Accumulation of altered serum bile acids predicts liver injury after portoenterostomy in biliary atresia

Background & Aims: Little is known about the mechanism of liver injury mediated by bile acids following Kasai portoenterostomy (KPE) for biliary atresia (BA). We sought to quantify individual serum bile acids, 7-alpha-hydroxy-4-cholesten-3-one (C4), and fibroblast growth factor 19 (FGF19) after KPE and to evaluate their prognostic utility and transcriptomic regulation. Methods: Serum (n = 244) and liver specimens (n = 105) prospectively obtained from patients with BA (n = 54) after KPE were included. Bile acids were analyzed using mass spectrometry, gene expression with quantitative PCR, and histopathology using a neural network model. Results: Following KPE, serum bile acids correlated positively with biochemical liver injury, pediatric end-stage liver disease score, liver stiffness, histological ductular reaction, and liver fibrosis. Bile acids were higher among patients who developed portal hypertension (79.6 vs. 11.9 μmol/L, p <0.0001), esophageal varices (91.6 vs. 16.2 μmol/L, p <0.0001), or required liver transplantation (LT, 115.3 vs. 22.0 μmol/L, p <0.0001) during follow-up; bile acids predicted these outcomes in time-dependent regression models. Accumulation of conjugated bile acids, cholic acid, and taurine conjugates predicted LT risk while associating with histological liver injury. Serum C4 (0.04 vs. 0.00 μmol/L, p = 0.04) and liver CYP7A1 were higher in native liver survivors than in LT recipients (fold-change 16.9 vs. 7.0, p = 0.02). Primary bile acids correlated negatively with C4 (R = -0.38, p <0.001) and CYP7A1 (R = -0.49, p = 0.01). Unlike in native liver survivors (R = -0.19, p = 0.66), serum FGF19 correlated with liver FGF19 (R = 0.59, p = 0.04) without an inverse association with serum primary bile acids in LT recipients (R = 0.26, p = 0.08). Conclusions: Accumulation and altered composition of serum bile acids predicted progressive liver disease and poorer transplant-free survival following KPE. Poor prognosis was associated with low bile acid synthesis and aberrantly increased liver FGF19. Impact and implications: Biliary atresia, a fibro-obliterating biliary disease of infants, remains the most common indication for pediatric liver transplantation because of the rapid progression of liver injury. To identify predictive biomarkers of disease progression and to elucidate the pathophysiology of liver injury in biliary atresia, we profiled serum bile acids and studied their liver metabolism after Kasai portoenterostomy. Accumulation and altered composition of circulating bile acids predicted progression of liver disease and need for liver transplantation. Patients with poor prognosis showed low bile acid synthesis and abnormal liver expression of fibroblast growth factor 19.