Hepatic steatosis, metabolic dysfunction and risk of mortality: findings from a multinational prospective cohort study
Ana‐Lucia Mayén, Mirna Sabra, Elom K. Aglago, Gabriel Perlemuter, Cosmin Sebastian Voican, Inés Llamas Ramos, Charlotte Debras, Jessica Blanco, Vivian Viallon, Pietro Ferrari, Anja Olsen, Anne Tjønneland, Fie Langmann, Christina C. Dahm, Joseph A. Rothwell, Nasser Laouali, Chloé Marques, Matthias B. Schulze, Verena Katzke, Rudolf Kaaks, Domenico Palli, Alessandra Macciotta, Salvatore Panico, Rosario Tumino, Claudia Agnoli, Marta Farràs, Esther Molina‐Montes, Pilar Amiano, María‐Dolores Chirlaque, Jesús Castilla, Mårten Werner, Stina Bodén, Alicia K. Heath, Kostas Tsilidis, Dagfinn Aune, Elisabete Weiderpass, Heinz Freisling, Marc J. Gunter, Mazda Jenab
Abstract
BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MetS) are implicated in the aetiology of non-communicable diseases. Our study aimed to evaluate associations between NAFLD and MetS with overall and cause-specific mortality. METHODS: We used dietary, lifestyle, anthropometric and metabolic biomarker data from a random subsample of 15,784 EPIC cohort participants. NAFLD was assessed using the fatty liver index (FLI) and MetS using the revised definition. Indices for metabolic dysfunction-associated fatty liver disease (MAFLD) were calculated. The individual associations of these indices with overall and cause-specific mortality were assessed using multivariable Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs). As a subobjective, risk associations with adaptations of new classifications of metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic and alcohol-related liver disease (MetALD) were also assessed. RESULTS: Among the 15,784 sub-cohort participants, a total of 1997 deaths occurred (835 due to cancer, 520 to CVD, 642 to other causes) over a median 15.6 (IQR, 12.3-17.1) years of follow-up. Compared to an FLI < 30, FLI ≥ 60 was associated with increased risks of overall mortality (HR = 1.44, 95%CI = 1.27-1.63), and deaths from cancer (HR = 1.32, 95%CI = 1.09-1.60), CVD (HR = 2.06, 95% CI = 1.61-2.63) or other causes (HR = 1.21, 95%CI = 0.97-1.51). Mortality risk associations were also elevated for individuals with MAFLD compared to those without. Individuals with MetS were at increased risk of all mortality endpoints, except cancer-specific mortality. MASLD and MetALD were associated with higher risk of overall mortality. CONCLUSIONS: Our findings based on a prospective cohort suggest that individuals with hepatic steatosis or metabolic dysfunction have a higher overall and cause-specific mortality risk.