Upregulated beta-defensin-1 in murine and human biliary atresia associates with human native liver survival

Abstract

Abstract Biliary atresia (BA) is a neonatal cholangiopathy that often progresses to cirrhosis despite timely Kasai portoenterostomy (KPE), and prognostic biomarkers remain undefined. Given its role in adult cholestasis, we evaluated human beta-defensin-1 (hBD1) in murine and human BA for associations with disease progression and outcome. This study analyzed hepatic expression of hBD1 and TGF-ß by qRT-PCR in BA at KPE ( n  = 36) and liver transplantation (LT, n  = 44), and compared with normal ( n  = 15) and cholestatic disease controls ( n  = 36). Serum hBD1 was measured by ELISA in BA ( n  = 23) and healthy infants ( n  = 11). Murine BD1 was assessed in a Rhesus rotavirus (RRV) BA model. BD1 was found to be upregulated in murine and human BA, with higher expression at LT than at KPE. Hepatic hBD1 correlated with TGF-ß (R 2 = 0.21), Ishak fibrosis score (R 2 = 0.36), and serum bile acids (R 2 = 0.23). Serum hBD1 was elevated in BA versus controls. Elevated hBD1 at KPE predicted persistent jaundice and reduced native liver survival (X 2 = 9.5), with ROC analysis showing good discrimination for failure of jaundice clearance at 3 months post-KPE (AUC 0.81 for liver and 0.87 for serum). Thus, hBD1 may serve as a negative predictor of jaundice clearance and native liver survival at the time of KPE.