Which anti-tuberculosis (TB) drug to stop first when Liver Function Tests (LFTs) are elevated?

Management of Anti-Tuberculosis Drug-Induced Hepatotoxicity

When liver function tests (LFTs) are elevated during tuberculosis treatment, rifampicin, isoniazid, and pyrazinamide should all be stopped simultaneously if AST/ALT rises to five times normal or if bilirubin levels rise. 1

Monitoring Liver Function During TB Treatment

• Regular monitoring of liver function is required for patients with known chronic liver disease (weekly for two weeks, then biweekly for the first two months) 1
• For patients without pre-existing liver disease and normal pre-treatment LFTs, routine monitoring is not required, but LFTs should be repeated if symptoms develop (fever, malaise, vomiting, jaundice, or unexplained deterioration) 1, 2
• If AST/ALT levels are two or more times normal, monitor liver function weekly for two weeks, then biweekly until normal 1
• If AST/ALT is under two times normal, repeat testing at two weeks 1

Management When Hepatotoxicity Occurs

• If AST/ALT rises to five times normal or bilirubin rises, stop rifampicin, isoniazid, and pyrazinamide immediately 1
• For non-infectious TB forms in patients who are not acutely ill, no treatment is needed until liver function normalizes 1
• For infectious TB (sputum smear positive) or acutely ill patients, use non-hepatotoxic drugs while waiting for liver function to normalize 1
  • Streptomycin and ethambutol are the preferred alternatives (with appropriate monitoring) 1, 3

Reintroduction of TB Drugs After Hepatotoxicity

Once liver function normalizes, reintroduce drugs sequentially with daily monitoring of clinical condition and liver function:

1. Start with isoniazid at 50 mg/day, increasing to 300 mg/day after 2-3 days if no reaction occurs 1, 2
2. After 2-3 days without reaction, add rifampicin at 75 mg/day, increasing to 300 mg after 2-3 days, then to full dose (450-600 mg based on weight) after another 2-3 days 1
3. Finally, add pyrazinamide at 250 mg/day, increasing to full dose gradually 1

Risk Factors for Hepatotoxicity

• Pre-existing liver disease 1, 4
• Advanced age 1, 4
• Alcohol consumption 1, 4
• Malnutrition 4
• HIV infection 4
• Abnormal baseline liver function tests 5
• Concomitant use of other hepatotoxic medications 6

Important Considerations

• Pyrazinamide and isoniazid are major hepatotoxins, while rifampicin and ethambutol are rarely or not hepatotoxic 3
• Rifampicin may enhance the hepatotoxicity of isoniazid through enzyme induction 3
• Two patterns of hepatotoxicity can occur: early onset (within first 15 days, likely rifampicin-induced isoniazid toxicity) and late onset (after one month, possibly pyrazinamide-related) 3
• If a specific drug is identified as the cause of hepatotoxicity, it should be permanently excluded from the regimen and a suitable alternative used 1
• Patient education about symptoms of hepatotoxicity is crucial for early detection and management 1, 2

Alternative Regimens

• If pyrazinamide is found to be the offending drug, treatment will need to be continued for nine months with rifampicin and isoniazid 1
• For patients who cannot tolerate standard first-line drugs, fluoroquinolones like ofloxacin/levofloxacin may be considered as part of non-hepatotoxic regimens 4