In G6PD deficiency, which of the following is the mechanism of hemolysis during oxidative stress?

## G6PD Deficiency: Oxidative Hemolysis Mechanism **Key Point:** G6PD deficiency impairs the pentose phosphate pathway, compromising the antioxidant defense system of the red cell. ### The Pentose Phosphate Pathway and Antioxidant Defense ```mermaid flowchart TD A[Glucose-6-phosphate]:::action --> B[G6PD enzyme]:::action B --> C[6-Phosphogluconolactone]:::outcome C --> D[NADPH production]:::outcome D --> E[Reduced Glutathione GSH]:::action E --> F[Neutralizes free radicals & H₂O₂]:::action F --> G[RBC survives oxidative stress]:::outcome H[Oxidative stress trigger]:::urgent --> I{G6PD deficient?}:::decision I -->|No| G I -->|Yes| J[NADPH depleted]:::urgent J --> K[GSH depleted]:::urgent K --> L[Free radicals accumulate]:::urgent L --> M[Hemoglobin denaturation Heinz bodies]:::urgent M --> N[Hemolysis]:::urgent ``` ### Step-by-Step Mechanism 1. **Normal state:** G6PD catalyzes oxidation of glucose-6-phosphate → generates NADPH 2. **NADPH role:** Reduces oxidized glutathione (GSSG) → regenerates reduced glutathione (GSH) 3. **GSH function:** Neutralizes hydrogen peroxide (H₂O₂) and free radicals via glutathione peroxidase 4. **In G6PD deficiency:** ↓ NADPH → ↓ GSH regeneration → ↑ free radicals 5. **Result:** Oxidative damage to hemoglobin → Heinz body formation → hemolysis ### Triggers of Hemolysis in G6PD Deficiency **Mnemonic:** **SANDS** = Sulfonamides, Aspirin, NSAIDs, Dapsone, Sulfa drugs Other triggers: - Infections (bacterial, viral, fungal) - Fava beans (hence "favism") - Oxidizing drugs (primaquine, nitrofurantoin, phenazopyridine) - Severe exercise **High-Yield:** Heinz bodies are precipitated denatured hemoglobin visible on supravital staining (brilliant cresyl blue or new methylene blue), pathognomonic for G6PD hemolysis. ### Laboratory Findings During Acute Hemolysis | Finding | Significance | | --- | --- | | **Heinz bodies** | Denatured Hb; seen on supravital stain | | **Bite cells** | RBCs with Heinz bodies removed by spleen | | **Elevated reticulocyte count** | Bone marrow response | | **Elevated indirect bilirubin & LDH** | Hemolysis markers | | **Low haptoglobin** | Consumed by free Hb | | **Hemoglobinuria** | Excess free Hb in urine | **Clinical Pearl:** G6PD deficiency is X-linked recessive; hemolytic episodes are typically self-limited because young RBCs (reticulocytes) have higher G6PD activity and survive better.