AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 10  

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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

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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.

DIFFERENTIALS

Section 4 of 10  

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Other Problems to be Considered

Toxicity from other drugs

Exclude exogenous hepatotoxins, such as chlorinated hydrocarbons, poisonous mushrooms, and halothane (where it is still used), by careful review of the patient's history.

Other drugs commonly used with isoniazid that also may produce hepatotoxicity include protease inhibitors (for treating HIV) and pyrazinamide.

WORKUP

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Lab Studies

• Diagnosis requires exclusion of other causes of hepatitis.
  
  
  • Serum transaminases (AST, ALT): Transaminase values that are elevated less than 3-fold in a patient who is asymptomatic allow cautious continued administration of isoniazid. However, additional testing to exclude other causes of hepatitis is usually indicated. Transaminase elevations greater than this level usually require discontinuation of isoniazid and any other potentially hepatotoxic drugs.
  • Viral serologies: Hepatitis A may be excluded by a negative anti-HAV (hepatitis A virus) immunoglobulin M (IgM). Hepatitis C is excluded by a negative anti-HCV (hepatitis C virus) antibody; however, this test occasionally may remain negative for several weeks after onset of hepatitis C. Hepatitis B may be excluded either by a negative hepatitis B surface antigen (HBsAg) or by a negative antibody to hepatitis B core antigen (anti-HBc). Testing for viral DNA or RNA also may be used, but it is more expensive.
  • Exclude other toxins: In patients with a compatible history, blood or urine levels of other potential hepatotoxins (eg, acetaminophen, ethanol) may be useful.
  • Prothrombin time: The international normalized ratio (INR) usually is normal in early and mild cases. Significant elevation of the INR that does not respond to parenteral vitamin K is a grave sign that should prompt hospitalization and consultation with a transplant hepatologist.
  • Serum iron studies: High transferrin saturations associated with high ferritin levels suggest hemochromatosis, which often presents with transaminase abnormalities. However, ferritin is an acute phase reactant that often is elevated in other types of hepatitis. Thus, the presence of high ferritin levels does not suggest hemochromatosis, unless the iron saturation also is high. Genetic testing for hemochromatosis may be useful in these patients.
  • Serum ceruloplasmin: In younger persons, exclude Wilson disease, especially if any neuropsychiatric components exist.

Imaging Studies

• Abdominal imaging (CT scan, sonogram, MRI): Imaging is not normally required and should only be considered in patients with symptoms suggesting biliary disease or to exclude biliary obstruction if the alkaline phosphatase is elevated more than the transaminases. Imaging may show hepatomegaly, but splenomegaly and ascites typically are absent.

Other Tests

• Liver biopsy: Biopsy rarely is indicated for evaluation of acute hepatitis because the histologic features typically are nonspecific.

Histologic Findings

Liver histology closely resembles that of acute viral hepatitis and includes ballooning degeneration, sinusoidal acidophilic bodies, and focal necrosis occasionally accompanied by slight cholestasis. Necrosis is more extensive in cases that are more severe. Inflammatory infiltrates with lymphocytes and plasma cells are common, while eosinophilic infiltrates rarely are seen.

TREATMENT

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Medical Care

• The medical care is supportive only.
• Discontinue isoniazid and any other potentially toxic drug, and closely monitor the patient.
• Hospitalize persons who are more severely affected (eg, with significant elevation of the prothrombin time) for monitoring and potential liver transplantation. Care of such patients is identical to that for other causes of fulminant hepatitis.

Consultations

• Patients with elevations of the serum transaminases greater than 3 times the normal level should be evaluated by a hepatologist or gastroenterologist to carefully consider all possible causes of hepatitis.
• • Consultation also should be obtained for those with lesser elevations that do not resolve within 2-3 months.
  • Elevation of the prothrombin time should prompt hospitalization with evaluation for possible liver transplantation.

Activity

No restrictions are necessary unless the prothrombin time is elevated. Activity often is limited by fatigue.

FOLLOW-UP

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Further Inpatient Care

• Monitor all patients until transaminases normalize.
• Patients with minor elevations of the transaminases who continue to take isoniazid require frequent monitoring (as much as twice weekly).
• Patients who have stopped using isoniazid because of transaminase elevations greater than 3 times the normal level should generally avoid subsequent use of isoniazid.
• Reintroduction of isoniazid does not always produce hepatitis, suggesting environmental factors (eg, other medications, illness, malnutrition), which also may be important.

Transfer

• Transfer patients with elevated prothrombin times to a hospital that offers access to liver transplantation. Early transfer carries less risk and permits more time to evaluate the patient for transplantation.

Deterrence/Prevention

The incidence of severe hepatitis and death may be reduced by the following:

• Avoid prophylactic use of INH in older persons (eg, >35 y), unless the potential benefit clearly outweighs the risk. Treatment of tuberculin reactors is more strongly indicated in immunosuppressed persons and in those with a recent exposure history.
• Obtain a baseline ALT prior to starting isoniazid when there is suspicion of prior liver disease.
• Educate the patient to immediately report possible adverse effects of isoniazid hepatotoxicity. Interview the patient on a regular basis (eg, monthly) for adverse effects or monitor transaminases on a monthly basis.
• Stop isoniazid immediately for any transaminase elevation greater than 3-fold above normal. Lesser elevations should prompt more frequent monitoring.
• Where possible, avoid simultaneous administration of drugs that induce the cytochrome P-450 system (eg, phenobarbital, rifampin).
• Avoid simultaneous use of other potentially hepatotoxic drugs (eg, pyrazinamide, protease inhibitors for HIV), unless the benefit of using them exceeds the risk of developing hepatitis.
• Avoid heavy consumption of ethanol while on isoniazid.
• Advise patients to avoid taking more than 3 g/d of acetaminophen (paracetamol) because of the reduced threshold for liver damage.
• Animal studies suggest that certain antioxidants may reduce the risk of isoniazid hepatitis. These include silymarin, vitamin E, N-acetylcysteine, and melatonin. While it is not known if these results apply to humans, correcting nutritional deficiencies prior to starting isoniazid may be warranted.

Prognosis

• Survival rates depend on the severity of the hepatitis.
• Case fatality rates from 10-20% have been reported for those with overt isoniazid hepatitis.
• Those who survive usually recover completely without residual liver damage.

Patient Education

• Warn all patients started on isoniazid to immediately report any symptoms suggestive of hepatitis, including nausea, fatigue, jaundice, and abdominal distress.
• Advise patients to avoid heavy use of alcohol or acetaminophen and to maintain good nutrition.

MISCELLANEOUS

Section 8 of 10  

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Medical/Legal Pitfalls

• Failure to obtain informed consent for the use of isoniazid
• Failure to advise patients to immediately report any symptoms suggesting hepatitis
• Failure to diagnose isoniazid hepatitis when symptoms are present
• Failure to stop isoniazid (and any other potentially hepatotoxic drug) promptly when symptoms are first reported or when transaminases are elevated more than 3 times greater than the normal level.
• Prophylactic use of isoniazid in older persons unless the benefits clearly outweigh the risks

MULTIMEDIA

Section 9 of 10  

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Media file 1:  Metabolism of isoniazid.
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Media type:  Graph

Media file 2:  Risk of developing overt hepatitis versus age. Risks are much greater for older persons. Data are from a series of 13,838 patients on prophylactic isoniazid therapy reported by Kopanoff and coworkers (1978).
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Media type:  Graph

Media file 3:  Risk of developing overt hepatitis versus duration of therapy. Most hepatitis presents early in the course of therapy.
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Media type:  Graph

REFERENCES

Section 10 of 10

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Article Last Updated: Jun 21, 2007