ATT-Induced Liver Injury (Anti-Tuberculosis Treatment Hepatotoxicity)

Complete 10-Mark Answer for MD Examinations

Definition

• Biochemical: ALT/AST >3x ULN with symptoms, OR >5x ULN without symptoms
• It constitutes the most common cause of drug-induced acute liver failure in developing nations

Causative Drugs and Their Hepatotoxic Potential

Combined HRZE regimens carry a cumulative risk of 2-28% for hepatotoxicity (higher in developing countries)

Pathophysiology

1. Isoniazid (INH) - Most studied mechanism

• INH → Acetyl-INH → Acetylhydrazine (toxic intermediate) → further oxidized by CYP2E1 → reactive electrophilic intermediates
• These covalently bind to hepatocyte macromolecules → oxidative stress, lipid peroxidation, cell membrane damage
• Slow acetylators accumulate more hydrazine (a direct hepatotoxin)
• Rapid acetylators produce more acetylhydrazine, increasing risk differently

2. Rifampicin's role

• Rifampicin itself rarely causes hepatitis alone
• It is a potent CYP inducer - increases conversion of INH to toxic metabolites, hence INH + RIF together are more hepatotoxic than INH alone
• Can cause isolated hyperbilirubinemia via competition with bilirubin for hepatic uptake (not true hepatitis)

3. Pyrazinamide

• Most dose-dependent hepatotoxicity among ATT drugs
• Metabolized to pyrazinoic acid → oxidized to 5-hydroxypyrazinoic acid → direct hepatocellular toxicity
• Risk is highest with higher doses (>30 mg/kg/day, now abandoned)

4. General DILI mechanisms (per Harrison's, 22e)

• Rupture of cell membrane via disruption of intracellular Ca²+ homeostasis
• Injury of bile canaliculus - disruption of transport pumps (MRP3)
• CYP450-drug covalent binding creating nonfunctioning adducts
• Migration of drug adducts to cell surface → T-cell mediated immune attack
• Activation of apoptotic pathway via TNF-α/Fas
• Inhibition of mitochondrial function → lactic acidosis, microvesicular steatosis

Risk Factors for ATT-DILI

• Advanced age (>35 years)
• Female sex
• Malnutrition
• Pre-existing liver disease (chronic hepatitis B or C, alcoholic liver disease, NAFLD/NASH)
• HIV co-infection (NASH, immune dysregulation, drug interactions with ART)
• Alcohol use disorder
• Slow NAT2 acetylator phenotype (more relevant for INH)
• Genetic polymorphisms in CYP2E1, GSTM1, GSTT1

• Combination therapy (HRZE > HR > H alone)
• Higher daily doses
• Prolonged treatment duration

Clinical Features

Spectrum of Presentation

• 10-20% on INH alone; may resolve spontaneously
• Detected only on monitoring

• Anorexia, nausea, vomiting, malaise, right upper quadrant discomfort
• Jaundice (icterus) appears when bilirubin >2.5 mg/dL
• Dark urine, pale stools
• Clinically resembles viral hepatitis

• More with rifampicin
• Jaundice, pruritus, pale stools

• Encephalopathy, coagulopathy (INR >1.5), deepening jaundice
• Can occur days to weeks after initial hepatitis onset
• Carries 30-70% mortality without transplant

• Onset typically within 4-8 weeks of starting ATT (may occur up to 6 months)
• Pyrazinamide tends to cause earlier injury; INH may present later

Diagnosis

Biochemical Criteria

• AST/ALT >3x ULN with symptoms (nausea, vomiting, jaundice, RUQ pain)
• AST/ALT >5x ULN without symptoms
• Elevated serum bilirubin, prolonged PT/INR (indicates severity)
• Elevated ALP (suggests cholestatic pattern)

Monitoring Protocol (WHO/National Guidelines)

• Baseline LFTs before starting ATT
• Monthly LFT monitoring for high-risk patients (HIV+, alcoholic liver disease, HBV/HCV co-infection, elderly)
• Symptomatic patients - immediate LFT testing

DILI Severity Grading (RUCAM/CIOMS Scale modified):

• Grade 1: ALT 1-3x ULN - continue with close monitoring
• Grade 2: ALT 3-5x ULN - caution, possible dose reduction
• Grade 3: ALT >5x ULN or symptomatic - STOP ATT
• Grade 4: ALT >10x ULN or acute liver failure - stop all ATT, urgent management

Histopathology (when done):

• Hepatocellular injury resembling viral hepatitis (lobular inflammation, spotty necrosis, lymphocytic infiltrate)
• No specific diagnostic features - diagnosis of exclusion
• INH pattern: hepatocellular necrosis (centrilobular in severe cases)

Exclusion of other causes:

• Viral hepatitis markers: HBsAg, Anti-HCV, IgM anti-HAV, IgM anti-HEV
• Autoimmune hepatitis: ANA, anti-LKM, ASMA
• Rule out Wilson's disease, other drug causes

Management

Step 1: Stop ATT

• ALT/AST >5x ULN (asymptomatic)
• ALT/AST >3x ULN with symptoms
• Any jaundice with transaminase elevation
• Clinical picture of acute liver failure

Step 2: Supportive Care

• Bed rest
• Adequate nutrition (high calorie, high protein unless encephalopathy)
• IV fluids if needed
• Avoid alcohol and other hepatotoxic drugs (NSAIDs, paracetamol)
• N-acetylcysteine (NAC) - may have adjuvant role in severe DILI (especially with acetaminophen-like mechanisms)
• Vitamin K for coagulopathy

Step 3: Treat Active TB During Hepatitis Recovery

• Streptomycin (S) + Ethambutol (E) + Fluoroquinolone (levofloxacin/moxifloxacin)
• Continue for 2-3 weeks until transaminases normalize

Step 4: Reintroduction of ATT (Sequential Rechallenge)

1. Day 1-3: Rifampicin 75 mg/day → increase to full dose over 3-7 days → check LFTs
2. Day 7-10: Add Isoniazid 50 mg/day → increase to full dose → check LFTs
3. Day 14 onwards: Add Ethambutol (already safe) if needed
4. Pyrazinamide: Often omitted permanently if it was the most likely culprit

Check LFTs after each reintroduction step. If hepatotoxicity recurs with a drug, that drug is permanently excluded.

• 9-month regimen: HR + E (without PZA)

Step 5: Management of Fulminant Hepatic Failure

• ICU admission
• Management of encephalopathy: lactulose, rifaximin, low-protein diet
• Coagulopathy: fresh frozen plasma, vitamin K
• Cerebral edema: mannitol, head elevation
• Avoid sedatives
• Liver transplantation evaluation (Kings College Criteria)
• Anti-TB drugs given cautiously via non-hepatotoxic route

Special Situations

HIV Co-infection

• Higher risk of ATT-DILI due to baseline hepatic dysfunction, IRIS, and drug interactions with ART
• Monthly LFT monitoring mandatory (per Symptom to Diagnosis guide, 4e)
• Rifabutin preferred over rifampicin to reduce drug interactions
• Nevirapine and isoniazid combination especially hepatotoxic - avoid if possible

Pre-existing Liver Disease (HBV/HCV/Cirrhosis)

• Very high risk group
• 2-weekly LFT monitoring recommended
• Consider pyrazinamide-free regimen from the outset
• Lower threshold to stop drugs

Pregnancy

• INH safe in pregnancy; supplement with pyridoxine (B6) to prevent neuropathy
• Rifampicin generally safe
• Pyrazinamide - WHO recommends in pregnancy; avoid streptomycin (ototoxic to fetus)
• Monitor LFTs closely

Prevention

1. Baseline LFT before starting ATT
2. Risk stratification - identify high-risk patients
3. Patient education - report jaundice, anorexia, dark urine immediately
4. Pyridoxine (B6) supplementation with INH (10-25 mg/day) - reduces neurotoxicity
5. Avoid alcohol during ATT
6. Regular monitoring: monthly LFTs for high-risk patients
7. Drug dose optimization: avoid excessive doses of pyrazinamide
8. Pharmacogenomics (emerging): NAT2 acetylator genotyping to individualize INH dosing

Key Points for Exam

• Stop ATT at ALT >5x ULN (asymptomatic) or >3x ULN (symptomatic)
• Isoniazid liver toxicity: transaminase elevation in 10-20% of patients; symptomatic hepatitis much less common (Symptom to Diagnosis, 4e)
• INH should be stopped if transaminase elevation exceeds 5x ULN even if asymptomatic
• Rechallenge is possible and necessary; omit the likely culprit drug permanently
• Most hepatotoxic combination: INH + RIF + PZA (first 2 months of standard therapy)
• INH-DILI morphology: hepatocellular injury resembling viral hepatitis (Harrison's, 22e)