Dissecting metabolic dysfunction- and alcohol-associated liver disease (MetALD) using proteomic and metabolomic profiles

作者：Jun Liu, Sihao Xiao, Sile Hu, Rui Huang, Lingyan Chen, Jeremy Tomlinson, Jeremy Cobbold, Joanna M. M. Howson, Cornelia M. van Duijn · 发表于：Journal of Hepatology · 年份：2025 · DOI：10.1016/j.jhep.2025.05.026 · 被引用次数：11 · 研究领域：Alcohol Consumption and Health Effects、Liver Disease Diagnosis and Treatment、Alcoholism and Thiamine Deficiency

BACKGROUND & AIMS: Metabolic dysfunction- and alcohol-associated liver disease (MetALD) is a poorly understood condition that bridges cardiometabolic and alcohol-related pathological characteristics. We aimed to differentiate patients with MetALD whose molecular signatures more closely resemble either alcohol-related liver disease (ALD) or metabolic dysfunction-associated steatotic liver disease (MASLD), and to assess their relative risks of complications and mortality. METHODS: We analysed data from 443,453 European participants in the UK Biobank, including 34,147 with MetALD, 11,220 with ALD, and 124,034 with MASLD. Elastic net regression was used to classify ALD and MASLD based on 249 plasma metabolites and/or 2,941 plasma proteins, with multiple sensitivity analyses. We then applied the resulting concise model to patients with MetALD to identify an alcohol-predominant group (classified as ALD) and a cardiometabolic-predominant group (classified as MASLD). Finally, we evaluated their 15-year risk of major outcomes (heart failure, myocardial infarction, stroke, cirrhosis, hepatocellular carcinoma, and mortality) using Cox regression. RESULTS: The metabolome alone discriminated ALD from MASLD with an AUC of 0.86, while the proteome alone achieved an AUC of 0.96. Adding age, sex, BMI, liver enzymes, or metabolome information did not enhance the AUC of the proteome model. A 10-protein model differentiated ALD from MASLD with an AUC of 0.93. This model identified that patients ...