G6PD Deficiency

Glucose-6-phosphate dehydrogenase (G6PD) is the rate-limiting enzyme of the hexose monophosphate shunt (pentose phosphate pathway), which is the ONLY source of NADPH in red blood cells. NADPH is essential for regenerating reduced glutathione (GSH) via glutathione reductase — GSH is the primary antioxidant defense in erythrocytes, neutralizing hydrogen peroxide (H2O2) and other reactive oxygen species (ROS) that would otherwise denature hemoglobin and damage the RBC membrane. G6PD deficiency is an X-linked recessive enzymopathy (gene on Xq28) affecting approximately 400 million people worldwide, with highest prevalence in malaria-endemic regions (Africa, Mediterranean, Middle East, Southeast Asia) due to heterozygote advantage against Plasmodium falciparum. When G6PD-deficient RBCs encounter oxidative stress (from drugs like primaquine, sulfonamides, rasburicase; infections; fava beans; or DKA), inadequate NADPH production leads to GSH depletion, causing oxidative denaturation of hemoglobin into Heinz bodies (insoluble hemoglobin precipitates that attach to the inner RBC membrane). Splenic macrophages phagocytose the Heinz body-containing portions of the membrane, producing characteristic 'bite cells' on peripheral smear. Severe oxidative damage leads to intravascular hemolysis with hemoglobinemia, hemoglobinuria (dark/cola-colored urine), and unconjugated hyperbilirubinemia. The WHO classifies G6PD variants by residual enzyme activity: Class I (<10%, chronic hemolysis), Class II (<10%, intermittent hemolysis — includes Mediterranean variant), Class III (10-60%, hemolysis only with triggers — includes A-minus variant common in African descent). A critical diagnostic pitfall is that G6PD enzyme levels may be falsely normal during acute hemolysis because older, more deficient RBCs are preferentially destroyed, leaving reticulocytes (which have higher G6PD activity) to be sampled — testing must be repeated 2-3 months post-crisis. The NP must maintain a high index of suspicion in at-risk populations, screen before prescribing known oxidant drugs (especially rasburicase, which generates H2O2 directly), and recognize the methylene blue paradox: methylene blue treats methemoglobinemia via NADPH-dependent reduction, making it ineffective and harmful in G6PD deficiency.