How should I manage a patient on standard anti‑tuberculosis therapy who develops drug‑induced hepatitis (elevated transaminases >3 × upper limit of normal with symptoms or >5 × without symptoms)?

Management of Anti-Tuberculosis Drug-Induced Hepatitis

Immediate Action Required

Stop isoniazid, rifampin, and pyrazinamide immediately when drug-induced hepatitis is confirmed (AST/ALT >3× upper limit of normal with symptoms OR >5× upper limit of normal without symptoms). 1

Initial Management Steps

Stop All Hepatotoxic Drugs

• Discontinue INH, RIF, and PZA immediately upon meeting hepatotoxicity criteria 1
• The FDA label for isoniazid specifically warns that continued use after hepatitis symptoms appear causes more severe liver damage 2

Exclude Alternative Causes

• Perform serologic testing for hepatitis A, B, and C (if not done at baseline) 1
• Question carefully about alcohol consumption and other hepatotoxins 1
• Evaluate for biliary tract disease, other hepatotoxic medications, and herbal/dietary supplements 1

Bridge Therapy with Non-Hepatotoxic Agents

• Continue treatment with two or more non-hepatotoxic drugs to prevent disease progression and resistance 1
• Recommended options include:
  • Ethambutol (EMB) 1, 3
  • Streptomycin (SM) if renal function permits 1, 3
  • Fluoroquinolones (levofloxacin, moxifloxacin, or gatifloxacin) 1, 4
  • Amikacin/kanamycin or capreomycin 1

Sequential Drug Reintroduction Protocol

Timing for Reintroduction

• Wait until AST/ALT decreases to less than 2 times the upper limit of normal 1
• Ensure symptoms have significantly improved before restarting 1
• Restart drugs sequentially, not simultaneously 1, 5

Reintroduction Sequence

The American Thoracic Society/CDC/IDSA guidelines recommend sequential reintroduction with the following approach 1:

1. Start with rifampin first (least hepatotoxic of the three) 6

   • Begin at full dose
   • Monitor daily with clinical assessment and liver function tests 5
   • Wait 3-7 days before adding next drug

2. Add isoniazid second 5, 6

   • Start at low dose, gradually increase to full dose 5
   • Monitor daily for 3-7 days

3. Add pyrazinamide last (most hepatotoxic) 5, 6, 7

   • Consider avoiding pyrazinamide reintroduction in patients with severe hepatotoxicity, as it has the highest hepatotoxic potential and poor prognosis if hepatitis recurs 6, 7
   • If reintroduced, use lowest therapeutic dose 6

Monitoring During Reintroduction

• Measure serum AST, ALT, and bilirubin daily during reintroduction 5
• Review symptoms at each visit 1, 5
• Stop immediately if AST/ALT rises to ≥3× upper limit of normal with symptoms or ≥5× without symptoms 1
• Stop immediately if bilirubin rises above normal at any level 1, 3, 5

Critical Monitoring Requirements

Close Surveillance Protocol

• Repeat liver function tests (AST, ALT, bilirubin, alkaline phosphatase) with each drug addition 1, 5
• Continue frequent monitoring (at least weekly) for the first month after complete regimen reintroduction 3, 8
• Educate patients to report immediately: unexplained anorexia, nausea, vomiting, dark urine, jaundice, abdominal pain, or fatigue >3 days 2

Alternative Regimen if Reintroduction Fails

If hepatotoxicity recurs with drug reintroduction 1:

• Use fluoroquinolone-based regimen: levofloxacin or moxifloxacin plus ethambutol, with or without streptomycin 5, 4
• Fluoroquinolones (levofloxacin and moxifloxacin) do not cause additional hepatotoxicity in patients with prior anti-TB drug-induced hepatitis 4
• Extend treatment duration as these regimens are less potent than standard therapy 1

High-Risk Patient Considerations

Patients at increased risk for severe hepatotoxicity require enhanced vigilance 1, 3:

• Advanced age (especially >50 years) 1, 9
• Female gender, particularly Black and Hispanic women 1, 2, 9
• Postpartum period 1, 2
• Chronic liver disease or baseline transaminase elevation 1, 4
• Daily alcohol consumption 1, 2, 9
• HIV infection 1, 9
• Malnutrition or hypoalbuminemia 10, 9
• Chronic kidney disease 5

Critical Pitfalls to Avoid

• Never continue hepatotoxic drugs after hepatitis criteria are met, as this causes more severe and potentially fatal liver injury 2
• Never ignore bilirubin elevation—any rise above normal mandates immediate cessation regardless of transaminase levels 1, 3, 5
• Do not reintroduce all three hepatotoxic drugs simultaneously—sequential reintroduction allows identification of the offending agent 1, 5
• Do not use pyrazinamide in patients with underlying liver disease or consider omitting it permanently after severe hepatotoxicity 6
• Rifampin must not be discontinued for minor side effects as it is critical for treatment success, but hepatotoxicity is not a minor side effect 1