Isoniazid Hepatotoxicity 

Isoniazid (isonicotinic acid hydrazide [INH]) has been used since 1952 as a front-line antimicrobial for tuberculosis. It is commonly used alone for prophylaxis of patients who have conversion of their purified protein derivative (PPD) and normal chest x-ray films, and it also is used in combination with other medications for active disease.

Isoniazid hepatotoxicity is a common complication of antituberculosis therapy that ranges in severity from asymptomatic elevation of serum transaminases to hepatic failure requiring liver transplantation. This is not caused by high plasma isoniazid levels but appears to represent an idiosyncratic response.^[1] It presents a difficult management problem for several reasons.

• Patients who are affected often are taking other potentially hepatotoxic drugs, such as pyrazinamide or protease inhibitors, making it difficult to determine which drug is causing the liver damage.
• Most cases of isoniazid hepatotoxicity are mild (ie, asymptomatic with < 3-fold elevation of serum aspartate aminotransferase [AST] and alanine aminotransferase [ALT]) and commonly resolve despite continued therapy with isoniazid. However, a small number of adult patients taking isoniazid develop severe hepatitis that may progress to liver failure and death if the drug is not stopped promptly.
• Lack of effective alternative drugs often requires that isoniazid be continued despite low-grade hepatotoxicity.
• Patients who are severely affected may have few symptoms until potentially lethal liver damage has occurred.

The biochemical mechanism of isoniazid hepatotoxicity remains incompletely defined.

The most widely accepted theory is that isoniazid metabolism produces reactive metabolites that bind to and damage cellular macromolecules in the liver. Most of isoniazid is acetylated and then further hydrolyzed to isonicotinic acid and acetylhydrazine (see the diagram below). Persons with the rapid acetylator phenotype have been proposed to be more likely to display toxicity; however, most studies have failed to show such a relationship.

On the contrary, some studies suggest that people who are slow acetylators are at greater risk of isoniazid hepatotoxicity, suggesting that slow metabolism results in diversion of isoniazid metabolism to an alternate (eg, cytochrome P-450-mediated) pathway that may produce a toxic metabolite. This latter interpretation is supported by observations that drugs that induce cytochrome P-450 levels (including rifampin, which is often prescribed with isoniazid) appear to increase the risk of isoniazid toxicity.

The mild elevation of transaminases seen in as many as 20% of patients who are treated during the first 2 months of therapy may reflect direct toxicity from hydrazine metabolites, which can covalently bind to cellular macromolecules, including DNA. The more severe hepatitis seen in up to 1% of adults who are treated may be a consequence of the production of more reactive species by the cytochrome P-450 enzyme system (refer to the diagram above).

Although the most common presentation of isoniazid hepatotoxicity is hepatocellular damage, patients occasionally may present with true drug hypersensitivity characterized by skin rash, fever, and eosinophilia.

Frequency

United States

The frequency of isoniazid hepatotoxicity depends on the threshold for making the diagnosis.

Approximately 10-20% of adult patients receiving isoniazid develop elevation of serum ALT and AST from 1-3 times the upper limit of normal during the first 2 months of therapy. These tests typically normalize within 3-6 weeks after discontinuing the drug. However, most patients who continue on isoniazid also normalize their transaminases within several months with no apparent adverse effects.

A small percentage of older patients progress to more severe disease if isoniazid is not stopped. A comprehensive study of 13,838 patients treated with isoniazid published by the US Public Health Service (USPHS) in 1978 indicated that about 10% of patients who developed mild transaminase elevations (1-2% of all adults treated) progress to severe hepatitis and liver failure unless the drug is discontinued.^[2] Death occurred in 8 patients (0.06%). When isoniazid is given together with other drugs for active tuberculosis, the incidence of severe hepatotoxicity is greater.

More recent retrospective studies suggest a much lower incidence of toxicity, providing that patients are monitored according to current guidelines. The reason for the apparent decline in reported cases of isoniazid toxicity since 1978 is not known.

International

Rates within different countries reflect the frequency of isoniazid use and tend to be highest in countries that have both sufficient public health resources to treat tuberculosis and large populations of patients infected with tuberculosis. Many of these persons are co-infected with the human immunodeficiency virus (HIV). Patients who are co-infected are at a particularly high risk of hepatitis because both antituberculosis therapy and antiviral therapy may produce hepatotoxicity.

Mortality/Morbidity

Mortality rates depend critically on early detection. If drug therapy is discontinued promptly when a 3-fold or greater transaminase elevation occurs, mortality should be negligible. In contrast, if isoniazid is continued after this point or after symptoms develop, mortality due to hepatic failure may exceed 50% unless liver transplantation is performed. The overall case fatality rate for overt hepatic disease in most series exceeds 10% and appears to be higher in those diagnosed after 2 months of therapy.

Race

Racial differences in susceptibility are relatively small.

A 1975 study of more than 14,000 persons who were treated with isoniazid found that hepatitis developed in 1.1% (55/5190) of whites, 0.6% (36/6140) of blacks, and 0.9% (23/2608) of Asians, although follow-up was incomplete.

Because a smaller percentage of Asians (34%) dropped out of this study than whites (52%) or blacks (59%), the data suggest that the risk is lowest in Asians. Black females appeared to be at particularly high risk. However, a more recent study by Yee and coworkers found a significantly elevated risk in Asians.^[3]

Sex

Isoniazid hepatotoxicity may be more common in females than in males, especially the more severe forms of hepatitis leading to liver failure and death. However, not all studies have shown this finding.

Women in the immediate postpartum period appear to be commonly affected. However, this may be because women are more likely to have their tuberculosis infection diagnosed during pregnancy with treatment delayed until after childbirth.

Age

Risk increases dramatically with age.

According to a USPHS study reported by Kopanoff and workers in 1978, of 13,838 patients on prophylactic isoniazid therapy, hepatitis was uncommon in patients younger than 20 years and occurred in 0.3% of patients aged 20-34 years, 1.2% of patients aged 35-49 years, and 2.3% of patients aged 50-64 years (see the bar chart below).^[2] Although the rate of hepatotoxicity is lower in more recent studies, age remains an important risk factor.