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Original research
Clinical, histological and molecular profiling of different stages of alcohol-related liver disease
  1. Meritxell Ventura-Cots1,2,3,
  2. Josepmaria Argemi1,2,4,
  3. Patricia D Jones5,
  4. Carolin Lackner6,
  5. Mohamed El Hag7,
  6. Juan G Abraldes8,
  7. Edilmar Alvarado1,9,10,
  8. Ana Clemente1,2,11,
  9. Samhita Ravi1,
  10. Antonio Alves12,
  11. Mohamed Alboraie13,
  12. Jose Altamirano14,
  13. Sergio Barace15,
  14. Francisco Bosques16,
  15. Robert Brown17,
  16. Juan Caballeria2,18,
  17. Joaquin Cabezas19,
  18. Sofia Carvalhana20,
  19. Helena Cortez-Pinto20,
  20. Adilia Costa21,
  21. Delphine Degré22,
  22. Carlos Fernandez-Carrillo1,2,23,
  23. Nathalie Ganne-Carrie24,
  24. Guadalupe Garcia-Tsao25,
  25. Joan Genesca2,3,
  26. John Koskinas26,
  27. Nicolas Lanthier27,28,
  28. Alexandre Louvet29,
  29. Juan José Lozano2,
  30. Michael R Lucey30,
  31. Steven Masson31,
  32. Philippe Mathurin29,
  33. Nahum Mendez-Sanchez32,
  34. Rosa Miquel33,
  35. Christophe Moreno34,
  36. Taofic Mounajjed35,
  37. Gemma Odena36,
  38. Won Kim37,
  39. Pau Sancho-Bru2,38,
  40. R Warren Sands1,
  41. Justyna Szafranska39,
  42. Laurine Verset40,
  43. Bern Schnabl41,
  44. Christine Sempoux42,
  45. Vijay Shah43,
  46. Debbie Lindsay Shawcross44,
  47. Rudolf E Stauber45,
  48. Beate K Straub46,
  49. Elizabeth Verna47,
  50. Dina Tiniakos48,49,
  51. Eric Trépo34,
  52. Victor Vargas2,3,
  53. Càndid Villanueva2,50,
  54. John T Woosley51,
  55. Marianne Ziol52,
  56. Sebastian Mueller53,
  57. Peter Stärkel54,
  58. Ramon Bataller1
  1. 1Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
  2. 2Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
  3. 3Liver Unit, Hospital Universitari Vall d'Hebron, Vall d'Hebron Institute of Research, Universitat Autònoma de Barcelona, Barcelona, Spain
  4. 4Liver Unit, Clinica Universitaria de Navarra, Pamplona, Spain
  5. 5Department of Medicine, Division of Gastroenterology and Hepatology, University of Miami Miller School of Medicine, Miami, Florida, USA
  6. 6Institute of Pathology, Medical University of Graz, Graz, Austria
  7. 7Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
  8. 8Division of Gastroenterology, Liver Unit, University of Alberta, Edmonton, Alberta, Canada
  9. 9Gastroenterology, Hospital of Santa Creu and Sant Pau, Autonomous University of Barcelona, Hospital Sant Pau Biomedical Research Institute (IIB Sant Pau), Barcelona, Spain
  10. 10Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
  11. 11Liver Unit and Digestive Department, H.G.U. Gregorio Marañon, Madrid, Spain
  12. 12Departament of Pathology, Hospital Prof. Doutor Fernando Fonseca. Instituto de Anatomia Patologica, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisboa, Portugal
  13. 13Department of Internal Medicine, Al-Azhar University, Cairo, Egypt
  14. 14Internal Medicine, Hospital Quironsalud Barcelona, Barcelona, Spain
  15. 15Centro de investigación Médica Aplicada (CIMA), Universidad de Navarra, Hepatology Program, Pamplona, Spain
  16. 16Hospital Sant José Tecnológico de Monterrey, Universidad Autonoma de Nuevo Leon, Monterrey, Monterrey, Mexico
  17. 17Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, New York, USA
  18. 18Liver Unit, Hospital Clinic de Barcelona, Barcelona, Catalunya, Spain
  19. 19Gastroenterology and Hepatology Department Marques de Valdecilla University Hospital, Valdecilla Research Institute - IDIVAL, Santander, Santander, Spain
  20. 20Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
  21. 21Department of Pathology, Hospital Santa Maria, Faculdade de Medicina de Lisboa, Universidade de Lisboa, Lisboa, Portugal
  22. 22Centre de ressources biologiques (BB-0033-00027) Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Brussels, Belgium
  23. 23Department of Gastroenterology and Hepatology, Hospital Universitario Puerta de Hierro, Puerta de Hierro Health Research Institute (IDIPHIM), Madrid, Spain
  24. 24Liver Unit, INSERM UMR 1162, Hôpitaux Universitaires Paris Seine Saint-Denis, APHP, Université paris 13 Sorbonne Paris Cité, Paris, France
  25. 25Section of Digestive Diseases, Yale University, New Haven, Connecticut. Department of Veterans Affairs Connecticut Healthcare, New Haven, Connecticut, USA
  26. 262nd Department of Medicine, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
  27. 27Service d'Hépato-Gastroentérologie, Cliniques universitaires Saint-Luc, UCLouvain, Bruxelles, Belgium
  28. 28Laboratory of Hepatogastroenterology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Brussels, Belgium
  29. 29University of Lille, Inserm, CHU Lille, U1286-INFINITI-Institute for Translational Research in Inflammation, F-590000, Lille, France
  30. 30Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
  31. 31Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
  32. 32Liver Research Unit, Medica Sur Clinic & Foundation and Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
  33. 33Liver Histopathology Laboratory, Institute of Liver Studies, Kings College London, London, UK
  34. 34Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme and Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
  35. 35Department of Laboratory Medicine and Pathology, Mayo Clinic Rochester, Rochester, Minnesota, USA
  36. 36Division 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
  37. 37Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Korea (the Republic of)
  38. 38Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
  39. 39Department of Pathology, Hospital de la Santa Creu i Sant Pau, Barcelona, Barcelona, Spain
  40. 40Department of Pathology, Hôpital Erasme, Université Libre de Bruxelles, Bruxelles, Belgium
  41. 41Medicine, University of California San Diego, La Jolla, California, USA
  42. 42Institute of Pathology, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
  43. 43Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
  44. 44Liver Sciences, James Black Centre, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King’s College, London, UK
  45. 45Department of Internal Medicine, Medical University of Graz, Graz, Austria
  46. 46Institute of Pathology, Universities of Mainz and Heidelberg, Mainz, Germany
  47. 47Division of Digestive and Liver Diseases, Department of Medicine, Columbia College of Physicians and Surgeons, Columbia University Medical Center, New York, New York, USA
  48. 48Institute of Cellular Medicine, Translational and Clinical Research Institute, Newcastle Univsersity, Newcastle upon Tyne, UK
  49. 49Department of Pathology, Aretaieion Hospital, Medical School, National & Kapodistrian University of Athens, Athens, Greece
  50. 50Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Autonomous University, Barcelona, Spain
  51. 51Pathology Department, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  52. 52Centre de ressources biologiques (BB-0033-00027) Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bondy, France
  53. 53Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Heidelberg, Germany
  54. 54Service d’Hépato-Gastroentérologie, Cliniques universitaires Saint-Luc, UCLouvain, Brussels, Belgium
  1. Correspondence to Dr Ramon Bataller, Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA; BATALLER{at}pitt.edu

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.

  • alcohol
  • alcoholic liver disease
  • histopathology
  • gene expression
  • alcohol-induced injury

Data availability statement

No data are available. Due to the nature of this research, participants of this study did not agree for their data to be shared publicly, so supporting data are not available. Microarray data have been deposited in NCBI’s Gene Expression Omnibus (GEO; accession numbers GSE28619 and GSE151353).

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Data availability statement

No data are available. Due to the nature of this research, participants of this study did not agree for their data to be shared publicly, so supporting data are not available. Microarray data have been deposited in NCBI’s Gene Expression Omnibus (GEO; accession numbers GSE28619 and GSE151353).

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Footnotes

  • MV-C, JA and PDJ are joint first authors.

  • Twitter @alboraie, @JCabezasGlez, @DrStevenMasson, @DebbieShawcros1, @Dina Tiniakos

  • Correction notice This article has been corrected since it published Online First. The author's names, Carlos Fernandez-Carrillo and Samhita Ravi, have been amended and the title corrected.

  • Contributors PDJ, MV-C, JA and RBa had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: RBa, PDJ and CL. Acquisition, analysis or interpretation of data: all authors. Drafting of the manuscript: PDJ, MV-C, JA and RBa. Critical revision of the manuscript for important intellectual content: JAl, MV-C, CL, PS, SM, MEH and RBr. Statistical analysis: MV-C, JA and PDJ. Study supervision: PDJ and RBa. Critical review manuscript: PDJ and RWS. RBa is responsible for the overall content as the guarantor.

  • Funding This work was supported by the National Institute on Alcohol Abuse and Alcoholism (NIAAA 1U01AA021908-01, 1U01AA020821 and P50AA011999) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK P30DK120531 and P30DK120515). PSwas supported by Fondo de Investigación Sanitaria Carlos III, cofinanced by Fondo Europeo de Desarrollo Regional (FEDER), Unión Europea, 'Una manera de hacer Europa' PI17/00673; PI20/00765 and Miguel Servet, CPII16/0004. MV-C is a recipient of the Juan Rodés JR19/00015. JA is a recipient of a grant from Agencia Estatal de Salud (PI20/01663).

  • Competing interests JAl has received support to attend conferences from Gilead. BS has been consulting for Ferring Research Institute, Intercept Pharmaceuticals, HOST Therabiomics and Patara Pharmaceuticals. BS’s institution UC San Diego has received grant support from BiomX, NGM Biopharmaceuticals, CymaBay Therapeutics and Synlogic Operating Company.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.