Treatment for Crigler-Najjar Syndrome
Liver transplantation is the only definitive treatment for Crigler-Najjar syndrome type I, and referral for liver transplant evaluation should be considered at the time of diagnosis before the development of brain damage. 1
Types and Pathophysiology
- Crigler-Najjar syndrome results from deficiency of the hepatocyte enzyme uridine diphosphate glucuronosyl transferase (UGT1A1), leading to severe unconjugated hyperbilirubinemia 1
- Type I (CNI) is characterized by complete enzyme deficiency, resulting in marked unconjugated hyperbilirubinemia that becomes apparent during the neonatal period 1
- Type II involves partial enzyme deficiency with less severe hyperbilirubinemia and responds to phenobarbital therapy 2
Acute Management for Type I
- Initial treatment consists of exchange transfusions during the neonatal period to prevent kernicterus 1
- In newborns with CNI, unconjugated bilirubin increases at a rate of approximately 4.3 mg/dL per day, reaching dangerous levels between 5-14 days of age 3
- Starting phototherapy after 13 days of age increases the risk of kernicterus 3.5-fold 3
- Peak bilirubin levels ≥30 mg/dL are highly predictive of perinatal brain injury 3
Long-term Management for Type I
- Long-term management requires intensive phototherapy to prevent kernicterus 1
- Successful phototherapy requires:
- Despite consistent phototherapy, patients with CNI experience worsening hyperbilirubinemia with advancing age (approximately 0.46 mg/dL increase per year) 3
- By age 18, bilirubin levels typically reach dangerous concentrations despite phototherapy 3
Definitive Treatment
- Liver transplantation is the only definitive treatment for Crigler-Najjar syndrome type I 1, 4
- Recommendations from guidelines:
- Referral for liver transplant evaluation should be considered for CNI patients before the development of brain damage, ideally at the time of diagnosis 1
- Living-related liver transplantation (LRLT) can be performed successfully 1
- For heterozygote donors (e.g., parents), LRLT has been successfully performed for Crigler-Najjar syndrome type I 1
Management of Type II
- Patients with Crigler-Najjar syndrome type II respond to phenobarbital therapy 2
- Phenobarbital can decrease bilirubin levels by 60-70% within 3 weeks 2
- Irinotecan (a chemotherapy drug) should be used with caution and at decreased doses in patients with Crigler-Najjar syndrome due to UGT1A1 deficiency 1
Emerging Therapies
- Gene therapy shows promising results in recent clinical trials:
- A single intravenous infusion of an adeno-associated virus serotype 8 vector encoding UGT1A1 at a dose of 5×10¹² vector genomes per kilogram resulted in decreased bilirubin levels 5
- Patients receiving this higher dose maintained bilirubin levels below 300 μmol per liter without phototherapy for at least 78 weeks after vector administration 5
Complications and Monitoring
- Without adequate treatment, patients risk developing kernicterus (bilirubin-induced neurological damage) 4, 3
- Kernicterus is characterized by mental retardation, central deafness, ophthalmoplegia, ataxia, athetosis, spasticity, and seizures 6
- Periods of fasting, stress, and illness can worsen unconjugated hyperbilirubinemia and should be managed aggressively 2
- Liver explants from patients with Crigler-Najjar syndrome show varying degrees of fibrosis from mild to severe 3
Treatment Algorithm
- Neonatal period: Immediate exchange transfusions and intensive phototherapy when diagnosis is suspected 1, 6
- Childhood: Maintain intensive phototherapy (8-12 hours daily minimum) 1, 3
- Definitive treatment: Refer for liver transplantation evaluation at diagnosis 1
- For Type II: Trial of phenobarbital therapy 2
- Consider: Enrollment in gene therapy clinical trials as they become available 5