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

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Meritxell Ventura-Cots, 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, Juan Caballeria, Joaquin Cabezas, Sofia Carvalhana, Helena Cortez-Pinto, Adilia Costa & 38 more Delphine Degré, Carlos Fernandez-Carrillo, Nathalie Ganne-Carrie, Guadalupe Garcia-Tsao, Joan Genesca, John Koskinas, Nicolas Lanthier, Alexandre Louvet, Juan José Lozano, Michael R. Lucey, 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, Vijay Shah, 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

Original languageEnglish
Article number324295
Pages (from-to)1856-1866
Number of pages11
JournalGut
Volume71
Issue number9
Early online date6 Jan 2022
DOIs
Accepted/In press6 Dec 2021
E-pub ahead of print6 Jan 2022
Published11 Aug 2022

Bibliographical note

Funding Information: 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. Funding Information: 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). Publisher Copyright: © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.

King's Authors

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.

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