Harrisons Principles of Internal Medicine Self-Assessment and Board Review 18th Ed.

SECTION X. Endocrinology and Metabolism

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 diabetes 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.

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 β-hydroxysteroid dehydrogenase) located in renal tubules inactivates glucocorticoid, allowing selective responses to mineralocorticoid. When there is glucocorticoid excess, the enzyme becomes oversaturated and glucocorticoid can exhibit mineralocorticoid effects. This effect is in contrast to the estrogen receptor, 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 hemorrhage 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 glucocorticoid 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 acromegaly, as in this patient, prolactinomas, and Cushing’s syndrome. Hypersecretion of growth hormone underlies this syndrome in patients with pituitary masses, though ectopic production of growth hormone, particularly by tumors, has been reported. Because growth hormone 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 made by the liver in response to growth hormone stimulation. An oral glucose tolerance test with growth hormone obtained at 0, 30, and 60 minutes may also be used to screen for acromegaly, as normal persons should suppress growth hormone to this challenge. Serum prolactin level is useful to screen for prolactinomas; 24-hour urinary free cortisol and ACTH assay are useful screens for Cushing’s disease.

X-8.    The answer is B. (Chap. 339) Hyperprolactinemia is the most common pituitary hormone hypersecretion syndrome in both men and women. Although pituitary adenoma is a frequent cause, there are several physiologic, medication-related, and potentially reversible etiologies. Prolactin is normally elevated during pregnancy and lactation, though levels should fall to normal within 6 months of cessation of breastfeeding. Nipple stimulation, sleep, and stress may all increase prolactin levels. Systemic disorders such as chronic renal failure and cirrhosis may also cause elevated prolactin levels. Prolactin levels are also typically elevated after generalized seizures, which may be useful in the evaluation of pseudoseizures. Drug-induced hypersecretion is associated with dopamine receptor blockers, dopamine synthesis inhibitors, opiates, H2 antagonists, imipramines, selective serotonin reuptake inhibitors, and calcium channel blockers. Hypothalamic-pituitary stalk damage may also cause hyperprolactinemia. Rathke’s cysts, which are benign intrasellar lesions, may produce endocrinologic abnormalities similar to pituitary adenomas.

X-9.    The answer is E. (Chap. 339) Tumors arising from the lactotrope cells of the pituitary account for half of all functioning pituitary tumors and most commonly affect women. The most common presentations are amenorrhea, infertility, and/or galactorrhea. Micro-adenomas rarely progress to become macroadenomas. For symptomatic disease, the primary goals of therapy are control of hyperprolactinemia, reduction of tumor size, restoration of menses and fertility, and resolution of galactorrhea. Usually oral dopamine agonists, such as carbergoline and bromocriptine, are used for this purpose.

X-10.   The answer is C. (Chap. 339) Adult growth hormone deficiency is usually caused by hypothalamic or pituitary damage. Because growth hormone is no longer important for achieving stature, the presentation is different from childhood growth hormone deficiency. Although growth hormone has direct tissue effects, it primarily acts through increasing secretion of IGF-1, which in turn stimulates lipolysis, increases circulating fatty acids, reduces omental fat mass, and enhances lean body mass. Thus, deficiency of growth hormone causes the opposite effects. In addition, hypertension, left ventricular dysfunction, and increased plasma fibrinogen levels may also be present with deficient growth hormone. Reduced, not increased, bone mineral density may also occur in adults with growth hormone deficiency.

X-11.   The answer is E. (Chap. 339) The patient has a clinical presentation consistent with Cushing’s syndrome. Although many cases of inappropriate elevation of ACTH are due to pituitary tumors, a substantial proportion are due to ectopic ACTH secretion. Clues to this diagnosis include a rapid onset of hypercortisolism features associated with skin hyperpigmentation and severe myopathy. Additionally, hypertension, hypokalemic metabolic alkalosis, glucose intolerance, and edema are more prominent in ectopic ACTH secretion than in pituitary tumors. Serum potassium below 3.3 mmol/L is present in 70% of ectopic ACTH cases, but in less than 10% of pituitary-dependent Cushing’s syndrome. ACTH levels will be high, as this is the underlying cause of both types of Cushing’s syndrome. Corticotropin-releasing hormone is rarely the cause of Cushing’s syndrome. Unfortunately, MRI of the pituitary gland will not visualize lesions less than 2 mm; thus occasional sampling of the inferior petrosal veins is required, but this is not indicated in the case presented at this time in the evaluation.

X-12.   The answer is C. (Chap. 339) The patient has panhypopituitarism and is unable to make TSH; thus her plasma TSH level will always be low, regardless of the adequacy of her T4 replacement. A free T4 level will allow the determination of whether her plasma level is in the normal range of thyroid hormone. This, coupled with her symptoms, will aid in the determination of proper levothyroxine dosing. There is no evidence of recurrent disease clinically; thus MRI is not useful. She is unlikely to have primary thyroid disease, and T4 level is unknown presently, so thyroid uptake scan is not indicated at this time.

X-13.   The answer is A. (Chap. 339) The diagnosis of Cushing’s syndrome relies on documentation of endogenous hypercortisolism. Of the list of choices, the most cost-effective and precise test is the 24-hour urine free cortisol. Failure to suppress plasma morning cortisol after overnight suppression with 1 mg dexamethasone is an alternative. Most ACTH-secreting pituitary adenomas are less than 5 mm in diameter, and approximately half are not detected even with sensitive MRI. Further, because incidental microadenomas are 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 distinguish 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 petrosal 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 laboratory 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 management 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 nephrogenic 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 deprivation 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 contribute 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. Folate deficiency in pregnant women is associated with an increased risk preterm labor and a number of congenital malformations, most notably involving the neural tube. Folate supplementation can lower the risk of spina bifida, anencephaly, congenital heart disease, cleft lips, and limb deformities. Vitamin A deficiency is a common cause of blindness in the developing world.

X-18.   The answer is E. (Chap. 341) T4 is secreted from the thyroid gland in approximately 20-fold greater quantities than T3. Both hormones are bound to plasma proteins including albumin, transthyretin, and thyroxine-binding protein. Thyroxine-binding protein has a high affinity for T4; thus despite its low concentration it carries 80% of the plasma hormone. It is followed by albumin and then transthyretin. Pregnant women may be euthyroid with elevated levels of total T4 because of the increase in thyroid-binding globulin. T3 is less protein bound than T4. Unbound hormone is thought to be biologically available to tissues, and normalization of the unbound fraction is the primary goal of homeostatic mechanisms. Measurement of free T4 is biologically more relevant than total T4. Thyroid peroxidase is an enzyme within the thyroid involved in the organification of iodine.

X-19.   The answer is C. (Chap. 341) There are a number of conditions associated with normal thyroid function, but hyperthyroxinemia. Although some of these are associated with clinical hyperthyroidism, many simply have elevated levels of total T4 and normal conversion to T3 and thus are clinically normal. Anything that increases liver production of thyroid-binding globulin will produce elevated total T4levels and normal free T4 and T3 levels. In this category are pregnancy, estrogen-containing oral contraceptives, cirrhosis, and familial excess thyroid-binding globulin production. Familial dysalbuminemic hyperthyroxinemia results in an albumin mutation and increased T4 with normal free T4 and T3 levels. Sick-euthyroid syndrome occurs during acute medical and psychiatric illness. In this syndrome, there is transiently increased unbound T4 and decreased TSH. Total T4 and T3 may be decreased, particularly later in the course of disease.

X-20.   The answer is D. (Chap. 341) Iodine deficiency remains the most common cause of hypothyroidism worldwide. It is present at relatively high levels even in the developed world including Europe. In areas of iodine sufficiency, autoimmune disease (Hashimoto’s thyroiditis) and iatrogenic hypothyroidism (treatment of hyperthyroidism) are the most common causes.

X-21.   The answer is B. (Chap. 341) There are a number of important effects of thyroid hormone (or its absence) on the cardiovascular system. Importantly, hypothyroidism is associated with bradycardia and reduced myocardial contractility, and thereby reduced stroke volume. Increased peripheral resistance may be accompanied by systemic hypertension, particularly diastolic hypertension in hypothyroidism. Pericardial effusions are found in up to 30% of patients with hypothyroidism, though they rarely cause decreased cardiac function. Finally, in hypothyroid patients, blood flow is directed away from the skin and thus produces cool extremities.

X-22.   The answer is B. (Chap. 341) The most common cause of hypothyroidism in the United States is autoimmune thyroiditis, as it is an iodine-replete area. Although earlier in the disease, a radioiodine uptake scan may have shown diffusely increased uptake from lymphocytic infiltration, at this point in the disease when the infiltrate is “burned out” there is likely to be little found on the scan. Likewise, a thyroid ultrasound would only be useful for presumed multinodular goiter. Antithyroid peroxidase antibodies are commonly found in patients with autoimmune thyroiditis, while antithyroglobulin antibodies are found less commonly. Antithyroglobulin antibodies are also found in other thyroid disorders (Graves’ disease, thyrotoxicosis) as well as systemic autoimmune diseases (SLEs). Thyroglobulin is released from the thyroid in all types of thyrotoxicosis with the exception of factitious disease. This patient, however, was hypothyroid, and thus serum thyroglobulin levels are unlikely to be helpful.

X-23.   The answer is D. (Chap. 341) An increase in TSH in a patient with hypothyroidism that was previously stable in dosing for many years suggests either a failure of taking the medication, difficulty with absorption from bowel disease, or medication interaction or drug-drug interaction affecting clearance. Patients with normal body weight taking more than 200 μg of levothyroxine per day who have elevated TSH strongly suggests noncompliance. Such patients should be encouraged to take two tablets at one time on the day they remember, to attempt to reach the weekly target dose; the long drug half-life makes this practice safe. Other causes of increased thyroxine requirements include malabsorption, such as with celiac disease or small bowel surgery, estrogen therapy, and drugs that interfere with T4 absorption (e.g., ferrous sulfate and cholestyramine) or clearance, such as lovastatin, amiodarone, carbamazepine, and phenytoin.

X-24.   The answer is A. (Chap. 341) The patient has myxedema coma. This condition of profound hypothyroidism most commonly occurs in the elderly, and often a precipitating condition may be identified such as myocardial infarction or infection. Clinical manifestations include altered level of consciousness, bradycardia, and hypothermia. Management includes repletion of thyroid hormone through IV levothyroxine, but also supplementation of glucocorticoids because there is impaired adrenal reserve in severe hypothyroidism. Care must be taken with rewarming as it may precipitate cardiovascular collapse. Therefore, external warming is indicated only if the temperature is below 30°C. Hypertonic saline and glucose may be used if hyponatremia or hypoglycemia is severe; however, hypotonic solutions should be avoided as they may worsen fluid retention. Because the metabolism of many substances is markedly reduced, sedation should be avoided or minimized. Similarly, blood levels of drugs should be monitored when available.

X-25.   The answer is A. (Chap. 341) Patients with Graves’ disease produce thyroid-stimulating immunoglobulins. They subsequently produce higher levels of T4 compared with the normal population. As a result, many patients with Graves’ disease are mildly iodine deficient, and T4 production is somewhat limited by the availability of iodine. Exposure to iodinated contrast thus reverses iodine deficiency and may precipitate worsening hyperthyroidism. Additionally, the reversal of mild iodine deficiency may make I-125 therapy for Graves’ disease less successful because thyroid iodine uptake is lessened in the iodine-replete state.

X-26.   The answer is C. (Chap. 341) Hyperthyroidism is associated with a number of cardiovascular complications including tachycardia, palpitations, high cardiac output with bounding pulse, widened pulse pressure, and aortic systolic murmur. This may lead to worsened angina in predisposed patients. Atrial fibrillation is more common in patients greater than 50 years of age, and treatment of thyroid state alone will lead to the reversal of atrial fibrillation in half of patients, suggesting underlying cardiac disorder in the remainder of unconverted patients.

X-27.   The answer is B. (Chap. 341) Although lid retraction can occur in any type of hyperthyroidism, Graves’ disease is associated with specific eye signs that are thought to be due to the interaction of autoantibodies with periorbital muscles. The onset of Graves’ ophthalmopathy may occur before or after hyperthyroidism, and rarely may not be associated with hyperthyroidism at all, but simply the effects of the presence of autoantibodies on the periorbital muscles. Subtle features are eye grittiness, discomfort, and excess tearing. Proptosis occurs in one-third of patients and may result in corneal abrasion if there is a failure of closure of the eyelids, particularly during sleep. The most serious manifestation is compression of the optic nerve at the apex of the orbit, which can lead to papilledema and permanent vision loss if left untreated.

X-28.   The answer is C. (Chap. 341) The main antithyroid drugs used in the treatment of Graves’ disease are propylthiouracil, carbimazole, and the active metabolite of carbimazole, methimazole. All act to inhibit the function of thyroid peroxidase. While propylthiouracil also reduces the peripheral conversion of T4 to T3, this is not its major mechanism of action and is not responsible for the majority of the drug’s utility in the therapy of Graves’ disease.

X-29.   The answer is C. (Chap. 341) Sick-euthyroid syndrome can occur in the setting of any acute, severe illness. Abnormalities in the levels of circulating TSH and thyroid hormone are thought to result from the release of cytokines in response to severe stress. Multiple abnormalities may occur. The most common hormone pattern is a decrease in total and unbound T3 levels as peripheral conversion of T4 to T3 is impaired. Teleologically, the fall in T3, the most active thyroid hormone, is thought to limit catabolism in starved or ill patients. TSH levels may vary dramatically, from 0.1 to above 20 mU/L, depending on when they are measured during the course of illness. Very sick patients may have a decrease in T4 levels. This patient undoubtedly has abnormal thyroid function tests as a result of his injuries from the motor vehicle accident. There is no indication for obtaining further imaging in this case. Steroids have no role. The most appropriate management consists of simple observation. Over the course of weeks to months, as the patient recovers, thyroid function will return to normal.

X-30 and X-31. The answers are E and B, respectively. (Chap. 341) Subacute thyroiditis, also known as de Quervain’s thyroiditis, granulomatous thyroiditis, or viral thyroiditis, is a multiphase illness that occurs three times more frequently in women than men. Multiple viruses have been implicated, but none have been definitively identified as the trigger for subacute thyroiditis. The diagnosis can be overlooked in patients as the symptoms mimic pharyngitis, and it frequently has a similarly benign course. In this patient, Graves’ disease is unlikely given her elevated TSH and negative antibody panel. Autoimmune hypothyroidism should be considered; however, the tempo of her illness, the tenderness of the thyroid on examination, and her preceding viral illness make this diagnosis less likely. Ludwig’s angina is a potentially life-threatening bacterial infection of the retropharyngeal and submandibular spaces, often caused by preceding dental infection. Cat-scratch fever is a usually benign illness that presents with lymphadenopathy, fever, and malaise. It is caused by Bartonella henselae and is frequently transmitted from cat scratches that penetrate the epidermis. It will not cause an elevated TSH. Subacute thyroiditis can present with hypothyroidism, thyrotoxicosis, or neither. In the first phase of the disease, thyroid inflammation leads to follicle destruction and release of thyroid hormone. Thyrotoxicosis ensues. In the second phase, the thyroid is depleted of hormone and hypothyroidism results. A recovery phase typically follows in which decreased inflammation allows the follicles to heal and regenerate hormone.

X-32.   The answer is B. (Chap. 341) Subacute thyroiditis, also known as de Quervain’s thyroiditis, granulomatous thyroiditis, and viral thyroiditis, is characterized clinically by fever, constitutional symptoms, and a painful, enlarged thyroid. The etiology is thought to be a viral infection. The peak incidence is between 30 and 50 years of age, and women are affected more frequently than men. The symptoms depend on the phase of the illness. During the initial phase of follicular destruction, there is a release of thyroglobulin and thyroid hormones. As a result, there is increased circulating T4 and T3, with concomitant suppression of TSH. Symptoms of thyrotoxicosis predominate at this point. Radioiodine uptake is low or undetectable. After several weeks, thyroid hormone is depleted and a phase of hypothyroidism ensues, with low unbound T4 levels and moderate elevations of TSH. Radioiodine uptake returns to normal. Finally, after 4–6 months, thyroid hormone and TSH levels return to normal as the disease subsides. Patient A is consistent with the thyrotoxic phase of subacute thyroiditis except for the increased radioiodine uptake scan. Patient C is more consistent with Graves’ disease with suppression of TSH, an elevated uptake scan, and elevated thyroid hormones as a result of stimulating immunoglobulin. Patient D is consistent with a neoplasm. Patient E is consistent with central hypothyroidism.

X-33.   The answer is E. (Chap. 341) Thyroid nodules are found in 5% of patients. Nodules are more common with age, in women, and in iodine-deficient areas. Given their prevalence, the cost of screening, and the generally benign course of most nodules, the choice and order of screening tests have been very contentious. A small percentage of incidentally discovered nodules will represent thyroid cancer, however. A TSH should be the first test to check after detection of a thyroid nodule. A majority of patients will have normal thyroid function tests. In the case of a normal TSH, fine-needle aspiration or ultrasound-guided biopsy can be pursued. If the TSH is low, a radionuclide scan should be performed to determine if the nodule is the source of thyroid hyperfunction (a “hot” nodule). In this case, this is the best course of action. “Hot” nodules can be treated medically, resected, or ablated with radioactive iodine. “Cold” nodules should be further evaluated with a fine-needle aspiration. Four percent of nodules undergoing biopsy are malignant, 10% are suspicious for malignancy, and 86% are indeterminate or benign.

X-34.   The answer is C. (Chap. 342) The adrenal gland has three major functions: glucocorticoid synthesis, aldosterone synthesis, and androgen precursor synthesis. Glucocorticoid synthesis is controlled by the pituitary secretion of ACTH. The primary stimulus for aldosterone synthesis is the renin-angiotensin-aldosterone system, which is independent of the pituitary. Thus, morning cortisol secretion and release of cortisol in response to stress are regulated by the pituitary gland, while regulation of sodium retention and potassium excretion by aldosterone is independent of the pituitary and would be preserved in this patient.

X-35.   The answer is A. (Chap. 342) Cushing’s syndrome is a constellation of features that result from chronic exposure to elevated levels of cortisol from any etiology. Although the most common etiology is ACTH-producing pituitary adenoma, which accounts for 75% of Cushing’s syndrome, 15% is due to ectopic ACTH syndromes such as bronchial or pancreatic tumors, small cell lung cancer, and others. ACTH-independent Cushing’s syndrome is much more rare. Adrenocortical adenoma underlies 5–10% of cases, and adrenocortical carcinoma is present in 1% of Cushing’s cases. McCune-Albright syndrome is a genetic cause of bone abnormalities, skin lesions (cafe au lait), and premature puberty, particularly in girls. Interestingly, it is caused by a sporadic in utero mutation, not an inherited disorder, and thus will not be passed onto progeny.

X-36.   The answer is B. (Chap. 342) Conn’s syndrome refers to an aldosterone-producing adrenal adenoma. Although it accounts for 40% of hyperaldosterone states, bilateral micronodular adrenal hyperplasia is more common. Other causes of hyperaldosteronism are substantially more rare, accounting for less than 1% of disease. The hallmark of Conn’s syndrome is hypertension with hypokalemia. Because aldosterone stimulates sodium retention and potassium excretion, all patients should be hypokalemic at presentation. Serum sodium is usually normal because of concurrent fluid retention. Hypokalemia may be associated with muscle weakness, proximal myopathy, or even paralysis. Hypokalemia may be exacerbated by thiazide diuretics. Additional features include metabolic alkalosis that may contribute to muscle cramps and tetany.

X-37.   The answer is B. (Chap. 342) Incidental adrenal masses are often discovered during radiographic testing for another condition and are found in approximately 6% of adult subjects at autopsy. Fifty percent of patients with a history of malignancy and a newly discovered adrenal mass will actually have an adrenal metastasis. Fine-needle aspiration of a suspected metastatic malignancy will often be diagnostic. In the absence of a suspected nonadrenal malignancy, most adrenal incidentalomas are benign. Primary adrenal malignancies are uncommon (<0.01%), and fine-needle aspiration is not useful to distinguish between benign and malignant primary adrenal tumors. Although 90% of these masses are nonsecretory, patients with an incidentaloma should be screened for pheochromocytoma and hypercortisolism with plasma free metanephrines and an overnight dexamethasone suppression test, respectively. When radiographic features suggest a benign neoplasm (<3 cm), scanning should be repeated in 3–6 months. When masses are larger than 6 cm, surgical removal (if more likely to be primary adrenal malignancy) or fine-needle aspiration (if more likely to be metastatic malignancy) is preferred.

X-38.   The answer is A. (Chap. 343) When the diagnosis of pheochromocytoma is entertained the first step is measurement of catecholamines and/or metanephrines. This can be achieved by urinary tests for vanillylmandelic acid, catecholamines, fractionated metanephrines, or total metanephrines. Total metanephrines have a high sensitivity and therefore are frequently used. A value of three times the upper limit of normal is highly suggestive of pheochromocytoma. Borderline elevations, as this patient had, are likely to be false positives. The next most appropriate step is to remove potentially confounding dietary or drug exposures, if possible, and repeat the test. Likely culprit drugs include levodopa, sympathomimetics, diuretics, tricyclic antidepressants, and alpha and beta blockers (labetalol in this case). Sertraline is an SSRI antidepressant, not a tricyclic. Alternatively, a clonidine suppression test may be ordered.

X-39.   The answer is E. (Chap. 343) Complete removal of the pheochromocytoma is the only therapy that leads to a long-term cure, although 90% of tumors are benign. However, preoperative control of hypertension is necessary to prevent surgical complications and lower mortality. This patient is presenting with encephalopathy in a hypertensive crisis. The hypertension should be managed initially with IV medications to lower the mean arterial pressure by approximately 20% over the initial 24-hour period. Medications that can be used for hypertensive crisis in pheochromocytoma include nitroprusside, nicardipine, and phentolamine. Once the acute hypertensive crisis has resolved, transition to oral α-adrenergic blockers is indicated. Phenoxybenzamine is the most commonly used drug and is started at low doses (5–10 mg three times daily) and titrated to the maximum tolerated dose (usually 20–30 mg daily). Once alpha blockers have been initiated, beta blockade can safely be utilized and is particularly indicated for ongoing tachycardia. Liberal salt and fluid intake helps expand plasma volume and treat orthostatic hypotension. Once blood pressure is maintained below 160/100 mmHg with moderate orthostasis, it is safe to proceed to surgery. If blood pressure remains elevated despite treatment with alpha blockade, addition of calcium channel blockers, angiotensin receptor blockers, or angiotensin-converting enzyme inhibitors should be considered. Diuretics should be avoided, as they will exacerbate orthostasis.

X-40.   The answer is C. (Chap. 344) The risk of both type 1 and type 2 diabetes mellitus is rising in all populations, but the risk of type 2 diabetes is rising at a substantially faster rate. In the United States, the age-adjusted prevalence of diabetes mellitus is 7.1% in non-Hispanic whites, 7.5% in Asian Americans, 11.8% in Hispanics, and 12.6% in non-Hispanic blacks. Comparable data are not available for individuals belonging to American Indian, Alaska Native, or Pacific Islander populations, but the prevalence is thought to be even higher than in the non-Hispanic black population.

X-41.   The answer is E. (Chap. 344) Glucose tolerance is classified into three categories: normal glucose tolerance, impaired glucose homeostasis, and diabetes mellitus. Normal glucose tolerance is defined by the following: fasting plasma glucose below 100 mg/dL, plasma glucose below 140 mg/dL following an oral glucose challenge, and hemoglobin A1C less than 5.6%. Abnormal glucose homeostasis is defined as fasting plasma glucose 100–125 mmol/dL or plasma glucose 140–199 following oral glucose tolerance test or hemoglobin A1C of 5.7–6.4%. Actual diabetes mellitus is defined by either a fasting plasma glucose above 126 mg/dL, glucose of 200 mg/dL after oral glucose tolerance test, or hemoglobin A1C of 6.5% or above.

X-42.   The answer is E. (Chap. 344) Because the patient has symptoms, she is not being screened for diabetes mellitus. For screening, the fasting plasma glucose or hemoglobin A1C is recommended. Because the patient has symptoms, a random plasma glucose of greater than 200 mg/dL is adequate to diagnose diabetes mellitus. Other criteria include fasting plasma glucose above 126 mg/dL or hemoglobin A1C above 6.4% or 2-hour plasma glucose above 200 during an oral glucose tolerance test. C peptide is a useful tool to determine if the normal cleavage of insulin from its precursor is occurring. A normal C-peptide level with hypoglycemia suggests surreptitious insulin use, and a low C-peptide with hyperglycemia suggests pancreatic failure.

X-43.   The answer is B. (Chap. 344) Risk factors for type 2 diabetes mellitus include family history of diabetes mellitus, including parent or sibling, BMI greater than 25 kg/m2, physical inactivity, race/ethnicity, previously identified impaired fasting glucose or hemoglobin A1C 5.7–6.4%, systemic hypertension, history of gestational diabetes or delivery of a baby greater than 4 kg, HDL less than 35 mmol/L and/or triglyceride level greater than 250 mg/dL, polycystic ovarian disease or acanthosis nigricans, and history of cardiovascular disease.

X-44.   The answer is A. (Chap. 344) Type 1 diabetes mellitus often has a more severe presentation with diabetic ketoacidosis and often presents in younger individuals compared with type 2 diabetes; however, there are some cases where the distinction of type 1 from type 2 is not straightforward. There is HLA-DR3 localization preferences for type 1 diabetes; several haplotypes are present in 40% of children with type 1 diabetes mellitus, but it is still the minority. Immunologic destruction of the beta cell is the primary cause of disease in type 1 diabetes, and islet cell antibodies are commonly present. GAD, insulin, IA/ICA-512, and ZnT-8 are the most common targets. Commercially available assays for GAD-65 autoantibodies are widely available and can demonstrate antibodies in more than 85% of individuals with recent-onset type 1 diabetes. These autoantibodies are infrequently present in type 2 diabetes; mellitus at 5–10%. There may be some residual insulin in the plasma in early type 1 diabetes; thus this will not distinguish the two conditions reliably. Polymorphisms of the peroxisome proliferator-activated receptor γ-2 have been described in type 2 diabetes mellitus, but cannot distinguish the two conditions.

X-45.   The answer is C. (Chap. 344) Type 2 diabetes mellitus is preceded by a period of impaired fasting glucose or impaired glucose tolerance, and a number of agents and interventions have been studied in this period to prevent progression to frank diabetes mellitus. The Diabetes Prevention Program demonstrated that intensive lifestyle changes including diet and exercise prevented or delayed the development of diabetes mellitus by 58% compared to placebo. Metformin was used in the same study and prevented the development of diabetes by 31%. Other drug therapies have been studied and showed delayed progression including alpha-glucosidase inhibitors, thiazolidinediones, and orlistat, though none are approved for this purpose, and the American Diabetes Association recommends only metformin for therapy in impaired glucose tolerance. Sulfonylureas, such as glyburide, stimulate glucose secretion and have not been shown to delay progression to type 2 diabetes.

X-46.   The answer is E. (Chap. 344) Diabetic ketoacidosis and hyperglycemic hyperosmolar state exist on a spectrum, with diabetic ketoacidosis being more common in patients with type 1 diabetes mellitus, but it does occur with some frequency in patients with type 2 diabetes. Both conditions include hyperglycemia, dehydration, absolute or relative insulin deficiency, and acid-base abnormalities. Ketosis is more common in diabetic ketoacidosis. In diabetic ketoacidosis, glucose normally ranges from 250 to 600 mg/dL, while it is frequently 600–1200 mg/dL in the hyperglycemic hyperosmolar state. Sodium is often mildly depressed in ketoacidosis and is preserved in the hyperosmolar state. Potassium is normal to elevated in diabetic ketoacidosis and normal in hyperglycemic hyperosmolar patients. Magnesium, chloride, and phosphate are normal in both conditions. Creatinine may be slightly elevated in diabetic ketoacidosis, but is often moderately elevated in the hyperglycemic hyperosmolar state. Plasma ketones may be slightly positive in hyperosmolar patients, but are always strongly positive in diabetic ketoacidosis. Because hyperosmolarity is the hallmark of hyperglycemic hyperosmolar patients, they have an osmolarity of 330–380 mosm/mL, while patients with diabetic ketoacidosis have a plasma osmolarity ranging from 300 to 320 mosm/mL. Serum bicarbonate is markedly depressed in diabetic ketoacidosis and normal or slightly depressed in the hyperosmolar state. Arterial pH is depressed at less than 7.3 in ketoacidosis and more than 7.3 in the hyperosmolar state. Finally, the anion gap is wide in diabetic ketoacidosis and normal to slightly elevated in the hyperglycemic hyperosmolar state.

X-47.   The answer is C. (Chap. 344) Diabetic retinopathy is the leading cause of blindness in adults aged 20–74 years in the United States. Blindness is the result of macular edema and progressive retinopathy, which can be divided into nonproliferative and proliferative retinopathy. Nonproliferative retinopathy tends to occur in the first and early second decades after diagnosis and is characterized by retinal vascular microaneurysms, blot hemorrhages, and cotton-wool spots. Neovascularization is the hallmark of proliferative retinopathy and occurs in response to retinal hypoxemia. Newly formed vessels occur in the retina and, because they are fragile, rupture easily and cause vitreous hemorrhage, fibrosis, and ultimately retinal detachment.

X-48.   The answer is C. (Chap. 344) Diabetic ulcers represent a major source of morbidity and even mortality in patients with diabetes mellitus. Although a number of interventions have been tried, only six interventions are recommended by the American Diabetes Association for demonstrated efficacy in the management of diabetic foot wounds: (1) off-loading, (2) debridement, (3) wound dressings, (4) appropriate use of antibiotics, (5) revascularization, and (6) limited amputation. Hyperbaric oxygen therapy has been used and is widely promoted through marketing, but rigorous proof of efficacy is lacking.

X-49.   The answer is D. (Chap. 344) Insulin preparations can be divided into short-acting and long-acting insulins. The short-acting insulins include regular and new preparations including aspart, glulisine, and lispro. Regular insulin has an onset of action of 0.5–1 hour and is effective for 4–6 hours. The other three short-acting insulins have an onset of action of less than 0.25 hours and are effective for 3–4 hours. Long-acting insulins include detemir, glargine, and NPH. Detemir and glargine have an onset of action of 1–4 hours and last up to 24 hours, while NPH has an onset of action of 1–4 hours and is effective for 10–16 hours. These insulins have a number of combination preparations that take advantage of the different durations of onset and action to provide optimal efficacy and compliance.

X-50.   The answer is D. (Chap. 344) First-line oral therapy for patients with type 2 diabetes mellitus is metformin. It is contraindicated in patients with GFR less than 60 mL/min, any form of acidosis, congestive heart failure, liver disease, or severe hypoxemia, but is well tolerated in most individuals. Insulin secretagogues, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, GLP-1 agonists, DPP-IV inhibitors, and insulin have all been approved as monotherapy for type 2 diabetes. Because of extensive clinical experience with metformin, favorable side effect profile, and relatively low cost, it is the recommended first-line agent. It has additional benefits of promotion of mild weight loss, lower insulin levels, and mild improvements in lipid profile. Sulfonylureas such as glyburide, GLP-1 agonists such as exenatide, and insulin dipeptidyl peptidase-4 inhibitors such as sitagliptin may be appropriate as combination therapy, but are not considered first-line therapy for most patients.

X-51.   The answer is A. (Chap. 344) The Diabetes Control and Complications Trial (DCCT) found definitive proof that a reduction in chronic hyperglycemia can prevent many of the complications of type 1 diabetes mellitus (DM). This multicenter randomized trial enrolled over 1400 patients with type 1 DM to either intensive or conventional diabetes management and prospectively evaluated the development of retinopathy, nephropathy, and neuropathy. The intensive group received multiple administrations of insulin daily along with education and psychological counseling. The intensive group achieved a mean hemoglobin A1C of 7.3% versus 9.1% in the conventional group. Improvement in glycemic control resulted in a 47% reduction in retinopathy, a 54% reduction in nephropathy, and a 60% reduction in neuropathy. There was a nonsignificant trend toward improvement in macrovascular complications. The results of the DCCT showed that individuals in the intensive group would attain up to 7 more years of intact vision and up to 5 more years free from lower limb amputation. Later, the United Kingdom Prospective Diabetes Study (UKPDS) studied over 5000 individuals with type 2 DM. Individuals receiving intensive glycemic control had a reduction in microvascular events but no significant change in macrovascular complications. These two trials were pivotal in showing a benefit of glycemic control in reducing microvascular complications in patients with type 1 and type 2 DM, respectively. Another result from the UKPDS was that strict blood pressure control resulted in an improvement in macrovascular complications.

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 counterregulatory 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 relationship 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 development of microalbuminuria (30–300 mg of albumin per 24 hours). The glomerular filtration 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 initial 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 systems to lower elevated blood glucose, but also to restore normal levels when hypoglycemia 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 that will lead the patient to find a source of food, and decreased cognition occurs with glucose less than 50 mg/dL.

X-56.   The answer is D. (Chap. 345) The patient presents with recurrent episodes of hypoglycemia that meet Whipple’s triad of symptoms, documented low glucose at the time of symptoms, and reversal of symptoms upon administration of glucose. The differential starts with measuring insulin levels during hypoglycemia. The levels must be obtained during an episode to be interpretable. If insulin is elevated, it suggests either endogenous hyperproduction from an insulin-secreting tumor or exogenous administration causing factitious hypoglycemia. Because C peptide is cleaved from native proinsulin to make the secreted product, it will be high in the case of endogenous hyperinsulinemia and low during an episode of factitious hypoglycemia. Surreptitious ingestion of sulfonylurea could cause hypoglycemia along with high insulin and C-peptide levels since the drugs stimulate pancreatic insulin secretion. In this case, a sulfonylurea drug screen would be indicated. Red flags in this case that point to surreptitious insulin use include the patient being a health care worker and the presence of symptoms only at work. Other groups in which this is common is relatives of patients with diabetes and patients with a history of other factitious disorders. It is possible that she has an insulin-secreting beta-cell tumor, but this is much less likely, and symptoms would be present during times other than work. Evaluation is aimed at demonstrating that pancreatic insulin secretion is suppressed during the episode of hypoglycemia. Although a failure of counterregulatory hormones can produce hypoglycemia, this is a very rare cause of hypoglycemia, and evaluation should be aimed at this only after surreptitious use is ruled out.

X-57.   The answer is E. (Chap. 345) The most common cause of hypoglycemia is related to the treatment of diabetes mellitus. Individuals with type 1 diabetes mellitus (T1DM) have more symptomatic hypoglycemia than individuals with type 2 diabetes mellitus (T2DM). On average, those with T1DM experience two episodes of symptomatic hypoglycemia weekly, and at least once yearly, individuals with T1DM will have a severe episode of hypoglycemia that is at least temporarily disabling. It is estimated that 2–4% of individuals with T1DM will die from hypoglycemia. In addition, recurrent episodes of hypoglycemia in T1DM contribute to the development of hypoglycemia-associated autonomic failure. Clinically, this is manifested as hypoglycemia unawareness and defective glucose counter-regulation, with lack of glucagon and epinephrine secretion as glucose levels fall. Individuals with T2DM are less likely to develop hypoglycemia. Medications that are associated with hypoglycemia in T2DM are insulin and insulin secretagogues, such as sulfonylureas. Metformin, thiazolidinediones, α-glucosidase inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-IV inhibitors do not cause hypoglycemia.

X-58.   The answer is D. (Chap. 346) Gynecomastia is a relatively common complaint in men and may be caused by either obesity with adipose tissue expansion in the breast or by an increased estrogen/androgen ratio in which there is true glandular enlargement, as in this case. If the breast is unilaterally enlarged or if it is hard or fixed to underlying tissue, mammography is indicated. Alternatively, if cirrhosis or a causative drug is present, these may be adequate explanations, particularly when gynecomastia develops later in life in previously fertile men. If the breast tissue is greater than 4 cm or there is evidence of very small testes and no causative drugs or liver disease, a search for alterations in serum testosterone, LH, FSH estradiol, and hCG levels should be undertaken. An androgen deficiency or resistance syndrome may be present or an hCG-secreting tumor may be found. In this case, spironolactone is the likely culprit, and it may be stopped or switched to eplerenone and gynecomastia reassessed.

X-59.   The answer is C. (Chap. 346) Many drugs may interfere with testicular function through a variety of mechanisms. Cyclophosphamide damages the seminiferous tubules in a dose-and time-dependent fashion and causes azoospermia within a few weeks of initiation. This effect is reversible in approximately half of these patients. Ketoconazole inhibits testosterone synthesis. Spironolactone causes a blockade of androgen action, which may also cause gynecomastia. Glucocorticoids lead to hypogonadism predominantly through inhibition of hypothalamic-pituitary function. Sexual dysfunction has been described as a side effect of therapy with beta blockers. However, there is no evidence of an effect on testicular function. Most reports of sexual dysfunction were in patients receiving older beta blockers such as propranolol and timolol.

X-60.   The answer is B. (Chap. 347) Women who have regular monthly bleeding cycles that do not vary by more than 4 days generally have ovulatory cycles, but several other indicators suggest that ovulation is likely. These include the presence of mittelschmerz, which is described as midcycle pelvic discomfort that is thought to be caused by rapid expansion of the dominant follicle at the time of ovulation or premenstrual symptoms such as breast tenderness, bloating, and food cravings. Additional objective parameters suggest the presence of ovulation including a progesterone level greater than 5 ng/mL 7 days before expected menses, an increase in basal body temperature more than 0.5°F in the second half of the menstrual cycle, and detection of urinary LH surge. Estrogen levels are elevated at the time of ovulation and during the secretory phase of the menstrual cycle, but are not useful in detection of ovulation.

X-61.   The answer is C. (Chap. 347) Infertility, defined as the inability to conceive after 12 months of unprotected intercourse, is a common problem in the United States with estimates of 15% of couples affected. Initial evaluation should include an evaluation of current menstrual history, counseling regarding the appropriate timing of intercourse, and education regarding modifiable risk factors such as drug use, alcohol intake, smoking, caffeine, and obesity. Male factors are at root of approximately 25% of cases of infertility, unexplained infertility is found in 17% of cases, and female causes underlie 58% of infertility. Among the female causes, the most common is amenorrhea/ovulatory dysfunction, which is present in 46% of cases. This is most frequently due to hypothalamic or pituitary cases or polycystic ovary syndrome. Tubal defects and endometriosis are less common.

X-62.   The answer is C. (Chap. 347) Evaluation of infertility should include evaluation of common male and female factors that could be contributing. Abnormalities of menstrual function are the most common cause of female infertility, and initial evaluation of infertility should include evaluation of ovulation and assessment of tubal and uterine patency. The female partner reports an episode of gonococcal infection with symptoms of pelvic inflammatory disease, which would increase her risk of infertility due to tubal scarring and occlusion. A hysterosalpingogram is indicated. If there is evidence of tubal abnormalities, many experts recommend in vitro fertilization for conception, as these women are at increased risk of ectopic pregnancy if conception occurs. The female partner reports some irregularity of her menses, suggesting anovulatory cycles, and thus evidence of ovulation should be determined by assessing hormonal levels. There is no evidence that prolonged use of oral contraceptives affects fertility adversely (A Farrow, et al: Hum Reprod 17: 2754, 2002). Angiotensin-converting enzyme inhibitors, including lisinopril, are known teratogens when taken by women but have no effects on chromosomal abnormalities in men. Recent marijuana use may be associated with increased risk of infertility, and in vitro studies of human sperm exposed to a cannabinoid derivative showed decreased motility (LB Whan, et al: Fertil Steril 85: 653, 2006). However, no studies have shown long-term decreased fertility in men who previously used marijuana.

X-63.   The answer is E. (Chap. 347) All of the choices have a theoretical efficacy in preventing pregnancy of more than 90%. However, the actual effectiveness can vary widely. Spermicides have the greatest failure rate of 21%. Barrier methods (condoms, cervical cap, diaphragm) have an actual efficacy between 82% and 88%. Oral contraceptives and intrauterine devices perform similarly, with 97% efficacy in preventing pregnancy in clinical practice.

X-64.   The answer is E. (Chap. 347) Pathologic gynecomastia develops when the effective testosterone-to-estrogen ratio is decreased owing to diminished testosterone production (as in primary testicular failure) or increased estrogen production. The latter may arise from direct estradiol secretion by a testis stimulated by LH or hCG, or from an increase in peripheral aromatization of precursor steroids, most notably androstenedione. Elevated androstenedione levels may result from increased secretion by an adrenal tumor (leading to an elevated level of urinary 17-ketosteroids) or decreased hepatic clearance in patients with chronic liver disease. A variety of drugs, including diethylstilbestrol, heroin, digitalis, spironolactone, cimetidine, isoniazid, and tricyclic antidepressants, also can cause gynecomastia. In this patient, the history of paternity and the otherwise normal physical examination indicate that a karyotype is unnecessary, and the bilateral breast enlargement essentially excludes the presence of carcinoma and thus the need for biopsy. The presence of a low LH and testosterone suggests either estrogen or hCG production. Because of the normal testicular examination, a primary testicular tumor is not suspected. Carcinoma of the lung and germ cell tumors both can produce hCG, causing gynecomastia.

X-65.   The answer is E. (Chap. 348) The Women’s Health Initiative was the largest study of hormone therapy to date including 27,000 postmenopausal women aged 50–79 for an average of 5–7 years. This trial was stopped early because of an unfavorable risk-to-benefit ratio in the estrogen-progestin arm and an increased risk of stroke that was not offset by lower coronary heart disease in the estrogen-only arm. Endometrial cancer risk was higher in patients with estrogen only and uterus. Use of progesterone eliminates this risk. Unopposed estrogen was associated with increased risk of stroke that far outweighed the decreased risk of coronary heart disease. Estrogen-progestin together was associated with an increased risk of coronary heart disease. Osteoporosis risk was decreased in both estrogen and estrogen-progestin groups. Venous thromboembolism risk was higher in both treatment groups as well. These therapies do reduce important menopausal symptoms such as hot flashes and vaginal drying. This seminal study caused a dramatic reevaluation of the use of estrogen/progesterone in postmenopausal women to reduce cardiovascular risk.

X-66.   The answer is C. (Chap. 349) Klinefelter’s syndrome is a chromosomal disorder with 47,XXY. Because the primary feature of this disorder is gonadal failure, low testosterone is present and thus increased LH and FSH are produced in an attempt to increase testosterone production in the feedback loop of sex hormones. Increased estrogen is often produced because of chronic Leydig cell stimulation by LH and because of aromatization of androstenedione by adipose tissue. The lower testosterone:estrogen ratio results in mild feminization with gynecomastia. Features of low testosterone are small testes and “eunuchoid” proportions with long legs and incomplete virilization. Biopsy of the testes, though rarely performed, shows hyalinization of the seminiferous tubules and azoospermia. Although severe cases are diagnosed prepubertally with small testes and impaired androgenization, approximately 75% of cases are not diagnosed and the frequency in the general population is 1/1000. Patients with Klinefelter’s syndrome are at increased risk of breast tumors, thromboembolic disease, learning difficulties, obesity, diabetes mellitus, and varicose veins.

X-67.   The answer is A. (Chap. 349) Turner’s syndrome most frequently results from a 45,X karyotype, but mosaicism (45,X/46,XX) also can result in this disorder. Clinically, Turner’s syndrome manifests as short stature and primary amenorrhea if presenting in young adulthood. In addition, chronic lymphedema of the hands and feet, nuchal folds, a low hairline, and high arched palate are also common features. To diagnose Turner’s syndrome, karyotype analysis should be performed. A Barr body results from inactivation of one of the X chromosomes in women and is not seen in males. In Turner’s syndrome, the Barr body should be absent, but only 50% of individuals with Turner’s syndrome have the 45,X karyotype. Thus, the diagnosis could be missed in those with mosaicism or other structural abnormalities of the X chromosome.

Multiple comorbid conditions are found in individuals with Turner’s syndrome, and appropriate screening is recommended. Congenital heart defects affect 30% of women with Turner’s syndrome, including bicuspid aortic valve, coarctation of the aorta, and aortic root dilatation. An echocardiogram should be performed, and the individual should be assessed with blood pressures in the arms and legs. Hypertension can also be associated 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 measurement. 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 alternative 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 demonstration of hypergastrinemia. Finally, although Zollinger-Ellison syndrome may be associated with multiple endocrine neoplasia type 1, which often has parathyroid hyperplasia or adenoma, this is less likely than isolated Zollinger-Ellison syndrome.

X-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 surgical 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 combination of histamine H1 and H2 receptor antagonists may control flushing, particularly in patients with foregut carcinoid tumors. Somatostatin analogues (octreotide, lanreotide) 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 α, alone or combined with hepatic artery embolization, controls flushing and diarrhea in 40–85% of these patients. Phenoxybenzamine is an α1-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, chemotherapy, 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 effective in preventing crises when administered before a known inciting event. Octreotide 150–250 μg subcutaneously every 6–8 hours should be started 24–48 hours before a procedure 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 hypochlorhydria (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 requires the demonstration of large-volume secretory diarrhea (>700 mL/d) and elevated serum VIP. CT scan of the abdomen will often demonstrate the pancreatic mass and liver metastases.

X-72.   The answer is B. (Chap. 351) Multiple endocrine neoplasia syndrome is defined as a disorder with neoplasms affecting two or more hormonal tissues in several members of the family. The most common of these is MEN 1, which is caused by the gene coding the nuclear protein called Menin. MEN 1 is associated with tumors or hyperplasia of the parathyroid, pancreas, pituitary, adrenal cortex, and foregut, and/or subcutaneous or visceral lipomas. The most common and earliest manifestation is hyperparathyroidism with symptomatic hypercalcemia. This most commonly occurs in the late teenage years and 93–100% of mutation carriers develop this complication. Gastrinomas, insulinomas, and prolactinomas are less common and tend to occur in patients in their 20s, 30s, and 40s. Pheochromocytoma may occur in MEN 1, but is more commonly found in MEN 2A or von Hippel-Lindau syndrome.

X-73.   The answer is A. (Chap. 351) This patient’s clinical scenario is most consistent with MEN 1, or the “3 Ps”: parathyroid, pituitary, and pancreas. MEN 1 is an autosomal dominant genetic syndrome characterized by neoplasia of the parathyroid, pituitary, and pancreatic islet cells. Hyperparathyroidism is the most common manifestation of MEN 1. The neoplastic changes affect multiple parathyroid glands, making surgical care difficult. Pancreatic islet cell neoplasia is the second most common manifestation of MEN 1. Increased pancreatic islet cell hormones include pancreatic polypeptide, gastrin, insulin, vasoactive intestinal peptide, glucagons, and somatostatin. Pancreatic tumors may be multicentric, and up to 30% are malignant, with the liver being the first site of metastases. The symptoms depend on the type of hormone secreted. The Zollinger-Ellison syndrome (ZES) causes elevations of gastrin, resulting in an ulcer diathesis. Conservative therapy is often unsuccessful. Insulinoma results in documented hypoglycemia with elevated insulin and C-peptide levels. Glucagonoma results in hyperglycemia, skin rash, anorexia, glossitis, and diarrhea. Elevations in vasoactive intestinal peptide result in profuse watery diarrhea. Pituitary tumors occur in up to half of patients with MEN 1. Prolactinomas are the most common. The multicentricity of the tumors makes resection difficult. Growth hormone–secreting tumors are the next most common, with ACTH- and corticotropin-releasing hormone (CRH)-secreting tumors being more rare. Carcinoid tumors may also occur in the thymus, lung, stomach, and duodenum.

X-74 and X-75. The answers are D and C, respectively. (Chap. 352) Hypophosphatemia results from one of three mechanisms: inadequate intestinal phosphate absorption, excessive renal phosphate excretion, and rapid redistribution of phosphate from the extracellular space into bone or soft tissue. Inadequate intestinal absorption is rare since antacids containing aluminum hydroxide are no longer commonly prescribed. Malnutrition from fasting or starvation may result in depletion of phosphate. This is also commonly seen in alcoholism. In hospitalized patients, redistribution is the main cause. Insulin promotes phosphate entry into cells along with glucose. When nutrition is initiated, refeeding further increases redistribution of phosphate into cells and is more pronounced when IV glucose is used alone. Sepsis may cause destruction of cells and metabolic acidosis, resulting in a net shift of phosphate from the extracellular space into cells. Renal failure is associated with hyperphosphatemia, not hypophosphatemia, and initial prerenal azotemia, such as in this presentation, can obscure underlying phosphate depletion.

The approach to treating hypophosphatemia should take into account several factors, including the likelihood (and magnitude) of underlying phosphate depletion, renal function, serum calcium levels, and the concurrent administration of parenteral glucose. In addition, the treating physician should assess the patient for complications of hypophosphatemia, which can include neuromuscular weakness, cardiac dysfunction, hemolysis, and platelet dysfunction. Severe hypophosphatemia generally occurs when the serum concentration falls below 2 mg/dL (<0.75 mmol/L). This becomes particularly dangerous when there is underlying chronic phosphate depletion. However, there is no simple formula to determine the body’s phosphate needs from measurement of the serum phosphate levels because most phosphate is intracellular. It is generally recommended to use oral phosphate repletion when the serum phosphate levels are greater than 1.5–2.5 mg/dL (0.5–0.8 mmol/L). The dose of oral phosphate is 750–2000 mg daily of elemental phosphate given in divided doses. More severe hypophosphatemia as in the case presented requires intravenous repletion. Intravenous phosphate repletion is given as neutral mixtures of sodium and potassium phosphate salts at doses of 0.2–0.8 mmol/kg given over 6 hours. Table X-75 outlines the total dose and recommended infusion rates for a range of phosphate levels. In this patient with a level of 1.0 mg/dL, the recommended infusion rate is 8 mmol/h over 6 hours for a total dose of 48 mmol. Until the underlying hypophosphatemia is corrected, one should measure phosphate and calcium levels every 6 hours. The infusion should be stopped if the calcium phosphate product rises to higher than 50 to decrease the risk of heterotopic calcification. Alternatively, if hypocalcemia is present coincident with the hypophosphatemia, it is important to correct the calcium prior to administering phosphate.

TABLE X-75 Intravenous Therapy for Hypophosphatemia

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X-76.   The answer is E. (Chap. 352) Magnesium sulfate is first-line therapy for seizures associated with eclampsia of pregnancy. A pregnant woman presenting with seizures and hypertension is initially treated with a bolus of magnesium sulfate at a dose of approximately 4 g followed by a continuous infusion at 1 g/h. While definitive treatment of eclampsia is delivery of the baby, ongoing therapy with magnesium sulfate for 24 hours following the last seizure is recommended. Patients should be monitored throughout the infusion for signs of hypermagnesemia, and levels should be measured at least every 6 hours. The usual magnesium concentration is 0.7–1 mmol/L (1.5–2 meq/L), and the desired level for treatment of preeclampsia is usually 1.7–3.5 mmol/L, although signs and symptoms of hypermagnesemia can develop with levels of 2 mmol/L or higher. The initial signs of hypermagnesemia include prolongation of the QRS complex, depression of deep tendon reflexes, and hypotension that is refractory to vasopressors. At concentrations greater than 4 mmol/L, nausea, lethargy, and weakness can appear and progress to paralysis and respiratory failure. The symptoms become increasingly severe, and asystole occurs when levels approach 10 mmol/L.

X-77.   The answer is B. (Chap. 352) Vitamin D deficiency is highly prevalent in the United States and is most common in older individuals who are hospitalized or institutionalized. Vitamin D deficiency can occur as a result of inadequate dietary intake, decreased production in the skin, decreased intestinal absorption, accelerated losses, or impaired vitamin D activation in the liver or kidney. Clinically, vitamin D deficiency in older individuals 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 individuals can experience diffuse muscle and bone pain. When assessing vitamin D levels, the appropriate test is 25-hydroxy vitamin D [25(OH)D] levels. Optimal 25(OH)D levels are greater than 80 nmol/L (32 ng/mL); however, an individual is not considered deficient until the level is less than 37 nmol/L (15 ng/mL). When the 25(OH)D level falls below this level, parathyroid hormone (PTH) may rise, and it is also associated with a lower bone density. Vitamin D deficiency leads to decreased intestinal absorption of calcium with resultant hypocalcemia and secondary hyperparathyroidism. In response to this, there is higher bone turnover, which can be associated with an increase in alkaline phosphatase levels. In addition, elevated PTH stimulates renal conversion of 25-hydroxy vitamin D to 1,25-hydroxy vitamin D, the activated form of vitamin D. Thus, even in the face of severe vitamin D deficiency, the activated 1,25(OH)D levels may be normal and do not accurately reflect vitamin D stores. Thus, 1,25(OH)D should not be used to make a diagnosis of vitamin D deficiency. While vitamin D deficiency may be associated with abnormalities in PTH, alkaline phosphatase, and calcium levels, these biochemical abnormalities are seen in many other diseases and are neither sensitive nor specific for the diagnosis of vitamin D deficiency.

X-78.   The answer is A. (Chap. 353) Granulomatous disorders including sarcoidosis, tuberculosis, and fungal infections can be associated with hypercalcemia-caused increased synthesis of 1,25-hydroxy vitamin D by macrophages within the granulomas. This process bypasses the normal feedback mechanisms, and elevated levels of both 25-hydroxy and 1,25-hydroxy vitamin can be seen. This does not normally occur as 1,25-hydroxy-vitamin D levels are normally tightly controlled through feedback mechanisms on renal 1-hydroxylase, the primary producer of activated vitamin D in normal circumstances. In addition, the normal feedback provided by parathyroid hormone concentrations is also bypassed and the PTH level may be low.

X-79.   The answer is D. (Chap. 353) This patient demonstrates evidence of tertiary hyper-parathyroidism, with inappropriate elevations in parathyroid hormone despite increases in calcium and phosphate. In addition, the patient is demonstrating clinical evidence of disease including bony pain and ectopic calcification. Tertiary hyperparathyroidism most commonly develops in individuals with long-standing renal failure who have been non-adherent to therapy. In this case scenario, the hypoxemia and ground-glass infiltrates on chest CT represent ectopic calcification of the lungs. This can be difficult to identify with typical imaging, and a technetium-99 bone scan will show increased uptake in the lungs. Treatment of tertiary hyperparathyroidism with severe clinical manifestations requires parathyroidectomy.

X-80.   The answer is B. (Chap. 353) Hypocalcemia can be a life-threatening consequence of thyroidectomy if the parathyroid glands are inadvertently removed during the surgery, as the four parathyroid glands are located immediately posterior to the thyroid gland. This is an infrequent occurrence currently as the parathyroid glands can be better identified both before and during surgery. However, hypoparathyroidism may occur even if the parathyroid glands are not removed by thyroidectomy due to devascularization or trauma to the parathyroid glands. Hypocalcemia following removal of the parathyroid glands may begin any time during the first 24–72 hours, and monitoring of serial calcium levels is recommended for the first 72 hours. The earliest symptoms of hypocalcemia are typically circumoral paresthesias and paresthesias with a “pins-and-needles” sensation in the fingers and toes. The development of carpal spasms upon inflation of the blood pressure cuff is a classic sign of hypocalcemia and is known as Trousseau sign. Chvostek sign is the other classic sign of hypocalcemia and is elicited by tapping the facial nerve in the preauricular area causing spasm of the facial muscles. A prolongation of the QT interval on ECG suggests life-threatening hypocalcemia that may progress to fatal arrhythmia, and treatment should not be delayed for serum testing to occur in a patient with a known cause of hypocalcemia. Immediate treatment with IV calcium should be initiated. Maintenance therapy with calcitriol and vitamin D is necessary for ongoing treatment of acquired hypoparathyroidism. Alternatively, surgeons may implant parathyroid tissue into the soft tissue of the forearm, if it is thought that the parathyroid glands will be removed. Hypomagnesemia can cause hypocalcemia by suppressing parathyroid hormone release despite the presence of hypocalcemia. However, in this patient, hypomagnesemia is not suspected after thyroidectomy, and magnesium administration is not indicated. Benztropine is a centrally acting anticholinergic medication that is used in the treatment of dystonic reactions that can occur after taking centrally acting antiemetic medications with dopaminergic activity, such as metoclopramide or Compazine. Dystonic reactions involve focal spasms of the face, neck, and extremities. While this patient has taken a medication (morphine) that can cause a dystonic reaction, the spasms that she is experiencing are more consistent with tetanic contractions of hypocalcemia than dystonic reactions. Finally, measurement of forced vital capacity is most commonly used as a measurement of disease severity in myasthenia gravis or Guillain-Barré syndrome. Muscle weakness is a typical presenting feature but not paresthesias.

X-81.   The answer is E. (Chap. 353) Malignancy can cause hypercalcemia by several different mechanisms, including metastasis to bone, cytokine stimulation of bone turnover, and production of a protein structurally similar to parathyroid hormone by the tumor. This protein is called parathyroid hormone–related peptide (PTHrp) and acts at the same receptors as parathyroid hormone (PTH). Squamous cell carcinoma of the lung is the most common tumor associated with the production of PTHrp. Serum calcium levels can become quite high in malignancy because of unregulated production of PTHrp that is outside of the negative feedback control that normally results in the setting of hyper-calcemia. PTH hormone levels should be quite low or undetectable in this setting. When hypercalcemia is severe (>15 mg/dL), symptoms frequently include dehydration and altered mental status. The electrocardiogram may show a shortened QTc interval. Initial therapy includes large-volume fluid administration to reverse the dehydration that results from hypercalciuria. In addition, furosemide is added to promote further calciuria. If the calcium remains elevated, as in this patient, additional measures should be undertaken to decrease the serum calcium. Calcitonin has a rapid onset of action with a decrease in serum calcium seen within hours. However, tachyphylaxis develops, and the duration of benefit is limited. Pamidronate is a bisphosphonate that is useful for the hypercalcemia of malignancy. It decreases serum calcium by preventing bone resorption and release of calcium from the bone. After IV administration, the onset of action of pamidronate is 1–2 days with a duration of action of at least 2 weeks. Thus, in this patient with ongoing severe symptomatic hypercalcemia, addition of both calcitonin and pamidronate is the best treatment. The patient should continue to receive IV fluids and furosemide. The addition of a thiazide diuretic is contraindicated because thiazides cause increased calcium resorption in the kidney and would worsen hypercalcemia.

X-82.   The answer is B. (Chap. 353) Hyperparathyroidism is the most common cause of hyper-calcemia and is the most likely cause in an adult who is asymptomatic. Cancer is the second most common cause of hypercalcemia but usually is associated with symptomatic hypercalcemia. In addition, there are frequently symptoms from the malignancy itself that dominate the clinical picture. Primary hyperparathyroidism results from autonomous secretion of parathyroid hormone (PTH) that is no longer regulated by serum calcium levels, usually related to the development of parathyroid adenomas. Most patients are asymptomatic or have minimal symptoms at the time of diagnosis. When present, symptoms include recurrent nephrolithiasis, peptic ulcers, dehydration, constipation, and altered mental status. Laboratory studies show elevated serum calcium with decreased serum phosphate. Diagnosis can be confirmed with measurement of parathyroid hormone levels. Surgical removal of autonomous adenomas is generally curative, but not all patients need to be treated surgically. It is recommended that individuals below age 50 undergo primary surgical resection. However, in those above 50 years, a cautious approach with frequent laboratory monitoring is often used. Surgery can then be undertaken if a patient develops symptomatic or worsening hypercalcemia or complications such as osteopenia. Breast cancer is a frequent cause of hypercalcemia because of metastatic disease to the bone. In this patient who has received routine mammography as part of age-appropriate cancer screening and is asymptomatic, this would be unlikely. Multiple myeloma is another malignancy frequently associated with hypercalcemia that is thought to be due to the production of cytokines and humoral mediators by the tumor. Multiple myeloma should not present with isolated hypercalcemia and is associated with anemia and elevations in creatinine.

Approximately 20% of individuals with hyperthyroidism develop hypercalcemia related to increased bone turnover. This patient exhibits no signs or symptoms of hyper-thyroidism, making the diagnosis unlikely. Vitamin D intoxication is a rare cause of hypercalcemia. An individual must ingest 40–100 times the recommended daily amount in order to develop hypercalcemia. Because vitamin D acts to increase both calcium and phosphate absorption from the intestine, serum levels of both minerals would be elevated, which is not seen in this case.

X-83.   The answer is B. (Chap. 353) Parathyroid hormone (PTH) is produced by the four small parathyroid glands that lie posterior to the thyroid gland and is the primary hormone responsible for regulating serum calcium and phosphate balance. PTH secretion is tightly regulated with negative feedback to the parathyroid glands by serum calcium and vitamin D levels. PTH primarily affects serum calcium and phosphate levels through its action in the bone and the kidney. In the bone, PTH increases bone remodeling through its actions on the osteoblasts and osteoclasts. It directly stimulates osteoblasts to increase bone formation, and this action of PTH has been utilized in the treatment of osteoporosis. Its action on osteoclasts, however, is indirect and likely is mediated through its actions on the osteoblasts. The osteoclast has no receptors for PTH. It has been hypothesized that cytokines produced by osteoblasts are responsible for increased osteoclastic activity that is seen after PTH administration, as PTH fails to have an effect on osteoclasts in the absence of osteoblasts. The net effect of PTH on the bone is to increase bone remodeling. Ultimately, this leads to an increase in serum calcium, an effect that can be seen within hours of drug administration. In the kidney, PTH acts to increase calcium reabsorption while increasing phosphate excretion. At the proximal tubule, PTH acts to decrease phosphate transport, thus facilitating its excretion. Calcium reabsorption is increased by the action of PTH on the distal tubule. A final action of PTH in the kidney is to increase the production of 1,25-hydroxycholecalciferol, the activated form of vitamin D, through stimulation of 1-α-hydroxylase. Activated vitamin D then helps to increase calcium levels by increasing intestinal absorption of both calcium and phosphate.

X-84.   The answer is B. (Chap. 354) Osteoporosis refers to a chronic condition characterized by decreased bone strength and frequently manifests as vertebral and hip fractures. In the Unites States, about 8 million women have osteoporosis compared to about 2 million men, for a ratio between men and women of 4 to 1. An additional 18 million individuals are estimated to have osteopenia. The risk of osteoporosis increases with advancing age and rapidly worsens following menopause in women. Most women meet the diagnostic criteria for osteoporosis between the ages of 70 and 80. White women have an increased risk for osteoporosis when compared to African-American women.

The epidemiology for bone fractures follows the epidemiology for osteoporosis. Fractures of the distal radius (Colles’ fracture) increases up to age 50 and plateaus by age 60, and there is only a modest increase in risk thereafter. This is contrasted with the risk of hip fractures. Incidence rates for hip fractures double every 5 years after the age of 70. This change in fracture pattern is not entirely due to osteoporosis, but is also related to the fact that fewer falls in the elderly occur onto an outstretched arm and are more likely to occur directly onto the hip. Black women experience hip fractures at approximately half the rate as white women. The mortality rate in the year following a hip fracture is 5–20%. Vertebral fractures are also common manifestations of osteoporosis. While most are found incidentally on chest radiograph, severe cases can lead to height loss, pulmonary restriction, and respiratory morbidity.

X-85.   The answer is C. (Chap. 354) There are multiple risks for osteoporotic bone fractures that can be either modifiable or nonmodifiable. These are outlined in Table X-85. Non-modifiable risk factors include a previous history of fracture as an adult, female sex, white race, dementia, advanced age, and history of fracture (but not osteoporosis) in a first-degree relative. Risk factors that are potentially modifiable include body weight less than 58 kg (127 lb), low calcium intake, alcoholism, impaired eyesight, recurrent falls, 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

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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 metabolism, 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 obstructive 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 corticosteroid use, frequent vitamin D deficiency, and low activity states. Other broad categories of disease that can lead to osteoporosis include rheumatologic disorders, hematologic malignancies, 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 formation 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 lumbar 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 evaluation 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 general, most women do not require screening for osteoporosis until after completion of menopause unless there have been unexplained fractures or other risk factors that would suggest osteoporosis. There is no benefit to initiating screening for osteoporosis in the perimenopausal period. Indeed most expert recommendations do not recommend routine screening for osteoporosis until age 65 or older unless risk factors are present. Risk factors for osteoporosis include advanced age, current cigarette smoking, low body weight (<57.7 kg), family history of hip fracture, and long-term glucocorticoid use. Inhaled glucocorticoids may cause increased loss of bone density, but as this patient is on a low dose of inhaled fluticasone and is not estrogen deficient, bone mineral densitometry cannot be recommended at this time. The risk of osteoporosis related to inhaled glucocorticoids is not well defined, but most studies suggest that the risk is relatively low. Delaying childbearing until the fourth and fifth decade does increase the risk of osteoporosis but does not cause early onset of osteoporosis prior to completion of menopause. The patient’s family history of menopause likewise does not require early screening for osteoporosis.

X-89.   The answer is D. (Chap. 354) Osteoporosis is defined as a reduction of bone mass or density or the presence of a fragility fracture. Operationally, the World Health Organization (WHO) defines osteoporosis as a bone density more than 2.5 SD less than the mean for young healthy adults of the same race and sex. Dual-energy x-ray absorptiometry (DXA) is the most widely used study to determine bone density. Bone density is expressed as a T-score, that is, the SD below the mean of young adults of the same race and gender. A T-score higher than 2.5 characterizes osteoporosis, and a T-score less than 1 identifies patients at risk of osteoporosis. The Z-score compares individuals with those in an age-, race-, and gender-matched population.

X-90.   The answer is E. (Chap. 354) Multiple treatment choices are available to prevent fractures and reverse bone loss in osteoporosis, and the side-effect profiles should be carefully considered when making the appropriate choice for this patient. Risedronate belongs to a family of drugs called bisphosphonates. Bisphosphonates act to inhibit osteoclast activity to decrease bone resorption and increase bone mass. Alendronate, risedronate, and ibandronate are approved for the treatment of postmenopausal osteoporosis, and alendronate and risedronate are also approved for the treatment of steroid-induced osteoporosis and osteoporosis in men. In clinical trials, risedronate decreases the risk of hip and vertebral fracture in women with osteoporosis by about 40% over 3 years. However, risedronate is not effective in decreasing hip fracture in women over the age of 80 without proven osteoporosis. The major side effect of bisphosphonate compounds taken orally is esophagitis. These drugs should be taken with a full glass of water, and the patient should remain upright for 30 minutes after taking the drug. There is also some concern about increased risk of osteonecrosis of the jaw in individuals treated with high doses of IV bisphosphonates or treated with oral therapy for prolonged periods, but in this patient with severe osteoporosis and a recent fracture, the benefits outweigh potential risks. Estrogens are also effective in preventing and treating osteoporosis. Epidemiologic data indicate that women taking estrogen have a 50% decreased risk of hip fracture. Raloxifene is a selective estrogen receptor modulator (SERM). The effect of raloxifene on bone density is somewhat less than that of estrogen, but it does decrease the risk of vertebral fracture by 30–50%. However, both drugs are contraindicated in this patient because of the recent occurrence of venous thromboembolic disease. Both estrogen and SERMs increase the risk of DVT and pulmonary embolus several-fold. If estrogen is to be used, it should be used in combination with a progestin compound in women with an intact uterus to decrease the risk of uterine cancer associated with unopposed estrogen stimulation. Both calcium and vitamin D supplementation are recommended as supplemental therapy, but given the degree of osteoporosis are inadequate alone. Calcitonin is available as an intranasal spray and produces small increases in bone density, but it has no proven effectiveness on the prevention of fractures.

X-91 and X-92. The answers are B and C, respectively. (Chap. 355) The most likely diagnosis in this case is Paget’s disease. A normal level of γ-glutamyl transferase localizes the cause of the elevated alkaline phosphatase to the bone. Thus, diseases of the liver and biliary tree are excluded. While both vertebral osteomyelitis and Paget’s disease could cause elevations in alkaline phosphatase, the patient has no symptoms of systemic illness that one would typically expect with vertebral osteomyelitis. Paget’s disease is a common dysplasia of the bone associated with localized bone remodeling that can affect numerous discreet areas of the skeleton. This disorder is relatively common. In autopsy series, Paget’s lesions can be demonstrated in about 3% of individuals older than 40 years of age, although clinical manifestations of the disease are far less common. Diagnosis is most often made in individuals with asymptomatic elevations of alkaline phosphatase or through characteristic radiographic changes in individuals who underwent biochemical or radiographic testing for other reasons. In symptomatic individuals, localized pain is most commonly seen. The bones most often affected include the femur, skull, pelvis, vertebral bodies, and tibia, and the specific symptoms depend on the location of the Paget’s lesion. When the vertebral bodies are involved, back pain can result from enlarged vertebrae, compression fractures of the spine, and spinal stenosis. In rare instances, spinal cord compression can occur. In this scenario, it is possible that the patient’s back pain is due to undiagnosed Paget’s disease. Diagnosis is typically made based on typical findings on radiographs and biochemical testing. Radiographs may demonstrate the enlargement or expansion of an entire bone, cortical thickening, coarsening of the trabecular markings, and both lytic and sclerotic changes. Characteristic findings of the vertebrae include cortical thickening of the superior and inferior endplates, creating a “picture frame” vertebra. If a vertebra is diffusely enlarged, the radiodensity created is known as an “ivory vertebra.” An elevation in alkaline phosphatase is the classic finding in Paget’s disease and is the test of choice for both diagnosis and assessing response to therapy. Serum osteocalcin, a marker of bone formation, is not always elevated in Paget’s disease for unknown reasons and is not recommended for either diagnosis or response to therapy. Serum or urine N-telopeptide or C-telopeptide are also bone resorption markers and are elevated in active Paget’s disease. These markers decrease more rapidly in response to therapy than alkaline phosphatase. Serum calcium and phosphate levels are normal in Paget’s disease unless a patient becomes immobilized.

X-93.   The answer is C. (Chap. 355) Paget’s disease of the bone is associated with localized bone dysplasia that can occur in numerous discreet areas of bone. Pathologically, the disease is initiated by overactivity of osteoclasts leading to high bone turnover and subsequent increase in osteoblastic activity, resulting in both lytic and sclerotic lesions in bone. Biochemically, there is typically evidence of high bone turnover, with an elevation in alkaline phosphatase being the characteristic biochemical abnormality that is used for both diagnosis of Paget’s disease as well as response to treatment. Other markers of high bone resorption are the C- and N-telopeptides, which are typically elevated in both the serum and urine. These proteins decline more rapidly in response to therapy than alkaline phosphatase. Serum osteocalcin is also a marker of high bone turnover, and it may be elevated or normal in those with Paget’s disease. However, serum calcium is always normal in those with Paget’s disease unless the person becomes immobilized.

X-94.   The answer is C. (Chap. 355) Despite her lack of symptoms this patient has enough evidence to diagnose her with Paget’s disease. Her radiographs show characteristic changes of active disease in the pelvis, which is one of the most common areas for Paget’s disease to present. Her elevated alkaline phosphatase provides further evidence of active bone turnover. The normal serum calcium and phosphate levels are characteristic for Paget’s disease. Management of asymptomatic Paget’s disease has changed since effective treatments have become available. Treatment should be initiated in all symptomatic patients and in asymptomatic patients who have evidence of active disease (high alkaline phosphatase or urine hydroxyproline) or disease adjacent to weight-bearing structures, vertebrae, or the skull. Second-generation oral bisphosphonates such as tiludronate, alendronate, and risedronate are excellent choices due to their ability to decrease bone turnover. The major side effect from these agents is esophageal ulceration and reflux. They should be taken in the morning, on an empty stomach, and sitting upright to minimize the risk of reflux. Duration of use depends on the clinical response; typically 3–6 months are needed to see the alkaline phosphatase begin to normalize. Intravenous zoledronate and pamidronate are adequate alternatives to oral bisphosphonates. While their IV administration avoids the risk of reflux, there is a potential of developing a flulike syndrome within 24 hours of use. The presence of this side effect 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 hypercholesterolemia. 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 hypercholesterolemia; 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, hepatosplenomegaly, 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 hypothyroidism, nephritic syndrome, cholestasis, acute intermittent porphyria, anorexia nervosa, hepatoma, and drugs such as thiazides, cyclosporine, and Tegretol. Cirrhosis is associated 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 disorder 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 demonstrating 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 management 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.

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 cardiomyopathy 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 findings 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 recommended 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 excessive 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-loading 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 μg/L and transferrin saturation of 50–100%. However, 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 (μg/g dry weight)/56 × age > 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 evaluation 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 vaccination. 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 evaluation 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 autosomal 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 hormone use, oral contraceptives, systemic illness, reduced caloric intake, and many other medications. This diagnosis should be considered in any individual with recurrent abdominal 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, the precursors of heme synthesis build up. Urine aminolevulinic acid (ALA) is also almost uniformly elevated during these attacks. The porphobilinogen level will drop in the recovery phase and be normal between attacks. Therapy for acute attack is with carbohydrate loading, narcotic pain control, anxiolysis, and IV hemin, which repletes the end product in heme synthesis.

X-102.  The answer is B. (Chap. 359) Hyperuricemia is a common finding, affecting approximately 5% of the general population and 25% of hospitalized individuals. Increased levels of plasma uric acid may be due to overproduction of uric acid (as in the presence of tumor) or underexcretion of uric acid, which is by far the most common mechanism. Because hyperuricemia is so common and most patients with this condition never develop a complication, asymptomatic hyperuricemia is not an indication for treatment. Patients with hyperuricemia are not known to be at increased risk for uric acid nephrolithiasis. Recently, the metabolic syndrome (central obesity, insulin resistance, dyslipidemia, and hypertension) has been linked to hyperuricemia. Hyperinsulinemia results in reduced renal excretion of uric acid and sodium; thus hyperuricemia may be an early indicatory of type 2 diabetes mellitus.

X-103.  The answer is D. (Chap. 359) Although most patients with hyperuricemia never develop any complications, several have been recognized. The most common complication is gouty arthritis, which depends on the duration and severity of hyperuricemia. Several renal diseases have been described in association with hyperuricemia including urate nephropathy, in which monosodium urate crystals deposit in the renal interstitium; uric acid nephropathy, in which large amounts of uric acid crystals deposit in the renal collecting ducts, pelvis, and ureters; and nephrolithiasis. Cardiovascular disease and renal disease are associated with hyperuricemia, but lowering uric acid levels is not shown to change these specific outcomes. There is no association between hyperuricemia and peripheral neuropathy.

X-104.  The answer is C. (Chap. 353) Lesch-Nyhan syndrome is characterized by the complete absence of the enzyme hypoxanthine phosphoribosyltransferase (HPRT), a component of purine metabolism that is related to purine recycling into guanosine monophosphate and inosine monophosphate. Hyperuricemia develops from urate overproduction. The gene for HPRT is located on the X chromosome, so Lesch-Nyhan disease is transmitted as an X-linked disorder. Homozygous males have the disease, and heterozygous carrier females are asymptomatic. Therefore, the daughter of a carrier has a 50% chance of being a carrier and a son has a 50% chance of having the disease. Carrier females do not have an increased risk of gout or urate nephropathy. Lesch-Nyhan syndrome is characterized by hyperuricemia, gouty arthritis, nephrolithiasis, self-mutilative behavior, choreoathetosis, and mental retardation. Treatment of affected patients with allopurinol will eliminate or prevent the problems related to hyperuricemia but will not have any beneficial effect on the behavioral or neurologic manifestations. Since it is an X-linked disorder, screening the husband has no value.

X-105 and X-106. The answers are E and D, respectively. (Chap. 360) The patient presents with liver disease, hemolysis, and psychiatric illness, which suggests the presence of Wilson’s disease. Wilson’s disease is an autosomal recessive disorder caused by mutations in the ATP7B gene, a copper-transporting ATP-asa. As a result of this mutation, patients store abnormally high levels of copper in their liver initially, but later in other organs such as the brain. While liver dysfunction is a hallmark of the disease, it may have several presentations: acute hepatitis, cirrhosis, or hepatic decompensation, as in this case. Hemolysis may complicate acute decompensation because of the massive release of copper from the liver into the blood leading to hemolysis. Accumulation of copper in the basal ganglia results in Parkinson-like syndromes. Up to 50% of patients with Wilson’s disease will have Kayser-Fleischer rings on ocular slit-lamp examination. These brownish rings surrounding the cornea are due to copper deposition within the cornea and are diagnostic when found. Twenty-four–hour urinary copper levels are universally elevated in this disease and are the primary diagnostic modality when Kayser-Fleischer rings are absent. Liver biopsy can also be used to confirm increased copper content. Although MRI will show basal ganglia damage, it is not specific for Wilson’s disease. HFE mutation is present in hemochromatosis, which this patient does not have. Urine iron levels are not indicated.

Therapy for Wilson’s disease is dependent on degree of disease at the time of presentation. 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 usually 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 genotype 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 connective 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 osteogenesis 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 techniques 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 characteristic physical examination findings, history of fractures, and often a positive family history. 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 characterized 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 TGFβ, recent work has highlighted the close interaction between fibrillin mutation and alterations in TGFβ signaling, 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 collagenmutations 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 for stabilization. The most dangerous form of EDS is the vascular or type 4 form. These patients have more skin than joint changes and are at risk of major vascular events or rupture of hollow organs (esophagus or bowel). Pregnant women with type 4 EDS are at risk of uterine rupture during pregnancy. Because of the overlapping clinical features, many patients and families cannot be given a firm type diagnosis of EDS. The diagnosis of EDS remains clinical because of the great phenotype-genotype variability. Genetic tests are most useful in familial cases of type 4 EDS because of the high risk of complications. Patients with Marfan’s syndrome who have mutations of the fibrillin gene are also at risk of aortic dissection or rupture. Mutations of the elastin gene are associated with supravalvular aortic stenosis and cutis laxa.