Cyclosporine is a calcineurin inhibitor and potent immunosuppressive agent used largely as a means of prophylaxis against cellular rejection after solid organ transplantation. Cyclosporine therapy can be associated with mild elevations in serum bilirubin and transient serum enzyme elevations, and to rare instances of clinically apparent cholestatic liver injury.
Cyclosporine (sye" kloe spor' in), also called cyclosporin A, is a cyclic polypeptide of 11 amino acids produced by a fungal species (Beaveria nivea) which has profound immunosuppressive properties, particularly affecting T cells and the cellular immune response. Cyclosporine acts as a inhibitor of calcineurin which is responsible for activating an important signal transduction pathway of T cell activation. The result of the inhibition is a decrease in maturation of T lymphocytes and reduction in lymphokine production, including IL-2. Cyclosporine was introduced into use in the United States in the early 1980s and rapidly became part of the primary regimen of immunosuppression after allogenic, solid organ transplantation. Current indications are for prevention of organ rejection after transplantation and for therapy of active and recalcitrant rheumatoid arthritis and psoriasis. Cyclosporine is available as capsules of 25 and 100 mg in generic forms and under the brand name of Sandimmune, and as a more reliably absorbed microemulsion formulation of 25 and 100 mg in generic forms and under the brand name of Neoral (2003). Cyclosporine is also available in solution for oral and for intravenous use. Because of variable absorption, the usual maintenance dose of cyclosporine varies greatly and proper dosing requires monitoring for drug levels, which is also important because of its many dose dependent side effects and drug-drug interactions. Common side effects of cyclosporine include headache, dizziness, paresthesias, neuropathy, tremor, hypertension, hyperlipidemia, nephropathy, acne, hirsutism and gum hyperplasia.
In several large clinical trials, initiation of cyclosporine therapy was associated with mild elevations in serum bilirubin levels, often without significant increases in serum ALT or alkaline phosphatase. Elevations in serum enzymes were also described, but less commonly. Recently, these complications appear to be less frequent, perhaps because of more careful dosing and monitoring of cyclosporine levels. Furthermore, in treatment of autoimmune diseases without the many complications of transplantation, cyclosporine therapy has been associated with mild serum alkaline phosphatase elevations in up to 30% of patients, but the abnormalities are asymptomatic, usually self-limiting and rarely require dose adjustment. In several case series, cyclosporine therapy has also been associated with biliary sludge and cholelithiasis. Isolated case reports of clinically apparent acute liver injury have been attributed to cyclosporine. The time to onset was within a few weeks of starting cyclosporine and the pattern of serum enzyme elevations was cholestatic. Recovery was prompt once cyclosporine was stopped and cases of chronic hepatitis or acute liver failure due to cyclosporine have not been reported.
Likelihood score: D (possible cause of clinically apparent liver injury).
Mechanism of Injury
Cyclosporine undergoes extensive hepatic metabolism, and because of its interaction with the cytochrome P450 system (CYP 3A4), is susceptible to severe drug-drug interactions. In animal models, cyclosporine decreases bile flow which may account for the mild hyperbilirubinemia that occurs with high doses.
Outcome and Management
The serum bilirubin and liver enzyme elevations that can accompany cyclosporine use are usually mild, asymptomatic and self-limiting; if not, they usually resolve rapidly upon dose reduction. The rare instances of cholestatic liver injury due to cyclosporine usually resolve with discontinuation and most (but not all) patients can tolerate switching to tacrolimus. Cyclosporine has not been associated with instances of acute liver failure or vanishing bile duct syndrome.
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