Cytokine profiles in acute liver injury—Results from the US Drug-Induced Liver Injury Network (DILIN) and the Acute Liver Failure Study Group

Numerous prescribed drugs and herbal and dietary supplements have been reported to cause drug-induced acute liver injury, which is a frequent cause of acute liver failure (ALF). It is a tremendous challenge with ever-increasing drug application in the medication system for huge populations. Drug-induced acute liver injury can lead to diverse pathologies similar to acute and chronic hepatitis, acute liver failure, biliary obstruction, fatty liver disease, and so on. Recently, extensive work demonstrated that isoflavones play an essential and protecting role in drug-induced liver injury (DILI). The isoflavones mediated hepatoprotection by modulating specific genes linked with control of cellular redox homeostasis and inflammatory responses. Isoflavones upregulate oxidative stress-responsive nuclear factor erythroid 2-like 2 (Nrf2), downregulate inflammatory nuclear factor-κB (NF-κB) signaling pathways, and modulate a balance between cell survival and death. Moreover, isoflavones actively inhibit the expression of cytochromes P450 (CYPs) enzyme during drug metabolism. Moreover, isoflavones are also linked with farnesoid X receptor (FXR) activation and signal transducer and activator of transcription factor 3 (STAT3) phosphorylation in hepatoprotection DILI. In vivo and in vitro studies clearly stated that isoflavones bear strong antioxidant potential and promising agents for hepatotoxicity prevention and stressed their potential role as therapeutic supplements in DILI. The current review will elaborate on isoflavones’ preventive and therapeutic potential concisely and highlight various molecular targets to exert a protective effect on DILI.

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921 CONTRIBUTION OF DRUG-INDUCED LIVER INJURY (DILI) IN LIVER TRANSPLANTATION (OLT) INDICATION FOR ACUTE LIVER FAILURE (ALF) IN ADULTS IN FRANCE

Journal of Hepatology ◽

10.1016/s0168-8278(11)60923-9 ◽

2011 ◽

Vol 54 ◽

pp. S368 ◽

Cited By ~ 1

Author(s):

P. Larrey ◽

G.-P. Pageaux ◽

E. Gulmez ◽

S. Lignot ◽

G. Thoni ◽

...

Keyword(s):

Liver Transplantation ◽

Liver Injury ◽

Liver Failure ◽

Acute Liver Failure ◽

Drug Induced ◽

Drug Induced Liver Injury

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A Patient with Nafcillin-Associated Drug-Induced Liver Failure

Case Reports in Gastroenterology ◽

10.1159/000480071 ◽

2017 ◽

Vol 11 (3) ◽

pp. 564-568 ◽

Cited By ~ 1

Author(s):

Qin Rao ◽

Isaiah Schuster ◽

Talal Seoud ◽

Kevin Zarrabi ◽

Nirvani Goolsarran

Keyword(s):

Liver Injury ◽

Liver Function ◽

Liver Failure ◽

Acute Liver Injury ◽

Early Recognition ◽

Antibiotic Use ◽

Liver Function Tests ◽

The United States ◽

Drug Induced ◽

Drug Induced Liver Injury

Nafcillin-induced acute liver injury is a rare and potentially fatal complication that has been known since the 1960s but inadequately studied. At this time, the only proven treatment is early discontinuation of the drug. Because of the high prevalence of nafcillin class antibiotic use in the United States, it is important for clinicians to have a high clinical suspicion for this diagnosis. We present a case of liver failure attributable to nafcillin use in a 68-year-old male with a history methicillin-sensitive Staphylococcus and L3/L4 osteomyelitis. After starting long-term antibiotic therapy, he presented with painless jaundice which necessitated discontinuation of the drug. At the time of presentation, the patient’s lab work exhibited a bilirubin/direct bilirubin of 9.4/8.2 mg/dL, alkaline phosphatase of 311 IU/L, and aspartate transaminase/alanine transaminase of 109/127 IU/L. The patient was switched to i.v. vancomycin given the concern for drug-induced liver injury. Imaging did not show obstruction of the hepatobiliary or pancreaticobiliary trees. Serology was unremarkable for viral etiology, autoimmune processes, Wilson disease, and hemochromatosis. A liver biopsy showed findings consistent with drug-induced liver injury. The patient’s liver function tests peaked at day 7 of admission and trended towards normal levels with cessation of nafcillin therapy. The patient was discharged with a diagnosis of nafcillin-induced acute liver injury. Our case highlights the importance of early recognition of the diagnosis and careful monitoring of liver function when nafcillin is employed in the clinical setting.

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Is Sensitivity the Key Measure to Predict Acute Liver Failure in Drug-Induced Liver Injury Patients?

Clinical Gastroenterology and Hepatology ◽

10.1016/j.cgh.2015.10.002 ◽

2016 ◽

Vol 14 (6) ◽

pp. 918

Author(s):

M. Robles-Diaz ◽

R.J. Andrade ◽

N. Kaplowitz

Keyword(s):

Liver Injury ◽

Liver Failure ◽

Acute Liver Failure ◽

Drug Induced ◽

Drug Induced Liver Injury

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PP025—Improving hy’s law definition to better predict the risk of developing acute liver failure in drug-induced liver injury (DILI)

Clinical Therapeutics ◽

10.1016/j.clinthera.2013.07.060 ◽

2013 ◽

Vol 35 (8) ◽

pp. e25

Author(s):

M. Robles-Díaz ◽

C. Stephens ◽

I. Medina-Cáliz ◽

A.F. González ◽

A. González-Jiménez ◽

...

Keyword(s):

Liver Injury ◽

Liver Failure ◽

Acute Liver Failure ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Hy’S Law

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Use of Hy's Law and a New Composite Algorithm to Predict Acute Liver Failure in Patients With Drug-Induced Liver Injury

Gastroenterology ◽

10.1053/j.gastro.2014.03.050 ◽

2014 ◽

Vol 147 (1) ◽

pp. 109-118.e5 ◽

Cited By ~ 138

Author(s):

Mercedes Robles–Diaz ◽

M. Isabel Lucena ◽

Neil Kaplowitz ◽

Camilla Stephens ◽

Inmaculada Medina–Cáliz ◽

...

Keyword(s):

Liver Injury ◽

Liver Failure ◽

Acute Liver Failure ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Hy’S Law

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Necrotic cell death and suppression of T-cell immunity characterized acute liver failure due to drug-induced liver injury

Cytokine ◽

10.1016/j.cyto.2016.07.010 ◽

2016 ◽

Vol 86 ◽

pp. 21-28 ◽

Cited By ~ 5

Author(s):

Keisuke Kakisaka ◽

Kojiro Kataoka ◽

Yuji Suzuki ◽

Yohei Okada ◽

Yuichi Yoshida ◽

...

Keyword(s):

Cell Death ◽

Liver Injury ◽

Liver Failure ◽

Acute Liver Failure ◽

T Cell Immunity ◽

Necrotic Cell Death ◽

Necrotic Cell ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Cell Immunity

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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.

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Drug Hepatotoxicity

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

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