Respuestas de Endocrinologia Harrison, Apuntes de Medicina

¡Descarga Respuestas de Endocrinologia Harrison y más Apuntes en PDF de Medicina solo en Docsity! ANSWERS X-1. The answer is D. (Chap. 338) Feedback control may be either positive or negative. The primary means of hormone control within the endocrine system is negative feedback. For example, when a steroid hormone level is sensed to be low by the hypothalamus a releasing hormone is released, which effects the release of a stimulatory hormone from the pituitary, and the target gland secretes the steroid hormone and plasma levels rise. The hypothalamus then senses this and decreases the release of the releasing hormone. This is employed by the endocrine system to control levels of thyroid hormone, cortisol, gonadal steroids, and growth hormone. The renin-angiotensin-aldosterone axis is independent of the pituitary and hypothalamus and involves the liver, lungs, and kidney. X-2. The answer is E. (Chap. 338) Hormone resistance may be due to receptor mutations or signaling pathway mutations, or, most commonly, postreceptor alterations. Type 2 dia- betes mellitus and leptin resistance are examples of postreceptor alterations resulting in hormone resistance. Pheochromocytoma and Graves’ disease are examples of organ hyperfunction, Hashimoto’s thyroiditis and Sheehan’s syndrome are diseases of organ hypofunction. In the case of Sheehan’s syndrome, the affected organ is the pituitary gland. 424 X-3. The answer is C. (Chap. 338) Intermittent pulses of GnRH are necessary to maintain pituitary sensitivity to the hormone. Continuous exposure to GnRH causes pituitary gonadotrope desensitization, which ultimately leads to decreased levels of testosterone. The relationship between GnRH and LH/FSH is a positive feedback loop where GnRH causes secretion of LH and FSH. Receptor translocation from the cytoplasm into the nucleus occurs with certain hormones (e.g., glucocorticoid); however, this receptor phenomenon is not specific to any regulatory mechanism. GnRH does not promote the production of sex hormone– binding globulin. Moreover, although binding globulins can decrease the amount of bound hormone measured in the serum, abnormal levels of binding globulins usually do not have any clinical significance because the free hormone levels usually increase. X-4. The answer is B. (Chap. 338) With few exceptions, hormone binding is highly specific for a single type of nuclear receptor. The mineralocorticoid-glucocorticoid hormones are a notable exception because the mineralocorticoid receptor also has a high, but not greater, affinity for glucocorticoid. An enzyme (11 F 0 6 2-hydroxysteroid dehydrogenase) located in renal tubules inactivates glucocorticoid, allowing selective responses to mineralocorticoid. When there is glucocorticoid excess, the enzyme becomes oversaturated and glucocorti- coid can exhibit mineralocorticoid effects. This effect is in contrast to the estrogen recep- tor, where different compounds confer unique transcription machinery. Mineralocorticoid hormones do not have serum-binding proteins. Examples of hormones that circulate with serum-binding proteins are T4, T3, cortisol, estrogen, and growth hormone. Most binding protein abnormalities have little clinical consequence because the free concentrations of the hormone often remain normal. X-5. The answer is C. (Chap. 339) Hormones produced by the anterior pituitary include adrenocorticotropic hormone, thyroid-stimulating hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, and growth hormone. The posterior pituitary produces vasopressin and oxytocin. The anterior and posterior pituitary has a separate vascular supply, and the posterior pituitary is directly innervated by the hypothalamic neurons via the pituitary stalk, thus making it susceptible to shear stress–associated dysfunction. Hypothalamic control of anterior pituitary function is through secreted hormones; thus it is less susceptible to traumatic injury. X-6. The answer is B. (Chap. 339) The patient has evidence of Sheehan’s syndrome postpartum. In this syndrome, the hyperplastic pituitary postpartum is at increased risk for hemor- rhage and/or infarction. This leads to bilateral visual changes, headache, and meningeal signs. Ophthalmoplegia may be observed. In severe cases, cardiovascular collapse and altered levels of consciousness may be observed. Laboratory evaluation commonly shows hypoglycemia. Pituitary CT or MRI may show signs of sellar hemorrhage if present. Involvement of all pituitary hormones may be seen, though the most acute finding is often hypoglycemia and hypotension from the failure of adrenocorticotropic hormone. The hypoglycemia and hypotension present in this case suggest failure of the glucocor- ticoid system; thus treatment with a corticosteroid is indicated. There is no evidence of sepsis; thus antibiotics and drotrecogin alfa are not indicated. With a normal hematocrit and no reported evidence of massive hemorrhage, packed red cell transfusion is unlikely to be helpful. Although thyroid-stimulating hormone production is undoubtedly low in this patient, the most immediate concern is replacement of glucocorticoid. X-7. The answer is D. (Chap. 339) Functional pituitary adenoma presentations include acro- megaly, as in this patient, prolactinomas, and Cushing’s syndrome. Hypersecretion of growth hormone underlies this syndrome in patients with pituitary masses, though ectopic produc- tion of growth hormone, particularly by tumors, has been reported. Because growth hor- mone is secreted in a highly pulsatile fashion, obtaining random serum levels is not reliable. Thus, the downstream mediator of systemic effects of growth hormone, IGF-1, is measured to screen for growth hormone excess. IGF-1 is 425 S E C T A N S WERS half are not detected even with sensitive MRI. Further, because incidental microadenomas are A N S WERS S E C T common in the pituitary, the presence of a small pituitary abnormality on MRI may not establish the source of ACTH production. Basal plasma ACTH levels are used to distin- guish between ACTH-independent (adrenal or exogenous glucocorticoid) and ACTH- dependent (pituitary, ectopic ACTH) sources of hypercortisolism. Mean basal ACTH levels are higher in patients with ectopic ACTH production than in patients with pituitary ACTH adenomas. There is significant overlap in ACTH levels, however, and this test should not be used as an initial diagnostic test. Rarely, patients have Cushing’s syndrome and elevated ACTH due to a CRH-releasing tumor. In this case, CRH levels are elevated. Inferior pet- rosal venous sampling can be used to identify a pituitary source of ACTH secretion when imaging modalities do not reveal a source. X-14. The answer is B. (Chap. 339) The identification of an empty sella is often the result of an incidental MRI finding. Typically these patients will have normal pituitary function and should be reassured. It is likely that the surrounding rim of pituitary tissue is functioning normally. An empty sella may signal the insidious onset of hypopituitarism, and labora- tory results should be followed closely. Unless her clinical situation changes, repeat MRI is not indicated. Endocrine malignancy is unlikely, and surgery is not part of the manage- ment of an empty sella. X-15. The answer is A. (Chap. 340) The patient has a classic presentation for a patient with idiopathic diabetes insipidus with long-standing urinary frequency, thirst, enuresis, and nocturia. Patients may also report mild fatigue from frequent nocturnal awakenings. Diabetes insipidus may be nephrogenic or central, though this case presentation is not specific for either etiology. Diabetes insipidus is confirmed by measurement of 24-hour urine volume, which is more than 50 mg/kg per day (3500 mL in a 70-kg male), and urine osmolarity of greater than 300 mosmol/L. In order to differentiate central from nephro- genic diabetes insipidus, history may be useful in determining prior head trauma, neuro- surgery, or granulomatous disease that may damage the neurohypophysis, or may suggest a medication such as lithium known to cause nephrogenic diabetes insipidus. The fluid dep- rivation test, in which a patient is deprived of fluid and hourly urine output; body weight; plasma osmolarity and/or sodium concentration; and urine osmolarity are measured. If fluid deprivation confirms persistent elevation of urine osmolarity, then severe diabetes insipidus is again confirmed. Desmopressin can be administered at this point and if the electrolyte, urinary, and clinical variables are corrected, central disease is confirmed. In nephrogenic diabetes insipidus, there is minimal response to ADH, as the primary defect is in the kidney. MRI of the brain is not useful until after central disease is confirmed. X-16. The answer is B. (Chap. 340) This patient presents with acute central diabetes insipidus (DI) in the context of AMML. MRI will most likely demonstrate a chloroma (myeloid tumor often seen in AMML) in the posterior pituitary, particularly given his history of other extra–bone marrow tumor nodules. The urine is dilute due to the ADH deficiency leading to hypernatremia. The altered mental status is likely due to the hypernatremia, which typically develops in central DI as water intake cannot keep up with urine output, which can exceed 5 L/d. Immediate replacement of ADH in the form of desmopressin will confirm the diagnosis of central DI if urine output drops and will provide symptomatic relief. Desmopressin may be administered nasally or intravenously with rapid onset of action. Hydrochlorothiazide is used in nephrogenic DI to increase proximal sodium and water reabsorption. ATRA is used to treat acute promyelocytic leukemia, not AMML. Hydrocortisone would be the therapy of choice for acute Addisonian crisis, not central DI. Lithium is a well-known cause of nephrogenic DI. X-17. The answer is B. (Chap. 341) Nutritional and maternal iodine deficiencies are common in many parts of the developing world and, when severe, can result in cretinism. Cretinism is characterized by mental and growth retardation but is preventable by administration of iodine and/or thyroid hormone early in life. Concomitant selenium deficiency can con- tribute to the neurologic manifestations. Iodine supplementation of bread, salt, and other foods has markedly decreased the rates of this disease. Beriberi disease is a nervous system ailment caused by a thiamine deficiency in the diet. Scurvy is due to vitamin C deficiency. S E C T E n d o c ri n o l o S E C T A N S WERS S E C T E n d o c ri n o l o S E C T A N S WERS Another result from the UKPDS was that strict blood pressure control resulted in an improvement in macrovascular complications. A N S WERS S E C T X-52. The answer is D. (Chap. 344) Tight glycemic control with a hemoglobin A1C of 7% or less has been shown in the Diabetes Control and Complications Trial (DCCT) in type 1 diabetic patients and the United Kingdom Prospective Diabetes Study (UKPDS) in type 2 diabetic patients to lead to improvements in microvascular disease. Notably, a decreased incidence of neuropathy, retinopathy, microalbuminuria, and nephropathy was shown in individuals with tight glycemic control. Interestingly, glycemic control had no effect on macrovascular outcomes. Instead, it was blood pressure control to at least moderate goals (142/88 mmHg) in the UKPDS that resulted in a decreased incidence of macrovascular outcomes, namely, DM-related death, stroke, and heart failure. Improved blood pressure control also resulted in improved microvascular outcomes. X-53. The answer is A. (Chap. 344) Diabetic ketoacidosis is an acute complication of diabetes mellitus. It results from a relative or absolute deficiency of insulin combined with a coun- terregulatory hormone excess. In particular, a decrease in the ratio of insulin to glucagons promotes gluconeogenesis, glycogenolysis, and the formation of ketone bodies in the liver. Ketosis results from an increase in the release of free fatty acids from adipocytes, with a resultant shift toward ketone body synthesis in the liver. This is mediated by the relation- ship between insulin and the enzyme carnitine palmitoyltransferase I. At physiologic pH, ketone bodies exist as ketoacids, which are neutralized by bicarbonate. As bicarbonate stores are depleted, acidosis develops. Clinically, these patients have nausea, vomiting, and abdominal pain. They are dehydrated and may be hypotensive. Lethargy and severe central nervous system depression may occur. The treatment focuses on replacement of the body’s insulin, which will result in cessation of the formation of ketoacids and improvement of the acidotic state. Assessment of the level of acidosis may be done with an arterial blood gas. These patients have an anion gap acidosis and often a concomitant metabolic alkalosis resulting from volume depletion. Volume resuscitation with intravenous fluids is critical. Many electrolyte abnormalities may occur. Patients are total-body sodium, potassium, and magnesium depleted. As a result of the acidosis, intracellular potassium may shift out of cells and cause a normal or even elevated potassium level. However, with improvement in the acidosis, the serum potassium rapidly falls. Therefore, potassium repletion is critical despite the presence of a “normal” level. Because of the osmolar effects of glucose, fluid is drawn into the intravascular space. This results in a drop in the measured serum sodium. There is a drop of 1.6 meq/L in serum sodium for each rise of 100 mg/dL in serum glucose. In this case, the serum sodium will improve with hydration alone. The use of 3% saline is not indicated because the patient has no neurologic deficits, and the expectation is for rapid resolution with IV fluids alone. X-54. The answer is E. (Chap. 344; Nathan, N Engl J Med 328:1676–1685, 1993.) Nephropathy is a leading cause of death in diabetic patients. Diabetic nephropathy may be functionally silent for 10–15 years. Clinically detectable diabetic nephropathy begins with the develop- ment of microalbuminuria (30–300 mg of albumin per 24 hours). The glomerular filtra- tion rate actually may be elevated at this stage. Only after the passage of additional time will the proteinuria be overt enough (0.5 g/L) to be detectable on standard urine dipsticks. Microalbuminuria precedes nephropathy in patients with both non–insulin-dependent and insulin-dependent diabetes. An increase in kidney size also may accompany the ini- tial hyperfiltration stage. Once the proteinuria becomes significant enough to be detected by dipstick, a steady decline in renal function occurs, with the glomerular filtration rate falling an average of 1 mL/min per month. Therefore, azotemia begins about 12 years after the diagnosis of diabetes. Hypertension clearly is an exacerbating factor for diabetic nephropathy. X-55. The answer is D. (Chap. 345) Maintenance of euglycemia involves a number of sys- tems to lower elevated blood glucose, but also to restore normal levels when hypogly- cemia is present or impending. Decreased insulin secretion is the primary glucose regulator factor and its secretion is inhibited with a plasma glucose of 80–85 mg/dL. Glucagon secretion is the second defense against hypoglycemia, secreted at a glucose of 65–70 mg/dL. Epinephrine and cortisol secretion are third and are released at a glucose of 65– 70 mg/dL. Finally, symptoms develop with a glucose of 50–55 mg/dL S E C T E n d o S E C T A N S WERS S E C T A N S WERS with structural abnormalities of the kidney and urinary tract, most commonly horseshoe kidney. A renal ultrasound is also recommended. Autoimmune thyroid disease affects 15–30% of women with Turner’s syndrome and should be assessed by screening TSH. Other comorbidities that may occur include sensorineural hearing loss, elevated liver function enzymes, osteoporosis, and celiac disease. X-68. The answer is B. (Chap. 350) The patient presents with recurrent peptic ulcers without evidence of H. pylori infection. The diagnosis of Zollinger-Ellison syndrome should be obtained. Additional features that suggest nonclassic idiopathic ulcer disease include the presence of diarrhea, which is commonly present in Zollinger-Ellison syndrome, but not idiopathic ulcers. The diagnosis is commonly made through measurement of plasma gastrin levels, which should be markedly elevated, but common use of proton pump inhibitors (PPIs) that potently suppress gastric acid secretion confound this measure- ment. Because PPI use suppresses gastric acid production, gastrin rises. Thus PPI use should be discontinued for 1 week prior to measurement of gastrin in plasma. Often this requires collaboration with gastroenterologists to ensure safety and potentially offer alter- native pharmacology during this time. Once hypergastrinemia is confirmed, the presence of low gastric pH must be confirmed, as the most common cause of elevated gastrin is achlorhydria due to pernicious anemia. Imaging of the abdomen is indicated after demon- stration of hypergastrinemia. Finally, although Zollinger-Ellison syndrome may be associ- ated with multiple endocrine neoplasia type 1, which often has parathyroid hyperplasia or adenoma, this is less likely than isolated Zollinger-Ellison syndrome. 69. and X-70. The answers are E and E, respectively. (Chap. 350) In patients with a non- metastatic carcinoid, surgery is the only potentially curative therapy. The extent of sur- gical resection depends on the size of the primary tumor because the risk of metastasis is related to the size of the tumor. Symptomatic treatment is aimed at decreasing the amount and effect of circulating substances. Drugs that inhibit the serotonin 5-HT1 and 5-HT2 receptors (methysergide, cyproheptadine, ketanserin) may control diarrhea but not flushing. 5-HT3 receptor antagonists (ondansetron, tropisetron, alosetron) control nausea and diarrhea in up to 100% of these patients and may alleviate flushing. A com- bination of histamine H1 and H2 receptor antagonists may control flushing, particularly in patients with foregut carcinoid tumors. Somatostatin analogues (octreotide, lanre- otide) are the most effective and widely used agents to control the symptoms of carcinoid syndrome, decreasing urinary 5-HIAA excretion and symptoms in 70–80% of patients. Interferon F 0 6 1, alone or combined with hepatic artery embolization, controls flushing and diarrhea in 40–85% of these patients. Phenoxybenzamine is an F 0 6 11- adrenergic receptor blocker that is used in the treatment of pheochromocytoma. Carcinoid crisis is a life-threatening complication of carcinoid syndrome. It is most common in patients with intense symptoms from foregut tumors or markedly high levels of urinary 5-HIAA. The crisis may be provoked by surgery, stress, anesthesia, chemother- apy, or physical trauma to the tumor (biopsy or, in this case, physical compression of liver lesions). These patients develop severe typical symptoms plus systemic symptoms such as hypotension and hypertension with tachycardia. Synthetic analogues of somatostatin (octreotide, lanreotide) are the treatment of choice for carcinoid crisis. They are also effec- tive in preventing crises when administered before a known inciting event. Octreotide 150–250 F 0 6 Dg subcutaneously every 6–8 hours should be started 24–48 hours before a pro- cedure that is likely to precipitate a carcinoid crisis. X-71. The answer is C. (Chap. 350) This patient presents with the classic findings of a VIPoma, including large-volume watery diarrhea, hypokalemia, dehydration, and hypochlorhy- dria (WDHA, or Verner-Morrison syndrome). Abdominal pain is unusual. The presence of a secretory diarrhea is confirmed by a stool osmolal gap [2(stool Na + stool K) – (stool osmolality)] below 35 and persistence during fasting. In osmotic or laxative-induced diarrhea, the stool osmolal gap is over 100. In adults, over 80% of VIPomas are solitary pancreatic masses that usually are larger than 3 cm at diagnosis. Metastases to the liver are common and preclude curative surgical resection. The differential diagnosis includes gastrinoma, laxative abuse, carcinoid syndrome, and systemic mastocytosis. Diagnosis S E C T E n d o c ri n o l o indi- viduals is most often silent. Often practitioners fail to consider vitamin D deficiency until a patient has been diagnosed with osteoporosis or suffered a fracture. However, some indi- viduals can experience diffuse muscle and bone pain. When assessing vitamin D levels, E n d o c ri n o l o S E C T A N S WERS S E C T S E C T E n d o c ri n o l o inadequate physical activity, poor health, and estrogen deficiency including menopause prior to age 45 or prolonged premenstrual amenorrhea. Current cigarette smoking is a risk factor for osteoporosis-related fracture while a prior history of cigarette use is not. TABLE X-85 Risk Factors for Osteoporosis Fracture Nonmodifiable Estrogen deficiency Personal history of fracture as an adult Early menopause ( F 0 3 C45 years) or bilateral ovariectomy History of fracture in first-degree relative Prolonged premenstrual amenorrhea (>1 year) Female sex Low calcium intake Advanced age Alcoholism White race Impaired eyesight despite adequate correction Dementia Potentially modifiable Recurrent falls Current cigarette smoking Inadequate physical activity Low body weight [ F 0 3 C58 kg (127 lb)] Poor health/frailty X-86. The answer is C. (Chap. 354) A variety of diseases in adults increase the risk of osteoporosis. First, diseases that lead to estrogen deficiency or hypogonadism can lead to osteoporosis. This would include Turner’s syndrome, Klinefelter’s syndrome, and hyperprolactinemia, among others. A wide range of endocrine disorders can also lead to abnormal bone metabo- lism, especially hyperparathyroidism and thyrotoxicosis. Poor nutrition and gastrointestinal disorders increase the likelihood of developing osteoporosis. Anorexia nervosa causes both hypogonadism and poor nutritional status. Malabsorption syndromes lead to decreased intake of calcium and vitamin D, which are essential to good bone health. Chronic obstruc- tive pulmonary disease also has a high prevalence of osteoporosis, which is may be related to a chronic inflammatory state with high bone turnover that is exacerbated by frequent corti- costeroid use, frequent vitamin D deficiency, and low activity states. Other broad categories of disease that can lead to osteoporosis include rheumatologic disorders, hematologic malig- nancies, and some inherited disorders such as osteogenesis imperfecta, Marfan’s syndrome, and porphyria, among many others. It is well known that immobilization, pregnancy, and lactation can lead to osteoporosis as well. X-87. The answer is B. (Chap. 354) Osteoporosis is a common disease affecting 8 million women and 2 million men in the United States. It is most common in postmenopausal women, but the incidence is also increasing in men. Estrogen loss probably causes bone loss by activation of bone remodeling sites and exaggeration of the imbalance between bone for- mation and resorption. Osteoporosis is diagnosed by bone mineral density scan. Dual- energy x-ray absorptiometry (DXA) is the most accurate test for measuring bone mineral density. Clinical determinations of bone density are most commonly measured at the lum- bar spine and hip. In the DXA technique, two x-ray energies are used to measure the area of the mineralized tissues and compared to gender- and race- matched normative values. The T-score compares an individual’s results to a young population, whereas the Z-score compares the individual’s results to an age-matched population. Osteoporosis is diagnosed when the T-score is –2.5 SD in the lumbar spine, femoral neck, or total hip. An evalua- tion for secondary causes of osteoporosis should be considered in individuals presenting with osteoporotic fractures at a young age and those who have very low Z-scores. Initial evaluation should include serum and 24-hour urine calcium levels, renal function panel, hepatic function panel, serum phosphorous level, and vitamin D levels. Other endocrine abnormalities including hyperthyroidism and hyperparathyroidism should be evaluated, and urinary cortisol levels should be checked if there is a clinical suspicion for Cushing’s syndrome. Follicle-stimulating hormone and luteinizing hormone levels would be elevated but are not useful in this individual, as she presents with a known perimenopausal state. X-88. The answer is C. (Chap. 354) Determination of when to initiate screening for osteoporosis with bone densitometry testing can be complicated by multiple factors. In E n d o c ri n o l o S E C T A N S WERS S E C T does not require drug discontinuation. The same time to response can be expected from these agents. X-95. The answer is D. (Chap. 356) Mutation of the LDL receptor results in hypercholestero- lemia. This mutation may be homozygous or heterozygous and occurs in approximately 1/500 people in its heterozygous form. Homozygous disease is more severe, with the development of symptomatic coronary atherosclerosis in childhood, while heterozygous patients have hypercholesterolemia from birth, and disease recognition is usually not until adulthood when patients are found to have tendon xanthomas or coronary artery disease. In patients with heterozygous disease, there is generally a family history on at least one side of the family. In familial hypercholesterolemia, there is an elevation of LDL-C between 200 and 400 mg/dL without alterations in chylomicrons or VLDL. Familial defective apoB-100 has a similar presentation but is less common (1/1000). Autosomal dominant history may be present in this family to suggest autosomal dominant hypercho- lesterolemia; however, this condition is quite rare (<1/1,000,000) and therefore much less likely. Familial hepatic lipase deficiency and lipoprotein lipase deficiency are associated with increased chylomicrons, not LDL-C, and present with eruptive xanthomas, hepato- splenomegaly, and pancreatitis. These conditions occur rarely (<1/1,000,000). X-96. The answer is B. (Chap. 356) There are many secondary forms of elevated LDL that warrant consideration in a patient found to have abnormal LDL. These include hypothy- roidism, nephritic syndrome, cholestasis, acute intermittent porphyria, anorexia nervosa, hepatoma, and drugs such as thiazides, cyclosporine, and Tegretol. Cirrhosis is associ- ated with reduced LDL because of inadequate production. Malabsorption, malnutrition, Gaucher’s disease, chronic infectious disease, hyperthyroidism, and niacin toxicity are all similarly associated with reduced LDL. X-97. The answer is D. (Chap. 356) This patient has signs and symptoms of familial hyper- cholesterolemia (FH) with elevated plasma LDL, normal triglycerides, tendon xanthomas, and premature coronary artery disease. FH is an autosomal codominant lipoprotein dis- order that is the most common of these syndromes caused by a single gene disorder. It has a higher prevalence in Afrikaners, Christian Lebanese, and French Canadians. There is no definitive diagnostic test for FH. It may be diagnosed with a skin biopsy that shows reduced LDL receptor activity in cultured fibroblasts (although there is considerable overlap with normals). FH is predominantly a clinical diagnosis, although molecular diagnostics are being developed. Hemolysis is not a feature of FH. Sitosterolemia is distinguished from FH by episodes of hemolysis. It is a rare autosomal recessive disorder that causes a marked increase in the dietary absorption of plant sterols. Hemolysis is due to incorporation of plant sterols into the red blood cell membrane. Sitosterolemia is confirmed by demonstrat- ing an increase in the plasma levels of sitosterol using gas chromatography. CT scanning of the liver does not sufficiently differentiate between the hyperlipoproteinemias. Many of the primary lipoproteinemias, including sitosterolemia, are inherited in an autosomal recessive pattern, and thus a pedigree analysis would not be likely to isolate the disorder. X-98. The answer is C. (Chap. 356) This patient has nephrotic syndrome, which is likely a result of multiple myeloma. The hyperlipidemia of nephrotic syndrome appears to be due to a combination of increased hepatic production and decreased clearance of very low- density lipoproteins, with increased LDL production. It is usually mixed but can manifest as hypercholesterolemia or hypertriglyceridemia. Effective treatment of the underlying renal disease normalizes the lipid profile. Of the choices presented, HMG- CoA reductase inhibitors would be the most effective to reduce this patient’s LDL. Dietary manage- ment is an important component of lifestyle modification but seldom results in a greater than 10% fall in LDL. Niacin and fibrates would be indicated if the triglycerides were higher, but the LDL is the more important lipid abnormality to address at this time. Lipid apheresis is reserved for patients who cannot tolerate the lipid-lowering drugs or who have a genetic lipid disorder refractory to medication. Cholesterol ester transfer protein inhibitors have been shown to raise high-density lipoprotein levels, and their role in the treatment of lipoproteinemias is still under investigation. A N S WERS S E C T X-99. The answer is C. (Chap. 357) Hereditary hemochromatosis is a common genetic condition, with 1 in 10 people of northern European ancestry being heterozygotes and 0.3–0.5% being homozygotes. The recessive condition occurs from a mutation in the gene HFE, which is involved in iron metabolism. Clinical manifestations include initially iron overload (as measured biochemically) without symptoms, then later iron overload with symptoms. Initial symptoms often include lethargy, arthralgia, change in skin color, loss of libido, and diabetes mellitus. Cirrhosis, cardiac arrhythmias, and infiltrative cardio- myopathy are later manifestations. Because the clinical manifestations of the disease can be prevented with iron chelation and the mutation is so common, some have advocated for screening the population for evidence of iron overload. Although routine screening is still controversial, recent studies indicate that it is highly effective for primary care physicians to screen subjects using serum iron, transferrin saturation, and serum ferritin levels. This will detect anemia and iron deficiency as well. Liver biopsy or MRI may demonstrate later find- ings of increased iron deposition and/or cirrhosis, but these are more costly and possibly invasive or risky, and are not recommended for screening. Genetic testing is also not recom- mended as a first step, though it is indicated if evidence of iron overload is found on serum iron studies, as described in this case. There is no HFE activity assay currently available. X-100. The answer is E. (Chap. 357) This patient presents with the classic finding of diffuse organ iron infiltration due to hemochromatosis. The iron accumulation in the pancreas, testes, liver, joints, and skin explain his findings. Hemochromatosis is a common disorder of iron storage in which inappropriate increases in intestinal iron absorption result in exces- sive deposition in multiple organs but predominantly in the liver. There are two forms: hereditary hemochromatosis, in which the majority of cases are associated with mutations of the HFE gene, and secondary iron overload, which usually is associated with iron-load- ing anemias such as thalassemia and sideroblastic anemia. In this case, without a history of prior hematologic disease, the most likely diagnosis is hereditary hemochromatosis. Serum ferritin testing and plasma iron studies can be very suggestive of the diagnosis, with the ferritin often greater than 500 F 0 6 Dg/L and transferrin saturation of 50–100%. How- ever, these tests are not conclusive, and further testing is still required for the diagnosis. Although liver biopsy and evaluation for iron deposition or a hepatic iron index ( F 0 6 Dg/g dry weight)/56 F 0 B 4F 0 2 0age > 2 is the definitive diagnosis, genetic testing is widely available today, and because of the high prevalence of HFE gene mutations associated with hereditary hemochromatosis, it is recommended for diagnostic evaluation. If the genetic testing is inconclusive, the invasive liver biopsy evaluation may be indicated. Anti–smooth muscle antibody testing is useful for the evaluation of autoimmune hepatitis and is indicated in any case of cryptogenic cirrhosis. Plasma ceruloplasmin is the initial study in the evalu- ation of Wilson’s disease, and is also a cause of occult liver disease. However, Wilson’s disease would not be likely to be associated with the pancreatic, joint, and skin findings. If chronic hepatitis B is suspected, a viral load or surface antigen test would be indicated. Hepatitis B surface antibody is useful to demonstrate resolved hepatitis B or prior vaccina- tion. Hepatic ultrasound is useful in the evaluation of acute and chronic liver disease to demonstrate portal flow or vascular occlusion. It may be useful in the physiologic evalua- tion of this patient but would have little diagnostic value. X-101. The answer is C. (Chap. 358) The patient has a classic presentation for acute intermittent porphyria, a disorder of hepatic (not bone marrow) heme synthesis. This is generally auto- somal dominant and is widespread, especially in Scandinavia and Great Britain. Although disease presentation and penetrance is highly variable, it is most commonly associated with attacks of abdominal pain and neurologic symptoms that develop after puberty. Often a precipitating cause of symptomatic episodes can be identified such as steroid hor- mone use, oral contraceptives, systemic illness, reduced caloric intake, and many other medications. This diagnosis should be considered in any individual with recurrent abdom- inal pain, especially when accompanied by neuropsychiatric complaints. The abdominal symptoms are often more prominent, sometimes including vomiting, diarrhea, and ileus. Neurologic findings may include peripheral neuropathy, sensory changes, and seizures. The diagnosis is made by measurement of urine porphyrobilinogens (PBG) during a spot urine taken during an attack. During an attack, Therapy for Wilson’s disease is dependent on degree of disease at the time of presen- tation. Patients with mild hepatitis may be treated with zinc, which blocks the intestinal absorption of copper and results in a negative copper balance, and also induces hepatic metallothionein synthesis, which sequesters additional toxic copper. Trientine serves as a copper chelator and is used for more severe liver dysfunction, or neurologic or psychiatric disease. Zinc should not be used acutely in hepatic decompensation because zinc may be chelated instead of copper. Liver transplantation is appropriate for patients who have failed the initial therapy. X-107. The answer is A. (Chap. 360) Wilson’s disease is an autosomal recessive disorder caused by mutations in the ATP7B gene, which leads to copper accumulation and toxicity. The ATP7B gene encodes a membrane-bound copper-transporting ATPase. Deficiency of this protein leads to decreased biliary copper excretion and resultant buildup of copper in the tissues. The two most affected organs are the liver and the brain. Patients may present with hepatitis, cirrhosis, hepatic failure, movement disorders, or psychiatric disorders. Serum copper levels are usually lower than normal due to low blood ceruloplasmin, which usu- ally binds serum copper. About 1% of the population are carriers of an ATP7B mutation; the disease is present in 1 in 30,000–40,000 people. The disease is close to 100% penetrant and requires treatment in almost all cases. DNA haplotype analysis can be used to geno- type siblings of an affected patient. Patients are treated with zinc, which induces a negative copper balance by blocking intestinal absorption; trientine, which acts as a potent copper chelator; or both. Severe hepatic decompensation may require liver transplantation. X-108. The answer is A. (Chap. 363) Osteogenesis imperfecta is a heritable disorder of connec- tive tissue in which there is a severe decrease of bone mass that makes bone brittle and prone to fracture. The disease is often inherited in an autosomal dominant fashion. There are several subtypes, with type 1 being the most mild and likely to present in adulthood. Most of the other subtypes present in early childhood and may be lethal. In type 1 osteo- genesis imperfecta, mutations in the type 1 procollagen gene are present in 90% of cases. Type 1 disease may present in adulthood, where abnormalities of teeth color and shape are common in addition to the characteristic blue sclera. Fractures tend to decrease after puberty in both sexes, but may increase in women at the time of pregnancy and after menopause. Decreased bone mineral density is demonstrated in a variety of imaging tech- niques including x-ray absorptiometry and plain radiographs. Bone biopsy is not required for diagnosis and may cause morbidity. The diagnosis is usually clinical with the charac- teristic physical examination findings, history of fractures, and often a positive family his- tory. Although bisphosphonates are well tolerated and often used for severe disease where they may decrease bone pain, their long-term effects and safety in osteogenesis imperfecta are unknown. X-109. The answer is C. (Chap. 363) Marfan’s syndrome is an autosomal dominant syndrome char- acterized by skeletal changes including long, thin extremities; loose joints; lens dislocation with reduced vision; and aortic aneurysms. The incidence is high, affecting 1 in 3000–5000 live births in most racial and ethnic groups. More than 90% of Marfan’s syndrome patients have mutations in the fibrillin-1 gene. Although Marfan’s syndrome is rarely associated with mutations in TGF F 0 6 2, recent work has highlighted the close interaction between fibril- lin mutation and alterations in TGF F 0 6 2F 0 2 0signaling, offering new therapeutic potential. BMPR2 mutation is associated with heritable pulmonary arterial hypertension. COL1A1 mutation is found in Ehlers-Danlos syndrome and osteogenesis imperfecta. Type IV collagen muta- tions have been described in Alport’s syndrome. X-110. The answer is B. (Chap. 363) This patient has Ehlers-Danlos syndrome (EDS), most likely type 2. There are over 10 types of EDS that vary clinically, biochemically, and genetically. Classic EDS has a severe (type 1) form that usually presents in childhood, and the milder type 2 form. These are characterized by joint hypermobility and velvety skin that scars easily and is hyperextensible. Patients with classic EDS are at risk of joint dislocation, including the hips and other large joints. Extreme joint extension in yoga is likely not advisable. Many patients with classic EDS benefit from braces or joint surgery E n d o c ri n o l o S E C T