9/10/2017 Isoniazid hepatotoxicity - UpToDate

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Isoniazid hepatotoxicity

Authors: Anne M Larson, MD, FACP, FAASLD, AGAF, Amy L Graziani, PharmD
Section Editor: C Fordham von Reyn, MD
Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Sep 2017. | This topic last updated: Feb 09, 2017.

INTRODUCTION Isoniazid (INH; isonicotinylhydrazide or isonicotinic acid hydrazine) is a synthetic antibiotic that is potently bactericidal against replicating
Mycobacterium tuberculosis. INH has since been associated with two syndromes of hepatotoxicity: mild INH hepatotoxicity and INH hepatitis [1-3].

Issues related to INH hepatotoxicity will be reviewed here. The clinical use of INH is discussed separately. (See "Treatment of latent tuberculosis infection in HIV-
uninfected adults" and "Treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected adults".)

MILD INH HEPATOTOXICITY Mild isoniazid (INH) hepatotoxicity refers to hepatic injury that is typically subclinical and evidenced only by mildly elevated serum
aminotransferases (usually <100 international units/L) [4-6]. It occurs in up to 20 percent of patients treated with isoniazid [7-11].

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.

Most cases are self-limited; in general, INH therapy can be continued with careful monitoring in the absence of dose adjustment. Typically aminotransferase levels
return to normal within several weeks after discontinuation of INH [12,13].

INH HEPATITIS Isoniazid (INH) hepatitis is a more serious liver injury syndrome than mild INH hepatotoxicity; it is usually symptomatic and may be fatal [14,15].
It is an idiosyncratic reaction that is not clearly related to dose or duration of therapy.

Prevalence and risk factors The risk of INH hepatitis associated with isoniazid therapy for treatment of latent tuberculosis is 0.5 to 1.0 percent; INH hepatitis is
fatal in 0.05 to 0.1 percent of cases [6,16-21].

Risk factors for the development of hepatotoxicity include [6,17,22-31]:

Increased age [17,32-34].

Regular alcohol intake [17,23]. It is possible that the use of alcohol may increase the risk of hepatotoxicity. One study noted development of hepatitis in 2.6
percent of patients treated with isoniazid who drank alcohol daily [35].

Concurrent use of medications that induce CYP (P450) oxidative enzymes (table 1) and/or are themselves hepatotoxic.

Previous INH intolerance (eg, headaches, dizziness, nausea). Rechallenge with INH may result in recurrence of hepatotoxicity; however, some studies have
shown that up to 80 percent of persons may be able to tolerate reintroduction of the drug [36,37].

Prior or concurrent liver disease, such as chronic viral hepatitis [38-41]. In one study of Vietnamese patients with hepatitis B treated with INH for latent
tuberculosis infection, patients with HBeAg positivity were more likely to develop severe INH toxicity than patients who were HBeAg negative [39]. However,
other studies have not observed an association between chronic viral hepatitis and risk for INH hepatotoxicity [42].

History of peripheral neuropathy or presence of risk factors for peripheral neuropathy (eg, due to diabetes mellitus or alcoholism).

Pregnancy and the immediate postpartum period.

Injection drug use.

Female gender (particularly if nonwhite) [33,43,44].

Genetic predisposition (as in the case of rapid acetylators) [45-48]. (See 'Mechanism of hepatotoxicity' below.)

Clinical manifestations Clinical manifestations of INH hepatitis typically occur within the first two to three months after initiation of therapy; they can occur as
late as 14 months after initiation of therapy [6,13,17,22].

Clinical manifestations include fatigue, malaise, anorexia, and/or nausea, with or without vomiting. Approximately one-third of patients have generalized flu-like
symptoms, and some have right upper quadrant pain. Liver injury is typically hepatocellular; however, jaundice is a presenting feature in approximately 10 percent of
cases and manifests days to weeks after onset of the above symptoms [22,49].

INH hepatitis may be associated with the development of hepatocellular necrosis and acute liver failure in up to 1 to 3 percent of cases; clinical manifestations may
include ascites, edema, and encephalopathy [6,17,33]. The physical examination is largely nonspecific. Jaundice and abdominal pain may be present. Fever, rash,
lymphadenopathy, and hepatomegaly are uncommon.

Laboratory evaluation characteristically demonstrates elevated aminotransferases (>10 times the upper limit of normal [ULN]) and variable elevations in alkaline
phosphatase (usually <2 times ULN), bilirubin, and prothrombin time [33].

Histologically, liver injury is predominantly hepatocellular in nature and ranges from focal mononuclear cell infiltrate to diffuse massive necrosis [13,49,50].

Diagnosis The diagnosis of INH hepatitis should be suspected in patients taking isoniazid who develop fatigue, malaise, anorexia, nausea, and/or vomiting in
association with elevated serum aminotransferases. The diagnosis is established clinically, based on clinical manifestations and exclusion of other causes; the
diagnosis is supported by resolution of elevated aminotransferases within several weeks after discontinuation of therapy [3].

There is overlap in the pattern of liver injury caused by isoniazid and other antituberculous agents including rifampin and pyrazinamide; all individually or in
combination may contribute to hepatotoxicity.

Clinical evaluation of patients with suspected INH hepatitis should include clinical history regarding alcohol use and exposure to other potential hepatotoxins.
Laboratory evaluation should include testing for viral hepatitis and autoimmune hepatitis. (See 'Differential diagnosis' below.)

Additional issues related to diagnostic evaluation of drug-induced liver injury are discussed separately. (See "Drug-induced liver injury", section on 'Diagnosis'.)

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Differential diagnosis The differential diagnosis of INH hepatitis includes other causes of elevated aminotransferases (see "Approach to the patient with
abnormal liver biochemical and function tests", section on 'Elevated serum aminotransferases'):

Viral hepatitis Viral hepatitis can occur as a result of infection due to hepatitis A, B, C, D, E, Epstein-Barr virus, cytomegalovirus, HIV, or other viral infections.
The clinical manifestations include fatigue, malaise, anorexia, nausea, and/or vomiting. The diagnosis is established via serology. (See related topics).

Drug-induced liver injury Drug-induced liver injury associated with medications or herbal therapies may present with mild, asymptomatic liver test
abnormalities, cholestasis with pruritus, acute jaundice, or acute liver failure. The diagnosis is established based clinically. (See "Drug-induced liver injury".)

Autoimmune hepatitis Clinical manifestations of autoimmune hepatitis include fatigue, anorexia, nausea, abdominal pain, and itching. Isoniazid can induce
development antinuclear antibodies, even without hepatotoxicity. In the setting of INH hepatitis, autoantibody titers are generally low and hyperglobulinemia is
not seen. The diagnosis of autoimmune hepatitis is based upon characteristic serologic and histologic findings. (See "Autoimmune hepatitis: Clinical
manifestations and diagnosis".)

Ischemic injury Ischemic hepatitis refers to diffuse hepatic injury resulting from acute hypoperfusion. Most patients have no symptoms referable to the liver but
have marked elevation of the serum aminotransferase levels (exceeding 1000 international units/L or 50 times the upper limit of normal) after an episode of
hypotension. (See "Ischemic hepatitis, hepatic infarction, and ischemic cholangiopathy".)

Management Management of INH hepatitis consists of timely discontinuation of INH and other potential hepatotoxins [6]. In severe cases, liver transplantation
may be required [17,51].

In general, hepatitis attributed to antituberculous drugs should prompt discontinuation of all hepatotoxic drugs if the serum bilirubin is 3 mg/dL or serum
transaminases are more than five times the upper limit of normal (algorithm 1) [1,3].

Once liver function tests return to baseline (or fall to less than twice normal), potentially hepatotoxic drugs can be restarted one at a time with careful monitoring
between resumption of each agent (algorithm 1). (See "Treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected adults", section on 'Hepatotoxicity'.)

The approach to regimen adjustment for drug intolerance is discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected
adults", section on 'Regimen adjustments for drug intolerance' and "Treatment of latent tuberculosis infection in HIV-uninfected adults", section on 'Monitoring'.)

Prevention Use of INH should be limited to appropriate clinical circumstances, and patients should be educated about the signs and symptoms of hepatic toxicity
[3,17,52].

Issues related to clinical and laboratory monitoring for patients on isoniazid for treatment of latent tuberculosis infection are discussed separately. (See "Treatment of
latent tuberculosis infection in HIV-uninfected adults", section on 'Monitoring' and "Treatment of latent tuberculosis infection in HIV-infected adults", section on
'Patient monitoring'.)

Issues related to clinical and laboratory monitoring for patients on isoniazid and other antituberculous drugs for treatment of active tuberculosis infection are
discussed separately. (See "Antituberculous drugs: An overview", section on 'Clinical and laboratory monitoring for adverse effects'.)

Prognosis The overall case-fatality rate in patients who develop clinically apparent hepatitis is approximately 10 percent [22]. Older adult patients or those who
present with INH hepatitis after taking the drug for more than two months have a worse prognosis [5,22,53,54]. Some studies have found a higher case-fatality rate
among African-American patients than other patients, as well as a higher case-fatality rate among African-American women than African-American men [22,29,55-
57].

MECHANISM OF HEPATOTOXICITY The mechanism of isoniazid (INH) hepatotoxicity is not completely understood [58]. Toxicity is likely associated with
metabolism of the drug [22,58-60]. Alternatively, liver injury may occur via induction of an immune response that causes liver injury [61].

INH is rapidly absorbed from the gastrointestinal tract and diffuses into all body tissues [62]. The plasma concentration reaches its peak approximately one to three
hours after ingestion of the medication [58]. Hepatic metabolism of INH creates numerous metabolites including isonicotinic acid (INA), hydrazine (HZ), ammonia,
N1-acetyl-N2-isonicotinylhydrazide (AcINH or acetylINH), monoacetylhydrazine (AcHZ), diacetylhydrazine (DiAcHZ), and oxidizing free radicals [63]. These
compounds are formed via three predominant reactions [64]:

Acyl amidase hydrolysis Forming INA and HZ

Cytochrome P450 oxidation Forming HZ, ammonia, and free radicals
N-acetyltransferase 2 (NAT2) activity Forming AcINH, AcHZ, and DiAcHZ

Hydrazine, AcHZ, and toxic free radicals are the drug metabolites that have been most consistently implicated in the pathogenesis of INH hepatitis [65,66]. INH is
first acetylated in the liver via NAT2 to form the inactive compound AcINH, which is then hydrolyzed to form AcHZ and INA [63]. Acetylhydrazine is usually further
acetylated to the nontoxic derivative diacetylhydrazine and excreted in the urine; it is also oxidized into ammonia by the liver (muscle, kidney, and brain also
contribute) [63]. In addition, acetylhydrazine can be oxidized by the cytochrome P450 pathway to form toxic reactive acetyl free radicals that can form covalent
bonds with liver cell macromolecules, interfering with their function and leading to hepatocellular necrosis and cell death [5,7,45,59,65,67-69]. Cytochrome isoforms
2E1, 2B1, and 1A1/A2 have been implicated in this process [70-72].

NAT2 is the primary enzyme involved in the metabolism of INH, and deficiency of this enzyme has been associated with INH hepatotoxicity. The mechanism by
which the NAT2 deficiency may cause hepatotoxicity is not known [58]. NAT2 is highly polymorphic, and genetic polymorphisms are associated with trimodal
pharmacokinetics of INH: slow, intermediate, and fast acetylation [73-77]. Data on the association between acetylator phenotype and risk of INH hepatotoxicity
remain conflicting [8,25,27,32,53,64,68,78-87]. In theory, rapid acetylation of AcHZ should reduce the formation of toxic acetylhydrazine oxidative metabolites [45].

Subsequent studies have demonstrated a higher rate of toxicity in slow acetylators, who have a higher concentration of AcHZ [45-47,77,82,88,89]. The AcHZ is then
diverted into an alternate CYP pathway, which results in the development of hepatotoxic metabolites. Data that show a higher risk of hepatitis when INH is combined
with rifampin and other CYP inducers support this theory [80]. In one study, for example, N-acetyltransferase (NAT2) and CYP2E1 testing was performed in 89
patients receiving INH for treatment of latent tuberculosis [72]. NAT2 testing was not predictive of hepatotoxicity, but the CYP2E1 *1a/*1a genotype (but not CYP2E1
overall) significantly correlated with the development of elevated liver enzymes. Other data suggest that individuals carrying the CYP2E1 c1/c1 genotype are at
greater risk for hepatotoxicity [83]. In a Chinese population, this genotype carried up to a 3.9-fold increased probability of hepatotoxicity in rapid acetylators and a
7.4-fold increased probability of hepatotoxicity in slow acetylators [83]. INH may also promote the development of hepatitis by inhibiting CYP2E and CYP2C, which
could increase levels of other hepatotoxic drugs that are metabolized by these enzymes (eg, phenytoin and carbamazepine) [3].

Rifampin is seldom hepatotoxic when used alone but increases the activity of the CYP system and thereby can increase the production of toxic metabolites from
INH. Toxic hepatitis is seen with the combination of INH and rifampin more frequently (5 to 8 percent) than with either drug alone [79,90-92], and hepatitis occurs
sooner, mainly during the first month [92]. (See "Rifamycins (rifampin, rifabutin, rifapentine)".)

INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education
pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition.

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These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are
longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth
information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient
education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Toxic hepatitis (The Basics)")

SUMMARY

Isoniazid (INH) is a synthetic antibiotic that is bactericidal against replicating Mycobacterium tuberculosis. INH has been associated with two syndromes of
hepatotoxicity: mild INH hepatotoxicity and INH hepatitis. (See 'Introduction' above.)

Mild INH hepatotoxicity refers to hepatic injury that is typically subclinical and evidenced only by mildly elevated serum aminotransferases (usually <100
international units/L). Most cases are self-limited; in general, INH therapy can be continued with careful monitoring. Typically, aminotransferase levels return to
normal within several weeks after discontinuation of INH. (See 'Mild INH hepatotoxicity' above.)

INH hepatitis is a more serious liver injury syndrome than mild INH hepatotoxicity; it is usually symptomatic and may be fatal. It is an idiosyncratic reaction that
is not clearly related to dose or duration of therapy. Risk factors include age, alcohol use, use of concomitant hepatotoxic drugs, and prior or concurrent liver
disease. (See 'INH hepatitis' above and 'Prevalence and risk factors' above.)

Clinical manifestations of INH hepatitis typically occur within the first two to three months after initiation of therapy; they include fatigue, malaise, anorexia,
and/or nausea, with or without vomiting. Approximately one-third of patients have generalized flu-like symptoms, and some have right upper quadrant pain.
Jaundice is a presenting feature in approximately 10 percent of cases and manifests days to weeks after onset of the above symptoms. (See 'Clinical
manifestations' above.)

The diagnosis of INH hepatitis should be suspected in patients taking INH who develop fatigue, malaise, anorexia, nausea, and/or vomiting in association with
elevated serum aminotransferases. The diagnosis is established clinically, based on clinical manifestations and exclusion of other causes; the diagnosis is
supported by resolution of elevated aminotransferases within several weeks after discontinuation of therapy. (See 'Diagnosis' above.)

Clinical evaluation of patients with suspected INH hepatitis should include clinical history regarding alcohol use and exposure to other potential hepatotoxins.
Laboratory evaluation should include testing for viral hepatitis and autoimmune hepatitis. (See 'Differential diagnosis' above.)

Management of INH hepatitis consists of timely discontinuation of INH and other potential hepatotoxins. In general, hepatitis attributed to antituberculous drugs
should prompt discontinuation of all hepatotoxic drugs if the serum bilirubin is 3 mg/dL or serum transaminases are more than five times the upper limit of
normal (algorithm 1). (See 'Management' above.)

Use of INH should be limited to appropriate clinical circumstances, and patients should be educated about the signs and symptoms of hepatic toxicity. Issues
related to clinical and laboratory monitoring for patients on isoniazid are discussed separately. (See "Treatment of latent tuberculosis infection in HIV-uninfected
adults", section on 'Monitoring' and "Treatment of latent tuberculosis infection in HIV-infected adults", section on 'Patient monitoring' and "Antituberculous drugs:
An overview", section on 'Clinical and laboratory monitoring for adverse effects'.)

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REFERENCES

1. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America
Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis 2016; 63:e147.
2. Lewinsohn DM, Leonard MK, LoBue PA, et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and
Prevention Clinical Practice Guidelines: Diagnosis of Tuberculosis in Adults and Children. Clin Infect Dis 2017; 64:e1.
3. 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.
4. Scharer L, Smith JP. Serum transaminase elevations and other hepatic abnormalities in patients receiving isoniazid. Ann Intern Med 1969; 71:1113.
5. 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.
6. Hayashi PH, Fontana RJ, Chalasani NP, et al. Under-reporting and Poor Adherence to Monitoring Guidelines for Severe Cases of Isoniazid Hepatotoxicity. Clin
Gastroenterol Hepatol 2015; 13:1676.
7. Mitchell JR, Zimmerman HJ, Ishak KG, et al. Isoniazid liver injury: clinical spectrum, pathology, and probable pathogenesis. Ann Intern Med 1976; 84:181.
8. Yamada S, Tang M, Richardson K, et al. Genetic variations of NAT2 and CYP2E1 and isoniazid hepatotoxicity in a diverse population. Pharmacogenomics
2009; 10:1433.
9. P V K, Palaian S, Ojha P, P R S. Pattern of adverse drug reactions experienced by tuberculosis patients in a tertiary care teaching hospital in Western Nepal.
Pak J Pharm Sci 2008; 21:51.
10. Vieira DE, Gomes M. Adverse effects of tuberculosis treatment: experience at an outpatient clinic of a teaching hospital in the city of So Paulo, Brazil. J Bras
Pneumol 2008; 34:1049.
11. Chalasani N, Fontana RJ, Bonkovsky HL, et al. Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United
States. Gastroenterology 2008; 135:1924.
12. Salpeter SR. Fatal isoniazid-induced hepatitis. Its risk during chemoprophylaxis. West J Med 1993; 159:560.
13. Metushi I, Uetrecht J, Phillips E. Mechanism of isoniazid-induced hepatotoxicity: then and now. Br J Clin Pharmacol 2016; 81:1030.
14. Garibaldi RA, Drusin RE, Ferebee SH, Gregg MB. Isoniazid-associated hepatitis. Report of an outbreak. Am Rev Respir Dis 1972; 106:357.
15. 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.
16. 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.
17. Centers for Disease Control and Prevention (CDC). Severe isoniazid-associated liver injuries among persons being treated for latent tuberculosis infection -
United States, 2004-2008. MMWR Morb Mortal Wkly Rep 2010; 59:224.

https://www.uptodate.com/contents/isoniazid-hepatotoxicity/print?source=search_result&search=TOXICIDAD%20HEPATICA&selectedTitle=5~150 3/8
9/10/2017 Isoniazid hepatotoxicity - UpToDate

18. Chalasani N, Bonkovsky HL, Fontana R, et al. Features and Outcomes of 899 Patients With Drug-Induced Liver Injury: The DILIN Prospective Study.
Gastroenterology 2015; 148:1340.
19. 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.
20. 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.
21. Young H, Wessolossky M, Ellis J, et al. A retrospective evaluation of completion rates, total cost, and adverse effects for treatment of latent tuberculosis
infection in a public health clinic in central massachusetts. Clin Infect Dis 2009; 49:424.
22. Black M, Mitchell JR, Zimmerman HJ, et al. Isoniazid-associated hepatitis in 114 patients. Gastroenterology 1975; 69:289.
23. Grnhagen-Riska C, Hellstrom PE, Frseth B. Predisposing factors in hepatitis induced by isoniazid-rifampin treatment of tuberculosis. Am Rev Respir Dis
1978; 118:461.
24. Centers for Disease Control and Prevention. Core curriculum on tuberculosis. What the clinician should know, 4th ed. .S. Department of Health and Human Se
rvices, Public Health Services; Atlanta, 2000.
25. Holdiness MR. Clinical pharmacokinetics of the antituberculosis drugs. Clin Pharmacokinet 1984; 9:511.
26. Maddrey WC. Drug-related acute and chronic hepatitis. Clin Gastroenterol 1980; 9:213.
27. Dickinson DS, Bailey WC, Hirschowitz BI, et al. Risk factors for isoniazid (NIH)-induced liver dysfunction. J Clin Gastroenterol 1981; 3:271.
28. 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.
29. Snider DE Jr, Caras GJ. Isoniazid-associated hepatitis deaths: a review of available information. Am Rev Respir Dis 1992; 145:494.
30. 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.
31. 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.
32. 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.
33. Liver Tox: Isoniazid. http://livertox.nlm.nih.gov/isoniazid.htm (Accessed on February 07, 2017).
34. Mach J, Huizer-Pajkos A, Mitchell SJ, et al. The effect of ageing on isoniazid pharmacokinetics and hepatotoxicity in Fischer 344 rats. Fundam Clin Pharmacol
2016; 30:23.
35. Pande JN, Singh SP, Khilnani GC, et al. Risk factors for hepatotoxicity from antituberculosis drugs: a case-control study. Thorax 1996; 51:132.
36. Durand F, Jebrak G, Pessayre D, et al. Hepatotoxicity of antitubercular treatments. Rationale for monitoring liver status. Drug Saf 1996; 15:394.
37. Saukkonen J. Challenges in reintroducing tuberculosis medications after hepatotoxicity. Clin Infect Dis 2010; 50:840.
38. Fernndez-Villar A, Sopea B, Vzquez R, et al. Isoniazid hepatotoxicity among drug users: the role of hepatitis C. Clin Infect Dis 2003; 36:293.
39. 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.
40. Yew WW. Risk factors for hepatotoxicity during anti-tuberculosis chemotherapy in Asian populations. Int J Tuberc Lung Dis 2001; 5:99.
41. Chang KC, Leung CC, Yew WW, et al. Hepatotoxicity of pyrazinamide: cohort and case-control analyses. Am J Respir Crit Care Med 2008; 177:1391.
42. 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.
43. Wu JC, Lee SD, Yeh PF, et al. Isoniazid-rifampin-induced hepatitis in hepatitis B carriers. Gastroenterology 1990; 98:502.
44. Shu CC, Lee CH, Lee MC, et al. Hepatotoxicity due to first-line anti-tuberculosis drugs: a five-year experience in a Taiwan medical centre. Int J Tuberc Lung
Dis 2013; 17:934.
45. 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.
46. Bose PD, Sarma MP, Medhi S, et al. Role of polymorphic N-acetyl transferase2 and cytochrome P4502E1 gene in antituberculosis treatment-induced hepatitis.
J Gastroenterol Hepatol 2011; 26:312.
47. Xiang Y, Ma L, Wu W, et al. The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association
with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1. PLoS One 2014; 9:e85905.
48. Seng KY, Hee KH, Soon GH, et al. Population pharmacokinetic analysis of isoniazid, acetylisoniazid, and isonicotinic acid in healthy volunteers. Antimicrob
Agents Chemother 2015; 59:6791.
49. Maddrey WC, Boitnott JK. Isoniazid hepatitis. Ann Intern Med 1973; 79:1.
50. Reddy KR, Schiff ER. Hepatotoxicity of antimicrobial, antifungal, and antiparasitic agents. Gastroenterol Clin North Am 1995; 24:923.
51. 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.
52. Israel HL, Gottlieb JE, Maddrey WC. Perspective: preventive isoniazid therapy and the liver. Chest 1992; 101:1298.
53. Girling DJ. The hepatic toxicity of antituberculosis regimens containing isoniazid, rifampicin and pyrazinamide. Tubercle 1978; 59:13.
54. Bailey WC, Weill H, DeRouen TA, et al. The effect of isoniazid on transaminase levels. Ann Intern Med 1974; 81:200.
55. Millard PS, Wilcosky TC, Reade-Christopher SJ, Weber DJ. Isoniazid-related fatal hepatitis. West J Med 1996; 164:486.
56. Levin ML, Moodie AS. Isoniazid prophylaxis and deaths in Baltimore, Maryland 1972. Bull Int Union Tuberc 1976; 51:213.
57. Long MW, Snider DE Jr, Farer LS. U.S. Public Health Service Cooperative trial of three rifampin-isoniazid regimens in treatment of pulmonary tuberculosis. Am
Rev Respir Dis 1979; 119:879.
58. Wang P, Pradhan K, Zhong XB, Ma X. Isoniazid metabolism and hepatotoxicity. Acta Pharm Sin B 2016; 6:384.
59. Metushi IG, Nakagawa T, Uetrecht J. Direct oxidation and covalent binding of isoniazid to rodent liver and human hepatic microsomes: humans are more like
mice than rats. Chem Res Toxicol 2012; 25:2567.

https://www.uptodate.com/contents/isoniazid-hepatotoxicity/print?source=search_result&search=TOXICIDAD%20HEPATICA&selectedTitle=5~150 4/8
9/10/2017 Isoniazid hepatotoxicity - UpToDate

60. Chowdhury A, Santra A, Bhattacharjee K, et al. Mitochondrial oxidative stress and permeability transition in isoniazid and rifampicin induced liver injury in mice.
J Hepatol 2006; 45:117.
61. 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.
62. Weber WW, Hein DW. Clinical pharmacokinetics of isoniazid. Clin Pharmacokinet 1979; 4:401.
63. Preziosi P. Isoniazid: metabolic aspects and toxicological correlates. Curr Drug Metab 2007; 8:839.
64. Boelsterli UA, Lee KK. Mechanisms of isoniazid-induced idiosyncratic liver injury: emerging role of mitochondrial stress. J Gastroenterol Hepatol 2014; 29:678.
65. 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.
66. Sarich TC, Youssefi M, Zhou T, et al. Role of hydrazine in the mechanism of isoniazid hepatotoxicity in rabbits. Arch Toxicol 1996; 70:835.
67. 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.
68. Timbrell JA, Wright JM, Baillie TA. Monoacetylhydrazine as a metabolite of isoniazid in man. Clin Pharmacol Ther 1977; 22:602.
69. 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.
70. Delaney J, Timbrell JA. Role of cytochrome P450 in hydrazine toxicity in isolated hepatocytes in vitro. Xenobiotica 1995; 25:1399.
71. 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.
72. 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.
73. Parkin DP, Vandenplas S, Botha FJ, et al. Trimodality of isoniazid elimination: phenotype and genotype in patients with tuberculosis. Am J Respir Crit Care
Med 1997; 155:1717.
74. Hein DW, Doll MA, Fretland AJ, et al. Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiol Biomarkers
Prev 2000; 9:29.
75. Cordes H, Thiel C, Aschmann HE, et al. A Physiologically Based Pharmacokinetic Model of Isoniazid and Its Application in Individualizing Tuberculosis
Chemotherapy. Antimicrob Agents Chemother 2016; 60:6134.
76. Sim E, Abuhammad A, Ryan A. Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery. Br J Pharmacol 2014;
171:2705.
77. Walker K, Ginsberg G, Hattis D, et al. Genetic polymorphism in N-Acetyltransferase (NAT): Population distribution of NAT1 and NAT2 activity. J Toxicol Environ
Health B Crit Rev 2009; 12:440.
78. 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.
79. Pessayre D, Larrey D. Acute and chronic drug-induced hepatitis. Baillieres Clin Gastroenterol 1988; 2:385.
80. Yamamoto T, Suou T, Hirayama C. Elevated serum aminotransferase induced by isoniazid in relation to isoniazid acetylator phenotype. Hepatology 1986;
6:295.
81. 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.
82. 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.
83. Huang YS, Chern HD, Su WJ, et al. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology 2003;
37:924.
84. Furet Y, Bechtel Y, Le Guellec C, et al. [Clinical relevance of N-acetyltransferase type 2 (NAT2) genetic polymorphism]. Therapie 2002; 57:427.
85. 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.
86. Cai Y, Yi J, Zhou C, Shen X. Pharmacogenetic study of drug-metabolising enzyme polymorphisms on the risk of anti-tuberculosis drug-induced liver injury: a
meta-analysis. PLoS One 2012; 7:e47769.
87. Huang YS. Recent progress in genetic variation and risk of antituberculosis drug-induced liver injury. J Chin Med Assoc 2014; 77:169.
88. Ng CS, Hasnat A, Al Maruf A, et al. N-acetyltransferase 2 (NAT2) genotype as a risk factor for development of drug-induced liver injury relating to
antituberculosis drug treatment in a mixed-ethnicity patient group. Eur J Clin Pharmacol 2014; 70:1079.
89. Teixeira RL, Morato RG, Cabello PH, et al. Genetic polymorphisms of NAT2, CYP2E1 and GST enzymes and the occurrence of antituberculosis drug-induced
hepatitis in Brazilian TB patients. Mem Inst Oswaldo Cruz 2011; 106:716.
90. Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest 1991; 99:465.
91. Lees AW, Allan GW, Smith J, et al. Toxicity form rifampicin plus isoniazid and rifampicin plus ethambutol therapy. Tubercle 1971; 52:182.
92. Emerit J, Decroix G, Chomette C, et al. Donnes nouvelles sur les hpitites observes au cours des traitements antituberculeux incluant la rifampicine. Revue
Franais des Maladies Respiratoires 1974; 2:565.

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GRAPHICS

Cytochrome P450 3A4 (CYP3A4) inhibitors and inducers*

Strong inhibitors Moderate inhibitors Strong inducers Moderate inducers

Atazanavir Amiodarone Carbamazepine Bexarotene

Boceprevir Aprepitant Enzalutamide Bosentan

Ceritinib Cimetidine Fosphenytoin Dabrafenib

Clarithromycin Conivaptan Lumacaftor Dexamethasone

Cobicistat and cobicistat containing Crizotinib Mitotane Efavirenz

Cyclosporine
coformulations
Phenobarbital Eslicarbazepine
Darunavir
Diltiazem Phenytoin Etravirine
Idelalisib
Dronedarone Primidone Modafinil
Indinavir
Erythromycin Rifabutin Nafcillin
Itraconazole
Fluconazole Rifampin (rifampicin) St. John's wort
Ketoconazole
Fosamprenavir Rifapentine

Fosaprepitant
Lopinavir

Mifepristone
Grapefruit juice
Nefazodone
Imatinib
Nelfinavir
Isavuconazole (isavuconazonium
Ombitasvir-paritaprevir-ritonavir sulfate)

Ombitasvir-paritaprevir-ritonavir plus Netupitant

dasabuvir
Nilotinib
Posaconazole
Ribociclib
Ritonavir and ritonavir containing
Schisandra
coformulations
Verapamil
Saquinavir

Telaprevir

Telithromycin

Voriconazole

Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of administration. Specific drug interactions and management
suggestions may be determined by using Lexi-Interact, the drug interactions program included with UpToDate. Refer to UpToDate topics on specific agents and indications for
further details.

* The CYP3A4 inhibitors and inducers listed in this table are relevant for determining potential interactions of drugs that are CYP3A subfamily substrates.
Weak effect on CYP3A4.

Data from: Lexicomp Online (Lexi-Interact). Copyright 1978-2017 Lexicomp, Inc. All Rights Reserved

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Approach to hepatotoxicity caused by first-line antituberculous drugs in adults*

* First-line antituberculous drugs include isoniazid, rifampin, pyrazinamide and ethabutol. Isoniazid, rifampin and pyrazinamide are potentially hepatotoxic; ethambutol is not hepatotoxic.
Liver function tests include measurement of serum bilirubin, alkaline phosphatase, and hepatocellular enzymes (alanine aminotransferase and aspartate aminotransferase).
Alternative causes of elevated liver function tests include alcohol, acetaminophen, viral hepatitis, gallstones, biliary obstruction, and others.
Signs and symptoms of hepatotoxicity include nausea, vomiting, malaise, low-grade fever, and anorexia. Refer to the UpToDate topic on drug-induced liver injury for further discussion.
The approach to subsequent monitoring depends on clinical circumstances; some favor checking liver function tests weekly until on a stable regimen, then every two to four weeks
thereafter.
There is overlap in the pattern of liver injury caused by rifampin, isoniazid, and pyrazinamide; all individually or in combination may contribute to hepatotoxicity.
Intervals of treatment interruption warranting resumption of therapy from the beginning vary between initiation and continuation phases; refer to text for further discussion.
Refer to UpToDate content on treatment of tuberculosis for further discussion.

References
1. Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, Third Edition.
2. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice
Guidelines: Treatment of Drug-Susceptible Tuberculosis. Clin Infect Dis 2016.

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Contributor Disclosures
Anne M Larson, MD, FACP, FAASLD, AGAF Nothing to disclose Amy L Graziani, PharmD Equity Ownership/Stock Options: Bristol-Myers Squibb; Johnson and
Johnson. C Fordham von Reyn, MD Grant/Research/Clinical Trial Support: Oxford Immunotec [Tuberculosis (vaccine)]. Elinor L Baron, MD, DTMH Nothing to
disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process,
and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to
UpToDate standards of evidence.

Conflict of interest policy

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