What is the management approach for Anti-Tuberculosis Treatment (ATT)-induced liver injury?

Management of Anti-Tuberculosis Treatment (ATT)-Induced Liver Injury

Stop rifampicin, isoniazid, and pyrazinamide immediately when AST/ALT rises to 5 times the upper limit of normal or when bilirubin rises, then reintroduce drugs sequentially once liver function normalizes, starting with isoniazid, followed by rifampicin, and finally pyrazinamide. 1, 2

Initial Assessment and Drug Discontinuation

When to Stop ATT

• Discontinue rifampicin, isoniazid, and pyrazinamide immediately if AST/ALT exceeds 5 times normal or if bilirubin rises. 1, 2
• Stop treatment if symptomatic hepatotoxicity develops (fever, malaise, vomiting, jaundice, unexplained deterioration), regardless of enzyme levels. 1
• The FDA warns that continued use of isoniazid after signs of hepatic damage can cause more severe liver injury. 3

Interim Management During Recovery

• For non-infectious TB in clinically stable patients: withhold all treatment until liver function normalizes. 1, 2
• For infectious TB (sputum smear-positive) or acutely ill patients: use streptomycin and ethambutol with appropriate monitoring while awaiting liver function recovery. 1, 2
• Consider virological testing to exclude coexistent viral hepatitis. 1

Sequential Drug Reintroduction Protocol

Once liver function returns to normal, reintroduce drugs one at a time with daily clinical and biochemical monitoring. 1, 2

Step 1: Isoniazid Reintroduction

• Start isoniazid at 50 mg/day. 1, 2, 4
• Increase to 300 mg/day after 2-3 days if no reaction occurs. 1, 2, 4
• Continue for an additional 2-3 days before adding the next drug. 1

Step 2: Rifampicin Reintroduction

• After 2-3 days without reaction on full-dose isoniazid, add rifampicin at 75 mg/day. 1, 2, 4
• Increase to 300 mg after 2-3 days. 1, 2
• Then increase to full dose: 450 mg if <50 kg or 600 mg if >50 kg after another 2-3 days without reaction. 1, 2

Step 3: Pyrazinamide Reintroduction

• After 2-3 days without reaction on full-dose rifampicin, add pyrazinamide at 250 mg/day. 1, 2, 4
• Increase to 1.0 g after 2-3 days, then to full dose: 1.5 g if <50 kg or 2.0 g if >50 kg. 1, 2

If Hepatotoxicity Recurs

• Permanently exclude the offending drug from the regimen. 2
• If pyrazinamide is the culprit, extend treatment to 9 months with rifampicin and isoniazid only. 2
• Research suggests pyrazinamide-induced hepatitis occurring late (>1 month) has a poor prognosis and should not be reintroduced. 5

Monitoring Strategy During Active Treatment

For Patients WITHOUT Pre-existing Liver Disease

• Routine monitoring is not required if baseline liver function is normal. 1, 2
• Repeat liver function tests only if symptoms develop (fever, malaise, vomiting, jaundice, unexplained deterioration). 1, 2

For Patients WITH Chronic Liver Disease

• Monitor liver function weekly for 2 weeks, then biweekly for the first 2 months. 1, 2

For Elevated Baseline Transaminases

• If AST/ALT is 2-5 times normal: monitor weekly for 2 weeks, then biweekly until normal. 1, 2
• If AST/ALT is <2 times normal: repeat at 2 weeks; if decreased, monitor only for symptoms. 1, 2

For High-Risk Populations

• The FDA recommends monthly symptom reviews for all patients, with hepatic enzyme monitoring before starting therapy and periodically throughout treatment for persons ≥35 years old. 3
• Recent evidence suggests more frequent monitoring may be warranted for all patients on multi-drug therapy. 6

Critical Risk Factors and Pitfalls

High-Risk Populations Requiring Enhanced Vigilance

• Advanced age (risk increases substantially after age 35, peaking at 23 per 1,000 in ages 50-64). 2, 3
• Female sex, particularly Black and Hispanic women, especially in the postpartum period. 3
• Daily alcohol consumption (significantly increases hepatotoxicity risk). 2, 3
• Pre-existing chronic liver disease. 1, 2
• HIV infection or other immunosuppression. 7

Common Pitfalls to Avoid

• Do NOT continue treatment when AST/ALT reaches 5 times normal, even if the patient appears clinically well—this can lead to fulminant hepatic failure. 1, 2
• Do NOT reintroduce pyrazinamide if it caused late-onset hepatotoxicity (>1 month), as this pattern has poor prognosis. 5
• Research shows that despite AST elevations up to 6 times normal, treatment can often be continued or reintroduced successfully in most cases, particularly in excessive alcohol consumers without jaundice. 8
• However, older patients, females without alcohol consumption, and those with jaundice are at higher risk for requiring modified regimens. 8

Patient Education is Essential

• Instruct patients to immediately report: unexplained anorexia, nausea, vomiting, dark urine, jaundice, persistent paresthesias, persistent fatigue/weakness, fever >3 days, or right upper quadrant discomfort. 1, 2, 3
• Inform general practitioners of these warning signs. 1

Special Considerations

Rifampicin Enhancement of Isoniazid Toxicity

• Rifampicin, as a powerful enzyme inducer, may enhance isoniazid hepatotoxicity, causing early-onset hepatitis (within 15 days) with generally good prognosis. 5
• This contrasts with late-onset pyrazinamide hepatotoxicity (>1 month), which has poorer prognosis. 5

Post-Liver Transplant Patients

• Rifampicin should be avoided in liver transplant recipients as it increases risk of acute rejection. 7
• Alternative non-hepatotoxic regimens with streptomycin and ethambutol can be successful in these patients. 7