Glucose-6-Phosphate Dehydrogenase Deficiency

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited enzyme disorder of red blood cells and the most common human enzymopathy. The enzyme protects red cells against oxidative stress; when it is deficient, exposure to certain oxidant drugs, infections, or fava beans can trigger acute hemolysis. The gene is X-linked, so the disorder is expressed most fully in males.

Definition

G6PD deficiency is an X-linked inherited deficiency of the red-cell enzyme glucose-6-phosphate dehydrogenase, which generates the reducing power (NADPH) that protects red cells from oxidative injury; the deficiency predisposes red cells to oxidative hemolysis on exposure to oxidant stressors.

Scope

This topic covers the biochemical role of G6PD in protecting red cells from oxidative damage, the X-linked genetics of the deficiency, the triggers and pattern of acute hemolytic episodes, and the malaria-related population distribution. Although grouped here with the inherited red-cell disorders of the hemoglobinopathies area, it is an enzymopathy rather than a defect of hemoglobin itself. This is a reference entry and does not provide individualized clinical guidance, including no drug-avoidance advice for individuals.

Core questions

• How does G6PD generate the reducing power that protects red cells from oxidative damage?
• Why does deficiency cause episodic rather than continuous hemolysis?
• How does X-linked inheritance shape the distribution of disease between males and females?

Key concepts

• Pentose phosphate pathway and NADPH generation
• Oxidative stress and glutathione regeneration
• Acute oxidative hemolysis
• Heinz bodies and bite cells
• X-linked inheritance
• Favism (hemolysis after fava-bean ingestion)
• Enzyme variants of differing severity

Mechanisms

G6PD catalyzes the first step of the pentose phosphate pathway, producing NADPH, the reducing equivalent that maintains glutathione in its reduced form. Reduced glutathione is the red cell's principal defense against oxidative damage. Because the mature red cell cannot synthesize new enzyme, a deficient cell has a limited and non-renewable capacity to counter oxidant stress. Under basal conditions many deficient individuals are asymptomatic, but exposure to an oxidant challenge—certain drugs, infection, or fava beans—overwhelms the depleted antioxidant defense. Hemoglobin then oxidizes and denatures, precipitating as Heinz bodies that the spleen removes, leaving characteristic bite cells and producing an acute, often self-limited hemolytic episode. The gene lies on the X chromosome, so hemizygous males are most fully affected, while heterozygous females show variable expression depending on X-inactivation.

Clinical relevance

G6PD deficiency is a common cause of drug- and infection-associated hemolysis and of neonatal jaundice, making awareness of the oxidative-hemolysis mechanism relevant to interpreting episodic anemia. This entry summarizes the disorder for reference and education; it does not provide individualized advice on diagnosis, drug exposure, or management.

Epidemiology

G6PD deficiency affects hundreds of millions of people worldwide and is most frequent in populations from sub-Saharan Africa, the Mediterranean, the Middle East, and Asia. As with the hemoglobin disorders, its high frequency in these regions is attributed to a protective effect of the deficiency against severe malaria, and Williams and Weatherall include it among the malaria-selected inherited red-cell traits of broad global distribution.

History

G6PD deficiency was clarified in the mid-twentieth century when investigation of hemolysis triggered by the antimalarial primaquine led to identification of the underlying enzyme defect, with Beutler among the central contributors. The recognition of its X-linked inheritance, the cataloguing of numerous enzyme variants of differing stability, and the link to malaria selection established it as a model inherited enzymopathy, a history Beutler later reviewed.

Key figures

• Ernest Beutler
• Maria Domenica Cappellini
• Lucio Luzzatto

Seminal works

• cappellini-2008
• beutler-2008
• williams-weatherall-2012

Frequently asked questions

Is G6PD deficiency a disorder of hemoglobin?

No. It is a deficiency of a red-cell enzyme that protects against oxidative stress, not a structural or synthetic defect of hemoglobin. It is grouped with the inherited red-cell disorders because, like the hemoglobinopathies, it causes inherited hemolytic anemia and shares a malaria-related distribution.

Why does hemolysis in G6PD deficiency come in episodes?

Many deficient individuals are well at baseline; hemolysis is typically triggered when an oxidant stressor—such as certain drugs, an infection, or fava beans—overwhelms the red cell's reduced antioxidant capacity, producing an acute, often self-limited episode.