The Lipidomic Profile Discriminates Between MASLD and MetALD

Kai Markus Schneider; Feng Cao; Helen Ye Rim Huang; Lanlan Chen; Yazhou Chen; Rongpeng Gong; Anastasia Raptis; Kate Townsend Creasy; Jan Clusmann; Felix van Haag; Paul-Henry Koop; Adrien Guillot; Tom Luedde; Rohit Loomba; Sven Francque; Carolin Victoria Schneider

doi:10.1111/apt.70012

The Lipidomic Profile Discriminates Between MASLD and MetALD

Aliment Pharmacol Ther. 2025 Feb 11. doi: 10.1111/apt.70012. Online ahead of print.

Authors

Kai Markus Schneider^{1

2

3

4}, Feng Cao¹, Helen Ye Rim Huang¹, Lanlan Chen⁵, Yazhou Chen¹, Rongpeng Gong¹, Anastasia Raptis¹, Kate Townsend Creasy⁶, Jan Clusmann^{1

4}, Felix van Haag¹, Paul-Henry Koop¹, Adrien Guillot⁵, Tom Luedde⁷, Rohit Loomba⁸, Sven Francque^{9

10}, Carolin Victoria Schneider^{1

11}

Affiliations

¹ Department of Internal Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
² Department of Medicine I, Deptartment of Gastroenterology and Hepatology, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany.
³ Center for Regenerative Therapies Dresden (CRTD), Technische Universität (TU) Dresden, Dresden, Germany.
⁴ Else Kroener Fresenius Center for Digital Health, Faculty of Medicine and University Hospital Carl Gustav Carus, TUD Dresden University of Technology, Dresden, Germany.
⁵ Department of Hepatology & Gastroenterology, Campus Virchow-Klinikum and Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.
⁶ Department of Biobehavioral Health Sciences, School of Nursing, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
⁷ Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany.
⁸ MASLD Research Center, Division of Gastroenterology and Hepatology, Department of Medicine, University of California at San Diego, San Diego, California, USA.
⁹ Department of Gastroenterology Hepatology, Antwerp University Hospital, Edegem, Belgium.
¹⁰ InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
¹¹ The Institute for Translational Medicine and Therapeutics, the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

PMID: 39935287
DOI: 10.1111/apt.70012

Abstract

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.

Keywords: HDL; Lipidomics; MASLD; MetALD; UK biobank; ethanol metabolism; liver disease; proton density fat fraction.

Abstract

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