A 28-year-old Indian male presents to the emergency department with acute haemolytic anaemia following consumption of fava beans at a wedding feast. Laboratory investigations reveal: Hb 7.2 g/dL, reticulocyte count 8%, indirect bilirubin 4.2 mg/dL, and LDH 1200 U/L. Peripheral blood smear shows bite cells and Heinz bodies. Urine dipstick is positive for blood but RBCs are absent. Which enzyme deficiency is most likely responsible for this clinical presentation?

Explanation

## Clinical Diagnosis: G6PD Deficiency ### Pathophysiology of the Presentation **Key Point:** Glucose-6-phosphate dehydrogenase (G6PD) deficiency causes acute haemolytic crises triggered by oxidative stress from fava beans, infections, or certain drugs. G6PD catalyzes the first committed step of the pentose phosphate pathway (PPP), generating NADPH: $$\text{Glucose-6-phosphate} + \text{NADP}^+ \xrightarrow{\text{G6PD}} \text{6-phosphogluconolactone} + \text{NADPH}$$ NADPH is essential for: 1. Reducing glutathione (GSSG → 2 GSH) via glutathione reductase 2. Maintaining reduced glutathione (GSH) pools 3. Protecting RBCs from oxidative damage **High-Yield:** Without adequate NADPH, RBCs cannot regenerate GSH, leading to accumulation of reactive oxygen species (ROS) that denature haemoglobin and damage the RBC membrane. ### Why This Case Fits G6PD Deficiency | Finding | Mechanism | |---------|----------| | Acute haemolysis after fava beans | Fava bean oxidants (divicine, isouramil) trigger ROS in G6PD-deficient cells | | Bite cells on smear | Splenic macrophages phagocytose denatured haemoglobin precipitates (Heinz bodies) | | Heinz bodies | Denatured haemoglobin polymers from oxidative damage | | Positive urine dipstick, no RBCs | Free haemoglobin in urine (haemoglobinuria) from intravascular haemolysis | | High reticulocyte count | Bone marrow compensatory response to acute RBC loss | | Elevated LDH & indirect bilirubin | Markers of intravascular haemolysis | **Clinical Pearl:** G6PD deficiency is X-linked recessive; males are predominantly affected. It is the most common enzymatic RBC disorder worldwide, particularly in Mediterranean, African, and Asian populations. ### Pentose Phosphate Pathway Context ```mermaid flowchart TD A[Glucose-6-phosphate]:::outcome --> B[G6PD<br/>G6PD Deficiency here]:::decision B -->|Normal| C[6-phosphogluconolactone]:::outcome C --> D[6-phosphogluconate]:::outcome D --> E[6PGD]:::action E --> F[Ribulose-5-phosphate]:::outcome F --> G[NADPH generated]:::action G --> H[Glutathione reduction<br/>GSH regeneration]:::action H --> I[RBC protection from ROS]:::outcome B -->|Deficient| J[Minimal NADPH]:::urgent J --> K[GSH depletion]:::urgent K --> L[Oxidative stress]:::urgent L --> M[Haemoglobin denaturation<br/>RBC haemolysis]:::urgent ``` **Mnemonic:** **NADPH** = **N**eed **A**ntioxidant **D**efense; **P**entose **P**athway **H**elps. G6PD deficiency → ↓ NADPH → ↓ GSH → ↑ ROS → haemolysis. **Warning:** Do not confuse G6PD deficiency with other causes of haemolytic anaemia (hereditary spherocytosis, autoimmune haemolytic anaemia, sickle cell disease). The trigger (fava beans), the presence of Heinz bodies and bite cells, and the X-linked inheritance pattern are pathognomonic for G6PD.