Cause-specific mortality in patients with steatotic liver disease in the United States.

Objective: Causes of death across steatotic liver disease (SLD) subtypes remain incompletely characterized in routine clinical practice. We aimed to quantify and compare cause-specific mortality in SLD.

Methods: We conducted a retrospective cohort study of adults with imaging-confirmed hepatic steatosis receiving outpatient care in the national Veterans Health Administration (2010-2021). The primary exposure was SLD subtype, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and their intersection (MetALD). The primary outcome was cause-specific mortality, stratified by baseline cirrhosis.

Results: Among 366,433 adults (mean age, 60.5 years; 7.7% female; 67.6% non-Hispanic White), 77.9% had MASLD, 17.5% had MetALD, and 4.6% had ALD. Over a median follow-up of 5.4 years, the 10-year cumulative incidence of cardiovascular disease (CVD)- and extrahepatic cancer-related deaths among patients without cirrhosis was 8.1% and 7.5% in MASLD, 7.5% and 7.4% in MetALD, and 8.1% and 7.4% in ALD. Among patients with cirrhosis, liver- and CVD-related deaths were 9.2% and 17.3% in MASLD, 17.7% and 13.0% in MetALD, and 22.1% and 11.5% in ALD. Compared with non-cirrhotic MASLD (0.04 per 100 person-years), liver-related mortality was higher in MetALD (0.19 per 100 person-years; HR, 3.38; 95% CI, 3.02-3.78) and highest in ALD (0.40 per 100 person-years; HR, 6.99; 95% CI, 6.08-8.04). This progressive increase persisted in cirrhosis but was less pronounced.

Conclusions: CVD and extrahepatic cancer were leading causes of death across SLD subtypes without cirrhosis, while liver- and CVD-related deaths predominated in cirrhosis. MetALD and ALD were associated with progressively higher risks of liver-related mortality compared with MASLD. These findings underscore the need for integrated strategies addressing alcohol use, cardiovascular risk, and cancer screening to reduce preventable deaths. Causes of death across the steatotic liver disease spectrum remains incompletely characterized in routine clinical settings. In this large nationwide cohort study, we evaluated cause-specific mortality in patients with MASLD, MetALD, and ALD. We showed that cardiovascular disease and extrahepatic cancer were the primary causes of death in patients without cirrhosis across SLD subtypes, while liver disease and cardiovascular disease were predominant in those with cirrhosis. Importantly, MetALD and ALD were associated with progressively increasing risks of liver-related mortality compared to MASLD. Our findings highlight the need for integrated care models that simultaneously addresses cardiovascular risk factors, implements strategies to reduce alcohol consumption, and promotes cancer screening to mitigate preventable deaths in SLD.