Abstract
Background and Objectives: The Hepatitis E Virus (HEV) is increasingly recognized as a cause of chronic infection in immunocompromised patients, but its precise role in cryptogenic cirrhosis (CC) is unclear. CC is defined as liver cirrhosis in which all known causes, including viral, autoimmune, metabolic, and alcohol-related etiologies, have been meticulously excluded. We aimed to address this gap by definitively assessing HEV's etiological contribution in CC through seroprevalence comparison and evaluating its long-term prognostic impact on disease progression and adverse clinical outcomes. Materials and Methods: This is a retrospective, single-center, observational, and longitudinal cohort study, conducted between July 2017 and June 2025. The study included 52 CC patients, whose diagnosis was strictly confirmed by excluding all known etiologies, and 900 healthy blood donors from the same region. CC patients were retrospectively followed for five years to assess long-term clinical outcomes. We compared HEV seropositive and seronegative patients for accelerated disease progression (assessed by follow-up MELD-Na scores) and cirrhosis-related death. We employed multivariable logistic regression to adjust for demographic confounders in the prevalence comparison and multivariable COX regression for survival analysis to determine the independent prognostic role of HEV seropositivity. Results: The anti-HEV IgG seroprevalence in CC patients (42.3%) was significantly higher than in healthy donors (12.8%) (p < 0.001). Multivariable logistic regression confirmed CC status as an independent predictor of HEV seropositivity (Adjusted OR = 6.142, p < 0.001). During the five-year follow-up, the cirrhosis-related death rate was significantly higher in the anti-HEV IgG positive group (36.4% vs. 13.4%; p = 0.047), and their follow-up MELD-Na score was significantly higher (p = 0.029). However, multivariable COX analysis did not sustain anti-HEV IgG positivity as an independent risk factor for death (p = 0.294). Conclusions: HEV exposure is independently and significantly higher in CC patients. While anti-HEV IgG positivity correlates with higher mortality and accelerated disease progression in univariable analysis, its lack of independent prognostic significance suggests it may primarily function as a marker for a more advanced stage of CC or underlying immune dysfunction. Further rigorous prospective studies are necessary to precisely define HEV's long-term prognostic role and evaluate its impact on disease progression.