scholarly journals Idiosyncratic Drug-Induced Liver Injury: Mechanistic and Clinical Challenges

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.

Drug Hepatotoxicity

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

Drug Hepatotoxicity

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

scholarly journals Inhibition of the Adaptive Immune Response following Drug‐Induced Liver Injury

2006 ◽  
Vol 20 (5) ◽  
Author(s):  
Mary Jane Masson ◽  
Christine J. Chung ◽  
Richard Peterson ◽  
Mary L. Graf ◽  
Jeffrey L Ambroso ◽  
...  
Keyword(s):  
Immune Response ◽  
Liver Injury ◽  
Adaptive Immune Response ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Adaptive Immune

Preface

Parasitology ◽  
1997 ◽  
Vol 115 (7) ◽  
pp. 3-3
Author(s):  
M. J. Doenhoff ◽  
L. H. Chappell
Keyword(s):  
Immune Response ◽  
Immune System ◽  
T Cell ◽  
Molecular Mimicry ◽  
Adaptive Immune System ◽  
T Cell Subsets ◽  
Survival Strategies ◽  
Molecular Component ◽  
Immunocompetent Host ◽  
Adaptive Immune

The papers in this volume draw attention to both new and recent information on the mechanisms employed by infectious pathogens to underpin their survival in the immunocompetent host and to facilitate their transmission between hosts. Classical survival strategies include induction of immuno- suppression, antigenic variety and variation, host antigen sequestration, molecular mimicry, antibody destruction and invasion of cells or privileged sites. To these we can now add novel and diverse mechanisms with which the invader may manipulate the host for its own ends. They range from making use of a single molecular component of the immune system, through more sophisticated mechanisms of evasion to modulation of the immune response in the pathogen's favour, particularly by manipulation of T cell subsets and cytokine fluxes. There are then examples of pure exploitation of the adaptive immune system by the generation of specific humoral and cell-mediated responses that prolong the invader's survival and aid transmission. The order of the chapters in this volume is intended to reflect this increasing level of complexity.It is our hope that the studies described in this multi-disciplinary assemblage of papers will stimulate further research in this important area. We would like to thank all our contributing authors and the anonymous refereees for their commitment and help in seeing this project through to completion.

scholarly journals The chemical, genetic and immunological basis of idiosyncratic drug–induced liver injury

2015 ◽  
Vol 34 (12) ◽  
pp. 1310-1317 ◽  
Author(s):  
A Tailor ◽  
L Faulkner ◽  
DJ Naisbitt ◽  
BK Park
Keyword(s):  
Liver Injury ◽  
Adaptive Immune System ◽  
Idiosyncratic Drug Reactions ◽  
Cellular Mechanisms ◽  
Drug Induced ◽  
Drug Induced Liver Injury ◽  
Chemical Genetic ◽  
Adaptive Immune ◽  
Drug Companies

Idiosyncratic drug reactions can be extremely severe and are not accounted for by the regular pharmacology of a drug. Thus, the mechanism of idiosyncratic drug–induced liver injury (iDILI), a phenomenon that occurs with many drugs including β-lactams, anti-tuberculosis drugs and non-steroidal anti-inflammatories, has been difficult to determine and remains a pressing issue for patients and drug companies. Evidence has shown that iDILI is multifactorial and multifaceted, which suggests that multiple cellular mechanisms may be involved. However, a common initiating event has been proposed to be the formation of reactive drug metabolites and covalently bound adducts. Although the fate of these metabolites are unclear, recent evidence has shown a possible link between iDILI and the adaptive immune system. This review highlights the role of reactive metabolites, the recent genetic innovations which have provided molecular targets for iDILI, and the current literature which suggests an immunological basis for iDILI.

scholarly journals Oxidative Stress in Drug-Induced Liver Injury (DILI): From Mechanisms to Biomarkers for Use in Clinical Practice

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 390
Author(s):  
Marina Villanueva-Paz ◽  
Laura Morán ◽  
Nuria López-Alcántara ◽  
Cristiana Freixo ◽  
Raúl J. Andrade ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Cell Death ◽  
Liver Injury ◽  
Molecular Mechanisms ◽  
Human Leukocyte ◽  
Metabolic Activation ◽  
Special Focus ◽  
Drug Induced ◽  
Drug Induced Liver Injury

Idiosyncratic drug-induced liver injury (DILI) is a type of hepatic injury caused by an uncommon drug adverse reaction that can develop to conditions spanning from asymptomatic liver laboratory abnormalities to acute liver failure (ALF) and death. The cellular and molecular mechanisms involved in DILI are poorly understood. Hepatocyte damage can be caused by the metabolic activation of chemically active intermediate metabolites that covalently bind to macromolecules (e.g., proteins, DNA), forming protein adducts—neoantigens—that lead to the generation of oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress, which can eventually lead to cell death. In parallel, damage-associated molecular patterns (DAMPs) stimulate the immune response, whereby inflammasomes play a pivotal role, and neoantigen presentation on specific human leukocyte antigen (HLA) molecules trigger the adaptive immune response. A wide array of antioxidant mechanisms exists to counterbalance the effect of oxidants, including glutathione (GSH), superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX), which are pivotal in detoxification. These get compromised during DILI, triggering an imbalance between oxidants and antioxidants defense systems, generating oxidative stress. As a result of exacerbated oxidative stress, several danger signals, including mitochondrial damage, cell death, and inflammatory markers, and microRNAs (miRNAs) related to extracellular vesicles (EVs) have already been reported as mechanistic biomarkers. Here, the status quo and the future directions in DILI are thoroughly discussed, with a special focus on the role of oxidative stress and the development of new biomarkers.

scholarly journals Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury

Gut ◽  
1997 ◽  
Vol 41 (4) ◽  
pp. 534-540 ◽  
Author(s):  
V A J Maria ◽  
R M M Victorino
Keyword(s):  
T Cell ◽  
Liver Injury ◽  
Mononuclear Cells ◽  
Diagnostic Value ◽  
Drug Induced ◽  
Cell Reactivity ◽  
Peripheral Blood Mononuclear ◽  
Drug Induced Liver Injury ◽  
Prostaglandin Inhibitor ◽  
T Cell Reactivity

Background—Diagnosis of drug induced liver injury is usually based on a temporal relation between drug intake and clinical picture as well as on the exclusion of alternative causes. More precise diagnosis has been attempted by using in vitro specific T cell reactivity to drugs but the test has never reached general acceptability because of frequent negative results which could be explained, in part, by prostaglandin producing suppressor cells (PPSC).Aim—To analyse the diagnostic value of a modified test where lymphocyte responses to drugs are detected in the presence of a prostaglandin inhibitor.Patients—Ninety five patients with a clinical diagnosis of drug induced liver injury, 106 healthy controls, 35 individuals with recent exposure to the same drugs without adverse effects, and 15 patients with liver disease unrelated to drugs.Methods—Peripheral blood mononuclear cells (PBMC) were cultured in the presence of drugs alone and in the presence of drugs and a prostaglandin inhibitor. Responses were assessed by3H-thymidine incorporation in lymphocytes. Results were expressed as counts per minute and as stimulation indexes (SI).Results—When PBMC were stimulated with drugs alone, lymphocyte sensitisation to drugs (SI>2) was detected in 26% of the cases. This was noticeably increased (56%) when a prostaglandin inhibitor was added to the cultures. No reactivity was found in controls. In patients with possible sensitivity to several drugs, lymphocyte reactivity was detected to only one drug. The severity of the lesions, as assessed by aminotransferase concentrations and disease duration, was lower in patients with evidence of PPSC.Conclusions—This new approach is useful for the diagnosis of drug induced liver injury, particularly in patients exposed to more than one drug; furthermore, the presence of putative PPSC is associated with less severe forms of drug induced hepatitis.

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