Glucose-6-Phosphate Dehydrogenase Deficiency

Basics

Description

Deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) in the RBC, which may result in hemolytic anemia. Several types of genetic mutations result either in deficient enzyme production or in production of an enzyme with diminished activity.

  • Although most patients with this deficiency are never anemic and have mild to no hemolysis, the classic manifestation is acute hemolytic anemia in response to oxidative stress.
  • World Health Organization classification of G6PD:
    • Class 1: congenital nonspherocytic hemolytic anemia: rare. Chronic hemolysis without exposure to oxidative stressors—splenomegaly in 40%. Affected individuals tend to be white males of Northern European background.
    • Class 2: severe deficiency (1–10% enzymatic activity): oxidative stress–induced hemolysis. Prototype is G6PD-Mediterranean.
    • Class 3: mild deficiency (10–60% enzymatic activity): most common type. Acute hemolytic anemia uncommon, occurs only with stressors
    • Class 4: nondeficient variant (60–100% enzymatic activity): no symptoms, even during oxidant stressors (e.g., G6PD A+ [variant with normal activity]); 20–40% allelic frequency in Africans
    • Class 5: >150% of normal activity
  • Deficient neonates may have hyperbilirubinemia out of proportion to their anemia.
    • May, in part, account for increased prevalence of African Americans among patients with bilirubin encephalopathy
    • Should be considered as cause of hyperbilirubinemia in neonates of appropriate racial background and may contribute to kernicterus

General Prevention

Avoid drugs and toxins known to cause hemolysis. Prompt follow-up with febrile illness and signs of hemolysis.

Epidemiology

Prevalence

  • Most common of all clinically significant enzyme defects, affecting ∼400 million people worldwide
  • X linked (Xq28): primarily affects males
  • Almost 400 allelic variants
  • Frequency of different mutations varies by population:
  • Africans: 20–40% of X chromosomes are G6PD A+ (mutant enzyme with normal activity).
  • Sardinians (some regions): 30% have G6PD-Mediterranean.
  • Saudi Arabians: 13% have G6PD deficiency.
  • African Americans: 10–15% have G6PD A− (mutant enzyme with decreased activity).
  • High incidence of mutant genes in some regions may relate to survival advantage against malarial infection (Plasmodium falciparum).

Genetics

Gene is on the X chromosome (Xq28).

  • Males express the enzyme (mutant or normal) from their single X chromosome (hemizygotes).
  • Female homozygotes (rare) are more severely affected than female heterozygotes.
  • Heterozygote females show variable intermediate expression because of random X inactivation.

Pathophysiology

  • RBCs lose G6PD activity throughout their lifespan; therefore, older cells are more prone to oxidative hemolysis.
  • Normal RBC lifespan of ∼120 days is unaffected in unstressed states, even with severe enzyme deficiency, but may be shortened during oxidant stress.
  • Enzyme-deficient RBCs are destroyed by intravascular hemolysis on exposure to the oxidative stressor and acute hemolytic anemia results.
  • Oxidant stressors include infections and chemicals (mothballs, antimalarials, some sulfonamides, methylene blue).
  • Hemolysis usually follows stressor by 1–3 days, and nadir occurs 8–10 days postexposure. Obtain hemoglobins for >1 week after the initial exposure.
  • Favism: severe hemolytic anemia in patients with more severe forms of G6PD deficiency after fava bean ingestion
  • Normal G6PD activity is 7–10 IU/g hemoglobin.

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