How to manage anti-tuberculosis (TB) treatment-induced hepatitis?

Management of Anti-TB Treatment-Induced Hepatitis

Stop rifampicin, isoniazid, and pyrazinamide immediately when ALT/AST rises to ≥5 times the upper limit of normal without symptoms, or ≥3 times the upper limit of normal with hepatitis symptoms (nausea, vomiting, abdominal pain, jaundice). 1, 2

Immediate Actions When Hepatotoxicity is Suspected

Diagnostic Workup

• Exclude other causes of liver injury before attributing hepatotoxicity to TB drugs, including viral hepatitis (A, B, C, Epstein-Barr virus, cytomegalovirus), biliary tract disease, alcohol, acetaminophen, other hepatotoxic medications, and herbal supplements 1, 2
• Measure ALT, AST, bilirubin, and alkaline phosphatase to assess severity 1
• Any bilirubin elevation mandates immediate cessation of all hepatotoxic TB drugs regardless of transaminase levels 1, 3

Stopping Treatment Thresholds

• ALT/AST ≥5× upper limit of normal (asymptomatic patients): Stop rifampicin, isoniazid, and pyrazinamide 1, 2
• ALT/AST ≥3× upper limit of normal with symptoms (fever, malaise, vomiting, jaundice, abdominal pain): Stop rifampicin, isoniazid, and pyrazinamide 1, 2
• ALT/AST 2-5× upper limit of normal (asymptomatic): Continue treatment with weekly monitoring for two weeks, then biweekly 1, 4

Bridging Therapy While Awaiting Liver Recovery

For Non-Infectious TB (Smear-Negative, Not Acutely Ill)

• No treatment is required until liver function normalizes (transaminases <2× upper limit of normal) 1, 3

For Infectious TB (Smear-Positive or Acutely Ill Patients)

• Use streptomycin and ethambutol as bridging therapy, preferably as an inpatient 1, 2
• Check renal function before using streptomycin or ethambutol; adjust doses in renal impairment and monitor serum drug concentrations 1, 4
• Alternative bridging regimen: Fluoroquinolone (levofloxacin or moxifloxacin) plus ethambutol if streptomycin is contraindicated 2, 4

Sequential Drug Reintroduction Protocol

Begin reintroduction only after liver function normalizes (ALT/AST <2× upper limit of normal and symptoms resolve) with daily clinical and biochemical monitoring 1, 2

Step 1: Isoniazid Reintroduction

• Start isoniazid at 50 mg/day 1, 2
• Increase to 300 mg/day after 2-3 days if no reaction occurs (no symptoms, no ALT/AST rise) 1, 2, 3
• Monitor liver function tests and clinical symptoms daily 1, 2

Step 2: Rifampicin Reintroduction

• After 2-3 additional days without reaction, add rifampicin at 75 mg/day 2, 3
• Increase to 300 mg after 2-3 days, then to full dose (450-600 mg based on weight) after another 2-3 days 2, 3
• Continue daily monitoring of liver function and symptoms 2

Step 3: Pyrazinamide Reintroduction (Use with Extreme Caution)

• Do not reintroduce pyrazinamide if it caused severe hepatotoxicity, as recurrence carries a poor prognosis 2, 3, 5
• If reintroduction is attempted, start at 250 mg/day and increase gradually to full dose 3
• Pyrazinamide is the most hepatotoxic first-line drug and most commonly causes late-onset (>1 month) severe hepatitis 5, 6

Alternative Regimens When Drugs Cannot Be Reintroduced

If Pyrazinamide Cannot Be Used

• Isoniazid, rifampicin, and ethambutol for 2 months, followed by 7 months of isoniazid and rifampicin (total 9 months) 2, 3

If Both Isoniazid and Pyrazinamide Cannot Be Used

• Rifampicin and ethambutol plus a fluoroquinolone, injectable agent, or cycloserine for 12-18 months depending on disease extent 2

If Rifampicin Cannot Be Used

• Omit rifampicin and extend treatment to 18 months 1

Monitoring Requirements

Pre-Treatment Screening

• Check baseline liver function tests in all patients before initiating TB treatment 1, 2
• Assess risk factors: chronic liver disease, hepatitis B/C, HIV infection, chronic alcohol use, advanced age, female sex, malnutrition 2, 7, 6

During Treatment Monitoring

• Patients with chronic liver disease: Weekly liver function tests for two weeks, then biweekly for first two months 1, 3
• Patients without pre-existing liver disease and normal baseline: No routine monitoring required, but repeat liver function tests if symptoms develop (fever, malaise, vomiting, jaundice, unexplained deterioration) 1, 3
• During drug reintroduction: Daily clinical and biochemical monitoring 1, 2, 3

Critical Pitfalls and Caveats

Patient Education

• Inform patients and their primary care providers about hepatotoxicity symptoms (nausea, vomiting, abdominal pain, jaundice, dark urine, light stools) and instruct them to stop medications immediately and seek care if symptoms develop 1, 2

Special Populations

• HIV-infected patients with CD4 <100/μL: Use daily or three-times-weekly therapy, never once-weekly regimens due to high relapse rates and acquired rifamycin resistance 2
• Elderly patients, females, and those with malnutrition: Higher risk for hepatotoxicity; consider more frequent monitoring 7, 6

Common Errors to Avoid

• Do not assume all transaminase elevations are drug-induced; TB itself can cause hepatic dysfunction 4
• Do not stop treatment prematurely in asymptomatic patients with ALT/AST 2-5× normal who have active TB, as this risks treatment failure and drug resistance 4
• Do not ignore bilirubin elevation; any rise mandates immediate cessation regardless of transaminase levels 1, 3
• Do not reintroduce pyrazinamide after severe hepatotoxicity due to poor prognosis with recurrence 2, 5