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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-2282
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The Journal of Clinical Endocrinology & Metabolism Vol. 93, No. 6 2239-2242
Copyright © 2008 by The Endocrine Society

3,5,3'-Triiodothyronine Thyrotoxicosis due to Increased Conversion of Administered Levothyroxine in Patients with Massive Metastatic Follicular Thyroid Carcinoma

Akira Miyauchi, Yuuki Takamura, Yasuhiro Ito, Akihiro Miya, Kaoru Kobayashi, Fumio Matsuzuka, Nobuyuki Amino, Nagaoki Toyoda, Emiko Nomura and Mitsushige Nishikawa

Departments of Surgery (A.M., Y.T., Y.I., A.M., K.K., F.M.) and Medicine (N.A.), Kuma Hospital, Kobe 650-0011, Japan; and Department of Medicine (N.T., E.N., M.N.), Kansai Medical University, Osaka 570-8506, Japan

Address all correspondence and requests for reprints to: Akira Miyauchi, M.D., Ph.D., Department of Surgery, Kuma Hospital, 8-2-35 Shimoyamate-dori, Chuo-ku, Kobe 650-0011, Japan. E-mail: miyauchi{at}kuma-h.or.jp.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Objective: Some patients with massive metastatic thyroid carcinoma exhibit T3 thyrotoxicosis. We investigated the prevalence and cause of T3 thyrotoxicosis and the clues to the diagnosis.

Design: Serum free T3 (FT3), free T4 (FT4), and TSH were measured in patients with massive metastases from papillary, follicular, or medullary thyroid carcinomas (31, 20, and seven patients, respectively). Patients without recurrence served as controls. Thyrotoxic patients were reexamined 1 wk after withdrawal of levothyroxine. Type 1 and type 2 iodothyronine deiodinase (D1 and D2) activities were measured in three tumor tissues from thyrotoxic patients.

Main Outcome: The serum FT3 level and FT3/FT4 ratio in the follicular carcinoma (FC) group were significantly higher than those in the papillary carcinoma group or patients without recurrence. Four patients (20%) in the FC group but none in the other groups demonstrated T3 thyrotoxicosis or a FT3/FT4 ratio greater than 3.5. One week after withdrawal of levothyroxine, both FT3 and FT4 levels decreased. Retrospective measurements of FT3 in frozen stored sera demonstrated that FT3 exceeded the upper normal limit when FT4 began to decrease but remained within the normal range. Tumor tissues showed high D1 and D2 activities.

Conclusions: Twenty percent of patients with massive metastatic FC exhibited T3 thyrotoxicosis, most likely due to increased conversion of T4 to T3 by tumor expressing high D1 and D2 activities. Occasional measurement of serum FT3 in addition to FT4 and TSH is recommended in patients with massive metastatic FC, especially when serum FT4 decreases on fixed doses of levothyroxine.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Patients with distant metastases from papillary or follicular thyroid carcinoma are treated with radioactive iodine after total thyroidectomy and are maintained on supraphysiological doses of levothyroxine to suppress TSH secretion (1). During TSH-suppressive therapy, serum levels of TSH and T4 or free T4 (FT4) as well as thyroglobulin (Tg) and Tg antibody are monitored to maintain sufficient suppression of TSH levels while avoiding thyrotoxicosis. T3 is the active form of thyroid hormone. However, serum T3 or FT3 is not measured routinely, not only because it usually remains in normal ranges even if the serum FT4 level slightly exceeds the normal upper limit but also because all of these tests are expensive.

The administered levothyroxine is deiodinated and converted to T3 by type 1 iodothyronine deiodinase (D1) and D2 (2, 3). In humans, the thyroid expresses both D1 and D2 (4). High expression of D2 in Graves’ thyroid tissue and in some thyroid adenomas has been reported to contribute to relatively high serum T3 levels (5). D3, which is not expressed in the thyroid, catalyzes the conversion of T4 to rT3 and T3 to 3,3'-diiodothyronine, thus inactivating these hormones (4). Overexpression of D3 has been reported to cause hypothyroidism due to excessive conversion of T4 to rT3, consumptive hypothyroidism, in infants and adults with large hemangiomas (6, 7).

Recently, we encountered two cases of massive metastatic follicular carcinoma with T3 thyrotoxicosis, which was most likely due to increased conversion of exogenous levothyroxine to T3 by the tumor tissue (8). The tumor tissues from one patient expressed high levels of D1 and D2 mRNA. Kim et al. (9) reported three patients with large primary or widely metastatic follicular carcinoma who demonstrated decreased serum T4 levels and increased ratio of serum T3 to T4. Tumor tissue from one of their patients demonstrated high D2 activity, and increased conversion physiology was suggested.

In this paper, we describe the prevalence of T3 thyrotoxicosis in patients with massive metastases of various types of thyroid cancer, the cause of T3 thyrotoxicosis, and the clues to the diagnosis.


   Patients and Methods
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 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
We identified 58 patients with metastatic thyroid cancer measuring more than 2 cm in diameter, who were currently being treated at Kuma Hospital. All of these patients had undergone total thyroidectomy. There were 31 patients with papillary, 20 patients with follicular, and seven patients with medullary thyroid carcinoma. The most common metastatic site was the lung followed by bone, liver, and others (42, 23, four, and 10 patients, respectively). Seventeen patients who underwent total thyroidectomy for papillary carcinoma without any sign of recurrence served as the control. There was no significant difference in mean age among the groups. We measured TSH, FT4, and FT3 to detect possible T3 thyrotoxicosis. In patients with papillary or follicular carcinoma, serum Tg and Tg antibody were also examined. The patients in the control group had nondetectable levels of serum Tg in the absence of Tg antibody. In patients with abnormally high FT3, thyroid function tests were repeated after stopping levothyroxine administration for 1 wk, and then doses of levothyroxine were reduced to allow recovery from the thyrotoxic status. Frozen stored sera remaining from past measurements were used to measure FT3 to clarify the course of change in these patients. Three frozen stored tumor tissues, two primary tumors, and one metastatic sc tumor from two patients with T3 thyrotoxicosis were used to measure D1 and D2 activities. Six normal thyroid tissues from the lobe contralateral to thyroid cancer served as control tissue.

TSH, FT4, and FT3 were measured with a chemiluminescent immunoassay (ARCHITECT i2000; Abbott Japan, Tokyo, Japan). For statistical calculation, less than 0.003 µIU/ml TSH was regarded as 0, and more than 8000 ng/ml Tg was regarded as 8000. Tg values in patients positive for Tg antibody were excluded from the calculation.

Measurement of D1 and D2 activities

The assays were performed as reported previously (5, 10). In brief, reactions contained 300 µg microsomal protein of tumor tissue, 0.1 nM [125I]T4, 2 nM cold T4, and 1 mM propylthiouracil in a final volume of 200 µl (D2 assay conditions) or 0.2 nM [125I]rT3 and 0.5 µM cold rT3 with or without 1 mM propylthiouracil (D1 assay conditions). After incubations for 60 or 120 min at 37 C, 125I was separated from unreacted substrate or iodothyronine products. Deiodination activity was presented as moles of I– released per milligram of protein per hour.

The present study was approved by the ethical committee, and all patients gave informed consent.


   Results
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 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
There was no significant difference in the mean levels of TSH and FT4 among the four groups (Table 1Go). Patients in the papillary or follicular carcinoma group were taking significantly larger doses of levothyroxine than the other groups (P < 0.05), having high Tg levels of similar values. However, the mean FT3 level and FT3/FT4 ratio in the follicular carcinoma group were significantly higher than those in the papillary carcinoma group or in patients without recurrence. The Tg levels did not correlate with the FT3 levels or FT3/FT4 ratios in the follicular carcinoma group.


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  		TABLE 1. Thyroid function data for the patient groups

 
Four patients with follicular carcinoma demonstrated abnormally high FT3 levels and a FT3/FT4 ratio larger than 3.5. None of the other patients had FT3 levels higher than 3.7 pg/ml or a FT3/FT4 ratio larger than 3.5. Clinical features and thyroid data of these four patients are summarized in Table 2Go. Pathology was of the well differentiated type and poorly differentiated type in two patients each. They had been treated with radioactive iodine, which could not control the disease. They had multiple metastases with the maximal diameter of the largest metastasis being greater than 4.6 cm. FT4 levels were within normal ranges in three patients and low in one. TSH levels were completely suppressed. Patients 1 and 2 had palpitation, tachycardia, and weight loss, whereas the remaining two had mild tachycardia only. Withdrawal of levothyroxine for 1 wk decreased both FT4 and FT3 levels in all patients, indicating that excess T3 was not produced by functioning metastatic foci but originated from exogenous levothyroxine due to increased conversion in metastatic foci. After the tests, doses of the levothyroxine were reduced to allow recovery from T3 thyrotoxicosis. Patient 1 died of the disease 6 months after the examination, whereas the remaining three are currently alive 3–24 months after the examination.


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  		TABLE 2. Clinical feature and thyroid data in four patients with increase conversion T3 thyrotoxicosis

 
Retrospective assays of FT3 using frozen stored sera from patients 1 and 2 demonstrated that gradual increases in FT3 levels had started about 2 and 4 yr earlier, respectively, in contrast to gradual decreases in FT4 values. FT3 already exceeded the upper limit of the normal range, whereas FT4 remained within the normal range (Fig. 1Go). Figure 1Go also shows that when levothyroxine was withheld for a month in preparation for radioactive iodine treatment, both FT4 and FT3 decreased to undetectable levels. This also indicates that serum T3 in this patient derived from administered levothyroxine by conversion.


Figure 1
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  		FIG. 1. Serial changes in thyroid function tests in patient 2. Solid squares and solid diamonds indicate FT3 and FT4 levels, respectively. Open squares indicate FT3 levels measured using frozen stored sera remaining from past measurements of FT4. Shaded areas indicate normal ranges for FT3 (upper) and FT4 (lower). Levothyroxine was withdrawn three times for radioactive iodine treatments as well as for the test in the present study. Note abnormally high FT3 levels with normal FT4 levels and gradual decreases in FT4 levels over time.

 
D1 and D2 activities in normal thyroid tissues are 140 ± 112 pmol/mg protein·h and 8.6 ± 8.6 fmol/mg protein·h, respectively (mean ± SD). Tumor tissues from patients with T3 thyrotoxicosis exhibited about eight times higher D1 activities (480–1778 pmol/mg protein·h) and about 250 times higher D2 activities (1479–2487 fmol/mg protein·h).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Two patients reported previously by us (8) and three patients reported by Kim et al. (9) shared common clinical features such as bearing massive metastatic or large primary follicular carcinoma and showing a decrease in serum T4 levels and increases in serum T3 levels and T3 to T4 ratios in the absence of functioning tumors. Excessive conversion of T4 to T3 in tumor tissue was suggested, and this hypothesis was supported by the detection of expression of D1 or D2 in tumor tissues from one of our patients and one of Kim’s patients. Lang and Flesch (11) reported a patient with follicular carcinoma on TSH-suppressive therapy, who showed T3 thyrotoxicosis with normal to low levels of T4. Reports of such cases are rare at present, and the prevalence of increased conversion of T4 in metastatic thyroid cancer is unknown.

In the present study, we identified four patients with excessive serum FT3 levels and a FT3/FT4 ratio larger than 3.5. All of them had metastatic follicular thyroid carcinoma. The prevalence of increased conversion T3 thyrotoxicosis was four of 20 patients (20%) with massive metastatic follicular carcinoma, whereas none of the patients with papillary or medullary carcinoma showed this phenomenon.

D1 and D2 levels are reported to be low in papillary thyroid carcinoma (12, 13). In the previous paper, we also reported low expression of D1 and D2 mRNA in papillary thyroid carcinoma in contrast to moderate to high expression in follicular adenoma and follicular carcinoma (8). In the present paper, we report high D1 activity and very high D2 activity in three tumor tissues from two patients with increased conversion T3 thyrotoxicosis. de Souza Meyer et al. (13) reported high D2 activity in metastatic follicular carcinoma samples. High expression of D1 and D2 activities in some follicular carcinoma lesions as well as large tumor volume explain the occurrence of increased conversion of T4 to T3 in patients with massive follicular carcinoma.

Three of the four patients with high FT3 levels reported here had normal FT4 levels, whereas one had obviously low levels. Retrospective measurements of FT3 using frozen stored serum indicated that increase in FT3 levels exceeding the upper normal range had occurred, whereas FT4 levels were slightly decreased but within the normal range. Decrease in serum FT4 levels while patients are maintained on a fixed dose of levothyroxine can be a clue to the early diagnosis of this physiology. Withdrawal of levothyroxine for 1 wk resulted in a decrease in serum FT4 and FT3. This withdrawal test seems to be an easy way to rule out the possibility of T3 production by functioning tumor.

The aim of TSH-suppressive therapy is to suppress serum TSH while avoiding thyrotoxicosis. Although two of our patients demonstrated mild symptoms such as palpitation and weight loss, these were common symptoms in patients with advanced cancer. Symptoms and clinical signs in the others were even vaguer. Therefore, if only FT4 and TSH had been measured, these cases would have been overlooked. On the contrary, doctors might increase the dose of levothyroxine, because the serum FT4 level was decreased. This is potentially dangerous, because it would promote more severe T3 thyrotoxicosis.

In conclusion, occasional measurement of FT3 in addition to FT4 and TSH is recommended in patients with massive metastatic follicular thyroid carcinoma under TSH-suppressive therapy, especially when serum FT4 levels decrease while the patients are maintained on fixed doses of levothyroxine.


   Acknowledgments
 
We thank Shinji Morita and Hiroshi Yoshida (Kuma Hospital) for assistance with the laboratory tests.


   Footnotes
 
Disclosure Information: All of the authors, A.M., Y.T., Y.I., A.M., K.K., F.M., N.A, N.T., E.N., and M.N., have nothing to declare.

First Published Online April 8, 2008

Abbreviations: D1, Type 1 iodothyronine deiodinase; FT4, free T4; Tg, thyroglobulin.

Received October 11, 2007.

Accepted March 27, 2008.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Grebe SK, Hay ID 1995 Follicular thyroid cancer. Endocrinol Metab Clin North Am 24:761–801[Medline]
  2. Bianco AC, Kim BW 2006 Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest 116:2571–2579[CrossRef][Medline]
  3. Maia AL, Kim BW, Huang SA, Harney JW, Larsen PR 2005 Type 2 iodothyronine deiodinase is the major source of plasma T3 in euthyroid humans. J Clin Invest 115:2524–2533[CrossRef][Medline]
  4. 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]
  5. 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]
  6. Huang SA, Tu HM, Harney JW, Venihaki M, Butte AJ, Kozakewich HP, Fishman SJ, 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. Huang SA, Fish SA, Dorfman DM, Salvatore D, Kozakewich HP, Mandel SJ, Larsen PR 2002 A 21-year-old woman with consumptive hypothyroidism due to a vascular tumor expressing type 3 iodothyronine deiodinase. J Clin Endocrinol Metab 87:4457–4461[Abstract/Free Full Text]
  8. Takano T, Miyauchi A, Ito Y, Amino N 2006 Thyroxine to triiodothyronine hyperconversion thyrotoxicosis in patients with large metastases of follicular thyroid carcinoma. Thyroid 16:615–618[CrossRef][Medline]
  9. Kim BW, Daniels GH, Harrison BJ, Price A, Harney JW, Larsen PR, Weetman AP 2003 Overexpression of type 2 iodothyronine deiodinase in follicular carcinoma as a cause of low circulating free thyroxine levels. J Clin Endocrinol Metab 88:594–598[Abstract/Free Full Text]
  10. Yasuzawa-Amano S, Toyoda N, Maeda A, Kosaki A, Mori Y, Iwasaka T, Nishikawa M 2004 Expression and regulation of type 2 iodothyronine deiodinase in rat aorta media. Endocrinology 145:5638–5645[Abstract/Free Full Text]
  11. Lang M, Flesch M 1996 [T3 hyperthyroidism with metastatic follicular thyroid carcinoma in substitution therapy]. Nuklearmedizin 35:186–189 (German)
  12. 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]
  13. de Souza Meyer EL, Dora JM, Wagner MS, Maia AL 2005 Decreased type 1 iodothyronine deiodinase expression might be an early and discrete event in thyroid cell dedifferentation towards papillary carcinoma. Clin Endocrinol (Oxf) 62:672–678[CrossRef][Medline]



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