Risk Heterogeneity of Liver-Related Events and Extrahepatic Outcomes Across MASLD Phenotypes and Risk Stratification...

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) has been newly proposed to characterize fatty liver disease. We aim to investigate the associations of different phenotypes of MASLD and related steatotic liver disease (SLD) with the risk of liver-related and extrahepatic outcomes. Methods: Among 368,886 United Kingdom's Biobank participants, those with MASLD and related SLD were categorized into pure MASLD, MASLD with increased alcohol intake (MetALD), MASLD with alcohol-related liver disease (ALD), and MASLD with other etiology. The primary outcome was liver-related events (LREs). Results: During a median follow-up of 13.7 years, 2095 participants developed LREs. The adjusted HRs (95% CIs) of LREs for pure MASLD, MetALD, MASLD with ALD, and MASLD with other etiology were 2.46 (2.21, 2.73), 2.77 (2.39, 3.21), 8.73 (7.59, 10.1), and 26.5 (17.1, 41.0), respectively. Participants with MetALD, MASLD with ALD, and MASLD with other etiology showed a considerably higher risk of liver-related outcomes but a modestly higher risk of extrahepatic cancer compared to those with pure MASLD. A remarkably higher risk of LREs was observed in participants with a fibrosis-4 > 2.67. Conclusion: MASLD and related SLD are associated with increased risks of LREs and extrahepatic outcomes, with heterogeneous risks across different phenotypes and significant risk stratification by liver fibrosis severity.