Abstract

Background: Alagille syndrome (ALGS) is a rare, autosomal dominant multisystem disorder characterized by cholestasis and extrahepatic manifestations. Given the current era of ileal bile acid transporter (IBAT) inhibitor therapies that reduce serum bile acid (SBA) levels, the aim of this study was to determine whether SBA are a predictor of clinical outcomes in ALGS.

Methods: Patients were ascertained from the GALA cohort, an international multicentre study including clinically and/or genetically diagnosed children with ALGS. Those with neonatal cholestasis and at least one SBA measurement during follow-up were eligible for inclusion. An established SBA threshold in progressive familial intrahepatic cholestasis (PFIC) (102 umol/L) was assessed as a time-dependent covariate in Cox regression analyses for native liver survival (NLS); liver transplantation and death as endpoints, overall and while adjusting for total bilirubin (TB) levels and stratified by geographical region. The association between median SBA in the first 3 years according to the PFIC threshold and NLS was also assessed. Patients who did not meet one of these endpoints were truncated at the time of biliary diversion, Kasai procedure, trial enrollment, or their last follow-up, up to a maximum of 18 years of age.

Results: 570 patients from GALA were included, of whom 348 (61.1%) were male with a median year of birth of 2012 (IQR 2007-2015). Rates of NLS at 1, 5 and 18 years were 97.2%, 81.8%, and 53.6%, respectively. There is a moderate positive correlation between SBA and total bilirubin (Pearson correlation=0.47, p<0.001). The was a significant predictor of outcome (HR = 3.78, 95% CI 2.39-5.99, p < 0.001) and there was no significant difference in the impact of SBA between the first (p = 0.32). SBA remained a significant factor for NLS while adjusting for TB clearance at 1 year (HR = 2.00, 95% CI 1.10-3.65, p = 0.02), where clearance is defined as TB <2 mg/dL. There was no significant interaction between the SBA threshold and clearance of TB. Furthermore, if median SBA in the first 3 years was above 102 umol/L, patients had lower NLS at 8 years of age (Figure, p=0.005), including in those with favourable bilirubin trends (90.9% vs. 95.9, p=0.04).

Conclusion: SBA is an independent predictive factor for NLS in children with ALGS and neonatal cholestasis. Of note, SBA is also associated with NLS in children with ALGS who clear their bilirubin i.e. those with anicteric cholestasis. This is relevant in the context of IBAT inhibitors that promote a reduction in SBA and are currently indicated for pruritus but may also impact additional important clinical outcomes.