Sepsis Drives Severity and Mortality in Acute-on-Chronic Liver Failure Among ICU Patients with Alcohol-Related Cirrhosis: A Retrospective Single-Center Study

<b>Background/Objectives:</b> Acute-on-chronic liver failure (ACLF) is a life-threatening complication of cirrhosis, characterized by organ failures and high short-term mortality. Alcohol-related cirrhosis is one of the most frequent underlying etiologies of ACLF in Europe. Infections, particularly those leading to sepsis are recognized triggers; however, their relative contribution, clinical features, and prognostic impact in critically ill patients with alcohol-related cirrhosis remain incompletely defined. This study aimed to systematically identify and characterize precipitating events of ACLF in this population and to compare outcomes between sepsis- and non-sepsis-related cases. <b>Methods:</b> We conducted a retrospective cohort study including 188 ICU patients with alcohol-related cirrhosis who were treated for ACLF at a tertiary university medical center. ACLF was defined and graded according to the European Association for the Study of the Liver-Chronic Liver Failure Consortium (EASL-CLIF) criteria, and sepsis was diagnosed according to Sepsis-3 definitions. Clinical data, precipitating events, microbiological evidence, organ support requirements, and in-hospital outcomes were systematically analyzed. <b>Results:</b> Sepsis was the most frequent precipitating event, identified in 118 patients (62.8%), while 70 patients (37.2%) developed ACLF due to non-septic triggers such as gastrointestinal bleeding. Patients with sepsis-associated ACLF presented with more advanced disease (ACLF grade 2-3 in 80.5% vs. 57.1%, <i>p</i> = 0.004), higher Chronic Liver Failure Consortium-Acute-on-Chronic Liver Failure Score (CLIF-C ACLF) scores (median 55 vs. 50, <i>p</i> = 0.04), longer ICU stays (median 11 vs. 4.5 days, <i>p</i> < 0.001), and markedly higher in-hospital mortality (60.2% vs. 20.0%, <i>p</i> < 0.001) compared to patients without sepsis. Pneumonia (48.3%), urinary infections (17.8%) and spontaneous bacterial peritonitis (16.1%) were the leading infectious foci triggering sepsis. Microbiological evidence was obtained in 82.2% of sepsis cases, with frequent polymicrobial infections and opportunistic pathogens including <i>Enterococcus faecium</i> and <i>Candida albicans</i>. <b>Conclusions:</b> In critically ill patients with alcohol-related cirrhosis, infections leading to sepsis are the predominant precipitating event of ACLF and the strongest determinant of short-term prognosis. Compared with non-sepsis triggers, sepsis-associated ACLF is characterized by more severe disease, greater need for organ support, longer ICU stays, and substantially higher mortality. These findings highlight the urgent need for early recognition, rapid diagnostic strategies, and optimized infection management to improve outcomes in this high-risk population.