Glucose-6-phosphate Dehydrogenase (G6PD) Deficiency

Epidemiology and Etiology

Epidemiology

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common genetic enzyme disorder in humans.
• Found in malarial endemic regions (as it offers relative resistance to Plasmodium falciparum infection): Mediterranean countries, Africa, the Middle East
• Presents exclusively in males as it is X-linked recessive
• Females can be silent carriers.

Etiology

• Mutation in the coding region of the G6PD gene 
• A single nucleotide base change (single missense point mutation) that results in a single amino acid substitution in the enzyme 
• Almost 200 different mutations are known.
• The mutation decreases the half-life of the enzyme. 
• G6PD deficiency results in a defect of the pentose phosphate shunt during glycolysis.
• Inheritance is X-linked recessive (band Xq28).

Pathophysiology

• G6PD is the rate-limiting enzyme in the pentose phosphate pathway.
• G6PD enzyme is responsible for:
  • Oxidation of glucose-6-phosphate 
  • Reduction of nicotinamide adenine dinucleotide phosphate (NADP+) to NADPH 
• NADPH maintains glutathione in its reduced form.
• Reduced glutathione is needed to neutralize oxidative metabolites.
• In RBCs, this is the only pathway that produces NADPH.
• Thus, a lack of G6PD results in a deficiency in NADPH and increased oxidative damage.
• Oxidative stressors can denature hemoglobin and cause intravascular hemolysis.
• Extravascular hemolysis would be due to splenic clearance of the deformed RBCs.

Clinical Presentation

• History of a trigger for the oxidative stress
• Episodic signs and symptoms of intravascular hemolytic anemia:
  • Pallor
  • Shortness of breath
  • Fatigue
  • Tachycardia
  • Flow murmur (best heard at upper sternal borders)
  • Jaundice
  • Hemoglobinuria (cola-colored urine), hematuria
  • Neonates (males): prolonged pathological jaundice/icterus

Diagnosis

Glucose-6-phosphate dehydrogenase deficiency is suspected in cases of episodic hemolytic symptoms. Diagnostic testing should include the following:

• CBC
  • ↓ Hb
  • ↑ Reticulocytes
  • ↑ Lactate dehydrogenase (LDH)
  • ↓ Haptoglobin
  • ↑ Bilirubin
• Peripheral blood smear
  • Heinz bodies (visible with supravital stains such as new methylene blue or crystal violet, but not with routine Romanowsky dyes; rarely performed today)
  • Bite cells, indicating RBC membrane damage
• Beutler test 
  • Done 2–3 weeks after an acute episode (which eliminates the oldest, most G6PD-deficient cells, so a period of time is allowed to pass to evaluate baseline levels)
  • Quantifies NADPH/G6PD levels

Management

• Prevention: avoid oxidative stressors (infections, drugs, consumption of fava beans)
• During hemolysis:
  • If Hb < 9 with hemolysis: blood transfusion
  • Neonatal jaundice: phototherapy or exchange transfusion
• Splenectomy should be considered in rare cases of chronic hemolytic anemia.

Differential Diagnosis

• Inherited hemolytic anemias:
  • Other enzyme deficiencies (e.g., pyruvate kinase)
  • Hemoglobinopathies (e.g., sickle cell disease, thalassemia)
  • Membrane/cytoskeletal defects of RBC (e.g., hereditary spherocytosis)
• Acquired hemolytic anemias: may have an immune or non-immune etiology