Is Isoniazid - Hepatotoxicity Induced by the Metabolite, Hydrazine?

Noda, Atsuko; Ky, Hsu; Noda, Hiroshi; Yamamoto, Yūzō; Kurozumi, Takeshi

doi:10.7888/juoeh.5.183

Cited by 34 publications

(21 citation statements)

References 2 publications

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“…A few cases may be due to allergic-type hypersensitivity reactions with prominent eosinophilia and rash. 39,40 While testing baseline and follow-up serum ALT and bilirubin levels before beginning INH therapy is desirable in all patients, it is strongly recommended for patients with an underlying liver disorder such as chronic hepatitis B and C, alcoholic hepatitis and cirrhosis, in patients who regularly consume alcohol, those with HIV infection being treated with HAART, pregnant women, and those who are up to 3 months postpartum. 41 INH should be discontinued when jaundice and/or hepatitis symptoms are reported and ALT is at least three times the ULN, or if ALT is at least five times the ULN in the absence of symptoms.…”

Section: First-line Drugs Isoniazidmentioning

confidence: 99%

A Guide to the Management of Tuberculosis in Patients with Chronic Liver Disease

Dhiman

Saraswat

Rajekar

et al. 2012

Journal of Clinical and Experimental Hepatology

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Tuberculosis remains one of the 'Captains of the Men of Death' even today, particularly in the developing world. Its frequency is increased 14-fold in patients with chronic liver diseases (CLD) and liver cirrhosis, more so in those with decompensated disease, probably due to the cirrhosis-associated immune dysfunction syndrome, and case-fatality rates are high. The diagnosis of tuberculosis, particularly the interpretation of the Mantoux test, is also fraught with difficulties in CLD, especially after previous BCG vaccination. However, the greatest challenge in the patient with CLD or liver cirrhosis and tuberculosis is managing their therapy since the best first-line anti-tuberculosis drugs are hepatotoxic and baseline liver function is often deranged. Frequency of hepatotoxicity is increased in those with liver cirrhosis, chronic hepatitis B and chronic hepatitis C, possibly related to increased viral loads and may be decreased following antiviral therapy. If hepatotoxicity develops in those with liver cirrhosis, particularly decompensated cirrhosis, the risk of severe liver failure is markedly increased. Currently, there are no established guidelines for anti-tuberculosis therapy (ATT) in CLD and liver cirrhosis although the need for such guidelines is self-evident. It is proposed that ATT should include no more than 2 hepatotoxic drugs (RIF and INH) in patients with CLD or liver cirrhosis and stable liver function [ChildTurcotte-Pugh (CTP) #7], only a single hepatotoxic drug (RIF or INH) in those with advanced liver dysfunction and no hepatotoxic drugs with very advanced liver dysfunction (CTP $11). A standard protocol should be followed for monitoring ATT-related hepatotoxicity and for stop rules and reintroduction rules in all these patients, on the lines proposed here. It is hoped that these proposals will introduce uniformity and result in streamlining the management of these difficult patients. ( J CLIN EXP HEPATOL 2012;2:260-270)

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Section: First-line Drugs Isoniazidmentioning

confidence: 99%

A Guide to the Management of Tuberculosis in Patients with Chronic Liver Disease

Dhiman

Saraswat

Rajekar

et al. 2012

Journal of Clinical and Experimental Hepatology

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“…It is unlikely that the rat model represents the same mechanism of INH-induced hepatotoxicity that occurs in humans because the characteristics are very different. Hydrazine has also been implicated as a potential hepatotoxic metabolite of INH (Blair et al, 1985;Gent et al, 1992;Noda et al, 1983;Sarich et al, 1996); however, given its potent hepatotoxic effects it is more likely that hydrazine would cause acute liver injury rather than liver injury with a delayed onset.…”

Section: Introductionmentioning

confidence: 99%

Isoniazid-induced liver injury and immune response in mice

Metushi¹,

Uetrecht

2013

Journal of Immunotoxicology

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Isoniazid (INH) is associated with one of the highest incidences of idiosyncratic drug-induced liver failure of any commonly prescribed drug. The mechanism of this liver injury remains uncertain, and a valid animal model would greatly facilitate mechanistic studies. Most studies of INH-induced liver toxicity have been acute studies performed in rats with high doses of the drug, and this is very different from the idiosyncratic liver injury that occurs in humans. It has previously been demonstrated that covalent binding of INH in the liver of mice is greater than in rats and more like that in humans. Therefore, mice should be a better species in which to develop an animal model of INH-induced liver injury. Treatment of Cbl-b À/À and PD1 À/À mice, which have impaired immune tolerance, resulted in greater injury than their C57BL/6 background, but not liver failure. This suggested that the injury was mediated by the adaptive immune system; however, Rag À/À mice, which do not have competent T-and B-cells, sustained more liver injury than C57BL/6 wild-type mice. This suggested that the adaptive immune system also played a protective role. INH treatment also led to a decrease in the inflammatory cytokines IL-1a and IL-12, which suggests that the drug may have immunosuppressive properties. In short, a mouse model was developed of INH-induced liver injury in which the immune system appears to play a both protective and pathogenic role, but this study was unable to develop a model of INH-induced liver failure.

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“…[18][19][20] In addition, these hepatotoxic metabolites induced the excessive production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the rat hepatocytes after being metabolized by 8 enzymes including CYP2E1. 20,21 In particular, nitric oxide (NO), one of the RNS, is produced by NO synthase (NOS).…”

Section: Introductionmentioning

confidence: 99%

Genetic variants in antioxidant pathway: Risk factors for hepatotoxicity in tuberculosis patients

et al. 2012

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SummaryTuberculosis (TB) treatment can cause serious sequelae including adverse effects such as anti-TB drug-induced hepatotoxicity (ATDH). We performed a candidate gene-based association study between single nucleotide polymorphisms (SNPs) in 10 genes in the antioxidant pathway and ATDH susceptibility. The subjects comprised 100 Japanese patients with pulmonary TB who received a treatment regimen including isoniazid and rifampicin. Out of them, 18 patients had ATDH. Thirty-four tag SNPs in 10 genes were analyzed by PCR-restriction fragment length polymorphism or PCR-direct DNA sequencing. The frequencies of alleles and genotypes between patients with and without ATDH were compared in three different genetic models. Statistical analyses revealed that a C/C genotype at rs11080344 in NOS2A, a C/C genotype at rs2070401 in

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Is Isoniazid - Hepatotoxicity Induced by the Metabolite, Hydrazine?

Cited by 34 publications

References 2 publications

A Guide to the Management of Tuberculosis in Patients with Chronic Liver Disease

A Guide to the Management of Tuberculosis in Patients with Chronic Liver Disease

Isoniazid-induced liver injury and immune response in mice

Genetic variants in antioxidant pathway: Risk factors for hepatotoxicity in tuberculosis patients

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