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

Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

G6PD deficiency is the most common human enzyme defect affecting over 400 million people worldwide, causing impaired protection against oxidative stress that leads to red blood cell damage and destruction when exposed to oxidant drugs, infections, or certain foods. 1

Pathophysiology

G6PD is a critical enzyme in the pentose phosphate pathway that:

• Generates NADPH, which protects cells from oxidative damage
• Is particularly important in red blood cells which lack other mechanisms to produce NADPH
• When deficient, causes red blood cells to be highly vulnerable to oxidative stress

The condition is X-linked, with:

• Males being hemizygous (fully affected or unaffected)
• Females being heterozygous with variable expression due to random X-chromosome inactivation 1

Epidemiology

• Most common human enzymopathy affecting over 400 million people worldwide 2
• Global distribution remarkably similar to that of malaria, supporting the "malaria protection hypothesis" 2, 3
• Higher prevalence in:
  • Mediterranean regions
  • Africa
  • Middle East
  • Southeast Asia
• Prevalence is particularly high in the Ashkenazi Jewish population (1/20,000) 1

Genetic Basis

• X-linked hereditary genetic defect due to mutations in the G6PD gene 2
• Over 200 mutations have been identified 3
• Most are single base changes leading to amino acid substitutions 2
• Common variants include:
  • GdA- variant (found in 10-15% of Black men and women) - causes milder, self-limited hemolysis
  • Gdmed variant - associated with more severe, potentially life-threatening hemolysis 1

Clinical Manifestations

G6PD deficiency can present with:

1. Acute hemolytic anemia:

   • Triggered by exposure to oxidative stressors
   • Presents with pallor, dark red urine, and jaundice within 24-72 hours of exposure 4
   • Common triggers include:
     • Medications (antimalarials, sulfonamides, certain NSAIDs)
     • Fava beans and other legumes
     • Infections (pneumonia, tonsillitis, typhoid fever) 4

2. Neonatal jaundice:

   • Can rapidly escalate to bilirubin-induced neurologic dysfunction
   • Often occurs without overt signs of hemolysis 5

3. Chronic hemolysis:

   • Rare variants cause congenital non-spherocytic hemolytic anemia 2

4. Increased susceptibility to infection:

   • Severe G6PD deficiency can impair neutrophil function
   • May lead to defective neutrophil extracellular trap (NET) formation 6

Diagnosis

When to Test

• Patients with unexplained hemolytic anemia
• Neonates with significant hyperbilirubinemia
• Patients requiring treatment with oxidative medications (e.g., antimalarials)
• Family members of affected individuals
• Patients from high-risk ethnic groups 1

Diagnostic Methods

1. Quantitative enzyme activity assay (gold standard):

   • Measures G6PD activity in U/g Hemoglobin
   • Can detect heterozygous females with intermediate deficiency 1

2. Fluorescent spot test (FST):

   • Widely used screening method
   • Based on NADPH generation which fluoresces under UV light
   • Results interpretation:
     • Absent fluorescence: severe deficiency
     • Intermediate fluorescence: partial deficiency
     • Bright fluorescence: normal activity 1

3. Point-of-care rapid diagnostic tests:

   • Similar performance to FST
   • 100% sensitivity for detecting severe and moderate deficiency (<30% activity)
   • Specificity >97% 1

Important Testing Considerations

• Avoid testing during acute hemolytic episodes (may yield falsely normal results)
• If G6PD deficiency is strongly suspected but initial test is normal during hemolysis, repeat testing 3 months after hemolytic episode resolves 1
• Heterozygous females may have normal, intermediate, or deficient enzyme activity due to random X-chromosome inactivation 1

Management

The most effective management strategy for G6PD deficiency is prevention through avoidance of oxidative stressors. 1

Prevention of Hemolytic Episodes

1. Avoid triggering medications:

   • Antimalarials (primaquine, tafenoquine)
   • Sulfonamides
   • Certain NSAIDs (diclofenac sodium, ibuprofen, aspirin)
   • Nitrofurantoin
   • Rasburicase
   • Methylene blue (contraindicated in G6PD deficiency) 1, 4

2. Avoid triggering foods:

   • Fava beans (most common dietary trigger)
   • Other legumes: falafel, chick pea, broad bean, green pea, peanuts, lentil 4

3. Prompt treatment of infections 4

Management of Acute Hemolysis

• Ensure adequate hydration
• Glucose administration
• For patients with high methemoglobin levels, use ascorbic acid (0.5-1.0 g/day in divided doses) instead of methylene blue 1
• Blood transfusion may be required in severe cases
• Monitor for acute kidney injury from hemoglobinuria

Special Considerations

• Screening programs are recommended in regions with high prevalence
• Neonates with G6PD deficiency require close monitoring for hyperbilirubinemia
• Patients with severe G6PD deficiency may have impaired neutrophil function similar to chronic granulomatous disease, potentially requiring antibiotic prophylaxis 6

Prognosis

Most individuals with G6PD deficiency remain asymptomatic throughout their lifetime if they avoid triggers. The prognosis is generally excellent with proper education and preventive measures, though severe variants may have more complications.