A 4-year-old girl of Amish descent presents with lifelong neonatal jaundice, chronic anemia (Hb 8.5 g/dL), splenomegaly, and pigment gallstones. Peripheral smear shows echinocytes with increased reticulocytes; osmotic fragility test is normal. Genetic testing reveals a homozygous missense mutation in the gene marked **A** on the diagram. Which of the following best explains why this patient tolerates her anemia better than the hemoglobin level would suggest?
A. Enhanced cardiac output and increased blood flow compensate for reduced hemoglobin without metabolic derangement
B. Accumulation of 2,3-bisphosphoglycerate (2,3-BPG) right-shifts the oxygen-hemoglobin dissociation curve, improving oxygen delivery to tissues
C. Compensatory polycythemia develops early in infancy, maintaining adequate oxygen-carrying capacity despite low hemoglobin
D. Increased fetal hemoglobin (HbF) production persists into childhood, providing superior oxygen affinity and tissue oxygenation
Explanation
Why accumulation of 2,3-BPG is correct
Pyruvate kinase catalyzes the final step of glycolysis (phosphoenolpyruvate → pyruvate). In PK deficiency, the block at this step causes accumulation of upstream glycolytic intermediates, particularly 2,3-bisphosphoglycerate (2,3-BPG). Elevated 2,3-BPG right-shifts the oxygen-hemoglobin dissociation curve, reducing hemoglobin's oxygen affinity and facilitating oxygen unloading to tissues. This metabolic adaptation partially compensates for the anemia, allowing patients to tolerate lower hemoglobin levels better than would be expected. The mutation in PKLR on chromosome 1q21 (marked A) is the genetic basis for this enzyme deficiency and the resulting 2,3-BPG accumulation.
Why each distractor is wrong
Compensatory polycythemia: Polycythemia does not develop in chronic hemolytic anemia from PK deficiency. The reticulocytosis seen reflects increased RBC production in response to hemolysis, but this does not raise hemoglobin to compensatory levels. Polycythemia is seen in chronic hypoxia or EPO-secreting tumors, not in hemolytic anemias.
Increased fetal hemoglobin (HbF) persistence: HbF normally switches to adult hemoglobin (HbA) by 6 months of age. Persistent HbF is seen in hereditary persistence of fetal hemoglobin (HPFH) and thalassemia, not in PK deficiency. The patient's hemoglobin is low (8.5 g/dL), not elevated as would occur with HbF compensation.
Enhanced cardiac output compensation: While cardiac output does increase in chronic anemia, this is a general compensatory mechanism and does not explain why PK deficiency patients tolerate anemia better than other hemolytic anemias with similar hemoglobin levels. The question specifically asks for the mechanism unique to PK deficiency, which is the 2,3-BPG effect.
High-YieldNEET PG
PK deficiency → ATP depletion + 2,3-BPG accumulation; the latter right-shifts the O₂-Hb curve and partially compensates for anemia, explaining better-than-expected clinical tolerance.
Harrison 21e Ch 96; Grace Blood 2018 PK deficiency
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