What are the considerations for using anti-tubercular (TB) drugs in patients with liver disease?

Management of Anti-Tubercular Drugs in Liver Disease

For patients with liver disease, anti-tubercular therapy should be modified based on the severity of hepatic impairment, with regimens containing fewer hepatotoxic agents as liver disease becomes more advanced. 1

Risk Assessment and Considerations

• Tuberculosis treatment in patients with preexisting liver disease poses significant challenges due to increased risk of drug-induced liver injury (DILI) and potentially life-threatening consequences in those with marginal hepatic reserve 1
• Baseline liver function abnormalities may be due to TB itself, which typically improve with effective treatment 1
• Risk factors for hepatotoxicity include advanced age, hepatitis virus infection, HIV infection, malnutrition, and alcohol consumption 2
• The three first-line anti-TB drugs with hepatotoxic potential (in decreasing order of risk) are isoniazid (INH), pyrazinamide (PZA), and rifampicin (RIF) 3
• Ethambutol (EMB) is not hepatotoxic and can be safely used in patients with liver disease 3

Treatment Regimens Based on Severity of Liver Disease

Mild Liver Disease (Normal or Minimally Elevated Liver Enzymes)

• Standard regimen with close monitoring: INH, RIF, PZA, and EMB for 2 months, followed by INH and RIF for 4 months 1
• Monitor liver function tests more frequently (every 1-4 weeks for first 2-3 months) 1

Moderate to Advanced Liver Disease

1. Treatment without PZA (preferred option):

   • INH, RIF, and EMB for 2 months, followed by INH and RIF for 7 months (total 9 months) 1
   • PZA is often implicated in severe and prolonged hepatotoxicity 1

2. Treatment without INH:

   • RIF, PZA, and EMB with or without a fluoroquinolone for at least 6 months 1
   • Although this regimen has two potentially hepatotoxic medications, it maintains the 6-month treatment duration 1

3. Treatment without INH and PZA:

   • RIF and EMB with a fluoroquinolone, injectable agent, or cycloserine for 12–18 months 1
   • Recommended for patients with advanced liver disease 1

4. Regimen with minimal hepatotoxicity:

   • For severe, unstable liver disease: EMB combined with a fluoroquinolone, cycloserine, and a second-line injectable for 18–24 months 1
   • Some experts avoid aminoglycosides in severe liver disease due to concerns about renal insufficiency or bleeding from injection sites due to coagulopathy 1

Monitoring Recommendations

• Baseline testing: All patients should undergo liver biochemistry tests, hepatitis B and C screening, and abdominal imaging before starting treatment 2
• Monitoring frequency:
  • Patients with known chronic liver disease: Monitor liver function weekly for two weeks, then biweekly for the first two months, then monthly 1
  • If ALT/AST increases to five times normal or bilirubin increases, discontinue RIF, INH, and PZA immediately 1, 4
• Clinical monitoring: Educate patients to report symptoms such as anorexia, nausea, vomiting, dark urine, jaundice, rash, persistent fatigue, or right upper quadrant discomfort 4

Management of Hepatotoxicity

• If DILI occurs, immediately discontinue all hepatotoxic drugs until liver function normalizes 2
• After normalization, drugs can be reintroduced sequentially with careful monitoring 1
• Reintroduction sequence:
  1. Start with INH at 50 mg/day, increase to 300 mg/day after 2-3 days
  2. Add RIF at 75 mg/day after 2-3 days without reaction, then increase to full dose
  3. Add PZA at 250 mg/day and increase to full dose (if necessary) 5

Special Considerations

• Expert consultation is strongly advised when treating TB in patients with advanced or unstable liver disease 1
• The crucial efficacy of INH and particularly RIF warrant their use and retention if at all possible, even with preexisting liver disease 1
• Drug susceptibility testing for fluoroquinolones and injectable agents is indicated if these drugs are being considered 1
• Avoid concurrent use of other hepatotoxic medications 2
• In patients with cirrhosis, extrapulmonary TB is more common than pulmonary TB 6

By carefully selecting appropriate regimens and implementing vigilant monitoring, effective TB treatment can be achieved even in patients with underlying liver disease, minimizing the risk of treatment-related hepatotoxicity while ensuring adequate treatment of tuberculosis.