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Q NO 101: A 60-year-old male has been experiencing exertional exertional chest pain that remits with rest for the past 6 months. His past medical history is significant for hypertension, hypertension, diabetes, and hypercholesterolemia. hypercholesterolemia. An exercise stress test is positive for inducible ischemia. Cardiac catheterization shows 80% occlusion of  the right coronary artery and 60% occlusion of the left coronary artery main stem. Which of the following types of cells was most likely involved in the initial pathogenesis of his condition? Interstitial fibroblasts B. Endothelial cells C. Macrophages D. Pericytes E. Mast cells F. Platelets G. Smooth muscle cells

A.

Explanation: This patient has a history and presentation consistent with coronary artery atherosclerosis. atherosclerosis. The pathogenesis of atherosclerosis is thought to begin with endothelial endothelial cell injury. In the response-to-injury response-to-injury model, chronic endothelial cell injury may result f rom hypertension (and related hemodynamic factors) hyperlipidemia, hyperlipidemia, smoking, diabetes, homocysteine, toxins (including alcohol), viruses, and/or immune reactions. Such injury results in endothelial cell dysfunction and/or exposure of subendothelial collagen (endothelial cell denudation). denudation). Endothelial Endothelial cell dysfunction dysfunction results in increased permeability, as well as monocyte and lymphocyte adhesion and migration into the intima. Endothelial denudation and exposure of subendothelial collagen promote platelet adhesion. Growth factors produced by monocytes and platelets stimulate medial smooth muscle cell (SMC) migration into and proliferation in the intima. At the same time, increased endothelial endothelial cell permeability allows LDL cholesterol into the intima, where it is phagocytosed by the accumulating macrophages and smooth muscle myocytes to produce foam cells. The repetitive endothelial injury results in a chronic inflammatory state within the underlying underlying intima. Cytokine and growth factor release by macrophages and lymphocytes lymphocytes maintains the inflammation, allows continued deposition of plasma LDL cholesterol, and stimulates the new intimal SMC to proliferate and to produce more extracellular matrix, including collagen and proteoglycans. This chronic inflammation can also result in necrosis of foam cells and release of their lipid contents (including toxic oxidized LDL from macrophages) into the extracellular matrix of the intima. As a result, the chronic inflammatory process initiated by endothelial injury may progress from a fatly streak within the intima (containing mainly lipid-laden foam cells) to a full1ledged fibrofatty atheroma. A core of lipid debris surrounded by monocytes, lymphocytes, lymphocytes, and a f ibrous cap with intermixed SMC causes marked intimal thickening. The atherogenic progression described above is summarized in the following illustrations:

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(Choice A) Fibroblasts are not thought to contribute significantly to the formation of  atheromas. The fibrous tissue— including the fibrous cap—of atheromas is synthesized by 3MG that have migrated to and proliferated in the intimal layer in which the plaque forms. (Choice C) Macrophages do play an important subsequent role in the continued pathogenesis of felt streaks and atheromas, but they must first be recruited to the sites of the atheroma lesions by injury to the overlying endothelium. (Choice D) Pericytes which are particularly numerous around post capillary venules are pluripotent cells that surround the smallest blood vessels. These cells are not directly involved in atherosclerosis, which affects large elastic arteries and large and medium-sized muscular arteries. (Choice E) Mast cells are not thought to be directly involved in the pathogenesis of  atherosclerotic lesions in the intima of elastic and muscular arteries. (Choice F) While platelets do play an important role in the continued pathogenesis of  fatty streaks and atheromas, their adhesion to the sites of the atheroma lesions is dependent upon injury to the overlying endothelium exposing subendothelial collagen. (Choice G) The initial pathogenesis of atherosclerosis involves endothelial cell injury. SMO do play an important subsequent role in the continued pathogenesis of fatty streaks and atheromas, but they must first be recruited to the sites of the atheroma lesions by injury to the overlying endothelium that promotes secretion of smooth muscle chemotactic and growth factors by platelets and monocytes. Educational Objective: Atherosclerosis is initiated by repetitive endothelial cell injury, which leads to a chronic inflammatory state in the underlying intima of large elastic arteries as well as large and medium-sized muscular arteries.

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Q NO 102: Some patients with tetralogy of Fallot (TOF) are cyanotic at birth. Others have relatively mild symptoms and experience only episodic cyanosis and dyspnea. The severity of symptoms in patients with this disorder largely depends on the severity of:

A. Right ventricular hypertrophy B. Ventricular septal defect C. Pulmonic stenosis D. Aortic insufficiency E. Atrial septal defect Explanation: TOF is typically characterized by: pulmonic stenosis, ventricular septal detect (VSD) right ventricular hypertrophy (RVH) and overriding aorta (straddling the VSD). The major physiologic problem in cyanotic TOE is right-to-left intracardiac shunting which results from the asymmetric division of the embryonic truncus arteriosus which causes significant stenosis of the pulmonic outflow tract. The degree of right-to-left shunting and associated cyanosis depends upon the degree of right ventricular (RV) outflow obstruction. In general the VSD in TOF patients is large and nonrestrictive. Because of the pulmonic stenosis, the pressure in the RV equals that of the left ventricle (LV). Blood flow follows the path of least resistance. If the pulmonic stenosis is severe the blood flows from the RV to the LV (right-to-left shunt) across the VSDI and causes cyanosis. If the systemic vascular resistance exceeds the pulmonary vascular resistance (determined by the degree of pulmonic stenosis), the blood flows from LV to RV via the VSD and to the pulmonary vascular bed. These patients are acyanotic. (Choice B) The VSD in TOE is generally large enough to permit unrestricted flow between the RV and LV. Thus the VSD is not one of the variables that determines the severity of the hypoxemia. (Choice D) Whereas some patients with severe TOF may develop aortic insufficiency, it is generally not a presenting feature of this condition. (Choice E) Patients with TOE generally do not have atrial septal defects.

Educational Objective: In patients with TOF the degree of RV outflow tract obstruction is the major determinant of the degree of right-to-left intracardiac shunting, and thus of  hypoxemic symptom severity.

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Q NO 103: A 54-year-old Caucasian female presents to your office with exertional dyspnea and fatigue. She also describes nocturnal episodes of dyspnea and orthopnea. After initial evaluation cardiac catheterization was performed that reveals the following findings (see the diagram below).

The pressure tracings shown in the diagram are most consistent with which of the following? A. Aortic stenosis B. Aortic regurgitation C. Mitral stenosis D. Mitral regurgitation E. Normal findings Explanation: This patient presents with nonspecific symptoms consistent with an inadequate ability to increase cardiac output during exertion as well as elevated pressures in the pulmonary circulation resulting in a degree of pulmonary edema. The v wave corresponding to left atrial filling during the patient’s cardiac catheterization is abnormal. See graph below.

Note that the peak v wave pressure corresponding to maximal left a trial filling just prior to the opening of the mitral valve (arrowheads) is elevated. These abnormalities are indicative of mitral regurgitation, with abnormal retrograde filling of the left atrium during ventricular systole. 64

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(Choice A) The major hemodynamic finding in a patient with aortic stenosis would be a pressure difference (gradient) between the left ventricle and the aorta in the interval delimited by points A and B on the graph in the explanation under (Choice D). A corresponds to opening of the aortic valve and B corresponds to its closure. Left ventricular pressure would be significantly higher than aortic pressure during the A-B interval. (Choice B) Aortic regurgitation would tend to elevate both the left ventricular (LV) and left atrial diastolic pressures above their normal values. However the contour of  the left atrial pressure tracing relative to the LV pressure curve would not be significantly altered—as it is altered in this patient.

(Choice C) Mitral stenosis affects the hemodynamic profile during cardiac catheterization as shown below. Note the pressure gradient between the left atrium and left ventricle during diastole (arrows). (Choice E) Only the aortic and left ventricular pressure tracings in this patient have a grossly normal relationship. Educational Objective: An abnormally prominent (regurgitant) left atrial v wave during cardiac catheterization is a major hemodynamic finding indicative of mitral regurgitation.

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Q NO 104: Cardiac catheterization is performed in a 7-year-old Caucasian male, demonstrating the following pattern of oxygen saturation in cardiac chambers and outflow tracts.

The patient most likely has which of the following findings on physical examination? A. Decreased femoral-to-brachial blood pressure ratio B. Fixed splitting of S2 on cardiac auscultation C. Holosystolic murmur over the left sternal border D. Mucosal cyanosis and fingernail clubbing E. Machinery-like murmur over the upper precordium F. Spike-and-dome carotid pulse upstroke Explanation: This patient has undergone cardiac catheterization to detect a possible intracardiac shunt via the oximetric method. When a shunt is suspected, direct measurement of  the PO2 and O2 saturation (SO2) in both right heart chambers (right atrium [PA] right ventricle [RV] and the pulmonary artery is performed. In normal individuals 302 is identical in these locations. However, this patient has an abnormal increase in 902 (an “oxygen step-up”) from the PA to the RV, indicating the presence of a leftto-right shunt. The most likely anatomic explanation is a ventricular septal defect (VSD)I which would allow left ventricular blood to enter the PV during systole. VSD is the most common congenital heart disease, accounting for about 25% of  cases. Most pediatric patients have small defects (restrictive defects), which produce high resistance to flow from the left side to the right side and thereby preserve a significant pressure gradient between the to ventricles. Turbulent, high-velocity blood flow across such a small VSD produces a loud holosystolic murmur best heard over the left sternal border in the third or fourth intercostal space. In larger (nonrestrictive) VSDs, this systolic murmur may be absent, due to decreased resistance across the VSD and a lower transseptal pressure gradient. (Choice A) A decreased femoral-to-brachial blood pressure ratio is found in congenital coarctation of the aorta. (Choice B) Fixed, wide splitting of S2 is present in patients with atrial septal defects (ASD). These lesions may produce SO2 increases from the vena cava to the PA but would not produce such an oxygen step-up from the PA to the PV. (Choice D) Mucosal cyanosis and fingernail clubbing could be observed in any of the cyanotic congenital heart diseases (e.g. transposition of the great vessels, truncus 66

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arteriosus, tetralogy of Fallot), or as late features of an atrial or ventricular septal defect (Eisenmenger’s syndrome). Transposition with a simultaneous VSD could produce oximetric findings on cardiac catheterization similar to those seen in this patient. However, transposition accounts for only about 5% of congenital heart disease cases, and would be a far rarer occurrence than an isolated VSD. Blood flow across the VSD in tetralogy is usually right to left as a result of pulmonic stenosis, thus producing an SO2 drop in the left ventricle. (Choice E) A precordial machinery-like murmur is a continuous murmur that occurs during both systole and most of diastole, and is heard in patients with patent ductus arteriosus (PDA). (Choice F) Spike-and-dome carotid pulse upstrokes are characteristic of hypertrophic obstructive cardiomyopathy, a condition associated with dynamic left ventricular outflow tract obstruction during systole. Hypertrophic obstructive cardiomyopathy would not alter the normally identical SO2 values in right-sided vessels and chambers. Educational Objective: A significant increase in blood oxygen saturation between two right-sided vessels or chambers indicates the presence of a left-to-right shunt. If such an oxygen step-up occurs from the IRA to the RV, a VSD is most likely responsible. VSD is the most common congenital heart disease. Small VSDs produce a holosystolic murmur that is loudest over the left mid-sternal border. Fixed splitting of S2 is f ound in patients with ASD. Aortic coarctation produces a decreased femoral-to-brachial blood pressure ratio. PDA produces a continuous systolic and diastolic, machinery-like murmur. The most common congenital heart disease producing early cyanosis is tetralogy of Fallot.

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Q NO 105: A 45-year-old Caucasian male presents to your office with abdominal discomfort and recent weight loss. Stool guaiac testis positive. If detected on further work-up, an ulcer in which of the following locations is most likely to be benign? A. Esophagus B. Stomach C. Duodenum D. Sigmoid colon E. Rectum Explanation: Gastrointestinal ulcers are defined as breaches of the alimentary tract mucosa that extend through the muscularis mucosae into the submucosa (or beyond). Those specifically designated as peptic ulcers are chronic lesions in areas exposed to acid and peptic juices: the most common locations of peptic ulcers include the proximal duodenum antral stomach, and gastroesophageal junction. Peptic ulcers are frequently associated with the presence of Helicobacter pylon, which increases the risk of developing gastric carcinoma five-fold. Colonization with this bacteria does not similarly elevate the risk of duodenal carcinoma, however. Adenocarcinoma of  the small intestine is an extremely rare neoplasm that appears to arise sporadically. (Choice A) Esophageal adenocarcinoma is typically associated with an ulcerated exophytic lesion at the gastroesophageal junction. Similarly, squamous cell carcinomas originate as plaque-like thickenings of the mucosa that may eventually become excavated and ulcerated. (Choice B) Gastric carcinoma is typically associated with a poorly defined, excavated ulcer bordered by irregular, heaped-up mucosa. (Choices D and E) Carcinomas of the distal colon tend to be annular lesions that result in “napkin-ring” constriction of the bowel, with heaped-up edges and an ulcerated central region. In addition, ulcerative colitis is associated with an increased risk of colorectal cancer. Accordingly, ulcers in the sigmoid colon and rectum are suspect for malignancy.

Educational Objective: Duodenal ulcers are not associated with an increased risk of carcinoma in the same location. In contrast, esophageal, gastric, and colorectal cancers are frequently identified as ulcerative lesions on endoscopy.

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Q NO 106: Patients with tetralogy of Fallot (TOE) may assume a squatting position during episodes of severe cyanosis and dyspnea (“tet spells”). The posture helps to:

A. Improve respirators muscle work B. Decrease pulmonary vascular resistance C. Increase systemic vascular resistance D. Decrease pulmonary flow E. Decrease left ventricular work load Explanation: Squatting increases the total systemic vascular resistance (SVR). In TOE, the amount of shunted blood bypassing the lungs decreases as the ratio SVR/PVR increases (where PVR denotes pulmonary vascular resistance). Thus, increases in SVR relative to PVR permit a greater fraction of the total cardiac output to pass through the lungs, improving arterial oxygenation. (Choice A) Squatting tends to increase intra-abdominal pressure, and thus would not decrease the work of breathing. (Choice B) In TOE the PVR is generally determined by the fixed infundibular stenosis in the right ventricular outflow tract. Thus, although squatting temporarily increases venous return it would be unlikely to affect PVR in these patients. In normal individuals, however squatting might decrease PVR somewhat, based on the increased pulmonary blood volume. (Choice D) Squatting increases SVR and decreases right-to-left shunting thereby increasing pulmonary blood flow. (Choice E) Since squatting simultaneously increases SVR and venous return, left ventricular (LV) stroke volume and mean arterial pressure both rise. Although there may also be a degree of reflex bradycardia, the net effect of increased LV preload and afterload would likely be to increase LV work done per unit time.

Educational Objective: In patients with TOE, squatting increases SVR and decreases right-to-left shunting, thereby increasing pulmonary blood flow. Squatting thus counteracts arterial desaturation during hypoxemic spells.

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Q NO 107: A 32-year-old Caucasian female who has suffered from progressive exertional dyspnea over several years dies suddenly. At autopsy her heart has the following appearance (RV = right ventricle, LV = left ventricle): This patient most likely suffered from:

A. Essential hypertension B. Dilated cardiomyopathy C. Primary pulmonary hypertension D. Myocardial infarction E. Acquired aortic stenosis F. Wolf-Parkinson-White syndrome

Explanation: The wall of the right ventricle (RV) is at least 2 cm in thickness and is markedly thicker than that of the left ventricle. In a normal heart, the RV thickness is 3-4 mm during diastole, and is significantly thinner than the LV wall during diastole (around 1 cm). Thus, this specimen demonstrates right ventricular hypertrophy (RVH). Cor pulmonale is defined as RVH (with or without congestive right heart failure) caused by pulmonary hypertension. Pulmonary hypertension can result from disease of the lung parenchyma or lung vasculature. The most common cause of pulmonary hypertension is obliteration of segments of the pulmonary vasculature by chronic obstructive pulmonary disease. However, in young women between the ages of 20 and 40, idiopathic (primary) pulmonary hypertension must be considered. In primary pulmonary hypertension, there is progressive proliferation of endothelial cells smooth muscle cells and intimal cells. There is striking medial hypertrophy of  arterioles and small arteries as well as concentric laminar intimal fibrosis. In some cases the lumina is narrowed to a pinpoint diameter. As with the patient in the vignette, patients may present first with dyspnea and fatigue. Respiratory distress, cyanosis and right ventricular hypertrophy ensue with death generally occurring within 2 to 5 years of the onset of decompensated cor pulmonale. (Choices A and E) Essential hypertension and aortic stenosis would cause left ventricular hypertrophy, not right ventricular hypertrophy. (Choice B) Dilated cardiomyopathy (DCM) typically increases the size of the four chambers of the heart. As is evident in the above gross specimen this patient’s left ventricular cavity is small or normal in size not enlarged. (Normal diameter at the level of the junction of the mitral valve with its chordae tendineae is 5 cm.) Moreover the LV here is relatively normal in shape (elliptical with a long axis about twice that of lateral short axis dimensions) which is not the case with LV dilatation. (Choice F) Wolf-Parkinson-White syndrome must be suspected in any case of sudden cardiac death in an otherwise healthy young individual. WPW is an electrophysiological abnormality of atrioventricular cardiac conduction and does not bear any consistent association with gross morphological changes to the ventricles. On histologic exam WPW shows small accessory atrioventricular impulse conduction pathway(s) anatomically separate from the AV node.

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Educational Objective: Under normal circumstances, the right ventricular (RV) thickness is between 3-4mm during diastole, significantly thinner than the left ventricular wall thickness (1 cm). RVH is a feature of cor pulmonale, a condition caused by pulmonary hypertension resulting from disease of the lung parenchyma or the pulmonary vasculature. In young females between the ages of 20 and 40, primary pulmonary hypertension may be responsible for cor pulmonale.

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Q NO 108: A 48-year-old Caucasian male presents with chest pain and syncope. Coronary arteriography demonstrates significant atherosclerotic involvement of  A. the left anterior descending and circumflex arteries. Which of the following cells provides major proliferative stimuli for the cellular components of atherosclerotic plaques? Neutrophils B. Eosinophils C. Mast cells D. Erythrocytes E. Platelets F. B lymphocytes Explanation: The pathogenesis of atherosclerotic plaques (atheromas) is thought to begin with endothelial cell injury, which results in endothelial cell dysfunction and/or exposure of subendothelial collagen (endothelial cell denudation). Exposure of subendothelial collagen promotes platelet adhesion, aggregation, and release of factors that promote migration of smooth muscle cells (SMC) from the media into the intima, as well as SMC proliferation. These factors include platelet-derived growth factor (PDGF) and transforming growth factor beta (TGF-13). PDGF is chemotactic and mitogenic for SMC. TGE-3 is chemotactic for SMC. (Choice A) Neutrophils do not appear to play a significant role in the chronic intimal inflammatory process that generates atheromas, nor do they release growth factors. (Choice B) Eosinophils do not play a significant role in the chronic intimal inflammatory process that generates atheromas. Rather, they are important in parasitic infections and IgE-mediated immune reactions. (Choice D) Erythrocytes are not known to release growth factors or mitogens that can cause SMC proliferation. (Choice F) B-lymphocytes are responsible for antibody production. Antibodies or auto-antibodies do not appear to play a role in the initiation or progression of  atherosclerosis. While cytokines released from B-lymphocytes may play a role in immune responses, they do not act as growth factors for SMC.

Educational Objective: In the pathogenesis of atherosclerotic plaques, release of PDGF by platelets adherent to areas of denuded vascular endothelium is thought to play an important role in promoting both the migration of SMC from the media into the intima, and their subsequent proliferation in the intima.

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Q NO 109: A 56-year-old male presents complaining of progressively worsening dyspnea. He says that he cannot walk more than few blocks without getting short of breath, and finds it particularly difficult to sleep while lying flat. He uses three pillows at night. The patient does not use tobacco, alcohol or drugs. He has been diagnosed with hypertension, but only takes his medication when he experiences headaches. His blood pressure today is 170/100mm Hg and his pulse is 80 beats per minute. On physical examination, there are basilar lung crackles bilaterally, jugular venous distention, and bilateral trace lower extremity edema. There is cardiomegaly on chest x-ray, and evidence of left ventricular hypertrophy on EKG. Echocardiogram shows significant pulmonary arterial hypertension. Which of the following is the most likely explanation for this patient’s pulmonary hypertension? Mechanical obstruction of the pulmonary arterial tree B. Hypoxia-induced pulmonary vasoconstriction C. Obliteration of the pulmonary vascular bed D. Inflammatory pulmonary vascular reaction E. Reactive vasoconstriction due to venous congestion F. Increased volume of flow and pressure in the pulmonary arteries

A.

Explanation: The patient in the vignette appears to have left sided heart failure (likely due to long-standing hypertension), which may have eventually led to pulmonary hypertension and right heart failure. Chronic hypertension is the most common cause of left ventricular (LV) diastolic dysfunction or hypertensive heart disease (HHD). HHD is characterized by concentric LV hypertrophy, which decreases LV diastolic compliance. As a result, steady state LV filling pressures rise to maintain stroke volume and cardiac output. Pulmonary venous pressures, and therefore pulmonary arterial pressures, increase as a result, causing pulmonary hypertension, which promotes the development of right sided heart failure. Additional mechanisms have been proposed to explain the pulmonary hypertension in chronic left-sided heart failure, including dysregulation of pulmonary vascular smooth muscle tone and structural remodeling of the pulmonary vasculature secondary to impaired nitric oxide availability and increased endothelin expression. A form of “reactive” pulmonary arterial vasoconstriction is thought to result. (Choice A) Mechanical obstruction of the pulmonary arterial tree occurs in massive pulmonary embolism. No features of the patient’s history or physical raise serious suspicion for pulmonary emboli. (Choices B and C) Hypoxia-induced vasoconstriction likely underlies the pathogenesis of pulmonary hypertension secondary to CCPD. Polycythemia and obliteration of the vasculature follow compounding the increase in pulmonary arterial pressure. The patient in the vignette appears to have left-sided heart failure (orthopnea, crackles) in addition to right-sided failure (elevated JVP and peripheral edema), rather than CCPD. Additionally, because he is nota smoker, CQPD is an unlikely diagnosis. (Choice D) Inflammatory pulmonary vascular reactions maybe seen in pulmonary vasculitides such as Wegener’s granulomatosis and Churg-Strauss syndrome. In rare instances, these may result in secondary pulmonary hypertension. (Choice F) Flow volume and pressure maybe increased in the pulmonary arteries in congenital heart diseases that cause left-to-right shunts. A large VSD will quickly cause pulmonary hypertension at young age, secondary to medial hyper trophy of 

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the pulmonary vasculature. An ASD will typically take longer to produce such effects, due to a lesser degree of volume and pressure overload. Educational Objective: Left ventricular dysfunction can lead to increased pulmonary arterial pressure. Reactive changes in the pulmonary vasculature (e.g. endothelial dysfunction resulting in vasoconstriction) may also contribute to pulmonary hypertension. Hypoxia-induced vasoconstriction probably plays the major role in the pathogenesis of pulmonary hypertension secondary to CC) PD.

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Q NO 110: A 44-year-old Caucasian male is successfully treated for infective endocarditis with a long course of antibiotics. Echocardiographic evaluation reveals significant aortic regurgitation as a consequence of the infection. A. Which of the following is the major hemodynamic compensation for this valvular abnormality? Increase in left ventricular afterload B. Increase in left ventricular preload C. Concentric left ventricular hypertrophy D. Sustained increase in heart rate E. Decrease in aortic elasticity Explanation: In a patient with relatively acute aortic regurgitation, the major hemodynamic adaptation to maintain cardiac output is an increase in the left ventricular end diastolic volume (EDV). Assuming no acute decrease in contractility, this preload increase allows forward LV stroke volume (FSV) in the new steady state to remain adequate, although reduced from normal. (Choice A) Left ventricular (LV) afterload is already increased in acute aortic regurgitation (AR), and is associated with a greatly increased LV total stroke volume and a widened pulse pressure. A further increase in afterload would increase the regurgitant stroke volume and further decrease the LV forward stroke volume (FSV), thereby further reducing cardiac output. This is why medical stabilization of patients with severe acute AR may include administration of a vasodilator (nitroprusside) in addition to an intravenous positive inotropic agent (dopamine or dobutamine). The vasodilator decreases after load in order to improve the FSV. (Choice C) Aortic regurgitation subjects the left ventricle (LV) to volume overload, not pressure overload. The adaptation to volume overload is eccentric hypertrophy, i.e. chamber dilation (due to increased end diastolic volume, EDV) with predominantly “in series synthesis” of new myocardial sarcomeres. Concentric hypertrophy, the response to pressure overload, involves “in parallel deposition” of  new sarcomeres, which produces net ventricular wall thickening and a reduction in ventricular chamber size (decreased EDV). Pressure overload may occur in aortic stenosis or systemic hypertension. (Choice D) This patient’s relatively acute aortic regurgitation (AR) would decrease the left ventricular forward stroke volume. The acute compensatory response to maintain cardiac output would include an increase heart rate. Patients with acute AR are usually tachycardic and poorly tolerant of lower heart rates. However this answer choice describes a sustained increase in heart rate. As the heart of a patient who survives acute AR adapts to volume overload, increased left ventricular end diastolic volume (LVEDV) and eccentric LV hypertrophy result in progressive increases in LV forward stroke volume. Heart rate therefore returns toward normal in chronic AR, so that sustained tachycardia is not the major final hemodynamic compensation. (Choice E) A decrease in aortic elasticity would tend to increase afterload. An increase in afterload would further decrease net left ventricular (cardiac) output.

Educational Objective: An increase in left ventricular preload (LV end-diastolic volume) in association with eccentric LV hypertrophy is the major lasting hemodynamic compensation to the volume overload of aortic regurgitation.

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Q NO 111: A 34-year-old female experiences nausea, abdominal pain and dizziness after a minor surgical procedure. One year ago, she was diagnosed with systemic lupus erythematosus (SLE) with significant renal involvement, and she has been on chronic corticosteroid therapy since that time. Her blood pressure is now 70/40 mmHg and her heart rate is 120 beats per minute. Which of the following changes in CRH, ACTH, and cortisol are most likely responsible for this patient’s symptoms?

A. B. C. D. E.

CRH Increased Increased Increased Decreased Decreased

ACTH Increased Increased Decreased Decreased Decreased

Cortisol Increased Decreased Decreased Increased Decreased

Explanation: The clinical features described in this vignette are suggestive of central adrenal insufficiency secondary to long-term pharmacological doses of glucocorticoids. Patients using pharmacological (i.e. in excess of physiological levels) doses of  glucocorticoids for more than 3 weeks are likely to develop hypothalamic-pituitaryadrenal (HPA) axis suppression. Biochemically HPA axis suppression is characterized by low CRH, low ACTHI and low cortisol. The level of HPA axis suppression depends upon the type and potency of glucocorticoid used. More potent glucocorticoids used for longer durations are more likely to cause suppression, whereas topical glucocorticoids (i.e. very low systemic doses) are less likely to produce suppression of the HPA axis. When pharmacological doses of glucocorticoid therapy are used for more than three weeks duration, treatment cessation should be gradual (i.e. a steroid taper) to prevent development of adrenal insufficiency. Rapid withdrawal of glucocorticoids after prolonged use can cause acute adrenal crisis in patients, especially those under stressful situations (i.e. infections, surgery). Cortisol plays an important cardiovascular role during stress. In normal individuals, there is a 3- to 9-fold increase in the level of endogenous glucocorticoids during stressful situations. In a patient with a suppressed HPA axis, this response is lacking. The patient in this vignette shows signs and symptoms of adrenal crisis (likely precipitated by her surgical procedure), characterized clinically by nausea, vomiting, hypotension, and tachycardia. (Choice B) In this choice CRH and ACTH are increased and cortisol is decreased, a pattern suggestive of a primary adrenocortical problem. Damage to the adrenal glands by an autoimmune process or infection can lead to primary hypoadrenalism. This causes an increase in CRH and ACTH via loss of negative feedback inhibition due to low serum cortisol levels. (Choice C) In this choice CRH is increased while ACTH and cortisol are decreased, a pattern suggestive of a primary pituitary problem. ACTH is secreted by the corticotrophs of the anterior pituitary. Damage to the pituitary gland by tumor, infarction or infection can cause decreased release of ACTHI which in turn leads to decreased cortisol production. (ACTH has a trophic effect on adrenocortical cells.) Decreases in cortisol increase hypothalamic CRH release. Here, however, the pituitary cannot respond with an increase in ACTH release because it is damaged. (Choice D) This scenario is suggestive of autonomous production of cortisol from an adrenal adenoma. Excessive cortisol production from an adrenal adenoma suppresses CRH and ACTH production by the hypothalamus and pituitary, respectively. 76

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Educational Objective: Depression of the entire hypothalamus-pituitary-adrenal axis by glucocorticoid therapy is the most common cause of adrenal insufficiency.

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Q NO 112: A 79-year-old male presents to your office with “aching bones.” He says that the pain is most pronounced in his back, pelvis, and lower extremities. Pain is dull and increases after weight bearing activities. He was diagnosed with actinic keratosis one year ago. and he has been avoiding sunlight religiously. After a thorough evaluation of this patient, you recommend him to spend about 15 minutes a day in the outdoors. Which of the following reactions of vitamin D metabolism underlies your recommendation?

A. B. C. D.

A B C D

Explanation: On exposure to sunlight1 7-dehydrocholesterol found in the skin (also called provitamin D3) absorbs ultraviolet-B rays from the sun. Rays with a wavelength between 290 and 350 nm open up the B-ring of 7-dehydrocholesterol, forming previtamin D3, which then undergoes thermal isomerization to form vitamin D3, or cholecalciferol. Excessive sunlight exposure, however, shunts previtamin D3to a pathway that forms inactive products, such as tachysterol and lumisterol, as a protective mechanism against excessive vitamin D. Too much vitamin D might cause electrolyte imbalances, renal stones, renal failure, and ectopic calcium deposition— paradoxically, it might also cause osteoporosis secondary to the excessive mobilization of bone minerals. On the other hand, there is no physiological mechanism to protect against too little vitamin D formation. Inadequate vitamin D is common in older patients and was even demonstrated in a number of younger hospitalized patients in a recent study. Factors that discourage vitamin D formation in the skin include dark coloring (melanin prevents the conversion of 7-dehydrocholesterol to previtamin D3), the use of sunscreen, old age, and a northern latitude. People living in northern latitudes do not form sufficient vitamin D, even with exposure to sunlight during winter months. The very oblique angle of the winter sun at northern latitudes allows penetration of  the atmosphere from only low energy ultraviolet-B rays. (Choice B) After entering the circulation, vitamin D (D2 and D3) undergoes two hydroxylation steps to form 1, 25- dihydroxy vitamin D. The first hydroxylation step occurs in the liver: cytochrome P450 25-hydroxylase converts vitamin D into 2578

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hydroxy vitamin D (calcidiol). The conversion of vitamin D to 25-hydroxy vitamin D is not tightly regulated; therefore, circulating 25-hydroxy vitamin D measurements accurately reflect the status of dietary and skin production of vitamin D and can be used to assess vitamin D deficiency. (Choices C and D) 25-hydroxy vitamin D is metabolically inactive and is converted to the active form by the next hydroxylation step which is performed by the kidney enzyme 1-alpha hydroxylase. Circulating parathyroid hormone (PTH) also augments the conversion of 25-hydroxy vitamin D to 1, 25-dihydroxy vitamin D. In the case of  1 25- dihydroxy vitamin D excess, kidneys have the enzyme 24-hydroxylase, which converts 25-hydrcxxyvitamin D to biologically-inactive 24, 25-dihyrox vitamin D. Educational Objective: Sunlight exposure catalyses the first reaction in the chain of active vitamin D synthesis: 7-dehydrocholesterol transforms to cholecalciferol (Vitamin D3). Then, 25-hydroxlation occurs in the liver and the kidney enzyme 1-alpha hydroxylase catalyzes the final step in the synthesis of active vitamin D.

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Q NO 113: A 34-year-old male who suffers from severe renal disease has a low serum calcium level. Further evaluation reveals an increased serum PTH level. Which of the following reactions of active vitamin D synthesis is most likely impaired in this patient (see graph)?

A. B. C. D.

A B C D

Explanation: On exposure to sunlight1 7-dehydrocholesterol——or provitamin D3—present in the skin absorbs ultraviolet-B rays from the sun. Rays between wavelengths of 290 and 350 nm open up the B-ring of 7-dehydrocholesterol, forming previtamin D3, which in turn undergoes isomerization induced by heat to form vitamin D3, or cholecalciferol. At this point either physiologically-produced D3 or plant-derived D2 will undergo two hydroxylation steps to form 1, 25- dihydroxyvitamin D, the active form of vitamin D. (Choice B) The first hydroxylation step occurs in the liver; the cytochrome P450 enzyme 25-hydroxylase converts vitamin D into 25-hydroxyvitamin D (calcidiol). (Choice D) Twenty-five-hydroxy vitamin D is metabolically inactive and must undergo one more hydroxylation step to become active; this final step is catalyzed by the kidney enzyme 1-alpha hydroxylase. Circulating parathyroid hormone (PTH) also encourages the conversion of 25-hydroxy vitamin D to 1, 25-dihydroxy vitamin D. If 1, 25-dihydroxy vitamin D excess occurs, kidneys have the enzyme 24hydrox’ylase, which converts 25-hydroxy vitamin D to biologically inactive 24, 25dihyroxy vitamin D. Excess vitamin D can cause electrolyte imbalances and kidney problems. The kidneys play a pivotal role in calcium metabolism. Chronic renal failure impairs the excretion of phosphorous, so hyperphosphatemia is commonly seen in these patients. In chronic kidney disease, the conversion of 25-hydroxy vitamin D to 1 , 25-dihydroxyvitamin D is impaired, so levels of active vitamin D decline. This stimulates PTH release; a decrease in serum calcium and hyperphosphatemia are also important in augmenting the increase in PTH. The compensatory PTH increase in renal failure is called “secondary hyperparathyroidism.” High levels of PTH are required to maintain calcium levels in patients with chronic renal failure. PTH increases serum calcium by the following three mechanisms: 1. Increasing bone resorption by osteoclastic activation, leading to an increase in efflux of calcium from bone to circulation 2. Increasing the renal absorption of calcium, and 80

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3. Increasing the formation of 1, 25-dihydroxy vitamin D. The secretion of PTH is directly suppressed by circulating levels of 1, 25 dihydroxyvitamin D. Educational Objective: One-alpha-hydroxylation transforms calcidiol to calcitriol in the renal tubules. In chronic kidney disease, the conversion of 25-hydroxyvitamin D to 1,25dihydroxyvitamin D is impaired, leading to decreased circulating levels of 1,25dihydroxyvitamin D. Low levels of the active form of vitamin D cause an increase in circulating PTHI called “secondary hyperparathyroidism.” Note that 24, 25dihydrocholecalciferol is an inactive substance.

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Q NO 114: Liver biopsy of 45-year-old Caucasian female with fatigue that developed over the course of a year and pale stool reveals dilated bile canaliculi with green-brown plugs and brawny pigmented hepatic parenchyma. Which of the following is the most likely associated condition in this patient? Seborrhea C. Osteomalacia D. Amnesia and confabulations E. Gastric atrophy F. Hypochromic anemia

A. Cardiac dilation B.

Explanation: Cholestasis can arise secondary to hepatocellular dysfunction or biliary obstruction, whether intrahepatic or extrahepatic. Both obstructive and nonobstructive cholestasis are characterized by the deposition of bile pigment within the hepatic parenchyma and the presence of green-brown plugs in the dilated bile canaliculi. When prolonged, this reduction in bile flow causes intestinal malabsorption and nutritional deficiencies of the fat-soluble vitamins (A, D, E and K) in particular. Therefore those conditions associated with fat-soluble vitamin deficiency—such as osteomalacia —would be most likely in a patient with prolonged cholestasis. Osteomalacia is one of the most common causes of reduced bone density and, in adults, is characterized by disordered mineralization of the newly formed bone matrix. (Choice A) Cardiac dilation can result from a number of causes, including viral myocarditis, immunological abnormalities, and familial or genetic factors. (Choice B) Seborrhea, also termed seborrheic dermatitis, is a chronic inflammatory condition characterized by the accumulation of scaly, greasy skin on the scalp, face, ears, and eyelids and eyebrows. Although seborrhea is not associated with cholestasis, xanthomas (cholesterol deposits in the skin) are. (Choice D) Amnesia and confabulations are findings commonly associated with Wernicke-Korsakoff syndrome, a condition seen in thiamine-deficient alcoholics. (Choice E) Gastric atrophy is commonly associated with chronic gastritis, a condition that may be caused by H. pylori infection pernicious anemia radiation and granulomatous conditions. (Choice F) Hypochromic anemia describes a state in which the circulating red blood cell mass is reduced below normal limits and demonstrates decreased hemoglobinization. It can arise secondary to a variety of conditions including iron deficiency anemia and thalassemia.

Educational Objective: Digestive disorders such as cholestasis can result in malabsorption and nutritional deficiencies of the fat-soluble vitamins leading to conditions such as osteomalacia (which is frequently associated with a deficiency of the fat soluble vitamin D).

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Q NO 115: A 60-year-oldfemale is being evaluated for weight gain and fatigue. After the initial laboratory valuation you decide to proceed with a metyrapone stimulation test. The changes in urinary 17-hydroxy-corticosteroid (17-OHS) excretion following metyrapone administration are shown on the graph below. Which of the following is most likely responsible for these findings?

A. Vasopressin overproduction B. ACTH surge C. Renin suppression D. Cortisol surge E. Aldosterone suppression

Explanation: Like most hormones cortisol secretion is regulated via a feedback loop. ACTH stimulates cortisol secretion from the zona fasciculata of the adrenal cortex. ACTH is itself regulated by CRH and arginine vasopressin from the hypothalamus. Cortisol suppresses both ACTH and CRH secretion in a negative feedback loop. Decreases in cortisol lead to increases in ACTH and CRH secretion from the pituitary and hypothalamus, respectively. Metyrapone testing is indicated when there is suspicion of an interruption in the hypothalamic-pituitary-adrenal (HPA) feedback loop. Metyrapone blocks cortisol synthesis by inhibiting the enzyme 11-β-hydroxylase, which is responsible for the conversion of 11-β-deoxycortisol to cortisol (see enzymatic pathway). Thus with metyrapone administration, serum cortisol levels are reduced, stimulating pituitary secretion of ACTH. In this setting, the high ACTH level stimulates the adrenal gland to produce more deoxycortisol (since cortisol cannot be produced due to inhibition of 11- 3-hydrorylase). Unlike cortisol, 11-deorycotsol does not cause feedback inhibition of pituitary ACTH production. 11- deoxycortisol metabolites are measurable in the urine as 11-hydroxy-corticosteroids. If the HPA axis is normal, administration of metyrapone will cause a significant increase in 11deorvcortisol in serum and 11-hydroxycorticosteroids in urine. The graph shows that following administration of metyrapone, there is a significant increase in urinary 11hydrox-corticosteroid secretion, indicating a normal HPA axis. (Choice A) Vasopressin is a hormone secreted by the posterior pituitary that is responsible for regulating water balance. Vasopressin causes absorption of water from the distal and collecting tubules in the kidney. Additionally, vasopressin stimulates pituitary ACTH secretion. However there is no clear feedback loop between cortisol and vasopressin. Thus vasopressin overproduction is unlikely to be responsible for increase in 17-hydroxy- corticosteroids in urine. (Choices C and E) Short-term decreases in cortisol will have minimal effects on renin production. The renin angiotensin system regulates aldosterone production by the zona glomerulosa. The zona glomerulosa lacks the enzyme 17-hydroxylase and therefore cannot synthesize cortisol. There is no significant effect of metyrapone on the aldosterone pathway. (Choice D) During metyrapone testing serum cortisol should significantly decrease not increase. Educational Objective: An ACTH surge with a resultant increase in steroid halfproduct excretion is a normal reaction to metyrapone administration because metyrapone blocks the last step of cortisol synthesis. 83

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Q NO 116: A 14-year-old female presents to your office complaining of intermittent shortness of breath. She is unable to link the episodes to specific events or exposures. Physical examination is normal and her FEV1/FVC ratio is 83%. Which of  the following would be most useful in excluding asthma in this patient?

A. Normal chest X-ray B. Negative methacholine challenge C. Absence of eosinophilia D. Normal serum IgE E. Negative skin tests to various allergens

Explanation: This patient is unable to link her symptoms to allergen exposures, the most common cause of asthma. Moreover, her FEV1/FVC ratio is close to normal (around 80%). In asthmatics FEV1/FVC is often reduced due to increased expiratory airflow resistance. The clinical suspicion here is reasonably low, thus, a test to rule out the diagnosis of  asthma would be appropriate. While there are few, if any, specific tests that can confirm (rule in) a diagnosis of  asthma, bronchial challenge testing is a highly sensitive but non-specific measure that can help exclude the diagnosis. Bronchial challenge testing assesses bronchial 84

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hyperreactivity (BHFR) a central pathophysiological feature of asthma. BHR can be quantified as the concentration of an inhaled aerosolized bronchoconstrictive substance required to produce a 20% decline in FEV1. Methacholine, a cholinergic muscarinic agonist, is commonly used as the inhaled test substance. (Choice A) During an asthma attack, the lungs may appear hyperinflated on chest xray. However, chest x-rays are often normal between attacks. Thus, a normal chest x-ray would not exclude asthma as a diagnosis here. (Choice C) Although eosinophil counts may be elevated in asthmatics, the presence of eosinophilia is not a sensitive or specific indicator of asthma. Sputum eosinophilia would be a more sensitive test, as eosinophilic infiltration of the bronchial mucosa is a common pathologic finding in allergic asthma. (Choice D) Although serum IgE levels are generally elevated in patients with atopic (extrinsic allergic) asthma, patients with non-immune-mediated asthma have normal levels of serum IgE. These types of “intrinsic” asthma can be precipitated by pulmonary infections (especially viral), aspirin ingestion, cold air, inhaled irritants, stress, and/or exercise. (Choice E) Skin tests to various allergens are often reactive in patients with atopic (extrinsic allergic) asthma, because these patients are inherently predisposed to develop localized immediate Type I hypersensitivity reactions to a variety of inhaled and ingested allergens. However, patients with intrinsic asthma would not have this predisposition to skin test allergen reactivity. Educational Objective: Airway challenge testing with methacholine is a highly sensitive but nonspecific measure that can detect the degree of bronchial hyperreactivity in patients suspected of having asthma. A negative methacholine challenge test can help to exclude (rule out) the diagnosis. Chest x-ray, blood eosinophil count, serum IgE level, and skin reactivity to various allergens are less sensitive; normal findings on these tests cannot exclude the diagnosis.

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Q NO 117: A 50-year-old female presents with abdominal pain, diarrhea, and weight loss. She was diagnosed with diabetes mellitus two months ago. Her A. serum somatostatin level is highly elevated. Further evaluation reveals biliary stones. Suppression of which of the following hormones is most likely responsible for biliary stones? Secretin B. Cholecystokinin C. Glucagon D. Insulin E. Gastrin F. Growth hormone Explanation: The term somatostatin was originally applied to the 14-aminoacid cyclic peptide that is secreted by the hypothalamus and that inhibits the production of growth hormone from the anterior pituitary gland. Somatostatin is now known to be secreted from other parts of the central nervous system and from pancreatic delta cells. Somatostatin secreted from pancreatic “delta cells” decreases the secretion of  secretin, cholecystokinin, glucagon, insulin, and gastrin. Somatostatinomas are rare pancreatic islet cell tumors that arise from delta cells. Patients with somatostatinomas present with hyperglycemia or hypoglycemia, steatorrhea (excessive fat in the feces), and gallbladder stones. Gallbladder stones form because of poor gallbladder contractility, which is secondary to inhibition of cholecystokinin release. (Choices C and D) Somatostatin decreases the release of glucagon as well as insulin. However, the secretion of insulin is more profoundly inhibited than is glucagon; therefore, the net result is hyperglycemia. (Choice A) Steatorrhea results from the decreased secretion of secretin as well as a decrease in gastrointestinal motility. (Choice E) A decrease in gastrin release causes hypochlorhydria. (Choice F) As indicated above somatostatin does decrease growth hormone secretion from the normal pituitary gland, and it does so in growth-hormone-secreting pituitary adenomas. However, somatostatin cannot be used in clinical practice because of its extremely short half-life. Somatostatin analogs (octreotide and lanreotide) have a longer plasma half-life and are available for clinical use.

Educational Objective: Reduced gallbladder contractility, due to decreased cholecystokinin secretion, is responsible for biliary stones in patients with somatostatinoma.

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