Identification and Characterization of Three Novel Biomarkers for Mixed/Cholestatic Drug-Induced Liver Injury

This study aimed to identify and establish novel biomarkers for human drug-induced liver injury (DILI).

Patients with DILI (N = 52) or other liver diseases (N = 486) and healthy participants (N = 60) were recruited from the hospitals enrolled in this study. Metabolomics was conducted using serum samples from patients with DILI and healthy participants to screen for candidate DILI biomarkers. Subsequently, the serum concentrations of the candidate biomarkers were determined using a validated assay to characterize their properties and evaluate their ability to differentiate the patients with DILI from those who recovered from DILI and those with other liver diseases.

Three metabolites, pyroglutamylglycine (pyroGluGly), phenylalanine (Phe), and phenylalanyltryptophan (PheTrp), were identified as candidate DILI biomarkers. The serum concentrations of pyroGluGly, Phe, and PheTrp demonstrated a high and similar differentiating ability (area under the receiver-operating characteristic curve [ROC-AUC] > 0.9) in patients with mixed and cholestatic DILI compared with those in patients who recovered from DILI, suggesting that these three metabolites are biomarkers for mixed/cholestatic DILI. All or some of them demonstrated a substantially high differentiating ability (ROC-AUC > 0.8) in patients with mixed/cholestatic DILI compared with patients with other liver diseases, except for obstructive jaundice.

We identified novel DILI biomarkers that can be used to clinically assess patients with mixed/cholestatic DILI and to differentiate these patients from recovered patients and those with other liver diseases.