Islet Cell Drug Toxicity

 

 The use of more potent immunosuppressive drugs such as cyclosporine and tacrolimus has markedly improved the outcome in pancreas transplantation.  In addition to nephrotoxicity, hirsutism/alopecia,  neurological and gastrointestinal side effects, both these drugs can cause abnormalities in glucose metabolism. Hyperglycemia is more commonly seen in patients receiving tacrolimus.

In the pre-cyclosporine era secondary to the use of large doses of corticosteroids, post-transplant diabetes mellitus occurred in almost half of renal transplant patients.  Older age, higher body weight, family history of abnormal glucose metabolism and African-American or Hispanic descent are associated with higher incidence of post-transplant diabetes mellitus. The latter is believed to result from insulin resistance with a relative deficiency of insulin. Insulin resistance results from decreased insulin receptor number and affinity, inpaired glucose uptake and probably inhibition on insulin secretion by beta cells.

In animal studies cyclosporine administration has been associated with reduction in insulin secretion, diminished beta cell density, decreased insulin synthesis and defective insulin secretion.

Similar morphological findings have been seen also with tacrolimus. 

The incidence of hyperglycemia in patients receiving cyclosporine and tacrolimus is considered to be 11-19% and 15-29% respectively. Most patients also receive steroids and this is a confounding factor. 

The morphological findings in biopsies from patients with clinical evidence of drug toxicity consist of cytoplasmic swelling and vacuolization of islet cells. The islets appear clear and stand-out from the more eosinophilic acinar parenchyma. In more severe cases islet cell drop-out with formation of spaces (lacunae) can be seen if there is confluent islet cell drop-out.  Rarely, apoptotic cell fragments can be identified.

Immunoperoxidase stains for insulin and glucagon shows diminished staining for insulin in beta cells in comparison to controls. This is the light microscopic counterpart of the marked loss of dense core granules seen in beta cells by electron microscopy. The latter study shows preservation of the peripheral non-beta cells in the islets. 

 

The histological changes and the clinical findings are reversible with reduction or discontinuation of the drug. In our experience, hyperglycemia and the histological evidence of drug toxicity was worsened with the concurrent use of pulse steroids to treat acute rejection.  Trials are being conducted to achieve steroid free immunosuppression in pancreas transplantation.    

 

The typical clinical scenario in drug toxicity consists of a patient presenting with hyperglycemia in association with higher than desired levels of tacrolimus or CSA.  The biopsy usually shows no evidence of significant acute or chronic rejection.  Glycemia should normalize after reduction of drug level.

References

 

Drachenberg CB, Klassen DK, Weir MR, Wiland A, Fink JC, Bartlett ST, Cangro CB, Blahut S, Papadimitriou JC: Islet cell damage assosociated with tacrolimus and cyclosporine: Morphological features in pancreas allograft biopsies and clinical correlation. Transplantation 1999;68:396.

 

Mayer AD, Dmitrewski J, Squifflet JP et al.: Multicenter randomized trial comparing FK506 and cyclosporin in the prevention of renal allograft rejection: a report of the European FK506 Multicenter Renal Study Group. Transplantation 1997;64:436.

 

HiranoY, Fujihara S, Ohara K, Katsuki S, Noguchi H: Morphological and functional changes in islets of Langerhans in FK506-treated rats. Transplantation 1992;53:889.

Tze WJ, Tai J, Murase N, Tzakis A, Starzl TE: Effect of FK506 on glucose metabolism and insulin in normal rats. Transplant Proc 1991;23:3158.

 

Krentz AJ, Dousset B, Mayer D, et al.: Metabolic effect of cyclosporine A and FK506 in liver transplant recipients. Diabetes 1993;42:1753.

 

Stratta RJ: Review of immunosuppressive usage in pancreas transplantation. Clin Transplant 1999;13:1.

 

Jordan ML, Chakrabarti P, Luke P, et al.: Results of pancreas transplantation after steroid withdrawal under tacrolimus immunosuppression. Transplantation 2000;69:265.