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?

Question

Accepted Answer

D. Glucose-6-phosphate dehydrogenase deficiency. ## 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:
$$	ext{Glucose-6-phosphate} \xrightarrow{G6PD} 	ext{6-Phosphogluconolactone}$$

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).

Answer

A. Pyruvate kinase deficiency

Answer

B. Hexokinase deficiency

Answer

C. Phosphofructokinase deficiency

Explanation

Favism and Hemolytic Anemia — G6PD Deficiency

Clinical Presentation

Pathophysiology of G6PD Deficiency

Epidemiology & Genetics

Diagnostic Approach

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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