Diagnostic exogenous probe strategy using ezetimibe-glucuronide effectively identifies metabolic...

Area of Science:

• Hepatology and Gastroenterology
• Pharmacology and Drug Metabolism
• Biomarker Discovery

Background:

• Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with limited diagnostic options.
• Liver biopsy is invasive, and current noninvasive tests lack accuracy.
• MASH impairs hepatic and renal transporters, affecting drug metabolism and clearance.

Purpose of the Study:

• To evaluate ezetimibe-glucuronide (EZEG) as a noninvasive, mechanism-based biomarker for MASH diagnosis.
• To assess the correlation between EZEG levels and MASH histologic features.
• To determine the utility of EZEG as a diagnostic function test for MASH.

Main Methods:

• Quantification of plasma and urine EZEG concentrations using liquid chromatography-tandem mass spectrometry.
• Administration of a subtherapeutic dose (1 mg) of ezetimibe to biopsy-confirmed MASH patients (NAS=5) and non-MASH individuals (NAS 0-4).
• Analysis of EZEG levels at 60 minutes postdose and correlation with nonalcoholic fatty liver disease activity scores (NAS) and hepatocyte ballooning.

Main Results:

• MASH patients exhibited approximately 4.5-fold higher plasma EZEG concentrations compared to non-MASH individuals.
• Plasma EZEG demonstrated excellent diagnostic discrimination for MASH (AUC=0.92).
• Elevated plasma EZEG strongly correlated with hepatocyte ballooning, a key MASH histologic feature.

Conclusions:

• Plasma EZEG is a sensitive and specific noninvasive biomarker for MASH.
• EZEG serves as a mechanism-based diagnostic function test reflecting MASH-associated transporter dysfunction.
• This approach offers a promising strategy for early MASH detection and disease stratification.