The mediating role of inflammation in cancer risk among individuals with metabolic dysfunction-associated steatotic liver disease: a cohort study

Background: Steatotic liver disease (SLD) is a new overarching term to replace the term fatty liver disease, which includes metabolic dysfunction associated steatotic liver disease (MASLD), metabolic dysfunction and alcohol associated steatotic liver disease (MetALD), and alcohol-related liver disease (ALD). We aimed to examine the association of MASLD, MetALD and ALD with cancer incidence, and the role of inflammation indicators in mediating these associations. Materials and Methods: Our analysis included 432,166 participants free of cancer from the UK Biobank. MASLD, MetALD and ALD were defined based on the nomenclature definitions. Cancer diagnoses were ascertained through linkage to hospitalization and death registration systems. Cox models were fitted to estimate the hazard ratios (HRs), adjusting for potential confounders. Causal mediation analysis was used to explore the mediating role of inflammation. Results: 48,739 incident cancers occurred over a median follow-up of 13.1 years. Compared to those without SLD, higher risk of all cancer was observed in participants with MASLD (HR = 1.13, 95% CI = 1.11-1.16), MetALD (1.07, 1.04-1.11) or ALD (1.22, 1.15-1.29). MASLD, MetALD and ALD were positively associated with obesity-related cancers, and esophageal, stomach, colorectum, liver, biliary tract, pancreas, postmenopausal breast, uterus, kidney, and bladder cancers (HRs: 1.18 ~ 4.97). Inflammation partially mediated the observed association of MASLD and cancer risk by 11.2% to 31.0%. Conclusion: Individuals with MASLD, MetALD, or ALD are at increased risk of all cancer, and the inflammation mediates the effect of MASLD. These findings highlight the importance of cancer screening and prevention in patients with MASLD or MetALD.