Comprehensive assessment of ECM turnover using serum biomarkers establishes PBC as a high-turnover autoimmune liver disease
Mette Vesterhus,
Mette Juul Nielsen,
Johannes Roksund Hov,
Francesca Saffioti,
Tina Manon-Jensen,
Diana Julie Leeming,
Bjørn Moum,
Kirsten Muri Boberg,
Massimo Pinzani,
Tom Hemming Karlsen,
Morten Asser Karsdal,
Douglas Thorburn
Affiliations
Mette Vesterhus
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Department of Internal Medicine, Haraldsplass Deaconess Hospital, Bergen, Norway; Department of Clinical Science, University of Bergen, Bergen, Norway; Corresponding author. Address: Department of Internal Medicine, Haraldsplass Deaconess Hospital, P.O. Box. 6165, N-5892 Bergen, Norway. Tel.: +47-5597-8500.
Mette Juul Nielsen
Fibrosis Biology and Biomarkers, Nordic Bioscience, Herlev, Denmark
Johannes Roksund Hov
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
Francesca Saffioti
UCL Institute for Liver and Digestive Health, Division of Medicine, University College London & Royal Free Hospital, London, UK; Department of Clinical and Experimental Medicine, Division of Clinical and Molecular Hepatology, University of Messina, Messina, Italy
Tina Manon-Jensen
Fibrosis Biology and Biomarkers, Nordic Bioscience, Herlev, Denmark
Diana Julie Leeming
Fibrosis Biology and Biomarkers, Nordic Bioscience, Herlev, Denmark
Bjørn Moum
Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Medicine, Department of Gastroenterology, Oslo University Hospital, Oslo, Norway
Kirsten Muri Boberg
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
Massimo Pinzani
UCL Institute for Liver and Digestive Health, Division of Medicine, University College London & Royal Free Hospital, London, UK
Tom Hemming Karlsen
Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section of Gastroenterology, Department of Transplantation Medicine, Oslo University Hospital, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway
Morten Asser Karsdal
Fibrosis Biology and Biomarkers, Nordic Bioscience, Herlev, Denmark
Douglas Thorburn
UCL Institute for Liver and Digestive Health, Division of Medicine, University College London & Royal Free Hospital, London, UK
Background & Aims: Primary sclerosing cholangitis (PSC), primary biliary cholangitis (PBC) and autoimmune hepatitis (AIH) are phenotypically distinct autoimmune liver diseases that progress to cirrhosis and liver failure; however, their histological fibrosis distribution differs. We investigated the extracellular matrix (ECM) profiles of patients with PSC, PBC, and AIH to establish whether the diseases display differential patterns of ECM turnover. Methods: Serum samples were retrospectively collected from the UK (test cohort; PSC n = 78; PBC n = 74; AIH n = 58) and Norway (validation cohort; PSC n = 138; PBC n = 28; AIH n = 27). Patients with ulcerative colitis without liver disease (n = 194) served as controls. We assessed specific serological biomarkers of ECM turnover: type III and V collagen formation (PRO-C3, PRO-C5), degradation of type III and IV collagen (C3M, C4M), biglycan (BGM) and citrullinated vimentin (VICM). Results: Most of the ECM markers showed elevated serum levels in PBC compared with PSC or AIH (p <0.01). PRO-C3 correlated well with liver stiffness and showed the most striking differences between advanced and non-advanced liver disease; several of the other ECM markers were also associated with stage. PRO-C3 and other ECM markers were inversely associated with ursodeoxycholic acid treatment response in PBC and remission in AIH. All ECM remodelling markers were significantly elevated (p <0.05) in patients with PSC, PBC, or AIH compared with ulcerative colitis. Conclusions: In this first study comparing ECM turnover in autoimmune liver diseases, we found increased ECM turnover in PBC compared with either PSC or AIH. The study indicates that ECM remodelling is different in PSC, PBC, and AIH, suggesting differing opportunities for therapeutic intervention. Lay summary: The level of scarring is linked to prognosis in autoimmune liver diseases such as primary sclerosing cholangitis, primary biliary cholangitis, and autoimmune hepatitis; hence, the scarring process is a possible target for novel therapy. Investigating the scarring process using highly specific technology, we show that the scarring process is different between the 3 autoimmune liver diseases, and this may have important implications for the development of medical treatment.
