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Isoniazid hepatotoxicity

INTRODUCTION

Isoniazid (INH, isonicotinylhydrazide) is a synthetic antibiotic that is bactericidal against replicating Mycobacterium tuberculosis. The drug acts by inhibiting the oxygen-dependent steps in the synthesis of mycolic acid, a component of the mycobacterial cell wall. INH has been associated with two syndromes of hepatotoxicity: mild INH hepatotoxicity and INH hepatitis.

The pathophysiology and prevention of INH hepatotoxicity will be reviewed here. The clinical use of INH is discussed separately. (See "Treatment of latent tuberculosis infection in HIV-negative adults" and "Treatment of pulmonary tuberculosis in HIV-negative patients".)

MILD INH HEPATOTOXICITY

Mild, nonspecific hepatic injury occurs in up to 20 percent of patients taking isoniazid (INH, isonicotinylhydrazide). This is typically subclinical and evidenced only by mildly elevated serum aminotransferases (usually <100 IU/L) [1-3]. Liver biopsy in such patients usually demonstrates minor focal hepatocellular damage [1]. Adults are more likely to be affected than children; men and women appear to be equally vulnerable. There is no relationship to race or the rate of hepatic acetylation of the drug.

The prognosis for mild INH hepatotoxicity is excellent, with an overall mortality rate of only 0.001 percent [4]. Virtually all cases are self-limited; INH therapy can be continued with careful clinical and laboratory monitoring.

INH HEPATITIS

INH hepatitis is a less common but more serious liver injury syndrome than mild isoniazid (INH, isonicotinylhydrazide) hepatotoxicity; it is typically symptomatic and may be fatal [5,6]. The features are generally indistinguishable from viral hepatitis [5,7-11].

               

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Literature review current through: Nov 2014. | This topic last updated: Apr 3, 2014.
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References
Top
  1. Scharer L, Smith JP. Serum transaminase elevations and other hepatic abnormalities in patients receiving isoniazid. Ann Intern Med 1969; 71:1113.
  2. Byrd CB, Nelson R, Elliott RC. Isoniazid toxicity. A prospective study in secondary chemoprophylaxis. JAMA 1972; 220:1471.
  3. Mitchell JR, Long MW, Thorgeirsson UP, Jollow DJ. Acetylation rates and monthly liver function tests during one year of isoniazid preventive therapy. Chest 1975; 68:181.
  4. Salpeter SR. Fatal isoniazid-induced hepatitis. Its risk during chemoprophylaxis. West J Med 1993; 159:560.
  5. Garibaldi RA, Drusin RE, Ferebee SH, Gregg MB. Isoniazid-associated hepatitis. Report of an outbreak. Am Rev Respir Dis 1972; 106:357.
  6. Lauterburg BH, Smith CV, Todd EL, Mitchell JR. Pharmacokinetics of the toxic hydrazino metabolites formed from isoniazid in humans. J Pharmacol Exp Ther 1985; 235:566.
  7. Kopanoff DE, Snider DE Jr, Caras GJ. Isoniazid-related hepatitis: a U.S. Public Health Service cooperative surveillance study. Am Rev Respir Dis 1978; 117:991.
  8. Black M, Mitchell JR, Zimmerman HJ, et al. Isoniazid-associated hepatitis in 114 patients. Gastroenterology 1975; 69:289.
  9. Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest 1991; 99:465.
  10. Nolan CM, Goldberg SV, Buskin SE. Hepatotoxicity associated with isoniazid preventive therapy: a 7-year survey from a public health tuberculosis clinic. JAMA 1999; 281:1014.
  11. LoBue PA, Moser KS. Use of isoniazid for latent tuberculosis infection in a public health clinic. Am J Respir Crit Care Med 2003; 168:443.
  12. Stead WW, To T, Harrison RW, Abraham JH 3rd. Benefit-risk considerations in preventive treatment for tuberculosis in elderly persons. Ann Intern Med 1987; 107:843.
  13. Chan CH, Or KK, Cheung W, Woo J. Adverse drug reactions and outcome of elderly patients on antituberculosis chemotherapy with and without rifampicin. J Med 1995; 26:43.
  14. Ohkawa K, Hashiguchi M, Ohno K, et al. Risk factors for antituberculous chemotherapy-induced hepatotoxicity in Japanese pediatric patients. Clin Pharmacol Ther 2002; 72:220.
  15. Grönhagen-Riska C, Hellstrom PE, Fröseth B. Predisposing factors in hepatitis induced by isoniazid-rifampin treatment of tuberculosis. Am Rev Respir Dis 1978; 118:461.
  16. Centers for Disease Control and Prevention. Core curriculum on tuberculosis. What the clinician should know, 4th ed. .S. Department of Health and Human Services, Public Health Services; Atlanta, 2000.
  17. Holdiness MR. Clinical pharmacokinetics of the antituberculosis drugs. Clin Pharmacokinet 1984; 9:511.
  18. Maddrey WC. Drug-related acute and chronic hepatitis. Clin Gastroenterol 1980; 9:213.
  19. Dickinson DS, Bailey WC, Hirschowitz BI, et al. Risk factors for isoniazid (NIH)-induced liver dysfunction. J Clin Gastroenterol 1981; 3:271.
  20. Acocella G, Bonollo L, Garimoldi M, et al. Kinetics of rifampicin and isoniazid administered alone and in combination to normal subjects and patients with liver disease. Gut 1972; 13:47.
  21. Snider DE Jr, Caras GJ. Isoniazid-associated hepatitis deaths: a review of available information. Am Rev Respir Dis 1992; 145:494.
  22. Ungo JR, Jones D, Ashkin D, et al. Antituberculosis drug-induced hepatotoxicity. The role of hepatitis C virus and the human immunodeficiency virus. Am J Respir Crit Care Med 1998; 157:1871.
  23. Targeted tuberculin testing and treatment of latent tuberculosis infection. This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America. (IDSA), September 1999, and the sections of this statement. Am J Respir Crit Care Med 2000; 161:S221.
  24. Pande JN, Singh SP, Khilnani GC, et al. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax 1996; 51:132.
  25. Fernández-Villar A, Sopeña B, Vázquez R, et al. Isoniazid hepatotoxicity among drug users: the role of hepatitis C. Clin Infect Dis 2003; 36:293.
  26. Patel PA, Voigt MD. Prevalence and interaction of hepatitis B and latent tuberculosis in Vietnamese immigrants to the United States. Am J Gastroenterol 2002; 97:1198.
  27. Bliven EE, Podewils LJ. The role of chronic hepatitis in isoniazid hepatotoxicity during treatment for latent tuberculosis infection. Int J Tuberc Lung Dis 2009; 13:1054.
  28. Wu JC, Lee SD, Yeh PF, et al. Isoniazid-rifampin-induced hepatitis in hepatitis B carriers. Gastroenterology 1990; 98:502.
  29. Centers for Disease Control and Prevention (CDC). Severe isoniazid-associated hepatitis--New York, 1991-1993. MMWR Morb Mortal Wkly Rep 1993; 42:545.
  30. Reddy KR, Schiff ER. Hepatotoxicity of antimicrobial, antifungal, and antiparasitic agents. Gastroenterol Clin North Am 1995; 24:923.
  31. Maddrey WC, Boitnott JK. Isoniazid hepatitis. Ann Intern Med 1973; 79:1.
  32. Saukkonen JJ, Cohn DL, Jasmer RM, et al. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006; 174:935.
  33. Farrell FJ, Keeffe EB, Man KM, et al. Treatment of hepatic failure secondary to isoniazid hepatitis with liver transplantation. Dig Dis Sci 1994; 39:2255.
  34. Centers for Disease Control and Prevention (CDC), American Thoracic Society. Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection--United States, 2003. MMWR Morb Mortal Wkly Rep 2003; 52:735.
  35. Centers for Disease Control and Prevention (CDC). Update: Fatal and severe liver injuries associated with rifampin and pyrazinamide for latent tuberculosis infection, and revisions in American Thoracic Society/CDC recommendations--United States, 2001. MMWR Morb Mortal Wkly Rep 2001; 50:733.
  36. Centers for Disease Control and Prevention (CDC). Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection--New York and Georgia, 2000. MMWR Morb Mortal Wkly Rep 2001; 50:289.
  37. Bass NM, Ockner RK. Drug-induced liver disease. In: Hepatopathology, Zakim D, Boyer TD (Eds), WB Saunders, Philadelphia 1996. p.962.
  38. Girling DJ. The hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide. Tubercle 1978; 59:13.
  39. Bailey WC, Weill H, DeRouen TA, et al. The effect of isoniazid on transaminase levels. Ann Intern Med 1974; 81:200.
  40. Metushi IG, Sanders C, Acute Liver Study Group, et al. Detection of anti-isoniazid and anti-cytochrome P450 antibodies in patients with isoniazid-induced liver failure. Hepatology 2014; 59:1084.
  41. Preziosi P. Isoniazid: metabolic aspects and toxicological correlates. Curr Drug Metab 2007; 8:839.
  42. Nelson, SD, Mitchell, JR, Timbrell, JA, et al. Isoniazid and iproniazid: Activation of metabolites to toxic intermediates in man and rat. Science 1976; 193:901.
  43. Sarich TC, Youssefi M, Zhou T, et al. Role of hydrazine in the mechanism of isoniazid hepatotoxicity in rabbits. Arch Toxicol 1996; 70:835.
  44. Mitchell JR, Thorgeirsson UP, Black M, et al. Increased incidence of isoniazid hepatitis in rapid acetylators: possible relation to hydranize metabolites. Clin Pharmacol Ther 1975; 18:70.
  45. Mitchell JR, Zimmerman HJ, Ishak KG, et al. Isoniazid liver injury: clinical spectrum, pathology, and probable pathogenesis. Ann Intern Med 1976; 84:181.
  46. Timbrell JA, Mitchell JR, Snodgrass WR, Nelson SD. Isoniazid hepatoxicity: the relationship between covalent binding and metabolism in vivo. J Pharmacol Exp Ther 1980; 213:364.
  47. Timbrell JA, Wright JM, Baillie TA. Monoacetylhydrazine as a metabolite of isoniazid in man. Clin Pharmacol Ther 1977; 22:602.
  48. Ono Y, Noda A, Zaima Y, et al. Determination of isonicotinic acid in the presence of isoniazid and acetylisoniazid. Studies on isonicotinic acid formation from isoniazid in isolated rat hepatocytes. J Chromatogr B Biomed Appl 1996; 677:339.
  49. Delaney J, Timbrell JA. Role of cytochrome P450 in hydrazine toxicity in isolated hepatocytes in vitro. Xenobiotica 1995; 25:1399.
  50. 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.
  51. Ellard GA, Mitchison DA, Girling DJ, et al. The hepatic toxicity of isoniazid among rapid and slow acetylators of the drug. Am Rev Respir Dis 1978; 118:628.
  52. Pessayre D, Larrey D. Acute and chronic drug-induced hepatitis. Baillieres Clin Gastroenterol 1988; 2:385.
  53. Yamamoto T, Suou T, Hirayama C. Elevated serum aminotransferase induced by isoniazid in relation to isoniazid acetylator phenotype. Hepatology 1986; 6:295.
  54. Gurumurthy P, Krishnamurthy MS, Nazareth O, et al. Lack of relationship between hepatic toxicity and acetylator phenotype in three thousand South Indian patients during treatment with isoniazid for tuberculosis. Am Rev Respir Dis 1984; 129:58.
  55. Huang YS, Chern HD, Su WJ, et al. Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology 2002; 35:883.
  56. Huang YS, Chern HD, Su WJ, et al. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology 2003; 37:924.
  57. Furet Y, Bechtel Y, Le Guellec C, et al. [Clinical relevance of N-acetyltransferase type 2 (NAT2) genetic polymorphism]. Therapie 2002; 57:427.
  58. Huang YS. Genetic polymorphisms of drug-metabolizing enzymes and the susceptibility to antituberculosis drug-induced liver injury. Expert Opin Drug Metab Toxicol 2007; 3:1.
  59. Vuilleumier N, Rossier MF, Chiappe A, et al. CYP2E1 genotype and isoniazid-induced hepatotoxicity in patients treated for latent tuberculosis. Eur J Clin Pharmacol 2006; 62:423.
  60. Lees AW, Allan GW, Smith J, et al. Toxicity form rifampicin plus isoniazid and rifampicin plus ethambutol therapy. Tubercle 1971; 52:182.
  61. Emerit, J, Decroix, G, Chomette, C, et al. Données nouvelles sur les hépitites observées au cours des traitements antituberculeux incluant la rifampicine. Revue Français des Maladies Respiratoires 1974; 2:565.
  62. Israel HL, Gottlieb JE, Maddrey WC. Perspective: preventive isoniazid therapy and the liver. Chest 1992; 101:1298.