Serum metabolome and targeted bile acid profiling reveals potential novel biomarkers for drug-induced liver injury

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Abstract

This study aims to determine the non-invasive, reliable and sensitive biochemical parameters for the diagnosis of drug-induced liver injury (DILI).

Ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) and selected reaction monitoring (SRM) were used to profile the serum metabolome and quantify 15 targeted bile acid metabolites, respectively, in samples obtained from 38 DILI patients and 30 healthy controls.

A comparison of the resulting serum metabolome profiles of the study participants revealed significant differences between DILI patients and healthy controls. Specifically, serum palmitic acid, taurochenodeoxycholic acid, glycocholic acid (GCA), and tauroursodeoxycholic acid (TUDCA) levels were significantly higher, and serum lysophosphatidylethanolamine levels were significantly lower in DILI patients vs healthy controls ( P < .001). Furthermore, the SRM assay of bile acids revealed that the increase in GCA, taurocholic acid (TCA), TUDCA, glycochenodeoxycholic acid (GCDCA), glycochenodeoxycholic sulfate (GCDCS), and taurodeoxycholic acid (TDCA) corresponded to a higher degree of liver damage. These results also indicate that serum concentrations of chenodeoxycholic acid (CDCA), deoxycholic acid (DCA) and lithocholic acid (LCA) were significantly lower in patients with severe DILI, when compared to healthy controls, and that this decrease was closely correlated to the severity of liver damage.

Taken together, these results demonstrate that bile acids could serve as potential biomarkers for the early diagnosis and severity of DILI.

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Most cited references 36

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Pharmaco-metabonomic phenotyping and personalized drug treatment.

T Clayton, John C. Lindon, Olivier Cloarec … (2006)

There is a clear case for drug treatments to be selected according to the characteristics of an individual patient, in order to improve efficacy and reduce the number and severity of adverse drug reactions. However, such personalization of drug treatments requires the ability to predict how different individuals will respond to a particular drug/dose combination. After initial optimism, there is increasing recognition of the limitations of the pharmacogenomic approach, which does not take account of important environmental influences on drug absorption, distribution, metabolism and excretion. For instance, a major factor underlying inter-individual variation in drug effects is variation in metabolic phenotype, which is influenced not only by genotype but also by environmental factors such as nutritional status, the gut microbiota, age, disease and the co- or pre-administration of other drugs. Thus, although genetic variation is clearly important, it seems unlikely that personalized drug therapy will be enabled for a wide range of major diseases using genomic knowledge alone. Here we describe an alternative and conceptually new 'pharmaco-metabonomic' approach to personalizing drug treatment, which uses a combination of pre-dose metabolite profiling and chemometrics to model and predict the responses of individual subjects. We provide proof-of-principle for this new approach, which is sensitive to both genetic and environmental influences, with a study of paracetamol (acetaminophen) administered to rats. We show pre-dose prediction of an aspect of the urinary drug metabolite profile and an association between pre-dose urinary composition and the extent of liver damage sustained after paracetamol administration.

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The continuing importance of bile acids in liver and intestinal disease.

A F HOFMANN (2015)

Bile acids, the water-soluble, amphipathic end products of cholesterol metabolism, are involved in liver, biliary, and intestinal disease. Formed in the liver, bile acids are absorbed actively from the small intestine, with each molecule undergoing multiple enterohepatic circulations before being excreted. After their synthesis from cholesterol, bile acids are conjugated with glycine or taurine, a process that makes them impermeable to cell membranes and permits high concentrations to persist in bile and intestinal content. The relation between the chemical structure and the multiple physiological functions of bile acids is reviewed. Bile acids induce biliary lipid secretion and solubilize cholesterol in bile, promoting its elimination. In the small intestine, bile acids solubilize dietary lipids promoting their absorption. Bile acids are cytotoxic when present in abnormally high concentrations. This may occur intracellularly, as occurs in the hepatocyte in cholestasis, or extracellularly, as occurs in the colon in patients with bile acid malabsorption. Disturbances in bile acid metabolism can be caused by (1) defective biosynthesis from cholesterol or defective conjugation, (2) defective membrane transport in the hepatocyte or ileal enterocyte, (3) defective transport between organs or biliary diversion, and (4) increased bacterial degradation during enterohepatic cycling. Bile acid therapy involves bile acid replacement in deficiency states or bile acid displacement by ursodeoxycholic acid, a noncytotoxic bile acid. In cholestatic liver disease, administration of ursodeoxycholic acid decreases hepatocyte injury by retained bile acids, improving liver tests, and slowing disease progression. Bile acid malabsorption may lead to high concentrations of bile acids in the colon and impaired colonic mucosal function; bile acid sequestrants provide symptomatic benefit for diarrhea. A knowledge of bile acid physiology and the perturbations of bile acid metabolism in liver and digestive disease should be useful for the internist.

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Causality assessment of adverse reactions to drugs--II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge.

G Danan, A Flahault, C Merlet-Bénichou (1993)

Standards are lacking for validation of drug causality assessment methods. An original model is proposed using a positive rechallenge as an external standard. This model was used to validate the novel causality assessment method (RUCAM) described in the previous article (Part I; J Clin Epidemiol 1993; 46: 1323). Seventy seven reports of drug-induced acute liver injuries with positive rechallenge were collected from the medical literature and divided into 49 cases and 28 controls. The RUCAM was applied to information obtained prior to readministration. The score was significantly higher (p < 10(-4)) in cases than in controls with high levels of sensitivity, specificity and predictive values. It is concluded that (1) adverse drug reaction reports with a positive rechallenge can provide a standard for validation of causality assessment methods, (2) RUCAM applied to drug-induced liver injuries has been validated.

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Author and article information

Journal

Journal ID (nlm-ta): Medicine (Baltimore)

Journal ID (iso-abbrev): Medicine (Baltimore)

Journal ID (publisher-id): MEDI

Title: Medicine

Publisher: Wolters Kluwer Health

ISSN (Print): 0025-7974

ISSN (Electronic): 1536-5964

Publication date Collection: August 2019

Publication date (Electronic): 02 August 2019

Volume: 98

Issue: 31

Electronic Location Identifier: e16717

Affiliations

[a ]Department of Hepatology, the First Hospital of Jilin University, Changchun

[b ]Department of Hepatology, the Affiliated Hospital of Beihua University, Jilin

[c ]CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning, China.

Author notes

[∗ ]Correspondence: Junqi Niu, The First Hospital of Jilin University, 71 Xinmin St, Changchun, Jilin 130000, China (e-mail: junqi_niu@ 123456163.com ); Guowang Xu, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, Liaoning 116023, China (e-mail: xugw@ 123456dicp.ac.cn ).

Article

Publisher ID: MD-D-18-07856 Accession ID: 16717

DOI: 10.1097/MD.0000000000016717

PMC ID: 6708818

PubMed ID: 31374067

SO-VID: 6f1c29b8-6813-4212-8d55-11380304bac3

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This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0

History

Date received : 25 October 2018

Date revision received : 08 July 2019

Date accepted : 11 July 2019

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Keywords: bile acid,biomarkers,drug induced liver injury,serum metabolic profiling,uhplc-ms/ms

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Keywords: bile acid, biomarkers, drug induced liver injury, serum metabolic profiling, uhplc-ms/ms

Serum metabolome and targeted bile acid profiling reveals potential novel biomarkers for drug-induced liver injury

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Journal of Circulating Biomarkers

Most cited references 36

Pharmaco-metabonomic phenotyping and personalized drug treatment.

The continuing importance of bile acids in liver and intestinal disease.

Causality assessment of adverse reactions to drugs--II. An original model for validation of drug causality assessment methods: case reports with positive rechallenge.

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