What should be done for a patient with tuberculosis (TB) who develops jaundice while taking TB medications, such as isoniazid (INH), rifampicin (RIF), or pyrazinamide (PZA)?

Management of Jaundice During TB Treatment

Stop all hepatotoxic TB drugs (isoniazid, rifampicin, and pyrazinamide) immediately when jaundice develops, and initiate non-hepatotoxic therapy with streptomycin and ethambutol until liver function normalizes. 1, 2

Immediate Actions

• Discontinue rifampicin, isoniazid, and pyrazinamide immediately upon detection of jaundice, regardless of transaminase levels, as bilirubin elevation indicates significant hepatic injury 1, 2

• Obtain urgent liver function tests including AST/ALT and bilirubin to assess severity 1, 3

• Perform virological testing for hepatitis A, B, C, and E to exclude alternative causes 1, 2

• Assess alcohol consumption history, as concurrent use significantly increases hepatotoxicity risk 1, 2

Bridge Therapy During Recovery

For patients who are unwell or have smear-positive sputum:

• Start streptomycin and ethambutol immediately as bridge therapy until liver function normalizes 1, 2
• Ethambutol should be dosed at 15-20 mg/kg daily 2
• This combination provides adequate coverage while avoiding hepatotoxic agents 1, 2

For patients who are not unwell with non-infectious TB:

• No treatment is required until liver function returns to normal 1, 2

Sequential Drug Reintroduction Protocol

Once liver function tests normalize completely, reintroduce drugs sequentially with daily clinical and laboratory monitoring 1, 2:

Step 1: Isoniazid reintroduction

• Start at 50 mg/day 1, 2
• Increase to 300 mg/day after 2-3 days if no reaction occurs 1, 2
• Continue for 2-3 days at full dose before adding next drug 1, 2

Step 2: Rifampicin reintroduction

• Start at 75 mg/day 1, 2
• Increase to 300 mg after 2-3 days without reaction 1, 2
• Further increase to 450 mg (<50 kg) or 600 mg (>50 kg) after another 2-3 days 1, 2
• Continue for 2-3 days at full dose before adding pyrazinamide 1, 2

Step 3: Pyrazinamide reintroduction (if needed)

• Start at 250 mg/day 1, 2
• Increase to 1.0 g after 2-3 days 1, 2
• Further increase to 1.5 g (<50 kg) or 2.0 g (>50 kg) 1, 2

Critical Monitoring During Reintroduction

• Check liver function tests (AST/ALT and bilirubin) daily during each drug reintroduction phase 1, 2

• Stop the most recently added drug immediately if any of the following occur 1, 2:

  • AST/ALT rises above 5 times upper limit of normal in asymptomatic patients 1, 2
  • AST/ALT rises above normal range with symptoms of hepatitis 1, 2
  • Bilirubin rises above normal range, with or without symptoms 1, 2
  • Development of fever, malaise, vomiting, jaundice, or abdominal pain 1, 2

Alternative Regimens When Drugs Cannot Be Reintroduced

If pyrazinamide is the offending drug:

• Use isoniazid and rifampicin for 9 months total, supplemented with ethambutol for the initial 2 months 1, 2
• This extended duration compensates for loss of pyrazinamide's sterilizing activity 2

If isoniazid cannot be tolerated:

• Use rifampicin, ethambutol, and a fluoroquinolone for 12 months 2

If multiple drugs cannot be reintroduced:

• Consult a TB specialist for alternative regimens using second-line agents 1, 2
• Consider cycloserine, ciprofloxacin, streptomycin, and ethambutol as non-hepatotoxic alternatives 4

Important Prognostic Considerations

Timing of jaundice predicts prognosis and likely causative agent:

• Early onset (<15 days): Likely rifampicin-enhanced isoniazid hepatotoxicity with generally good prognosis 5
• Late onset (>1 month): Likely pyrazinamide-induced hepatitis with poor prognosis 1, 5

Avoid pyrazinamide reintroduction in patients with severe initial hepatotoxicity, particularly if jaundice occurred late in treatment, as recurrence carries poor prognosis 2, 5

Common Pitfalls to Avoid

• Never continue hepatotoxic drugs while "monitoring closely" once jaundice develops—this can lead to fulminant hepatic failure requiring transplantation 4, 6

• Do not reintroduce all drugs simultaneously—sequential reintroduction identifies the offending agent 1, 2

• Avoid concurrent hepatotoxic medications including over-the-counter acetaminophen during TB treatment 1, 7

• Ensure weight-based dosing as overdosing significantly increases hepatotoxicity risk 8

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