Duc Vu and Lynn Macdonald, Bureau of Licensed Product Assessment, Therapeutic Products Directorate, Health Canada

According to the latest edition of the Canadian Tuberculosis Standards (1) Canada has one of the lowest reported incidence rates of tuberculosis (TB) in the world. However, in Canada, the high-risk groups for Mycobacterium tuberculosis infection are HIV-positive people, Aboriginals, foreign-born people from countries with a high prevalence of TB, intravenous drug users and homeless people.

The Canadian Lung Association recommends two standard drug regimens for the treatment of TB: a combination of isoniazid (INH), rifampicinn (RI) and pyrazinamide (PY) with or without ethambutol (EMB) and a combination of INH and RI with or without EMB. Of these agents, INH, PY and RI have been associated with liver toxicity. INH and PY are considered to be major hepatotoxins, whereas RI is considered to be relatively less hepatotoxic but is a powerful enzyme inducer, which may enhance the hepatotoxicity of INH (2).

Severe and sometimes fatal hepatitis associated with regimens containing INH, PY and RI has been well documented. Two cases were recently published of liver failure in patients receiving combination therapy with RI and PY for latent TB; one patient died (3).

The Canadian Adverse Drug Reaction Monitoring Program (CADRMP) reviewed 420 suspected domestic reports of hepatobiliary adverse reactions associated with different combinations of INH, PY and RI that were received from the time of their introduction in Canada to May 18, 2001. (Each report may have contained more than one of the following reaction terms; however, each report was included only under the most important reaction term):

• INH alone: 258 reports of hepatic reactions (7 deaths).

• PY alone: 4 reports: 2 of hepatitis, and 1 each of hepatic failure and jaundice.

• RI alone: 27 reports: 12 of jaundice, 6 of hepatitis, 5 of abnormal liver enzyme levels, 3 of hepatocellular damage (1 death), and 1 of hepatomegaly.

• INH and PY: 1 report of hepatic failure (1 death).

• INH and RI: 110 reports: 50 of abnormal liver enzyme levels (1 death), 27 of hepatitis (2 deaths), 18 of jaundice (2 deaths), 9 of hepatocellular damage, 1 death), 2 each of hepatic failure and hepatomegaly, and 1 each of cholelithiasis and hepatic cirrhosis.

• RI and PY: 1 report of jaundice.

• INH, RI and PY: 19 reports: 7 of abnormal liver enzyme levels, 6 of hepatitis, 4 of jaundice and 1 each of hepatic coma and hepatic necrosis.

These reports suggest that liver toxicity may occur in patients receiving any of the drugs alone or in combination. The Canadian Tuberculosis Standards recommends baseline liver function testing when INH is used and regular monitoring only in patients who have pre-existing liver disease or a history of alcohol abuse or who are 35 years of age or older (1). The usefulness of liver function monitoring to detect fulminant liver failure is a controversial issue and needs to be further investigated. However, health care professionals are reminded that monitoring for liver toxicity (either through liver enzyme measurement or clinical monitoring) is important during treatment with any antitubercular regimen (2). It is essential to instruct patients to watch for symptoms suggestive of hepatitis (nausea, vomiting, stomach pain, lack of appetite, tiredness, dark urine or yellowing of the skin), and to stop taking their antitubercular medication and to consult their physician immediately if these symptoms occur (3).

References

1. Canadian Lung Association. Canadian tuberculosis standards. 5th ed. Ottawa, 2000.

2. Durand, F., Jebrak, G., Pessayre, D. et al. Hepatotoxicity of antitubercular treatments: rationale for monitoring liver status. Drug Safety, 15: 394-405 (1996).

3. Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection. Mortality and Morbidity Weekly Report, 50: 289-291 (2001).