Background & aims: Primary biliary cholangitis (PBC) is a chronic cholangiopathy characterised by immuno-mediated injury of interlobular bile ducts leading to intrahepatic cholestasis and progressive liver fibrosis. PBC histology is characterised by portal inflammation, progressive fibrosis, ductopenia, and the appearance of the so-called ductular reaction. The aim of the present study was to investigate the pathogenetic relevance of ductular reaction in PBC.
Methods: Liver biopsies were collected from naïve people with PBC (N = 87). Clinical-serological parameters were obtained at diagnosis and after 1 year of ursodeoxycholic acid (UDCA) treatment. Histological staging was performed on all slides according to multiple scoring systems and criteria for PBC. Liver samples were obtained from Mdr2 -/- mice treated with or without UDCA. Samples were processed for histology, immunohistochemistry, and immunofluorescence.
Results: Ductular reaction in people with PBC correlated with the disease stage and liver fibrosis, but not with disease activity; an extensive ductular reaction correlated with serum alkaline phosphatase levels at diagnosis, response to UDCA, and individuals' estimated survival, independently from other histological parameters, including disease stage. In people with PBC, reactive ductules were associated with the establishment of junctions with bile canaliculi and with fibrogenetic cell activation. Consistently, in a mouse model of intrahepatic cholestasis, UDCA treatment was effective in reducing ductular reaction and fibrosis and increasing ductular-canalicular junctions.
Conclusions: Extensive ductular reaction outlines a severe histologic phenotype in PBC and is associated with an inadequate therapy response and a worse estimated prognosis.
Lay summary: In people affected by primary biliary cholangitis (PBC), the histological appearance of extensive ductular reaction identifies individuals at risk of progressive fibrosis. Ductular reaction at diagnosis correlates with the lack of response to first-line therapy with ursodeoxycholic acid and serves to restore ductular-canalicular junctions in people with PBC. Assessing ductular reaction extension at diagnosis may add valuable information for clinicians.
Keywords: AE2, anion exchanger 2; ALP, alkaline phosphatase; ALPt0, ALP at diagnosis; ALPt12, ALP at 12 months after UDCA therapy; ALT, alanine aminotransferase; ALTt0, ALT at diagnosis; AMA, antimitochondrial antibody; ANA, antinuclear antibody; AST, aspartate aminotransferase; ASTt0, AST at diagnosis; BAC, bile acid control; BIL, bilirubin; BILt0, BIL at diagnosis; CA, cholangitis activity; CK19, cytokeratin 19; CK7, cytokeratin 7; Cholangiopathy; Cholestasis; DCJ, ductular–canalicular junction; DCJ/d, DCJ per ductule; DCJ/pt, DCJ per portal tract; DR, ductular reaction; EpCAM, epithelial cell adhesion molecule; GGT, gamma-glutamyl transferase; HA, hepatitis activity; HSC, hepatic stellate cell; Histology; IH, intermediate hepatocyte; Liver biopsy; MF, myofibroblast; Muc-1, mucin 1; PBC, primary biliary cholangitis; PCNA, proliferating cell nuclear antigen; RT-qPCR, real-time quantitative PCR; Regeneration; SCTR, secretin receptor; SQ, semiquantitative; UDCA, ursodeoxycholic acid; ULN, upper limit of normal; URS, UDCA response score; Ursodeoxycholic acid; WT, wild type; αSMA, α-smooth muscle actin.
© 2022 The Author(s).