What is the management of Isoniazid (INH)-induced hepatotoxicity in patients with tuberculosis (TB)?

Management of Isoniazid (INH)-Induced Hepatotoxicity in Tuberculosis Patients

When INH-induced hepatotoxicity occurs, all hepatotoxic drugs (INH, rifampin, and pyrazinamide) should be immediately discontinued and the patient should be switched to non-hepatotoxic alternatives until liver function normalizes.

Diagnosis of INH-Induced Hepatotoxicity

Drug-induced hepatitis is defined as:

• Serum AST level >3 times the upper limit of normal with symptoms, OR
• Serum AST level >5 times the upper limit of normal without symptoms 1

Common symptoms include:

• Unexplained anorexia, nausea, vomiting
• Dark urine, jaundice
• Right upper quadrant discomfort/pain
• Persistent fatigue, weakness
• Fever lasting >3 days 2

Immediate Management Steps

1. Stop all hepatotoxic TB medications immediately (INH, rifampin, pyrazinamide) 1
2. Rule out other causes of hepatitis before attributing to INH:
   • Viral hepatitis (A, B, C)
   • Biliary tract disease
   • Alcohol use
   • Other hepatotoxic medications
   • Herbal/dietary supplements 1
3. Initiate alternative non-hepatotoxic regimen with two or more of:
   • Ethambutol
   • Streptomycin
   • Amikacin/kanamycin
   • Capreomycin
   • Fluoroquinolone (levofloxacin, moxifloxacin, or gatifloxacin) 1
4. Monitor liver function tests until AST decreases to <2 times the upper limit of normal and symptoms significantly improve 1

Reintroduction of First-Line Drugs

Once liver function normalizes (AST <2 times upper limit of normal and symptoms resolve):

1. Sequential reintroduction of first-line TB medications:

   • Start with rifampin at full dose
   • If tolerated for 1 week (no symptoms, normal LFTs), add INH
   • If both tolerated, consider adding pyrazinamide (highest risk)
   • Stop any drug immediately if symptoms recur or LFTs rise 1

2. Close monitoring during reintroduction:

   • Repeat LFTs and symptom review with each drug addition
   • More frequent monitoring for high-risk patients 1

Special Considerations

High-Risk Patients

More careful monitoring is needed for:

• Patients >35 years old (risk increases with age)
• Women, particularly Black and Hispanic women
• Postpartum period
• Daily alcohol users
• Those with underlying liver disease
• HIV-infected individuals 2

Alternative Regimens

If first-line drugs cannot be reintroduced:

• Consider regimens with two or more non-hepatotoxic drugs
• Extend treatment duration appropriately
• Consult TB experts for complex cases 1

Prevention of Recurrence

• Avoid alcohol consumption during TB treatment
• Avoid concomitant use of other hepatotoxic medications
• Patient education about symptoms requiring immediate medical attention
• Consider dose reduction for essential medications in patients with elevated bilirubin 3

Monitoring Recommendations

• All patients should be educated about hepatotoxicity symptoms
• For patients ≥35 years old: baseline LFTs and periodic monitoring throughout treatment
• For patients with pre-existing liver disease: weekly LFTs for first 2 weeks, then biweekly for first 2 months
• Immediate LFT testing if symptoms develop in any patient 1, 2

Remember that continued use of INH after symptoms appear can lead to severe liver damage, and patients who continue taking the drug for 10 days or more after symptom onset are at risk for fulminant hepatic failure 1, 4.