Which Anti-TB Medications to Hold with Very High LFTs
When AST/ALT rises to 5 times the upper limit of normal OR bilirubin rises, you must immediately stop rifampicin, isoniazid, and pyrazinamide 1.
The Three Hepatotoxic Drugs to Stop
The British Thoracic Society guidelines are explicit and unequivocal on this point. These three drugs—rifampicin, isoniazid, and pyrazinamide—are the hepatotoxic agents in standard TB therapy and must all be discontinued simultaneously when liver injury reaches this threshold 1.
What Defines "Very High" LFTs
The specific thresholds that mandate stopping treatment are:
- AST or ALT ≥5 times the upper limit of normal (regardless of symptoms)
- Any elevation in bilirubin (in conjunction with transaminase elevation)
- AST or ALT ≥3 times the upper limit of normal WITH hepatitis symptoms (fever, malaise, vomiting, jaundice) 2, 3
What to Continue: The Non-Hepatotoxic Drugs
Streptomycin and ethambutol should be continued (with appropriate monitoring) unless clinically contraindicated or drug resistance is suspected 1. These drugs have minimal to no hepatotoxicity:
Clinical Decision Algorithm
For patients who are unwell OR sputum smear-positive:
- Continue treatment with streptomycin + ethambutol while awaiting liver function normalization
- Manage as inpatient preferably 1
For patients who are not unwell AND have non-infectious TB:
- No treatment needs to be given until liver function normalizes 1
Drug Reintroduction Strategy After Recovery
Once liver function returns to normal, the guidelines provide a specific sequential rechallenge protocol 1:
- Isoniazid first: Start 50 mg/day → increase to 300 mg/day over 2-3 days if no reaction
- Rifampicin second (after 2-3 days): Start 75 mg/day → 300 mg → 450-600 mg based on weight over successive 2-3 day intervals
- Pyrazinamide last: Start 250 mg/day → 1.0 g → 1.5-2 g based on weight
Monitor liver function and clinical condition daily during rechallenge 1.
Critical Nuance: Pyrazinamide Carries the Worst Prognosis
Research evidence indicates two distinct patterns of fulminant liver injury 4:
- Early pattern (within 15 days): Likely rifampicin-enhanced isoniazid hepatotoxicity—generally good prognosis
- Late pattern (>1 month): Likely pyrazinamide-related—generally poor prognosis 4
If pyrazinamide is identified as the offending drug, do NOT reintroduce it. Instead, extend treatment to 9 months with rifampicin and isoniazid, supplemented with ethambutol for the initial 2 months 1.
Common Pitfalls to Avoid
- Do not stop just one or two drugs—all three hepatotoxic agents must be discontinued simultaneously when criteria are met
- Do not use pyrazinamide in patients with pre-existing liver test abnormalities 4
- Do not rechallenge with pyrazinamide if it caused severe hepatotoxicity due to high recurrence risk and poor prognosis 4
- Do not forget to exclude other causes of liver injury: viral hepatitis (A, B, C), biliary disease, alcohol, other hepatotoxic drugs, herbal supplements 3