Differential Cancer Risks and Noninvasive Predictors in MASLD, MetALD, and ALD: A Longitudinal Analysis

Background/Aims: The recently proposed classification of steatotic liver disease (SLD) comprises metabolic dysfunction-associated steatotic liver disease (MASLD), MASLD with increased alcohol intake (MetALD), and alcohol-related liver disease (ALD). Long-term cancer risk across these phenotypes remains incompletely characterized, and was investigated in this study. Methods: This longitudinal cohort study included 43,994 adults who underwent health check-ups in 2010-2011. Liver steatosis was diagnosed by ultrasonography. The Fibrosis-4 (FIB-4) and steatosis-associated fibrosis estimator (SAFE) scores were evaluated as predictors of cancer incidence. Results: Over a median 10.5 years (398,202 person-years), 3,169 cancers occurred (795.8 per 100,000 person-years). Versus no SLD, overall cancer risk was elevated in ALD (incidence rate ratio [IRR], 1.38; 95% confidence interval, 1.08 to 1.79) but not MASLD or MetALD. Hepatocellular carcinoma risk increased across all SLD groups, most strongly in the MetALD and ALD groups, with a more modest association in the MASLD group that was attenuated in sensitivity analyses. ALD was associated with an elevated risk of esophageal cancer (IRR, 5.98) and stomach cancer (IRR, 2.41), and MetALD with an increased risk of stomach cancer (IRR, 1.61). FIB-4 and SAFE showed dose-response associations with cancer that were substantially attenuated after age adjustment, persisting mainly at the highest categories. Conclusions: Cancer risk differs across MASLD, MetALD, and ALD, with alcohol-related phenotypes carrying the highest burden. Noninvasive fibrosis indices such as FIB-4 and SAFE may help stratify risk-though largely age-related-and could inform risk-based surveillance in SLD.