Long-Term Major Adverse Liver Outcomes and Oncological Outcomes Across Steatotic Liver Disease Subtypes Classified Using the MetALD-ALD Prediction Index.

BACKGROUND: Long-term adverse liver and oncological risks across steatotic liver disease (SLD) subtypes remain uncertain, and alcohol underreporting may cause misclassification. AIMS: To evaluate long-term risks of major adverse liver outcomes (MALO) and cancer across SLD subtypes by the MetALD-ALD Prediction Index (MAPI) and self-reported alcohol intake. METHODS: Participants with SLD at baseline and free of cancer in the UK Biobank were classified as MASLD, MetALD, or ALD. The primary outcome was incident MALO. Secondary outcomes included incident all cancers, cancer-related death, hepatocellular carcinoma (HCC), extrahepatic cancers, digestive cancers excluding HCC, and site-specific digestive cancers. Multivariable Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), with MASLD as the reference group. RESULTS: Among 138,996 participants, 51,633 were classified as MASLD, 27,231 as MetALD, and 60,132 as ALD. Compared with MASLD, MetALD exhibited higher risks of all cancers (HR, 1.07; 95% CI, 1.04-1.11) and extrahepatic cancers (HR, 1.07; 95% CI, 1.03-1.11), but not of MALO, cancer-related death, HCC, or digestive cancers excluding HCC. ALD showed the greatest risks, with increased risks of MALO (HR, 1.70; 95% CI, 1.54-1.88), all cancers (HR, 1.12; 95% CI, 1.08-1.15), cancer-related death (HR, 1.07; 95% CI, 1.01-1.14), HCC (HR, 3.07; 95% CI, 2.23-4.23), extrahepatic cancers (HR, 1.11; 95% CI, 1.08-1.14), and digestive cancers excluding HCC (HR, 1.20; 95% CI, 1.11-1.29). CONCLUSIONS: MAPI-informed SLD subtypes showed distinct risk profiles. MetALD exhibited higher risks of all cancers and extrahepatic cancers, whereas ALD conferred the highest risks across MALO and cancer outcomes, particularly for HCC and digestive cancer.