What are the Philippine guidelines for managing liver enzyme elevations in symptomatic and asymptomatic patients on anti-tuberculosis (TB) therapy, specifically regarding isoniazid (INH), rifampicin (RIF), and pyrazinamide (PZA)?

Management of Liver Enzyme Elevations in Patients on Anti-TB Therapy in the Philippines

For patients with liver enzyme elevations during anti-tuberculosis therapy, treatment should be stopped if AST/ALT rises to five times the upper limit of normal in asymptomatic patients or three times the upper limit of normal in symptomatic patients, followed by sequential reintroduction of drugs once liver function normalizes. 1

Monitoring Recommendations

Baseline Assessment

• Perform liver function tests (LFTs) for all patients before starting anti-TB treatment
• Identify high-risk patients:
  • Age >35 years
  • Pre-existing liver disease
  • History of alcohol consumption
  • HIV co-infection
  • Pregnancy or immediate postpartum period
  • Concurrent use of other hepatotoxic medications

Monitoring Schedule

1. For patients with normal baseline LFTs and no risk factors:

   • Routine monitoring not required
   • Test only if symptoms develop (fever, malaise, vomiting, jaundice)

2. For patients with pre-existing liver disease:

   • Weekly LFTs for first 2 weeks
   • Biweekly for first 2 months
   • Monthly thereafter

3. For patients with elevated baseline transaminases:

   • Weekly for 2 weeks if AST/ALT ≥2× normal
   • Biweekly until normal

Management of Hepatotoxicity

When to Stop Treatment

• Asymptomatic patients: Stop treatment if AST/ALT rises to ≥5× upper limit of normal
• Symptomatic patients: Stop treatment if AST/ALT rises to ≥3× upper limit of normal
• All patients: Stop if bilirubin rises above normal range

Immediate Actions

1. Stop all potentially hepatotoxic drugs (isoniazid, rifampicin, pyrazinamide)
2. Investigate other causes of liver injury (viral hepatitis, alcohol)
3. Monitor liver function until normalization

Management Based on Clinical Status

• For non-infectious TB and clinically stable patients:

  • Withhold all TB medications until liver function normalizes

• For infectious TB or clinically unstable patients:

  • Continue treatment with non-hepatotoxic drugs (ethambutol, streptomycin)
  • Hospitalize for close monitoring

Reintroduction Protocol

Once liver function normalizes, reintroduce drugs sequentially with daily monitoring of liver function:

1. Start with isoniazid at low dose (50 mg/day), increasing to full dose over 3-7 days if no reaction
2. Add rifampicin starting at low dose after 3-7 days, increasing to full dose if no reaction
3. Consider adding pyrazinamide last (highest risk for severe hepatotoxicity) or omit completely

This sequential approach has been shown to reduce hepatotoxicity recurrence rates compared to reintroduction of full-dose regimens 2.

Special Considerations

Symptomatic vs. Asymptomatic Patients

• Patients should be educated about symptoms requiring immediate medical attention:
  • Unexplained anorexia, nausea, vomiting
  • Dark urine, jaundice
  • Persistent fatigue, weakness
  • Abdominal tenderness, especially right upper quadrant discomfort 3

Alternative Regimens

If pyrazinamide is identified as the cause of hepatotoxicity:

• Continue treatment for 9 months with rifampicin and isoniazid
• Add ethambutol for the initial 2 months 1

If isoniazid cannot be reintroduced:

• Consider a regimen of rifampicin, ethambutol with a fluoroquinolone for 12-18 months 4

Prevention Strategies

• Avoid alcohol consumption during treatment
• Avoid concurrent use of other hepatotoxic medications
• Use lowest effective dosages of hepatotoxic anti-TB drugs
• Ensure regular follow-up and monitoring
• Provide patient education about early signs of hepatotoxicity

Important Cautions

• Liver function tests are not a substitute for clinical evaluation
• Patients with fatty liver disease are at significant risk of liver injury, particularly with rifampicin 1
• The risk of hepatitis is increased with daily consumption of alcohol 3
• Women, particularly Black and Hispanic women, may have an increased risk of fatal hepatitis associated with isoniazid 3

By following these guidelines for monitoring and management, clinicians can effectively address liver enzyme elevations in both symptomatic and asymptomatic patients on anti-TB therapy, minimizing the risk of severe hepatotoxicity while ensuring successful treatment completion.