What is G6PD (Glucose-6-Phosphate Dehydrogenase)?
G6PD is a critical enzyme that catalyzes the first step of the pentose phosphate pathway in red blood cells, producing NADPH which protects erythrocytes from oxidative damage—deficiency of this enzyme is the most common red blood cell enzymopathy worldwide, affecting approximately 400 million people. 1, 2
Biochemical Function and Protective Role
G6PD serves as the primary antioxidant defense system in red blood cells, which lack mitochondria and peroxisomes yet are exposed to high oxidative stress from their oxygen-carrying function. 1
- The enzyme generates NADPH, which serves as a cofactor for glutathione reductase (GR), converting oxidized glutathione (GSSG) into its reduced form (GSH). 1
- GSH is essential for detoxification and survival of erythrocytes against oxidative damage. 1
- This pathway represents the only mechanism by which red blood cells can generate NADPH, making G6PD-deficient erythrocytes uniquely vulnerable to oxidative stress. 3
Genetic Basis and Inheritance Pattern
G6PD deficiency is inherited as an X-linked recessive disorder, with the gene (G6PC) located on chromosome 17q21. 1, 4
- Males are affected much more frequently than females due to X-linked inheritance. 5
- Over 250 genetic variants exist, divided into five classes based on residual enzyme activity and clinical manifestations. 5
- The two most clinically significant variants are the Mediterranean variant (Gdmed) and the African variant (GdA-), which differ substantially in severity. 6, 7
Geographic Distribution and Prevalence
The highest prevalence occurs in Africa, southern Europe, the Middle East, Southeast Asia, and the central and southern Pacific islands, though migration has made it a worldwide disease. 2
- The Mediterranean variant predominates in men from Mediterranean regions, India, and Southeast Asia. 7
- The African variant (GdA-) affects 10-15% of Black men and women. 7
- Global prevalence is estimated at 4.9% of the world population. 8
Clinical Significance and Pathophysiology
Most G6PD-deficient individuals remain asymptomatic under normal conditions, but acute hemolytic crises occur when exposed to oxidative stressors. 2, 5
Triggers for Hemolysis:
- Oxidant drugs including dapsone, primaquine, sulfonamides, and methylene blue (absolutely contraindicated). 6, 7
- Infections that increase oxidative stress. 2
- Metabolic conditions causing oxidative damage. 2
- Ingestion of fava beans (favism). 2
Severity by Variant:
- Mediterranean variant causes life-threatening hemolysis requiring strict avoidance of all oxidant drugs. 6, 7
- African variant produces milder, self-limited hemolysis that may allow modified treatment regimens under close monitoring. 6, 7
Role in Neonatal Hyperbilirubinemia
G6PD deficiency is a critical cause of severe neonatal jaundice, identified in 31.5% of infants who developed kernicterus in one series. 6
- Quantitative G6PD testing is recommended for infants with rapidly rising total serum bilirubin approaching exchange transfusion levels. 6
- Testing should be considered when jaundice appears in the first 24 hours of life or when bilirubin rises unexpectedly despite phototherapy. 1, 6
- A critical caveat: G6PD levels can be falsely elevated during acute hemolysis, potentially obscuring the diagnosis—repeat testing at 3 months of age is necessary if deficiency is strongly suspected but initial testing is normal. 1
Evolutionary Advantage
Despite its clinical disadvantages, G6PD deficiency has been positively selected by malaria, conferring protection against severe malaria infection. 3
- Recent evidence suggests it may also reduce risk of coronary disease, confer advantages against cancer development, and have beneficial effects on longevity. 3