A 28-year-old Indian male presents to the emergency department with acute hemolytic anemia following ingestion of fava beans at a wedding. Laboratory investigations reveal: Hemoglobin 7.2 g/dL, reticulocyte count 8.5%, peripheral smear shows Heinz bodies, and urine is dark brown. Serum bilirubin is elevated at 4.2 mg/dL. The patient's mother mentions a family history of similar episodes triggered by infections or certain medications. Which enzyme deficiency is most likely responsible for this clinical presentation?

Explanation

## Clinical Diagnosis: G6PD Deficiency ### Pathophysiology **Key Point:** G6PD deficiency is an X-linked disorder affecting the pentose phosphate pathway (PPP), the primary source of NADPH in red blood cells. NADPH is essential for maintaining reduced glutathione (GSH), which protects RBCs from oxidative stress. ### Why This Patient Has Hemolytic Crisis 1. **Oxidative trigger**: Fava beans contain divicine and isouramil, potent oxidizing agents. 2. **Deficient NADPH production**: Without adequate G6PD activity, the PPP cannot generate sufficient NADPH. 3. **Glutathione depletion**: Low NADPH → reduced GSH regeneration → oxidative damage to RBC membranes. 4. **Hemolysis**: Heinz bodies (denatured hemoglobin precipitates) form and are removed by splenic macrophages, causing intravascular and extravascular hemolysis. ### Clinical Features Matching This Case | Feature | Explanation | |---------|-------------| | **Acute hemolytic anemia** | Oxidative stress overwhelms antioxidant defenses | | **Heinz bodies on smear** | Pathognomonic for G6PD deficiency | | **Dark urine (hemoglobinuria)** | Intravascular hemolysis releases free hemoglobin | | **Elevated reticulocyte count** | Bone marrow compensatory response | | **Elevated bilirubin** | Hemolysis → unconjugated hyperbilirubinemia | | **Family history pattern** | X-linked inheritance (more common in males) | | **Fava bean trigger** | Classic oxidative stressor | ### High-Yield Biochemistry **High-Yield:** The pentose phosphate pathway produces NADPH in two oxidative steps: - Glucose-6-phosphate → 6-phosphogluconolactone (via G6PD) - 6-phosphogluconate → Ribulose-5-phosphate (via 6-phosphogluconate dehydrogenase) NADPH is then used by glutathione reductase to regenerate reduced GSH from oxidized GSSG: $$GSSG + NADPH + H^+ \rightarrow 2 \ GSH + NADP^+$$ Without G6PD, this cycle fails, and RBCs cannot defend against oxidative insults. ### Diagnostic Confirmation - **G6PD enzyme assay**: Quantitative measurement of enzyme activity (gold standard) - **Heinz body stain**: Brilliant cresyl blue or methylene blue staining (visible in acute hemolysis) - **Osmotic fragility test**: May show increased fragility - **Flow cytometry**: Can detect G6PD-deficient RBC populations **Clinical Pearl:** Acute hemolytic episodes in G6PD deficiency are self-limited if the oxidative trigger is removed. Most patients remain asymptomatic between crises because older RBCs (with some residual G6PD activity) are preferentially hemolyzed, leaving younger RBCs with higher enzyme levels. **Mnemonic: FAVA BEANS trigger G6PD crisis** — Fava, Aspirin, Sulfonamides, Antimalarials (primaquine), Nitrofurantoin, Sulfa drugs, Infections, Neonatal jaundice.