Can Diflucan (fluconazole) cause elevated Alanine Transaminase (ALT) and Aspartate Transaminase (AST) levels, hypercalcemia, and changes in hematocrit?

Can Diflucan (Fluconazole) Cause Elevated ALT, AST, Calcium, and Hematocrit?

Yes, fluconazole can cause elevated ALT and AST levels, particularly in patients with underlying liver dysfunction or HIV-positive status, but there is no established association with elevated calcium or hematocrit changes. 1

Hepatotoxicity from Fluconazole

Liver Enzyme Elevations (ALT/AST)

• Fluconazole is documented to cause hepatotoxicity with elevations in AST, ALT, and total bilirubin, with changes occurring as early as the second day of therapy. 1

• Patients with pre-existing liver dysfunction are at particular risk for worsening liver function when treated with fluconazole. 1

• HIV-positive patients appear to be at increased risk for hepatotoxicity with fluconazole therapy based on published case reports. 1

• Liver function should be monitored during fluconazole therapy, especially in patients with underlying hepatic impairment. 1

Pattern and Severity of Liver Injury

• Drug-induced liver injury (DILI) from prescription medications like fluconazole typically causes hepatocellular injury (defined as ALT ≥5× upper limit of normal), though the elevations may be less severe than those seen with herbal medications. 2, 3

• The hepatocellular pattern is most common with prescription medications, characterized by an R ratio (ALT/ULN divided by ALP/ULN) >5. 2

• ALT is the most specific marker for liver injury as it is primarily concentrated in the liver with minimal presence in other tissues. 4, 5

Monitoring Recommendations

• For patients on fluconazole with ALT/AST elevations ≥3× upper limit of normal, repeat liver function tests within 48-72 hours. 6

• If ALT increases to >3× ULN or if there are symptoms of liver injury (fatigue, nausea, vomiting, right upper quadrant pain, jaundice), consider discontinuing fluconazole and assessing for other etiologies. 6

• Complete liver panel should include AST, ALT, alkaline phosphatase, total and direct bilirubin, albumin, and prothrombin time. 6, 5

Calcium and Hematocrit

No Established Association

• There is no documented association between fluconazole use and elevated calcium levels or changes in hematocrit in the medical literature or guidelines reviewed. 6

• Hypercalcemia and hematocrit changes are not listed among the common or documented adverse effects of azole antifungal therapy. 1

Alternative Explanations to Consider

• If calcium or hematocrit abnormalities are present, investigate alternative causes unrelated to fluconazole:
  • Hypercalcemia: malignancy, hyperparathyroidism, vitamin D toxicity, immobilization
  • Elevated hematocrit: dehydration, polycythemia vera, chronic hypoxia, testosterone use
  • Decreased hematocrit: anemia from various causes including chronic disease

Clinical Approach When Liver Enzymes Are Elevated on Fluconazole

Immediate Assessment

• Obtain complete liver panel including AST, ALT, alkaline phosphatase, total and direct bilirubin, albumin, and PT/INR. 5

• Assess for symptoms of liver injury: fatigue, nausea, vomiting, anorexia, right upper quadrant pain, fever, rash, jaundice, or pruritus. 6

• Review all concomitant medications and supplements that may contribute to hepatotoxicity. 5

Decision Algorithm Based on Severity

• ALT/AST <3× ULN: Continue fluconazole with repeat testing in 2-4 weeks; assess risk-benefit of continuing therapy. 5

• ALT/AST ≥3× ULN but <5× ULN: Hold fluconazole, repeat tests within 48-72 hours, and assess for other causes of liver injury. 6

• ALT/AST ≥5× ULN or any elevation with bilirubin >2× ULN: Permanently discontinue fluconazole unless another clear explanation exists for liver injury; consider hepatology referral. 6, 5

Common Pitfalls to Avoid

• Do not attribute mild ALT/AST elevations (>1× to <3× ULN) solely to fluconazole without considering alternative causes such as nonalcoholic fatty liver disease, dietary changes, or vigorous exercise. 6, 4

• Remember that AST is less specific for liver injury and can be elevated in cardiac disease, skeletal muscle injury, or hemolysis; check creatine kinase if muscle injury is suspected. 5, 7

• Patients with underlying chronic liver disease or those on multiple hepatotoxic medications require more frequent monitoring (every 1-2 weeks initially). 5