Data-driven cluster analysis identifies distinct types of metabolic dysfunction-associated steatotic liver disease PMID: 39653777

Target-related Cytokines

2026-09-23

Data-driven cluster analysis identifies distinct types of metabolic dysfunction-associated steatotic liver disease

Nat Med. 2024 Dec;30(12):3624-3633. doi: 10.1038/s41591-024-03283-1.

Violeta Raverdy ^# ¹ ² , Federica Tavaglione ^# ³ ⁴ , Estelle Chatelain ^# ⁵ , Guillaume Lassailly ^# ⁶ , Antonio De Vincentis ⁷ ⁸ , Umberto Vespasiani-Gentilucci ³ ⁴ , Sami F Qadri ⁹ ¹⁰ , Robert Caiazzo ¹ ² , Helene Verkindt ¹ ² , Chiara Saponaro ¹ , Julie Kerr-Conte ¹ , Gregory Baud ¹ ² , Camille Marciniak ¹ ² , Mikael Chetboun ¹ ² , Naima Oukhouya-Daoud ¹ ² , Samuel Blanck ¹¹ , Jimmy Vandel ⁵ , Lisa Olsson ¹² , Rima Chakaroun ¹² , Viviane Gnemmi ¹³ ¹⁴ , Emmanuelle Leteurtre ¹³ ¹⁴ , Philippe Lefebvre ¹⁵ , Joel T Haas ¹⁵ , Hannele Yki-Järvinen ⁹ ¹⁰ , Sven Francque ¹⁶ ¹⁷ , Bart Staels ¹⁵ , Carel W Le Roux ¹⁸ , Valentina Tremaroli ¹² , Philippe Mathurin ⁶ , Guillemette Marot ¹¹ ¹⁹ , Stefano Romeo ²⁰ ²¹ ²² ²³ ²⁴ , François Pattou ²⁵ ²⁶

Affiliations

1. Translational Research for Diabetes UMR 1190, University of Lille, Inserm, Institut Pasteur Lille, CHU Lille, Lille, France.
2. Department of General and Endocrine Surgery, Centre Hospitalier et Universitaire de Lille, Lille, France.
3. Operative Unit of Clinical Medicine and Hepatology, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.
4. Research Unit of Clinical Medicine and Hepatology, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy.
5. US 41 - UAR 2014 - PLBS Bilille, University of Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, F-59000, Lille, France.
6. Department of Hepato-Gastroenterology CHU Lille, University of Lille, Inserm INFINITE-U1286, Lille, France.
7. Operative Unit of Internal Medicine, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy.
8. Research Unit of Internal Medicine, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy.
9. Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
10. Minerva Foundation Institute for Medical Research, Helsinki, Finland.
11. ULR 2694 METRICS: Évaluation des technologies de santé et des pratiques médicales, University of Lille, CHU Lille, F-59000, Lille, France.
12. Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
13. Cancer Heterogeneity Plasticity and Resistance to Therapies, CANTHER-UMR9020-U1277 - CNRS, Inserm, CHU Lille, University of Lille, Lille, France.
14. Department of Pathology, CHU Lille, University of Lille, Lille, France.
15. Nuclear Receptors, Metabolic and Cardiovascular Diseases - U1011, University of Lille, Inserm, CHU Lille, Institut Pasteur Lille, Lille, France.
16. Department of Gastroenterology Hepatology, Antwerp University Hospital, Edegem, Belgium.
17. 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.
18. Diabetes Complications Research Centre, University College Dublin, Dublin, Ireland.
19. MODAL: Models for Data Analysis and Learning, Inria, F-59000, Lille, France.
20. Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden. [email protected].
21. Clinical Nutrition Unit, Department of Medical and Surgical Sciences, University Magna Graecia, Catanzaro, Italy. [email protected].
22. Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden. [email protected].
23. Department of Medicine Huddinge (H7), Karolinska Institutet and University Hospital, Stockholm, Sweden. [email protected].
24. Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University, Gothenburg, Sweden. [email protected].
25. Translational Research for Diabetes UMR 1190, University of Lille, Inserm, Institut Pasteur Lille, CHU Lille, Lille, France. [email protected].
26. Department of General and Endocrine Surgery, Centre Hospitalier et Universitaire de Lille, Lille, France. [email protected].
# Contributed equally.

Abstract

Metabolic dysfunction-associated steatotic Liver Disease (MASLD) exhibits considerable variability in clinical outcomes. Identifying specific phenotypic profiles within MASLD is essential for developing targeted therapeutic strategies. Here we investigated the heterogeneity of MASLD using partitioning around medoids clustering based on six simple clinical variables in a cohort of 1,389 individuals living with Obesity. The identified clusters were applied across three independent MASLD cohorts with liver biopsy (totaling 1,099 participants), and in the UK Biobank to assess the incidence of chronic Liver Disease, Cardiovascular Disease and Type 2 Diabetes. Results unveiled two distinct types of MASLD associated with steatohepatitis on histology and liver imaging. The first cluster, liver-specific, was genetically linked and showed rapid progression of chronic Liver Disease but limited risk of Cardiovascular Disease. The second cluster, cardiometabolic, was primarily associated with dysglycemia and high levels of triglycerides, leading to a similar incidence of chronic Liver Disease but a higher risk of Cardiovascular Disease and Type 2 Diabetes. Analyses of samples from 831 individuals with available liver transcriptomics and 1,322 with available plasma metabolomics highlighted that these two types of MASLD exhibited distinct liver transcriptomic profiles and plasma metabolomic signatures, respectively. In conclusion, these data provide preliminary evidence of the existence of two distinct types of clinically relevant MASLD with similar liver phenotypes at baseline, but each with specific underlying biological profiles and different clinical trajectories, suggesting the need for tailored therapeutic strategies.