Metabolomic Analysis of Pediatric Patients with Idiosyncratic Drug-Induced Liver Injury According to the Updated RUCAM

Abstract

Hepatotoxicity, a common adverse drug effect, has been extensively studied in adult patients. However, it is equally important to investigate this condition in pediatric patients to develop personalized treatment strategies for children. This study aimed to identify plasma biomarkers that characterize hepatotoxicity in pediatric patients through an observational case-control study. Metabolomic analysis was conducted on 55 pediatric patients with xenobiotic liver toxicity and 88 healthy controls. The results revealed clear differences between the two groups. Several metabolites, including hydroxydecanoylcarnitine, octanoylcarnitine, lysophosphatidylcholine, glycocholic acid, and taurocholic acid, were identified as potential biomarkers (area under the curve: 0.817; 95% confidence interval: 0.696-0.913). Pathway analysis indicated involvement of primary bile acid biosynthesis and the metabolism of taurine and hypotaurine (p < 0.05). The findings from untargeted metabolomic analysis demonstrated an increase in bile acids in children with hepatotoxicity. The accumulation of cytotoxic bile acids should be further investigated to elucidate the role of these metabolites in drug-induced liver injury.

Keywords: DILI; bile acids; children; liver injury; metabolomics; updated RUCAM.

Figure 1

Total ion current for all plasma samples included in the analysis.

Figure 2

Principal component analysis for all samples included in the analysis. Principal components 1 and 2 (PC1 and PC2) representing the most variation and the second most variation in the data, respectively. Red circles correspond to quality control (QC) samples, orange circles correspond to samples from control subjects (C), and blue circles correspond to samples from children with hepatotoxicity (P).

Figure 3

Multivariate analysis using unsupervised and supervised methods. (A) Principal component analysis for the four groups. Red circles: non-oncological children with hepatotoxicity. Green circles: non-oncological children without hepatotoxicity. Dark-blue circles: oncological children with hepatotoxicity. Light-blue circles: oncological children without hepatotoxicity. (B) Regression by partial least squares for the two groups. Green circles: controls. Red circles: children with hepatotoxicity.

Figure 4

Quality and design of the suggested model. (A) Permutation test with 100 observations. (B) Graph representing the 30 variables with the best projection in the partial least squares regression analysis.

Figure 5

Summary of altered metabolic pathways analysis with MetaboAnalyst 5.0 reflecting the impact on the pathway and the level of significance. The colors of dots (varying from yellow to red) indicates the significance of the metabolites in the data. The size of the dot is positively correlated with the impact of the metabolic pathway.

Figure 6

Model validation. (A) Area under the curve for the model with five tentatively identified metabolites (hydroxydecanoylcarnitine, octanoylcarnitine, lysophosphatidylcholine (16:1/0:0), glycocholic acid, and taurocholic acid). (B) Classification of individuals using a 100-fold cross-validation for each simple.