What is the best course of action for a patient with severe transaminitis (elevated Serum Glutamic-Oxaloacetic Transaminase (SGOT) and Serum Glutamic-Pyruvic Transaminase (SGPT)) without significant hyperbilirubinemia, who developed this condition after starting anti-tubercular medication, including Isoniazid, Rifampicin (Rifampin), and Pyrazinamide?

Management of Severe Transaminitis Without Significant Hyperbilirubinemia on Anti-Tubercular Therapy

Stop rifampicin, isoniazid, and pyrazinamide immediately if AST/ALT rises to five times the upper limit of normal, regardless of bilirubin levels or symptoms. 1

Immediate Actions

Discontinue all hepatotoxic anti-tubercular drugs (rifampicin, isoniazid, and pyrazinamide) when transaminases reach ≥5× upper limit of normal, even if the patient is asymptomatic and bilirubin remains normal. 1

Assess Clinical Status and Disease Severity

• If the patient is unwell or has smear-positive sputum within two weeks of starting treatment: Initiate streptomycin and ethambutol immediately as bridge therapy until liver function normalizes. 1
• If the patient is not unwell and has non-infectious tuberculosis: No treatment is required until liver function returns to normal. 1
• Monitor renal function and visual acuity appropriately when using streptomycin and ethambutol. 2

Exclude Other Causes of Hepatotoxicity

• Perform virological tests for hepatitis A, B, C, and E. 1, 3
• Obtain ultrasound to exclude biliary tract disease. 3
• Assess alcohol consumption history, as concurrent alcohol use significantly increases hepatotoxicity risk. 1, 3

Sequential Drug Reintroduction Protocol

Once transaminases normalize, reintroduce drugs sequentially with daily monitoring of clinical condition and liver function tests. 1, 2

Step 1: Reintroduce Isoniazid First

• Start at 50 mg/day
• Increase to 300 mg/day after 2-3 days if no reaction occurs
• Continue for 2-3 days at full dose before adding next drug 1, 2

Step 2: Add Rifampicin Second

• Start at 75 mg/day
• Increase to 300 mg after 2-3 days
• Further increase to 450 mg (<50 kg) or 600 mg (>50 kg) after another 2-3 days without reaction 1, 2

Step 3: Add Pyrazinamide Last (If Needed)

• Start at 250 mg/day
• Increase to 1.0 g after 2-3 days
• Further increase to 1.5 g (<50 kg) or 2.0 g (>50 kg) 1, 2

Critical caveat: If hepatotoxicity recurs during reintroduction of any specific drug, that drug must be permanently excluded from the regimen. 1, 3

Alternative Regimens If Drugs Cannot Be Reintroduced

If Pyrazinamide Is the Offending Drug

Extend treatment to 9 months total with rifampicin and isoniazid, supplemented with ethambutol for the initial 2 months. 1, 2 This extended duration is necessary because pyrazinamide's sterilizing activity contributes to treatment shortening (adjusted OR 1.6,95% CI 1.3-2.1 for cure versus failure/relapse/death). 2

If Isoniazid Cannot Be Tolerated

Use rifampicin, ethambutol, and a fluoroquinolone for 12 months. 2

If Multiple Drugs Cannot Be Tolerated

Consider a regimen containing only one potentially hepatotoxic drug plus ethambutol and a fluoroquinolone. 4

Monitoring During Reintroduction

• Check liver function tests (AST/ALT) daily during the reintroduction phase. 1, 3
• Assess for symptoms of hepatotoxicity daily: fever, malaise, vomiting, jaundice, or unexplained deterioration. 1, 3
• Stop the most recently added drug immediately if transaminases rise again or symptoms develop. 1, 3

Critical Pitfalls to Avoid

Do not reintroduce pyrazinamide if it caused late-onset hepatotoxicity (>1 month after treatment initiation), as pyrazinamide-induced hepatitis occurring late has a poor prognosis. 2, 5 The second pattern of fulminant liver injury, characterized by late transaminase elevation, is likely related to pyrazinamide and carries generally poor prognosis. 5

Never add a single drug to a failing regimen, as this promotes drug resistance. During desensitization, the procedure must be carried out under cover of two other antituberculosis drugs. 1, 3

Avoid alcohol completely during anti-tuberculosis treatment due to additive hepatotoxicity risk. 1, 3

Recognize that rifampicin enhances isoniazid hepatotoxicity through enzyme induction. Early-onset hepatotoxicity (within first 15 days) is likely caused by rifampicin-induced isoniazid hepatotoxicity and generally has good prognosis. 5, 6

Special Considerations

Patients with pre-existing liver disease require more intensive monitoring: weekly liver function tests for two weeks, then biweekly for the first two months. 1 These patients should not receive pyrazinamide. 5

For extrapulmonary tuberculosis, particularly TB meningitis, treatment duration may need extension to 9-12 months even with standard regimens. 2