Does tamoxifen increase liver enzymes?

Tamoxifen and Liver Enzymes

Tamoxifen can cause elevations in liver enzymes and, in rare cases, more serious liver abnormalities including fatty liver, cholestasis, hepatitis, and hepatic necrosis. While routine liver function monitoring is not specifically recommended in guidelines, clinicians should be aware of this potential adverse effect.

Liver Effects of Tamoxifen

Evidence from Drug Labeling

The FDA label for tamoxifen 1 indicates:

• Tamoxifen has been associated with changes in liver enzyme levels
• In rare cases, more severe liver abnormalities can occur, including:
  • Fatty liver
  • Cholestasis
  • Hepatitis
  • Hepatic necrosis
• Some cases have resulted in fatalities
• Positive rechallenges and dechallenges have been reported

Clinical Evidence

• A 2024 case report described a woman in her 50s who developed malaise with moderate aminotransferase elevation 6 months after starting tamoxifen 2
• Long-term tamoxifen use significantly increases the risk of fatty liver compared to aromatase inhibitors (HR: 1.598,95% CI: 1.173-2.177) 3
• Tamoxifen can cause both development of de novo fatty liver (HR: 1.519) and worsening of pre-existing fatty liver (HR: 2.103) 3

Mechanism

• Tamoxifen induces expression of xenobiotic metabolizing enzymes in the liver similar to phenobarbital, though with a different induction profile 4
• It increases CYPIIB1, CYPIIB2, CYPIIIA, and microsomal epoxide hydrolase mRNA and protein levels 4

Monitoring Recommendations

The National Comprehensive Cancer Network (NCCN) guidelines 5 note:

• Routine performance of alkaline phosphatase and liver function tests are not specifically included in follow-up recommendations
• In the NSABP P-1 trial, few grade 3-4 changes in liver function (SGOT, SGPT, bilirubin, alkaline phosphatase) were observed (10 on placebo and 6 on tamoxifen) 1

Clinical Implications

Risk Assessment

• The risk of serious liver toxicity appears to be low based on clinical trial data
• In the NSABP P-1 trial, only one case of liver cancer was reported in a participant randomized to tamoxifen 1
• The Swedish trial using adjuvant tamoxifen 40 mg/day reported 3 cases of liver cancer in the tamoxifen group versus 1 in the observation group 1

Management Considerations

• Patients should be educated about potential symptoms of liver dysfunction (jaundice, right upper quadrant pain, fatigue, nausea)
• Consider baseline liver function tests before initiating therapy
• Evaluate promptly if symptoms of liver dysfunction develop
• If significant liver enzyme elevations occur, consider tamoxifen discontinuation and alternative therapies

Special Considerations

Protective Effect in Certain Contexts

Interestingly, one study found that tamoxifen may actually reduce liver enzyme elevations caused by certain chemotherapy regimens:

• Adjuvant tamoxifen reduced the increase in liver enzymes caused by CMF/CNF chemotherapy 6

Drug Interactions

• CYP2D6 inhibitors should be avoided in patients on tamoxifen as they may reduce its efficacy 7
• The NCCN recommends avoiding strong CYP2D6 inhibitors in patients on tamoxifen 7

Conclusion

While tamoxifen can cause liver enzyme elevations and rarely more serious liver toxicity, routine liver function monitoring is not specifically recommended in current guidelines. However, clinicians should maintain vigilance for symptoms of liver dysfunction in patients taking tamoxifen and evaluate promptly if such symptoms develop.