Clinical, histological and molecular profiling of different stages of alcohol-related liver disease
Meritxell Ventura-Cots 1 2 3 , Josepmaria Argemi 1 2 4 , Patricia D Jones 5 , Carolin Lackner 6 , Mohamed El Hag 7 , Juan G Abraldes 8 , Edilmar Alvarado 1 9 10 , Ana Clemente 1 2 11 , Samitha Ravi 1 , Antonio Alves 12 , Mohamed Alboraie 13 , Jose Altamirano 14 , Sergio Barace 15 , Francisco Bosques 16 , Robert Brown 17 , Juan Caballeria 2 18 , Joaquin Cabezas 19 , Sofia Carvalhana 20 , Helena Cortez-Pinto 20 , Adilia Costa 21 , Delphine Degré 22 , Carlos Fernandez-Carillo 1 2 23 , Nathalie Ganne-Carrie 24 , Guadalupe Garcia-Tsao 25 , Joan Genesca 2 3 , John Koskinas 26 , Nicolas Lanthier 27 28 , Alexandre Louvet 29 , Juan José Lozano 2 , Michael R Lucey 30 , Steven Masson 31 , Philippe Mathurin 29 , Nahum Mendez-Sanchez 32 , Rosa Miquel 33 , Christophe Moreno 34 , Taofic Mounajjed 35 , Gemma Odena 36 , Won Kim 37 , Pau Sancho-Bru 2 38 , R Warren Sands 1 , Justyna Szafranska 39 , Laurine Verset 40 , Bern Schnabl 41 , Christine Sempoux 42 , Vijay Shah 43 , Debbie Lindsay Shawcross 44 , Rudolf E Stauber 45 , Beate K Straub 46 , Elizabeth Verna 47 , Dina Tiniakos 48 49 , Eric Trépo 34 , Victor Vargas 2 3 , Càndid Villanueva 2 50 , John T Woosley 51 , Marianne Ziol 52 , Sebastian Mueller 53 , Peter Stärkel 54 , Ramon Bataller 55
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.