Methods: Tissues and serum were obtained from 8 BA children and 4 non-cholestatic control (NC; hepatoblastoma, hepatic hemanigoma, urea cycle disorder). Serum FGF19 level was measured by ELISA. Total RNA was extracted from hepatocytes dissected using laser micro-dissection system and expression levels of CYP7A1, FXR, small heterodimer partner (SHP), FGF19, FGFR4, KLB and sprouty homolog
2 (SPRY2) were examined by qPCR. Phosphorylation of FGFR4, Src homology 2 (SHP2), c-Raf and ERK were detected by immu-noprecipitation and Western blotting. Permission to perform this study was given by the Ethics Committee in our institute, HKI-272 supplier and written informed consent was obtained from parents of all of the patients. Results: Expression of CYP7A1 mRNA was not suppressed in the isolated hepatocytes from BA children despite high concentration of serum bile acids. To Investigate mechanisms of this dysregulation, we found the expression of FXR and
SHP were upregulated in BA hepatocytes. Regarding the FGF19 signaling pathway, both serum and tissue levels of FGF19 were significantly increased and FGF19 was aberrantly synthesized in hepatocytes from BA children. Expression of both FGFR4 and KLB mRNA were increased in BA hepatocytes and FGFR4 was phosphorylated in both BA and NC livers, but phosphorylation of SHP2, c-Raf and ERK was significantly decreased in BA livers. To investigate the down regulation mechanisms of MAP kinase, we studied SPRY2 which inhibits ERK pathway
at downstream of FGFR. Expression of Crenolanib mouse SPRY2 mRNA was significantly increased in BA hepatocytes. Conclusion: Bile acids biosynthesis was not properly suppressed by FGF19/FGFR4 as well as classical pathways in BA hepato-cytes. SPRY2 may be involved in the dysregulation and this might be one of the mechanisms which deteriorates cholestatic cirrhosis in BA children. Disclosures: The following people have nothing to disclose: Yasuhiro Hasegawa, Hiroki Kon-dou, click here Kazuhiko Bessho, Masanobu Kawai, Kie Nakao, Takehisa Ueno, Yoshinori Satomura, Akiko Konishi, Takeshi Kimura, Kayo Ikeda, Makiko Tachibna, Yoko Miyoshi, Toshimi Michigami, Keiichi Ozono Background & Aims. Biliary atresia, the most frequent cause of cirrhosis in children, carries a risk of gastrointestinal bleeding due to portal hypertension. Our goal was to define the factors associated with the emergence of endoscopic signs carrying a high risk of bleeding in children who did not display these signs at the first upper gastrointestinal endoscopy. Methods. From 1989 to 2013, 242 children with low-risk signs at first endoscopic examination underwent > 2 upper gastrointestinal endoscopic examinations. The emergence of high-risk gastro-esophageal varices was observed in 82 children (median age, 60 months; range, 9–309 months).