Clinical, histological and molecular profiling of different stages of alcohol-related liver disease.

Vijay Shah, Steven Masson, Philippe Mathurin, Nahum Mendez-Sanchez, Rosa Miquel, Christophe Moreno, Taofic Mounajjed, Gemma Odena, Won Kim, Pau Sancho-Bru, R Warren Sands, Justyna Szafranska, Laurine Verset, Bern Schnabl, Christine Sempoux, Michael R Lucey, Debbie Lindsay Shawcross, Rudolf E Stauber, Beate K Straub, Elizabeth Verna, Dina Tiniakos, Eric Trépo, Victor Vargas, Càndid Villanueva, John T Woosley, Marianne Ziol, Sebastian Mueller, Peter Stärkel, Ramon Bataller, Juan Caballeria, Josepmaria Argemi, Patricia D Jones, Carolin Lackner, Mohamed El Hag, Juan G Abraldes, Edilmar Alvarado, Ana Clemente, Samhita Ravi, Antonio Alves, Mohamed Alboraie, Jose Altamirano, Sergio Barace, Francisco Bosques, Robert Brown, Meritxell Ventura-Cots, Joaquin Cabezas, Sofia Carvalhana, Helena Cortez-Pinto, Adilia Costa, Delphine Degré, Carlos Fernandez-Carrillo, Nathalie Ganne-Carrie, Guadalupe Garcia-Tsao, Joan Genesca, John Koskinas, Nicolas Lanthier, Alexandre Louvet, Juan José Lozano

Journal: Gut 2022;71(9):1856-1866

PMID: 34992134

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Abstract

OBJECTIVE

Alcohol-related liver disease (ALD) ranges from never-decompensated ALD (ndALD) to the life-threatening decompensated phenotype, known as alcohol-related hepatitis (AH). A multidimensional study of the clinical, histological and molecular features of these subtypes is lacking.

DESIGN

Two large cohorts of patients were recruited in an international, observational multicentre study: a retrospective cohort of patients with ndALD (n=110) and a prospective cohort of patients with AH (n=225). Clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis of both disease phenotypes were performed.

RESULTS

Age and mean alcohol intake were similar in both groups. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma-glutamyl transferase levels than in ndALD patients. Patients with AH demonstrated profound liver failure and increased mortality. One-year mortality was 10% in ndALD and 50% in AH. Histologically, steatosis grade, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and ductular reaction were more frequent among AH patients. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. While ndALD was characterised by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism.

CONCLUSIONS

Despite comparable alcohol intake, AH patients presented with worse liver function compared with ndALD patients. Bilirubinostasis, severe fibrosis and ductular reaction were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared with ndALD patients.

Address: Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain.; Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Barcelona, Spain.; Liver Unit, Clinica Universitaria de Navarra, Pamplona, Spain.; Department of Medicine, Division of Gastroenterology and Hepatology, University of Miami Miller School of Medicine, Miami, Florida, USA.; Institute of Pathology, Medical University of Graz, Graz, Austria.; Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.; Division of Gastroenterology, Liver Unit, University of Alberta, Edmonton, Alberta, Canada.; Gastroenterology, Hospital of Santa Creu and Sant Pau, Autonomous University of Barcelona, Hospital Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.; Liver Unit and Digestive Department, H.G.U. Gregorio Marañon, Madrid, Spain.; Departament of Pathology, Hospital Prof. Doutor Fernando Fonseca. Instituto de Anatomia Patologica, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisboa, Portugal.; Department of Internal Medicine, Al-Azhar University, Cairo, Egypt.; Internal Medicine, Hospital Quironsalud Barcelona, Barcelona, Spain.; Centro de investigación Médica Aplicada (CIMA), Universidad de Navarra, Hepatology Program, Pamplona, Spain.; Hospital Sant José Tecnológico de Monterrey, Universidad Autonoma de Nuevo Leon, Monterrey, Monterrey, Mexico.; Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York, USA.; Liver Unit, Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain.; Gastroenterology and Hepatology Department Marques de Valdecilla University Hospital, Valdecilla Research Institute - IDIVAL, Santander, Santander, Spain.; Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.; Department of Pathology, Hospital Santa Maria, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisboa, Portugal.; Centre de ressources biologiques (BB-0033-00027) Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Brussels, Belgium.; Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro, Puerta de Hierro Health Research Institute (IDIPHIM), Madrid, Spain.; Liver Unit, INSERM UMR 1162, Hôpitaux Universitaires Paris Seine Saint-Denis, APHP, Université paris 13 Sorbonne Paris Cité, Paris, France.; Section of Digestive Diseases, Yale University, New Haven, Connecticut. Department of Veterans Affairs Connecticut Healthcare, New Haven, Connecticut, USA.; 2nd Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.; Service d'Hépato-Gastroentérologie, Cliniques universitaires Saint-Luc, UCLouvain, Bruxelles, Belgium.; Laboratory of Hepatogastroenterology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium.; University of Lille, Inserm, CHU Lille, U1286-INFINITI-Institute for Translational Research in Inflammation, F-590000, Lille, France.; Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.; Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.; Liver Research Unit, Medica Sur Clinic & Foundation and Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico.; Liver Histopathology Laboratory, Institute of Liver Studies, Kings College London, London, UK.; Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme and Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium.; Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, Minnesota, USA.; Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition and Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina, USA.; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea (the Republic of).; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.; Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Barcelona, Spain.; Department of Pathology, Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium.; Medicine, University of California San Diego, La Jolla, California, USA.; Institute of Pathology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland.; Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.; Liver Sciences, James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College, London, UK.; Department of Internal Medicine, Medical University of Graz, Graz, Austria.; Institute of Pathology, Universities of Mainz and Heidelberg, Mainz, Germany.; Division of Digestive and Liver Diseases, Department of Medicine, Columbia College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA.; Institute of Cellular Medicine, Translational and Clinical Research Institute, Newcastle Univsersity, Newcastle upon Tyne, UK.; Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece.; Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Autonomous University, Barcelona, Spain.; Pathology Department, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.; Centre de ressources biologiques (BB-0033-00027) Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France.; Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Heidelberg, Germany.; Service d'Hépato-Gastroentérologie, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium.; Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA [email protected].

DOI: 10.1136/gutjnl-2021-324295