Unmasking the Hidden Prognostic Impact of MAFLD in Hepatocellular Carcinoma Surgery

Introduction The rising incidence of hepatocellular carcinoma (HCC) in North America mirrors the growing prevalence of metabolic-associated fatty liver disease (MAFLD). Though MAFLD is now a recognized driver of HCC, its precise influence on tumor biology and patient prognosis remains incompletely understood. This study examines whether MAFLD-associated HCC constitutes a distinct clinical phenotype and explores its prognostic and therapeutic implications. Methods We conducted a retrospective cohort study of 154 adult patients who underwent curative-intent hepatic resection for HCC at a leading U.S. university medical center between January 1, 2011, and December 31, 2020, with follow-up through December 31, 2023. Patients were stratified into MAFLD-positive (n=89) and MAFLD-negative (n=67) groups. Demographic, clinical, and oncologic characteristics were compared. Survival outcomes were assessed using Kaplan-Meier estimates, while multivariate Cox regression was employed to adjust for confounding variables and identify independent prognostic factors. Results Compared to their MAFLD-negative counterparts, MAFLD-positive patients were older (mean age 70.1 vs. 67.4 years, p=0.043), more frequently obese (55% vs. 18%, p<0.001), and less likely to have cirrhosis (27% vs. 64%, p<0.001). They also presented with larger tumors (mean diameter 5.6 cm vs. 3.8 cm, p=0.004), although tumor differentiation and T stage were comparable between groups. Progression-free survival (PFS) was longer among MAFLD-positive patients (median 2.80 vs. 1.21 years, p=0.002), with a hazard ratio of 0.64 (95% CI: 0.42–0.96). Median overall survival (OS) was also numerically higher (4.55 vs. 2.54 years), though the difference did not reach statistical significance (p=0.09). After adjustment for confounders, MAFLD was not independently associated with OS or PFS. In contrast, cirrhosis, serum AFP >100 ng/mL, and advanced tumor stage emerged as independent predictors of poorer outcomes. Conclusions Despite prior suggestions of a unique clinical trajectory for MAFLD-associated HCC, our findings suggest that MAFLD status alone does not independently predict survival following curative-intent resection. Once key oncologic factors are accounted for, outcomes appear similar between MAFLD-positive and MAFLD-negative patients. These results underscore the importance of risk stratification based on established prognostic markers rather than liver disease etiology alone.