A 28-year-old woman from Kerala presents with acute hemolytic anemia and jaundice 2 days after consuming fava beans. Laboratory studies show reduced hemoglobin, elevated indirect bilirubin, and decreased haptoglobin. Which is the most common enzymatic defect responsible for this clinical presentation?

Explanation

## Favism and Hemolytic Anemia — G6PD Deficiency ### Clinical Presentation The patient presents with the classic triad of **favism** (acute hemolytic anemia triggered by fava bean consumption): - Acute hemolysis (low hemoglobin, elevated indirect bilirubin) - Jaundice (unconjugated hyperbilirubinemia) - Reduced haptoglobin (consumed by hemoglobin-haptoglobin complexes) **Key Point:** G6PD deficiency is the most common **enzymatic defect of the pentose phosphate pathway** and the most frequent cause of acute hemolytic anemia triggered by oxidative stress in susceptible populations. ### Pathophysiology of G6PD Deficiency **High-Yield:** G6PD catalyzes the first committed step of the pentose phosphate pathway: $$\text{Glucose-6-phosphate} \xrightarrow{G6PD} \text{6-Phosphogluconolactone}$$ This reaction generates **NADPH**, which is essential for: 1. Reducing oxidized glutathione (GSSG) → reduced glutathione (GSH) 2. Maintaining GSH-dependent antioxidant systems (glutathione peroxidase, glutathione reductase) 3. Protecting RBC membranes from lipid peroxidation **Without adequate NADPH:** - Oxidative stress (from fava bean oxidants, sulfonamides, infections) overwhelms antioxidant defenses - RBC membranes undergo oxidative damage - Hemoglobin denatures → Heinz bodies form - Hemolysis ensues ### Epidemiology & Genetics | Feature | Detail | |---------|--------| | **Inheritance** | X-linked recessive (males > females) | | **Prevalence** | 400 million people worldwide; highest in Mediterranean, African, Asian populations | | **Variants** | >400 alleles; Class I–V severity | | **Triggering Agents** | Fava beans, sulfonamides, aspirin, antimalarials (primaquine), infections | **Clinical Pearl:** Fava beans contain **vicine** and **convicine**, which are oxidizing compounds. In G6PD-deficient RBCs, these overwhelm the glutathione antioxidant system, leading to acute hemolysis within 24–72 hours. ### Diagnostic Approach ```mermaid flowchart TD A[Acute Hemolytic Anemia + Oxidative Trigger]:::outcome --> B{Heinz Bodies on Supravital Stain?}:::decision B -->|Yes| C[Suspect RBC Enzyme Defect]:::action C --> D{G6PD vs. Other Enzymes?}:::decision D -->|Fava beans, sulfonamides, infections| E[G6PD Deficiency Most Likely]:::action D -->|Chronic hemolysis, splenomegaly| F[Pyruvate Kinase Deficiency]:::outcome E --> G[Confirm: G6PD Activity Assay]:::action G --> H[Reduced NADPH Production]:::outcome ``` **Mnemonic:** **FAGS** — Fava beans, Aspirin, G6PD deficiency, Sulfonamides (triggers of hemolysis in G6PD-deficient patients).