Sorafenib-Induced Hypothyroidism Is Associated with Increased Type 3 Deiodination

Background: Therapy with tyrosine kinase inhibitors is associated with thyroid dysfunction. Decreased serum thyroid hormone levels during tyrosine kinase inhibitors are also observed in athyreotic patients with thyroid carcinoma. We therefore hypothesized that tyrosine kinase inhibitors may influence thyroid hormone metabolism. Aim: The aim was to study the effects of sorafenib therapy on serum thyroid hormone concentrations and iodothyronine deiodination in athyreotic patients. Design: The design included a prospective open, single-center, single-arm 26-wk study. Methods: We measured serum thyroxine (T-4), free T-4, 3,5,3-triiodothyronine (T-3), free T-3, reverse T-3 (rT(3)), and TSH concentrations at baseline and after 26 wk in 21 patients with progressive non-medullary thyroid carcinoma treated with sorafenib. Ratios of T-3/T-4 and T-3/rT(3), which are independent of substrate availability and reflect iodothyronine deiodination, were calculated. Results: Serum free T-4 and T-3 levels, adjusted for levothyroxine dose per kilogram body weight, decreased by 11 and 18%, respectively, whereas TSH levels increased. The serum T-3/T-4 and T-3/rT(3) ratios decreased by 18 and 22%, respectively, which is compatible with increased type 3 deiodination. Conclusions: Sorafenib enhances T-4 and T-3 metabolism, which is probably caused by increased type 3 deiodination. (J Clin Endocrinol Metab 95: 3758-3762, 2010)