A 28-year-old Indian male presents with hemolytic anemia triggered by fava bean ingestion. Enzyme assay reveals G6PD deficiency. Which metabolic consequence best distinguishes G6PD deficiency from transketolase deficiency?

Explanation

## G6PD Deficiency vs Transketolase Deficiency: Metabolic Consequences ### G6PD Deficiency Pathophysiology **Key Point:** G6PD catalyzes the first committed step of the oxidative phase of the pentose phosphate pathway. Its deficiency leads to impaired NADPH generation, which is critical for maintaining the reduced form of glutathione (GSH) in red blood cells. **High-Yield:** NADPH is essential for: 1. Reduction of oxidized glutathione (GSSG → GSH) via glutathione reductase 2. Protection against oxidative stress from free radicals and electrophiles 3. Detoxification of H₂O₂ via the glutathione peroxidase system **Clinical Pearl:** When oxidative stress occurs (fava beans, sulfonamides, aspirin), RBCs cannot regenerate GSH, leading to accumulation of reactive oxygen species, lipid peroxidation of the RBC membrane, and hemolytic anemia. ### Transketolase Deficiency Pathophysiology **Key Point:** Transketolase is a key enzyme of the non-oxidative phase. Its deficiency impairs the rearrangement of sugar phosphates but does NOT directly affect NADPH generation. **Clinical Pearl:** Transketolase deficiency (seen in thiamine deficiency / Wernicke-Korsakoff syndrome) causes: - Impaired non-oxidative phase reactions - Accumulation of pentose phosphates upstream - Neurological manifestations (due to impaired carbohydrate metabolism in the CNS) - NOT hemolytic anemia or oxidative stress in RBCs ### Comparison Table | Feature | G6PD Deficiency | Transketolase Deficiency | |---------|-----------------|-------------------------| | **Affected phase** | Oxidative | Non-oxidative | | **NADPH production** | ↓↓ Severely impaired | Normal | | **Oxidative stress in RBCs** | Yes (hemolytic anemia) | No | | **Ribose-5-phosphate synthesis** | Normal (via non-oxidative phase) | Impaired (cannot rearrange pentose phosphates) | | **Triggered by** | Oxidative stressors (fava beans, drugs) | Thiamine deficiency | | **Neurological symptoms** | No | Yes (Wernicke-Korsakoff) | | **RBC lifespan** | Shortened (hemolysis) | Normal | ### Metabolic Consequence Diagram ```mermaid flowchart TD A[Glucose-6-phosphate]:::outcome --> B{G6PD present?}:::decision B -->|Yes| C[Oxidative phase proceeds]:::action B -->|No| D[NADPH not generated]:::urgent C --> E[NADPH produced]:::outcome E --> F[GSH reduced via GR]:::action F --> G[RBC protected from oxidative stress]:::outcome D --> H[GSSG accumulates, GSH depleted]:::urgent H --> I[Oxidative damage to RBC membrane]:::urgent I --> J[Hemolysis]:::urgent K[Transketolase] --> L{Transketolase present?}:::decision L -->|Yes| M[Non-oxidative phase proceeds]:::action L -->|No| N[Pentose phosphate rearrangement blocked]:::urgent M --> O[Ribose-5-phosphate available]:::outcome N --> P[Neurological dysfunction]:::urgent ``` **Mnemonic:** **G6PD = NADPH = GSH = RBC protection**. Transketolase = Sugar shuffling = CNS metabolism.