Divergent expression of liver transforming growth factor superfamily cytokines after successful portoenterostomy in biliary atresia

Abstract

Background: Pathogenesis of progressive liver fibrosis in biliary atresia after successful portoenterostomy remains unclear. We related hepatic expression of transforming growth factor beta (TGF-β) superfamily cytokines to histologic liver injury after successful portoenterostomy. Methods: Enrolled in our study were 28 patients with biliary atresia who had liver biopsies obtained during and after successful portoenterostomy, which normalized serum bilirubin (< 20 μmol/l). Biopsies were evaluated for cholestasis, inflammation, ductal reaction, and fibrosis and were stained immunohistochemically for transforming growth factor beta 1, transforming growth factor beta 2, connective tissue growth factor, and decorin. Respective gene expression (TGFB1, TGFB2, TGFB3, CTGF, DCN) was analyzed at follow-up using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results were compared with fibrotic and healthy control livers. Results: After median follow-up of 3.0 years, histologic cholestasis resolved, whereas fibrosis had progressed only in isolated biliary atresia. Liver protein expression of transforming growth factor beta 1 and connective tissue growth factor (P < .001 for both), but not that of transforming growth factor beta 2 or decorin, decreased after successful portoenterostomy, although expression of all four cytokines remained elevated. In accordance with postportoenterostomy changes in protein expression, follow-up ribonucleic acid expression of TGFB2 and DCN, but not that of TGFB1 and CTGF, was upregulated when compared with the controls. Both protein and gene expression of transforming growth factor beta 1 and protein expression of transforming growth factor beta 2, connective tissue growth factor and decorin correlated with METAVIR fibrosis stage. Syndromic patients (n = 12) showed milder fibrosis and lower transforming growth factor beta 1 expression than patients with isolated biliary atresia. Conclusion: These findings support a central role of transforming growth factor beta superfamily in mediating continuing liver fibrogenesis after successful portoenterostomy. Transforming growth factor beta pathway cytokines responded divergently to clearance of jaundice, which was reflected by differential progression of fibrosis between syndromic and isolated patients.

Liver secretin receptor predicts portoenterostomy outcomes and liver injury in biliary atresia

“…The association between SCTR and liver fibrosis was further strengthened by close correlations of SCTR with TGF-β and PDGF , growth factors known to mediate liver fibrosis 31 , 32 . However, unlike in previous experimental studies, SCTR associated with TGFB2 rather than TGFB1 , which is less abundantly expressed TGF-β isoform in BA 17 , 33 , 34 . Additional studies in cholestatic experimental animal models are needed to clarify whether the secretin/SCTR axis could be targeted to reduce fibrosis and biliary damage in BA 20 , 22 , 25 .…”

Biliary Epithelial Senescence in Liver Disease: There Will Be SASP

“…In this study, inhibition of TGF-β1 reduced biliary SASP secretion and increased hepatocyte proliferation and liver function (Ferreira-Gonzalez et al, 2018). Kasai portoenterostomy may resolve some features of cholestasis and fibrosis, but in a select group of patients' fibrosis can remain following surgery (Kerola et al, 2019). In biliary atresia, TGF-β1 and decorin expression was elevated in lobular hepatocytes and fibrotic areas and correlated with liver fibrosis (Kerola et al, 2019).…”

“…In biliary atresia, TGF-β1 and decorin expression was elevated in lobular hepatocytes and fibrotic areas and correlated with liver fibrosis (Kerola et al, 2019). At 3-year follow-up, successful Kasai portoenterostomy significantly reduced hepatic TGF-β1 and connective tissue growth factor (CTGF) expression, while TGF-β2 expression was found to be increased (Kerola et al, 2019), signifying a central role for the TGF-β superfamily in promoting continued liver fibrosis after Kasai portoenterostomy. Considering that CTGF drives senescence in fibroblasts (Capparelli et al, 2012) it is reasonable to expect cholangiocyte SASP paracrine communication as central to biliary atresia progression and successfulness of Kasai portoenterostomy.…”

“…Biliary atresia is a devastating pediatric cholestatic and fibrogenic liver disease with a multifactorial etiology and unknown molecular mechanism of pathogenesis (Bezerra et al, 2018;Kerola et al, 2019). Early intervention with Kasai hepatic portoenterostomy, to restore bile flow, and eventual liver transplantation increases survival of biliary atresia patients (Bezerra et al, 2018).…”

“…Kasai portoenterostomy may resolve some features of cholestasis and fibrosis, but in a select group of patients' fibrosis can remain following surgery (Kerola et al, 2019). In biliary atresia, TGF-β1 and decorin expression was elevated in lobular hepatocytes and fibrotic areas and correlated with liver fibrosis (Kerola et al, 2019). At 3-year follow-up, successful Kasai portoenterostomy significantly reduced hepatic TGF-β1 and connective tissue growth factor (CTGF) expression, while TGF-β2 expression was found to be increased (Kerola et al, 2019), signifying a central role for the TGF-β superfamily in promoting continued liver fibrosis after Kasai portoenterostomy.…”