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

Abstract

ObjectiveAlcohol-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.DesignTwo 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.ResultsAge 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.ConclusionsDespite 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.

Review article: current and emerging therapies for acute alcohol‐associated hepatitis

“…Whilst patients with never-decompensated ALD had dysregulated expression of genes in involved in the immune response and extracellular matrix deposition, those with AH had more dysregulation in the products of hepatic reprogramming and bile acid metabolism genes. 41 As these unbiased discovery approaches using multiomics data evolve, the potential of novel therapeutic targets remains very promising. In the interim, hypothesis-based targeting of the known pathophysiological mechanisms has formed the current basis of existing and potential therapies for AH.…”

“…The particular factors influencing this acute worsening to AH in a subset of those with progressive ALD have yet to be described. However, recent studies have explored significant changes in the metabolomic, 37 epigenomic 38,39 and genomic 40,41 profiles of AH patients, indicating the potential of profiling these disease states with multiomics data. Specifically, Ventura‐Cots et al showed that the transcriptome of cohorts with AH, ‘never‐decompensated’ ALD and controls without ALD differed significantly.…”

“…Specifically, Ventura‐Cots et al showed that the transcriptome of cohorts with AH, ‘never‐decompensated’ ALD and controls without ALD differed significantly. Whilst patients with never‐decompensated ALD had dysregulated expression of genes in involved in the immune response and extracellular matrix deposition, those with AH had more dysregulation in the products of hepatic reprogramming and bile acid metabolism genes 41 . As these unbiased discovery approaches using multiomics data evolve, the potential of novel therapeutic targets remains very promising.…”

Narrative Review: Glucocorticoids in Alcoholic Hepatitis—Benefits, Side Effects, and Mechanisms

“…Additionally, sAH patients with elevated blood ferritin, an indicator of iron overload and cirrhosis [ 143 ], do not respond well to GC therapy [ 144 ]. A recent histological study of 225 AH patients shows that bridging fibrosis or cirrhosis is present in 81.8% of AH patients [ 145 ]. Thus, as blood biomarkers of good GC responsiveness in sAH, high keratin-18 fragments, low ferritin, and NLR of 5–8 will indicate acute severe, but still controllable, inflammation and apoptosis without prominent fibrosis/cirrhosis and GCR, which is consistent with the known potent anti-inflammatory and anti-apoptotic effects of GC/GR on the liver [ 44 , 56 ].…”

Substance use disorders in organ transplantation: perennial challenges and interprofessional opportunities

“…Though they are referred to separately, there is substantial histological and diagnostic overlap between AAH and alcohol-related cirrhosis [5,6] meaning that alcohol-related challenges in liver transplantation extend far beyond AAH. Indeed, acute presentations of all severe alcohol-related liver disease (ALD) with short alcohol sobriety represent a confluence of challenges requiring interprofessional experts: severe medical disease, urgent clinical timetables, active SUD, risk of altered mental status, and life-and-death decisions.…”