Z Gastroenterol 2018; 56(08): e250
DOI: 10.1055/s-0038-1668785
Kurzvorträge
Leber und Galle
Leber: Fibrose, Steatose, Speicherkrankheiten – Donnerstag, 13. September 2018, 09:50 – 11:18, 22a
Georg Thieme Verlag KG Stuttgart · New York

A potential novel biomarker for Drug-induced Liver Injury by Diclofenac identified by the combination of MH cells and proteomics

A Benesic
1   Klinikum der LMU München-Grosshadern, Medizinische Klinik 2, München, Deutschland
,
D Dragoi
2   MetaHeps GmbH, Martinsried, Deutschland
,
G Pichler
3   Max-Planck-Institut für Biochemie, Proteomics und Signaltransduktion, Martinsried, Deutschland
,
N Kulak
4   Max-Planck-Institut für Biochemie, Signaltransduktion und Proteomics, Martinsried, Deutschland
,
H Bartsch
5   Klinikum der LMU München-Grosshadern, Institut für Pathologie, München, Deutschland
,
A Gerbes
1   Klinikum der LMU München-Grosshadern, Medizinische Klinik 2, München, Deutschland
› Author Affiliations
Further Information

Publication History

Publication Date:
13 August 2018 (online)

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Background and aims:

Drug-induced liver injury (DILI) is the most frequent cause of acute liver failure and the single most important reason for regulatory actions on drugs. Idiosyncratic DILI (iDILI) is not predictable by pre-clinical models and its diagnosis is very challenging. Drug causality may be impossible to determine in polymedicated patients. These difficulties in case characterization impede with efficient development of novel iDILI biomarkers. We have developed a method to diagnose or exclude iDILI using hepatocyte-like cells derived from peripheral monocytes (MH cells) which can improve causality assessment in polymedication. Aim of this study was to investigate whether proteomics analyses of patient derived MH cells allow the identification of novel specific iDILI biomarkers.

Method:

MH cells were generated from 22 donors (study NCT02353455): 12 exposed to diclofenac (3 diclofenac tolerators, 4 patients with iDILI by diclofenac, 2 patients with iDILI by another drug and 3 patients with acute liver injury (ALI) of non-drug cause). 10 patients without diclofenac intake were used as additional controls (3 healthy, 4 iDILI by other drugs and 3 ALI patients). MH cells were treated with diclofenac in vitro and analysis of MH cells was performed using mass spectrometry (MS)- based proteomics. From over 2700 proteins that could be quantified in MH cells derived from individual patients, we identified Integrin Beta 3 (ITGB3) to be specifically upregulated in Diclofenac-treated MH cells from Diclofenac-DILI patients compared to control groups.

Results:

Flow cytometry of whole blood and histological staining of liver biopsies derived from additional patients diagnosed with Diclofenac-DILI showed distinct changes of ITGB3 in Diclofenac-DILI.

Conclusion:

ITGB3 as identified biomarker candidate showed distinct changes in blood samples and liver biopsies from patients with diclofenac DILI. The combination of MH cells and MS-based proteomics may present a novel tool to identify drug-specific biomarkers for iDILI.