According to ICMR guidelines, how should anti‑tubercular therapy be modified in a patient on ATT who develops abnormal liver function tests, based on the level of transaminase elevation and presence of hepatic symptoms?

Management of Anti-Tubercular Drugs in Deranged Liver Function Tests (ICMR Guidelines)

Critical Thresholds for Stopping Hepatotoxic Drugs

Stop rifampicin, isoniazid, and pyrazinamide immediately if: AST/ALT ≥5× upper limit of normal in asymptomatic patients, AST/ALT ≥3× upper limit of normal WITH hepatitis symptoms (fever, malaise, vomiting, nausea), or ANY rise in bilirubin above normal range. 1, 2, 3, 4

Specific Stop Criteria:

• Asymptomatic patients: Stop all hepatotoxic drugs (H, R, Z) when transaminases reach ≥5× ULN 1, 3
• Symptomatic patients: Stop all hepatotoxic drugs when transaminases ≥3× ULN with symptoms of hepatitis 2, 3
• Any bilirubin elevation: Stop immediately regardless of transaminase level - this is an absolute contraindication to continuing hepatotoxic drugs 1, 4

Monitoring Protocol Based on Transaminase Levels

AST/ALT <2× ULN:

• Continue all anti-TB drugs at full doses without interruption 1, 2, 3
• Repeat liver function tests at 2 weeks 1
• If levels fall, further testing only needed if symptoms develop 1
• If levels rise above 2× ULN on repeat, escalate to weekly monitoring 1

AST/ALT 2-5× ULN (Asymptomatic):

• Continue all anti-TB medications without dose reduction 1, 2, 3
• Monitor liver function tests weekly for 2 weeks, then biweekly until normalization 1, 3
• Counsel patient about hepatotoxicity symptoms and advise complete alcohol avoidance 1
• Exclude other causes: viral hepatitis (HBV, HCV), biliary disease, alcohol, other hepatotoxic medications 1, 3

AST/ALT >5× ULN or Bilirubin Elevated:

• Stop rifampicin, isoniazid, and pyrazinamide immediately 1, 2, 3, 4
• Continue ethambutol and add streptomycin (if renal function permits and patient has infectious TB or is acutely ill) 1, 3
• If patient is not unwell and TB is non-infectious, no treatment needed until liver function normalizes 1
• Repeat liver function tests within 2-3 days 1

Sequential Drug Reintroduction Protocol

Once liver function returns to normal (transaminases and bilirubin within normal range), reintroduce drugs sequentially with daily clinical and biochemical monitoring: 1, 5

Step 1: Isoniazid Reintroduction

• Start isoniazid 50 mg/day 1
• Increase to 300 mg/day after 2-3 days if no reaction 1
• Continue for 2-3 days at full dose before adding next drug 1
• Monitor liver function tests daily during escalation 1

Step 2: Rifampicin Reintroduction

• Start rifampicin 75 mg/day (only after isoniazid tolerated for 2-3 days) 1
• Increase to 300 mg after 2-3 days if no reaction 1
• Increase to 450 mg (<50 kg) or 600 mg (>50 kg) after further 2-3 days 1
• Continue for 2-3 days at full dose before adding pyrazinamide 1

Step 3: Pyrazinamide Reintroduction

• Start pyrazinamide 250 mg/day (only after rifampicin tolerated) 1
• Increase to 1.0 g after 2-3 days 1
• Increase to 1.5 g (<50 kg) or 2.0 g (>50 kg) after further 2-3 days 1

Critical: If hepatotoxicity recurs during reintroduction, the offending drug must be permanently excluded and alternative regimen used 1, 5

Alternative Regimens When Hepatotoxic Drugs Cannot Be Used

If Pyrazinamide is the Offending Drug:

• Use rifampicin + isoniazid for 9 months total duration 1
• Add ethambutol for initial 2 months 1

If Multiple Hepatotoxic Drugs Cannot Be Reintroduced:

• Use ethambutol + streptomycin as cornerstone agents 1, 4
• Add fluoroquinolone (levofloxacin or moxifloxacin) - these cause no additional hepatotoxicity in patients with drug-induced liver injury 6
• Avoid pyrazinamide completely in patients with pre-existing liver abnormalities 4, 5

Management in Pre-Existing Liver Disease

Patients with Stable Liver Disease (Normal Baseline LFTs):

• Use standard 2HRZE/4HR regimen 7
• Avoid pyrazinamide if any baseline liver function abnormality exists 4, 5
• Monitor liver function tests every 2 weeks for first 2 months, then monthly 4, 5
• Prophylactic pyridoxine 10 mg/day recommended 7

Patients with Severe Liver Dysfunction:

• Avoid all hepatotoxic drugs (H, R, Z) 4
• Use non-hepatotoxic regimen: ethambutol + fluoroquinolone + streptomycin 4
• Treatment duration must be extended beyond standard 6 months 4

Critical Pitfalls to Avoid

Common Errors:

• Never continue treatment if bilirubin rises - any bilirubin elevation is an absolute stop indication, even with normal transaminases 1, 4
• Never use pyrazinamide in patients with pre-existing liver abnormalities - it carries the highest hepatotoxicity risk and poor prognosis if hepatitis develops 4, 5
• Never stop treatment prematurely in asymptomatic patients with transaminases <5× ULN and normal bilirubin - this risks treatment failure and drug resistance 2
• Never reintroduce pyrazinamide if it was the offending drug - risk of recurrence with poor prognosis 1, 5

Two Patterns of Hepatotoxicity Recognition:

• Early pattern (within 15 days): Likely rifampicin-enhanced isoniazid hepatotoxicity - generally good prognosis 5
• Late pattern (>1 month): Likely pyrazinamide hepatotoxicity - generally poor prognosis, do not reintroduce pyrazinamide 5

High-Risk Patients Requiring Enhanced Monitoring:

• Elderly patients, female gender, chronic kidney disease, diabetes mellitus, poor nutritional status, chronic viral hepatitis B or C carriers 2
• These patients need more frequent monitoring: twice weekly for first 2 weeks, then every 2 weeks for 2 months 5