Crigler Najjar Syndrome

Crigler Najjar syndrome is a rare autosomal recessive disorder of UGT1A1 deficiency causing severe unconjugated hyperbilirubinaemia.

• Type I: absent enzyme activity. Bilirubin 20 to 50 mg/dL from birth, no response to phenobarbital, high risk of kernicterus.
• Type II (Arias syndrome): reduced activity (under 10%). Bilirubin 6 to 25 mg/dL, responds to phenobarbital.
• Prevalence about 1 per million.
• Bilirubin crosses the blood brain barrier when unbound bilirubin is high, especially with illness, fasting, hypoalbuminaemia, acidosis and displacing drugs (sulfonamides, ceftriaxone, salicylates).
• Complications: kernicterus (bilirubin encephalopathy) with dystonia, athetosis, hearing loss, gaze palsy and death.

• Type I: severe jaundice in the first days of life, persisting, with lethargy, hypotonia, poor feeding, then opisthotonos and seizures.
• Type II: jaundice often recognised later, with lower risk of kernicterus (still possible during intercurrent illness).
• Pale stools are absent, urine is normal in colour (bilirubin is unconjugated). Normal liver function and histology.

• Unconjugated hyperbilirubinaemia with normal liver enzymes, no haemolysis and normal liver histology.
• Bile lacks bilirubin glucuronides in type I; trace in type II.
• Phenobarbital response test: bilirubin falls by over 25% in type II, none in type I.
• UGT1A1 gene sequencing confirms the diagnosis.
• Monitor total and albumin bound bilirubin, auditory brainstem responses, MRI (globus pallidus).

• Phototherapy (blue light 460 to 490 nm, high intensity) 12 to 16 hours daily from birth in type I, declining effect with age as skin thickens.
• Acute crises: intensive phototherapy, plasmapheresis or exchange transfusion for bilirubin above 25 to 30 mg/dL, IV albumin 1 g/kg, calcium phosphate binding agents (oral calcium phosphate, orlistat, cholestyramine).
• Type II: phenobarbital 3 to 5 mg/kg/day (lowers bilirubin by 25 to 80%), maintained lifelong; avoid displacing drugs.
• Avoid fasting, infections and dehydration; treat intercurrent illness early with enhanced phototherapy.
• Definitive therapy for type I: liver transplantation, ideally before neurological damage. Auxiliary liver transplantation preserves native liver.
• Gene therapy (AAV vectors for UGT1A1) is in clinical trials. Hepatocyte transplantation is a bridge.
• Genetic counselling. Neurodevelopmental follow up.