Drug-induced liver injury
Drug-induced Liver Injury (DILI) is the most important cause for acute liver failure and a major risk in Drug development. In contrast to dose-dependent hepatotoxicity (e.g. acetaminophen [Paracetamol]), idiosyncratic DILI (iDILI) affects only susceptible patients (e.g. 1 in 10.000) after a latency from weeks to months without clear dose-dependence.
The diagnosis of iDILI relies on exclusion of other causes for liver injury (e.g. viral hepatitis, autoimmune diseases and metabolic liver diseases). Thus, iDILI is one of the most challenging diagnoses in hepatology and identification of the causative agent (causality assessment) may be impossible in polymedicated patients1,2.
The current gold standard for iDILI diagnosis and causality assessment is expert opinion supported by diagnostic scales such as CIOMS/RUCAM (see also: http://livertox.nih.gov/Causality.html).
- Expert opinion causality assessment is based on Exclusion of other causes
- Time course of liver injury in relation to drug therapy
- Drug “signature” (i.e. typical pattern of injury, if known)
- Response to re-challenge (Deliberate re-challenge is not recommended, typically this occurs inadvertently)
- Chalasani NP et al. Am J Gastroenterol. 2014; 109(7):950-66
- Teschke R et al. Ann Hepatol. 2014 Mar-Apr;13(2):248-55.
Our research focuses on a new model for in vitro toxicology:
MetaHeps® generated from peripheral blood monocytes is a personalized cell model allowing individual prediction of hepatotoxicity. A simple blood sample (10-20 ml) enables even the use in children and high availability ensures the application in virtually every patient.
These cells exhibit donor specific characteristics (http://www.ncbi.nlm.nih.gov/pubmed/22469698)
and seem to reflect individual susceptibilty to iDILI (http://www.ncbi.nlm.nih.gov/pubmed/26045135).
In our ongoing study we investigate the diagnostic value of MetaHeps® as a clinical tool to positively identify iDILI patients and the offending drugs in invdividual cases (https://clinicaltrials.gov/ct2/show/NCT02353455).
This work shall enable more exact characterisation of iDILI cases as well as causality assessment, finally allowing the identification of novel biomarkers for iDILI (Biomarker research in cooperation with Max-Planck-Institute for Biochemistry, Prof. Mann. Funded by m4-Award of the Bavarian State Ministry of Technology).
By identifying and protecting patients at risk for DILI, MetaHeps can save lives, ensure innovation and protect investments.
See also “Studies on iDILI”
Translational Safety Biomarker Pipeline (TransBioLine) Project, a five-year program to generate exploratory and confirmatory data supporting regulatory qualification and acceptance of novel safety biomarkers for five target organ systems (kidney, liver, pancreas, vascular and central nervous system) for application in drug development
Cells of Monocytic Origin as Surrogate Markers for Individual Drug Effects and Hepatotoxicity
Prospective European Drug-Iinduced Liver Injury Registry – PRO-EURO-DILI REGISTRY
Personalized Liver Protection (PerLiPro) funded by m4-Award (STMWiVT Grant No. 1330/68362/34/2013)
Aim: Use of MetaHeps® to discover novel iDILI biomarkers
Benesic A and Gerbes AL
Drug-induced Liver Injury and individual cell models. Digestive Diseases (2015); 33(4) 2015
Benesic A, Leitl, A and Gerbes AL
Monocyte-derived hepatocyte-like cells for causality assessment of idiosyncratic drug-induced liver injury. Gut (2015) online first June 4 2015; Gut doi-10.1136: gutjnl-2015-309528
Benesic A, Rahm NL, Ernst S and Gerbes AL
Human monocyte-derived cells with individual hepatocyte characteristics: a novel tool for personalized in vitro studies. Laboratory Investigation (2012) 92, 926–936; doi:10.1038/labinvest.2012.64; published online 2 April 2012
Gerbes AL, Zoulim F, Tilg H, Dufour JF, Bruix J, Paradis V, Salem R, Peck-Radosavljevic M, Galle PR, Greten TF, Nault JC, Avila MA.
Gut roundtable meeting paper: selected recent advances in hepatocellular carcinoma. Gut 2018; 67:380-388.
Benesic A, Rotter I, Dragoi D, Weber S, Buchholtz M, Gerbes AL.
Development and validation of a test to identify drugs that cause idiosyncratic drug-induced liver injury. Clin Gastro Hep 2018; 16(9):1488-1494.e5.
Dragoi D, Benesic A, Pichler G, Kulak NA, Bartsch HS, Gerbes AL.
Proteomics analysis of Monocyte-Derived Hepatocyte-Like Cells Identifies Integrin Beta 3 as a Specific Biomarker for Drug-Induced Liver Injury by Diclofenac. Frontiers in Pharmacology 2018; Jul 4;9:699, doi: 10.3389/fphar.2018.00699
Weber S, Benesic A, Rotter I, Gerbes AL.
Early ALT response to corticosteroid treatment distinguishes idiosyncratic Drug-induced Liver Injury from Autoimmune Hepatitis. Liver International 2019, published. doi:10.1111/liv.14195
Benesic A, Jalal K, Gerbes AL.
Drug-Drug Combinations can Enhance Toxicity as shown by Monocyte-Derived Hepatocyte-like Cells from Patients with Idiosyncratic Drug-Induced Liver Injury. Toxicological Sciences, Volume 171, Issue 2, October 2019, Pages 296–302, https://doi.org/10.1093/toxsci/kfz156