Role of ductular reaction and ductular–canalicular junctions in identifying severe primary biliary cholangitis
Diletta Overi,
Guido Carpino,
Laura Cristoferi,
Paolo Onori,
Lindsey Kennedy,
Heather Francis,
Nicola Zucchini,
Cristina Rigamonti,
Mauro Viganò,
Annarosa Floreani,
Daphne D’Amato,
Alessio Gerussi,
Rosanna Venere,
Gianfranco Alpini,
Shannon Glaser,
Domenico Alvaro,
Pietro Invernizzi,
Eugenio Gaudio,
Vincenzo Cardinale,
Marco Carbone
Affiliations
Diletta Overi
Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
Guido Carpino
Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome ‘Foro Italico’, Rome, Italy; Corresponding author. Address: Department of Movement, Human and Health Sciences, Division of Health Sciences, University of Rome ‘Foro Italico’, Rome, Italy. Piazza Lauro De Bosis 6, 00135-Rome, Italy. Tel./Fax: +39-06-36733-202..
Laura Cristoferi
Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
Paolo Onori
Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
Lindsey Kennedy
Hepatology and Gastroenterology, Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
Heather Francis
Hepatology and Gastroenterology, Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
Nicola Zucchini
Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
Cristina Rigamonti
Department of Translational Medicine, Università degli Studi del Piemonte Orientale ‘A. Avogadro’, Novara, Italy
Mauro Viganò
Division of Hepatology, Ospedale San Giuseppe, University of Milan, Milan, Italy
Annarosa Floreani
Studiosa Senior, University of Padua, Padua, Italy; Scientific Consultant, IRCCS Negrar, Verona, Italy
Daphne D’Amato
Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
Alessio Gerussi
Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
Rosanna Venere
Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
Gianfranco Alpini
Hepatology and Gastroenterology, Medicine, Indiana University School of Medicine, Indianapolis, IN, USA; Richard L. Roudebush VA Medical Center, Indianapolis, IN, USA
Shannon Glaser
Department of Medical Physiology, Texas A&M University College of Medicine, Bryan, TX, USA
Domenico Alvaro
Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
Pietro Invernizzi
Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
Eugenio Gaudio
Department of Anatomical, Histological, Forensic Medicine and Orthopedic Sciences, Sapienza University of Rome, Rome, Italy
Vincenzo Cardinale
Department of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
Marco Carbone
Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, Monza, Italy
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.
