Isoniazid-induced hepatotoxicity

The widespread use of isoniazid prophylaxis for tuberculosis has focused attention on the liver injury caused by this drug. About 20% of patients treated with isoniazid will show elevated blood concentrations of liver enzymes and bilirubin that subside as treatment is continued (25). However/ clinical hepatitis develops in some patientS/ and these reactions can prove fatal. Current understanding of the mechanism of isoniazid-induced hepatotoxicity is based on the metabolic pathways shown in Figure 16.6 (26/ 27). It has been demonstrated in an animal model that hepatotoxicity is correlated with plasma concentrations of hydrazine but not of acetylhydrazine or isoniazid (28)/ and that pretreatment with an amidase inhibitor can prevent toxicity (27). However/ it is postulated that hydrazine is further metabolized to a chemically reactive he pa to toxin by the cytochrome P450 system/ and in vitro studies with hepatocytes have implicated CYP2E1 as the cytochrome P450 isoform responsible for cytotoxic metabolite formation (29). 

Despite these advances in our understanding of the risk factors that predispose to isoniazid-induced hepatotoxicity/ it remains unclear whether age/ the predominant risk factor (Table 16.3)/ exerts its effects either on isoniazid metabolism or on protective mechanisms that as yet remain undefined. Clearly/ more work is needed in this area/ especially because understanding the biochemical basis of these risk factors plays a central role in developing guidelines for using isoniazid for chemoprophylaxis of tuberculosis (35). 

Sarich TC, Adams SP, Petricca G, Wright JM. Inhibition of isoniazid-induced hepatotoxicity in rabbits by pretreatment with an amidase inhibitor. J Pharmacol Exp Ther 1999 289 695-702. 

The use of prophylactic isoniazid therapy for transplant patients with evidence of exposure to M. tuberculosis (those with a positive purified protein derivative skin test) remains controversial. Risk of reactivation and development of clinical tuberculosis is enhanced with posttransplant immunosuppression. Some clinicians believe, however, that the risk of isoniazid-induced hepatotoxicity, especially in liver transplant recipients, in whom the rate of hepatotoxicity has been reported as high as 40%, outweighs the benefits of treatment. High-risk patients who may be considered for isoniazid prophylaxis include those with a positive skin test, those with previously diagnosed tuberculosis who may not have been treated adequately, patients in close contact with individuals with active pulmonary disease, and patients with abnormal chest radiographs consistent with old tuberculosis who have not received prior prophylaxis. " ... 

Saiuie I, Mommeja-Marin H, Hinkle J et al (2005) Severe hepatotoxicity associated with nevirapine use in HIV-infected subjects. J Infect Dis 191 825-829 Sarich TC, Zhou T, Adams SP et al (1995) A model of isoniazid-induced hepatotoxicity in rabbits. J Pharmacol Toxicol Methods 34 109-116... 

Prabakan, M., R. Anandan, and T. Devaki. 2000. Protective effect of Hemidesmus indicus against rifampicin and isoniazid-induced hepatotoxicity in rats. Fitoterapia 71(l) 55-59. 

Santos NP, Callegari-Jacques SM, Ribeiro Dos Santos AK, Silva CA, ValHnoto AC, Fernandes DC, et al. N-acetyl transferase 2 and cytochrome P450 2E1 genes and isoniazid-induced hepatotoxicity in Brazilian patients. Int J Tuberc Lung Dis 2013 17(4) 499-504. 

Serum chemistry markers play an important role in hepatotoxicity evaluation in human and animal safety studies. The classic markers of hepatotoxicity are alanine aminotransferase (ALT), aspartate aminotrasnferase (AST) and alkaline phosphatase (ALP) [124—127]. Drug-induced hepatotoxicity can be difficult to assess in some circumstances. Hepatotoxic responses can be intrinsic (predictable, dose-related) or idiosyncratic (unpredictable, non-dose-related). ALT, AST and ALP are generally not useful for predicting idiosyncratic responses. The administration of some drugs, such as isoniazid, can lead to a high incidence of ALT elevation, but are tolerated by most patients without severe hepatotoxicity. Adverse drug reactions can be masked... 

Tayal, V. et al. (2007) Hepatoprotective effect of tocopherol against isoniazid and rifampicin induced hepatotoxicity in albino rabbits. Indian Journal of Experimental Biology, 45 (12), 1031-1036. 

Rifampicin is an enzyme inducer and can increase the incidence and severity of isoniazid-induced hepatitis. Carbamazepine is an enzyme induction agent and interacts with isoniazid, increasing its hepatotoxicity. Isoniazid toxicity is associated with fast acetylator genotype. Although his phenotype was unknown, the interaction with carbamazepine increases risk of this toxicity. 

Ohno M, Yamaguchi I, Yamamoto I, Fukuda T, Yokota S, Maekura R, Ito M, Yamamoto Y, Ogura T, Maeda K, Komuta K, Igarashi T, Azuma J. Slow N-acetyltransferase 2 genotype affects the incidence of isoniazid and rifampicin-induced hepatotoxicity. Int J Tuberc Lung Dis 2000 4(3) 256-61. 

Liver damage usually appears 1-2 months after the start of therapy. In children, raised liver enzymes are common during the first few months of treatment, but withdrawal is seldom necessary. A careful watch should be kept for early symptoms of isoniazid-induced hepatitis, such as malaise, fatigue, nausea, and epigastric distress. The dangers of continuing isoniazid after the onset of symptoms of toxicity have been highlighted (30). The earhest symptoms of isoniazid toxicity should be clearly described to the patient, particularly to hepatitis B carriers, who may be more susceptible to hepatotoxicity (26). 

Carbamazepine potentiates isoniazid, the use of which may induce hepatotoxicity. 

Role of Reactive Metabolites in Drug-Induced Hepatotoxicity Isoniazid... 

Hepatotoxicity can occur with several antituberculous drugs including ethionamide, isoniazid, pyrazinamide and rifampicin and high alcohol consumption/chronic alcoholism has been reported to increase the risk. However, one study in patients with active tuberculosis taking rifampicin and pyrazinamide, found that of the 14 patients who developed hepatotoxicity, only 5 of these reported alcohol use (not quantified), and alcohol was not found to be associated with an increased risk of hepatotoxicity. Similarly, another study found that alcohol consumption was not a risk factor for antimycobacterial-induced hepatotoxicity. ... 

Isoniazid-induced fulminant liver failure occurred in a 16-year-old girl taking carbamazepine and clonazepam, within 5 days of starting isoniazid, rifampicin and pyrazinamide. She recovered with supportive measures and later tolerated the antiepileptics with concurrent rifampicin and pyrazinamide. Isoniazid hepatotoxicity has also occurred in a 74-year-old woman and a 10-year-old boy" taking carbamazepine, shortly after treatment with isoniazid, rifampicin, and ethambutol, with or without pyrazinamide, was started. 

Liver Isoniazid-induced Uver damage is histologically indistinguishable from viral hepatitis and is related to individual susceptibility in patients who hydrolyse the drug to isonicotinic add at different rates. Histologically proven isoniazid hepatotoxicity in complicated tuberculous salpingitis has been reported [70 ]. 

The mechanism of toxification of isoniazid was investigated in rats pretreated with inducers or inhibitors of microsomal enzymes or an inhibitor of acylamidases. In animals pretreated with the acylamidase inhibitor bis(4-nitrophenyl) phosphate, isoniazid and acetylisoniazid produced less liver necrosis than in control animals. The treatment had no effect on the necrosis due to acetylhydrazine [173], In animals pretreated with inducers of microsomal cytochrome P450 such as phenobarbital, acetylisoniazid, and acetylhydrazine caused markedly increased necrosis, while pretreatment with cytochrome P450 inhibitors decreased necrosis. In contrast, the toxicity of isoniazid and hydrazine was not modified by phenobarbital pretreatment. From these observations, Trimbell et al. [173] concluded that the hydrolysis of acetylisoniazid is a prerequisite for hepatotoxicity, and that microsomal enzymes transform acetylhydrazine, the product of hydrolysis, to a toxic species. 

Interesting information stems from studies of the hepatotoxic effect of the concomitant administration of rifampicin, another antituberculostatic drug (and a potent inducer of cytochrome P450) often used in combination with isoniazid. Rifampicin alone is not hepatotoxic but increases significantly the incidence of hepatitis in patients simultaneously dosed with isoniazid. In human volunteers (6 slow and 8 rapid acetylators), daily administration of rifampicin increased the release of hydrazine from isoniazid [180], In slow acetylators, the proportion of the dose metabolized to hydrazine increased... 

Recently, the role of hydrazine in the mechanism of isoniazid hepatotox-icity was confirmed by Sarich et al. [181]. Using a model of isoniazid-in-duced hepatotoxicity in rabbits, they found that hydrazine plasma concentrations correlated significantly with plasma argininosuccinic acid lyase, a sensitive marker of hepatic necrosis. In contrast, no correlation was found between plasma levels of isoniazid or acetylisoniazid and the markers of induced hepatic necrosis. 

A. Noda, K.-Y. Hsu, H. Noda, Y. Yamamoto, T. Kurozumi, Is Isoniazid-Hepatotoxicity Induced by the Metabolite Hydrazine , Sangyo IkaDaigaku Zasshi 1983, 5, 183-190. 

Isoniazid can induce a wide variety of potentially serious adverse reactions. Some hepatotoxicity can manifest itself as transient elevations of liver enzymes and this occurs in 10-20% of patients. Progressive and potentially fatal liver damage is age dependent with a very low incidence below the age of... 

Numerous studies have demonstrated an apparent relationship between metabolite formation and toxicity. The N-hydroxylation of phenacetin may play a role in drug-induced hepatic necrosis . Similarly, N-hydroxylation may mediate acetaminophen hepatotoxicity . Acetylhydrazine and isopropylhydrazine, metabolites of isoniazid and iproniazid, may initiate hepatotoxicity through covalent binding of an electrophilic intermediate (see Chapter 32) . 

The discovery of polymorphic N-acetylation was linked to observations on the safety, metabolism, and pharmacokinetics of the antitubercular drug, isoniazid. When urinary excretion of isoniazid was evaluated in identical twins, fraternal twins, and unrelated subjects, the variability in its excretion depended upon genetic similarity. Ultimately, in a classic experiment by Evans and colleagues that measured the plasma isoniazid concentration in subjects who had taken a single 10 mg/kg dose of isoniazid, a clear polymorphic frequency distribution was revealed with an antimode of 2.5 ug/mL. Thus, two acetylator phenotypes were identified, and the slow acetylator phenotype had a frequency of 52%, and was an autosomal recessive trait. The slow acetylator phenotype, if treated with isoniazid (INH) is at increased risk of INH-induced arthralgias, neuropathy, and hepatotoxicity. 

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