What is the recommended initial treatment regimen for a newly diagnosed tuberculosis (TB) patient with impaired liver function (deranged Liver Function Tests (LFTs))?

Initial Treatment for Newly Diagnosed TB with Deranged LFTs

For a newly diagnosed TB patient with deranged liver function tests, the initial treatment approach depends critically on the degree of transaminase elevation and whether the patient is symptomatic or has infectious disease.

Assess the Severity of Liver Dysfunction

The first step is to determine the exact degree of transaminase elevation, as this dictates management:

• If AST/ALT is less than 2 times normal: Start standard four-drug therapy (isoniazid, rifampicin, pyrazinamide, and ethambutol) and repeat LFTs at 2 weeks 1

• If AST/ALT is 2-5 times normal: Start standard four-drug therapy with weekly LFT monitoring for two weeks, then biweekly until normal 1, 2

• If AST/ALT is 5 times normal or higher, OR any bilirubin elevation: Do NOT start rifampicin, isoniazid, or pyrazinamide 1, 2, 3

Initial Drug Selection Based on LFT Abnormalities

For Mild-to-Moderate Elevation (AST/ALT <5x Normal, Normal Bilirubin)

Start the standard four-drug regimen: isoniazid, rifampicin, pyrazinamide, and ethambutol 1. This approach is justified because:

• The four-drug regimen provides coverage against potential drug resistance (recommended when isoniazid resistance >4%) 1
• Modest transaminase elevations are common in TB patients even before treatment 1
• Close monitoring allows early detection of worsening hepatotoxicity 1, 2

Critical monitoring requirements:

• Weekly LFTs for 2 weeks, then biweekly for the first 2 months 1, 2
• Educate patient to stop medications immediately if fever, malaise, vomiting, jaundice, or abdominal pain develop 1, 2
• Inform the general practitioner of these warning signs 1

For Severe Elevation (AST/ALT ≥5x Normal or Any Bilirubin Rise)

Use streptomycin and ethambutol as initial therapy until liver function normalizes 1, 2. This non-hepatotoxic regimen is particularly important when:

• The patient is acutely unwell 1
• The patient has infectious TB (sputum smear positive) 1, 2
• There is any elevation in bilirubin, regardless of transaminase levels 1, 3

If the patient is not acutely ill and has non-infectious TB: No treatment is required until liver function normalizes 1, 2

Important Pre-Treatment Checks

Before initiating therapy with alternative drugs:

• Check renal function before using streptomycin or ethambutol, as both require dose adjustment in renal impairment 1, 4, 3
• Check visual acuity using Snellen chart before prescribing ethambutol 1, 4
• Consider viral hepatitis testing to exclude coexistent viral hepatitis as a cause of liver dysfunction 1

Sequential Drug Reintroduction Protocol

Once liver function normalizes (after starting with streptomycin/ethambutol), reintroduce hepatotoxic drugs sequentially with daily clinical and biochemical monitoring 1, 2:

1. Start isoniazid at 50 mg/day, increase to 300 mg/day after 2-3 days if no reaction 1, 2, 4

2. Add rifampicin after 2-3 days without reaction: start at 75 mg/day, increase to 300 mg after 2-3 days, then to full dose (450 mg if <50 kg, 600 mg if >50 kg) after another 2-3 days 1, 2, 4

3. Add pyrazinamide last at 250 mg/day, increase to 1.0 g after 2-3 days, then to full dose (1.5 g if <50 kg, 2.0 g if >50 kg) 1, 2, 4

If hepatotoxicity recurs during reintroduction: The offending drug must be permanently excluded and an alternative regimen used 1, 2. If pyrazinamide is the culprit, extend treatment to 9 months with rifampicin and isoniazid plus ethambutol for the initial 2 months 1, 2

Critical Pitfalls to Avoid

• Never ignore bilirubin elevation: Any rise in bilirubin mandates immediate cessation of all hepatotoxic drugs (rifampicin, isoniazid, pyrazinamide), regardless of transaminase levels 1, 3

• Do not use streptomycin without checking renal function: Streptomycin requires dose adjustment and therapeutic drug monitoring in renal impairment 1, 3

• Do not add a single drug to a failing regimen: This promotes drug resistance 5

• Do not stop treatment prematurely in infectious TB: Patients with smear-positive disease require continuous treatment, even if it means using non-hepatotoxic alternatives temporarily 1

Risk Factors Requiring Enhanced Vigilance

Patients with the following characteristics require more intensive monitoring:

• Pre-existing chronic liver disease 1, 2
• Advanced age 2
• Alcohol consumption 2
• Diabetes mellitus 3
• Chronic kidney disease 3
• Poor nutritional status 3