Testes and Testicular Disorders
1. A 76-year-old man is being evaluated for osteoporosis. He had a hip fracture 4 weeks ago. A dual-energy absorptiometry scan showed a decrease in bone mineral density consistent with osteoporosis. The serum concentration of total testosterone is in the low-normal range.
Which of the following is the most accurate description of the physiologic changes in testosterone seen with senescence?
A. With aging, there is a large decrease in serum total testosterone level; this decrease is related to a decrease in the concentration of sex hormone-binding globulin (SHBG)
B. With aging, there is a relatively small decrease in serum total testosterone level; free testosterone decreases to a greater degree; SHBG increases
C. With aging, serum estradiol concentration increases secondary to a decrease in the total testosterone concentration
D. With aging, the total testosterone level remains unchanged
Key Concept/Objective: To understand the physiologic changes in testosterone levels seen with aging
As men age, their serum total testosterone concentration decreases. The decrease in the serum concentration of total testosterone is very gradual and of relatively small magnitude. SHBG, however, increases with increasing age, so the free testosterone concentration decreases to a greater degree than the total. By 80 years of age, according to cross-sectional studies, the free testosterone concentration is one half to one third that at 20 years of age. The decrease in testosterone appears to result from both decreased luteinizing hormone (LH) secretion and decreased responsiveness of the Leydig cells. The serum estradiol concentration also decreases with increasing age. (Answer: B—With aging, there is a relatively small decrease in serum total testosterone level; free testosterone decreases to a greater degree; SHBG increases)
2. A 36-year-old man comes to your clinic complaining of lack of energy. He was diagnosed with diabetes 2 years ago. Review of systems is positive for decreased libido and energy for the past several months. He has been married for 3 years. He and his wife have been trying to conceive a child for the past year. Physical examination shows decreased pubic and axillary hair; his testicular volume is 15 ml. Total testosterone levels are low; LH and follicle-stimulating hormone (FSH) are in the low-normal range. The prolactin level is normal.
Which of the following would be the most appropriate test in the evaluation of this patient?
A. Testicular biopsy
B. Head MRI
C. Testicular ultrasound
D. Karyotype
Key Concept/Objective: To be able to recognize secondary hypogonadism
Male hypogonadism can occur as a consequence of a disease of the testes (primary hypogonadism) or as a consequence of a disease of the pituitary or hypothalamus (secondary hypogonadism). The clinical findings of hypogonadism result from either decreased spermatogenesis or decreased testosterone secretion. The sole clinical finding of decreased spermatogenesis is infertility. In contrast, decreased testosterone secretion causes a wide variety of clinical findings; specific findings depend on the stage of life in which the deficiency occurs. In adults, common manifestations are decreases in energy, libido, sexual hair, muscle mass, and bone mineral density, as well as the presence of anemia. Once the diagnosis of hypogonadism is suspected on the basis of symptoms and physical examination, the diagnosis must be confirmed by documenting decreased production of sperm or testosterone. If hypogonadism is confirmed, the next step is to measure LH and FSH levels. Elevated serum concentrations of LH and FSH indicate primary hypogonadism, whereas subnormal or normal values indicate secondary hypogonadism. In patients with secondary hypogonadism, MRI of the sellar region is indicated. This patient has secondary hypogonadism, so testicular biopsy and ultrasound are not indicated. Furthermore, testicular biopsy usually provides no more information about spermatogenesis than does sperm analysis. Karyotype should be considered in the evaluation of some congenital disorders, such as Klinefelter syndrome; however, this disorder causes primary hypogonadism. (Answer: B—Head MRI)
3. A 55-year-old man presents to your clinic complaining of swollen breasts. His symptoms started 3 or 4 months ago, when he noticed tenderness and swelling in both breasts. His medical history includes congestive heart failure and hypertension. His medications are benazepril, metoprolol, furosemide, and spironolactone. Review of systems is positive only for occasional dyspnea on exertion. Physical examination shows bilateral gynecomastia in the periareolar area, with some tenderness to palpation. Testicular examination is normal.
Which of the following would be the best step to take next in the evaluation and management of this patient?
A. Liver ultrasound
B. Mammography
C. Testicular ultrasound
D. Cessation of spironolactone
Key Concept/Objective: To know that spironolactone can cause gynecomastia
Gynecomastia is the development of glandular breast tissue in a man. In most cases of gynecomastia, the stimulation of glandular tissue appears to result from an increased ratio of estrogen to androgen. Mechanisms behind this change in the estrogen-to-androgen ratio include exposure to exogenous estrogen, increased estrogen secretion, increased peripheral conversion of androgens to estrogens, and inhibition of androgen binding. The diagnosis of gynecomastia is confirmed by physical examination. Mammography is usually unnecessary. Gynecomastia is generally bilateral, although it is occasionally unilateral. If the tissue is tender, the gynecomastia is more likely to be of recent origin. Gynecomastia must be distinguished from carcinoma of the breast. Breast cancer should be suspected when the breast enlargement is unilateral, nontender, not centered directly under the nipple, and hard. Many drugs that cause gynecomastia appear to do so by binding to the androgen receptor and thereby blocking endogenous testosterone. Spironolactone is one of these drugs. Although gynecomastia can be a sign of testicular cancer or cirrhosis, there is no other evidence of these disorders in this patient, and further imaging studies would not be indicated at this time. The most likely etiology is gynecomastia secondary to spironolactone, and the best intervention would be to stop this medication and then reevaluate the patient. (Answer: D—Cessation of spironolactone)
For more information, see Snyder PJ: 3 Endocrinology: II Testes and Testicular Disorders. ACP Medicine Online (www.acpmedicine.com). Dale DC, Federman DD, Eds. WebMD Inc., New York, September 2003
The Adrenal
4. A 44-year-old African-American woman presents to your clinic with a complaint of weight gain. She reports increasing weight gain over the past year despite any noticeable change in her dietary intake. She notes that most of the added weight is around her abdomen. During the review of symptoms, she notes recent onset of amenorrhea without associated hot flushes. All women in her family experienced menopause after 50 years of age. On physical examination, the patient is hypertensive, with a blood pressure of 152/94 mm Hg. You notice that she has classic moon facies with purple abdominal striae.
Which of the following statements regarding the testing for Cushing syndrome is true?
A. The single best biochemical marker of Cushing syndrome is an elevation in the 8:00 A.M. cortisol count of greater than 20 µg/dl
B. Patients with a random plasma adrenocorticotropic hormone (ACTH) level of greater than 10 pg/ml should undergo a corticotropin-releasing hormone (CRH) challenge
C. A random plasma ACTH level greater than 10 µg/ml is indicative of ACTH-dependent Cushing syndrome
D. Patients with ACTH-independent Cushing syndrome should undergo inferior petrosal sinus sampling
Key Concept/Objective: To understand the diagnosis of Cushing syndrome
The classic clinical presentation of Cushing syndrome includes central obesity, striae, moon facies, supraclavicular fat pads, diabetes mellitus, hypertension, hirsutism and oligomenorrhea in women, and erectile dysfunction in men. The diagnosis of Cushing syndrome is principally clinical. Typically, patients will have some, but not all, of the clinical manifestations of Cushing syndrome. The diagnosis is confirmed by an elevation in urinary free cortisol excretion on 24-hour urine testing; this is the single best biochemical marker of Cushing syndrome. Once the diagnosis is secure, the first step in the differential diagnosis is to determine whether the condition is ACTH-dependent or ACTH-independent. This is most easily done by measuring the level of circulating plasma ACTH. Although an ACTH level greater than 10 pg/ml indicates ACTH dependence, this threshold will fail to identify 5% of ACTH-dependent cases. Consequently, patients with a random plasma ACTH level of less than 10 pg/ml should undergo a corticotropin-releasing hormone challenge. Patients with ACTH-dependent Cushing syndrome should undergo an inferior petrosal sampling procedure to search for a gradient in ACTH levels between blood draining the pituitary gland (inferior petrosal sinus blood) and peripheral antecubital blood. An ACTH gradient of greater than 3 between simultaneously sampled central and peripheral blood confirms a pituitary etiology for Cushing syndrome. If the gradient is less than 3, the search for an ectopic source of ACTH should be undertaken. (Answer: C—A random plasma ACTH level greater than 10 µg/ml is indicative of ACTH-dependent Cushing syndrome)
5. A woman was admitted this morning in the medical intensive care unit for elective cholecystectomy. Before surgery, her physical examination, including vital signs, was normal. The procedure went well, and there were no noticeable complications. However, 3 hours after returning to her room, she was noted to be unresponsive and her blood pressure was barely palpable. She was intubated for respiratory failure. Her blood pressure has been refractory to intravenous fluids and pressors. You are consulted to help in the workup of suspected adrenal insufficiency.
Which of the following statements regarding adrenal insufficiency is true?
A. The most common cause of adrenal insufficiency in the United States is tuberculosis
B. The critical test for the diagnosis of chronic adrenal insufficiency is the cosyntropin test
C. Chronic secondary adrenal insufficiency is treated with hydrocortisone and fludrocortisone, whereas chronic primary adrenal insufficiency is treated with hydrocortisone alone
D. In idiopathic or autoimmune adrenal insufficiency, CT of the abdomen shows enlarged adrenal glands
Key Concept/Objective: To understand the diagnosis and treatment of adrenal insufficiency
Primary adrenal insufficiency results from destruction of the adrenal cortex. The list of causes of primary adrenal insufficiency is long. In the industrialized nations, idiopathic or autoimmune adrenal destruction is the most common cause. Secondary adrenal insufficiency results from disruption of pituitary secretion of ACTH. By far the most common cause of secondary adrenal insufficiency is prolonged treatment with exogenous glucocorticoids. The acute syndrome is closely analogous to cardiogenic or septic shock and involves reduced cardiac output and a dilated and unresponsive vascular system. Symptoms include prostration, as well as all of the signs and symptoms of the shock syndrome. With both chronic and acute syndromes, the diagnosis should be suspected on clinical grounds but requires laboratory confirmation. The critical test for the diagnosis of chronic adrenal insufficiency is the cosyntropin stimulation test. Synthetic ACTH (cosyntropin) is administered in a 250 µg intravenous bolus, and plasma cortisol levels are measured 45 and 60 minutes afterward. Values greater than 20 µg/dl exclude adrenal insufficiency as a cause of the clinical findings. Values less than 20 µg/dl suggest that adrenal compromise could be a contributing factor. In this situation, treatment with a glucocorticoid is mandatory until the clinical situation is clarified with more precision. The differential diagnosis of adrenal insufficiency requires the discrimination of primary and secondary causes. The most useful test for this is measurement of the circulating plasma ACTH level. ACTH levels greater than normal define primary disease; values in the normal range or below define secondary disease. Primary chronic adrenal insufficiency is treated with 12 to 15 mg/m2 of oral hydrocortisone a day. Hydrocortisone is best given as a single daily dose with breakfast. Fludrocortisone is given at a dose of 0.1 mg a day. Chronic secondary adrenal insufficiency is treated in the same way as chronic primary disease but with replacement of hydrocortisone only, not aldosterone. (Answer: B—The critical test for the diagnosis of chronic adrenal insufficiency is the cosyntropin test)
6. A 32-year-old man presents to your clinic for evaluation of headaches. He has had episodic pounding headaches for 6 months. He never had headaches like this before in his life. He denies using illicit drugs. He has no family history of hypertension. On physical examination, the patient is hypertensive, with a blood pressure of 180/105 mm Hg. No further abnormalities are noted. You begin a workup for secondary causes of hypertension.
Which of the following statements regarding pheochromocytomas is true?
A. 90% of pheochromocytomas are malignant
B. Almost all patients with pheochromocytomas have episodic hypertension, making diagnosis difficult in a single clinic visit
C. The incidence of pheochromocytoma is increased in patients with multiple endocrine neoplasia type 1
D. Treatment of pheochromocytoma is surgical; alpha blockade should be induced with phenoxybenzamine, beginning 7 days before surgery
Key Concept/Objective: To understand the clinical presentation and treatment of pheochromocytoma
The primary disease of the adrenal medulla is pheochromocytoma; 90% of pheochromocytomas occur in the adrenal medulla. The main clinical manifestation of pheochromocytomas is hypertension. The hypertension can be sustained or episodic; the two forms occur with equal frequency. The incidence of pheochromocytoma is markedly increased in several genetic syndromes: multiple endocrine neoplasia type 2a and type 2b; and the phakomatoses, including neurofibromatosis, cerebelloretinal hemangioblastosis, tuberous sclerosis, and Sturge-Weber syndrome. The treatment of pheochromocytoma is surgical. Before the surgical procedure, complete alpha blockade should be induced to avoid intraoperative hypertensive crisis. Preparation should begin 7 days before the planned procedure, using phenoxybenzamine at an initial dosage of 10 mg by mouth twice daily. The dose should be increased daily so that by the seventh day, the patient is taking at least 1 mg/kg/day in three divided doses. (Answer: D—Treatment of pheochromocytoma is surgical; alpha blockade should be induced with phenoxybenzamine, beginning 7 days before surgery)
7. A 32-year-old man presents to your clinic as a new patient to establish primary care. He has a 2-year history of hypertension, which is managed with a calcium channel blocker. He has no knowledge of the cause of his hypertension. He is currently without complaints and only wants a refill on his medication. His physical examination is unremarkable, but laboratory results show hypokalemia.
Which of the following statements regarding hyperaldosteronism is true?
A. The most common causes of secondary hyperaldosteronism are congestive heart failure and cirrhosis with ascites
B. Treatment of primary adrenal hyperaldosteronism is spironolactone
C. Patients with primary adrenal hyperaldosteronism usually present with hypertension, hypokalemia, and metabolic acidosis
D. Diagnosis of primary adrenal hyperaldosteronism is confirmed by elevations in the levels of both renin and aldosterone
Key Concept/Objective: To understand the clinical presentation, diagnosis, and treatment of hyperaldosteronism
Hyperaldosteronism can be primary or secondary. In primary hyperaldosteronism, there is disordered function of the renin-aldosterone feedback axis; in secondary hyperaldosteronism, the renin-aldosterone axis responds normally to chronic intravascular volume deficiency. Primary hyperaldosteronism is caused by benign adrenal adenomas, which are typically unilateral and are usually less than 2.5 cm in diameter. They secrete aldosterone independently of renin-angiotensin stimulation. Patients present with hypertension. Primary adrenal hypersecretion of aldosterone is thought to account for about 2% of cases of hypertension. Laboratory testing shows hypokalemia and metabolic alkalosis, with a serum sodium level that is usually in the high normal range. Diagnosis is confirmed by demonstrating normal or elevated plasma aldosterone levels (> 14 ng/dl) in the presence of suppressed stimulated plasma renin activity (< 2 ng/ml/hr). The treatment of primary adrenal hyperaldosteronism is unilateral adrenalectomy, preferably by a laparoscopic procedure. Secondary hyperaldosteronism may or may not be associated with hypertension. Probably the most common causes are chronic heart failure and cirrhosis of the liver with ascites. (Answer: A—The most common causes of secondary hyperaldosteronism are congestive heart failure and cirrhosis with ascites)
For more information, see Loriaux DL: 3 Endocrinology: IV The Adrenal. ACP Medicine Online (www.acpmedicine.com). Dale DC, Federman DD, Eds. WebMD Inc., New York, October 2004
Calcium Metabolism and Metabolic Bone Disease
8. A 54-year-old woman comes to your clinic for a routine visit. She has no active complaints. Her medical history is positive only for mild asthma and arterial hypertension. Her only medications are albuterol, which she administers with a measured-dose inhaler as needed, and an angiotensin-converting enzyme inhibitor. She smokes one pack of cigarettes a day. She has a strong family history of osteoporosis. Her physical examination is unremarkable. You have a discussion with her regarding her risk of osteoporosis, and you decide to obtain a dual-energy x-ray absorptiometry (DEXA) scan for screening. The results show a T score of –2.6. Her creatinine and albumin levels are normal, her liver function tests are normal except for a slightly elevated alkaline phosphatase level, and her calcium level is 11 mg/dl.
What is the most appropriate step to take next in the treatment of this patient?
A. Start bisphosphonate, calcium, and vitamin D, and reassess in 6 months
B. Measure the parathyroid hormone (PTH) level with a two-site immunoradiometric assay (IRMA, or so-called intact PTH) and assess 24-hour urinary calcium output
C. Order CT scans of the chest and abdomen to look for an occult malignancy
D. Start hormone replacement therapy with estrogens and progestins
Key Concept/Objective: To understand the appropriate initial evaluation of a patient with hypercalcemia
This patient presents with mild, asymptomatic hypercalcemia. The most common cause of hypercalcemia in outpatients is hyperparathyroidism. The differential diagnosis of hypercalcemia is extensive. Once hypercalcemia is confirmed, the next step is to measure the serum PTH concentration. Several PTH assays are commercially available. The most commonly utilized test is the intact PTH. Other helpful tests include blood urea nitrogen (BUN), serum creatinine, alkaline phosphatase, and serum inorganic phosphorus assays; an electrolyte panel; and an assessment of 24-hour urinary calcium output. If the levels of PTH are elevated or inappropriately normal, the hypercalcemia is said to be PTH mediated. When PTH levels are suppressed, the hypercalcemia is said to be non–PTH mediated. Patients with hyperparathyroidism typically have a serum calcium concentration of less than 12 mg/dl; mild to moderate hypophosphatemia; and non–anion gap acidosis (from renal tubular acidosis). Urinary calcium excretion is usually increased; in these patients, the reduction of fractional calcium excretion by PTH is overcome by the high filtered calcium load, which may result in nephrolithiasis. The levels of alkaline phosphatase can be elevated as well. Before starting a more extensive evaluation in this patient, it is necessary to exclude the possibility of primary hyperparathyroidism. (Answer: B—Measure the parathyroid hormone [PTH] level with a two-site immunoradiometric assay [IRMA, or so-called intact PTH] and assess 24-hour urinary calcium output)
9. A 45-year-old man with a history of primary hyperparathyroidism comes to your clinic for a follow-up visit. He was diagnosed 3 years ago after routine blood tests revealed an elevation in calcium level. He has no complaints. Review of systems is negative, and his physical examination is unremarkable. His family history is negative for similar problems. His calcium level is 11.5 mg/dl. A DEXA scan shows a T score of –2 at the hip.
What is the most appropriate treatment regimen for this patient?
A. Observation, with routine follow-up visits that include assessment of calcium levels and DEXA scans
B. Start a bisphosphonate
C. Refer to an experienced surgeon for parathyroid surgery
D. Administer calcium, 1,000 to 1,500 mg/day, and vitamin D, 400 to 800 IU/day
Key Concept/Objective: To understand the surgical indications for hyperparathyroidism
Treatment of the patient with hyperparathyroidism must take into account the degree of the hypercalcemia, the presence of symptoms, and the severity of any end-organ damage. Because many patients with hyperparathyroidism are either asymptomatic or minimally symptomatic, there is controversy over which patients require definitive therapy with surgery. The 2002 National Institutes of Health Workshop on Asymptomatic Primary Hyperparathyroidism defined the following indications for surgical intervention: (1) significant bone, renal, gastrointestinal, or neuromuscular symptoms typical of primary hyperparathyroidism; (2) elevation of serum calcium by 1 mg/dl or more above the normal range; (3) marked elevation of 24-hour urine calcium excretion (> 400 mg); (4) decreased creatinine clearance (reduced by 30%); (5) significant reduction in bone density (T score < –2.5); (6) consistent follow-up is not possible or is undesirable because of coexisting medical conditions; and (7) age less than 50 years. Because of this patient’s age, surgery is indicated. (Answer: C—Refer to an experienced surgeon for parathyroid surgery)
10. A 66-year-old woman presents to a walk-in clinic with muscle spasms. She complains that for the past 2 days she has had muscle spasms in her hands, arms, and legs. She has a medical history of cervical Hodgkin lymphoma, which was treated with radiation. She does not take any medications or vitamins. On physical examination, the Trousseau sign is positive. Her calcium level is 6.8 mg/dl; the albumin level is normal.
On the basis of this patient’s history, what is the most likely diagnosis, and what should be the treatment?
A. Hypoparathyroidism secondary to radiation therapy; start PTH injections
B. Vitamin D deficiency secondary to poor intake and lack of sunlight; start calcitriol
C. Vitamin D deficiency secondary to poor intake and lack of sunlight; start cholecalciferol
D. Hypoparathyroidism secondary to radiation therapy; start calcium and calcitriol
Key Concept/Objective: To understand the most common causes of hypocalcemia and its treatment
Hypocalcemia is defined as a serum calcium level of less than 9 mg/dl. Hypocalcemia is most often related to disorders of the parathyroid glands. Removal of or vascular injury to the parathyroids during neck surgery can result in hypoparathyroidism, which is manifested by hypocalcemia, hyperphosphatemia, and inappropriately low concentrations of PTH. Autoimmune destruction of the parathyroid glands may be seen in other autoimmune conditions, such as polyglandular syndrome type 1. Certain infiltrative diseases, such as hemochromatosis, may also adversely affect parathyroid function, as may external beam radiation to the neck. In this patient, the history of radiation to the neck suggests the possibility of hypoparathyroidism secondary to radiation injury. Despite the fact that vitamin D deficiency is common in elderly patients, serum calcium concentrations are usually not severely affected thanks to compensatory increases in PTH levels. In patients with symptoms associated with hypocalcemia (e.g., neuromuscular irritability), calcium volume should be repleted with a slow intravenous infusion of calcium salts. In most patients, vitamin D should also be provided. If dietary deficiency is suspected, plain cholecalciferol is adequate. In cases of hypoparathyroidism, however, calcitriol will be required. (Answer: D— Hypoparathyroidism secondary to radiation therapy; start calcium and calcitriol)
11. A 55-year-old woman comes to your office with the results of a screening DEXA scan. Her T score is –2.7. She has not had any symptoms and denies having any previous fractures. She underwent menopause 3 years ago. Six months ago, she underwent mammography and had a Pap smear, both of which were negative. She has no family history of breast cancer. Her physical examination, including examination of the breasts, is normal. Her laboratory workup shows no evidence of conditions that are secondary causes of osteoporosis.
What is the most appropriate recommendation regarding the management of this patient’s osteoporosis?
A. Start bisphosphonate therapy, start calcium and vitamin D therapy, and recommend exercise
B. Start hormone replacement therapy, start calcium and vitamin D therapy, and recommend exercise
C. Start calcitonin, calcium, and vitamin D therapy, and recommend exercise
D. Do not start therapy until the osteoporosis becomes symptomatic
Key Concept/Objective: To understand the appropriate management of osteoporosis
Osteoporosis is defined as decreased bone mass (or density) with abnormal skeletal microarchitecture that increases the risk of fracture. The diagnostic criteria of the World Health Organization are based on the results of standardized bone mass measurements: osteoporosis is present when the bone mineral density (BMD) is decreased to more than 2.5 standard deviations below that of a normal, young control population (T score). Osteopenia is present when the BMD falls between –1.0 and –2.5 from peak bone mass. In patients with osteoporosis, an adequate amount of calcium should be provided. This patient should take 1,000 to 1,500 mg of calcium a day. Also, the patient should receive 400 to 800 IU of vitamin D. Osteoporosis is most often treated with antiresorptive agents; these drugs include bisphosphonates, estrogen, selective estrogen receptor modulators (e.g., raloxifene), and calcitonin. All of these agents reduce fracture rates substantially, but estrogen and bisphosphonates appear to produce the greatest improvement in bone density. Until recently, estrogen replacement therapy was widely recommended as first-line therapy for both prevention and treatment of osteoporosis. Advocates argued that estrogen directly corrected the chief pathophysiologic defect of the menopause-estrogen deficiency. They also cited other benefits, such as relief from vasomotor disturbances, mood swings, sleep disturbance, and urogenital atrophy. Estrogen therapy was also thought to offer cardiovascular benefits, possibly related to its positive effects on plasma lipid levels. Recently, the multicentric Women’s Health Initiative study was stopped prematurely because of a significant increase in the risk of breast cancer, myocardial infarction, strokes, and thromboembolic events. As a result of these findings, estrogen should no longer be considered the optimal first-line preventive or therapeutic agent for osteoporosis. Bisphosphonates should be considered the optimal choice for the initial therapy for osteoporosis. Calcitonin’s effects on bone density appear to be weaker than those of estrogen or the bisphosphonates. Raloxifene can be used for osteoporosis prevention and treatment; it appears to have a less potent effect on bone density than either estrogens or bisphosphonates. (Answer: A—Start bisphosphonate therapy, start calcium and vitamin D therapy, and recommend exercise)
For more information, see Inzucchi SE: 3 Endocrinology: VI Diseases of Calcium Metabolism and Metabolic Bone Disease. ACP Medicine Online (www.acpmedicine.com). Dale DC, Federman DD, Eds. WebMD Inc., New York, March 2003
Genetic Diagnosis and Counseling
12. A 37-year-old man presents to the local emergency department with a swollen and tender right calf. The patient has had these symptoms for 4 days. He denies having undergone any trauma. He has no history of cancer, and he has had no similar episodes in the past. He denies having a family history of venous thrombosis. Ultrasound confirms deep vein thrombosis, and the patient is provided with appropriate anticoagulation. Several days later, the patient sees you for a follow-up visit. The laboratory studies made in the emergency department included a factor V Leiden mutation analysis.
Which of the following statements is true regarding this patient’s test for factor V Leiden mutation?
A. The clinical setting and the patient’s risk factors for deep vein thrombosis have no bearing on the decision to conduct factor V Leiden mutation testing
B. It is estimated that 25% of whites and 50% of those with venous thromboembolism are heterozygous for factor V Leiden mutation
C. Factor V Leiden mutation analysis is a DNA test with low sensitivity, low specificity, and high positive predictive value for this mutation
D. Factor V Leiden mutation analysis is a DNA test with high sensitivity, low specificity, and low positive predictive value for this mutation
Key Concept/Objective: To understand the limitations and characteristics of DNA-based testing
The clinical setting and risk factors given for a particular patient have great implications on the use of genetic testing. Although factor V Leiden is the most common known thrombophilic risk factor, only a small proportion of patients with this genetic disorder ever experience an episode of thrombosis (the risk of thrombosis is 2.4-fold greater in those with the mutation than in those without the mutation). It is estimated that 5% of whites are heterozygous for factor V Leiden and that approximately 20% of all persons with venous thromboembolism are heterozygous for factor V Leiden. Factor V Leiden mutation analysis, the most commonly ordered genetic test, is an example of a direct DNA-based test with 100% sensitivity but low specificity and low positive predictive value. (Answer: D— Factor V Leiden mutation analysis is a DNA test with high sensitivity, low specificity, and low positive predictive value for this mutation)
13. A 21-year-old man comes to your office to establish primary care. He states that he has been generally healthy but that he has multiple colon polyps. He states that he tested positive for familial adenomatous polyposis (FAP). He says that his former physician told him that this illness can run in families, and he asks your opinion on whether or not his family needs further testing.
Which of the following statements regarding FAP and the APC gene mutation is true?
A. Persons with the APC gene mutation develop colorectal adenomas starting at around age 30
B. FAP is an autosomal dominant disorder with 50% to 70% penetrance of the disease-causing gene mutation
C. Presymptomatic testing has never been shown to reduce morbidity or increase life expectancy
D. Testing of the APC gene has been shown to be cost-effective when used to identify carriers of the APC gene mutation among at-risk relatives of individuals with FAP
Key Concept/Objective: To understand the value and utility of presymptomatic genetic testing
FAP is a devastating, life-shortening condition when it is not recognized. FAP is an autosomal dominant disorder with 100% penetrance of the disease-causing gene. Persons with an APC gene mutation develop adenomas in the colorectum starting at around 16 years of age; in these individuals, the number of adenomas increases to hundreds or thousands, and colorectal cancer develops at a mean age of 39 years. The mean age at death is 42 years in those who go untreated. Testing of the APC gene has been shown to be cost-effective when used to identify carriers of the disease-causing APC gene mutation among at-risk relatives of individuals with FAP. Early diagnosis via presymptomatic testing reduces morbidity and increases life expectancy through improved surveillance and timely prophylactic colectomy. FAP is an example of a condition in which presymptomatic testing may be lifesaving. (Answer: D—Testing of the APC gene has been shown to be cost-effective when used to identify carriers of the APC gene mutation among at-risk relatives of individuals with FAP)
14. A 23-year-old female patient presents to your office for a routine annual visit. She mentions that her mother tested positive for the “breast cancer genes.” She asks you for general information regarding these tests and about the need for her and her family to be tested for these mutations.
Which of the following statements is correct regarding BRCA1 and BRCA2 testing?
A. It is clear that all women should have genetic testing for the BRCA1 and BRCA2 mutations, because the efficacy of measures to reduce cancer risk for individuals with these mutations is well described
B. In general, breast cancer is a simple disorder caused by heritable gene mutations only
C. Only 5% to 10% of cases of breast cancer are attributed to mutations in single genes, including BRCA1 and BRCA2
D. If this patient tests negative for the BRCA1 and BRCA2 mutations, she will have no future need for routine breast cancer screening
Key Concept/Objective: To understand the importance and limitations of testing for BRCA mutations
The efficacy of measures to reduce cancer risk for individuals with BRCA1 and BRCA2 cancer-predisposing mutations is unknown. Breast cancer, like such other common disorders as coronary artery disease, diabetes mellitus, and Alzheimer disease, is regarded as a complex disorder. Complex disorders have multiple etiologies, including heritable single genes, multiple genes with an additive effect that interact with often undefined environmental influences, and acquired environmental or genetic changes. Single heritable genes may represent a relatively small contribution to the overall incidence and morbidity from common diseases, including breast cancer, which affects one in nine women. Only 5% to 10% of cases of breast cancer are attributed to mutations in single genes, including BRCA1 and BRCA2. For a woman whose relatives have a known BRCA1 mutation but who has tested negative for the mutation known to be in the family, the chance of the development of breast cancer is still one in nine. This patient therefore has the same need for close surveillance as women in the general population. (Answer: C—Only 5% to 10% of cases of breast cancer are attributed to mutations in single genes, including BRCA1 and BRCA2)
15. A 24-year-old man with a history of increasing muscle cramps, myalgias, and calf muscle hypertrophy was recently diagnosed with Becker muscular dystrophy (BMD) through muscle biopsy. The lab report of the patient’s leukocyte DNA analysis, however, states, “no mutation known to be associated with BMD found.” On further questioning, you discover that the patient has a reportedly healthy 2-year-old daughter; a 16-year-old maternal cousin who recently began suffering from muscle cramps similar to those of the patient; a sister in her teens who is reportedly healthy; a mother with a “big heart”; and a maternal grandfather who died of an unspecified heart problem 20 years ago. You suggest further genetic linkage analysis and counseling for this patient and his extended family.
Which of the following facts would serve as the basis of your recommendation?
A. Even though the patient cannot pass on the gene for BMD, his apparently healthy sister might be a carrier
B. This patient’s offspring and other relatives are at risk for BMD, and a genetic linkage analysis would help define their genotypic risk status
C. Analysis of family members might help define the mutation in this patient and therefore help guide his therapies
D. You should not suggest further counseling or testing because the lack of a specific gene mutation in the proband means you will not be able to determine the degree to which the patient’s asymptomatic relatives are at risk
E. The mother’s mutation probably represents germline mosaicism; linkage analysis would help determine both her risk and her other children’s risk
Key Concept/Objective: To understand the pattern of inheritance of X-linked diseases and to know their implications
Because dystrophinopathes are inherited in an X-linked recessive manner, the risk to the siblings of a proband depends upon the carrier status of the mother. In this case, the mother is an obligate heterozygote (because both her son and nephew have a disease-causing gene). As such, she is a carrier with a 50% chance of transmitting the BMD mutation to each of her children. Her sons who inherit the mutation will develop clinical symptoms of BMD; her daughters who inherit the mutation will be carriers. Were men with BMD to have daughters, those daughters would be carriers; were men with BMD to have sons, those sons would inherit their father’s BMD mutation. When it is likely that a family member of a pregnant woman has the BMD gene, prenatal testing of the fetus for the presence of the gene is possible; such testing involves a search for linked markers. It is important that all female carriers be identified so that they can be advised of their risk for dilated cardiomyopathy and that the appropriate surveillance can be provided. Unfortunately, there is no therapy for BMD. (Answer: B—This patient’s offspring and other relatives are at risk for BMD, and a genetic linkage analysis would help define their genotypic risk status)
16. A 34-year-old banker has just finished 6 months of warfarin therapy after a pulmonary embolus resulting from deep vein thrombosis. During her hospital stay, she was told she has a factor V Leiden mutation, which makes her prone to clotting. Her husband and two children have now all been tested as well; those test results are as follows:
Patient: Arg 506 Gln; increased activated protein C (APC) resistance
Husband: Normal
Daughter 1: Arg 506 Gln; increased APC resistance
Son 1: Normal
On the basis of these test results, what steps should be taken now?
A. The proband and the daughter carrying her mutant allele will require anticoagulation for a minimum of 6 months to 2 years
B. The patient and her family should be advised that heterozygosity for factor V Leiden is associated with neither an increase in mortality nor a reduction in normal life expectancy
C. The daughter with a factor V Leiden mutation should be counseled not to take oral contraceptives
D. The family should be tested for other thrombophilic disorders as well, such as lupus anticoagulant
E. The proband should be counseled about her need for anticoagulant therapy if she should choose to become pregnant again
Key Concept/Objective: To understand that in cases involving factor V Leiden mutation, treatment decisions should be guided by the clinical situation of each patient and family member, not the presence or absence of a mutation
Heterozygosity for the factor V Leiden allele confers only a mildly increased risk of thrombosis. Routine testing of family members at risk is not recommended. In the absence of evidence that early diagnosis of the heterozygous state reduces morbidity or mortality, the decision to test family members who are at risk should be made on a case-by-case basis. Individuals requesting screening for factor V Leiden should be counseled regarding the implications of the diagnosis. Specifically, they should be informed that although the factor V Leiden mutation is an established risk factor, it does not predict the occurrence of pathologic thrombosis with certainty, even among heterozygotes of the same family. With this in mind, symptomatic individuals with a known factor V Leiden mutation should be screened for other potentially comorbid thrombophilias. Finally, the minimum period that symptomatic patients with factor V Leiden mutations should remain on anticoagulant therapy is unclear; current recommendations are that they receive therapy for a minimum of 6 months. (Answer: B—The patient and her family should be advised that heterozygosity for factor V Leiden is associated with neither an increase in mortality nor a reduction in normal life expectancy)
17. A 12-month-old baby is brought in for a well-baby visit, during which the baby is noted to have leukokoria (a white pupillary reflex). On further evaluation, it is determined that the child has an ablatable, unifocal retinoblastoma, with an RB1 cancer-predisposing mutation in a tumor and no evidence of a germline RB1 in white cell DNA. The parents are concerned about the risk of retinoblastoma if they have other children.
Regarding these parents’ concern, which of the following statements is true?
A. Absence of a germline RB1 mutation on the patient’s DNA screening reduces the risk in the rest of the family to chance; there is no need for further family testing
B. Both parents should be screened; if a germline mutation is not identified, the risk to future siblings is not increased
C. The patient’s future siblings may be at increased risk and should have aggressive surveillance and genetic screening
D. The patient’s future siblings would not be at increased risk, but the patient’s offspring would be and should be screened for RB1 mutations prenatally
E. Testing for RB1 is presymptomatic, and the patient—but not future siblings—will need continued aggressive surveillance to ensure that another retinoblastoma does not arise de novo
Key Concept/Objective: To understand genetic mosaicism
The gold standard for detecting RB1 gene defects is gene sequencing, which detects mutations in 80% of patients. Because the proband does not have a germline mutation for RB1, there is most likely a genetic mosaicism for the mutation, which must have arisen as a postzygotic event. This means that the parents and future siblings are not at increased risk for retinoblastoma, but the patient’s children would be (they would have a 3% to 5% risk). DNA-based testing of the proband’s children, however, could reduce the need for screening for retinoblastoma. Without DNA screening, offspring would need to be reevaluated regularly by an ophthalmologist. Children who test negative for an RB1 mutation could be spared unnecessary screening protocols. It is important to note that DNA screening for RB1 is predispositional, and even patients who have unilateral retinoblastoma with RB1 cancer-predisposing mutations in a tumor and no evidence of a germline RB1 cancer-predisposing mutation are at increased risk for developing additional tumors. (Answer: D—The patient’s future siblings would not be at increased risk, but the patient’s offspring would be and should be screened for RB1 mutations prenatally)
18. A 25-year-old Ashkenazi Jewish woman is concerned about her risk of breast cancer. Her 60-year-old mother was recently diagnosed with stage II breast cancer and underwent bilateral mastectomy. Her grandmother was killed in World War II, so she does not know whether her grandmother had breast cancer. She read in a newspaper article that the prevalence of BRCA1 and BRCA2 genes is increased in Ashkenazi Jewish women and that, as a result, this population is at increased risk for breast cancer. Now she would like to be tested for these genes because she is concerned about her risk status and wonders whether she needs a prophylactic mastectomy.
Of the following statements, which would be appropriate to tell this patient?
A. Testing for the BRCA1 and BRCA2 genes is not indicated, because the efficacy of measures to reduce risk in asymptomatic patients, even those with a mutation, is not known
B. You would be happy to arrange for BRCA mutation screening, but she should undergo testing in conjunction with appropriate genetic counseling
C. It would be more appropriate for the patient’s mother to be tested first; if a cancer-predisposing mutation were found, then—and only then— would genetic testing for the patient be appropriate
D. Testing in this patient is not indicated; even if she tests negative for an inherited cancer-predisposing mutation in the BRCA1 or BRCA2 gene, she may still have a mutation in another gene that predisposes to breast cancer
E. It is very important that the patient and her family undergo genetic analysis of both the BRCA loci and other cancer-predisposing loci as soon as possible, because her mother’s breast cancer demonstrates that her family is at increased risk
Key Concept/Objective: To understand the role of testing in determining whether a disease-modifying gene is contributing to a complex disorder
BRCA1 or BRCA2 mutations are more likely to be found in families of Ashkenazi Jewish ancestry; in families in which a family member was diagnosed with breast cancer before 50 years of age; and in families in which a family member was diagnosed with bilateral breast cancer, ovarian cancer, or both breast cancer and ovarian cancer. It is important to note, however, that BRCA1 and BRCA2 mutations cause only a small increase in the overall incidence of breast cancer. In patients undergoing genetic testing because of a suggestive family history, it is highly recommended that there be pretest and posttest counseling. If a cancer-predisposing mutation is identified, BRCA1 or BRCA2 mutation analysis is more informative for unaffected relatives. However, depending on the type of analysis done, mutations of uncertain clinical significance may be identified; such findings are difficult (at best) to interpret. If a cancer-predisposing mutation is found in the mother, the patient should be counseled not to desist from rigorous screening for breast cancer.
Given the high prevalence of breast cancer in the general population and in the Ashkenazi Jewish population in particular, regardless of this patient’s BRCA status, a negative result would not indicate that she is at reduced risk relative to that of the general population. Furthermore, in individuals from high-risk ethnic groups, such as Ashkenazi Jews, it might be reasonable to test for all the cancer-predisposing mutations known to be common in that population, even if a single cancer-predisposing mutation had already been identified in an affected family member. Unfortunately, there are no unique interventions of proven benefit for those individuals in whom a genetic susceptibility to breast cancer is found, beyond the routine mammography screening recommended for women of average risk beginning at 40 or 50 years of age. Additional recommendations for women in higher risk categories are made on the basis of presumptive benefit and have not yet been supported in clinical studies. (Answer: C—It would be more appropriate for the patient’s mother to be tested first; if a cancer-predisposing mutation were found, then—and only then—would genetic testing for the patient be appropriate)
For more information, see Pagon RA: 3 Endocrinology: VIII Genetic Diagnosis and Counseling. ACP Medicine Online (www.acpmedicine.com). Dale DC, Federman DD, Eds. WebMD Inc., New York, May 2002
Hypoglycemia
19. A 32-year-old man presents to your clinic for a routine follow-up visit. He complains of intermittent episodes of shaking, palpitations, sweating, and anxiety. The episodes generally occur between meals. He has a friend who is a hypoglycemic and is on a special diet, and he wonders if he too may have low blood sugar. While in the waiting room, he develops symptoms, and your nurse obtains a blood glucose level. The result is 74 mg/dl.
What is the most appropriate step to take next in the workup of this patient?
A. Admit the patient to the hospital for a prolonged fast
B. Send the patient for an endoscopic ultrasound, looking for insulinoma
C. Measure the insulin and C-peptide levels, assess for insulin antibodies, and have the patient follow up in 1 month
D. Refer the patient directly to surgery for resection of presumed insulinoma
E. No further workup for hypoglycemic disorder is necessary at this time
Key Concept/Objective: To understand that a normal serum glucose concentration in a symptomatic patient rules out hypoglycemic disorders
A normal serum glucose concentration, reliably obtained during the occurrence of spontaneous symptoms, eliminates the possibility of a hypoglycemic disorder; no further evaluation for hypoglycemia is required. Glucometer measurements made by the patient during the occurrence of symptoms often are unreliable, because nondiabetic patients usually are not experienced in this technique and the measurements are obtained under adverse circumstances. However, a reliably measured capillary glucose level that is in the normal range eliminates the possibility of hypoglycemia as the cause of symptoms. Normoglycemia during symptoms cannot be ascribed to spontaneous recovery from previous hypoglycemia. In fact, the reverse is true; symptoms ease before the serum glucose achieves a normal level. Workup for insulinoma is not warranted. (Answer: E—No further workup for hypoglycemic disorder is necessary at this time)
20. A 53-year-old woman presents to your clinic complaining of transient episodes of diaphoresis, asthenia, near syncope, and clouding of thought process; she has had these symptoms for several months. These episodes most commonly occur several hours after she eats. She has no other significant medical history and takes no medications. A prolonged fast is begun, during which the patient becomes symptomatic. Her serum glucose concentration at the time is 43 mg/dl. The insulin level is elevated, and no insulin antibodies are present. The C-peptide level is high, and tests for the use of sulfonylureas and meglitinides are negative.
What is the most effective therapy for this patient’s condition?
A. Observe the patient and schedule a follow-up fast 2 to 3 months from now
B. Adjust the patient’s diet to include smaller, more frequent meals
C. Obtain a transabdominal ultrasound and refer the patient to surgery for resection
D. Begin diazoxide, 400 mg t.i.d., and verapamil, 180 mg q.d., and have the patient appear for a follow-up visit in 3 months
E. Begin phenytoin and octreotide and have the patient appear for a follow-up visit in 3 months
Key Concept/Objective: To understand the diagnosis and treatment of insulinoma
Insulinoma is characterized by hypoglycemia caused by elevated levels of endogenous insulin. Confirmation of the diagnosis requires exclusion of hypoglycemia from exogenous sources. Once a biochemical diagnosis of insulinoma is made, the next step is localization. The effective modalities are center dependent and include abdominal ultrasound, triple-phase spiral computed tomography, magnetic resonance imaging, and octreotide scan. After localization, the treatment of choice for insulinomas is surgical removal. Depending on the lesion, surgery may range from enucleation of the insulinoma to total pancreatectomy. Medical therapy is less effective than tumor resection but can be used in patients who are not candidates for surgery. The most effective medication for controlling symptomatic hypoglycemia is diazoxide, which lowers insulin production. Other medications for insulinomas include verapamil, phenytoin, and octreotide. (Answer: C—Obtain a transabdominal ultrasound and refer the patient to surgery for resection)
21. A 31-year-old woman presents to the emergency department complaining of episodes of dizziness, lightheadedness, palpitations, sweats, anxiety, and confusion. On the morning of admission, she reports that she almost passed out. Her husband, who is a diabetic patient who requires insulin, checked her blood sugar level and noted it to be low. Her symptoms resolved after drinking some orange juice. She is admitted to the hospital for a prolonged fast. After 18 hours, she becomes symptomatic, and her blood is drawn. The serum glucose concentration is 48 mg/dl, the serum insulin level is high, and test results are negative for insulin antibodies. The C-peptide level is low, and tests for sulfonylurea and meglitinides are negative.
Which of the following is the most likely diagnosis for this patient?
A. Insulinoma
B. Factitial hypoglycemia
C. Noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS)
D. Insulin autoimmune hypoglycemia
Key Concept/Objective: To be able to recognize the patient with factitial hypoglycemia
Factitial hypoglycemia is more common in women and occurs most often in the third or fourth decade of life. Many of these patients work in health-related occupations. Factitial hypoglycemia results from the use of insulin or drugs that stimulate insulin secretion, such as sulfonylureas or meglitinides. The possibility of factitial hypoglycemia should be considered in every patient undergoing evaluation for a hypoglycemic disorder, especially when the hypoglycemia has a chaotic occurrence—that is, when it has no relation to meals or fasting. The diagnosis of factitial hypoglycemia can usually be established by measuring serum insulin, sulfonylurea, and C-peptide levels when the patient is hypoglycemic. In a patient whose hypoglycemia results from covert use of a hypoglycemic agent, the agent will be present in the blood. In insulin-mediated factitial hypoglycemia, the serum insulin level is high and the C-peptide level is suppressed, usually close to the lower limit of detection, as seen in this patient. (Answer: B—Factitial hypoglycemia)
22. A 38-year-old man is brought to the emergency department after a generalized seizure. Blood glucose in the field is noted to be 45 mg/dl. The complete blood count and results of a blood chemistry 7 panel are normal, with the exception of a low glucose level. A head CT is negative, and a lumbar puncture reveals no evidence of infection. After the patient is stabilized and able to give a history, he tells you that he has been experiencing episodes of dizziness, confusion, headache, blurred vision, and weakness for the past month. The episodes always occur about 2 hours after he eats. He has no other significant medical history and takes no medications. He is admitted. Results of a supervised 72-hour fast are normal.
Which of the following is the probable diagnosis for this patient?
A. NIPHS
B. Insulinoma
C. Factitial hypoglycemia
D. Insulin autoimmune hypoglycemia
Key Concept/Objective: To be able to distinguish NIPHS from insulinoma
NIPHS is a recently described entity. Like insulinoma, it affects patients across a broad age range (16 to 78 years) and causes severe neurohypoglycemia, with loss of consciousness and, in some cases, generalized seizures. Unlike insulinoma, it occurs predominantly in males (70%). Histologic analysis of pancreatic tissue from patients with NIPHS shows cells budding off ducts, seen best by chromogranin A immunohistochemical staining. Islet cell hypertrophy is also evident. No gross or microscopic tumor has been identified in any patient with NIPHS. Symptoms of NIPHS occur primarily in a postprandial state, usually 2 to 4 hours after eating. Although patients with insulinoma may experience symptoms postprandially, they also have symptoms during food deprivation. It is extremely rare for insulinoma patients to have symptoms solely in the postprandial state. Results of supervised 72-hour fasts have always been negative in NIPHS patients. A negative 72-hour fast in a patient with insulinoma is a rare occurrence. Gradient-guided partial pancreatectomy has been effective in relieving symptoms in patients with NIPHS, though recurrence of hypoglycemia after a few symptom-free years has been reported in a few patients. (Answer: A—NIPHS)
For more information, see Service FJ: 3 Endocrinology: IX Hypoglycemia. ACP Medicine Online (www.acpmedicine.com). Dale DC, Federman DD, Eds. WebMD Inc., New York, May 2002
Obesity
23. A 42-year-old white woman comes to your office to establish primary care. She reports no previous medical history except “fibroids,” for which she underwent a vaginal hysterectomy. She currently takes no medications. The results of physical examination are as follows: blood pressure, 136/81 mm Hg; heart rate, 87 beats/min; weight, 180 lb (82 kg); height, 5’7″ (1.71 m). Other than the fact that she appears obese, there are no pertinent findings on physical examination. You are concerned with the long-term implications related to her being overweight.
On the basis of the available data, what is the calculated body mass index (BMI) for this patient?
A. 28
B. 24
C. 32
D. 34
Key Concept/Objective: To understand how to calculate BMI
Measures that were once used to determine excess mortality risk of obesity included the percentage of what was termed desirable weight or ideal body weight, which was based on data from the life-insurance industry. This form of measurement has been replaced by a classification system that attempts to allow comparison of weights independent of stature across populations. It is based on the BMI, which is calculated by dividing the body weight (in kilograms) divided by height (in meters) squared. In nonselected populations, BMI does correlate with percentage of body fat, but this relationship is independently influenced by sex, age, and race. In this patient, BMI is calculated as follows: 82 kg ÷ (1.71 m × 1.71 m) = 28 kg/m2. (Answer: A—28)
24. A 38-year-old woman who is a longtime patient of yours comes to the clinic for her annual appointment. Despite multiple attempts at dietary and behavior modification, she has been gaining weight regularly since she was 23 years of age. In addition to obesity, she has moderately controlled hypertension and glucose intolerance and worsening osteoarthritis in her knees bilaterally. She requests to be placed on a more intensive weight-loss therapy.
On the basis of this patient’s current BMI of 36 kg/m2, which of the following would likely be the most appropriate therapy?
A. 3 to 6 months of intensive dietary restriction
B. 3 to 6 months of intensive dietary restriction and exercise
C. Initiation of pharmacologic therapy
D. Referral for bariatric surgery
Key Concept/Objective: To understand how BMI determines treatment of obese patients
The approach to the treatment of obesity is similar to that of other chronic conditions, such as hypertension, hypercholesterolemia, and diabetes. Patients are first managed with lifestyle measures for 3 to 6 months. For obesity, these lifestyle interventions include improved diet and increased activity. For patients whose weight does not change with lifestyle intervention alone or whose weight loss is insufficient to lower their long-term health risk, consideration is then given to pharmacologic or surgical management. A National Institutes of Health expert panel has suggested that patients whose BMI is 30 kg/m2 or more or who have a BMI of 27 kg/m2 or more plus obesity-related risk factors (i.e., diabetes, hypertension, or hyperlipidemia) could be considered for pharmacologic therapy. Patients with a BMI of 40 kg/m2 or more or a BMI of 35 kg/m2 or more plus obesity-related risk factors could be considered for surgical therapy. In this patient, the combination of hypertension, glucose intolerance, osteoarthritis, and a BMI greater than 35 kg/m2 warrants referral for bariatric surgery. (Answer: D—Referral for bariatric surgery)
25. A 46-year-old African-American man presents to your office for a routine visit. On his last visit, which was 18 months ago, he was noted to be mildly hypertensive and obese. He underwent blood test screening for high lipid levels, thyroid disease, and glucose intolerance; all results were normal. His chief complaint today is excess fatigue. He reports that he frequently falls asleep during the day, occasionally when driving a car. He also reports occasional morning headaches.
Which of the following approaches are more likely to disclose the cause of this patient’s fatigue?
A. Repeat thyroid function tests
B. Transthoracic echocardiogram
C. Pulmonary function tests
D. The patient should be asked about his sleeping habits and referred for a sleep study
Key Concept/Objective: To understand that sleep apnea is a common complication of obesity
In epidemiologic studies, persons who are overweight or obese and have central adiposity are at increased risk for hyperlipidemia, hypertension, and cardiovascular disease mortality. Sleep apnea is likely underdiagnosed in overweight and obese patients and should be strongly considered in patients with complaints of fatigue, daytime somnolence, snoring, restless sleep, and morning headaches. In this patient, the results of repeat thyroid function tests are likely to be normal, given this patient’s constellation of symptoms and the fact that the results of recent testing were normal. Although fatigue can be attributed to primary cardiac or pulmonary disease, neither would explain the daytime somnolence and the morning headaches. (Answer: D—The patient should be asked about his sleeping habits and referred for a sleep study)
26. A 35-year-old white woman comes to your office requesting your opinion on how to lose weight. She has no known complications or associated comorbidities secondary to obesity. She read on the Internet that approaches to weight loss are based on the calculation of BMI. She tells you that because her BMI is 33 kg/m2, medical therapy is indicated. Her sister has had great success taking orlistat, having lost 20 lb without having any significant side effects.
Which of the following statements regarding the use of orlistat therapy in this patient is true?
A. Orlistat is generally safe and well tolerated by most patients; the patient should be started on orlistat therapy in conjunction with a diet-and-exercise program
B. The patient should be started on orlistat therapy; there is no need to prescribe
C. Orlistat is generally safe, but a significant number of patients experience side effects; the patient should be started on orlistat therapy in conjunction with a diet-and-exercise program
D. Orlistat is poorly tolerated by most patients and has life-threatening side effects
Key Concept/Objective: To know the side effects of orlistat
Diet and exercise are the cornerstones of any weight loss program. Medication, including orlistat, should be considered as an adjunct to diet and exercise. Orlistat inhibits lipases in the gastrointestinal lumen, thereby antagonizing triglyceride hydrolysis and reducing fat absorption by roughly 30%. Gastrointestinal side effects may occur in up to 80% of patients when they begin therapy with orlistat (such side effects are also seen in 50% to 60% of patients given placebo), but this incidence diminishes with time. Symptoms include abdominal discomfort, flatus, fecal urgency, oily spotting, and fecal incontinence. When administered to patients who adhere to a low-fat diet, orlistat is generally well tolerated. Other than the gastrointestinal symptoms, orlistat is well tolerated without any other significant side effects. In one study, only 2.4%, 3.1%, and 1.6% of orlistat-treated patients had documented below-normal levels of ß-carotene, vitamin D, and vitamin E, respectively. Nevertheless, orlistat should not be given to patients with existing malabsorptive states, and it is recommended that a daily multivitamin supplement be taken by patients during therapy. (Answer: C—Orlistat is generally safe, but a significant number of patients experience side effects; the patient should be started on orlistat therapy in conjunction with a diet-andexercise program)
For more information, see Purnell JQ: 3 Endocrinology: X Obesity. ACP Medicine Online (www.acpmedicine.com). Dale DC, Federman DD, Eds. WebMD Inc., New York, June 2003