Liver and Bile
Hepatology. 2025;82(1):127-139
Viral antibody response predicts morbidity and mortality in alcohol-associated hepatitis
Background and aims: Alcohol-associated hepatitis (AH) is associated with very high mortality despite abstinence from alcohol; up to 40% of patients die within 6 months of diagnosis. Patients with AH are especially prone to infections, which can lead to multiorgan dysfunction and poorer prognosis.
Approach and results: The authors performed comprehensive serological profiling of the viral and bacterial infection history of 36 healthy controls, 48 patients with alcohol use disorder, and 224 patients with AH from 2 multicenter observational studies. The authors used systematic viral and bacterial epitope scanning by VirScan, a phage-display immunoprecipitation and sequencing technology that detects the peptides recognized by antibodies in patient sera, to comprehensively analyze antiviral and antibacterial antibodies and identify serologic biomarkers to predict patient outcomes. The authors found significant differences in the serological profiles of the 3 populations. The number of serum antibody epitopes in patients with alcohol use disorder during abstinence was increased compared with during active alcohol use. A decreased number and diversity of viral and bacterial antibody targets were detected in the sera of patients with AH, particularly those with a higher Child-Pugh score. In patients with AH, a decrease in the serum antiviral, but not antibacterial, antibody repertoire was associated with decompensation and mortality. Ninety-day mortality in AH could be predicted using a serum viral epitope signature.
Conclusions: Abstinence from alcohol is associated with a significant increase in serum viral and bacterial antibody response. Decreased serum antiviral antibody repertoire is predictive of decompensation of liver disease and mortality in patients with AH.
DOI: 10.1097/hep.0000000000001046
Prof. Dr. Tobias Böttler
Head of Gerok Liver Center, University Medical Center Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany
Loss of antimicrobial antibody diversity due to alcohol abuse – Reversible only as long as the liver still works
liver still works
Advanced liver disease is associated with impaired immune competence and multiple infectious complications. The study by Hsu et al. demonstrates that alcohol abuse alone can profoundly alter the immune repertoire, even before the development of advanced liver disease. Using a high-throughput immunoserologic profiling approach, the authors show that both harmful alcohol consumption and alcohol-associated liver disease correlate with a reduced diversity of pathogen-specific antibody responses. Whereas alcohol abstinence in individuals without liver disease led to a marked recovery of antibody diversity, this effect was absent in those with advanced liver disease. Notably, the diversity of antiviral—but not antibacterial—antibodies was identified as an independent predictor of mortality and hepatic decompensation, whereas no such association was observed for antibacterial antibodies.
The study compellingly illustrates that alcohol abuse and the resulting liver disease represent two additive yet partly independent determinants of humoral immune dysfunction. This finding is particularly relevant with regard to the reversibility of immune dysregulation, which appears to be lost once advanced liver disease has developed. This observation is consistent with the concept of cirrhosis-associated immune dysfunction (CAID), a systemic immune dysregulation commonly observed in patients with cirrhosis and characterized by functional immune impairment, increased susceptibility to infections, and diminished vaccine responsiveness. Paradoxically, advanced liver disease is often accompanied by elevated serum levels of immunoglobulins (particularly IgG and IgA), although their antigen specificity remains largely undefined. Possible explanations include unspecific immune activation with reactivation of antibody-producing memory B cells or, alternatively, systemic exposure to intestinal antigens resulting from portal hypertension, leading to de novo immune responses against irrelevant peripheral targets. The observed decline in antimicrobial antibody diversity with progression of liver disease rather supports the latter mechanism. As the study primarily included patients with alcohol-associated steatohepatitis, it remains unclear to what extent the cohort also comprised individuals with advanced portal hypertension—an aspect of particular relevance for interpreting the immunological significance of these findings.
Another key observation is the selective association between reduced antiviral, but not antibacterial, antibody diversity and mortality and hepatic decompensation. Clinically, both bacterial and viral infections are well-known triggers of decompensating events, yet viral infections—such as herpesvirus reactivations, influenza, respiratory viruses, or hepatitis E virus—are rarely identified in a systematic manner. The present findings therefore highlight the need for more detailed differentiation between viral and bacterial triggers of decompensation, with important implications for vaccination strategies and antiviral prophylaxis in high-risk patients with alcohol-associated liver disease.