Author information

¹Nutrition and Metabolism Branch, International Agency for Research On Cancer (IARC-WHO), 25 Avenue Tony Garnier, Lyon, 69007, France.

²Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

³INSERM U996, Intestinal Microbiota, Macrophages and Liver Inflammation, DHU HepatinovLabex LERMIT, Clamart, France.

⁴Faculté de Médecine Paris-Sud, Univ Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.

⁵Service d'hépato-Gastroentérologie, Hôpital Antoine-Béclère, Hôpitaux Universitaires Paris-Sud, Assistance Publique-Hôpitaux de Paris, Clamart, France.

⁶Danish Cancer Society Research Center, Diet, Cancer and Health, Strandboulevarden 49, Copenhagen, 2100, Denmark.

⁷Department of Public Health, Aarhus University, Bartholins Alle 2, Aarhus C, 8000, Denmark.

⁸Université Paris-Saclay, UVSQ, Inserm "Exposome and Heredity" Team, CESP U1018, Gustave Roussy, Villejuif, France.

⁹Dept. of Molecular Epidemiology, German Institute of Human Nutrition, Arthur-Scheunert-Allee 114-116, Nuthetal, 14558, Germany.

¹⁰Department of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

¹¹Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy.

¹²Department of Clinical and Biological Sciences, Centre for Biostatistics, Epidemiology, and Public Health (C-BEPH), University of Turin, Turin, Italy.

¹³Dipartimento Di Medicina Clinica E Chirurgia, Federico II University, Naples, Italy.

¹⁴Hyblean Association for Epidemiological Research, AIRE-ONLUS Ragusa, Ragusa, Italy.

¹⁵Department of Research Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, 20133, Italy.

¹⁶Unit of Nutrition and Cancer, Epidemiology Research Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, L'Hospitalet de Llobregat, 08908, Spain.

¹⁷Department of Nutrition and Food Science, Campus of Cartuja, University of Granada, Granada, 18071, Spain.

¹⁸Spanish Consortium for Research On Epidemiology and Public Health (CIBERESP), Instituto de Salud Carlos III, Madrid, 28029, Spain.

¹⁹Instituto de Investigación Biosanitaria Ibs. Granada, Granada, 18012, Spain.

²⁰Institute of Nutrition and Food Technology (INYTA) 'José Mataix', Biomedical Research Centre, University of Granada, Granada, 18071, Spain.

²¹Ministry of Health of the Basque Government, Sub Directorate for Public Health and Addictions of Gipuzkoa, San Sebastian, Spain.

²²Biodonostia Health Research Institute, Epidemiology of Chronic and Communicable Diseases Group, San Sebastián, Spain.

²³Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca,, Murcia University, Murcia, Spain.

²⁴Navarra Public Health Institute - IdiSNA, Pamplona, Spain.

²⁵Department of Public Health and Clinical Medicine, Medicine, Umeå University, Umeå, SE-901 87, Sweden.

²⁶Department of Clinical Sciences, Pediatrics, Umeå University, Umeå, SE-901 87, Sweden.

²⁷Department of Nutrition, Oslo New University College, Oslo, Norway.

²⁸Department of Endocrinology, Morbid Obesity and Preventive Medicine, Oslo University Hospital Ullevål, Oslo, Norway.

²⁹Office of the Director, International Agency for Research On Cancer (IARC-WHO), Lyon, France.

³⁰Nutrition and Metabolism Branch, International Agency for Research On Cancer (IARC-WHO), 25 Avenue Tony Garnier, Lyon, 69007, France. jenabm@iarc.who.int.

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.