Management of Tuberculosis with Pre-existing Liver Disease / Hepatitis

Introduction

1. Three of the four first-line anti-tuberculosis drugs (ATT) - isoniazid (H), rifampicin (R), and pyrazinamide (Z) - are potentially hepatotoxic.
2. Pre-existing liver disease increases the risk of ATT-induced drug-induced liver injury (DILI).
3. In patients with diminished hepatic reserve, even mild hepatotoxicity can precipitate fulminant liver failure.
4. Monitoring is confounded because baseline LFTs are already deranged.
5. Untreated TB itself can worsen liver function (paradoxically, ATT may improve TB-related hepatic dysfunction).

Hepatotoxicity Profile of Anti-TB Drugs

Pre-Treatment Evaluation

• Hepatitis serology: HBsAg, anti-HCV, IgM anti-HAV, IgM anti-HEV
• LFT baseline: ALT, AST, bilirubin, ALP, PT/INR, serum albumin
• Ultrasound of liver for morphology, portal hypertension
• Child-Pugh (Child-Turcotte-Pugh, CTP) score - this is the key scoring system used to guide ATT selection

Regimen Selection Based on Severity of Liver Disease

Category 1 - Acute Hepatitis (HAV, HEV, Acute HBV)

• If TB is not immediately life-threatening: defer ATT until acute hepatitis resolves.
• If TB is life-threatening (meningeal TB, miliary TB, pericardial TB, sputum-positive pulmonary TB): use non-hepatotoxic regimen = Streptomycin + Ethambutol + Fluoroquinolone, given for 3 months, then resume standard 2HRZE/4HR once acute hepatitis subsides.

Category 2 - Chronic Liver Disease / Cirrhosis (Child-Pugh Score Based)

Child-Pugh A (Score 1-6) - Stable/Compensated Liver Disease

• Use two potentially hepatotoxic drugs - standard regimen without pyrazinamide
• Recommended: 9HRE (9 months of H + R + E), OR 2HRE/7HR
• Avoid pyrazinamide (most hepatotoxic)
• Close monitoring with monthly LFTs

Child-Pugh B (Score 7-10) - Advanced/Decompensated Liver Disease

• Use one potentially hepatotoxic drug only
• Preferred: Rifampicin (least hepatotoxic, highest efficacy)
• Regimen options: RIF + EMB + Fluoroquinolone ± Aminoglycoside for 9-12 months
• OR: INH + EMB + Fluoroquinolone ± Aminoglycoside for 9-12 months (if rifampicin not preferred)

Child-Pugh C (Score ≥ 11) - Very Advanced / End-Stage Liver Disease

• Use no potentially hepatotoxic drugs
• Regimen: EMB + Fluoroquinolone + Aminoglycoside (streptomycin/amikacin) ± Cycloserine
• Duration extended to 18-24 months (due to lower drug efficacy)
• ATS guideline: EMB + fluoroquinolone + cycloserine + capreomycin/aminoglycoside for 18-24 months

Summary Table:

CTP Score	Status	Regimen
≤7	Stable	2 hepatotoxic drugs (H+R; avoid Z) - e.g., 9HRE
8-10	Advanced	1 hepatotoxic drug (R preferred) + EMB + FQ ± aminoglycoside, 9-12 months
≥11	Very advanced	0 hepatotoxic drugs - EMB + FQ + aminoglycoside ± cycloserine, 18-24 months

Management of ATT-Induced Hepatitis (DILI) During Treatment

Definition of ATT-DILI

• AST/ALT ≥5x ULN (without symptoms), OR
• AST/ALT ≥3x ULN with symptoms (nausea, vomiting, abdominal pain, fatigue), OR
• Jaundice (bilirubin ≥2x ULN)

Step 1 - Stop Hepatotoxic Drugs

• Stop H, R, Z (and cotrimoxazole if HIV patient).
• If ATT cannot be stopped (life-threatening TB): switch to a non-hepatotoxic bridging regimen - EMB + fluoroquinolone + aminoglycoside.

Step 2 - Investigate

• Exclude other causes: viral hepatitis (HAV, HEV reactivation), alcohol, drug interactions, TB itself worsening liver disease.
• Obtain PT/INR, ultrasound.

Step 3 - Monitor LFT

• Recheck LFTs weekly.
• Refer to hepatology/higher center if: jaundice + coagulopathy/encephalopathy (fulminant hepatic failure).

Reintroduction of ATT (Sequential Rechallenge)

Sequential Reintroduction Protocol (ICMR / Standard):

1. Day 1-3: Start rifampicin 150 mg/day → increase gradually to full dose (10 mg/kg) by Day 4. Check LFT at Day 7.
2. Day 8-10: If LFTs normal, add isoniazid 100 mg/day → increase to full dose (5 mg/kg) by Day 11. Check LFT at Day 14-15.
3. Day 15-18: If LFTs still normal, add pyrazinamide 500 mg/day → increase to full dose (25 mg/kg) by Day 18.

Note: Reintroduce one drug at a time - this helps identify the culprit drug if hepatitis recurs.

If Hepatitis Recurs on Rechallenge:

• The last drug added is the likely culprit - stop it permanently.
• In severe ATT hepatitis (liver failure, coagulopathy, encephalopathy): do not reintroduce pyrazinamide.
• Duration of ATT is counted from when the full regimen is restarted.

Monitoring During Treatment

Special Scenarios

TB + Active Hepatitis B (Chronic HBV)

• HBV can be reactivated or worsen with ATT-DILI.
• Monitor HBV DNA.
• Consider adding tenofovir or entecavir to protect the liver.
• Rifampicin is still the preferred drug.

TB + Compensated HCV Cirrhosis

• If direct-acting antivirals (DAAs) planned: potential drug interactions - rifampicin significantly reduces DAA levels (strong P-glycoprotein/CYP3A4 inducer).
• Manage TB first with close monitoring, then treat HCV.

TB + Alcoholic Liver Disease

• Chronic alcohol use is an independent risk factor for ATT hepatotoxicity.
• Abstinence from alcohol is mandatory.
• Similar Child-Pugh-based approach; nutritional support important.

Latent TB Infection (LTBI) with Liver Disease

• Rifampicin alone for 4 months, or isoniazid for 9 months, are alternatives.
• Rifampicin preferred (shorter duration, less hepatotoxic than H, lower DILI rate).
• Check baseline ALT - if ≥3x ULN or bilirubin >2x ULN, defer treatment and re-evaluate.

Key Points for Exam

1. Pyrazinamide is the most hepatotoxic first-line ATT drug and should be avoided in liver disease.
2. Rifampicin is the least hepatotoxic of the three hepatotoxic drugs and is the preferred single hepatotoxic agent in advanced liver disease.
3. Use CTP score to guide regimen choice - this is the cornerstone classification.
4. Non-hepatotoxic drugs: ethambutol, fluoroquinolones, aminoglycosides, cycloserine.
5. Stop all hepatotoxic ATT when ALT ≥5x ULN asymptomatic OR ≥3x ULN with symptoms OR jaundice.
6. Reintroduce sequentially - rifampicin first, then isoniazid, then pyrazinamide (one drug at a time, 1 week apart).
7. Extended treatment duration (18-24 months) is needed when using non-hepatotoxic regimens.
8. TB itself can cause hepatic dysfunction - this may improve with ATT (paradox of rising LFTs at start).
9. Always rule out viral hepatitis at baseline (HBsAg, anti-HCV, IgM anti-HAV/HEV).
10. Jaundice + coagulopathy/encephalopathy on ATT = refer immediately to higher center (acute liver failure).