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Overexpression of Type 2 Iodothyronine Deiodinase in Follicular Carcinoma as a Cause of Low Circulating Free Thyroxine Levels

University of Sheffield Clinical Sciences Centre (A.P.W.) and Departments of Surgery (B.J.H.) and Clinical Chemistry (A.P.), Northern General Hospital, Sheffield, S5 7AU, United Kingdom; Thyroid Division (B.W.K., J.W.H., P.R.L.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115; and Thyroid Unit (G.H.D.) and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02108

Address all correspondence and requests for reprints to: Prof. A. P. Weetman, University Clinical Sciences Centre, Northern General Hospital, Sheffield, S5 7AU, United Kingdom. E-mail: k.f.watson{at}sheffield ac.uk.

Thyroid function is normally undisturbed in patients with thyroid carcinoma. We have identified three patients with large or widely metastatic follicular thyroid carcinoma who had a persistently increased ratio of serum T₃ to T₄ in the absence of autonomous production of T₃ by the tumor. To investigate the possibility of tumor-mediated T₄ to T₃ conversion, we assayed types 1 and 2 iodothyronine selenodeiodinase (D1 and D2) activity in a 965-g follicular thyroid carcinoma resected from one of these patients. The V_max for D2 was 8-fold higher than in normal human thyroid tissue. Resection of this tumor, leaving the left thyroid lobe intact, normalized the serum T₃ to T₄ ratio. In two other patients, treatment with sufficient levothyroxine to suppress TSH was associated with a high normal T₃ and a subnormal free T₄ index. In one, concomitant administration of the D1 inhibitors, propylthiouracil and propranolol, did not decrease the elevated serum T₃ to T₄ ratio. These data illustrate that increased T₄ to T₃ conversion in follicular thyroid carcinomas, probably by D2, can cause a significant perturbation in peripheral thyroid hormone concentrations.

This work was supported by Grants DK36256 and DK07529 from the National Institutes of Health.

Abbreviations: CT, Computed tomography; D1, type 1 iodothyronine deiodinase; D2, type 2 iodothyronine deiodinase; D3, type 3 iodothyronine deiodinase; DTT, dithiothreitol; FT₄I, free T₄ index; PTU, propylthiouracil; Tg, thyroglobulin.

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