USMLE PRACTICE QUESTION #118

TOPIC: Pathology of the Glycolytic Pathway

Dec 30, 2024

USMLE practice question #118 will test your understanding of a commonly tested biochemistry concept linked to the glycolytic pathway.

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A 7-year-old boy presents with chronic pallor and occasional jaundice. He has a history of mild splenomegaly noted on previous examinations. Laboratory results show a normocytic, normochromic anemia with an elevated reticulocyte count. Direct antiglobulin test is negative. Further evaluation reveals increased levels of 2,3-bisphosphoglycerate within his red blood cells. A defect in which of the following enzymes is most likely causing this clinical picture?

A) Glucose-6-phosphate dehydrogenase
B) Hexokinase
C) Pyruvate kinase
D) Phosphofructokinase-1
E) Lactate dehydrogenase

Detailed Breakdown of Answers + Correct Answer Below ⏬

ANSWER + QUESTION BREAKDOWN

It’s important to adopt the correct MENTAL MODEL when answering USMLE questions; it saves time and increases accuracy. The mental model outlined below is a foundational component of our test-taking skills masterclass (check it out if you want to elevate your skills). Here’s how to think through this question:

Step 1. Read the last line to get to the heart of the question: “A defect in which of the following enzymes is most likely causing this clinical picture?”

Step 2: Is this a first-, second-, or third-order question?
Answer: 2nd order. 1st: Identify the condition; 2nd: Isolate the responsible enzyme.

Step 3: Read the vignette carefully and ask yourself: “Based on the given information, which enzyme is most likely deficient/defective?”

Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.

GENERAL ANALYSIS

This vignette describes a 7-year-old boy with chronic pallor, occasional jaundice, and a history of mild splenomegaly. Laboratory findings reveal a normocytic, normochromic anemia with an elevated reticulocyte count, suggesting hemolysis. The direct antiglobulin test is negative, ruling out autoimmune hemolytic anemia. Elevated levels of 2,3-bisphosphoglycerate (2,3-BPG) in red blood cells (RBCs) point to a metabolic defect in glycolysis.

ANSWER CHOICES:

CHOICE A: Glucose-6-phosphate dehydrogenase

Explanation: Glucose-6-phosphate dehydrogenase (G6PD) deficiency causes episodic hemolysis triggered by oxidative stress (e.g., infections or certain drugs). It affects the pentose phosphate pathway, not glycolysis.

Why Incorrect: G6PD deficiency does not cause chronically elevated 2,3-BPG levels or chronic hemolysis with splenomegaly. It is associated with oxidative damage rather than glycolytic defects.

CHOICE B: Hexokinase

Explanation: Hexokinase catalyzes the first step of glycolysis, converting glucose to glucose-6-phosphate. A deficiency would impair all downstream glycolytic steps, leading to severe ATP depletion.

Why Incorrect: Hexokinase deficiency is extremely rare and would cause more severe systemic effects due to impaired glucose metabolism in all cells, not just RBCs.

CHOICE C: Pyruvate kinase

Explanation: Pyruvate kinase catalyzes the final step of glycolysis, converting phosphoenolpyruvate (PEP) to pyruvate with ATP generation. A deficiency leads to ATP depletion in RBCs, causing membrane instability and chronic hemolysis. The block in glycolysis increases upstream intermediates like 2,3-BPG.

Why Correct: Pyruvate kinase deficiency explains the elevated 2,3-BPG levels, chronic hemolysis (normocytic anemia with reticulocytosis), splenomegaly, and occasional jaundice seen in this patient.

CHOICE D: Phosphofructokinase-1

Explanation: Phosphofructokinase-1 (PFK-1) is a key regulatory enzyme in glycolysis that converts fructose-6-phosphate to fructose-1,6-bisphosphate. A deficiency would impair glycolysis upstream.

Why Incorrect: While PFK-1 deficiency can cause hemolysis (as seen in glycogen storage disease type VII), it does not lead to elevated 2,3-BPG levels because it blocks glycolysis before 2,3-BPG production.

CHOICE E: Lactate dehydrogenase

Explanation: Lactate dehydrogenase converts pyruvate to lactate during anaerobic metabolism. A deficiency would impair lactate production but does not directly affect 2,3-BPG levels.

Why Incorrect: Lactate dehydrogenase deficiency does not explain the elevated 2,3-BPG levels or chronic hemolysis seen in this patient.

FINAL VERDICT…

The patient's symptoms—chronic pallor, occasional jaundice, splenomegaly, normocytic anemia with reticulocytosis—are consistent with a chronic hemolytic anemia caused by a metabolic defect in RBCs. The elevated 2,3-BPG levels point specifically to a defect in glycolysis at or near pyruvate kinase. Pyruvate kinase deficiency leads to ATP depletion in RBCs and increased shunting of intermediates into the Rapoport-Luebering pathway, which produces 2,3-BPG. This condition results in chronic hemolysis and compensatory reticulocytosis.

KEY CONCEPTS:

Pyruvate kinase deficiency is an autosomal recessive disorder that results in impaired ATP production in RBCs due to defective conversion of phosphoenolpyruvate (PEP) to pyruvate.
ATP depletion leads to loss of RBC membrane integrity, resulting in chronic hemolysis and splenomegaly.
In pyruvate kinase deficiency, 2,3-BPG levels are elevated because the glycolytic pathway is disrupted upstream of pyruvate kinase. This shunts intermediates into the Rapoport-Luebering pathway, increasing 2,3-BPG production.

CORRECT ANSWER: C) Pyruvate kinase