A 1-year-old boy is brought to the physician by his mother because he has become increasingly pale over the past several months. He has otherwise been healthy. Apart from his maternal grandfather, who had a blood disorder and required frequent blood transfusions since birth, the rest of his family, including his parents and older sister, are healthy. Examination shows conjunctival pallor. Laboratory studies show:
Hemoglobin 7.7 g/dL
Mean corpuscular volume 64.8 μm3
Serum
Iron 187 μg/dL
Ferritin 246 ng/mL
A bone marrow aspirate shows numerous ringed sideroblasts. The patient is most likely deficient in an enzyme responsible for which of the following reactions?
Q112
A 65-year-old homeless man with a history of hospitalization for alcohol intoxication is brought in confused. His serum glucose is 39mg/dl. Which of the following best explains his hypoglycemia?
Q113
A 6-year-old Hispanic male was admitted to the hospital for pain in his left thigh that has increased in severity over the past several months to the point that he can no longer walk. His mother explained that he had the pain about a year ago that resolved spontaneously. She also explained that he has had nose bleeds frequently for the past 6 months. On physical exam, hepatosplenomegaly was observed and he was noted to have a low-grade fever. A CT with intravenous contrast demonstrated aseptic necrosis of the left femoral head. Based on the clinical presentation, the attending physician ordered an assay showing significantly low levels of beta-glucocerebrosidase in peripheral blood leukocytes. Which of the following diseases shares a similar mode of inheritance as the disease experienced by this patient?
Q114
An investigator is studying the structural integrity of collagen. Human fibroblasts are cultured on a medium and different enzymes are applied. One of the cultures is supplemented with an enzyme that inhibits lysyl oxidase, preventing the formation of covalent cross-links between collagen α-chains. Which of the following processes is most likely to be impaired as a result?
Q115
A 56-year-old man presents to the emergency room with severe substernal chest pain associated with a 2-hour history of breathlessness and sweating. An electrocardiogram shows an ST-segment elevation myocardial infarction. Cardiac enzyme levels confirm a diagnosis of acute myocardial infarction. The patient is rushed to the catheter lab for angioplasty with stenting. The patient complains of recurrent chest pain in the ICU 56 hours post-angioplasty. Which of the following enzymes facilitates the patient’s diagnosis based on his current symptoms?
Q116
A 37-year-old man is brought to the emergency department because he was found down on a city sidewalk. Upon presentation he is found to be disheveled with multiple poorly healed wounds on his hands and feet. He has had dozens of previous presentations for alcohol intoxication and is currently known to be homeless. Physical examination reveals multiple minor wounds, alopecia, and decreased axillary hair. Upon being aroused, the patient reveals that he has had difficulty with taste and smell and has also had severe diarrhea over the last week. The deficient substance most likely responsible for this patient's symptoms is associated with which of the following proteins?
Q117
A 22-year-old medical student decides to fast for 24 hours after reading about the possible health benefits of fasting. She read that blood glucose levels are maintained by metabolic processes such as hepatic glycogenolysis and hepatic gluconeogenesis during the initial 3 days of fasting. During the day, she did not suffer from the symptoms of hypoglycemia. Which of the following signaling molecules most likely stimulated the reaction which maintained her blood glucose after all her stored glucose was broken down and used up?
Q118
A 17-year-old high school student presents to your office for recent mood and skin changes. The patient is a high school senior who is competing on the wrestling team and recently has lost weight to drop two weight classes over the past several months. He states he has dry, cracking, and irritated skin, as well as a sensation of tingling in his hands and feet. The patient also states that he has not been feeling himself lately. He finds himself more irritable and no longer enjoys many of the activities he once enjoyed. He finds that he often feels fatigued and has trouble concentrating. The patient does not have a significant past medical history and is not on any current medications. The patient admits to drinking alcohol and smoking marijuana on special occasions. He states that he uses supplements that his other team members use. Physical exam is significant for acne, dry, cracked skin around the patient's mouth in particular, and decreased sensation in his lower extremities. Laboratory values are as follows:
Serum:
Na+: 137 mEq/L
Cl-: 101 mEq/L
K+: 4.1 mEq/L
HCO3-: 24 mEq/L
BUN: 15 mg/dL
Glucose: 79 mg/dL
Creatinine: 0.9 mg/dL
Ca2+: 9.2 mg/dL
Mg2+: 1.5 mEq/L
Homocysteine: 11.2 µmol/L (normal: 4.6 to 8.1 µmol/L)
AST: 11 U/L
ALT: 11 U/L
Alkaline phosphatase: 27 U/L
Albumin: 4.5 g/dL
Total protein: 6.9 g/dL
Total bilirubin: 0.5 mg/dL
Direct bilirubin: 0.3 mg/dL
Which of the following is the most likely diagnosis?
Q119
A 5-year-old boy is brought to the physician’s office with complaints of being tired constantly, which has limited his ability to walk or play with his friends. Physical examination in the physician’s office is normal. Further testing reveals that the patient has a genetic mutation in an enzyme and muscle biopsy shows high levels of alpha-ketoglutarate and low levels of succinyl-CoA as compared to normal. The enzyme that is most likely deficient in this patient requires which of the following as a cofactor?
Q120
A 26-year-old African American man comes to the physician because of a 3-day history of fatigue, back pain, and dark urine. One week ago, he developed a headache and was treated with aspirin. He does not smoke or use illicit drugs. Physical examination shows conjunctival pallor. A peripheral blood smear shows erythrocytes with inclusions of denatured hemoglobin. Which of the following enzymes is involved in providing precursors for nucleotide synthesis in this patient?
Metabolism US Medical PG Practice Questions and MCQs
Question 111: A 1-year-old boy is brought to the physician by his mother because he has become increasingly pale over the past several months. He has otherwise been healthy. Apart from his maternal grandfather, who had a blood disorder and required frequent blood transfusions since birth, the rest of his family, including his parents and older sister, are healthy. Examination shows conjunctival pallor. Laboratory studies show:
Hemoglobin 7.7 g/dL
Mean corpuscular volume 64.8 μm3
Serum
Iron 187 μg/dL
Ferritin 246 ng/mL
A bone marrow aspirate shows numerous ringed sideroblasts. The patient is most likely deficient in an enzyme responsible for which of the following reactions?
A. Aminolevulinic acid → porphobilinogen
B. Uroporphyrinogen III → coproporphyrinogen III
C. Glycine + succinyl-CoA → aminolevulinic acid (Correct Answer)
D. Glucose-6-phosphate → 6-phosphogluconate
E. Protoporphyrin → heme
Explanation: ***Glycine + succinyl-CoA → aminolevulinic acid***
- The patient presents with **microcytic anemia** (low MCV) and **sideroblastic anemia** (ringed sideroblasts in bone marrow), along with elevated iron and ferritin, indicating a defect in heme synthesis despite adequate iron.
- The synthesis of **aminolevulinic acid (ALA)** from **glycine and succinyl-CoA** is the *rate-limiting step* in heme synthesis and requires the enzyme **ALA synthase**, which is often deficient in X-linked sideroblastic anemia.
*Aminolevulinic acid → porphobilinogen*
- This reaction is catalyzed by **ALA dehydratase** (also known as porphobilinogen synthase). A deficiency here would lead to an accumulation of ALA, often seen in **lead poisoning**, which is not indicated by the patient's presentation.
- While it's part of the heme synthesis pathway, the specific findings of ringed sideroblasts and elevated iron are more characteristic of a defect earlier in the pathway or an issue with mitochondrial iron utilization.
*Uroporphyrinogen III → coproporphyrinogen III*
- This step is part of the porphyria pathway and is catalyzed by **uroporphyrinogen decarboxylase**, a deficiency of which causes **porphyria cutanea tarda**.
- This condition primarily presents with **photosensitivity** and skin lesions, not typical symptoms of the patient's congenital sideroblastic anemia.
*Glucose-6-phosphate → 6-phosphogluconate*
- This reaction is catalyzed by **glucose-6-phosphate dehydrogenase (G6PD)**, an enzyme central to the **pentose phosphate pathway**.
- A G6PD deficiency causes **hemolytic anemia** triggered by oxidative stress, characterized by **Heinz bodies** and **bite cells**, which is distinct from the microcytic sideroblastic anemia described.
*Protoporphyrin → heme*
- This final step in heme synthesis involves the insertion of iron into protoporphyrin, catalyzed by **ferrochelatase**.
- A deficiency in ferrochelatase would lead to accumulation of protoporphyrin and potentially **erythropoietic protoporphyria**, but the presence of **ringed sideroblasts** and high iron stores points to a mitochondrial defect *before* iron insertion, or a problem with ALA synthesis.
Question 112: A 65-year-old homeless man with a history of hospitalization for alcohol intoxication is brought in confused. His serum glucose is 39mg/dl. Which of the following best explains his hypoglycemia?
A. He has decreased activity of alcohol dehydrogenase
B. Hepatic gluconeogenesis is elevated
C. His hepatic NADH/NAD+ ratio is high (Correct Answer)
D. He has also been using cocaine
E. His hepatic glycogen stores are depleted
Explanation: ***His hepatic NADH/NAD+ ratio is high***
- **Ethanol metabolism** by **alcohol dehydrogenase** and **aldehyde dehydrogenase** generates a large amount of **NADH**, significantly increasing the hepatic NADH/NAD+ ratio.
- This high NADH/NAD+ ratio inhibits several key enzymes in **gluconeogenesis** (e.g., pyruvate carboxylase, malate dehydrogenase), leading to **hypoglycemia** in malnourished individuals, especially after alcohol consumption.
*He has decreased activity of alcohol dehydrogenase*
- **Decreased alcohol dehydrogenase activity** would lead to a slower metabolism of alcohol, potentially prolonging its effects but not directly causing severe hypoglycemia in this manner.
- Individuals with decreased activity metabolize alcohol less efficiently, typically resulting in a **delayed rise in NADH** and potentially less severe metabolic derangements related to ethanol.
*Hepatic gluconeogenesis is elevated*
- The elevated **NADH/NAD+ ratio** due to alcohol metabolism actually **inhibits hepatic gluconeogenesis**, rather than elevating it.
- This **inhibition** contributes to the observed **hypoglycemia**, especially in a patient with likely **depleted glycogen stores** due to malnourishment or chronic alcohol use.
*He has also been using cocaine*
- While possible, the clinical picture of **confusion** and **hypoglycemia** in a chronic alcoholic is most directly explained by the metabolic effects of alcohol itself, particularly its impact on **glucose metabolism**.
- **Cocaine use** would typically present with different symptoms such as **tachycardia**, **hypertension**, or agitation, and is not the most likely explanation for severe hypoglycemia.
*His hepatic glycogen stores are depleted*
- While it is very likely that a homeless, alcoholic individual would have **depleted hepatic glycogen stores** due to poor nutrition, this option alone does not fully explain the **acute hypoglycemia** precipitated by alcohol.
- The combination of **depleted glycogen** and **inhibited gluconeogenesis** (due to the high NADH/NAD+ ratio) is what leads to severe hypoglycemia in this scenario.
Question 113: A 6-year-old Hispanic male was admitted to the hospital for pain in his left thigh that has increased in severity over the past several months to the point that he can no longer walk. His mother explained that he had the pain about a year ago that resolved spontaneously. She also explained that he has had nose bleeds frequently for the past 6 months. On physical exam, hepatosplenomegaly was observed and he was noted to have a low-grade fever. A CT with intravenous contrast demonstrated aseptic necrosis of the left femoral head. Based on the clinical presentation, the attending physician ordered an assay showing significantly low levels of beta-glucocerebrosidase in peripheral blood leukocytes. Which of the following diseases shares a similar mode of inheritance as the disease experienced by this patient?
A. Alport's syndrome
B. Menke's disease
C. Phenylketonuria (Correct Answer)
D. Hemophilia A
E. von Willebrand disease Type 1
Explanation: ***Phenylketonuria***
- The patient's clinical presentation, specifically **aseptic necrosis of the femoral head**, **hepatosplenomegaly**, frequent **nosebleeds**, and significantly low levels of **beta-glucocerebrosidase**, is highly indicative of **Gaucher disease**.
- **Gaucher disease** is an **autosomal recessive** lysosomal storage disorder, and Phenylketonuria (PKU) also follows an **autosomal recessive** inheritance pattern, making it the best answer.
*Alport's syndrome*
- While Alport's syndrome can have an **autosomal recessive** form, the **most common form (85%) is X-linked dominant**, making it a less appropriate answer than PKU which is **always autosomal recessive**.
- This disorder affects the kidneys, ears, and eyes, with key features including **hematuria**, **sensorineural hearing loss**, and ocular abnormalities.
*Menke's disease*
- This is an **X-linked recessive** disorder of copper transport, presenting with clinical features such as **sparse, kinky hair**, developmental delay, and severe neurological degeneration, distinct from Gaucher disease.
- The mode of inheritance (**X-linked recessive**) differs from Gaucher disease's **autosomal recessive** pattern.
*Hemophilia A*
- This is an **X-linked recessive** bleeding disorder caused by a deficiency in factor VIII, characterized by **spontaneous bleeding** into joints and muscles.
- Its **X-linked recessive** inheritance differs from the **autosomal recessive** pattern of Gaucher disease.
*von Willebrand disease Type 1*
- This is a common **autosomal dominant** bleeding disorder caused by a quantitative defect in von Willebrand factor.
- The **autosomal dominant** inheritance pattern is different from the **autosomal recessive** inheritance of Gaucher disease.
Question 114: An investigator is studying the structural integrity of collagen. Human fibroblasts are cultured on a medium and different enzymes are applied. One of the cultures is supplemented with an enzyme that inhibits lysyl oxidase, preventing the formation of covalent cross-links between collagen α-chains. Which of the following processes is most likely to be impaired as a result?
A. Internal elastic lamina formation
B. Ligament relaxation
C. Osteoclast activation
D. Bone matrix synthesis (Correct Answer)
E. Cartilaginous growth plate mineralization
Explanation: ***Bone matrix synthesis***
* **Collagen** is the primary organic component of the bone matrix (osteoid), and its proper cross-linking through **lysyl oxidase-mediated covalent bonds** is crucial for structural integrity and subsequent mineralization.
* **Lysyl oxidase** converts lysine and hydroxylysine residues to aldehydes (allysine and hydroxyallysine), which then form **aldol condensations and Schiff bases** to create stable cross-links between collagen fibrils.
* Inhibiting lysyl oxidase directly compromises the formation of stable collagen fibrils, which are essential for **osteoid production** and bone strength, leading to conditions like **lathyrism** (seen with β-aminopropionitrile exposure).
*Incorrect Option: Internal elastic lamina formation*
* The **internal elastic lamina** is primarily composed of **elastin**, not collagen, and provides arterial elasticity.
* While elastin also requires lysyl oxidase for cross-linking (desmosine and isodesmosine formation), the question specifically asks about **collagen α-chains**, making bone matrix synthesis the more direct answer.
*Incorrect Option: Ligament relaxation*
* **Ligament relaxation** refers to increased laxity, primarily influenced by hormones like relaxin during pregnancy.
* Impairing collagen cross-linking would lead to **ligament weakness and fragility** rather than physiologic relaxation, potentially causing joint instability.
*Incorrect Option: Osteoclast activation*
* **Osteoclast activation** involves bone resorption, regulated by **RANK/RANKL/OPG signaling**, and is independent of newly synthesized collagen cross-linking.
* While collagen integrity affects bone quality, lysyl oxidase inhibition impairs **osteoblast-mediated bone formation**, not osteoclast function.
*Incorrect Option: Cartilaginous growth plate mineralization*
* **Growth plate mineralization** involves calcium phosphate crystal deposition within cartilage matrix, regulated by chondrocytes and factors like alkaline phosphatase.
* While collagen integrity is important in cartilage, the defect in collagen cross-linking most critically affects **bone matrix (osteoid)** synthesis, where type I collagen predominates and provides the scaffold for mineralization.
Question 115: A 56-year-old man presents to the emergency room with severe substernal chest pain associated with a 2-hour history of breathlessness and sweating. An electrocardiogram shows an ST-segment elevation myocardial infarction. Cardiac enzyme levels confirm a diagnosis of acute myocardial infarction. The patient is rushed to the catheter lab for angioplasty with stenting. The patient complains of recurrent chest pain in the ICU 56 hours post-angioplasty. Which of the following enzymes facilitates the patient’s diagnosis based on his current symptoms?
A. Creatine kinase (CK)-MB (Correct Answer)
B. Creatine kinase – MM
C. Troponin T
D. Troponin I
E. Lactate dehydrogenase (LDH)
Explanation: ***Creatine kinase (CK)-MB***
- **CK-MB** is elevated in myocardial infarction, rising within 4-6 hours, peaking at 24 hours, and **returning to baseline within 48-72 hours** after the initial event.
- At **56 hours post-angioplasty**, CK-MB levels should have normalized from the initial MI, making a **new elevation highly specific** for reinfarction or new myocardial injury.
- This makes CK-MB particularly useful for detecting **early reinfarction** when the timing allows it to have cleared from the initial event.
- **Clinical pearl**: This represents classical teaching about cardiac enzyme kinetics, though modern practice increasingly uses serial troponin measurements with delta criteria.
*Creatine kinase – MM*
- **CK-MM** is the predominant isoform of creatine kinase found in **skeletal muscle**, not cardiac muscle.
- While total CK (which includes CK-MM) increases in MI, CK-MM elevation is **not specific to cardiac injury** and can be elevated from skeletal muscle damage or other causes.
- Its lack of cardiac specificity makes it a **poor indicator for myocardial reinfarction**.
*Troponin T*
- **Troponin T** is highly sensitive and specific for myocardial injury, but levels remain **elevated for 7-10 days** following an acute MI.
- At 56 hours post-angioplasty, troponin T would **still be elevated from the initial MI**, making it difficult to distinguish baseline elevation from a new acute event.
- While a **significant rise (>20%) from the previous value** can indicate reinfarction, the persistently elevated baseline makes interpretation more complex compared to CK-MB which should have normalized.
*Troponin I*
- **Troponin I** remains elevated for **5-7 days** following an acute MI, similar to troponin T.
- At 56 hours post-initial MI, troponin I levels would **still be elevated**, making it challenging to clearly identify a new ischemic event without comparing to prior values.
- Though troponins are the **gold standard for MI diagnosis**, their prolonged elevation window makes CK-MB more straightforward for detecting reinfarction at this specific timepoint (when CK-MB should have returned to baseline).
*Lactate dehydrogenase (LDH)*
- **LDH** elevation occurs later in MI (24-48 hours after onset) and remains elevated for **10-14 days**.
- Due to its **delayed rise and prolonged elevation**, LDH is not useful for diagnosing acute reinfarction in the early post-MI period.
- LDH lacks the rapid kinetics and cardiac specificity needed for timely diagnosis of new myocardial injury.
Question 116: A 37-year-old man is brought to the emergency department because he was found down on a city sidewalk. Upon presentation he is found to be disheveled with multiple poorly healed wounds on his hands and feet. He has had dozens of previous presentations for alcohol intoxication and is currently known to be homeless. Physical examination reveals multiple minor wounds, alopecia, and decreased axillary hair. Upon being aroused, the patient reveals that he has had difficulty with taste and smell and has also had severe diarrhea over the last week. The deficient substance most likely responsible for this patient's symptoms is associated with which of the following proteins?
A. Tyrosinase
B. Hemoglobin
C. Glutathione peroxidase
D. RNA polymerase (Correct Answer)
E. Thyroid hormone
Explanation: ***Correct: RNA polymerase***
* The clinical presentation of **poorly healed wounds, alopecia, decreased axillary hair, dysgeusia/anosmia, and diarrhea** in a homeless patient with chronic alcoholism is classic for **zinc deficiency**.
* **Zinc is an essential cofactor for RNA polymerase**, the enzyme responsible for DNA transcription and ultimately protein synthesis. Zinc deficiency impairs cellular proliferation and protein synthesis, which explains the poor wound healing, hair loss, and other manifestations.
* Zinc is also a cofactor for over 300 enzymes including alkaline phosphatase, carbonic anhydrase, superoxide dismutase, and various matrix metalloproteinases critical for wound healing and tissue maintenance.
*Incorrect: Glutathione peroxidase*
* **Glutathione peroxidase requires SELENIUM, not zinc**, as its essential cofactor. This enzyme protects against oxidative damage by reducing hydrogen peroxide.
* Selenium deficiency presents with **cardiomyopathy (Keshan disease), myopathy, and thyroid dysfunction**, not the constellation of symptoms seen in this patient.
*Incorrect: Tyrosinase*
* **Tyrosinase is a copper-dependent enzyme** involved in melanin synthesis. Copper deficiency causes **anemia, neutropenia, and neurological symptoms** (myelopathy), not the dermatologic and sensory changes seen here.
* While copper deficiency can occur in alcoholism, the specific symptoms of taste/smell disturbances and characteristic skin findings point to zinc deficiency.
*Incorrect: Thyroid hormone*
* Thyroid hormone synthesis requires **iodine**, not zinc. Hypothyroidism presents with **fatigue, weight gain, cold intolerance, and bradycardia**.
* The patient's acute presentation with diarrhea, taste/smell disturbances, and poor wound healing does not fit thyroid dysfunction.
*Incorrect: Hemoglobin*
* Hemoglobin requires **iron** for oxygen transport. Iron deficiency causes **microcytic anemia with fatigue, pallor, and koilonychia**.
* While chronic alcoholics may develop anemia (often macrocytic from folate/B12 deficiency), the specific symptoms of dysgeusia, anosmia, and characteristic dermatologic findings indicate zinc deficiency as the primary issue.
Question 117: A 22-year-old medical student decides to fast for 24 hours after reading about the possible health benefits of fasting. She read that blood glucose levels are maintained by metabolic processes such as hepatic glycogenolysis and hepatic gluconeogenesis during the initial 3 days of fasting. During the day, she did not suffer from the symptoms of hypoglycemia. Which of the following signaling molecules most likely stimulated the reaction which maintained her blood glucose after all her stored glucose was broken down and used up?
A. Adenosine diphosphate
B. Acetyl CoA (Correct Answer)
C. Acetate
D. Citrate
E. Adenosine monophosphate
Explanation: ***Acetyl CoA***
- **Acetyl CoA** is the key **allosteric activator of pyruvate carboxylase**, the first committed enzyme of gluconeogenesis that converts pyruvate to oxaloacetate.
- During prolonged fasting after glycogen stores are depleted, the body shifts to **fatty acid oxidation** (β-oxidation), which produces large amounts of **Acetyl CoA**.
- High **Acetyl CoA** levels signal that fat is being oxidized for energy, and simultaneously **activate gluconeogenesis** to maintain blood glucose for glucose-dependent tissues (brain, RBCs).
- This is the primary signaling mechanism that directly stimulates the gluconeogenic pathway after glycogen is exhausted.
*Adenosine monophosphate (AMP)*
- **AMP** levels rise during energy depletion and activate **AMP-activated protein kinase (AMPK)**.
- However, AMPK **inhibits gluconeogenesis** (not stimulates it) because gluconeogenesis is an **ATP-consuming** anabolic process (requires 6 ATP per glucose).
- AMPK promotes ATP-generating catabolic processes like fatty acid oxidation, but suppresses ATP-consuming processes like gluconeogenesis and fatty acid synthesis.
*Adenosine diphosphate (ADP)*
- **ADP** accumulates when ATP is hydrolyzed and signals moderate energy deficit.
- ADP is primarily a substrate for ATP regeneration via oxidative phosphorylation and does not directly regulate gluconeogenesis.
- Its role in metabolic regulation is less specific than allosteric activators like Acetyl CoA.
*Acetate*
- **Acetate** can be converted to Acetyl CoA but is not a direct signaling molecule for gluconeogenesis.
- It is a minor metabolite that may be produced in specific conditions (e.g., alcohol metabolism, ketoacidosis) but does not play a primary role in fasting-induced glucose homeostasis.
*Citrate*
- **Citrate** is a Krebs cycle intermediate that inhibits **phosphofructokinase-1 (PFK-1)** in glycolysis, thus reducing glucose breakdown.
- While citrate inhibition of glycolysis indirectly favors gluconeogenesis by preventing futile cycling, citrate does not **directly activate** gluconeogenic enzymes.
- Citrate primarily signals energy sufficiency and promotes fatty acid synthesis in the fed state, not fasting gluconeogenesis.
Question 118: A 17-year-old high school student presents to your office for recent mood and skin changes. The patient is a high school senior who is competing on the wrestling team and recently has lost weight to drop two weight classes over the past several months. He states he has dry, cracking, and irritated skin, as well as a sensation of tingling in his hands and feet. The patient also states that he has not been feeling himself lately. He finds himself more irritable and no longer enjoys many of the activities he once enjoyed. He finds that he often feels fatigued and has trouble concentrating. The patient does not have a significant past medical history and is not on any current medications. The patient admits to drinking alcohol and smoking marijuana on special occasions. He states that he uses supplements that his other team members use. Physical exam is significant for acne, dry, cracked skin around the patient's mouth in particular, and decreased sensation in his lower extremities. Laboratory values are as follows:
Serum:
Na+: 137 mEq/L
Cl-: 101 mEq/L
K+: 4.1 mEq/L
HCO3-: 24 mEq/L
BUN: 15 mg/dL
Glucose: 79 mg/dL
Creatinine: 0.9 mg/dL
Ca2+: 9.2 mg/dL
Mg2+: 1.5 mEq/L
Homocysteine: 11.2 µmol/L (normal: 4.6 to 8.1 µmol/L)
AST: 11 U/L
ALT: 11 U/L
Alkaline phosphatase: 27 U/L
Albumin: 4.5 g/dL
Total protein: 6.9 g/dL
Total bilirubin: 0.5 mg/dL
Direct bilirubin: 0.3 mg/dL
Which of the following is the most likely diagnosis?
A. Depression secondary to dietary changes
B. Anabolic steroid use
C. Dermatologic fungal infection
D. Viral infection
E. Water soluble vitamin deficiency (Correct Answer)
Explanation: ***Water soluble vitamin deficiency***
- The patient's symptoms (irritability, fatigue, poor concentration, dry cracking skin around the mouth, tingling in hands and feet) coupled with a history of rapid weight loss for wrestling ("cutting weight") and elevated **homocysteine** levels are highly suggestive of a vitamin deficiency, specifically **B vitamins** (e.g., B6, B9, B12) which are water-soluble and easily depleted with poor dietary intake and increased metabolic demand.
- The elevated **homocysteine** is a key indicator, as vitamins B6, B9 (folate), and B12 are crucial cofactors in its metabolism. Deficiencies in these vitamins lead to hyperhomocysteinemia, which can cause neurological symptoms and skin manifestations.
*Depression secondary to dietary changes*
- While the patient exhibits mood changes (irritability, anhedonia, fatigue), these symptoms are better explained within the context of **nutritional deficiency**, which can directly impact neurotransmitter synthesis and overall neurological function.
- Depression alone would not typically account for the specific dermatological findings (**dry, cracking skin around the mouth**) or the **peripheral neuropathy** (tingling, decreased sensation) in conjunction with elevated homocysteine.
*Anabolic steroid use*
- Anabolic steroid use can cause **acne** and mood changes (irritability, aggression), but typically does not cause **dry, cracking skin around the mouth** or specific **tingling/numbness** in the extremities or elevated **homocysteine levels**.
- While the patient admits to using supplements, there's no direct evidence to suggest anabolic steroid use, and the constellation of symptoms points more strongly to a nutritional cause.
*Dermatologic fungal infection*
- A fungal infection might explain some skin changes, but it would not account for the systemic symptoms like **mood changes**, **fatigue**, **tingling in the hands and feet**, or the elevated **homocysteine**.
- The description of "dry, cracking skin around the patient's mouth" is more consistent with **cheilosis** or **angular stomatitis**, commonly associated with B vitamin deficiencies, rather than a typical fungal infection.
*Viral infection*
- A viral infection could cause **fatigue** and general malaise, but it would not explain the specific skin findings like **dry, cracking skin around the mouth**, **tingling in hands and feet**, or the elevated **homocysteine** levels, which are long-standing signs of nutritional deficiencies.
- The patient's symptoms have been ongoing for "several months," which is less typical for an acute viral illness.
Question 119: A 5-year-old boy is brought to the physician’s office with complaints of being tired constantly, which has limited his ability to walk or play with his friends. Physical examination in the physician’s office is normal. Further testing reveals that the patient has a genetic mutation in an enzyme and muscle biopsy shows high levels of alpha-ketoglutarate and low levels of succinyl-CoA as compared to normal. The enzyme that is most likely deficient in this patient requires which of the following as a cofactor?
A. Vitamin B6
B. NADH
C. Carbon dioxide
D. ATP
E. Vitamin B1 (Correct Answer)
Explanation: ***Vitamin B1***
- The patient's symptoms of fatigue and exercise intolerance, along with high levels of **alpha-ketoglutarate** and low levels of **succinyl-CoA**, indicate a defect in the **alpha-ketoglutarate dehydrogenase complex**.
- This enzyme complex, crucial for the **Krebs cycle**, requires **thiamine pyrophosphate (TPP)**, a derivative of **Vitamin B1**, as a vital cofactor.
*Vitamin B6*
- **Vitamin B6 (pyridoxine)** is a cofactor for enzymes involved in amino acid metabolism, such as **transaminases** and **decarboxylases**, but not specifically for alpha-ketoglutarate dehydrogenase.
- A deficiency in Vitamin B6 would lead to different metabolic profiles, not the specific accumulation of alpha-ketoglutarate.
*NADH*
- **NADH** is a product of several enzymatic reactions within the Krebs cycle, including the one catalyzed by alpha-ketoglutarate dehydrogenase, rather than a cofactor for this specific enzyme.
- While essential for the electron transport chain, NADH's role is as an electron carrier, not a direct cofactor for the alpha-ketoglutarate dehydrogenase complex's catalytic activity.
*Carbon dioxide*
- **Carbon dioxide** is often a product of decarboxylation reactions within the Krebs cycle (e.g., isocitrate dehydrogenase and alpha-ketoglutarate dehydrogenase), but it does not serve as a cofactor.
- Its presence or absence as a cofactor would not directly explain the enzymatic deficiency observed in this patient.
*ATP*
- **ATP** (adenosine triphosphate) is the primary energy currency of the cell, consumed or produced by many metabolic pathways, but it is not a direct cofactor for the alpha-ketoglutarate dehydrogenase complex.
- While energy is needed for many cellular processes, a direct ATP deficiency would manifest differently and would not specifically cause a buildup of alpha-ketoglutarate.
Question 120: A 26-year-old African American man comes to the physician because of a 3-day history of fatigue, back pain, and dark urine. One week ago, he developed a headache and was treated with aspirin. He does not smoke or use illicit drugs. Physical examination shows conjunctival pallor. A peripheral blood smear shows erythrocytes with inclusions of denatured hemoglobin. Which of the following enzymes is involved in providing precursors for nucleotide synthesis in this patient?
A. Glucose-6-phosphatase
B. Carbamoyl phosphate synthetase I
C. Pyruvate carboxylase
D. Transaldolase (Correct Answer)
E. Enolase
Explanation: ***Transaldolase***
- This patient likely has **glucose-6-phosphate dehydrogenase (G6PD) deficiency**, indicated by fatigue, dark urine (hemolysis), and **Heinz bodies** (erythrocytes with inclusions of denatured hemoglobin) after aspirin exposure, which is an **oxidative stressor**.
- **Transaldolase** is an enzyme in the **non-oxidative phase of the pentose phosphate pathway (PPP)**, which produces **ribose-5-phosphate**, a precursor for nucleotide synthesis.
*Glucose-6-phosphatase*
- **Glucose-6-phosphatase** is involved in **gluconeogenesis** and glycogenolysis, primarily in the liver and kidneys, to release free glucose into the bloodstream.
- Deficiency leads to **Von Gierke disease**, characterized by hypoglycemia, hepatomegaly, lactic acidosis, and hyperlipidemia, which are not described here.
*Carbamoyl phosphate synthetase I*
- **Carbamoyl phosphate synthetase I (CPS I)** is a mitochondrial enzyme that catalyzes the first committed step in the **urea cycle**, converting ammonia and bicarbonate into carbamoyl phosphate.
- Its deficiency causes **hyperammonemia**, not hemolytic anemia or issues with nucleotide synthesis.
*Pyruvate carboxylase*
- **Pyruvate carboxylase** is a mitochondrial enzyme that converts **pyruvate to oxaloacetate**, a crucial step in **gluconeogenesis** and replenishing intermediates of the citric acid cycle.
- Deficiency can lead to lactic acidosis and hypoglycemia, which are not the primary symptoms here.
*Enolase*
- **Enolase** is an enzyme in **glycolysis** that catalyzes the dehydration of 2-phosphoglycerate to phosphoenolpyruvate.
- It is not directly involved in providing precursors for nucleotide synthesis.
