[en] Background: Keratin 7 positive (K7+) cells are considered to be activated in case of impaired hepatocyte replication. Their exact role and their interaction with hepatocytes and macrophages also implicated in liver regeneration remain poorly characterized in humans. The aim of this study is to evaluate hepatocyte, K7+ cells and macrophage populations in severe alcohol-related steatohepatitis (sASH) and to link them with liver injury and patients’ outcomes. Methods: Immunohistochemical and morphometric studies for total K7+ cells, macrophages (CD68+ cells), proliferative hepatocytes (Ki67+ hepatocytes) and proliferative K7+ cells (double K7+ and Ki67+) were performed on liver biopsies of patients with sASH recruited prospectively in 16 different centres. Patients were divided into improvers or non-improvers, according to mortality and model for end-stage liver disease (MELD) score change at 3 months. Results: Fifty-seven cases were included for histological and morphometrical assessment. Liver total K7+ cell expansion was positively correlated to the severity of the disease evaluated by the MELD score. A proportion of these K7+ cells were proliferating. The number of proliferating K7+ cells was less than the number of proliferating hepatocytes. Increased hepatocyte replication was correlated to a higher proliferative K7+ cell count. A higher number of macrophages was associated with a higher proliferation of both hepatocytes and K7+ cells. No difference of total K7+ cells, proliferative K7+ cells, proliferative hepatocytes or macrophages was observed between improvers and non-improvers. Conclusions: In biopsy-proven cases of sASH, proliferation of hepatocytes and K7+ cells occurs in parallel. This could suggest that liver progenitor cells begin to replicate even in the absence of massive hepatocyte senescence in humans, or that proliferating progenitor cells are capable of giving rise to hepatocytes with replicative skills. This is associated with macrophagic expansion, which is therefore considered beneficial. However, in this severe, life-threatening disease, these mechanisms remain insufficient to improve patient prognosis.
Disciplines :
Gastroenterology & hepatology
Author, co-author :
Lejeune, Adrienne ; Service d’Hépato-Gastroentérologie, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium ; Laboratory of Gastroenterology and Hepatology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
Stärkel, Peter ; Service d’Hépato-Gastroentérologie, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium ; Laboratory of Gastroenterology and Hepatology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
Louvet, Alexandre ; Service des Maladies de l’Appareil Digestif, Hôpital Huriez, Lille, France
Hittelet, Axel ; Department of Gastroenterology, Hôpital Ambroise Paré, Mons, Belgium
Bazille, Céline ; Service d’Anatomie Pathologique, Centre Hospitalier Universitaire de Caen, Caen, France
Bastens, Boris; Department of Gastroenterology, Clinique Saint-Joseph, Liège, Belgium
Orlent, Hans ; Department of Gastroenterology and Hepatology, AZ Sint Jan AV, Brugge, Belgium
Lasser, Luc ; Department of Hepatogastroenterology, Centre Hospitalier Universitaire Brugmann, Brussels, Belgium
Dekoninck, Xavier; Department of Gastroenterology, Clinique Saint-Pierre, Ottignies, Belgium
Dastis, Sergio Negrin ; Department of Gastroenterology, Hôpital Saint-Joseph, Mons, Belgium
Delwaide, Jean ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gastroentérologie, hépatologie, onco. digestive ; Université de Liège - ULiège > Département des sciences cliniques
Geerts, Anja ; Ghent University Hospital, Ghent, Belgium
Moreno, Christophe ; Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
de Galocsy, Chantal ; Department of Gastroenterology, Hôpitaux Iris Sud, Brussels, Belgium
Putzeys, Virginie ; Department of Gastroenterology, CHR La Citadelle, Liège, Belgium
Langlet, Phillippe ; Department of Gastroenterology, Centre Hospitalier Interrégional Edith Cavell, Brussels, Belgium
Reynaert, Hendrik ; Department of Hepatogastroenterology, Universitair Ziekenhuis Brussel, Brussels, Belgium
Francque, Sven ; Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium ; InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium
Komuta, Mina ; Service d’Anatomie Pathologique, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium
Lanthier, Nicolas ; Service d’Hépato-Gastroentérologie, Cliniques Universitaires Saint-Luc, UCLouvain, Brussels, Belgium ; Laboratory of Gastroenterology and Hepatology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
Belgian Association for the Study of the Liver (BASL)
Reporting Checklist: The authors have completed the MDAR reporting checklist. Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-92/rc
Data Sharing Statement: Available at https://tgh.amegroups.com/article/view/10.21037/tgh-24-92/dss
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Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups. com/article/view/10.21037/tgh-24-92/coif). C.M. received consulting fees from Surrozen, Echosens, Julius Clinical, Ipsen and Roche; received travel grants from Abbvie, Gilead Sciences and Norgine. He also participated on a data safety monitoring board for GSK. S.F. holds a senior clinical investigator fellowship from the Research Foundation Flanders (FWO) (1802154N). He has been lecturer for Abbvie, Allergan, Bayer, Eisai, Genfit, Gilead Sciences, Janssens Cilag, Intercept, Inventiva, Merck Sharp & Dome, Novo Nordisk, Promethera, Siemens. His institution has received grants from Astellas, Falk Pharma, Genfit, Gilead Sciences, GlympsBio, Janssens Pharmaceutica, Inventiva, Merck Sharp & Dome, Pfizer, Roche. He has acted as consultant for Abbvie, Actelion, Aelin Therapeutics, AgomAb, Aligos Therapeutics, Allergan, Alnylam, Astellas, Astra Zeneca, Bayer, Boehringer Ingelheim, Bristoll-Meyers Squibb, CSL Behring, Coherus, Echosens, Dr. Falk Pharma, Eisai, Enyo, Galapagos, Galmed, Genetech, Genfit, Genflow Biosciences, Gilead Sciences, Intercept, Inventiva, Ipsen, Janssens Pharmaceutica, PRO.MED.CS Praha, Julius Clinical, Madrigal, Medimmune, Merck Sharp & Dome, Mursla Bio, NGM Bio, Novartis, Novo Nordisk, Promethera, Roche, Siemens Healthineers, Weatherden. N.L. reports that the cost of immunostainings for this study was paid by a grant from BASL. He also received grants from Gilead Sciences, Echosens, UCLouvain and FNRS (for other research). He acted as a consultant for Ipsen and have received honoraria for presentations for Gilead Sciences, Orphalan and Fresenius Kabi. He has received support for attending scientific meetings from Abbvie, Gilead Sciences and Norgine. The other authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The initial multicentre clinical trial performed in 18 Belgian and 2 French hospitals was approved by the ethical committee of Cliniques universitaires de Bruxelles (CUB) Hôpital Erasme (reference P2009/333) and by the local institutional review board or ethics committee at each participating hospital. All research was conducted in accordance with the Declarations of Helsinki (as revised in 2013). Written informed consent was obtained from all participants. The present additional retrospective study was approved by the Comité d’Ethique Hospitalo-Facultaire of Cliniques universitaires Saint-Luc (reference CEHF: 2016/01JUI/239).
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the noncommercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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