How to manage anti-tubercular (anti-tuberculosis) drug-induced hepatitis?

Management of Anti-Tubercular Drug-Induced Hepatitis

When anti-tubercular drug-induced hepatitis occurs, immediately stop all hepatotoxic drugs (isoniazid, rifampicin, and pyrazinamide), evaluate the patient thoroughly, and institute a non-hepatotoxic regimen until liver function normalizes before sequential reintroduction of first-line drugs. 1

Diagnosis of Anti-Tubercular Drug-Induced Hepatitis

Drug-induced hepatitis is defined as:

• ALT/AST ≥3 times the upper limit of normal (ULN) with symptoms, OR
• ALT/AST ≥5 times ULN without symptoms 1

Clinical Presentation

• Unexplained anorexia, nausea, vomiting
• Dark urine, jaundice
• Right upper quadrant abdominal tenderness
• Fatigue, weakness, or fever lasting >3 days 2

Evaluation

1. Physical examination focusing on signs of liver dysfunction
2. Liver function tests (ALT, AST, bilirubin, alkaline phosphatase)
3. Exclude other causes of abnormal liver function:
   • Viral hepatitis (A, B, C, EBV, CMV, HSV in immunosuppressed)
   • Biliary tract disease
   • Alcohol consumption
   • Other hepatotoxic drugs (acetaminophen, lipid-lowering agents)
   • Herbal and dietary supplements 1

Management Algorithm

Step 1: Immediate Actions

• Stop all hepatotoxic anti-TB drugs (isoniazid, rifampicin, pyrazinamide) 1
• Continue clinical monitoring
• Perform liver function tests and serologic testing for viral hepatitis 1

Step 2: Interim Treatment

• For non-infectious TB or clinically stable patients:

  • No anti-TB treatment until liver function normalizes 1

• For infectious TB (sputum smear-positive) or clinically unstable patients:

  • Institute a non-hepatotoxic regimen with 2 or more drugs:
    • Ethambutol
    • Streptomycin/amikacin/kanamycin
    • Fluoroquinolone (levofloxacin, moxifloxacin) 1

Step 3: Monitoring

• Monitor liver function tests regularly until normalization
• ALT/AST should decrease to <2 times ULN before reintroduction 1
• Continue to monitor symptoms

Step 4: Reintroduction of First-Line Drugs

Once liver function normalizes (ALT/AST <2 times ULN and symptoms significantly improved):

1. Sequential reintroduction:

   • Start with isoniazid at 50 mg/day, increasing to 300 mg/day after 2-3 days if no reaction 1
   • After 3-7 days at full dose with normal LFTs, add rifampicin at low dose, increasing to full dose
   • If both drugs are tolerated, consider adding pyrazinamide or continue without it 1

2. Monitoring during reintroduction:

   • Monitor liver function tests and symptoms daily during reintroduction
   • If symptoms recur or ALT/AST increases, stop the most recently added drug 1

Special Considerations

Risk Factors for Hepatotoxicity

• Advanced age (risk increases with age)
• Female sex (particularly Black and Hispanic women)
• Postpartum period
• Daily alcohol consumption
• Malnutrition
• HIV infection
• Pre-existing liver disease 3, 2

HIV Co-infection

• HIV-infected patients require closer monitoring due to:
  • Potential for drug interactions with antiretroviral therapy
  • Higher risk of adverse effects
  • Importance of maintaining both TB and HIV treatment 1
• Rifampin interactions with protease inhibitors may require substitution with rifabutin or alternative regimens 1

Prevention of Recurrence

• Consider avoiding pyrazinamide in the reintroduced regimen, as pyrazinamide-induced hepatitis has a poorer prognosis 4
• For patients who cannot tolerate standard regimens, consider:
  • Extended regimens without the offending drug(s)
  • Non-hepatotoxic regimens with fluoroquinolones for severe cases 5

Monitoring Recommendations

For Patients Without Risk Factors

• Regular clinical monitoring for symptoms
• Liver function tests not required routinely unless symptoms develop 1

For Patients With Risk Factors

• Baseline liver function tests before treatment
• Regular monitoring of liver function:
  • Weekly for first 2 weeks
  • Every 2 weeks for first 2 months
  • Monthly thereafter 1, 4

Common Pitfalls and Caveats

1. Do not ignore minor symptoms - Early recognition of hepatotoxicity can prevent progression to severe liver injury 3

2. Do not continue hepatotoxic drugs when hepatotoxicity is suspected - Even if TB is severe, stop the hepatotoxic drugs immediately 1

3. Do not reintroduce all drugs simultaneously - Sequential reintroduction allows identification of the offending drug 1

4. Do not confuse transient elevations with true hepatitis - Transient elevations of liver enzymes at the beginning of treatment are common and do not usually indicate hepatitis 1

5. Do not restart pyrazinamide in patients with severe hepatotoxicity - Consider alternative regimens without pyrazinamide 4