Extrahepatic Events in Patients With Metabolic Dysfunction‐Associated Steatotic Liver Disease and the Impact of Genetics and Alcohol Intake

ABSTRACT Aims The Delphi consensus established new criteria for steatotic liver disease (SLD), but the extrahepatic complications in patients with metabolic dysfunction‐associated steatotic liver disease (MASLD) remain unclear. In this study, we investigated the clinical course of MASLD patients compared to those with MASLD and increased alcohol intake (MetALD) and alcohol‐associated liver disease (ALD). Methods A total of 1150 Asian patients with SLD were enrolled and categorized into the MASLD ( n = 803), MetALD ( n = 81), and ALD ( n = 266) groups. The incidence levels of extrahepatic malignancies and cardiovascular disease (CVD) events were compared among the three groups. Genetic alterations in PNPLA3 , HSD17B13 , GCKR , and GDF15 were analyzed in 201 MASLD cases. Results MASLD patients were significantly younger (MASLD, MetALD, ALD; 53, 65, and 62 years), had a lower proportion of males (49.3%, 82.7%, and 86.8%), and had a higher BMI (26.7, 24.1, and 22.6 kg/m 2 ) than MetALD and ALD patients. During a median follow‐up of 10.6 years, the proportions of patients who developed extrahepatic malignancies were 7.2%, 9.9%, and 5.6%, and those who experienced CVD events were 5.7%, 3.7%, and 4.1% in the MASLD, MetALD, and ALD groups, respectively. However, Cox proportional hazards analysis revealed no significant difference in the risk of extrahepatic complications among the groups after adjusting for baseline characteristics. A single nucleotide polymorphism in PNPLA3 was associated with the development of CVD events in MASLD patients. Conclusions Extrahepatic events were observed at similar rates among patients with SLD after adjusting for confounding factors. However, overall mortality and the risk of HCC were significantly higher in the MetALD and ALD groups.