Unequal mortality risks in steatotic liver disease beyond liver: influence of disease subtypes and fibrosis

Background and aims To examine mortality risks associated with steatotic liver disease (SLD), focusing on how disease subtypes (MASLD, MetALD, ALD), and fibrosis severity shape cause-specific mortality across a broad spectrum of diseases. Methods We analysed 486156 UK Biobank participants. Causes of death were summarised by SLD subtypes. Multivariable Cox models estimated associations between SLD, its subtypes, and fibrosis severity (FIB4 score), with cause-specific mortality outcomes across ICD10 disease categories. Results Among 178336 participants with SLD, 20766 died over a median follow up of 13.8 years. The leading causes of deaths were neoplasm (46.4%), circulatory disease (24.2%), respiratory disease (7.0%), and digestive disease (4.8%). Compared to participants without SLD ( n = 307820), those with SLD had significantly higher mortality from neoplasm (HR 1.24 (1.20, 1.28)), circulatory (1.57 (1.50, 1.64)), and digestive diseases (1.85 (1.67, 2.05)), as well as from metabolic, and genitourinary diseases, across all FIB4 score levels. Elevated risks were also observed for mortality from diabetes (3.40 (2.59, 4.46)), Covid-19 (1.97 (1.76, 2.21)), myocardial infarction (1.69 (1.53, 1.86)), stroke (1.24 (1.04, 1.48)), and several cancers, such as breast (1.50 (1.35, 1.68)), colorectal (1.22 (1.11, 1.34)), and prostate cancer (1.22 (1.09, 1.37)). Importantly, SLD subtypes exhibited distinct and unequal patterns of cause-specific mortality, with further stratification by fibrosis severity revealing graded risk differentials. Conclusion SLD is associated with unequal mortality risks across a wide range of disease categories, driven by substantial heterogeneity across subtypes, fibrosis severity and outcomes. Extrahepatic cancers and circulatory diseases contribute most to overall mortality, but the magnitude of risk varies markedly. These findings highlight the need for risk-stratified, multidisciplinary management strategies that account for both subtypes and fibrosis stage, targeting liver progression, cardiometabolic burden, and cancer prevention.