Metabolomic Profiling for Histologically Fibrotic Stage in Chronic Drug-Induced Liver Injury

Abstract

Background and aims: Chronic drug-induced liver injury (DILI) is a rare but under-researched adverse drug reaction–related disease, which is highly likely to progress into liver fibrosis and even cirrhosis. In this study, metabolomics was used to screen out characteristic metabolites related to the histological progression of fibrosis in chronic DILI and analyze the metabolic changes during the development of fibrosis to explain the underlying mechanism.Methods: Chronic DILI patients who underwent liver biopsy were divided into different fibrosis grades. Serum was analyzed by untargeted metabolomics to find serological characteristic metabolite fingerprints. The screened fingerprints were validated by the validation group patients, and the identification ability of fingerprints was compared using FibroScan.Results: A total of 31 metabolites associated with fibrosis and 11 metabolites associated with advanced fibrosis were identified. The validation group confirmed the accuracy of the two metabolite fingerprints [area under the curve (AUC) value 0.753 and 0.944]. In addition, the fingerprints showed the ability to distinguish the grades of fibrosis by comparing using FibroScan. The metabolite fingerprint pathway showed that bile acid synthesis is disturbed while lipid metabolism is extremely active, resulting in an overload of lipid metabolites in the occurrence and development of chronic DILI–associated fibrosis.Conclusions: Our metabolomic analysis reveals the unique metabolomic fingerprints associated with chronic DILI fibrosis, which have potential clinical diagnostic and prognostic significances. The metabolomic fingerprints suggest the disturbance of the lipid metabolites as the most important factor in the development of DILI fibrosis.

A two-way street – cellular metabolism and myofibroblast contraction

“…Nevertheless, this was a serum analysis and therefore might not represent the metabolic environment in fibrotic tissues. Other metabolomics studies performed on patients’ biopsies from idiopathic pulmonary fibrotic lungs 67 and fibrotic liver 68 support the results found for the glucose flux towards the TCA cycle. This is in line with the higher availability of glucose for biosynthesis and mitochondrial oxidation upon TGF-β stimulation.…”

Schizandrin C regulates lipid metabolism and inflammation in liver fibrosis by NF-κB and p38/ERK MAPK signaling pathways

“…The liver controls the central processes of lipid homeostasis, and disturbed lipid metabolism can contribute to the occurrence and progression of liver fibrosis ( Moustafa et al, 2012 ; He et al, 2022 ). Here, lipidomics was performed, and the results displayed that lipid profiles were varied between the CCl 4 model and normal liver samples, and treatment with Schizandrin C can regulate lipid species in CCl 4 liver.…”

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

“…Recent studies in adults showed that metabolomics can help establish markers of severity and/or chronicity of DILI. He et al (May 2022) concluded in a study conducted in patients with DILI fibrosis that metabolomic fingerprints suggest that alteration of lipid metabolites is the most important factor in the development of DILI fibrosis [49]. Zhao et al (April 2022), after performing a metabolomic study in patients with DILI, revealed that bile acids and polyunsaturated fatty acids were closely related to the severity and chronicity of DILI, respectively, thus potentially representing potent markers of DILI severity and chronicity [50].…”