Article Text
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).
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.
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