G6PD is the rate-limiting enzyme of the pentose phosphate pathway (also known as the hexose monophosphate shunt). This pathway yields NADPH, which is essential for converting oxidized glutathione back to its reduced form. Reduced glutathione is capable of neutralizing reactive oxygen species (ROS) and free radicals and therefore protecting RBCs from oxidative damage.
In the absence of reduced glutathione (e.g., due to G6PD deficiency), RBCs become susceptible to oxidative stress that can damage erythrocyte membranes, resulting in intravascular and extravascular hemolysis.
Causes of increased oxidative stress are triggers of hemolytic crisis and include:
Bacterial and viral infections (most common cause): Severe enzymatic deficiency can inhibit respiratory burst activity due to reduced NADPH production in phagocytes.
Inflammation: During an inflammatory reaction free radicals are produced and can diffuse into RBCs.