A model of isoniazid induced hepatotoxicity in rabbits. Its major influence is on the important cause of liver injury. Kleiner, md, phd, laboratory of pathology, national cancer institute. Saroufim 2 department of pharmacy practice, school of pharmacy, lebanese american university lau, p. Isoniazid inh is highly effective for the management of tuberculosis. It is a small molecule mw7 that is freely soluble in water. Inh and rif induced hepatotoxicity has been studied using rodent models, the most important being wistar albino rats. Treatment finally consisted of rifampicin 600mg, ethambutol 1 g, pyrazinamide 15g, and ofloxacin 400mgday.
Isoniazid induced hepatotoxicity 2 linkedin slideshare. Transporters, enzymes, and excretion drug induced liver injury. Druginduced hepatic injury accounts for more than 50 percent of cases of acute liver failure in the united states. In the usphs study 63, there were 8 deaths among,838 enrolled subjects 0. We describe druginduced liver injury dili secondary to antituberculous treatment att in a large tuberculosis tb centre in london. The base of evidence for isoniazid hepatotoxicity, including a level of risk in the range of 5 to 20 cases of hepatotoxicity expected per persons receiving treatment with a 1% to 10% casefatality rate, is composed of studies done more than 20 years ago. Druginduced liver injury dili therefore poses a major clinical problem. The manifestations of druginduced hepatotoxicity are highly variable, ranging from asymptomatic elevation of liver enzymes to fulminant hepatic failure. Hepatotoxicity induced by acute and chronic paracetamol. Isoniazid metabolism and hepatotoxicity sciencedirect. Paracetamol poisoning data can reveal the weaknesses of paracetamol poisoning management guidelines. Druginduced liver injury clinical infectious diseases. There is evidence that the inh metabolite hydrazine plays an important role in the mechanism of this toxicity. Case report acute and fatal isoniazidinduced hepatotoxicity.
American journal of respiratory and critical care medicine. Pdf protective effects of quercetin against isoniazid and. Background isoniazid inh, a key drug of antituberculosis therapy, is metabolized by arylamine nacetyltransferase2 nat2, cytochrome p450 2e1 cyp2e1 and glutathione stransferase gst. Drug induced liver injury covers a variety of types, and includes most of the clinical and pathological expressions of liver damage 6. Animal models of drug induced liver injury dili are commonly used to study the dynamics and interventions of dili. Mar 24, 2017 we describe drug induced liver injury dili secondary to antituberculous treatment att in a large tuberculosis tb centre in london. Drug induced hepatotoxicity of antituberculosis drugs and their serum levels the correlation between serum antituberculosis tb drug levels and the drug induced hepatotoxicity dih remains unclear. Idiosyncratic unpredictable druginduced liver injury is one of the most challenging liver disorders. Isoniazid inh, a widely used drug in the prophylaxis and treatment of tuberculosis, is associated with a 1 to 2% risk of severe and potentially fatal hepatotoxicity. Pdf cyp2e1 genotype and isoniazidinduced hepatotoxicity. The various types are shown in figure 1 and discussed below in brief. A model of isoniazidinduced hepatotoxicity in rabbits. The pattern of hepatotoxicity observed during therapy with the vasodilator.
Inh metabolism has been thought to be associated with inhinduced liver injury. Druginduced liver injury from antituberculous treatment. The incidence rate of antitb induced hepatotoxicity is found to be 2% to 28%. More than 75 percent of idiosyncratic drug reactions result in liver transplantat. There are few data on hepatotoxicity induced by acute or chronic paracetamol poisoning in the pediatric population. Ecd was administered orally for 21 days 150 and 300mgkg body weight. An infrequent but preventable cause of liver failure in children treated for latent tuberculosis infection dan desrochers, 1 regino p. Hepatotoxicity was induced by oral administration of inh 50mgkg and rif 100mgkg on every 72hrs for a period of 21days. Protective effects of quercetin against isoniazid and rifampicin induced hepatotoxicity in rats article pdf available july 2014 with 493 reads how we measure reads. Life expectancy is prolonged, and quality of life is much improved.
The standard therapies for tb include a combination treatment of isoniazid inh, rifampicin, pyrazinamide, and ethambutol2. We studied the possible influence of genetic polymorphisms of inhmetabolizing enzymes on serum concentrations of inh and its metabolites, as well as on the incidence of hepatotoxicity. Dili has become the leading cause of acute liver failure and transplantation in western. Many of the commonly used antitb drugs are associated with significant potential of causing hepatotoxicity.
Druginduced liver injury covers a variety of types, and includes most of the clinical and pathological expressions of liver damage 6. The bulk of adverse hepatic drug reactions present with an acute hepatitis, cholestasis or mixed signature. Treatment of isoniazid induced hepatotoxicity as regards the treatment of inh induced hepatotoxicity, it presents a difficult challenge to manage due to a number of factors such as, patients affected are often on other potentially hepatotoxic drugs, making it more. Hepatoprotective activity of canthium dicoccum in isoniazid. Druginduced hepatotoxicity of antituberculosis drugs and their serum levels the correlation between serum antituberculosis tb drug levels and the druginduced hepatotoxicity dih remains unclear. Sterling, on behalf of the ats hepatotoxicity of antituberculosis therapy subcommittee this of. Capitals indicate lifethreatening, underlines indicate most frequent. Diagnosis, management and prevention of druginduced liver. Although druginduced liver injury dili caused by different drugs is somewhat different, the clinical characteristics of inhinduced liver injury. Severe hepatotoxicity serum transaminase 10 times the upper limit of normal occurred in 6.
Antituberculosis drug induced hepatitis a case report. The advances in science and medicine we are now experiencing are unprec edented and exciting. Inhibition of isoniazidinduced hepatotoxicity in rabbits by. Antihypertensive agents have been associated with adverse reactions that, if unrecognized by health practitioners, may have devastating consequences. Drug induced alf is also associated with high morbidity and mortality, only a 20% survival in the absence of liver transplantation. Fatal hepatotoxicity induced by hydralazine or labetalol.
Cyp2e1 genotype and isoniazid induced hepatotoxicity in patients treated for latent tuberculosis article pdf available in european journal of clinical pharmacology 626. Drug induced hepatotoxicity is a frequent cause of liver injury. However, it can cause liver injury and even liver failure. The predominant clinical presentation is acute hepatitis andor cholestasis, although almost any clinical pathological pattern of acute or chronic liver disease can occur. Although these hla associations have contributed to our understanding of the immunopathogenesis of dili, the very poor positive. Isoniazid isonicotinylhydrazine, inh is the most active drug for the treatment of tuberculosis caused by susceptible strains. There is currently no way to reimburse for the absence of liver function. She was admitted to the hospital for epigastric and right sided flank pain of oneweek duration. Fatal hepatotoxicity induced by hydralazine or labetalol janice l. Drug hepatotoxicity, is the leading cause of acute liver failure alf.
Previous studies have established and used a dosage of 50 mgkg b. Severe hepatotoxicity serum transaminase 10 times the upper limit of. Drug induced hepatic injury accounts for more than 50 percent of cases of acute liver failure in the united states. The incidence of isoniazid inh and rifampicin rifinduced abnormal liver enzyme activity is 27% but only 19% with inh alone. In this case, the patient was receiving antitubercular drugs from 3 months and developed hepatitis which is a severe adverse drug reaction. Druginduced hepatotoxicity of antituberculosis drugs and. Inh has since been associated with two syndromes of hepatotoxicity. Hepatotoxicity associated with isoniazid preventive therapy. Diagnosis, management and prevention of druginduced liver injury. Druginduced alf is also associated with high morbidity and mortality, only a 20% survival in the absence of liver transplantation.
Cytochrome p450 2e1 cyp2e1 is thought to contribute to the synergistic effects of rif and inh. Zidovudine and isoniazid induced liver toxicity and oxidative stress. The purpose of this study was to investigate whether antitb dih is associated with basal serum drug levels. Metabolism of inh leads to the production of hydrazine via both direct and indirect pathways. Hepatotoxicity induced by antituberculosis drugs among. Isoniazid, rifampicin, gsp method, mannitol, tuberculosis, hepatotoxicity. Of the 17 patients with hepatotoxicity by definition iii, 3 presented no side effects and treatment was well tolerated. Current concepts of mechanisms in druginduced hepatotoxicity. Selected pharmaceutical excipient prevent isoniazid and. Mar 23, 2011 isoniazidinduced severe hepatotoxicity.