Glucose-6-phosphate dehydrogenase deficiency (favism)

Definition

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzyme defect of the hexose monophosphate shunt and the most common metabolic disorder of red cells. The cells are unprotected against oxidative stress; after infections or exposure to oxidising substances, acute, usually self-limiting hemolytic episodes occur. Favism refers to hemolysis after eating fava (broad) beans.

Classification

The G6PD gene is highly polymorphic; residual activity ranges from normal to severely reduced. The former WHO system divided variants into classes I to V according to enzyme activity. Since 2022 a revised WHO classification applies: class A (residual activity below 20 %, chronic hemolytic anemia), class B (below 45 %, neonatal jaundice and acute hemolysis triggered by certain medicines, fava beans or infections), class C (above 60 %, no hemolysis) and class U (uncertain clinical significance); the former classes II and III are now merged into class B. The lower the activity, the more pronounced the hemolysis; rare variants cause chronic hemolysis even without a trigger.

Occurrence & epidemiology

The defect is particularly common in people of African origin – in the USA in more than 10 % of African American men – and less common in people from the Mediterranean (e.g. of Italian, Greek, Persian, Arab or Sephardic Jewish origin) and from Asia. Because of X-linked inheritance, mainly men are clinically affected; women are affected if homozygous or with skewed X inactivation.

Aetiopathogenesis

In the hexose monophosphate shunt, G6PD provides the NADPH with which the red cell regenerates reduced glutathione and protects itself against peroxides. In deficiency, hemoglobin and membrane are oxidised; denatured hemoglobin precipitates as Heinz bodies and the damaged cells are prematurely destroyed.

Triggers of hemolysis:

• most commonly fever, acute viral or bacterial infections, diabetic ketoacidosis
• less commonly oxidising drugs, e.g. certain antimalarials, sulfonamides, nitrofurans, salicylates, some vitamin K derivatives and urate-degrading agents
• naphthalene (mothballs) and in some cases fava beans

Clinical features

Outside episodes most affected people are asymptomatic. Acute hemolysis usually affects less than 25 % of red cell mass and causes transient jaundice and dark urine, sometimes back or abdominal pain. In severe enzyme deficiency, marked intravascular hemolysis can lead to hemoglobinuria and acute kidney injury. In newborns, the deficiency may present as neonatal jaundice.

Histology

Blood smear

Early in the hemolytic episode, blister cells (hemoglobin displaced to the cell edge, blister-like clearing) and bite cells (red cells that look as if bitten) are found; special (supravital) stains show Heinz bodies of denatured hemoglobin. With an intact spleen these cells rapidly disappear from the blood.

Diagnosis

• Suspicion: acute hemolysis, particularly in men with Coombs-negative hemolytic anemia after infection or exposure to a trigger; also in neonatal jaundice or unexplained hemolysis
• Signs of hemolysis: anemia, reticulocytosis, indirect bilirubin and LDH raised, haptoglobin low, hemoglobinuria in intravascular hemolysis
• Blood smear with bite and blister cells, Heinz body stain
• G6PD activity assay: qualitative rapid tests (including point-of-care) and quantitative measurement for confirmation. During and shortly after hemolysis the test may be falsely normal, because the oldest, most deficient cells have been destroyed and young reticulocytes contain more G6PD; repeating it after several weeks is then informative.
• Testing of asymptomatic family members is possible

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Further reading (open access)

1. MSD Manual Professional: Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
2. MSD Manual Professional: Overview of Hemolytic Anemia
3. Bulletin of the World Health Organization (2024): New WHO classification of genetic variants causing G6PD deficiency

Cross-references