What is the diagnosis for a patient with a history of drug-induced liver injury from HRZE (rifampicin, isoniazid, pyrazinamide, ethambutol) therapy for Pulmonary Tuberculosis presenting with acute abdominal symptoms?

Drug-Induced Liver Injury (DILI) from Anti-Tuberculosis Therapy

The diagnosis is anti-tuberculosis drug-induced liver injury (ATB-DILI), specifically hepatotoxicity caused by the HRZE regimen, with acute abdominal symptoms representing a clinical manifestation of hepatitis that requires immediate discontinuation of all hepatotoxic anti-TB drugs. 1, 2

Diagnostic Confirmation

Drug-induced hepatotoxicity is diagnosed when ALT is ≥3 times the upper limit of normal WITH hepatitis symptoms (including abdominal pain, nausea, vomiting), OR when ALT is ≥5 times the upper limit of normal even WITHOUT symptoms, OR when any bilirubin elevation above normal occurs. 1, 2

The acute abdominal symptoms in this patient—particularly the combination of unexplained nausea, vomiting, and abdominal pain—are classic hepatitis symptoms that mandate immediate evaluation with liver function tests including ALT, AST, bilirubin, and alkaline phosphatase. 1

Critical Differential Diagnoses to Exclude

Before confirming ATB-DILI, you must systematically rule out: 1, 2

• Viral hepatitis (hepatitis A, B, and C in all patients; EBV, CMV, HSV in immunosuppressed patients)
• Biliary tract disease (cholangitis, choledocholithiasis)
• Alcohol use
• Other hepatotoxic drugs (acetaminophen, lipid-lowering agents, herbal supplements)
• Hepatic tuberculosis itself

Hepatotoxicity Profile of HRZE Components

Among first-line anti-TB agents, pyrazinamide is the most hepatotoxic, followed by isoniazid and rifampin. 1 The combination of rifampin and pyrazinamide carries particularly high risk, with hospitalization rates of 3.0 per 1,000 treatment initiations and death rates of 0.9 per 1,000—substantially higher than isoniazid alone (hospitalization rate 0.15 per 1,000, mortality 0.04 per 1,000). 1

Immediate Management Algorithm

Step 1: Stop All Hepatotoxic Drugs Immediately

When diagnostic criteria are met, immediately discontinue isoniazid, rifampin, AND pyrazinamide together—do not wait to determine which specific drug is responsible. 2 This is critical because the patient presents with acute symptoms suggesting active hepatitis. 1

Step 2: Assess Severity and Need for Continued TB Treatment

For patients with severe or extensive tuberculosis requiring continued treatment while hepatotoxic drugs are held: 2

• Switch to streptomycin plus ethambutol until liver function normalizes
• Alternative non-hepatotoxic regimens: ethambutol with fluoroquinolone, cycloserine, and injectable agents

Step 3: Monitor for Recovery

For hepatocellular injury, a decrease in peak serum ALT of at least 50% within 8 days is highly suggestive of drug-induced injury, while a decrease of at least 50% within 30 days is considered important. 3 This rapid normalization after drug discontinuation helps confirm the diagnosis. 3

Risk Factors Present in This Clinical Scenario

The patient's exposure to the complete HRZE regimen places them at elevated risk, particularly if any of these cofactors exist: 1

• Concurrent hepatotoxic medications
• Excessive alcohol consumption
• Underlying liver disease
• History of previous INH-associated liver injury
• Advanced age (particularly >40 years)
• Female sex 4

Common Pitfalls to Avoid

Do not continue anti-TB drugs while "monitoring" liver enzymes if diagnostic criteria are already met. 2 The acute abdominal symptoms combined with a history of HRZE exposure warrant immediate action, not observation. 1

Do not assume that asymptomatic transaminase elevations are benign. Even without symptoms, ALT ≥5× ULN requires immediate drug discontinuation. 1, 2

Do not rechallenge with the same drugs if severe liver injury occurred, especially if jaundice was present. 3 Only 2% of patients require permanently modified regimens, but these are typically older patients with jaundice and extensive disease. 4

Timing Considerations

The majority of severe liver injuries from rifampin-pyrazinamide combinations occur after the fourth week of therapy, with 69% of cases occurring in the second month of treatment. 1 However, hepatotoxicity can occur at any point during therapy, necessitating vigilance throughout the entire treatment course. 1