At what level of elevated liver enzymes can anti-tuberculosis (TB) therapy be initiated?

Management of Anti-TB Therapy with Elevated Liver Enzymes

Anti-tuberculosis therapy can be initiated with liver enzyme elevations up to five times the upper limit of normal (ULN) in asymptomatic patients, but should be stopped if enzymes exceed this threshold or if the patient develops symptoms of hepatotoxicity. 1

Baseline Assessment and Monitoring

• Perform liver function tests (LFTs) for all patients before starting anti-TB treatment
• Identify high-risk patients:
  • Pre-existing liver disease
  • History of alcohol consumption
  • HIV co-infection
  • Pregnancy or immediate postpartum period
  • Concurrent use of other hepatotoxic medications
  • Age >55 years (21.1% develop ALT/AST ≥3×ULN) 2

Monitoring Protocol

• For patients with normal baseline LFTs and no risk factors:

  • No routine monitoring required
  • Test if symptoms develop (fever, malaise, vomiting, jaundice)

• For patients with pre-existing liver disease:

  • Weekly LFTs for first 2 weeks
  • Biweekly for first 2 months
  • Monthly thereafter 1

Thresholds for Action

1. Continue treatment normally if:

   • AST/ALT <5×ULN in asymptomatic patients
   • AST/ALT <3×ULN in symptomatic patients
   • Bilirubin remains within normal range 1

2. Stop potentially hepatotoxic drugs (isoniazid, rifampicin, pyrazinamide) if:

   • AST/ALT ≥5×ULN in asymptomatic patients
   • AST/ALT ≥3×ULN in symptomatic patients
   • Bilirubin rises above normal range
   • Patient develops jaundice 3, 1

Management of Hepatotoxicity

• 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 and streptomycin)
  • Consider hospitalization for close monitoring 1

Reintroduction Protocol After Hepatotoxicity

1. Wait for liver enzymes to normalize
2. Reintroduce drugs sequentially with daily monitoring of liver function:
   • Start with isoniazid at low dose, increase to full dose over 3-7 days if no reaction
   • Add rifampicin if no reaction to isoniazid
   • Consider adding pyrazinamide last or omitting it completely due to high hepatotoxicity risk 1

Alternative Regimens

• If pyrazinamide is the cause: Continue for 9 months with rifampicin and isoniazid, plus ethambutol for initial 2 months
• If isoniazid cannot be reintroduced: Consider rifampicin, ethambutol, and a fluoroquinolone for 12-18 months 1

Special Considerations

• Asian patients have higher risk of enzyme elevations (85.1% on isoniazid-containing regimens) 2
• Hepatotoxicity typically occurs early (median 28 days) in treatment 2
• Monitoring hepatic enzymes during first 2 months detects approximately 75% of patients with peak enzyme elevation ≥3×ULN 2
• Despite enzyme elevations up to 6×ULN, treatment can often be continued or reintroduced in full in most cases 4

Patient Education

• Advise patients to avoid alcohol during treatment
• Instruct patients to report symptoms requiring immediate attention:
  • Unexplained anorexia, nausea, vomiting
  • Dark urine, jaundice
  • Persistent fatigue, weakness
  • Abdominal tenderness, especially right upper quadrant discomfort 1

Remember that untreated TB can be fatal, and the risk of mortality from TB often outweighs the risk of drug-induced liver injury when properly monitored 3.