Crigler-Najjar syndrome type 1: pathophysiology, natural history, and therapeutic frontier.

Background and Aims We describe the pathophysiology, treatment, and outcome of Crigler-Najjar type 1 syndrome (CN1) in 28 UGT1A1 c.222C>A homozygotes followed for 520 aggregate patient-years. Approach and Results Unbound ("free") bilirubin (B-f) was measured in patient sera to characterize the binding of unconjugated bilirubin (B-T) to albumin (A) and validate their molar concentration ratio (B-T/A) as an index of neurological risk. Two custom phototherapy systems were constructed from affordable materials to provide high irradiance in the outpatient setting; light dose was titrated to keep B-T/A at least 30% below intravascular B-T binding capacity (i.e., B-T/A = 1.0). Categorical clinical outcomes were ascertained by chart review, and a measure (L-f) was used to quantify liver fibrosis. Unbound bilirubin had a nonlinear relationship to B-T (R-2 = 0.71) and B-T/A (R-2 = 0.76), and B-f as a percentage of B-T correlated inversely to the bilirubin-albumin equilibrium association binding constant (R-2 = 0.69), which varied 10-fold among individuals. In newborns with CN1, unconjugated bilirubin increased 4.3 +/- 1.1 mg/dL per day. Four (14%) neonates developed kernicterus between days 14 and 45 postnatal days of life; peak B-T >= 30 mg/dL and B-T/A >= 1.0 mol:mol were equally predictive of perinatal brain injury (sensitivity 100%, specificity 93.3%, positive predictive value 88.0%), and starting phototherapy after age 13 days increased this risk 3.5-fold. Consistent phototherapy with 33-103 mu W/cm(2)center dot nm for 9.2 +/- 1.1 hours/day kept B-T and B-T/A within safe limits throughout childhood, but B-T increased 0.46 mg/dL per year to reach dangerous concentrations by 18 years of age. Liver transplantation (n = 17) normalized B-T and eliminated phototherapy dependence. Liver explants showed fibrosis ranging from mild to severe. Conclusion Seven decades after its discovery, CN1 remains a morbid and potentially fatal disorder.