How is Glucose-6-phosphate dehydrogenase (G6PD) deficiency related to hyperbilirubinemia?

G6PD Deficiency and Hyperbilirubinemia

G6PD deficiency is directly linked to hyperbilirubinemia through increased hemolysis and impaired bilirubin clearance, requiring early screening and more aggressive management to prevent kernicterus. 1

Pathophysiological Relationship

G6PD deficiency affects bilirubin metabolism in two primary ways:

1. Increased Hemolysis:

   • G6PD deficiency reduces the red blood cell's ability to protect against oxidative stress
   • When exposed to oxidative agents, G6PD-deficient cells undergo hemolysis
   • This hemolysis releases hemoglobin which is metabolized to bilirubin
   • The increased bilirubin production overwhelms the liver's conjugation capacity 2

2. Impaired Bilirubin Clearance:

   • G6PD deficiency disrupts the oxidant-antioxidant balance in the liver
   • This affects the recycling of peroxiredoxin 2, which impairs bilirubin clearance
   • Unlike classic favism (acute hemolytic anemia), neonatal hyperbilirubinemia from G6PD deficiency often occurs without overt signs of hemolysis 2

Clinical Significance

G6PD deficiency significantly increases the risk of severe hyperbilirubinemia:

• It is one of the three most common causes of pathologic hyperbilirubinemia 3
• G6PD-deficient infants have higher bilirubin levels at admission (22.26 ± 8.36 mg/dl vs. 18.14 ± 3.85 mg/dl in non-deficient infants) 4
• G6PD deficiency was identified as the cause of hyperbilirubinemia in 31.5% of infants who developed kernicterus in one report 1
• Up to 50.9% of G6PD-deficient infants with hyperbilirubinemia may require exchange transfusion 4

Screening and Management

The American Academy of Pediatrics recommends:

• Screening for G6PD deficiency in infants with significant hyperbilirubinemia 1
• More aggressive intervention at lower total serum bilirubin (TSB) levels for G6PD-deficient infants 1
• Close monitoring as G6PD-deficient infants may develop sudden increases in TSB 1

Important Clinical Considerations

1. Diagnostic Challenges:

   • G6PD levels can be falsely elevated during active hemolysis
   • A normal G6PD level in a hemolyzing neonate does not rule out G6PD deficiency
   • If G6PD deficiency is strongly suspected despite normal levels, repeat testing at 3 months of age 1

2. Demographic Considerations:

   • G6PD deficiency occurs in 11-13% of African Americans 1
   • Higher prevalence in Mediterranean, African, and Asian populations
   • Males are more commonly affected (75.5% of cases) as G6PD is X-linked 4

3. Treatment Precautions:

   • Methylene blue is contraindicated in G6PD deficiency as it may cause hemolysis and paradoxically worsen methemoglobinemia 5
   • Dapsone and other oxidative drugs should be avoided as they can trigger hemolysis in G6PD-deficient patients 1

Prevention Strategies

1. Early Detection:

   • Universal screening for G6PD deficiency is recommended in regions with high prevalence 3
   • Risk assessment before discharge is essential for all newborns 1

2. Close Monitoring:

   • More frequent follow-up for G6PD-deficient infants
   • Lower threshold for phototherapy initiation
   • Earlier intervention to prevent progression to kernicterus 6

3. Parental Education:

   • Provide written and verbal information about jaundice monitoring
   • Educate about avoiding triggers of hemolysis (certain medications, fava beans, etc.)
   • Emphasize the importance of prompt medical attention if jaundice develops 1

G6PD deficiency represents a significant risk factor for severe hyperbilirubinemia and kernicterus. Early identification through screening programs and appropriate management with lower treatment thresholds are essential to prevent the devastating neurological consequences of kernicterus in affected infants.