At what level of liver function test abnormality should Anti-Tuberculosis Treatment be modified?

Anti-Tuberculosis Treatment Modification Based on Liver Function Test Abnormalities

Anti-tuberculosis treatment should be stopped when ALT/AST levels reach ≥5 times the upper limit of normal (ULN) in asymptomatic patients or ≥3 times ULN in symptomatic patients, or when bilirubin rises above normal range. 1

Monitoring Recommendations

Baseline Assessment

• Perform liver function tests (LFTs) for all patients before starting anti-TB treatment 1, 2
• Identify high-risk patients:
  • Pre-existing liver disease
  • History of alcohol consumption
  • HIV co-infection
  • Pregnancy or immediate postpartum period
  • Concurrent use of other hepatotoxic medications
  • Elderly patients (risk increases with age) 2, 1

Monitoring Schedule

• Regular patients: Monthly monitoring during treatment 3
• High-risk patients (especially those with pre-existing liver disease): Weekly LFTs for first 2 weeks, biweekly for first 2 months, then monthly 1
• For persons 35 and older: Measure hepatic enzymes (AST/ALT) prior to starting therapy and periodically throughout treatment 2

Thresholds for Treatment Modification

Continue Treatment Normally

• AST/ALT <5× ULN in asymptomatic patients
• AST/ALT <3× ULN in symptomatic patients
• Bilirubin within normal range 1

Stop Hepatotoxic Drugs (Isoniazid, Rifampicin, Pyrazinamide)

• AST/ALT ≥5× ULN in asymptomatic patients
• AST/ALT ≥3× ULN in symptomatic patients
• Bilirubin rises above normal range
• Development of jaundice 1, 3

Management of Hepatotoxicity

When Hepatotoxicity Occurs

1. Stop all potentially hepatotoxic drugs (isoniazid, rifampicin, pyrazinamide) 1, 3
2. Rule out other causes of liver injury (viral hepatitis, alcohol, other medications) 3
3. Wait for liver function to normalize before reintroduction 3

Reintroduction Strategy

• For non-infectious or clinically stable TB: Withhold all TB medications until liver function normalizes
• For infectious or unstable TB: Continue with non-hepatotoxic drugs (ethambutol, streptomycin) 1

Sequential Reintroduction

1. Start with isoniazid at low dose, increase to full dose over 3-7 days if no reaction
2. Add rifampicin if no reaction to isoniazid
3. Consider adding pyrazinamide last or omitting it completely due to high hepatotoxicity risk 1

Alternative Regimens

• If pyrazinamide is the cause: Continue for 9 months with rifampicin and isoniazid, plus ethambutol for initial 2 months
• If isoniazid cannot be reintroduced: Consider rifampicin, ethambutol, and a fluoroquinolone for 12-18 months 1

Patient Education and Prevention

• Advise patients to report immediately any symptoms of liver dysfunction:
  • Unexplained anorexia, nausea, vomiting
  • Dark urine, jaundice
  • Persistent fatigue, weakness
  • Abdominal tenderness (especially right upper quadrant) 2, 1
• Avoid alcohol consumption during treatment 2, 3
• Avoid concurrent use of other hepatotoxic medications 1
• Encourage consumption of antioxidant-rich foods, which may help reduce hepatotoxicity 4

Special Considerations

• Mortality from untreated TB often outweighs the risk of drug-induced liver injury when properly monitored 1
• Regular liver function monitoring facilitates early identification of hepatotoxicity, leading to less severe liver injury 5, 6
• Women (particularly Black and Hispanic women) and patients in the postpartum period may have increased risk of fatal hepatitis with isoniazid 2
• Risk of hepatotoxicity increases with age: <1 per 1,000 for persons under 20 years, rising to 23 per 1,000 for persons 50-64 years 2

By following these guidelines for monitoring and modifying anti-TB treatment based on liver function abnormalities, the risk of severe hepatotoxicity can be significantly reduced while ensuring effective TB treatment.