How to manage a patient with hepatitis due to anti-tubercular (antituberculosis) treatment?

Management of Anti-Tubercular Drug-Induced Hepatitis

Stop rifampicin, isoniazid, and pyrazinamide immediately when AST/ALT rises to ≥5 times the upper limit of normal (ULN) or when bilirubin becomes elevated, regardless of symptoms. 1, 2, 3

Immediate Actions Upon Detection

• Discontinue all hepatotoxic TB drugs (rifampicin, isoniazid, pyrazinamide) when AST/ALT exceeds 5× ULN in asymptomatic patients, or when AST/ALT exceeds 3× ULN with hepatitis symptoms (fever, malaise, vomiting, jaundice). 1, 2, 3

• Exclude other causes of hepatitis before attributing liver injury to TB drugs: test for hepatitis A, B, C viruses, assess for biliary tract disease, review all concurrent medications (including over-the-counter drugs like acetaminophen), and evaluate alcohol consumption. 1, 2

• Continue TB treatment with non-hepatotoxic alternatives if the patient is acutely ill or has smear-positive/infectious tuberculosis: use streptomycin and ethambutol (with appropriate renal function monitoring), or substitute with fluoroquinolones (levofloxacin/moxifloxacin). 1, 2, 3, 4

• Suspend all treatment if the patient has non-infectious TB and is clinically stable until liver function normalizes. 1, 3

Sequential Drug Reintroduction Protocol

Once AST/ALT decreases to <2× ULN and symptoms resolve, reintroduce drugs one at a time with daily clinical and biochemical monitoring. 1, 2, 3

Reintroduction Sequence:

1. Start with isoniazid first at 50 mg/day, increasing to 300 mg/day after 2-3 days if no reaction occurs (no symptoms, stable liver enzymes). 1, 2

2. Add rifampicin next after 2-3 additional days without reaction, beginning at 75 mg/day and increasing to full dose (typically 600 mg/day) after 2-3 days. 1, 2

3. Add pyrazinamide last using the same gradual approach if the first two drugs are tolerated. 1, 2

• Monitor liver function tests and clinical symptoms daily during the entire reintroduction process. 1, 2, 3

• Stop the drug immediately if AST/ALT rises above 2× ULN or any hepatitis symptoms appear during reintroduction—this identifies the culprit drug. 1, 2

Critical Pitfall:

Never restart all three hepatotoxic drugs simultaneously, as this prevents identification of the offending agent and risks severe recurrent liver injury with potentially fatal outcomes. 3, 5

Alternative Regimens When Drugs Cannot Be Reintroduced

If Pyrazinamide is the Culprit:

• Use isoniazid, rifampicin, and ethambutol for 2 months, followed by 7-9 months of isoniazid and rifampicin (total 9-11 months). 6, 2, 3

• Do not reintroduce pyrazinamide if it caused severe hepatotoxicity, as recurrence carries poor prognosis with high mortality risk. 2, 5

If Both Isoniazid and Pyrazinamide Cannot Be Used:

• Use rifampicin and ethambutol plus a fluoroquinolone (levofloxacin 750-1000 mg daily or moxifloxacin 400 mg daily), with or without an injectable agent (streptomycin, amikacin, kanamycin, or capreomycin) for 12-18 months depending on disease extent and severity. 6, 2

If All Three Hepatotoxic Drugs Must Be Avoided:

• Use a combination of ethambutol, a fluoroquinolone, streptomycin (or another injectable), and cycloserine for 18-24 months. 2, 4

Special Populations Requiring Intensive Monitoring

Patients with Pre-existing Liver Disease:

• Check liver function weekly for 2 weeks, then biweekly for the first 2 months in patients with known chronic liver disease, hepatitis B/C infection, or cirrhosis. 1, 3

• Consider avoiding pyrazinamide entirely in patients with baseline liver abnormalities, as they have significantly higher risk of severe hepatotoxicity. 5, 4

• In patients with hepatitis B and cirrhosis, use non-hepatotoxic regimens from the start (levofloxacin, ethambutol, streptomycin) and initiate or continue antiviral therapy (tenofovir) to prevent hepatitis B flares. 4, 7

High-Risk Features for Severe Hepatotoxicity:

• High HBV viral load (odds ratio 2.066 for liver failure). 7
• Hypoalbuminemia and low prothrombin activity correlate with progression to liver failure. 7
• Female sex, older age (>35 years), and extensive tuberculosis increase hepatotoxicity risk. 1, 8
• Concurrent use of other hepatotoxic medications or excessive alcohol consumption (>60 g/day). 1, 8

Monitoring Strategy for Patients Without Pre-existing Liver Disease

• Baseline liver function tests (AST, ALT, bilirubin, albumin) are mandatory before starting treatment. 1, 3

• Routine monitoring is NOT required if baseline tests are normal and patient remains asymptomatic. 1

• Repeat liver function tests immediately if fever, malaise, vomiting, jaundice, or unexplained deterioration occur at any time during treatment. 1, 3

• If baseline AST/ALT is 2-5× ULN: monitor weekly for 2 weeks, then biweekly until normalized before starting treatment. 1

Patient Education Requirements

Inform patients and their general practitioners to stop all TB medications immediately and seek urgent medical attention if they develop: 1, 3

• Jaundice (yellowing of eyes or skin)
• Dark/tea-colored urine
• Persistent nausea or vomiting
• Abdominal pain
• Unexplained fatigue or malaise
• Fever without obvious cause

Key Clinical Pearls

• Rifampicin and isoniazid are the most critical drugs for TB cure—every effort should be made to retain them even after hepatotoxicity, as their efficacy far exceeds alternatives. 6, 3

• Early hepatotoxicity (within first 2 weeks) is typically rifampicin-enhanced isoniazid toxicity with generally good prognosis. 5

• Late hepatotoxicity (>1 month) is more likely pyrazinamide-related with poorer prognosis and higher mortality risk. 5

• Despite AST/ALT elevations up to 6× ULN, full treatment can often be continued or successfully reintroduced in most patients, particularly those with alcohol-related baseline elevations. 8

• In post-liver transplant patients, avoid rifampicin due to enzyme induction causing acute rejection episodes; use fluoroquinolone-based regimens instead. 9