure.   • Cirrhosis — distortion and destruction of the hepatic  vascular architecture causes sinusoid occlusion   • Non-cirrhosis fibrosis — where fibrotic damage to  the liver does not amount to true cirrhosis, e.g. schis-  tosomiasis infection   • Extrahepatic — portal vein obstruction (thrombosis,  extrinsic compression) or hepatic artery occlusion  (thrombosis, embolism)   Obstruction of the portal vein results in portal hyperten-  sion and its associated complications. The causes may  be thrombotic or non-thrombotic.   • inflammatory — thrombophlebitis and intra-abdom-  inal sepsis (e.g. appendicitis, cholecystitis, pan-  creatitis)   • neoplastic — hepatocellular carcinoma, metastatic  liver tumours and haematological malignancies  (e.g. polycythaemia rubra vera, essential thrombocy-  tosis, myelofibrosis)   • splenic vein thrombosis (often secondary to pancre-  atitis) may propagate into the portal vein.   Non-thrombotic conditions are external compres-  sion (e.g. by tumour masses) and cirrhosis.   True infarction of the liver is rare because of its dual  blood supply and rich anastomosis of blood flow  through the sinusoids. However, hepatic blood flow  may be compromised in the following conditions:   • therapeutic arterial embolization of the liver or ther-  apeutic hepatic arterial ligation (performed to treat  isolated neoplastic masses)   These typically affect premenopausal women, and they  are predisposed by oestrogen-containing oral contra-  ceptives.   The macroscopic appearance is of well-circumscribed  nodules up to 20 cm in size.    The microscopic appearance closely resembles that of  a normal liver, except that no portal structures are seen.   Complications — the majority of lesions are asymp-  tomatic, but subcapsular adenomas are prone to rup-  ture, leading to intra-abdominal bleeding.   These are very common lesions composed of abnormal  bile ducts in a collagenous stroma that appear as small  white nodules, often beneath the liver capsule. They  may be mistaken for metastatic tumour deposits at  laparotomy.   These are common hamartomas composed of abnor-  mal vascular channels in a collagenous stroma. They  are found at autopsy in 2-5% of the population and  are typically seen just beneath the capsule as a dark  lesion (usually 2-3 cm in size).   Carcinoma of hepatocytes is the commonest primary  tumour of the liver. Uncommon in the UK (affects  about 1 per 100 000) it is up to 100 times more com-  mon in parts of Africa and the Far East, probably be-  cause of the higher incidence of hepatitis B and  contaminating mycotoxins. Males are affected more  than females.   Tumours may consist of a single mass or multiple  nodules. Hepatocellular carcinomas often produce  a-feto-protein, which is secreted into the blood and is  useful as a diagnostic marker. Prognosis is very poor  with median survival of less than 6 months from  diagnosis.   This is an adenocarcinoma anywhere in the biliary tree.  Within the liver, it may arise from the intrahepatic bile  duct epithelium, accounting for 5-10% of all cases of  primary liver tumours.   • chronic inflammatory disease of the intrahepatic  biliary tree, particularly sclerosing cholangitis   Lesions tend to be detected late and are associated  with a very poor prognosis; most patients do not survive  more than 6 months from diagnosis.   These highly malignant tumours are derived from vas-  cular endothelium, and characterized by multifocal  haemorrhagic nodules within the liver. The tumours  are rare but can be associated with exposure to sub-  stances such as vinyl chloride monomer (used to make  PVC) and anabolic steroids.   The majority of malignant liver tumours are metastatic.  The most common primary carcinomas, which metasta-  size to the liver, are of the lung, breast, colon and stom-  ach. However, any cancer may spread to the liver,  including leukaemias and lymphomas.   Mode of spread is via the bloodstream, through the  portal vein (tumours of the GI tract) and the systemic  circulation (other tumours). There are usually multiple  nodular deposits with a central area of necrosis.   Extensive metastases can cause compression of the  intrahepatic bile ducts leading to obstructive jaundice.   Biliary cirrhosis is the result of the long-standing  obstruction of bile ducts leading to the development  of obstructive jaundice, liver cell necrosis and fibrosis  with regenerative nodules. The main causes:   • primary sclerosing cholangitis — inflammation and  fibrosis of bile ducts (both intrahepatic and  extrahepatic).   Biliary obstruction causes oedema and expansion  of intrahepatic portal tracts with portal tract fibrosis.  Bile droplets develop in biliary canaliculi, which  may rupture and cause death of adjacent hepatocytes  (so-called 'bile infarct'). Over a long period of time,  liver cell death, regeneration and fibrosis result in  cirrhosis.   This cirrhosis occurs as a result of a chronic destruction  of intrahepatic bile ducts. It affects 5 per 100 000 in the  UK, typically among the middle-aged population.  Females are affected more than males by 10:1.   Aetiology is unknown, but it is thought to involve  immune phenomena (antimitochondrial antibodies  in more than 90% of cases).   It is often associated with other autoimmune diseases,  e.g. rheumatoid arthritis (RA), thyroiditis, systemic   Pathogenesis is progressive, chronic, granulomatous  and inflammatory. Inflammatory damage with fibrosis  may spread from portal tracts to the liver parenchyma.  The condition eventually leads to cirrhosis and its com-  plications over a period of about 10 years.   This occurs as a result of prolonged mechanical obstruc-  tion to bile flow in large ducts outside the liver or within  the porta hepatis. Causes are:   • tumours, e.g. carcinoma of bile duct, carcinoma of  the pancreas   Histological features — Bile pigment accumulates in  hepatocytes, in dilated biliary canaliculi and in Kupffer  cells. Prolonged obstruction causes:   Initially, primary biliary cirrhosis causes fatigue,  arthralgia, pruritus and mild jaundice. This progresses  following cirrhosis to:   • liver function tests — features of cholestasis (raised  alkaline phosphatase, cholesterol and bile acids)   • endoscopic retrograde cholangiopancreatography  (ERCP) — rules out obstructive causes of cirrhosis.    Complications are cholangitis (inflammation of the  bile ducts, usually as a result of superimposed infection)  and those of cirrhosis.   Chronic inflammation and obliterative fibrosis of bile  ducts with stricture formation causes progressive ob-  structive jaundice. The condition affects 1 per 100 000  with peak incidence between 25 and 40 years, males  more so than females. Aetiology is unknown but is  probably autoimmune in nature. However, unlike pri-  mary biliary cirrhosis, only 10% of patients have detect-  able autoantibodies.   Ulcerative colitis is also present in 60% of patients  with primary sclerosing cholangitis.   • large intrahepatic and extrahepatic bile ducts — devel-  opment of fibrous strictures with segmental dilatation  causing the 'beaded' appearance on endoscopic  retrograde cholangiopancreatography (ERCP)    • small bile ducts in portal tracts — replaced by collag-  enous scarring (vanishing bile ducts).   Clinical features — patients develop cholestatic jaun-  dice (pale stools, dark urine and pruritus) with progres-  sion to cirrhosis over a period of about 10 years. There is  an increased risk of developing cholangio-carcinomas.   Gallstones (stones formed in the gall bladder) are the  most common cause of disease affecting the biliary tree.  They occur in 1 0% of all adults in the UK, females more  often than males by 2.5: 1 . The number of stones per pa-  tient has varied from 1 to 26 000.   However, despite the high incidence of gallstones,  only about 1% of total patients with gallstones develop  complications.   There are two types of gallstone — predominantly cho-  lesterol stones (80% of all stones) and predominantly   Males > females with peak  incidence between 25 and 40 years    pigment stones (20% of all stones). Both types also con-  tain calcium salts, e.g. bilirubinate, carbonate, phosphate  and palmitate.   The major constituent of the stone is cholesterol, which  reaches levels beyond the solubilizing capacity of bile  (supersaturation). This may occur because of:   • decreased secretion of bile salts, due to either defec-  tive bile synthesis or excessive intestinal loss of bile  salts   • abnormal gall bladder function, usually hypomobility.  Risk factors for cholesterol stones are shown in   The major constituent of the stones is bile pigment  (calcium bilirubinate). These stones are typically found  in patients with chronic haemolysis due to increased  bilirubin production, hence pigment stones are typi-  cally black.   Gallstones may be asymptomatic (80% of cases), symp-  tomatic (pain and other symptoms) or complicated.  Complications include:   • cholecystitis — inflammation of gall bladder caused  by impaction of a stone in the neck of the gall blad-  der or cystic duct   • jaundice — impaction of stone in common bile duct  (choledocholithiasis), leading to biliary obstruction  and symptoms of biliary colic   • cholangitis — inflammation of bile duct usually as a  result of biliary obstruction complicated with bacte-  rial infection   • abdominal X-ray — but stones are calcified in only  10-20% of cases   • bile acids (e.g. ursodeoxycholic acid) — can dissolve  stones in some patients   • extracorporeal shock-wave lithotripsy — useful for  those patients unsuitable for surgery.   This is inflammation of the gall bladder. Aetiology is al-  most always associated with gallstones. There are two  types, acute and chronic.   This acute inflammation of the gall bladder is precipi-  tated by the chemical effects of concentrated static bile.  It is typically due to obstruction of outflow by stones at  the gall bladder neck or cystic duct, and it may be exac-  erbated by secondary infection with enteric organisms  such as Escherichia coli.   In severe cases, the lumen distends with pus causing  increased risk of perforation and peritonitis.   Empyema may occur in an inflamed gall bladder  greatly distended with pus.   Invariably associated with gallstones. The wall of  the gall bladder is thickened and rigid from fibrosis,  with variable chronic inflammatory infiltration of the  mucosa and submucosa. The thickened wall may  contain mucosal outpouches (Rokitansky-Aschoff  sinuses).   Hartmann's pouch is a pathological dilatation in  the neck of the gall bladder formed by increased  intraluminal pressure or stone.   This is sterile obstruction of the neck by a gallstone.  A lack of inflammation permits the gall bladder to fill  with mucus and distend.   This is usually an adenocarcinoma, invariably associ-  ated with gallstones and chronic cholecystitis. Most  cases are seen in women over the age of 70 years. There  is a poor prognosis due to liver invasion.   This acute inflammation of the pancreas is caused by the  destructive effect of enzymes released from pancreatic  acini. It is relatively common, affecting 10-20 per  100 000 per year in Western communities. By far the  most common causes of acute pancreatitis are gallstones  (50% of cases) and alcohol ingestion (20%). These and  other causes are classified in Figure 8.26.   Impaction of a gallstone distal to the site of union of a  common bile duct and pancreatic duct results in:   Pancreatic proenzymes (zymogens) are inappropri-  ately activated at some stage in this process, allowing  autodigestion of pancreatic tissue. It is believed that  the conversion of trypsinogen to trypsin is central to  an activation cascade.   Note — chronic alcohol ingestion may also produce  increased intraductal pressure due to production of a  protein-rich pancreatic fluid, which can form solid  plugs in smaller pancreatic ducts.   Less common causes of pancreatitis (e.g. viruses, drugs  and trauma) may produce direct acinar damage.   A useful mnemonic for memorizing the causes of  pancreatitis is GET SMASHED: Gallstones, Ethanol,  Trauma, Shock, Mumps, Autoimmune (PAN), Scorpion  bites (rare in the UK!), Hyperlipidaemia (also  hypercalcaemia and hypothermia), ERCP and Drugs.   Irrespective of the cause of pancreatitis, acinar damage  leads to the liberation of lytic enzymes (proteases and  lipases) causing necrosis of normal tissue. The three  patterns of pancreatic necrosis are:   • perilobular — necrosis of the periphery of lobules.  Caused by poor vascular perfusion usually as a result  of shock   • panlobular — necrosis affects all portions of the  pancreatic lobule. This often develops from  initial periductal or perilobular necrosis.   A vicious circle of necrosis occurs in which enzymatic  release results in further acinar damage and further en-  zyme release:   • Elastase and other enzymes — > vascular damage with  haemorrhage into pancreas or peritoneum. Exten-  sive haemorrhage is known as acute haemorrhagic  pancreatitis.   • signs — tachycardia, fever, jaundice, shock, ileus,  rigid abdomen, discoloration around the umbilicus  (Cullen's sign) or in the flanks (Grey Turner's sign).    • systemic — shock, renal failure, acute respiratory dis-  tress syndrome (ARDS), hyperglycaemia, hypocal-  caemia, peritonitis.   Diagnosis of acute pancreatitis is made by an ele-  vated serum amylase (or lipase) alongside evidence of  pancreatic swelling (on ultrasound or CT). Liver func-  tion tests tend to be deranged (| bilirubin, | alkaline  phosphatase, ( albumin).   Management is by physiological support and treat-  ment of shock, respiratory failure and pain.   Mortality is about 10-15% (negligible in mild cases, but  up to 50% in cases with a severe haemorrhagic  pancreatitis).   Death may be from shock, renal failure, sepsis or  respiratory failure with contributory factors being  protease-induced activation of complement, kinin and  the fibrinolytic and coagulation cascades.   This is chronic inflammation and fibrosis of the pan-  creas with a relapsing and remitting course.   It is a relatively rare disease but with increasing inci-  dence due to a rise in the incidence of alcoholism. Typ-  ically, it occurs between the ages of 35 and 45 years;  males more so than females.   Aetiology — the main causes of chronic pancreatitis  are outlined in Figure 8.27.   Pathogenesis — thought to be similar to the mecha-  nisms involved in acute pancreatitis. However, there is  permanent impairment of function.   • Malabsorption due to reduced exocrine function  (decreased lipase and protease secretion) — steator-  rhea (fat in faeces)   • Diabetes mellitus (destruction of pancreatic paren-  chyma) — this effect on the endocrine pancreas oc-  curs in advanced disease.   Imaging is by plain radiograph (for calcification of  the pancreas), ultrasound, CT and ERCP.   Management is based on alcohol abstinence, pain  relief, dietary fat restriction and surgery for correctable  causes.   A collection of fluid and necrotic inflammatory debris is  localized either within the pancreas itself or, more com-  monly, in the adjacent tissue, particularly the lesser sac.  They are not 'true' cysts (because they have no epithelial  lining) but they are surrounded by a zone of inflamma-  tory granulation tissue and they communicate into the  pancreatic duct system. They occur in both acute and  chronic forms of pancreatitis.   Although many pseudocysts spontaneously resolve,  there is a risk of infection, compression or perforation.   These benign, well-circumscribed masses are composed  of multiple cystic cavities lined by either serous or  mucin-secreting epithelium.   This common tumour accounts for 3-5% of cancer  deaths in the UK. Most tumours are adenocarcinomas  arising from the pancreatic ducts. Incidence rises with  age, and the cancer is twice as common in males as in  females.   Associations include cigarette smoking, chronic pan-  creatitis, a diet high in fat and carbohydrate and diabe-  tes in women. Around 10% of cases have a clear genetic  association (e.g. hereditary pancreatitis, multiple endo-  crine neoplasia).   The development of pancreatic cancer follows an  adenoma-adenocarcinoma sequence similar to that  seen in colonic cancer (see Chapter 3). Precursor lesions  with the potential to form adenocarcinomas are termed  pancreatic intraepithelial neoplasias.   The tumour arises with different frequencies in dif-  ferent parts of the pancreas: 60% in the head, 15% in  the body, 5% in the tail; 20% of pancreatic cancers  exhibit a diffuse pattern.   Carcinoma in the head of the pancreas tends to  present early with obstructive jaundice. As a result,  tumours are on average smaller at diagnosis than in  other sites.   Microscopic appearance — lesions are typically moder-  ately differentiated adenocarcinomas composed of  glandular spaces in a fibrous stroma.   • Weight loss, anorexia and chronic persistent pain in  epigastrium radiating to the back   • Obstructive jaundice with painless palpable dilata-  tion of gall bladder (Courvoisier's sign)   • Rarely, there may be vomiting (duodenal obstruction),  venous thrombosis (migratory thrombophlebitis),  acute pancreatitis or diabetes mellitus (destruction of  islets of Langerhans with carcinoma).   • Curative resection (Whipple's procedure) — rarely  possible due to extensive disease    • Palliative surgery — often performed to bypass  obstruction of the bile duct (relieving jaundice)  and obstruction of the duodenum.   Diverticulum (outpouching) of the ileum is caused  by incomplete regression of part of the yolk stalk (the  vitelline duct) during the embryonic period.   Meckel's diverticulum occurs in 2% of the popula-  tion and in males more than females by about 3:1.    Macroscopically, it is up to 5 cm long and located  around 60 cm from the ileocaecal junction.   Microscopically, it is true diverticulum, consisting of all  three layers of bowel: mucosa, submucosa and muscularis  propria. About half of cases also contain heterotopic  gastric acid-secreting epithelium or pancreatic tissue.   Complications — the majority of these diverticula are  asymptomatic; however, the complications include vol-  vulus, inflammation, peptic ulceration and intussuscep-  tion (telescoping of one portion of intestine into  another) .   This congenital condition is characterized by dilatation  of the colon due to the absence of the normal myenteric  plexus distal to the dilatation. It results from the failure  of neuroblast cells to migrate from the vagus into the de-  veloping gut. It occurs in 1 per 5000 live births.   This condition always involves the rectum, and it  may be present in continuity for a variable distance  along the bowel.   Macroscopically, there is a narrowing of an abnor-  mally innervated bowel segment and dilatation and  muscular hypertrophy of the bowel segment proximal  to this.    Microscopically, there is an absence of normal myen-  teric and submucosal plexus ganglion cells, and hyper-  trophy of nerve fibres within submucosa and  muscularis mucosae, with extension of abnormal axons  up into the lamina propria.   Clinical features — the disease usually presents in early  childhood with symptoms of colonic obstruction, i.e.  constipation, abdominal distension and vomiting.   Diagnosis — barium enema reveals a small, empty rec-  tum and dilatation above the narrowed segment. A bi-  opsy of the rectal mucosa will confirm the diagnosis.   Treatment is by excision of the abnormal segments of  colon and rectum.   Note that megacolon can also be a result of acquired dis-  ease. However, acquired megacolon differs macroscop-  ically, from Hirschsprung's disease in that there is no  narrowed segment, dilatation extends down to the anus,  and the rectum is full of faeces.   • Psychogenic megacolon — disregard for the urge to  defaecate (usually in children or the depressed)   • Chagas' disease — infection by Trypanosoma cruzi  with destruction of myenteric plexus. Common in  South America   Diarrhoea is hard to define. Many consider it to mean  frequent bowel evacuation or the passage of abnormally  soft or liquid faeces, although it is clinically defined as  the passage of more than 200 g of stool per day.   Dysentery is an inflammatory disorder of the intesti-  nal tract causing severe diarrhoea with blood and mucus.   • secretory — diarrhoea caused by a combined effect of  excessive intestinal secretions and decreased absorp-  tion. Stool volumes may be very high and diarrhoea  persists even when there is total fasting   • osmotic — diarrhoea caused by the presence of  unabsorbed solute in the colon, which prevents  the absorption of fluid. Ceases on fasting long  enough to empty the small bowel   • deranged motility — diarrhoea as a result of either in-  creased or decreased motility of the small intestine   The classification and causes of diarrhoea are  described in Figure 8.28   Enterocolitis (inflammation of the colon and small  intestine) is common and is often a result of infection.   Viruses are the most common cause of gastroenteritis in  infants and young children; they account for 10% of all  food poisoning outbreaks in the UK. Transmission is  typically by a faecal-oral route. Symptoms are cramps,  vomiting and fever but no blood in stools.   • Rotavirus — causes 50% of infantile diarrhoea and  accounts for some adult cases   • Adenovirus (especially types 40, 41) — second to ro-  tavirus as cause of acute diarrhoea in young children   In adults, the Norwalk virus accounts for 30% of  cases of gastroenteritis. It is responsible for the 'winter  vomiting disease'.   • Preformed toxin — ingestion of food contaminated  with bacterial toxins, e.g. from Staphylococcus aureus,  Bacillus cereus, Clostridium perfringens. Incubation  period is very short (1-7 hours).   • Toxigenic organism — ingestion of bacteria that pro-  duce toxins in the gut, e.g. Vibrio cholerae, enterotoxi-  genic Escherichia coli (ETEC), and Clostridium  perfringens. So-called 'traveller's diarrhoea' usually  occurs by this mechanism and is extremely common.   • Enteroinvasive organism — ingestion of bacteria that  invade the intestinal mucosa and may cause dysen-  tery as a result of severe inflammation, e.g. Salmonella  typhi, Campylobacter jejuni, Shigella, enterohaemor-  rhagic Escherichia coli (EIIEC).   • Antibiotic-associated diarrhoea — occurs as a result  of overgrowth of one type of bacteria because of dis-  ruption of normal gut flora following antibiotic  treatment. Main culprit is Clostridium difficile, which  causes necrosis of the colonic mucosa and pseudo-  membranous colitis (a false membrane in the co-  lon). Patients develop fever, abdominal pain and   Infections: bacteria producing enterotoxins, viral diarrhoea, Giardia  Irritants: laxatives, bile acids, hydroxyl fatty acids   Hormonal: VIP, glucagon, medullary carcinoma of the thyroid, Addison's disease  Mucosal infiltration: villous adenoma, lymphoma, collagen diseases  Congenital: chloridorrhea   Inflammatory diseases, e.g. ulcerative colitis, Crohn's disease  Infections: bacteria causing invasion of the mucosa, i.e. enteroinvasive bacteria  such as Shigella, Campylobacter, enterohaemorrhagic Escherichia coli', and  Entamoeba histolytica   May be a mixture of secretory, osmotic and exudative diarrhoea (see Fig. 8.33)    diarrhoea. Clostridial overgrowth is also promoted  by surgery, ischaemia, shock and burns. Other path-  ogens of antibiotic-associated diarrhoea are Clostrid-  ium perfringens and Staphylococcus aureus.   • Necrotizing enterocolitis — rare condition arising  through a combination of ischaemia and infection.  Ischaemia progresses to intestinal infarction and ne-  crosis of the intestines. Infection of infarcted tissue  results in gas gangrene (see Chapter 2), sepsis and  shock with paralytic ileus. Most cases are seen in  neonates. Adult cases are related to Clostridium per-  fringens infection.   • Chagas' disease — infection by Trypanosoma cruzi re-  sults in the destruction of the myenteric plexus over  a period of years with resulting dilatation of various  parts of the alimentary canal, especially the colon  and oesophagus. Common in South America.   • Amoebic dysentery — this infection by Entamoeba his-  tolytica is common throughout the tropics where it is    spread by faecal-oral transmission of amoebic cysts.  The condition follows a chronic course with abdom-  inal pains. Periods of diarrhoea alternating with  constipation are common.   • Giardiasis — This disease is caused by the parasitic  protozoan Giardia lamblia in the small intestine. In-  fection occurs by eating food or water contaminated  with parasitic cysts. Symptoms include diarrhoea,  nausea, abdominal pain and flatulence, as well as  the passage of pale, fatty stools. The disease occurs  worldwide and it is particularly common in  children.   • Schistosomiasis (Schistosoma mansoni and S. haema-  tobium) - eggs from these worms are laid in the mu-  cosa of small and large bowel causing inflammation,  ulceration and bleeding.   • Strongyloidiasis ( Strongyloides stercoralis) - a chronic  nematode infection that can become a hyper-  infection and virulent if the patient's cellular im-  mune status declines.   B, blood in the stools; C, abdominal cramps; EHEC, enterohaemorrhagic Escherichia coli;  ETEC, enterotoxigenic Escherichia coli; F, fever; V, vomiting.   The most important of these are idiopathic in origin,  namely Crohn's disease and ulcerative colitis (together  termed 'inflammatory bowel disease') . These conditions  are characterized by chronic, relapsing inflammation of  the intestinal wall.   A granulomatous inflammation of unknown cause that  affects the full thickness of the bowel wall anywhere in  the GI tract from mouth to anus, this disease is charac-  terized by a relapsing and remitting course. Its incidence  is about 5-7 per 1 00 000 in the UK, but this is increasing.   It usually presents in early adult life, with 90% of  patients aged between 10 and 40 years, although a sec-  ondary peak occurs in the elderly. Females are affected  slightly more than males. There is a higher incidence in  northern Europe and the USA than elsewhere.   Cause and pathogenesis are unknown, however there is  a genetic predisposition with the NOD2/CARD15 gene  on chromosome 16. This gene codes for a protein which  facilitates opsonization of gut bacteria; however, the  putative infectious organism has not been confirmed.   Site — most commonly affects the terminal ileum, but it  may affect any part of the GI tract from the mouth to the  anus in a discontinuous pattern. Two-thirds of cases  affect only the terminal ileum, one-sixth affect only  the colon, and one-sixth are in the terminal ileum  and colon.   • 'Skip' lesions — normal bowel areas are present be-  tween diseased segments, with a sharp demarcation  between the two   • Haemorrhagic ulcers — initially small and discrete,  these progress to form deep, linear, fissured ulcers  ('rose thorn' ulcers)   • Cobblestone pattern of bowel mucosa due to  submucosal oedema and interconnecting deep  fissured ulcers   • Transmural inflammation — all layers of bowel wall  are affected. Forms basis of fissures, adhesions, fistu-  lae and sinuses   • Non-caseating granulomas present in inflamed  bowel wall and in mesenteric lymph nodes in about  60% of cases   • Evidence of persistent and inappropriate T-cell and  macrophage activation with increased production  of inflammatory cytokines.   Clinical features are symptoms of abdominal pain, diar-  rhoea (possibly bloody) and weight loss, with signs of   The natural history of Crohn's disease is one of remis-  sions and relapses of inflammation punctuated by   • severe inflammation — this may be life threatening,  often with dilatation of the colon and passage of bac-  terial toxins into the bloodstream (toxic megaco-  lon). There is a risk of bowel perforation   • fistulae and sinuses — inflammation of serosal layer  leads to the formation of adhesions to other bowel  loops, to parietal peritoneum of anterior abdominal  wall, or to the bladder   This is a diffuse superficial inflammation of the colo-  rectum of unknown cause, and characterized by relapses  and remissions. It affects about 10 per 100 000 in the  UK, with much lower rates in developing countries with  warmer climates. Ulcerative colitis has a similar age dis-  tribution to Crohn's but the sex incidence is equal.   This is unknown, but the same hypotheses as for Crohn's  have been proposed with the exception of smoking,  which unusually is associated with a decreased risk.  Again, inappropriate and persistent T-cell activation  may play an important role in the pathogenesis.   Site — ulcerative colitis usually begins distally as proctitis  and then spreads proximally. It may affect the whole of  the large bowel (pancolitis), and can, therefore, reach  the terminal ileum ('backwash' ileitis).   The pattern is one of shallow ulceration (which may  become confluent), with 'pseudopolyps', hyperaemia    and haemorrhage. The diseased bowel is continuous,  without gaps of normal tissue.   Inflammation is diffuse and is limited to mucosa and sub-  mucosa, with infiltration of both acute and chronic in-  flammatory cells. Other features are crypt abscesses with  ulceration, crypt atrophy and Paneth cell metaplasia.   Clinical features are symptoms of bloody diarrhoea,  mucus, cramping discomfort and weight loss, signs of  fever, tachycardia, pallor and abdominal tenderness.   Acute local complications include perforation, dilata-  tion, haemorrhage and dehydration (blood and fluid  loss from extensive ulceration).   Chronic local complications include strictures, dys-  plasia and carcinoma (higher cancer risk than Crohn's).   Systemic complications are identical to those seen in  Crohn's, except for an additional association with  primary sclerosing cholangitis.   Both Crohn's and ulcerative colitis are examples of  inflammatory bowel disease and they have many fea-  tures in common. However, in the majority of cases  (about 90%), it is possible to distinguish between these  two conditions (Figs 8.30, 8.31).   Diagnosis is by colonoscopy, barium and small bowel  enema. Colonoscopy is the most sensitive test and bi-  opsy specimens can be taken for histological examina-  tion (see Figure 8.32 for differences in microscopic  appearance). This investigation is also important in   Fig. 8.31 Depth and distribution of  lesions in the bowel wall.    Fig. 8.32 Comparison of the basic features of Crohn's disease and ulcerative colitis    the surveillance of patients with long-standing colitis as  it allows severe dysplasia and early invasive cancer to be  detected.   Rectal sparing, discrete patchy ulceration and peri-  anal disease are classically seen on Crohn's colonos-  copy. This contrasts with ulcerative colitis, with its  confluent ulceration, which is most severe in the distal  colon. Long-standing severe disease may show loss   • 5 -Aminosalicylic acid (5-ASA) compounds — can be  used to maintain remission once remission has been  induced by corticosteroids   • TNFa blockers (infliximab) — used in active, fistulat-  ing Crohn's disease that is unresponsive to other  treatments.   • Minimal resections for strictures, fistulae or perfo-  rations (more common in Crohn's).   • Colectomy — indicated in cases of extensive disease  affecting quality of life, failed medical therapy,  fulminant colitis and severe dysplasia or cancer on  colonoscopy surveillance. Pouch-forming opera-  tions preserve sphincter function and avoid an  ileostomy. This is suitable in ulcerative colitis but  not in Crohn's, where recurrent disease may affect  the pouch.   • intraluminal digestion — assisted by, for example,  gastric juices and pancreatic digestive enzymes (these  are necessary for breakdown of macromolecules)   • terminal digestion — enzymes located on the brush  border of the small intestinal mucosa hydrolyse  large molecules for absorption, especially complex  sugars (e.g. sucrase for sucrose and lactase for  lactose)   • transepithelial transport — mucosa is specialized for  absorption. Transverse mucosal folds and finger-like  villi provide a vast surface area.   • Steatorrhoea — malabsorption of fat, producing  pale, foul-smelling stools that characteristically float  in water   This is caused by a chronic inflammatory response to  the protein gliadin, a component of gluten (found in  wheat, oats, barley and rye) . Atrophy of small intestinal  villi and crypt hyperplasia are the result. It affects about  1 per 1000 in most Caucasian populations of Western  Europe; it is rare in other ethnic origins.   It can present at any age but it is an important cause  of failure to thrive in infants and children.   Antigliadin antibodies are present in the majority of  cases, although anti-endomyseal antibodies have a  greater sensitivity and specificity as a diagnostic aid.  Other tests that may be used are small-bowel biopsy  and a gluten challenge, in which symptoms improve  on a gluten-free diet, but relapse once this is stopped.   There is an increased incidence of disease in first-  degree relatives of those affected. It sometimes occurs  concurrently with dermatitis herpetiformis (itchy,  blistering skin disease).   Macroscopically, the luminal surface becomes flat-  tened, developing a mosaic-like pattern of crypt  openings (Fig. 8.34).   • loss of villous architecture ranging from blunting  (partial villous atrophy) to complete flattening (to-  tal villous atrophy) due to a high rate of cell loss   • increase in the depth of crypts with epithelial cell  hyperplasia to compensate for those lost through  damage.   Management is by the complete withdrawal of glia-  din from the diet (i.e. a gluten-free diet), which leads  to gradual recovery of the villous structure. This may  be partial or complete.   This chronic and progressive malabsorption syndrome  without a definable cause is seen in patients who live  or have lived in the tropics, and in the absence of other  intestinal disease or parasites. The disease occurs mainly  in the West Indies and Asia.   Aetiology is unclear; however, the condition is  thought to be infective, probably toxigenic Escher-  ichia coli.   Clinical features and histological appearances resem-  ble those of coeliac disease. However, a gluten-free diet  has little beneficial effect.   Drugs that bind bile salts, e.g. cholestyramine  and some antibiotics such as neomycin  (which causes steatorrhoea)   Whipple disease is a multisystem disorder involving mal-  absorption, weight loss, lymphadenopathy and joint  pain. The causative agent is the Gram-positive bacillus  Tropheryma whippelii. This rare condition is characterized  by tissue infiltration with foamy macrophages that are  periodic acid-Schiff (PAS) reagent positive.   In this syndrome, there is malabsorption secondary to  excessive bacteria in the small intestine, usually the  jejunum.   Causes of small intestinal bacterial overgrowth are  outlined in Figure 8.35.   • damage to the small intestinal mucosa, probably by  bacterial products    • binding of vitamin B 12 by bacteria, hence vitamin  B 12 deficiency.   Diarrhoea is both secretory (due to bacterial prod-  ucts affecting mucosa) and osmotic (due to unabsorbed  products and deficiency of disaccharidases because of  mucosal damage).   Clinical features are weight loss, diarrhoea and anae-  mia (due to vitamin B 12 deficiency).   Management is by antibiotic therapy and surgical re-  section for a localized abnormality, e.g. stricture, fistula.   The most important disaccharidase is lactase, which  is essential for the digestion of milk sugar (lactose).  All babies have lactase in their intestines but the  enzyme disappears later in life in about 10% of  northern Europeans, 40% of Greeks and Italians,  and 80% of Africans and Asians. The presence of  undigested lactose in the small intestine (following    Fig. 8.34 Comparison of normal  jejunal mucosa (A) and jejunal mucosa  in coeliac disease with total villous  atrophy (B).   Blind loops  Enterocolic fistulae  Jejunal diverticula  Strictures or other obstruction  Continent ileostomy   • Simple mechanical obstruction — the bowel above  the obstructing lesion becomes distended with fluid  and gas.   • Strangulation obstruction — occlusion of the blood  supply by constricting agents.   • Paralytic ileus — may arise as a consequence of  peritonitis, pancreatitis or retroperitoneal bleeding.   • Pseudo-obstruction — abnormal gut motility rather  than an organic obstructive lesion.   This is the protrusion of the whole or part of a viscus  from its normal position through a defect in the cavity  wall in which it is contained. About 1 per 100 people  has a hernia at some time. Hernias can be congenital  or acquired. Acquired hernias are:   • secondary to increased intra-abdominal pressure —  resulting from cough, straining at the stool, cysts,  carcinoma, pregnancy   • Irreducible/incarcerated — content of sac cannot be  completely returned to the abdominal cavity.  Common sites of abdominal hernias are inguinal   (70%), femoral (20%) and umbilical (10%). Others  are supraumbilical or linea alba, incisional hernias  and hiatus hernia.   • Obstruction — constriction at the neck of the hernial  sac causes obstruction of bowel loops within it.   • Strangulation — constriction at the neck of sac pre-  vents venous return leading to venous congestion,  arterial occlusion and gangrene. This may result in  perforation leading to peritonitis/groin abscess.    Note that strangulation can occur without obstruc-  tion if only one wall of the viscus pouches into the  sac (Richter's hernia).   Hernias must be repaired because of potential com-  plications. The principles of surgical repair are identifi-  cation of the sac and contents, mobilization of the sac,  reduction of the contents, ligation of the sac and repair-  ing the fascial defect.   The most common type of hernia, this is much more  prevalent in men than in women. There are two types:  indirect inguinal (85%) and direct inguinal (15%).   In indirect cases, the hernial sac enters the inguinal  canal through the deep ring (lateral to the inferior epi-  gastric artery) and then traverses through the canal to  the superficial ring, where it may eventually reach the  scrotum or labium major. It is the result of a congenital  abnormality. Strangulation is a common complication  due to the narrow neck of the hernial sac.   In direct cases, the hernial sac protrudes through a  weakness in the fascia transversalis (medial to inferior epi-  gastric artery) and it does not normally descend into the  scrotum or labium major. It originates as a result of weak-  ened abdominal muscles (usually acquired in the elderly) .  The neck of the sac is wide so strangulation is rare.   Clinically, it is difficult (often impossible) to distin-  guish between direct and indirect inguinal hernias.   The hernial sac protrudes through the femoral canal in-  ferior to the inguinal ligament (Fig. 8.37). There is an  increasing incidence with age, and females are affected  more than males by 2:1 (but inguinal hernia is still   Fig. 8.37 Sites of direct inguinal, indirect inguinal and femoral  herniations. (Adapted with permission from Principles and  Practice of Surgery, 3rd edn, by APM Forrest, PC Carter and IB  Macleod, Churchill Livingstone, 1995.)    more common in both males and females). The most  common complication is strangulation.   Adhesions are by far the most common cause of mechan-  ical obstruction in the small bowel, and they are defined  as areas of fibrosis between adjacent membranes or  organs resulting in their fusion. The causes can be  congenital (e.g. bands in small children) or acquired.  Acquired causes are as follows:   This is invagination of one part of the bowel into the ad-  joining segment (Fig. 8.38). The ileocaecal valve is the  most common site, with the ileum invaginating into  the caecum. It typically affects children under the age  of 4 years.   Adult cases are extremely rare, and they are almost  invariably precipitated by an intraluminal mass (e.g.  tumour) or structural abnormality (e.g. Meckel's  diverticulum) .   As the contents of the intestine are pushed onwards  by muscular contraction, more and more intestine is  dragged into the adjoining bowel. The net effect is ve-  nous congestion of the invaginated portion, which  may suffer infarction if mesenteric vessels are trapped.    Management is by barium reduction in children or  by resection in adults because of the high incidence of  organic causes.   This is a twisting of part of the GI tract, usually leading  to partial or complete obstruction (Fig. 8.39). It is most  commonly seen in redundant loops of the sigmoid co-  lon, but may also occur in the caecum, small intestine  and stomach.   The most common complication is strangulation  (causing infarction and possibly gangrene).   A diverticulum is a sac or pouch formed at weak points  in the wall of the alimentary tract; diverticulosis means  that there is no evidence of inflammation. Diverticulitis  is inflammation of a diverticulum, which commonly  occurs in one or more colonic diverticula.   Congenital diverticula are true diverticula containing  all three coats of the bowel wall, e.g. Meckel's  diverticulum.   Acquired diverticula may contain some (false diver-  ticula) or all (true diverticula) coats of the bowel wall.  They typically develop during adult life as a result of:    • pulsion from increased intraluminal pressure (e.g.  straining at the stool) causing protrusion at points  of focal weakness (e.g. at the sites of penetration  of blood vessels)   Colonic diverticulosis is caused by a chronic lack of  dietary fibre.   Although rare before 35 years of age, by 65 years  of age at least one-third of the population of developed  countries is affected. Rare in countries with high-fibre  diets.   Diverticula are most common in the sigmoid colon  emerging between mesenteric and antimesenteric  taeniae.   • Inflammation (diverticulitis) — may cause severe  pain and tenderness in left iliac fossa, alteration of  bowel habit, fever, leucocytosis. There may be a pal-  pable mass   • Obstruction — due to oedema or fibrosis in the in-  flamed segment of colon or to adherence of small  bowel loops   • Stricture formation — long-standing diverticular dis-  ease may cause stricture formation and subacute  intestinal obstruction   The clinical course of colonic diverticular disease may  be asymptomatic, but sometimes causes left-sided  colicky abdominal pain and alteration of bowel habit  (usually constipation) or rectal bleeding.   Diverticula can be visualized and diagnosed by  barium enema and/or colonoscopy.   • Surgery — sigmoid colectomy with end-to-end  anastomosis if there are persistent symptoms or when  carcinoma cannot be excluded by radiology or  colonoscopy.   Ischaemic bowel disease may affect the small or large  bowel, and it is most commonly seen in elderly patients  with severe atherosclerosis. The causes are discussed  below.   • vascular occlusion — emboli lodge in the superior  mesenteric artery, which supplies all the small intes-  tine except for the first part of the duodenum.  Emboli are usually derived from cardiac mural  thrombus   • vascular stenosis (less common) — occurs with  thrombosis in a severely atherosclerotic mesenteric  artery. Typically located near its origin from aorta.  Resultant small bowel infarction is extensive and  usually fatal   Thin-walled veins which drain blood from the small  bowel become occluded by extrinsic pressure, e.g. from:   Venous occlusion causes congestion and oedema  of the bowel wall. Increased pressure prevents entry  of oxygenated arterial blood leading to ischaemic  necrosis.   • Mucosal infarction — transient or reversible infarc-  tion which may be followed by complete regenera-  tion. However, increased permeability to toxic  substances can cause gradual progression to a trans-  mural infarct.   • Mural infarction — infarction of mucosa and submu-  cosa up to the muscularis propria. The mucosa is ul-  cerated, oedematous and haemorrhagic. Healing  occurs by granulation tissue formation. Mural in-  farction may lead to the development of fibrous  strictures (occurs in about half of patients with  ischaemic bowel disease).   • Transmural infarction — necrosis extends through  the muscularis propria. The bowel is flaccid, di-  lated and liable to perforation. Surgical resection  is an option, but many patients already have peri-  tonitis, endotoxaemia and severe circulatory prob-  lems at the time of diagnosis, so the prognosis  is poor.   The splenic flexure is a common and early site of  ischaemic damage, as it is a watershed area between  the distribution of superior and inferior mesenteric  arteries.   In this condition, abnormal venous dilatations develop  in the submucosa of the large intestine (typically the  right side) often causing occult or massive intestinal  bleeding. It occurs in the elderly and is associated with  aortic valve disease.   It is thought to be a degenerative process resulting in  increasing obstruction of the mucosal veins, which  become tortuous and prone to bleeding.   These are dilated varicose veins forming in the anal  canal. The most common of all anal conditions, they  affect as much as 40% of the population at some time.  Haemorrhoids develop as a result of increased intra-  abdominal pressure, e.g. constipation and straining at  the stool, pregnancy.   Two anatomical areas are affected, although both are  often involved at the same time:   1. Internal haemorrhoids — proximal to superior hae-  morrhoidal plexus, above the anorectal margin.  These most commonly occur at three main points  equidistant to the circumference of the anus  (Fig. 8.40).   Haemorrhoids are associated with bright red rec-  tal bleeding after defaecation, pain and pruritus ani.   Fig. 8.40 Diagram to illustrate the 3, 7, 11 distribution of  haemorrhoids around the anus. (Adapted with permission  from Lecture Notes in General Surgery, 12th edn, by H Ellis,  Wiley-Blackwell, 2010.)   Diagnosis is by proctoscopy (to visualize the hae-  morrhoids) or by sigmoidoscopy (to exclude coexisting  rectal pathology).   Treatment involves reducing constipation and strain-  ing with a high fibre diet, or direct therapy to the  haemorrhoid with injection sclerotherapy or band liga-  tion. Surgical removal of the haemorrhoid (haem-  orrhoidectomy) is rarely required.   Primary tumours of the small intestine are rare; those  that do arise are outlined in Figure 8.41. In contrast, tu-  mours of the large bowel are extremely common. The  colon and rectum are frequently affected by both benign  and malignant tumours.   These premalignant tumours are derived from the glan-  dular epithelium of the large bowel. Common in older  subjects, they are present in up to 50% of persons aged  over 60, males more than females by 2:1.   Aetiology is probably multifactorial. Both genetic  and environmental (dietary) factors have been  implicated.   1. Tubular — rounded lesions (0.5-2 cm in size). Often  pedunculated (i.e. have a stalk of normal mucosa).  Microscopically composed of tube-shaped glands.   2. Villous — frond-like lesions about 0.6 cm thick,  which occupy a broad area of mucosa (1-5 cm in  diameter). Microscopically composed of fingerlike  epithelial projections.   3. Tubulovillous — raised lesions (1-4 cm in size).  Pedunculated but composed of both tube-shaped  glands and finger-like epithelial projections.  Epithelium of all three types shows dysplastic   features, which can be subjectively graded as mild,  moderate or severe.   Adenomatous polyps (in familial  adenomatous polyposis and  Gardner's syndrome)  Inflammatory fibroid polyps   Hyperplastic polyps: small, flat, pale lesions typically  5 mm in size, which occur most commonly in the  rectum and sigmoid colon   Hamartomatous polyps: typically occur in childhood  and in adolescence, eg. Peutz-Jeghers syndrome  juvenile polyps (autosomal dominant), sporadic  Inflammatory 'pseudopolyps' (of ulcerative colitis)   Benign: lipoma, neurogenic tumours,  leiomyoma and haemangioma  Malignant: some smooth muscle  tumours (leiomyosaracomas)   Rare; usually incidental findings or at post-mortem;  seldom responsible for symptoms; lipomas,  leiomyomas, haemangiomas, neurofibromas   Common site for primary lymphoma  of the Gl tract; coeliac disease is a  major predisposing factor   Most common site for carcinoid tumours  (especially appendix); lesions typically  scattered singly throughout Gl tract;  may secrete gut hormones, e.g.  somatostatin, cholecystokinin,  pancreatic polypeptide and VIP   Most carcinomas of the colon develop from previous  adenomas. Progression from adenoma to carcinoma  is the well-established basis of the polyp-cancer  sequence for development of carcinoma of the colon.   Risk of malignant change is greatest where adenomas  show the following features:   • Large — less than 1 cm (1% malignant); 1-2 cm  (12% malignant); more than 2 cm (30% malignant)   • Villous — villous adenomas are more likely to  undergo malignant transformation   Familial adenomatous polyposis (FAP) is a rare auto-  somal dominant condition caused by a mutation in  the APC gene located on the long arm of chromosome  5. It is characterized by the presence of innumerable ad-  enomata of the large bowel from about the age of 25.    There is a 90% risk of developing a carcinoma of the  colon by the age of 45.   This is an inherited form of colon cancer, without  adenomas, which is due to mutation in DNA mismatch  repair genes. This is associated with microsatellite  instability.   This adenocarcinoma is derived from the glandular  epithelium of the large bowel mucosa.   It is the second most common cause of death from  neoplasia, with a peak incidence between 60 and 70  years of age; it is rare under the age of 40.   There is a high incidence in developed countries. 55  per 1 00 000 males and 35 per 1 00 000 females in the UK  are diagnosed each year, with a higher incidence in  Scotland for both sexes. Environmental factors are    thought to play a large role in the aetiology of colorectal  cancer. Risk factors are:   • high-fat, high-protein, low-fibre diets (effects on  bowel transit time, bacterial flora and levels of cellu-  lose, amino acids and bile acids in the bowel contents)   Macroscopically, the most common sites for colo-  rectal carcinomas are illustrated in Figure 8.42.   • diffusely infiltrative — rare, but virtually identical to  that seen in stomach. Often associated with carci-  noma that develops in association with inflamma-  tory bowel disease.   • Presentation — later than for left-sided carcinomas.  Left-sided carcinomas (descending colon):   Microscopic features — 98% of all cancers in the large  intestine are adenocarcinomas; the majority of    Fig. 8.42 Site and incidence of carcinomas of the large  intestine.    colorectal carcinomas are, therefore, moderately or  well-differentiated adenocarcinomas forming recogniz-  able glandular structures.   Poorly differentiated carcinomas have a poorer prog-  nosis. Overall, 5-year survival is around 50%.   modified Dukes system (Fig. 8.43). Five-year survival is  over 90% in Dukes A cancer, but less than 5% in Dukes  D. Dukes C and D cancers (common presentations)  require adjuvant chemotherapy and/or radiotherapy  after surgical resection.   This can either be of primary or secondary infection. Pri-  mary infection (less common) is seen in patients with  nephrotic syndrome (peritoneal dialysis), cirrhosis with  ascites or abdominal trauma.   Secondary infection (most common) is typically an  extension of inflammatory processes from the abdomi-  nal cavity. For example:   • chlamydial infection — a complication of female pelvic  inflammatory disease that is increasing in incidence   Organisms involved are typically a mixture of nor-  mal gut commensals with a predominance of anaerobic  bacteria and coliforms.   Irritation of the peritoneum by leaking bile, gastric  juice, pancreatic enzymes or urine produces an exudate  that is initially sterile but which usually becomes  infected within 6-12 hours.   As peritonitis develops, inflammation of visceral and  parietal peritoneum produces a purulent exudate; the  intestine becomes flaccid, dilated and covered with  fibrinous plaques that form adhesions between bowel  loops.    Fig. 8.43 Staging of carcinoma of the colon using the Dukes  system.   • paralytic ileus — paralysis of gut motility as a result of  inflammation of the serosa of the small bowel   • fibrous adhesions as a result of organization of fibri-  nous adhesion by granulation tissue   • abscesses, particularly in the paracolic gutters and  beneath the diaphragm (subphrenic recesses)   • portal pyophlebitis — spread via the portal vein to  the liver.   Diagnosis is by clinical examination and erect  abdominal X-ray, which may show air under the  diaphragm from perforated viscus. Blood cultures may  reveal the organism responsible.   This dense progressive fibrosis of the peritoneum partic-  ularly affects the visceral peritoneum of the small intes-  tine. In most cases no cause is found, although there are  rare associations with some medications (practolol and  methysergide) . It is also seen in patients undergoing  long-term continuous ambulatory peritoneal dialysis.   These are cysts found within the mesenteries of the  abdominal cavity, or attached to the peritoneal lining.   These cystic developmental abnormalities of lymphoid  type are typically asymptomatic and discovered inciden-  tally at laparotomy or autopsy.   These common lesions are found either incorporated in  the bowel wall or in mesentery detached and separated  from the tract.   This localized peritonitis is due to the capacity of omen-  tum to wall-off infection (pseudocysts).   A rare condition, this is associated with exposure to  asbestos. It corresponds to the much more common  pleural mesothelioma (see Chapter 7).   Primary infection (less common): nephrotic syndrome,  peritoneal dialysis, cirrhosis with ascites, abdominal trauma  Secondary infection (most common): typically an  extension of inflammatory processes from abdominal  cavity, e.g. appendicitis, ruptured ulcers (peptic, ulcerative  colitis, typhoid ulcers, ulcerated neoplasms), cholecystitis,  pancreatitis, salpingitis, diverticulitis, strangulated bowel   Leaking bile, gastric juice, pancreatic enzymes or urine  cause irritation and inflammation of peritoneum  producing an exudate that typically becomes infected;  intestine becomes flaccid, dilated and covered with  fibrinous plaques forming adhesions between bowel loops   Guarding and rebound tenderness  Board-like abdominal rigidity  Absent bowel sounds (paralytic ileus)  Increased pulse and temperature   Local: ileus, fibrinous adhesions, abscesses, portal pyophlebitis  Systemic: hypovolaemic shock, severe toxaemia   The peritoneal cavity is a common site of metastases;  malignancy of any organ within the peritoneal cavity  may lead to peritonitis.    Metastases result in the effusion of protein-rich fluid  into the cavity (i.e. an exudate) containing neoplastic  cells, which also grow as tiny white nodules on the me-  sothelial surface of the cavity. Nodules eventually coa-  lesce to form tumour sheets over the surface of the  viscera.   These most common tumours metastasize to the perito-  neal cavity of the stomach, ovary, pancreas and colon.   • Describe abnormalities of kidney structure, notably the common cystic diseases.   • Understand the patterns of glomerular disease and common mechanisms of injury.   • Describe common glomerular diseases and how pathology relates to clinical presentation.   • Recognize that glomerular lesions occur in systemic diseases, giving common examples.   • Understand the neoplasms commonly encountered within the kidney and urinary tract.   • Describe disorders of the urinary tract, focusing on causes of obstruction.   Congenital anomalies of kidneys are common, affecting  3-4% of newborn infants.   Unilateral agenesis occurs in 1 in 1000 births. It may oc-  cur alongside other congenital disease such as spina  bifida. The solitary kidney undergoes marked hyper-  trophy and is susceptible to infections, trauma and pro-  gressive glomerulosclerosis. It affects males more than  females by 2:1; the left kidney is usually the absent one.   Occurrence of bilateral agenesis is 1 in 3000 births,  as part of Potter's syndrome. Affected infants have ab-  normal facies, and they often have abnormalities of  the lower urinary tract, lungs and nervous system.   Characteristically, there is oligohydramnios in preg-  nancy as the kidneys are not present to contribute to  amniotic fluid (absence of fetal urine). The disorder is  not compatible with postnatal life.   Kidneys fail to reach the normal adult size either as a re-  sult of a congenital maldevelopment or due to shrink-  age, which may have occurred as a result of chronic  infection in early life.   The poles of the kidneys are fused, usually inferiorly, to  form a large U-shaped (horseshoe) kidney. This affects  about 1 in 500 people, but it is typically asymptomatic  as the collecting system develops normally. However,  Wilms' tumours are 2 to 8 times more frequent in chil-  dren with horseshoe kidneys than in the general  population.   Each disease is distinguished by a characteristic  distribution of cysts, illustrated in Figure 9.1.   Figure 9.2 provides a summary of cystic diseases of  the kidney.   1 . Appropriate patient management to delay onset  of renal failure   2. Appropriate genetic counselling in the case of  hereditary cystic diseases.   The failure of differentiation of metanephric tissues affects  the whole or just one segment of a kidney, either unilater-  ally or bilaterally. Affected areas are replaced by solid or  cystic masses, in which cartilage is usually prominent.   The condition often presents in childhood as an  abdominal mass and it requires surgical excision to  exclude a malignant tumour (e.g. nephroblastoma).  Prognosis is good for unilateral lesions.   Adult polycystic kidney disease (APKD) is a hereditary  disease. Both kidneys are progressively replaced by  fluid-filled cysts, which develop and enlarge over a  period of years.   Incidence is 1 per 1250 live births, accounting for 8%  of all end-stage renal disease, with the sexes equally  affected.   It is inherited as an autosomal dominant disorder;  85% of cases are linked to the a-globin cluster located  on the small arm of chromosome 16 (autosomal dom-  inant polycystic kidney disease-1; ADPKD-1). ADPKD-2  gene mutations (15% of cases) have a slower disease on-  set. Both mutations are associated with berry aneurysms  of the cerebral arteries and with cysts of the liver, pan-  creas and lung.   The condition is asymptomatic at first but —  eventually — replacement and compression of the func-  tioning renal parenchyma by the enlarging cysts leads to  slowly progressive impairment of renal function.   Macroscopically, in fully developed APKD, the kid-  neys are asymmetrically enlarged and are composed  of numerous large cysts (each up to 5 cm in diameter).  Haemorrhage into the cysts is common, leading to  bloodstained contents.   Microscopically, the cysts are lined by flattened cu-  boidal epithelium and communicate both with calyces  and with each other. Surrounding parenchyma often  shows extensive fibrosis and arteriosclerosis.    • subarachnoid haemorrhage (10% of cases) —  predisposed by the combination of berry aneurysms  and hypertension.   APKD typically presents in the fourth decade or later,  often with a large lobulated abdominal mass, pain or  haematuria.   Diagnosis is by ultrasound, which shows multiple  bilateral cysts. Screening susceptible 1 8-year-olds has a  95% successful diagnosis rate. Genetic analysis is  sometimes used to exclude disease.   This is a less common autosomal recessive disorder, in  which there is cystic replacement of both kidneys pre-  sent at birth. Cysts are composed of dilated tubules  and collecting ducts.   This is a rare condition (at 1 per 10 000 live births),  and is associated with cysts of the liver, pancreas, and  lungs.   It presents in stillborn or neonates with enlarged kid-  neys (12-16 times normal size) containing a radiating  cystic pattern in the medulla and cortex ('sunburst' pat-  tern; see Fig. 9.1). Rarely, it may present in childhood  with renal insufficiency.   Prognosis — affected infants often die within the first  2 months of life; those that survive tend to develop a  form of hepatic fibrosis.   Multiple cysts develop in renal papillae, with an inci-  dence of 1 in 20 000. Renal function is not usually im-  paired and the main clinical problem is the  development of renal stones that predispose to renal  colic and infection.   This describes a group of hereditary diseases character-  ized by development of cysts at the corticomedullary  junction of the kidney. These diseases are associated  with tubular atrophy and interstitial fibrosis. Important  examples are:    • juvenile nephronophthisis — autosomal recessive  disease presenting at about 1 1 years of age   Clinically, these conditions are characterized by  thirst (polydipsia) and polyuria (due to nephrogenic  diabetes insipidus; see Chapter 10) and eventually  result in early-onset chronic renal failure. Together, they  account for about 20-25% of cases of end-stage renal  failure in the first three decades of life.   These common lesions occur as solitary or occasionally  multiple cystic spaces in otherwise normal kidneys. In-  cidence increases with age.   The abnormality is widely believed to be acquired,  but the cause is unknown.   Macroscopically, cysts are of variable size (generally  smaller than 5 cm), and they contain clear watery fluid.   Microscopically, they are lined by flattened cuboidal ep-  ithelium and surrounded by a thin fibrous capsule. Clini-  cally, cysts may cause renal enlargement, but they have no  effect on renal function. However, they require clinical  differentiation from tumours and other cystic disorders.   3. Mesangium, i.e. the supporting mesentery to the  capillary, which comprises mesangial cells (phago-  cytic support cells) and associated extracellular  material (mesangial matrix)   4. Epithelial cells or podocytes, which form an outer  coating to the capillary. These cells are in contact  with the outer surface of the basement membrane  via a series of foot processes.    Thus a glomerular disease may be described as one of  diffuse global', 'diffuse segmental', 'focal global' or 'fo-  cal segmental'. The vast majority are either 'diffuse  global' or 'focal segmental'.   This explains how some glomerular diseases cause  sudden acute renal failure (diffuse global diseases),  whereas others cause a selective partial renal failure  focal segmental diseases).   Glomerular pathology produces a spectrum of presenta  tions from pure proteinuria (reflects injury to podocytes  and architecture) to pure haematuria (inflammatory  proliferative changes). Many diseases lie somewhere  along this spectrum with a mixture of proteinuria anc  haematuria to differing degrees.   • hereditary — Alport's syndrome, Fabry's syndrome  and congenital nephrotic syndrome.   This is haematuria without significant proteinuria  which may be continuous or intermittent, varying in  severity from macroscopic to microscopic.   Polyarteritis nodosa  Wegener's granulomatosis  Haemolytic uraemic syndrome  Idiopathic thrombocytopenic purpura  Disseminated intravascular coagulation    Fig. 9.4 Clinical manifestations of glomerular disease and the conditions  that cause them   Exercise haematuria  IgA nephropathy  Henoch-Schonlein purpura  Bacterial endocarditis  Systemic lupus erythematosus  Polyarteritis nodosa   • Immune complex-mediated conditions  Systemic lupus erythematosus  Henoch-Schonlein purpura  Infective endocarditis   This proteinuria (> 0.3 g every 24 hours) without hae-  maturia may be continuous, orthostatic (postural) or  transient. It is typically detected at a routine medical  examination.   This presents with a sudden onset of haematuria, pro-  teinuria (often with urinary casts) and hypertension.  Loin pain and headache may be present and the patient  will often feel unwell.   Here, there is proteinuria (usually > 3 g every 24 hours)  with hypoproteinemia and oedema. There is also  hypercholesterolaemia, an increased tendency to clot-  ting and greater risk of infection. It may be due to pri-  mary or secondary glomerular disease.   This is an irreversible deterioration in renal function  caused by the destruction of more and more individual  nephrons over a long period of time. Impairment of ex-  cretory metabolic and endocrine functions of the kidney  leads to the clinical syndrome of uraemia.   Management — excretory function of the kidney can  be partially replaced by dialysis. However, replacement    of the endocrine and metabolic functions can only be  achieved by successful renal transplantation.   Unless some form of supportive therapy — such as  dialysis or transplantation — is available, chronic renal  failure is eventually fatal.   Many glomerular diseases are caused by immune-  mediated damage (listed below). Different patterns of  immune-mediated damage point to different diagnoses.  It is therefore important to identify the site, type and  pattern of immune complexes and complement within  the glomerulus by immunohistochemistry and electron  microscopy.   Soluble antigen-antibody complexes circulating in the  blood are trapped at the basement membrane, the  mesangium or both. Complexes activate the comple-  ment cascade via the classical pathway. Activated com-  ponents of complement bring about the characteristic  acute inflammation of glomerulonephritis by attracting  neutrophil polymorphs, increasing vascular permeabil-  ity and causing membrane damage (see Fig. 2.7).   A focal proliferative glomerulonephritis  Serum IgA levels are raised and IgA is deposited  in the mesangium and basement membrane   The Goodpasture antigen is a domain of  type IV collagen in the basement membrane;  this is a target for the autoantibodies   An immune complex disease thought to involve a  disorder of complement, characterized by  subendothelial deposits  There is a persistently low serum C3   An autoimmune-mediated abnormality of  complement. There is marked thickening of the  capillary walls due to deposition of C3 (dense  deposit disease)   SLE: depending on the size and charge of the immune  complexes, they may get trapped at the endothelial,  intramembranous or subepithelial region of the GBM  or mesangium.   Circulating antigens become 'planted' or trapped in the  glomerulus, where they are targeted by circulating anti-  bodies such that immune complexes are formed within  the glomerulus itself. This in-situ formation explains  why, unlike circulating immune complex nephritis de-  scribed above, there is little complement and no inflam-  matory or proliferative responses.   Post-streptococcal glomerulonephritis: streptococcal  antigens are implanted into the GBM during infection  and are implanted into the glomerulus   This is the basis of Goodpasture's syndrome, in which  autoantibodies target a domain on the a3 type IV colla-  gen chain. These antibodies may cross-react with colla-  gen of the lung, producing simultaneous lung and  kidney disease.   The alternative complement pathway is normally acti-  vated by the presence of bacterial cell walls, and it  is independent of immune complex formation (see  Fig. 2.6). However, in certain disease conditions, the al-  ternative pathway can be activated by different  mechanisms.   In type II membranoproliferative glomerulonephritis, a  circulating autoantibody (termed 'C3 nephritic factor')  activates complement via the alternative pathway by  stabilizing the enzyme C3-convertase. This enzyme  normally activates C3 but has a very short half-life.  Thus, stabilization of C3-convertase prolongs the activa-  tion of C3.   This group of disorders is characterized histologically by  varying degrees of proliferation of mesangial and epi-  thelial (and sometimes endothelial) cells within the  glomerulus.   The majority of cases of glomerulonephritis (over  70%) belong to this group.   However, it must be emphasized that these subdivi-  sions are not diagnoses but rather describe a pattern of  reaction caused by glomerular insult.   Diffuse, global, acute inflammation of glomeruli is  caused by the deposition of immune complexes in the  glomeruli, stimulated by a preceding infection.  Aetiology is as follows:   • Poststreptococcal (most common) — onset is  1-2 weeks after a primary pharyngeal or skin infec-  tion with group A /i-haemolytic streptococci.   • Non-streptococcal (less common) — a range of  bacterial, viral and protozoal infections can also  stimulate this pattern of disease.   Those antibodies produced to combat initial infec-  tion cross-react with cellular antigens producing im-  mune complexes. These complexes circulate in the  blood and are filtered-out in the glomerulus, producing  four main histological changes:   1. Immune complex deposition — in lumps on the ep-  ithelial side of the glomerular basement membrane.   2. Neutrophil infiltration — activation of complement  attracts neutrophils into the glomerulus.   3. Endothelial cell proliferation — degranulation of  neutrophils damages endothelial cells, stimulating  their proliferation.   4. Mild mesangial cell proliferation — mediated by  factors derived from complement and platelets.   Rapidly progressive glomerulonephritis (RPGN) is a  manifestation of severe glomerular injury characterized  by the formation of cellular crescent-shaped masses  within the Bowman's space. It occurs in a small percent-  age of patients with poststreptococcal glomeruloneph-  ritis (see above) but it can also be associated with  many other forms of glomerular damage.    If damage to the glomerular capillaries is severe, fi-  brin and blood leak into Bowman's space stimulating  epithelial cell proliferation, and entry of inflammatory  infiltrate. Crescent-shaped cellular masses composed  of epithelial cells, macrophages and monocytes are  formed within the Bowman's space. These crescents  are associated with glomerular ischaemia and ulti-  mately they result in permanent glomerular damage.   Here, there is an acute inflammation with cellular pro-  liferation occurring in only a proportion of all glomeruli  (focal) and usually affecting only one segment of the  glomerular tufts (segmental). Therefore, the condition  is more accurately described as focal segmental prolifer-  ative glomerulonephritis.   Several diseases can cause this pattern of response.  These can be classified into two groups:   2. Secondary — associated with other systemic diseases  including infective endocarditis, vasculitis and con-  nective tissue diseases.   Membranoproliferative glomerulonephritis (MPGN)  is a diffuse, global pattern of glomerulonephritis with  features of both proliferation and membrane thickening  (hence the name). It is also known as mesangiocapillary  glomerulonephritis.   1 . Primary (majority) — idiopathic. Subdivided accord-  ing to clinical and pathological features into type I  (90% of cases) and type II (10% of cases) (see  Table 9.5)   2. Secondary — a few are secondary to systemic dis-  orders such as SLE, infective endocarditis, malaria  and infected ventricular cerebrospinal fluid (CSF)  shunts.   There is a pattern of reaction in which the glomerular  capillary basement membrane is uniformly thickened,  partly due to immunoglobulin-based deposits. Unlike  the proliferative types of glomerulonephritis, membra-  nous nephropathy has no associated inflammation  or endothelial/epithelial proliferation, although the  mesangial cell population may be slightly increased.   Systemic lupus erythematosus  (10% of renal involvement is of  the membranous pattern)    It affects all age groups, but the highest incidence is  between fifth and seventh decades. Males are affected  more than females.   • Primary — 80-90% of cases have no apparent reason  for development of immune complexes, and are  classed as primary or idiopathic membranous  nephropathy.   • Secondary — membranous nephropathy is found in  association with a number of conditions which are  listed in Figure 9.6.   1 . In-situ formation of immune complexes on the ep-  ithelial side of the basement membrane (diffuse,  global pattern)   4. Immune complex deposits disappear, leaving thick-  ened 'lacy' basement membrane.   Over many years, the abnormal glomeruli develop  increased mesangial matrix produced by the mesangial  cells. This, together with membrane thickening, causes  gradual hyalinization of the glomeruli (glomerulo-  sclerosis) and death of individual nephrons.   Abnormality of the basement membrane renders it  unusually permeable resulting in heavy proteinuria.   Membranous nephropathy is the most common cause  of nephrotic syndrome in adults.   Prognosis is variable and related to cause but in crude  figures: one-third of patients undergo spontaneous    remission without treatment, one-third are stabilized  with persisting proteinuria and one-third progress to  develop chronic renal failure.   Long-term prognosis may be improved by treatment  with high-dose corticosteroids and alkylating agents  (e.g. cyclophosphamide), although there are significant  side effects.   The characteristic feature in this nephropathy is that no  significant abnormalities can be detected by light  microscopy.   It is the most common cause of nephrotic syndrome  in children. Males are affected more than females, how-  ever it is less common in adults, but still accounts for  25% of cases of nephrotic syndrome.   Aetiology is unknown, although in some cases an as-  sociation with respiratory infection has been noted.   Pathogenesis is postulated to be immunologically  related (cell-mediated damage to the basement mem-  brane) because of the near universal response to  corticosteroid therapy. Ultimately, polyanionic charges  of the glomerular basement membrane are depleted,  leading to failure of protein retention.   Morphological features — with electron microscopy,  there is a diagnostic loss of epithelial foot processes.  Tubules may show accumulation of lipid in lining cells,  giving rise to the alternative name of 'lipoid nephrosis'.   Prognosis in children is good, with no permanent  renal damage. In adults, the outlook is variable.   The glomerulus is partially replaced by hyaline material,  which, in most cases, is excess mesangial matrix.   • Primary (most common) — idiopathic disease affect-  ing children and young adults. Focal deposition of  IgM are seen at biopsy.   Focal glomerulosclerosis initially affects the juxta-  medullary glomemli, causing an increase in mesangial  matrix, which gradually expands to destroy the sur-  rounding lobule, until global sclerosis occurs. In time,  similar lesions appear in glomeruli throughout the  cortex.   It is useful to remember that the clinical syndromes of  glomerulonephritis broadly relate to histological findings:  •Asymptomatic proteinuria and nephrotic syndrome  are associated with basement membrane thickening  as a result of either structural change or deposition of  excessive mesangial matrix, e.g. membranous  nephropathy, glomerulosclerosis.   • Asymptomatic haematuriaand nephritic syndrome are  associated with proliferation of the endothelial or  mesangial cells, e.g. diffuse, global glomerulonephritis.   • Mixed nephritic/nephrotic syndrome is associated  with combined damage to the basement membrane  and cell proliferation, e.g. membranoproliferative  glomerulonephritis.   This syndrome is characterized by the clinical triad of  deafness, glomerulonephritis and ocular lesions. Inher-  itance is complex; it is X-linked in most families (a mu-  tation of the COLIVu.5 gene), with an autosomal  recessive pattern in the rest. Both types of disease are  clinically indistinguishable. The genes affected encode  basement membrane collagens that are found in the  glomerulus and elsewhere in the body, e.g. the cochlea.  The clinical features are:   • glomerulonephritis — usually presents as microscopic  haematuria and proteinuria in childhood. There is  subsequent development of nephrotic syndrome  with progression to renal failure, occurring by the sec-  ond decade in males, but often not until the fifth de-  cade in females, as they are only carriers of the disease  in the X-linked form   • Deafness — only for high-pitched sounds; this may  be difficult to demonstrate.   A rare, X-linked recessive syndrome of glycosphingolipid  metabolism resulting in painful extremities, red hyper-  keratotic papules on skin, proteinuria and renal failure.   Chronic renal failure associated with small, contracted  kidneys, in which all the glomeruli are hyalinized (end-  stage kidneys). It may be caused by many diseases, partic-  ularly proliferative types of acute glomerulonephritis.    In patients who present for the first time with chronic  glomerulonephritis, it is often not possible to ascertain  the cause because of diffuse global glomerular destruc-  tion. However, it is likely that many patients presenting  for the first time have had IgA nephropathy   Macroscopically, affected kidneys are small and there is  granularity of the external surface, reflecting fine scarring  due to nephron hyalinization. However, the pelvicalyceal  system is normal, an important distinction from cases of  end-stage kidney disease due to chronic pyelonephritis.   Microscopically, there is hyalinization of the glomer-  uli, tubular atrophy and interstitial fibrosis.   Transplantation is the only method of fully correcting the  loss of renal function in chronic renal failure. Renal  replacement therapy (e.g. haemodialysis) maintains  low levels of blood purification, but cannot fully  replace the metabolic functions of a kidney. It is also  time consuming, so affecting quality of life. Renal  transplantation has become increasingly successful, with  3-year graft survival now reaching 80% due to better  matching of donors (ABO and HLA matching) and  improved post-transplantation immunosuppression.   Around half of all SLE patients will display renal in-  volvement within 5 years of diagnosis. The majority  of these cases are glomerular lesions, which may be of  numerous histological patterns. Clinically, there is a po-  tential spectrum from minor abnormalities such as  asymptomatic proteinuria to severe glomerular disease  leading to renal failure.   The basis of glomerular damage is immune-complex  deposition in the basement membrane (leading to base-  ment membrane thickening) or in the mesangium  (leading to mesangial expansion).   • diffuse MPGN — associated with a mixed nephritic/  nephrotic syndrome and rapid progression to renal  failure   • focal segmental proliferative glomerulonephritis —  associated with haematuria, proteinuria and slow  progression   • diffuse membranous nephropathy — associated with  nephrotic syndrome and slow progression to  chronic renal failure.   The immune complexes of SLE are characterized by the  presence of IgG, IgA, IgM, C3 and Clq (known as a 'full-  house' of deposits). The detection of this pattern of im-  munoglobulins and complement factors, together with  the particular location of the immune complexes in  relation to the glomerular basement membrane, is an  important factor in distinguishing lupus glomerulo-  nephritis from non-lupus patterns.   Note that, although glomerular lesions are the main  abnormalities of renal involvement in SLE, there may  also be extraglomerular vascular abnormalities and  tubular damage, particularly interstitial nephritis.   This immune complex-mediated systemic vasculitis  affects small arteries in the skin, joints, intestine, and  kidneys (see Chapters 6 and 13). Light microscopy  reveals mesangial IgA deposits.   Significant renal damage occurs in over one-third of  cases, ranging from proteinuria, possibly with nephrotic  syndrome, to RPGN.   Diabetic glomerular damage causes an increase in the  permeability of the glomerular capillary basement  membrane, leading to proteinuria and occasionally  nephrotic syndrome.   The pathogenesis of basement membrane changes is  probably related to the persistent insulin deficiency  and/or hyperglycaemia of the diabetic state. This stimu-  lates biochemical alterations in the composition of the  basement membrane, most notably a deficiency of pro-  teoglycans with an excess of collagen IV and fibronectin.  Glomerular hypertrophy may occur in response to  hyperfiltration (increased glomerular blood flow in di-  abetes). It is likely that the increased glycosylation of  proteins also contributes to glomerular damage.   Histologically, three types of glomerular lesion  occur, representing a continuous spectrum of increasing  severity:   3. Nodular glomerulosclerosis (Kimmelstiel -Wilson  nodules) — nodular expansion of the mesangium  at the tips of the glomerular lobules is very character-  istic of diabetes.    Diabetic sclerosis causes progressive hyalinization of  glomeruli with obliteration of capillary loops and death  of individual nephrons. Over a period of years this leads  to chronic renal failure.   Prognosis — approximately 10% of all diabetics die in  renal failure. This rises to 50% if patients developing  diabetes in childhood are considered separately.   This is a condition in which amyloid — an extracellular  fibrillar protein — is deposited in a variety of tissues  (see Chapter 13). Amyloidosis is an important cause  of the nephrotic syndrome in adults.   Amyloid is deposited as fibrils in the glomerular  basement membrane and in the mesangium of the kid-  ney, resulting in membrane thickening and increased  mesangial matrix formation. The net result is the devel-  opment of:   • chronic renal failure — combined effect of amyloid  deposition and increased mesangial matrix forma-  tion eventually leads to expansion of the mesan-  gium causing compression of the glomerular  capillary system and transition into chronic renal  failure.   Amyloid is also deposited in the walls of intrarenal  vessels, particularly the afferent arterioles.   Polyarteritis nodosa is a systemic disease characterized  by inflammatory necrosis of the walls of small and  medium-sized arteries (see Chapter 6). Necrosis of me-  dium-sized arteries causes small infarcts in the kidney;  necrosis of arterioles and the glomerular tuft produces  infarction of entire glomeruli or segments. This is visible  as fibrinoid necrosis.   This immune complex-mediated systemic necrotizing  vasculitis primarily affects the nose, upper respiratory  tract and kidneys. Renal involvement is of variable  severity causing one of the following:   This acute, but usually reversible, renal failure is caused  by necrosis of renal tubular epithelial cells resulting  from ischaemic, metabolic or toxic disturbances. The  causes of acute tubular necrosis (ATN) are shown in  Figure 9.7.   • ischaemic (most common) — caused by failure of re-  nal perfusion, typically the result of hypotension  and hypovolaemia in shock   There are three phases to ATN (oliguric, polyuric and  recovery) as follows:   1. Oliguric phase — necrosis of renal tubular cells and  interstitial oedema causes tubule blockage and  reduced glomerular blood flow and filtration.   2. Polyuric phase — tubules slowly open as phagocytic  cells begin to remove necrotic material. Polyuria is  caused by the temporary loss of the medullary con-  centration gradient. Regenerated renal tubule cells  are undifferentiated.   • Ischaemic ATN — kidneys are pale and swollen. His-  tology reveals flattened, vacuolated epithelial cells  along the entire length of the tubules.   Endogenous products:  haemoglobinuria and myoglobinuria  Heavy metals: lead, mercury  Organic solvents: chloroform,  carbon tetrachloride  Drugs: antibiotics, NSAIDs, ciclosporin  Others: paraquat, phenol,  ethylene glycol, poisonous fungi    restricted to proximal tubular cells, those of the  distal tubule being spared.   Clinical features are oliguria (less than 500 mL urine  output per day) with features of renal failure (see  Fig. 9.8). As mentioned, some patients develop polyuria  during recovery.   A knowledge of the aetiology (ischaemic versus toxic)  and an understanding of the pathogenesis (oliguric and  polyuric phases) of ATN make the morphological and  clinical features easy to remember.   The prognosis depends on the speed and efficiency  with which corrective measures are put into operation,  and the severity of the causal disorder.   This is acute suppurative inflammation of the tubules  and interstitium caused by bacterial infection. There  are three age peaks: childhood, pregnancy and in the  elderly.   Most cases of infection are caused by enterobacteria  from the patient's faecal flora (e.g. Escherichia coli, Pro-  teus and Klebsiella species) or by staphylococci from skin    (perineal) flora. The organism may enter the kidney by  one of two routes: ascending infection from the lower  urinary tract (promoted by pregnancy, glycosuria in di-  abetes, stasis of urine) or via the blood in bacteraemia/  septicaemia.   Macroscopically, the condition is characterized by  numerous abscesses throughout the kidney:   • Cortical abscesses — small, yellowish-white abscesses,  usually spherical, less than 2 mm in diameter and  sometimes surrounded by a zone of hyper-  aemia. Most prominent on subcapsular surface.   • Medullary abscesses — yellowish-white linear streaks  that converge on the papilla. Pelvicalyceal mucosa is  hyperaemic or covered with a fibrinopurulent  exudate.   Microscopically, there is focal inflammation with in-  filtration of tubules by neutrophils, interstitial oedema  and tubular necrosis.   This condition is often associated with dysuria and  urgency of micturition — signs of a lower urinary tract  infection.   Acute pyelonephritis may resolve with or without  scarring or chronic infection. In severe cases, pyone-  phrosis (pus-filled kidney associated with obstruction),  renal papillary necrosis, perinephric abscess or death  may occur.   Diagnosis is by examination of midstream urine, es-  pecially cultured to demonstrate responsible organisms:   • Significant bacteriuria is defined as >10 5 culture-  forming units per mL (to eliminate cases of extrane-  ous bacterial contamination).   • Significant pyuria is defined as > 1 0 neutrophil poly-  morphs per high power field.   Treatment is by oral antibiotic therapy (e.g. tri-  methoprim, ampicillin or amoxicillin, which are active  against Escherichia coli). Intravenous antibiotic therapy  is used for more severe or septicaemic cases.   Untreated, infection may spread to cause Gram-  negative septicaemia with shock.   Chronic inflammation of the tubules and interstitium is  associated with nephron destruction and coarse scarring  of the kidneys. The two forms — obstructive and reflux-  associated — are described below.   Reflux of urine from the bladder into the ureter pre-  disposes to recurrent bouts of inflammation. It is most  common in childhood and early adult life, with males  affected more than females.    Normally, the ureter enters the bladder obliquely  so that contraction of the bladder wall during micturi-  tion closes the ureteric orifice. In patients with vesi-  coureteric reflux, the terminal portion of the ureter is  short and oriented at approximately 90° to the mucosal  surface. Contraction of the bladder tends to hold the  ureteric orifice open, thus facilitating reflux of urine,  enabling organisms to gain access to the kidney from  the bladder.   Macroscopically, the kidneys have irregular areas of  scarring seen as depressed areas, 1-2 cm in size, most  commonly sited in the renal calyces at the poles of  the kidney but often associated with fibrous scarring  of the renal papilla. Involvement may be either bilateral  or unilateral.   Microscopically, kidneys have irregular areas of  interstitial fibrosis with chronic inflammatory cell in-  filtration (chronic interstitial nephritis). Tubules  are atrophic, or they may be dilated and contain  proteinaceous casts. Glomeruli show periglomerular  fibrosis and many demonstrate complete  hyalinization.   Clinical features are symptoms of urinary tract infec-  tion and of uraemia.   • intravenous urography — reveals reduction in kidney  size and focal scarring associated with clubbing of  the adjacent calyces   Treatment is by antibiotic therapy, control of  hypertension, and removal of the source of obstruction.   Prognosis — the course is usually long and punctuated  by acute exacerbations.   Other diseases of the tubules and interstitium are  illustrated in Figure 9.9.   This hyaline sclerosis of the arterioles and small arteries  of the kidney is associated with benign hypertension  and worsened by diabetes mellitus.   The condition is an important complication of long-  standing benign hypertension, chronic renal failure  being one of its major sequelae.   This is the most common form of nephropathy found in  approximately 75% of autopsies over the age of 60 years.   In long-standing benign hypertension, there is re-  duced flow of blood to the glomeruli caused by vascular  changes that affect:   • branches of the renal artery — thickening of arterial walls  due to fibroelastic intimal proliferation, elastic lamina  reduplication and muscular hypertrophy of the media.  Results in focal areas of ischaemia with scarring.   • afferent arterioles — undergo hyalinization (arterio-  losclerosis), their muscular walls being replaced by  a rigid and inelastic amorphous material.   A progressive reduction in blood flow to the neph-  rons leads to chronic ischaemia with slow conversion  of individual glomeruli into a mass of hyaline tissue de-  void of capillary lumina (Fig. 9.10).   Blood supply to the tubules is also derived from  glomerular blood flow. There is, therefore, eventual  ischaemic destruction of the associated tubule.   The process gradually destroys individual nephrons  over a period of many years.   Clinical features — no clinical symptoms initially, al-  though a gradual increase in blood levels of urea and a  reduction in glomerular filtration rate occur.   Inflammation of the renal interstitium and tubules  (tubulointerstitial nephritis) due to exposure to  toxic agents. Two types: acute and chronic   Some types of myeloma are characterized by  proliferating plasma cells, which produce  monoclonal free light chains (Bence Jones  proteins). These cause physical obstruction  and damage to the tubules    Pathogenesis — in accelerated hypertension, the rise  in blood pressure is very rapid, causing a pattern of renal  damage that differs from that seen in benign hypertension:   • Larger muscular vessels undergo fibroelastic prolifer-  ation of the intima, but no muscular hypertrophy.  This is stimulated by factors such as platelet-derived  growth factor.   • Afferent arterioles frequently undergo necrosis, often  with fibrin in their damaged walls (fibrinoid necro-  sis) following exposure to the sudden high pressures.   • Glomerular capillary network — segmental fibrinoid  necrosis of glomerular tuft.   The patient develops acute renal failure when suffi-  cient nephrons are rendered non-functional. Afferent  arteriole necrosis stimulates the renin-angiotensin  system, which contributes to ischaemia by promoting  intrarenal vasoconstriction.   The renal changes seen in benign and accelerated hy-  pertensive nephrosclerosis are summarized in Figure 9.2.   Untreated accelerated hypertension causes death  from renal failure in 90% of cases, usually with marked  rapidity. However, if hypertension is treated adequately,  before there is evidence of impairment of renal function  by a raised blood urea, then prognosis is good and  subsequent renal failure unusual.    Eventually, critical numbers of nephrons become  dysfunctional and the patient develops manifestations  of chronic renal failure.   Prognosis — less than 5% of patients with well-  developed benign nephrosclerosis die from renal fail-  ure. Death in the great majority of cases of benign hy-  pertension occurs from congestive heart failure,  coronary insufficiency, cerebrovascular accidents, or  the development of malignant hypertension.   Renal disease is associated with malignant, accelerated  hypertension. This form of hypertension usually  develops in individuals with pre-existing benign  hypertension.   This narrowing of the renal arteries is typically caused  by generalized atherosclerosis but rarely by arterial  fibromuscular dysplasia.   Atherosclerotic occlusion of the renal artery is usually  most severe at its origin from the aorta. Renal artery ste-  nosis at this point can lead to two main pathological  processes:   1 . Chronic ischaemia of the affected kidney — reduction  in function of all nephrons on that side produces an  end-stage shrunken kidney. However, the contra-  lateral kidney undergoes compensatory hypertrophy  so that renal function is largely unaffected.   2. Renovascular hypertension — inadequate perfusion of  the kidney caused by renal artery stenosis may lead to  hyper-reninism and subsequent abnormal activation  of the renin-angiotensin system. This condition is im-  portant in that it is one of the rare recognized causes of  hypertension that is amenable to surgical correction.   Haemolytic uraemic syndrome (HUS) is a complex syn-  drome of disordered platelet function that is character-  ized by the triad of thrombocytopenia, haemolysis and  acute renal failure.   This usually affects children under 4 years of age.  Many cases are associated with intestinal infection by  verocytotoxin-producing Escherichia coli (notably type  0157). The immediate prognosis is better than for adult  and secondary types, but future risk of renal disease is  increased.   This is more frequently fatal than childhood I IUS and is  associated with the following conditions:   • Oestrogen therapy — contraceptive pills or oestrogen  therapy for men with prostatic carcinoma   Platelets adhere to damaged endothelium of small ves-  sels, including the glomerular capillaries, where they  undergo aggregation and trigger fibrin deposition. Re-  duced prostaglandin and nitric oxide production from  the damaged endothelium promotes platelet aggrega-  tion. Fibrin strands form a tight mesh that deforms  the erythrocytes as they are forced through the obstruc-  tion (microangiopathic haemolysis).   • luminal narrowing — arterioles and small arteries show  fibrin and erythrocytes in the walls, often with thrombo-  sis which, when extensive, can result in cortical necrosis.   • sudden onset of oliguria with haematuria and occa-  sionally melaena   In childhood HUS, symptoms are often preceded by  a prodromal episode of diarrhoea or flu-like illness  lasting for 5-15 days.   Prognosis depends on the severity of attack, but  mortality may be as high as 40%.   Thrombotic thrombocytopenic purpura (TTP) and HUS  are thought to represent the same disease process, but  with a different distribution of thrombotic lesions. In  TTP, occlusive plugs lead to widespread ischaemic organ  damage, often affecting the brain more than the kidney,  resulting in early neurological abnormalities and  progressive renal impairment.   There are two mechanisms of renal infarction: embolic  infarction and diffuse cortical necrosis.   Renal infarcts are usually due to the passage of emboli  down renal arterial branches. The most common  causes are:   • 'cholesterol emboli' — these are showers of choles-  terol microemboli that may occur as a complication  of arterial interventions (e.g. arteriography) in those  with severe atheromatous disease   • mural thrombotic material arising from the left side  of the heart, most commonly after myocardial  infarction   • bacterial vegetation from infective endocarditis.  Resultant infarcts may be clinically silent or may re-  sult in haematuria and loin pain. Macroscopically, in-  farcts are pale or white and they have a characteristic  wedge shape with the apex directed towards the hilum.   This rare pattern of renal infarction is associated with  conditions resulting in severe hypotension, the most  common of which are hypovolaemic shock, severe  sepsis and eclampsia of pregnancy.   The pathogenesis is uncertain, but diffuse spasm of  renal blood vessels is thought to play a major part in  precipitating ischaemic damage.   Macroscopically, necrosis is confined to the outer  part of the renal cortex, which in the acute stages is pale  and focally haemorrhagic.   This condition results in acute renal failure, and  prognosis depends on the extent of the damage.   These are common incidental findings at post mortem  examination in about 20% of all patients; however, they  rarely cause clinical problems.   Macroscopically, they are discrete nodules, usually  less than 20 mm in diameter, situated in the cortex of  the kidney.   Microscopically, appearances are similar to those of  renal cell carcinomas, both being composed of well-  differentiated large clear cells with small nuclei.   Difficulty in differentiating between these tumours  had prompted the adoption of an arbitrary cut-off of  3 cm in size to distinguish between the smaller adeno-  mas and the typically larger carcinomas. However, the  distinction has proved unreliable and it is now consid-  ered that all adenomas should be treated.   This is the most common benign tumour of the kidney.  It is composed of renal interstitial cells.   Macroscopically, there are firm white nodules situ-  ated in the medulla, typically 3-10 mm in size.   Microscopically, it is composed of spindle cells that  surround the adjacent tubules.   These tumours are of no functional or clinical signif-  icance and do not undergo malignant transformation.   An adenocarcinoma derived from the renal tubular  epithelium in adults, this tumour accounts for about  3% of all carcinomas and about 90% of primary malig-  nant renal tumours. It is usually seen after the age of  50 years. Males are more often affected than females  by 3:1.   There is an increased incidence in those who smoke  tobacco (double the relative risk of non-smokers) and  also in patients with von I Iippel-Lindau syndrome,  a rare hereditary condition (this suggests a genetic  predisposition).   Macroscopically, tumours occur most commonly at  the upper pole of a kidney. They are usually rounded  masses, with a yellowish cut surface marked with areas  of haemorrhage and necrosis.   Microscopically, they are composed of either clear or  granular cell types. The most common is the 'clear cell  pattern', in which tumour cells have clear cytoplasm be-  cause of the high content of glycogen and lipid. Granu-  lar cell types are derived from tubular and papillary  carcinomas.   • blood-borne metastasis — involving the lungs, bone,  brain and other sites as a result of tumour invasion  of the renal vein. A characteristic feature is that large  tumours may grow as a solid core along the main  renal vein even entering the inferior vena cava.   Prognosis depends on the stage at presentation. If the  tumour is confined within a renal capsule there is a 75%  5-year survival. However, prognosis is very poor if  metastases are present at diagnosis.   This malignant tumour of the renal pelvis is derived  from the transitional cells of the urothelium, and it is  histologically identical to transitional cell carcinoma  of the bladder. Indeed, coexistence with bladder cancer  occurs in half of cases. It is associated with analgesic  abuse and exposure to aniline dyes used in the dye, rub-  ber and plastics industries. Some cases have also been  reported to develop many years after the use of 'Thoro-  trast', an a-particle-emitting contrast agent used in retro-  grade pyelography.   This malignant embryonal tumour is derived from the  primitive metanephros. It is the most common child-  hood urological malignancy, with a peak incidence  between the ages of 1 and 4 years. Males and females  are equally affected.   At least three different types of genes are important in  the formation of Wilm's tumour. The most character-  ized of these is the tumour suppressor gene WT1,  located on chromosome 1 1 .   Macroscopically, large amounts of kidney are  replaced by rounded masses of solid, fleshy, white le-  sions with frequent areas of necrosis. The tumour is  aggressive and grows rapidly; extension beyond the cap-  sule into perinephric fat and even into the root of mes-  entery is frequent. Spread to lungs occurs early and is  identified in a high proportion of cases at the time of  diagnosis.   Clinical presentation — large abdominal mass, ab-  dominal pain, haematuria and hypertension are all rec-  ognized presentations.   Prognosis is related to the spread of the tumour at di-  agnosis. Treatment is by surgical nephrectomy with ad-  juvant chemotherapy (and potentially radiotherapy).  Survival rates 5 years after diagnosis have increased  to 80%.   These occur in up to 3% of people, although they have  no clinical significance in most cases.   The most common ureteric abnormality. These  often occur in association with the duplication of  the renal pelvis. They may be associated with vesico-  ureteric reflux and are predisposed to recurrent  infections.   This is most commonly caused by a stricture that may be  either intrinsic (within the wall of the ureter) or extrinsic  (associated with external factors such as an aberrant ves-  sel). This appears to provide a barrier to the conduction  of a wave of contraction of the ureter, and is the most  common cause of hydronephrosis in children.   Congenital diverticula are rare and are more often ac-  quired as a result of bladder outlet obstruction. Symp-  toms are due to stasis and the resultant infection.   The urethra opens on to the underside of the penis,  either on the glans (glandular hypospadias), at the  junction of the glans with the shaft (coronal hypospadias)  or on the shaft itself (penile hypospadias).   The urethra opens on to the dorsal (upper) surface of  the penis.   This is obstruction of urine drainage from the kidney oc-  curring at any level within the urinary tract. Obstruction  may be caused by either a structural lesion (majority) or  congenital neuromuscular defects that prevent contrac-  tion waves, and thus the flow of urine.   • intrinsic lesions — within the urinary tract, e.g.  stones, caseous or necrotic debris, fibrosis following  trauma or infection, tumour   • extrinsic lesions — cause pressure from without, e.g.  tumours of the rectum, prostate and the bladder,  aberrant renal arteries, retroperitoneal fibrosis,  pregnancy.   Causes vary according to the site of the obstruction  (Fig. 9.11). In the list below, * indicates the most com-  mon sites of obstruction:    Pathogenesis — obstruction at any point in the urinary  tract causes increased pressure superior to the blockage,  with dilatation of the renal pelvis and calyces  (hydronephrosis) :   • Obstruction of the ureter — > hydroureter with sub-  sequent development of hydronephrosis   • Obstruction of the bladder neck or urethra — + blad-  der distension with hypertrophy of its muscle (seen  on cystoscopic examination as trabeculation) . Sub-  sequently leads to hydroureter and hydronephrosis.   • unilateral — caused by unilateral obstruction any-  where above the bladder. It is typically detected late,  because renal function is maintained by the non-  obstructed kidney. Renal parenchyma becomes   • bilateral — caused by obstruction at the level of the  bladder or urethra. Obstruction is typically detected  at an earlier stage, as renal failure develops before se-  vere atrophy of both kidneys.   In both forms, urinary tract obstruction predisposes  to cystitis and pyelonephritis as well as stone formation.   The net result of hydronephrosis is that fluid entering  the collecting ducts cannot empty into the renal pelvis  and intrarenal resorption of fluid occurs.   If the obstruction is removed at this stage then renal  function returns to normal. However, persistence of  obstruction leads to atrophy of the renal tubules and  promotes interstitial inflammation, which leads to  glomerular hyalinization and fibrosis.   Clinical features depend on the cause and site of the  lesion.   Obstruction above the bladder will cause either an  acute onset of renal colic or a gradual onset of aching  pain in the loins, sometimes aggravated by drinking.   The clinical feature of obstruction below the bladder  is difficulty in micturition, occasionally with distension  of the bladder; it may progress to bilateral loin pain.   Management is by removal of the obstruction and  treatment of the infection.   This is the formation of stones in the urinary tract. It  affects 1-5% of the population in the UK and onset is  typically after 30 years of age, with males affected more  than females.   Stones can form anywhere in the urinary tract but the  most common site is within the renal pelvis.  Composition of stones:   • Acquired — as a result of obstruction, persistent  infection, or reduced urine volume   The mechanism of stone formation is not well under-  stood, but it is thought to involve an excess of solute in  the urine (due to either a primary increase in metabolite  or to stasis) or reduced solubility of solute in the urine  (due to persistently abnormal urinary pH).    Calculi vary greatly in size, from sand-like particles to  large round stones.   • renal colic often with nausea and vomiting — caused  by the passage of small stones along the ureter   • dull ache in the loins — due to the presence of stones  in the kidney   • recurrent and intractable urinary tract infection, hae-  maturia or renal failure.   Occasionally, the condition is asymptomatic and dis-  covered only during radiological examination for  another disease.   Management is by bed rest, application of warmth to  the site of pain and administration of analgesia.   Small stones (< 0.5 cm) in diameter are usually  passed naturally. Larger stones may require lithotripsy  or endoscopic surgery.   This is inflammation of the bladder and it is extremely  common — most women will have one or more epi-  sodes of cystitis. Females are affected more often than  males because they have a shorter urethra (i.e. less trav-  elling distance for bacteria).   The condition is most commonly due to infection but it  is occasionally caused by physical agents, e.g. radiation  or mechanical irritants. Infective causes are:   • Bacterial infection (most common) — usually Gram-  negative coliform bacilli, e.g. Escherichia coli and  Proteus species, but Streptococcus faecalis, Pseudomonas  aeruginosa and staphylococci are also common   • Parasites — Schistosoma haematobium, which is com-  mon in Africa   • urinary retention — due to obstruction, bladder pa-  ralysis, diverticula, calculi, foreign bodies, tumours,  uterine prolapse   • infection of adjacent structures, e.g. prostatitis, ure-  thritis and diverticular disease of the colon   Infection normally ascends from the urethra but may  descend from the kidney in some cases of renal infec-  tion (e.g. renal tuberculosis). Direct spread from adja-  cent organs (e.g. diverticulitis) may occur but  haematogenous and lymphatic spread are rare.    Macroscopically, there is acute inflammation with  oedema, erythema and later ulceration of bladder  mucosa.   Clinical features — the classic triad of increased uri-  nary frequency, lower abdominal pain and dysuria are  common. Systemic effects of inflammation (e.g. fever)  may also occur.   Treatment — with antibiotics (e.g. trimethoprim),  high fluid intake and addressing underlying causes such  as obstruction.   This inflammation of the ureter is usually due to an  ascending urinary tract infection.   Causative organisms are the same as for cystitis; an  acute bacterial cystitis may lead to an ascending ureteritis.   Complications — organisms may gain access to the renal  parenchyma to produce acute pyelonephritis, with the  formation of abscesses in the renal medulla and cortex.   These small, rounded collections of urothelial cells are  found just below the urothelial surface (Brunn's nests).  They develop a central lumen surrounded by cuboidal  or columnar cells. They are quite common and often  seen in the normal bladder.   Occasionally, there is metaplasia to an intestinal var-  iant of cystitis glandularis, lined by colonic, mucin-  secreting epithelium.   This benign condition is characterized by metaplasia of  the urothelium to cuboidal epithelium. Metaplastic  areas resemble collecting tubules of the kidney. It is  associated with chronic infections, e.g. tuberculosis.   1. Keratinizing squamous metaplasia (leucoplakia) —  the bladder mucosa develops white plaques, which    are often secondary to chronic irritation, e.g. calculi.  A significant proportion progresses to squamous  carcinoma of the bladder.   2. Non-keratinizing squamous metaplasia (vaginal  metaplasia) — white plaques are seen on the trigone.  This only occurs in women and it has no patholog-  ical significance.   These are rare, benign tumours of the bladder that may  represent the first stage of transitional cell carcinoma.  A fibrovascular stalk attaches their branched structure  to the mucosa.   These are tumours of the urothelium, affecting 1 in  5000 in the UK and accounting for 3% of all cancer  deaths. They are most commonly found in those aged  60-70 years, with males affected more than females  by 3:1. Cigarette smoking is an important cause.  Aetiology is as follows:   • Chemicals — exposure to environmental agents ex-  creted in high concentrations in the urine. Known  carcinogens are associated with cigarette smoking,  aniline dyes and the rubber industry.   Most tumours are at the base of trigone and around  the ureteric orifices.   • Papillary (most common) — warty masses projecting  into the lumen with little or no invasion of the blad-  der wall. Only a small percentage evolves into  invasive carcinoma.   • Solid — tumours grow directly into the bladder wall  and are often ulcerated or encrusted. Most are  invasive from the outset.   The majority of urothelial cancers are caused by  exposure to environmental agents. Therefore, bladder    tumours are usually multiple, and they are often found  in conjunction with urothelial tumours at other sites of  the lower urinary tract, e.g. renal pelvis, ureters or  urethra.   Only a small proportion of bladder cancers are of squa-  mous origin (squamous cell carcinoma). They are  most often associated with schistosomiasis infection.  Adenocarcinomas and mesenchymal tumours are rare.  Secondary tumours usually occur following direct inva-  sion from the cervix, prostate or rectum.   The degree of differentiation (grade) and extent of  spread (stage) are important indicators for prognosis.  Transitional cell carcinomas are graded I— III:   • Grade I (well differentiated) — vast majority are pap-  illary growths with no evidence of invasion.   • Grade II (moderately well differentiated) — usually  papillary but many are either invasive at presenta-  tion or become so. Cells show significant atypicality  and an increase in mitotic figures.   • Grade III (poorly differentiated) — mainly solid  lesions which are extensively invasive. Cells are pleo-  morphic with numerous mitoses.   Clinically, the disease classically presents with pain-  less haematuria, but symptoms of recurrent urinary tract  infections may occur. Rarely, it may present with hydro-  nephrosis (from ureteric obstruction), pneumaturia  from vesicocolic fistula, or incontinence from vesico-  vaginal fistula.   Treatment usually involves transurethral resection of  tumour, with the potential for intravesical chemotherapy  in multiple tumours. Radical cystectomy may be consid-  ered for patients with invasive disease.   Prognosis depends on the histological type of the  tumour and extent of spread. Papillary, non-invasive  tumours have an excellent prognosis, whereas solid, in-  vasive, urothelial tumours have an overall 5-year  survival rate of only 35%.   • Describe disorders of the pituitary gland leading to hyperpituitarism and hypopituitarism.   • Briefly describe endocrine tumours including the important multiple endocrine neoplasia syndromes.    The pituitary (hypophysis) is a small (500-1000 mg),  bean-shaped gland lying in the sella turcica in the base  of the skull. It is composed of two parts:   1. Anterior lobe (adenohypophysis) — synthesizes and  secretes a number of hormones (Fig. 10.1), most of  which act on other endocrine glands.   2. Posterior lobe (neurohypophysis) — stores and se-  cretes two hormones synthesized in the hypothala-  mus: antidiuretic hormone (ADH; vasopressin) and  oxytocin. This lobe is in direct continuity with the  hypothalamus, to which it is connected via the pitu-  itary stalk.   Secretion of the pituitary hormones is regulated by  neural and chemical stimuli from the hypothalamus,  diseases of which cause secondary abnormalities in  pituitary function.   This cooperation between the nervous system and  endocrine apparatus is referred to as neuroendocrine  signalling. Figure 10.2 shows the integration of signals  between the hypothalamus, pituitary and thyroid gland  in the release of thyroid hormones, with feedback loops  acting at each level.   Neuroendocrine cells are defined as those that  release a hormone in response to a neural stimulus.  Important examples include:   • neurons of the supra-optic nucleus (projecting into  the posterior pituitary), which release ADH   • chromaffin cells of the adrenal medulla, which  release epinephrine (adrenaline).   Hyperpituitarism is defined as excessive secretion of one  or more of the pituitary hormones. Its most common  causes are functioning (hormone-secreting) adenomas  of the anterior lobe.   Anterior lobe adenomas comprise about 10% of all  intracranial tumours (posterior lobe adenomas do not  occur). These tumours do not usually metastasize, but  they are often life threatening because of their position  and ability to secrete excess hormone.   Pituitary adenomas cause problems because of a combi-  nation of endocrine effects (excessive secretion of a par-  ticular hormone) and compressive effects, caused by an  increase in local pressure of the following:   • Cavernous sinus — > CN III, IV or VI nerve palsies.  The endocrine effects depend on which hormone is   adrenocorticotrophic hormone (ACTH)  thyroid stimulating hormone (TSH)  melanocyte stimulating hormone (MSH)   • Imaging — plain X-ray (can detect enlargement of  sella turcica and erosion of the clinoid processes)  and MRI (for visualization and sizing of the tumour;  this is superior to CT scanning) .   • Functional testing of the pituitaryadrenal axis, e.g.  ACTH stimulation test in which a dose of adreno-  corticotrophic hormone (ACTH) is given and the  plasma cortisol response measured.   Functioning adenomas may produce any of the anterior  lobe (adenophyseal) hormones but the majority pro-  duce prolactin (prolactinomas-lactotroph adenomas),  growth hormone (somatotroph adenomas) or ACTH  (corticotroph adenomas).   This most common pituitary tumour (30% of all pitui-  tary tumours) has abnormally raised serum prolactin  levels associated with amenorrhea and galactorrhea,  and with ejaculatory failure or impotence in men. Mild  prolactin increases are seen with compression of the hy-  pothalamus by any pituitary adenoma (the 'stalk  effect').   The second most common pituitary tumour, it results in  hypersecretion of growth hormone, the effects of which  depend on the developmental stage of the affected  individual:   • Pre-epiphyseal union (prepubertal) leads to gigan-  tism, i.e. excessive growth in a regular and initially  well-proportioned manner.   • Postepiphyseal union (adults) leads to acromegaly,  which is characterized by enlargement of the hands,  feet and head. They may also present with secondary  diabetes (growth hormone is an insulin antagonist)  or cardiovascular effects (Fig. 10.3).   Overproduction of ACTH by the pituitary gland (Cush-  ing's disease) causes adrenal hyperplasia, resulting in  the excessive secretion of glucocorticoids causing Cush-  ing's syndrome, the effects of which are described later  (see page 182).    Fig. 10.2 Schematic representation of the integration between  the higher centre, hypothalamus, pituitary and target organ  signalling. The example is for cortisol, highlighting the feedback  loops that control hormone release at each level. (CRH;  corticotropin-releasing hormone, ACTH; adrencorticotropic  hormone). (Redrawn with permission from medicshandbook.com).   Other endocrine secreting adenomas, e.g. of thyroid-  stimulating hormone (TSF1), luteinizing hormone  (LH) and follicle-stimulating hormone (FSH), are ex-  tremely rare.   Hypopituitarism is defined as insufficient secretion of  the pituitary hormones. The clinical features depend  on the patient's age and on the type and severity of  the hormone deficiencies (Fig. 10.4).   Hypopituitarism can be caused by either hypotha-  lamic lesions or pituitary lesions.   • idiopathic deficiency of one or more of the releasing  factors, e.g. gonadotrophin-releasing hormone  (GnRH; Kallmann's syndrome), growth-hormone  releasing factor (GHRH) or, more rarely, thyrotro-  phin-releasing hormone (TRH) or corticotrophin-  releasing factor (CRF)   • suprasellar tumours, e.g. craniopharyngioma or,  more rarely, pinealoma, teratoma or a secondary  tumour from another site.   • idiopathic deficiency of one or more of the pituitary  hormones    • sheehan's syndrome — ischaemic necrosis of the an-  terior pituitary due to hypotensive shock occurring  as a result of obstetric haemorrhage. Initially there  is a loss of gonadotrophins, then subsequent loss  of TSH and ACTH   • empty sella syndrome — an enlarged, empty sella tur-  cica that is not filled with pituitary tissue. This may  be a primary anatomical variant or it may follow  spontaneous infarction, surgery, or radiotherapy of  a tumour   Management is by substitution therapy according to the  deficiencies demonstrated, e.g. cortisol replacement for  ACTH deficiency, thyroid hormone replacement for  TSH deficiency.   Diseases of the posterior pituitary are much less com-  mon than those of the anterior pituitary and are usually  the result of damage to the hypothalamus by tumour  invasion or infarction. Posterior pituitary diseases  typically cause disorders of abnormal ADH secretion.  There are no known effects of abnormal oxytocin  secretion.   Diabetes insipidus (DI) is a rare condition characterized  by the persistent excretion of excessive quantities of  dilute urine (polyuria) and by constant thirst  (polydipsia).   2. Nephrogenic DI — distal tubules are refractory to the  water reabsorptive action of ADH.   Clinical features — irrespective of aetiology, reabsorp-  tion of water from the glomerular filtrate in the renal  collecting ducts does not occur, resulting in polyuria  (up to 20 L per day is possible) and high risk of body  water depletion. DI is potentially lethal without appro-  priate therapy.   Investigations — there is high clinical suspicion if a  patient has a high plasma osmolality with low or immea-  surable plasma ADH, and a non-maximally concentrated  urine. A water deprivation test is run for 8 hours or until  3% of the body weight is lost. Demonstration of contin-  ued polyuria and increased haemoconcentration indi-  cates DI. This test serves to differentiate DI from   psychogenic polydipsia. The test is then followed by  ADI I administration to differentiate between cranial DI  (kidneys are responsive to ADH) or nephrogenic DI (kid-  neys are unresponsive to ADH).   Treatment of mild DI — the effects of dehydration can  be counteracted by greatly increasing water intake  (polydipsia).   • Nephrogenic DI — treatment with thiazide di-  uretics, producing a decrease in urine volume by  approximately 50%.   Diabetes insipidus and diabetes mellitus are two distinct  conditions that both feature polyuria.   Increased secretion of ADI I occurs as a complication of  other diseases (primary hypersecretion of ADH is not  recognized). The condition is characterized by water  retention with haemodilution and by inappropriately  concentrated urine. In severe cases, cerebral oedema  supervenes with impaired consciousness, but body  oedema is not usually seen as free water is evenly distrib-  uted to all body compartments.   • tumours — ectopic secretion of ADH, especially by  small cell carcinomas of the lung and some other  neuroendocrine tumours   Surgical damage, usually in the  course of tumour removal  Head injury, usually transient  Hypothalamic tumour (either  primary or secondary)  Hypothalamic inflammatory  lesions, e.g. sarcoidosis,  encephalitis, meningitis   Recessive: DIDMOAD syndrome-  association of DI with diabetes  mellitus (DM), optic atrophy  (OA) and deafness (D)    • non-neoplastic lung disease (e.g. pneumonia, pul-  monary embolus) probably due to involvement of  intrathoracic baroreceptors.   Figure 10.6 shows a comparison table of features of  DI with those of inappropriate ADI I secretion.   As the embryo grows, the thyroid descends into the  neck, during migration; the gland remains connected  to the tongue by a narrow canal, the thyroglossal duct,  which later becomes solid and finally disappears.   Cystic remnants of parts of the thyroglossal duct are  known as thyroglossal cysts (Fig. 10.7). These cysts may  form anywhere along the course of descent but are al-  ways located near or in the midline of the neck. Cysts  usually develop as painless, progressively enlarging  and movable masses. It does not lead to any alterations  in thyroid function.   This syndrome is caused by the excessive secretion of  thyroid hormones — typically both thyroxine (T 4 ) and  tri-iodothyronine (T 3 ) — in the bloodstream. Symptoms  include tachycardia, sweating, tremor, anxiety, in-  creased appetite, loss of weight and intolerance of heat.   • primary hyperthyroidism (j thyroid hormones,  l TSFI) — hypersecretion of thyroid hormones, which  is not secondary to increased levels of TSH (the rise in  thyroid hormones actually suppresses TSH)   • secondary hyperthyroidism (f thyroid hormones,  t TSH) — overstimulation of the thyroid gland  caused by excess TSH produced by a tumour in the  pituitary or elsewhere (rare).   • Graves' disease (exophthalmic goitre) — the most  common cause of thyrotoxicosis, characterized by  a diffusely enlarged thyroid gland that is stimulated  to produce excess hormone by an IgG autoantibody   • toxic multinodular goitre (Plummer's disease) —  second most common cause of hyperthyroidism    Fig. 10.6 Comparison of features of diabetes insipidus with those of inappropriate ADH secretion   • thyroiditis — inflammation of the thyroid causing  hyperthyroidism (e.g. De Quervain's thyroiditis).  Note that thyroiditis is more commonly associated  with hypothyroidism (see below)   • drugs — either direct ingestion of large doses of thy-  roid hormone (thyrotoxicosis factitia) or through  iodide-inducing drugs (e.g. amiodarone).   Signs and symptoms of thyrotoxicosis are a conse-  quence of an increase in the body's metabolism, which  occurs as a direct result of increased concentrations of  the thyroid hormones.    Fig. 10.8 Summary diagram illustrating features of  thyrotoxicosis. (* = additional features seen only in Graves'  disease.)    Other symptoms are summarised in Figure 10.8.  Investigations — hyperthyroidism is confirmed by  raised serum thyroxine and/or lowered serum TSH.  Management — options in thyrotoxicosis are:   • drugs (such as carbimazole or propylthiouracil) —  interfere with the production of thyroid hormones.   Graves' disease is an autoimmune disorder that results  in thyrotoxicosis due to over-stimulation of the thyroid  gland by autoantibodies. It is the most common form of  thyrotoxicosis, females being affected more than males  by 8:1. It is usually associated with a diffuse enlarge-  ment of the thyroid.   Pathogenesis — IgG-type immunoglobulins bind to  TSH membrane receptors and cause prolonged stimula-  tion of the thyroid, lasting for as long as 12 hours (cf. 1  hour for TSH). The autoantibody binds at a site different  to the hormone-binding locus and is termed the TSH-  receptor autoantibody (TRAb); 95% of Graves' disease  patients are positive for TRAbs.   Histologically, the gland shows diffuse hypertrophy  and hyperplasia of acinar epithelium, reduction of  stored colloid and local accumulations of lymphocytes  with lymphoid follicle formation.   The clinical features of Graves' disease are similar to  those of general thyrotoxicosis but with some addi-  tional features (see Fig. 10.8), namely:   • exophthalmos (protrusion of the eyeballs in their  sockets) — due to the infiltration of orbital tissues  by fat, mucopolysaccharides and lymphocytes.  May cause compression of the optic nerve, hence  blindness. However, only about 5% of Graves'  patients show signs of exophthalmos   • pretibial myxoedema — accumulation of mucopro-  teins in the deep dermis of the skin.   Decreased activity of the thyroid gland results in de-  creased production of thyroid hormones. There are  two forms:   This condition occurs as a result of extreme hypothy-  roidism during fetal life, infancy or childhood. It has  the following types and aetiology:   • endemic cretinism — occurs in iodine-deficient  countries where goitre is common    • sporadic cretinism — caused by congenital hypo-  plasia or absence of the thyroid gland and often  associated with deaf mutism   • dyshormonogenesis — a congenital familial recessive  enzyme defect causing an inability to complete the  formation of thyroid hormones. TSH is increased,  and the thyroid gland is enlarged and shows epithe-  lial hyperplasia.   Management is by early detection and treatment with  thyroxine, which can prevent an irreversible mental de-  fect and cerebellar damage. Many countries now have  screening programmes to measure serum TSH and/or  thyroxine levels on heel-prick blood samples taken on  the fourth or fifth day of life.   This common clinical condition is associated with de-  creased function of the thyroid gland and a decrease  in the circulating level of thyroid hormones. It affects  1% of people in the UK, with females more than males  by 6: 1 . It can present at any age but most commonly be-  tween 30 and 50 years of age.   Note that, strictly speaking, myxoedema describes a  non-pitting, oedematous reaction characteristic of hy-  pothyroidism caused by the deposition of a mucoid  substance (myxa- is a Greek prefix denoting mucus) in  the skin and elsewhere in the body. However, the terms  'myxoedema' and 'hypothyroidism of adults' are now  frequently used interchangeably.   • Primary (J. thyroid hormones, | TSH) — failure of the  thyroid gland itself. This is much more common  than secondary hypothyroidism. Note that subclin-  ical hypothyroidism describes an increase in TSII  but with normal thyroid hormone levels, and is in-  creasingly being treated with the aim of reducing  progression to full disease.   • autoimmune thyroiditis — atrophic form, e.g. pri-  mary atrophic thyroiditis and goitrous form (such  as Hashimoto's thyroiditis)    Fig. 10.9 Summary diagram illustrating features of  hypothyroidism in the adult (myxoedema).   • Graves' disease — approximately 5% of patients with  thyrotoxicosis develop hypothyroidism in later years,  unrelated to treatment. Probably caused by a spec-  trum of antithyroid antibodies, some of which stim-  ulate TSH receptor and some of which are destmctive   • severe iodine deficiency (rare in the UK) — iodine  must be virtually absent from the diet before myx-  oedema develops.   Signs and symptoms of hypothyroidism are both  widespread (due to reduced body metabolism) and  localized (myxoedema due to the accumulation of  mucoproteins). The most important symptoms  diagnostically are:   • serum TSH concentration (reduced in secondary  hypothyroidism but increased in primary  hypothyroidism).   This inflammation of the thyroid gland can have a viral  or autoimmune aetiology.   This autoimmune disease results in destructive thyroid-  itis. It can occur at any age, but typically affects the  middle-aged, and females more than males by 12:1.   Thyroid peroxidase antibodies are most commonly  found in the serum of affected individuals (90% of  cases). The disease is associated with the HLA-DR5  and HLA-B8 haplotypes, and patients with Hashimoto's  disease (and Graves' disease) show a high incidence of  other autoimmune diseases.   • white or grey on a cut surface as a result of the disap-  pearance of brown (iodine-rich) colloid (thyroglob-  ulin), and its replacement by lymphocytes.  Microscopically, the thyroid gland shows:   • acini lined with abnormal, highly eosinophilic epi-  thelial cells (proliferation of mitochondria) known  as Askanazy or Hurthle cells   The condition may present due to goitre formation  or because of the symptoms of hypothyroidism. The  hypothyroid state tends to develop slowly. However,  damage to thyroid follicles may lead to the release of  thyroglobulin into the circulation causing transient thy-  rotoxicosis. Some cases proceed to primary atrophic  thyroiditis. Furthermore, there is an increased incidence  of non-Hodgkin's lymphoma originating in the thyroid  of patients with Hashimoto's thyroiditis.   Treatment is by oral thyroxine, which overcomes  hypothyroidism and reduces the size of the goitre.   A rare, viral thyroiditis seen in young and middle-aged  women as a slightly diffuse tender swelling of the thy-  roid; this is also known as subacute, giant cell or gran-  ulomatous thyroiditis. The condition usually occurs in  association with a transient febrile illness, often during  various viral epidemics.   The most commonly associated viruses are Cox-  sackie, mumps and adenovirus.   • painful enlargement of the thyroid (about twice nor-  mal size; normal weight is 20-30 g)   • inflammation with a giant cell granulomatous reac-  tion engulfing leaked colloid (hence the synonyms  giant cell or granulomatous thyroiditis)   • degeneration of follicles with inflammatory cell in-  filtration (neutrophils, plasma cells, lymphocytes  and histiocytes)   The illness is usually self-limiting and settles in a few  weeks. Transient hyperthyroidism can result from the  release of thyroglobulin and excessive amounts of thy-  roid hormone.   This form of autoimmune thyroiditis is characterized by  focal lymphocytic infiltration of the thyroid (also  known as focal lymphocytic thyroiditis).   Histological changes are similar to those in  Hashimoto's thyroiditis, but they are focal rather than  diffuse. The disease is less severe than Hashimoto's    thyroiditis, and it is often asymptomatic. It may also  present with the symptoms of hyperthyroidism.   A comparison of the main types of thyroiditis is pro-  vided in Figure 10.10.   A goitre is any enlargement of the thyroid gland. There  are two types:   2. Non-toxic goitre, i.e. goitre associated with normal  or reduced levels of thyroid hormones.   This is the most common cause of toxic goitre (de-  scribed above).   This results from the development of hyperthyroidism  in a multinodular goitre (see below).   This diffuse enlargement of the thyroid gland is classi-  fied into:   • sporadic goitre — caused by goitrogenic agents (sub-  stances that induce goitre formation) or familial in  origin. Examples of goitrogenic agents include certain  cabbage species, because of their thiourea content,  and specific drugs or chemicals, such as iodide, para-  minosalicylic acid and drugs used in the treatment of  thyrotoxicosis. Familial cases show inherited autoso-  mal recessive traits, which interfere with hormone  synthesis via various enzyme pathways   • physiological goitre — enlargement of the thyroid  gland in females during puberty or pregnancy.   This is the most common cause of thyroid enlargement  and is seen particularly in the elderly (nearly all simple  goitres eventually become multinodular). The exact  aetiology is uncertain but it may represent an uneven re-  sponsiveness of various parts of the thyroid to fluctu-  ating TSH levels over a period of many years.  Morphological features are:   • irregular hyperplastic enlargement of the entire  thyroid gland due to the development of well-  circumscribed nodules of varying size   • larger nodules filled with brown, gelatinous colloid;  consequently, it is often termed multinodular col-  loid goitres.   Most patients have normal thyroid function and  generally seek treatment for cosmetic reasons (an un-  sightly swelling in the neck) or compression symp-  toms, e.g. pressure on the trachea producing stridor  or pressure on the recurrent laryngeal nerve producing  hoarseness.   However, toxic changes occasionally occur in a  multinodular goitre resulting in hyperthyroidism, when  it is termed a toxic multinodular goitre.   Tumours of the thyroid are generally benign. Carcino-  mas are rare and lymphomas are rarer still.   These are solitary, or multiple, encapsulated solid nod-  ules. Compression of the adjacent gland is a common  feature, and the centre may show areas of haemorrhage  and cystic changes. The most common type is follicular    adenoma, which consists of colloid-containing microfol-  licles and columns of larger cells of alveolar arrangement.   A reminder of the differences between primary and  secondary hyperthyroidism and hypothyroidism:    Rarely, follicular adenomas may synthesize excess  thyroid hormones ('toxic adenomas'), causing thyro-  toxicosis.   These rare tumours account for less than 1% of total  cancer deaths in the UK, with females affected more  than males by 3:1. Types of malignant thyroid tumours  and their basic features are outlined in Figure 10.11.   This is the most common thyroid cancer. It is a  well-differentiated tumour most commonly found in  younger patients. It presents as a non-encapsulated  infiltrative mass. It is a slow growing tumour with an  excellent prognosis.   Histologically it consists of epithelial papillary pro-  jections into gland-like spaces and calcified spherules    may be present (psoammoma bodies). Epithelial cell  nuclei are large with clear areas centrally (described as  'Orphan Annie nuclei').   Characterized histologically by uniform follicles,  spread is usually to bones, lungs and brain via the  bloodstream.   Many of these tumours retain the ability to take up  radioactive iodine ( 131 I), which may be used as a highly  effective targeted form of radiotherapy, usually after sur-  gical thyroidectomy. The prognosis, therefore, is good.   This highly malignant, poorly differentiated adenocarci-  noma usually presents in the elderly as a diffusely infil-  trative mass. In about half of cases there is a history of  multinodular goitre.   Histologically, the dominant features are those of a  spindle cell tumour with or without giant cell areas,  or a small cell pattern.   The prognosis is very poor due to the rapid local in-  vasion of structures such as the trachea, producing respi-  ratory obstruction.   This rare neuroendocrine tumour arises from parafollicu-  lar C cells, which commonly synthesize and secrete calci-  tonin but which may also secrete 5-hydroxytryptamine  (serotonin), various peptides of the tachykinin family,  ACTH and prostaglandins.   High levels of serum calcitonin are useful diagnosti-  cally but produce no clinical effects.   Although medullary carcinoma is most common in  the elderly, it also occurs in younger individuals, where  it is commonly associated with other endocrine tu-  mours, such as phaeochromocytoma as part of the mul-  tiple endocrine neoplasia (MEN) syndromes Ha and lib  (see p. 201).   Most thyroid lymphomas are regarded as tumours of  mucosa-associated lymphoma tissue. Interestingly,  non-Hodgkin's B cell lymphomas occasionally arise in  long-standing, autoimmune thyroiditis, especially  Hashimoto's disease.   Parathyroid hormone (PTH) is a polypeptide (84  amino acid residues) secreted by the chief cells of the  parathyroid glands. The main action of PTH is to in-  crease serum calcium and decrease serum phosphate.    In bone, PTH stimulates osteoclastic bone resorption  and inhibits osteoblastic bone deposition. The net effect  is the release of calcium from bone.   Hyperparathyroidism is defined as an elevated secretion  of PTI I, of which there are three main types:   2. Secondary — physiological increase in PTH secretions  in response to hypocalcaemia of any cause   Understanding the physiological functions of  PTH is essential to an understanding of the  clinical effects produced by its hypo- or  hypersecretion.   This is the most common of the parathyroid disorders,  and is an important cause of hypercalcaemia. More than  90% of patients are over 50 years of age and the condi-  tion affects females more than males by nearly 3:1. The  aetiology of primary hyperparathyroidism is outlined in  Figure 10.12.   The clinical effects are the result of hypercalcaemia and  bone resorption.   • Exacerbation of hypertension and potential shorten-  ing of the QT interval   • Thirst and polyuria (may be dehydrated due to im-  paired concentrating ability of kidney)   Orange-brown,  well-encapsulated  tumour of various size but  seldom > 1 cm diameter  Tumours are usually solitary,  affecting only one of the  parathyroids, the others often  showing atrophy; they are  deep seated and rarely  palpable   • 'Brown tumours' — haemorrhagic and cystic tumour-  like areas in the bone, containing large masses of gi-  ant osteoclastic cells.   • Osteitis fibrosa cystica (von Recklinghausen disease  of bone) — multiple brown tumours combined with  fibrous replacement of resorbed bone.   • Changes may present clinically as bone pain, frac-  ture or deformity.   However, about 50% of patients with biochemical evi-  dence of primary hyperparathyroidism are asymptomatic.  Investigations are:   plasma calcium using bisphosphonates and eventual  surgical removal of abnormal parathyroid glands.   This is compensatory hyperplasia of the parathyroid  glands, occurring in response to diseases of chronic  low serum calcium or increased serum phosphate.   • chronic renal failure and some renal tubular disor-  ders (most common cause)   • steatorrhoea and other malabsorption syndromes.  Morphological changes of the parathyroid glands are:   • hyperplastic enlargement of all parathyroid glands,  but to a lesser degree than in primary hyperplasia   • increase in 'water clear' cells and chief cells of the  parathyroid glands, with loss of stromal fat cells.  Clinical manifestations — symptoms of bone resorp-  tion are dominant.   Skeletal abnormalities, arising as a result of raised PTI I  secondary to chronic renal disease, are known as renal  osteodystrophy.   Abnormalities vary widely according to the nature of  the renal lesion, its duration and the age of the patient,  but include:   • rickets or osteomalacia due to reduced activation of  vitamin D   • osteosclerosis — increased radiodensity of certain  bones, particularly the parts of vertebrae adjacent  to the intervertebral discs.   Note that the symptoms of hypercalcaemia are not a  feature of secondary hyperparathyroidism; calcium  levels are likely to be decreased as this is driving the  compensatory PTH secretion.   The investigations are both biochemical (raised PTI I  and normal or lowered Ca 2+ ) and radiological (bone  changes) .   This condition, resulting from chronic overstim-  ulation of the parathyroid glands in renal failure,  causes one or more of the glands to become an auton-  omous hypersecreting adenoma with resultant  hypercalcaemia.   Figure 10.14 gives a comparison of primary, second-  ary and tertiary hyperparathyroidism.   Renal diseases + -> J, serum Ca 2+ -> TPTH -> Tbone resorption   Hypoparathyroidism is a condition of reduced or ab-  sent PTH secretion, resulting in hypocalcaemia and  hyperphosphataemia. It is far less common than  hyperparathyroidism.   • autoimmune parathyroid disease — usually occurs in  patients who have another autoimmune endocrine  disease, e.g. Addison's disease   • congenital deficiency (DiGeorge syndrome) — rare,  congenital disorder caused by arrested development  of the third and fourth branchial arches, resulting in  an almost complete absence of the thymus (see  Chapter 13) and parathyroid gland.   • Psychiatric disturbances, e.g. depression, confu-  sional state and even psychosis   • Rarely — cataracts, parkinsonian-like movement dis-  orders, alopecia, brittle nails.   Management is by treatment with large doses of oral  vitamin D; the acute phase requires intravenous calcium  and calcitriol (1,25-dihydroxycholecalciferol, i.e. acti-  vated vitamin D).   The adrenal gland has two structurally and functionally  distinct endocrine components derived from different  embryonic tissue: the cortex and the medulla.   This is the outer part of the gland, which is derived from  the mesoderm. It synthesizes, stores, and secretes vari-  ous cholesterol-derived hormones, namely:   • sex steroids, i.e. oestrogens and androgens — from  the zona reticularis.   This is the inner part of the gland, which is derived from  the neuroectoderm, forming part of the sympathetic  nervous system. Chromaffin cells synthesize and secrete  the vasoactive amines epinephrine (adrenaline) and  norepinephrine (noradrenaline).   The symptoms and signs of Cushing's syndrome are as-  sociated with prolonged inappropriate elevation of free  corticosteroid levels (Fig. 10.15).   - skeletal muscle weakness  and wasting (causes thin  arms and legs)    Clinical features — the main effects of sustained eleva-  tion of glucocorticoid secretion are:   Aetiopathogenesis — patients with Cushing's syn-  drome can be classified into two groups on the basis  of whether the aetiology of the condition is ACTH-  dependent or independent (Fig. 10.16).   • Pituitary hypersecretion of ACTH (Cushing's  disease) — bilateral adrenal hyperplasia secondary   Pituitary hypersecretion of ACTH  Ectopic ACTH syndrome (benign  or malignant non-endocrine tumour)    to excessive secretion of ACTH by a corticotroph  adenoma of the pituitary gland (see p. 182).   • Production of ectopic ACTH or corticotrophin-  releasing hormone (CRIT) by non-endocrine neo-  plasm, e.g. small cell lung cancer and some carcinoid  tumours. In cases of malignant bronchial tumour,  the patient rarely survives long enough to develop  any physical features of Cushing's syndrome.  Non-ACTH-dependent aetiology:   • Iatrogenic steroid therapy — most common cause of  Cushing's syndrome.   • Adrenal cortical adenoma — extremely common as  an incidental finding in up to 30% of all post-  mortem examinations. The yellow colour is due to  stored lipid (mainly cholesterol) from which the  hormones are synthesized. The vast majority have  no clinical effects (i.e. they are non-functioning ad-  enomas), with only a small percentage producing  Cushing's syndrome.   • Adrenal cortical carcinoma — rare and almost always  associated with the overproduction of hormones,  usually glucocorticoids and sex steroids. Patients  usually have features of Cushing's syndrome mixed  with androgenic effects which are particularly no-  ticeable in women. Local invasion and metastatic  spread are common.   The therapeutic administration of glucocorticosteroids  (e.g. prednisolone) is a common cause of the  features of Cushing's syndrome. Avoid confusing  the disease and the syndrome. Remember: Cushing's  disease is used specifically to describe Cushing's  syndrome secondary to excessive pituitary  ACTH secretion.    Irrespective of the aetiology, the diagnosis is based  on clinical features and the demonstration of a raised  plasma cortisol level.   • raised urinary cortisol in the first instance, but fur-  ther testing is required.   • low-dose dexamethasone suppression test (suppres-  sion of cortisol levels in Cushing's disease due to  suppression of pituitary ACTH secretion, but a lack  of suppression suggests ACTH-independent Cush-  ing's syndrome).   • MRI and CT scan visualization of pituitary and adre-  nal glands.   • analysis of blood ACTH (high = pituitary adenoma  or ectopic ACTH source; low = primary adrenal tu-  mour due to feedback suppression).    Treatment of the underlying cause is essential as  untreated Cushing's syndrome has a 50% 5-year mortal-  ity rate.   Excessive production of aldosterone by the zona glo-  merulosa of the adrenal cortex results in increased  Na + retention and increased K + loss.   • Primary hyperaldosteronism — autonomous hyper-  secretion of aldosterone, usually caused by adrenal  cortical adenomas (Conn's syndrome).   • Secondary hyperaldosteronism — hypersecretion of al-  dosterone secondary to increased serum renin. May be  precipitated by renal tumours and oedema (congestive  cardiac failure, cirrhosis or nephrotic syndrome) . This is  more common than the primary form of the disorder.   • Hypertension — often the only presenting feature.  Commonly occurs in the younger age group.   • Hypokalaemia — usually accompanies hypertension  and may give rise to polyuria, nocturia, polydipsia,  paraesthesia, cardiac arrhythmias, muscle weakness  or paralysis.   Secondary hyperaldosteronism also has additional  features of underlying disease. Biochemical diagnosis:   Radiological diagnosis is by visualization of adrenal  cortical adenoma by CT scan or MRI.   • Primary hyperaldosteronism — medical aldosterone  antagonism (e.g. spironolactone) or surgical re-  moval of the affected adrenal.   This autosomal recessive disorder is usually caused by a  deficiency of the enzyme 21 -hydroxylase, required for the  synthesis of both cortisol and aldosterone. 21 -Hydroxylase  acts on 170H-progesterone and, consequently, raised  levels of 170H-progesterone are measured in the blood  of affected individuals; this is routinely tested in the first  week of life. Failure of cortisol production produces an in-  crease in ACTH secretion by the pituitary and hyperplasia  of the adrenal cortex.   Production of androgens by the adrenal cortex does  not require 21 -hydroxylase. Consequently adrenal hy-  perplasia causes excessive secretion of androgens  resulting in masculinization of females and precocious  puberty in males. Aldosterone deficiency is serious,  causing a life-threatening salt loss ('salt wasting syn-  drome') unless replacement therapy is given.   This rare condition of chronic adrenal insufficiency is  due to a lack of glucocorticoids and mineralocorticoids.   The clinical features outlined in Figure 10.18 are a  result of glucocorticoid and mineralocorticoid insuffi-  ciency, loss of adrenal androgen production and in-  creased ACTH secretion.    Aetiology — autoimmune destruction of the cortex of  both adrenals is the most common cause of Addison's  disease, commonly associated with other autoimmune  diseases. Addison's disease can also be caused by tuber-  culosis (previously most common cause) and metastatic  cancers.   • ACTH stimulation test — ACTH is administered  and plasma cortisol levels are monitored.  Failure of cortisol levels to rise indicates Addison's  disease   Management is by glucocorticoid replacement ther-  apy and usually mineralocorticoid therapy.   • iatrogenic — abrupt cessation of prolonged high-  dose therapeutic corticosteroids (prolonged corti-  costeroid therapy produces lowered endogenous  steroid production, leading to atrophy of the  adrenal cortex)   • bilateral massive adrenal haemorrhage — caused by  Gram-negative (usually meningococcal) septicae-  mia (Waterhouse-Friderichsen syndrome) produc-  ing haemorrhage and disseminated intravascular  coagulation. Adrenal haemorrhage is also seen in  neonates following traumatic birth.   Vomiting and loss of appetite  Weight loss  Lethargy and weakness  Postural hypotension  Hypoglycaemia   An adrenal crisis is a medical emergency and requires  intravenous hydrocortisone and fluid replacement. The  precipitating cause should be sought and if possible  treated.   • hypothalamic or pituitary disease (tumours, infec-  tion, infarction, surgical destruction), which pro-  duces lowered ACTH, hence lowered endogenous  glucocorticoids and aldosterone   • glucocorticoid therapy, which produces lowered  ACTH (suppression), hence lowered endogenous  glucocorticoids and aldosterone.   This is a rare tumour of the chromaffin cells — the cells that  secrete epinephrine (adrenaline) and norepinephrine  (noradrenaline) in the adrenal medulla (see p. 193).   These rare catecholamine producing tumours are de-  rived from neuroblasts. They originate from the adrenal  medulla and can present with an abdominal mass.   Neuroblastomas are almost exclusively tumours of  children, occurring very rarely over the age of 5 years.  They are highly malignant and usually inoperable.   Diabetes mellitus (DM) is a multisystem disease of an  abnormal metabolic state characterized by hyperglycae-  mia due to inadequate insulin action/production. It can  be classified into primary and secondary.    Primary DM is a disorder of insulin production/  action. It accounts for 95% of diabetic cases.   • hypersecretion of hormones that antagonize the ef-  fects of insulin, e.g. glucocorticoids in Cushing's  syndrome, growth hormone in acromegaly, epi-  nephrine (adrenaline) in pheochromocytomas.  Primary DM is by far the most important cause of di-  abetes and it is further classified into:   • Type I, also known as insulin-dependent DM  (IDDM) or juvenile-onset diabetes.   • Type II, also known as non-insulin-dependent DM  (NIDDM) or mature-onset diabetes.   The basic features of these two types of diabetes are  described in Figure 10.19.   Aetiology and pathogenesis — type 1 diabetes mellitus is  an organ specific, autoimmune-induced disorder char-  acterized by antibody-mediated destruction of the (3-cell  population of the islet of Langerhans.   1. Genetic predisposition — 90-95% of patients with  type I diabetes are HLA-DR3 or HLA-DR4 positive,  a feature that is also seen in other organ-specific au-  toimmune diseases. However, identical twins show  a 40% concordance in the development of the dis-  ease, indicating the additional importance of envi-  ronmental factors.   2. Viral infection — viral infection may trigger the auto-  immune reaction; viruses implicated include  mumps, measles and Coxsackie B.   One postulated mechanism is that viruses induce  mild structural damage to the islet cells, thereby releas-  ing previously shielded (3-cell antigens and leading to  the recruitment and activation of lymphocytes in the  pancreatic tissue.   Histologically, the pancreas shows lymphocytic infil-  tration and destruction of insulin-secreting cells of islets  of Langerhans ((3-cells). This results in insulin deficiency  with hyperglycaemia and other secondary metabolic  complications.   Aetiology and pathogenesis — the precise aetiopathogen-  esis of type II diabetes is unclear but the following fac-  tors are thought to be involved:   • Genetic factors — familial tendency with up to 90%  concordance rate amongst identical twins. How-  ever, there are no LILA associations and inheritance  is considered to be polygenic.    Fig. 10.19 Table comparing type I and type II diabetes mellitus (DM)    • Insulin resistance — tissues are unable to respond to  insulin because of an impairment in the function of  insulin receptors on the surface of target cells. This  is associated with obesity, sedentary lifestyle and  poor diet; it is increasingly being seen in younger  (even adolescent) individuals.   Fig. 10.20 Diagnostic criteria for diabetes mellitus  using an oral glucose tolerance test   Irrespective of aetiology, the diagnosis of DM depends  on the finding of hyperglycaemia. However, the distri-  bution curve of blood glucose concentration for whole  populations is unimodal, with no clear division be-  tween normal and abnormal values.   Diagnostic criteria (Fig. 10.20) are, therefore, arbitrary  and, in general, diabetes mellitus is indicated by either:   A distinction is made between diabetes mellitus and  impaired glucose tolerance in cases where fasting or ran-  dom blood sugar level is borderline; in this case, the re-  sponse to an oral load of glucose can be assessed via a  glucose tolerance test.   Individuals with diabetes are particularly prone to sev-  eral types of coma. These result from (in decreasing or-  der of frequency):   • lactic acidosis — increased concentrations of lactic  acid (produced as an end product of glycolysis in-  stead of pyruvate) may cause coma.   The complications of DM are important; 80% of adults  with diabetes die from cardiovascular disease and  patients frequently develop serious renal and retinal  disease.   In recent years, with the advent of insulin therapy and  various oral hypoglycaemic agents, morbidity and mor-  tality associated with DM are more commonly the result  of the chronic rather than the acute complications of the  disorder (Fig. 10.21).    The complications of diabetes are macrovascular  (affecting large and medium-sized muscular arteries)  and microvascular (small vessel microangiopathy).   Macrovascular changes involve accelerated athero-  sclerosis. In diabetic microangiopathy, small arterioles  and capillaries show a characteristic pattern of wall  thickening, which is due to a marked expansion of the  basement membrane (termed hyaline arteriolosclerosis).   • macrovascular accelerated atherosclerosis increas-  ing stroke and myocardial infarction risk   Compared with non-affected people of the same age  and sex, individuals with diabetes suffer from an  increased severity of atherosclerosis, probably due to  the increased plasma levels of cholesterol and  triglycerides.   Diabetes is now one of the most common causes of  end-stage renal failure. Associated renal disease can be  divided into three forms:   • Complications of diabetic vascular disease —  macrovascular atherosclerosis affecting aorta and  renal arteries — > ischaemia; microvascular glomeru-  lar capillary basement membrane thickening  (hyaline arteriolosclerosis) — ► ischaemic glomerular  damage. Microalbuminuria is a reliable marker of  the progression of diabetic nephropathy.   • Diabetic glomerulosclerosis (diffuse and nodular  types) — t leakage of plasma proteins through capil-  lary wall into glomerular filtrate — > proteinuria and  progressive glomerular hyalinization with eventual  chronic renal failure.   • Increased susceptibility to infections — > papillary ne-  crosis. Acute pyelonephritis is a common complica-  tion of diabetes mellitus and occurs as a result of the  relative immunosuppression of diabetes together  with reduced neutrophil function.   Diabetes is the most common cause of acquired blind-  ness in the Western world. It can affect the eyes in five  main ways:   1. Background retinopathy — small vessel abnormali-  ties in the retina leading to hard exudates, haemor-  rhages and microaneurysms. Does not usually affect  acuity.   2. Proliferative retinopathy — extensive proliferation of  new capillaries in the retina. Sudden deterioration in  vision may result from vitreous haemorrhage as a  consequence of proliferating new vessels or from  the development of retinal detachment.    3. Maculopathy — caused by oedema, hard exudates or  retinal ischaemia and results in a marked reduction  of acuity.   5. Glaucoma — increased incidence in those with dia-  betes due to neovascularization of the iris (rubeosis  iridis).   Patients with diabetes have an increased tendency to de-  velop infections, usually of a bacterial or fungal nature.  The main target organs are:   • urinary tract — increased predisposition to acute  pyelonephritis, often associated with recurrent lower  urinary tract infections.   Persistent glycosuria in individuals with poorly con-  trolled diabetes predisposes to urinary and genital  infection.   Clinically, most cases of diabetic neuropathy affect the  peripheral nervous system, although central nervous  system pathology does occur. The main effects are:   • microvascular thickening of basement membrane  and microthrombi formation in small vessels sup-  plying peripheral nerves   The presentation may be of polyneuropathy (classi-  cally 'glove and stocking' sensory impairment), mono-  neuropathy (e.g. carpal tunnel syndrome) or  autonomic neuropathy (symptoms include postural hy-  potension, nausea, vomiting, impotence and gustatory  sweating) .   Blood glucose control in diabetes lowers the incidence  and progression of vascular complications. This can be  achieved by:   • diet and oral hypoglycaemic drugs (e.g.  sulphonylureas, biguanides, thiazolidinediones) — in  type II patients who fail on diet alone   • diet and insulin — all type I patients and some type II.  Pancreatic transplantation is curative in type I   diabetes but is limited by organ availability. Islet cell  transplants are a potential future therapy.   These tumours are rare compared with those of the exo-  crine pancreas. They occur most commonly in individ-  uals aged 30-50 years.   The most common tumour of the islet cells. Insulino-  mas are derived from pancreatic (3-cells:   • May produce attacks of confusion, stupor and loss of  consciousness   This syndrome of gastric hypersecretion, multiple peptic  ulcers and diarrhoea is caused by the gastrin-secreting  tumour (gastrinoma) of the pancreatic G cells. Tumours  are multiple in 50% of cases and are often malignant,  with 10-20% occurring in other sites, e.g the  duodenum.   It may also be part of the MEN I syndrome, with ad-  enomas also present in other endocrine glands (see  below).   These produce vasoactive intestinal polypeptide (VIP),  resulting in a syndrome of watery diarrhoea, hypo-  kalaemia and achlorhydria (WDHA).   These glucagon-secreting tumours are derived from pan-  creatic a-cells and cause secondary diabetes mellitus  (usually mild), necrolytic migratory erythema (skin  rash) and uraemia.   These somatostatin-producing tumours derived from  pancreatic <5-cells are associated with diabetes mellitus,  cholelithiasis and steatorrhoea.    These are syndromes in which patients develop tumours  in a number of different endocrine organs. Patients are  younger than those who develop single sporadic tu-  mours and usually have a strong family history of mul-  tiple endocrine tumours with autosomal dominant  inheritance.   Patients usually show a combination of hyper-  parathyroidism (chief cell hyperplasia and adenomas),  pituitary adenomas (usually prolactinomas) and pan-  creatic tumours (gastrin and insulin producing). Rarely,  there may also be thyroid tumours and adrenal cortical  adenomas. MEN I syndrome is caused by a germ-line  mutation in the MEN-1 tumour suppressor gene.   Patients have a combination of phaeochromocytoma  (50% bilateral) and medullary carcinoma of the thyroid  and hyperparathyroidism due to parathyroid hyperpla-  sia. MEN Ha and lib syndromes have been linked to mu-  tations in the RET oncogene, with near 100% disease  penetrance.   In contrast to MEN Ila it does not induce hyperparathy-  roidism, and has the additional features of mucocutane-  ous neuromas and ganglioneuromas.   Genetic screening of at-risk family members in MEN  II families now allows prophylactic thyroidectomy in  those with RET mutations to avoid the near certainty  of medullary carcinoma.   • Describe infection and neoplasia of the vulva, vagina and cervix, particularly cervical cancer.   • Understand inflammatory and neoplastic disease of the uterus and endometrium.   • Recall disorders of the ovary and fallopian tubes, with the focus on ovarian cancer.   • Describe ectopic pregnancies, spontaneous abortion and other disorders of the placenta and pregnancy.   • Understand the common forms of breast disease, particularly breast carcinoma.   • Recall testicular cancer and other disorders of the testis and epididymis.   This common, benign, mucus-secreting cyst on the vulva  is derived from Bartholin's glands (mucus-secreting  glands in the posterior part of the labia majora). Fre-  quently there is superimposed infection — Bartholin's  abscess.   Viral infections of the vulval skin are typically due to ei-  ther herpes simplex virus (HSV) or human papilloma-  virus (HPV).   HSV type 2 infection of the vulva (herpes vulvitis) pro-  duces initially painless blisters, which subsequently  break down to form a painful, sore, eroded area. LISV-  2 infection is now a major sexually transmitted disease  and is becoming more common in young women.   This sexually transmitted disease may present with a  thickening of the vulval skin and mucosa (flat condy-  loma) in the labia minora, or as multiple protuberant  warts (condylomata acuminata) that can be either ses-  sile or pedunculated. There is a strong link between  HPV infections of the vulva and intraepithelial neo-  plastic change in both the vulva (see below) and cervix.   This Gram-negative coccobacillus is often associated  with other sexually spread infections. The patient com-  plains of a foul-smelling discharge, which is thin, greyish  and sometimes shows bubbles. Examination confirms  both the discharge and the odour.   One of the most common sexually transmitted diseases  in the UK; 80% of women are asymptomatic, increasing  the likelihood of silent spread amongst the population.  Ascending infection into the upper genital tract (pelvic  inflammatory disease) is increasingly common; this is  an important cause of tubal infertility.   Genital infection with Chlamydia trachomatis may  produce painful superficial groin nodes (lymphogranu-  loma venereum), which develop over weeks from ini-  tially painless vulval papules. Later, chronic lymphatic  obstruction may lead to non-pitting oedema of the ex-  ternal genitalia.   This sexually transmitted flagellated protozoan is typi-  cally asymptomatic in men, but in women it often pro-  duces an intensely irritating vaginal discharge with  inflammation of the vulva, vagina and cervix. The dis-  charge is often frothy and offensive.   Now rarely sexually transmitted, this spirochaetal bac-  terium is responsible for syphilis. This granulomatous  disease typically involves three stages (primary.    secondary and tertiary). It affects the penis in the  primary stage:   • Primary — small indurated lesions (chancres) de-  velop at the site of entry but then spontaneously heal.   • Secondary — occurs several weeks later and is charac-  terized by multiple, moist, warty, vulvovaginal  lesions (condylomata lata), with skin rashes and  generalized illness (fever, malaise).   Fungal infections are usually caused by either superficial  dermatophytes or Candida albicans. There is usually  associated fungal vaginitis, presenting with a copious  vaginal discharge and vulval reddening and soreness.   This is a normal commensal of the vagina but its prolif-  eration is usually suppressed by commensal vaginal flora.   • glycosuria, e.g. diabetes, pregnancy (due to lowering  of the renal threshold for sugar)   • chronic anaemia — iron stores are needed to main-  tain an adequate immune reaction.  Macroscopically, white plaques of fungal hyphae de-  velop on inflamed vaginal mucosa. Vaginal discharge is  associated with severe vulval irritation. Infections are  often severe in people with diabetes.   Infection of vulval skin with dermatophytic fungi pro-  duces a similar superficial inflammation and soreness.   Both candidal infections and dermatophytes can be  treated with antifungal pessaries or systemic therapy.   Figure 11.1 shows the organisms that cause infec-  tions of the lower genital tract.   This is the most common malignant tumour of the  vulva, typically occurring in elderly women and often  showing extensive local invasion and metastases to    the inguinal lymph nodes. The majority of cases appear  to arise de novo, but some form from dysplastic epithe-  lium amounting to carcinoma in situ, known as vulval  intraepithelial neoplasia.   It is also thought that squamous cell carcinoma may  develop from areas of lichen sclerosus (atrophic lesions  that are most common after the menopause).   This is generally seen in patients younger than those  with invasive tumours. In 90% of cases there is coexis-  tent evidence of incorporated HPV DNA (especially se-  rotypes 16 and 18), usually with visible warty change in  the affected and adjacent epithelium. Although invasive  carcinoma and vulval intraepithelial neoplasia (VIN)  do occasionally coexist in elderly women, it is thought  that progression of VIN to invasive carcinoma is not  common.   Vaginal intraepithelial neoplasia (VAIN) is rare com-  pared with cervical intraepithelial neoplasia (CIN).  Most cases are found in women previously treated for  CIN or invasive cervical cancer.   Primary malignant tumours of the vagina are extremely  rare, but include squamous cell carcinomas and  adenocarcinomas.   Secondary tumours are more common, particularly  from malignant tumours of the cervix, endometrium  and ovary. Vaginal bleeding after hysterectomy for uter-  ine or ovarian malignancy should always be investi-  gated and biopsied because of the frequency of  metastatic tumour in the residual vaginal vault.   Acute and chronic inflammation of the cervix is partic-  ularly common in the presence of an intrauterine con-  traceptive device.   There is acute inflammation of the cervix with erosion.  It is occasionally seen in herpes simplex infection, typ-  ically with herpetic disease of the vulva and vagina.   This chronic inflammation of the cervix is typically  caused by the same organisms responsible for infective  vaginitis: Trichomonas, Candida and Gardnereila species  and the gonococci. It is characterized by a heavy plasma  cell and lymphocytic infiltrate.   These common abnormalities derived from the endo-  cervix affect up to 5% of women. Large polyps may pro-  trude from the cervix through the external os and can  cause intermenstrual bleeding from erosion and  ulceration.   Macroscopically, these are smooth, rounded or pear-  shaped polyps about 1-2 cm in diameter.   Microscopically, they are composed of endocervical  stroma and glands. The surface of the polyp may show  ulceration and inflammation, often accompanied by  squamous metaplasia.   Cervical intraepithelial neoplasia (CIN) is the pre-  neoplastic (dysplastic) proliferation of epithelium of  the transformation zone of the cervix.   Aetiology — there is a strong association with HPV in-  fection, particularly serotypes 16 and 18.   • sexual intercourse — very low incidence in virgins,  with increased risk in those who have had multiple  sexual partners and first intercourse at an early age.   • human papillomavirus — DNA from HPV types 16,  18, 31 or 33 has been identified in over 90% of cer-  vical carcinomas. Proteins produced by HPV are  thought to inactivate products of tumour suppres-  sor genes thereby facilitating tumour development.  For example, the viral protein E6 of IIPV subtype 16  can bind and inactivate the function of the p53  tumour suppressor protein (see Chapter 3). It is  likely that new HPV vaccines targeted against    serotypes 16 and 18 will reduce HPV infection  and CIN development   • combined oral contraceptive pill — prolonged use is  associated with an increased risk in those who carry  HPV infection (may be linked to increased sexual  risk-taking when on contraceptive pill)   Three grades of severity are recognized. Grading de-  pends on the proportion of the cervical epithelium wall  that is replaced by atypical cells:   1. CIN I (mild dysplasia) — upper two-thirds of the  epithelium normal, basal third atypical cells   2. CIN II (moderate dysplasia) — upper third of the  epithelium normal, atypical cells occupy the lower  two-thirds   3. CIN III (severe dysplasia) — corresponds to carci-  noma in situ. Atypical cells extend throughout the  full thickness of the epithelium with minimal differ-  entiation and maturation on the surface.   CIN is associated with a risk of progression to an inva-  sive carcinoma, the risk for CIN I being lowest and for  CIN III being the highest.   The natural history of CIN is important as it deter-  mines how often screening is required to detect progres-  sion of the disease.   Cervical screening aims to detect preinvasive  atypical cells by cytological examination of surface  epithelial cells. Smears repeated every 3 years are  considered adequate for population screening  (from 20 to 65 years old). In the UK it is estimated  that regular attendance at screening prevents up  to 90% of cervical cancer. Management of CIN is  by the local destruction of abnormal epithelium  using cryotherapy, laser therapy or cone  biopsy following histological confirmation of its  nature.   The vast majority of cervical carcinomas are squamous  cell carcinomas arising from the transformation zone  or ectocervix.   There are around 3000 cases of cervical cancer in the  UK each year, with 1300 deaths. This equates to a life-  time risk of around 1% (similar across the developed  world), compared to 5% in parts of the developing    world where screening programmes do not exist. This  type of carcinoma occurs in all ages from late teens  onwards, but the average age is 45 years.   The carcinoma is preceded by the preinvasive phase  of CIN (see above and Fig. 11.2). Risk factors are as  for CIN.   • Early — areas of granular irregularity of the cervical  epithelium, with progressive invasion of the stroma  causing abnormal hardness of the cervix   The common presenting symptom is vaginal bleed-  ing in the early stages. Advanced neglected tumours  may cause urinary obstruction due to bladder  involvement.   Invasive carcinomas are managed according to the  degree of local invasion and survival is related to the  stage of the disease (Fig. 11.3).   Early invasive carcinoma is usually managed by  radical hysterectomy and/or radiotherapy, whereas  advanced disease is usually only amenable to radiother-  apy and/or chemotherapy. Involvement of the para-  aortic lymph nodes is associated with a very poor  prognosis.   An inflammation of the endometrium, chronic endo-  metritis is typically associated with menstrual irregular-  ities and is often found in women who are being  investigated for infertility.   Microscopically there is lymphoid and plasma cell  infiltration of the endometrium.   Risk factors — the majority of cases are associated with  a definite clinical risk factor for developing inflam-  mation:   • chronic pelvic inflammatory disease, e.g. following  chlamydial infection (25% of cases)   • use of an intrauterine contraceptive device (about  20% of cases)   Fig. 11.2 Cervical intraepithelial neoplasia (CIN) and  invasive squamous carcinoma. (A) Increasing dysplasia of  CIN grades l-lll. (B) Early stromal invasion of<1 mm.   (D) Occult invasive carcinoma with invasion >500 mm 3 .  There is some risk of spread to the lymph nodes but the  tumour is still clinically undetectable. (Adapted from  Underwood, 2000.)   This is a condition in which the endometrium grows  down to develop deep within the myometrium, occur-  ring in 20% of women. This may cause enlargement of  the uterus and is sometimes associated with menstrual  abnormalities and dysmenorrhoea.   Macroscopically, there are small, irregular, endo-  metrial lesions — some of which are cystic — that can  be seen within the affected myometrium. Involvement  of the myometrium may be diffuse (more common)  or focal with deep nodules of endometrium (nodular  adenomyosis).   Microscopically, irregular nests of endometrial  stroma are found deep within muscle but in continuity  with surface endometrium.   This is defined as endometrial glands or stroma occur-  ring outside the uterus, and still capable of responding  to cyclical hormonal stimulation. Phases of prolifera-  tion and breakdown are associated with the develop-  ment of the fibrous adhesions and accumulation of  haemosiderin pigment. This affects 1 in 15 women of  reproductive age. There are numerous sites:   The aetiopathogenesis of endometriosis remains  unclear but three main theories operate to various  degrees:    3. Metastatic spread of endometrium, via the blood or  lymphatic vessels.   Macroscopically, the foci of endometriosis appear as  cystic and solid masses, which are characteristically dark  brown because of accumulated iron pigment from  repeated bleeding.   Microscopically, solid masses of endometriosis are  composed of endometrial glands and stroma, fibrosis  and macrophages containing iron pigments.   • infertility (about 30% of cases) — often due to adhe-  sions and blockages affecting ovulatory pathways   • chocolate cysts — the whole of the fallopian tube and  ovary may be converted into a cystic mass containing  brown, semi-liquid material.   Endometriosis is dependent on oestrogen for con-  tinued growth and proliferation, with the disease  becoming inactive after oophorectomy or onset of the  menopause. Thus, induction of the hypo-oestrogenic  state by suppression of ovulation is effective in many  cases (e.g. continuous progesterone therapy).   An anovulatory cycle is one that is not associated with  the development and release of the ovum from the  ovary. This is normal and common at both the start  and end of reproductive life. Several follicles may start  to develop and for a time produce hormones. However,  the attempt ends in atresia and the atretic follicle is  absorbed.   It is associated with irregular menstruation, although  the effects of excessive oestrogen stimulation are mani-  fest in the endometrium as the proliferation of glands.  Other causes of anovulation are listed in Figure 1 1.4.   Cystic glandular hyperplasia with characteristic  appearance of 'Swiss cheese'. (Previously known as  metropathia haemorrhagica.) Cells show no  cytological atypia   Crowding of glands in a back-to-back fashion.  Epithelium is stratified and mitoses are relatively  frequent. Cells show no cytological atypia   Cellular atypia is prominent, glands are distorted by  intraglandular polypoid formations, and  mitoses are frequent   The irregular ripening of a follicle is associated with in-  fertility. This may be caused by failure of the production  of progesterone by the corpus luteum or by defective re-  ceptors for progesterone within the endometrium. Ex-  amination of the endometrium in the second half of  the menstrual cycle shows inadequate or absent devel-  opment of secretory changes.   Hyperplasia of the endometrium typically occurs  in the third and fourth decades of life, in response  to oestrogenic stimulation. It presents with haemor-  rhage but the severity or frequency is not related    to the degree of pathological change. Certain types  of endometrial hyperplasia are associated with a de-  gree of risk for malignant change (severe/atypical  hyperplasia).   The importance of endometrial hyperplasia is that it is  associated with an increased risk of the development of  endometrial adenocarcinoma, i.e. it is thought to be  preneoplastic.   These localized overgrowths of endometrial glands and  stroma are very common and are typically seen in the  perimenopausal age range. They are caused by inappro-  priate proliferation of glands in response to oestrogenic  stimuli.   Macroscopically, they are found in the uterine  fundus projecting into the endometrial cavity; their  size is variable but they are usually 1-3 cm in diame-  ter. They have a firm, smooth, nodular appearance  within the endometrial cavity but occasionally pro-  lapse through the cervical os. They may ulcerate or un-  dergo torsion.   Microscopically, they are cystically dilated endome-  trial glands in a vascular stroma.   These benign, smooth muscle tumours arise in the mus-  cle wall of the uterus (myometrium). They are the most  common of all pelvic tumours, affecting over half of all  women over the age of 30, usually becoming symptom-  atic in the decade before the menopause. Their cause is  unknown but risk factors include:   • rounded, rubbery, pale nodules with whorled ap-  pearance on cut surface   • well circumscribed with pseudocapsule that may be-  come pedunculated forming polyps   • variable in size. Most common are 2-4 cm but they  range from < 1 cm to 20-30 cm in diameter   - lacking cellular atypia and with very few mitoses  (compared to malignant leiomyosarcomas). Malig-  nant change in leiomyomas is considered extremely  rare.   Clinical features — leiomyomas may present with abnor-  mal menstrual bleeding, dysmenorrhoea and infertility.   • medical — uterine leiomyomas may be shrunk by go-  nadotrophin-releasing hormone (GnRII) agonists,  which induce hypo-oestrogenism. This allows easier  surgical removal by myomectomy.   Remember that fibroids are not fibromas. Fibroids are  benign tumours of smooth muscle (leiomyomas).   Adenocarcinomas of the endometrium are the second  most common gynaecological malignancy. The mean  age of presentation is 56 years and 80% of women are  postmenopausal.   • hyperoestrogenic state — obesity, diabetes, late men-  opause, prolonged use of unopposed oestrogens,  oestrogen-secreting tumours   Hyperoestrogenic tumours (type 1 disease) — these are  associated with a generally good prognosis. They occur  in patients close to the menopause, associated with an  abnormal oestrogenic stimulation of the endometrium  and endometrial hyperplasia. Most tumours are adeno-  carcinomas (60%) and are graded (I-III) according to  the amount of glandular and solid pattern within the tu-  mour. High-grade tumour is associated with a worse  prognosis.   Non-hyperoestrogenic tumours (type 2 disease) — these  are more often associated with a poor prognosis, occur  in older postmenopausal women and are not associ-  ated with oestrogenic stimulation or endometrial  hyperplasia.   • larger tumours — fill and distend the endometrial  cavity with soft, white, friable tissue.  Microscopically, they are seen as:   • non-hyperoestrogenic tumours — typically poorly  differentiated with deep myometrial invasion.   The main route of spread is by local invasion to the  fallopian tubes, ovaries, bladder or rectum.   If venous and lymphatic invasion occurs, there may  be involvement of the vagina and para-aortic nodes.    Widespread haematogenous metastasis is uncommon  except with papillary serous carcinomas and clear cell  carcinomas.   The amount of direct invasion into the myometrium  is closely correlated with prognosis.   The prognosis of uterine carcinoma is related to stage  (Fig. 11.7).   Aetiology — it is almost always caused by ascending in-  fection from the uterine cavity.   Macroscopically, tubes are swollen and congested,  and the serosal surface appears red and granular due  to vascular dilatation.   Microscopically, tubal epithelium shows neutrophil  infiltration and the lumen may contain pus.   Chronic inflammation may supervene, with se-  quelae of fibrosis and occlusion of the tubal lumen  on resolution.    • hydrosalpinx — dilatation of a fallopian tube by clear  watery fluid (product of the proteolysis of pus on  resolution of an infection).   Pelvic inflammatory disease (PID) is a combined infec-  tion of the fallopian tubes, ovaries and peritoneum. It is  typically a result of ascending infection or, less com-  monly, postoperative infection. Predisposing factors  are as for suppurative salpingitis (see above).   Neisseria gonorrhoeae and Chlamydia trachomatis are  the most common responsible organisms, although an-  aerobic organisms are often found in pelvic abscesses.   Inflammation is initially acute and, without prompt  treatment, may progress to chronic PID, which often re-  sults in tubal infertility.   • symptoms — gradual onset of pelvic pain, irregular  bleeding, vaginal discharge, fever   • signs — abdominal tenderness and guarding; ex-  treme tenderness of the adnexa.   Treatment is by the removal of an IUD (if present)  and the use of broad-spectrum antibiotics.   Ovarian cystic lesions are extremely common. They can  be either neoplastic or non-neoplastic. The majority of  non-neoplastic cysts arise from developing Graafian fol-  licles; a minority is derived from surface epithelium.   These unruptured, enlarged Graafian follicles are lined  by granulosa cells, with an outer coat of thecal cells.  Normal ovaries commonly contain one or more small  cysts (< 5 cm in diameter), which typically disappear  by the resorption of fluid. However, multiple follicular  cysts are found in:   Most cysts are clinically insignificant though some  may be a cause of hyperoestrogenism.   This is a complex adrenal-ovarian disorder in which  multiple small follicular cysts develop beneath a thick-  ened, white ovarian capsule as a result of increased an-  drogenic activity. This is thought to be secondary to a  decrease in peripheral insulin sensitivity (promoted  by obesity) causing hyperinsulinaemia.    Clinical features — patients have a persistent anovula-  tory state, high levels of luteinizing hormone (LH) and  oestrogen, low levels of follicle-stimulating hormone  (FSH) and high levels of circulating androgen.  Common presenting symptoms are:   Complications — high oestrogen levels may cause en-  dometrial hyperplasia and increase the risk of the devel-  opment of endometrial carcinoma. Cardiovascular  disease, diabetes mellitus and breast cancer are also in-  creased in this group.   Ovarian cancer is responsible for more deaths than any  other gynaecological malignancy (5000 cases per year in  the UK, with 3700 deaths), largely because it often pre-  sents at an advanced stage. The ovarian tumour marker  CA125 is used routinely to monitor for relapse in pa-  tients who have undergone treatment. CA125, along  with other markers, may be used in future screening  programmes for ovarian cancer.   Primary ovarian cancers account for 6% of all malig-  nancies in women, but only 5-10% have a direct  hereditary component. In these women, mutations  are usually found on either the BRCA1 or BRCA2 tu-  mour suppressor genes (see Chapter 3). Ninety-five  per cent of ovarian cancer cases are sporadic and show  complex genetic abnormalities including a high inci-  dence ofp53 mutation (50% of cases) and amplification  of the erbB-2 (HER-2/neu) oncogene (30% of cases).  There are several different tumour types.   A logical way of classifying ovarian tumours is  according to the normal tissue constituents from which  they are derived:   Epithelial tumours of the ovary comprise about 70% of  all ovarian tumours and about 90% of malignant tu-  mours. They are typically found in adult life.   As with all ovarian tumours, it appears that there is a  decreased risk associated with pregnancy and the oral  contraceptive pill. This is part of the 'incessant    ovulation' hypothesis, whereby continuous monthly re-  pair of the ovarian epithelium has been suggested as one  factor in the development of ovarian cancer.   Types — epithelial tumours are derived from surface  epithelium, which in turn is derived from embryonal  coelomic epithelium. Tumours with this origin can dif-  ferentiate along different pathways into different types  of tumours: tubal differentiation (serous tumours),  endometrial differentiation (endometrial and clear cell  tumours), endocervical differentiation (mucinous tu-  mours) and transitional differentiation (Brenner  tumours).   Microscopically, these tumours are classified into  benign, malignant and borderline (abnormal tissue  architecture with atypical cells but no evidence of  invasion). The majority of borderline tumours behave  in a benign fashion but some appear capable of low-  grade malignancy.   These ovarian cystic tumours of tubal differentiation  contain a watery fluid; the majority (70%) are benign:   • Benign (serous cystadenoma) — thin-walled, uni-  locular cystic tumour lined by cuboidal regular  epithelium.   • Malignant (serous cystadenocarcinoma) — character-  ized by pleomorphic cells and mitoses with invasion  of the ovarian stroma. Over half of cases occur bilater-  ally. A frequent histological finding is concentrically  laminated calcified concretions called psammoma  bodies.   • Borderline serous tumours — presence of cellular  atypia but with no invasion.   These multilocular cystic ovarian tumours of endo-  cervical differentiation contain gelatinous material:   • Malignant (mucinous cystadenocarcinoma) —  invasion of the ovarian stroma. Less than 10% of  mucinous tumours are malignant.   • Borderline mucinous tumours — presence of cellular  atypia but with no invasion.   These ovarian tumours show endometrial differentia-  tion. The vast majority are malignant (endometrioid  carcinomas), accounting for 20% of all ovarian  carcinomas.   The clear cell carcinoma is a variant of endometrioid  carcinoma, characterized by the presence of cells with  clear cytoplasm and containing abundant glycogen.   Tumours are composed of nests of epithelium resem-  bling the transitional cell epithelium of the urinary tract;  they are associated with a spindle-cell stroma. The epi-  thelial component may be benign, borderline or malig-  nant. The majority are unilateral and benign.   Germ cell and sex-cord stromal tumours are illus-  trated in Figure 11.8.   The ovary is a common site of tumour metastasis. This  may be of Mullerian origin (e.g. uterus, fallopian tubes)  or from extra-Mullerian sites (typically the breast and  gastrointestinal tract).   This describes bilaterally enlarged ovaries containing  metastatic signet ring-cell adenocarcinoma (typically  of gastric origin).   This describes any fertilized ovum that is implanted out-  side the uterine cavity. Ectopics occur in about 1 in 300  pregnancies. The fallopian tube (especially in the am-  pulla) is by far the most common site for this; other sites  of abnormal implantation are very rare but include the  peritoneal cavity, the ovary and the cervix.   The aetiology is uncertain but ectopic pregnancies  are possibly the result of some structural abnormality  of the fallopian tube, e.g. scarring or adhesions resulting  from previous episodes of salpingitis or endometriosis,  or previous tubal surgery for contraceptive purposes, i.e.  sterilization. However, half of ectopic pregnancies occur  without such predisposing factors.   Pathogenesis — following implantation, the prolifera-  tion of trophoblasts erodes the submucosal blood ves-  sels, precipitating severe bleeding into the tubal  lumen (haematosalpinx) . The muscular wall of the fal-  lopian tube is unable to undergo hypertrophy or disten-  sion, and so tubal pregnancy almost always results in  the rupture of the fallopian tube and death of the fertil-  ized ovum. This typically occurs in the early stages of  pregnancy and often before the patient is even aware  of being pregnant.   • into the lumen of the fallopian tube — common in  ampullary pregnancy. Conceptus is extruded to-  wards the fimbriated end of the tube. Mild   Composed of a variety of tissues, including cartilage,  smooth muscle, or epithelium    haemorrhage into the peritoneal cavity occurs,  which may collect as a clot in the pouch of Douglas  • into the peritoneal cavity — occurs most commonly  from the isthmus of the tube, either spontaneously  or as a result of pressure (e.g. straining at the stool,  coitus or pelvic examination). Haemorrhage is likely  to be severe. Retroperitoneal (rare) — rupture occurs  into the potential space between the leaves of the  broad ligament. Haemorrhage into the site is more  likely to be controlled.   Many fertilized ova fail to implant successfully. It has  been estimated that around 40% of all conceptions fail  to convert into recognizable pregnancies. Of those that  survive this far, 15% terminate in a clinically recognized  spontaneous abortion.   Aetiology — causes of spontaneous abortion differ  according to the stage of pregnancy, as shown in  Figure 11.9.   • shock may occurif haemorrhage is severe and rapid, e.g.  due to large vessel erosion. This is the most dangerous  and dramatic consequence of tubal pregnancy.   To remember the causes of abortion at different  stages of pregnancy, learn the following rules of  thumb:   Endocrine abnormalities: diabetes, hypothyroidism, deficiency of  progesterone or luteinizing hormone  Trauma: surgical operation, blow to abdomen,  or hypotensive shock   This is high blood pressure (> 140/90 mmHg), peripheral  oedema and proteinuria, developing during pregnancy in  a woman whose blood pressure was previously normal.  An increase in blood pressure alone is termed gestational  hypertension. Hypertensive disorders occur in about 10%  of all pregnant women. The aetiology is unknown.   • medical comorbidities — diabetes, pre-existing hy-  pertension, systemic lupus erythaematosus (SLE)   The pathogenesis is unclear but probably relates to  inadequate placental invasion by spiral arteries, leading  to placental ischaemia. This is thought to release a  chemical factor that triggers vasoconstriction and endo-  thelial damage to promote hypertension.   Endothelial cells of kidney arterioles become swollen  and fibrin deposition occurs in glomeruli leading to  proteinuria (Fig. 11.10).    Pre-eclampsia may be mild or severe according to the  level of blood pressure derangement. Severe proteinuria  leads to peripheral oedema.   Reduced placental blood flow causes an increased risk  of fetal hypoxia in late pregnancy, particularly during  labour, with resultant perinatal mortality. The fetus  may also suffer intrauterine growth retardation and have  a low birth weight.   Maternal problems are less common, being largely  confined to severe pre-eclampsia, which may progress  into full-blown eclampsia (see below).   This is the occurrence of one or more convulsions not  caused by other conditions such as epilepsy or cerebral  haemorrhage in a woman with pre-eclampsia.   Incidence is rare; only a small proportion of patients  with severe pre-eclampsia develop eclampsia.   Clinical features are severe systemic disturbance, i.e.  frontal headaches, visual disturbance, rapid and sus-  tained rise in blood pressure, severe epigastric pain.    shock, anuria and fits. A main cause of death is intra-  cerebral haemorrhage.   There is disseminated intravascular coagulation with  widespread occlusion of blood vessels, fibrinoid necro-  sis of vessel walls and, in fatal cases, widespread micro-  infarcts in the brain, liver, kidneys and other organs.   Eclampsia is associated with a maternal mortality of  2% and a neonatal mortality of 3.5%. However, fatal  eclampsia is now rare because of screening and treat-  ment for the pre-eclamptic syndrome.   This is the abnormal development of a gestational tro-  phoblast leading to the formation of a benign mass of  cystic vesicles derived from chorionic villi. It occurs in  1 in 2000 pregnancies in the UK and USA, but it is seen  more frequently amongst some racial groups such as the  Japanese population.   The disease is the result of an error in embryogenesis.  There are two types:   1 . Partial — a partial mole is triploid with most contain-  ing one maternal and two paternal haploid sets of    chromosomes. Cystic vesicles are found in only a  part of the placenta. Fetal parts and some normal  placental villi are present along with the abnormal  trophoblastic tissue. There is a low risk of subse-  quent development of a malignant tumour of the  trophoblast (choriocarcinoma).   2. Complete — a complete mole is entirely of paternal  origin (no maternal genetic contribution) and usu-  ally forms a bulky mass that may fill the uterine cav-  ity. No fetal parts or normal placental villi are  present. The risk of subsequent choriocarcinoma is  greater than in a partial mole, occurring in about  3% of cases.   • amenorrhoea and other symptoms of pregnancy,  followed by continuous or intermittent vaginal  bleeding. Many molar pregnancies spontaneously  miscarry   Diagnosis is by elevated human chorionic gonado-  trophin (hCG) excretion in urine (typically much  greater than in normal pregnancies) and by ultrasound  for the absence of the fetus. Very high hCG levels may   Treatment is by evacuation of the uterus, with a sec-  ond aspiration or curettage 2-4 weeks later to ensure  complete removal of the mole.   Follow-up is by regular estimations of hCG for at least  a year. Detection of hCG after 1 month may suggest in-  complete removal and the persistence of trophoblastic  disease. Untreated, this carries a risk of subsequent  choriocarcinoma.   This is a hydatidiform mole that invades through the de-  cidua into the myometrium and associated blood ves-  sels. Perforation of the uterus may occur, resulting in  invasion of the parametrium. True malignant transfor-  mation is rare.   These malignant tumours of trophoblastic tissue have a  propensity for invading vessel walls and blood-borne  metastases occur early to many sites, particularly the  lung and brain.   They are rare in the UK and USA (at 1 per 50 000  pregnancies) but more common in Asia, South America  and Africa.   Aetiology — about 50% develop from a hydatidiform  mole and about 20% arise after a normal pregnancy  with a variable time lag (a few months to many years).   The prognosis is excellent as the tumours respond  well to cytotoxic chemotherapy (particularly if post-  treatment monitoring of hCG levels is carried out).   This is a rare tumour in which the bulk of the tissue con-  sists of chorionic epithelium but with very few villi. Typ-  ically benign, it may undergo malignant change.   These are uncommon and are usually complications of  lactation. The most frequent organism is Staphylococcus  aureus, which gains access through cracks and fissures of  the nipple and areola. An abscess may form if drainage  is inadequate.   There is an abnormal progressive dilatation of the large  breast ducts, which accumulate inspissated (thickened)  secretions. The aetiology is unknown and it affects older  women (perimenopausal age range) . Patients develop a  firm breast lump, but this does not mimic a carcinoma.  There may also be a clear or green-coloured discharge.   This is usually caused by trauma. Histology shows ne-  crosis with multinucleated giant cells and later fibrosis.  It may cause a discrete lump mimicking a carcinoma.   This is a generic term for a number of benign lesions  that may occur together, producing lumpiness in the  breast tissue. Peak incidence is around the menopause.  It is thought that fibrocystic change is caused by hor-  monal imbalance.   • cysts — ranging in size from microscopic to palpable  lesions 1-2 cm in diameter. Diagnosis is confirmed  by needle aspiration of clear fluid (blood-stained as-  pirate requires further investigation)   • apocrine metaplasia — epithelial lining of hyperplas-  tic ducts undergoes metaplasia to that of normal  apocrine glands   • fibrosis — replacement of breast tissue by dense fi-  brous tissue, which can be due to cyst rupture   • sclerosing adenosis — marked proliferation of spe-  cialized hormone-responsive stromal tissue and  myoepithelial cells, i.e. the number of acini per lob-  ule increases. This forms localized areas of irregular  stellate, collagenous sclerosis in which epithelial el-  ements are also present. Occasionally difficult to dis-  tinguish from some patterns of invasive carcinoma.   There is no increased risk of a carcinoma unless there  is accompanying epithelial hyperplasia (see below) .   This describes the proliferation of epithelial cells within  ducts or lobules (ductal hyperplasia and lobular hyper-  plasia respectively). There are two types:   1 . Hyperplasia of the usual type — normal cytology and  tissue architecture with no signs of malignancy   The risk of subsequent invasive breast carcinoma is  increased in individuals with florid usual hyperplasia.    further increased in subjects with atypical hyperplasia  and much higher in those specifically with lobular car-  cinoma in situ.   Breast lumps are relatively common presentations. The  following benign pathologies may cause discrete breast  lumps or nipple discharge that mimic carcinomas:   The best form of management is so-called 'triple  assessment.' This consists of:   This is the most common benign tumour of the female  breast. There is proliferation of both stroma and epithe-  lium, usually in young women (most frequently the  25-35 age group). It produces discrete but mobile breast  lumps typically 1 -4 cm in size, often multiple and bilateral.   This is a tumour composed of both stroma and epithe-  lium, but the stroma is more cellular than in fibroadeno-  mas. It is less common than fibroadenoma and occurs in  the older age group (peak incidence being 45 years of  age). Clinically, the tumour presents as a breast lump.   Macroscopically, there are rubbery white lesions con-  sisting of a whorled pattern of slit-like spaces and solid  areas.   Microscopically, there is a variable appearance, clas-  sified into benign (90% of cases), or of borderline ma-  lignant potential or definitely malignant.   There is the potential for local recurrence with increas-  ing aggressiveness, and the tumour may eventually me-  tastasize. Phyllodes tumours are therefore excised with  a wide margin or, if necessary, are treated by mastectomy.    usually solitary with no increased risk of a carcinoma.  However, a rare condition of multiple intraduct papillo-  mas is premalignant.   Incidence — this comprises 30% of all cancers in women  and is the most common cause of death in 35- to 55-  year-old women, increasing with age steeply to 45 years  and continuing to increase less steeply thereafter. There  are around 40 000 cases each year in the UK; 5-year sur-  vival is 80%.   There is a 200-fold female preponderance, with the  highest rates in America, Western Europe and the Anti-  podes, and the lowest rates in Africa and Southeast Asia.   • mutations of BRCA1 (chromosome 17) and BRCA2  genes (chromosome 13) — 5% of cases   • first-degree relative with breast cancer — increased  risk independent of BRCA mutations   • long interval between menarche and menopause, i.e.  early menarche and/or late menopause   • ionizing radiation, as seen in those receiving in-  tensive radiotherapy for Hodgkin's disease (up to  30% risk of breast cancer within 30 years of  treatment)   All breast carcinomas are adenocarcinomas derived  from epithelial cells of the terminal ductal lobules. Car-  cinoma in situ refers to neoplastic cells confined to the  ducts and lobules, with no evidence of invasion through  the basement membrane. Ductal carcinoma in situ  (DCIS) is the more common form, presenting as micro-  calcifications on mammography. Lobular carcinoma in  situ (LCIS) is more common in younger women and is  more likely to affect both breasts. LCIS is not associated  with calcifications on mammography or a mass, and is  therefore often an incidental finding on biopsy.   DCIS may progress to invasive carcinoma, but is  highly treatable at the in situ stage. LCIS may progress  to invasive carcinoma, but is predominantly thought  to be a strong risk marker for carcinoma in either breast.   Invasive carcinomas are tumours that have eroded  through the basement membrane of their tissue of ori-  gin to invade surrounding structures. The most com-  mon presentation is a painless palpable mass,    excluding those detected early by mammographic  screening (see below). Large masses may cause skin  dimpling or interfere with lymphatic drainage to pro-  duce classic skin changes (e.g. peau d'orange). Nipple re-  traction can also occur. Axillary lymph nodes may be  palpable, reflecting metastasis from the primary site.   Investigation is by ultrasound, mammography, core  biopsy or fine-needle aspiration cytology. Invasive  carcinomas are categorized histologically:   Macroscopic features — a discrete lump with tether-  ing to the skin or surrounding connective tissue. The  macroscopic appearance of the tumour depends on  the amount and type of stroma within the carcinoma.  Spread is as follows (Fig. 11.12):   The mainstay of treatment is surgical excision, often  with axillary node clearance. Radiotherapy and chemo-  therapy are often used after surgery to reduce the risk of  relapse.   Prognosis — related to tumour grade and type (tubu-  lar has the best prognosis), size of the tumour, lymph  node status and oestrogen receptor status (usually re-  sponds to tamoxifen if positive). C-erbB-2 (HER-2) is  a proto-oncogene that is found in 15-20% of breast  cancers. It is associated with poorer prognosis but this   There is no direct screening method equivalent to the cy-  tology of the uterine cervix. The primary screening mo-  dality is mammography which is more effective in older  women with less radiodense breast tissue. Abnormali-  ties seen on mammograms include calcification and soft  tissue deformity. In the UK there is a National Health  Service Breast Screening Programme with 3 -yearly  mammography for all women over the age of 50 (until  70 years). Long-term studies suggest that such screening  successfully reduces the mortality from breast carci-  noma; it is possible that the age range screened may  be extended in the future.   Aetiology — hormonal influences including in-  creased oestrogen production or receptor sensitivity.  It is associated with liver cirrhosis, stilboestrol therapy  for prostate carcinoma and drugs such as  chlorpromazine.   Less than 1% of breast carcinomas occur in men. The  condition is associated with Klinefelter's syndrome  and is usually of the ductal type; the lobular type is ex-  tremely rare.   T1 tumour 20 mm or less;  no fixation or nipple retraction   T2 tumour 20-50 mm, or  less than 20 mm with fixation   T3 tumour 50-100 mm, or  less than 50 mm with fixation   Common viral infections of the penis include genital  herpes and genital warts (condyloma acuminatum) .   This is an acute infection of the penile mucosa by the  herpes simplex virus with the formation of typical her-  petic vesicles on the glans penis. The vesicles soon burst  to produce shallow painful ulcers.   The virus may remain latent for many years. Recur-  rent herpes infections are caused by reactivation of  the virus, which may be precipitated by a febrile illness,  immune suppression, emotional stress or UV light.   These cauliflower-like warts are seen on the penis and  around the perineum. They are caused by the human  papillomavirus subtypes ITPV6 and HPV11, which are  sexually transmitted.   Inflammation of the glans (balanitis) and prepuce  (posthitis) can be caused by a variety of bacterial organ-  isms, the most common of which are staphylococci, co-  nforms, gonococci and Chlamydia.   The appearance is that of marked congestion and oe-  dema with exudate on the surface of the glans. Ulcera-  tion with chronic scarring may occur if untreated; this  is a common cause of phimosis.   Infection with Candida albicans is common in men with  diabetes mellitus.   Penile carcinoma in situ is seen in two forms: Bowen  disease (opaque plaques with shallow ulceration) af-  fecting the shaft and scrotum, and erythroplasia of  Queyrat, which is restricted to the glans, presenting with  flat, red, glistening plaques. There is a spectrum of  changes from dysplasia to carcinoma in situ grouped to-  gether as penile intraepithelial neoplasia. Many cases  are associated with HPV infection (most commonly se-  rotype 16).   Penile carcinoma in situ is a precancerous condition  and may lead to invasive cancer unless treated vigor-  ously with local irradiation or 5-fluorouracil cream.   This is a well-differentiated, keratinising, invasive tu-  mour usually seen in elderly men. It occurs most com-  monly in uncircumcised men and is thought to be  associated with a previous infection with human  papillomavirus.   It presents as a warty, cauliflower-like growth that  bleeds easily. It is typically slow growing but it is often  neglected because of patient embarrassment.   This is a condition caused by maldescent of the testes,  affecting about 5% at birth, and 1 % by the first birthday.   Fig. 11.14 Maldescended testes showing common sites of  arrest. (Adapted with permission from Lecture Notes on  Urology, 5th edn, by J Blandy, Blackwell Science, 1998.)   In the embryo, the testes develop from the genital  ridge high on the posterior wall.   At about 7 months' gestation, the testes migrate  down the posterior abdominal wall. They are guided  by a cord (the gubernaculum) through the inguinal ring  into the scrotum.   Occasionally, migration fails to occur and one (75%  of cases) or both (25% of cases) testes become arrested  somewhere along the route (Fig. 11.14). There are three  conditions:   2. Inguinal testicle — in the inguinal canal, particularly  exposed to trauma   3. Retractile testicles (most common) — either high or  low, depending on ability to be manoeuvered into  correct position. Usually settles at puberty and does  not need an operation.   • infertility — temperature of aberrant locations is  higher than in the scrotum and prevents normal  germ cell development. The testis remains small  and incapable of producing effective spermatozoa   • malignancy — more common in an undescended tes-  tis; about 1 in 10 of all testicular tumours arise in as-  sociation with cryptorchidism   • inguinal hernia — there is nearly always a patent tu-  nica vaginalis that predisposes to the development  of an inguinal hernia   Management is by detection and correction of testic-  ular maldescent. This is important because of the in-  creased risk of testicular carcinoma. Some restoration  of function may be achieved by 'orchidopexy' at an early  stage (the testis is surgically pulled down and fixed to  the scrotum).   The tunica vaginalis and tunica albuginea (membrane  sheaths surrounding the testes) are invested with meso-  thelial cells and may be the site of fluid accumulation,  inflammation or (uncommonly) tumour formation.   Fluid accumulates in the cavity bounded by the tunica  vaginalis. This is the most common cause of swelling  within the scrotum.   • congenital patency of the processus vaginalis, often  with continuity into the peritoneal cavity   Blood accumulates in the cavity bounded by the tunica  vaginalis, usually due to trauma or torsion and rarely  due to tumour spread.   Indirect inguinal hernias (described in Chapter 8) typi-  cally occur as a result of patent processus vaginalis.   There is twisting of a testicle on its pedicle with obstruc-  tion of venous return such that blood continues to enter  the testis but cannot leave. The testis is engorged and  painful, eventually becoming infarcted (venous infarc-  tion). In advanced torsion, the testis is almost black  as a result of vascular congestion.   Early detection and surgical relief are required to save  testicular viability. Surgical removal is necessary for ad-  vanced disease.   This describes variceal dilatation of the veins of the  pampiniform plexus of the spermatic cord.   Tumours of the testis, although relatively uncommon, are  important because many occur in young men; they are  the most common tumour among 15- to 35-year-olds.    The exact aetiology is unknown but there are links  with testicular maldescent and/or dysgenesis, possibly  with some genetic susceptibility.   • endocrine effects — gynaecomastia, precocious pu-  berty (typically from Leydig or Sertoli cell tumours).   1. Germ cell tumours (97% of cases) — derived from  multipotential germ cells of the testis arising mainly  as teratomas and seminomas   2. Non-germ cell tumours (3% of cases) — derived  from specialized and non-specialized support cells  of the testis.   The most common malignant testicular tumour, account-  ing for about 50% of all malignant germ cell tumours,  with a peak age of onset between 30 and 40 years. The tu-  mour shows spermatogenic differentiation.   • classic seminoma (most common subtype) —  characteristic feature is the presence of fibrous septa  with lymphocytic infiltrate   This tumour of germ cell origin is composed of several  types of tissue representing endoderm, ectoderm and  mesoderm. The tumours retain their totipotentiality    for differentiation and are more aggressive than semino-  mas. The peak age of onset is 20-30 years.   Teratomas are classified according to their histologi-  cal pattern; two systems exist (Fig. 11.15), with the  British classifications described below:   • Differentiated teratoma — a rare type of teratoma of  mature and well-differentiated tissue, producing a  wide range of organoid structures (e.g. skin, hair, car-  tilage and bone). Lesions are usually seen in young  children. They behave in a benign fashion.   • Malignant teratoma intermediate — partly solid and  partly cystic tumour, with less maturity and areas  of malignancy with cellular pleomorphism and  necrosis.   • Malignant teratoma undifferentiated — completely  undifferentiated tumour with marked nuclear pleo-  morphism and a high mitotic rate.   • Malignant teratoma trophoblastic — identical to cho-  riocarcinoma in the placenta (see page 215), this  highly malignant tumour contains areas of syncy-  tiotrophoblast and cytotrophoblast cells. hCG and  a-fetoprotein (AFP) are useful markers.   • Yolk sac tumour (orchioblastoma) — the pure form  is seen in children up to 3 years old and has a good  prognosis. The adult (mixed) form is more aggres-  sive. AFP is a useful marker.   Between 10 and 15% of germ cell tumours consist of a  mixture of seminomatous and teratomatous elements.   The prognosis of testicular teratomas has improved  greatly with the use of cytotoxic chemotherapy, and it  is related to histological type, as well as to tumour stage.  Seminomas are more likely to respond to radiotherapy.  In general, germ-cell tumours containing trophoblastic,  yolk sac and undifferentiated elements have the worst  prognosis.    Fig. 11.15 Comparison of the British and WHO classifications of teratomas   This rare tumour arises from the interstitial or Leydig  cells of the testis. It may produce androgens, oestro-  gens or both, causing precocious development of sec-  ondary sexual characteristics in childhood or loss of  libido/gynaecomastia in adults. Ninety per cent are  benign.   This well-circumscribed tumour is composed of cells re-  sembling normal Sertoli cells of the tubules. Most le-  sions are benign.   The non-Hodgkin's-type lymphoma is usually a  poorly differentiated B cell lymphoma with a diffuse  pattern. These comprise about 5% of testicular tu-  mours with a peak incidence between 60 and 80 years  of age.   The spread of other tumours to the testis may occasion-  ally occur, particularly in acute leukaemia.   Differentiated teratoma  Malignant teratoma intermediate  Malignant teratoma undifferentiated  Malignant teratoma trophoblastic  Yolk sac tumour   Many testicular tumours have useful cell markers:  •Trophoblastic germ cell tumours — | hCG   N on-neoplastic enlargement of the prostate is the most  common disorder of the prostate, affecting almost all  men over the age of 70. However, it is found with in-  creasing frequency and severity from about 45 years.   The aetiopathogenesis is uncertain but believed to be  a result of androgen-oestrogen imbalance. Central  (periurethral) prostatic glands are hormone sensitive  and they undergo hyperplasia. Their continuing en-  largement compresses peripheral prostatic glands lead-  ing to their collapse, leaving only fibrous supporting  stroma (Fig. 11.17).   • posterior lobe (uncommon), causing an obstruction  of the urinary outflow tract at the internal urinary  meatus at the bladder neck.   Bladder fails to empty completely after micturition,  and residual urine is liable to infection   • Nodular pattern of hyperplastic glandular acini  lined with tall columnar epithelial cells and sepa-  rated by fibrous stroma   • Some nodules are cystically dilated and contain a  milky fluid   Infarction causes necrotic areas with a haemorrhagic  margin. There is often muscular hypertrophy particu-  larly in the region of the bladder neck.   Clinical presentation — compression of the prostatic  urethra by the enlarged prostate causes difficulties with  micturition, mainly hesitation, poor stream and termi-  nal dribbling.    median groove  is obliterated by  carcinoma in posterior  subcapsular zone  (invasion of capsule)   This is an adenocarcinoma of the prostate and it is  shown in Figure 11.19. It is the second most common  cause of cancer death in males and its detected incidence  is increasing (30 000 per year in the UK) . It is rare before  55 years of age with a peak incidence between 60 and  85 years; 5-year survival is 65%.   Its aetiology is uncertain but there is probably hor-  monal involvement (reduced androgens).   Unlike benign hyperplasia, carcinoma usually arises  in the peripheral zone of the prostate and it is, therefore,  often well established before the development of   urinary symptoms. Indeed, some tumours may remain  silent even in the presence of widespread metastases.   Types are divided into three groups on the basis of  their behaviour:   1. Latent — small foci of well-differentiated carcinoma,  frequently an incidental finding in prostatic glands  of elderly men. Remain confined to the prostate  for a long period   3. Occult — not clinically apparent in primary site  (small tumour) but present as widespread symp-  tomatic metastatic disease.    Macroscopically, there are diffuse areas of firm, white  tissue merging into fibromuscular prostatic stromal tis-  sues. Distortion and extension outside the prostatic cap-  sule is common, producing a firm, craggy mass that can  be palpated on rectal examination.   Microscopically, the majority has a well-differentiated  glandular pattern (good prognosis); a minority has  poorly differentiated sheets of cells with no acinar pattern  (poor prognosis).   • direct — to the base of the bladder and adjacent tis-  sues. May cause obstruction of the urethra (difficulty  in micturition) and may block the ureters, causing  hydronephrosis   • haematogenous — most commonly to bone, but also  to the lungs and liver. Bone metastases are typically  sclerotic with bone production (dense on radio-  graph) rather than lytic with bone destruction.   • Imaging — ultrasound, X-ray, isotope bone scan (for  bony metastases).   • Needle biopsy — histological examination together  with immunohistochemical detection of prostate-  specific antigen (PSA) and prostate-specific acid  phosphatase (PSAP) in biopsy material.    • Serology — PSA and PSAP may also be used as serum  markers for disease, levels being particularly raised  when there is metastatic disease. However, raised  PSA alone is relatively non-specific for prostate car-  cinoma, meaning that screening programs are likely  to have a high false-positive rate.   Treatment — if tumour is confined to prostate,  radical prostatectomy or radiotherapy may be  curative. If spread has occurred, androgen  suppressing drugs (e.g. luteinizing hormone releasing  hormone analogues) suppress testosterone and  improve survival from this slow-growing tumour.  Orchidectomy is occasionally performed for the  same effect.   • Describe common disorders of bone structure, particularly osteoporosis and Paget's disease.   • Recall the infectious causes of bone disease and their manifestations.   • Describe fractures and bone healing, including the complications that may occur.   • Describe in detail osteoarthritis, rheumatoid arthritis and the wider effects of rheumatoid disease.   This hereditary disorder of endochondral ossification is  the most common cause of true dwarfism, occurring in  approximately 1 per 50 000 births.   Aetiology — autosomal dominant with a high inci-  dence of spontaneous mutation accounting for the  80% of cases in which an achondroplastic child is bom  to unaffected parents (increased incidence with paternal  age) . The affected gene is for fibroblast growth factor re-  ceptor (chromosome 4).   Pathogenesis — the mutation suppresses cartilage pro-  liferation in the growth plate, resulting in diminished  lengthening of cartilage bones (e.g. long bones, base  of the skull and pelvis). Periosteal bone formation is  normal. Cartilage bones are, therefore, shortened but  thick and strong. Membranous bone (such as the vault  of the skull) is not affected.   This heterogeneous group of rare congenital disorders is  characterized by abnormal collagen formation with un-  usually brittle and fragile bones.   Achondroplasia results in non-proportional dwarfism,  i.e. the trunk appears too long compared to the length  of the arms and legs. The head is also enlarged, with a  depression at the root of the nose. Other common  types of dwarfism (e.g. pituitary hormone deficiency or  malnutrition) are typically proportional, with all bones  being affected equally.    Aetiology — mutation of genes coding for type I colla-  gen results in abnormal collagen formation in the oste-  oid. The pattern of inheritance can be either dominant  or recessive, and it involves mutation at sites on chro-  mosomes 7 and 17.   Appearance — there is a marked variation in severity  but widespread weakness of bone results in multiple  fractures frequently leading to severe deformity. Lax  joint ligaments, blue sclera and hearing loss are also of-  ten seen, once more reflecting decreased collagen  synthesis.   This slowly progressive disorder is characterized by re-  duced bone mass as a result of a relative increase in bone  erosion. The bone structure remains qualitatively nor-  mal, but there is less of it.    Incidence — the most common metabolic bone dis-  ease. Peak bone mass is achieved in early adulthood,  with bone density decreasing with age from the third  or fourth decade of life. A high peak bone mass protects  against future osteoporosis.   Osteoporosis is widespread in the elderly, where it  is an important cause of morbidity and even mortal-  ity, as weakened bone predisposes to minimal trauma  fractures. Bone loss in women is accelerated by oestro-  gen deficiency, making postmenopausal women a  high-risk group for osteoporosis. Hormone replace-  ment therapy is partly protective (see Chapter 11).  The risk factors for osteoporosis are illustrated in  Figure 12.1.   Macroscopically — bones are lighter in weight, less  dense on radiography (Fig. 12.2) and show thin-  ning of the cortex. Lumbar vertebral bodies are  more biconcave than normal, such that the interver-  tebral disc space appears more spherical ('fish  vertebrae') .   Microscopically — bone trabeculae are thinner and re-  duced in number, and there is a decrease in the number  of osteoblasts. Mineralization is not affected.  Complications are:   • bone pain — especially in the back because of com-  pression of vertebral bodies. This may reduce overall  height and cause an anteroposterior bending of the  spine (kyphosis)   Metabolic: low calcium intake, impaired supply of protein  (e.g. nephritic syndrome or cirrhosis of liver), scurvy  Assorted endocrine disorders: thyrotoxicosis,  panhypopituitarism and Cushing's syndrome  Steroid therapy  Cigarette smoking  Alcohol abuse  Reduced physical activities  Aluminium antacids   The mnemonic 'MASCARA' can be used to help remember the causes of secondary generalized osteoporosis.    • pathological fractures — following minimal trauma,  especially of the femur (hip fracture), neck and at  the wrist.   Osteoporosis may also develop in a localized area of  bone secondary to disuse, surrounding inflammation or  in conditions such as myeloma (see Chapter 13).   Diagnosis is by bone densitometry scanning at the  hip and spine to show the degree of bone loss. Osteope-  nia describes reduced bone density that has not yet  reached osteoporotic levels.    Management — emphasis is on prevention rather  than treatment, namely avoidance of risk factors, with  encouragement of physical exercise and adequate cal-  cium intake. Bisphosphonates are highly effective drugs  for reducing the rate of decline in osteoporosis.   Osteomalacia is a disease of defective bone mineraliza-  tion that is most commonly seen in the developing  world. It is usually due to a lack of vitamin D or distur-  bances in its metabolism (e.g. conversion to active vita-  min D via the liver and kidney).   Bone is incompletely calcified, with the development  of wide 'seams' of osteoid. The bone is weak and prone  to fracture.   Rickets — the same disorder — occurs in the growing  bones of children, leading to characteristic skeletal  changes, e.g. bowing of long bones.   Both disorders are potentially reversible with early  dietary supplementation to correct deficiencies or treat-  ment of underlying disorders of vitamin D metabolism.   This rare inherited disorder is characterized by increased  density of all cartilaginous bones, especially the verte-  brae, pelvic bones and ribs.   Appearance — there is no discernible differentiation  of cartilaginous bones into cortex and medulla: the cor-  tical compact bone extends into the medulla, which is  thus devoid of cancellous bone.   Effect — bones are excessively dense, yet extremely brittle  and prone to fracture. There is a lack of bone marrow func-  tion predisposing to infection and increased risk of cranial  nerve compression within the base of the skull.   This chronic disease of excessive uncontrolled resorption  and deposition of bone particularly affects the skull,  backbone, pelvis and long bones. It is rare before  40 years of age, but increases in incidence with age there-  after. It is relatively common in the UK, affecting 3% of  those over 40, but rare in Asia, Africa and the Middle East.   Aetiology — unknown, but recent evidence suggests a  paramyxovirus infection of the osteoclasts. Electron mi-  croscope studies have demonstrated probable viral in-  clusions in the nuclei of osteoclasts.    Pathogenesis — large, abnormal, multinucleated oste-  oclasts cause excessive bone erosion with destruction of  trabecular and cortical bone. Each wave of bone destruc-  tion is followed by a vigorous but uncoordinated oste-  oblastic response, producing new osteoid to fill the  defects left by the osteoclasts. However, both osteoclas-  tic erosion and osteoblastic deposition are random,  haphazard and unrelated to functional stresses on the  bone, resulting in greatly distorted bone architecture.   Morphology — bone shows a characteristic woven,  non-lamellar pattern indicative of rapid reparative de-  position. Well-marked 'cement lines' are often visible,  producing the characteristic 'mosaic' or 'crazy-paving'  appearance. The bone becomes increasingly sclerotic  and brittle, thereby prone to fracture.   Disruption of bone architecture is followed by pro-  gressive increased vascularity in the spaces between  the thickened bone trabeculae.   The effects of Paget's disease can be widespread (affect-  ing many bones) or localized (15% of cases confined to  one area in a single-bone — monostotic — Paget's disease).   Most patients present with one or both of the follow-  ing features:   Complications — some patients occasionally present  with the complications of Paget's disease:   • Nerve compression symptoms — usually seen in asso-  ciation with Paget's disease of the skull, in which en-  largement of the pagetic bone can lead to cranial  nerve palsies (e.g. CN VIII compression results in deaf-  ness) . Spinal stenosis may compress spinal nerve roots   • Pathological fracture — bone is increased in bulk but  is weaker than normal and more likely to fracture  with trivial trauma   • Malignant tumour (1% of cases) — usually osteosar-  coma, which may develop in areas of long-standing ac-  tive Paget's disease. This is the most common cause of  osteosarcoma in the elderly and has a poor prognosis.    • X-ray — localized bone enlargement, altered  trabecular pattern and alternating areas of rarefaction  and increased density.   Management is by analgesia for bone pain, and  calcitonin or bisphosphonates for severe bone pain not  controlled by analgesics. The latter inhibit bone resorption.   This infection of bone typically affects the cortex, me-  dulla and periosteum, and it is most commonly en-  countered in children under the age of 12 years. Adult  onset is usually due to compromised host resistance  (e.g. severe debilitation, immunosuppression). The  most common causative organisms are Staphylococcus  aureus (over 80% of identified cases), Mycobacterium  tuberculosis, Escherichia coli (particularly in infants and  the elderly) and Salmonella species (particularly in  patients with sickle-cell disease).   Infective organisms gain access to the medullary cav-  ity of the bone by two main routes:   1. Direct access through an open wound, particularly  when open fractures are involved. This route is also  important in postoperative orthopaedic patients (par-  ticularly those with prosthetic joint replacements).   2. Blood-borne spread: following bacteraemia from a  focus of sepsis elsewhere.   Clinical features — abrupt onset of severe pain at the site  of bone infection accompanied by fever and malaise.  Complications and sequelae:   • Pathological fracture — purulent acute inflammatory  exudate formed in closed compartment of marrow  cavity causes compression of vessels with necrosis  of medullary bone trabeculae, resulting in increased  predisposition to fractures   • Adjacent sepsis — destruction of cortical bone may  lead to discharge of pus into extraosseous connective  tissue, and infection may track through to the skin sur-  face producing a chronic discharging sinus. Spread  may also occur to other bones (malignant osteomye-  litis) or neighbouring joints (septic arthritis - see later)   • Chronicity — in chronic osteomyelitis, the organisms  may remain viable within the marrow cavity for  many years. Chronicity results in extensive bone de-  struction, marrow fibrosis and recurrent focal sup-  puration (Brodie's abscess). There is also reactive  new bone formation, particularly around inflamed  periosteum, leading to a thickened and abnormally    shaped bone. Given that osteomyelitis is most com-  mon in children, growth disturbance may occur if  the physis is damaged.   Diagnosis is by blood culture and isotope scan.  Management is by analgesia, antibiotic therapy and  potential surgical drainage of abscesses.   A fracture is a break in the structural continuity of bone.  Note that any break, even of only one cortex, constitutes  a fracture. Fractures are the most common abnormality  of bone and they are caused by physical trauma.   There are several ways of classifying fractures, e.g.  according to causation, according to pattern of  fracture, or according to their relation to surrounding  tissues. The latter is the simplest method.   Fractures can be classified into two main types accord-  ing to their relation to surrounding tissues:   1. Simple (closed) — without contact with external en-  vironment, i.e. skin or mucous membrane overlying  bone is intact. Simple fractures are less likely to be-  come infected.   2. Compound (open) — with direct contact between  the fracture and external environment, e.g. a fracture  of the tibia with laceration of overlying skin. Com-  pound factures are more likely to become infected.  Other descriptive terms for fractures are:   • greenstick — usually seen in children, this is where  only one side of a bone is fractured, leaving it bent  but intact.   Bone fractures heal by granulation tissue formation  with fibrous repair, followed by new bone formation  in the fibrous granulation tissue (see Chapter 2 for  wound healing of the skin).   The sequence of events in healing of a simple undis-  placed fracture is illustrated in Figure 12.3.   Fig. 12.3 Healing of a simple fracture. (A) Haematoma formation, due to tearing of medullary blood vessels. (B) Organization:  migration of neutrophils and macrophages into fracture with organization of haematoma within about 24 hours. Capillaries  and fibroblasts proliferate forming fibrovascular granulation tissue. New osteoprogenitor cells (derived from mesenchymal  precursor cells) mature into osteoblasts, and they migrate into granulation tissue. (C) Callus formation: osteoblasts deposit large  quantities of osteoid collagen in a haphazard way producing a woven bone pattern. Fracture is bridged on outside by external  callus (may contain cartilage) and it is bridged in medullary cavity by internal callus (rarely contains cartilage). However,  direct ossification may occur between fractured ends if they are closely apposed. (D) Remodelling: about 3 weeks post fracture,  callus is well established and undergoes remodelling. Osteoclastic resorption and osteoblastic osteoid synthesis removes surplus  calcified callus, replacing bulky, woven bone with compact, organized, lamellar bone. Process takes several months.   (E) Completion: formation of new lamellar trabecular bone is complete. Bone is orientated in a direction determined by stresses  to which it is exposed with mobilization. However, even after remodelling, cortical irregularities and minor marrow space  fibrosis persist at site of fracture.   Bones show great capacity for healing, but certain com-  plications can occur:   • Delayed union — this is common, and it is said to have  occurred when a fracture has not united in a reasonable  time (defined as 25% longer than the average time).   • Non-union — if union has not occurred within 1 year  then the terminology is changed from one of 'delayed  union' to one of 'non-union'. The defect is typically  filled with fibrous tissue/fibrous ankylosis.   Efficient healing of fractures requires optimal condi-  tions. Factors that prevent efficient healing are:   Most common tumours in bone are blood-borne metas-  tases from other primary sites or are tumours of the hae-  mopoietic cells located within the marrow spaces of  bones, particularly myeloma.   There are five common carcinomas that have a predilec-  tion for metastasizing to bone:   Metastases are typically multifocal, occurring most  commonly in parts of the skeleton that contain vascular  marrow, especially vertebral bodies, ribs, the pelvis, and  upper ends of the femur and humerus.   Most metastatic tumour cells within bone marrow  spaces lead to erosion of bone (osteolytic metastases),  through the release of substances that promote    osteo-clastic resorption (e.g. prostaglandins, parathyroid-  hormone-related peptide; PRIIRP). However, prostatic  carcinoma (and very rarely breast carcinoma) produces  metastatic deposits in which there is osteoblastic stimula-  tion of new bone formation (osteosclerotic metastases)  particularly in the lumbosacral vertebrae.   • leucoerythroblastic anaemia — a result of extensive  replacement of bone marrow   • symptoms of hypercalcaemia — caused by the release  of calcium from bone by osteolytic process   Haematopoietic malignancies found in bone (e.g. mye-  lomas, lymphomas, leukaemias) are discussed in  Chapter 13.   Secondary tumours of bone are more common in  adults than children, whereas primary tumours of bone  are generally more common in children than adults.   These are rare primary bone tumours, derived from cells  involved in bone formation and modelling.   Benign, smooth, rounded bone tumour is seen on the  surface of long bones or skull bone. Apart from visible  or palpable swelling, there are usually no symptoms.  Such tumours are slow-growing and do not undergo  malignant transformation. Patients with Gardner's  syndrome have multiple osteomas and intestinal  polyps.   Rarely causing severe bone pain, this typically arises be-  tween the ages of 10 and 30 years. It is more common in  males. Most frequently it affects long bones of the lower  leg but it may occur in any bone except the skull.    Tumours are composed of active osteoblasts, which  deposit large, irregular masses of osteoid collagen in a  haphazard manner.   Osteoid osteomas are painful; pain is usually relieved  by aspirin but not by rest. Radiographs characteristically  show a central dense area surrounded by a halo of trans-  lucency. Excision is usually curative and lesions do not  recur.   This large tumour with identical histological features to  osteoid osteoma mainly affects the bones of the hands,  feet and vertebrae. Tumours are typically more locally  aggressive, generating a dull achy pain that is unrespon-  sive to aspirin.   This malignant tumour of osteoblasts occurs most often  in adolescent children, with a second peak in the fifth  decade of life linked to highly active Paget's disease.  Some cases are associated with familial cancer syn-  dromes of retinoblastoma syndrome (defect in RBI )  and the Li-Fraumeni syndrome (defect in p53). The ma-  jority arise around the knee (lower femur or upper tibia)  and a minority in other long bones such as the upper  end of humerus or femur.   Symptoms are bone pain increasing gradually with  tumour growth, but the tumour is often well-advanced  at the time of diagnosis. A progressively enlarging bony  lump may be palpable.   Spread — the tumour grows rapidly within the medul-  lary cavity, eventually eroding through the cortical plate  into soft tissue. Metastasis occurs early via the blood-  stream, usually to the lung.   Prognosis has improved with the adoption of earlier  surgical treatment combined with chemotherapy. How-  ever, 5-year survival is still only 50%.   This is the most common tumour of bone. It is benign,  growing as an exophytic nodule from metaphyses  of long bones. It is also known as a 'cartilage-capped  exostosis' as it is composed of protuberant bone covered  with a cap of cartilage and an outer layer of perichon-  drium.   Lesions are found most commonly in the humerus,  femur and the upper end of the tibia. They may be sol-  itary or multiple (typically autosomal dominant condi-  tion, hereditary multiple exostoses). Solitary lesions  usually first develop in adolescence. Chondrosarcoma-  tous change is rare in solitary lesions but more common  in hereditary multiple exostoses.   This is a benign tumour of hyaline cartilage, composed  of well-circumscribed nodules of cytologically benign  chondrocytes embedded in a cartilaginous matrix.   Tumours are thought to originate from residual nests  of cartilage cells left behind in metaphysis as bone  growth proceeds. They are found most commonly in  small bones of hands and feet.   They may be single (solitary enchondroma) or mul-  tiple (enchondromatosis or Ollier's disease). The term  'enchondroma' is used to indicate that the tumour arises  and grows within the medullary cavity of bone (com-  pared to osteochondroma, which grows as a nodular  exophytic lesion). A solitary chondroma rarely un-  dergoes malignant change, but occasionally it occurs  in multiple enchondromatosis.   This slow-growing malignant tumour often reaches a  large size, eventually breaking through the periosteum  into surrounding soft tissue, but usually maintaining  a clearly defined border.   Macroscopically, there is a glistening white appear-  ance, similar to that of normal cartilage.  Microscopically:   • The majority are low-grade, well-differentiated tu-  mours that metastasize very late, and are histologi-  cally similar to benign cartilaginous tumours.  Radical local surgery may be curative.   • The minority are high-grade, poorly differentiated  tumours with marked pleomorphism, high mitotic  activity and grow rapidly with early blood-borne  metastases.   A highly malignant bone tumour probably derived  from primitive neuroendocrine cells, this affects chil-  dren between the ages of 5 and 15 years. It has a char-  acteristic chromosomal translocation — t(ll;22) (q24;  ql2) — that results in the fusion of the FLT-1 gene from  chromosome 11 with the EWS gene on chromosome  22. The sarcoma usually arises in the diaphyses of long  bones, particularly the femur.   Areas of osteolytic bone destruction surrounded by  layers of new periosteal bone give the tumour a charac-  teristic 'onion skin' appearance on X-ray. Pain, swelling  and tenderness may be associated with fever and leuco-  cytosis (thus tumours are sometimes mistaken for  osteomyelitis). Effective chemotherapy, radiotherapy  and surgical excision (often amputation) has increased  5-year survival to 75%.   Carcinoma of bronchus (especially small cell)  Adenocarcinomas of the breast,  kidney and thyroid  Prostate   Metastases occur most commonly to vertebral  bodies, ribs, pelvis and upper ends of femur  and humerus   Osteolytic lesions arise in the epiphyses of long bones,  typically in young and middle-aged adults. It only oc-  curs in bones where the epiphyses have fused.   The tumour is composed of a mass of large multi-  nucleated giant cells resembling large osteoclasts em-  bedded in a supporting spindle-celled stroma. There is  a gradual expansion of lesions into the metaphysis  and the erosion of cortical bone; penetration of the peri-  osteum or articular cartilage may occur.   Osteoclastoma is generally classed as benign, although  a significant number become locally invasive and tend to  recur after removal. About 10% of cases are truly malig-  nant and metastasize to the lung via the bloodstream.   Several diseases of muscle have been shown to result  from disorders affecting transmission at the neuromus-  cular junction (NMJ).   • Fatigability — primarily affecting proximal limb mus-  cles, extraocular muscles (causing ptosis or diplopia)   Disorders can be classified into two types, pre- and  postsynaptic abnormalities, depending on which of  the synaptic membranes is affected.   This rare form of food poisoning is caused by ingestion  of a toxin produced by the bacterium Clostridium botuli-  num, found in imperfectly treated tinned food or pre-  served fish contaminated with the microbe.   Pathogenesis — the toxin binds irreversibly to those  presynaptic nerve terminals of axons whose impulse  transmission is acetylcholine (ACh) mediated. These in-  clude the NMJ, autonomic ganglia and parasympathetic  nerve terminals. Binding of the toxin prevents fusion of  ACh vesicles with the neuronal membrane, thereby pre-  venting ACh release.   Clinical symptoms are chiefly vomiting and paresis  of skeletal, ocular, pharyngeal and respiratory muscles.  Antitoxin is available, but it has no effect once the toxin  is bound. Recovery of transmission is achieved by termi-  nal axonal sprouting and the formation of new synaptic  contacts. Mortality can be high.   This autoimmune disorder is characterized by abnor-  mal fatigability and is often found in patients with  lung cancer (when it is considered a paraneoplastic  syndrome). Autoantibodies are thought to bind to pre-  synaptic voltage-dependent calcium channels at motor  nerve terminals to cause functional loss. This in turn  causes the reduced release of ACh in response to nerve  stimulation. Small cell lung carcinoma cells express  calcium channels, suggesting that cross-reactive auto-  antibody production is triggered by these tumour  antigens.   This autoimmune disease is characterized by a progres-  sive failure to sustain a maintained or repeated contrac-  tion of sniated muscle. Prevalence is about 1 in 30 000.  The disease usually appears between the ages of 15 and  50 years, and females are more often affected than  males.   Aetiology — autoantibodies against the post-synaptic  acetylcholine receptor are produced by B lymphocytes  that are defectively controlled by T lymphocytes as a  result of a disorder of the thymus gland. As a result  of this interaction, receptors are degraded via a com-  plement reaction, or blocked to activation by acetyl-  choline. This severely hampers neurotransmission.  About 15% of cases have a thymoma (see  Chapter 13) and 65% of patients have thymic gland  hyperplasia.   There is a strong link to other autoimmune diseases,  including thyrotoxicosis (Graves' disease), diabetes  mellitus, rheumatoid arthritis (RA), and systemic lupus  erythaematosus (SLE). There is linkage with various  human leucocyte antigens (HLA), such as Al, B7  and DRw3.   • Early symptoms — intermittent ptosis or diplopia,  weakness of chewing, swallowing, speaking or of  moving the limbs. Movement is initially strong,  but it rapidly weakens by the end of the day or after  exercise   • Later symptoms — respiratory muscles may be in-  volved and respiratory failure is not an uncommon  cause of death. Asphyxia occurs readily as the cough  may be too weak to clear foreign bodies from the air-  ways. Muscle atrophy may occur in long-standing  cases.   The disease runs a remitting/ relapsing course, and re-  lapses may be precipitated by emotional disturbances,  infections, pregnancy or severe muscular effort.    The prognosis is variable. If the disorder is confined  to eye muscles, then the prognosis for life is normal  and disability slight. A prognosis of myasthenia associ-  ated with thymoma is markedly worse.   • Tensilon test — short-acting, anticholinesterase  drug trial increases acetylcholine (ACh)  concentrations in the synaptic cleft and transiently  relieves symptoms   • Medical — anticholinesterase drugs (prevent ACh  breakdown); immunological treatment: plasma  exchange (removes autoantibody), intravenous  immunoglobulin, immunosuppressant treatment   Myopathy is any condition that primarily affects muscle  physiology, structure or biochemistry.   Muscular dystrophy is the term used to describe inher-  ited degenerative muscle diseases.   X-linked muscular dystrophy is characterized by the  progressive degeneration of single muscle cells over a  prolonged period of time. It results in muscle fibre de-  struction with the development of fibrosis.   The pattern of inheritance is X-linked recessive (p2 1 re-  gion); hence the disorder is almost exclusively seen in  males. This is the most common form of muscular dys-  trophy in childhood, affecting 1 in 3500 male births.   The disorder is due to a mutation of the gene coding  for dystrophin, a protein that normally anchors the  actin cytoskeleton of muscle fibres to the basement  membrane via a membrane glycoprotein complex  (Fig. 12.5). Dystrophin helps to transmit the forces of   Fig. 12.5 Anchorage role of dystrophin. Dystrophin molecule  is a long, rod-shaped protein, one end binding to membrane  glycoprotein, the other to actin, with middle rod region.    contraction, meaning that muscle fibres in Duchenne  patients are liable to tearing with repeated contraction.   Different degrees of severity of Duchenne dystrophy  result from different mutations within the dystrophin  gene:   • Severe Duchenne dystrophy — complete failure to  produce dystrophin as a result of mutations causing  gene frameshifts   • Moderate to severe forms of Duchenne dystrophy —  dystrophin is produced but anchorage is inefficient  because of mutations in binding sites for either mem-  brane glycoprotein complex or actin cytoskeleton   • Mild form of Duchenne dystrophy (Becker's dystro-  phy) — mutation in the middle rod region produces  an abnormally weighted dystrophin protein which  is still capable of anchoring muscle to basement  membrane. Becker's dystrophy has a later onset than  Duchenne.   Clinical features — childhood onset of muscle weak-  ness is associated with a high serum creatine phosphoki-  nase level (caused by muscle necrosis) and calf  hypertrophy due to fatty replacement of muscle (pseudo-  hypertrophy; Fig. 12.4). Cardiac muscle is also affected  leading to cardiomyopathy (see Chapter 6).   The prognosis depends on the degree of severity. For  severe Duchenne it is very poor; most affected individ-  uals are wheelchair dependent in their early teens and  dead by their early twenties.   Myotonic disorders are diseases in which there is a con-  tinuing contraction of muscle after voluntary contrac-  tion has ceased.   This autosomal dominant disorder is characterized by  muscle weakness, myotonia (inability to relax muscles)  and several non-muscle features including cataracts,  frontal baldness in males, gonadal atrophy, cardiomy-  opathy and (in some cases) dementia.   This is the most common inherited muscle disease of  adults, affecting 1 in 8000.   The genetic abnormality is an unstable CTG repeat  sequence in a cAMP-dependent protein kinase located  on chromosome 19. The disease shows anticipation,  meaning that it appears at a younger age in each suc-  ceeding generation. The mechanism by which this mu-  tation causes myotonia is unknown.   Microscopically, affected muscles show abnormali-  ties of fibre size with fibre necrosis, abundant internal  nuclei and replacement by fibrofatty tissue.   The disorder usually becomes apparent in adoles-  cence or early adulthood with facial weakness and dis-  turbed gait.   Prognosis — death is commonly due to involvement  of respiratory muscles in middle-age.   There is primary inflammation of muscle with resulting  fibre necrosis. The inflammatory infiltrate is mainly  composed of T lymphocytes and monocytes as part of  an abnormal autoimmune response. There are three    main types of inflammatory myopathies, any of which  may occur as part of an immune-mediated systemic dis-  ease such as systemic sclerosis.   This inflammatory muscle disorder is characterized by  weakness, pain and swelling of proximal limb muscles  and facial muscles, often with ptosis and dysphagia.  It is the most common inflammatory muscle disorder,  though still relatively rare. It occurs most frequently  in adults, with females affected more than males  by 3:1.   Aetiology — cytotoxic T cells and other lymphoid cells  are found within the endomysium suggesting autoim-  mune injury of myocytes, but the mechanism of sensi-  tization is unknown.   • Malignancy — particularly in association with non-  Hodgkin's lymphoma, lung and bladder cancer.  Microscopically, there is a lymphocytic infiltration of   Clinical features — an insidious onset in the third to  fifth decade of life, with symmetrical proximal muscle  weakness initially affecting the lower limbs. Progression  is typically slow but it may eventually involve pharyn-  geal, laryngeal and respiratory muscles leading to dys-  phagia, dysphonia and respiratory failures.   Investigations — blood: increased muscle enzymes  (e.g. creatine kinase); tests for rheumatoid factor and  antinuclear factor are often positive. Electromyography:  useful for demonstrating myopathy without neuropa-  thy. Muscle biopsy: muscle necrosis and regeneration  in association with inflammatory cell infiltrate. Mag-  netic resonance imaging: non-invasive detection of ac-  tive myositis.   Treatment — it may respond to immunosuppressive  treatment such as corticosteroids and azathioprine.   This has the muscle components of polymyositis ac-  companied by periorbital oedema and a characteristic  purple 'heliotrope' rash on the upper eyelids. Often,  there is also an erythaematous, scaling rash on the face,  shoulders, upper arms and chest with red patches over  the knuckles, elbows and knees. Arthralgia, weight loss  and fever sometimes occur.   Dermatomyositis has an even stronger association  with malignancy than polymyositis, especially affecting  the ovary, pancreas, colon, lung and stomach.   This slowly progressive inflammatory muscle disorder is  similar to polymyositis, but typically affects distal mus-  cles in an asymmetric pattern. It also occurs mainly in  the elderly. By light microscopy, histological features  also appear similar to polymyositis, but with electron  microscopy vacuoles containing filamentous inclusion  bodies can be seen within fibres.   There is a weakness and wasting of muscle associated  with endocrine disease. The main causes are:   • corticosteroid-induced myopathy — either therapeu-  tic or in Cushing's disease. Corticosteroids are associ-  ated with type 2 muscle fibre atrophy   Osteoarthritis (OA) is a degenerative disease of articular  cartilage. It is associated with secondary changes in un-  derlying bone resulting in pain and impaired function  of the affected joint. Although the name suggests that  primary OA is an inflammatory process, its main effects  on the erosion of cartilage are independent of acute or  chronic inflammation, even though inflammatory cells  may be present in the affected joint.   It is extremely common — 80% of the elderly popula-  tion show radiographic evidence of OA, although only  around 25% of these are symptomatic.   Females are affected more than males, except at the  hip where both genders are equally prone to OA. It is  increasingly common above 60 years of age, but it  may also occur in younger age groups following any  form of mechanical derangement.   OA affects joints that are constantly exposed to wear  and tear, typically large weight-bearing joints (e.g. those  of the hip and knee), but also small joints in the hands,  particularly the base of the thumb. The aetiology is as  follows:   • Secondary — arising as a complication of other joint  disorders, mainly inflammatory joint disease, con-  genital joint deformities, trauma to joints, avascular  necrosis of bone.    Secondary OA is also an important component of oc-  cupational joint disease, e.g. OA of the fingers in typists  and of the knee in professional footballers.   Pathological changes involve cartilage, bone, synovium  and joint capsule with secondary effects on muscle  (Fig. 12.7).   • Erosion and destruction of articular cartilage —  degenerate superficial cartilage splits along lines of  fibres to produce fronds (fibrillation). Narrowing  of the joint space can be seen on radiography   (A) Normal joint. (B) Early stages of OA. (C) Later stages of OA.   • Sclerosis of subarticular bone — caused by constant  friction of naked bone surfaces which now articulate  in the absence of cartilage (bone eburnation).   • Osteophytes form around the periphery of the joint  by irregular outgrowth of bone. Some may break off  to form loose bodies within the joint. In distal inter-  phalangeal joints of the fingers, osteophytes appear  as small nodules (Heberden's nodes); in proximal  interphalangeal joints, they are called Bouchard's  nodes.   • Small cysts may develop in areas where the bone is  not thickened as a result of synovial fluid accumula-  tion in underlying bone.   • Reactive thickening of synovium and joint capsule  due to inflammation caused by bone and cartilage  debris.   • Disuse atrophy of muscle due to immobility of the  diseased joint.   OA can be classified according to the main present-  ing features as follows:   • Primary generalized OA — usually associated with  development of Heberden's nodes on fingers. It is  most common in postmenopausal women   • Erosive inflammatory OA — form of OA in which  there is severe inflammation and erosion of carti-  lage, with rapid progression   • Hypertrophic OA — florid osteophyte formation and  bone sclerosis, but with slow progression and a  relatively good prognosis.   The main symptoms of OA are pain and limitation in  the movement of the affected joint, which often leads  to functional impairment (e.g. difficulty walking in  hip OA). Sometimes OA is associated with visible swell-  ing around the joint margins (usually as an effect of  osteophytes) .   In OA of the cervical vertebrae (cervical spondylosis),  osteophytes compressing emerging spinal nerves are  responsible for much of the symptomatology.   OA diagnosis is largely clinical, although there are four  classic X-ray signs (of which one or more may be seen):   • Medical — analgesics and NSAIDs for pain relief; intra-  articular or periarticular corticosteroid injections if  severe pain (especially knee OA)   Rheumatoid arthritis (RA) is a chronic inflammatory  joint disease caused by a multisystem connective tissue  autoimmune disorder, rheumatoid disease (see below).  It affects about 1% of the UK population, females more  than males by about 3:1. Onset is typically between 35  and 45 years of age, but it follows a normal distribution  curve and no age group is exempt.   RA mainly affects peripheral synovial joints such as  the fingers and wrists, but it can also affect the knees  and more proximal joints. The most common presenta-  tions are symmetrical.   The aetiology is autoimmune and there is an associ-  ation with HLA-DR4 haplotype in most ethnic groups.  The condition is characterized by autoimmune-  mediated activation of CD4+ T cells within affected  joints. The antigen for this reaction is unknown, but  once it has been triggered, the release of proinflamma-  tory cytokines drives the destruction of the joint.   Many RA patients have a circulating autoantibody di-  rected against the Fc portion of native immunoglobulins  (rheumatoid factor). The presence of rheumatoid factor  (seropositive arthritis) helps to distinguish RA from sev-  eral other inflammatory joint diseases (seronegative ar-  thritis), but not all RA patients are rheumatoid factor  positive. The exact role and underlying stimulus of rheu-  matoid factor is uncertain. However, immunological  techniques have demonstrated it in plasma cells located  in the synovium of affected joints. There is increasing ev-  idence to suggest that RA is a disease of both cellular and  humoral immune mechanisms.   The synovium becomes swollen and shows a villous pat-  tern. Chronic inflammatory cells (mainly lymphocytes  and plasma cells) increase in number within the synovial   Fig. 12.8 Pathological changes in rheumatoid arthritis (RA).  (A) Rheumatoid synovitis. (B) Articular cartilage destruction.  (C) Focal destruction of bone.   stroma, often forming an exudate that effuses into the  joint space. Fibrin is deposited on the surface of the syno-  vium, which undergoes hypertrophy. Soft tissue swelling  from synovial inflammation may be marked.   Inflammatory granulation tissue grows across the sur-  face of the cartilage (pannus) from the edges of the  joint. The articular surface shows the loss of cartilage be-  neath the extending pannus, most marked at joint  margins.   Osteolytic destruction of bone occurs at the edges of the  joint. Bone 'erosions' can be seen on radiography and  are associated with joint deformity. There is also in-  creased soft tissue swelling due to inflammation and  thickening of the synovium and capsule.   The insidious onset of arthritis first attacks finger joints  (mainly metacarpophalangeal and proximal inter-  phalangeal joints) followed by metatarsophalangeal  joints and joints of the ankles, wrists, knees, shoulders,  elbows and hips (in decreasing order of frequency). RA  can also affect synovial joints of the spine (particularly  cervical). Affected joints become swollen, painful and  warm, often with redness of overlying skin. Stiffness  tends to be worse in the mornings or following inactivity.   In the hands, rheumatoid arthritis tends to affect  metacarpophalangeal (MCP) and proximal  interphalangeal (PIP) joints whereas OA tends to affect  PIP and distal interphalangeal (DIP) joints.   As the disease progresses, muscle atrophy and joint de-  struction result in limitation of joint motion, joint insta-  bility, subluxation and deformities. Subluxation is the  partial dislocation of a joint such that the bone ends still  make contact, but are misaligned. There are also flexion  contractures of small joints of the hands and feet, knees,  hips and elbows.   • Anterior subluxation of the metacarpophalangeal  (MCP) joints with ulnar deviation of the fingers   • 'Swan neck' deformity — hyperextension of proximal  interphalangeal (PIP) joint with fixed flexion at dis-  tal interphalangeal (DIP) joints   • Boutonniere (buttonhole) deformity — fixed flexion  of proximal interphalangeal joint and extension of  the terminal interphalangeal joint   • Z deformity of the thumbs — fixed flexion at meta-  carpophalangeal joint and hyperextension at inter-  phalangeal joint.   In the wrists there is often a fixed flexion deformity  with a prominent, tender ulnar styloid process and pain  on pronation/supination.   In the knees, Baker's cyst (cystic swelling in the pop-  liteal fossa) is seen.   In the cervical spine, there is atlantoaxial subluxation.  Deformities are initially correctable but permanent  contractures eventually develop such that joints become  completely disorganized.   Joint changes are often associated with development of  subcutaneous rheumatoid nodules, usually located over  the extensor aspect of the forearm but occasionally    found overlying other bony prominences. Nodules  are composed of extensive areas of fibrinoid material  surrounded by a giant cell granulomatous reaction.  They occur elsewhere in the body as part of the rheuma-  toid disease (see below).   • Secondary OA as a result of loss of articular surface,  particularly in weight-bearing joints such as the knee   • Septic arthritis — infection of the joint secondary to  invasion from an ulcerated nodule or infected skin  lesion   • Amyloidosis — found in 25-30% of RA patients at  autopsy   • Radiography — periarticular osteopenia, loss of artic-  ular cartilage (joint space), erosions, subluxation  and ankylosis   • Serology — rheumatoid factors (IgG- or IgM-type im-  munoglobulins that react with the Fc portion of  IgG). This is present in 60-80% of those with RA  and in 10% of people without RA   • Measuring acute phase response — usually present in  widespread RA as measured by, e.g. erythrocyte sed-  imentation rate (ESR), C-reactive protein (CRP).   Diagnosis of RA can be made with four or more of the  following criteria (which have been taken from the  American Rheumatism Association, 1988 revision):   • Morning stiffness (> 1 hour), of at least 6 weeks'  duration   • Arthritis of three or more joint areas, of at least  6 weeks' duration   • Arthritis of hand joints, of at least 6 weeks' duration   • disease-modifying anti-rheumatic drugs  (DMARDs) — improve symptoms and reduce  radiological progression, e.g. sulfasalazine,  methotrexate. Newer anti-TNFa monoclonal  antibody agents are used in refractory disease    RA is associated with increased mortality, reducing  lifespan by an average of 8-15 years. Worse prognosis  is associated with being female, being positive for  rheumatoid factor and having MTP joint or systemic  involvement.   Pulmonary involvement causes interstitial pneumoni-  tis and fibrosing alveolitis, which eventually leads to a  pattern of interstitial pulmonary fibrosis. Also, patients  may develop lesions similar to the subcutaneous rheu-  matoid nodule, both within the lungs and on the  pleural surfaces. These rheumatoid granulomas are  particularly common in patients who already have  industrial lung disease caused by inhaling various  types of silica; the association of coal-worker's lung  with rheumatoid granulomas in seropositive miners  is called Caplan's syndrome. Pleural effusions, bron-  chitis and bronchiectasis are all more common in  rheumatoid patients.   Dry eye syndrome (keratoconjunctivitis sicca) is caused  by lymphocytic inflammation of both lacrimal and mu-  cous glands (secondary Sjogren's syndrome, present in  15% of all RA patients). Lack of tears leads to secondary  inflammation of the cornea. In addition, sight-  threatening scleritis may occur because of degeneration  of collagenous tissue in the eye.   Anaemia of chronic disease is common in rheumatoid  patients and a minority develops hypersplenism or  lymphadenopathy. The risk of lymphoma is also in-  creased in longstanding rheumatoid disease. Felty's syn-  drome describes splenomegaly, lymphadenopathy,  anaemia and leucopenia with RA. Sepsis is an important  and common cause of death in these patients.   Hypertrophied synovium and joint deformities increase  the likelihood of peripheral compression neuropathies.  Bilateral carpal tunnel syndrome is a relatively common    early manifestation of RA. Spinal nerve compression  also occurs; severe and potentially fatal cord compres-  sion may follow atlantoaxial subluxation.   About one-third of RA patients develop asymptomatic  pericarditis, which occasionally becomes complicated  by a pericardial effusion. Rheumatoid nodules may  cause heart block, cardiomyopathy and ischaemia (by  coronary artery compression).   A summary of the effects of rheumatoid disease is  provided in Figure 12.9.   This accounts for approximately 15% of cases of juve-  nile chronic arthritis. By definition, it begins before  1 6 years of age. Clinical features are similar to those  of adults but smaller joints tend to be spared, rheuma-  toid nodules are usually absent and rheumatoid factor is  often negative. Systemic manifestations are more com-  mon and prognosis is considered worse than for adults.   This is an example of a seronegative arthritis (rheumatoid  factor negative). It is an inflammatory arthritic disorder  characterized by a rigid spine due to ossification of the spi-  nal joints and ligaments. The condition begins in the lum-  bar vertebral spine and sacroiliac joints, extending  upwards to involve thoracic and cervical vertebrae over  a period of months or years. There may also be involve-  ment of peripheral joints, mainly the hips and knees.   It affects 0.5% of the population in the UK, typically  presenting in late adolescence and young adults (age 15-  30 years of age), and in males more than females by 3:1.   The aetiology is unknown but more than 90% of  individuals with ankylosing spondylitis have the HLA-  B27 antigen (less than 10% of the normal population  have this antigen), which suggests an autoimmune dis-  order. HLA-B27 positivity is a common feature of the  seronegative arthritides.   Morphological changes — chronic inflammation of  vertebral ligaments slowly heals by dense fibrosis and  ossification ('bony ankylosis') to form a rigid shell that  links the periphery of the vertebral bodies. Eventually  the vertebral column becomes fused, inflexible and rigid  ('bamboo spine').   There is typically an insidious onset of recurring epi-  sodes of low back pain and stiffness, sometimes radiating  to the buttocks or thighs. Symptoms are characteristically  worse in early morning and after inactivity.   Systemic manifestations include aortic valve incom-  petence (as a result of rheumatoid aortitis), anterior  uveitis and amyloidosis.   On investigation, ESR and CRP are usually raised but  may be normal, serology is negative for rheumatoid fac-  tor and X-rays may show sacroiliitis and bridging syn-  desmophytes between vertebrae.   • lifestyle — regular physiotherapy and exercise (e.g.  non-weight-bearing sports like swimming) to  maintain as full mobility as possible and prevent  deformity   Seventy-five per cent of individuals with ankylosing  spondylitis maintain a good quality of life with minimal  disability.   A comparison of joint diseases is provided in infec-  tion (Fig. 12.10).   This inflammatory syndrome is characterized by  the triad of arthritis, urethritis and conjunctivitis.  It complicates 0.8% of urethral infection in males and  0.2% of cases of dysentery. It occurs in males more than  females by 15:1 and the usual age of onset is 20-  40 years of age. More than 80% of patients are HLA-  B27 positive.   • Genital type — usually follows non-specific (non-  gonococcal) urethritis or, less commonly, cystitis  or prostatitis   • Intestinal or postdysenteric type — in some parts of  the world it may follow dysentery or occasionally  non-specific diarrhoea, occurring 10-30 days after  intestinal manifestations.   The underlying pathological mechanism is unknown  but is probably autoimmune, triggered by the prior  infection.   • arthritis, usually affecting knee or ankle, and de-  veloping within weeks of the infectious episode.  Clinically and histologically, arthritis resembles  rheumatoid arthritis with chronic inflammatory  synovitis   Prognosis — the first attack typically resolves spontane-  ouslywithin6 months. However, 50% of patients relapse  and some have continued relapsing chronic arthritis,  causing disability but seldom deformity. In a minority  of cases, there is development of severe spondylitis and  features very similar to ankylosing spondylitis.   About 5% of psoriasis patients develop arthropathy,  which characteristically involves the distal interphalan-  geal joints (see Chapter 14).   Ulnar deviation of MCP joints  Swan neck deformity  Boutonniere deformity  Z deformity of thumbs  Prominent ulnar styloid process   Like Reiter's syndrome, this is a reactive arthritis, occur-  ring after infection with Salmonella, Yersinia or Campylo-  bacter species. HLA-B27 antigen is again present in 80%  of affected patients.   Enteropathic arthritis is seen at some stage in up to  20% of patients with ulcerative colitis and Crohn's  disease. Typically it involves knee joints, but occasion-  ally also ankles, elbows and small digital joints. Sacroi-  liitis and ankylosing spondylitis are also much  more frequent in patients with inflammatory bowel  disease.   This joint disease occurs secondary to the loss of pain  and position sense within the joint, which is swollen  and deformed but not painful. Possible causes of loss    of joint sensation include diabetic neuropathy, tabes  dorsalis, syringomyelia, leprosy and cauda equina  lesions (e.g. myelomeningocele).   Arthritis occurs in 10% of patients with sarcoidosis,  with onset typically in the first year of the disease. It  may be of two types:   1. Early acute transient type — polyarticular symmetri-  cal arthritis typically affecting knees and ankles,  and usually associated with erythema nodosum. Ar-  thritis is typically self-limiting   These diseases are characterized by deposition of crys-  tals in joints and soft tissues. Affected patients usually  present with an episode of acute arthritis, inflammation  being caused by the deposition of the crystals, some-  times called a 'chemical arthritis'. With time, inflamma-  tory changes lead to the development of chronic  arthritis with features of OA (secondary OA).   The term 'gout' is used as a clinical description of joints  affected by crystal deposition. This term is then refined  by demonstrating the type of crystal involved. There are  two main types of crystal arthropathies: urate gout ('true  gout' or simply 'gout') and calcium pyrophosphate gout  ('pseudogout' ). A comparison of the two types is shown  in Figure 12.11.   This acute inflammatory crystal arthropathy is caused  by the deposition of urate crystal in joints and soft tis-  sues as a result of hyperuricaemia. Prevalence is about  1% of the UK population and it is largely confined to  men (90%), although some women develop the condi-  tion postmenopausally. It can present at anytime above  the age of 20.   Aetiology — uric acid is normally derived from the  breakdown of purines and is excreted in the urine.  Increased concentrations of serum uric acid (hyperuri-  caemia) can result in gout.   1. Underexcretion of uric acid (most common) — of  uncertain origin but clinically associated with hyper-  lipidaemia, renal failure, lactic acidosis (alcohol, ex-  ercise, starvation, vomiting) and thiazide diuretics   2. Overproduction of uric acid (least common) — a  result of either high cell turnover (e.g. leukaemia,  chemotherapy, severe psoriasis) or rare congenital  enzyme defects of purine metabolism.   However, it should be noted that the majority of pa-  tients who have a raised blood uric acid level will never  develop gout or any of its complications. The condition  has a familial tendency, and it is believed to be poly-  genically inherited.   Gout affects the joints, soft tissues and kidney, as dis-  cussed below.   Joints — supersaturation of urate in synovial fluid  results in the precipitation of urate crystals in certain    joints, forming white powdery deposits on the surface  of articular cartilage, beneath which degenerative  changes can be seen. Crystal release into the synovial  fluid stimulates an acute inflammatory reaction lead-  ing to the excruciating pain, oedema and the redness  seen in acutely inflamed joints. Microscopically, neu-  trophil polymorphs can be seen to phagocytose urate  crystal in the joint fluid. Repeated acute attacks even-  tually produce chronic arthritis and large urate crystal  aggregations (tophi).   Soft tissues — uric acid crystals are also deposited in  the soft tissues around joints, where their presence ex-  cites a foreign body, giant cell reaction. These soft tissue  masses may also enlarge to produce tophi, especially  around the pinna of the ear.   Kidney — in 10% of patients, urate crystals deposited  in the kidney may lead to an interstitial nephritis and  to renal calculi composed of uric acid. Crystals may  also cause urinary obstruction, increasing  the likelihood of complications such as pyelonephritis.   • intermittent attacks of excruciating pain, oedema  and redness (acute gouty arthritis)   • metatarsophalangeal joint of the big toe is most  commonly affected (podagra, 75% of cases), but  gout occasionally affects the ankle and, less com-  monly, the knee and hip.   Recurrent attacks affecting the same joint eventually  lead to articular cartilage destruction, chronic synovial  thickening and secondary OA-chronic gouty arthritis.  Diagnosis:   • Presence of crystals of sodium urate in aspirated  synovial fluid from joint (detected with polarizing  light).    Management — analgesia for acute attacks: NSAIDs  (e.g. indometacin) and colchicine. Preventative mea-  sures in recurrent disease:   • Diet — excessive purine intake and overindulgence in  alcohol should be avoided.   Prognosis — some patients have only a single attack or  suffer another only after an interval of many years. More  often there is a tendency towards recurrent attacks that  increase in frequency and duration so that, eventually,  attacks merge and the patient remains in a prolonged  state of subacute gout.   This acute inflammatory crystal arthropathy is caused  by deposition of calcium pyrophosphate crystals in ar-  ticular cartilage of joints (chondrocalcinosis). It is most  common in the elderly and affects males more than  females.   • Sporadic — in the vast majority of cases, the cause of  pyrophosphate deposition is unknown but it is  probably an age-related phenomenon   • Metabolic — in patients under the age of 60 years, the  disease is often associated with hyperparathyroid-  ism, haemochromatosis or other less common met-  abolic or endocrine disorders   • Familial — in a minority of patients, the disease is  inherited as an autosomal dominant disorder.   Chondrocalcinosis is often asymptomatic. However, if  crystals are shed into the joint space, patients develop  an acute arthritis similar to that seen in urate gout. This  shedding of crystals may be precipitated by trauma or  intercurrent illness, or it may be spontaneous.   With time, damage to cartilage leads to the develop-  ment of secondary OA.   Clinical features — as with gout, the affected joint be-  comes suddenly painful, warm, swollen and tender.  However, the most commonly affected joint is the knee  (> 50% of cases), followed by the wrist, shoulder and  ankle. The duration of the attack can vary from days  to weeks and recurrent attacks are uncommon.   Diagnosis is by X-ray - cartilaginous calcification is  usually obvious on X-ray - and by the presence of cal-  cium pyrophosphate dihydrate crystals in aspirated sy-  novial fluid from the joint (detected with polarizing  light).   Intra-articular aspiration and corticosteroids are  the most effective treatment for acute pseudogout    (anti-inflammatory drugs and colchicine also work  but are often avoided in the elderly).   This inflammation of a joint is caused by infection — typ-  ically bacterial. This may affect any age group but children  and young adults are the most commonly affected. It is a  medical emergency, with a mortality rate of 1 0%. In older  adults, most cases are associated with penetrating injury.  Males are affected more often than females by 2:1. The  knee and hip are the most common sites.   Aetiology — a wide range of bacteria may be responsi-  ble, but Staphylococcus aureus, streptococci and Haemo-  philus species are the most important. Patients who  have developed septic arthritis always have bacteraemia.   Risk factors are diabetes, RA, joint puncture, surgery  and immunosuppressive treatment.   • local trauma — well-recognized complication of pen-  etrating injury such as open fractures, insertion of  surgical prosthesis and non-sterile, intra-articular  injection of steroids for established autoimmune  arthritis   • haematogenous spread — most common route, usually  from the skin or upper respiratory tract. Intravenous  drug users are particularly likely to develop septic arthri-  tis associated with Gram-negative bacteraemia.   Clinical features — there is an abrupt onset of severe  pain, tenderness, swelling and erythema. The majority  of cases affect a single joint only but some cases of gon-  ococcal arthritis and arthritis in intravenous drug  abusers may affect more joints.   Complications — untreated, it proceeds rapidly to  joint destruction often with osteomyelitis, sinus forma-  tion, ankylosis and dislocation of the hip.   Septic arthritis is one of a group of conditions that may  cause gait abnormalities in children (the limping child').  Trauma and septic arthritis occur throughout  childhood, but other disorders are relatively age-  specific:   • 1-5 years — developmental dysplasia of the hip  (DDH): unstable hip joints more common in girls   • 5-10 years — Perthes' disease: avascular necrosis of  the femoral head   • 10-15 years — slipped upper femoral epiphysis  (SUFE): displaced femoral head, most commonly in  pubertal boys.    Diagnosis — radiographs are normal at first but useful  to exclude fractures or other bony injury. Later in the  course of the disease, features of periarticular osteopo-  rosis, joint space narrowing, periostitis and articular  erosions may become apparent. Examination and cul-  ture of aspirated joint space fluid is essential for identi-  fication of the causative organism.   The prognosis for recovery without joint damage is  directly related to the speed with which antibiotic  therapy is instituted.   • Recall the causes of increased and decreased numbers of white blood cells.   • Discuss neoplasms of white blood cells, focusing on lymphomas, leukaemias and myelomas.   • Logically describe the causes for the common clinical presentation of anaemia.   • Discuss common disorders of haemostasis affecting blood vessel walls, platelets and clotting factors.    Autoimmune diseases that cause damage in many tis-  sues and organs, involving a number of systems, are  termed 'multisystem' or 'systemic' autoimmune diseases  (Fig. 13.1).   This inflammatory disorder of connective tissues is asso-  ciated with autoantibodies to a variety of autoantigens.  Many tissues are affected but synovial joints, skin,  kidneys and the brain are the major target organs  (Fig. 13.2).   Systemic lupus erythematosus (SLE) affects 30 per  100 000 of the UK population, and it presents most  commonly in the young and middle-aged with a peak  incidence between 20 and 30 years of age. Females are  more affected than males by about 8:1.   The aetiology is unknown but there is a strong famil-  ial tendency. Drugs (hydralazine, phenytoin, procaina-  mide), chemicals and unidentified viral infections have  all been postulated as the sensitizing stimulus to auto-  antibody production.   Pathogenesis — SLE appears to be a disorder of im-  mune system self-tolerance, as patients develop autoan-  tibodies to a wide array of self-antigens. Antibodies are  produced against components of both nucleic acids and  cytoplasmic phospholipids:    • Antibodies to other nuclear components — anti-Ro,  anti-La and anti-Sm   • Antiphospholipid (cardiolipin) — causes thrombotic  tendency, recurrent abortions and false-positive test  for syphilis   None of these antibodies is specific for SLE and most  have been detected in other connective tissue disorders  or in diseases with an immunological basis.   Microscopically, fibrinoid necrosis is typically seen  in vessels of affected organs, especially small arteries, ar-  terioles and capillaries. In chronic SLE, fibrous thicken-  ing of vessels may lead to luminal narrowing.   The disease commonly presents with malaise, weight  loss, fever, marked musculoskeletal symptoms and a  rash. However, the range of features that may occur is  vast as demonstrated in the list below.   • Discoid skin rash — round ('discoid'), red, scaly,  telangiectatic plaques, usually on the face and scalp  and less commonly on the hands.   • Neurological disorder — most common feature is  non-organic psychiatric disorder, thought to be  due to vasculitides in the brain. Vessel occlusion  due to the prothrombotic action of antiphospholi-  pid antibody on platelets can cause infarction and  neuronal loss; this may present with symptoms such  as seizure or psychosis.   Weakness, pain and swelling of  proximal limb muscles and  facial muscles  Ptosis and dysphagia  Dermatomyositis (= additional  features of erythematous,  scaling rash)   Malar skin rash — symmetrical erythematous rash on  the cheeks and the bridge of the nose (butterfly rash).  Skin photosensitivity — malar or discoid rash on sun-  exposed areas. Caused by immune complex deposits  on the dermal side of the basement membrane.  Oral ulceration — red erosions closely resembling  oral lichen planus.    Renal abnormality (lupus nephritis) — variable pat-  tern from asymptomatic proteinuria to severe glomer-  ular disease leading to renal failure (see Chapter 9).  Evidence of immunological disorder — presence of  autoantibodies, particularly of the antinuclear type.  Haematological disorders — normocytic hypochro-  mic anaemia, autoimmune haemolytic anaemia,   leucopenia (usually due to lymphopenia), throm-  bocytopenia (sometimes associated with anti-  platelet antibodies), predisposition to thrombosis  (especially if antiphospholipid antibody positive).   • Arthritis, bone disease and/or myalgia — often mis-  diagnosed as rheumatoid arthritis, SLE arthritis is  non-erosive and involves two or more peripheral  joints. Myalgia in the form of skeletal muscle pain  is common and it is thought to be caused by a lym-  phocytic vasculitis.   Diagnosis is based on a combination of clinical features  and the result of laboratory investigation, primarily the  identification of autoantibodies, especially those di-  rected against nuclear DNA. The condition is frequently  underdiagnosed.   Treatment is by systemic corticosteroid therapy for  acute and life-threatening manifestations of SLE. Immu-  nosuppressive drugs are often used to aid maintenance  with less exposure to severe steroid side effects. Lifelong  warfarin is needed in antiphospholipid syndrome to re-  duce the risk of thrombosis.   The disorder follows a protracted course of relapses  and remissions. Renal, CNS and cardiac lesions are  the most important prognostically. With treatment, in  excess of 90% of patients can be anticipated to survive  for 10 years.   Rheumatoid disease is a common and important auto-  immune presentation with widespread effects on the  musculoskeletal, cardiovascular, respiratory, haemato-  logical, ocular and neurological systems. It is covered  in detail in Chapter 12.   Autoimmune diseases involving a single organ or cell-  type are known as organ-specific or cell-type specific au-  toimmune diseases. Figure 13.3 is an overview of these  conditions, providing page references to the detailed  discussions of each condition elsewhere.   Although organ -specific autoimmune diseases  specifically affect one organ, they frequently occur  together, e.g. Addison's disease is often associated  with autoimmune gastritis.   This causes hypothyroidism as a result of antibody-  mediated destruction of the thyroid gland.   Thyrotoxicosis is due to overstimulation of thyroid-  stimulating hormone (TSH) receptors by autoanti-  bodies. This condition is discussed in more detail in  Chapter 10.   Type 1 (insulin-dependent) diabetes mellitus is charac-  terized by hyperglycaemia, which is responsive to insu-  lin. The disorder is caused by antibody-mediated  destruction of the insulin-secreting (1-cell population  of the pancreas.   As well as being an organ-specific disease (of the pan-  creas), the resultant hyperglycaemia has effects on many  other systems. Consequently, diabetes mellitus is also  classified as a multisystem disease.   This rare condition of chronic adrenal insufficiency is  most commonly caused by the autoimmune-mediated  destruction of the adrenal cortex. It is often associated  with other autoimmune endocrine disease, e.g. of the  thyroid.   Chronic inflammation of the gastric mucosa is caused  by the autoimmune destruction of gastric parietal cells,  with or without intrinsic factor autoantibodies (cause  pernicious anaemia).   The autoimmune destruction of acetylcholine receptors  occurs at the neuromuscular junction.   Immunodeficiency can be defined as the occurrence of,  or increased susceptibility to, severe and prolonged in-  fection caused by a specific defect in the immune sys-  tem. Primary immunodeficiencies are a rare group of  diseases, which usually result from genetic defects in  one or more of the effector components of the immune  system. Symptoms commonly develop in infancy, after  the initial protection of maternal antibodies has ended  (Fig. 13.4). More than 95 inherited immunodeficiency  disorders have now been identified. Secondary immuno-  deficiencies are acquired disorders that result from  extrinsic or environmental causes. There are many ori-  gins of secondary immunodeficiencies.   Fig. 13.4 Serum immunoglobulin levels in the neonate.  (Adapted with permission from Lecture Notes in Paediatrics 8 th  Ed., by S Newell, Blackwell Publishing, London, 2008).   The type of infection associated with diseases of  immune deficiency depends on the category of  immune disorder:   • B cell deficiencies (defective antibody response) —  increased susceptibility to opportunistic infections  caused by extracellular organisms   • T cell deficiencies (defective cell-mediated  immunity) — increased susceptibility to opportunistic  infections caused by intracellular organisms   • Mixed B and T cell deficiencies (defective antibody  response and cell-mediated immunity) — increased  susceptibility to most infections.   This natural transient trough in antibody levels usually  occurs between 3 and 6 months of age. It is caused by  falling levels of maternally derived IgG prior to the ap-  pearance of the infant's own antibody (IgM followed by  IgG and IgA; see Fig. 13.4). It can be more prolonged  and more severe in premature infants.   In this X-linked recessive disorder, affected males pre-  sent with recurrent infections from between 4 months  and 2 years of age (maternal IgG protects against earlier  infection). Pre-B cells are unable to differentiate into  mature B cells because of a lack of an enzyme called    Bruton's tyrosine kinase (located on chromosome  Xq22). This kinase normally transduces maturation sig-  nals from the antigen receptor of a pre-B cell. The dis-  ease is characterized by:   T cell numbers and functions are normal and  infections are, therefore, primarily bacterial. Recurrent  bacterial infections of the upper respiratory tract (e.g.  by Streptococcus pneumoniae) are a common first  presentation.   Treatment is with long-term prophylactic immuno-  globulin-replacement therapy and the rigorous use of  antibacterial agents.   This is a heterogeneous group of conditions, many of  which are inherited, although sporadic cases do occur.  The common feature is agammaglobulinaemia, charac-  terized by an increased susceptibility to bacterial infec-  tions, and presenting in late childhood or adolescence.  Both sexes are affected equally.   The marrow contains normal numbers of immature  B cells but there is a failure of differentiation of B cells  into plasma cells. This may be due to a defect in T cell  signalling.   The disease is more common and more variable than  the X-linked form (hence the name); however, the pat-  tern of infection is similar, chiefly affecting the lungs, si-  nuses and gastrointestinal (GI) tract. The risk of  autoimmune disease is also increased in these patients.  Treatment is as for X-linked deficiency.   The commonest form of immunodeficiency, this affects  1 in 700 Caucasians. Circulating B cells bearing surface  IgA are immature and fail to differentiate into IgA-  secreting plasma cells.   Patients are prone to sinopulmonary infections and  bowel colonization with Giardia, Salmonella and other  enteric pathogens.   This rare, congenital disorder is caused by the arrested  development of the third and fourth branchial arches,  resulting in an almost complete absence of the thymus  and parathyroid gland. The genetic defect has been  mapped to chromosome 22qll.   Immunoglobulin levels are normal, but affected in-  dividuals have decreased circulating levels of T lympho-  cytes, resulting in impaired cell-mediated immunity.   Patients typically develop a triad of infections: candidi-  asis, pneumocystis pneumonia and persistent diarrhoea.    The syndrome is also characterized by tetany from  hypocalcaemia (due to hypoparathyroidism) and is as-  sociated with abnormalities of the great vessels (e.g.  transposition or Fallot's tetralogy).   The condition can be X-linked (gamma chain of in-  terleukin-2 receptor at Xql3-21.1) or an autosomal re-  cessive disorder. It presents during the first few months  of life with a failure to thrive and persistent infections.  In addition infants are at risk from graft-versus-host dis-  ease. One example of this occurs when maternal T cells  cross the placenta; another involves T cells in non-  irradiated blood products.   Death usually occurs within the first 2 years of life  from multiple infections, although a bone marrow  transplant can be an effective cure in some cases. X-  linked SCID has become the first human disease to be  successfully corrected by gene therapy, although work  is continuing on a possible increased risk of leukaemia  following such procedures.   Secondary immunodeficiencies are those that result  from extrinsic or environmental causes, as listed in  Figure 13.7. The pathologies of most of these diseases  are covered in other chapters.   Acquired immunodeficiency syndrome (AIDS) is  caused by infection with the human immunodeficiency  virus (HIV). It is characterized by a profound defect in  cell-mediated immunity with lymphopenia and dimin-  ished T lymphocyte responses.   The usual cause is FIIV-1 (Fig. 13.5). Routes of trans-  mission are threefold: sexual contact, blood-borne  (transfusions or contaminated needles) and maternal  (placental or via breast milk).   HIV is an enveloped RNA retrovirus that binds to CD4  receptors present on T helper cells and various cells of  the monocyte/macrophage system via its cell surface  heterodimer of glycoproteins, gpl20/gp41:   • Following cell entry, the virus loses its coat and  utilizes its enzyme, reverse transcriptase, to make   • Viral replication is initially repressed by intracellular  factors and by cell-mediated immunity mediated  by CD8+ cytotoxic T cells, and so the virus can  remain latent (i.e. dormant) for months or even  years.   • Activation of latently infected T cells triggers  viral replication, and infectious virus particles are -  released, resulting in the infection of more CD4+  cells.   Eventually, there is depletion of T helper cells, which  results in a severely impaired cell-mediated immunity,  with a high risk of multiple opportunistic infections.   There is a correlation between the fall in the CD4 cell  count and increasing viral antigen levels (Fig. 13.6).   The clinical outcome of HIV infection has been classi-  fied into four stages (Figure 13.8).   The duration of each stage is highly variable - some  patients pass directly through stages II and III to AIDS-  related conditions or even to fully developed ('full  blown') AIDS, whereas others remain in the earlier  stages for months or years. Opportunistic infections  tend to develop when the CD4 count drops below  200 cells/mm 3 . A small proportion of HIV-infected  patients do not develop clinical AIDS.   The reasons for these variations in the course of  the disease are poorly understood and the factors that    Fig. 13.6 CD4 count, viral antigen (p24) and antibody levels  following HIV infection. (AIDS, acquired immunodeficiency  syndrome; ARC, AIDS-related complex; p24, nucleocapsid  protein; PGL, persistent generalized lymphadenopathy.)   The prognosis for HIV patients with access to combina-  tion anti-retroviral therapy (cART) is dramatically im-  proved. Combination means administering two or  more anti-HIV drugs, so as to minimize the develop-  ment of drug resistance. These include a reverse tran-  scriptase and a protease inhibitor, as well as newer  drugs targeting other parts of the virus replication cycle.  In addition, antimicrobial therapy is given with the aim  of preventing or treating infection (prophylactic anti-  biotics or antifungals). The intention is to attain a  near-normal life expectancy - similar to treatment of  insulin-dependent diabetes mellitus.   In the initial stages of HIV infection, viral load and  CD4 cell counts are monitored only; cART treatment  is generally delayed unless the patient is critically ill,  has developed an opportunistic disease, or their CD4  count has dropped below a critical level (currently  350 cells/cu mm 3 ). Unfortunately, many AIDS patients  in developing countries have a very poor prognosis be-  cause these expensive therapies are unavailable.   cART is not risk-free, there being many toxicities,  which dominate the management of HIV-infected pa-  tients in rich countries. These include liver fibrosis and  steatosis, kidney damage and deranged lipid metabolism.  Also, as the patient's cellular immune status improves  on cART, there is a risk of immunological over-reaction  to infection antigens, with severe imflammatory reactions  and organ damage: this is termed 'IRIS' - the immune  reconstitution inflammatory syndrome. It is most  commonly seen with tuberculosis co-infection.   Chronic lymphocytic leukaemia  Post-bone marrow transplantation  Post-chemotherapy/radiotherapy  Chronic renal failure  Splenectomy   Chronic asymptomatic infection: laboratory tests typically normal  but may have anaemia, neutropenia, thrombocytopenia, low  CD4 lymphocytes, lymphopenia and hypergammaglobulinaemia   Persistent generalized lymphadenopathy:  with or without laboratory test abnormalities  as in stage II   AIDS-related complex: generalized lymphadenopathy  with persistent fever, weight loss, unexplained diarrhoea,  CNS manifestations and haematological abnormalities  including thrombocytopenia, leucopenia and anaemia  Fully developed AIDS:   • Wide spectrum of opportunistic infections including  Pneumocystis carinii, toxoplasmosis, Cryptococcus,  cryptosporidiosis, atypical mycobacteria, herpes  simplex or zoster, oral hairy leucoplakia, histoplasmosis,  candidiasis, cytomegalovirus, Salmonella   • Secondary cancers, e.g. Kaposi's sarcoma,  non-Hodgkin's lymphoma, squamous carcinoma  of the mouth or rectum   Amyloidosis is the pathological deposition of abnormal  extracellular fibrillar protein, amyloid, in different tis-  sues. Amyloid is composed of a meshwork of rigid,  straight fibrils formed from precursor peptides (immu-  noglobulin light chains, serum amyloid protein A, pep-  tide hormones) lined up in a cross- (3-pleated sheet  structure. The (3-pleated sheet structure is important be-  cause enzymes in the body are incapable of digesting  such large molecules in this form. It is detected histolog-  ically as a bright pink hyaline material that readily takes  up Congo red stain, which is used in diagnosis.   It is important to note that it is the physical  arrangement of the constituent amino acids that make  a protein an amyloid rather than any specific amino  acid sequence.   There are many different types of amyloid, each  being formed from different precursor amino acids with  the precursors themselves often being fragments of  larger proteins.   Fifteen distinct forms of amyloid have been described,  but three predominate:   2. AL (amyloid light chain) — immunoglobulin light  chains derived from plasma cells   • abnormal amounts of normal precursor peptide  (common), e.g. immunoglobulin light chains in mul-  tiple myeloma or serum amyloid A protein in acute-  phase response. It may be a result of overproduction,  reduced degradation or reduced excretion of protein   • normal amounts of abnormal (amyloidogenic) pep-  tide (rare), e.g. due to transthyretin polymorphisms,  which make these proteins more prone to misfold-  ing and aggregation.   Normally, misfolded proteins would be degraded  by proteosomes within a cell or by macrophages    extracellularly. In amyloidosis, however, the macro-  phage control mechanisms appear to fail and the mis-  folded proteins aggregate extracellularly.   • systemic — may involve many tissues as it is particu-  larly deposited in the blood vessel walls and base-  ment membranes. Usually fatal, death generally  occurring from renal or cardiac disease   • localized — affects only one organ or tissue. Rarely, it  may be found without any obvious predisposing  cause. The skin, lungs and urinary tract are the most  frequent sites.   In both cases, the progressive accumulation of amy-  loid leads to cellular dysfunction by preventing the nor-  mal processes of diffusion through extracellular tissues  and by physical compression of functioning parenchy-  mal cells.   This amyloid is composed of protein A and is termed the  AA type. It is derived from serum amyloid A (SAA) pro-  tein, which is an acute-phase reactant synthesized in the  liver. SAA increases are seen in response to a variety of  diseases, invariably featuring chronic inflammation:   • Rheumatoid arthritis (most common cause): in up  to 3% of rheumatoid patients   Such reactive disease in response to chronic inflam-  matory disorders tends to produce more severe systemic  involvement when compared to other forms of amy-  loidosis. AA-type amyloid is deposited in many organs,  but it has a predilection for the liver, spleen and kidney.  It results in hepatosplenomegaly with or without renal  vein thrombosis and nephrotic syndrome.   This amyloid is composed of immunoglobulin light  chains (and/or parts of their variable regions) and is  termed AL type. Immunoglobulin light chains are formed  by proliferating plasma cells usually in association with:   • multiple myeloma — occurs in up to 15% of patients  with this condition    Primary amyloidosis is a myeloma-associated amy-  loidosis that occurs in the absence of any clinically ob-  vious myeloma. It is caused by a clinically occult  plasma cell tumour, which is revealed only by serum  electrophoresis showing the presence of a monoclonal  immunoglobulin band. It is also known as benign  monoclonal gammopathy.   AL-type amyloid is deposited in many organs, in-  cluding the tongue, skin, heart, nerves, kidneys, liver  and spleen. It has a predilection for connective tissue  within these organs.   A common presentation of advanced AL amyloidosis  is nephrotic syndrome and biventricular cardiac failure.  Macroglossia (enlarged tongue), peripheral neuropa-  thy, carpal tunnel syndrome and overt renal failure are  also seen.   Hereditary forms of amyloidosis are rare, and they in-  clude familial Mediterranean fever (AA type) and famil-  ial neuropathic forms (pre-albumin, AF type).   The most common example of amyloid deposition oc-  curs in the nervous system, in both Alzheimer's disease  (see Chapter 5) and in normal ageing (cerebral angiopa-  thy). The amyloid (A(3) is composed of peptide frag-  ments termed P-protein or A4 protein, both of which  are derived from a normal, neuronal membrane pro-  tein — amyloid precursor protein (APP).   Minute deposits of amyloid usually derived from serum  transthyretin (pre-albumin) are found in the heart and  in the walls of blood vessels in many organs of elderly  people. However, cardiomyopathy and/or arrhythmias  occur in only a few cases.   Leucopenia is defined as a reduction in circulating leu-  cocytes. The classification of leucocytes is shown in  Figure 13.9.   Neutropenia, a deficiency of neutrophil granulocytes, is  the most important form of leucopenia. The lower limit  of normal neutrophil count is 2.5 x 10 9 /L (except in  Black people and in the Middle East, where it is 1.5 x  10 9 /L). Levels of less than these values are classified as  neutropenia.   • eosinophils (0.05 - 0.4 x 10 9 /L)  . basophils (0.01 -0.1 x 10 9 /L)    Neutropenia may be selective or part of a general  pancytopenia. The causes of both types are listed in  Figure 13.10.   • moderate to severe (<0.5 x 1 0 9 /L) — associated with  a progressive increase in risk and severity of infection   • levels of < 0.2 x 10 9 /L are associated with a high  mortality from overwhelming infection.   Severe neutropenia is termed agranulocytosis. Infec-  tions are predominantly bacterial and are usually oppor-  tunistic, most commonly Gram-positive skin organisms  (e.g. Staphylococcus and Streptococcus species) or Gram-  negative gut bacteria (e.g. Pseudomonas, Escherichia  col, etc.).   They can be either localized (e.g. of the mouth,  throat, skin or anus) or generalized (neutropenic sep-  sis). The latter may be rapidly fatal.   Treatment is of the underlying cause and with anti-  microbial therapy.   Leucocytosis is defined as an increase in numbers of cir-  culating white blood cells.   Each type of leucocyte (see Fig. 13.9) may be increased  in number (neutrophilia, eosinophilia, etc.). Monocy-  tosis and lymphocytosis are the terms used for increases  in monocytes and lymphocytes, respectively.   Neutrophilia is the most common cause of leuco-  cytosis, produced by common events such as acute bac-  terial infection or acute inflammation.   or precursor marrow cells can occur via direct  toxicity or immune-mediated mechanisms  in susceptible individuals; examples of such  drugs include:    • secondary — caused by the normal response of bone follicular), and the clinical course (Hodgkin's disease  marrow to abnormal conditions, e.g. infection. Also or non-Hodgkin's lymphomas),  known as reactive leucocytosis (Figure 13.11).   Lymphomas are clonal, neoplastic proliferations of  lymphoid cells, and can be classified via cell types  (B cells or T cells), tumour architecture (diffuse or   Hodgkin's disease is characterized by the painless en-  largement of one or more groups of lymph nodes (pain-  less lymphadenopathy) and the presence of large  binucleate cells (Reed-Sternberg cells) within them.   Acute infections  Haemorrhage/hemolysis  Inflammation and tissue necrosis  Metabolic disorders  Myeloproliferative diseases  Neoplasia  Steroid therapy  Strenuous exercise   Chronic infections, e.g. tuberculosis  Rickettsiosis and malaria  Inflammatory disorders,  e.g. rheumatoid disease,    It affects 4 per 100 000 in the UK, with a slight male  excess. It can occur at any age but there are two peaks of  incidence: one in young adults (15-20 years old) and  the other in late middle age (40-60 years old).   The aetiology of Hodgkin's disease is obscure, as is  the origin of the malignant Reed-Sternberg (RS) cells.  Although no causal link has been established with  Epstein-Barr virus (EBV), Hodgkin's disease sufferers  are three times more likely to have had glandular fever  in the past.   Hodgkin's disease often presents clinically as the en-  largement of accessible nodes, most often in the upper  half of the body (e.g. cervical or axillary) . The disease is ini-  tially localized to a single peripheral lymph node region,  but it spreads in a fairly consistent pattern to adjacent  nodes via the lymphatics, and then, following splenic in-  volvement, to other organs via the bloodstream.   One-third of patients have systemic symptoms (so-  called 'B symptoms'), notably weight loss, pyrexia (Pel  Epstein fevers are epsiodic fevers) and night sweats.   The stage (extent of spread) of Hodgkin's disease is  determined by the Ann Arbor staging system  (Fig. 13.12). A clinical addition is the presence of ‘B  symptoms' — systemic features associated with poorer  prognosis, namely weight loss, night sweats and  unexplained fever.   Treatment depends on the stage: either localized  (radiotherapy) or generalized (systemic  chemotherapy). Five-year survival is approximately  75 % , but long-term survivors of chemotherapy and/or  radiotherapy are at increased risk of second cancers.    Diagnosis of Hodgkin's disease can only be made on  examination of biopsied lymph nodes:   • Macroscopically — affected lymph nodes are en-  larged, with a smooth surface and the lymph node  capsule is rarely breached (cf. non-Hodgkin's  lymphomas).   lymph node region (1)  or of single extralymphatic  organ or site (hence le)   Involvement of two or more lymph  node regions, with all lesions confined  to the same side of the diaphragm (II),  or localized involvement of an  extralymphatic site and one or more  lymph node regions confined to one  side of the diaphragm (lie)   Involvement of lymph node regions on  both sides of the diaphragm (III) which  may also involve the spleen (Ills),  localized extralymphatic sites (1 1 le)  or both (1 Use)   Widespread involvement of  extralymphoid sites such as the liver,  lung and bone marrow with or without  lymph node involvement   Suffix A indicates the absence of systemic symptoms ;  suffix B indicates the presence of systemic symptoms.  For example, stage llleB denotes involvement of lymph  nodes on both sides of the diaphragm accompanied by  localized involvement of an extralymphatic site with  systemic symptoms.    Fig. 13.13 Rye classification of Hodgkin's disease. (Adapted with permission from medicshandbook.com, 2011.)    • Microscopically — four subtypes of Hodgkin's dis-  ease are recognized and classified according to the  Rye classification system (Fig. 13.13).   Non-Hodgkin's lymphomas (NHLs) include all lym-  phomas other than Hodgkin's disease. They are pre-  dominantly diseases of middle and later life, with  males slightly more affected than females.   The aetiology of NHLs is poorly understood but sev-  eral factors have been implicated:   • Immunosuppression — increased incidence in pri-  mary immunosuppressive diseases, e.g. X-linked  agammaglobulinaemia and in secondary immuno-  suppression, e.g. drug induced after transplantation   • Viral infection — with lymphotropic viruses, e.g.  EBV, human T-lymphotropic vims (HTLV-1), HIV   Chromosomal translocations are a feature of many  types of lymphoma, for example:   • Follicular B cell lymphoma — translocation 14:18.  These translocations cause a neoplastic transforma-  tion as a result of the transfer of an oncogene or onco-  gene-regulatory gene to an abnormal site. This causes  the increased expression of these oncogenes, e.g bcl-2  in follicular lymphoma, which inhibits apoptotic  cell death.    The majority (70%) of NHLs are B-cell lymphomas,  which are derived from follicle centre cells. These  tumours have either follicular or diffuse architecture.   Recognizing the normal development of lymphocytes  (Fig. 13.14) is essential to understanding lymphomas  and other neoplastic proliferations of white blood cells.   The clinical manifestations of NHLs are similar to those  of Hodgkin's disease but they are more varied because of  their heterogeneous nature. The majority of cases pre-  sent with asymmetric, painless enlargement of lymph  nodes in one or more peripheral lymph node regions.  However, extranodal presentation is more frequent  than in Llodgkin's disease, with 20% of all NHLs origi-  nating within extranodal sites.   Systemic symptoms are often prominent in extensive  disease, along with hepatosplenomegaly.   The Ann Arbor staging system is used to stage NHL.  However, systemic symptoms are much less common  compared to Hodgkin's disease (Fig. 13.15).   Treatment is by single or combination chemotherapy  with which some patients show long-term remission if  not cure.   The prognosis depends on the type of lymphoma and  varies widely from highly proliferative and rapidly fatal    Fig. 13.14 Normal lymphocyte development. (Adapted with  permission from Essential Hematology, 5th Edition, by V  Hoffbrand and J Pettit, Wiley-Blackwell, 2005.)   Fig. 13.15 Ann Arbor staging system of Non- Hodgkin's disease  (Adapted with permission from medicshandbook.com, 2011.)   diseases (e.g. immunoblastic lymphoma) to indolent  and well-tolerated malignancies with a mean survival  of about 7 years (e.g. follicular centrocytic lymphoma).    Classification — leukaemias are classified into acute  or chronic based on clinical progression:   1. Acute — characterized by numerous immature 'blast'  cells (leucocyte precursors) and rapid disease  progression   2. Chronic — characterized by large numbers of  precursor cells that are more differentiated than  blast cells and associated with slower disease  progression.   These groups are then further classified into two  main groups depending on neoplastic cell types:   Aetiology — in the majority of cases, the cause of leu-  kaemia is unknown. However, certain factors are known  to initiate leukaemic transformation:   • Genetics — slight familial tendency (high concor-  dance in monozygotic twins); chromosome abnor-  malities (both quantitative and qualitative) are  present in about 50% of patients; increased inci-  dence in Down syndrome   • Ionizing radiation — excessive exposure in therapy,  e.g. for ankylosing spondylitis, malignant disease;  nuclear explosions/accidents as at Hiroshima and  Chernobyl   • Viruses — e.g. HTLV-I causes adult T cell leukaemia/  lymphoma; HTLV-II is associated with hairy cell  leukaemia   Leukaemias are neoplastic proliferations of white blood  cell precursors in the bone marrow.   Increased cell turnover leads to increased uric acid syn-  thesis, which may result in gout.   There is infiltration of organs such as the liver, spleen,  lymph nodes, meninges and gonads by the leukaemic  cells.   Acute leukaemia is a malignant disorder in which hae-  mopoietic blast cells constitute > 20% of bone marrow  cells.   There are two main types: acute lymphoblastic leu-  kaemia (ALL) and acute myeloblastic leukaemia  (AML). These are further subclassified according to cyto-  logical features of the blast cells. There are three sub-  types for ALL (Lj-L 3 ) based on the degree of  uniformity of cell size and vacuolation. There are eight  subtypes for AML (M 0 -M 7 ) based on the degree of cyto-  plasmic granularity. Figure 13.16 outlines the features  of ALL and AML.   The clinical features of both AML and ALL are simi-  lar. They commonly present with symptoms of anaemia  (e.g. tiredness, malaise, breathlessness, angina) and  their course is typified by a series of overwhelming in-  fections and mucosal haemorrhage.   Onset is frequently rapid and progression to death  from anaemia, haemorrhage or infection occurs within  weeks if no treatment is given.   • thrombocytopenia — petechiae, purpura, epistaxis,  bleeding gums, GI haemorrhage, cerebral  haemorrhage   • blood film — this shows blast cells and can be diag-  nostic. If not clear from blood film, diagnosis is  sought from bone marrow biopsy. This shows a  hypercellular marrow with normal elements replaced  by blast cells. If Auer rods are present in the cytoplasm  of these cells, the pattern is AML. Cytogenetics and  immunological staining can help diagnosis.  Involvement of other organs:   • Skeleton (bone pain, especially in children) —  probably caused by osteolytic lesions   • Supportive therapy — this actually increases survival  and involves correction of anaemia, thrombocyto-  penia (i.e. blood product transfusions) and treat-  ment of infections   Mainly (>90%) affects  children of < 14 years  with highest incidence  at 3-4 years   Occurs at all ages and is the  commonest form of acute  leukaemia in adults   Children aged 2-9 years:  50-75% cure rate  Adults: 35% cure rate with  chemotherapy; 50% with  allogeneic bone marrow  transplant   20-25% cure rate with  standard chemotherapy  50% with allogeneic  bone marrow transplant    • Bone marrow transplantation — usually reserved for  those in relapsing chemotherapy-induced remis-  sion. Encouraging results in younger patients but  largely depends on availability of suitable tissue-  matched donor.   Chronic myeloid leukaemia (CML) is a disorder of pro-  liferation, with excessive and uncontrolled neoplastic  proliferation of an abnormal myeloid clone of leucocyte  precursors in the bone marrow.   About 90% of cases are characterized by the presence  of a specific karyotypic abnormality — the Philadelphia  chromosome — within the haemopoietic stem cells. This  involves reciprocal translocation of part of the long arm  (q) of chromosome 22 with the long arm of chromo-  some 9. This creates a chimeric gene (BCR-abl), which  produces a tyrosine kinase thought to be involved in  the pathogenesis of CML.   CML occurs in all age groups, but most frequently be-  tween the ages of 40 and 60 years. The disease has three  recognized stages:   2. Accelerated phase — due to the emergence and dom-  inance of a more malignant clone of myeloid cells.  Disease becomes harder to control   3. Blast crisis phase — transformation to an acute leu-  kaemia (usually AML), often rapidly fatal. Progres-  sion from chronic phase is unpredictable and may  occur at any time.   Haematological investigation reveals leucocytosis  and normocytic anaemia. Note that in contrast to acute  leukaemias, neutropenia, lymphopenia and thrombo-  cytopenia are not common in the chronic phase and  that infection and bleeding are not typical.   There is sometimes massive splenomegaly (10% of  cases), and often hepatomegaly.   Treatment of Philadelphia-chromosome-positive  CML has recently been transformed by the drug imati-  nib. This novel tyrosine kinase inhibitor blocks the  product of the chimeric BCR-abl gene and appears to of-  fer long-term remission as long as the patient remains  on the drug.   This chronic lymphoproliferative disorder is character-  ized by the proliferation of an abnormal lymphoid  clone of leucocyte precursors in the bone marrow.   Chronic lymphocytic leukaemia (CCL) is the most  common leukaemia of adults, comprising about 30%    of all leukaemias, with males affected more than fe-  males by 2: 1 . It is a disease predominantly of the elderly,  with peak incidence at 65 years old.   This disease is much less aggressive than other leu-  kaemias, following a predictable course over a period  of years.   The lymph nodes, liver and spleen are characteristi-  cally involved and normal architecture may become  completely effaced by the infiltrating cells.   The staging of CLL is summarized in Figure 13.17.  Clinical features are similar to a low-grade lymphoma,  but with the eventual development of bone marrow  failure (anaemia, thrombocytopenia, infection).   Treatment is often reserved for the later stages,  comprising combined chemotherapy and occasionally  splenectomy   Survival for more than 10 years from diagnosis is  common, and where CLL affects the elderly, death is  often from an unrelated cause. CLL in younger  individuals tends to be more aggressive.   This group of acquired neoplastic disorders of the bone  marrow is characterized by increasing bone marrow fail-  ure with quantitative and qualitative abnormalities of  all three myeloid cell lines (red cell, granulocyte/    Fig. 13.17 Clinical features and staging of chronic  lymphocytic leukaemia according to the RAI classification   Haemoglobin <11 g/d L, with features  of stages 0, 1 or II   Platelet count < 100 x 10 9 /L, with features  of stages, 1, II or III    monocyte and platelets) due to a defect of stem cells.  They are also known as refractory anaemias.   In most cases, the disease arises tie novo and the  aetiology is likely to be as for the leukaemias. The disor-  ders are seen as steps in the progression to leukaemia  (preleukaemic) and AML develops in many instances,  often after many years. However, in a significant propor-  tion of cases, the disease is secondary to treatment with  chemotherapy (with or without radiotherapy) for a pre-  vious neoplastic disease.   The hallmark of the disease is ineffective haemopoi-  esis resulting in pancytopenia despite a marrow of either  normal or increased cellularity   Bone marrow contains morphologically abnormal  cells including ring sideroblasts and hypogranular white  cells, often with abnormal chromosomes.   Clinical features — more than half the patients are  over 70 years old and more than 75% are over 50; males  are affected more often than females. Symptoms are  generally sequelae of the variable cytopenia, and in-  clude anaemia, infection and haemorrhage.   Diseases are subclassified depending on the presence  of ring sideroblasts and the proportion of leukaemic-  type blast cells in the bone marrow (Figure 13.18).   Treatment is largely supportive, by blood transfusion  and treatment of infection.   Morbidity and deaths are largely attributable to the  refractory cytopenias either directly (e.g. from haemor-  rhage) or indirectly (e.g. from transfusion-related  haemosiderosis).   This rare, B cell leukaemia is characterized by variable  numbers of 'hairy' cells in the blood, bone marrow, liver  and other organs. Hairy cells are so named because of  their characteristic irregular outline caused by cytoplas-  mic projections or 'hairs'.   The disease has a peak incidence at 40-60 years old,  affecting males more than females by 6:1.   It is characterized clinically by features of pancytope-  nia (mainly recurrent infections) and splenomegaly.   The disorder typically runs a chronic course and re-  mission is common with chemotherapy or interferon  treatment. Splenectomy is also useful in management.   These are autonomous proliferations of one or more  myeloid cells (erythroid, granulocytic, megakaryocytic)  with differentiation to mature forms (Figure 13.19).  Progression from one disorder to another within the  group is common.   This idiopathic condition is characterized by an above  normal increase in red cell concentration, usually with  concomitant increases in haemoglobin concentration  and haematocrit. Red cell mass is greatly increased.   Erythrocytosis with increased H b and PCV  Often neutrophilia and thrombocytosis  Pruritus (relating to basophilia)  Thrombosis or haemorrhage  Splenomegaly    The disorder has a prevalence of 1 per 100 000 in the  UK. It typically affects the middle-aged, and males more  so than females.   Progression of this disease is chronic, but about 20%  of cases evolve into myelofibrosis and another 5% into  acute leukaemia.   Onset is usually insidious and non-specific, e.g. mal-  aise, fatigue, headache and dizziness. The principle  symptoms are caused by vascular engorgement, in-  creased haematocrit and thrombosis, with or without  haemorrhage. Diagnosis requires raised red cell mass  without another cause and palpable splenomegaly.   Treatment is by venesection or myelosuppression  using chemotherapy or radioactive 32 P. Treated patients  have a mean survival of about 13 years, with increased  morbidity and mortality from coronary and cerebral  disease related to the raised haematocrit.   This condition is characterized by a proliferation of  fibroblasts in the bone marrow and obliterative marrow  fibrosis, with a corresponding massive extra-medullary  haemopoiesis in the liver and spleen.   The condition is a chronic disorder of late and mid-  dle age. It may arise de novo (with unknown aetiology)  or as an end-stage of other myeloproliferative disorders  (e.g. polycythaemia rubra vera).   The disease is usually slowly progressive, with a me-  dian survival of 4 years. Acute leukaemic transforma-  tion sometimes occurs.   poiesis is ineffective leading to anaemia with marked  anisocytosis (unequal sized blood cells) and tear-  drop poikilocytes (tear-drop shaped red cells)   Symptoms are usually caused by anaemia and  massive splenomegaly. Systemic symptoms (e.g. fever,  weight loss) are usually late features.   This condition is characterized by increased platelet pro-  duction due to a clonal proliferation of megakaryocytes  without a systemic cause. It is most commonly seen in  patients over 50 years of age. Its features are:   • large, atypical platelets with increased platelet count,  often > 600 x 10 9 /L   • spleen may be enlarged, but it is usually normal or  reduced in size because of thromboembolic  infarction.   Treatment with chemotherapy and antiplatelet drugs  (e.g. aspirin) is effective and median survival with treat-  ment is 8-10 years.   This describes the malignant, monoclonal proliferation  of plasma cells in the marrow. Most cases affect multiple  sites (multiple myeloma), although solitary myeloma  does occur (see below).   This typically affects the elderly, with almost all cases oc-  curring after the age of 40. There is a male predominance.   Pathogenesis — normal plasma cells produce poly-  clonal immunoglobulins. In myeloma, only monoclonal  immunoglobulins or light chains are produced; these are  referred to as the 'M component' or paraprotein.   The M component is usually IgG (> 60%), but may  be IgA (20%) or just the immunoglobulin light chain [k  (kappa) being more frequent than X (lambda)]. IgM-  producing plasma cells are a feature of Waldenstrom's  macroglobulinaemia.   Serum protein electrophoresis, which shows normal  levels of a- and (i-globulins, but a dramatic increase in  the levels of gamma-globulins (Fig. 13.20).   Diagnosis of myeloma requires two out of the  following three findings:   Fig. 13.20 Serum electrophoresis showing characteristic  gamma band of multiple myeloma. (Adapted with permission  from Essential Hematology, 5th Edition, by V Hoffbrand and J  Pettit, Wiley-Blackwell, 2006.)   In two-thirds of cases of IgG and IgA myelomas, mono-  clonal free light chains are also produced, which are  small enough to enter the urine, where they are called  Bence-Jones proteins.   During passage through the tubules, the protein pre-  cipitates as 'casts', causing damage to the tubular epithe-  lial cells, with concomitant formation of surrounding  giant cells.   Light chains that pass through capillaries are incor-  porated into amyloid (systemic amyloidosis); causing  damage to many organs including the kidneys.   Raised blood uric acid (from increased cell turnover)  worsens renal impairment (urate nephropathy), as  does increased blood calcium from bone osteolysis  (hypercalcaemia) .   • Hypercellular marrow with a large proportion of  abnormal plasma cells, especially in the skull, ribs,  vertebrae and pelvis   • Osteolysis of medullary and cortical bone due to  increased numbers of bone-resorbing osteoclasts:  thought to be stimulated by interleukin 1 produced  by the malignant plasma cells   • Osteolytic lesions are seen as 'punched out' defects  in the bones, the skull showing this appearance par-  ticularly well ('pepper-pot skull')   • Generalized osteoporosis may result in pathological  fractures or vertebral compression.   • Abnormal plasma cells — occasionally seen in pe-  ripheral blood, but most are in the marrow   • Neutropenia and thrombocytopenia — common fea-  tures of bone marrow failure in late stages.   may interfere with platelet function and coagulation  factors; thrombocytopenia in advanced disease   • Features of renal failure and/or hypercalcaemia.  Treatment involves chemotherapy and radiotherapy   but median survival is only 3 years with treatment.  Allogeneic bone marrow transplant may benefit some  patients.   This rare disease is characterized by discrete solitary  tumours of proliferating monoclonal plasma cells,  usually in the bone.   Proliferation does not occur in parts of the skeleton  beyond the primary lesion and marrow aspirates distant  from the primary tumour are usually normal.   The associated M component usually disappears  following radiotherapy to the primary lesion.  However, a minority of cases progress to multiple  myeloma.   The spleen serves as the site of filtration and phagocyto-  sis of the following:   Splenomegaly (enlargement of the spleen) is a com-  mon physical sign. It can have many causes, the main  types of which are summarized in Figure 13.21.   A palpable spleen is at least twice its normal size and  it is vulnerable to traumatic rupture.   Irrespective of the cause, enlargement of the spleen  may result in the development of hypersplenism,  i.e. a decrease in the circulating numbers of   Due to persistent elevation of splenic venous blood pressure, the cause of which may be:   • Posthepatic: raised venous pressure of inferior vena cava, e.g. due to right-sided heart failure,  which is transmitted to the spleen via the portal system   Heritable enzyme deficiencies, which result in storage of material in splenic macrophagic cells,  e.g. Gaucher's disease, Niemann-Pick disease and Tay-Sachs disease   • Metastases: splenic metastases from solid tumours, e.g. carcinomas or sarcomas, are rare   • Extramedullary haemopoiesis, e.g. in myeloproliferative diseases and diseases with diffuse  marrow replacement by tumour   Haematological anaemias, e.g. hereditary spherocytosis, p-thalassaemia, autoimmune haemolysis  Autoimmune thrombocytopenia: destruction of antibody-coated platelets in spleen results in  accumulation of foamy histiocytes in sinuses   Felty's syndrome: follicular hyperplasia in spleen associated with hypersplenism and  rheumatoid disease,    erythrocytes, leucocytes and platelets (pancytopenia),  resulting from the destruction or pooling of these cells  by the enlarged spleen.   Hypersplenism is often accompanied by a compen-  satory response — hyperplasia of the bone marrow.   This is enlargement of the spleen caused by any condi-  tion that leads to a persistent elevation of splenic venous  blood pressure. Causes of raised splenic venous pressure  are outlined in Figure 13.22.   Morphological features — sinusoids of the spleen are  initially distended with red cells. Fibrosis of both the  spleen and capsule eventually occurs and sinusoids then  appear ectatic and empty.   The cut surface of the spleen has a purple-red colour  with an inconspicuous white pulp and it is often flecked  with firm, brown nodules (called Gamna-Gandy nod-  ules) that represent foci of fibrosis.   Foci of extramedullary haemopoiesis are an occa-  sional feature and are thought to be secondary to local  hypoxia.   A quick revision of splenic venous anatomy is helpful in  understanding the causes of raised splenic venous    pressure (Fig. 13.22). These are heart failure, cirrhosis  and venous thrombosis.   Splenic infarction follows occlusion of the splenic artery  or its branches and it may be caused by:   • emboli that arise in the heart (most common). May  be septic if associated with infective endocarditis.   • local thrombosis, e.g. in sickle-cell diseases, myelo-  proliferative disorders and malignant infiltrates.  Infarcts may be single or multiple and are generally   The thymus is composed of lymphoid cells and specia-  lised epithelial cells; it is known as the 'primary' lym-  phoid organ. It is concerned with the development  and processing of the long-lived T lymphocytes prior  to their distribution to lymphoid tissues and to a circu-  lating pool of T lymphocytes.   Thymic activity is maximal in fetal and childhood  stages; regression is rapid after puberty.   • lymphoid tissue — severe combined immunodefi-  ciency syndromes, ataxia, telangiectasia and reticular  dysgenesis.   Both types of developmental disorder result in T-cell  deficiency associated with a disordered, cell-mediated  immune response.   This is a rare condition in which lymphoid follicles (ger-  minal centres) composed of B cells develop in the thy-  mic medulla. It is often accompanied by an increase in  the size of the thymus and is associated with autoim-  mune disease, especially myasthaenia gravis. In some  cases autoantibodies are thought to be produced by  the lymphoid tissue.   These rare tumours are derived from thymic epithelial  cells; they can be benign or malignant.    Histologically thymomas are composed of uniform  epithelial cells variably mixed with reactive lymphoid  cells.   The majority (80-90%) of thymomas are benign, well-  circumscribed, encapsulated, lobulated tumours. Most  are asymptomatic, but some present with local disease  caused by the compression of adjacent mediastinal  structures:   Around 10-20% of thymomas are malignant and in-  vade the local tissues. There are two types:   1. Type 1 — appears cytologically benign but invades  local tissues, e.g. pericardium, lungs, pleura. Rarely  spread outside the thorax   2. Type 2 (thymic carcinoma) — rare malignant thymo-  mas appearing cytologically malignant. Most are  squamous cell carcinomas with a poor prognosis.   Many haematological and systemic disorders are associ-  ated with specific abnormalities of red-cell size (anisocy-  tosis) and/or abnormal red-cell shape (poikilocytosis)  Figure 13.23.   Anaemia can be defined as a state in which the blood  haemoglobin level is below the normal range for the pa-  tient's age and sex. The normal haemoglobin range in  males is 13.0-18.0 g/dL (130-180 g/L) and in females  is 11.5-16.5 g/dL (115-165 g/L). Anaemia can be clas-  sified by the underlying mechanism for reduced haemo-  globin, as shown in Figure 13.24.   It is worth noting that, in clinical practice, anaemias  are usually classified by the mean cell volume (MCV) of  red cells — this can be increased (macrocytic anaemia),  normal (normocytic) or reduced (microcytic). In gen-  eral terms:   • macrocytic — megaloblastic anaemias (vitamin B 12  or folate deficiency) or haemolytic anaemias (new  immature red blood cells are large in size)    Fig. 13.23 Diagrammatic representation of (A) abnormalities  in red cell size (anisocytosis) and (B) abnormalities in red cell  shape (poikilocytosis). (Adapted from Underwood, 2009.)   hereditary (membrane defects, enzyme  defects, haemoglobinopathies) and  acquired (paroxysmal nocturnal  haemoglobinuria)   • Extrinsic abnormalities of red cells:  antibody-mediated red cell  destruction and mechanical trauma  to red cells    • normocytic — anaemia of chronic disease or hypo-  plastic anaemias (bone marrow suppression)   • microcytic — iron-deficiency anaemia (most com-  mon cause of anaemia) or thalassaemia.   The colour (quantity of haemoglobin) of a red cell  is also described with the terms hypochromic (low),  normochromic (normal) and hyperchromic (high).   The sections that follow describe the mechanisms  that cause these anaemias.   Following acute blood loss, a state of cardiovascular col-  lapse may occur. On cessation of haemorrhage, the  plasma volume begins to be restored from the intersti-  tial fluid compartment; this results in haemodilution  and anaemia becomes apparent.   • plasma proteins and other biochemical constituents  are restored rapidly (in 2-3 days). Full red cell resto-  ration may take up to 6 weeks.   Chronic blood loss is the most common cause of  iron-deficiency anaemia, causing a hypochromic micro-  cytic blood picture. The main causes of chronic haemor-  rhage are:   • diseases of the gastrointestinal tract — particularly  peptic ulceration, carcinoma (colorectal, stomach)   Patients with unexplained iron-deficiency anaemia  require careful screening for an occult cause of  blood loss.   The basic pathological change in all haemolytic anae-  mias is a reduction in the lifespan of the red cells due  to an increased rate of destruction; this is termed hae-  molysis. The effects of increased haemolysis are:   • anaemia — commonly macrocytic due to increased  reticulocytes (large cells) in the blood, but may be  normocytic   • unconjugated hyperbilirubinaemia due to red cell  breakdown, which may lead to the development  of pigment gall stones and jaundice (kernicterus in  neonates)   • extrinsic abnormalities of red cells —  antibody-mediated red-cell destruction, mechanical  trauma to red cells.   Hereditary spherocytosis is the most common cause of  hereditary haemolytic anaemia in the UK. It is usually  an autosomal dominant condition caused by an abnor-  mality of spectrin, the cytoskeletal-associated mem-  brane protein.   Reduced deformability of the spherical red cells  causes their retention in the splenic microcirculation  where they undergo metabolic stress caused by a lack  of glucose and acidosis. Increased fragility of metaboli-  cally stressed cells causes spontaneous lysis or prema-  ture phagocytosis by the splenic macrophages.   The general clinical features are anaemia, splenomeg-  aly (splenectomy usually performed) and jaundice.   Hereditary elliptocytosis is similar to spherocytosis  but the red cells are elliptical. This is caused by abnor-  malities of the cytoskeletal-associated membrane pro-  teins ankyrin, spectrin or band 42 protein.   This condition is not as severe as hereditary sphero-  cytosis and does not usually cause anaemia or jaundice.   In erythrocytes, 90% of glucose is metabolized anaero-  bically to lactate via the Embden-Meyerhof glycolytic  pathway (pathway is similar to regular glycolysis except  that the end product is lactate not pyruvate) ; 1 0% of glu-  cose is used in the hexose monophosphate shunt  (also known as the pentose phosphate pathway) to in-  crease the levels of NADPEI to those required for the  reduction of glutathione. Reduced glutathione is essen-  tial for maintaining haemoglobin (Mb) in the reduced  (ferrous) state (Fig. 13.25).   Pyruvate kinase deficiency is a rare, autosomal recessive  defect that results in congenital chronic haemolytic  anaemia. Red cells become rigid due to reduced ATP  formation, and they are removed by the spleen.   This is characterized by mild anaemia, jaundice and  gallstones. The blood film shows raised poikilocytosis  and distorted 'prickle cells'.   Many other enzymopathies of glycolytic enzymes  exist but they are extremely rare, e.g. deficiencies of  hexokinase, glucose phosphate isomerase and phos-  phofructokinase. The effects are similar to pyruvate  kinase deficiency.   Fig. 13.25 Metabolic pathways of the red cell. (Fructose-6-P,  fructose-6-phosphate; glucose-6-P, glucose-6-phosphate;  GSH, GSSG, reduced and oxidized glutathione; H 2 0 2 , hydrogen  peroxide; NADP, NADPH, oxidized and reduced nicotinamide-  adenine dinucleotide phosphate.)   The most common deficiencies are glucose-6-phosphate  dehydrogenase (G6PD) deficiency and glutathione  synthetase deficiency.   G6PD deficiency is an X-linked recessive condition  that is especially common among Black races. It results  in a decreased ratio of NADPH/NADP, which impairs  reduction of glutathione and so increases susceptibility  to oxidative stress.   Spontaneous anaemia is rare but haemolytic crises are  frequently precipitated by infections, certain foods (e.g.  fava (broad) beans) or certain drugs (quinine, phenacetin) .    Blood film during haemolytic crises shows raised  poikilocytosis with bite-shaped defects ('bite' cells)  or surface blebs ('blister' cells) and Heinz bodies  (red cells containing oxidized, denatured haemoglo-  bin). The blood picture is normal between haemolytic  episodes.   Female heterozygotes have the advantage of being  resistant to falciparum malaria.   A deficiency of glutathione synthetase leads to defec-  tive synthesis of glutathione causing a similar syndrome  to G6PD deficiency.   • synthesis of abnormal haemoglobin — e.g. sickle-cell  disease, unstable haemoglobins.   Anaemias are usually a combined result of both  dyshaemopoiesis and haemolysis.   Normal adult haemoglobin (HbA) is composed of two  ct-globin chains and two (1-globin chains (a 2 p 2 ). The  anaemia of thalassaemias is hypochromic, with exces-  sive production of the non-affected haemoglobin chain  often producing insoluble red cell inclusions, which  affect the marrow (ineffective erythropoiesis) and cause  premature cell death (haemolysis).   The disease is inherited and many different causative  mutations have been identified. It is common in the  Mediterranean, the Middle and Far East and South-East  Asia, where carrier rates of 10-15% are found.   a-thalassaemia — mainly caused by deletion (rather  than mutation) of parts of the a-globin genes. Normal  individuals have four copies of the a-globin gene, two  copies on each chromosome 16. There are, therefore,  four possible degrees of a-thalassaemia, depending on  how many genes are abnormal (Figure 13.26). Haemo-  lysis is less severe than in p-thalassaemia.   P-thalassaemia — caused by a mutation of the P-  globin gene(s) leading to either reduced (P + ) or absent  (P0) synthesis of the P-globin chain. Normal individ-  uals have two copies of each P-globin gene (one on each  chromosome 11). There are, therefore, two possible de-  grees of P-thalassaemia:   This is caused by an abnormal form of haemoglobin —  HbS ( 0 C 2 P 2 ) — which is caused by a point mutation  (resulting in the substitution of valine for glutamate)  in the gene coding for the P-globin chain.   The disease is common in west and central Africa, the  Mediterranean and the Middle East. In areas of Africa  where malaria is endemic, up to 30% of the population  is heterozygous. This is thought to be because carriage of  the gene confers some protection against falciparum  malaria.   HbS polymerises at low oxygen saturations, causing  an abnormal rigidity and deformity of red cells, which  assume a sickle shape (Fig. 13.27). As a result, deoxy-  genated red cells undergo aggregation (causing vascular  occlusion of small vessels) and haemolysis (due to  increased fragility).   • Heterozygous condition — sickle-cell trait in which  only 30% of the haemoglobin is HbS, resulting in  no significant clinical abnormality   • Homozygous condition — sickle-cell disease in  which more than 80% of the haemoglobin is HbS,  the rest being HbF (fetal haemoglobin) and HbA.  It is associated with serious clinicopathological  features.   Figure 13.28 shows the pathogenesis and clinical fea-  tures of sickle-cell disease.   In addition to the effects of aggregation and haemolysis,  sickle-cell disease is characterized by various 'crises' that  occur after the age of 1 or 2 years, when HbF levels have  fallen and the proportion of HbS has increased. HbF in-  hibits HbS polymerization, initially preventing these  crises. There are three main patterns:   1 . Sequestration crises — sudden pooling of red cells in  the spleen and/or liver, which can lead to death  from a rapid fall in haemoglobin   2 . Infarctive crises — blood vessel occlusion in bone, caus-  ing the 'painful crises' (especially femoral head), spleen  (leading to splenic atrophy) and skin (leg ulcers)   3. Aplastic crises — infection with parvovirus B19, which  targets erythroblasts and lyses them, cause the aplas-  tic crisis with rapid fall in blood haemoglobin.   Treatment of sickle cell disease includes the avoid-  ance of factors known to precipitate crises, especially  hypoxia. Regular blood transfusions are given to raise  the haemoglobin level and reduce the proportion of  HbF. Hydroxyurea chemotherapy also raises the HbF  % in red cells.   Mean survival figures are variable reflecting differing  standards of medical care. However, death in infancy or  childhood is usual in underdeveloped countries.   This rare disorder of young adults is caused by a clonal  abnormality of erythrocytes, which renders them abnor-  mally sensitive to lysis by complement. The cells lack  the enzyme required for the synthesis of phosphatidyl  inositol, which usually anchors several proteins to the  red cell membrane. This may arise de novo or follow  an episode of aplastic anaemia. Venous thrombosis is  a frequent complication.   Haemosiderinuria is common and can cause iron  deficiency. However, nocturnal haemolysis is present    in only about 25% of cases. Chronic haemolysis is  more usual.   This classic example of red cell haemolysis is caused by  iso-antibodies (Figure 13.29).   For example, if donor blood is group A (cells contain  A antigen) and recipient blood is group O (plasma con-  tains both anti-A and anti-B antibodies), then anti-A   Fig. 13.27 Aggregation of sickle-cell haemoglobin in  conditions of low oxygen.    antibodies of the recipient will cause agglutination and  haemolysis of donor red blood cells.   • Massive intravascular haemolysis leading to collapse,  hypotension and lumbar pain   • Disseminated intravascular coagulation may be  triggered by red cell lysis.   The effects may be precipitated with only a few  millilitres of incompatible red cells.   Transfusion-induced haemolysis due to  incompatibility of the rhesus system is generally milder,  since antibodies to the rhesus system are not  complement fixing.   Jaundice and gall stones  Haemochromatosis (due to iron overload  in transfused patients)   This haemolysis of red blood cells in rhesus (Rh)-  positive fetuses is caused by the placental passage of ma-  ternal anti-rhesus IgG antibodies from rhesus-negative  mothers. It is particularly associated with D antigen of  the rhesus blood group. The pathogenesis is as follows:   • First pregnancy — Rh-positive fetus in Rh-negative  mother with no antibodies: healthy baby. However,  if fetal red blood cells enter maternal circulation dur-  ing breach of placental barrier (e.g. at birth or mis-  carriage), then isoimmunization of mother will  occur   • Subsequent pregnancies — anti-Rh antibodies ac-  quired by mother during previous pregnancy cause  haemolytic disease of the newborn (HDN) in  Rh-positive fetuses.   Incidence is now reduced by prophylactic anti-D  injection in Rh-negative mothers before isoimmuniza-  tion can occur.   This is the most common type of haemolytic anaemia,  caused by the immune destruction of red blood cells by  the host's own antibodies. It may be idiopathic, second-  ary to other diseases or drug related.   It is divided into two main groups according to the  temperature at which haemolytic reactions occur.   The more common form, with IgG autoantibody most  reactive at 37 °C leads to chronic anaemia with micro-  spherocytes. Red cell destruction occurs in the spleen.   Clinical features are those of haemolytic anaemia:  pallor, jaundice, and splenomegaly (Fig. 13.30).    Fig. 13.30 'Warm' antibody-type haemolysis. The red cell  membrane is modified and becomes a microspherocyte with  consequences similar to hereditary spherocytosis: early  sequestration in the spleen, etc. (Adapted with permission from  Pathology Illustrated, 6th Edition, Churchill Livingstone, 2005.)   Autoantibody is IgM and is most reactive at 4 °C but it  can still bind complement and agglutinate red cells at  30 °C, the temperature of peripheral tissues (hands,  feet, nose and ears). There is destruction of red cells  by Kupffer cells of the liver.   Clinical features are of anaemia and of blueness and  coldness of the extremities, occasionally progressing to  ischaemia and ulceration. Disorder is chronic and usu-  ally mild (Fig. 13.31).    Fig. 13.31 ‘Cold’ antibody-type haemolysis. The antibody  combines with red blood cells, resulting in agglutination  (clinically presenting as painful hands and feet) or the  amboceptor effect (clinically presenting as paroxysmal cold  haemoglobinuria-haemoglobinaemia and haemoglobinuria).  (Adapted with permission from Pathology Illustrated, 6th  Edition, Churchill Livingstone, 2005.)   • thrombotic thrombocytopenic purpura (TIP).  Blood film shows the presence of schistocytes,   Mechanical damage to red cells may lead to reduced life-  span and haemolysis.   Haemolysis is caused by physical trauma to erythrocytes  as they are forced through narrow areas in the vascula-  ture. It is commonly present in:   This is caused by physical trauma to erythrocytes as they  are forced through prosthetic (usually mechanical)  heart valves.   Haemolysis is common in malaria. Plasmodium species  enter the erythrocytes where they multiply and mature  to form schizonts, which eventually escape by rupturing  the erythrocytes. Extreme splenomegaly is often present.   This type of anaemia is the result of impaired DNA syn-  thesis in marrow precursor cells and it is caused by a  deficiency of vitamin B 12 or folic acid (folate).   In the marrow, lack of vitamin B 12 or folate causes  the development of abnormally large red cell precursors  (megaloblasts), which develop into abnormally large  red cells (macrocytes):   • Macrocytic anaemia, neutropenia and thrombocyto-  penia — bone marrow becomes hypercellular with  megaloblasts   The effects of B 12 and folate deficiency occur in most  organs of the body and are prominent where cell turn-  over is rapid, e.g. in the marrow and mucous mem-  branes of the alimentary tract and genitalia.   Requirements are 1 gg per day but up to several years'  supply are stored in the liver.   Absorption — vitamin B 12 is normally absorbed in the  terminal ileum, via binding to intrinsic factor (IF),  which is secreted by gastric parietal cells. The causes  of vitamin B 12 deficiency are as follows:   • Pernicious anaemia — most common cause of vita-  min B 12 deficiency, and in females more than males.  Caused by autoimmune atrophic gastritis resulting  in lack of production of IF and malabsorption of vi-  tamin B 12 . Corrected by injections of vitamin B 12   • Disease of terminal ileum (e.g. Crohn's disease) —  loss of vitamin B 12 absorption site   • lesions of the nervous system — myelin degeneration  of posterior and lateral columns of spinal cord —  subacute combined degeneration of the cord (see  Chapter 5)   Treatment is by correction of the underlying cause  (if possible), and/or injections of vitamin B 12 .   Requirements are up to 200 gg per day and only 50-  1 00 days supply is stored in the liver.   Absorption — folic acid is normally absorbed from the  diet in the jejunum. The causes of folate deficiency are as  follows:   • Malnutrition, e.g. from anorexia, alcoholism, poor  diet, overcooking of food. This is the most common  cause of deficiency and occurs more rapidly than  vitamin B 12 deficiency because of the smaller body  stores   • Drugs may cause malabsorption (e.g. anticonvul-  sants) or may block utilization, e.g. methotrexate.   The effects of folate deficiency — blood and bone mar-  row changes are identical to those in vitamin B 12 defi-  ciency. However, deficiency of folate is not associated  with the neurological features of vitamin B 12 deficiency  (Figure 13.33).   Treatment is by oral folic acid supplements, resulting  in a complete reversal of the pathological features, even  in malabsorption states.   Absorption is via the duodenum and upper jejunum  in the ferrous (Fe 2+ ) form.   • chronic blood loss — most common cause (e.g. dis-  eases of the GI tract, menorrhagia, lesions of the  urinary tract)   Laboratory findings are as follows: reduced total serum  iron, reduced serum ferritin (iron storage protein), and re-  duced transferrin saturation (iron carrying protein), but  with a greatly increased total iron binding capacity.   Treatment is of the underlying cause and iron supple-  mentation (ferrous sulphate).   • pica (indiscriminate eating of non-nutritious  substances such as grass, stones or clothing).   This group of disorders is characterized by the produc-  tion of defective red cells.   Chronic disorders are a common cause of anaemia,  being second only to iron-deficiency. It may develop  in patients with:   Blood film — mainly normocytic and normochromic  but a mild degree of microcytic, hypochromic anaemia.   Laboratory findings — a reduced serum iron and re-  duced serum iron-binding capacity, but the iron stores  (ferritin) are normal or increased (cf. iron-deficiency  anaemia).   Erythropoietin (EPO, the hormone that stimulates  erythropoiesis) is reduced, possibly due to cytokines  produced by chronic disease processes. EPO injections  in rheumatoid arthritis improve the anaemia.   This anaemia, caused by defective haem synthesis, re-  sults in the accumulation of excess iron in the cytoplasm  of red blood cell progenitors in the form of haemosi-  derin, forming cells termed ring sideroblasts.   This anaemia is due to the failure or suppression of red  cell production in the bone marrow.   A severe life-threatening disease caused by failing bone  marrow stem cells, this is characterized by pancytope-  nia. The marrow is hypocellular, and it is replaced by fat.  It may be idiopathic or secondary to:   This anaemia is caused by the suppression of red cell pro-  genitor cells only. In contrast to aplastic anaemia, other  blood cells are not affected. There are three main types:   1 . Self-limited red cell aplasia — occurs after parvovirus  infection or exposure to certain toxins   2. Chronic acquired red cell aplasia — autoimmune  and it may be associated with thymomas   3. Chronic constitutional red cell aplasia — due to a  hereditary defect in progenitor cells.   Extensive infiltration of the bone marrow may cause the  obliteration of normal haemopoietic elements. It is  caused by:   Patients develop leucoerythroblastic anaemia charac-  terized by circulating erythroblasts and primitive white  cells. Extramedullary haemopoiesis commonly develops.   Polycythaemia (erythrocytosis) is essentially the oppo-  site of anaemia, defined as a sustained increase in red  cell numbers, usually with a corresponding increase in  haemoglobin concentration and haematocrit.   This occurs when the haematocrit reading is raised due  to a decrease in plasma volume, usually as a result of  fluid loss (haemoconcentration). This is not 'true'  (absolute) polycythaemia.   Primary polycythaemia occurs in a rare condition  termed polycythaemia rubra vera, which is one of the  myeloproliferative disorders.   Most cases of polycythaemia are secondary to condi-  tions resulting in:   • chronic hypoxia (common) — 'appropriate' polycy-  thaemia, e.g. high altitude, cyanotic heart disease,    respiratory disease (such as chronic bronchitis, emphy-  sema), smoking, haemoglobinopathies (resulting in  defective release of 0 2 to tissues)   • renal tumours and ischaemia (rare) — 'inappropri-  ate' polycythaemia, e.g. renal carcinomas or cysts,  renal artery stenosis.   Both chronic hypoxia and renal tumours/ischaemia  result in increased erythropoietin hormone production,  which stimulates the bone marrow production of  red cells.   Figure 13.34 compares the main features of primary  and secondary polycythaemia.   This skin rash results from bleeding into the skin from  capillaries. It is caused either by defects in capillaries or  by defects or deficiencies of blood platelets. Individual  small purple spots of the rash are called petechiae.   This is a bruise, presenting as a bluish-black mark on the  skin resulting from the release of blood into the tissues  either through injury or through the spontaneous leak-  ing of blood from the vessels.   This heterogeneous group of conditions (the 'non-  thrombocytopenic purpuras') is characterized by easy  bruising and spontaneous bleeding from small vessels.  The underlying lesions are of two main types:    1. Abnormal perivascular connective tissue which  leads to inadequate vessel support   2. Intrinsically abnormal or damaged vessel wall.  Haemorrhages are mainly in the skin, causing pete-  chiae, ecchymoses or both. In some disorders there is  also bleeding from the mucous membranes. Bleeding  is not usually serious.   Some bacterial and viral infections cause purpura as a  result of either vascular damage (vasculitis) by the or-  ganism or through disseminated intravascular coagula-  tion (DIC), e.g. measles, meningococcal septicaemia.   Vitamin C is required for the hydroxylation of proline as  a step in collagen synthesis. In both Ehlers-Danlos syn-  drome (an inherited disorder of collagen synthesis) and  scurvy (vitamin C deficiency) capillaries are fragile  because of defective collagen synthesis.   Long-term steroid therapy or Cushing's syndrome  results in purpura caused by loss of vascular supportive  tissue.   This immune complex (type III) hypersensitivity reac-  tion is usually found in children and often follows an  acute infection. It is characterized by red wheals and a  purple rash on the buttocks and lower legs due to bleed-  ing into the skin from inflamed capillaries and venules.    Fig. 13.34 Comparison of main features of primary and secondary polycythaemia   It is a self-limiting condition but occasionally  patients develop renal failure.   This is the most common cause of thrombocytopenia  (normal platelet count 150-350 x 10 9 /L).   Seen in aplastic anaemia and marrow infiltration (e.g.  haematological malignancies) that obliterates normal  haemopoietic elements.   • Megaloblastic anaemia (folate or vitamin B 12 defi-  ciency) — is characterized by decreased numbers of  platelets or increased numbers of megakaryocytes   The destruction of antibody-coated platelets by the  reticuloendothelial system, especially the spleen, in-  creases the likelihood of haemorrhage:   • Mucous membranes — e.g. epistaxis, bleeding gums,  menorrhagia, haematuria, melaena   • acute — often in children and usually self-limiting  with spontaneous resolution. May be post-infective,  e.g. measles   • chronic — usually in adults, mainly idiopathic but  occasionally related to chronic lymphocytic leukae-  mia (CLL) or lymphoma. Or it may occur in associ-  ation with another autoimmune disease, e.g.  rheumatoid arthritis, SLE   This is mainly through thrombotic thrombocytopenic  purpura (TTP) and haemolytic-uraemic syndrome  (HUS).   HUS and TTP are thought to represent the same dis-  ease process but with different distributions of throm-  botic lesions.    Thrombocytopenia occurs due to abnormal plate-  let activation and consumption. Platelets adhere to  the endothelium of capillaries and precapillary arteri-  oles where they undergo aggregation, with fibrin  deposition, which results in microvascular occlusive  platelet plugs and microangiopathic haemolytic  anaemia.   Aetiology — the underlying cause of the disorder is  obscure but the following pathogenic factors have been  implicated:   • Platelet hyperaggregation due to deficiency of an IgG  inhibitor of platelet-agglutinating factor in normal  plasma   • Excess of high-molecular-weight multimers of von  Willebrand's factor, which interact with platelet ag-  glutinating factor, causing platelet adhesion to vas-  cular endothelium.   In TTP, occlusive plugs lead to widespread ischaemic  organ damage, especially of the brain and kidney,  resulting in neurological abnormalities and progressive  renal impairment. In HUS, organ damage is limited  to the kidney. Children tend to develop 1IUS rather  than TTP.   Disseminated intravascular coagulation can also  cause widespread consumption of platelets, resulting  in simultaneous thrombosis and haemorrhage.   Platelets are unstable at 4 °C and so blood transfusions  contain few viable platelets. Therefore, transfusion with  massive amounts of stored blood may cause thrombo-  cytopenia. The effect can be minimized by replacement  with specific screened products, e.g. fresh frozen plasma  and platelet concentrates.   This rare disease causes life-threatening haemorrhages.  The platelets are deficient in glycoprotein receptors (gly-  coprotein Ib/IX complex), which are essential for the  binding of von Willebrand's factor. The platelets are  larger than normal and there is defective adherence to  exposed subendothelial connective tissues and defective  platelet aggregation. There is also a variable degree of  thrombocytopenia.   This failure of primary platelet aggregation is due to  a deficiency of membrane receptors (glycoprotein  Ilb-IIIa complex) for fibrinogen binding.   A common, mild defect of platelet function. It causes  easy bruising and bleeding after trauma. It is caused  by a deficiency of 'dense granules' within the platelets,  which normally store ADP. The decreased storage pool  of ADP prevents complex platelet functions such as  thromboxane release.   Aspirin therapy is the most common cause of defective  platelet function, and it produces an abnormal bleeding  time.   Aspirin irreversibly inhibits cyclooxygenase, causing  impairment in thromboxane A 2 synthesis, which is nec-  essary for the platelet release reaction and aggregation.  After a single dose the effects last 7-10 days.   Bleeding tendency is mild, with increased skin bruis-  ing and bleeding after surgery. The use of aspirin may  contribute to GI haemorrhage associated with acute  mucosal erosions. It can be life threatening.   In uraemia, defects may be caused by an abnormal  arachidonate metabolism with reduced synthesis of  thromboxane. Platelet interactions with the subendo-  thelium are abnormal and bleeding may be severe.   This is the most common of the hereditary coagulation  disorders. It is usually an autosomal dominant disorder  of abnormal platelet adhesion associated with low  factor VIII activity. The primary defect is the reduced  production of von Willebrand's factor, a protein synthe-  sized by platelets and endothelial cells which has two  main functions:   2. Carrier molecule for factor VIII, protecting it from  premature destruction.   The disease is characterized by operative and post-  traumatic haemorrhage, mucous membrane bleeding  (e.g. epistaxis, menorrhagia) and excessive blood loss  from superficial cuts and abrasions.   Severe bleeding episodes are treated with intermedi-  ate-purity factor VIII concentrates that contain both von  Willebrand's factor and factor VIII.   A common hereditary disorder of blood coagulation. It  is characterized by the absence or low levels of plasma  factor VIII.   Inheritance is X-linked but 33% of patients have no  family history and the disorder presumably results from  spontaneous mutation; it affects 1 per 10 000 in the UK.   Blood clotting time is prolonged and, in severe  disease, the blood is incoagulable.    Operative and post-traumatic haemorrhage is life  threatening, both in severely and mildly affected  patients.   Mild, moderate and severe forms of the disease are  recognized, depending on the residual clotting factor ac-  tivity (Figure 13.36). Haemophilia A 'breeds true' in that  the same severity of disease is seen in all affected mem-  bers of a family.   Treatment — control can be achieved by intravenous  clotting factor replacement, although antibodies against  the factor VIII develop in some cases.   Haemophilia A is characterized by frequent episodes of  spontaneous haemorrhage into a major joint, especially  knees, hips, elbows and ankles. Without factor  replacement therapy, bleeding continues until the  intra-articular pressure rises sufficiently to prevent  further haemorrhage (tamponade).   Resolution of acute haemarthrosis occurs slowly with  recurrent bleeds producing massive synovial    hypertrophy, erosion of joint cartilage and bone and  changes of severe osteoarthritis.   Inheritance, clinical features and treatment principles of  factor IX deficiency are identical to those of haemophi-  lia A. However, factor IX deficiency is less common, the  incidence being only about one-fifth of that of haemo-  philia A.   The features of the most common hereditary  clotting factor deficiencies are summarized in  Figure 13.37.   Acquired disorders of coagulation are far more common  than the inherited disorders, and multiple clotting  factor deficiencies are usual.   Vitamin K is essential for the y-carboxvlation and hence  activation of factors II, VII, IX and X, as well as proteins  C and S (inhibitors). The deficiency is associated  with decreased activity of these proteins, leading to  coagulopathies. This may present in the newborn or  in later life.   Vitamin K is obtained from green vegetables and bac-  terial synthesis in the gut. It is a fat-soluble vitamin and  requires bile for its absorption.   • drugs — warfarin (a vitamin K antagonist). A very  commonly used drug requiring regular monitoring  of blood clotting (via the international normalized  ratio; 1NR). In emergency life-threatening bleeds,  vitamin K supplementation is used.   Neonates are particularly susceptible to vitamin K de-  ficiency because of their lack of gut bacteria and low  concentrations of the vitamin in breast milk. Vitamin  K can be prophylactically supplemented at birth in  at-risk babies.   • impaired absorption of vitamin K caused by biliary  obstruction, producing decreased activation of  factors II, VII, IX and X and proteins C and S   • reduced synthesis of clotting factors and of fib-  rinogen, and increased amounts of plasminogen  activator in severe hepatocellular disease and  cirrhosis   • dysfibrinogenemia: functional abnormality of fibrin-  ogen found in many patients with liver disease   Disseminated intravascular coagulation (DIC) is char-  acterized by increased coagulation, which leads not  only to widespread thrombosis but also to haemorrhage  due to consumption of platelets and coagulation fac-  tors. Thus both thrombosis and haemorrhage are  features of this disorder.   The disorder may cause a severe haemorrhagic syn-  drome with high mortality or may run a milder, more  chronic course.   • release of procoagulant material into circulation, e.g.  obstetric disorders, certain malignancies, liver dis-  ease, severe falciparum malaria and haemolytic  transfusion reactions   • widespread endothelial damage, e.g. septicaemia,  certain viral infections, severe burns or hypothermia   • platelet aggregation: some bacteria, viruses and  immune complexes may have a direct effect on  platelets.   • consumption of platelets, clotting factors and fibrin-  ogen causes haemorrhage   Burns, major accidental trauma, major surgery, shock,  intravascular haemolysis, dissecting aortic aneurysm   Remember that it causes both thrombosis and  haemorrhage. It may be triggered by a wide variety of  conditions (Table 13.23) and can be rapidly fatal if not  recognized quickly.    • Activation of fibrinolytic system results in increased  fibrin degradation products (e.g. D-dimer, which is  measurable). These products may themselves have  anticoagulant effects causing further haemorrhage.    Treatment is of the underlying cause, with clotting  factor and platelet replacement.   Thrombosis is the formation of a solid mass of blood  constituents — a thrombus — within the vascular system  during life. It is not to be confused with a clot, which  occurs in non-flowing blood.   Thrombosis can affect both arteries and veins. It is  considered in detail in Chapter 6.   • Use the correct terms for macroscopic and microscopic appearances in dermatology.   • Describe acne vulgaris, rosacea and disorders of hair and nails.   • Describe the disorders of too little and too much skin pigmentation.   • Discuss the benign tumours of the skin, including the common forms of naevi.   • Describe malignant melanoma, basal cell carcinoma and squamous cell carcinoma.   This localized, flat area of altered skin colour can be  hyperpigmented as in a freckle, hypopigmented as in  vitiligo, or erythematous as in a capillary haemangioma.   A small, raised, solid lesion of the skin. This is generally  defined as being less than 5 mm in diameter.   This is similar to a papule but greater than 5 mm in  diameter. It may be solid or oedematous and can in-  volve any layer of the skin.   An extended papule that forms a plateau-like elevation  of skin. A plaque is usually more than 20 mm in diam-  eter, but rarely more than 5 mm in height.   This is similar to a papule or plaque but transitory and  compressible. It is caused by dermal oedema, is red or  white in colour and usually signifies urticaria.   This fluid-filled space within the skin is caused by the  separation of cells and the leakage of plasma into the  space.   This small blister (less than 5 mm in diameter) contains  clear fluid within or below the epidermis.   This is similar to a vesicle but larger than 5 mm in  diameter.   A small, pus-containing blister, a pustule commonly in-  dicates infection, but not always (e.g. those seen in pso-  riasis are not infected).   This thickened, horny layer of keratin forms readily de-  tached fragments of skin. Scaling is caused by distur-  bances in the processes of keratinization and usually  indicates inflammation of the epidermis (Fig. 14. 1A).   There is a thickening of the epidermis with exaggeration  of the normal skin creases caused by abnormal scratch-  ing or rubbing of skin (Fig. 14. IB).   This is caused by the destruction or removal of the sur-  face of the skin usually by scratching, but also by chem-  ical application or other means.   This is the separation of part or all of a nail from its bed.  It may occur in psoriasis and in fungal infections of the  skin and nail bed, and it is more common in women.   Figure 14.2 is a diagrammatical representation of nor-  mal skin and normal epidermis.   Thickening of the outer horny layer of the skin (stratum  corneum) occurs.   This diffuse thickening of the epidermis is caused by an  increased number of prickle cells in the stratum spino-  sum (prickle cell layer) .   There is an abnormal premature keratinization of cells  in the prickle cell layer.   The loss of cellular cohesion and separation of epider-  mal keratinocytes is due to the rupture of intercellular  bridges. Bulla formation often results.   In this condition, many papillomas grow on an area of  skin or mucous membranes.   This describes skin whose increased pigmentation is a  result of increased numbers of melanocytes.   This is the loss of all or part of the epidermis that does  not extend into the dermis, but which heals without  scarring.   The vocabulary of dermatology is quite distinct from  that of other specialties.   Learning the common dermatological terms is  essential to correctly describe different skin disorders.   Psoriasis is a chronic, non-infectious, inflammatory dis-  ease of the skin characterized by erythematous plaques  covered with thick, silvery scales.    It affects about 5% of the population in the UK and it  can start at any age, but the peak onset is in the second  and third decades of life.   The aetiology of psoriasis is unclear; however, about  35% of patients show a family history. It is associated  with HLA haplotypes Cw6, B13 and B17.   Environmental factors are thought to trigger the  disease in genetically susceptible individuals.  Pathogenesis'.   Hyperproliferation of keratinocytes occurs  Epidermal turnover time is greatly reduced  Keratinocytes are normal, but the stem cell number is  increased.   Thus, there is an increase in skin turnover and the  granular layer is often absent. Epidermal cells are imma-  ture and there is accumulation of abnormal keratin,  which results in scale. Characteristic histological  features are:   • long rete ridges separated by a markedly oedematous  papillary dermis in which there are large numbers of  dilated capillaries   • neutrophil polymorphs migrate through the epider-  mis and they may be trapped beneath the thickened  horny layer forming small aggregates (spongiform  pustules).   Precipitating factors — a number of factors have been  identified that can precipitate psoriasis:   • Drugs: |3-blockers, lithium and antimalarials can  precipitate or worsen psoriasis.   Psoriasis most commonly affects the extensor sur-  faces of the knees and elbows, the trunk and the scalp  (Fig. 14.3). Nail involvement is frequent. Pitting and  subungual hyperkeratosis may be followed by  onycholysis.   Several types of psoriasis exist, which are of variable  appearance and behaviour (Fig. 14.4).   About 7% of psoriasis patients develop arthropathy,  which takes one of four forms:   1 . Distal arthritis — the most common form. Affects the  distal interphalangeal joints of the hands and feet,  causing 'sausage-like' swelling of the digits   2. Rheumatoid-like arthritis — polyarthropathy similar  to rheumatoid disease, but usually symmetrical and  negative for rheumatoid factor (seronegative arthri-  tis). More common in women    3. Arthritis mutilans — progressive deformity of the  hands and feet caused by erosion of the small bones.  Often associated with severe psoriasis   Management of psoriasis includes topical therapy  such as tar preparations, topical corticosteroids and  keratolytics. Systemic therapies such as photo-  chemotherapy, retinoids and cyclosporin are used  in severe cases.   Eczema and dermatitis are synonymous terms for non-  infective inflammatory conditions of the skin. They  are not diseases but reactive conditions occurring in re-  sponse to certain stimuli, many of which are unknown.  They can be acute or chronic.   • erythema — caused by chronic inflammatory cell  infiltrate (lymphocytes) around dilated vessels in  the upper dermis   Scratching of the itchy, acute-stage lesions causes  secondary changes, which result in the chronic form  of the condition. It is characterized by:   • dilation of dermal vessels and infiltration of the  dermis with inflammatory cells.   Characteristic thickening, which occurs as a result of  scratching, is termed lichenification.   This chronic form of eczema is often associated with a  strong family history of other atopic diseases such as  asthma and hay fever. Uncontrollable itching is common.  The condition follows a remitting/relapsing course.   Most common type. Disc shaped, erythematous plaques  covered with white silvery scale   Symmetrical 'drop-like' lesions. May be associated with  streptococcal infection in the young   Scalp, palmoplantar pustulosis, napkin (nappy area in infants),  and acrodermatitis of Hallopeau (nails) types    Although 10-15% of the population are atopic, only  about 5% of these individuals will develop atopic eczema.   The aetiology of atopic eczema and other atopic dis-  eases is not well understood. However there is a genetic  predisposition.   • Individuals prone to atopy have higher circulating  levels of IgE antibodies than nonatopic individuals.   • On exposure to certain allergens, IgE-mediated, type  I hypersensitivity reactions are triggered, causing  mast-cell degranulation with the release of hista-  mine and other inflammatory mediators.   • In the skin, this type of hypersensitivity reaction  results in the histological changes of acute eczema,  which on scratching becomes chronic eczema.   Atopic eczema presents at an early age, with 60%  presenting before 1 year and 90% by 5 years.   The appearance of atopic eczema varies between dif-  ferent age groups (see below and Fig. 14.5):   • Infancy — babies develop the typical acute form of  eczema on the face and hands, often with secondary  infection   • Childhood — progression from acute to chronic condi-  tion. Usually involves flexural areas such as the ante-  cubital and popliteal fossae, neck, wrists and ankles   • Adults — chronic condition with lichenified (and  sometimes nodular) lesions. The hands are most com-  monly affected but a few adults also develop the  chronic, severe form of generalized atopic eczema,  which is often precipitated by stressful situations.   The prognosis from infantile eczema (starting before  the age of 2) is actually pretty good — 50% of cases will  clear by 5 years and 90% will clear by 12 years of age.   • viral infection — increased susceptibility to the devel-  opment of viral warts, molluscum contagiosum and  to widespread eruption following secondary infec-  tion with herpes simplex (eczema herpeticum)   The treatment for atopic eczema is topical therapy  (emollients, topical steroids and antibiotics), systemic  therapy (antihistamines and antibiotics) and allergen  avoidance (e.g. house-dust mite, rarely certain foodstuffs).   Contact dermatitis is a form of dermatitis precipitated  by exogenous agents (Fig. 14.6). It can be classified into:   • irritant contact dermatitis — the most common form.  Caused by contact of the skin with abrasives, acids,  alkalis, solvents or detergents   • allergic contact dermatitis — caused by a type IV  (delayed-type) hypersensitivity reaction to allergens  such as nickel.   Lesions are localized to the site of contact, and they  are most common on the hands and face.   Management is by identification and reduction in  contact of the allergen/irritant (e.g. by protective gloves)  and by topical therapy (e.g. steroids).   This is a common, chronic inflammatory condition in  which the skin is reddened and covered by thick, waxy  or white scale. The eruption often occurs in the seba-  ceous gland areas of the scalp and face, although other  areas may also be involved.   The aetiology is unknown but genetic factors and  overgrowth of the yeast commensal Pityrosporum ovale  have been implicated.   There are four common patterns in the clinical pre-  sentation (as shown in Fig. 14.7):   1. Scalp and facial involvement — affects the side of the  nose, scalp margin, eyebrows and ears; excessive  dandruff is usually present. Most common in young  males. Causes 'cradle cap' in infants   4. Flexural — involvement of the axillae, groin and sub-  mammary areas, often secondarily colonized by  Candida albicans.   A condition of unknown aetiology, this is characterized  by 'coin-shaped', symmetrical, eczematous lesions,  which typically affect the limbs of elderly men and  young men who drink alcohol excessively. Secondary  bacterial infection is common.   This dry eczema with cracking of the skin appears as a  fine, 'crazy-paving' pattern of fissuring, commonly af-  fecting the limbs and trunk of the elderly. Causes are  the overwashing of patients in institutions, a dry winter  climate, hypothyroidism or the use of diuretics.   3. Pityrosporum folliculitis — erythematous follicular  eruption with papules or pustules, typically affecting  the back    are often used interchangeably, eczema is sometimes  used to describe the reaction that occurs in response  to an endogenous stimulus, whereas dermatitis is  used to describe the reaction that occurs in response  to an exogenous stimulus.   The skin is colonized by numerous microorganisms  known as micro flora or commensals (see Chapter 4).  Some examples are:   • Trichomycosis axillaris — overgrowth of coryne-  bacteria, which form yellow concretions on axil-  lary hair   • Pitted keratolysis — overgrowth of micrococci, which  digest keratin causing malodorous and pitted ero-  sions with depressed discoloured areas, often on  the feet. Occurs with high humidity and hyper-  hidrosis (increased sweating).   This highly contagious superficial skin infection is  caused by either group A streptococci or Staphylococcus  aureus. It is relatively rare in the UK, typically affecting  children with poor hygiene.   • Characterized by circumscribed, ulcerated and  crusted infected lesions that eventually heal with  scarring   Impetigo is characterized by the development of large,  thin-walled bullae, often on the face, which leave areas  of yellow crusted exudate (classically described as  honey-coloured). Satellite lesions of impetigo occur  due to autoinfection from the primary site.   The management of impetigo is by the removal of  crusts with saline soaks and the application of topical  antibiotics (usually penicillins); widespread infection  can be treated with systemic antibiotics.    • Occurs most commonly on the legs, usually as a  result of an insect bite or neglected minor injury   • May also be seen in drug addicts due to the use of  contaminated needles.   This infection of multiple hair follicles is usually caused  by Staphylococcus aureus.   • characterized by the production of tiny pustules  located in the necks of hair follicles (superficial  folliculitis)   • in women, it commonly affects the legs after hair  removal by shaving or waxing.   A furuncle (boil) is when a deep inflammatory nod-  ule develops within folliculitis, resulting in an expand-  ing collection of pus that destroys the follicle and  extends into the surrounding dermis.   A carbuncle is a deep abscess formed in a group of  follicles with multiple drainage channels, resulting in  a painful suppurating mass; it may cause systemic  symptoms.   An acute toxic illness usually of infants, this is character-  ized by the shedding of sheets of skin, and it is caused by  the potent exotoxin (exfoliatoxin) produced by a spe-  cific strain of Staphylococcus aureus.   • Extensive disruption of the epidermis, with wide-  spread confluent blistering and denuded erythema-  tous areas resembling scalding of the skin    • May follow impetigo, due to the spread of localized  staphylococci into the bloodstream.   • Usually affects the face or the lower leg and appears  as a painful red swelling   • Lesion is usually well demarcated and often oedema-  tous and tender   • Streptococci usually gain entry to the skin via a  fissure.   Severe infection requires parenteral antibiotic treat-  ment, usually penicillin. Less severe cases can be treated  with oral antibiotics.   A deep-spreading infection of the fat, fascia and muscle,  this is caused by Streptococcus pyogenes.   The condition presents as an ill-defined erythema  typically affecting the leg and associated with a high  fever. Infected tissues become rapidly necrotic.   It usually occurs in otherwise healthy subjects after  minor trauma. It may lead to toxaemia and multisystem  organ failure.   Management — is by extensive emergency surgical de-  bridement (removal of dead tissue); systemic antibiotics  are essential.   Tuberculosis (TB) of the skin is uncommon in the UK  but is occasionally seen in the elderly and in recent im-  migrants from Asia.   • Lupus vulgaris — the most common Mycobacterium  tuberculosis skin infection in the UK. It usually occurs  following reactivation of pre-existing disease and  presents as a slowly progressive chronic skin lesion  characterized by reddish-brown plaques. Typically,  it affects the head or neck.   • Scrofuloderma — cutaneous involvement resulting  from spread of infection from an underlying lymph  node (usually cervical). Fistulae and scarring may  occur.    hands, knees or buttocks. Rare in Western countries,  this is the most common form of cutaneous TB in  developing countries.   All types are characterized by giant cell granuloma-  tous inflammation in the dermis leading to the destruc-  tion of dermal collagen and skin appendages. Scarring is  common and sometimes destruction of deeper tissues  such as cartilage occurs.   Syphilis is a chronic infectious disease caused by the spi-  rochaete Treponema pallidum, which is usually transmit-  ted by sexual intercourse. Skin manifestations tend to  present during the secondary stage, in which there is  an inflammatory response in the skin and mucous  membranes.   • Presents about 4-12 weeks after the onset of primary  chancre (primary stage)   • Characterized by a non-itchy, pink or copper-  coloured papular eruption on the trunk, limbs,  palms and soles of the feet. It is often accompanied  by lymphadenopathy and general malaise   • Other signs are moist warty papules (condylomata  lata) in the anogenital area, buccal erosions and dif-  fuse patchy alopecia   • Untreated, the eruption resolves in 1-3 months.  Management is by intramuscular penicillin. Sexual   This cutaneous and systemic infection is caused by the  spirochaete Borrelia burgdorferi and spread by certain  ticks. The majority of cases develop a slowly-extending  erythematous rash at the site of the tick bite. Intermit-  tent systemic symptoms include fever, malaise, head-  ache, neck stiffness, and muscle and joint pain.   This rare infection is caused by Bacillus anthracis associ-  ated with farm animals, particularly cattle.   A haemorrhagic bulla forms at the site of inocula-  tion. This may be followed by vasculitis and a necro-  tizing, haemorrhagic inflammation of the skin.   The disease has a variable clinical course but death  can occur if it is not rapidly diagnosed and treated.   These common, benign, hyperkeratotic, papillomatous  growths on the skin are caused by infection with human  papillomavirus (HPV). The link between HPV infection  of the skin and future skin cancer risk is currently  unclear.   Keratinocytes in the stratum granulosum (granular  layer) beneath the wart are often vacuolated due to  the viral infection.   Firm, dome-shaped, horny papules (1-10 mm across),  and usually multiple, warts are found mainly on the  hands; they can also affect the feet, face and genitalia.   These occur on the soles of the feet and are often covered  by callus (hyperkeratosis). Pressure causes inward  growth, which results in tenderness.   Flat, skin-coloured papules usually found on the face.  These are usually multiple. They resist treatment but  eventually resolve spontaneously.   These affect the genitalia and the perianal region, and  are linked to increased cervical cancer risk in women  (see Chapter 11).   Hand and foot warts frequently disappear spontane-  ously. Resistant varieties are treated with topical 'wart  paints' (salicylic acid, lactic acid, gluteraldehyde, etc.)  or with cryotherapy. Genital warts generally require  cryotherapy or curettage and cautery with a local  anaesthetic.   This presents as discrete, multiple, pale papules with a  central depression. It is caused by a DNA poxvirus.   Clinical presentation — mainly affects children or  young adults. The most commonly affected areas are  the face, neck and trunk, but it can affect the upper  thighs when sexually acquired.   The virus is transmitted by contact, including sexual  transmission, or on towels.   Untreated, the papules disappear in 6-9 months.  The treatment is by curettage, cryotherapy or by  expressing the content of the papule under local  anaesthetic.   A common, acute vesicular eruption of the skin or mu-  cous membranes, this is caused by infection with herpes  simplex virus (HSV).   • HSV blisters are highly contagious and they are  transmitted through direct contact   • virus penetrates the epidermis or mucous membrane  and replicates in the epithelial cells   • following primary infection, the virus enters a latent  stage within infected cells or the dorsal root ganglion  (e.g. cold sores — herpes labialis)   • reactivation can occur at any time, even years after  initial infection   • recurrence is thought to be precipitated by respira-  tory infection, sunlight or local trauma.   1. HSV type 1 — primary infection usually occurs in  childhood and causes the common cold sore, pre-  sent on or around the lips. Epithelial infection  may be accompanied by fever, malaise or local  lymphadenopathy. Lasts for about 2 weeks    2. HSV type 2 — this is mainly associated with genital  herpes and it is sexually transmitted (see  Chapter 11).   However, both type 1 and 2 viruses can cause genital  herpes and cold sores, depending on the site of the ini-  tial infection.   • eczema herpeticum — atopic eczema may be compli-  cated by herpes simplex infection. Causes corneal  dendritic ulceration that can threaten sight. Rarely,  eczema herpeticum can be fatal   • disseminated herpes simplex — occasionally occurs  in the newborn or in immunosuppressed patients.  Active HSV is transmissible from mother to baby  at birth and is an indication for elective caesarian  section   • erythema multiforme — immune-mediated disease  characterized by erythematous lesions on the hands  and feet.   Management is by topical aciclovir (used for mild fa-  cial or genital herpes simplex) and oral aciclovir (pre-  scribed for severe episodes of HSV infection).   This acute, vesicular eruption occurs in a dermatomal  distribution. It is caused by the reactivation of latent var-  icella zoster virus (VZV).   Following an attack of chickenpox, the virus remains  dormant in the dorsal root ganglion of the spinal cord.  On reactivation (the causes of which are unknown), the  virus migrates down the sensory nerve to affect one or  more dermatomes on the skin.   • Densely grouped vesicles and erythema in the  distribution of one dermatome   • Usually thoracic dermatomes, except in the elderly (in  whom the ophthalmic division of the trigeminal nerve  is more common)   • Vesicles become pustular and form crusts, which  separate after 2-3 weeks to leave scarring   • Vesicular blisters contain virus, which when shed may  cause chickenpox in VZV-naTve contacts   • postherpetic neuralgia — occurs in one-third of  those over 60 years old, but infrequently in patients  under 40 years old. Pain usually subsides within 6  months   • motor palsy — rare; viral involvement may spread  from the posterior horn of the spinal cord to the an-  terior horn to infect motor nerves, resulting in  palsies or paralysis of individual muscles or muscle  groups   • disseminated herpes zoster — may occur in the  immunosuppressed leading to potentially fatal vari-  cella pneumonia or encephalitis.   taken within 48 hours of onset, decreases the dura-  tion and the intensity of the disease; it may also pre-  vent post-herpetic neuralgia. Symptomatic treatment  with rest, analgesia and calamine lotion is also  important.   Dermatophytes are filamentous (hyphal) fungi, which  reproduce by spore formation. They commonly inhabit  the keratin of the skin, hair and nails producing super-  ficial mycoses (Figure 14.9).   3. Epidermophyton, e.g. Epidermophyton floccosum.  Management is either topical or systemic depending   on the extent of infection. Humid and sweaty con-  ditions, including occlusive footwear, should be  minimized.   Candida albicans is a yeast-type fungus. It is a commensal  of the vagina and alimentary canal and commonly pro-  duces opportunistic infections. Predisposing factors  may be humidity, obesity, diabetes and oral antibiotic  therapy.   Clinical presentation — in infection, hyphal forms of  Candida albicans are seen, and the infection is termed  candidosis (or candidiasis), which can present in nu-  merous patterns as discussed below.   Single or multiple ring lesions with scaling and erythema,  especially at the edges  Usually asymmetrical   Redness, erosion and scaling which is often interdigital,  but diffuse involvement of skin also occurs  Common in young men; increased predisposition by  communal washing, swimming baths,  occlusive footwear, and hot weather  Most common form of ringworm in the UK   Red, scaly, itchy rash with brown patches; more common  in men and often seen in athletes ('jock itch')   Thick, crumbling nails more commonly affecting toenails  Incidence of onychomycosis increases with age   This is especially common in the vagina ('thrush')  where white-yellowish plaques on the inflamed mucous  membranes produce itching/discomfort, and some-  times a white vaginal discharge.   A superficial inflammation of two skin surfaces that are  in contact (e.g. between the thighs or under the breasts)  is often aggravated by Candida albicans infection.   This pattern of candidiasis occurs in individuals with T  cell defects, most commonly occurring in Addison's dis-  ease and hypoparathyroidism. It causes chronic Candida  albicans intertrigo and nail and mouth infections.   • systemic therapy — a short course is useful for recur-  rent or persistent candidosis (reduces bowel carriage),  also as long-term treatment for mucocutaneous  candidiasis.   These are a cutaneous inflammatory reaction to insect  parts or to injected foreign substances. Common cul-  prits include garden insects (gnats, etc.), insects of  household pets (fleas, mites) and bedbugs.   Bites are usually grouped on a limb and lesions  vary from itchy wheals to quite large bullae, depend-  ing on the insect and the type of immune response  elicited.   It can be managed by the elimination of the cause, if  within the household, and with topical hydrocortisone  or calamine lotion.   Scabies is caused by the burrowing of the female mite  Sarcoptes scabiei through the stratum corneum where  she lays her eggs. After a few days the eggs hatch into lar-  vae, which moult and mature in the epidermis. The new  mites mate in the stratum corneum. The male dies and  the fertilized female burrows into the skin and con-  tinues the cycle.   Clinical presentation — very itchy, raised lesions, of-  ten red and scaling, typically arise on the sides of fingers,  palms, nipples and genitalia.    Fig. 14.10 Skin involvement in lepromatous and tuberculoid forms of leprosy   Raised, red plaques with hypopigmented centre  Sensation is often impaired within the plaque   Progression causes  a thickened, furrowed  appearance of face (leonine  facies) with eyebrow loss   Progression is slow; combined effect of extensive  destruction of tissue by immune response and  repeated trauma to desensitised areas results in  severe disfigurement, especially to hands and feet   Untreated, this form is lethal  due to the impaired  immune response    Linear tracks (the burrows), about 1 cm long, are of-  ten seen, and the mite can sometimes be removed by  blunt needle to confirm the diagnosis.   Itching causes excoriation that frequently results in  secondary bacterial infection. Untreated, the condition  becomes chronic.   Management — scabies is transmitted by direct trans-  fer and, therefore, all contacts require treatment.   Treatment — is with topical scabicides applied to the  whole body.   Leprosy is rare in the UK but is common in tropical  and subtropical areas. There are about 10 million pa-  tients worldwide.   Transmission is by the inhalation of nasal droplets,  after which the incubation period may be many years.   The clinicopathological features of leprosy depend  on the degree of cell-mediated immunity instigated  against the infection by the host. This may vary in a  spectrum from strong (tuberculoid leprosy) to weak  (lepromatous leprosy).    Chapter 5) and the skin. Figure 14.10 shows the skin in-  volvement in the lepromatous and tuberculoid forms of  leprosy.   Management — is by antibiotic treatment (usually  multiple) for at least 2 years.   A common disease in the tropics and subtropics caused  by the protozoan Leishmania, this is transmitted by sand  flies. Three forms of the disease exist, caused by different  species of Leishmania (Figure 14.11)   Management — cutaneous leishmaniasis often heals  spontaneously over several months. Ilowever, other  forms require pentavalent antimonials intravenously  for 10-21 days.   Also known as 'creeping eruption', this is caused by the  larvae of dog hookworms. Larvae burrow through the  skin (most commonly the feet), leaving intensely itchy  tracks in their wake. Treatment is with topical tiabenda-  zole, although the larvae die spontaneously after a few  weeks, as they cannot complete their life cycle in humans.   • blastomycosis — wart-like ulcers on the face, neck  and limbs, plus lung disease   Affects lymphatic system, spleen and bone marrow, causing  splenomegaly, hepatomegaly, anaemia and disability; patchy  pigmentation may occur on face, hands and abdomen   Characterized by 'oriental sore', a red-brown nodule that  appears at site of inoculation and which either ulcerates  or spreads slowly to form crusty plaque   Characterized by a skin lesion similar to that of oriental sore  but is followed by necrotic ulcers which cause deformity of  nose, lips and palate   This endemic disease of Africa and Central America is  caused by the nematode worm Onchocerca volvulus,  which is transmitted to humans by a gnat. The worms  cause an itchy papular eruption on the skin, which pro-  gresses to form fibrous nodules with lichenification and  pigmentary change. Microfilariae also invade the eye,  resulting in total or partial blindness (called 'river blind-  ness' in Africa).   This inflammatory disorder of the pilosebaceous appa-  ratus is characterized by comedones (blackheads and  whiteheads), papules, pustules, nodules, cysts and scars.  It is extremely common in adolescents, the peak age for  clinical acne being 18 years.   Aedopathogenesis — the cause of acne is uncertain but  the androgen-sensitive sebaceous glands show a hyper-  responsiveness to testosterone that results in the follow-  ing sequence of events:    • Blockage of pilosebaceous units with excess keratin  and sebum, causing comedo formation   Figure 14.12 illustrates the pathogenesis of acne.  Clinical presentation — comedones (singular com-  edo) tend to be limited to the face, shoulders, upper  chest and back. They are of two types:   2. Closed as in whiteheads — small, cream-coloured,  dome-shaped papules formed through sebum  and keratin accumulations deeper in the ducts.   Usually combined with an oestrogen and  prescribed to females over a period of  6-12 months; suppresses sebum  production and is also a contraceptive   Isotretinoin: reduces sebum excretion,  inhibits Propionibacterium acnes and  is anti-inflammatory; 4- to 6-month  course; very effective but side  effects common    The colonization of ducts with Propionibacterium  acnes causes the evolution of comedones into inflam-  matory papules, nodules or cysts, which often form  scars on healing. This may persist until the early  twenties and even into the fifth decade of life in a few  patients, especially in women.   This chronic inflammatory disease of the face is charac-  terized by erythema, telangiectasia and pustules.   Telangiectatic dilatation of the upper dermal ves-  sels is common, and it causes erythema. Fragments  of the mite Demodex folliculorum are commonly  found in follicles but its role in the pathogenesis is  unclear.   Rupture of the follicles stimulates a granulomatous  reaction that leads to a florid, lumpy form of rosacea.   Rosacea typically affects the middle-aged or elderly.  There is intermittent facial flushing on top of persistent  erythema. Rosacea is often complicated by:    • eye involvement — blepharitis (inflammation of the  eyelids) and conjunctivitis   Management is by oral tetracycline but this will not  reverse telangiectasia or prevent erythema. Plastic  surgery may be required for rhinophyma.   This describes the loss of hair. It is commonly classified  into three main types: diffuse non-scarring, localized  non-scarring and scarring (cicatricial).   There is a diffuse reduction in hair density. The patient  usually notices excessive numbers of hairs on the  pillow, brush or comb.   • male pattern/androgenic alopecia — inherited, an-  drogen-dependent hair loss. Extremely common in  men but it also occurs in women, becoming more  pronounced after the menopause    • nutrition related — iron or zinc deficiency, malnutri-  tion especially kwashiorkor (protein deficiency)   • telogen effluvium — hair follicles, which are usually  out of phase, can, under certain circumstances, be-  come synchronized into the resting phase (telogen)  and then shed in unison 3 months later. The causes  of synchronization are high fever, childbirth, sur-  gery, drugs or stress   • alopecia areata — common condition associated  with autoimmune disorders, atopy and Down syn-  drome. The growth phase of hair is prematurely  arrested   • infections, e.g. with scalp ringworm (tinea capitis) or  secondary syphilis   It typically presents in the second or third decade of  life with bald patches on the scalp, but the eyebrows and  beard can also be affected. The nails may show pitting.   The course is unpredictable, varying from the pro-  gressive enlargement of bald patches to the regrowth  of hair (more common).   A poor prognosis is indicated if the onset is pre-  pubertal, associated with atopy or shows extensive  involvement.   Rarely, complete scalp alopecia (totalis) or loss of all  bodily hair (universalis) occurs.   This is caused by scarring of the scalp with the destruc-  tion of hair follicles.   • infection, e.g. shingles of the ophthalmic division of  the trigeminal nerve, tinea capitis or tertiary syphilis   This is the growth of coarse, pigmented hair with an an-  drogenic distribution in a female.   This is excessive growth of hair in a non-androgenic dis-  tribution. It is less common than hirsutism and can be:   Most common form; probably  due to increased hypersensitivity  of end-organ to androgens    • localized, e.g. on melanocytic naevi or following  topical steroid usage   • generalized — fine terminal hair appears on the face,  limbs and trunk. Mostly drug induced but it can also  be caused by anorexia nervosa (or malnutrition),  porphyria, cutanea tarda or underlying malignancy.   • Nail-patella syndrome — nails (and patellae) are ab-  sent or rudimentary   • Pachyonychia congenita — rare autosomal dominant  condition causing thickened, discolored nails pre-  sent from birth.   • Subungual haematoma — bleeding under the nail  following trapping of a finger- or toenail   • Splinter haemorrhages — almost always occur with  infective endocarditis, but they may also be trauma  or psoriasis induced   • Onychogryphosis — big toenails become thickened  and horn-like, usually in response to trauma   • psoriasis — pitting, nail thickening, onycholysis,  brown patches, subungual hyperkeratosis, splinter  haemorrhages   • acute paronychia — typically, a bacterial infection of  the nails usually caused by staphylococci.   • malignant melanoma — subungual malignant mela-  noma, which produces a pigmented longitudinal  streak in a nail and may cause its destruction.   This common disorder (1% of the population) is char-  acterized by the appearance of symmetrical white or  pale macules on the skin, which are caused by focal me-  lanocyte loss.   Aetiopathogenesis — it has been suggested that vitiligo is  an autoimmune disease of melanocytes, as it is often asso-  ciated with other autoimmune diseases, such as pernicious  anaemia, thyroid disease and Addison's disease.   The exact aetiology is unknown but about 30% of pa-  tients have a family history.   Clinical presentation — vitiligo affects all races, but is  more conspicuous in dark-skinned individuals.   Onset is usually between 10 and 30 years of age. It  commonly affects the hands, wrists, knees, neck and  areas around orifices (e.g. mouth). It has an unpredict-  able course, ranging from progression to repigmenta-  tion (rarely).   Vitiligo is managed with camouflage cosmetics and  sunscreens (for both cosmetic reasons and to reduce risk  of burning and skin cancer). Topical steroids occasion-  ally induce repigmentation in darker skins. PUVA (pso-  ralen and UV-A) is occasionally beneficial.   This is a rare (1 in 20 000) autosomal recessive disease  characterized by the lack of pigmentation in the skin,  hair and eyes. Melanocyte numbers are normal but mel-  anin production fails because of a deficiency or defect in  the enzyme tyrosinase.   The skin is white or pink, the hair is white and pig-  mentation is lacking in the eye. It is associated with poor  sight, photophobia and nystagmus. Albinos have an in-  creased risk of skin tumours on exposure to UV light.  Prenatal diagnosis is possible.   This autosomal recessive inborn error of metabolism is  caused by a deficiency of phenylalanine hydroxylase,  which normally converts phenylalanine to tyrosine.   Patients also have fair hair and skin because of im-  paired melanin synthesis (tyrosine is a precursor of  melanin). The concentration of phenylalanine and its  metabolites is increased and damages the neonatal  brain. Untreated, mental retardation and choreo-  athetosis develop, although a low phenylalanine diet  can prevent neurological damage.   The prevalence is 1 per 25 000 and it is detected by  routine screening tests (heel-prick or Guthrie test  performed around day 5 of life) .   A summary of the causes of hypopigmentation is  given in Figure 14.16.   Freckles are small, light-brown, well-demarcated mac-  ules that darken on exposure to sunlight. They contain  normal numbers of melanocytes but melanin produc-  tion is increased. They are common in childhood, espe-  cially in fair-skinned children. No treatment is required.   Lentigines (also known as lentigos) are similar in ap-  pearance to freckles but they are more scattered and they  do not darken in the sun. Their outline may be more ir-  regular than freckles. They contain increased numbers  of melanocytes and may develop in childhood, but they  are more common in a sun-exposed, elderly skin. They  respond to cryotherapy.   This can be caused by stimulation of melanogenesis or  by drug deposition in the skin. Drugs commonly re-  sponsible include amiodarone, bleomycin, psoralens,  chlorpromazine and minocycline.    Severe illnesses that affect nail growth,  e.g. pneumonia or myocardial infarction   Swelling of nail with loss of angle  between nail-fold and nail plate  \^^normal   Separation of part or all of nail from its bed Psoriasis, tinea unguium, trauma,   Acanthosis nigricans, malignant melanoma, naevi, argyria  (deposition of silver), chronic renal failure   This is characterized by hypoadrenalism, with overpro-  duction of adrenocorticotrophic hormone (ACTH) by  the pituitary gland. ACTH stimulates melanogenesis,  resulting in hyperpigmentation of mucosae and skin  creases.   Addisonian-like pigmentation is also seen in Cush-  ing's syndrome, hyperthyroidism and acromegaly.   This rare, autosomal dominant disorder is characterized  by perioral lentigines and intestinal polyps.    Blisters are fluid-filled spaces within the skin caused by  the separation of two layers of tissue and the leakage of  plasma into the space. The type of blister formed  (Fig. 14.18) depends on the level of separation. Itcanbe:   This rare but potentially fatal group of autoimmune dis-  orders is marked by successive outbreaks of blisters on  the skin and in the mouth.   Inflammatory cells attracted by complement activa-  tion release proteolytic enzymes resulting in subepider-  mal bullae formation, which tend to remain intact.   Clinical presentation — large, tense blisters com-  monly appear on the limbs, trunk and flexures, but  are occasionally localized to one site, often the lower  leg. Oral lesions occur in only 10% of cases. An urticar-  ial eruption may precede the onset of blistering.   The disease is self-limiting in about 50% of cases and  is managed with systemic steroids and other immuno-  suppressants.    Aetiopathogenesis — patients have circulating IgG au-  toantibodies that bind to intercellular junctions in the  epidermis. Binding of IgG activates complement and  adjacent keratinocytes are induced to release proteolytic  enzymes. Cellular adhesion is lost (acantholysis), and  an intraepidermal separation occurs.   This is also associated with other organ-specific auto-  immune disorders, such as myasthenia gravis.   Clinical presentation — the most common form is  pemphigus vulgaris, which typically affects middle-  aged people. Oral erosions precede cutaneous blister-  ing in 50% of cases. Flaccid, superficial blisters de-  velop over the scalp, face, back, chest and flexures.   If left untreated, the blistering is progressive and ul-  timately fatal (due to the loss of electrolytes and pro-  tein). Pemphigus is associated with a 15% mortality  rate. It is managed with systemic steroids and other im-  munosuppressive agents.   Aetiopathogenesis — an autoimmune disorder, in  which IgG antibodies are deposited at the basement  membrane.   This presents as a rare eruption of symmetrical itchy  blisters on the extensor surfaces.   Aetiopathogenesis — the aetiology is unknown but as-  sociated with coeliac disease (see Chapter 8). It is char-  acterized by granular IgA at the dermal papillae of  normal-looking skin and villus atrophy of the small  intestine.   It usually presents in the third or fourth decade of  life, with males more often affected than females by  2:1. There are groups of small, intensely itchy vesicles  on the knees, elbows, scalp, buttocks and shoulders.   Despite villus atrophy in most patients, symptoms of  gastrointestinal (GI) disturbances are uncommon. It  should be managed with a gluten-free diet with or with-  out dapsone.   Blistering diseases are rare but important because they can  be severe and are potentially fatal. Pemphigus vulgaris is  the most life-threatening type of blistering disorder.   Large, tense bullae  More common in elderly  Self-limiting in about 50% of cases   This common, benign tumour of basal keratinocytes  typically occurs on the trunk, face and arms of the el-  derly. The aetiology of these tumours is unknown. They  are also known as basal cell papilloma:   • Warts are often greasy looking (hence seborrhoeic),  but they are not associated with seborrhoea nor with  sebaceous glands   • Rare before 35 years old, then usually multiple, vary-  ing in size from a few millimetres to several  centimetres   • Progress from lightly pigmented, small papules to  darkly pigmented, warty nodules   • Often have a 'pasted on' appearance with well-  defined edges.   Microscopically, all lesions show basal cell proli-  feration, hyperkeratosis and a variable degree of  pigmentation.   This presents as roughened, scaly brownish-to-red  lesions, usually less than 1 cm across, which bleed when  rubbed. They typically arise on sun-exposed areas (also  known as solar keratosis), especially the face, scalp and  hands of the middle-aged and elderly.   Histologically, they show hyperkeratosis and para-  keratosis, abnormal keratinocytes with loss of matura-  tion, and a mild to moderate degree of pleomorphism  and mitotic figures.   The lesions are considered as premalignant, with  20% of them evolving into squamous cell carcinoma.   These benign, keratin-filled, firm, skin-coloured cysts  are normally 1-3 cm in diameter.   Common types are epidermal cysts (derived from the  epidermis) and pilar cysts (derived from the outer root  sheath of the hair follicle). These are often incorrectly  grouped together as sebaceous cysts.   These firm, reddish-brown papules are common in  young adults, females more than males, and usually ap-  pear on the lower legs.   Histologically, they consist of intertwining bands  of collagen fibres formed by proliferating fibroblasts,  with reactive hyperplasia and hyperpigmentation  of overlying epidermis. Dermatofibroma can be   A benign, rapidly growing, bright-red nodule arising  mainly on the fingers or face, typically at a site of trauma  (e.g. a thorn prick) and more commonly in young  adults and children. It is neither pyogenic nor granulo-  matous but is a well-circumscribed dermal lesion of pro-  liferating capillaries and inflammation that closely  resembles a haemangioma.   Excision and histological examination are required  to rule out malignant melanoma.   This is an excessive proliferation of connective tissue oc-  curring in previously injured skin (a form of scar), but  extending beyond the margin of the original injury.  Commonly seen in the healing of acne vulgaris. Charac-  teristics are:   • firm, smooth, erythematous nodules of irregular  shapes, occurring mainly over the upper back, chest  or ear lobes   • highest incidence in second to fourth decades of life.  Treatment is by steroid injection into the keloid.   Small, bright-red papules (1-2 mm diameter) com-  posed of benign capillary proliferations commonly arise  on the trunk in elderly or middle-aged patients.   A soft, subcutaneous tumour of mature adipocytes. This  is often multiple and mostly found on the trunk, neck  and upper extremities.   Naevi are benign, coloured lesions on the skin formed  from a proliferation of one or more of the normal con-  stituent cells of the skin. Although often congenital  (birthmarks), they may be acquired.   These consist of localized benign proliferations of mel-  anocytic cells and are the most common type of naevus  (also known as 'moles'). They present in most Cauca-  sians but they are less prevalent in those with Down syn-  drome; they are also less common in Black people.   The aetiology of naevi development is unknown but  it seems to be an inherited trait in many families:   • Majority develops during childhood or adolescence;  numbers reach a peak at puberty and they have a ten-  dency to decline during adult life   • A few new naevi develop during the third and fourth  decade of life, especially if provoked by excessive sun  exposure or pregnancy.   • Junctional naevi — flat circular macules consisting of  rounded nests of melanocytes in the lower epidermis  at the dermoepidermal junction   • Compound naevi — papules or nodules with an ir-  regular surface, which consist of junctional nests of  melanocytes combined with an intradermal mass  of melanocytic cells   • Intradermal naevi — dome-shaped papules/nodules  composed entirely of melanocytic cell clusters within  the upper dermis (no junctional component present) .  These different types of naevi are thought to arise   • congenital naevi — usually over 1 cm in diameter;  they may be protuberant or hairy and have a risk  of malignant change, which is believed to be propor-  tional to the size of the lesion   • blue naevi — steely blue intradermal naevus, usually  solitary and most commonly found on the  extremities   • halo naevi — white halo of depigmentation sur-  rounds naevi. Represents involution of naevus fol-  lowing immune response against naevus cells.  Mainly seen in children and adolescents   • familial dysplastic naevus syndrome — familial con-  dition characterized by large numbers of atypical  and 'dysplastic' naevi. Affected individuals have a  greatly increased risk of developing malignant  melanoma.   The majority of naevi are entirely benign but malig-  nant changes can occur. Junctional components of junc-  tional or compound naevi carry the highest risk for  malignancy. Invasion is preceded by nuclear pleo-  morphism with increased mitoses and cellular atypia.  Clinically, malignant naevi appear larger than normal  and have an irregular edge, surface and pigmentation.  They are also more likely to be itchy and to bleed.   • Increase public awareness about significance of  change in pigmented lesions   These common naevi are usually congenital or devel-  oped soon after birth. They are composed of small der-  mal blood vessels. There are four main types:   1. Salmon patch — most common type (present in  about 50% of neonates), typically on neck or eye-  lids. Usually fades quickly   2. Port wine stain naevus — irregular red/purple mac-  ule, which often affects one side of the face    3. Capillary haemangioma (strawberry naevus) —  common, red, nodular lesion, which develops dur-  ing the first few weeks of life, reaches its maximum  size in the first 12 months and then involutes. Most  cases have regressed by 5-7 years of age   4. Cavernous haemangioma — similar to strawberry  naevus but composed of larger and deeper channels  and presents as a nodular swelling. Regression is not  as complete.   The treatment is by camouflage cosmetics or laser  treatment for port wine stains. Strawberry naevi are usu-  ally left to involute but cavernous haemangiomas may  require surgery.   These warty, pigmented and often elongated naevi are  usually congenital or develop in early childhood. Most  are a few centimetres long but they can be extensive.  Treatment is by excision but recurrence is common.   Rare, skin-coloured papules composed of coarse colla-  gen bundles in the dermis. Common in tuberous  sclerosis.   This malignant tumour of melanocytes usually arises  in the skin. Incidence in the UK is 10 per 100 000  per year but it is rising steadily. Five-year survival  is nearly 80% in males and over 90% in females,  although women are more often affected than men  by 2:1.   It occurs in all races but it is more common in Cau-  casian races. Incidence is proportional to geographical    latitude, which suggests an effect of UV radiation. The  most common site in males is on the back but in fe-  males it is the lower leg.   The aetiology is unknown but repeated exposure to  UV radiation is thought to play an important role.   Major risk factors for the development of malignant  melanoma (with decreasing risk) are:   • familial dysplastic naevus syndrome — rare but life-  time risk of melanoma is over 50%   A flat tumour with variable pigmentation and irregular  edges. This is the most common type, accounting for  50% of all UK cases. There is a female preponderance  and it is most common on the lower leg.   A nodular lesion arising in a pre-existing lentigo  maligna. This typically occurs in sun-damaged skin of  the face in elderly patients. It comprises about 15% of  UK cases.   Lentigo maligna is similar to a benign lentigine but it  is generally larger, at over 2 cm, and it has atypical  melanocytes.   This resembles the lentigo malignant melanoma  but it affects the palms, soles and nail-beds (subungual  melanoma). It comprises 10% of UK cases but it is the   Very common, usually multiple, pigmented and benign  Consists of nests of melanocytic cells  Classified into junctional, compound and intradermal  Types are congenital, blue, halo, Becker's and dysplastic    most common form of malignant melanoma in oriental  people, suggesting it develops independently of UV  radiation exposure. It is often diagnosed late and conse-  quently has poor survival figures.   A pigmented nodule that may grow rapidly and ulcer-  ate, this accounts for 25% of UK melanomas. It is more  common in males, typically arising on the trunk. The  preceding in-situ phase of growth is very difficult to  identify in nodular melanoma.   Local invasion of the malignant melanoma is assessed  using the Breslow method (Fig. 14.23). The Breslow  thickness is the measured thickness in millimetres (on  a histological section) from the granular layer of the epi-  dermis to the deepest identifiable melanoma cell.   The Breslow thickness is directly related to the risk of  metastasis (Fig. 14.24). Tumours are divided into one of  three prognostic groups — good, intermediate or poor —  depending on their Breslow thickness.   Fig. 14.23 Staging of malignant melanomas using the Breslow  thickness technique.    Fig. 14.24 Five-year survival rates for malignant  melanomas of different Breslow thickness    Diagnosis — one or more of the following changes  observed or reported in a naevus or pigmented lesion  may suggest malignant melanoma:   A malignant tumour that arises from the basal keratino-  cytes of the epidermis, this is the most common form of  human cancer, typically seen on the face in elderly or  middle-aged subjects. It is five times more common  than squamous cell carcinoma (see below).   Risk factors for the development of basal cell carci-  noma include:   • repeated UV exposure — tumours are more common  in light-skinned races, with increasing incidence  towards the Equator   Management is by surgical excision (rarely plus  radiotherapy) with regular follow-up to detect  recurrence, which may be:   Tumours are typically composed of basophilic cells  that invade the dermis. They appear as well-defined  lobules and islands of cells.   Clinical presentation — they typically occur on sun-  exposed sites, commonly around the nose, inner can-  thus of the eyelids and the temple.    Tumours grow slowly but relentlessly and they may  destroy underlying cartilage, bone and soft-tissue  structures.   1. Nodular — most common form. Skin-coloured  nodule, which may show numerous telangiectatic  vessels and a glistening pearly edge. Often has  central ulceration with an adherent crust   2. Superficial (or multifocal) — flat, red plaque often  with an irregular rim-like edge and light pigmentation.  Often multiple and most commonly seen on the trunk   3. Morpheic — flat, thickened, whitish-yellowish waxy  plaque with indistinct edges. These may have focal  areas of ulceration.   Management — complete excision is usually the  best treatment but is not always possible. Radiother-  apy or cryotherapy is often used for non-excisable  tumours. Recurrence is about 5% at 5 years for most  methods of treatment.   This malignant tumour is derived from keratinocytes of  the upper layers of the epidermis. Typically seen on the  face in elderly or middle-aged subjects, with a male pre-  ponderance. Tumours are locally invasive and they may  also metastasize.   keratinocytes with typical malignant cytology, which  destroy the dermoepidermal junction and form invad-  ing strands into the dermis. Foci of keratinization are  seen within the tumour.   • dome-shaped nodules, which usually arise in sun-  exposed sites such as the face, neck, forearm or hand   • less aggressive form may arise within actinic kerato-  sis as a small papule, which progresses to ulcerate  and then crust over   • more aggressive forms may arise at the edge of  chronic skin ulcers (rare) .    Management — the treatment of choice is surgical ex-  cision. Radiotherapy can be used in some cases.   There are only two skin neoplasms in which metastasis  is a common feature:   2. Squamous cell carcinoma tumour of upper epidermal  keratinocytes, which metastasizes late.   This carcinoma in situ typically occurs on the lower leg  in elderly women. Its predisposition is associated with  previous exposure to arsenicals. It is characterized by:   • slowly extending, pink or lightly pigmented, scaly  plaques up to several centimetres in size. Can look  like psoriatic plaques   • full-thickness dysplasia with prominent nuclear  pleomorphism and large numbers of mitoses.  Carcinomas usually remain in situ for many years   This benign, self-limiting tumour typically arises on  the face of elderly white males. It grows very rapidly,  changing from a small, red papule to a large, domed  nodule with raised edges and a central mass of keratin  within a few weeks. It resembles a squamous cell  carcinoma but does not invade deeply and never  metastasizes.   This rare, slowly progressive (years) tumour of CD4 + (T  helper) lymphocytes evolves in the skin. There are four  stages:   This is a locally invasive dermal tumour of proliferating  myofibroblasts with low-grade malignancy. It is similar  in appearance to dermatofibromas but tends to be more  invasive and is characterized by protuberant nodules on  the epidermis. It does not metastasize but often recurs  following excision.   This malignant disorder is characterized by bluish-  brown plaques or nodules formed from a proliferation  of small blood vessels and spindle cells in the dermis. It    is caused by infection with the Kaposi sarcoma virus  (human herpes virus 8 (HHV8)).   It commonly occurs in association with acquired im-  munodeficiency syndrome (AIDS) but is also endemic  with cytomegalovirus in certain African regions. The le-  sions may be single or multiple, often beginning on the  feet and with a tendency to metastasize.    Single best answer questions (SBAs) . . .  Extended matching questions (EMQs) . .   1. A 12-year old boy with a 1-day history of sore throat  was seen by his CP. On physical examination, the most  prominent finding was a purulent pharyngeal exudate.  He most likely has an acute inflammation. In acute  inflammation which of the following is true?   2. The histopathology report for a tissue biopsy shows  that it is acute inflammation. Which of the following  features is seen in a tissue undergoing acute  inflammation?   4. Apototic cells usually exhibit distinctive morphological  features. Which of the following is true of pure  apoptosis?   5. The histopathology report for a tissue biopsy shows that  it is fat necrosis. Which of the following situation is most  likely to exhibit fat necrosis?    6. During an oncology department MDT meeting, the  oncologist mentions some medical terminology. Which  of the following definition is correct?   a. Dysplasia is a change from one type of  differentiated tissue to another   d. Metaplasia is the disordered development of cells  with loss of organization   8. You are reading a histopathology report which describes  the excised tumour as malignant. Which of the  following are common features of malignant tumours?   9. Which of the following statement about tumour  suppressor genes is correct?   a. Tumour suppressor genes encode proteins that  positvely regulate cell growth   c. Cain of function of tumour suppressor genes results  in neoplastic growth    c. If of the non-enveloped type, may release new  particles by budding   1 1 . A 34-year-old man who presented with infection with a  resistant species of enterobacteria was commenced on  oral ciprofloxacin. Which of the following is true of  bacterial antibiotic resistance?   d. May occur through the alteration of the target site  for an antibiotic   12 . A 65-year-old woman presented with headache,  vomiting, nausea, papilloedma. Upon admission to  hospital, the patient was noticed to have gait instability,  urinary incontinence and focal neurological signs.   A diagnosis of hydrocephalus was made. Which of the  following is true of hydrocephalus?   a. Is a decrease in the volume of CSF within the brain   c. Increased absorption of CSF at the arachnoid villi is  the commonest form   13 . A 34-year-old woman was hit in the head by a cricket  ball. After she was hit, she managed to walk off the field  without any symptoms. By the time she reached  hospital, she had died. Upon autoposy a diagnosis of  extradural haemorrhage was made. Which of the  following is true of extradural haemhorrages?   a. Occurs between the dura and outer surface of the  arachnoid membrane   14 . Upon autopsy an incidental finding of Alzheimer's  dieases was made. Which of the following is true of  Alzheimer's disease?   d. Affects half of all people over the age of 80 years   15. A patient with an intracranial neoplasm was  informed by the neurosurgeon that he had a tumour.    Which of the following is true about the neoplasms of  the CNS?   16. A 24-year-old man was found to have a ventricular  septal defect upon echocardiogram. Which of the  following is true of ventricular septal defect:   17. Coarctation of the aorta was diagnosed in a 4-year-old  child. Which of the following is true of coarctation of the  aorta?   18. Upon autoposy an incidental finding of atherosclerosis  was made. Which of the following is true of  atherosclerosis?   a. It is characterized by the accumulation of protein  rich material in the intima of arteries   d. It may be seen as a pathological response to  endothelial injury   e. It is characterized by neutrophil lipid uptake to form  foam cells   19 . During a routine checkup in the GP, a 34-year-old man  had consistently high blood pressure of 149 mmPIg  systolic. Benign hypertension is characterized by:   20 . A 56-year-old man has arrived in hospital complaining  of chest pains which radiated to his left hand, and upon  investigation had ECG changes concurrent with acute  myocardial infarction. Which of the following is true of  myocardial infarction?   d. Occlusion of the left anterior descending coronary  artery results in an inferior Ml   21. A 67-year-old man presents to the CP with  breathlessness upon exertion, orthopnea and oedema  of legs, feet and ankles. Which of the following of heart  failure is true?   a. Is when the heart is unable to maintain cardiac  output or can do so only by increasing filling  pressure   b. Right-sided heart failure is more common than left-  sided failure   c. Left-sided heart failure may commonly develop as a  result of right-sided failure   22. After a 12-hour plane flight, a 53-year-old female flight  attendent noticed a heavy ache over the right calf, with  associated swelling and tenderness. Which of the  following is true of thrombosis?   d. The most common site of venous thrombosis is the  portal vein   23. A 45-year-old man presented to his GP due to a slow  growing lump in his neck and hoarseness of voice. Upon  biopsy carcinoma of the larynx was diagnosed. Which  of the following is true of carcinoma of the larynx?   24. A 56-year-old man who is a chronic smoker presented  to hospital with an acute exacerbation of chonic  obstructive pulmonary disease. Which of the following  is true of chronic obstructive pulmonary disease?   b. The obstructive lung disease can be completely  reversed with bronchodilators   1 month of the year for at least 2 successive years   c. Hypersecretion of mucus is associated with  hypotrophy of the bronchial mucus-secreting  glands   26. A 12-year-old boy presents to his GP with coughing,  wheezing and shortness of breath. The CP subsequently  diagnosed him with asthma. Which of the following is  true of asthma:   b. May be caused by a type 1 1 hypersensitivity reaction   e. Is due to a mutation in a gene on chromosome 9   28. A 67-year-old man has come into hospital with  bronchial breathing in the right lung base, and  associated crackles. A clinical diagnosis of pneumonia  was made. Which of he following is true of pneumonia?   b. Most cases of bacterial community-acquired  pneumonia are due to Cram-negative organisms   e. Is less likely to occur if there is pre-existing  pulmonary oedema   29. A 29-year-old woman with cervical lymphadenopathy is  seen in a surgical outpatient clinic. An excision biopsy  was performed and sent for histopathology. Which of  the following is true of pulmonary tuberculosis?   b. Is caused by direct cytopathic effects of the infecting  organism   30. A 78-year-old smoker complaining of a persistent dry  cough had a chest X-ray which showed a 2 cm mass  lesion in the right upper zone. Biopsies was sent for    histological examination. Which of the following is true  of lung carcinoma:   e. Is the most common cause of death from neoplasia  in the UK   31. Which of the following is true of idiopathic pulmonary  fibrosis?   32. A 48-year-old man has suddenly developed sudden  onset of chest pain, cough, dyspnoea, tachypnoea and  marked anxiety. Two days ago he had just underwent  an operation. Which of the following is true of a  pulmonary embolism?   c. Can cause pulseless electrical activity  (electromechanical dissociation) of the heart   34. Which of the following is true of squamous cell  carcinoma of the oral cavity?   c. Adenocarcinoma is the most likely pattern in heavy  smokers or drinkers   37. Which of the following is true of Helicobacter pylori  associated gastritis?   b. Helicobacter pylori colonizes the epithelium above  a layer of mucus   c. Epithelial damage is caused by the immune response  against Helicobacter pylori   a. A reversible condition in which the liver's normal  architecture is diffusely replaced by nodules   d. Nodules are formed from regenerated hepatocytes  separated by bands of collagenous fibrosis   41. A 65-year-old has noticed that he has a full distended  abdomen and has complained of shortness of breath.  Which of the following is true of ascites?   a. Is the accumulation of free fluid in the peritoneal  cavity   b. It results from a mutation in a gene for a copper  transporter protein   c. Free copper overspills into the blood and deposits in  the cornea and the brain    43 . Which of the following is true of Hepatitis B?   e. Cirrhosis and hepatocellular carcinoma are not  complications of chronic infection   44 . A 54-year-old woman presented with increasing  abdominal distension. Physical examination revealed an  enlarged liver. Her serum alpha-fetoprotein is 40 times  the upper limit of normal. Which of the following is true  of hepatocellular carcinoma (HCC)?   45 . A 43-year-old woman is noted to have mild jaundice  and some weight loss. Her alkaline phosphatase level is  elevated and she has a positive anti-mitochondrial  antibody. She was subsequently diagnosed with  primary biliary cirrhosis. Which of the following is true of  primary biliary cirrhosis?   46 . Which of the following is true of carcinoma of the  pancreas?   e. Usually occurs in subjects older than 60 years of age   47 . A 25-year-old woman presented with a 1-week history  of right lower-quadrant pain and fever. She has also  noticed an increase in the frequency of stools and  occasional bloody diarrhoea. Following endoscopic  biopsy, a diagnosis of Crohn's disease was made. Which  of the following is true of Crohn's disease?   48 . A 45-year-old man has developed iron deficiency  anaemia secondary to chronic bloody diarrhoea.   A colonic biopsy showed the presence of ulcerative  colitis. Which of the following is true of ulcerative  colitis?   49 . Which of the following is true of coeliac disease?   d. Anti-endomyseal antibodies are a useful blood test  to aid diagnosis   e. A gluten-free diet improves symptoms but the  intestinal changes are irreversible   50 . Which of the following is true of colorectal carcinoma?   b. Familial adenomatous polyposis patients rarely  develop colorectal cancer if untreated   51 . Which of the following is true of adult polycystic kidney   52 . Which of the following is true in glomerular disease?   a. Nephrotic syndrome in an adult is strongly  suggestive of minimal change nephropathy   c. Minimal change disease rapidly progresses to renal  failure in children   d. A focal proliferative glomerulonephritis with  autoantibodies against type III collagen is indicative  of Goodpasture's syndrome   e. Streptococcal sore throat may be a cause of  proliferative glomerulonephritis   53 . Which of the following is true of renal cell carcinoma?   e. All cases are sporadic as no genetic association has  been identified   d. Most commonly arises at the base of trigone and  around the ureteric orifaces   b. A minority of individuals are positive for thyroid-  stimulating hormone (TSH)-receptor antibodies in  their serum   e. Causes the same change in thyroid hormone levels  as Hashimoto's thyroiditis   56. Which of the following is true of malignant thyroid  tumours?   e. Anaplastic carcinoma is not associated with a history  of multinodular goitre   58. Which of the following is true of Type I diabetes  mellitus?   d. Shows destruction of insulin secreting cells of the  islets of Langerhans   59. Which of the following is true of Type II diabetes  mellitus?   60. Which of the folowing is true of carcinoma of the  uterine cervix?   c. Has no association with some serotypes of human  papilloma virus (HPV)   61. A 26-year-old woman is diagnosed with endometrosis.  Which of the following statements regarding  endometriosis is correct?   a. Is defined as endometrial glands or stroma occurring  outside of the uterus   62. Which of the following is true of pelvic inflammatory  disease?   a. Is a combined inflammatory disorder of the fallopian  tubes, ovaries and peritoneum   63. A 30-year-old woman is diagnosed with ectopic  pregnancy, which of the following statements about  ectopic pregnancy is true?   d. Proliferation of the ectoblast causes erosion of the  submucosa and bleeding   a. Is defined as high blood pressure during pregnancy  where it was previously normal   b. Is more common in a first pregnancy or with  multiple pregnancies   d. The main risks are to the mother rather than the  fetus   a. Most common cause of death in women aged over  60 years of age   66. A 76-year-old man presents with urinary retention  had a digital rectal examination which suggested  that he had an enlarged prostate with a craggy  nodular feel. Biopsy of the lesion suggested  malignancy. Which of the following is true of prostate  carcinoma?   c. Is more likely to cause urinary symptoms than  benign prostatic hyperplasia   e. Bones appear less dense on X-ray and lumbar  vertebral bodies often appear more biconcave than  normal   68. A 56-year-old woman is on long-term corticosteroid  therapy for severe rheumatoid arthritis. Which of the  following is true of rheumatoid arthritis?   b. The likelihood of onset increases with age, therefore  peaking in the elderly   d. Causes the development of a pannus and  inflammatory joint destruction   69. Which of the following is true of the human  immunodeficiency virus (HIV)-I.   d. The most common amyloid in reactive systemic  amyloidosis is the AL type   71. Which of the following is true of leucopenia and  leucocytosis?   c. Leucocytosis is most commonly caused by an  increase in lymphocytes   72. A lymph node biopsy was performed on a 45-year-old  man who presented with a low-grade fevers, night  sweats and generalized malaise for a couple of months.  He was found to have cervical lymphadenomapthy.   A diagnosis of Hodgkin's disease was confirmed upon  biopsy. Which of the following is true of Hodgkin's  disease?   e. Of the mixed cellularity type has the most  favourable prognosis   74. A 67-year-old man was found to have numerous small,  mature lymphocytes. A diagnosis of chronic lymphocytic  leukaemia was made. Which of the following statements  is correct regarding chronic lymphocytic leukaemia?   a. Is caused by a point mutation in the DNA coding for  the a-globin chain   77. Which of the following definitions are correct regarding  skin pathology?   a. Nodule is a raised lesion less than 5 mm across   b. Is less common where there is a strong family history   e. Dermatitis herpetiformis involves granular IgG  deposition at the dermal papillae of normal looking  skin   c. Has no increase in incidence with familial dysplastic  naevus syndrome   d. With a depth of invasion of 3.5 mm has a good  prognosis    In each of the following questions, select the condition listed  that is most likely to fit the given description.   I. The diagnosis in a patient with diffuse ventricular  dilatation on CT scanning of the brain, who has had  ventriculopertioneal shunt surgery.   2. A possible diagnosis in a 70-year-old woman whose  husband complains that she has been getting  increasingly forgetful over a period of months.   B. The diagnosis in a 23-year-old man presenting with  rapidly developing focal neurological signs several hours  after he sustained a head injury in a motorbike accident.   4 . A condition that causes episodes of acute CNS  demyelination separated in time and space.   5. The diagnosis in a patient with an infection of the  leptomeninges that has caused brain abscess. Lumbar  puncture revealed a cloudy CSF with increased protein  and decreased glucose.   I. A condition that causes headache, dizziness, intercostal  bruits and radiofemoral pulse delay.    2. The diagnosis in a patient with sudden onset chest pain,  radiating to between the scapulae, who develops  asymmetry of pulses in his arms and legs. Chest X-ray  reveals mediastinal widening.   3. The diagnosis in an elderly patient who has an ejection  systolic murmur and a propensity for syncope. A narrow  pulse pressure and slow-rising carotid pulse are also  detected.   4 . A condition that has the potential to cause scalp  tenderness, headache and blindness. Erythrocyte  sedimentation rate is significantly raised.   5. A condition that causes a left-to-right shunt with  pansystolic murmur.   I. A response to noxious agents causing reduced FEV-i,  reduced FEV-|/FVC ratio and characterized by a CD8 +  T-cell infiltration.   2. The likely diagnosis in a 45-year-old non-smoker, with  no past history of respiratory illness, who presents with  shortness of breath and wheezing. Salbutamol inhaler  completely resolves the breathing difficulties.   3. The cause of abnormally thickened mucus affecting  both the lung and pancreas.   4 . A lung condition that may cause cough, haemoptysis,  shortness of breath and chest pain, and which is  exquisitely sensitive to chemotherapy and radiotherapy  in its early stages.   5. The likely diagnosis in a patient with a granulomatous  condition affecting the lung and other organs. Blood  tests reveal hypercalcaemia and a raised serum  angiotensin converting enzyme.   I. The most likely diagnosis in a 25-year-old woman  complaining of a 3-month history of diarrhoea,  who has recently developed a blistering rash on her  elbows.   2. The diagnosis in a 27-year-old female who presents  with intermittent diarrhoea and weight loss. Endoscopy  reveals multiple small bowel strictures occurring  between areas of normal looking bowel.   5. The diagnosis in a 50-year-old male with leaden grey  pigmentation of his groins and axillae. A liver biopsy  shows increased iron deposition and some hepatic  fibrosis.   I. The likely diagnosis in a 5-year-old boy who develops  facial swelling. Urinalysis reveals heavy proteinuria, but  no blood. A kidney biopsy shows no abnormality on  light microscopy.   2. The likely diagnosis in a 25-year-old man who is being  investigated for renal failure. He is complaining that he is  having to change the prescription for his glasses every  few weeks to see clearly and that he is struggling to hear  some sounds.   3. Describes a form of acute renal failure that is normally  reversible and may be caused by an ischaemic or toxic  insult.   5. The diagnosis in a 55-year-old man presenting with  haemoptysis and haematuria. A renal biopsy shows  crescentic change and IgG deposits in the basement  membrane.   I . The most likely diagnosis in a patient who presents with  diarrhoea, vomiting, abdominal pain and profound  hypotension. She has been on regular prednisolone to  treat her temporal arteritis for over a year, but recently  suddenly stopped taking it because she was worried  about the side effects.   3. Is the most likely diagnosis in a patient who has recently  had mumps infection, with persisting fatigue in  recovery. She has now developed a painful lump in her  neck, and has noticed that she has cold hands and is  'really suffering the cold weather'.   4. Is characterized by central obesity, moon face,  hypertension, osteoporosis, menstrual irregularity and  hirsutism.   5. Is a disorder of polyuria and polydipsia that is caused by  a failure of hormone production from the posterior  pituitary. 
CrashCourseFoundationDoctorsGuideToMedicineAndSurgery2ePDFtahir99VRG CrashCoursePathology4epdftahir99Vrg_djvu.txt