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Monocyte-derived hepatocyte-like cells for causality assessment of idiosyncratic drug-induced liver injury.

Abstract

BACKGROUND

Idiosyncratic drug-induced liver injury (iDILI) is a frequent cause of acute liver injury and a serious problem in late stage drug-development. Its diagnosis is one of the most challenging in hepatology, since it is done by exclusion and relies on expert opinion. Until now no reliable in vitro test exists to support the diagnosis of iDILI. In some instances it is impossible to determine the causative drug in polymedicated patients.

AIM

To investigate if monocyte-derived hepatocyte-like (MH) cells might be a tool supporting clinical judgment for iDILI diagnosis and causality assessment.

METHODS

This prospective study included 54 patients with acute liver injury and intake of at least one drug. Thirty-one patients were diagnosed with iDILI based on causality likelihood. MH cells were generated from every patient and in vitro toxicity of the respective drugs was assessed by lactate-dehydrogenase release. The results from MH cells and RUCAM, the most widely used scoring system as methods to support clinical judgement were compared.

RESULTS

MH cells showed enhanced toxicity in 29 of the 31 patients with iDILI, similar to RUCAM score. MH cells exhibited negative results in the 23 non-DILI cases, whereas RUCAM indicated possible iDILI in six cases. Analysis of the comedications also showed superior specificity of MH cells. No MH cell toxicity of the drugs showing toxicity in patients with iDILI was observed in MH cells of healthy donors.

CONCLUSIONS

In this pilot study in vitro testing using MH cells derived from patients with acute liver injury was able to identify patients with iDILI with an excellent sensitivity and a higher specificity than RUCAM, the most widely used current causality assessment score. Therefore, MH cells could be useful to identify the causative drugs even in polymedicated patients by adding objective data to causality assessment.

TRIAL REGISTRATION NUMBER

NCT02353455.

Links

  • Publisher Full Text
  • Authors+Show Affiliations

    ,

    Liver Center Munich, Department of Internal Medicine II, University Hospital Munich, Campus Grosshadern, Munich, Germany MetaHeps GmbH, Planegg/Martinsried, Germany.

    ,

    Liver Center Munich, Department of Internal Medicine II, University Hospital Munich, Campus Grosshadern, Munich, Germany.

    Liver Center Munich, Department of Internal Medicine II, University Hospital Munich, Campus Grosshadern, Munich, Germany.

    Source

    Gut 65:9 2016 09 pg 1555-63

    MeSH

    Causality
    Chemical and Drug Induced Liver Injury
    Dietary Supplements
    Female
    Germany
    Hepatocytes
    Humans
    Liver Function Tests
    Macrophages
    Male
    Middle Aged
    Pilot Projects
    Plant Preparations
    Prescription Drugs
    Prospective Studies
    Reproducibility of Results
    Sensitivity and Specificity

    Pub Type(s)

    Clinical Trial
    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    26045135

    Citation

    Benesic, Andreas, et al. "Monocyte-derived Hepatocyte-like Cells for Causality Assessment of Idiosyncratic Drug-induced Liver Injury." Gut, vol. 65, no. 9, 2016, pp. 1555-63.
    Benesic A, Leitl A, Gerbes AL. Monocyte-derived hepatocyte-like cells for causality assessment of idiosyncratic drug-induced liver injury. Gut. 2016;65(9):1555-63.
    Benesic, A., Leitl, A., & Gerbes, A. L. (2016). Monocyte-derived hepatocyte-like cells for causality assessment of idiosyncratic drug-induced liver injury. Gut, 65(9), pp. 1555-63. doi:10.1136/gutjnl-2015-309528.
    Benesic A, Leitl A, Gerbes AL. Monocyte-derived Hepatocyte-like Cells for Causality Assessment of Idiosyncratic Drug-induced Liver Injury. Gut. 2016;65(9):1555-63. PubMed PMID: 26045135.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Monocyte-derived hepatocyte-like cells for causality assessment of idiosyncratic drug-induced liver injury. AU - Benesic,Andreas, AU - Leitl,Alexandra, AU - Gerbes,Alexander L, Y1 - 2015/06/04/ PY - 2015/03/06/received PY - 2015/05/08/accepted PY - 2015/6/6/entrez PY - 2015/6/6/pubmed PY - 2017/7/1/medline KW - DRUG DEVELOPMENT KW - DRUG INDUCED LIVER INJURY KW - DRUG TOXICITY KW - HEPATOCYTE KW - LIVER SP - 1555 EP - 63 JF - Gut JO - Gut VL - 65 IS - 9 N2 - BACKGROUND: Idiosyncratic drug-induced liver injury (iDILI) is a frequent cause of acute liver injury and a serious problem in late stage drug-development. Its diagnosis is one of the most challenging in hepatology, since it is done by exclusion and relies on expert opinion. Until now no reliable in vitro test exists to support the diagnosis of iDILI. In some instances it is impossible to determine the causative drug in polymedicated patients. AIM: To investigate if monocyte-derived hepatocyte-like (MH) cells might be a tool supporting clinical judgment for iDILI diagnosis and causality assessment. METHODS: This prospective study included 54 patients with acute liver injury and intake of at least one drug. Thirty-one patients were diagnosed with iDILI based on causality likelihood. MH cells were generated from every patient and in vitro toxicity of the respective drugs was assessed by lactate-dehydrogenase release. The results from MH cells and RUCAM, the most widely used scoring system as methods to support clinical judgement were compared. RESULTS: MH cells showed enhanced toxicity in 29 of the 31 patients with iDILI, similar to RUCAM score. MH cells exhibited negative results in the 23 non-DILI cases, whereas RUCAM indicated possible iDILI in six cases. Analysis of the comedications also showed superior specificity of MH cells. No MH cell toxicity of the drugs showing toxicity in patients with iDILI was observed in MH cells of healthy donors. CONCLUSIONS: In this pilot study in vitro testing using MH cells derived from patients with acute liver injury was able to identify patients with iDILI with an excellent sensitivity and a higher specificity than RUCAM, the most widely used current causality assessment score. Therefore, MH cells could be useful to identify the causative drugs even in polymedicated patients by adding objective data to causality assessment. TRIAL REGISTRATION NUMBER: NCT02353455. SN - 1468-3288 UR - https://www.unboundmedicine.com/medline/citation/26045135/Monocyte_derived_hepatocyte_like_cells_for_causality_assessment_of_idiosyncratic_drug_induced_liver_injury_ L2 - http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=26045135 DB - PRIME DP - Unbound Medicine ER -