A 32-year-old woman of Indian origin presents with recurrent haemolytic episodes triggered by fava bean consumption and sulfonamide antibiotics. Laboratory investigation reveals reduced erythrocyte NADPH levels and decreased glutathione reductase activity. Which is the most common enzyme deficiency responsible for this clinical presentation?

## G6PD Deficiency and Haemolytic Crisis **Key Point:** G6PD deficiency is the most common enzyme deficiency worldwide (affecting >400 million people) and is the most frequent cause of acute haemolytic anaemia triggered by oxidative stress. ### Clinical Presentation of G6PD Deficiency **High-Yield:** The classic triad: 1. **Trigger:** Oxidative stress (fava beans, sulfonamides, antimalarials, aspirin, infections) 2. **Mechanism:** Deficient NADPH → impaired glutathione reduction → loss of antioxidant defence 3. **Result:** Haemolysis (acute intravascular or extravascular) ### Biochemical Basis ```mermaid flowchart TD A[Glucose-6-phosphate]:::outcome --> B[G6PD enzyme]:::action B -->|Normal| C[6-Phosphogluconolactone]:::outcome C --> D[NADPH production]:::outcome D --> E[Glutathione reduction<br/>GSH regeneration]:::action E --> F[RBC antioxidant defence]:::outcome A2[Glucose-6-phosphate]:::outcome --> B2[G6PD DEFICIENCY]:::urgent B2 -->|Blocked| C2[Minimal NADPH]:::urgent C2 --> D2[Glutathione remains<br/>in oxidized form GSSG]:::urgent D2 --> E2[Loss of antioxidant capacity]:::urgent E2 --> F2[Oxidative damage to RBC<br/>Haemolysis]:::urgent ``` ### Why RBCs Are Most Vulnerable | Feature | Significance | |---------|-------------| | **No mitochondria** | Cannot generate NADPH via TCA cycle | | **Rely solely on PPP** | G6PD is the only source of NADPH | | **High oxidative stress** | Exposed to O₂, iron, reactive oxygen species | | **Long lifespan** | 120 days of cumulative oxidative damage | **Clinical Pearl:** Haemolysis is **episodic**, not chronic, because: - Older RBCs (with lower G6PD activity) are preferentially lysed - Reticulocytes (high G6PD activity) replace them - Steady state is reached until next oxidative trigger ### Diagnostic Clues in the Stem - **Fava beans** → pathognomonic for G6PD deficiency ("favism") - **Sulfonamides** → classic oxidative trigger - **Reduced NADPH** → direct evidence of PPP blockade - **Decreased glutathione reductase activity** → secondary consequence (enzyme is present but substrate GSH is depleted) **Mnemonic:** **AAAS** — Antimalarials, Aspirin, Antibiotics (sulfonamides), Sulphones → triggers for G6PD haemolysis. ### Epidemiology - **Most common** enzyme deficiency: ~400 million affected globally - **Higher prevalence** in Mediterranean, African, and Asian populations - **X-linked recessive** inheritance (males predominantly affected) - **Heterozygous females** may have mild or variable phenotype