How should I manage a patient with lymph‑node tuberculosis in the continuation phase on isoniazid and rifampicin who develops hepatotoxicity with transaminases greater than five times the upper limit of normal?

Management of Hepatotoxicity with Transaminases >5× ULN in Lymph-Node TB on Continuation Phase

Stop isoniazid and rifampicin immediately—transaminases exceeding five times the upper limit of normal mandate immediate discontinuation of all hepatotoxic anti-TB drugs, regardless of symptoms or bilirubin levels. 1, 2

Immediate Actions

• Discontinue rifampicin and isoniazid immediately when transaminases reach ≥5× ULN, even in asymptomatic patients with normal bilirubin 1, 2
• Exclude competing causes of hepatotoxicity by testing for viral hepatitis (A, B, C, E), documenting alcohol consumption history, and reviewing all concurrent medications 2
• Assess disease severity and infectiousness: lymph-node TB is non-infectious (extrapulmonary), so the patient does not require bridging therapy with alternative agents 2

Bridging Therapy Decision

• For stable, non-infectious TB (including lymph-node TB): withhold all anti-TB therapy until liver enzymes normalize—no treatment is required during the recovery period 2, 3
• For infectious TB (sputum smear-positive) or acutely ill patients: initiate streptomycin plus ethambutol as temporary bridge therapy until liver function recovers 2, 3

Monitoring During Recovery

• Check transaminases and bilirubin weekly until values return to normal (or <2× ULN if baseline was mildly elevated) 2
• Monitor for symptoms of worsening hepatitis: abdominal pain, vomiting, jaundice, or clinical deterioration 1, 2

Sequential Drug Reintroduction Protocol

Once transaminases normalize, reintroduce drugs one at a time with daily clinical and biochemical monitoring 2, 3:

Step 1: Isoniazid

• Start at 50 mg once daily 2, 3
• If no reaction after 2–3 days, increase to 300 mg daily 2, 3
• Continue full dose for 2–3 days before adding rifampicin 2

Step 2: Rifampicin

• Start at 75 mg once daily 2, 3
• If tolerated for 2–3 days, increase to 300 mg daily 2, 3
• After another 2–3 days, escalate to weight-based full dose: 450 mg (<50 kg) or 600 mg (≥50 kg) 2, 3
• Continue full dose for 2–3 days to confirm tolerance 2

Monitoring During Reintroduction

• Measure transaminases and bilirubin daily after each drug addition 2
• Stop the most recently added drug immediately if enzymes rise or hepatic symptoms appear 2, 3

Alternative Regimen if Reintroduction Fails

• If a specific drug causes recurrent hepatotoxicity, permanently exclude that agent and construct an alternative regimen 2
• If rifampicin cannot be tolerated: use isoniazid + ethambutol + fluoroquinolone (levofloxacin or moxifloxacin) for 18–24 months 2
• If isoniazid cannot be tolerated: use rifampicin + ethambutol + fluoroquinolone for 12 months 3

Continuation Phase Completion

• For lymph-node TB on standard continuation phase (isoniazid + rifampicin): once both drugs are successfully reintroduced, complete the remaining duration of the continuation phase (typically 4 months total from the start of continuation) 2
• If pyrazinamide was part of the original regimen and cannot be reintroduced (not applicable in continuation phase, but relevant if intensive phase was incomplete): extend total treatment to 9 months with isoniazid + rifampicin 2, 3

Critical Pitfalls to Avoid

• Do not resume therapy prematurely—wait for complete normalization of transaminases before any reintroduction attempt 2
• Do not reintroduce multiple drugs simultaneously—sequential addition is essential to identify the offending agent if hepatotoxicity recurs 2, 3
• Do not ignore bilirubin elevation—any rise in bilirubin mandates immediate cessation, even if transaminases are <5× ULN 1, 2
• Do not use pyrazinamide in continuation phase—it is not part of standard continuation therapy for lymph-node TB 2

Enhanced Monitoring for High-Risk Patients

• Patients with pre-existing chronic liver disease require weekly liver function tests for 2 weeks, then biweekly for 2 months after reintroduction 2
• Alcohol abstinence is mandatory throughout treatment, as concurrent alcohol significantly increases hepatotoxicity risk 1, 2