Steatotic Liver Disease Subtypes Face Varying Risk of Adverse Liver Outcomes, Mortality

New research is shedding light on differents in long-term adverse outcomes across steatotic liver disease subtypes, highlighting the importance of alcohol use and fibrosis assessments for identifying high risk individuals.1

The retrospective cohort study examined national Veterans Health Administration (VHA) data and found patients with metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD) had increased risks of adverse liver outcomes and all-cause mortality than those with metabolic dysfunction-associated steatotic liver disease (MASLD), with similar risks of major adverse cardiovascular events (MACE).1

“As one of the largest and most sociodemographically diverse cohorts with detailed clinical data, quantification of alcohol use using a validated instrument, and more than 12 years of follow-up, this study provides robust estimates of adverse liver outcomes, MACE, and mortality across the steatotic liver disease spectrum in clinical practice,” Pedro Ochoa-Allemant, MD, an NIH T-32 fellow in Gastroenterology at the University of Pennsylvania, and colleagues wrote.1

In 2023, a modified Delphi process led by the American Association for the Study of Liver Disease, the European Association for the Study of the Liver, and the Latin American Association for the Study of the Liver yielded new liver disease nomenclature to address concerns regarding the terminology “nonalcoholic fatty liver disease” and “metabolic-associated fatty liver disease,” introducing MASLD and MetALD.2 Estimates of the incidence of long-term adverse outcomes in population-based cohorts with steatotic liver disease remain limited, with most existing epidemiological studies facing notable limitations and leaving important evidence gaps.1

To compare the risks of adverse liver outcomes, MACE, and all-cause mortality across steatotic liver disease subtypes, investigators conducted a retrospective cohort study of adults with imaging-confirmed hepatic steatosis receiving outpatient care within the national VHA. They derived the study cohort from a 5% random sample of patients with ≥ 1 outpatient visit, stratified by fiscal year and Veterans Integrated Service Network for nationwide representation. The cohort was restricted to veterans ≥ 18 years of age with hepatic steatosis on abdominal imaging and regular care, defined as ≥ 1 clinical encounter in each of the 2 years before the index date.1

The primary exposure was steatotic liver disease subtype, categorized using a combination of cardiometabolic risk factors (CMRFs), the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) questionnaire, and alcohol use disorder diagnosis, adapting the revised nomenclature:

• MASLD: ≥ 1 CMRF with none to mild alcohol use and no alcohol use disorder
• MetALD: ≥ 1 CMRFs with moderate alcohol use (with or without alcohol use disorder) or none to mild alcohol use with alcohol use disorder.
• ALD: ≥ 1 CMRF with severe alcohol use or any alcohol use without CMRFs

The primary outcomes were the incidence of adverse liver outcomes, MACE, and all-cause mortality. Investigators defined adverse liver outcomes as the first occurrence of cirrhosis, decompensation, hepatocellular carcinoma, liver transplant, or liver-related death, identified either by 1 primary inpatient discharge diagnosis or 2 outpatient diagnoses separated by 30 days after the index date. They defined MACE as the first occurrence of acute myocardial infarction, stroke, heart failure, or cardiovascular death, identified by 1 primary inpatient discharge diagnosis after the index date.1

In total, the study cohort included 264,192 patients with MASLD (77.3%), 61,070 with MetALD (17.9%), and 16,339 with ALD (4.8%), with a median follow-up of 5.5 (interquartile range, 3.0-8.4) years.1

Compared with MASLD, MetALD had a greater incidence of adverse liver outcomes (1.12 vs 0.61 per 100 person-years; hazard ratio [HR], 1.56; 95% CI, 1.50-1.62) and all-cause mortality (2.74 vs 2.60 per 100 person-years; HR, 1.08; 95% CI, 1.05-1.10), but similar incidence of MACE. Similarly, investigators noted ALD had a greater incidence of adverse liver outcomes (1.78 vs 0.61 per 100 person-years; HR, 2.33; 95% CI, 2.20-2.47) and all-cause mortality (3.42 vs 2.60 per 100 person-years; HR, 1.42; 95% CI, 1.36-1.48) than MASLD, but similar incidence of MACE.1

Further analysis revealed the incidence of adverse liver outcomes per 100 person-years increased 10-fold with a higher degree of fibrosis (Fibrosis-4 score <1.30 vs >2.67) across MASLD (0.28 vs 3.02), MetALD (0.39 vs 4.31), and ALD (0.61 vs 5.05).1

The individual components of the steatotic liver disease definition most strongly associated with adverse liver outcomes were severe alcohol use (subdistribution hazard ratio [SHR], 1.77; 95% CI, 1.66-1.89), alcohol use disorder (SHR, 1.58; 95% CI, 1.53-1.66), and diabetes (SHR, 1.44; 95% CI, 1.39-1.50), while the individual components most strongly associated with MACE were hypertension (SHR, 1.67; 95% CI, 1.60-1.75) and diabetes (SHR, 1.55; 95% CI, 1.51-1.60).1

“The findings of this cohort study suggest important differences in long-term adverse outcomes across steatotic liver disease subtypes,” investigators concluded.1 “These findings underscore the role of alcohol and fibrosis assessments in clinical practice for risk stratification.”

References

1. Ochoa-Allemant P, Hubbard RA, Kaplan DE, Serper M. Adverse Liver Outcomes, Cardiovascular Events, and Mortality in Steatotic Liver Disease. JAMA Intern Med. Published online June 16, 2025. doi:10.1001/jamainternmed.2025.1809

2. Brooks A. From NAFLD to MASLD: 2023 Brings New Liver Disease Nomenclature. HCPLive. December 13, 2023. Accessed June 19, 2025. https://www.hcplive.com/view/from-nafld-to-masld-2023-new-liver-disease-nomenclature