Serum FGF19 predicts outcomes of Kasai portoenterostomy in biliary atresia

Abstract

Background and Aims: Outcomes after Kasai portoenterostomy (KPE) for biliary atresia remain highly variable for unclear reasons. As reliable early biomarkers predicting KPE outcomes are lacking, we studied the prognostic value of FGF19. Approach and Results: Serum and liver specimens, obtained from biliary atresia patients (N=87) at KPE or age-matched cholestatic controls (N=26) were included. Serum concentration of FGF19 and bile acids, liver mRNA expression of FGF19, and key regulators of bile acid synthesis were related to KPE outcomes and liver histopathology. Immunohistochemistry and in situ hybridization were used for the localization of liver FGF19 expression. Serum levels (223 vs. 61 pg/mL, p<0.001) and liver mRNA expression of FGF19 were significantly increased in biliary atresia. Patients with unsuccessful KPE (419 vs. 145 pg/mL, p=0.047), and those subsequently underwent liver transplantation (410 vs. 99 pg/mL, p=0.007) had significantly increased serum, but not liver, FGF19, which localized mainly in hepatocytes. In Cox hazard modeling serum FGF19 <109 pg/mL predicted native liver survival (HR: 4.31, p<0.001) also among patients operated <60 days of age (HR: 8.77, p=0.004) or after successful KPE (HR: 6.76, p=0.01). Serum FGF19 correlated positively with increased serum primary bile acids (R=0.41, p=0.004) and ductular reaction (R=0.39, p=0.004). Conclusions: Increased serum FGF19 at KPE predicted inferior long-term native liver survival in biliary atresia and was associated with unsuccessful KPE, elevated serum primary bile acids, and ductular reaction.

Deep learning quantification reveals a fundamental prognostic role for ductular reaction in biliary atresia

“…While reasons for these reversed associations of FGF19 and bile acids require further investigations, they indicate differential regulation of DR in different stages of BA. Accordingly, serum matrix metalloproteinase 7 and cysteine-X cysteine motif chemocine ligand 8, which have been previously connected with the progression of DR following KPE, 25 , 26 showed more uniform and stronger correlations with CharBADR components during follow-up than at KPE.…”

“…In line with our findings, a recent study linked high total serum bile acids measured at 6 months after successful KPE to decreased NLS and development of portal hypertension. 45 In another study, serum FGF19 measured at KPE predicted NLS with an association with DR. 25 Herein, CharBADR biliary components showed positive correlations with serum FGF19 at KPE, but not at post-KPE follow-up. While reasons for these reversed associations of FGF19 and bile acids require further investigations, they indicate differential regulation of DR in different stages of BA.…”

“…Here, we aimed to address the prognostic and pathophysiological significance of DR in BA by developing and applying a histopathological neural network model to a large cohort of native liver biopsies obtained over different disease stages, at KPE and during postoperative follow-up until LT. Model components were related to essential outcome variables and to explanatory factors including serum liver biochemistry, bile acids, and novel biomarkers previously shown to associate the progression of DR in a limited series of BA. 23 – 25 …”

Bile acid profiles in adult patients with biliary atresia who achieve native liver survival after portoenterostomy

“…The typical characteristics of advanced cirrhosis, such as decreased serum CA to CDCA ratios, decreased serum glycine-to-taurine-conjugated ratios, and elevated urinary total and primary bile acids, were not observed 10 – 12 . High bile acid levels in biliary atresia, even after normalization of bilirubin levels, have been attributed to the destruction of the small bile ducts 13 . Prolonged impairment of bile acid transport proteins, such as sodium-taurocholate cotransporting polypeptide (NTCP) and organic solute transporter (OST) α/β, could also explain why serum bile acid levels can remain elevated and fluctuate after the improvement of cholestasis 2 .…”

Progress in Biomarkers Related to Biliary Atresia

“…Although the study by Nyholm et al . 54 had a relatively large sample size, their serum and biopsy samples were stored for more than 14 years. The degradation of protein and mRNA may have affected the accuracy of the results.…”