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Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury.

ABSTRACT: BACKGROUND & AIMS:The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls. METHODS:An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candidate proteins together with proposed DILI biomarker candidates generated a DILI array of 251 proteins for subsequent target analysis and verifications. In total, 1196 samples from 241 individuals across four independent cohorts were profiled: healthy volunteers receiving acetaminophen, patients with human immunodeficiency virus and/or tuberculosis receiving treatment, DILI cases originating from a wide spectrum of drugs, and healthy volunteers receiving heparins. RESULTS:We observed elevated levels of cadherin 5, type 2 (CDH5) and fatty acid-binding protein 1 (FABP1) in DILI cases. In the two longitudinal cohorts, CDH5 was elevated already at baseline. FABP1 was elevated after treatment initiation and seemed to respond more rapidly than alanine aminotransferase (ALT). The elevations were verified in the DILI cases treated with various drugs. In the heparin cohort, CDH5 was stable over time whereas FABP1 was elevated. CONCLUSIONS:These results suggest that CDH5 may have value as a susceptibility marker for DILI. FABP1 was identified as a biomarker candidate with superior characteristics regarding tissue distribution and kinetics compared to ALT but likely with limited predictive value for the development of severe DILI. Further studies are needed to determine the clinical utility of the proposed markers.

SUBMITTER: Mikus M

PROVIDER: S-EPMC5215406 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury.

Mikus Maria M Drobin Kimi K Gry Marcus M Bachmann Julie J Lindberg Johan J Yimer Getnet G Aklillu Eleni E Makonnen Eyasu E Aderaye Getachew G Roach James J Fier Ian I Kampf Caroline C Göpfert Jens J Perazzo Hugo H Poynard Thierry T Stephens Camilla C Andrade Raúl J RJ Lucena M Isabel MI Arber Nadir N Uhlén Mathias M Watkins Paul B PB Schwenk Jochen M JM Nilsson Peter P Schuppe-Koistinen Ina I

Liver international : official journal of the International Association for the Study of the Liver 20160622 1

<h4>Background & aims</h4>The occurrence of drug-induced liver injury (DILI) is a major issue in all phases of drug development. To identify novel biomarker candidates associated with DILI, we utilised an affinity proteomics strategy, where antibody suspension bead arrays were applied to profile plasma and serum samples from human DILI cases and controls.<h4>Methods</h4>An initial screening was performed using 4594 randomly selected antibodies, representing 3450 human proteins. Resulting candida ...[more]

PMID: 27224670

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Project description:Acetaminophen (APAP)-induced acute liver failure (ALF) is associated with significant mortality. Traditional prognostic scores lack sensitivity. Serum liver-type fatty acid binding protein (FABP1) early (day 1) or late (day 3-5) levels are associated with 21-day mortality in the absence of liver transplant. Serum samples from 198 APAP-ALF patients (nested case-control study with 99 survivors, 99 nonsurvivors) were analyzed by enzyme-linked immunosorbent assay with clinical data from the US Acute Liver Failure Study Group registry (1998-2014). APAP-ALF survivors had significantly lower serum FABP1 levels early (238.6 versus 690.8 ng/mL, P < 0.0001) and late (148.4 versus 612.3 ng/mL, P < 0.0001) compared with nonsurvivors. FABP1 > 350 ng/mL was associated with significantly higher risk of death at early (P = 0.0004) and late (P < 0.0001) time points. Increased serum FABP1 early (log FABP1 odds ratio = 1.31, P = 0.027) and late (log FABP1 odds ratio = 1.50, P = 0.005) were associated with significantly increased 21-day mortality after adjusting for significant covariates (Model for End-Stage Liver Disease, vasopressor use). Areas under the receiver operating characteristic curve for early and late multivariable models were 0.778 and 0.907, respectively. The area under the receiver operating characteristic curve of the King's College criteria (early, 0.552 alone, 0.711 with FABP1; late, 0.604 alone, 0.797 with FABP1) and the Acute Liver Failure Study Group prognostic index (early, 0.686 alone, 0.766 with FABP1; late, 0.711 alone, 0.815 with FABP1) significantly improved with the addition of FABP1 (P < 0.002 for all).ConclusionIn patients with APAP-ALF, FABP1 may have good potential to discriminate survivors from nonsurvivors and may improve models currently used in clinical practice; validation of FABP1 as a clinical prediction tool in APAP-ALF warrants further investigation. (Hepatology 2017;65:938-949).

Dataset Information

Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury.

Publications

Elevated levels of circulating CDH5 and FABP1 in association with human drug-induced liver injury.

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