95-Draznin-Chap95.indd 520 3/31/2011 8:59:29 PM POSTPRANDIAL REACTIVE HYPOGLYCEMIA (PRH) 521 Management Diet \200 Frequent, small, low-carbohydrate, high-protein meals \200 Avoid r apidly absorbed carbohydrates \200 Avoid sugary drinks, especially in combination with al cohol \200 Addition of soluble dietary \201 bers, e.g., 5 \200\22310 g guar gum, or pec tin, or hemicellulose per meal, delays absorption and lowers the glycemic and insulinemic indices ( especially effective in rapid gut transit time). Drugs \200 Acarbose, an intestinal A-glucosidase inhibitor, delays sugar and starch absorption, thus reducing the insulin response to a meal. Metformin 500 mg can be useful with meals. \200 Supplemental chromium is reported to down -regulate B-cell activity and increase glucagon secretion. In exceptional cases, with debilitating PRH, diazoxide (side effects are water retention, h ypertrichosis, digestive disorders), or somatostatin analogs may be required. Propranolol and calcium antagonists have been used; however, controlled studies are lacking. Further reading Brun JF, Fedou C, Mercier J (2000). Postprandial reactive hypoglycemia. Dia bet Metab 26:337 \200\223351. Gama R, Teale JD, Marks V (2003). Clinical and laboratory inv estigation of adult spontaneous hypoglycemia. J Clin Pathol 56:641 \200\223646. Teale JD, Wark G (2004). The effectiveness of different treatment options for non-islet cel l tumor hypoglycemia. Clin Endocrinol 60:457 \200\223460. 95-Draznin-Chap95.indd 521 3/31/2011 8:59:29 PM CHAPTER 96 Obesity 522 Obesity De \201 nition Obesity is de \201 ned as an excess of body fat (adiposity) suf \201 cien t to adversely affect health. In the almanac of direct measurements of body fat mass, body mass index (BMI) is a commonly used surrogate marker (see Box 96.1 ). \200 Obesity is oft en de \201 ned in terms of BMI. \200 BMI does not take body build or fat distribution in to consideration, and thus can be misleading in the presence of large muscle mass. Lower cutoff values may be applicable to non-Caucasian ethnic groups. \200 Fat distributi on: central (abdominal) obesity ( \200\234apple shape \200\235) vs. gluteofemoral obesity ( \200\234pear shape \200\235). Apple-shaped people have an i cardiovascular risk compared to that of pear-shaped people. Adverse consequences of central obesity may re \202 ect i visceral (intra- abdominal fat) stores, (blood draining into the portal vein may expose the liver directly to the ef \202 uent from visceral fat). Assess fat distribution using waist circumference (see Boxes 96.2 and 96.3). Box 96.1 BMI BMI (kg/m 2 ) = weight (kg) / [height (m)] 2 Classi \201 cation BMI (kg/m 2 ) WHO class <18.5 18.5 \200\22324.9 25.0 \200\22329.9 30.0 \200\22334.9 35.0 \200\22339.9 >40.0 Underweight Healthy Pre-obese (overweight) Obese class I (obese) Obese class II (obese) Obe se class III (severely obese) 96-Draznin-Chap96.indd 522 3/31/2011 4:25:06 PM EPIDEMIOLOGY 523 Box 96.2 Waist circumference Suggested indicators of central obesity (and i cardiovascular risk): Waist circumference \200 Men >40 in (102 cm) \200 Women >35 in (88 cm) Another s tudy suggested a waist circumference of <100 cm makes insu- lin resistance unlikely (irresp ective of sex). tain racial and ethnic backgrounds. Waist circumference cutoffs should be adjusted for individuals of cer- Box 96.3 Measurement of waist circumference Measurements should be recorded over underwear or light clothing. The subject should stand with their arms by their sides. The position of the waist is midway between the lower rib margin and the iliac crest. 1. Identify the bony landmarks in the mid-axillary line. a. The lower rib margin (bottom of the rib cage) b. The iliac crest (highest bony part of the pelvis) 2. Measure the vertical distance between them. Note the midpoint. 3. Ask the subject to sta nd with their feet 23 \200\22330 cm apart. 4. Ensure that the tape measure is at the same l evel around the body at the midpoint. Gently tighten the tape measure so that it is taut bu t not too tight. 5. Ask the subject to breathe normally and record the measurement at the end of normal expi ration. 6. Record waist circumference. Epidemiology There has been a rapid increase in obesity in both the developed and developin g worlds. In the United States, the prevalence of obesity has increased \200\224in 1980, 12% of men a nd 16% of women were obese. By 2004, the \201 gures had increased to 31% and 33%, respect ively. Now, 2/3 of the population is either overweight or obese. Prevalence in children has also increased rapidly (17% of adolescents in 2004) with an attendant risk of type 2 diabetes. In some ethnic populations, prevalence of overweight is >75%. Prevalence varies with age (p eak prevalence at 50 \200\22370 years) and socio- economic class. 96-Draznin-Chap96.indd 523 3/31/2011 4:25:06 PM CHAPTER 96 Obesity 524 Etiology Genetic factors Monogenic This is rare. \200 Leptin de \201 ciency or resistance (massive obesity and hy perphagia in early childhood) (see Box 96.4 ) Prader \200\223Willi syndrome (obesity, learning dif \201 culties, chromosome 15) \200 L awrence \200\223Moon \200\223Biedl syndrome (obesity, polydactyly, learning dif \201 culties, retinitis pigmentosa) Melanocortin 4 receptor (MC4R) de \201 ciency (obesity, hyperphagia, dominant inheritance (see Box 96.5 ) Box 96.4 Leptin \200 First hormone described to be secreted from adipose tissue \200 En coded by Lep gene (chromosome 7q31.3) \200 Synthesized in and secreted by adipose tissue \200 Affects the hypothalamus to decrease food intake and increase energy expenditure (by sympathetic activation) Primary role in humans may be to indicate nutritional depletion or fasting and for falling leptin levels to indicate insuf \201 cient energy reserves for growth and reproduction Exerts potent anti-obesity effects in animals such as the ob / ob (leptin de \201 cient) mouse Leptin therapy bene \201 ts humans with congenital leptin de \201 ciency and leptin-de \201 cient partial lipodystrophy. Most obese humans do not have abnormalities of the leptin gene. Plasma leptin i in obese hu mans, and obese humans appear to be leptin resistant. Reduced leptin transportation to the brain has been suggested as a potential mechanism of leptin resistance in humans. Trials in humans with polygenic obesity are equivocal (high doses of SC leptin lead to more weight loss than placebo, but long- term consequences of supraphysiological doses are unkn own; sympathetic activation for weight loss by other agents has unwanted side effects). Loss of function mutations in the leptin receptor gene is associated with hyperphagia and e arly-onset obesity; serum leptin levels do not predict leptin receptor mutations. \200 Le ptin is stimulated by glucocorticoids. 96-Draznin-Chap96.indd 524 3/31/2011 4:25:06 PM ETIOLOGY 525 Box 96.5 Melanocortin peptides \200 Melanocortin peptides are derived by cleavage from pr o- opiomelanocortin (POMC). Mutations result in ACTH de \201 ciency, obesity, and pale skin (and no hair in Caucasians). Mutations in the receptor (MC4R) are the most common mongenic causes of obesity found \200 \2241% of adults with BMI >30 kg/m 2 and 5 \200\2236% of overly obese children under the ag e of 10. MC4R mutations are dominantly inherited. Polygenic Estimates of heritability range from 40 to 80%, thus genetic factors play a major role in obesity. Environmental factors Excess energy intake or d energy expenditure due to physical inactivi ty are major determinants of obesity in genetically susceptible individuals. Secondary causes These include Cushing \200\231s disease or syndrome, hypothyroidism, and h ypothalamic lesions ( i appetite). 96-Draznin-Chap96.indd 525 3/31/2011 4:25:06 PM CHAPTER 96 Obesity 526 Pathophysiology There is complex regulation of appetite and energy expenditure that is stil l not fully understood. Understanding has not yet been translated into therapeutic modaliti es (perhaps re \202 ecting that long-term attempts to change one pathway leads to compensa tory changes in other pathways). Long-term signals associated with body-fat stores are prov ided by leptin and insulin. These circulating molecules also modulate short-term signals th at determine meal initiation and termination. Short-term information about hunger and satiety is provided by gut hor- mones, such as chol ecystokinin, ghrelin (Box 96.6), and peptide YY 3 \200\22336 (PYY), and signals from vagal afferent neurons within the GI tract that respond to mechanical deformation, macronutrient balance, pH, tonicity, and hormones. Neural and humoral signals from speci \201 c regions of the hypothalamus, brain stem, and neural networks are involved in regulation of energy homeostasis and are regulated by perip heral signals such as leptin, which regulates neuropeptides and neurotransmitters expressed in these brain areas. In fat vs. carbohydrates , overall, there is close regulation of metabolism and storage of carbohydrates, but not of fat. In terms of weight homeostasis , overeating increases both fat-free mass (FFM) and fat mass ( 1 kg FFM gain for 2 kg fat gain). FFM is the major determinant of resting energy expend iture. Box 96.6 Ghrelin \200 Plasma concentrations inversely proportional to degree of obesity \200 Peptide (28 amino acids) from oxyntic cells in the stomach fundus \200 Acts on GH s ecretagogue receptors to increase release of GH from the pituitary Also important in energy homeostasis \200 Appears to regulate pre-meal hunger and meal in itiation \200 Circulating ghrelin concentrations increase preprandially and decrease postprandially. Ghrelin increases food intake through the stimulation of ghrelin receptors on hypothalamic neuropeptide Y \200\223expressing neurons and agouti-related prot ein-expressing neurons ( b see Box 96.7 ). \200 Patients with Prader \200\223Willi syndro me have disproportionately elevated levels of ghrelin, although the relevance of this \201 nding is unclear. 96-Draznin-Chap96.indd 526 3/31/2011 4:25:06 PM CONSEQUENCES OF OBESITY 527 Box 96.7 Neuropeptide Y (NPY) \200 Synthesized in the arcuate nucleus of the hypothalamus and transported axonally to the hypothalamic paraventricular nucleus \200 A potent appetite s timulant and reduces sympathetic output, thus reducing energy expenditure i By insulin and glucocorticoids, and d by leptin and estrogen \200 Genetic studies have not shown any association between the genes for NPY or its receptor in human obesity. Consequences of obesity Increased body fat is associated with i morbidity and mortality, bu t the causal link is unclear. For example, low cardiorespiratory \201 tness is an inde- p endent predictor of cardiovascular disease, irrespective of body fat. Standardized mortality rates rise sharply at BMI of 30 kg/m 2 . Diseases associated with ob esity include the following: Type 2 diabetes (BMI >40 in <55-year-old leads to i risk 18-fold in men, 13-fold in women) Hypertension (BMI 25 \200\22329.9 leads to i risk 1.6-fold; BMI >40 leads to i risk 5.5-fold) Dyslipidemia (moderate relationship with total cholesterol, closer relationship with i triglycerides, d HDL cholesterol) \200 Cardiovascular disease (BMI >2 9 leads to i risk 4-fold) \200 Gall bladder disease (men, BMI >40 leads to i risk 21-fold ; women, BMI >40 leads to i risk 5-fold). Osteoarthritis, varicose veins, obstructive sleep apnea, some cancers (e.g., endometrium, breast, ovary, prostate, colon) However, obesity protects against osteoporosis. 96-Draznin-Chap96.indd 527 3/31/2011 4:25:06 PM CHAPTER 96 Obesity 528 Evaluation of an obese patient \200 Weight history from birth on (early onset is associat ed with genetic syndromes) Previous treatment or management strategies and their success \200 Current eating habits and activity levels \200 Triggers for eating \200 Family history of obesity \200 Como rbidities such as cardiovascular disease, diabetes, psychological issues (depression, low s elf-esteem), osteoarthritis, obstructive sleep apnea, polycystic ovarian syndrome Assess for coexistent cardiovascular risk factors such as smoking and diabetes, family history of cardiovascular disease. Look for eruptive xanthomata (hypertriglyceridemia), acanthosis nigricans (insulin resistan ce), skin tags (insulin resistance), striae (Cushing \200\231s syndrome), and fat distribut ion (Cushing \200\231s, partial lipodystrophy \200\224probably underdiagnosed). Consider a secondary cause if there are additional clinical features: \200 Hypothyroidism (measure TSH) \200 Cushing \200\231s syndrome (measure 24-hour urinary free cortisol and consider dexamethasone suppression testing) Hypothalamic disorder (uncontrolled appetite \200\224MRI) \200 Prader \200\223Willi syndr ome \200 Lawrence \200\223Moon \200\223Biedl syndrome Consider coexistent conditions, e.g ., polycystic ovary syndrome. Box 96.8 Metabolic syndrome \200 A clustering of metabolic risk factors: hyperinsulinemia , impaired glucose tolerance or frank diabetes, i triglycerides, d HDL cholesterol, hypertension, and central obesity Associated with i risk of vascular disease. Data suggest that >95% of centrally obese patients have some risk factors; <50% of subcutaneously obese patie nts do as well. Different diagnostic criteria exist. A typical de \201 nition is three of the following cr iteria: \200 Abdominal obesity (see abdominal circumference cutoff values) \200 Raised plasma triglyceride concentrations \200 Low plasma HDL-cholesterol concentrations \200 Raised blood pressure \200 Impaired fasting glucose 96-Draznin-Chap96.indd 528 3/31/2011 4:25:06 PM INVESTIGATIONS 529 Investigations Consider the following: \200 CBC (polycythemia) \200 Electrolytes \200 Liver function tests (LFTs) (nonalcoholic steatohepatitis, subsequent cirrhosis) Glucose (impaired fasting glucose, diabetes) \200 Fasting lipid pro \201 le (raised trig lycerides, total and LDL-cholesterol, lowered HDL cholesterol) TSH (hypothyroidism) \200 Urine dipstick (glycosuria with diabetes, proteinuria with glom erular hyper \201 ltration) ECG (coronary vascular disease, left ventricular hypertrophy) \200 Waist circumference \200 Height and weight 96-Draznin-Chap96.indd 529 3/31/2011 4:25:06 PM CHAPTER 96 Obesity 530 Management Weight normalization and maintenance rarely occurs. Even in the best weight mana gement programs about 10% of weight is lost, but most people regain 2/3 of the lost weight in a year, and 95% of it is gained in 5 years. A weight loss of 5 \200\22310% of the initia l body weight reduces the health risks associated with obesity. The aims should be modest weight loss maintained for the long term, with treatment methods and goals being decided for each individual after careful assessment of the degree of overw eight and any associated comorbid conditions. See Box 96.9. There is a limited range of treatments available. The \201 rst-line strategy for weight l oss and its maintenance is a combination of supervised diet, exercise, and behavior modi \201 cation. Diet Diet alone does not usually maintain weight loss, and most dieters regain weight withi n 3 years. Reduce calorie intake to 500 kcal below current intake. Reduce fat intake \200\224standard dietary advice is to limit fat intake to 20 \200\22335% of total calorie intake. Reduction of fat intake can lead to weight loss, often with- out a conscious reduction in calorie int ake. Extreme diets may have problems: Very low \200\223calorie diets (<600 \200\223800 kcal/day) are used occasionally for up to 26 weeks in specialized centers in combination with high-q uality pro- teins (daily intake of 1 g/kg of ideal body weight), electrolytes, vitamins, an d trace elements. These can produce weight loss of 2 kg/week (more in the \201 rst week as glycogen-bound \202 uid is lost). Weight is often regained after stopping the diet. Side effects include fatigue, malaise, and electrolyte disturbances. Very high \200\223carbohydrate/low-fat diets have been associated with hypertrig- lyceridemia and lower LDL-cholesterol concentrations. Box 96.9 Effects of losing weight \200 Diabetes: weight loss of 5 kg Halves the risk of developing type 2 diabetes \200 Improves glycemic control Hypertension: weight loss of 1 kg reduces blood pressure by 1 \200\2232 mmHg. \200 Dyslip idemia : weight loss of 1 kg: Lowers LDL cholesterol by 0.77 mg/dL \200 Lowers triglycerides by 1.33 mg/dL \200 Raise s HDL cholesterol by 0.35 mg/dL Obesity-related cancers: weight loss of 0.5 \200\2239 kg is associated with a 53% reduction in cancer-related deaths. Osteoarthritis and obstructive sleep apnea: weight loss has signi \201 cant mechanical bene \201 ts. Gallstones: weight loss (or weight gain) can provoke gallstone formation by altering the cholesterol saturation of bile. 96-Draznin-Chap96.indd 530 3/31/2011 4:25:06 PM MANAGEMENT 531 Low-carbohydrate/high-protein diets (>25% of calories as protein) have lit- tle or no long- term safety data (especially on renal disease, ischemic heart disease; diets tend to be hig h in saturated fat and cholesterol). Side effects include constipation, renal stones, and i urinary calcium losses. They can be effective in inducing weight loss. They probably work by i sense of satiety, leading to a d calorie intake. Exercise Exercise is the most effective method of maintenance of weight loss when combined with calorie restriction and behavioral modi \201 cation. It pro- motes the preservation o f FFM (the major determinant of resting energy expenditure) in the face of weight loss. Current recommendations are 20+ minutes exercise 3 \200\2235 times/week. Regular exercise i nduces cardiorespiratory \201 tness and leads to a ben- e \201 cial effect on other risk factors, with a reduction in blood pressure and improvement in lipid pro \201 le. Interestingly, nonvoluntary activity ( \200\234 \201 dgeting \200\235) is a signi \201 ca nt deter- minant of resting energy expenditure. Factors controlling nonvoluntary activity a re unclear. Behavioral interventions Few relevant data are available, but these should probably include self- monitoring of behavior and progress, stimulus control, goal setting, slow- ing rate of eating, social support, problem solving, assertiveness, cognitive restructuring (modifyi ng thoughts), reinforcement of changes, relapse pre- vention, and strategies for dealing wi th weight regain. A formal psychological assessment of patients with eating disorders (a minority of obese patients) is helpful. Drug treatment This should be used in combination with other treatments (exercise, cal- ori e restriction, behavior modi \201 cation). It is for the following patients: Those at medical risk from obesity (BMI >30kg/m 2 ); or \200 Those with BMI >27 with esta blished comorbidities (e.g., diabetes, heart disease, severe respiratory problems, dyslipidemia). Use drug treatment only after dietary and lifestyle modi \201 cations have been unsuccessf ul (de \201 ned as not achieving a 10% weight reduction after at least 3 months of supervi sed care). Not all obese patients respond to drug therapy. Stop drug treatment if 5% weight reduction is not achieved. \200 If a 5% weight loss is a ttained, treatment may be continued, provided body weight is continually monitored and weig ht is not regained. \200 Rapid weight regain is common after short-term use of anti-obesi ty drugs (12 weeks or less). Fat-absorption inhibitors Orlistat \200 Intestinal pancreatic lipase inhibitor; reduces fat absorption 96-Draznin-Chap96.indd 531 3/31/2011 4:25:06 PM CHAPTER 96 Obesity 532 Increases dietary fat loss to 30% (compared to <5% on placebo) \200 Average weight loss o f 5 \200\22310% \200 Licensed for use up to 2 years. \200 Contraindications: cholestasi s, malabsorption syndromes \200 Drug interactions with warfarin (possible d vitamin K abs orption) and cyclosporine (reduced serum drug levels) No data on patients aged >75 years \200 Dosing: 60 \200\223120 mg with main meals \200 Consider vitamin supplementation (especially vitamin D) if there is concern about fat-soluble vitamin de \201 ciency. Side effects include \202 atus (24%), oily rectal discharge, fatty stool (20%), fecal urg ency (22%), fat-soluble vitamin de \201 ciency, and incontinence (8%). Side effects are li mited by dietary fat reduction (to <35% of energy). Appetite-suppressant drugs Phentermine \200 Centrally acting noradrenergic/dopamine relea se inhibitor \200 Decreases food intake \200 Average weight loss 5% \200 Cautions: hy pertension, vascular disease \200 Drug interactions: sympathomimetics, MAO inhibitors, ot her anorexants Side effects: increased BP and HR, insomnia, agitation, dry mouth, headache, tremor Approved for only 3 months use only \200 Dosing between 15 and 37.5 mg daily Other appeti te-suppressant drugs, such as fen \202 uramine and dexfen \202 u- ramine, have been withd rawn because of associations with valvular heart disease and pulmonary hypertension. Surgery Bariatric \200 Associated with signi \201 cant weight loss for at least 8 years \200 I mproves QoL, hypertriglyceridemia, and hyperuricemia, and reduces the incidence of type 2 diabetes Data on bene \201 t to BP and cholesterol concentrations unclear \200 Jejunoileal bypass and jaw wiring are not recommended. \200 Only indicated in severely obese (>100% above i deal weight, BMI >40 or BMI >35 with serious comorbidities) adults (>18 years) \200 Failure to lose weight bef ore surgery is not a contraindication. \200 Candidates for surgery should be thoroughly a ssessed with multidisciplinary assessment (including a biopsychosocial assessment). Long-term follow-up is required. Malabsorptive bariatric surgery: \200 Shortening the length of gut so that the amount of food absorbed by the body is reduced 96-Draznin-Chap96.indd 532 3/31/2011 4:25:07 PM MANAGEMENT 533 Most common procedure now is Roux-en-Y gastric bypass. Jejunoileleal or biliopancreatic diversions are less common and associated with dumping syn drome or recurrent hypoglycemia. Restrictive bariatric surgery: \200 Induces early satiety, limits rate of food intake, or both \200 E.g., laparoscopic gastric banding (reduction in functional capacity of stomach by partitioning off part of the body of the stomach) Liposuction The bene \201 t of liposuction on metabolic parameters is equivocal. One study has shown that removal of 10 kg SC abdominal adipose tissue by liposuction failed to improve parameters such as BP, plasma glucose, and insulin concentrations. Further reading Brennan AM, Mantzoros CS (2006). Drug insight: the role of leptin in human physiology and patho- physiology \200\224emerging clinical applications. Nat Clin Pract End ocrinol Metab 2(6):318 \200\223327. Kahn R, Buse J, Ferrannini E, et al. (2005). The metabolic syndrome: time for a critical ap praisal joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 28(9):2289 \200\2232304. National Institute for Health and Clinical Excellence (NICE) Clinical guideline 43: Obesity guidance on the prevention, identi \201 cation, assessment, and management of overweight and obesity in adults and children. http://www.nice.org.uk/page.aspx?o=91525 Rucher D, Padwal R, Li SK, et al. (2007). Long term pharmacotherapy for obesity and overwei ght: updated meta-analysis. BMJ 335(7631):1194 \200\2231199. Sj str m L, Narbo K, Sj str m CD, et al. (2007). Effects of bariatric surgery on mortal ity in Swedish obese subjects. N Engl J Med 357(8):741 \200\223752. 96-Draznin-Chap96.indd 533 3/31/2011 4:25:07 PM CHAPTER 97 Endocrinology and aging 534 Endocrinology and aging Introduction Aging causes changes in many hormonal axes. How much of this change is normal physiology associated with aging and how much represents true endocrine dysfunction and thu s warrants treatment is unclear. Concomitant disease and polypharmacy are common in the elderly population, with frequent secondary effects on the endocrine system. 97-Draznin-Chap97.indd 534 4/1/2011 6:25:40 PM FLUID AND ELECTROLYTE HOMEOSTASIS IN THE ELDERLY 535 Fluid and electrolyte homeostasis in the elderly Elderly patients are particularly prone to \202 uid and electrolyte distur- bances due to changes associated with aging, concomitan t disease, and drug usage. Elderly patients have d renal function compared with that of younger patients: \200 d Glomerular \201 ltration rate (GFR) with creatinine clearance d by 8 mL/min/1.73 m 2 per decade after age 30 i Renovascular disease \200 d Renal sensitivity to circulating hormones Aldosterone \200 Vasopressin \200 Atrial natriuretic peptide (probable) \200 d Abilit y to dilute or concentrate urine Elderly patients have d renin levels with secondary decrea ses of aldoster- one levels (both basal and stimulated levels). Aldosterone levels may be < 50% normal by 70 years of age. Increased renal sensitivity to aldosterone may result in iso lated mineralocorticoid de \201 ciency (distal renal tubular acidosis [type 4] with hypona tremia, hyperkalemia, hyperchloremia, and normal anion gap acidosis); this is more common w ith diabetes mellitus. Vasopressin and ADH Unlike many other hormones, vasopressin (ADH) responses are poten- tiat ed in elderly patients with i release from the neurohypophysis in response to an osmotic st imulus and less effective suppression. Normal vasopressin release is a balance of inhibitory and stimulatory effects at barorecept ors and osmoreceptors. It may be that loss of inhibi- tion with aging due to degenerative c hanges results in relatively unop- posed stimulation of ADH and a d ability to suppress ADH release. In addition, altered renal sensitivity to vasopressin results in d ability to excrete free water. Hypernatremia and dehydration Perception of thirst is altered in elderly persons (in younge r people, thirst is perceived at plasma osmolalities >292 mOsm/kg, whereas in older peo- pl e, thirst is perceived at plasma osmolalities >296 mOsm/kg). Elderly patients may also be u nable to ingest \202 uids because of other disabilities and/or effects of medications. Thus, elderly persons are particularly susceptible to dehydration (e.g., during hot summers). Hyponatremia This is particularly common in elderly patients (prevalence of 2 \200\22320%). In hospital patients, overall incidence of hyponatremia (Na <137mmol/L) is 7%, but in geri atric facilities it is 18 \200\22322%, with 53% incidence of one or more episodes of hypona tremia at any time during admission to geriatric care facilities. 97-Draznin-Chap97.indd 535 4/1/2011 6:25:40 PM CHAPTER 97 Endocrinology and aging 536 Mortality rates in hospitalized elderly patients with hyponatremia are high (in patients ag ed >65 years, 16% mortality in those with hyponatremia compared with 8% without hyponatremi a). Hyponatremia is often associated with medication (e.g., diuretics). It is the most common e lectrolyte disturbance in cancer ( b see SIADH due to ectopic vasopressin production, p. 55 0). Symptoms include confusion, lethargy, coma, and seizures. The overall approach to investiga tion and management is similar to that for hyponatremia in younger patients ( b see Hyponatremia, p. 156). Mild idiopathic hyponatremia is also recognized in elderly patients, with- out necessarily having a sinister cause or consequence, and is thought to be secondary to an altered thresh old for ADH secretion. 97-Draznin-Chap97.indd 536 4/1/2011 6:25:40 PM BONE DISEASE 537 Bone disease Osteoporosis Osteoporosis is not an inevitable part of aging but it is a commo n disease in elderly people and is associated with high morbidity and mortality in both mal es and females. b See Osteoporosis (p. 405). Vitamin D de \201 ciency and osteomalacia This is very common in the elderly. Vitamin D in suf \201 ciency (evidence of secondary hyperparathyroidism, i bone turnover, BMD loss) occ urs at levels of 25OH-vitamin D <50 nmol/L. Vitamin D de \201 ciency is usually de \201 ned at levels <30 nmol/L (with addi- tional p roblems of myopathy, i sway, d psychomotor function, and frank osteomalacia). Vitamin D de \201 ciency and/or insuf \201 ciency is common particularly in eld- erly ins titutionalized patients in extreme latitudes and in fracture patients. In a Danish study, 4 0% of postmenopausal women had vitamin D levels of 25 \200\22350 nmol/L, with a further 7% with frank de \201 ciency (<25 nmol/L). 80% of elderly men and women (aged >65 years) have vitamin D insuf \201 ciency. 44% of nursing home patients have severe vitamin D de \201 ciency (25OH vitamin D <12 nmol/L). In patients with hip fracture, 75% have vitamin D insuf \201 ciency, 25% have vitamin D de \201 ciency, and 5% have severe vitamin D de \201 ci ency (25OH vitamin D <12.5 nmol/L). Supplementation with 800 IU vitamin D and 1200 mg calcium daily in insti- tutionalized elde rly patients reduces falls and fractures Supplementation in free-living elderly patients (> 65 years of age) also d fracture risk. Vitamin D is known to have an antitumor effect with d proliferation, i differentiation of c ells, and i apoptosis of malignant cells. Vitamin D may also boost the immune response with further antitumor effect. Vitamin D insuf \201 ciency and/or de \201 ciency may contribute to higher rates of malig nancy in elderly patients (e.g., breast, colon, and prostate). Therapeutic use of vitamin D in malignant disease is limited by hypercalcemia. Primary hyperparathyroidism Prevalence of primary hyperparathyroidism is 10/100,000 in wome n <40 years old, rising to 190/100,000 in women >65 years old. Half of all cases of primary hyperparathyroidism occur in women >60 years old. Elderly people are more prone to symptoms (weakness, fatigue, confu- sion) at relatively mild levels of hypercalcemia (2.8 \200\2233.0 mmol/L). Other causes of hypercalcemia must be excluded. Coexisting vitamin D insuf \201 ciency and de \201 ciency is common. Management is similar to that described in b Chapter 68, Hyperc alcemia (p. 376). Surgery is not contraindicated by age alone. Paget \200\231s disease b See Chapter 73, Paget \200\231s disease (p. 421). Further reading Mosekilde L (2005). Vitamin D and the elderly. Clin Endocrinol 62:265 \200 \223281. 97-Draznin-Chap97.indd 537 4/1/2011 6:25:40 PM CHAPTER 97 Endocrinology and aging 538 GH and IGF-1 in the elderly Many of the features of aging resemble growth hormone de \201 ciency. Changes in body composition include d lean body mass ( d body water, d muscle mass, and d bone mass) and i total body fat and visceral fat mass, associated with abnormal lipi d pro \201 le ( i total and LDL cholesterol, i TGs), insulin resistance, and cardiovascula r disease. Overall, integrated GH concentrations show a decrease with age with d GH pulse amplitude and duration, but pulse frequency unchanged. IGF-1 falls with i age (re \202 ected in age-adjusted normative ranges). IGF- BP3 also falls with age (and is also GH dependent). Older patients with GH de \201 ciency related to pituitary disease are usu- ally easily di fferentiated from other subjects with age-related decline in IGF-1 using standard provocati ve testing (GH response to insulin-induced hypoglycemia, arginine, or glucagon). Treatment with GH in patients with clear GH de \201 ciency results in i lean body mass and bone mine ral den- sity, and d adipose tissue, as well as possibly psychological and functional impro vement. Small, frequently open-label studies of supraphysiological doses of GH given to healthy old er persons have shown that GH may result in improved body composition (improved physiologic al function has not been observed). Side effects are frequently observed in the treated gro up (edema, arthralgias, carpal tunnel syndrome, glucose intolerance) and the- oretical conc erns of malignancy related to raised IGF-1 levels remain. GH is not approved for healthy elderly people without clear evidence of GH de \201 ciency. 97-Draznin-Chap97.indd 538 4/1/2011 6:25:40 PM GONADAL FUNCTION IN THE ELDERLY 539 Gonadal function in the elderly Women The mean age of menopause is 51 years (range 35 \200 \22358 years) and is de \201 ned retrospectively after 12 months of amenorrhea as the perm anent cessa- tion of menstruation due to loss of ovarian follicular activity. FSH 10 \200\22315 x higher than premenopausal levels \200 LH 3 \200\2235 x higher \200 Estrogen 10% of previous level (often lower than those of men of similar age) Inhibin is often undetectable. The adrenal gland is the major source of sex steroids postme nopausally, with estrogen production mainly from aromatization of adrenal androgens (andros tenedione) in adipose tissue. Low FSH/LH may indicate hypopituitarism, although gonadotropins may be depressed by serious illness. b See Chapter 51, Menopause (p. 264) for further discussion. Men Men may remain potent and fertile until their death. However, sexual activ- ity, libido , and potency decline gradually and progressively from midlife. As with GH, there is an overlap between clinical features of hypogonad- ism and normal agin g (loss of lean body mass and muscle function, increase in fat mass, loss of virility, loss of libido, and d sexual and overall well- being). Functional secondary hypogonadism is com mon in serious chronic illness, especially when associated with malnutrition and debilitati on. Normal ranges for testosterone in men of different ages have not been well established. Free testosterone levels decrease slowly with age, but there is signi \201 cant intra- and interindividual variation. SHBG increases with age. Testicular weight, Leydig cell functio n, and FSH/LH response to GnRH stimulation all decrease with age. The extent to which lower testosterone per se and/or a lower free androgen index explain th e age-related decline in sexual function is not clear. Although testosterone levels may be lower than in younger men, testosterone levels are still suf \201 cient for normal libido and sexual func- tion. Profoundly low testosterone levels (<230 ng/dL in an A.M. blood samp le) in the appropriate clinical setting should prompt investigation for hypoandrogenism. Gonadotropins should be raised in primary testicular failure. Low lev- els associated with low testosterone should prompt a search for second- ary causes, although gonadotropins may be low because of other serious disease. Fat body mass increases more than lean body mass with age. Thus there is i aromatization of androgens to estrogens. The effects of this are unclear. Hypoandrogenism may also result from hyperprolactinemia due to pituitary/hypothalamic disea se, renal dysfunction, hypothyroidism, or drugs 97-Draznin-Chap97.indd 539 4/1/2011 6:25:40 PM CHAPTER 97 Endocrinology and aging 540 (psychotropic and antidopaminergic agents), all more common in the eld- erly population. Testosterone therapy There are a few small studies in elderly men, either as replacement in patients with clear hypogonadism or in healthy men. Data point toward a positive effect on well-being, muscle mass, and strength and in d fat m ass in elderly patients, the greatest effect being in patients with clear hypogonadism. Risks include secondary polycythemia, liver dysfunction (particularly if testosterone is ta ken orally), prostatic hyperplasia, exacerbation of pros- tate adenocarcinoma, and possibly dyslipidemia. Erectile dysfunction This is common in elderly men; 50% of men >60 have erectile dysfunctio n; 90% of these men have concurrent medical problems or are on medica- tion potentially cau sing impotence. Etiology is often multifactorial: Atherosclerosis \200\224most common cause with both macro- and microvascular disease Penile denervation \200\224autonomic neuropathy (most commonly due to diabetes mellitus); p elvic surgery (including prostatectomy \200\22430% of men >75 develop erectile dysfunction after prostatectomy [cf. 7% of younger men after prostatectomy]) Drugs ( B-blockers, calcium channel antagonists, other antihypertensive agents, psychotropic drugs) Psychogenic Delayed or absent ejaculation Increased incidence is common with age, due to au tonomic nerve dys- function, drugs, previous surgery, and is usually the harbinger of erect ile dysfunction. Evaluation is similar to that of younger patients ( b see Evaluation, p. 308). Management i s similar to that for younger patients, with the caveat that phosphodiesterase inhibitors m ay interact with nitrates and antihyperten- sive agents. Fertility Spermatogenesis persists into old age. There are very few data regarding spermato zoa number, motility, and morphology in elderly men. However, errors in DNA replication increase with age, as re \202 ected in paternal age effects in some genetic disorders. 97-Draznin-Chap97.indd 540 4/1/2011 6:25:41 PM ADRENAL FUNCTION IN THE ELDERLY 541 Adrenal function in the elderly Cortisol Overall, cortisol secretion in elderly persons is generally very similar to that in younger persons. Dynamic testing shows more prolonged release of ACTH and cortisol to stress (physiological, insulin-induced hypoglycemia, and/or CRH admin- istration) and slower inhibition of ACTH s ecretion by cortisol. Dehydroepiandrosterone sulfate DHEA and DHEAS levels peak in humans aged 20 \200\22330 year s and thereafter decline with age (20% of peak values in men and 30% of peak values in wome n by age 70 years). Responsiveness to ACTH-stimulated secretion also reduces with age. The physiological relevance of the fall of DHEA and DHEAS levels with age is not established. Replacement in otherwise healthy elderly patients has not consistently demonstrated improve d longevity, well-being, bone density, cognitive function, body mass composition, or cardio vascular status in double-blind placebo-controlled trials, despite many Internet claims to the contrary. Aldosterone b See Fluid and electrolyte homeostasis in the elderly (p. 535). 97-Draznin-Chap97.indd 541 4/1/2011 6:25:41 PM CHAPTER 97 Endocrinology and aging 542 Thyroid disease Thyroid disease is twice as common in the elderly as in younger patients. Goiter Diffuse goiter becomes less frequent with age in both men and women (found in 31% of women aged <45 years compared with 12% of women aged >75 years on clinical examination). Multinodular goiter as assessed by both clinical and US examination increases with age (inc idence of US-detected multinodular goiter is 90% of women >70 years, 60% of men >80 years). Management is similar to that of multinodular goiter in younger patients ( b see Multinodular goiter and solitary adenomas, p. 44). Abnormal thyroid function tests Concomitant disease and polypharmacy are common in the elde rly and may alter the interpretation of results. For example, glucocorticoids (pre- scribed to 2.5% of the population aged 70 \200\22379 years) cause decreased TSH, d thyroid hormone release, d concentration of thyroid hormone binding proteins, and d T 4 -to-T 3 conversion . Sick euthyroid syndrome is more common in the elderly because of frequent, concurrent nonth yroidal illness, with reduced free tri-iodothyro- nine (FT 3 ), i reverse free tri-iodothyr onine, and (less commonly) reduced free thyroxine (FT 4 ), along with inappropriately norma l or suppressed TSH levels.