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KCUMB Step 1 Review in Biochemistry John Pelley, PhD Texas Tech HSC, Lubbock, TX [email protected] www.ttuhsc.edu/SOM/success 1. A 3-year-old African-American male has been diagnosed with malaria. He has become anemic after starting therapy with primaquine. Laboratory analysis reveals an increase in circulating reticulocytes and urine analysis reveals hemoglobinuria. Which of the following is the most likely cause of the hemoglobinuria? A. B. C. D. E. Defect in the β-globin chain Defect in β-globin chain synthesis Deficiency of glucose-6-phosphate dehydrogenase (G6PD) Inhibition of pyruvate kinase Reduced dietary iron absorption Correct Response Option C. G6PD deficiency reduces NADPH production by the pentose phosphate pathway. NADPH is required to maintain reduced glutathione during oxidative stress from primaquine. Incorrect Responses Option A This abnormality is characteristic of several diseases that are typically not caused by the use of medications, such as sickle cell disease, hemoglobin C disease, and β-thalassemia. Option B This feature is characteristic of β-thalassemia, an inherited hemolytic disease not caused by the use of medications. Option Primaquine does not inhibit pyruvate kinase. However, patients with a genetic deficiency of this enzyme would experience a hemolytic anemia. Option E Iron deficiency leads to anemia but not to hemoglobinuria. Also, primaquine does not affect the absorption of iron from the diet and would not cause iron deficiency anemia. 2. A 20-year-old male reports painful cramps during exercise. The cramps are usually followed by a red tint in his urine. Consumption of glucose containing electrolyte replacement drinks before exercising does not alleviate the symptoms. Additional tests indicate that he has a mild case of hemolytic anemia. The patient most likely has a deficiency of which of the following enzymes? A. B. C. D. E. Branching enzyme Glucose-6-phosphatase α-Glucosidase Liver phosphorylase Phosphofructokinase (PFK) Correct Response Option E. A deficiency of PFK blocks production of ATP from glycolysis producing painful cramps during exercise and rhabdomyolysis with concomitant myoglobinuria. It also reduces the half-life of red blood cells. Incorrect Responses Option A A deficiency of branching enzyme, Andersen's disease, produces cirrhosis of the liver due to abnormal branching of glycogen. Option B A deficiency of glucose-6-phosphatase, von Gierke's disease, produces massive hepatomegaly and fasting hypoglycemia within the first few months after birth. -glucosidase, Pompe's disease, produces cardiomegaly. This lysosomal disorder is generalized to all tissues, with the heart being the most vulnerable organ. Option D A deficiency of liver phosphorylase, Hers' disease, produces hepatomegaly, growth retardation, and fasting hypoglycemia. Symptoms improve with age and typically disappear by puberty. 3. A 1-year-old boy has liver cirrhosis and hypotonia. His urine is negative for reducing substances. What enzyme associated with carbohydrate metabolism is most likely causing this child’s condition? A. B. C. D. E. Aldolase B Galactose-1-phosphate uridyltransferase Glucose-6-phosphatase Glucosyl (4:6) transferase Liver phosphorylase Correct Response Option D (glucosyl (4:6) transferase) is correct. This child is exhibiting symptoms of type IV glycogen storage disease known as Andersen disease, a condition related to a deficiency of the glycogen branching enzyme glucosyl (4:6) transferase. This deficiency classically causes cirrhosis of the liver or cardiac tissue damage, usually with death occurring within the first 1 or 2 years of life. Incorrect Responses Option A (aldolase B) is incorrect. Deficiency of aldolase B, the enzyme that cleaves fructose 1phosphate, causes hereditary fructose intolerance and leads to fructose (a reducing sugar) in the urine. Option B (galactose-1-phosphate uridyltransferase) is incorrect. Deficiency of this enzyme, which is responsible for galactosemia, leads to the presence of galactose (a reducing sugar) in the urine. Option C (glucose-6-phosphatase) is incorrect. Glucose-6-phosphatase deficiency leads to type I glycogen storage disease (von Gierke disease). Key features of this condition include a massively enlarged liver (although usually without cirrhosis), severe hypoglycemia, and failure to thrive. Option E (liver phosphorylase) is incorrect. Deficiency of liver phosphorylase causes the rare type VI glycogen storage disease (Hers disease). The presenting symptoms of this type of glycogen storage disease are similar to those of type I disease, but typically the course of the condition is milder. 4. A 3-month-old boy has progressive hepatomegaly and mild fasting hypoglycemia. Laboratory studies show that when the boy is fasting lactic acidosis is absent. A biopsy of liver tissue shows that the glycogen granules have an abnormal structure. The patient most likely has a deficiency of what enzyme? A. B. C. D. E. Branching enzyme Debranching enzyme Glucose-6-phosphatase α-Glucosidase Liver phosphorylase Correct Response Option B (debranching enzyme) is correct. Debranching enzyme deficiency leads to Cori disease, which is characterized by hepatomegaly and hypoglycemia. Debranching enzyme is required for the proper metabolism of glycogen near its branch points. Without it, glycogenolysis ceases when all terminal chains are at branch points, and no further hydrolysis of glucose residues is possible. The absence of lactic acidosis implies that pyruvate is not being generated because of the slow operation of the glycolytic pathway. Treatment of Cori disease, a glycogen storage disease, involves avoidance of fasting and liberal access to dietary protein for gluconeogenesis. Incorrect Responses Option A (branching enzyme) is incorrect. Deficiency of branching enzyme leads to Andersen disease. The abnormal branching pattern (lack of branches) in the glycogen molecule is believed to result in cirrhosis of the liver. Affected patients typically present with failure to thrive within the first 18 months of life and die by 5 years of age. Option C (glucose-6-phosphatase) is incorrect. Deficiency of glucose-6-phosphatase leads to von Gierke disease, which affects the liver and kidneys. Children with this enzyme deficiency typically present at 3 to 4 months of age with massive hepatorenomegaly and fasting hypoglycemia. -glucosidase leads to Pompe disease, a lysosomal glycogen storage disease. This condition is generalized to all tissues; the heart is the most vulnerable organ. Option E (liver phosphorylase) is incorrect. Liver phosphorylase deficiency leads to Hers disease. This rare disease initially manifests in childhood as hepatomegaly and fasting hypoglycemia. Both symptoms improve with age and typically disappear by puberty. 5. A 2-month-old female infant has coarse facial features, mental retardation, corneal clouding, and hepatomegaly. Analysis of fibroblasts cultured from the patient most likely shows a deficiency in what enzyme? A. B. C. D. E. Glucosidase Hexosaminidase α-l-Iduronidase Phosphotransferase Sphingomyelinase Correct Response Option C (α-l-iduronidase) is correct. The infant has the classic features of Hurler syndrome, an autosomal recessive lysosomal storage disease caused by a deficiency of the enzyme α-l-iduronidase. This condition, which is classified as a mucopolysaccharidosis, leads to an accumulation of dermatan and heparan sulfate. Analysis of fibroblast cultures provides evidence for the presence or absence of many enzymes. Incorrect Responses -glucosidase causes Gaucher disease, an autosomal recessive condition that leads to the accumulation of glucocerebroside in reticuloendothelial cells (Gaucher cells). This disorder is the most frequent form of the sphingolipidoses and is characterized by splenomegaly, increased skin pigmentation, and bone lesions. Option B (hexosaminidase) is incorrect. A deficiency of hexosaminidase A results in the accumulation of GM2 ganglioside, which is seen in patients with Tay-Sachs disease and Sandhoff disease. Mental retardation and blindness are associated with both disorders, but they progress more rapidly in patients with Sandhoff disease. Option D (phosphotransferase) is incorrect. Loss of a phosphotransferase that tags lysosomal enzymes for compartmentation in lysosomes causes I-cell disease. Affected individuals have mental deterioration, skeletal deformities, and elevated lysosomal enzymes in the plasma and urine. Option E (sphingomyelinase) is incorrect. A deficiency of sphingomyelinase causes NiemannPick disease, an autosomal recessive disorder that leads to the accumulation of sphingomyelin. Signs of this disorder include an enlarged liver and spleen and mental retardation of rapid onset, usually within the first 6 months of life (type A disease). 6. A 25-year-old male medical student who has had diabetes mellitus since the age of 11 is unconscious when admitted to the emergency department. His wife suspects that he has not been injecting his insulin on a regular basis. His breath has a fruity odor and his blood glucose is 600 mg/dL. Glucose and ketone bodies are present in the urine. What substance is most responsible for the patient’s hyperglycemia? A. B. C. D. E. Cortisol Epinephrine Glucagon Growth hormone Thyroxine Correct Response Option C (glucagon) is correct. Glucagon is the principal hormone that stimulates liver glycogenolysis and gluconeogenesis, which are primarily responsible for maintaining the hyperglycemic state. Incorrect Responses Option A (cortisol) is incorrect. Cortisol functions in the liver to block insulin action, but this patient has not been taking his insulin. Option B (epinephrine) is incorrect. Epinephrine acts primarily on adipose tissue (free fatty acids) and skeletal muscle (glycogen) to mobilize energy. Neither of these tissues releases glucose. Option D (growth hormone) is incorrect. Growth hormone is not appreciably increased in the untreated diabetic. Option E (thyroxine) is incorrect. Thyroxine primarily functions in controlling metabolic rate and in regulating growth and development and is not altered in diabetic ketoacidosis. 7. A 5-year-old male has had psychomotor retardation and a chronic lactic acidosis since birth. His fasting blood glucose is 100 mg/dL and he is not anemic. Which of the following is most likely deficient in this patient? A Phosphoenolpyruvate carboxykinase B. Pyruvate carboxylase C. Pyruvate dehydrogenase D. Pyruvate kinase Correct Response Option C. The patient most likely has a deficiency of pyruvate dehydrogenase resulting in an accumulation of pyruvate with concomitant formation of lactate and reduced ATP production leading to nervous system dysfunction. Incorrect Responses Option A A deficiency of phosphoenolpyruvate carboxykinase, a gluconeogenic enzyme, results in hypoglycemia; this patient has a normal fasting blood glucose. Option B A deficiency of pyruvate carboxylase produces lactic acidosis, but it also causes fasting hypoglycemia and is frequently fatal by 6 months. Option D A deficiency of pyruvate kinase produces a hemolytic anemia; this patient has a normal hematocrit. Lactic acidosis is not a characteristic of this enzyme deficiency. 8. A 3-year-old male is brought to the pediatrician with failure-to-thrive. Physical examination of the patient reveals hepatomegaly. The fasting blood glucose is 30 mg/dL and no increase in the fasting blood glucose is seen with a glucagon challenge test is performed. The patient most likely has a deficiency of which of the following enzymes? A Aldolase B B. Fructokinase C. Galactokinase D. Galactose-1-phosphate uridyltransferase E. Glucose-6-phosphatase Correct Response Option E The patient has von Gierke’s disease which produces a fasting hypoglycemia. Accumulation of glycogen leads to hepatomegaly. Glucagon cannot increase in the fasting blood glucose. Incorrect Responses Option A A deficiency of aldolase B produces hereditary fructose intolerance. Fructose ingestion produces failure to thrive, hepatomegaly, and hypoglycemia, but the liver would show a normal response to glucagon. Option B A deficiency of fructokinase produces a benign, asymptomatic disease. The only symptom is an accumulation of fructose in the blood and urine. Option C Galactokinase deficiency produces cataracts due to an increased conversion of galactose to galactitol in the lens of the eye. Fasting blood glucose would be normal. Option D Deficiency of galactose-1-phosphate uridyltransferase produces classic galactosemia with poor weight gain, hepatosplenomegaly, cataracts, and vomiting. Fasting blood glucose would be normal. 9. An 18-year-old male has a history of episodes of jaundice since birth. Physical examination shows conjunctival pallor and splenomegaly. Blood analysis reveals slightly increased indirect bilirubin, no elevation of homocysteine, and normocytic anemia with increased peripheral blood reticulocytes. Numerous spiculated red blood cells (RBCs) are apparent in the peripheral smear. The patient most likely has impaired activity for which of the following enzymes? A Homocysteine methyltransferase B. Glucose-6-phosphate dehydrogenase (G6PD) C. Pyruvate dehydrogenase D. Pyruvate kinase Correct Response Option D Pyruvate kinase deficiency leads to a decrease in cellular ATP. Dehydration causes cells to appear spiculated and splenic removal of damaged cells increases unconjugated bilirubin. Incorrect Responses Incorrect Responses Option A The activity of homocysteine methyltransferase is impaired in either a folate or a B12 deficiency. This produces elevated blood homocysteine and a megaloblastic anemia instead of the normocytic anemia seen here. Option B G6PD deficiency leads to a deficiency of glutathione in RBCs producing anemia due to oxidant damage. RBCs do not show spiculation (due to dehydration) and splenomegaly is not a feature of the disease. Option C Pyruvate dehydrogenase deficiency does not cause a hemolytic anemia. Pyruvate dehydrogenase is a mitochondrial enzyme and RBCs do not contain mitochondria. 10. A 25-year-old male of Greek descent complains of prolonged fatigue after a recent illness. Blood analysis shows normocytic anemia and urine analysis shows hemoglobinuria. Which of the following is the most likely cause of this patient’s anemia? A decreased glutathione peroxidase activity B. iron deficiency C. folate deficiency D. reduced concentrations of ATP E. reduced concentrations of NADH Correct Response Option A Glutathione peroxidase activity is limited by reduced glutathione availability. This patient has a glucose 6-phosphate dehydrogenase deficiency and cannot maintain adequate reduced glutathione concentrations. Incorrect Responses Option B Iron deficiency would cause an anemia but not hemoglobinuria. Option C Folate deficiency would cause megaloblastic anemia without hemoglobinuria. Option D A pyruvate kinase deficiency would lead to energy deficient RBCs that are removed by the spleen. Splenomegaly and jaundice with spiculated RBCs are characteristic of this anemia. Option E NADH concentrations are already maintained at low concentrations. Instead, reduced concentrations of NADPH underlie the symptoms in this patient. 11. A 33-year-old female alcoholic complains of tiredness and disorientation approximately 6 hours after a cocktail party. Her blood glucose is at 25 mg/dL. Which of the following would you expect to find elevated in her bloodstream? A Ethanol B. Lactic acid C. Chylomicrons D. Acetate Correct Response Option B The metabolism of ethanol produces an excess of NADH that pushes pyruvate toward lactate removing it as a substrate for gluconeogenesis leading to a drop in blood glucose. Incorrect Responses Option A Ethanol would have been metabolised by the liver within 6 hours. Option C Chylomicron remnants would have been removed from the circulation by the liver within 6 hours. Option D Acetate produced from the oxidation of ethanol is further metabolized in the liver to acetylCoA. It would not build up and spill into the blood. 12. A 7 year old male was brought to the clinic by his mother with the complaint that he was having episodes of acting and talking “as if he were drunk.” These episodes occurred after stressful periods such as a febrile illness or fatigue. On examination the boy showed rapid breathing and rapid heart rate. Laboratory analysis showed elevated blood lactate and blood pyruvate, although the lactate to pyruvate ratio was normal. Blood pH was slightly acid at 7.30 (normal 7.35-7.45). Blood glucose and ketones were normal. No ragged red fibers were observed in a skeletal muscle biopsy. What is the most likely diagnosis? A B. C. D. hypoxia pyruvate carboxylase deficiency mitochondrial disease pyruvate dehydrogenase deficiency Correct Response Option D Pyruvate dehydrogenase deficiency results in the simultaneous appearance of lactate and pyruvate and the neurological symptoms observed. Incorrect Responses Option A Hypoxia would only elevate lactate. The simultaneous appearance of lactate and pyruvate indicate an inability to metabolize pyruvate. Option B Pyruvate carboxylase deficiency would be accompanied by hypoglycemia (the blood glucose was normal). Option C Mitochondrial disease is ruled out since ragged red fibers are absent 13. A 6 day-old female full term infant was brought to the emergency room with an enlarged liver, jaundice, failure-to-thrive, and urinary excretion of reducing sugars and albumin. Blood analysis showed a normal hemoglobin level and an elevated serum AST and ALT. Urinalysis with glucose oxidase was negative. She tolerated feeding with sucrose, maltose, glucose, and fructose at doses of 2 g/kg, but she vomited after lactose feeding. What other tissues will be affected by this disease? A B. C. D. E. Red blood cells spleen Heart muscle Lens of the eye CNS Correct Response Option D The reducing sugar with negative glucose oxidase indicates that this patient has galactosemia, a disease that produces cataracts. Incorrect Responses Option A The reducing sugar with negative glucose oxidase indicates that this patient has galactosemia, a disease that does not affect red blood cells. Option B The reducing sugar with negative glucose oxidase indicates that this patient has galactosemia, a disease that does not increase the activity of the spleen. Option C The reducing sugar with negative glucose oxidase indicates that this patient has galactosemia, a disease that does not affect the heart. Option E The reducing sugar with negative glucose oxidase indicates that this patient has galactosemia, a disease that does not affect CNS function. 14. A 56-year-old male complains of chest pain associated with shortness of breath and fatigue. A coronary angiogram indicates 85% blockage of the left anterior descending coronary artery. Which of the following pumps is most directly affected by this myocardial ischemia? A Calcium B. bicarbonate C. Potassium D. Proton E. Sodium Correct Response Option D Reduced blood flow to the heart slows mitochondrial electron transport and the proton pumps that are coupled to it since oxygen is the terminal electron acceptor of the electron-transport chain. This leads to a drop in the supply of ATP in the myocardium. Incorrect Responses Option A Reduced availability of oxygen most directly affects the proton pumps coupled to the electron transport chain. Eventually the decreasing supply of ATP affects the other active ion pumps such as the calcium pumps. Option B Reduced availability of oxygen most directly affects the proton pumps coupled to the electron transport chain. Bicarbonate is transported in exchange for chloride and does not require energy. Option C Reduced availability of oxygen most directly affects the proton pumps coupled to the electron transport chain. Eventually the decreasing supply of ATP affects the other active ion pumps such as the potassium pumps. Option E Reduced availability of oxygen most directly affects the proton pumps coupled to the electron transport chain. Eventually the decreasing supply of ATP affects the other active ion pumps such as the sodium pumps. 15. A 25-year-old male is brought to the emergency room after falling from a ladder. He has sustained a ruptured spleen and is going into hypovolemic shock as a result of blood loss. He is conscious and his respiratory rate is elevated. Which of the following biochemical processes is most likely increased in this patient? A anion gap B. electron transport chain C. Na+,K+ATPase D. citric acid cycle activity E. oxidative phosphorylation Correct Response Option A Anaerobic metabolism in the hypoxic peripheral tissues increases the production of lactic acid leading to a lactic acidosis anion gap. Incorrect Responses Option B Anaerobic metabolism in the hypoxic peripheral tissues reduces the amount of oxygen as a terminal electron acceptor and slows the electron transport chain. Option C Anaerobic metabolism in the hypoxic peripheral tissues results in decreased synthesis of ATP leading to a decrease in the ATP-dependent Na /K+ pump. Option D Anaerobic metabolism in the hypoxic peripheral tissues leads to an increase in NADH which allosterically inhibits isocitrate dehydrogenase, the rate controlling step in the citric acid cycle. Option E Anaerobic metabolism in the hypoxic peripheral tissues slows the flow of electrons through the electron transport chain which is tightly coupled to oxidative phosphorylation. 16. A 5 year old male is examined by his pediatrician for fatigue, nausea, and lightheadedness brought on when meals are skipped. Physical examination reveals hepatomegaly. Laboratory results indicate lactic acidosis, hyperlipidemia, elevated serum uric acid, and marked hypoglycemia. Administration of fructose did not result in conversion to glucose. What other organs would be expected to be enlarged? A kidney B. spleen C. heart D. brain E. skeletal muscle Correct Response Option A When the G6P concentrations increase due to the absence of the glucose 6-phosphatase enzyme, glycogen synthase is stimulated to synthesize additional glycogen and enlarging the kidney. Incorrect Responses Option B The spleen is not enlarged in Von Gierke’s disease. Option C Von Gierke’s disease is not characterized by heart enlargement. Heart muscle already lacks the glucose 6-phosphatase enzyme. Option D The brain does not store significant glycogen and would consume any excess glucose, thus preventing excess glycogen storage. Option E Skeletal muscle already lacks the glucose 6-phosphatase enzyme. 17. A 59 year old male complained during an annual physical exam of aching in his thighs during his 5 mile morning runs. No significant changes were made in the length or speed of the running schedule. He has a history of elevated blood lipids and has been taking a standard daily dose of a statin drug for the past two years. A routine laboratory profile was normal, but the creatine phosphokinase (CPK) value was elevated. What deficiency is created by the statin drug that is causing the symptoms? A isoprene B. cholesterol C. dehydroepiandrosterone D. vitamin D Correct Response Option A Ten isoprene units are needed to form the tail on Coenzyme Q10. A deficiency in isoprene in the cholesterol pathway would create a coenzyme Q10 deficiency and impair energy metabolism in muscle. Incorrect Responses Option B Statins lower cholesterol but do not create a deficiency. Option C The reduced synthesis of cholesterol with statin therapy is not sufficient to limit precursors for steroid hormone synthesis. Option D The reduced synthesis of cholesterol with statin therapy is not sufficient to limit precursors for vitamin D synthesis. 18. A 52-year-old man with chronic alcoholism has a plasma lipid profile that contains an increase in very-low-density lipoprotein (VLDL). The mechanism that best explains the increase in VLDL in both the blood and liver in chronic alcoholics is A. B. impaired function of apolipoprotein B-100 inactivation of capillary lipoprotein lipase C. D. increased β-oxidation of fatty acids increased synthesis of glycerol 3-phosphate Correct Response Option D (increased synthesis of glycerol 3-phosphate) is correct. Ethanol is metabolized in the liver and eventually forms acetate, with NADH as another major product. Chronic consumption of ethanol causes a shift in the cytosolic balance between NAD+ and NADH in favor of NADH. The altered NAD+/NADH ratio causes less effective operation of the citric acid cycle, halts efficient oxidation of fatty acids, and causes a shift from dihydroxyacetone phosphate to glyceraldehyde 3-phosphate and eventually to glycerol 3-phosphate. The abundance of glycerol and free fatty acids results in an increased production of triacylglycerol, with increased export from the liver as VLDL, and fatty liver. These conditions are often seen in chronic alcoholics. Incorrect Responses Option A (impaired function of apolipoprotein B-100) is incorrect. Alcohol consumption alone does not cause impairment of the function of any of the apolipoproteins. However, this impairment, which occurs in abetalipoproteinemia, does result in fatty liver. Option B (inactivation of capillary lipoprotein lipase) is incorrect. Alcohol consumption has not been shown to inhibit the activity of peripheral tissue lipoprotein lipase. Such inhibition leads to an increase in triacylglycerol levels in the plasma; it is a stimulus for hepatic production of VLDL. -oxidation of fatty acids) is incorrect. The reducing environment in the cell from the excess NADH+ leads to a decrease in the oxidation of fatty acids, as stated in the discussion of Option D. 19. A 3-month-old boy has rapidly progressive central nervous system (CNS) deterioration, spasticity, and failure to thrive. Physical examination is significant for marked hepatosplenomegaly. Liver biopsy shows an increase of sphingomyelin in the lysosomes. What enzyme is most likely deficient in this infant? A. B. C. D. Arylsulfatase A Hexosaminidase A Liver phosphorylase Sphingomyelinase Correct Response Option D (sphingomyelinase) is correct. A deficiency of sphingomyelinase causes Niemann-Pick disease, an autosomal recessive disease that results in the accumulation of sphingomyelin in the lysosomes. Signs of the disorder include an enlarged liver and spleen and mental retardation of rapid onset, usually within the first 6 months of life. Incorrect Responses Option A (arylsulfatase A) is incorrect. A deficiency of arylsulfatase A, which results in the accumulation of a sulfate-containing ceramide in the lysosomes, causes metachromatic leukodystrophy, an autosomal recessive disease. Mental retardation and demyelination are typical in patients with this deficiency. Option B (hexosaminidase A) is incorrect. A deficiency of hexosaminidase A results in the accumulation of GM2 ganglioside, which is seen in patients with Tay-Sachs disease and Sandhoff disease. Mental retardation and blindness are associated with both disorders, but they progress more rapidly in patients with Sandhoff disease. Option C (liver phosphorylase) is incorrect. A deficiency in liver phosphorylase causes Hers disease, an autosomal recessive disease that results in the inability of the liver to mobilize glucose from glycogen. Hepatomegaly is present, but there are no symptoms of CNS deterioration or failure to thrive, nor is sphingomyelin increased in lysosomes. 20. A 25-year-old woman sees her physician because of exhaustion and diarrhea. Physical examination shows that she has low blood pressure, and blood studies show that she is anemic. Other studies show that she has a tumor of the pituitary gland that could produce hypofunction. Which of the following metabolic conversions is most likely affected by this pituitary tumor? A. B. C. D. E. cortisol from cholic acid 7-dehydrocholesterol from cholesterol mevalonate from HMG CoA pregnenolone from cholesterol progesterone from pregnenolone Correct Response Option D (pregnenolone from cholesterol) is correct. The patient has signs of pituitary hypofunction (exhaustion, diarrhea, low blood pressure, and anemia) and is diagnosed with a tumor of the pituitary gland, in the sella turcica. Formation of pregnenolone from cholesterol is the rate-limiting step in the synthesis of steroid compounds. It is regulated by the action of ACTH on the cytochrome P450 sidechain cleavage enzyme. Incorrect Responses Option A (cortisol from cholic acid) is incorrect. Cholic acid, a bile salt, is not found in the steroid pathway. Option B (7-dehydrocholesterol from cholesterol) is incorrect. The sterol 7-dehydrocholesterol is an intermediate substance in the conversion of lanosterol to cholesterol. It accumulates in the skin as a precursor to cholecalciferol (vitamin D3). Option C (mevalonate from HMG CoA) is incorrect. HMG-CoA reductase is the rate-limiting step in cholesterol synthesis, not steroid hormone synthesis. Option E (progesterone from pregnenolone) is incorrect. Formation of progesterone from pregnenolone is not directly affected by loss of ACTH. 21. A 3-year-old girl who is listless about 4 hours after eating is found to have a deficiency of carnitine. What substrate is most likely the child’s primary energy source? A. B. C. D. E. Branched-chain amino acids Fatty acids Fructose Glucose Ketone bodies Correct Response Option D (glucose) is correct. This child is lethargic, although the mobilization of free fatty acids from adipose tissue and -oxidation in the liver is occurring. The lack of carnitine causes the carnitine shuttle, which transports fatty acids from the cytosol to the mitochondrial matrix, to be inoperative. Therefore, 12 ATP derived from acetyl CoA, 3 ATP from NADH, and 2 ATP from FADH2 are not available. Therefore, the child is subsisting primarily on glucose derived from glycogenolysis as the primary source of energy for all tissues. Gluconeogenesis is suppressed because it relies on fatty acid catabolism as an energy source. This condition produces hypoglycemia. Treatment often involves fatty acids that contain less than 12 carbons, which can pass directly into the mitochondria without the carnitine shuttle. Incorrect Responses Option A (branched-chain amino acids) is incorrect. The metabolism of branched-chain amino acids supplies succinyl CoA for gluconeogenesis. However, without the ATP supplied by fatty acid oxidation, gluconeogenesis cannot operate optimally. Option B (fatty acids) is incorrect. Without carnitine, fatty acids with more than 12 carbons cannot enter the mitochondria to be oxidized to acetyl CoA; therefore, they provide no energy. Option C (fructose) is incorrect. The body does not store fructose in appreciable quantities to supply energy during fasting conditions. Option E (ketone bodies) is incorrect. Ketone bodies are produced from large excesses of acetyl CoA (i.e., from oxidation of fatty acids). Because carnitine is not available to shuttle fatty acids into the mitochondrion, no ketone bodies are produced in the liver. 22. A 22-year-old woman with poorly controlled gestational diabetes delivers a large-for-gestational age infant at 24 weeks. Within 6 hours after birth, the newborn has respiratory difficulties associated with tachypnea and cyanosis. What substance is most likely deficient in this newborn? A. B. C. D. E. Cardiolipin Ceramide Dipalmitoyl phosphatidylcholine Ganglioside Sphingomyelin Correct Response Option C (dipalmitoyl phosphatidylcholine) is correct. The newborn has respiratory distress syndrome (RDS), which is caused by a lack of production of lung surfactant by type II pneumocytes in the lungs. Dipalmitoyl phosphatidylcholine (lecithin), the primary lung surfactant, reduces surface tension, preventing the collapse of alveoli. RDS is very common in premature infants (usually <32 weeks' gestation) because of lung immaturity. Additionally, RDS frequently occurs in infants born to diabetic mothers as the result of fetal hyperglycemia and hyperinsulinemia, which delay surfactant production. Incorrect Responses Option A (cardiolipin) is incorrect. Cardiolipins are lipids that occur in high concentration in the inner mitochondrial membrane. Option B (ceramide) is incorrect. Ceramide, which is a precursor to sphingomyelin and ganglioside, occurs primarily in the myelin sheath. Option D (ganglioside) is incorrect. Gangliosides are cerebrosides that occur in myelin. Option E (sphingomyelin) is incorrect. Sphingomyelins occur in nerve tissue and blood. 23. A 3-year-old child has ambiguous genitalia, diffuse pigmentation, and hypertension. Laboratory studies show an increase in plasma adrenocorticotropic hormone, a decrease in serum cortisol, and an increase in urine 17-ketosteroids. Chromosome analysis shows an XX genotype. What enzyme involved in adrenal steroid synthesis is most likely deficient in this patient? A. B. C. D. 11β-Hydroxylase 17α-Hydroxylase 18-Hydroxylase 21-Hydroxylase Correct Response Option A (11β-hydroxylase) is correct. This child has adrenogenital syndrome, which consists of a group of autosomal recessive conditions that involve enzyme deficiencies in adrenal steroid synthesis, leading to hypocortisolism. A deficiency of 11β-hydroxylase results in an increase in steroid compounds proximal to the enzyme block and a decrease in those compounds distal to the block. Levels of the 17ketosteroids dehydroepiandrosterone and androstenedione are increased because they are proximal to the block. Androstenedione is converted to testosterone, which is converted to dihydrotestosterone by 5αreductase. Dihydrotestosterone is primarily responsible for producing ambiguous genitalia in females. 11Deoxycortisol is increased, because it is proximal to the enzyme block, and cortisol is decreased, because it is distal to the block. There is also an increase in 11-deoxycorticosterone, a weak mineralocorticoid that is responsible for salt retention, leading to hypertension. Incorrect Responses -Hydroxylase is responsible for the conversion of pregnenolone to 17-hydroxypregnenolone and progesterone to 17-hydroxyprogesterone. Each compound is again converted to 17-ketosteroids. Because the 17-ketosteroi hydroxylase deficiency is not a possible cause of the symptoms. Option C (18-hydroxylase) is incorrect. 18-Hydroxylase, which converts corticosterone to aldosterone, does not cause hypocortisolism or any of the symptoms evident in this patient. Option D (21-hydroxylase) is incorrect. In 21-hydroxylase deficiency, the 17-ketosteroids are increased, but the 17-hydroxycorticoids and the mineralocorticoid compounds (11-deoxycorticosterone, corticosterone, and aldosterone) are decreased. Mineralocorticoid deficiency leads to the loss of sodium in the urine and retention of potassium in the blood. Sodium loss results in hypotension, not hypertension. 24. A 1-year-old child has hypertension, diffuse pigmentation, and female external genitalia. A chromosome analysis shows an XY genotype. The plasma adrenocorticotropic hormone concentration is increased, serum cortisol is decreased, and a random urine potassium is increased. What enzyme involved in adrenal steroid synthesis is most likely deficient in this patient? A. B. C. D. 11 -Hydroxylase 17 -Hydroxylase 18-Hydroxylase 21-Hydroxylase Correct Response Option B (17 -hydroxylase) is correct. The child has adrenogenital syndrome, which consists of a group of autosomal recessive conditions that involve enzyme deficiencies in adrenal steroid synthesis, leading to hypocortisolism. 17 -Hydroxylase converts pregnenolone and progesterone to 17 hydroxypregnenolone and 17-hydroxyprogesterone, respectively, which are further converted to the ketosteroids dehydroepiandrosterone and androstenedione. Androstenedione is converted to dihydrotestosterone, a strong androgen. Without the stimulation of dihydrotestosterone, the external genitalia in a male fetus has the appearance of a female. Therefore, this patient, who has an XY genotype and external female genitalia, is a male pseudohermaphrodite. Cortisol is decreased because it is distal to the block. Hypocortisolism causes an increase in adrenocorticotropic hormone (loss of negative feedback), resulting in excessive stimulation of the adrenal cortex (bilateral hyperplasia) and an accumulation of compounds proximal to the enzyme block. Because 17 -hydroxylase is not involved in mineralocorticoid synthesis, 11-deoxycorticosterone, corticosterone, and aldosterone are all increased, leading to sodium retention and hypertension. Incorrect Responses -hydroxylase leads to an increase in 11-deoxycortisol (a 17-hydroxycorticoid); 17-ketosteroids; testosterone; dihydrotestosterone (ambiguous genitalia in females, precocious puberty in males); and 11-deoxycorticosterone, a weak mineralocorticoid that leads to salt retention and hypertension. Option C (18-hydroxylase) is incorrect. 18-Hydroxylase converts corticosterone to aldosterone. Absence of 18-hydroxylase would not cause hypocortisolism or any of the symptoms evident in this patient. Option D (21-hydroxylase) is incorrect. A deficiency of 21-hydroxylase in females leads to ambiguous genitalia (female pseudohermaphroditism) and to precocious puberty in males. The 17hydroxycorticoids (11-deoxycortisol and cortisol) and all mineralocorticoids are decreased, because they are distal to the enzyme block. Loss of mineralocorticoid activity leads to sodium loss in the urine, volume depletion, and hypotension. 25. A 23-year-old woman has just eaten a meal consisting mainly of carbohydrates. What best describes the activity of capillary lipoprotein lipase and hormone-sensitive lipase in the adipose tissue of this individual? A. B. C. D. Decreased capillary lipoprotein lipase Decreased capillary lipoprotein lipase Increased capillary lipoprotein lipase Increased capillary lipoprotein lipase Decreased hormone-sensitive lipase Increased hormone-sensitive lipase Decreased hormone-sensitive lipase Increased hormone-sensitive lipase Correct Response Option C (increased capillary lipoprotein lipase; decreased hormone-sensitive lipase) is correct. In the well-fed state, insulin stimulates the synthesis of capillary lipoprotein lipase, and apolipoprotein CII activates the enzyme. These actions result in hydrolysis of circulating chylomicrons derived from the diet and very-low-density lipoprotein synthesized in the liver, causing the release of fatty acids and monoglycerides. Insulin inactivates hormone-sensitive lipase in adipose tissue by activating phosphatase, which dephosphorylates the enzyme. Incorrect Responses Option A (both capillary lipoprotein lipase and hormone-sensitive lipase are decreased) and Option D (both capillary lipoprotein lipase and hormone-sensitive lipase are increased) are incorrect. Neither type of lipase in the adipose tissue of this individual is decreased nor increased at the same time, because capillary lipoprotein lipase is associated with fat storage and hormone-sensitive lipase is associated with fat mobilization. Option B (decreased capillary lipoprotein lipase and increased hormone-sensitive lipase) is incorrect. In the fasting state, capillary lipoprotein lipase activity is decreased, whereas hormone-sensitive lipase is increased via activation by epinephrine and absence of insulin. This releases fatty acids and glycerol into the circulation. 26. A 75-year-old man develops urinary retention. Findings on physical examination include an enlarged, soft prostate gland and a bladder that is distended to the height of the umbilicus. A renal ultrasound shows enlargement of the bladder, both ureters, and the calyceal system of both kidneys. The hormone responsible for the enlarged prostate is most likely produced by what enzyme? A. B. C. D. E. Aromatase 17α-Hydroxylase 21-Hydroxylase Oxidoreductase 5α-Reductase Correct Response Option E (5α-reductase) is correct. The enzyme 5α-reductase converts testosterone to dihydrotestosterone, the hormone that is mainly responsible for benign prostatic hyperplasia (BPH) and prostate cancer. The patient has BPH, which is the most common cause of urinary retention with hydronephrosis (distention of the kidney) in elderly men. Incorrect Responses Option A (aromatase) is incorrect. Aromatase irreversibly converts androgens (e.g., dihydrotestosterone, testosterone, androstenedione) to estrogens (e.g., estradiol, estrone). Aromatase does not convert androgens to other types of androgens. -Hydroxylase is important in the conversion of 17hydroxypregnenolone to dehydroepiandrosterone and 17-hydroxyprogesterone to androstenedione. Production of these two weak androgens (dehydroepiandrosterone and androstenedione), which are also known as 17-ketosteroids, are produced in both the adrenal cortex and Leydig cells in the testes. These hormones are not involved in the pathogenesis of BPH. Option C (21-hydroxylase) is incorrect. This enzyme is important in the conversion of 17hydroxyprogesterone to 11-deoxycortisol in steroid synthesis in the adrenal cortex. These compounds are not involved in the pathogenesis of BPH. Option D (oxidoreductase) is incorrect. This enzyme converts androstenedione to testosterone in the adrenal cortex and the Leydig cells. These hormones are not involved in the pathogenesis of BPH. 27. A 2-year-old child suffers from a rare genetic disease that is characterized by fat malabsorption, spinocerebellar degeneration, hemolytic anemia, and pigmented retinopathy. Total cholesterol and triacylglycerol levels are extremely low, and levels of chylomicrons, very low-density lipoprotein (VLDL), and low-density lipoprotein (LDL) are not detectable. The patient most likely has an abnormality associated with what apolipoprotein? A. B. C. D. Apolipoprotein A (apoA) Apolipoprotein B (apoB) Apolipoprotein C-II (apoC-II) Apolipoprotein E (apoE) Correct Response Option B (apolipoprotein B) is correct. The patient has abetalipoproteinemia, a rare autosomal recessive disease characterized by the inability to form chylomicrons or VLDL. ApoB is necessary for the formation of chylomicrons (apoB-48), VLDL (apoB-100), and LDL (apoB-100). The absence of chylomicrons, which carry diet-derived triacylglycerol (TG), and VLDL, which carries endogenously synthesized TG, accounts for the markedly decreased levels of TG in the blood. Furthermore, LDL is the major carrier for cholesterol and is derived from hydrolysis of VLDL, so serum cholesterol levels are also very low. The clinical findings in this patient (like most patients with abetalipoproteinemia) result from vitamin E deficiency. This fat-soluble vitamin is normally reabsorbed with fat. In abetalipoproteinemia, TG and the fat-soluble vitamins cannot be packaged into chylomicrons in the small intestine. TG accumulates in the lamina propria of the villi and prevents the reabsorption of fat and fat-soluble vitamins from the intestinal lumen, which leads to steatorrhea (excess fat in stools). Vitamin E deficiency is associated with spinocerebellar degeneration and hemolytic anemia. Treatment involves megadoses of vitamin E. Incorrect Responses Option A (apolipoprotein A) is incorrect. ApoA is unique to high-density lipoprotein (HDL). Deficiency of apoA, a rare disease, is associated with the absence of HDL and a predisposition for premature coronary artery disease. Option C (apolipoprotein C-II) is incorrect. ApoC-II is important in the activation of capillary lipoprotein lipase, which hydrolyzes TG and VLDL to release fatty acids and glycerol. ApoC-II is deficient in familial hyperchylomicronemia syndrome (type I hyperlipoproteinemia) and is associated with an increase in chylomicrons that begins in early childhood. Option D (apolipoprotein E) is incorrect. Apo E is present on chylomicrons, VLDL, and intermediate-density lipoproteins (IDL). A mutant form of apoE characterizes familial dysbetalipoproteinemia (type III hyperlipoproteinemia). The apoB and apoE receptors in the liver cannot remove chylomicron remnants and IDL that have the mutant form of apoE, so these remnants accumulate in the blood and increase TG and cholesterol levels. 28. A 16-year-old boy has bilateral Achilles tendon xanthomas. His father died of an acute myocardial infarction at 32 years of age. What biochemical defect is most likely responsible for the physical finding in this patient? A. B. C. D. E. Decreased clearance of very-low-density lipoprotein (VLDL) Deficient levels of apolipoprotein C-II Deficient levels of apolipoprotein E Deficient levels of capillary lipoprotein lipase Deficient levels of low-density-lipoprotein (LDL) receptors Correct Response Option E (deficient levels of low-density-lipoprotein receptors) is correct. Achilles tendon xanthomas are pathognomonic for familial hypercholesterolemia (type II hyperlipoproteinemia), which is inherited in an autosomal dominant fashion. Absent or defective LDL receptors lead to an increase in the level of serum cholesterol, which deposits in the tendon sheaths. Patients die at an early age of an acute myocardial infarction or stroke. Incorrect Responses Option A (decreased clearance of very-low-density lipoprotein) is incorrect. Decreased clearance of VLDL is called type IV hyperlipoproteinemia. Only plasma levels of triacylglycerol are primarily increased. Option B (deficient levels of apolipoprotein C-II) is incorrect. Apolipoprotein C-II activates capillary lipoprotein lipase in the fed state. Capillary lipoprotein lipase hydrolyzes triacylglycerol in chylomicrons and VLDL, which causes the release of glycerol and fatty acids into the peripheral circulation. Deficiency of apolipoprotein C-II is rare and occurs mainly in children (as type I hyperlipoproteinemia). In this condition, chylomicron levels are markedly elevated, and hence serum triacylglycerol levels are increased. Option C (deficient levels of apolipoprotein E) is incorrect. Apolipoprotein E primarily mediates the uptake of chylomicrons and intermediate-density lipoproteins by hepatocytes. Deficiency of apolipoprotein E is manifested phenotypically as type III hyperlipoproteinemia, also known as dysbetalipoproteinemia or remnant disease, because levels of chylomicron remnants and intermediatedensity lipoproteins are increased. Both serum cholesterol and triacylglycerol levels are increased. Option D (deficient levels of capillary lipoprotein lipase) is incorrect. Genetic absence of this enzyme is a rare childhood disease (type I hyperlipoproteinemia) and is characterized by an increase in chylomicron levels, similar to the situation in apolipoprotein C-II deficiency. 29. A 48-year-old man is scheduled for a lipid profile. He is instructed to fast for 12 hours before the blood sample is drawn at 8 am the next day. Lipid analysis shows: Serum cholesterol: 250 mg/dL Serum high-density lipoprotein cholesterol: 25 mg/dL Serum triacylglycerol: 300 mg/dL A refrigerated plasma sample shows a creamy layer on the surface of the plasma, but the plasma itself is clear. What change best explains the appearance of the refrigerated sample? A. B. C. D. E. Increased level of chylomicrons Increased level of chylomicrons and low-density lipoproteins (LDL) Increased level of chylomicrons and very-low-density lipoproteins (VLDL) Increased level of LDL Increased level of VLDL Correct Response Option A (increased level of chylomicrons) is correct. Chylomicrons consist of mainly diet-derived triacylglycerol. An increase in triacylglycerol produces turbidity in plasma. Because chylomicrons are the least dense of the lipoprotein fractions, they normally float on top of plasma (supranate) after the sample is refrigerated. The turbid supranate in the patient’s sample indicates a high level of chylomicrons. This result suggests that the patient had not fasted, but instead probably ate a breakfast containing saturated fats before the blood sample was obtained. Incorrect Responses Option B (increased level of chylomicrons and LDL) and Option D (increased level of LDL) are incorrect. The level of chylomicrons is increased in this patient (see discussion for Option A). LDL carries cholesterol, but an increase in cholesterol does not produce turbidity. Option C (increased level of chylomicrons and VLDL) and Option E (increased level of VLDL) are incorrect. The chylomicron level is increased in this patient. VLDL is the primary vehicle for carrying endogenously synthesized triacylglycerol. Because VLDL is slightly denser than is the chylomicron fraction, an increased level of VLDL would cause the entire tube of plasma to be turbid and there would be no supranate. The plasma in this patient’s sample is clear, however, which indicates that the VLDL concentration is not increased. 30. A 25-year-old female has just finished eating a lunch consisting of a ham sandwich, potato salad, orange juice, and vanilla ice cream. Which of the following is most likely to be increased? A adenylate cyclase activity B. protein kinase A activity C. hormone-sensitive lipase activity D. lipoprotein lipase activity Correct Response Option D Insulin which is increased by consumption of carbohydrates leads to an increase in lipoprotein lipase activity on the endothelial surface to break down triglycerides in chylomicrons. Incorrect Responses Option B (increased level of chylomicrons and LDL) and Option D (increased level of LDL) are incorrect. The level of chylomicrons is increased in this patient (see discussion for Option A). LDL carries cholesterol, but an increase in cholesterol does not produce turbidity. Option C (increased level of chylomicrons and VLDL) and Option E (increased level of VLDL) are incorrect. The chylomicron level is increased in this patient. VLDL is the primary vehicle for carrying endogenously synthesized triacylglycerol. Because VLDL is slightly denser than is the chylomicron fraction, an increased level of VLDL would cause the entire tube of plasma to be turbid and there would be no supranate. The plasma in this patient’s sample is clear, however, which indicates that the VLDL concentration is not increased. 31. A 43-year-old man with chronic renal failure, who requires hemodialysis, complains of generalized bone pain. Physical examination shows bowing of the legs and a sallow complexion. When the man’s blood pressure is taken, his thumb flexes into his palm. A radiograph of the bones shows generalized osteopenia. The patient most likely has a deficiency of which of the following vitamins? A Niacin B. ascorbic acid C. Vitamin A D. Vitamin D E. Vitamin K Correct Response Option D Chronic renal failure can render a patient unable to form 1,25-dihydroxycholecalciferol producing hypocalcemia and signs of tetany. Calcium is mobilized from bone producing osteopenia. Incorrect Responses Option A Niacin deficiency (pellagra) is characterized by diarrhea, dermatitis, and dementia and is not directly involved in bone or calcium metabolism. Option B Ascorbic acid is involved in the proper formation of collagen and a deficiency would lead to fragile capillaries due to abnormal connective tissue, but not to osteopenia. Option C Vitamin A toxicity can produce pain in the long bones, but it does not have a role in bone maintenance or calcium homeostasis. Option E Vitamin K deficiency is not directly involved in bone resorption or calcium homeostasis. 32. A 2-month-old male is brought to the pediatrician to treat a worsening cough. Physical examination reveals a diaper rash and oral thrush. Radiography reveals a chest infiltrate consistent with Pneumocystis carinii pneumonia. Blood analysis shows a complete lack of lymphocytes. Which of the following enzymes is most likely deficient in this infant A B. C. D. Adenosine deaminase Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) Orotate phosphoribosyl transferase Xanthine oxidase Correct Response Option A Severe combined immunodeficiency disease (SCID) is a result of a deficiency of the enzyme adenosine deaminase. SCID is characterized by decreased production of both B- and T-cell precursors. Incorrect Responses Option B HGPRT deficiency produces Lesch-Nyhan syndrome which is characterized by mental retardation and self-mutilation. Option C Orotate phosphoribosyl transferase deficiency produces orotic aciduria Option D Xanthine oxidase deficiency produces hypouricemia and increased excretion of xanthine and hypoxanthine. 33. A neonatal nurse notices that the urine produced by a newborn infant has the odor of maple syrup. What biochemical reaction is most likely defective? A. Metabolism of aromatic amino acids B. Metabolism of branched-chain amino acids C. Metabolism of sulfur-containing amino acids D. One-carbon transfer reactions E. Transformation of carbohydrates to amino acids Correct Response Option B (metabolism of branched-chain amino acids) is correct. A defect in the oxidation of the branched-chain amino acids valine, leucine, and isoleucine (all of which are essential amino acids) leads to a build-ketoacids. The accumulation of these acids in the urine leads to its pathognomonic maple-syrup odor. Incorrect Responses Option A (metabolism of aromatic amino acids) is incorrect. The aromatic amino acids phenylalanine, tyrosine, and tryptophan, which are primarily increased in chronic liver disease, contribute to the mental status abnormalities associated with hepatic encephalopathy. Branched-chain amino acids are used to reduce the effect of the aromatic amino acids in patients with chronic liver disease. Option C (metabolism of sulfur-containing amino acids) is incorrect. This action would be more likely with homocystinuria, which is caused by a deficiency of cystathionine synthetase. Homocystinuria is characterized by mental retardation, osteoporosis, and lens dislocation. Option D (one-carbon transfer reactions) is incorrect. This is seen most often in cases of folate deficiency. Tetrahydrofolate transfers methylene groups (–CH2–) to serine to produce 5,10-methylene tetrahydrofolate, which in turn transfers the methylene group to deoxyuridine monophosphate to produce deoxythymidine monophosphate for DNA synthesis. Option E (transformation of carbohydrates to amino acids) is incorrect. The urine of individuals with this wide variety of deficiencies does not have the characteristic odor of maple syrup. 34. A healthy adult is placed on a diet that lacks tyrosine, but is otherwise balanced. As a result of this diet, nitrogen balance is most likely to A. be achieved B. become negative C. become positive D. progress from a negative state to equilibrium E. progress from a positive state to equilibrium Correct Response Option A (be achieved) is correct. A state of nitrogen balance exists when the amount of nitrogen excreted is equal to the amount ingested. This is seen in healthy adults whose intake of dietary protein is adequate. Tyrosine, a nonessential amino acid, is synthesized from phenylalanine in the diet. Failure to include tyrosine in the diet would not affect the nitrogen balance in this individual, who should experience no adverse effects from the diet. Incorrect Responses Option B (become negative) is incorrect. A negative nitrogen balance exists when more nitrogen is excreted than is ingested. This occurs when the protein intake is insufficient or of low quality (e.g., the diet does not provide the correct amounts of all of the essential amino acids) or during catabolic states. Option C (become positive) is incorrect. A positive nitrogen balance exists when more nitrogen is ingested than is excreted. This occurs primarily in anabolic states (e.g., during a "growth spurt"). Option D (progress from a negative state to equilibrium) and Option E (progress from a positive state to equilibrium) are incorrect. Transitional stages of nitrogen balance are not common (whether the end state is positive or negative), because the conditions that lead to a nitrogen imbalance are chronic in nature. For example, a negative nitrogen balance is common following surgery, during advanced stages of cancer, or in individuals with starvation syndromes (e.g., kwashiorkor). 35. A 42-year-old man is taking isoniazid to treat tuberculosis. He is most at risk of developing a deficiency of what amino acid? A. Arginine B. Aspartate C. Glutamate D. Glutamine E. Glycine Correct Response Option B (aspartate) is correct. Patients who take isoniazid are at risk for developing pyridoxine (vitamin B6) deficiency. Pyridoxine is required for the proper functioning of the transaminases, the -amino acids. Aspartate is produced from transamination of oxaloacetate by aspartate aminotransferase (AST). Incorrect Responses Option A (arginine) is incorrect. Synthesis of arginine, an essential amino acid, also occurs during the urea cycle and does not require pyridoxine. Option C (glutamate) is incorrect. Although glutamate can be produced from the reverse action of the transaminase -ketoglutarate by glutamate dehydrogenase, which does not require pyridoxine. Option D (glutamine) is incorrect. Glutamine is synthesized from glutamate by glutamine synthetase, which does not require pyridoxine. Option E (glycine) is incorrect. Glycine is synthesized from serine by a hydroxymethyl transferase, which does not require pyridoxine. 36. A 48-year-old man with cirrhosis of the liver is not oriented to time or place. After he is placed on a low-protein diet, he experiences some improvement in mental status. What enzyme is most likely responsible for these abnormalities in mental status? A. Arginase B. Argininosuccinate lyase C. Argininosuccinate synthetase D. Carbamoyl phosphate synthetase I E. Ornithine carbamoyltransferase Correct Response Option D (carbamoyl phosphate synthetase I) is correct. This patient is suffering from hepatic encephalopathy, which is most likely induced by a high-protein diet. The excess nitrogen waste from protein is usually handled by the liver (urea cycle), which is damaged in this patient. The ammonia from protein degradation by urease-producing organisms in the bowel is converted to urea in the liver via the urea cycle. The rate-limiting step is the synthesis of carbamoyl phosphate from NH3 and CO2, which is catalyzed by carbamoyl phosphate synthetase I. Because the urea cycle is dysfunctional, blood NH3 levels increase and blood urea nitrogen decreases. A low-protein diet decreases the amount of NH3 that the urea cycle must metabolize. Incorrect Responses Option A (arginase) is incorrect. Arginase helps cleave arginine to produce ornithine and urea. Option B (argininosuccinate lyase) is incorrect. Argininosuccinate lyase catalyzes the conversion of argininosuccinate to arginine and fumarate. Option C (argininosuccinate synthetase) is incorrect. Argininosuccinate synthetase catalyzes the condensation of aspartate and citrulline to form argininosuccinate. Option E (ornithine carbamoyltransferase) is incorrect. Ornithine transcarbamoylase catalyzes the condensation of ornithine and carbamoyl phosphate to form citrulline. 37. A 1-year-old child with mental retardation has a deficiency of dihydrobiopterin reductase. This enzyme deficiency is most closely related to what disorder? A. Galactosemia B. Maple syrup urine disease C. Niemann-Pick disease D. Phenylketonuria (PKU) E. Wilson disease Correct Response Option D (phenylketonuria) is correct. The secondary form of PKU results from an inability to regenerate tetrahydrobiopterin. This lack of tetrahydrobiopterin affects not only the conversion of phenylalanine to tyrosine, but also the hydroxylation of tyrosine and tryptophan, leading to deficiencies of neurotransmitters and additional central nervous system effects. Dietary restriction of phenylalanine is not sufficient to reverse the neurologic effects. Control of the primary form of PKU, which is caused by phenylalanine hydroxylase deficiency, involves dietary restriction of phenylalanine and tyrosine supplementation. Incorrect Responses Option A (galactosemia) is incorrect. Galactosemia, which may present as mental retardation, is caused by a deficiency in galactose-1-phosphate uridylyl transferase. The enzyme does not require tetrahydrobiopterin as a cofactor. Option B (maple syrup urine disease) is incorrect. Maple syrup urine disease is caused by a deficiency of branched-keto acid dehydrogenase. This enzyme does not require tetrahydrobiopterin as a cofactor. Option C (Niemann-Pick disease) is incorrect. Niemann-Pick disease also presents as mental retardation with hepatosplenomegaly. It is caused by a defect in the lysosomal hydrolytic enzyme sphingomyelinase. This enzyme does not require tetrahydrobiopterin as a cofactor. Option E (Wilson disease) is incorrect. Wilson disease is caused by a defect in the excretion of copper into the bile. Excess copper in the liver leads to chronic liver disease and decreased synthesis of ceruloplasmin, a copper-binding protein. Excess copper in the blood leads to deposits in the eye (KayserFleischer rings) and the lenticular nuclei in the brain, resulting in movement disorders. Ceruloplasmin does not require tetrahydrobiopterin as a cofactor. 38. A 42-year-old man who works in a battery factory complains of fatigue, headaches, abdominal pain, and chronic diarrhea. Laboratory studies show a hemoglobin of 10 g/dL and a mean corpuscular coarse basophilic stippling. What is an additional expected laboratory finding? A. Decreased serum ferritin B. Decreased zinc RBC protoporphyrin C. Increased hemoglobin A2 (HbA2 ) and hemoglobin F (HbF) D. -aminolevulinic acid (ALA) Correct Response Option D (increased urinary -aminolevulinic acid) is correct. The patient has lead poisoning, which commonly occurs in battery factory employees. Elevation of ALA is usually a clue that lead poisoning is present, because lead denatures ALA dehydratase, which converts ALA to porphobilinogen. Increased levels of ALA, along with lead, produce demyelination in the brain and increased vessel permeability leading to cerebral edema. Lead poisoning often results in a microcytic anemia, with characteristic coarse basophilic stippling of RBCs because of denaturation of ribonuclease, the enzyme that degrades ribosomes. Incorrect Responses Options A (decreased serum ferritin) is incorrect. Serum ferritin, a circulating soluble protein storage form of iron, correlates with iron stores in the bone marrow macrophages. It is elevated in lead poisoning, where iron accumulates in the mitochondria in developing nucleated RBCs and produces ringed sideroblasts, which contain iron-laden mitochondria surrounding the nucleus. When the sideroblasts die in bone marrow, the iron is stored in macrophages, leading to an increase in iron stores in the marrow as well as iron in the blood. Option B (decreased zinc RBC protoporphyrin) is incorrect. In lead poisoning, denaturation of ALA dehydratase and ferrochelatase reduces the amount of zinc protoporphyrin in the RBCs that is available to combine with iron to form heme. In the past, zinc RBC protoporphyrin levels were used to screen for lead poisoning. However, these values are also increased in other conditions (e.g., iron deficiency), which limits the usefulness of the test. Currently, the blood lead level is used as the screening and confirmatory test for lead poisoning. Option C (increased hemoglobin A2 and hemoglobin F) is incorrect. Lead denatures enzymes involved in hemoglobin synthesis (e.g., ALA dehydratase and ferrochelatase) and in the degradation of -thalassemia minor is characterized by an increase in HbA2 and HbF. I -globin 39. A 1-year-old male child is brought to the pediatrician because his parents have noticed that the boy is mutilating himself by chewing on his lips. On examination, the child is found to be mentally retarded and manifesting signs of gouty arthritis. What enzyme involved in nucleoside metabolism is most likely deficient in this child? A. Adenosine deaminase B. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) C. Phosphoribosylpyrophosphate synthase D. Thymidine kinase E. Xanthine oxidase Correct Response Option B (hypoxanthine-guanine phosphoribosyltransferase) is correct. This child is manifesting signs and symptoms of Lesch-Nyhan syndrome, an X-linked recessive disorder. A complete deficiency of HGPRT causes this condition. HGPRT is responsible for the salvage of purines by converting hypoxanthine and guanine to their monophosphated forms. Lack of this enzyme leads to destruction of free hypoxanthine and guanine, increased uric acid levels, and ensuing mental retardation and, less importantly, gout. The cause of the self-mutilating behavior in Lesch-Nyhan syndrome is unknown. Incorrect Responses Option A (adenosine deaminase) is incorrect. Adenosine deaminase catalyzes the conversion of adenosine to inosine in the degradation pathway of adenosine. A deficiency of this enzyme leads to a form of severe combined immunodeficiency disease (SCID). Option C (phosphoribosylpyrophosphate synthase) is incorrect. Phosphoribosylpyrophosphate synthase catalyzes the rate-limiting step in the synthesis of purine nucleotides and plays an important role in many other pathways. The most common alteration of this synthase is overactivity, which leads to an overproduction of purines and ensuing hyperuricemia and gout. Option D (thymidine kinase) is incorrect. Thymidine kinase is an enzyme in the salvage pathway for pyrimidines (specifically thymine) that converts thymidine to TMP. Drugs, such as acyclovir, which are used primarily to treat herpes, inhibit viral versions of this enzyme. Option E (xanthine oxidase) is incorrect. Xanthine oxidase, the terminal enzyme in the degradation pathway of purines, converts xanthine to uric acid. This enzyme can be inhibited by allopurinol, which reduces the production of uric acid and abates the occurrences of gout in individuals prone to attacks. 40. A 1-year-old boy has a history of recurrent bacterial and fungal infections. Serum protein -globulin region. Further testing shows increased concentrations of dATP in white blood cells. What is the most likely diagnosis? A. Adenosine deaminase deficiency B. Bruton agammaglobulinemia C. Lesch-Nyhan syndrome D. Oroticaciduria E. Purine nucleoside phosphorylase deficiency Correct Response Option A (adenosine deaminase deficiency) is correct. Adenosine deaminase deficiency leads to an extremely large accumulation of dATP, which inhibits ribonucleotide reductase. The resulting impairment in both T-cell (recurrent fungal infections) and B-cell function (hypogammaglobulinemia -globulin region) has led to the name severe combined immunodeficiency disease or SCID. Incorrect Responses Option B (Bruton agammaglobulinemia) is incorrect. Bruton agammaglobulinemia is an X-linked recessive disorder in which pre-B cells cannot mature into B cells, causing an isolated hypogammaglobulinemia. Option C (Lesch-Nyhan syndrome) is incorrect. Lesch-Nyhan syndrome results from a genetic deficiency in hypoxanthine-guanine phosphoribosyltransferase, which prevents the salvage of both hypoxanthine and guanine. The blocked salvage simultaneously leads to a decrease in the concentrations of inosine monophosphate and guanosine monophosphate (feedback inhibitors of the first step in purine synthesis) and an increase in phosoribosylpyrophosphate (the limiting substrate in the first step of purine synthesis). Option D (oroticaciduria) is incorrect. Oroticaciduria results from a deficiency of the enzymes -monophosphate. The buildup of orotic acid leads to abnormal growth and megaloblastic anemia. Treatment with a uridine-rich diet is successful. Option E (purine nucleoside phosphorylase deficiency) is incorrect. Purine nucleoside phosphorylase deficiency results in an accumulation of dGTP and dATP, both of which inhibit ribonucleotide reductase. This causes impairment of T-cell (but not B-cell) function. 41. A full-term male infant begins to show irritability and lethargy 36 hours after birth. Laboratory studies show a plasma ammonia level that is 60 times normal and a urinary orotate level that is 100 times normal. What enzyme is most likely defective in this infant? A. Arginase B. Carbamoyl phosphate synthetase II C. Ornithine transcarbamoylase D. Serine hydroxymethyltransferase Correct Response Option C (ornithine transcarbamoylase) is correct. Defects of the urea cycle retard the disposal of free NH3, causing it to accumulate in the bloodstream. The more proximal the enzyme defect in the urea cycle, the more pronounced the increase in NH3 in the blood. A deficiency of ornithine transcarbamoylase in the mitochondrion blocks the entry of nitrogen into the urea cycle as carbamoyl phosphate by preventing its conversion to citrulline. The carbamoyl phosphate in the mitochondrion eventually leaks into the cytoplasm, where it accelerates the pyrimidine pathway, leading to the appearance of orotic acid in the urine. Incorrect Responses Option A (arginase) is incorrect. Arginase is responsible for cleaving arginine to urea and ornithine; a deficiency of arginase leads to a buildup of arginine. Typically, the metabolism of arginine by other pathways (creatine and nitric acid synthase) or its elimination in the urine prevents this accumulation. In rare instances of excessive protein intake, a deficiency of arginase may lead to a mild-tomoderate hyperammonemia. Option B (carbamoyl phosphate synthetase II) is incorrect. Carbamoyl phosphate synthetase II, the cytosolic form of the enzyme, catalyzes one of the initial steps in pyrimidine synthesis. If this enzyme were deficient, the urea cycle, which would have a functional carbamoyl phosphate synthetase I, would remove any accumulated ammonia. Option D (serine hydroxymethyltransferase) is incorrect. Serine hydroxymethyltransferase reversibly transfers a single-carbon unit from methylene tetrahydrofolate to glycine to synthesize serine. A deficiency of this enzyme does not result in hyperammonemia. 42. A 4-day-old infant has physiologic jaundice of the newborn. She receives phototherapy with blue light to reduce the level of bilirubin in her blood and eliminate jaundice in the skin. What mechanism best explains the manner in which phototherapy reduces jaundice? A. Increases conjugating enzymes in the liver B. Increases synthesis of vitamin D in the skin C. Metabolizes bilirubin to biliverdin D. Oxidizes bilirubin to a water-soluble form Correct Response Option D (oxidizes bilirubin to a water-soluble form) is correct. Water-soluble forms of bilirubin are nontoxic and are excreted in the urine. Phototherapy with blue light causes bilirubin to undergo photooxidation, which produces the water-soluble form. Incorrect Responses Option A (increases conjugating enzymes in the liver) is incorrect. Phototherapy does not increase the synthesis of conjugating enzymes in the liver. Option B (increases synthesis of vitamin D in the skin) is incorrect. Ultraviolet light increases vitamin D synthesis in the skin. Vitamin D does not alter the concentration of bilirubin in the skin or blood. Option C (metabolizes bilirubin to biliverdin) is incorrect. Biliverdin, which is more watersoluble than bilirubin, is converted to bilirubin in macrophages before it is conjugated in the liver. Conversion of biliverdin to bilirubin is an energy-requiring reaction and is not reversed by phototherapy. 43. A 28-year-old woman has an intermittent history of severe abdominal pain that typically occurs after she has consumed a few glasses of wine or after she has been on "crash diets." In visits to many different physicians over the past few years, she has undergone several laboratory tests (e.g., complete blood cell count, electrolytes), barium studies, and laparoscopic examinations, none of which has revealed the cause of her pain. Her physician now orders a urine specimen for culture. The woman collects the specimen and leaves it near a window for about 30 minutes, when she notices that the urine color has changed from pale yellow to wine-red. What compound is most likely responsible for the color change? A. Hemoglobin B. Myoglobin C. Porphobilin D. Urobilin E. Uroporphyrin I Correct Response Option C (porphobilin) is correct. Porphobilinogen, which is excreted in the urine, is colorless, but in the presence of light, it is oxidized to porphobilin, which has a wine-red color. The recurrent, neurologically induced abdominal pain precipitated by either drugs that induce the liver cytochrome P450 system or dietary restriction is characteristic of acute intermittent porphyria, an autosomal dominant disease caused by a deficiency of uroporphyrinogen I synthase. This enzyme catalyzes the conversion of porphobilinogen to hydroxymethylbilane, one of the reactions in heme synthesis. Deficiency of the enzyme leads to a proximal accumulation of both porphobilinogen and aminolevulinic acid. Confirmation of the diagnosis involves documentation of the enzyme deficiency in red blood cells. Treatment involves carbohyd -aminolevulinic acid synthase, the rate-limiting enzyme in heme synthesis. Incorrect Responses Option A (hemoglobin) is incorrect. The presence of hemoglobin in the urine, or hemoglobinuria, occurs primarily with intravascular hemolysis. Hemoglobinuria is characterized by red-colored urine that does not change in color after exposure to light. Option B (myoglobin) is incorrect. The presence of myoglobin, or myoglobinuria, occurs primarily after strenuous exercise, leading to rhabdomyolysis (rupture of muscle). Myoglobinuria is characterized by red-colored urine that does not change in color after exposure to light. Option D (urobilin) is incorrect. Urobilin, the oxidation product of urobilinogen, is the pigment normally responsible for the yellow color of urine. This substance normally occurs in trace amounts in urine. An increase in urobilin turns the urine dark yellow. It does not turn a wine-red color upon exposure to light. Option E (uroporphyrin I) is incorrect. Levels of uroporphyrin I are increased in porphyria cutanea tarda, a disorder characterized by a deficiency of uroporphyrinogen decarboxylase. The presence of uroporphyrin I in urine colors it wine-red when voided. Porphyria cutanea tarda is associated with photosensitive skin lesions, such as vesicles and bullae, fragile skin, and fine hair on the face. 44. A 5-year-old black child is brought to a medical missionary hospital in Africa. The child is apathetic, and physical examination shows reddish brown hair, a protuberant abdomen, hepatomegaly by percussion, ascites, and pitting edema of the lower extremities. What feature is most likely responsible for the hepatomegaly in this patient? A. Decreased albumin content of the blood B. Dec -oxidation of fatty acids C. Decreased synthesis of apolipoproteins D. Increased intake of fatty food E. Increased synthesis of fatty acids Correct Response Option C (decreased synthesis of apolipoproteins) is correct. The patient has kwashiorkor, which is a result of a decreased protein intake despite a normal total calorie intake. A diet consisting primarily of carbohydrates results in an increase in glycerol-3-phosphate, an intermediate in glycolysis. Glycerol is the carbohydrate backbone of triacylglycerol, which, in turn, is packaged into very-low-density lipoprotein (VLDL) in hepatocytes. Proteins are water soluble, so circulating lipoproteins, including VLDL, are protected by a covering that includes apolipoproteins. In kwashiorkor, apolipoprotein synthesis is decreased as a result of the low protein intake. Thus, triglyceride accumulates in the hepatocytes, with the accumulation producing fatty changes in the liver and massive hepatomegaly. The reddish-colored hair found in patients with kwashiorkor is a result of copper deficiency (flag sign); the ascites and pitting edema are related to hypoalbuminemia, which leads to a decrease in plasma oncotic pressure and leakage of a transudate into interstitial tissue and body cavities. Incorrect Responses Option A (decreased albumin content of the blood) is incorrect. Hypoalbuminemia is caused by decreased protein intake, but it is not the cause of the fatty changes in the liver. It is directly responsible for the ascites and pitting edema in the patient. -oxidation of fatty acids) and Option E (increased synthesis of fatty acids) are -oxidation of fatty acids provide more fatty acids for synthesis of triacylglycerol, these mechanisms are not the primary ones for the fatty liver changes seen in kwashiorkor. They assume a more prominent role in producing the fatty liver associated with excessive alcohol intake. Option D (increased intake of fatty food) is incorrect. Patients with kwashiorkor eat primarily carbohydrates. An increase in consumption of fatty food does not lead to a fatty liver, because VLDL derives from carbohydrates, not saturated fats. 45. A 53-year-old male with chronic myelogenous leukemia has begun treatment with multiple antineoplastic agents. He soon develops renal failure. Urinalysis shows an acid pH and the presence of crystals that have become deposited in the renal tubules. What treatment will most likely help reduce the deposition of the crystals in the renal tubules? A. increased fluids B. allopurinol C. ciprofloxacin D. lithotripsy E. hydrochlorothiazides Correct Response Option B (allopurinol) is correct. The crystals in this patient are uric acid produced from degradation of dead cancer cells. This complication is prevented by allopurinol, which prevents the conversion of xanthine to uric acid. Incorrect Responses Option A (increased fluids) is incorrect. Renal stones are often treated with increased fluids that allow the stones to pass naturally. The crystals in this patient are uric acid produced from degradation of dead cancer cells and are trapped in renal tubules making this therapy ineffective. Option C (ciprofloxacin) is incorrect. The crystals in this patient are not because of a bacterial infection. They are uric acid produced from degradation of dead cancer cells. Option D (lithotripsy) is incorrect. Lithotripsy breaks renal stones down into smaller particles that can be passed. The uric acid crystals in this patient are already small particles, but they are trapped in the renal tubules. Option E (hydrochlorothiazides) is incorrect. Hydrochlorothiazide is prescribed for calcium containing renal stones. The crystals in this patient are uric acid produced from degradation of dead cancer cells. 46. A 38-year-old male has been diagnosed with tuberculosis. He is treated with isoniazid and rifampin. He develops a microcytic anemia associated with a high serum ferritin concentration. A bone marrow examination shows increased iron stores and numerous ringed sideroblasts. What enzyme is most likely affected by the chemotherapy? A. Glucose-6-phosphate dehydrogenase B. Methylmalonyl CoA mutase C. Glutathione reductase D. D-aminolevulinic acid synthase E. Methemoglobin reductase Correct Response Option D (d-aminolevulinic acid synthase) is correct. Isoniazid is a competitive inhibitor for pyridoxine and prevents its action as a cofactor for delta-aminolevulinic acid synthase. This reduces the amount of protoporphyrin available to form heme. Incorrect Responses Option A (Glucose-6-phosphate dehydrogenase) is incorrect. Inhibition of glucose 6-phosphate dehydrogenase would produce a normocytic type of hemolytic anemia, but it is not affected by isoniazid or rifampin. Option B (Methylmalonyl CoA mutase) is incorrect. Inhibition of methylmalonyl CoA mutase would produce a megaloblastic anemia, but it is not affected by isoniazid or rifampin. Option C (glutathione reductase) is incorrect. Inhibition of glutathione reductase would lead to hemolytic anemia, but it is not affected by isoniazid or rifampin. Option E (Methemoglobin reductase) is incorrect. Inhibition of methemoglobin reductase would not produce anemia, but would stimulate red cell synthesis. It is not affected by isoniazid or rifampin. A 42-year-old male who works at a firing range complains of headaches, loss of sensation, weakness, a metallic taste in the mouth, and uncoordinated walking. Laboratory studies show a hemoglobin of 9 g/dL and a mean corpuscular volume (MCV) of 70 mm3. His red blood cells (RBCs) are hypochromic with coarse basophilic stippling. What is an additional expected laboratory finding? A. Decreased serum ferritin B. Decreased zinc RBC protoporphyrin C. Increased hemoglobin A2 (HbA2) and hemoglobin F (HbF) D. Increased urinary d-aminolevulinic acid (ALA) Correct Response Option D (Increased ALA) is incorrect. Elevation of ALA is usually a clue that lead poisoning is present, because lead denatures ALA dehydratase, which converts ALA to porphobilinogen. Incorrect Responses Option A (Decreased serum ferritin) is incorrect. Serum ferritin is elevated in lead poisoning. Option B (Decreased zinc RBC protoporphyrin) is incorrect. Zinc RBC protoporphyrin levels are also increased by lead poisoning and also in other conditions (e.g., iron deficiency). Option C (Increased HbA2 and HbF) is incorrect. Lead does not interfere with globin chain synthesis. 47. A 32-year-old male complains of skin lesions that develop whenever his skin is exposed to sunlight. The problem is so severe that he always avoids sunlight. He also notes that his urine has become a wine-red color. Physical examination shows numerous fluid-filled vesicles on areas of skin most exposed to sunlight. Laboratory studies, including a complete blood cell count and electrolytes, are normal. He has a history of chronic hepatitis C. Which of the following is most likely responsible for the color change in the urine? A Heme B. Urobilin C. Porphobilin D. Uroporphyrin I Correct Response Option D (uroporphyrin I) is correct. Uroporphyrin I gives urine a wine-red color, a characteristic symptom of porphyria cutanea tarda. The disorder may be acquired by patients with hepatitis C. Incorrect Responses Option A (heme) is incorrect. Heme from hemoglobin or myoglobin is red before exposure to light. Heme is also unlikely since hemoglobin levels are normal and muscle damage is not reported. Option B (urobilin) is incorrect. Urobilin is the pigment normally responsible for the yellow color of urine. An increase in urobilin causes the urine to be dark yellow. It does not turn wine-red color upon exposure to light. Option C (porphobilin) is incorrect. Porphobilin is increased in acute intermittent porphyria, an autosomal recessive disease caused by a deficiency of uroporphyrinogen I synthase. 48. A 4-year-old male has been deaf since birth and has a history of multiple fractures. Physical examination reveals a bluish discoloration of the sclera. Which of the following proteins is most likely defective? A fibrillin B. a-l-iduronidase C. type I collagen D. type III collagen E. Elastin Correct Response Option C Type I collagen defects produce osteogenesis imperfecta. Symptoms include deafness is due to malformation of the auditory ossicles, bluish discoloration of the sclera, and bone fragility. Incorrect Responses Option A Fibrillin defects are associated with Marfan syndrome which does not have bone fractures or blue sclera. -L-iduronidase deficiency produces Hurler's syndrome which has skeletal deformities, but there is no bone fragility or blue sclera. Option D Type III collagen defects lead to Ehlers-Danlos syndrome characterized by vascular weakness. Option E Elastin defects produce Williams syndrome which produces a supravalvular aortic stenosis. 49. A 58-year-old female complains that her heart does “flip-flops” that keep her awake at night. Physical examination reveals bilateral exophthalmos, enlarged thyroid, and pretibial myxedema. Which of the following glycosaminoglycans is producing the pretibial myxedema? A Chondroitin sulfate B. Dermatan sulfate C. Heparin D. Hyaluronic acid E. Keratan sulfate I Correct Response Option B Pretibial myxedema results from excessive deposition of the glycosaminoglycan dermatan sulfate in the interstitial tissue. This patient has Graves' disease which is characterized by myxedema. Incorrect Responses Option A Chondroitin sulfate is found principally in cartilage and is not found in interstitial tissue. Option C Heparin is found in the granules of mast cells and in liver, lung, and skin, and is not found in interstitial tissue. Option D Hyaluronic acid is the major component of synovial fluid, where it serves as a joint lubricant and is not found in interstitial tissue. Option E Keratan sulfate I is found in cornea where it is associated with chondroitin sulfate and is not found in interstitial tissue. 50. A 28-year-old man has a family history of a disabling disorder that has caused the deaths of his father, grandfather, and two paternal aunts. The father and aunts died at a younger age than did his grandfather, and it appears that the condition progressively worsens with each generation. What disorder is most likely? A. B. C. D. E. Cystic fibrosis Duchenne muscular dystrophy Huntington disease Metachromatic leukodystrophy Parkinson disease Correct Response Option C (Huntington disease) is correct. Huntington disease is an example of a triplet repeat disorder with an amplification of the CAG trinucleotide in the translated region of the gene. More triplet repeats occur with each generation, leading to earlier appearance of the disease (anticipation). The disorder is autosomal dominant and affects both men and women. Incorrect Responses Option A (cystic fibrosis) is incorrect. Cystic fibrosis is caused by a defective protein known as cystic fibrosis transmembrane conductance regulator. The condition has an autosomal recessive pattern of inheritance; it is not a trinucleotide repeat disorder. Option B (Duchenne muscular dystrophy) is incorrect. Duchenne muscular dystrophy is caused by an absence or defect of the protein dystrophin, which is a membrane protein important in maintaining the integrity of the muscle fiber. Duchenne muscular dystrophy has an X-linked pattern of inheritance; it is not a trinucleotide repeat disorder. Option D (metachromatic leukodystrophy) is incorrect. The primary cause of metachromatic leukodystrophy is the absence of lysosomal arylsulfatase A activity, resulting in an accumulation of sulfolipids in lysosomes. The condition has an autosomal recessive pattern of inheritance; it is not a trinucleotide repeat disorder. Option E (Parkinson disease) is incorrect. Parkinson disease is caused by loss of the neurons that generate dopamine in the substantia nigra. Some forms of the disease are autosomal dominant, but none has yet shown a tendency to occur prior to the expected onset. 51. A cell culture of a tumor biopsy is suspected of containing a ras oncogene. Which protein is most likely to confirm this diagnosis? A. B. C. D. G protein Growth factor Growth factor receptor Nuclear transcription factor Correct Response Option A (G protein) is correct. Ras is a mutated G protein that has lost its "off" switch, which is a GTPase. The increase in signaling that results from a permanently activated G protein leads to generation of a "growth" signal and unregulated growth of the cell line, which often leads to cancer. Incorrect Responses Option B (growth factor) is incorrect. An altered growth factor (e.g., platelet-derived growth factor) is a product of a mutated gene for that growth factor, leading to overproduction (e.g., sis oncogene), which may result in an astrocytoma or osteogenic sarcoma. Option C (growth factor receptor) is incorrect. An altered growth factor receptor (e.g., epidermalderived growth factor, which is a mutated erb-B2 oncogene) produces a receptor that is active in the absence of the growth factor. Altered growth factor may result in breast cancer. Option D (nuclear transcription factor) is incorrect. A mutated nuclear transcription factor (e.g., a mutated myc oncogene) may result in Burkitt lymphoma or neuroblastoma. 52. A 48-year-old woman with type 2 diabetes mellitus complains of intermittent problems with blurry vision. Physical examination shows a normal lens and mild diabetic retinopathy. What would best evaluate the possibility that chronically elevated glucose levels contribute to this patient’s condition? A. B. C. D. Blood glucose (fasting) Blood ketones Hemoglobin A1c concentration Serum C-peptide Correct Response Option C (hemoglobin A1c concentration) is correct. Blurry vision in this patient most likely results from poor glycemic control and the effect of glucose conversion to sorbitol by aldose reductase in the lens. Sorbitol, which is osmotically active, causes water to move into the lens with subsequent alteration in its refraction to light. Hemoglobin A1c measures the average level of glucose in the blood over the previous 4 to 8 weeks; it is the product of a concentration-dependent nonenzymatically catalyzed condensation of glucose and hemoglobin. Incorrect Responses Option A (blood glucose) is incorrect. Blood glucose only provides information about insulin levels over the previous 4 to 6 hours. Option B (blood ketones) is incorrect. Blood ketones are not an indicator of glycemic control. They are an indication that insulin levels are very low or absent. Option D (serum C-peptide) is incorrect. C-peptide levels are an indicator of endogenous insulin 53. A 53-year-old farmer has a raised crateriform lesion on the inner aspect of the bridge of his nose and numerous gray-white hyperkeratotic lesions on the face, hands, back of the neck, and forearms. What is most likely responsible for the pathogenesis of these lesions? A. B. C. D. Cleavage of DNA strands Defects in DNA repair enzymes Point mutations resulting in stop codons Pyrimidine dimers resulting in distortion of the DNA helix Correct Response Option D (pyrimidine dimers resulting in distortion of the DNA helix) is correct. Ultraviolet B (UVB) light (nonionizing radiation) is responsible for sunburn and the rapid increase of skin cancers in the United States. UVB light excites adjacent pyrimidine bases on DNA strands, causing them to form thymine-thymine dimers. In this patient, the crateriform lesion on the nose is a basal cell carcinoma, the most common cancer caused by excessive exposure to UVB light. The gray-white hyperkeratotic lesions on sun-exposed areas are actinic (solar) keratoses, which are precursors of squamous cell carcinoma of the skin. Incorrect Responses Option A (cleavage of DNA strands) is incorrect. Ionizing radiation is responsible for cleavage of DNA strands. Option B (defects in DNA repair enzymes) is incorrect. Defects in DNA repair enzymes are more often inherited than acquired. Xeroderma pigmentosum is an autosomal recessive disease characterized by a deficiency of DNA repair enzymes. Option C (point mutations resulting in stop codons) is incorrect. These nonsense mutations are -thalassemia). 54. A 3-year-old black girl is brought to a physician’s office for a routine physical examination. During the examination, pallor of the conjunctiva and mucous membranes is observed. The patient is of normal height for her age, but her weight is below normal. The girl’s cousin has sickle cell disease. A PCR-based restriction (polymerase chain reaction-based) analysis produces three bands of 103 bp, 191bp, -globin DNA, and a single 234-bp band is diagnostic for sickle cell anemia, what is the most likely diagnosis? A. B. C. D. E. Further studies are necessary Results of blood studies are normal Sickle cell disease Sickle cell trait -Thalassemia minor Correct Response Option D (sickle cell trait) is correct. Patients with sickle cell trait are most often asymptomatic and carry -globin gene sickle cell gene causes the replacement of gluta -globin. Because of this mutation, the PCR product cannot be cleaved by the restriction enzyme and a single band results at 294 bp. Because patients with sickle cell trait have one normal and one sickle cell gene, bands are seen at 294 bp, 103 bp, and 191 bp. The appearance of this single 294-bp band alone is diagnostic for sickle cell anemia. Incorrect Responses Option A (further studies are necessary) is incorrect. Sickle cell trait can be diagnosed by PCR-based restriction analysis for the sickle cell gene. Option B (results of blood studies are normal) is incorrect. Healthy patients have bands at 103 bp and 191 bp only. Option C (sickle cell disease) is incorrect. Sickle cell patients have a single 294-bp band. Op -thalassemia minor, the mutation occurs in the -globin. The electrophoresis reveals bands at 103 bp and 191 bp that are charact -globin genecoding sequence. There is no single 294-bp band, which is diagnostic for sickle cell trait or sickle cell anemia. 55. A 50-year-old man complains of weight loss, fatigue, weakness, and a sense of fullness in the left upper abdominal quadrant. Physical examination shows pallor, splenomegaly, and hepatomegaly; there is no lymphadenopathy. Bone marrow aspirate shows 30% blasts. Laboratory studies show a leukocyte count of 300,000/mm3 and the Philadelphia chromosome. What gene is most likely associated with these findings? A. B. C. D. E. abl brcal c-myc p53 Rb Correct Response Option A (abl) is correct. The patient’s clinical manifestations and laboratory findings are typical of chronic myelogenous leukemia. This type of leukemia is characterized by overproduction of granulocytes, especially neutrophils, leading to very high leukocyte counts and a marked splenomegaly. A characteristic abnormality is the presence of the Philadelphia chromosome. This chromosome is a result of the translocation of the proto-oncogene c-abl on chromosomes 9 to 22. The breakpoint on chromosome 22 occurs within the bcr (breakpoint cluster region) gene. The result is the chimeric gene bcr-abl, which is expressed and encodes a novel tyrosine kinase. Incorrect Responses Option B (brca1) is incorrect. The brca1 gene is a tumor suppressor gene, which is missing in about 10% of patients with breast cancer. Option C (c-myc) is incorrect. The c-myc oncogene is characteristic of Burkitt lymphoma, a disease that occurs mainly in children, with the mean age of onset of 7 years. In Burkitt lymphoma, the c-myc oncogene from chromosome 8 is translocated into the heavy-chain-joining region of the immunoglobulin gene (Jh) on chromosome 14. This results in the c-myc oncogene fusing with the Jh gene and being under the control of the Jh promoter. The product of this fusion gene binds to DNA and stimulates further cell division. Option D (p53) is incorrect. The p53 gene is a tumor suppressor gene. Mutations in the p53 gene are the most common DNA abnormality in tumors, occurring in more than 50% of cancers. Mutated p53 produces a defective 53-kd protein that is unable to induce apoptosis in a cell with damaged DNA. Option E (Rb) is incorrect. The Rb gene is the retinoblastoma gene, a tumor suppressor gene. The absence of Rb is associated with retinoblastoma, lung cancer, and other tumors. Homozygous individuals with two defective copies of the Rb gene have a virtual certainty of developing a malignant retinoblastoma within the first few months of life. 56. A 48-year-old African-American woman who has widespread thickening of the skin is diagnosed with diffuse cutaneous scleroderma. Laboratory studies show the presence of autoantibodies to a nuclear enzyme that relieves torsional stress in DNA. This patient most likely produces autoantibodies to what enzyme? A. Endonuclease B. C. D. E. Exonuclease Helicase Ligase Topoisomerase I Correct Response Option E (topoisomerase I) is correct. Scleroderma is a connective tissue disease characterized by fibrosis of the skin and multiple internal organs, small-vessel vasculopathy, and specific autoimmune response associated with autoantibodies. Up to 40% of patients with diffuse scleroderma develop antibodies to topoisomerase I. Other autoantibodies seen in patients with scleroderma include those against centromere; RNA polymerases I, II, and III; endoribonuclease; and U1snRNP. Topoisomerase I relieves torsional stress in DNA by inducing reversible single-strand breaks in front of the replication fork. Incorrect Responses Option A (endonuclease) is incorrect. Endonucleases cleave nucleotides at internal positions in the polynucleotide (DNA or RNA). Option B (exonuclease) is incorrect. Exonucleases cleave mononucleotides one at a time from the ends of a polynucleotide. Option C (helicase) is incorrect. Helicase unwinds the DNA double helix in front of the replication fork, causing positive supercoiling in front of the replication fork. This tight coiling must be removed by topoisomerase for the replication fork to proceed. Option D (ligase) is incorrect. Ligase is an enzyme that joins breaks in the DNA strand by forming phosphodiester bonds. 57. The parents of a 2-year-old child bring their son to the pediatrician’s office during a family vacation in Florida. They have noticed that after playing on the beach for several days, the boy has developed blisters and redness on his face, extremities, and trunk. He also has multiple freckles over the face, lips, and extremities, as well as pigmented patches interspersed with hypopigmented areas. What process is most likely to be defective in this child? A. B. C. D. E. DNA repair DNA replication mRNA splicing Protein translation RNA transcription Correct Response Option A (DNA repair) is correct. This child’s symptoms are characteristic of xeroderma pigmentosum. It is a rare, heterogenous group of diseases in which patients have a hereditary deficiency of an enzyme that repairs ultraviolet light–induced damage to DNA in keratinocytes and melanocytes. The most common form of the disease is caused by the absence of the ultraviolet-specific endonuclease that normally removes pyrimidine dimers. Extreme sensitivity to ultraviolet light, multiple freckles, and eventually skin cancer result from the inability of these patients to maintain the integrity of DNA. Individuals with this disorder should avoid exposure to sunlight. Incorrect Responses Option B, Option C, Option D, and Option E are incorrect. Refer to the discussion for Option A. 58. A 20-year-old healthy woman with a family history of hereditary nonpolyposis colorectal cancer (HNPCC) has genetic testing and is found to be a carrier of the HNPCC gene. Genetic testing shows a mutation in a gene encoding a DNA repair protein. This protein most likely participates in which type of DNA repair? A. B. C. D. E. Base excision Depurination Nucleotide excision Postreplication mismatch Recombinational Correct Response Option D (postreplication mismatch) is correct. HNPCC is caused by mutations in four genes that encode proteins involved in DNA mismatch repair. DNA mismatch repair proteins are an excision system that recognizes mismatched bases incorporated during DNA replication. Many such mismatched bases are removed by the proofreading activity of DNA polymerase. Those that are missed are subject to later correction by the DNA mismatch repair system. HNPCC is one of the most commonly inherited diseases, affecting as many as 1 in 200 individuals. It accounts for up to 15% of all colon cancers. Incorrect Responses Option A (base excision) is incorrect. Base excision repair functions correctly in individuals with HNPCC. This repair system involves several enzymes called DNA glycosylases. These enzymes remove damaged pyrimidine or purine bases from the DNA, creating an apyridimic or apurinic site (an AP site) in DNA. Remaining sugars are removed by AP endonucleases and phosphodiesterases. The gap of a single nucleotide is then filled by DNA polymerase and ligase. Option B (depurination) is incorrect. The depurination repair system is intact in individuals with HNPCC. Depurination is a spontaneous hydrolytic chemical reaction known to create serious DNA damage in cells. About 5,000 purine bases are lost per day from the DNA of each human cell. Depurination removes a purine base (adenine and guanine), leaving a deoxyribose sugar. This sugar is removed by AP endonucleases and phosphodiesterases, and the DNA sequence is restored by DNA polymerase and DNA ligase. Option C (nucleotide excision) is incorrect. This system removes bulky lesions, such as pyrimidine dimers caused by sunlight or DNA bases ligated to large hydrocarbons. The nucleotide excision repair system scans for DNA distortion rather than for a specific base change. An entire region of DNA surrounding the lesion is removed by DNA helicase and then repaired by DNA polymerase and DNA ligase. This system is defective in individuals with xeroderma pigmentosum. Option E (recombinational) is incorrect. Recombinational repair depends on one strand of parental DNA being undamaged. The gap in the DNA molecule synthesized on the damaged DNA molecule can be filled with a DNA fragment from the undamaged parental DNA by recombination. 59. A child of healthy parents has an autosomal recessive disorder. The 0.5 kb DNA fragment of the normal gene amplified by polymerase chain reaction (PCR) contains a BamHI restriction site. On digestion with BamHI, this fragment yields two fragments, which are 0.2 kb and 0.3 kb long. This restriction site is lost in the mutated gene; thus PCR amplification yields a 0.5 kb DNA fragment that is not sensitive to digestion with BamHI. The PCR-amplified 0.5 kb DNA fragments from both parents are subjected to BamHI treatment and electrophoresis. Which of the following DNA patterns is most likely seen on the gel? A. B. DNA of at least one parent has no 0.5 fragment DNA of at least one parent has neither 0.2 nor 0.3 kb fragments C. D. E. DNA of each parent separates into 0.2, 0.3, and 0.5 kb fragments Maternal DNA migrates as a single 0.5 kb fragment Paternal DNA migrates as a single 0.5 kb fragment Correct Response Option C (DNA of each parent separates into 0.2, 0.3, and 0.5 kb fragments) is correct. This child has an autosomal recessive disorder, which is manifested when there is homozygosity for a mutant allele. Both parents of the affected offspring are obligate heterozygotes and are healthy, with no features to show that they are carriers. Each parent has one normal and one mutant allele. Thus, the DNA of each parent separates on the electrophoretic gel into three fragments: 0.2, 0.3, and 0.5 kb. Incorrect Responses Option A (DNA of at least one parent has no 0.5 fragment), Option D (maternal DNA migrates as a single 0.5 kb fragment), and Option E (paternal DNA migrates a single 0.5 kb fragment) are incorrect. If the DNA of one parent had no 0.5 kb fragment, which is characteristic in a recessive trait, the child would have normal alleles. A child cannot be affected with a recessive autosomal disease if one parent is not a carrier of this recessive trait. Option B (DNA of at least one parent has neither 0.2 nor 0.3 kb fragments) is incorrect. If the DNA of one parent had neither 0.2 nor 0.3 kb fragments, which are characteristic for a normal allele, both alleles of the child would be mutated. Thus, the child would not be healthy. 60. A 27-year-old man complains of genital sores. The patient reports recent unsafe sexual contact. Examination of fluid from a bulla reveals multinucleated giant cells with intranuclear inclusions (Tzank cells). Which of the following enzymes is the best target for therapy? A Adenosine deaminase B. Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) C. Phosphoribosylpyrophosphate (PRPP) synthase D. Thymidine kinase E. Xanthine oxidase Correct Response Option D (thymidine kinase) is correct. This patient has a herpesvirus infection, most likely type 2. The medication prescribed by the physician was probably acyclovir (or a more recent derivative). This agent mimics a nucleoside and must be phosphorylated by thymidine kinase to block viral replication. Notably, some virions of the herpes family have been found that do not contain thymidine kinase; therefore, they are resistant to acyclovir and its congeners. Incorrect Responses Option A (adenosine deaminase) is incorrect. Adenosine deaminase is responsible for the conversion of adenosine to inosine in the degradation pathway of adenosine. A deficiency of this enzyme leads to a form of severe combined immunodeficiency disease (SCID). Option B (hypoxanthine-guanine phosphoribosyltransferase) is incorrect. HGPRT is responsible for the salvage of purines by converting hypoxanthine and guanine to their monophosphated forms. Lack of HGPRT leads to destruction of free hypoxanthine and guanine, increased uric acid levels, ensuing mental retardation, and, less importantly, gout. Option C (phosphoribosylpyrophosphate synthase) is incorrect. PRPP synthase, which catalyzes the ratelimiting step in the synthesis of purine nucleotides, plays an important role in many other pathways. The most common alteration of PRPP synthase is overactivity, which leads to an overproduction of purines and the development of hyperuricemia and gout. Option E (xanthine oxidase) is incorrect. Xanthine oxidase, a terminal enzyme in the degradation pathway of purines, helps convert xanthine to uric acid. Allopurinol, which decreases the production of uric acid as well as the frequency of gout in individuals prone to attacks, may inhibit this enzyme. 61. A 59-year-old male complains of a progressively worsening cough, drenching night sweats, and increasing fatigue. He is diagnosed with Mycobacterium tuberculosis infection. The patient is prescribed a four-drug regimen, including rifampin. Which of the following bacterial sites is inhibited by the rifampin? A acyl carrier protein B. RNA polymerase C. arabinosyl transferase D. ribosomal protein Correct Response Option B Rifampin is a first-line drug in the treatment of tuberculosis. Its mode of action involves inhibition of RNA polymerase. Incorrect Responses Option A Isoniazid blocks an acyl carrier protein in mycobacteria, but not rifampin Option C Ethambutol inhibits arabinosyl transferase in mycobacteria, but not rifampin. Option D Streptomycin inhibits ribosomal assembly by binding to a 30S subunit protein in mycobacteria, but not rifampin. 62. A three year old male is brought to the pediatrician because he has begun to stumble and has obvious difficulty running, jumping, and climbing stairs. His calf muscles have also become noticeably enlarged. Deletion scanning PCR revealed an absent band from the dystrophin gene after electrophoresis and blotting. What does the missing band represent? A promoter B. exon C. enhancer D. splice site Correct Response Option B The mutation that causes Duchenne muscular dystrophy is a deletion in one of the exons that produces a dysfunctional dystrophin protein. Incorrect Responses Option A The mutation that causes Duchenne muscular dystrophy is a deletion in one of the exons, not in the promoter site. Option C The mutation that causes Duchenne muscular dystrophy is a deletion in one of the exons, not in an enhancer. Option D The mutation that causes Duchenne muscular dystrophy is a deletion in one of the exons, not in a splice site. 63. A 24-year-old man returns from a trip to India and has profuse, watery diarrhea and a feeling of lightheadedness when he stands. A Gram stain of stool shows comma-shaped gram-negative organisms and an absence of an inflammatory reaction. What most accurately describes the biochemical alterations underlying this patient’s diarrhea? A. B. C. D. Activation of a Gq protein Activation of a Gs protein Inactivation of a Gi protein Inhibition of a Cl¯ channel E. Stimulation of guanylyl cyclase activity Correct Response Option B (activation of a Gs protein) is correct. The history and stool findings in this patient are characteristic of cholera caused by Vibrio cholerae. The cholera toxin acts on the intestinal mucosa and produces diarrhea by covalently modifying a Gs protein by ADP ribosylation. This is effective in permanently turning the protein "on," thus elevating intracellular levels of cAMP. This action stimulates the opening of chloride channels, resulting in a secretory diarrhea. Cholera is a toxin-induced disease and has no inflammatory component. Treatment involves fluid and electrolyte replacement to prevent dehydration (manifested as orthostatic symptoms in this case) and electrolyte imbalance. Incorrect Responses Option A (activation of a Gq protein) is incorrect. Gq proteins activate phospholipase C, which cleaves phosphatidylinositol diphosphate to diacylglycerol and inositol triphosphate, in turn raising intracellular calcium concentrations. Examples of Gq receptors are type 1 muscarinic cholinergic -adrenergic receptors in the autonomic nervous system. Option C (inactivation of a Gi protein) is incorrect. Gi proteins, when activated, inhibit the formation of cAMP. Permanent inactivation of the Gi protein, which leads to elevated levels of cAMP, is the mechanism of action of the pertussis toxin in respiratory epithelium. Option D (inhibition of a Cl channel) is incorrect. The Cl channel, the final step in the generation of secretions from part of the intestines, is activated in this patient. Inhibition of the channel leads to a lack of secretions; this condition is often seen in patients with defective channels (e.g., with cystic fibrosis). Option E (stimulation of guanylyl cyclase activity) is incorrect. Guanylyl cyclase, which produces cGMP from GTP, is part of the mechanism of action of a number of molecules, including the atrial natriuretic peptides and all agents that produce nitric oxide for vasodilation. Drugs, such as sildenafil, inhibit the breakdown of cGMP, thereby increasing cGMP concentrations and producing vasodilatory effects. 64. After exercising strenuously for 1 hour, a 23-year-old healthy man drinks two glasses of wine. He suddenly feels dizzy and has a rapid heartbeat and clammy skin. Which mechanism is most likely responsible for this man’s reaction to alcohol? A. B. C. D. E. Gluconeogenesis is inhibited by the abundance of oxaloacetate Gluconeogenesis is inhibited by the abundance of pyruvate Glycogenolysis is inhibited by ethanol NADH is used in ethanol metabolism Oxaloacetate and pyruvate are diverted from the gluconeogenetic pathway Correct Response Option E (oxaloacetate and pyruvate are diverted from the gluconeogenetic pathway) is correct. Alcohol is metabolized in the liver by two oxidation reactions that generate large quantities of NADH. Because the reduction of pyruvate to lactate and oxaloacetate to malate are favored by the abundance of NADH, pyruvate and oxaloacetate are diverted from gluconeogenesis. Individuals with depleted liver glycogen stores, which occur during extended periods of strenuous exercise, are dependent on gluconeogenesis to maintain adequate blood glucose levels. In these individuals, the consumption of ethanol can rapidly result in hypoglycemia. Incorrect Responses Option A (gluconeogenesis is inhibited by the abundance of oxaloacetate) is incorrect. Oxaloacetate is an intermediate in the synthesis of glucose by gluconeogenesis; thus its abundance does not inhibit gluconeogenesis. Option B (gluconeogenesis is inhibited by the abundance of pyruvate) is incorrect. Pyruvate is a precursor of glucose produced in gluconeogenesis; thus abundance of pyruvate does not inhibit gluconeogenesis. Option C (glycogenolysis is inhibited by ethanol) is incorrect. Ethanol metabolism has no effect on glycogenolysis. Option D (NADH is used in ethanol metabolism) is incorrect. NADH is not used but is generated in alcohol metabolism. See discussion for Option E. 65. An 18-year-old male complains of a rash and hair loss to his physician. He reports that in addition to a balanced diet he eats about 20 raw eggs per day to enhance his body-building exercises. What additional symptom is most likely in this patient? A. B. C. D. E. bleeding gums dementia glossitis lactic acidosis nystagmus Correct Response Option D (lactic acidosis) is correct. Raw eggs contain avidin, a protein that binds to biotin preventing its absorption. Impaired pyruvate carboxylase activity leads to lactic acidosis. Incorrect Responses Option A (bleeding gums) is incorrect. Vitamin C deficiency produces bleeding gums, but not dermatitis and hair loss seen in biotin deficiency. Option B (dementia) is incorrect. Niacin deficiency produces dermatitis as part of the pellagra syndrome, but not hair loss seen in biotin deficiency. Option C (glossitis) is incorrect. Riboflavin deficiency produces glossitis, but not dermatitis and hair loss seen in biotin deficiency. Option E (nystagmus) is incorrect. Thiamine deficiency produces Wernicke-Korsakoff syndrome with symptoms like confusion, ataxia, nystagmus, but not dermatitis and hair loss seen in biotin deficiency. 66. A 62-year-old woman whose husband died recently has developed a vitamin deficiency due to adopting a diet consisting of cereal and diet cola. She complains of bleeding gums after brushing her teeth and pain in her legs when she walks. Physical examination shows a smooth red tongue, gingivitis, carious teeth, scattered ecchymoses over the trunk, and pinpoint areas of hemorrhage around the hair follicles. Which one of the following reactions most likely accounts for these physical findings? A. B. C. D. E. Cleavage of N- and C-terminal propeptide fragments Formation of pro-α-chains Glycosylation of side-chain residues Hydroxylation of proline and lysine side-chains Triple helix assembly of procollagen Correct Response Option D (hydroxylation of proline and lysine side-chains) is correct. Vitamin C, as well as molecular oxygen and α-ketoglutarate, are the requirements for the proper function of prolyl hydroxylase, the enzyme responsible for hydroxylation of the proline side-chains in collagen. Collagen lacking such side-chain hydroxyl groups cannot be stabilized by interchain hydroxyl groups. This lowers the melting point of collagen and weakens the connective tissues that contain it, leading to hemorrhage. Incorrect Responses Option A (cleavage of N- and C-terminal propeptide fragments) is incorrect. This process occurs extracellularly, yielding the collagen molecule (monomer). The monomers later associate and are further cross-linked by lysyl oxidase for stability while in the extracellular matrix. The cleavage process occurs via propeptidases and does not depend on vitamin C. Option B (formation of pro-α-chains) is incorrect. This step, which involves translation of the mRNA to form the peptide chains found in the endoplasmic reticulum, does not depend on vitamin C. Option C (glycosylation of side-chain residues) is incorrect. This step, which involves the addition of glucose and galactose sugars to selected proline and lysine residues, does not depend on vitamin C. Option E (triple helix assembly of procollagen) is incorrect. This spontaneous process, which occurs in the Golgi apparatus, yields a procollagen molecule and does not require vitamin C. 67. A 42-year-old woman with severe rheumatoid arthritis begins taking an immunosuppressive drug. A few weeks later, she develops moderately severe macrocytic anemia, with pancytopenia and hypersegmented neutrophils. The most likely mechanism underlying this drug-induced anemia involves inhibition of A. B. C. D. Dihydrofolate reductase Intestinal conjugase Production of intrinsic factor Reabsorption of folate Correct Response Option A (dihydrofolate reductase) is correct. The patient is most likely taking methotrexate, which is a competitive inhibitor of dihydrofolate reductase. The lack of dihydrofolate reductase leads to a lack of tetrahydrofolate, and therefore inhibits the conversion of dUMP to TMP. This process stops proper DNA synthesis and occurs primarily in rapidly dividing cells, which are cells of hematopoietic origin. Incorrect Responses Option B (intestinal conjugase) is incorrect. Intestinal conjugase is responsible for the conversion of the polyglutamate form of folate to the more readily absorbed monoglutamate form. Inhibition of intestinal conjugase is not a known side effect of immunosuppressive agents. Option C (production of intrinsic factor) is incorrect. Intrinsic factor is secreted by the parietal cells of the stomach and binds to vitamin B12 in foodstuffs. Intrinsic factor is required for proper absorption of vitamin B12 in the terminal ileum. Lack of vitamin B12 can lead to a macrocytic anemia, but it would be unlikely to do so within a few weeks. Furthermore, methotrexate does not interfere with the production of intrinsic factor. Option D (reabsorption of folate) is incorrect. Alcohol and oral contraceptives are known to interfere with absorption of the monoglutamate form of folate in the jejunum. 68. A 38-year-old woman with chronic alcoholism has been homeless for the past year. Her diet consists primarily of starchy processed "junk" foods, in addition to alcoholic beverages. Physical examination shows noticeably thickened skin and the presence of hyperkeratotic hair follicles. The conjunctivae are dry, and tear production is reduced. What other finding is most likely to be expected? A. B. C. D. E. Bleeding gums Hemolytic anemia Impaired night vision Osteomalacia Pain in the long bones Correct Response Option C (impaired night vision) is correct. This patient shows signs of vitamin A deficiency (thick skin, follicular hyperkeratosis, dry eyes), which are probably caused by a diet lacking in sources of vitamin A (retinol), such as vegetables. Other than keratotic thickening of the epithelium, a major symptom of this vitamin deficiency is impaired night vision as a result of the reduced synthesis of visual purple. Incorrect Responses Option A (bleeding gums) is incorrect. A deficiency of vitamin C leads to defective collagen formation and causes bleeding gums. This condition is often manifested by weakened mucous membranes. Vitamin C (ascorbic acid) is found in citrus fruits, broccoli, tomatoes, and strawberries. Option B (hemolytic anemia) is incorrect. Vitamin E deficiency causes hemolytic anemia. Vitamin E prevents lipid peroxidation of cell membranes; its deficiency damages red blood cell membranes. Vitamin E (tocopherol) is found in vegetable oils and wheat germ. Option D (osteomalacia) is incorrect. Vitamin D deficiency causes osteomalacia, or softening of the bones, a condition that leads to decreased mineralization of bone. Vitamin D (calcitriol) is found in fortified milk or is manufactured in the body from 7-dehydrocholesterol. Option E (pain in the long bones) is incorrect. Vitamin A overdose or vitamin D deficiency may cause pain in the long bones, with associated osteomalacia and an increase in pathologic fractures. Sources of vitamin A (retinol) are liver and yellow and dark green leafy vegetables. 69. A 25-year-old medical student who has had diabetes mellitus since childhood is unconscious when admitted to the emergency room. His wife states that he has been studying for an examination for the past 2 days and has not been injecting his insulin on a regular basis. Physical examination shows a blood pressure of 80/40 mm Hg, heart rate of 124 beats/min, and respiratory rate of 35 breaths/min. His breath has a fruity odor, and his skin turgor is poor. What additional finding is most likely to be increased? A. blood sodium B. blood lactate C. blood pH D. serum bicarbonate E. anion gap Correct Response Option E (anion gap) is correct. The patient is in a coma and has diabetic ketoacidosis. The increased concentration of ketones in the blood will produce an increase in the calculated anion gap. Incorrect Responses Option A (blood sodium) is incorrect. The patient is in diabetic ketoacidosis, which is characterized by sodium depletion. Option B (blood lactate) is incorrect. The patient is in diabetic ketoacidosis, which is -hydroxybutyrate, not lactate. Option C (blood pH) is incorrect. The patient is in diabetic ketoacidosis, which is characterized by a decrease in blood pH. Option D (serum bicarbonate) is incorrect. The patient is in diabetic ketoacidosis, which is characterized by bicarbonate depletion as it is converted to carbon dioxide to buffer the acidity. 70. A 25-year-old man who has been homeless for several months is admitted to the hospital in a state of starvation. He has not eaten anything in the past week. He is started on a diet in which 60% of the calories come from carbohydrates. This diet would most likely increase the activity of what enzyme? A. B. C. D. E. Carnitine acyltransferase Citrate synthase Glucokinase Glucose-6-phosphatase HMG-CoA synthase Correct Response Option C (glucokinase) is correct. The restoration of ample carbohydrate to the diet would increase insulin concentrations. Glucokinase, located in liver and pancreatic cells, is increased in concentration and activity by insulin. Hexokinase, which is located in extrahepatic cells, is not regulated by insulin. Incorrect Responses Option A (carnitine acyltransferase) is incorrect. Carnitine acyltransferase is already maximally increased in order to oxidize fatty acids released during starvation. Option B (citrate synthase) is incorrect. Citrate synthase is already maximally increased in order to metabolize the acetyl CoA from fatty acid oxidation. Option D (glucose-6-phosphatase) is incorrect. Glucose-6-phosphatase is already maximally increased in order to release glucose produced in the liver via gluconeogenesis into the bloodstream. Option E (HMG-CoA synthase) is incorrect. To adapt to starvation, HMG-CoA synthase, the rate-limiting enzyme in ketogenesis, is already maximally increased in order to form ketone bodies. 71. A 23-year-old woman, who has had diabetes mellitus since the age of 10, is unconscious when admitted to the emergency room. Physical examination shows a blood pressure of 80/40 mm Hg, heart rate of 124 beats/min, and respiratory rate of 35 breaths/min. She has poor skin turgor and a fruity odor to her breath. Her blood glucose level is 750 mg/dL. What enzyme is most likely responsible for the presence of a fruity odor on this patient’s breath? A. B. C. Acetyl-CoA carboxylase Citrate lyase HMG-CoA reductase D. E. HMG-CoA synthase Pyruvate dehydrogenase Correct Response Option D (HMG-CoA synthase) is correct. HMG-CoA synthase, the rate-limiting step in the production of ketones from acetyl CoA, accounts for the fruity odor. The smell of acetone on the breath, the signs of volume depletion (poor skin turgor), and the hyperglycemia indicate that the patient is in a state of diabetic ketoacidosis. Lack of insulin leads to elevated levels of free fatty acids and increased fatty acid oxidation in the liver, with concomitant ketogenesis. Incorrect Responses Option A (acetyl-CoA carboxylase) is incorrect. Acetyl-CoA carboxylase, the enzyme that forms malonyl CoA, is the rate-limiting enzyme in the biosynthesis of fatty acids. Fatty acid oxidation is occurring, and fatty acid synthesis is inhibited. Option B (citrate lyase) is incorrect. Citrate lyase converts citrate to oxaloacetate and acetyl CoA, generating cytosolic acetyl CoA for the synthesis of fatty acids. This system is inactive during times of fatty acid oxidation. Option C (HMG-CoA reductase) is incorrect. HMG-CoA reductase is related to cholesterol metabolism and not to ketone metabolism. It converts HMG-CoA to mevalonate. Option E (pyruvate dehydrogenase) is incorrect. This patient’s symptoms are the result of excessive ketone production, which decreases the activity of this enzyme. Acetyl CoA inhibits pyruvate dehydrogenase. 72. During a physical examination of a 24-year-old man who is mentally retarded, the physician notices clumsiness and spasticity of the patient's limbs, emotional lability, and decreased visual-spatial discrimination. Laboratory studies show spherical granular masses in urinary sediment that stain positive with PAS and Alcian blue. The patient most likely has a deficiency of what enzyme? A. B. C. D. E. Arylsulfatase A -Glucosidase Hexosaminidase A Muscle phosphorylase Sphingomyelinase Correct Response Option A (arylsulfatase A) is correct. A deficiency of arylsulfatase results in metachromatic leukodystrophy, an autosomal recessive disease. The disorder causes an accumulation of a sulfatecontaining ceramide (positive PAS and Alcian blue stain) in lysosomes. Demyelination of nerve cells leads to mental retardation and motor abnormalities, which are the most common symptoms of arylsulfatase deficiency. Incorrect Responses -glucosidase results in Gaucher disease, an autosomal recessive disease. This disorder is the most frequently occurring form of sphingolipidosis. It causes accumulation of ceramide with an attached glucose moiety and has different staining properties and tissue localization than metachromatic leukodystrophy. Gaucher cells in the adult form are found in the reticuloendothelial system. Presenting symptoms may include mental retardation, but there are no signs of adverse effects on myelin production. Option C (hexosaminidase A) is incorrect. A deficiency of hexosaminidase A results in TaySachs disease, an autosomal recessive disorder, causing the accumulation of GM2 ganglioside. Symptoms of Tay-Sachs disease include mental retardation and blindness. Option D (muscle phosphorylase) is incorrect. A deficiency in muscle phosphorylase results in McArdle disease, an autosomal recessive disorder. The disease causes the loss of an immediate source of glucose to support muscle contraction, which leads to muscle cramping with exercise (a common presenting symptom). Option E (sphingomyelinase) is incorrect. A deficiency in sphingomyelinase results in NiemannPick disease, an autosomal recessive disorder. This disorder causes sphingomyelin to accumulate in the lysosomes, which produces symptoms such as liver and spleen enlargement in addition to mental retardation. It is usually fatal early in life. 73. An otherwise healthy 1-year-old girl has fasting hypoglycemia after eating a meal containing carbohydrates. Extended fasting does not result in ketosis or lactic acidosis. The patient most likely has what disorder? A. B. C. D. Glycogen storage disease type VI Medium-chain acyl CoA dehydrogenase deficiency Pyruvate carboxylase deficiency Thiamine deficiency Correct Response Option B (medium-chain acyl CoA dehydrogenase deficiency) is correct. Medium-chain acyl CoA dehydrogenase deficiency leads to abnormal formation of carnitine esters excreted in the urine. The resulting carnitine deficiency prevents both the utilization of long-oxidation for fuel -oxidation of fatty acids. The reduced availability of fatty acids for oxidation leads to a reduction in gluconeogenesis, resulting in hypoglycemia. Incorrect Responses Option A (glycogen storage disease type VI) is incorrect. Glycogen storage disease type VI (Hers disease) is caused by a deficiency in liver glycogen phosphorylase, which also produces a fasting hypoglycemia. However, the activation of the gluconeogenic pathway and mobilization of fatty acids to provide energy leads to ketosis in these patients. Option C (pyruvate carboxylase deficiency) is incorrect. Pyruvate carboxylase is a gluconeogenic enzyme that helps convert pyruvate to oxaloacetate. A deficiency of this enzyme leads to lactic acidosis, because pyruvate is unable to be otherwise used in the gluconeogenic pathway. Option D (thiamine deficiency) is incorrect. Thiamine deficiency causes defective operation of pyruvate dehydrogenase, leading to an accumulation of pyruvate and subsequent lactic acidosis. 74. A 65-year-old man with a known history of chronic alcoholism complains of severe chest pain that radiates down the inside of his left arm. An ECG shows a prior acute anterior myocardial infarction (MI). A complete blood cell count shows a macrocytic anemia with hypersegmented neutrophils and mild pancytopenia. No neurologic abnormalities are evident. The plasma homocysteine level is increased. What best explains the increase in plasma homocysteine in this patient? A. Decreased level of cystathionine synthase B. C. D. E. Decreased level of dihydrofolate reductase Decreased level of thymidylate synthetase Decreased serum folate Decreased serum vitamin B12 Correct Response Option D (decreased serum folate) is correct. Alcoholism is the most common cause of folate deficiency. Alcoholism accompanied by a poor diet leads to decreased liver stores of folate and decreased reabsorption of the monoglutamate form of folate in the jejunum. Vitamin B12 (cobalamin) removes the methyl group from N5-methyltetrahydrofolate (circulating form of folate) to produce methyl–vitamin B12 and tetrahydrofolate. The methyl group is then transferred to homocysteine to produce methionine. Therefore, a decrease in either N5-methyltetrahydrofolate or vitamin B12 results in increased plasma homocysteine levels. An increase in plasma homocysteine levels leads to damage of endothelial cells and the potential for vessel thrombosis, which may have played a role in this patient’s MI. Incorrect Responses Option A (decreased level of cystathionine synthase) is incorrect. Deficiency of cystathionine synthase is present in homocystinuria, a rare autosomal recessive disease. Cystathionine synthase catalyzes the reaction that converts homocysteine to cystathionine. Elevated plasma homocysteine and methionine (regenerated from homocysteine) as well as a propensity for vessel thrombosis are characteristic of this disorder. Option B (decreased level of dihydrofolate reductase) is incorrect. Dihydrofolate reductase converts oxidized dihydrofolate back to tetrahydrofolate. The amount of dihydrofolate reductase increases during deficiency of folate by gene amplification. Option C (decreased level of thymidylate synthetase) is incorrect. Thymidylate synthetase converts deoxyribose uridine monophosphate to deoxyribose thymidine monophosphate, which is used in DNA synthesis. This enzyme requires folate, and although the amount of enzyme present is not decreased, its activity will be decreased. Option E (decreased serum vitamin B12) is incorrect. Vitamin B12 deficiency produces neurologic abnormalities in the spinal cord and central nervous system. Because there are no neurologic findings in this case, vitamin B12 deficiency is unlikely. 75. A 52-year-old man with chronic bronchitis requires continuous supplementary O2 to maintain an adequate arterial PO2. What would most likely improve O2 delivery to this patient’s tissues? A. B. C. D. Decreased arterial pH Decreased red blood cell 2,3-bisphosphoglycerate (2,3-BPG) Decreased temperature Hyperventilation Correct Response Option A (decreased arterial pH) is correct. Hemoglobin exists in two forms: the relaxed, or R form, which has high O2 affinity; and the taut, or T form, which has low O2 affinity. By stabilizing the T form, acidosis decreases the affinity of hemoglobin for O2 (i.e., causes a right-shift of the O2-binding curve), thus releasing more O2. This action is referred to as the Bohr effect. Incorrect Responses Option B (decreased red blood cell 2,3-bisphosphoglycerate) is incorrect. The T form of hemoglobin is stabilized by 2,3-BPG, encouraging hemoglobin to release its O2 load. Decreased red blood cell 2,3-BPG increases the affinity of hemoglobin for O2, causing a left shift of the O2-binding curve. Option C (decreased temperature) is incorrect. Elevated temperatures stabilize the T form of hemoglobin. Therefore, decreased temperatures (hypothermia) increase the affinity of hemoglobin for O2, causing the O2-binding curve to shift to the left. Option D (hyperventilation) is incorrect. Hyperventilation increases the loss of CO2, causing respiratory alkalosis and a left-shift of the O2-binding curve. 76. A 3-year-old child shows signs of mental deterioration and skeletal deformities. Microscopic and laboratory analyses show enlarged lysosomes and increased levels of lysosomal enzymes in the serum. These findings are most likely caused by a defect in what process? A. B. C. D. Gene amplification Mannose 6-phosphate attachment Nuclear localization signal Transferrin receptor mRNA Correct Response Option B (mannose 6-phosphate attachment) is correct. This patient has I-cell (inclusion cell) disease (also known as mucolipidosis II), which is caused by defective shuttling of lysosomal enzymes into lysosomes. Enzymes destined for lysosomes normally receive a mannose 6-phosphate marker in the Golgi apparatus. In I-cell disease, the enzymatic ability to phosphorylate mannose in the Golgi apparatus is lacking, and enzymes are targeted at extracellular sites other than lysosomes. Because the lysosomes lack enzymes, undegraded molecules accumulate in the lysosomes and form inclusion bodies. Incorrect Responses Option A (gene amplification) is incorrect. Gene amplification is the process of simultaneously activating multiple copies of DNA fragments that code for the same RNA, thus leading to a drastic increase in the concentration of the final product. This process occurs during both the development of resistance to methotrexate (via amplification of the dihydrofolate reductase gene) and the early stages of development in the ovum (primarily for ribosomal RNA needs). It does not play a role in the targeting of lysosomal enzymes. Option C (nuclear localization signal) is incorrect. The nuclear localization signal, which is a sequence that contains five positively charged amino acids (usually lysine residues), directs proteins into the nucleus. It does not influence the targeting of lysosomal enzymes. Option D (transferrin receptor mRNA) is incorrect. Transferrin, a protein, is responsible for the shuttling of iron in the body. The level of iron in cells directly influences the transcription of the transferrin receptor gene. Therefore, low levels of iron lead to an increased expression of the receptor and, hence, an increased uptake of iron via transferrin endocytosis. However, transferrin receptor mRNA is not related to the targeting of lysosomal enzymes. 77. A 25-year-old woman complains of chest pain. On physical examination, a midsystolic click is audible, followed by a late systolic murmur, indicating a valvular disease. What glycosaminoglycan is associated with the valvular lesion? A. B. C. D. Chondroitin sulfate Dermatan sulfate Heparan sulfate Hyaluronic acid E. Keratan sulfate Correct Response Option B (dermatan sulfate) is correct. This patient has mitral valve prolapse, which is characterized by redundancy of the mitral valve leaflets, causing them to prolapse into the left atrium during systole. This results in a click during prolapse, followed by a short systolic murmur because of mitral regurgitation. The glycosaminoglycan dermatan sulfate is found in valvular tissue in the heart. Glycosaminoglycans, the major components of ground substance in the interstitial tissue, are complexes of branched, negatively charged polysaccharide chains that contain amino sugars (e.g., glucosamine or galactosamine) and acid sugars (iduronic acid or glucuronic acid). Sections through the mitral valve in a patient with mitral valve prolapse would show myxomatous degeneration involving loss of dermatan sulfate. Incorrect Responses Option A (chondroitin sulfate) is incorrect. This glycosaminoglycan is found primarily in cartilage. Option C (heparan sulfate) is incorrect. This glycosaminoglycan is found primarily in the glomerular basement membrane, where it is responsible for the strong negative charge that repels albumin. Option D (hyaluronic acid) is incorrect. This glycosaminoglycan is the major component of synovial fluid, where it serves as a joint lubricant. Option E (keratan sulfate) is incorrect. This glycosaminoglycan is found in cartilage, where it is associated with chondroitin sulfate. 78. A 40-year-old man of Scandinavian descent sees his physician with complaints of shortness of breath and a nonproductive cough. He has smoked one pack of cigarettes daily for 30 years. A chest radiograph shows increased lung volume, and the diaphragm appears flatter than normal. The suspected diagnosis is emphysema because of an enzyme deficiency. This deficiency most likely results in A. B. C. D. E. decreased collagen cross-linking defective collagen fiber synthesis de -keratin synthesis increased neutrophil elastase mutated elastin protein Correct Response Option D (increased neutrophil elastase) is correct. Toxic substances in cigarette smoke trigger a release of inflammatory agents, attracting activated neutrophils to the alveolar region. Neutrophil elastase is released by the activated neutrophils as a part of their antimicrobial action. In the absence of the inhibiting -antitrypsin, neutrophil elastase remains active and destroys alveolar walls, causing panlobular emphysema. Incorrect Responses Option A (decreased collagen cross-linking) is incorrect. Although the crosslinking of collagen is -antitrypsin has no role in this process. Option B (de -Antitrypsin has no role in collagen fiber synthesis. -Keratin is found in hair, nails, and the outer -Antitrypsin has no role in its synthesis. -antitrypsin deficiency, neutrophil elastase cannot be -antitrypsin does not cause a mutation in elastin protein. 79. A 3-year-old male with nephrotic syndrome has a urine protein level >4 g/day. Physical examination reveals generalized edema and ascites. What best describes the effect on calcium in his serum? A. B. C. D. Decreased ionized calcium Decreased total calcium Normal total calcium Increased ionized calcium Correct Response Option B (decreased total calcium) is correct. In nephrotic syndrome the loss of albumin in the urine leads to hypoalbuminemia. Total serum calcium includes calcium bound to albumin (40%) and ionized calcium. Incorrect Responses Option A (decreased ionized calcium) is incorrect. In nephrotic syndrome the ionized calcium fraction remains at normal concentrations. The total calcium is reduced because of the removal of albumin calcium binding capacity. Option C (normal total calcium) is incorrect. Nephrotic syndrome creates a hypoalbuminemia that lowers the total serum calcium by reducing the binding sites normally available on albumin. Option D (increased ionized calcium) is incorrect. In nephrotic syndrome the ionized calcium fraction remains at normal concentrations. The total calcium is reduced because of the removal of albumin calcium binding capacity. 80. A 23-year-old male is admitted to the emergency room after an evening of dancing at a rock concert. He reports that he took a large number of “poppers” to increase his enjoyment at the concert. He has a bluish discoloration to his lips, palms of his hands, and his fingernails. Arterial blood gas analysis shows a normal p02 but the blood is a chocolate-brown color. Administration of pure O2 does not improve the bluish discoloration. Which of the following is the most likely diagnosis? A glucose 6-phosphate deficiency B. carbon monoxide poisoning C. methemoglobinemia D. iron deficiency anemia Correct Response Option C Methemoglobinemia, caused by the amyl nitrate (poppers), has heme iron in the ferric state which cannot bind O2 leading to cyanosis and chocolate-brown color of the blood. Incorrect Responses Option A Several drugs such as salicylates can precipitate a hemolytic anemia in glucose 6-phosphate deficiency but not amyl nitrite. Option B carbon monoxide poisoning produces a cherry red appearance in some severe cases, and it is characterized by headache, dizziness, and nausea, none of which were evident in this patient. Option D Iron deficiency would produce a pallor to the skin, not cyanosis. 81. A 15 year old female complains of fatigue. Her laboratory results indicate her serum iron is 7.5 mmole/liter. Which of the following will most likely be elevated by the indicated therapy? A transferrin B. ceruloplasmin C. ferritin D. haptoglobin E. albumin Correct Response Option A This patient has iron deficiency anemia and requires iron supplements. Transferrin is a serum protein that transports iron to the tissues. Incorrect Responses Option B Ceruloplasmin oxidized iron in the serum to Fe+++ which is the form that binds to transferrin. Option C Ferritin is the protein apoferritin with iron bound to it. It is a storage protein found in the tissues. Option D Haptoglobin is a plasma glycoprotein that binds free (extracorpuscular) hemoglobin preventing it from passing through the glomerulus. Option E Albumin is not involved in the transport of iron. 82. A 45 year old woman developed dementia, myoclonus, weakness and spasticity. She became comatose within months after onset of neurological signs. Postmortem brain biopsy showed spongiform encephalopathy consistent with Creutzfeldt-Jakob disease. Several encephalopathies including Creutzfeldt-Jakob are thought to be caused by prions. What level of protein structure is altered by prions? A primary structure B. secondary structure C. tertiary structure D. quaternary structure Correct Response Option B Prions induc -structure in the native protein in neuronal membranes. This creates a secondary alteration in tertiary structure. Incorrect Responses -globin. Prions do not affect primary structure. Option C Tertiary structure alterations are exemplified by Duchenne muscular dystrophy that produces dystrophin molecules lacking one or more domains. Prions alter secondary structure. Option D Quaternary structur tetramers) . Prions don’t have quaternary structure. Incorrect Responses Option A (bleeding gums) is incorrect. Vitamin C deficiency produces bleeding gums, but not dermatitis and hair loss seen in biotin deficiency. Option B (dementia) is incorrect. Niacin deficiency produces dermatitis as part of the pellagra syndrome, but not hair loss seen in biotin deficiency. Option C (glossitis) is incorrect. Riboflavin deficiency produces glossitis, but not dermatitis and hair loss seen in biotin deficiency. Option E (nystagmus) is incorrect. Thiamine deficiency produces Wernicke-Korsakoff syndrome with symptoms like confusion, ataxia, nystagmus, but not dermatitis and hair loss seen in biotin deficiency.