Life-threatening hypothyroidism associated with administration of cyclosporine in a patient treated with reduced-intensity hematopoietic stem-cell transplantation for metastatic renal-cell carcinoma.

Abstract

Thyroid dysfunction as a late complication of bone-marrow transplantation has been recognized (1). In regards to early onset posttransplant thyroid dysfunction, little information is available (2). Here, we report a case of hypothalamic hypothyroidism, in the early phase of reduced-intensity hematopoietic stem-cell transplantation (RIST), which can be attributed to cyclosporine. A 26-year-old female with metastatic renal-cell carcinoma underwent RIST from a human–leukocyte-antigen (HLA)-identical sibling at our institute. Preceding therapies included right nephrectomy, pelvic radiotherapy, and interferon, and none of these was known to be related to thyroid dysfunction. The conditioning regimen consisted of busulfan, fludarabine, and antithymocyte globulin (3). Cyclosporine of 3 mg/kg was administered as graft-versus-host disease (GvHD) prophylaxis. Her posttransplant course was uneventful until cyclosporine was tapered off by day 45 to induce graft-versus-tumor effect (4), and grade II acute GvHD occurred on day 54. Intravenous cyclosporine at 2 mg/kg was promptly initiated, and, thereafter, she developed severe malaise and hepatorenal dysfunction. Cyclosporine was discontinued on day 62, and her symptoms completely disappeared. Oral cyclosporine was resumed at 2 mg/kg on day 69 in attempt to induce graft-versus-tumor effect. Then she again complained of generalized fatigue, followed by paralytic ileus and lethargy on day 71. Cyclosporine was suspected to be the culprit and was discontinued. Her clinical conditions immediately improved. Her thyroid function was normal before transplantation. Surprisingly, on day 72, serum thyroid-stimulating hormone, free triiodothyronine, and free thyroxine were below detectable levels (Fig. 1). A thyrotropin-releasing hormone loading test showed a low and delayed response, which is compatible with secondary hypothalamic dysfunction. Other anterior pituitary functions remained normal. Although metastatic pituitary tumor and microadenoma are known to cause secondary disorders of the thyroid, magnetic resonance imaging of the brain performed at the onset of thyroid dysfunction failed to show any organic lesions (Fig. 2), neither hypothalamic nor pituitary occupying lesions. In addition, none of the preceding treatment administered before transplantation appeared to contribute to thyroid dysfunction. In consideration of the close chronological relationship between the emergence or disappearance of symptoms and the use of cyclosporine, it is likely that her hypothalamic hypothyroidism was best attributed to the medication.Figure 1: Chronological correlation between the clinical course and thyroid function test. The patient’s thyroid function and serum levels of thyroid-stimulating hormone were severely suppressed while receiving cyclosporine, which suggested inhibition of the hypothalamus-pituitary-thyroid axis. These symptoms reversed to normal after discontinuation of cyclosporine.Figure 2: Brain magnetic resonance imaging at the onset of thyroid dysfunction. Magnetic resonance imaging of the brain failed to show any organic lesions in hypothalamus or pituitary. The patient had functional disorder of hypothalamic-pituitary neuroendocrine system.Although cyclosporine toxicities on the central nervous system (5) including cyclosporine-induced encephalopathy are well known, neither thyroid nor hypothalamic dysfunction associated with cyclosporine has been reported. This case showed that cyclosporine could suppress the hypothalamus-pituitary-thyroid axis, which might be easily overlooked or misdiagnosed as a complication related to allogeneic hematopoietic stem-cell transplantation. Although the mechanism for this is unknown, hypothalamic hypothyroidism should draw attention as an adverse event associated with cyclosporine.