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

Abstract

Background & aims: 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 patients with 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 incidences of cardiovascular disease (CVD)- and extrahepatic cancer-related deaths among patients without cirrhosis were 8.1% and 7.5% for MASLD, 7.5% and 7.4% for MetALD, and 8.1% and 7.4% for ALD. Among patients with cirrhosis, the 10-year cumulative incidences of liver- and CVD-related deaths were 9.2% and 17.3% for MASLD, 17.7% and 13.0% for MetALD, and 22.1% and 11.5% for ALD. Compared with non-cirrhotic MASLD (0.04 per 100 person-years), liver-related mortality was higher for MetALD (0.19 per 100 person-years; hazard ratio 3.38; 95% CI 3.02-3.78) and highest for ALD (0.40 per 100 person-years; hazard ratio 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 in the absence of cirrhosis, while liver- and CVD-related deaths predominated in patients with 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.

Impact and implications: Causes of death across the steatotic liver disease (SLD) spectrum remain 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 address cardiovascular risk factors, implement strategies to reduce alcohol consumption, and promote cancer screening to mitigate preventable deaths in SLD.

Keywords: Alcohol-associated liver disease; MASLD; MetALD; metabolic dysfunction and alcohol-associated liver disease; metabolic dysfunction-associated steatotic liver disease.

Fig. 1.. Distribution of causes of death across steatotic liver disease subtypes stratified by baseline cirrhosis

ALD, alcohol-associated liver disease; AUD, alcohol use disorder; CRC, colorectal cancer; CVD, cardiovascular disease; DM, diabetes mellitus; GI, gastrointestinal; HCC, hepatocellular carcinoma; ID, infectious disease; MASLD, metabolic dysfunction-associated steatotic liver disease; MetALD, metabolic dysfunction and alcohol-associated liver disease; Resp, respiratory. Note: (A) Percentages represent the proportion of all-cause deaths within each cirrhosis status group. (B) Percentages represent the proportion of cancer-related deaths within each cirrhosis status group

Fig. 2.. Ten-year cumulative incidence of cause-specific mortality across steatotic liver disease subtypes stratified by baseline cirrhosis and age

ALD, alcohol-associated liver disease; CVD, cardiovascular disease; HCC, hepatocellular carcinoma; MASLD, metabolic dysfunction-associated steatotic liver disease; MetALD, metabolic dysfunction and alcohol-associated liver disease. Note: Cumulative incidences were estimated using the Aalen-Johansen estimator.