Pathophysiology of G6PD

G6PD enzyme is required by all cells to protect them from damage by oxidation. It catalyses the first step in the pentose phosphate pathway, whereby glucose-6-phosphate is oxidised to form 6-phosphogluconate. This reaction is linked to the reduction of NADP (nicotinamide adenosine phosphate) to NADPH (nicotinamide adenosine dinucleotide phosphate), which is used to generate reduced glutathione.

The diagram below shows role of G6PD enzyme in the pentose phosphate pathway

Role of glucose-6-phosphate dehydrogenase in the pentose phosphate pathway resulting in the generation of nicotinamide adenosine dinucleotide phosphate (NADPH) and reduced glutathione (GSH), products required to protect the red cell from oxidative stress

For the red cell, this is the sole source of protection against oxidative damage. Red blood cells are constantly challenged by oxidants in the form of free radicals generated by the conversion of oxyhaemoglobin to deoxyhaemoglobin and by peroxides generated by phagocytosing granulocytes.

 Normal red cells can increase generation of NADPH in response to oxidative stress; this capacity is impaired in patients with G6PD deficiency. Failure to withstand oxidative stress damages sulphydryl groups in haemoglobin and the red cell membrane and causes haemolysis. Cells in other tissues and organs have alternate pathways for the generation of NADPH and can thus withstand such oxidative stress. In contrast, red cells are metabolically extremely simple; they lack a nucleus and mitochondria, cannot carry out protein synthesis, and exclusively metabolise glucose for ATP production. The activity of all red cell enzymes, including G6PD, is highest in young red cells (reticulocytes), and progressively declines as the cell ages.

Following a haemolytic episode, the rate of red cell production is accelerated and the increased proportion of young red cells with higher levels of G6PD limits further red cell lysis. Haemolytic episodes are therefore usually self-limiting in those with moderately deficient (class III) variants (for example, G6PD A-) but may result in more severe and progressive anaemia in patients with severely deficient (class II) variants.

Complete lack of the enzyme is incompatible with life. Rarely, male patients with class I variants have profoundly low G6PD activity, such that the red cells are constantly undergoing lysis (chronic non-spherocytic haemolytic anaemia). Almost all deficient people, however, have one of the polymorphic enzyme variants (e.g., G6PD Mediterranean, class II, or G6PD A-, class III) that bestow sufficient residual activity to maintain the person in an asymptomatic state under non-stressed conditions. However, when provoked by oxidative stress (e.g., ingestion of certain drugs, exposure to certain chemicals or glycosides in broad beans, and infection), red cell lysis occurs.

Some drugs are known to pose an oxidative challenge to the red cells and to induce haemolytic anaemia in patients with G6PD deficiency. For some drugs (e.g., dapsone, primaquine, sulphonamides), the association is very clear and consistent, and haemolysis will be observed in virtually all patients, irrespective of residual enzyme activity.  For others (for example, aspirin) the clinical association is less consistent and reflects an interplay of inherited (e.g., residual enzyme activity, pharmacokinetics) and acquired (e.g., dose, absorption and drug metabolism, co-existing infection) factors.