Serum metabolomics-based heterogeneities and screening strategy for metabolic dysfunction-associated fatty liver disease (MAFLD).

Background And Aims: Metabolic dysfunction-associated fatty liver disease (MAFLD) brings heavy clinical and economic burdens to society, while understandings on heterogeneities are limited.

Materials And Methods: We conducted a serum metabolomics study to reveal the metabolic heterogeneities and develop a diagnostic strategy for MAFLD using a discovery set consisting of 122 biopsy-proven MAFLD patients [lean (n = 12), overweight (n = 20), obese (n = 74), type 2 diabetes mellitus (T2DM, n = 16)] and 35 controls, and a validation set containing 60 biopsy-proven MAFLD patients (20 lean, 20 obese and 20 T2DM) and 20 controls.

Results: Mitochondrial dysfunction, destructed phospholipids homeostasis, and folate deficiency were most severe in MAFLD concurrent T2DM patients. Formiminoglutamate, sphinganine and sphingosine correlated positively with HbA1c, while glycoursodeoxycholicacidsulfate correlated positively with AST. Additionally, the linear discriminant analysis (LDA) model using metabolites 5-hydroxyhexanoate, ribitol and formiminoglutamate demonstrated pretty good performance in screening for MAFLD patients, with AUC for validation samples being 0.94 (CI: 0.88-1.0). For easier clinical applications, an M-index based on the three metabolites was further designed.

Conclusion: Our study supports that MAFLD concurrent T2DM patients deserve particular attentions in clinical follow-up, and paves the way for developing more effective diagnostic options in future studies.