How to manage Anti-Tuberculosis Treatment (ATT)-induced elevated bilirubin?

Management of ATT-Induced Elevated Bilirubin

When bilirubin levels rise during anti-tuberculosis treatment (ATT), all hepatotoxic drugs (rifampicin, isoniazid, and pyrazinamide) should be immediately stopped and alternative non-hepatotoxic drugs (streptomycin and ethambutol) should be used until liver function returns to normal. 1

Initial Assessment and Monitoring

Baseline Evaluation

• Check liver function tests before starting ATT 1
• Inform patients about symptoms of hepatotoxicity (malaise, nausea, vomiting, jaundice) 1
• Advise patients to avoid alcohol during treatment 1

Monitoring Requirements

• For patients with normal baseline LFTs and no pre-existing liver disease:
  • Routine monitoring is not required 1
  • Repeat LFTs if symptoms develop (fever, malaise, vomiting, jaundice) 1
• For patients with known chronic liver disease:
  • Weekly LFT monitoring for first 2 weeks
  • Then biweekly monitoring for first 2 months 1

Management Algorithm for ATT-Induced Elevated Bilirubin

When to Stop ATT

• Stop rifampicin, isoniazid, and pyrazinamide immediately if:
  • Bilirubin level rises above normal 1
  • AST/ALT rises to 5× upper limit of normal 1

Management Based on Clinical Status

1. For non-infectious TB with patient clinically stable:

   • Discontinue all hepatotoxic drugs
   • Wait until liver function normalizes before reintroduction 1

2. For infectious TB (sputum smear positive) or clinically unstable patient:

   • Admit patient to hospital for close monitoring 1
   • Switch to non-hepatotoxic regimen: streptomycin and ethambutol 1
   • Continue until liver function normalizes

Drug Reintroduction Protocol

Once liver function returns to normal, reintroduce drugs sequentially with daily monitoring of LFTs 1:

1. Isoniazid reintroduction:

   • Start with 50 mg/day
   • Increase to 300 mg/day after 2-3 days if no reaction
   • Continue for 2-3 days

2. Rifampicin reintroduction:

   • Start with 75 mg/day
   • Increase to 300 mg after 2-3 days
   • Increase to full dose (450-600 mg based on weight) after another 2-3 days
   • Continue for 2-3 days

3. Pyrazinamide reintroduction:

   • Start with 250 mg/day
   • Increase to 1.0 g after 2-3 days
   • Increase to full dose (1.5-2.0 g based on weight)

If Hepatotoxicity Recurs

• Identify the offending drug and permanently exclude it 1
• Design an alternative regimen with specialist consultation
• If pyrazinamide is the offending drug, extend treatment to 9 months with rifampicin and isoniazid, plus ethambutol for initial 2 months 1

Special Considerations

HIV Co-infection

• Higher risk of LFT abnormalities in patients on concurrent ATT and ART 2
• Consider drug interactions between rifampicin and antiretrovirals 1

Risk Factors for ATT-Induced Hepatotoxicity

• Chronic alcohol intake significantly increases risk (OR=9.3) 3
• Pre-existing liver disease 1
• Hepatitis B carriers may have higher baseline transaminases 4

Importance of Monitoring

Regular monitoring of liver function in high-risk patients is crucial, as studies show that patients without follow-up monitoring have more severe liver injuries and higher mortality than those with monitoring 4. The onset of hepatotoxicity typically ranges from 13-58 days (median 26 days) after treatment initiation 3.

Pitfalls to Avoid

• Do not continue hepatotoxic drugs when bilirubin rises, even if transaminases are normal 1
• Do not reintroduce all drugs simultaneously after hepatotoxicity 1
• Do not overlook other causes of abnormal LFTs (viral hepatitis, alcohol, other medications) 1
• Rifampicin can have a biphasic effect on bilirubin - initial increase followed by normalization 5