Serum Metabolomic Analysis of Chronic Drug-Induced Liver Injury With or Without Cirrhosis

Abstract

Background: Chronic drug-induced liver injury (DILI) occurs in up to 20% of all DILI patients. It presents a chronic pattern with persistent or relapsed episodes and may even progress to cirrhosis. However, its underlying development mechanism is poorly understood.Aims: To find serum metabolite signatures of chronic DILI with or without cirrhosis, and to elucidate the underlying mechanism.Methods: Untargeted metabolomics coupled with pattern recognition approaches were used to profile and extract metabolite signatures from 83 chronic DILI patients, including 58 non-cirrhosis (NC) cases, 14 compensated cirrhosis (CC) cases, and 11 decompensated cirrhosis (DC) cases.Results: Of the 269 annotated metabolites associated with chronic DILI, metabolic fingerprints associated with cirrhosis (including 30 metabolites) and decompensation (including 25 metabolites), were identified. There was a significantly positive correlation between cirrhosis-associated fingerprint (eigenmetabolite) and the aspartate aminotransferase-to-platelet ratio index (APRI) (r = 0.315, P = 0.003). The efficacy of cirrhosis-associated eigenmetabolite coupled with APRI to identify cirrhosis from non-cirrhosis patients was significantly better than APRI alone [area under the curve (AUC) value 0.914 vs. 0.573]. The decompensation-associated fingerprint (eigenmetabolite) can effectively identify the compensation and decompensation periods (AUC value 0.954). The results of the metabolic fingerprint pathway analysis suggest that the blocked tricarboxylic acid cycle (TCA cycle) and intermediary metabolism, excessive accumulation of bile acids, and perturbed amino acid metabolism are potential mechanisms in the occurrence and development of chronic DILI-associated cirrhosis.Conclusions: The metabolomic fingerprints characterize different stages of chronic DILI progression and deepen the understanding of the metabolic reprogramming mechanism of chronic DILI progression to cirrhosis.

The Potential Role of Metabolomics in Drug-Induced Liver Injury (DILI) Assessment

“…All this is consistent with a mitochondrial impairment that can lead to the inability to oxidise pyruvate by the pyruvate dehydrogenase leading to its reduction to lactate triggering lactic acidosis. Accordingly, an increase in pyruvate and alterations in the citric acid cycle as a consequence of mitochondrial dysfunction are observed in three [74,79,84] and four [84,86,91,95] studies, respectively. A decrease in citrate acid is expected to correlate with suppressed oxidative phosphorylation and increased anaerobic glycolysis.…”

“…High levels of uric acid, the final oxidation product of purine metabolism, were also found in [79,84,86,88], whose increase has also been described to be an independent risk factor for liver diseases [104]. Another common observation was the presence of elevated levels of amino acids [47,[74][75][76]79,84,90,91,95]. These are referred to as glutamic acid, alanine, L-glutamine, Leucine/Isoleucine, glycine, tyrosine, and L-histidine and could be attributed to increased proteolysis.…”

“…Attention was paid principally to their links to the DILI and not to the drug causing the event. Among them, few studies addressed the identification of specific markers for DILI prediction or individual susceptibility determination [43,47,[74][75][76] while the vast majority were focused on DILI diagnosis and follow-up [55,[77][78][79][80][81][82][83][84][85][86][87][88][89][90][91][92][93][94][95].…”

Pharmacodynamic Evaluation of the Gexia Zhuyu Decoction in the Treatment of NAFLD and the Molecular Mechanism Underlying the TRPM4 Pathway Regulation

“…Therefore, symptomatic treatment is often employed clinically, including lipid-lowering and glucose and lipid metabolism improvements. However, most lipid-lowering drugs degrade blood lipid levels and promote lipid entry into the liver for metabolism and excretion, which can easily lead to liver damage and liver fat deposition [ 6 ]. Therefore, it has become an urgent task to find a drug that has clear therapeutic effects, is safe, and has minimal side effects.…”

Metabolic Analysis of Potential Key Genes Associated with Systemic Lupus Erythematosus Using Liquid Chromatography-Mass Spectrometry

“…For example, Guo et al identified a series of potential biomarkers for the diagnosis of fatty liver hemorrhagic syndrome by serum metabolic profiling [ 12 ]. Chen et al reported blocked tricarboxylic acid (TCA) cyclic metabolism plays an important role in chronic DILI-associated cirrhosis [ 13 ]. Zhang et al identified 11 metabolites, such as hexadecanoic acid (C16:0), as potential serum biomarkers for diabetic kidney disease [ 14 ].…”