A patient with drug‑sensitive tuberculosis started on isoniazid, rifampicin, pyrazinamide, and ethambutol develops clinical jaundice with liver enzymes less than twice the upper limit of normal; how should the anti‑TB regimen be managed?

Management of Jaundice with Elevated LFTs (<2× ULN) During HRZE Treatment

All hepatotoxic anti-tuberculosis drugs (isoniazid, rifampicin, and pyrazinamide) must be stopped immediately when clinical jaundice appears, regardless of the degree of transaminase elevation, because jaundice indicates significant hepatic injury and any rise in bilirubin mandates immediate cessation of hepatotoxic drugs. 1, 2

Immediate Actions

Stop Hepatotoxic Drugs

• Discontinue rifampicin, isoniazid, and pyrazinamide immediately upon detection of jaundice 1, 2
• The presence of jaundice itself is a critical stopping criterion, independent of transaminase levels 3, 2
• Even though transaminases are <2× ULN, bilirubin elevation (manifesting as jaundice) takes precedence as the stopping criterion 1, 2

Continue Non-Hepatotoxic Therapy

• Continue ethambutol to maintain some anti-TB activity while hepatotoxic drugs are held 3, 2
• Consider adding streptomycin (if the patient has infectious TB or is acutely ill) to prevent treatment interruption 2
• This bridging regimen prevents disease progression during the recovery period 3, 2

Monitoring During Recovery

Laboratory Assessment

• Measure liver function tests (AST, ALT, bilirubin) at least twice weekly until normalization 2, 4
• Exclude other causes of hepatotoxicity: viral hepatitis (B and C), biliary tract disease, alcohol consumption, and other hepatotoxic medications 1
• Document baseline characteristics including any pre-existing liver disease 3

Clinical Monitoring

• Assess for symptoms of worsening hepatitis: abdominal pain, vomiting, worsening jaundice, or clinical deterioration 3
• Monitor for signs of hepatic decompensation, particularly in patients with any underlying liver disease 3

Sequential Drug Reintroduction

Once liver function tests normalize completely (transaminases and bilirubin return to normal), reintroduce drugs one at a time with close monitoring: 2

Step 1: Reintroduce Isoniazid First

• Start isoniazid at 50 mg/day 2
• Monitor clinical condition and liver function tests daily 2
• If no reaction after 2-3 days, increase to 300 mg/day 2
• Wait another 2-3 days while monitoring before proceeding 2

Step 2: Add Rifampicin Second

• Start rifampicin at 75 mg/day 2
• Monitor for 2-3 days, then increase to 300 mg/day 2
• After another 2-3 days without reaction, increase to full dose (450-600 mg based on weight) 2

Step 3: Add Pyrazinamide Last

• Start pyrazinamide at 250 mg/day 2
• Gradually increase to full dose over several days 2
• Caution: Pyrazinamide-induced hepatitis occurring late in treatment (>4 weeks) carries a poor prognosis 4

Monitoring During Reintroduction

• Check liver function tests daily during the reintroduction phase 2
• Stop the most recently added drug immediately if AST/ALT rises to ≥3× ULN with symptoms or ≥5× ULN without symptoms 1, 2
• If bilirubin rises at any point, stop all hepatotoxic drugs immediately 1, 2

Alternative Regimens if Reintroduction Fails

If Pyrazinamide Cannot Be Reintroduced

• Use isoniazid, rifampicin, and ethambutol for 2 months, followed by 7 months of isoniazid and rifampicin (total 9 months) 3, 2
• This is the preferred alternative as it retains the two most crucial drugs (isoniazid and rifampicin) 3

If Multiple Drugs Cannot Be Reintroduced

• Consider rifampicin, ethambutol, and a fluoroquinolone (with or without an injectable agent) for 12-18 months 3
• For severe cases where no hepatotoxic drugs can be used: ethambutol, fluoroquinolone, cycloserine, and injectable agent for 18-24 months 3

Critical Pitfalls to Avoid

• Never continue hepatotoxic drugs in the presence of jaundice, even if transaminases are only mildly elevated 1, 2
• Never reintroduce pyrazinamide if it was definitively identified as the causative agent, as recurrence carries poor prognosis 2, 4
• Never reintroduce multiple drugs simultaneously, as this prevents identification of the offending agent 2
• Never ignore bilirubin elevation—any rise mandates immediate cessation regardless of transaminase levels 1, 2