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Predisposing factors in hepatitis induced by isoniazid-rifampin treatment of tuberculosis
Abstract:
Seventy-five patients who developed mild hepatic reactions (serum transaminase concentrations of 45 to 149 units per liter) and 50 patients who showed more serious liver damage (serum transaminase values greater than 150 units per liter) were compared with 261 consecutive patients who had no liver reactions during treatment with rifampin and isoniazid. Generally, liver toxicity occurred in 18 per cent of patients receiving combined anti-tuberculous drug therapy. Small increases in transaminase occurred in 14 per cent of the patients; large increases occurred in 4 per cent. Elderly women comprised a risk group. Among patients exhibiting a more serious hepatic lesion (transaminase values greater than 150 units per liter), alcoholics, mostly men, formed another risk group, together with other patients with a history of previous liver or biliary disease. Of 261 patients who did not develop a liver reaction, 57 per cent were slow INH acetylators. In this study, the groups with small and large increases in transaminase were clearly separated; in the former group there was no preponderance of phenotype, whereas in the latter group, slow acetylators clearly dominated among early (first 4 weeks of treatment) hepatic reactions (P less than 0.01). Studies of single-drug regimens of isoniazid have shown that neither slow nor rapid acetylation has any causal influence on isoniazid-induced hepatitis. Because the metabolism of rifampin is independent of the acetylation process, rifampin and isoniazid in combination seem to cause a toxic hepatitis that differs from the hepatitis induced by either drug separately.
Insights
Combined anti-tuberculosis therapy with rifampin and isoniazid can cause liver toxicity, particularly in elderly women and alcoholics. Slow acetylators are at higher risk for early, severe liver reactions.
Area of Science:
- Pharmacology
- Hepatology
- Infectious Diseases
Background:
- Tuberculosis treatment often involves combination therapy with rifampin and isoniazid.
- Hepatotoxicity is a known side effect of anti-tuberculosis drugs.
- The role of acetylator phenotype in drug-induced liver injury requires further investigation.
Purpose of the Study:
- To investigate the incidence and risk factors of liver toxicity associated with combined rifampin and isoniazid therapy.
- To determine the association between acetylator phenotype and the development of hepatic reactions.
Main Methods:
- Retrospective comparison of patients with mild hepatic reactions, severe liver damage, and no liver reactions during rifampin and isoniazid treatment.
- Analysis of patient demographics, medical history, and acetylator phenotype (slow vs. rapid INH acetylators).
Main Results:
- Overall liver toxicity occurred in 18% of patients receiving combined therapy.
- Elderly women and alcoholics with a history of liver disease were identified as risk groups for severe hepatic reactions.
- Slow isoniazid acetylators were significantly associated with early (within 4 weeks) severe hepatic reactions (P < 0.01).
Conclusions:
- Combined rifampin and isoniazid therapy can lead to significant liver toxicity.
- Specific patient groups, including elderly women and alcoholics, are at increased risk.
- Slow isoniazid acetylator phenotype is a key factor in the development of early, severe hepatic reactions to this drug combination.