A 28-year-old Indian male presents with acute haemolytic anaemia following ingestion of fava beans. Laboratory investigations reveal haemoglobin 7.2 g/dL, reticulocyte count 8%, and elevated indirect bilirubin. Peripheral blood smear shows bite cells and Heinz bodies. Enzyme assay confirms deficiency of glucose-6-phosphate dehydrogenase (G6PD). Which of the following best explains the mechanism of haemolysis in this patient?

Explanation

## Pathophysiology of G6PD Deficiency and Haemolysis ### Role of G6PD in Antioxidant Defence **Key Point:** G6PD catalyses the first committed step of the pentose phosphate pathway, generating NADPH from NADP^+^. NADPH is essential for maintaining reduced glutathione (GSH), which protects RBCs from oxidative stress. ### Mechanism of Haemolysis in G6PD Deficiency 1. **Impaired NADPH generation** → Reduced capacity to regenerate GSH from oxidised glutathione (GSSG) 2. **Loss of antioxidant defence** → RBCs become vulnerable to oxidative stress from: - Fava bean compounds (divicine, isouramil) - Sulphonamides, aspirin, antimalarials - Infections (oxidative burst from neutrophils) 3. **Oxidative damage** → Lipid peroxidation of RBC membrane, haemoglobin denaturation (Heinz bodies), and membrane fragmentation 4. **Haemolysis** → Extravascular destruction by spleen (bite cells seen on smear) ### Biochemical Pathway ```mermaid flowchart TD A[Glucose-6-phosphate]:::outcome --> B[G6PD enzyme]:::action B --> C[6-Phosphogluconolactone]:::outcome C --> D[NADPH generation]:::outcome D --> E[Glutathione reduction cycle]:::action E --> F[GSH maintains RBC integrity]:::outcome G[G6PD Deficiency]:::urgent --> H[Reduced NADPH]:::urgent H --> I[Impaired GSH regeneration]:::urgent I --> J[Oxidative stress]:::urgent J --> K[Haemolysis]:::urgent ``` **High-Yield:** The pentose phosphate pathway's primary role in RBCs is NOT energy (ATP) production — it is NADPH generation for antioxidant defence. RBCs rely on glycolysis for ATP. **Clinical Pearl:** Bite cells (RBCs with a "bite" taken out) and Heinz bodies (denatured haemoglobin precipitates) are pathognomonic findings in acute haemolytic episodes of G6PD deficiency. ### Why This Deficiency Matters | Feature | G6PD Deficiency | Normal | | --- | --- | --- | | NADPH production | ↓ Severely reduced | Normal | | GSH regeneration | ↓ Impaired | Normal | | Antioxidant capacity | ↓ Low | Normal | | RBC survival (with oxidative stress) | Shortened (haemolysis) | Normal | **Mnemonic:** **G6PD = GSH Protection Deficiency** — Remember that G6PD's critical role is making NADPH to keep glutathione (GSH) in its reduced, protective form. [cite:Lehninger Principles of Biochemistry 8e Ch 20]