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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 2 594-598
Copyright © 2003 by The Endocrine Society

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

B. W. Kim, G. H. Daniels, B. J. Harrison, A. Price, J. W. Harney, P. R. Larsen and A. P. Weetman

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.


   Abstract
Top
 Abstract
Introduction
 Case Reports
 Materials and Methods
 Results and Discussion
 References
 
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 Vmax 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.


   Introduction
Top
 Abstract
 Introduction
Case Reports
 Materials and Methods
 Results and Discussion
 References
 
THYROID FUNCTION IS normally undisturbed in patients with thyroid carcinoma. The rare exceptions include hyperthyroidism due to functional metastases from well differentiated thyroid carcinoma, release of preformed thyroid hormone (malignant pseudothyroiditis), and malignant autonomously functioning carcinomas (1, 2). Most differentiated thyroid carcinomas function less well than normal thyroid tissue but continue to secrete thyroglobulin (Tg), which can be iodinated to form T3 and T4.

Normal thyroid tissue expresses the type 1 and type 2 iodothyronine deiodinases (D1 and D2), enzymes that are responsible for catalyzing deiodination of T4 to T3, thus contributing to the plasma T3 pool (3). Type 3 deiodinase (D3), which is not expressed in the thyroid, catalyzes the conversion of T4 to reverse T3 and the conversion of T3 to 3,3'-diiodothyronine, inactivating these hormones. D2 is highly expressed in Graves’ disease thyroid tissue and in some adenomas in which it may contribute to the relatively high circulating T3 levels (3, 4). D2 levels are reported to be low in papillary carcinoma of the thyroid (5).

Generalized disturbances in deiodinase levels typically contribute to the changes in thyroid function seen with acute illness or amiodarone therapy. Primary overexpression of a deiodinase has been reported to alter thyroid function in patients with large infantile hemangiomas containing high levels of D3 (6). In these infants, excessive hemangioma D3 activity resulted in hypothyroidism with low or undetectable serum T3 and T4 levels and elevated reverse T3 levels. We have recently identified three patients with large or metastatic follicular carcinomas in whom an increased ratio of circulating T3 to T4 suggested excessive D1 or D2 activity. In one patient, analysis of the tumor tissue revealed excessive D2 activity. The clinical course of the three patients suggested that the tumor was converting circulating T4 to T3, resulting in a euthyroid state despite low circulating T4 in one patient and mild hyperthyroidism in the others.


   Case Reports
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 Abstract
 Introduction
 Case Reports
Materials and Methods
 Results and Discussion
 References
 
Patient 1

In November 1999, a 79-yr-old man presented to a chest physician with a cough, hemoptysis, and weight loss of 1.5 kg. Chest x-ray revealed a large mass in the right upper lobe (Fig. 1Go). Ultrasound examination revealed a 4-cm highly vascular mass largely replacing the right lobe and extending into the chest. The left lobe was normal. Chest computed tomography (CT) revealed a 15-cm heterogeneous soft tissue mass extending from the lung apex to the bronchus intermedius, with extension into the mediastinum and compression of the trachea above the carina. This mass was contiguous with the neck mass. A technetium 99m (99mTc) uptake showed an enlarged right lobe with patchy uptake. No uptake was noted in the left lobe or in the chest.



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  		Figure 1. Chest radiograph of patient 1 at presentation, showing a large right-sided intrathoracic goiter.

 
The patient refused biopsy or surgery to remove the mass. He presented again in March 2001 with dyspnea, hoarse voice, cough, and further weight loss. A wheeze was present throughout the right lung. His only medication was a nonprescription vitamin tablet. Flexible nasoendoscopy revealed a right vocal cord palsy. Thyroid function tests included a normal serum TSH of 1.04 mU/liter (reference range, 0.5–4.4 mU/liter), low free T4 (3.4 pmol/liter; reference range, 9.6–28.1 pmol/liter), and normal free T3 (6.9 pmol/liter; reference range, 3.0–8.2 pmol/liter; Table 1Go). TSH was measured by a noncompetitive electrochemiluminescent immunoassay (Elecsys 2010, Roche Diagnostic Systems, Inc., Mannheim, Germany); free T3 and free T4 were measured by direct, labeled antibody, competitive immunoassay (Vitros Immunodiagnostic Products, Ortho-Clinical Diagnostics, Raritan, NJ). The normal TSH and low free T4 were confirmed on a subsequent sample by a separate method (Centaur). Free T4 by equilibrium dialysis was also low at 6.2 pmol/liter (reference range, 10–36 pmol/liter). After iv administration of 200 µg TRH, serum TSH values at 0, 20, and 60 min were 0.44, 3.58, and 3.52 mU/liter, respectively. The T4 binding globulin level (Tg) was 28.5 pmol/liter (reference range, 18–45 pmol/liter; Tg), and the reverse T3 level measured by RIA (BioChem ImmunoSystems, Freiburg, Germany) was low (80 pmol/liter; reference range, 90–350 pmol/liter). In view of the low free T4 with a normal serum TSH, anterior pituitary function was assessed and found to be normal, i.e. testosterone, 9.4 µmol/liter (reference range, 7–24 µmol/liter); LH, 7.2 IU/liter; FSH, 6.7 IU/liter; prolactin, 180 mIU/liter; cortisol (0900 h), 387 nmol/liter; {alpha} subunit, 0.45 IU/liter (<1.0). Magnetic resonance imaging of the pituitary was also normal.


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  		Table 1. Laboratory results for patient 1

 
Repeat CT scanning revealed enlargement of both lobes of the thyroid, much greater on the right, extending in to the right hemithorax, displacing the right upper lobe of the lung and surrounding the trachea by 270° (Fig. 2Go). The trachea was narrowed for 5 cm from 1.5 cm above the carina, and in the upper sections some thyroid tissue appeared to be extending into the trachea. A repeat 99mTc scan was similar to the one 15 months previously, but faint patchy uptake was noted in the right side of the chest and mediastinum. Ultrasound-guided biopsy of the chest mass revealed small fragments of thyroid tissue with a follicular architecture without obvious evidence of atypia.



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  		Figure 2. CT scan of the chest of patient 1 showing an intrathoracic goiter compressing the trachea.

 
The patient still refused further treatment, but by the beginning of June his dyspnea had worsened, and his appetite was reduced. The low free T4 persisted. Due to swallowing difficulties, the patient was aspirating food intermittently. A right-sided Horner’s syndrome was noted. At the end of June, transcervical, trans-sternal right thyroidectomy was performed. The weight of thyroid tissue removed was 965 g. A multinodular thyroid was found. Histological examination revealed microfollicles of varying size and colloid content. The cells had mild nuclear pleomorphism and occasional mitotic activity. There was multifocal capsular invasion and widespread invasion of large caliber blood vessels. A diagnosis of widely invasive follicular carcinoma was made.

The patient made an uneventful recovery from surgery, with much improved breathing and swallowing. Twelve days after surgery, the free T4 level had risen to 8.6 pmol/liter, and 18 d after surgery it was within the reference range (11.3 pmol/liter) for the first time during the course of the patient’s illness. At 12 and 18 d post surgery, the free T3 (3.8 and 5.4 pmol/liter) and reverse T3 (233 and 194 pmol/liter) had also returned to normal.

Patient 2

In November 1985, a 65-yr-old man underwent a left thyroid lobectomy for a large thyroid nodule. The tumor, which weighed 100 g, was diagnosed as a follicular adenoma with mixed macro- and microfollicular patterns with focal oncocytic change. Ten years later, the patient developed intractable back pain leading to the discovery of multiple lytic bone lesions involving the thoracic, lumbar, and sacral spine, pelvis, femur, and multiple ribs. Biopsy of a right ilium lesion revealed well differentiated metastatic follicular thyroid carcinoma. In June 1995, he was receiving no thyroid hormone, but other medications were atenolol, chlorthalidone, and demerol. Thyroid function tests showed a low T4, low free T4 index (FT4I), high normal T3 RIA, and low normal serum TSH (Table 2Go).


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  		Table 2. Laboratory results for patient 2

 
The pathology specimen from the original thyroidectomy was reviewed, with additional sections obtained from the paraffin blocks. A diagnosis of malignancy could not be confirmed on these specimens. External beam radiation to the lumbosacral spine, both femurs, and right upper chest led to near complete resolution of his pain, and a completion thyroidectomy was performed in July 1995. The residual left lobe revealed follicular carcinoma, and the right lobe was unremarkable. Postoperatively, levothyroxine was withheld for 131I-therapy; in September 1995 his serum T4, FT4I, and T3 RIA were all low, and the TSH was elevated.

The patient was treated with radioactive iodine in 1995, 1996, 1997, and 1998. Additional external beam therapy was administered to his cervical spine in 1995. Between treatments, he was maintained on 150 µg levothyroxine, with low or low normal serum T4 and FT4I, normal to elevated T3 RIA, and low serum TSH. When levothyroxine supplementation was held, the patient’s thyroid hormone levels fell, and his TSH rose above normal. The patient died from extensive metastatic disease in early 2001.

Patient 3

In 1963, a 32-yr-old man underwent surgery for a right lobe thyroid nodule. The final pathology was follicular adenoma, and thyroid hormone therapy was begun. Although not recognized initially, he had received external irradiation therapy for acne at age 14. In 1967, a left lobe thyroid nodule was noted, which proved to be a follicular carcinoma. Armour Thyroid 3 g was prescribed.

He was first seen at the Massachusetts General Hospital in June 1971 for resection of a 10 x 15-cm soft left-sided neck mass. Pathology revealed a solid follicular carcinoma with capsular and impressive vascular invasion, identical to the specimen from 1968. He developed recurrent left neck disease in January 1973 with the same histology.

In 1975, the patient developed a neck mass and hilar adenopathy. A nodal biopsy revealed poorly differentiated adenocarcinoma, thought to be of thyroidal origin. Off levothyroxine, his serum T4 was 19.3 nmol/liter, and the TSH was 19 mU/liter (Table 3Go, March to April, 1975). Thyroid scan showed small uptake in the right thyroid bed and none in the region of the tumor mass. Radioactive iodine therapy was not given, and levothyroxine 0.2 mg/d was prescribed. He was subsequently treated with external radiation to the neck, mediastinum, left distal femur, knee, and upper tibia for painful metastatic disease. Pulmonary nodules and pleural effusion were discovered and treated with local irradiation and quinacrine hydrochloride.


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  		Table 3. Laboratory results for patient 3

 
In 1977, the patient was maintained on 200 µg levothyroxine with persistently low total free T4, high normal serum T3 concentration, and a suppressed TSH (Table 3Go, June to September, 1977). When his levothyroxine dose was lowered to 150 µg/d, his T4 levels remained low, and his TSH remained undetectable. In early winter, the patient’s heart rate rose to 130 beats per minute, making it difficult for him to sleep. With propranolol, his pulse fell to 90 beats per minute. In December 1977, the patient had a pathological fracture of the femoral shaft. His pulse was 108 beats per minute and regular, and he was tachypneic. Propylthiouracil (PTU) was started at 100 mg every 6 h in an attempt to block T4 to T3 conversion. However, his thyroid hormone profile remained the same with a low T4 and suppressed TSH. He died in 1978 in lactic acidosis.


   Materials and Methods
Top
 Abstract
 Introduction
 Case Reports
 Materials and Methods
Results and Discussion
 References
 
All studies were done under an approved Institutional Review Board protocol at the Brigham and Women’s Hospital (Boston, MA). Six randomly selected fragments from the thyroid tumor of patient 1 were individually homogenized in five volumes of ice-cold 50 mM Tris-HCl buffer (pH 7.5) containing 10 mM dithiothreitol (DTT), 0.25 M sucrose, and 1 mM EDTA. Protein concentration was quantitated by Bradford assay using BSA as a standard. For the determination of the Km(T4) and Vmax(T4) of the tumor D2, deiodination assays were performed using 300 µg homogenized protein and 0.5–10 nM unlabeled T4 in 300 µl PE buffer [(pH 6.9) 0.1 M potassium phosphate, 1 mM EDTA buffer] containing 20 mM DTT, 1 mM PTU, and approximately 80,000 cpm 125I-labeled T4 (Perkin-Elmer Life Sciences, New England Nuclear, Boston, MA). All samples expressed similar activities for D1 and D2. Kinetic studies were performed using one sample. For Km(T4) and Vmax(T4) for D1 assays, 300 µg protein and 0.5–10 µM unlabeled T4 were used in 300 µl of PE buffer containing 10 mM DTT. In addition, the Km(reverse T3) and Vmax(reverse T3) of the tumor D1 was determined using 0.05–3 µM of unlabeled reverse T3, 10 mM DTT, and approximately 100,000 cpm 125I-reverse T3 (Perkin-Elmer Life Sciences, New England Nuclear).

To define the deiodination pathway for T4 to T3 conversion at a physiological T4 concentration, 100–300 µg sonicate protein were incubated with 2, 10, or 100 nM unlabeled T4 in 300 µl PE buffer containing 20 mM DTT and 125I-T4 as previously described (3). The total 5' deiodination (T4 to T3 conversion by both D1 and D2) was the difference between the 125I- released at 2 nM T4 and that of assay blank. The fraction of 5' T4 deiodination by D2 was the difference in 125I- released at 2 nM and that released at 100 nM T4. Incubations were for 60–120 min at 37 C, and 125I- was separated via trichloroacetic acid precipitation (7). Under the conditions used, deiodination was linear both with time and protein, and protein was adjusted to consume less than 30% of the substrate. Samples were analyzed in duplicate. Deiodinase activity was expressed as femtomoles per minute per milligram protein for D2 or picomoles per minute per milligram protein for D1.


   Results and Discussion
Top
 Abstract
 Introduction
 Case Reports
 Materials and Methods
 Results and Discussion
References
 
We report three patients with follicular carcinoma whose laboratory tests suggested increased fractional conversion of T4 to T3. At presentation, patient 1 had an intact thyroid gland with a large thyroid cancer. Serum free T4 was low, whereas free T3 and TSH were normal. A subsequent TRH-induced TSH response was normal, as were serum T3 concentrations, eliminating a diagnosis of autonomous T3 production as has been reported for some thyroid tumors (8, 9, 10).

An alternative explanation for these findings would be tumor-mediated T4 to T3 conversion, with plasma T3 replacing T4 as the predominant feedback regulator of the hypothalamic-pituitary-thyroid axis. We tested this possibility by assaying D1 and D2 activities in six samples of the 965-g tumor resected from patient 1. The Km(T4) and Km(reverse T3) for D1 and the Km(T4) for D2 in the tumor homogenates were typical for these enzymes (Table 4Go). The Vmax for D2, 4.1 fmol/min/mg protein, was about 8-fold higher than in normal human thyroid tissue using similar conditions (0.49 fmol/min/mg). In keeping with this higher D2 activity per milligram protein, 73 ± 3% of T4 to T3 conversion at 2 nM T4 was catalyzed by tumor D2, compared with values of 26 ± 3% in homogenates of normal human thyroid in which D1 catalyzes the bulk of this reaction.


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  		Table 4. 5' Deiodination kinetics and fractional 5' deiodination by D2 in the tumor of patient 1

 
In euthyroid humans, about 30–40% of daily T4 production ultimately undergoes 5' deiodination to T3. Indirect evidence suggests that a significant fraction of this conversion is catalyzed by the PTU-insensitive D2 enzyme, possibly in skeletal muscle (11). If the efficiency of peripheral 5' deiodination were increased significantly, the increased serum T3 concentration would feedback on the hypothalamic-pituitary-thyroid axis, reducing T4 secretion to a rate that would provide sufficient substrate to generate an approximately normal T3 concentration. If no exogenous thyroid hormone was given, the patient would remain in the euthyroid state, with a normal TSH. If the cause of this increased peripheral conversion were then removed, the circulating hormone pattern would return to normal. This is precisely what occurred in patient 1 before and after removal of the large thyroid tumor. Given the results of the in vitro analysis of the conversion pathway, tumor D2 is the most likely explanation for enhanced T4 to T3 conversion in this patient.

The results seen with patient 2 illustrate the effect of hyperconversion when exogenous thyroid hormone is given. In June 1995, when patient 2 returned with widely metastatic disease but still had residual normal thyroid tissue, his serum T4 was low, and TSH was normal. After thyroidectomy, the low peripheral thyroid hormones and elevated serum TSH (September 1995, Table 2Go) demonstrate that the metastatic tumor was not producing thyroid hormone autonomously. When levothyroxine was then started, the serum T3 increased and the serum TSH fell, but TSH suppression occurred while the FT4I was in the low-normal range. This finding suggests that increased T4 to T3 conversion by the metastatic cancer deiodinase is the most likely explanation for these and the subsequent laboratory tests (see results for 1998–2000, Table 2Go).

Hyperconversion physiology is also illustrated in the laboratory results of patient 3, whose significant metastatic tumor burden was not autonomously producing thyroid hormone (see result for 1975, Table 3Go), but whose TSH was suppressed with a high T3 but a low normal serum T4 when he was receiving 200 µg levothyroxine. The later course of patient 3 provides indirect evidence suggesting that D2 is causing the hyperconversion in that treatment with 400 mg PTU, which inhibits D1 but not D2, did not change his thyroid hormone profile (see 1977–1978 results, Table 3Go; Ref. 12).

The results in these patients illustrate that increased T4 to T3 conversion in follicular thyroid carcinomas may cause a significant increase in the ratio of T3 to T4 in the circulation without causing hyperthyroidism. A similar patient has been reported in whom widely metastatic follicular thyroid cancer and levothyroxine therapy were associated with a high normal or high T3, low serum free T4, and suppressed TSH (13). In patient 1, T4 to T3 conversion can be attributed to D2 with reasonable certainty because removal of the large tumor mass expressing high levels of the deiodinase reversed the peripheral hormone pattern. In patient 3, D2 is also favored because 400 mg PTU did not affect the ratio of circulating T3 to T4, although it does so in hyperthyroid patients in whom T4 to T3 conversion by D1 is enhanced (12). Although we have neither direct nor indirect results to indicate which deiodinase is involved in patient 2, the fact that the increased T3/T4 ratio during levothyroxine therapy was associated with a subnormal FT4I favors the low Km D2 as the cause, but this is not definitive.

Although patients such as these are not common, it is conceivable that T4 hyperconversion physiology may be present in patients with Graves’ disease, during treatment with antithyroid drugs, in whom a normal or elevated serum T3 accompanies a low serum T4. This pattern could be explained by intrathyroidal D2-mediated hyperconversion of autonomously produced T4. There are other potential explanations, such as intrathyroidal iodine deficiency induced by the antithyroid drug treatment, but given the propensity for high D2 expression in Graves’ thyroid tissue, a large goiter with high blood flow could potentially perform the same function as the tumor tissue in the patients in this report (3).

Another potential setting for D2 catalyzed T4 hyperconversion has been suggested by the recent finding of a human mesothelioma cell line that expresses very high D2 activity (~9 fmol/min/mg protein; Ref. 4). Whether some patients with large mesotheliomas might also develop a high serum T3 to T4 ratio remains to be determined.


   Acknowledgments
 


   Footnotes
 
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.

Received June 12, 2002.

Accepted October 24, 2002.


   References
Top
 Abstract
 Introduction
 Case Reports
 Materials and Methods
 Results and Discussion
 References
 

  1. Salvatori M, Saletnich I, Rufini V, Dottorini ME, Corsello SM, Troncone L, Shapiro B 1998 Severe thyrotoxicosis due to functioning pulmonary metastases of well-differentiated thyroid cancer. J Nucl Med 39:1202–1207[Abstract/Free Full Text]
  2. Ikejiri K, Furuyama M, Muranaka T, Anai H, Takeo S, Sakai K, Saku M, Yoshida K 1997 Carcinoma of the thyroid manifested as hyperthyroidism caused by functional bone metastasis. Clin Nucl Med 22:227–230[CrossRef][Medline]
  3. Salvatore D, Tu H, Harney JW, Larsen PR 1996 Type 2 iodothyronine deiodinase is highly expressed in human thyroid. J Clin Invest 98:962–968[Medline]
  4. Ishii H, Inada M, Tanaka K, Mashio Y, Naito K, Nishikawa M, Imura H 1981 Triiodothyronine generation from thyroxine in human thyroid: enhanced conversion in Graves’ thyroid tissue. J Clin Endocrinol Metab 52:1211–1217[Abstract]
  5. Murakami M, Araki O, Hosoi Y, Kamiya Y, Morimura T, Ogiwara T, Mizuma H, Mori M 2001 Expression and regulation of type II iodothyronine deiodinase in human thyroid gland. Endocrinology 142:2961–2967[Abstract/Free Full Text]
  6. Huang SA, Tu HM, Harney JW, Venihaki M, Butte AJ, Kozakewich HP, Fishman S, Larsen PR 2000 Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. N Engl J Med 343:185–189[Free Full Text]
  7. Berry MJ, Kates AL, Larsen PR 1990 Thyroid hormone regulates type I deiodinase messenger RNA in rat liver. Mol Endocrinol 4:743–748[Abstract]
  8. Hasen J, Goldiner M 1977 Triiodothyronine-producing metastatic follicular thyroid carcinoma. Horm Res 8:219–223[Medline]
  9. Kabadi UM 1978 T3 euthyroidism in follicular thyroid carcinoma. Ann Intern Med 88:359–360
  10. Nakashima T, Inoue K, Shiro-ozu A, Yoshinari M, Okamura K, Itoh M 1981 Predominant T3 synthesis in the metastatic thyroid carcinoma in a patient with T3-toxicosis. Metabolism 30:327–330[Medline]
  11. Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR 2002 Biochemistry, cellular and molecular biology and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23:38–89[Abstract/Free Full Text]
  12. Abuid J, Larsen PR 1974 Triiodothyronine and thyroxine in hyperthyroidism. J Clin Invest 54:201–208
  13. Lang M, Flesch M 1996 T3 hyperthyroidism with metastatic follicular thyroid carcinoma in substitution therapy. Nuklearmedizin 35:186–189[Medline]
  14. Curcio C, Baqui MMA, Salvatore D, Rihn BH, Mohr S, Harney JW, Larsen PR, Bianco AC 2001 The human type 2 iodothyronine deiodinase is a selenoprotein highly expressed in a mesothelioma cell line. J Biol Chem 276:30183–30187[Abstract/Free Full Text]



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