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Isoniazid hepatotoxicity

Isoniazid hepatotoxicity
Literature review current through: Jan 2024.
This topic last updated: Mar 30, 2023.

INTRODUCTION — Isoniazid (INH; isonicotinylhydrazide or isonicotinic acid hydrazine) is a synthetic antimycobacterial that inhibits cell wall synthesis and is potently bactericidal against replicating Mycobacterium tuberculosis.

INH has been associated with two syndromes of hepatotoxicity: mild INH hepatotoxicity and INH hepatitis [1-4]. It is the second most common drug causing liver injury [5].

Issues related to INH hepatotoxicity will be reviewed here. The clinical use of INH is discussed separately. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection".)

MILD INH HEPATOTOXICITY — Mild INH hepatotoxicity refers to hepatic injury that is typically subclinical and asymptomatic. It is evidenced by transiently mildly elevated serum aminotransferases (usually <100 international units/L or less than three-fold increase above the upper limit of normal [ULN]) [5-7]. It develops in up to 20 percent of patients treated with INH [8-12].

Adults are more likely to be affected than children; males and females appear to be equally vulnerable [13]. 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 [14,15].

INH HEPATITIS — INH hepatitis is a potentially fatal liver injury. It is usually symptomatic and may be fatal [16,17]. The occurrence is idiosyncratic and is not clearly related to dose or duration of therapy.

Prevalence and risk factors — The risk of INH hepatitis associated with INH therapy for treatment of tuberculosis (TB) infection (latent TB) is 0.5 to 1.0 percent; INH hepatitis is fatal in 0.05 to 0.1 percent of cases [5,18-23].

Risk factors for the development of hepatotoxicity include [5,19,24-33]:

Increased age [19,31,34-38] with an odds ratio for adverse events of 1.8 for individuals 35 to 64 years and 3.0 for individuals aged 65 to 90 years [39]. The severity of hepatotoxicity and mortality are also associated with increasing age [4].

Regular alcohol intake [19,25]. It is possible that alcohol use may increase the risk of hepatotoxicity; one study noted development of hepatitis in 2.6 percent of patients treated with INH who drank alcohol daily [40].

Concurrent use of medications that induce CYP (P450) oxidative enzymes (table 1) and/or are themselves hepatotoxic (eg, anticonvulsants, azole antifungals, phenobarbital, pyrazinamide, acetaminophen-containing preparations, lipid-lowering agents, herbal supplements, and others) [1,41,42]. Concurrent use of rifampin appears to promote formation of toxic INH metabolites [4].

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 [43,44].

Prior or concurrent liver disease, such as chronic viral hepatitis [41,45-47]. 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 [46]. However, other studies have not observed an association between chronic viral hepatitis and risk for INH hepatotoxicity [48]. The presence of elevated liver enzymes is an independent risk factor for INH hepatotoxicity [4].

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 with an odds ratio for hepatoxicity of 1.64 [49]. However, the data regarding risk to pregnancy outcomes remain inconsistent.

Injection drug use.

Female sex has been reported as a risk factor for hepatotoxicity; however not all studies have found this association [34,37,50,51].

Genetic predisposition (particularly acetylator status) with three variant alleles on the N-acetyltransferase 2 (NAT2) gene leading to slow acetylation: position 481C>T, position 590G>A, and position 857G>A [52-57]. Polymorphisms in cytochrome P450 2E1 have also been shown to predispose to hepatotoxicity. A sevenfold increased risk of hepatotoxicity has been noted in patients with CYP2E1 c1/c1 and slow-acetylator status [53,58,59]. Testing for NAT2 polymorphisms may allow for adjustment in drug dosing to improve therapeutic effect and to reduce toxicity [60-64]. (See 'Mechanism of hepatotoxicity' below.)

Severely immunocompromised patients with advanced HIV infection [65].

Clinical manifestations — Clinical signs of INH hepatitis typically develop within the first two to three months after initiation of therapy, although they can occur as late as 14 months after initiation of therapy [5,15,19,24].

Clinical manifestations occur in up to 75 percent of patients and include fatigue, malaise, anorexia, and/or nausea, with or without vomiting [8,34,66]. Approximately one-third of patients have generalized flu-like symptoms, and some have right upper quadrant pain. Fever is seen in approximately 10 percent and rash in 5 percent of cases. 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 [24,67].

INH hepatitis may be associated with the development of severe hepatocellular necrosis and acute liver failure in up to 3 percent of cases. The clinical manifestations in this setting may include ascites, edema, and hepatic encephalopathy [5,19,34]. Liver enzymes >10-fold upper limit of normal (ULN) and presence of encephalopathy of jaundice are poor prognostic signs.

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 (may be >10 times the ULN) and variable elevations in alkaline phosphatase (usually <2 times ULN), bilirubin, and prothrombin time [34].

Histologically, liver injury is predominantly hepatocellular in nature and ranges from focal mononuclear cell infiltrate to diffuse massive necrosis [15,67,68].

Diagnosis — 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 [3].

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

Clinical evaluation of patients with suspected INH hepatitis should include a complete 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'.)

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 are similar to those seen in INH hepatotoxicity and 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 clinically. (See "Drug-induced liver injury".)

Autoimmune hepatitis – Clinical manifestations of autoimmune hepatitis include fatigue, anorexia, nausea, abdominal pain, and itching. INH can induce development antinuclear antibodies, even without hepatotoxicity. In the setting of INH hepatitis, autoantibody titers are generally low, and hypergammaglobulinemia is not seen, which helps to differentiate it from classic autoimmune hepatitis. The diagnosis of autoimmune hepatitis is based upon characteristic serologic and histologic findings. (See "Overview of autoimmune hepatitis".)

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 early recognition with timely discontinuation of INH and other potential hepatotoxins [5]. In severe cases, liver transplantation may be required [19,69].

In general, hepatitis attributed to antituberculosis 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 and algorithm 2) [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 and algorithm 2). (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection".)

The approach to regimen adjustment for drug intolerance is discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection", section on 'Regimen adjustments for drug intolerance'.)

Prevention — Use of INH should be limited to appropriate clinical circumstances, and patients should be educated about the signs and symptoms of hepatic toxicity; should toxicity be suspected, patients should be instructed to stop the medication and contact their provider [3,19,70].

Interest exists in development of newer formulations of INH which are less toxic. Examples include a cocrystal formulation (INH-quercetin), an alpha-lipoic acid formulation, hydrazide and aurone derivatives, and INH-a (INH-benzaldehyde) [71-75].

Issues related to clinical and laboratory monitoring for patients on INH for treatment of latent tuberculosis infection are discussed separately. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection", section on 'Monitoring and adherence'.)

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

Prognosis — The overall case-fatality rate in patients who develop clinically apparent hepatitis is approximately 10 percent [24]. Older adult patients or those who present with INH hepatitis after taking the drug for more than two months have a worse prognosis [7,24,76,77]. 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 females than African-American males [24,31,66,78,79].

MECHANISM OF HEPATOTOXICITY — The mechanism of INH hepatotoxicity remains incompletely understood [80]. Toxicity is likely associated with metabolism of the drug [24,80-82]. Alternatively, liver injury may occur via induction of an immune response that causes liver injury [83,84].

INH is rapidly absorbed from the gastrointestinal tract and diffuses into all body tissues [85]. The presence of food in the stomach significantly hinders absorption [86]. The plasma concentration reaches its peak approximately one to three hours after ingestion of the medication [80]. Hepatic metabolism of INH creates numerous metabolites including isonicotinic acid (INA), hydrazine (HZ), ammonia, N1-acetyl-N2-isonicotinylhydrazide (AcINH or acetylINH), acetylhydrazine (AcHZ), diacetylhydrazine (DiAcHZ), and oxidizing free radicals [87]. These compounds are formed via three predominant reactions [88]:

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

AcHZ, toxic free radicals, and particularly hydrazine are the drug metabolites that have been most consistently implicated in the pathogenesis of INH hepatitis [89,90]. INH is first acetylated within the liver via NAT2 to form the inactive compound AcINH, which is then hydrolyzed to form AcHZ and INA [87]. AcHZ is usually further acetylated to the nontoxic derivative DiAcHZ and excreted in the urine [17]. It is also oxidized into ammonia by the liver, with contributions from the muscle, kidney, and brain [87]. In addition, AcHZ 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 [7,8,52,81,89,91-93]. Cytochrome isoforms 2E1, 2B1, and 1A1/A2 have been implicated in this process [58,94,95].

NAT2 is a phase II enzyme and is the primary enzyme involved in the metabolism of INH [56]. Deficiency of this enzyme has been associated with INH hepatotoxicity. The exact mechanism by which the NAT2 deficiency may cause hepatotoxicity is not known [80]. NAT2 is highly polymorphic, and these genetic polymorphisms are associated with trimodal pharmacokinetics of INH with three phenotypes: slow, intermediate, and fast acetylation [75,96-100]. The NAT2 polymorphisms significantly affect the plasma concentrations of INH, with fast acetylators having lower plasma concentrations than slow acetylators [101,102]. There is a strong association between the polymorphisms and risk of hepatotoxicity from INH [103]. (See "Drugs and the liver: Metabolism and mechanisms of injury".)

Data on the association between acetylator phenotype and risk of INH hepatotoxicity remains conflicting [9,27,29,59,76,88,92,104-112]. Rapid acetylation of AcHZ should in theory reduce the formation of toxic AcHZ oxidative metabolites [52]. However, some have shown that rapid acetylators are more susceptible to liver injury due to increased production of hepatotoxins [113]. Studies have shown a higher rate of toxicity in slow acetylators carrying homozygous mutant alleles, leading to a higher concentration of AcHZ [52-54,100,108,111,114-116]. Meta-analysis has shown that genetic variants of NAT2 play a role in INH hepatotoxicity, particularly with three variant alleles: position 481C>T, position 590G>A, and position 857G>A [56,117].

Excess AcHZ is diverted into an alternate CYP pathway, resulting 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 [106]. In one study, for example, NAT2 and CYP2E1 testing was performed in 89 patients receiving INH for treatment of latent tuberculosis [58]. NAT2 testing was not predictive of hepatotoxicity. However, the CYP2E1 *1a/*1a genotype (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, particularly in the presence of slow acetylator NAT2 [59]. 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 [59,118,119]. 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 [105,120-122], and hepatitis occurs sooner, mainly during the first month [122]. (See "Rifamycins (rifampin, rifabutin, rifapentine)".)

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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 topic (see "Patient education: Drug-induced 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 are many and 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 but may occur later; 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 and algorithm 2). (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 INH are discussed separately. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection", section on 'Monitoring and adherence' and "Antituberculous drugs: An overview", section on 'Clinical and laboratory monitoring'.)

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Topic 477 Version 28.0

References

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