Drug Hepatotoxicity

Mapping Intimacies ◽

10.2310/gastro.14006 ◽

2018 ◽

Author(s):

Fernando Bessone ◽

Raúl J Andrade

Keyword(s):

Immune System ◽

Liver Injury ◽

Liver Failure ◽

Acute Liver Failure ◽

Causality Assessment ◽

Adaptive Immune System ◽

Genome Wide Association Studies ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Adaptive Immune

Idiosyncratic drug-induced liver injury (DILI) caused by xenobiotics (drugs, herbals, and dietary supplements) is an elusive liver disease presenting with a range of phenotypes and severity, including acute hepatitis that is indistinguishable from viral hepatitis, autoimmune hepatitis, steatosis, fibrosis or rare chronic vascular syndromes, asymptomatic liver test abnormalities,and acute liver failure. Case definition and characterization using liver biochemistry and histology are crucial for appropriate phenotyping. The incidence of DILI is probably higher than expected by the cases that are identified in clinical practice because of misdiagnosis and underreporting.The pathogenesis of DILI is complex, depending on the interaction of a drug’s physicochemical properties and host factors. Genome-wide association studies have identified several alleles from the major histocompatibility complex system, indicating a fundamental role of the adaptive immune system in DILI pathogenesis. As specific biomarkers for hepatotoxicity are still not available, the diagnosis of DILI remains one of exclusion of the alternative causes of liver damage. Structured causality assessment using the Roussel Uclaf Causality Assessment Method (RUCAM) or previously Council for International Organizations of Medical Sciences (CIOMS) instrument adds consistency to the diagnostic process, although there is room for improvement in the scale domains and score weighting. The therapy for idiosyncratic hepatotoxicity is supportive and relies on the prompt withdrawal of the offending agent. Corticosteroid therapy for hypersensitivity reactions or ursodeoxycholicacid for prolonged cholestasis is empirically used, although the degree of evidence is low. Existing databases have enabled a better prediction of immediate and long-term DILI prognosis. Multivariate models have identified clinical and analytical variables as predictive of acute liver failure and mortality as well as of chronic DILI. This review contains 2 figures, 5 tables, and 55 references Key Words: adaptive immune system; causality assessment; drug-induced liver injury; epidemiology; HLA alleles; pharmacogenetics; registries; risk factors

Download Full-text

Drug Hepatotoxicity

10.2310/im.14006 ◽

2018 ◽

Author(s):

Fernando Bessone ◽

Raúl J Andrade

Keyword(s):

Immune System ◽

Liver Injury ◽

Liver Failure ◽

Acute Liver Failure ◽

Causality Assessment ◽

Adaptive Immune System ◽

Genome Wide Association Studies ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Adaptive Immune

Idiosyncratic drug-induced liver injury (DILI) caused by xenobiotics (drugs, herbals, and dietary supplements) is an elusive liver disease presenting with a range of phenotypes and severity, including acute hepatitis that is indistinguishable from viral hepatitis, autoimmune hepatitis, steatosis, fibrosis or rare chronic vascular syndromes, asymptomatic liver test abnormalities,and acute liver failure. Case definition and characterization using liver biochemistry and histology are crucial for appropriate phenotyping. The incidence of DILI is probably higher than expected by the cases that are identified in clinical practice because of misdiagnosis and underreporting.The pathogenesis of DILI is complex, depending on the interaction of a drug’s physicochemical properties and host factors. Genome-wide association studies have identified several alleles from the major histocompatibility complex system, indicating a fundamental role of the adaptive immune system in DILI pathogenesis. As specific biomarkers for hepatotoxicity are still not available, the diagnosis of DILI remains one of exclusion of the alternative causes of liver damage. Structured causality assessment using the Roussel Uclaf Causality Assessment Method (RUCAM) or previously Council for International Organizations of Medical Sciences (CIOMS) instrument adds consistency to the diagnostic process, although there is room for improvement in the scale domains and score weighting. The therapy for idiosyncratic hepatotoxicity is supportive and relies on the prompt withdrawal of the offending agent. Corticosteroid therapy for hypersensitivity reactions or ursodeoxycholicacid for prolonged cholestasis is empirically used, although the degree of evidence is low. Existing databases have enabled a better prediction of immediate and long-term DILI prognosis. Multivariate models have identified clinical and analytical variables as predictive of acute liver failure and mortality as well as of chronic DILI. This review contains 2 figures, 5 tables and 55 references Key Words: adaptive immune system;causality assessment;drug-induced liver injury; epidemiology; HLA alleles; pharmacogenetics; registries; risk factors

Download Full-text

Drug-Drug Combinations Can Enhance Toxicity as Shown by Monocyte-Derived Hepatocyte-like Cells From Patients With Idiosyncratic Drug-Induced Liver Injury

Toxicological Sciences ◽

10.1093/toxsci/kfz156 ◽

2019 ◽

Vol 171 (2) ◽

pp. 296-302 ◽

Cited By ~ 2

Author(s):

Andreas Benesic ◽

Kowcee Jalal ◽

Alexander L Gerbes

Keyword(s):

Liver Injury ◽

Liver Failure ◽

Drug Interactions ◽

Acute Liver Failure ◽

Causality Assessment ◽

Drug Combinations ◽

Positive Interactions ◽

In Vitro Test ◽

Drug Induced ◽

Drug Induced Liver Injury

Abstract Drug-induced liver injury (DILI) is a major cause for acute liver failure and regulatory actions on novel drugs. Individual patient characteristics are the main determinant of idiosyncratic DILI, making idiosyncratic DILI (iDILI) one of the most challenging diagnoses in hepatology. Individual drug-drug interactions might play a role in iDILI. However, the current approaches to iDILI diagnosis are focused on single drugs as causative agents. For the present analysis, 48 patients with acute liver injury who took 2 drugs and who were diagnosed as iDILI were investigated. A novel in vitro test was employed using monocyte-derived hepatocyte-like cells (MH cells) generated from these patients. iDILI diagnosis and causality were evaluated using clinical causality assessment supported by Roussel-Uclaf Causality Assessment Method. In 13 of these 48 patients (27%), combinations of drugs increased toxicity in the MH test when compared with the single drugs. Interestingly, whereas in 24 cases (50%) drug-drug combinations did not enhance toxicity, in 11 cases (23%) only the combinations caused toxicity. The incidence of severe cases fulfilling Hy’s law was higher in patients with positive interactions (57% vs 43%; p = .04), with acute liver failure occurring in 40% versus 8% (p = .01). The most common drug combinations causing increased toxicity were amoxicillin/clavulanate (8 of 9 cases) and diclofenac in combination with steroid hormones (4 of 9 cases). Drug-drug interactions may influence the incidence and/or the severity of idiosyncratic DILI. MH cell testing can identify relevant drug-drug interactions. The data generated by this approach may improve patient safety. Study identifier ClinicalTrials.gov NCT 02353455.

Download Full-text

Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges

International Journal of Molecular Sciences ◽

10.3390/ijms22062954 ◽

2021 ◽

Vol 22 (6) ◽

pp. 2954

Author(s):

Alison Jee ◽

Samantha Christine Sernoskie ◽

Jack Uetrecht

Keyword(s):

Immune Response ◽

Immune System ◽

T Cell ◽

Liver Injury ◽

Clinical Manifestations ◽

Adaptive Immune System ◽

Human Leukocyte ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Adaptive Immune

Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the adaptive immune system; one example being the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature of these reactions. The T cell receptor repertoire likely also contributes to the idiosyncratic nature. Although most of the liver injury is likely mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation first requires an innate immune response to activate antigen presenting cells and produce cytokines required for T cell proliferation. This innate response is likely caused by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it possible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, such as mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most cases, it is likely that they are also involved in the initiation of an immune response rather than representing a completely separate mechanism. Using the clinical manifestations of liver injury from a number of examples of IDILI-associated drugs, this review aims to summarize and illustrate these mechanistic hypotheses.

Download Full-text