UWorld Review 5/18

A 62-year-old man with diabetes, hypertension, and hyperlipidemia comes to the emergency department of an academic medical center with chest pain, nausea, vomiting, and diaphoresis. An electrocardiogram demonstrates ST elevation in the anterior leads, and cardiac enzymes are markedly elevated. Investigators at the center are designing a randomized control trial to test the hypothesis that drug B will decrease the mortality associated with acute ST-elevation myocardial infarction compared to standard of care. To ensure that investigators will not miss a difference between drug B and standard of care (if a difference truly exists), which of the following would they want to maximize?

1 - β - Statistical power, (1 - β), represents a study's ability to detect a difference when one exists. It is the probability of rejecting the null hypothesis when it is truly false - ie, the probability of finding a true relationship. Power depends on sample size and the difference in outcome between the groups being tested. In this study, the researchers want to detect a difference between drug B and standard of care if one exists; they want to maximize power. β is the probability of committing a type II error. Type II error occurs when researchers fail to reject the null hypothesis when it is truly false. This causes investigators to miss true relationships. An example of a type II error would be a study finding that aspirin does not affect platelet function when, in fact, it does. Therefore, if β is set at 0.2, the power will be (1 - β) = 80%; there will be an 80% chance of rejecting the null hypothesis when it is truly false.

A 73-year-old woman is brought to the clinic by her niece due to a 10-day history of abdominal pain and loss of appetite. The patient does not like "going to the doctor" and has not been seen by a physician in many years. Frequent loose stools and loss of appetite have been present since the pain began. Family history is significant for colon cancer in a maternal aunt. Temperature is 37.8 C (100 F) and pulse is 98/min. Abdominal examination is significant for tenderness on deep palpation of the left lower quadrant, along with an appreciable mass. There is no inguinal lymphadenopathy. White blood cell count is 15,000/mm3. Which of the following is the most likely cause of the abdominal pain in this patient?

Acute diverticulitis - This patient with abdominal pain, leukocytosis, low-grade fever, and a mass palpated in the left lower quadrant likely has acute diverticulitis. Diverticulitis is characterized by inflammation of colonic diverticula (ie, herniated outpouchings of the colonic mucosa and submucosa through the muscularis mucosae) and is caused by trapped food particles and elevated intraluminal pressure within a diverticulum, resulting in microperforation. The risk increases with age (particularly in those age ≥60). Patients commonly present with constant abdominal pain, classically in the left lower quadrant, signifying sigmoid colon involvement. Other symptoms include nausea, vomiting, and changes in bowel habits (constipation or diarrhea). Patients often have low-grade fever, and examination may reveal lower abdominal tenderness and, often, a palpable mass due to inflammation or abscess formation. Mild leukocytosis is a common laboratory finding; occult blood may be present, but gross hematochezia is rare.

A 45-year-old woman suffers from recurrent nonpitting edema of the hands. She often wears warm gloves indoors because her fingers turn blue when they are cold. She also complains of retrosternal burning and regurgitation, especially when supine. Which of the following antibodies is most likely to be found in this patient?

Anti-centromere - There are two main subtypes of systemic sclerosis: diffuse scleroderma, which is characterized by diffuse skin and visceral involvement, and CREST syndrome, which is associated with localized skin involvement and a more benign course. "CREST" is an acronym for the signs and symptoms: Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Sclerodactyly and Telangiectasias. Anti-centromere antibodies are specific for CREST syndrome and found in 40% of cases. Anti-DNA topoisomerase I (Scl-70) antibodies are highly specific for systemic sclerosis (diffuse scleroderma). The patient in the vignette has CREST syndrome. Raynaud's phenomenon causes painful episodes of pallor, cyanosis, and erythema of the hands in response to cold or emotional stress. These episodes of vasospasm can last minutes to hours. Esophageal dysmotility is the result of fibrosis of the distal esophagus with associated esophageal hypomotility. It manifests with symptoms of gastroesophageal reflux (heartburn and regurgitation). Sclerodactyly is thickening of the skin of the hands and feet. It begins as non-pitting edema of the hands and fingers. Later in the course of the disease, the skin becomes thickened, tight and shiny. Thinning of the skin (atrophy) follows. Telangiectasias (dilated blood vessels) occur on the skin of the face, hands and upper trunk, and on mucosal surfaces. Calcinosis refers to subcutaneous calcium deposits which may be asymptomatic or painful.

A 62-year-old woman is being evaluated for worsening anemia. The patient was admitted to the hospital 2 days ago due to acute pyelonephritis. She has been treated with intravenous ceftriaxone, and her fever and urinary symptoms have gradually improved. The patient has no history of anemia and has had no symptoms of urinary or gastrointestinal bleeding. Laboratory results are as follows: On admission Hemoglobin12.3 g/dL Platelets 285,000/mm3 Leukocytes 14,800/mm3 Serum creatinine 1.0 mg/dL Serum bilirubin 0.8 mg/dL Prothrombin time 12 sec 2 days later Hemoglobin 8.4 g/dL Platelets 300,000/mm3 Leukocytes 10,000/mm3 Serum creatinine 0.8 mg/dL Serum bilirubin 2.4 mg/dL Prothrombin time 11 sec Her antibiotics are changed to a different medication class, and the patient is discharged a few days later. At a follow-up office visit 2 weeks later, her laboratory abnormalities have resolved. Which of the following is the most likely cause of this patient's anemia?

Antibody-mediated erythrocyte injury - This patient developed anemia and hyperbilirubinemia during treatment with ceftriaxone, raising strong suspicion for drug-induced hemolytic anemia. The most common triggers of drug-induced hemolysis are anti-inflammatory medications, penicillins, and cephalosporins (eg, ceftriaxone). Although the mechanism of erythrocyte injury (eg, oxidative, complement mediated) varies depending on the medication, penicillins and cephalosporins typically cause hemolysis by binding to the erythrocyte surface, which creates a hapten for IgG attachment. Antibody-coated erythrocytes are then partially or wholly phagocytized by splenic macrophages, leading to extravascular hemolysis. Hemolysis is often associated with symptomatic anemia (eg, fatigue, pallor) and signs of hyperbilirubinemia (eg, jaundice, dark urine). Laboratory evaluation will typically reveal elevated indirect bilirubin (heme breakdown product), elevated lactate dehydrogenase (intracellular enzyme), reticulocytosis (increased immature RBCs), and lowered haptoglobin (binds free hemoglobin). The diagnosis is confirmed with the direct antiglobulin (Coombs) test, which detects IgG or C3 (a complement fragment) on the erythrocyte surface. Because hemolysis is triggered by the direct binding of the penicillin or cephalosporin to the erythrocyte membrane, cessation of the offending drug eliminates the antibody target and generally leads to complete resolution of symptoms within days.

A newborn undergoes an abdominal ultrasound that shows kidneys of normal size, structure, and location. The patient does not appear to be in distress, and physical examination reveals no abnormalities. If this patient were to be diagnosed with renal disease later in life, it would most likely be which of the following?

Autosomal dominant polycystic renal disease - Autosomal dominant polycystic kidney disease (ADPKD), like many autosomal dominant diseases, manifests later in life (eg, age 40-50). Microscopic cysts are present at birth but are too small to be detected by abdominal ultrasound. Over the years, the cysts enlarge, compression of the renal parenchyma occurs, and patients become symptomatic (eg, flank pain, hypertension). In contrast, autosomal recessive polycystic kidney disease (ARPKD) presents at birth or during the first year of life with bilateral flank masses. Cysts are formed by dilated distal tubules and collecting ducts. Abdominal ultrasonography demonstrates enlarged kidneys at birth and often shows cysts, which are visualized if they are >1 cm in diameter.

A 45-year-old woman calls 911 due to severe chest pain and dyspnea. The emergency medical team finds the patient unresponsive with no pulse, and she does not revive despite extensive cardiopulmonary resuscitation efforts. She had a prolonged history of systemic lupus erythematosus treated with multiple medications and was recently evaluated for progressive muscle weakness. Records from the patient's most recent office visit show an elevated blood pressure and examination findings of facial plethora, truncal obesity, and skin ecchymoses. She was also found to have mild hyperglycemia. Medical history included a left hip replacement for osteonecrosis of the femoral head 1 year ago. At autopsy, she is found to have an occluding thrombus in the left main coronary artery, which likely led to sudden cardiac death. Examination of this patient's adrenal glands is most likely to reveal which of the following findings?

Bilateral cortical atrophy - This patient has features of hypercortisolism, including hypertension, central obesity, muscular weakness, ecchymoses, and hyperglycemia. She most likely developed iatrogenic Cushing syndrome due to prolonged administration of glucocorticoids for management of systemic lupus erythematosus (SLE). Chronic glucocorticoid use can also cause osteonecrosis, and both Cushing syndrome and SLE itself can increase the risk for atherosclerosis and acute coronary events (as in this patient). Exogenous glucocorticoid use inhibits the entire hypothalamic-pituitary-adrenal axis, leading to low levels of corticotropin-releasing hormone (CRH), ACTH, and endogenous cortisol. ACTH exerts a potent trophic (ie, growth promoting) effect on the adrenal zona fasciculata and reticularis; long-term suppression leads to adrenocortical atrophy (the zona glomerulosa is spared as angiotensin II is its primary trophic hormone). Sudden cessation of glucocorticoids after prolonged use can precipitate adrenocortical insufficiency and adrenal crisis.

A primary care physician is invited to give a presentation to a local employer. He is a member of a large multi-specialty medical group, which he joined less than a year ago after completing residency. During the presentation, the physician discusses the various medical specialties available within the group, as well as the range of ancillary services the group offers at its facilities. In the ensuing discussion, the physician learns that the employer has been facing financial difficulties. The employer wishes to continue offering health care coverage to its employees but needs to reduce expenditures. As a result, the employer would like to negotiate a contract in which the medical group would provide care to all the company's employees in exchange for a set monthly fee per employee. Which of the following payment methods best describes this type of health care financing arrangement?

Capitation - An arrangement in which a payor (individual, employer, or government entity) pays a fixed, predetermined fee per patient to cover all required medical services is termed capitation. Capitation is the payment structure underlying health maintenance organization (HMO) provider networks. Under capitation, there is an incentive for the provider and patient to reduce expenses, usually by restricting patients to a limited panel of providers within the plan, requiring referrals from a primary care provider prior to specialist consultations, and denying payment for services that do not meet established evidence-based guidelines. Capitation payments are often made to a private insurance company, which then negotiates with individual physicians or physician networks to provide care. Alternately, a very large physician group (including primary and specialty physicians) may contract directly with employers to provide capitated care for their employees.

A 46-year-old man comes to the office due to abdominal discomfort and diarrhea. The symptoms began 6 months ago, and he has now developed significant weight loss. The patient does not use tobacco or alcohol. Intestinal biopsy is performed, and a periodic acid-Schiff (PAS) stained section is shown. Which of the following is the most likely cause of this patient's symptoms?

Chronic bacterial infection - This patient with abdominal pain and malabsorption has intestinal biopsy findings consistent with Whipple disease, a rare, systemic, chronic bacterial infection that most commonly presents in middle-aged men (age 40-60). It is caused by Tropheryma whipplei, a gram-positive, rod-shaped actinomycete. Following ingestion, the bacteria are engulfed by macrophages in the small intestine mucosa. T whipplei interferes with phagolysosome development and antigen presentation, allowing the organism to replicate within macrophages with minimal inflammatory response. Buildup of infected macrophages can block lymphatic channels, leading to malabsorption (eg, diarrhea, steatorrhea, weight loss, abdominal pain). T whipplei can also spread to the joints, causing arthralgia. In later stages of the disease, the infection can involve the central nervous system (eg, dementia) and heart (eg, endocarditis). Diagnosis can be confirmed with biopsy of the small intestine. Microscopic examination of the lamina propria shows numerous foamy macrophages distended by bacilli that are characteristically positive for periodic acid-Schiff (PAS) stain. PAS stains polysaccharides in the T whipplei membrane, imparting a magenta color.

A 13-year-old boy comes to the office for evaluation of worsening scoliosis. He lost the ability to walk a year ago and has since been wheelchair bound. He has significant back pain and difficulty sitting in his wheelchair for extended periods. The patient also feels "too weak" to cough or take a deep breath. Review of medical records shows genetic studies confirming a mutation of the dystrophin gene on X chromosome p21. Histopathology of the patient's calf most likely indicates which of the following findings?

Fibrofatty muscle replacement - Deletion of the dystrophin gene causes Duchenne muscle dystrophy (DMD). The condition is X-linked recessive and therefore affects primarily boys. Dystrophin is a structural protein of muscle fibers, and its absence causes muscle fiber destruction (myonecrosis). Variation in muscle fiber shape and size, regenerating fibers, and increased amounts of connective tissue are seen on light microscopy. Disease onset is age 2-5. Muscles of the proximal lower extremities, back, and pelvic and shoulder girdles are affected first. Symptoms of DMD include the following: Ambulation difficulties: Clumsy, slow, waddling gait; cannot keep up with peers Gower sign: Progressive weakness in proximal musculature, resulting in use of the hands to support weight on standing (as shown in the image above) Calf pseudohypertrophy: Calf muscles hypertrophy initially in response to proximal muscle weakness and are later replaced by fat and connective tissue Asymmetric weakening of the paraspinal muscles, leading to kyphoscoliosis Most patients with DMD are wheelchair bound by age 12. Scoliosis progresses rapidly due to muscle imbalance and body positional changes. Worsening scoliosis is complicated by restrictive pulmonary function (decreased vital capacity and total lung capacity).

A 24-year-old man is evaluated for episodic anemia, jaundice, and dark urine. These episodes typically occur after the use of certain drugs or following infection. Additional history reveals that he has a brother who experiences similar episodes. Peripheral blood smear reveals red blood cells with the findings shown. Deficiency of which of the following enzymes would most likely result in a condition similar to this patient's presentation?

Glutathione reductase - This patient likely has glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked recessive disorder causing hemolytic anemia and jaundice in response to oxidant stressors (eg, sulfonamide & antimalarial drugs, infection). Heinz bodies (oxidized hemoglobin conglomerates) precipitate in red blood cells and are removed by splenic macrophages, leaving behind characteristic bite cells. G6PD is an enzyme of the pentose phosphate pathway. It generates the reducing agent NADPH, which is essential for detoxification of hydrogen peroxide produced by partial reduction of molecular oxygen in red blood cells. In the absence of NADPH, reduced glutathione (the molecule required for reduction of hydrogen peroxide to water) remains in an oxidized state, and red blood cells become susceptible to oxidative damage. Glutathione reductase catalyzes the reduction of oxidized glutathione. Its absence leads to an inability to use NADPH to reduce glutathione, resulting in a clinical scenario similar to G6PD deficiency.

A 32-year-old woman comes to the office due to a 2-month history of dull pain in the right upper quadrant. The pain is worse with deep inspiration. The patient has no fever or weight loss. She drinks alcohol socially but does not use tobacco or recreational drugs. The patient has no significant family history of cancer. Temperature is 37.1 C (98.8 F), blood pressure is 130/78 mm Hg, pulse is 82/min, and respirations are 16/min. BMI is 36 kg/m2. There is no jaundice. On examination, mild hepatomegaly is noted; there is no ascites. Abdominal ultrasonography reveals a solitary 4.5-cm mass in the right lobe of the liver. The patient undergoes surgical resection. On gross examination, the mass is soft and smooth with a tan appearance. On cut surface, areas of hemorrhage and necrosis are noted. Microscopic examination shows cells that are larger than normal hepatocytes and have small, regular nuclei without mitoses. There are scattered prominent arteries; no portal tracts or interlobular bile ducts are present. Which of the following is the most likely diagnosis?

Hepatocellular adenoma - This patient's pathologic features are consistent with hepatocellular adenoma (HCA), an uncommon benign liver tumor found predominantly in young women. It is associated with estrogen exposure (eg, oral contraceptive pills), anabolic steroid use, and obesity. The pathogenesis is thought to be hormonally mediated but is not fully understood. Macroscopically, HCA is typically a well-circumscribed, solid, solitary, unencapsulated mass arising in the right liver lobe. The cut surface is often soft and tan with areas of hemorrhage and necrosis. Histologically, HCA is composed of sheets or plates of benign hepatocytes. The cells may be larger than normal hepatocytes but have small, uniform nuclei (ie, no cytologic atypia) and rare mitotic figures. The normal hepatic architecture is absent; instead, there are prominent arteries without normal portal tracts or interlobular bile ducts. The uninvolved liver is usually noncirrhotic. Patients may be asymptomatic (ie, diagnosed incidentally by imaging) or have epigastric or right upper quadrant pain (due to hepatomegaly or intralesional bleeding or necrosis). Because HCA is an unencapsulated and vascular lesion, there is risk for rupture with life-threatening intraabdominal bleeding (eg, severe abdominal pain, hypotension). For this reason, large or symptomatic HCAs are usually surgically resected.

A 62-year-old man is evaluated for shortness of breath. During pulmonary function testing, the patient performs a forceful and complete exhalation after maximal inhalation. The results (red curve) are compared to a healthy individual of the same age and sex (black curve), as shown. Which of the following is the most likely cause of this patient's dyspnea?

Idiopathic pulmonary fibrosis - Pulmonary function testing (PFT) usually involves spirometry, during which the patient completely inhales (to reach total lung capacity) and then forcefully exhales as much air as possible as quickly as possible. The graph in this question depicts the measured results following this procedure. The volume of air expelled during the first second of exhalation is the forced expiratory volume in 1 second (FEV1), and the total volume of air expelled represents the forced vital capacity (FVC). The black curve on the graph depicts normal PFT results with an FEV1 of 4 liters, an FVC of 5 liters, and an FEV1/FVC ratio of 80%. The patient's red curve shows a reduced FEV1 of 3 liters, a reduced FVC of 3.5 liters, and a slightly increased FEV1/FVC ratio of 86%. These findings are consistent with a restrictive pattern; therefore, the patient's dyspnea is most likely due to interstitial lung disease. Neuromuscular weakness and obesity hypoventilation syndrome also demonstrate a restrictive pattern on PFT.

A 6-year-old boy is brought to the office by his mother due to recurrent episodes of sinusitis. He also has a chronic cough that never seems to go away. The mother says that his previous pediatrician performed a "sweat test" to help determine the cause of his frequent infections, but results were normal. DNA testing was inconclusive. Despite these results, the new physician suspects that the patient has an inherited disorder and orders nasal transepithelial potential difference measurements. In this test, an isotonic solution of sodium chloride is applied to the nasal mucosal surface, and the electrical potential overlying the mucosa is compared with that of the interstitial fluid. The results show a transepithelial potential difference that is more negative than normal. This patient's nasal mucosa is most likely to demonstrate which of the following physiologic changes?

Increased sodium absorption - Chronic cough and recurrent sinusitis in a young patient should raise suspicion for cystic fibrosis (CF). The diagnosis of CF typically is based on elevated sweat chloride concentrations, characteristic clinical findings (recurrent sinopulmonary infections, pancreatic insufficiency), and/or a positive family history. However, patients with mild mutations of the CF transmembrane conductance regulator (CFTR) gene may have normal sweat testing. In these cases, a useful diagnostic adjunct involves measuring the nasal transepithelial potential difference. In intestinal and respiratory epithelia, the CFTR channel secretes chloride ions into the lumen and also has a tonic inhibitory effect on the opening of the epithelial sodium channel (ENaC), which decreases sodium reabsorption into the cell. This high luminal salt content helps retain water in the lumen, forming well-hydrated mucus. During the nasal transepithelial potential difference test, a saline solution is applied to the nose. Because patients with CF have increased sodium absorption via the ENaC, sodium is absorbed intracellularly but chloride in the saline solution is retained in the lumen. The higher relative amounts of negatively charged chloride on the epithelial surface result in a more negative transepithelial voltage difference. CFTR channel functioning is reversed in sweat ducts compared with that in respiratory and intestinal glands. CFTR reduces the salt content of sweat by reabsorbing luminal chloride and stimulating ENaC to increase sodium absorption from the lumen into the cells. CFTR mutations therefore result in the production of sweat with high chloride and sodium content.

A 62-year-old man with a long history of hypertension comes to the clinic for a routine physical examination. Blood pressure is 150/90 mm Hg and pulse is 74/min and regular. Cardiac auscultation reveals a low-frequency, presystolic sound that immediately precedes S1 and is best heard during expiration when the patient is lying on his left side. Chest x-ray reveals extensive calcification around the mitral and aortic valves. Which of the following is the most likely explanation for the additional heart sound?

Increased stiffness of the left ventricular wall - This patient has an S4 (low-frequency sound occurring just before S1), which is most likely secondary to concentric left ventricular hypertrophy (LVH) from longstanding hypertension (hypertensive heart disease). The calcifications revealed on chest x-ray likely represent degenerative mitral and aortic valve calcification, which is age related and typically accelerated by systemic hypertension. An S4 is a sign of diastolic dysfunction. It occurs due to blood striking a stiffened ventricular wall during atrial contraction at the end of diastole. An S4 may be present in any condition that causes reduced ventricular compliance (eg, hypertensive heart disease, restrictive cardiomyopathy, acute myocardial infarction). A left-sided S4 is best heard with the bell of the stethoscope over the cardiac apex with the patient in the left lateral decubitus position; it will intensify during expiration due to increased blood flow from the lungs to the left atrium.

A 55-year-old man comes to the office due to swelling in his groin that he first noticed 2 weeks ago. Physical examination shows a bulge above the inguinal ligament that increases in size when the patient is asked to cough. He is referred to a surgeon and scheduled to undergo elective laparoscopic hernia repair. Which of the following landmarks will best aid the surgeon in distinguishing an indirect from a direct inguinal hernia?

Inferior epigastric vessels - Inguinal hernias are located above the inguinal ligament and are much more common in men. The inferior epigastric vessels are clearly visible on the anterior abdominal wall during laparoscopic hernia repair and can be used as a landmark to distinguish between direct and indirect inguinal hernias. Indirect inguinal hernias occur due to failure of the processus vaginalis to obliterate, allowing abdominal contents to protrude lateral to the inferior epigastric vessels through the deep (internal) inguinal ring. The abdominal contents follow the path of the inguinal canal and may exit through the superficial (external) inguinal ring into the scrotum. Direct inguinal hernias occur due to weakness in the transversalis fascia that allows abdominal contents to protrude medial to the inferior epigastric vessels into the Hesselbach triangle. Compared to indirect inguinal hernias, direct hernias are less prone to incarceration due to their wide neck. It is also uncommon for them to descend into the scrotum as there is no direct path through the abdominal fascia.

A 67-year-old woman comes to the office due to polymyalgia rheumatica. She was diagnosed a year ago and has required supraphysiologic doses of prednisone to control her symptoms. The patient has no other medical conditions. She has adequate intake of calcium and vitamin D from her diet and supplements. The patient does not use tobacco or alcohol. Physical examination is unremarkable. Laboratory evaluation shows normal serum creatinine, 25-hydroxyvitamin D, and calcium levels. Bone density measured by dual x-ray absorptiometry (DXA) reveals a significant decline when compared to her bone density measured at age 65. Which of the following is most likely contributing to this patient's bone loss?

Inhibition of osteoblast precursor cell replication and differentiation - Chronic or recurrent glucocorticoid (eg, prednisone) use, as is needed in patients with polymyalgia rheumatica, is associated with an increased risk for osteoporosis. Glucocorticoids accelerate the development of osteoporosis by a number of mechanisms: Decreased osteoblast effect: Glucocorticoids inhibit the proliferation and differentiation of osteoblast precursor cells. They also induce increased rates of apoptosis in mature osteoblasts. Increased osteoclast effect: Osteoclast differentiation and activity are promoted by the receptor activator of nuclear factor kappa B (RANK)/RANK-ligand; this effect is inhibited by osteoprotegerin, which acts as a decoy receptor. Glucocorticoids increase the expression of RANK and RANK-ligand and decrease the expression of osteoprotegerin, leading to increased bone resorption. Renal and intestinal calcium wasting: Glucocorticoids suppress intestinal calcium absorption and renal calcium reabsorption, requiring increased release of calcium from bone to maintain calcium homeostasis.

A 51-year-old woman comes to the office due to progressively worsening fatigue, weight gain, and constipation for the past 6 months. The patient has had difficulty performing daily activities due to her fatigue. She has no significant medical history and takes no medications. The patient has no drug allergies and does not use tobacco, alcohol, or illicit drugs. Blood pressure is 110/80 mm Hg and pulse is 55/min. Physical examination shows mild, diffuse enlargement of the thyroid gland. Cardiopulmonary and abdominal examinations are normal. Biopsy of this patient's thyroid is most likely to show which of the following findings?

Intense lymphoplasmacytic infiltrate with active germinal centers - This patient has chronic lymphocytic (Hashimoto) thyroiditis presenting with hypothyroidism (eg, fatigue, weight gain, constipation) and a diffuse goiter. This autoimmune disease occurs predominately in women, has a peak incidence at age 45-65, and is the most common cause of hypothyroidism in iodine-sufficient regions such as the United States. In all forms of primary hypothyroidism, laboratory studies show low serum thyroxine (T4) levels and elevated TSH. Antithyroid peroxidase antibody levels are usually elevated, although they are not specific to Hashimoto thyroiditis and are also seen in other autoimmune thyroid disorders (eg, postpartum thyroiditis, Graves disease). If the diagnosis is uncertain (eg, thyroid nodularity), a biopsy can be performed to rule out malignancy. Characteristic findings of Hashimoto thyroiditis include a lymphoplasmacytic infiltrate with the formation of germinal centers. Residual follicles are often surrounded by Hürthle cells (large cells with granular, eosinophilic cytoplasm) representing follicular epithelial cells that have undergone metaplastic change in response to inflammation.

A 65-year-old man comes to the emergency department due to fevers and malaise for the last 48 hours. The patient initially experienced fevers and chills, which subsequently progressed to fatigue to the point that he had difficulty performing routine tasks this morning. He has also had a mild headache. The patient lives in eastern Massachusetts with his wife. He is retired and spends time gardening and swimming at a local public pool. The patient traveled to Thailand 2 years ago with his family and to Florida 2 months ago. Temperature is 38.9 C (102 F), blood pressure is 122/70 mm Hg, and pulse is 114/min and regular. The oropharynx is dry and has no lesions. Lung examination demonstrates coarse crackles bilaterally. The abdomen is soft and mildly tender throughout with palpable splenomegaly. He has no rash or open wounds. Peripheral blood smear is shown in the exhibit. Which of the following is the most likely source of this patient's infection?

Ixodes tick - This patient with an acute febrile illness has a peripheral blood smear showing intraerythrocytic ring inclusions. Parasites that can potentially cause disease in red blood cells include Plasmodium (malaria) and Babesia (babesiosis). In this patient, the epidemiology (residence in northeastern United States, outdoor exposure in the summer) is suggestive of babesiosis. This organism is transmitted by the Ixodes scapularis tick, which is also a vector for Borrelia burgdorferi (Lyme disease) and Anaplasma (human granulocytic anaplasmosis).

An apparently healthy 6-year-old boy is enrolled in a research study designed to assess the absorptive capacity of the small intestine. As part of the investigation, he is administered an oral solution containing free amino acids and amino acid derivatives. Blood samples are then obtained at 15-minute intervals for the next 2 hours. The patient is found to have significantly decreased intestinal absorption of lysine, arginine, ornithine, and cystine as compared to the other study participants. If the condition is left untreated, which of the following complications is this patient at greatest risk of developing?

Kidney stones - Cystine (a cysteine homodimer forming disulfide bonds) and the dibasic amino acids ornithine, lysine, and arginine (cola) share a common transporter in the intestinal lumen and kidneys. In patients with cystinuria, this transporter is defective, resulting in impaired intestinal absorption and renal reabsorption. In the intestine, this impairment causes absent (or diminished) intestinal absorption of ornithine, lysine, and arginine. However, patients do not develop amino acid deficiencies because these amino acids are absorbed in sufficient quantities as oligopeptides. In the kidneys, impaired tubular reabsorption leads to a high urinary cystine concentration, resulting in the formation of cystine kidney stones. The amino acids ornithine, lysine, and arginine are relatively soluble in urine and do not result in the formation of kidney stones. Risk factors for cystine precipitation include low urine pH (pH <7), the presence of a preexisting crystal nidus, and urine supersaturation.

A 50-year-old woman comes to the physician due to periodic reddening of her skin that is starting to become bothersome. The redness involves mainly her face and neck and is accompanied by mild warmth. The episodes initially lasted only a few minutes, but now they sometimes exceed 20 minutes. The patient has also had persistent watery diarrhea and associated abdominal cramping for the last several months. Physical examination shows several, purple vascular lesions surrounding her nose. Urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA) over 24 hours is increased. Abdominal imaging shows a tumor in the small intestine. Which of the following is most likely responsible for this patient's condition?

Metastatic carcinoid - Carcinoid tumors most frequently arise from the enterochromaffin (endocrine) cells of the intestinal mucosa. These cells produce a number of vasoactive substances, such as serotonin (5-HT), bradykinin, and prostaglandins. When the tumor is confined to the intestine, these secretory products are metabolized by the liver and patients do not develop carcinoid syndrome. In contrast, if intestinal carcinoid metastasizes to the liver, these vasoactive substances bypass the liver and enter the systemic circulation, resulting in carcinoid syndrome. Extraintestinal carcinoid tumors (eg, bronchial carcinoid) can cause carcinoid syndrome without metastasizing as the vasoactive substances are secreted directly into systemic circulation (again bypassing hepatic metabolism). Increased level of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) in a 24-hour urine sample is the most useful initial test for confirming carcinoid syndrome.

A 15-month-old boy is brought to the clinic for evaluation of recurrent mouth ulcers. Over the past 5 months, his mother has noted that he has had periodic episodes of mouth pain and oral ulcers. She says the episodes usually last for a couple of days and then resolve without intervention. The boy has no known medical conditions and takes no medications. Vital signs are normal. Examination shows mucositis. The rest of the examination is unremarkable. Complete blood count (CBC) reveals an absolute neutrophil count of 390/mm3. Hemoglobin level and platelet count are normal. Serial CBC results are documented over the next 6 weeks. The patient returns to the clinic on Day 39. Examination of this patient's bone marrow would most likely reveal an abnormal increase in which of the following?

Myeloid progenitors with nuclear fragmentation and membrane blebbing - This patient has isolated, severe neutropenia defined by an absolute neutrophil count (ANC) <500/mm3. It resolves and recurs in a predictable pattern, a finding characteristic of cyclic neutropenia. Cyclic neutropenia occurs due to a mutation in the gene encoding neutrophil elastase. This enzyme is normally packaged within neutrophil granules and plays a role in the degradation of virulence factors on bacterial pathogens. Misfolded neutrophil elastase increases endoplasmic reticulum stress, causing a portion of the neutrophil precursors in the bone marrow to undergo apoptosis. Bone marrow aspirate would show myeloid progenitor cells with features characteristic of apoptosis (eg, nuclear fragmentation, membrane blebbing). The depressed ANC is thought to transiently upregulate granulocyte colony-stimulating factor (G-CSF), which stimulates neutrophil production from the hematopoietic stem cells that did not undergo apoptosis. As neutrophil numbers normalize, G-CSF production decreases, allowing neutrophil counts to decline again. Clinical manifestations of cyclic neutropenia correlate with neutrophil nadirs, which typically occur every 3 weeks, and include recurrent episodes of fever, fatigue, and mucositis (eg, gingival ulcers, inflammation) in young children. Life-threatening infection in cyclic neutropenia is rare due to the brief duration of neutropenic periods, and patients are typically asymptomatic between episodes. Serial ANC measurements over 6-8 weeks showing predictable oscillations support the diagnosis, and genetic testing is confirmatory.

Researchers are observing how coronary blood flow changes in response to progressive increases in the mean arterial blood pressure. The mostly horizontal portion of the slope indicates a region where coronary blood flow is relatively insensitive to blood pressure changes. Within this zone of autoregulation, the metabolic demands of the myocardium are the main determinant of coronary blood flow. Which of the following endogenous factors is most responsible for controlling coronary blood flow within this range?

Nitric oxide - The myocardium has the highest resting oxygen requirement of any tissue in the body, extracting >70% of available oxygen from the blood at baseline (compared to ~30% in most other tissues). As such, a significant increase in myocardial oxygen demand can only be met through a corresponding increase in coronary blood flow. Coronary autoregulation is a process that maintains myocardial blood flow in settings of decreased coronary perfusion pressure (eg, hemorrhage, sepsis). Within the region of autoregulation (eg, 60-140 mm Hg), changes in coronary blood flow are driven primarily by myocardial oxygen demand. This is accomplished mostly by automated alterations in vascular resistance via the release of locally acting mediators, namely adenosine (released from cardiomyocytes as ATP is broken down for energy) and nitric oxide (synthesized by endothelial cells in response to chemical mediators and mechanical stress). When myocardial perfusion pressure decreases, there is decreased oxygen delivery to the myocardium and less ATP is regenerated via oxidative metabolism, resulting in increased levels of adenosine. Myocardial hypoxia also triggers increased synthesis of nitric oxide. Increased levels of both adenosine and nitric oxide act on vascular smooth muscle to stimulate vasodilation, allowing for a relative increase in coronary blood flow at the new, lower perfusion pressure (ie, coronary blood flow is maintained). A similar process occurs when coronary perfusion pressure increases; decreased levels of adenosine and nitric oxide increase vascular resistance, causing coronary blood flow to remain relatively unchanged at the new, higher perfusion pressure.

A 24-year-old previously healthy man is brought to the emergency department after a motor vehicle collision in which he sustained trauma to the left side of the chest and the abdomen. On arrival, the patient is hypotensive and tachycardic. Evaluation reveals left-sided rib fractures and hemoperitoneum due to splenic laceration. Urgent exploratory laparotomy under general anesthesia is planned. In the operating room, etomidate is administered for rapid sequence induction. Which of the following characteristics best describes etomidate as compared to propofol?

No cardiovascular depressant effect - This patient is hemodynamically unstable (ie, hypotensive, tachycardic). Prior to operative intervention, anesthesia must be induced. Three medications are commonly used because of their rapid onset of action and short duration of effect: Propofol: A highly lipophilic GABA agonist that has the advantage of reducing airway resistance. Disadvantages include vasodilation, which can result in hypotension and an increase in serum triglycerides and lipase. Etomidate: A GABA agonist that has the advantage of being the most hemodynamically neutral. It does not cause changes in heart rate, blood pressure, or cardiac output. However, it inhibits cortisol synthesis, which can lead to adrenocortical suppression that is typically reversible. Because of this, etomidate is often avoided in patients with septic shock, and it should not be used as maintenance of sedation after induction. Ketamine: An N-methyl-d-aspartate antagonist that is similar to PCP, it preserves the respiratory drive during induction of anesthesia. Ketamine also provides an analgesic effect. It stimulates the release of catecholamines, which can cause bronchodilation but also increase heart rate, myocardial contractility, and cerebral blood flow. In hypotensive patients, anesthesia is often induced with either a hemodynamically neutral agent (etomidate) or one that may improve hemodynamics due to catecholamine release (ketamine).

A 66-year-old woman is brought to the emergency department due to left leg pain. Five days ago, the patient underwent elective right hip arthroplasty for advanced osteoarthritis. She had been recovering well at an acute rehabilitation facility until she woke today with severe left calf pain and swelling. The patient has taken daily subcutaneous, low-molecular-weight heparin and as-needed acetaminophen since the surgery. She has no other medical conditions. Temperature is 37 C (98.6 F), blood pressure is 130/70 mm Hg, and pulse is 92/min. The surgical incision over her right hip is healing well. Her left posterior calf is tender and swollen to the knee. Three days ago, complete blood count was normal, but platelet count is now 70,000/mm3. Peripheral blood smear shows decreased platelet number but no other abnormalities. Which of the following is the most likely cause of this patient's thrombocytopenia?

Platelet removal by splenic macrophages - This patient on low-molecular-weight heparin developed thrombocytopenia and deep venous thrombosis (calf pain/swelling), raising strong suspicion for heparin-induced thrombocytopenia (HIT) type 2. In HIT type 2, heparin induces a conformational change in platelet-factor 4, leading to the formation of a neoantigen. IgG antibodies form against the neoantigen (heparin-platelet factor 4), which results in antibody aggregation on the platelet surface. Patients generally develop manifestations 5-10 days after heparin initiation. Thrombocytopenia is the hallmark feature due to the clearance of antibody-coated platelets by splenic macrophages. Antibody aggregation on the platelet surface also results in wide-spread platelet aggregation, which worsens the thrombocytopenia and significantly increases the risk of venous and arterial thrombosis. Patients with HIT-type 2 should immediately stop heparin and be initiated on a nonheparin anticoagulant (eg, argatroban) to help prevent/treat thrombosis.

A 55-year-old man is immediately brought to the hospital after experiencing a sudden collapse at home 20 minutes ago. The patient reported chest pain and then collapsed to the floor while trying to sit down. Medical history is significant for type 2 diabetes mellitus and hypertension. Temperature is 36.7 C (98.1 F), blood pressure is 80/50 mm Hg, pulse is 120/min, and respirations are 22/min. On examination, the patient is in marked respiratory distress. Bilateral crackles are present. An S3 is audible. ECG reveals ST-segment elevation in leads V2 through V6. Which of the following hemodynamic changes are most likely present in this patient?

Pulmonary capillary wedge pressure: increased Central venous pressure: increased Coronary perfusion pressure: decreased This patient with sudden-onset chest pain and ST-segment elevation in contiguous ECG leads has an ST-elevation myocardial infarction (MI). Hypotension, pulmonary crackles, and an audible S3 suggest MI-induced acute left ventricular (LV) failure and cardiogenic shock. In cardiogenic shock, LV systolic failure causes increased LV end-diastolic pressure, which is transmitted backward to cause increased pulmonary capillary wedge pressure (PCWP) (an estimate of left atrial pressure) and pulmonary edema. The increased pressure also impairs right ventricular function, resulting in increased central venous pressure (CVP). Markedly decreased cardiac output leads to hypotension with decreased coronary perfusion pressure (as coronary perfusion pressure is driven by aortic diastolic pressure). In response to the reduced cardiac output, compensatory peripheral vasoconstriction occurs to increase systemic vascular resistance in an effort to maintain organ and tissue perfusion.

A 45-year-old woman brings her stepson to the office for a well-child visit. She never wanted children due to her unhappy childhood and wishes her marriage did not include being a stepmother to her husband's 5-year-old son. In the waiting room, the woman seems excessively concerned when the boy accidentally trips and is clearly uninjured. During the visit, she tells the physician that she adores the child and describes her elaborate preparations for his birthday party. Which of the following defense mechanisms best explains this woman's behavior?

Reaction formation - Reaction formation is a defense mechanism in which an individual transforms unacceptable feelings or impulses into their extreme opposites. This woman does not want to be a stepmother, and her resentment toward the child is masked with declarations of love. Her negative feelings toward the child are transformed into oversolicitous behavior in response to his tripping and excessive preparations for his birthday party.

A 64-year-old man comes to the office due to several episodes of intermittent hematuria over the past 2 months. He has had no abdominal pain, burning on urination, or fever but has lost 4.5 kg (10 lb) since the onset of symptoms. The patient has smoked a pack of cigarettes daily for 30 years. Vital signs are within normal limits. The abdomen is soft, nontender, and nondistended. An enlarged and firm prostate is palpated on digital rectal examination. Serum calcium is 12.3 mg/dL. Urinalysis shows 30-40 red blood cells/hpf, negative protein, and no casts. A CT scan of the abdomen is shown. What is the most likely diagnosis?

Renal cell carcinoma - This patient with an extensive smoking history, 4.5-kg weight loss, painless hematuria, hypercalcemia, and renal mass likely has renal cell carcinoma (RCC). RCC originates in the renal cortex and accounts for up to 90% of primary renal tumors. It is often identified incidentally on radiographic imaging, and many individuals remain asymptomatic until the disease is relatively advanced. Hematuria is the most common symptom, and painless hematuria in an older adult should raise suspicion for a genitourinary malignancy. Patients may also have flank pain and a palpable abdominal mass at the time of presentation. Paraneoplastic syndromes are common in RCC due to the secretion of biologically active substances by the tumor cells. Hypercalcemia is frequently seen due to increased production of parathyroid hormone-related peptide or overproduction of prostaglandins that promote bony resorption. Erythrocytosis due to ectopic erythropoietin production may also be seen.

Researchers are studying how the membrane potential of a postsynaptic neuron changes in response to neurotransmitter stimulation. Baseline measurements determine that the resting membrane potential is generated by high membrane permeability for a particular ion. When neurotransmitter stimulation begins, ligand-gated ion channels open (black arrow) and increase the membrane permeability for a different ion, causing a change in membrane potential. This triggers the delayed opening of voltage-gated ion channels (red arrow), which increase the membrane permeability for a third type of ion. The results of the experiment are shown. The equilibrium potentials of different ions under physiologic conditions are as follows: ENa=+60 mV EK=−90 mV ECl=−75 mV ECa=+125 mV Which of the following options would best explain the changes in this neuron's membrane potential during the experiment?

Resting membrane permeability: potassium Ligand-gated ion channel permeability: sodium Voltage-gated ion channel permeability: chloride Equilibrium potentials of cellular ions reflect how they affect the membrane potential if the membrane were permeable solely for that ion. The resting membrane potential shown in the graph is negative, indicating that at rest, the membrane is permeable to an ion with a negative equilibrium potential (potassium or chloride). Opening of ligand-gated ion channels in response to neurotransmitter binding (black arrow) causes an increase in membrane potential to above zero. This indicates that the membrane has become permeable for an ion with a positive equilibrium potential (sodium or calcium). Opening of voltage-gated ion channels in response to the change in membrane potential (red arrow) causes a drop in membrane potential, indicating that the membrane becomes permeable to an ion with a negative equilibrium potential (potassium or chloride).

A 65-year-old man comes to the office due to several weeks of nonproductive cough. The patient also has anorexia and unintentional weight loss. His medical history includes hypothyroidism due to Hashimoto thyroiditis and a 50-pack-year smoking history. Examination shows an enlarged right supraclavicular lymph node. Imaging reveals a large mediastinal mass causing tracheal deviation. The enlarged node is biopsied, and microscopy demonstrates clusters of small, ovoid cells with scant cytoplasm and a high mitotic count. Immunohistochemical staining is positive for chromogranin. This patient most likely has which of the following conditions?

Small cell cancer - This patient with a heavy smoking history, weight loss, cough, and a mediastinal mass with evidence of metastases (ie, supraclavicular node elargement) has small cell lung cancer (SCLC), also known as oat cell carcinoma. SCLC makes up 10%-20% of all primary lung malignancies and is strongly associated with smoking. It is usually centrally located and arises from the primitive cells of the basal layer of the bronchial epithelium. On light microscopy, small, round or oval cells with scant cytoplasm, hyperchromatic (blue) nuclei, and granular chromatin are visualized. The cells, which may resemble lymphocytes but are typically larger, form clusters or sheets. Abundant mitoses are usually seen. Small cell carcinomas can display varying degrees of neuroendocrine differentiation. Immunohistochemical stains are frequently positive for neuroendocrine markers, such as neuron-specific enolase, chromogranin, neural cell adhesion molecule (CD56), and synaptophysin. On electron microscopy, some of the cells have secretory granules in the cytoplasm.

A 53-year-old woman comes to the clinic due to a rash. For the past 3 weeks, she has had a pruritic rash of worsening severity involving the posterior thighs. The patient recently began an exercise program to lose weight and has been applying a topical analgesic cream to her thighs and buttocks after her workouts to relieve muscle aches. Medical history is unremarkable, and she does not use tobacco, alcohol, or recreational drugs. On physical examination, there is an erythematous rash with blisters, erosions, and weeping drainage involving the posterior thighs bilaterally, which is shown. Which of the following is the most likely finding on skin biopsy?

Spongiosis - This patient developed pruritic, erythematous blisters and erosions on the thighs following application of a topical cream. This presentation is consistent with acute allergic contact dermatitis (ACD), a type of eczematous dermatitis. Eczematous dermatitis is a class of skin conditions that vary in etiology but demonstrate similar clinical findings (eg, pruritic, erythematous, weeping papulovesicular rash) and are microscopically characterized by spongiosis. ACD is caused by a type IV (delayed) hypersensitivity reaction to an external antigen (eg, analgesic cream) on the skin surface, which incites an inflammatory response and causes pruritus and erythema at the site of contact. Increased vascular permeability in the dermis results in dermal edema, which can leak into the epidermis and accumulate in the intercellular spaces (ie, spongiosis). Microscopically, spongiosis appears as increased space between keratinocytes with prominent intercellular attachments (ie, desmosomes). Continued fluid accumulation can break the desmosomes, causing intraepidermal vesicles. With persistent antigen exposure, eczematous lesions may become less edematous and weepy over time and appear as raised, thickened (ie, lichenified), scaly plaques. Histology of chronic lesions typically shows thickening of the stratum spinosum (ie, acanthosis), stratum granulosum (ie, hypergranulosis), and stratum corneum (ie, hyperkeratosis).