How does Glucose-6-phosphate dehydrogenase (G6PD) deficiency cause hemolysis?

Mechanism of G6PD Deficiency-Induced Hemolysis

G6PD deficiency causes hemolysis through impaired protection against oxidative stress, leading to red blood cell damage and destruction when exposed to oxidant drugs, infections, or certain foods.

Pathophysiological Mechanism

G6PD (Glucose-6-phosphate dehydrogenase) is a critical enzyme in the pentose phosphate pathway that catalyzes the first step in this metabolic process. The mechanism of hemolysis follows a specific sequence:

1. NADPH Production Impairment:

   • G6PD normally converts glucose-6-phosphate to 6-phosphogluconolactone while reducing NADP+ to NADPH
   • NADPH is essential for maintaining glutathione in its reduced form (GSH)
   • In G6PD deficiency, insufficient NADPH is produced

2. Glutathione Depletion:

   • Reduced glutathione (GSH) is the primary antioxidant protecting red blood cells
   • Without adequate NADPH, GSH cannot be regenerated from its oxidized form (GSSG)
   • This leads to depletion of GSH stores in red blood cells

3. Oxidative Damage:

   • When exposed to oxidative stressors, reactive oxygen species accumulate
   • Hemoglobin becomes oxidized to methemoglobin
   • Sulfhydryl groups in red cell proteins and membranes are oxidized
   • Heinz bodies (denatured hemoglobin precipitates) form within red blood cells

4. Cell Membrane Damage:

   • Oxidative damage to cell membrane proteins and lipids occurs
   • Membrane becomes rigid and loses flexibility
   • Potassium leaks out of the cell
   • Cell membrane integrity is compromised

5. Hemolysis:

   • Damaged red blood cells are recognized by the reticuloendothelial system
   • Cells are removed from circulation (extravascular hemolysis)
   • In severe cases, intravascular hemolysis occurs

Triggering Factors

The most common triggers for hemolytic episodes in G6PD deficiency include 1:

• Medications:

  • Antimalarials (primaquine, chloroquine)
  • Sulfonamides
  • Dapsone
  • Nitrofurantoin
  • Certain NSAIDs

• Foods:

  • Fava beans (most common dietary trigger)
  • Falafel
  • Other legumes (chickpeas, broad beans)

• Infections:

  • Pneumonia
  • Tonsillitis
  • Typhoid fever
  • Hepatitis A
  • Urinary tract infections

Clinical Variants and Severity

The severity of hemolysis depends on the specific G6PD variant 1:

• GdA- variant (African variant):

  • Found in 10-15% of Black men and women
  • Causes milder, self-limited hemolysis
  • May still tolerate some oxidant drugs with careful monitoring

• Gdmed variant (Mediterranean variant):

  • Found predominantly in men from Mediterranean regions, India, and Southeast Asia
  • Associated with life-threatening hemolysis
  • Requires strict avoidance of all oxidant stressors

Management Considerations

When managing patients with G6PD deficiency 1, 2:

1. Screening:

   • Test for G6PD deficiency before starting oxidant drugs in high-risk populations
   • Screen first-degree relatives of affected individuals

2. Prevention:

   • Avoid oxidative stressors - the most effective management strategy
   • Educate patients about triggering medications, foods, and conditions

3. Acute Hemolytic Crisis Management:

   • For symptomatic patients with high methemoglobin levels:
     • Methylene blue (1-2 mg/kg IV over 3-5 minutes) is first-line treatment
     • CAUTION: Methylene blue is contraindicated in G6PD deficiency as it may worsen hemolysis 1, 2
     • Alternative: Ascorbic acid (0.5-1.0 g/day in divided doses)
     • Ensure adequate hydration and glucose administration

Clinical Presentation

Patients with G6PD deficiency experiencing hemolysis typically present with 3:

• Pallor (100%)
• Dark red urine (89.6%)
• Jaundice (87.8%)
• Symptoms appearing 24-72 hours after exposure to triggers

Key Points for Clinical Practice

• G6PD deficiency is the most common enzymatic disorder of red blood cells worldwide, affecting approximately 400 million people 4
• The condition has the highest prevalence in Africa, southern Europe, the Middle East, Southeast Asia, and Pacific islands 4
• Laboratory findings during hemolytic episodes include normocytic normochromic anemia, reticulocytosis, and Heinz bodies 3
• The most effective management strategy is prevention through avoidance of oxidative stressors 4

Remember that G6PD deficiency can vary in severity, and patients with milder variants may tolerate some oxidative challenges that would cause severe hemolysis in those with more severe variants.