Medications That Can Cause Acute Liver Injury
Numerous medications across various drug classes can cause acute liver injury, with antibiotics, anti-tuberculosis drugs, and acetaminophen being among the most common culprits. Understanding which medications pose hepatotoxicity risks is essential for clinical monitoring and early intervention.
Common Hepatotoxic Medications
Antibiotics
- Amoxicillin-clavulanate: Can cause delayed-onset liver injury 1
- Cefazolin: Can lead to liver injury 1-3 weeks after a single infusion 1
- Macrolides (Clarithromycin, Azithromycin): Can cause hepatitis requiring monitoring of liver enzymes for the first 3 months 2
Anti-tuberculosis Drugs
Isoniazid: Causes severe and sometimes fatal hepatitis with age-related risk (highest in 50-64 year age group at 23 per 1,000) 3
Rifampin: Can cause hepatotoxicity of hepatocellular, cholestatic, and mixed patterns ranging from asymptomatic enzyme elevations to fulminant liver failure 4
- Monitoring: Every 2-4 weeks during therapy in patients with impaired liver function 4
Rifampin-Pyrazinamide combination: Associated with severe liver injury and death (hospitalization rate of 3.0 per 1,000 treatment initiations) 2, 5
- Significantly higher risk of grade 3 or 4 hepatotoxicity compared to isoniazid alone (7.7% vs 1%) 5
Other Common Hepatotoxic Medications
Acetaminophen: Dose-related toxin; most ingestions leading to ALF exceed 10 gm/day, but severe injury can occur rarely with doses as low as 3-4 gm/day 6
- Treatment: N-acetylcysteine (NAC) should be given as early as possible 6
Statins: Cause transaminase elevations in approximately 1% of patients 2
Immune checkpoint inhibitors: Can cause immune-mediated hepatitis requiring monitoring before each infusion 2
Antiepileptic drugs: Associated with hepatotoxicity, particularly valproate
Nevirapine: Can cause severe clinical hepatitis in up to 12% of female patients 2
Patterns of Drug-Induced Liver Injury
The pattern of liver injury is classified according to R value (ALT × ULN/ALP × ULN) 6:
- Hepatocellular: R ≥5
- Cholestatic: R <2
- Mixed: R between 2 and 5
Monitoring Recommendations
General Monitoring Guidelines
- Baseline liver function tests before starting potentially hepatotoxic medications 2
- For elevations <2× ULN: Continue medication and repeat testing in 2-4 weeks 2
- For elevations ≥2× but <3× ULN: Consider dose reduction, close monitoring 2
- For elevations ≥3× but <5× ULN: Consider temporary discontinuation or dose reduction 2
- For elevations >5× ULN: Discontinue medication and consider hepatology consultation 2
High-Risk Patient Monitoring
More careful monitoring should be considered in high-risk groups 2, 3:
- Pre-existing liver disease
- Alcohol consumption
- Obesity
- Diabetes
- Advanced age
- Concomitant use of multiple hepatotoxic drugs
Warning Signs and Management
Warning Signs of Hepatotoxicity
Patients should be instructed to immediately report 3:
- Unexplained anorexia, nausea, vomiting
- Dark urine, jaundice
- Rash
- Persistent paresthesias of hands and feet
- Persistent fatigue, weakness
- Fever lasting >3 days
- Abdominal tenderness, especially right upper quadrant discomfort
Management of Suspected Hepatotoxicity
- Promptly discontinue the suspected hepatotoxic medication 3, 4
- Perform comprehensive evaluation for competing etiologies 6
- For acetaminophen overdose, administer N-acetylcysteine 6
- For immune checkpoint inhibitor-related liver injury, consider steroids based on severity 2
Pitfalls and Caveats
- Delayed presentation: Some medications (e.g., amoxicillin-clavulanate) can cause liver injury weeks after exposure 1
- Chronic injury risk: In rare cases, drug-induced hepatotoxicity can lead to chronic injury and vanishing bile duct syndrome 1
- Idiosyncratic reactions: Many cases of drug-induced liver injury are idiosyncratic and not dose-dependent, making prediction difficult 7
- Drug interactions: Concomitant use of multiple hepatotoxic drugs significantly increases risk 2
- Underlying liver disease: Patients with pre-existing liver disease may have worse outcomes when DILI occurs 6
Special Considerations
- Acetaminophen in combination products: Limit fixed-dose combinations containing acetaminophen to ≤325mg per dosage unit 2
- Restarting hepatotoxic medications: If a medication must be reintroduced after liver injury, start with very small doses and increase gradually, with immediate withdrawal if any sign of recurrent liver involvement 3
- Alcohol use: Patients should be advised against alcohol consumption while taking hepatotoxic medications 2
Drug-induced liver injury remains a significant cause of acute liver failure, with antibiotics being the most commonly implicated drug class. Early recognition, prompt discontinuation of the offending agent, and appropriate supportive care are essential for improving outcomes.