glucose-6-phosphate dehydrogenase
Summary
Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the pentose phosphate pathway, catalyzing the first step that generates NADPH. G6PD deficiency is the most common human enzyme deficiency, an X-linked recessive disorder causing episodic hemolytic anemia triggered by oxidative stress. It predominantly affects males and is more common in individuals of African, Mediterranean, and Southeast Asian descent, likely conferring malaria resistance.
Detail
G6PD converts glucose-6-phosphate to 6-phosphogluconate while reducing NADP+ to NADPH. NADPH is essential for regenerating reduced glutathione, which protects red blood cells (RBCs) against oxidative damage from reactive oxygen species. RBCs are particularly vulnerable because they lack mitochondria and rely solely on the pentose phosphate pathway for NADPH production.
In G6PD deficiency, insufficient NADPH leads to accumulation of oxidized glutathione and oxidative damage to hemoglobin and RBC membranes. This causes hemoglobin denaturation and precipitation, forming Heinz bodies (visible with supravital stains like crystal violet), which are then removed by splenic macrophages, creating 'bite cells' seen on peripheral smear. Severe oxidative stress can cause intravascular hemolysis.
Clinical triggers include oxidative stressors: certain drugs (sulfonamides, primaquine, dapsone, nitrofurantoin), fava beans (favism), and infections. Patients are typically asymptomatic between hemolytic episodes. Acute hemolysis presents with fatigue, jaundice, dark urine (hemoglobinuria), and back pain, often 1-3 days after exposure.
Diagnosis: G6PD enzyme activity assay (best performed 2-3 months after an acute hemolytic episode, as older RBCs with lower enzyme levels have already been destroyed, potentially masking the deficiency if tested during/immediately after a crisis).
Inheritance is X-linked recessive, so males are more commonly and severely affected; heterozygous females can have mosaic expression due to X-inactivation (Lyonization).
Management includes avoidance of triggers and supportive care during hemolytic episodes (transfusion if severe).
High-yield associations: malaria resistance (selective advantage), Heinz bodies, bite cells, X-linked recessive inheritance, drug-induced hemolysis.
Sources
- First Aid for the USMLE Step 1
- Robbins Basic Pathology
- Harrison's Principles of Internal Medicine
- Kaplan USMLE Step 1 Biochemistry Lecture Notes
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