Prevalence and clinical impact of alcohol withdrawal syndrome in alcohol-associated hepatitis and the potential role of prophylaxis : a multinational, retrospective cohort study

The prevalence and impact of alcohol withdrawal syndrome (AWS) in patients with alcohol-associated hepatitis (AH) are unknown. In this study, we aimed to investigate the prevalence, predictors, management, and clinical impact of AWS in patients hospitalized with AH. A multinational, retrospective cohort study enrolling patients hospitalized with AH at 5 medical centres in Spain and in the USA was performed between January 1st, 2016 to January 31st, 2021. Data were retrospectively retrieved from electronic health records. Diagnosis of AWS was based on clinical criteria and use of sedatives to control AWS symptoms. The primary outcome was mortality. Multivariable models controlling for demographic variables and disease severity were performed to determine predictors of AWS (adjusted odds ratio [OR]) and the impact of AWS condition and management on clinical outcomes (adjusted hazard ratio [HR]). In total, 432 patients were included. The median MELD score at admission was 21.9 (18.3-27.3). The overall prevalence of AWS was 32%. Lower platelet levels (OR = 1.61, 95% CI 1.05-2.48) and previous history of AWS (OR = 2.09, 95% CI 1.31-3.33) were associated with a higher rate of incident AWS, whereas the use of prophylaxis decreased the risk (OR = 0.58, 95% CI 0.36-0.93). The use of intravenous benzodiazepines (HR = 2.18, 95% CI 1.02-4.64) and phenobarbital (HR = 2.99, 95% CI 1.07-8.37) for AWS treatment were independently associated with a higher mortality. The development of AWS increased the rate of infections (OR = 2.24, 95% CI 1.44-3.49), the need for mechanical ventilation (OR = 2.49, 95% CI 1.38-4.49), and ICU admission (OR = 1.96, 95% CI 1.19-3.23). Finally, AWS was associated with higher 28-day (HR = 2.31, 95% CI 1.40-3.82), 90-day (HR = 1.78, 95% CI 1.18-2.69), and 180-day mortality (HR = 1.54, 95% CI 1.06-2.24). AWS commonly occurs in patients hospitalized with AH and complicates the hospitalization course. Routine prophylaxis is associated with a lower prevalence of AWS. Prospective studies should determine diagnostic criteria and prophylaxis regimens for AWS management in patients with AH. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors

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

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. 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. 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. 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

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

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