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. Hypothyroidism This is the most common thyroid problem in elderly people, affecting 2 \200 \2237% of elderly people. The male-to-female ratio increases with aging. The most common causes are autoimmune thyroiditis, previous sur- gery, or radioiodine therapy. Only 25% present with classical symptoms of hypothyroidism. An insidi- ous decline in healt h and mobility is more common than cold intolerance, hair loss, or skin coarsening. The elderly are more susceptible to hypothyroid (myxedema) coma than younger people; it remains rare, however. Hypothyroidism should be considered in elderly patients with increased CK or transaminases, d Na, macrocytic anemia, or dyslipidemia. Thyroid replacement therapy should be done cautiously as ischemic heart disease may be unma sked or exacerbated, e.g., 12.5 \200\22325 mcg/day of levothyroxine i by 12 \200\22325 mcg increments every 3 \200\2238 weeks until TSH is normalized. Total replacement T 4 dosage is lower in the elderly than in younger patients (in younger p atients approximately 1.6 mcg/kg is required but older patients may require 20 \200\22330% less). Hyperthyroidism This affects 2% of elderly people. Presentation is often atypical, often wi th few signs or symptoms. 97-Draznin-Chap97.indd 542 4/1/2011 6:25:41 PM THYROID DISEASE 543 Commonly, symptoms are mainly in a single, vulnerable organ system, e.g., depression, letha rgy, anxiety, confusion and agitation; muscle wasting and weakness; heart failure, arrhythm ias, atrial \201 brillation; weight loss; and osteoporotic fracture. An isolated suppressed TSH concentration is associated with an i car- diovascular mortality and a 3-fold higher risk of atrial \201 brillation in the next 10 years. From 2 to 24% o f elderly patients with atrial \201 brillation are hyperthyroid and 9 \200\22335% of elde rly patients with hyperthyroidism have atrial \201 brillation. The underlying cause may be toxic multinodular goiter or Graves \200\231 disease. Treatment options are similar to those in younger patients ( b see Treatment p. 21). Radioactive iodine is favored because it is de \201 nitive and it avoids risks of surgery. Hypothyroidism is common after radioiodine therapy. Thyroid cancer The total incidence rate for all thyroid cancers is unchanged in the elderly , but the relative frequencies are altered. Papillary carcinoma is more com- mon in young a nd middle-aged patients, but the prognosis is poorer in the elderly. Follicular carcinoma i s more common with aging. Anaplastic thyroid carcinoma occurs almost exclusively in patients >65 years. It presents w ith a rapidly growing hard mass that is often locally invasive and may be associated with m etastatic lesions. The prognosis is poor. Sarcomas and primary thyroid lymphomas are more common in elderly patients. Overall evaluation and treatment are similar to that of younger patients, but accurate preo perative histology is very important, as tumors not treated surgically (e.g., anaplastic ca rcinoma and lymphoma) are relatively more common. Glucose homeostasis Elderly patients have impaired glucose homeostasis and are more likely to manifest hyperglycemia in response to acute illness and stress (e.g., post \200\223 myoc ardial infarction). Further reading Grimley Evans J, Williams TF, Michel J-P, et al. (eds.) (2000). Oxford Text book of Geriatric Medicine . Oxford, UK: Oxford University Press. Vermeulen A (Ed.) (1997) Endocrinology of aging. Baillieres Clin Endocrinol Metab 11:223 \200\223250. 97-Draznin-Chap97.indd 543 4/1/2011 6:25:41 PM CHAPTER 98 Endocrinology of critical illness 544 Endocrinology of critical illness Endocrine dysfunction and AIDS Wasting syndrome De \201 nition This is the involuntary los s of >10% of baseline body weight in combination with diarrhea, weakness, or fever. Wasting is an AIDS-de \201 ning condition. Cause The cause is unknown but in part re \202 ects d calorie intake due to anorexia assoc iated with secondary infection. Underlying i resting energy expendi- ture is associated wit h HIV infection per se. Hypogonadism is common in men with wasting syndrome. Treatment Highly active antiretroviral therapy (HAART) HAART is associated with overall weight gain, though lean body mass may remain unchanged. Nutritionally based strategies Adequate caloric intake is required to meet metabolic demand s. Ef \201 cacy is limited as refeeding generally increases fat body mass with little or l ess effect on lean body mass. Appetite stimulants Megestrol acetate increases caloric intake and weight compared to pla- cebo, although most of the weight gain is due to i fat mass. Dronabinol stimulates appetite but weight gain is minimal. Exercise Although exercise can increase total and lean body mass in patients with AIDS, its role in patients with wasting syndrome is not known. Androgen therapy In hypogonadal male patients with wasting syn-drome, testosterone increase s overall weight and in particular lean body mass. Both IM and transdermal testosterone are effective. Testosterone therapy not indi- cated in eugonadal men with wasting. Growth hormone therapy Patients with the wasting syndrome generally have GH resistance, as sug- gested by high serum GH and low IGF-1 levels. The most likely cause for this is undern utrition. 98-Draznin-Chap98.indd 544 4/1/2011 5:57:19 PM ENDOCRINE DYSFUNCTION AND AIDS 545 High-dose GH has shown improvements in lean body mass and protein balance in patients with acquired GH de \201 ciency or severe catabolic states. Side effects (peripheral edema, art hralgias, myalgias) are common due to the high doses required. GH may improve fat redistrib ution that occurs with refeeding. Cytokine modulators Although many in \202 ammatory cytokines are i during acute illness an d sepsis, their speci \201 c role in wasting syndrome is not known. Thalidomide, a potent inhibitor of tumor necrosis factor (TNF), can increase body weight and reduce protein catab olism but has a very high rate of serious side effects and is contraindicated in women of c hildbearing age due to phocomelia. Lipodystrophy Loss of SC fat occurs, particularly in the face, peripheries, and buttocks, i n some cases with concomitant SC fat deposition, particularly in the abdominal area, neck, dorsocervical area ( \200\234buffalo hump \200\235). Visceral fat deposition also occurs. Lipodystrophy is associated with dyslipidemia with hypertriglyceridemia, low HDL cholestero l, insulin resistance, glucose intolerance, and (less commonly) frank diabetes mellitus. Th ere is i cardiovascular mortality from myocardial infarction. It is also associated with HIV-1 protease inhibitors (PIs), used as part of HAART. 40% of p atients treated with PIs will develop lipodystrophy by 1 year. HIV PI-naive patients have s imilar body composition and fat distribution to that of non-HIV-infected men. Indinavir may be less potent in inducing lipodystrophy than ritonavir and saquinavir. Abnormal body composition and hypertriglceridemia may be part of the refeeding phenomenon f ollowing improved well-being and loss of anorexia. Nucleoside reverse transcriptase inhibit ors may be associated with fat loss and accumulation as well, but this may be a separate ph enome-non from that seen with PIs. Management \200 Observation in mild cases \200 Very low \200\223fat diets and exercise (particular resistance exercise) \200 Withdrawal or switching of PIs in some circumstance s may be warranted. \200 Anabolic agents (testosterone, GH) are not effective. \200 Lip osuction from areas of fat accumulation; fat pad insertions for areas of lipoatrophy also used Standard lipid-lowering agents for hypertriglyceridemia (e.g., gem \201 brozil) HMG CoA reductase inhibitors metabolized by P4503A4 (which is inhibited by PIs) so risk of myopathy may be i The role for thiazolidinediones is unclear. Adrenal Adrenal insuf \201 ciency This is uncommon (<4% of patients with AIDS). In patient s with clinical signs suggestive of adrenal insuf \201 ciency (hyponatremia, and hypovolem ia), there is a 30% incidence of inadequate response to Cortrosyn. 98-Draznin-Chap98.indd 545 4/1/2011 5:57:20 PM CHAPTER 98 Endocrinology of critical illness 546 Causes Infection This is histologically common. Adrenal function is usually maintained, sin ce 10% of residual adrenal tissue is adequate for normal function. \200 CMV (adrenalitis found postmortem in 40 \200\22390% of patients dying of AIDS) Mycobacterium avium intracellulare (MAI) complex, tuberculosis \200 Cryptococcus Neoplasm \200 Lymphoma, Kaposi \200\231s sarcoma Hemorrhage Drug induced \200 Rifampicin induces i hepatic metabolism of corticosteroids. In patients with already compromised adrenal reserve, this may precipitate an addisonian crisis. Ketoconazole inhibits cortisol synthesis. \200 Megestrol acetate possesses glucocorticoid activity and may cause secondary adrenal insuf \201 ciency. Abrupt cessation after long-t erm treatment may precipitate an adrenal crisis. Secondary adrenal insuf \201 ciency \200 Drugs (megestrol acetate) \200 Hypopituitaris m secondary to toxoplasmosis, Cryptococcus , CMV \200 Idiopathic anterior pituitary necro sis Hypercortisolism Mild hypercortisolemia is common in all stages of HIV infection, without c linical manifestation of Cushing \200\231s syndrome. Possible causes \200 Chronic stress \200 Proin \202 ammatory cytokines \200 Binding protein dysfunction \200 Glucocorticoid resistance Gonads Males Testosterone de \201 ciency is common in male patients with AIDS (6% of patie nts with asymptomatic HIV infection compared with 50% of patients with AIDS). Hypogonadism is associated with wasting, d muscle mass, fatigue, loss of libido, and impote nce. Hypogonadism may be primary or secondary; up to 75% of patients with hypogonadism have low or inappropriately normal gonadotropins. 98-Draznin-Chap98.indd 546 4/1/2011 5:57:20 PM ENDOCRINE DYSFUNCTION AND AIDS 547 Causes Primary hypogonadism \200 Testicular destruction/in \201 ltration: due to infecti on (CMV most commonly, MAI, toxoplasma, TB) or neoplasm (lymphoma, Kaposi \200\231s sarcoma, germ cell t umors) Drug induced: ketoconazole (inhibits steroidogenesis causing lowered testosterone levels); megestrol acetate, other glucocorticoids Secondary hypogonadism This is due to malnutrition, severe acute illness, destructive disor ders of pituitary/hypothalamus (CMV, toxoplasmosis, lymphoma), and medica- tions such as me gestrol acetate (glucocorticoid-like action causes hypogo- nadotropic hypogonadism). Females Hypogonadism in women as evidenced by oligo- and amenorrhea is less common than in men unless there is advanced disease. Fertility rates are not affected until there is advan ced disease. Hypoandrogenism (testosterone, DHEA) is common in women with wasting syndrome. Electrolyte disturbance due to endocrine pertubation in HIV/AIDS Hyponatremia This is very common in advanced disease and is due to SIADH in 50%. Adrenal insuf \201 ciency also a co mmon cause. Calcium disorders Hypocalcemia \200 Common (18% of patients with AIDS). Main cause is vit amin D de \201 ciency. Other causes include severe illness; hypomagnesemia; altered PTH secretion /metabolism; malabsorption of calcium and vitamin D due to GIT opportunistic infection; and medications (foscarnet [complexes with calcium], pentamidine [induces renal magnesium wast ing and secondary PTH de \201 ciency]). Hypercalcemia \200 Rare. It may relate to lymphoma or granulomatous disease. Thyroid Overt thyroid dysfunction is uncommon. The most common thyroid dys- function is sic k euthyroid syndrome (nonthyroidal illness). Increased thy- roid-binding globulin is often observed (signi \201 cance is unknown). Subclinical hypothyroidism may occur during HAART. Infections These are rare and are usually postmortem diagnoses. Thyroid function is usually euthyroid or sick euthyroid. \200 Pneumocystis jirovecii (may also cause a thyroiditis) \200 Mycobacteria 98-Draznin-Chap98.indd 547 4/1/2011 5:57:20 PM CHAPTER 98 Endocrinology of critical illness 548 Cryptococcus neoformans \200 Aspergillosis Neoplasm This is rare and is usually euthyroid or sick euthyroid. It may be hypothy- roid d ue to in \201 ltrative destruction. \200 Kaposi \200\231s sarcoma \200 Lymphoma Pituitary \200 Anterior hypopituitarism is very rare. \200 Posterior pituitary dysfunct ion causing diabetes indipidus (DI) is common. Infection, toxoplasmosis, TB \200 Neoplasm, cerebral lymphoma 98-Draznin-Chap98.indd 548 4/1/2011 5:57:20 PM CANCER 549 Cancer Chemotherapy and radiotherapy may have endocrine effects. Anticancer chemotherapy There are three types of anticancer chemotherapeutic agents. Cytotoxics These have no direct hormonal sequelae. Alkylating agents are more likely to ind uce permanent male sterility (without affecting potency) and in women they may induce prema ture menopause, which may increase the likelihood of osteoporosis. Immunomodulators Prednisolone in excess causes Cushing \200\231s syndrome, and acute withdr awal may precipitate adrenal insuf \201 ciency. Cyclophosphamide in particular may cause e arly menopause. Thyroid dysfunction has been reported rarely with tacrolimus and inter- feron- A and - B therapy. Hormones Progestogens are used in breast cancer. Of these, megest rol acetate has potent glucocorticoid activity and thus may cause Cushing \200\231s syndrom e in excess or adrenal insuf \201 ciency if abruptly withdrawn. Aromatase inhibitors such as aminoglutethimide may cause adrenal insuf- \201 ciency and corticosteroid replacement is necessary. Trilostane , which inhibits 3 B-hydroxysteroid dehydrogenase, may also cause adrenal insuf \201 ciency. Gonadorelin analogs , used for prostatic cancer and breast cancer, cause an initial increas e in LH levels and then suppression and cause side effects similar to those of orchiectomy in men and menopause in women. Antiandrogens used in prostatic cancer have predictable side effects such as gynecomastia, hot \202 ashes, impotence, and impaired libido. Radiotherapy Cranial radiotherapy whose \201 eld encompasses the hypothalamic \200\223 pi tuitary area may result in hypopituitarism (see Chapter 13, Hypopituitarism, p. 94). Head and neck irradiation may result in hypothyroidism and hypoparat- hyroidism. After 5 or more years of follow-up, 50% of patients treated with radio- therapy only for la ryngeal and pharyngeal carcinoma will develop hypothy- roidism. Combined surgery and radiot herapy results in roughly 90% of patients developing hypothyroidism. The rates for hypopara thy-roidism are 88% and 90%, respectively. Radiotherapy affects the testes dose dependently. Fertility is af-fected much more than and rogensynthesizing capacity, so most men have normal testosterone levels unless given testic ular doses >20 \200\22330 Gy. The effects of radiotherapy to both ovaries are ampli \201 ed with age. Premature menopause may be elicited by doses >10 Gy. 98-Draznin-Chap98.indd 549 4/1/2011 5:57:20 PM CHAPTER 98 Endocrinology of critical illness 550 Syndromes of ectopic hormone production De \201 nition The secretion into the systemic cir culation, of a hormone or other biologi- cally active molecule, by a neoplasm (benign or ma lignant) that has arisen from tissue that does not normally produce that hormone or molecul e, results in a clinically signi \201 cant syndrome. See Table 98.1 for common syndromes a ssociated with ectopic hormone production. SIADH due to ectopic vasopressin production Diagnosis \200 Hyponatremia (Na <130 mmol/L) \200 Dilute plasma (serum osmolality <270 mmol) \200 Inappropriately concentrated urine (in the face of hyponatremia and plasma hypoosmolality, any urine osmolality >plasma osmol ality is inappropriate) Persistant renal Na excretion \200 Euvolemia (or very mild hypervolemia) \200 Normal re nal, adrenal, and thyroid function Plasma urea and uric acid levels can be helpful markers of plasma dilution. The most common tumors causing SIADH are tumors with neuroen- docrine f eatures, most commonly small-cell lung carcinoma and carcinoid tumors. Small-cell lung carc inomas have usually metastasized by the time SIADH is present. Lung diseases and neurological disorders (including malignancies) may cause SIADH due to ab errant hypothalamic vasopressin release rather than vasopressin release from the tumor per se. In SIADH due to ectopic hormone secretion, release of vasopressin from the neurohypophy sis may be suppressed. Other causes of SIADH must be excluded (b see Syndrome of inappropriate ADH, p. 159). Management Hyponatremia The initial management is \202 uid restriction with daily monitor ing of the plasma sodium and osmolality. Hyponatremia has usually developed grad- ually, an d its correction should be similarly gradual. Fluid restriction to 500 mL total \202 uid intake per day may be needed for several days. Urate levels can be useful as a marker of water intoxication and its resolution. As hyponat remia is corrected, \202 uid restriction can be relaxed depending on the plasma sodium; 1 500 \200\2232000 mL/day is usual. For patients in whom \202 uid restriction is insuf \201 cient or not possible, demeclocy cline (150 \200\223300 mg daily) can be used to produce a nephrogenic diabetes insipidus to achieve a normal plasma sodium. Demeclocyline can result in photosensitivity,thus patients should be warned to avoid pro- longed exposure to sunlight. Life-threatening hyponatremia (e.g., convulsions) may rarely require hyper- tonic saline an d furosemide. However, rapid correction of hyponatremia may 98-Draznin-Chap98.indd 550 4/1/2011 5:57:20 PM SYNDROMES OF ECTOPIC HORMONE PRODUCTION 551 Table 98.1 Common syndromes associated with ectopic hormone production Syndrome Ectopic hormone Typical tumor types Hypercalcemia of malignancy PTHrP Squamous cell lung carcinoma Other squamous cell carcinoma (skin, esophagus, head, and neck ) Renal cell carcinoma Breast adenocarcinoma Adult T-cell lymphoma associated with HTLV-1 1,25(OH) 2 cholecalciferol Lymphomas SIADH Vasopressin/ADH Small-cell lung carcinoma Squamous-cell lung carcinoma Bronchial carcinoid Mesothelioma Pan creatic or gut carcinoid Adenocarcinoma of the duodenum, pancreas, prostate Pheochromocytom a Medullary thyroid carcinoma Hematopoietic malignancies (lymphoma, leukemia) Cushing \200\231s syndrome ACTH (most commonly) Small cell lung carcinoma Thymic carcinoid tumor Bronchial carcinoid tumor Pancreatic endoc rine tumors (including carcinoid tumors) Carcinoid tumors of the gut Pheochromocytoma Medul lary thyroid carcinoma Other lung cancers (adenocarcinoma, squamous cell carcinoma) CRH (rarely) Carcinoid tumor Ectopic expression of receptors for GIP; LH Macronodular adrenal hyperplasia Non \200\223islet cell hypoglycemia IGF-2 Mesenchymal tumors Mesothelioma Fibrosarcomas Oncogenic osteomalacia FGF-23 Sarcomas Hemangiomas Fibromas Prostate adenocarcinoma Osteoblastomas Male feminization hCG Testicular neoplasms (seminomas, teratomas) Germinomas Choriocarcinomas Acromegaly GHRH Pancreatic islet cell tumors Carcinoid tumors GH Lung, pancreatic islet cell tumors 98-Draznin-Chap98.indd 551 4/1/2011 5:57:20 PM CHAPTER 98 Endocrinology of critical illness 552 result in central pontine myelinolysis and in the vast majority of cases, water restriction is safe, effective, and suf \201 cient. Management of the underlying tumor Curative surgery will also cure the SIADH, as will curat ive chemother- apy and/or radiotherapy. Chemotherapy and radiotherapy may have an important palliative role, as the tumor is usually incurable by the time hyponatremia is detected. Humeral hypercalcemia of malignancy Hypercalcemia is a common complication of malignancy. I t may be due to ectopic hormone secretion (PTHrP; rarely 1,25(OH) 2 cholecalciferol), cytok ine and in \202 ammatory mediators that activate osteoclastic bone resorption (such as IL- 6 and RANK-L production by myeloma cells), or bone destruction by metastases. Parathyroid hormone-related peptide (PTHrP) PTHrP binds to and activates PTH/PTHrP receptor type 1, resulting in osteoclast-mediated bone resorption and reduced renal excretion of ca lcium. The biochemical picture of hypercalcemia and hypophosphatemia may be indistinguishable from that of primary hyperparathyroidism. However, PTH levels are suppressed in PTHrP-mediated hypercalcemia (primary hyperparathyroidism can coexist with malignancy). PTHrP secretion by metastatic cells within bone also causes hypercal- cemia by causing local osteolysis. PTHrP can be measured directly and is elevated in 80% of cancer patients with hypercalcemia. Tumors that metastasize to bone are more prone to produce PTHrP than tumors that do not met astasize to bone (50% of primary breast can- cer express PTHrP compared with 92% of metasta ses of breast cancer to bone). This may be due to induction of PTHrP secretion by the bone microenvironment; alternatively PTHrP production by tumor cells may enhance their ability t o metastasize to bone. b For tumors associated with humoral hypercalcemia see Table 98.1. Management This is as per normal management of hypercalcemia ( b see Other causes of hyperc alcemia, p. 385). Glucocorticoids may be particularly effective in treatment of hypercal- cemia associated wi th malignancy. This may be due to direct effects of glucocorticoids on the tumor cells (e.g ., hemopoietic malignancies) and/or down-regulation of production of 1,25(OH) 2 cholecalcif erol. Bisphosphonates may also have antitumor effects in myeloma as well as control osteoclastic destruction of bone. Cushing \200\231s syndrome due to ectopic ACTH production Ectopic ACTH production is respon sible for 10 \200\22320% of all endogenous Cushing \200\231s syndrome. The most common tumor types are those with neuroendocrine features. Half of ectopic ACTH-se cretion is due to small-cell lung carcinoma. Carcinoid 98-Draznin-Chap98.indd 552 4/1/2011 5:57:20 PM SYNDROMES OF ECTOPIC HORMONE PRODUCTION 553 tumors are also very common (thymic carcinoid 15%; pancreatic endocrine tumors including pa ncreatic carcinoids 10%; bronchial carcinoid 10%). Diagnosis Despite often extremely high cortisol levels, patients often do not mani- fest ce ntral weight gain, due to the underlying malignant process with its rapid progress and asso ciated cachexia. Hypertension, hypokalemia, and metabolic alkalosis are common fea- tures (overwhelming of t he 11B-hydroxysteroid dehydrogenase enzyme resulting in exposure of the mineralocorticoid r eceptor to high circulating glucocorticoids). Glucose intolerance, susceptibility to infection, thin skin, poor wound healing, and steroi d-associated mood disturbance are all common features. Patients may be pigmented from MSH a rising from high POMC levels. ACTH levels may be extremely high (usually >100 pg/mL). In 90 % of ectopic ACTH-secreting tumors, high-dose dexamethasone testing (2 mg qds) shows a fail ure of cortisol levels to drop to 50% of base- line values, due to a lack of any normal phy siological feedback on ACTH production. However, some carcinoid tumors may behave indisting uishably from pituitary-dependent ACTH production. CRH testing and/or inferior petrosal sin us sampling may be necessary to distinguish these conditions. Ectopic ACTH-producing tumors can be extremely dif \201 cult to localize and may require multiple modalities of imaging. Management Excision of the underlying tumor may be possible. Other options include medical management using metyrapone and/or ketoconazole, although very high doses may be needed. Bilateral adrenalectomy with glucocorticoid and mineralocorticoid replacement is also an option. Macronodular adrenal hyperplasia \200 A rare cause of ectopic Cushing \200\231s syndrome \200 Most commonly due to synthesis of ectopic GIP receptors in adrenal tissues GIP secretion associated with meals results in activation of adrenal glands and food-related hypercortisolemia. Other ectopic receptors reported include B-adrenergic receptors and LH receptors. Carcinoid tumors and ectopic hormone production b See p. 465 and Table 98.1 (p. 551). 98-Draznin-Chap98.indd 553 4/1/2011 5:57:20 PM CHAPTER 98 Endocrinology of critical illness 554 Liver disease Sex hormones \200\224males See Table 98.2. Hypogonadism occurs in 70 \200\22380% of men with chronic liver disease. There is a combina tion of primary testicular failure and failure of hypoth- alamo \200\223pituitary regulatio n. Alcohol acts independently to produce hypogonadism, leading to a com- bination of primary t esticular failure and failure of hypothalamic \200\223pituitary regulation. The effects of elevated estrogens result in i loss of the male escutch- eon, loss of body h air, redistribution of body fat, palmar erythema, spider nevi, and gynecomastia. The i conversion of testosterone and androstenedione to estrone is attributed at least in p art to portosystemic shunting. In addition, the large increase in SHBG concentration will i ncrease the estrogen/testosterone ratio as testosterone has a higher af \201 nity for SHBG . Spironolactone may result in iatrogenic feminization by inhibiting tes- tosterone action. There is no evidence that exogenous administration of androgens reverses hypogonadism in chronic liver disease. Sex hormones \200\224females See Table 98.2. Alcoholism increases the frequency of menstrua l disturbances and sponta- neous abortion but does not affect fertility. Liver dysfunction of whatever etiology is associated with an early menopause. Alcohol rather than liver disease is the prime cause of hypogonad- ism. Nonalcoholic liver disease is only associated with hypogonadism in advanced liver failure when it is accompani ed by encephalopathy and impaired GnRH secretion. Table 98.2 Sex hormone changes in liver disease Hormone Level di i i i/normal Inappropriately low/normal Testosterone SHBG Estrone Estradiol LH FSH Inappropriately low/normal i/normal d d Prolactin IGF-1 IGFBP-3 98-Draznin-Chap98.indd 554 4/1/2011 5:57:20 PM LIVER DISEASE 555 Table 98.3 Thyroid function changes in liver disease Hormone Acute hepatitis id i l d d i i i CAH/PBC i l i d l i i Cirrhosis d i d d il il l T 4 fT 4 T 3 fT 3 rT 3 TSH TBG CAH, chronic active hepatitis; PBC: primary biliary cirrhosis. Plasma testosterone and estrone concentrations are usually normal, androstenedione concentr ation is increased, and dehydroepiandros-tene- dione and dehydroepiandrostenedione sulfate levels are reduced. Thyroid The liver synthesizes albumin, T 4 -binding prealbumin (TBPA), and T 4 - binding go bulin (TBG), all of which bind thyroid hormones covalently and reversibly. Thyroid function tests (TFTs) must be interpreted with caution in patients with liver disea se. In acute liver disease, e.g., acute viral hepatitis, TBG levels are increased, which in creases the measured total circulating T 4 and T 3 levels. In biliary cirrhosis and chronic active hepatitis, TBG may be increased. In other chronic liver disease and in hepatomas, TBG is also increased. In severe cases of acute liver disease, TBG may be low due to reduced synthesis. The liver deiodinates T 4 to T 3 and this is impaired in liver dis- ease. The T 4 is preferentially c onverted to rT 3 and there is an increase in the rT 3 /T 3 ratio. In liver cirrhosis, TBG, T 4 , and T 3 are low. Table 98.3 summarizes the changes in TFTs with liver disease. Free T 4 and T 3 assays are e ssential for the accurate interpretation of thyroid status in liver disease. Adrenal hormones Patients who abuse alcohol may develop a clinical phenotype of Cushing \200\231s syndrome with moon faces, centripetal obesity, striae, and muscle wasting, and ma y have increased plasma cortisol concentrations. This is termed pseudo-Cushing \200\231s sy ndrome . Reversible (on abstention) adrenocorticorticoid hyperresponsiveness occurs in alcoholics. I n liver disease, cortisol metabolism may be impaired, leading to elevated plasma cortisol l evels, loss of diurnal cortisol variation, and failure to suppress with dexamethasone. Further reading Malik R, Hodgson H (2002). The relationship between the thyroid gland and t he liver. Q J Med 95:559 \200\223569. 98-Draznin-Chap98.indd 555 4/1/2011 5:57:20 PM CHAPTER 98 Endocrinology of critical illness 556 Renal disease Calcitriol There is impaired renal conversion of 25-hydroxyvitamin D 3 to 1,2 5 (OH) 2 D 3 in end-stage renal failure (ESRF) leading to metabolic bone disease. Parathyroid hormone and renal osteodystrophy Serum parathyroid hormone (PTH) secretion is s timulated by low serum calcium in ESRF. This is due to the following: \200 d Renal phosph ate clearance (resulting in i cacium/phosphate mineral ion product, precipitation of vascul ar calci \201 cation with consequent hypocalcemia triggering PTH release). Vascular calci \201 cation is a major contributor to vascular death in ESRF. High phosphate may increase PTH secretion directly, but evidence of the mechanism for this is lacking. Impaired renal calcitriol secretion As renal function declines, an elevated PTH and a d cal citriol can be detected with creatinine clearance of 50 mL/min. This rise in PTH is ini- ti ally suf \201 cient to maintain the serum calcium in the normal range. In ESRF, patients are markedly hyperphosphatemic and hypocalcemic. The degree of hyperparat hyroidism progresses inversely with the fall in renal function. Tertiary hyperparathyroidis m occurs when PTH secretion becomes autonomous, and hypercalcemia will persist even after r enal transplantation. Hyperparathyroid bone disease and osteomalacia are the main mech- ani sms behind the development of high-turnover bone disease in renal osteodystrophy. Hypogonad ism is also common in both men and women with ESRF. Adynamic bone disease also contributes, probably due to direct toxic effects from urea and other nitrogenous compounds on bone cel ls. Renal osteodystrophy causes bone pain and fractures. Treatment of renal osteodystrophy The goals are maintenance of normal phosphate levels with phosphate binders (such as calcium carbonate) and treatment of osteomalacia. The i use of calcium carbonate has been suggested as the cause of the i inci- dence of adynamic renal os teodystrophy, but intensive vitamin D therapy and peritoneal dialysis are probably also con tributory. Calcitriol (which does not require renal 1 A-hydroxylation) is effective in treating osteom alacia. A dose of 1 \200\2232 mcg/day is used for established renal osteodystrophy. Lower d oses of calcitriol (0.25 \200\2230.5 mcg/day) are used in early ESRF to prevent the devel-o pment of renal osteodystrophy. Parathyroidectomy is advocated in bone disease uncon-trolled by vitamin D therapy or the development of tertiary hyperpara-thyroidism. Cinacalcet acts directly at the calcium-sensing receptor to lower PTH secretion. This marke dly improves secondary hyperparathy-roidism, cal- cium and phophate levels, and renal osteo dystrophy. Improvement in mortality due to d vascular calci \201 cation has not yet been d emonstrated. 98-Draznin-Chap98.indd 556 4/1/2011 5:57:20 PM RENAL DISEASE 557 Prolactin Hyperprolactinemia is common in ESRF but is usually mild, i.e., <100 mcg/L. The c ause is both i secretion and d renal clearance. Gonadal function Hypogonadism \200\224clinical and biochemical \200\224is common in ESRF. In men, there is impaired pulsatile release of LH, although basal LH lev- els are usually e levated because of impaired renal clearance. Serum FSH is usually normal or mildly elevated .