eMedicine Specialties > Gastroenterology > Liver

Isoniazid Hepatotoxicity

Author: Richard A Weisiger, MD, PhD, Director, GI and Liver Faculty Practice, Professor, Department of Internal Medicine, University of California San Francisco
Contributor Information and Disclosures

Updated: Jun 21, 2007

Introduction

Background

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. 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.

Pathophysiology

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 isoniazid is acetylated and then further hydrolyzed to isonicotinic acid and acetylhydrazine (see Media file 1). 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, 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 often is prescribed together 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 (see Media file 1).

While 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. 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.³²

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 Media file 2).¹⁶ Although the rate of hepatotoxicity is lower in more recent studies, age remains an important risk factor.

Clinical

History

Isoniazid hepatitis typically develops within the first few months of therapy, but it may present later (see Media file 3). Symptoms may remain mild until after potentially lethal liver damage has occurred. Thus, patients taking isoniazid should be educated to look for signs of liver toxicity and to report them immediately if they occur.

• Symptoms
• • Symptoms typically precede jaundice and liver failure by only a few days.
  • Constitutional symptoms include fatigue, anorexia, nausea, myalgia, and arthralgia.
  • Symptoms due to liver failure include jaundice, dark urine, light-colored stools, bleeding diathesis, pruritus, confusion, and coma.
  • Symptoms due to hepatic inflammation include right upper quadrant tenderness and gastrointestinal distress.
• Immediate cessation of isoniazid and any other potentially hepatotoxic drugs is required.

Physical

• Physical findings are characteristic of other forms of acute hepatitis.
• Jaundice, evidenced by yellowing of the skin, sclera, or mucous membranes, is present in more severe cases as a late manifestation.
• Right upper quadrant tenderness may occur.
• Hepatomegaly may occur, but splenomegaly and ascites usually are absent.
• Stigmata of chronic liver disease typically are absent unless prior liver disease exists.
• In advanced cases, patients may exhibit bleeding from the gingiva or ecchymoses or have other manifestations of coagulopathy.
• Hepatic encephalopathy or coma may develop after onset of other symptoms of severe disease.
• Signs of hypersensitivity, such as fever and skin rash, usually are absent.

Causes

Risk factors for development of severe isoniazid hepatitis include the following:

• Genetic predisposition is an important factor, but the specific genes responsible have not been adequately defined.
• Age is an important risk factor, presumably reflecting aged-related changes in hepatic metabolism (see Media file 2).
• Female gender increases both the risk of developing isoniazid hepatitis and the risk of death once hepatitis develops.
• Animal studies suggest that low levels of certain antioxidants, such as glutathione, which are associated with poor nutrition, increase risk. However, human studies are lacking.
• Prior or concurrent exposure to drugs that induce cytochrome P-450 enzymes increases the risk. These drugs include the following:
  
  
  • Phenobarbital
  • Rifampin
  • Alcohol
• Ethionamide and paraaminosalicylic acid may worsen isoniazid toxicity by interfering with its acetylation.
• Higher plasma levels of isoniazid do not increase the risk of hepatitis. Conversely, use of lower isoniazid doses or monitoring of plasma levels during therapy does not help decrease the risk of toxicity.

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