What is Glucose-6-phosphate dehydrogenase (G6PD) deficiency?

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

G6PD deficiency is the most common human enzyme deficiency worldwide, affecting over 400 million people, characterized by an X-linked genetic mutation that makes red blood cells vulnerable to oxidative damage and susceptible to hemolysis when triggered by certain medications, foods (particularly fava beans), or infections. 1, 2

Pathophysiology and Genetics

G6PD is an essential enzyme in the pentose phosphate pathway that:

• Protects red blood cells from oxidative damage
• Generates NADPH, which maintains glutathione in its reduced form
• When deficient, causes red cells to become highly vulnerable to oxidative stress

The condition is X-linked, meaning:

• Males are more commonly affected (having only one X chromosome)
• Females can be carriers or affected depending on X-chromosome inactivation
• Over 200 mutations have been identified in the G6PD gene 2

Epidemiology

• Affects approximately 500 million people globally
• Geographic distribution correlates remarkably with past/present malaria endemicity
• Represents a unique example of an X-linked human polymorphism that provides protection against malaria mortality 2
• Highest prevalence in:
  • Africa
  • Mediterranean region
  • Middle East
  • Southeast Asia
  • Parts of the Indian subcontinent

Clinical Manifestations

G6PD deficiency can present with:

1. Acute hemolytic anemia

   • Triggered by oxidative stressors:
     • Medications (primaquine, dapsone, sulfonamides, nitrofurantoin, rasburicase)
     • Foods (particularly fava beans and other legumes)
     • Infections
   • Symptoms typically appear 24-72 hours after exposure 3
   • Clinical features include:
     • Pallor (100% of cases)
     • Dark red urine (89.6%)
     • Jaundice (87.8%)
     • Fatigue
     • Shortness of breath
     • Back/abdominal pain

2. Neonatal jaundice

   • Common manifestation in newborns with G6PD deficiency
   • May require phototherapy or exchange transfusion in severe cases

3. Chronic nonspherocytic hemolytic anemia

   • Rare presentation associated with specific severe mutations
   • Presents with ongoing hemolysis even without triggers

Common Triggers

1. Dietary triggers (most common - 83.4% of cases) 3:

   • Fava beans (32.6%)
   • Falafel (19.4%)
   • Other legumes including chickpeas, broad beans, green peas, peanuts, lentils

2. Infections (12.4% of cases):

   • Pneumonia (3.4%)
   • Tonsillitis (3.2%)
   • Typhoid fever (2.8%)
   • Hepatitis A (1.8%)
   • Urinary tract infections (1.2%)

3. Medications (4.2% of cases):

   • NSAIDs (diclofenac, ibuprofen, aspirin)
   • Antimalarials (primaquine)
   • Antibiotics (sulfonamides, nitrofurantoin)
   • Rasburicase

Diagnosis

Diagnostic approaches include:

1. Quantitative enzyme activity testing (gold standard)

   • Indications:
     • Before administering primaquine for malaria
     • Patients with unexplained hemolysis
     • Individuals from high-prevalence regions 1

2. Screening tests:

   • Fluorescent spot test (FST)
     • Absent fluorescence: severe deficiency
     • Intermediate fluorescence: partial deficiency
     • Bright fluorescence: normal activity 1
   • Point-of-care rapid diagnostic tests
     • ~100% sensitivity for severe/moderate deficiency 1

3. Laboratory findings during hemolytic episodes:

   • Decreased hemoglobin
   • Reticulocytosis
   • Presence of Heinz bodies
   • Elevated indirect bilirubin
   • Decreased haptoglobin
   • Hemoglobinuria

Management

1. Prevention:

   • Avoid known triggers (medications, foods)
   • Maintain adequate hydration, especially during illness 1
   • Document G6PD status prominently in medical records

2. Management of acute hemolytic episodes:

   • Discontinue the offending agent immediately
   • Provide supportive care:
     • Intravenous hydration
     • Blood transfusion for severe anemia
   • Monitor with serial hemoglobin measurements 1

3. Safe medication alternatives:

   • Safe antibiotics: penicillins, cephalosporins, macrolides, most tetracyclines 1
   • Medications to avoid:
     • Sulfonamides
     • Nitrofurantoin
     • Dapsone
     • Primaquine/tafenoquine
     • Methylene blue
     • Rasburicase

Special Considerations

1. Pregnancy and breastfeeding:

   • Avoid primaquine due to risk to the fetus
   • Breastfeeding women should avoid primaquine or discontinue nursing 1

2. Pediatric patients:

   • Highest prevalence of hemolytic crisis in the 1-3 year age group (92% of cases) 3
   • Mean age of first presentation: 22.8±15.54 months
   • Require careful monitoring for neonatal jaundice

3. Heterozygous females:

   • May have intermediate enzyme deficiency
   • Can still experience clinical symptoms under severe oxidative stress 1

Prognosis

With proper management and avoidance of triggers, most individuals with G6PD deficiency can lead normal lives. The condition is generally benign when properly managed, though acute hemolytic episodes can be severe and potentially life-threatening if not promptly recognized and treated.