Sirolimus-associated hepatotoxicity in liver transplantation.
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.
Neff
Guy W
GW
University of Cincinnati, Cincinnati, OH, USA. guy.neff@uc.edu
Ruiz
Phillip
P
Madariaga
Juan R
JR
Nishida
Seigo
S
Montalbano
Marzia
M
Meyer
Doug
D
Levi
David M
DM
Tzakis
Andreas G
AG
O'Brien
Christopher B
CB
D000410:Alanine Transaminase / Q000097:blood; D001219:Aspartate Aminotransferases / Q000097:blood; D056486:Chemical and Drug Induced Liver Injury; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D016031:Liver Transplantation; D012189:Retrospective Studies; D020123:Sirolimus / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use; D015996:Survival Rate
D007166:Immunosuppressive Agents; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D020123:Sirolimus