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

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.

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Publication Details

Journal
Nature Medicine
Published
2024-12-01
DOI
https://doi.org/10.1038/s41591-024-03283-1
Citations
102
Primary Topic
Liver Disease Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
39.44

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article

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

Bart Staels, S. U. Qadri, François Pattou, Carel Wynand le Roux et al.
102 citations
Nature Medicine
Liver Disease Diagnosis and Treatment
39.44
article

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

Bart Staels, S. U. Qadri, François Pattou, Carel Wynand le Roux, Chiara Saponaro, Stefano Romeo, Samuel Blanck, Viviane Gnemmi, Lisa Olsson, Hannele Yki‐Järvinen, Umberto Vespasiani‐Gentilucci, Philippe Lefèbvre, Robert Caïazzo, Jimmy Vandel, Violeta Raverdy, Grégory Baud, Hélène Verkindt, Guillemette Marot, Emmanuelle Leteurtre, Joel T. Haas, Estelle Chatelain, Mikaël Chetboun, Camille Marciniak, Rima Chakaroun, Naima Oukhouya‐Daoud, Sven Francque, Guillaume Lassailly, Antonio De Vincentis, Valentina Tremaroli, Julie Kerr‐Conte, Federica Tavaglione, Philippe Mathurin
article en
102 citations

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.

Nature MedicineVol. 30(12)
University College Dublin (IE), Centre National de la Recherche Scientifique (FR), Institut national de recherche en sciences et technologies du numérique (FR), Karolinska University Hospital (SE), University of Helsinki (FI), University of Antwerp (BE), Inserm (FR), Università Campus Bio-Medico (IT), Université de Lille (FR), Helsinki University Hospital (FI), Institut Pasteur de Lille (FR), Sahlgrenska University Hospital (SE), Agostino Gemelli University Polyclinic (IT), Karolinska Institutet (SE), Centre Hospitalier Universitaire de Lille (FR), Magna Graecia University (IT), Minerva Foundation (FI), Antwerp University Hospital (BE), Wallenberg Wood Science Center (SE), Lille Inflammation Research International Center (FR), Campus Bio Medico University Hospital (IT), European Genomic Institute for Diabetes (FR), Institute for Translational Research in Inflammation (FR), Recherche translationnelle sur le diabète, Evaluation des technologies de santé et des pratiques médicales (FR), University of Gothenburg (SE)
Suomen Lääketieteen Säätiö, Yrjö Jahnssonin Säätiö, Université de Lille, European Genomic Institute for Diabetes, Agence Nationale de la Recherche, Cancerfonden, Biomedicum Helsinki-säätiö, Knut och Alice Wallenbergs Stiftelse, Vetenskapsrådet, Emil Aaltosen Säätiö, Orionin Tutkimussäätiö, Novo Nordisk Fonden, Centre hospitalier régional universitaire de Lille
Good health and well-being
Openalex Percentile: Top 0%
Liver Disease Diagnosis and Treatment
39.44
DOIOpen Access PDFOpenAlex
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