Glucose-6-Phosphate Dehydrogenase Deficiency

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DESCRIPTION

Deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) that leads to increased RBC vulnerability to oxidative stress and may cause hemolytic anemia; several types of genetic mutations (pathogenic variants) result in either deficient enzyme production or diminished enzyme 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 variants:
    • 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 bilirubin encephalopathy in African Americans; in the United States, ~20% of kernicterus is G6PD related; should be considered in the evaluation of neonatal hyperbilirubinemia in infants of appropriate ethnicity.

EPIDEMIOLOGY

Prevalence

  • Most common of all clinically significant enzyme defects, affecting >500 million people worldwide; estimate of 4.9–7.5% of the world’s population carries one or two variants for G6PD deficiency.
  • X linked (Xq28) with 400 allelic variants (192 disease causing)
  • Frequency of different pathogenic variants varies by population with higher prevalence in areas with endemic malaria possibly due to a survival advantage for malarial infections (Plasmodium falciparum and Plasmodium vivax).
    • Africans: 20–40% of X chromosomes have the A+ variant (mutant enzyme with normal activity); A− in 10–15% (reduced enzyme activity)
    • Sardinians (some regions): 30% have G6PD- Mediterranean (variant with 1–10% enzymatic activity).
    • Saudi Arabians: 25% have G6PD deficiency.
    • African Americans: 10–15% have G6PD A− (mutant enzyme with <30% normal activity).

Genetics

G6PD deficiency is an X-linked dominant disease caused by variants in the G6PD gene, which 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.

GENERAL PREVENTION

  • Avoid drugs and toxins known to cause hemolysis (see “Pathophysiology” section).
  • Prompt follow-up with febrile illness and signs of hemolysis.

PATHOPHYSIOLOGY

  • G6PD catalyzes the production of reduced nicotinamide adenine dinucleotide phosphate (NADPH) that protects RBCs from oxidative damage.
  • Normal G6PD activity is 7 to 10 IU/g hemoglobin. Following exposure to oxidative stress, G6PD-deficient RBCs are destroyed by intravascular hemolysis resulting in hemolytic anemia.
  • Oxidant stressors include infections and chemicals (e.g., mothballs, antimalarials, some sulfonamides, rasburicase, methylene blue). 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.
  • Hemolysis usually follows stressor by 1 to 3 days, and the nadir occurs 8 to 10 days postexposure.
  • Favism: severe hemolytic anemia in patients with more severe forms of G6PD deficiency that occurs after fava bean ingestion

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