A 6-year-old boy of South Asian descent presents to the pediatric emergency department with acute hemolytic anemia, jaundice, and dark urine following ingestion of fava beans at a family meal. Peripheral blood smear shows Heinz bodies and bite cells. The enzyme marked **A** in the diagram is suspected to be deficient. Which of the following is the PRIMARY mechanism by which deficiency of this enzyme predisposes to hemolysis in this clinical scenario?

Explanation

## Why option 1 is correct The enzyme marked **A** is Glucose-6-Phosphate Dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway. G6PD catalyzes the first committed step, producing NADPH. NADPH is essential for regenerating reduced glutathione (GSH) via glutathione reductase, which neutralizes reactive oxygen species (ROS) and protects RBC membranes from oxidative damage. In G6PD deficiency, RBCs cannot generate sufficient NADPH, leading to depletion of GSH, accumulation of ROS, and oxidative denaturation of hemoglobin (forming Heinz bodies). Oxidant triggers—including fava bean components (divicine and isouramil)—overwhelm the already-compromised antioxidant defense, precipitating acute hemolytic anemia. This is the pathognomonic mechanism of G6PD-deficiency hemolysis (Harper 32e Ch 21; Robbins 10e Ch 14). ## Why each distractor is wrong - **Option 2**: While the pentose phosphate pathway does produce ribose-5-phosphate (structure **D**) for nucleotide synthesis, RBCs are mature cells lacking nuclei and do not perform DNA synthesis or repair. Nucleotide deficiency does not cause hemolysis in G6PD deficiency. - **Option 3**: G6PD deficiency does not directly impair glycolytic ATP generation. Glycolysis proceeds normally via the main glucose pathway. ATP depletion is not the primary mechanism of G6PD-deficiency hemolysis. - **Option 4**: Accumulation of glucose-6-phosphate in G6PD deficiency does not cause glycogen synthesis (RBCs lack glycogen synthase and do not store glycogen). This is biochemically implausible and not a recognized pathophysiology of G6PD hemolysis. **High-Yield:** G6PD deficiency → ↓NADPH → ↓GSH → ↑ROS → Heinz bodies + hemolysis (especially with oxidant triggers). Most common enzymopathy worldwide; X-linked recessive; high prevalence in Mediterranean, African, and South Asian populations. [cite: Harper 32e Ch 21; Robbins 10e Ch 14]