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Development and Validation of a Test to Identify Drugs That Cause Idiosyncratic Drug-Induced Liver Injury

  • Andreas Benesic
    Correspondence
    Reprint requests Address requests for reprints to: Andreas Benesic, MD, Department of Medicine 2, Liver Centre Munich, University Hospital Munich (KUM), Campus Großhadern, LMU Munich, Germany. fax: (49) 89-44007-6000.
    Affiliations
    Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany

    MetaHeps GmbH, Martinsried, Germany
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  • Isabelle Rotter
    Affiliations
    Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany
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  • Diana Dragoi
    Affiliations
    Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany

    MetaHeps GmbH, Martinsried, Germany
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  • Sabine Weber
    Affiliations
    Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany
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  • Marie-Luise Buchholtz
    Affiliations
    Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany

    Institute of Laboratory Medicine, University Hospital, Ludwig-Maximilians-Universität Munich, Germany
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  • Alexander L. Gerbes
    Affiliations
    Department of Internal Medicine 2, Liver Centre Munich, University Hospital Munich (Klinikum der Universität München), Campus Großhadern, Ludwig-Maximilians-Universität Munich, Germany
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Published:April 30, 2018DOI:https://doi.org/10.1016/j.cgh.2018.04.049

      Background & Aims

      Idiosyncratic drug-induced liver injury (iDILI) is one of the most challenging diagnoses in hepatology. It is frequently impossible to identify the agent that has caused iDILI in patients who take multiple medicines. We developed an in vitro method to identify drugs that cause liver injury in patients, based on drug toxicity to monocyte-derived hepatocyte-like (MH) cells from patient blood samples. We then collected data on patients who were re-exposed to drugs found to be toxic in the MH test to validate test performance.

      Methods

      We performed a prospective study of patients referred to the University Hospital in Munich, Germany, with acute liver injury believed to be caused by medications (300 patients were enrolled in the study and we present data from 40 patients with iDILI and re-exposure to implicated drugs). We collected data from patients on medical history, laboratory test and imaging results, findings from biopsy analyses, and medications taken. Blood samples were collected from all patients and MH cells were isolated and cultured for 10 days. MH cells were then incubated with drugs to which each patient had been exposed, and toxicity was measured based on release of lactate dehydrogenase. Agents found to be toxic to MH cells were considered as candidates for the cause of liver injury. Patients were followed up for up to 6 months after liver injury and data on drug re-exposures and subsequent liver damage within the following 3 to 24 months were associated with findings from MH tests.

      Results

      Our test identified 10 drugs that were toxic to MH cells from 13 patients (amoxicillin/clavulanate to cells from 2 patients; diclofenac to cells from 2 patients; methylprednisolone to cells from 2 patients; and atorvastatin, metamizole, pembrolizumab, piperacillin/tazobactam, moxifloxacin, duloxetine, or sertraline each to cells from 1 patient). Thirteen patients had a recurrence of liver injury after inadvertent re-exposure to a single drug, and the MH test correctly identified 12 of the 13 drugs that caused these liver re-injury events. All 86 drugs that were not toxic to MH cells in our assay were safely resumed by patients and were not associated with liver re-injury in 27 patients. Therefore, the MH test identifies drugs that cause liver injury with 92.3% sensitivity and 100% specificity (1 false-negative and 12 true-positive results).

      Conclusions

      We developed a test to identify drugs that cause liver injury in patients based on their toxicity to MH cells isolated from patients with DILI. We validated results from the assay and found it to identify drugs that cause DILI with 92.3% sensitivity and 100% specificity. The MH cell test could be a tool to identify causes of iDILI, even in patients taking multiple medications. ClinicalTrials.gov no: NCT 02353455.

      Keywords

      Abbreviations used in this paper:

      DILI (drug-induced liver injury), iDILI (idiosyncratic drug-induced liver injury), MH cells (monocyte-derived hepatocyte-like cells), RUCAM (Roussel Uclaf Causality Assessment Method), ULN (upper limit of normal)
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        Clinical Gastroenterology and HepatologyVol. 17Issue 5
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          Benesic A, Rotter I, Dragoi D, et al. Development and validation of a test to identify drugs that cause idiosyncratic drug-induced liver injury. Clin Gastroenterol Hepatol 2018;16:1488–1494.
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