TY - JOUR
T1 - Sunitinib-induced hypothyroidism is due to induction of type 3 deiodinase activity and thyroidal capillary regression
AU - Kappers, Mariëtte H.W.
AU - Van Esch, Joep H.M.
AU - Smedts, Frank M.M.
AU - De Krijger, Ronald R.
AU - Eechoute, Karel
AU - Mathijssen, Ron H.J.
AU - Sleijfer, Stefan
AU - Leijten, Frank
AU - Danser, A. H.Jan
AU - Van Den Meiracker, Anton H.
AU - Visser, Theo J.
PY - 2011/10
Y1 - 2011/10
N2 - Context: Anticancer treatment with the tyrosine kinase inhibitor sunitinib causes thyroid dysfunction. Objective: Our objective was to investigate the time course and underlying mechanisms of sunitinib-induced thyroid dysfunction. Design: Thyroid function tests of 83 patients on sunitinib were collected retrospectively for their total treatment duration between January 2006 and November 2009 and prospectively in 15 patients on sunitinib for 10 wk. Additionally, thyroid function and histology were assessed in rats on sunitinib (8 d; n = 10) and after sunitinib withdrawal (11 d; n = 7) and compared with controls (n = 7). Setting: Patients were seen at a university outpatient oncology clinic. Patients and Animals: Patients with metastatic renal cell carcinoma or gastrointestinal stromal tumors participated in the clinical study and Wistar Kyoto rats were used in the rat study. Intervention: Sunitinib was taken according to a 4 wk "on," 2 wk "off" treatment regimen. Blood samples for measurement of thyroid function were collected at baseline and at wk 4 and 10. In rats, blood, liver, and thyroid were collected to assess thyroid hormones, deiodinase activity, and thyroid histology. Main Outcome Measures: TSH and free T 4 levels, deiodinase activity, and thyroid histology were assessed. Results: Forty-two percent of patients in the retrospective study developed elevated TSH levels. Prospective analysis showed increased TSH levels within 10 wk of treatment, accompanied by a decreased T 3/rT 3 ratio. In rats, serum T 4 and T 3 decreased, hepatic type 3 deiodinase activity increased, andthyroid histology showed marked capillary regression, which all but thyroid hormones reversed after sunitinib withdrawal. Conclusion: Sunitinib induces hypothyroidism due to alterations in T 4/T 3 metabolism as well as thyroid capillary regression.
AB - Context: Anticancer treatment with the tyrosine kinase inhibitor sunitinib causes thyroid dysfunction. Objective: Our objective was to investigate the time course and underlying mechanisms of sunitinib-induced thyroid dysfunction. Design: Thyroid function tests of 83 patients on sunitinib were collected retrospectively for their total treatment duration between January 2006 and November 2009 and prospectively in 15 patients on sunitinib for 10 wk. Additionally, thyroid function and histology were assessed in rats on sunitinib (8 d; n = 10) and after sunitinib withdrawal (11 d; n = 7) and compared with controls (n = 7). Setting: Patients were seen at a university outpatient oncology clinic. Patients and Animals: Patients with metastatic renal cell carcinoma or gastrointestinal stromal tumors participated in the clinical study and Wistar Kyoto rats were used in the rat study. Intervention: Sunitinib was taken according to a 4 wk "on," 2 wk "off" treatment regimen. Blood samples for measurement of thyroid function were collected at baseline and at wk 4 and 10. In rats, blood, liver, and thyroid were collected to assess thyroid hormones, deiodinase activity, and thyroid histology. Main Outcome Measures: TSH and free T 4 levels, deiodinase activity, and thyroid histology were assessed. Results: Forty-two percent of patients in the retrospective study developed elevated TSH levels. Prospective analysis showed increased TSH levels within 10 wk of treatment, accompanied by a decreased T 3/rT 3 ratio. In rats, serum T 4 and T 3 decreased, hepatic type 3 deiodinase activity increased, andthyroid histology showed marked capillary regression, which all but thyroid hormones reversed after sunitinib withdrawal. Conclusion: Sunitinib induces hypothyroidism due to alterations in T 4/T 3 metabolism as well as thyroid capillary regression.
UR - http://www.scopus.com/inward/record.url?scp=80053470531&partnerID=8YFLogxK
U2 - 10.1210/jc.2011-1172
DO - 10.1210/jc.2011-1172
M3 - Article
C2 - 21816788
AN - SCOPUS:80053470531
SN - 0021-972X
VL - 96
SP - 3087
EP - 3094
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 10
ER -