In a patient being treated for pulmonary tuberculosis who develops hepatitis, what is the most likely cause and how should the anti‑tuberculosis drugs be managed?

Drug-Induced Hepatitis in Pulmonary Tuberculosis Treatment

Most Likely Causative Agent

Pyrazinamide is the most common cause of drug-induced hepatitis during anti-tuberculosis treatment, with an incidence rate of 3.71 per 100 person-months compared to 0.59 for isoniazid and 0.69 for rifampin. 1 When hepatitis occurs with the combination of isoniazid, rifampin, and pyrazinamide, two distinct patterns emerge: early hepatotoxicity (within 15 days) typically reflects rifampin-enhanced isoniazid toxicity with good prognosis, while late-onset hepatitis (>1 month) is usually pyrazinamide-related and carries a poor prognosis. 2

Immediate Management: Stop All Hepatotoxic Drugs

• Discontinue isoniazid, rifampin, and pyrazinamide immediately when AST/ALT rises ≥5× upper limit of normal in asymptomatic patients, or ≥3× upper limit of normal with symptoms (jaundice, nausea, vomiting, abdominal pain), or when bilirubin reaches ≥2× upper limit of normal. 3

• Initiate a non-hepatotoxic bridge regimen of streptomycin plus ethambutol (15-20 mg/kg daily) immediately if the patient is unwell or has smear-positive sputum, continuing until liver function normalizes. 3 If the patient is clinically stable with non-infectious tuberculosis, no treatment is required during the recovery period. 3

• Exclude alternative causes including viral hepatitis A, B, C, and E, alcohol use, other hepatotoxic medications, and biliary tract disease before attributing hepatitis to anti-tuberculosis drugs. 3

Sequential Drug Reintroduction Protocol

Begin reintroduction only after transaminases return to normal (or <2-3× upper limit of normal if baseline was already elevated). 3

Step 1: Reintroduce Isoniazid First

• Start at 50 mg/day, increase to 300 mg/day after 2-3 days if no reaction occurs. 3
• Monitor liver function tests daily during this phase. 3

Step 2: Add Rifampin Second

• After 2-3 days of full-dose isoniazid without reaction, start rifampin at 75 mg/day. 3
• Increase to 300 mg after 2-3 days, then to 450 mg (<50 kg) or 600 mg (≥50 kg) after another 2-3 days. 3

Step 3: Add Pyrazinamide Last (If Needed)

• Start at 250 mg/day, increase to 1.0 g after 2-3 days, then to 1.5 g (<50 kg) or 2.0 g (≥50 kg). 3
• Do NOT reintroduce pyrazinamide in patients who experienced severe initial hepatotoxicity, especially with late-onset jaundice (>1 month after treatment start), due to poor prognosis and high recurrence risk. 3, 2

Stopping Rules During Reintroduction

• Immediately discontinue the most recently added drug if any of the following occur: AST/ALT >5× upper limit of normal, transaminase elevation with hepatitis symptoms, bilirubin elevation, or symptoms of fever, malaise, vomiting, jaundice, or abdominal pain. 3

Alternative Regimens When Drugs Cannot Be Reintroduced

If Pyrazinamide Is the Offending Drug

• Use isoniazid + rifampin + ethambutol for 2 months, followed by isoniazid + rifampin for 7 months (total 9 months). 3 This extended duration compensates for the loss of pyrazinamide's sterilizing activity. 3

If Isoniazid Cannot Be Tolerated

• Use rifampin + ethambutol + a fluoroquinolone (levofloxacin or moxifloxacin) for 12 months. 3

If Rifampin Cannot Be Tolerated

• Use isoniazid + ethambutol + a fluoroquinolone for 18-24 months, following an MDR-TB protocol approach. 3

Monitoring Protocol

• Check liver function tests weekly for the first 2 weeks after each drug reintroduction, then every 2 weeks for the first 2 months. 3
• Educate patients about hepatotoxicity symptoms (fever, malaise, vomiting, jaundice, unexplained deterioration) and instruct them to stop medication immediately and seek urgent care if symptoms appear. 3
• Avoid all concurrent hepatotoxic agents, including over-the-counter acetaminophen and alcohol. 3

Absolute Contraindications to Rechallenge

• Do NOT rechallenge if the patient meets Hy's Law criteria (ALT ≥3× upper limit of normal AND bilirubin ≥2× upper limit of normal). 3
• Rechallenge is contraindicated with hepatic decompensation (ascites, encephalopathy) or hypersensitivity features (rash, fever, eosinophilia, lymphadenopathy). 3
• Cirrhosis or advanced liver disease generally precludes rechallenge due to high risk of further hepatic deterioration. 3

High-Risk Patient Populations Requiring Intensive Monitoring

• Advanced age, female sex, malnutrition, HIV infection, chronic hepatitis B or C, chronic alcohol use, slow acetylator status (NAT2 polymorphism), and pre-existing liver disease all increase hepatotoxicity risk. 4, 1, 5
• Patients with pre-existing liver disease require weekly liver function tests for two weeks, then biweekly for the first two months. 3
• Patients with history of isoniazid-associated liver injury should NOT be offered rifampin-pyrazinamide regimens due to increased recurrence risk. 3

Critical Pitfalls to Avoid

• Never continue hepatotoxic drugs while "monitoring closely" after hepatitis onset—this can lead to fulminant hepatic failure requiring transplantation. 6
• Never reintroduce all drugs simultaneously—sequential reintroduction is essential to identify the offending agent. 6
• Never attribute hepatitis to normal physiological changes without excluding drug toxicity, especially in high-risk populations. 6
• The combination of rifampin and pyrazinamide for latent TB infection carries unacceptably high rates of severe liver injury (hospitalization rate 3.0 per 1,000, death rate 0.9 per 1,000) and should generally not be offered. 7