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Drug-induced liver injury: recent advances in diagnosis and risk assessment

Kullak-Ublick, Gerd A, Andrade, Raul J, Merz, Michael, End, Peter, Benesic, Andreas, Gerbes, Alexander L, Aithal, Guruprasad P·2017·Gut
DOI 10.1136/gutjnl-2016-313369PMC PMC5532458
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Abstract

Idiosyncratic drug-induced liver injury (IDILI) is a rare but potentially severe adverse drug reaction that should be considered in patients who develop laboratory criteria for liver injury secondary to the administration of a potentially hepatotoxic drug. Although currently used liver parameters are sensitive in detecting DILI, they are neither specific nor able to predict the patient's subsequent clinical course. Genetic risk assessment is useful mainly due to its high negative predictive value, with several human leucocyte antigen alleles being associated with DILI. New emerging biomarkers which could be useful in assessing DILI include total keratin18 (K18) and caspase-cleaved keratin18 (ccK18), macrophage colony-stimulating factor receptor 1, high mobility group box 1 and microRNA-122. From the numerous in vitro test systems that are available, monocyte-derived hepatocytes generated from patients with DILI show promise in identifying the DILI-causing agent from among a panel of coprescribed drugs. Several computer-based algorithms are available that rely on cumulative scores of known risk factors such as the administered dose or potential liabilities such as mitochondrial toxicity, inhibition of the bile salt export pump or the formation of reactive metabolites. A novel DILI cluster score is being developed which predicts DILI from multiple complimentary cluster and classification models using absorption–distribution–metabolism–elimination-related as well as physicochemical properties, diverse substructural descriptors and known structural liabilities. The provision of more advanced scientific and regulatory guidance for liver safety assessment will depend on validating the new diagnostic markers in the ongoing DILI registries, biobanks and public–private partnerships.

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Figure 1 Impact of idiosyncratic drug-induced liver injury (IDILI) on drug attrition. Pie charts showing the occurrence of liver test abnormalities in clinical trials with drugs withdrawn or stopped due to DILI. Blue: percentage of study participants with normal liver tests and Red: percentage of patients with possibly drug-related liver enzyme elevations.
Figure 1 Impact of idiosyncratic drug-induced liver injury (IDILI) on drug attrition. Pie charts showing the occurrence of liver test abnormalities in clinical trials with drugs withdrawn or stopped due to DILI. Blue: percentage of study participants with normal liver tests and Red: percentage of patients with possibly drug-related liver enzyme elevations.CC BY-NC · PubMed Central
Figure 2 Roussel-Uclaf Causality Assessment Method (RUCAM) diagnostic score.
Figure 2 Roussel-Uclaf Causality Assessment Method (RUCAM) diagnostic score.CC BY-NC · PubMed Central
Figure 3 Flow diagram of diagnostic workup of drug-induced liver injury (DILI). The phenotypes of liver injury are categorised according to the R value, defined as the ratio ALT/ULN:ALP/ULN. An R value of ≥5 indicates hepatocellular injury, ≤2 cholestatic injury and 2–5 mixed-type injury. ALP, alkaline phosphatase; ALT, alanine aminotransferase; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HC, hepatocellular; HDSs, herbal and dietary supplements; OTC, over-the-counter drugs; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; ULN, upper limit of normal.
Figure 3 Flow diagram of diagnostic workup of drug-induced liver injury (DILI). The phenotypes of liver injury are categorised according to the R value, defined as the ratio ALT/ULN:ALP/ULN. An R value of ≥5 indicates hepatocellular injury, ≤2 cholestatic injury and 2–5 mixed-type injury. ALP, alkaline phosphatase; ALT, alanine aminotransferase; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HC, hepatocellular; HDSs, herbal and dietary supplements; OTC, over-the-counter drugs; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; ULN, upper limit of normal.CC BY-NC · PubMed Central
Figure 4 (A) Example for a monocyte-derived hepatocyte-like (MH) cell test result from a patient with acute liver injury during treatment with sunitinib (for renal cell carcinoma), phenprocoumon (for atrial fibrillation) and metformin (for diabetes type II). MH cell toxicity is shown in a spiderweb graph. Sunitinib exerts marked toxicity in MH cells of this patient, whereas phenprocoumon and metformin do not show any effects. The red circle represents the individual cut-off for test positivity. (B) MH cell test results in 31 patients with idiosyncratic drug-induced liver injury (IDILI) and 23 patients with acute liver injury of other origin (non-DILI) using the drugs most likely to have caused liver injury in these cases. The MH cell test correctly identifies 29 of the 31 IDILI cases and shows no false-positive results. (C) MH cell test results using all drugs involved in the IDILI cases. Only four of the 84 comedications show positive results, suggesting that the MH cell test could be useful to identify the causative drug in complex IDILI cases. TWEEN, polyethylene glycol sorbitan monolaurate; ULN, upper limit of normal.
Figure 4 (A) Example for a monocyte-derived hepatocyte-like (MH) cell test result from a patient with acute liver injury during treatment with sunitinib (for renal cell carcinoma), phenprocoumon (for atrial fibrillation) and metformin (for diabetes type II). MH cell toxicity is shown in a spiderweb graph. Sunitinib exerts marked toxicity in MH cells of this patient, whereas phenprocoumon and metformin do not show any effects. The red circle represents the individual cut-off for test positivity. (B) MH cell test results in 31 patients with idiosyncratic drug-induced liver injury (IDILI) and 23 patients with acute liver injury of other origin (non-DILI) using the drugs most likely to have caused liver injury in these cases. The MH cell test correctly identifies 29 of the 31 IDILI cases and shows no false-positive results. (C) MH cell test results using all drugs involved in the IDILI cases. Only four of the 84 comedications show positive results, suggesting that the MH cell test could be useful to identify the causative drug in complex IDILI cases. TWEEN, polyethylene glycol sorbitan monolaurate; ULN, upper limit of normal.CC BY-NC · PubMed Central
Figure 5 Interaction between drugs and human leucocyte antigen (HLA) molecule leading to an adaptive immune response. (A) Hapten hypothesis: drug–protein adducts (blue circles with red semicircle) released from dying hepatocytes are phagocytosed by antigen-presenting cells (APCs) and presented with major histocompatibility complex (MHC) II molecules. These hapten–carrier complexes bind to the peptide-binding groove on T cell receptors, leading to CD4+ cell activation and an effector T cell response. (B) Pharmacological interaction concept: drugs or metabolites can bind to HLA molecules directly and activate T cells. (C) Altered repertoire model: drug changes the shape and chemistry of the antigen-binding cleft, altering the repertoire of endogenous peptides that subsequently bind; the ‘altered self’ activates drug-specific T cells. (D) CD8+ cells recognise drug–protein adducts on the plasma membrane of hepatocytes when presented with MHC I molecules, leading to immunological destruction of hepatocytes.
Figure 5 Interaction between drugs and human leucocyte antigen (HLA) molecule leading to an adaptive immune response. (A) Hapten hypothesis: drug–protein adducts (blue circles with red semicircle) released from dying hepatocytes are phagocytosed by antigen-presenting cells (APCs) and presented with major histocompatibility complex (MHC) II molecules. These hapten–carrier complexes bind to the peptide-binding groove on T cell receptors, leading to CD4+ cell activation and an effector T cell response. (B) Pharmacological interaction concept: drugs or metabolites can bind to HLA molecules directly and activate T cells. (C) Altered repertoire model: drug changes the shape and chemistry of the antigen-binding cleft, altering the repertoire of endogenous peptides that subsequently bind; the ‘altered self’ activates drug-specific T cells. (D) CD8+ cells recognise drug–protein adducts on the plasma membrane of hepatocytes when presented with MHC I molecules, leading to immunological destruction of hepatocytes.CC BY-NC · PubMed Central

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Metadata

Authors
Kullak-Ublick, G. A., Andrade, R. J., Merz, M., End, P., Benesic, A., Gerbes, A. L., & Aithal, G. P.
Affiliations
  • Department of Clinical Pharmacology and Toxicology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
  • Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga-IBIMA, Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Málaga, Spain
  • Novartis Institutes for BioMedical Research, Novartis Campus, Basel, Switzerland
  • Department of Medicine II, Klinikum Grosshadern of the University of Munich (KUM), University of Munich, Munich, Germany
  • National Institute for Health Research (NIHR), Nottingham Digestive Diseases Biomedical Research Unit, Nottingham University Hospitals NHS Trust and the University of Nottingham, Nottingham, UK
ORCID
Benesic, Andreas
Venue
Gut
Publisher
BMJ
Published
2017-03-23
Volume
66
Issue
6
Pages
1154-1164
ISSN
  • 0017-5749
  • 1468-3288
DOI
10.1136/gutjnl-2016-313369
PMC
PMC5532458
Cited by
438
References
9
Language
en
Funders
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (320030_144193)

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