Does Fluconazole Cause Liver Injury?
Yes, fluconazole can cause liver injury, ranging from asymptomatic transaminase elevations in 1-13% of patients to rare cases of fatal hepatitis and acute liver failure. 1, 2
Spectrum of Hepatotoxicity
Fluconazole-associated liver injury occurs along a spectrum of severity:
- Asymptomatic transaminase elevations are the most common manifestation, occurring in 1-13% of patients receiving azole antifungals 3, 1
- Clinical hepatitis occurs less frequently but has been documented in multiple guidelines 3
- Serious hepatic toxicity including fatal outcomes has been reported, though rare, primarily in patients with serious underlying medical conditions 2
- Acute liver failure (ALF) is exceptionally rare, with incidence rates ranging from 0.0 to 31.6 per 10,000 patients, but can occur even in low-risk populations without pre-existing liver disease 4
Key Clinical Characteristics
No clear dose-response relationship exists - fluconazole hepatotoxicity shows no obvious relationship to total daily dose, duration of therapy, sex, or age 2. This is critical because even standard doses can cause severe injury 4.
The FDA label explicitly warns that fluconazole should be administered with caution to patients with liver dysfunction, and hepatotoxicity has usually (but not always) been reversible upon discontinuation 2.
High-Risk Populations
Certain patient groups face substantially elevated risk:
- Patients with pre-existing chronic liver disease have a 4.68-fold increased risk of aminotransferases >200 U/L and a 5.62-fold increased risk of severe acute liver injury 5
- Patients with cirrhosis - 77.3% met Drug-Induced Liver Injury Network (DILIN) criteria in one study (OR 4.84) 6
- Critically ill patients with septic shock - 76.3% met DILIN criteria (OR 4.56) 6
- HIV-positive patients may be at particular risk for hepatotoxicity 7
Monitoring Strategy
Baseline and periodic liver function monitoring is essential, particularly with prolonged therapy 1:
- Obtain baseline liver function tests before initiating fluconazole 1
- Monitor at 2 weeks, 4 weeks, then every 3 months during prolonged therapy 1
- Patients who develop abnormal liver function tests should be monitored closely for progression to more severe hepatic injury 2
Warning Signs Requiring Immediate Action
Discontinue fluconazole immediately if clinical signs and symptoms consistent with liver disease develop 2:
- Dark-colored urine 2
- Light-colored stools 2
- Severe skin itching 2
- Jaundice (yellowing of skin and eyes) 2
- Vomiting, loss of appetite, or tiredness 2
Important Caveats
Weight-based dosing does not appear to increase hepatotoxicity risk - patients receiving fluconazole doses ≥6 mg/kg did not have higher rates of meeting DILIN criteria compared to those receiving <6 mg/kg (46.9% vs 55%, p=0.20) 6. This suggests that appropriate weight-based dosing for therapeutic efficacy should not be avoided due to hepatotoxicity concerns alone.
DILIN criteria may overestimate liver injury in critically ill patients - while many ICU patients meet biochemical criteria for drug-induced liver injury, only 14.5% of those meeting DILIN criteria also met definitions for true hepatocellular damage 6. This highlights the importance of clinical context when interpreting elevated transaminases in complex patients.
Comparative risk among azoles - fluconazole, ketoconazole, and itraconazole have similarly low rates of acute liver injury (13.0,19.3, and 24.5 events per 1000 person-years respectively), while voriconazole and posaconazole show substantially higher rates (181.9 and 191.1 events per 1000 person-years) 5.