The Lipidomic Profile Discriminates Between MASLD and MetALD.

Background: The recent consensus statement redefined steatotic liver diseases. Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction and alcohol-related liver disease (MetALD) now represent distinct disease entities. However, biomarkers that differentiate MASLD and MetALD remain largely unknown.

Aims: To identify lipidomic biomarkers with discriminatory potential for distinguishing MetALD from MASLD.

Methods: Using the UK Biobank dataset, 40,534 people with available MRI liver scans were analysed. A total of, 11,217 cases with a proton density fat fraction (PDFF) ≥ 5% were identified as having steatotic liver disease. Among these, lipidomic profiles were obtained for 5539 MASLD and 462 MetALD cases. A total of, 250 plasma lipidomic and metabolomic parameters were analysed. Mendelian randomisation (MR) analysis was used to confirm the association between alcohol consumption and the lipidomic biomarkers.

Results: When comparing the top 30 differentially expressed lipidomic biomarkers predicting MetALD compared to MASLD, the majority were related to HDL and were significantly overrepresented at both analysed time points. The top five metabolites were: acetoacetate, 3-hydroxybutyrate, phospholipids in Large HDL, concentration of large HDL particles, free cholesterol in large HDL. The sensitivity analysis comparing alcohol-related liver disease to MASLD revealed similar associations, suggesting that the HDL signature is stable over time. Additionally, MR analysis further confirmed that alcohol consumption was associated with increased levels of HDL-related metabolites.

Conclusion: Our findings indicate that HDL-centric lipidomic markers, particularly those within the larger and medium HDL subfraction, may differentiate MetALD from MASLD. Further longitudinal and experimental studies are warranted to validate these findings and assess their clinical implications.