BACKGROUND: Early identification of those with NAFLD activity score ≥ 4 and significant fibrosis (≥F2) or at-risk metabolic dysfunction-associated steatohepatitis (MASH) is a priority as these patients are at increased risk for disease progression and may benefit from therapies. We developed and validated a highly specific metabolomics-driven score to identify at-risk MASH. METHODS: We included derivation (n = 790) and validation (n = 565) cohorts from international tertiary centers. Patients underwent laboratory assessment and liver biopsy for metabolic dysfunction-associated steatotic liver disease. Based on 12 lipids, body mass index, aspartate aminotransferase, and alanine aminotransferase, the MASEF score was developed to identify at-risk MASH and compared to the FibroScan-AST (FAST) score. We further compared the performance of a FIB-4 + MASEF algorithm to that of FIB-4 + liver stiffness measurements (LSM) by vibration-controlled transient elastography (VCTE). RESULTS: The diagnostic performance of the MASEF score showed an area under the receiver-operating characteristic curve, sensitivity, specificity, and positive and negative predictive values of 0.76 (95% CI 0.72-0.79), 0.69, 0.74, 0.53, and 0.85 in the derivation cohort, and 0.79 (95% CI 0.75-0.83), 0.78, 0.65, 0.48, and 0.88 in the validation cohort, while FibroScan-AST performance in the validation cohort was 0.74 (95% CI 0.68-0.79; p = 0.064), 0.58, 0.79, 0.67, and 0.73, respectively. FIB-4+MASEF showed similar overall performance compared with FIB-4 + LSM by VCTE ( p = 0.69) to identify at-risk MASH. CONCLUSION: MASEF is a promising diagnostic tool for the assessment of at-risk MASH. It could be used alternatively to LSM by VCTE in the algorithm that is currently recommended by several guidance publications.

Biocruces Bizkaia Health Research Institute Barakaldo Spain

Biodonostia Research Institute Donostia University Hospital University of the Basque Country CIBERehd IKERBASQUE Donostia Spain

CIC bioGUNE Basque Research and Technology Alliance Derio Spain

Clinic University Hospital University of Valladolid Valladolid Spain

Department of Biochemistry and Genetics School of Sciences University of Navarra Pamplona Spain

Department of Gastroenterology School of Medicine Pontificia Universidad Católica de Chile Santiago Chile

Department of Physiology Faculty of Medicine and Nursing University of the Basque Country UPV EHU Leioa Spain

Division of Liver Diseases Icahn School of Medicine at Mount Sinai New York City New York USA

General University Hospital and the 1st Faculty of Medicine Charles University Prague Czech Republic

Gregorio Marañón University Hospital Madrid Spain

Houston Methodist Hospital Houston Research Institute Houston Texas USA

Houston Research Institute Houston Texas USA

Karsh Division of Gastroenterology and Hepatology Cedars Sinai Medical Center Los Angeles CA

Marqués de Valdecilla University Hospital Cantabria University IDIVAL Santander Spain

National Institute for the Study of Liver and Gastrointestinal Diseases Madrid Spain

OWL Metabolomics Derio Spain

Pinnacle Clinical Research San Antonio Texas USA

Príncipe de Asturias University Hospital Alcalá University Madrid Spain

Puerta del Hierro University Hospital Madrid Spain

Translational and Clinical Research Institute Faculty of Medical Sciences Newcastle University Newcastle upon Tyne United Kingdom

University of Florida Gainesville Florida USA

Valme University Hospital CIBERehd Seville Spain

Virgen del Rocío University Hospital Sevilla Spain

Virginia Commonwealth University Medical Center Richmond Virginia USA

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