What is the treatment for Crigler-Najjar syndrome?

Treatment of Crigler-Najjar Syndrome

Liver transplantation is the only definitive treatment for Crigler-Najjar syndrome type I and should be performed early, ideally at the time of diagnosis, before the development of brain damage. 1

Understanding Crigler-Najjar Syndrome

Crigler-Najjar syndrome is a rare genetic disorder characterized by:

• Type I (CNI): Complete deficiency of the hepatocyte enzyme uridine diphosphate glucuronosyl transferase (UGT), resulting in severe unconjugated hyperbilirubinemia from birth
• Type II: Partial enzyme deficiency with less severe hyperbilirubinemia

The condition manifests with marked unconjugated hyperbilirubinemia in the neonatal period, placing patients at high risk for kernicterus (bilirubin-induced brain damage) if not properly managed.

Treatment Algorithm

1. Initial Management (Neonatal Period)

• Exchange transfusions for immediate reduction of dangerously high bilirubin levels
• Intensive phototherapy (20-24 hours/day during hyperbilirubinemic crises)
  • Requires maximal body irradiance in the blue-green light spectrum (460-490 nm) 1
  • Monitor bilirubin levels closely to ensure adequate response

2. Long-term Management

• Continuous phototherapy:

  • Minimum of 8-12 hours daily maintenance therapy 1
  • Goal: Maintain bilirubin to albumin concentration ratio <0.5 in neonates and <0.7 in older children 2
  • Custom high-irradiance phototherapy systems may be necessary 3

• Monitor for complications:

  • Cholelithiasis (50% of patients may require cholecystectomy) 2
  • Worsening hyperbilirubinemia with age (increases ~0.46-0.8 mg/dL per year) 2, 3
  • Neurological assessment for early signs of kernicterus

3. Definitive Treatment

• Liver transplantation:
  • The American Association for the Study of Liver Diseases strongly recommends referral for liver transplantation evaluation at the time of diagnosis (Level 1A evidence) 1
  • Living-related liver transplantation is a viable option after confirmation of donor phenotype 1
  • Timing is critical - should be performed before development of neurological damage 4

Monitoring and Follow-up

• Regular measurement of total and unbound bilirubin levels
• Neurological assessments to detect early signs of kernicterus
• Monitor bilirubin to albumin molar ratio (should be kept <0.7) 3
• Avoid medications known to displace bilirubin from albumin 2
• Regular screening for gallstones

Outcomes and Prognosis

• With proper phototherapy management, kernicterus can be prevented in the short term 2
• Without liver transplantation, bilirubin levels continue to increase with age, reaching dangerous levels by late adolescence 3
• Liver transplantation normalizes bilirubin levels immediately and eliminates phototherapy dependence 3, 5
• Post-transplant survival is excellent, though standard transplant-related complications may occur 2

Important Considerations

• Critical timing: In newborns with CNI, unconjugated bilirubin increases 4.3 ± 1.1 mg/dL per day 3
• Risk factors for kernicterus: Peak bilirubin ≥30 mg/dL, bilirubin/albumin ratio ≥1.0, and starting phototherapy after 13 days of age 3
• Disease burden: Phototherapy poses significant challenges to patients and families, affecting quality of life 6
• Progressive nature: Despite consistent phototherapy, hyperbilirubinemia worsens with age 6, 3

Crigler-Najjar syndrome type I represents a significant treatment challenge requiring intensive management until definitive liver transplantation can be performed. Early transplantation before neurological damage occurs offers the best chance for normal development and quality of life.