When should isoniazid, rifampicin, and pyrazinamide be stopped in a patient with suspected anti‑tuberculosis drug‑induced hepatotoxicity, based on alanine aminotransferase, aspartate aminotransferase, bilirubin, INR levels, or clinical signs of acute liver failure?

When to Stop Anti-TB Drugs in Liver Toxicity

Stop isoniazid, rifampicin, and pyrazinamide immediately when any of the following occur: ALT/AST ≥5× upper limit of normal (regardless of symptoms or bilirubin), any elevation of bilirubin above normal, clinical jaundice (regardless of transaminase levels), or any transaminase elevation with symptoms of hepatitis (fever, malaise, vomiting, abdominal pain). 1, 2, 3

Specific Stopping Criteria

Biochemical Thresholds

• ALT/AST ≥5× ULN: Discontinue all three hepatotoxic drugs immediately, even if the patient is completely asymptomatic and bilirubin remains normal 1, 2, 3
• Any bilirubin elevation: Stop all hepatotoxic drugs immediately when bilirubin rises above the upper limit of normal, regardless of transaminase levels 1, 2, 3
• Clinical jaundice: The presence of visible jaundice mandates immediate discontinuation of all hepatotoxic anti-TB drugs, even before laboratory confirmation 2, 3

Clinical Thresholds

• Symptomatic hepatitis at any transaminase level: Stop drugs immediately if the patient develops fever, malaise, vomiting, jaundice, abdominal pain, or unexplained clinical deterioration, even if ALT/AST is <5× ULN 1, 2, 3
• INR elevation: While not explicitly stated as a standalone criterion in guidelines, INR elevation suggests synthetic dysfunction and warrants immediate drug discontinuation as part of acute liver failure assessment 2

Immediate Management After Stopping

Bridge Therapy Selection

• For infectious TB (smear-positive sputum) or acutely ill patients: Start streptomycin and ethambutol (15-20 mg/kg daily) immediately to maintain anti-TB coverage while liver recovers 1, 2, 3
• For non-infectious TB (extrapulmonary, smear-negative) in stable patients: No treatment is required until liver function normalizes 1, 3

Diagnostic Workup

• Obtain urgent comprehensive liver panel including ALT, AST, bilirubin, alkaline phosphatase, and INR 2
• Test for viral hepatitis A, B, C, and E to exclude alternative causes 1, 2
• Document alcohol consumption history, as concurrent use dramatically increases hepatotoxicity risk 1, 2

Drug Reintroduction Protocol (After Normalization)

Sequential Reintroduction Strategy

The American Thoracic Society recommends a specific stepwise approach once all liver tests return completely to normal 1, 2, 3:

1. Isoniazid first: Start 50 mg/day, increase to 300 mg/day after 2-3 days if no reaction 1, 2, 3
2. Rifampicin second: After 2-3 days of full-dose isoniazid without reaction, start rifampicin 75 mg/day, increase to 300 mg after 2-3 days, then to 450 mg (<50 kg) or 600 mg (>50 kg) after another 2-3 days 1, 2, 3
3. Pyrazinamide last: Start 250 mg/day, increase to 1.0 g after 2-3 days, then to 1.5 g (<50 kg) or 2.0 g (>50 kg) 1, 2, 3

Monitoring During Reintroduction

• Check ALT/AST and bilirubin daily during each drug reintroduction phase 1, 2, 3
• Stop the most recently added drug immediately if transaminases rise above 5× ULN, rise above normal with symptoms, or if bilirubin rises 1, 2

Critical Prognostic Considerations

Timing of Hepatotoxicity Predicts Outcome

• Early onset (<15 days): Likely rifampicin-enhanced isoniazid hepatotoxicity with generally good prognosis 4
• Late onset (>1 month): Likely pyrazinamide-induced hepatitis with poor prognosis—avoid pyrazinamide reintroduction in these cases 1, 2, 4

When Pyrazinamide Cannot Be Reintroduced

• Use isoniazid, rifampicin, and ethambutol for 2 months, followed by isoniazid and rifampicin for 7 additional months (total 9 months) 1, 3
• This preserves the two most potent first-line agents while avoiding the hepatotoxic pyrazinamide 1, 3

Common Pitfalls to Avoid

• Never continue drugs while "monitoring closely" once stopping criteria are met—this can progress to fulminant hepatic failure requiring transplantation 2
• Never reintroduce all drugs simultaneously—sequential reintroduction identifies the specific offending agent 1, 2, 3
• Do not reintroduce pyrazinamide in patients who developed severe initial hepatotoxicity, particularly if jaundice occurred late (>1 month), as recurrence carries poor prognosis 1, 2, 4
• Avoid concurrent hepatotoxic medications including over-the-counter acetaminophen during TB treatment 1, 2

High-Risk Populations Requiring Intensive Monitoring

Patients with pre-existing liver disease, chronic alcohol use, hepatitis B/C, HIV, malnutrition, or advanced age require more intensive monitoring with liver function tests weekly for 2 weeks, then biweekly for the first 2 months 1, 3