How to manage raised bilirubin due to anti-tubercular (antituberculosis) drug-induced hepatitis?

Management of Raised Bilirubin Due to Anti-Tuberculosis Drug-Induced Hepatitis

Immediately stop all potentially hepatotoxic anti-tuberculosis drugs when bilirubin rises above the normal range, regardless of whether symptoms are present. 1

Assessment and Initial Management

When elevated bilirubin is detected during anti-TB therapy:

1. Stop all hepatotoxic drugs immediately (isoniazid, rifampicin, pyrazinamide)
2. Consider hospitalization for close monitoring, especially in severe cases 1
3. Evaluate severity with comprehensive liver function tests:
   • Serum aminotransaminases (ALT/AST)
   • Bilirubin (direct and indirect)
   • Prothrombin time/INR
   • Albumin

Monitoring Guidelines

The European Respiratory Society recommends specific thresholds for action 1:

• Stop treatment when:
  • AST/ALT ≥5× upper limit of normal (ULN) in asymptomatic patients
  • AST/ALT ≥3× ULN in symptomatic patients
  • Bilirubin rises above normal range
  • Patient develops jaundice

Reintroduction Strategy

After liver function tests normalize, reintroduce drugs sequentially 1:

1. Start with isoniazid at a low dose
2. Monitor liver function tests after 3-7 days
3. If no reaction, add rifampicin
4. Monitor liver function tests again after 3-7 days
5. Consider avoiding pyrazinamide reintroduction due to poor prognosis of pyrazinamide-induced hepatitis 2

Alternative Regimens

When hepatotoxicity occurs, the following alternative regimens are recommended 1:

• Isoniazid, rifampicin, and ethambutol for 12-18 months
• Rifampicin, ethambutol, and a fluoroquinolone for 12-18 months
• Isoniazid and rifampicin for 9 months (with ethambutol for initial 2 months if pyrazinamide caused hepatotoxicity)

Prevention Strategies

To reduce risk of severe hepatic adverse effects 2:

1. Avoid pyrazinamide in patients with underlying liver abnormalities
2. Use lowest effective dosages of hepatotoxic anti-TB drugs
3. Monitor serum transaminase levels:
   • Twice weekly during first 2 weeks
   • Every 2 weeks during rest of first 2 months
   • Monthly thereafter

Risk Factors to Consider

Several factors increase risk of anti-TB drug-induced hepatotoxicity 3, 4:

• Advanced age
• Female sex
• Slow acetylator status
• Malnutrition
• HIV co-infection
• Pre-existing liver disease
• Alcohol consumption
• Concurrent use of other hepatotoxic medications

Patient Education

Educate patients about symptoms requiring immediate medical attention 1:

• Unexplained anorexia
• Nausea or vomiting
• Dark urine
• Jaundice
• Persistent fatigue or weakness
• Right upper quadrant discomfort

Special Considerations

• Dispense no more than a 2-week supply of medications to facilitate frequent monitoring 5
• Reassess patients in person at 2,4,6, and 8 weeks of treatment 5
• Ensure provider continuity for optimal monitoring 5
• Consider non-hepatotoxic regimens (e.g., with fluoroquinolones) in patients with severe hepatic dysfunction 4

Common Pitfalls

• Failure to recognize early signs of hepatotoxicity
• Continuing hepatotoxic drugs despite elevated liver enzymes
• Reintroducing all drugs simultaneously rather than sequentially
• Inadequate monitoring of high-risk patients
• Not educating patients about warning symptoms

By following these guidelines, clinicians can effectively manage raised bilirubin due to anti-tubercular drug-induced hepatitis while ensuring successful treatment of tuberculosis.