Background and Aims Alagille syndrome (ALGS) is a multisystem disorder, characterized
by cholestasis. Existing outcome data are largely derived from tertiary centers, and
real-world data are lacking. This study aimed to elucidate the natural history of
liver disease in a contemporary, international cohort of children with ALGS. Approach
and Results This was a multicenter retrospective study of children with a clinically
and/or genetically confirmed ALGS diagnosis, born between January 1997 and August
2019. Native liver survival (NLS) and event-free survival rates were assessed. Cox
models were constructed to identify early biochemical predictors of clinically evident
portal hypertension (CEPH) and NLS. In total, 1433 children (57% male) from 67 centers
in 29 countries were included. The 10 and 18-year NLS rates were 54.4% and 40.3%.
By 10 and 18 years, 51.5% and 66.0% of children with ALGS experienced >= 1 adverse
liver-related event (CEPH, transplant, or death). Children (>6 and <= 12 months) with
median total bilirubin (TB) levels between >= 5.0 and <10.0 mg/dl had a 4.1-fold (95%
confidence interval [CI], 1.6-10.8), and those >= 10.0 mg/dl had an 8.0-fold (95%
CI, 3.4-18.4) increased risk of developing CEPH compared with those 10.0 mg/dl were
associated with a 4.8 (95% CI, 2.4-9.7) and 15.6 (95% CI, 8.7-28.2) increased risk
of transplantation relative to <5.0 mg/dl. Median TB <5.0 mg/dl were associated with
higher NLS rates relative to >= 5.0 mg/dl, with 79% reaching adulthood with native
liver (p < 0.001). Conclusions In this large international cohort of ALGS, only 40.3%
of children reach adulthood with their native liver. A TB <5.0 mg/dl between 6 and
12 months of age is associated with better hepatic outcomes. These thresholds provide
clinicians with an objective tool to assist with clinical decision-making and in the
evaluation of therapies.
