Serum LEAP2 Levels Across the Spectrum of Metabolic Dysfunction-Associated Fatty Liver Disease: A Potential Noninvasive Biomarker for Severity Stratification

Abstract

Purpose: To evaluate circulating liver-expressed antimicrobial peptide 2 (LEAP2) as a potential noninvasive biomarker for the presence of metabolic dysfunction-associated fatty liver disease (MAFLD) and its progression to metabolic dysfunction-associated steatohepatitis (MASH). Patients and Methods: This prospective observational study enrolled obese patients with MAFLD, categorized into simple steatosis (SS) or MASH based on liver histopathology, along with healthy controls (HC). Serum levels LEAP2 were quantified using enzymelinked immunosorbent assay (ELISA). Baseline characteristics were compared among groups, followed by univariable and multivariate ordinary logistic regression to identify MAFLD predictors. The diagnostic performance of LEAP2 was evaluated through receiver operating characteristic (ROC) curve analysis. Additionally, Hepatic LEAP2 transcriptomic data from public Gene Expression Omnibus (GEO) datasets (GSE126848, GSE135251) were analyzed for validation. Results: Seventy-four participants (24 HC, 24 SS, 26 MASH) were analyzed. Serum LEAP2 levels significantly and progressively increased with MAFLD severity (median ng/mL: HC 11.54, SS 13.62, MASH 18.34; P<0.001), correlating positively with disease stage (Spearman’s ρ=0.526, P<0.001). This pattern was validated using hepatic LEAP2 transcript data from GEO datasets (P<0.001; Spearman’s ρ=0.317, P<0.001). Multivariate logistic regression identified serum LEAP2 as an independent factor associated with MAFLD presence (OR=1.14, 95% CI 1.03–1.26; P=0.014), alongside BMI and ALT, while HDL was protective. ROC analysis demonstrated good diagnostic performance for distinguishing MASH from HC (AUC=0.86) and moderate performance for adjacent stages (HC vs SS, AUC=0.70; SS vs MASH, AUC=0.70). Conclusion: Serum LEAP2 levels progressively increase with MAFLD severity and are independently associated with the disease. LEAP2 demonstrates potential as a noninvasive biomarker for assessing MAFLD severity, particularly in distinguishing MASH from healthy individuals. These findings warrant further investigation into LEAP2’s pathophysiological role and therapeutic potential.