Sirolimus-associated hepatotoxicity in liver transplantation

Guy W. Neff, Phillip Ruiz, Juan R. Madariaga, Seigo Nishida, Marzia Montalbano, Doug Meyer, David M. Levi, Andreas G. Tzakis, Christopher B. O'Brien

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Sirolimus is an immunosuppressant that exerts anti-rejection activity by inhibiting T-cell activity and is used to treat chronic rejection and calcineurin-related nephrotoxicity. Unlike tacrolimus and cyclosporine, it has no effect on calcineurin activity in liver transplant recipients. OBJECTIVE: To report correlates of survival outcomes in a series of patients with putative sirolimus-related hepatotoxicity after liver transplant. METHODS: We retrospectively reviewed the medical records of patients who underwent a liver transplant for chronic hepatitis C virus (HCV) and who received sirolimus immunosuppressive therapy between November 2000 and November 2003. Extracted data included sirolimus serum concentrations, frequency of sirolimus-related adverse effects, drug-related clinical hepatitis, and survival outcomes. RESULTS: Ten patients were found to have been treated with sirolimus for either renal insufficiency (n = 6) or chronic rejection (n = 4). Six patients had liver biopsies, while the remaining 4 patients were clinically diagnosed with rejection. Two of the 6 patients demonstrated changes consistent with sinusoidal congestion and one with eosinophilia, consistent with an allergic drug reaction. HCV viral load increased slightly, from 600 000 to 700 000 IU/mL. Mean baseline transaminase levels were 45 IU/L for aspartate aminotransferase and 50 IU/L for alanine aminotransferase, with peak levels of 210 and 180 IU/L, respectively. The time to transaminase increase was a mean of 21 days when sirolimus was added, with resolution within 27 days (mean) after its discontinuation. No changes were evident in antiviral therapy. Combination sirolimus and tacrolimus concentrations were maintained at >10 ng/mL; average monotherapy with sirolimus was 12 ng/mL, and average time on therapy was 25 weeks. CONCLUSIONS: Sirolimus-related hepatotoxicity is an important complication after liver transplant. Immediate recognition is critical to avoid confusion with other causes of abnormal serum aminotransferases after liver transplant, and discontinuation of the drug may be required.

Original languageEnglish
Pages (from-to)1593-1596
Number of pages4
JournalAnnals of Pharmacotherapy
Volume38
Issue number10
DOIs
Publication statusPublished - Oct 2004

Keywords

  • Hepatotoxicity
  • Liver transplantation
  • Sirolimus

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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