TABLE IV-114 Risk Factors for Active Tuberculosis Among Persons Who Have Been Infected With Tubercle Bacilli 33 page

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 o f 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.

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