Phenotypic Expression and Challenges of a Distinct Form of Thyrotoxicosis: Triiodothyronine-Predominant Graves Disease—Aggressive, Refractory, and Anything but Banal : The Endocrinologist

Journal Logo

You can read the full text of this article if you:

Access through Ovid
00019616-200803000-00012ReviewThe EndocrinologistThe Endocrinologist© 2008 Lippincott Williams & Wilkins, Inc.18March 2008 p 90-94Phenotypic Expression and Challenges of a Distinct Form of ThyrotoxicosisTriiodothyronine-Predominant Graves Disease—Aggressive, Refractory, and Anything but BanalCME Review Article #5Dalan, Rinkoo MBBS, MRCP (UK)*; Kon, Winston MBBS (Lond), FRCP (Edin), FAMS (Endocrinology)†; Leow, Melvin Khee Shing MBBS, FACP (USA), FACE (USA)†*Associate Consultant; and †Consultant, Department of Endocrinology, Tan Tock Seng Hospital, Singapore.The authors have disclosed that they have no significant relationships with or financial interests in any commercial organizations pertaining to this educational activity.All staff in a position to control the content of this CME activity have disclosed that they have no financial relationships with, or financial interests in, any commercial companies pertaining to this educational activity.Lippincott CME Institute has identified and resolved all faculty and staff conflicts of interest regarding this educational activity.Reprints: Rinkoo Dalan, MBBS, MRCP (UK), Department of Endocrinology, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433. E-mail: [email protected] Editor’s Note:This article is the 5th of 18 that will be published in 2008 for which a total of up to 18 AMA PRA Category 1 Credits™ can be earned. Instructions for how credits can be earned precede the CME Examination at the back of this issue.AbstractTriiodothyronine (T3)-predominant Graves disease is characterized by persistently high serum T3 level and normal or low serum thyroxine (T4) level during thionamide drug therapy. Graves disease is much more aggressive in this form and has a lower remission rate with antithyroid drugs (ADI) and radioiodine (I-131) therapy. An 18-year-old Chinese woman had thyrotoxicosis with overt features of T3-predominant Graves disease. She failed to achieve a remission despite ADI treatment for 4 years and 3 doses of I-131 therapy. She finally underwent a total thyroidectomy followed by I-131 remnant ablation. The pathogenetic mechanisms, and the reasons for a tendency for nonremission with ADI, and I-131 therapy are discussed.Learning ObjectivesDescribe the presenting physical signs in this patient with triiodothyronine-predominant Graves’ disease and her clinical course as it related to a variety of treatments.Recall the incidence of this disorder and the mechanisms that may be responsible for its development.Identify the available treatment options, focusing on the role and timing of total thyroidectomy.Triiodothyronine (T3)-predominant Graves disease is characterized by a persistently high serum T3 level and normal or low serum thyroxine (T4) level during thionamide drug therapy.1 T3-predominant Graves disease is much more aggressive and resistant to remission with antithyroid drugs (ATD) and radioiodine (I-131) therapy.2 We report a case of T3-predominant Graves disease and discuss the associated pathogenetic mechanisms and the reasons for refractoriness to remission with ATD and I-131 therapy.CASE REPORTAn 18-year-old Chinese woman was referred to our Endocrinology service for management of hyperthyroidism from Graves disease. She had classic thyrotoxic symptoms for 6 months and had also noticed an anterior neck swelling which progressively enlarged over time. She had always lived in Singapore, an iodine sufficient country.She was born of nonconsanguinous parents and denied any major health issues in her childhood. Her mother apparently had a thyroidectomy for Graves disease and had been on l-thyroxine replacement ever since.Her height was 152 cm and she weighed 40 kg. Her heart rate was regular at 120 per minute and her blood pressure was 110/70 mm Hg. Her palms were moist with fine peripheral hand tremors. There was a massive diffuse goitre with a bruit. However, neither retrosternal extension nor Pemberton sign was demonstrable. There were no palpable thyroid nodules or cervical lymphadenopathy. She had no evidence of Graves orbitopathy, pretibial myxoedema, or thyroid acropachy. Thyroid ultrasound showed a diffusely enlarged gland greater than 200 g with markedly increased vascularity. Her serum free T4 was raised at 80 pmol/L (reference interval: 8–21 pmol/L) and thyroid-stimulating hormone (TSH) was suppressed to less than 0.005 mIU /L (RI: 0.34–5.60 mIU/L). Her TSH receptor autoantibody (TRAb) titer was markedly elevated at 311.8 U/L (RI: 1.0–3.4 U/L) (Table 1, Figure 2).JOURNAL/endst/04.03/00019616-200803000-00012/table1-12/v/2021-02-17T201845Z/r/image-tiff Clinical Course and InvestigationsJOURNAL/endst/04.03/00019616-200803000-00012/figure1-12/v/2021-02-17T201845Z/r/image-tiff Graphical representation of the clinical course.She was started on methimazole (Thyrozol) 30 mg daily which required an increase in dose to 40 mg daily on the subsequent visit. After 5 months on methimazole 30 to 40 mg daily, she was still clinically thyrotoxic. By then, the free T4 had declined to 5 pmol/L, and the TSH was undetectable. Serum free T3 was elevated at 32 pmol/L (RI: 4–8 pmol/L), confirming the diagnosis of severe T3 toxicosis. Thyrotoxicosis persisted despite 2 years of methimazole 20 to 30 mg/d, followed by another 2 years of carbimazole. She was periodically noncompliant. The patient finally agreed to I-131 therapy in March 2004, though it was expected that she would likely require more than one dose to achieve a favorable therapeutic objective.She was given 18 mCi of I-131 after carbimazole was withdrawn for 3 days. Four months later, she was still clinically thyrotoxic, with a free T4 of 22 pmol/L and a TSH <0.005 mIU/L. The goitre was estimated at more than 100 g, and a bruit still present. A second dose of 20 mCi I-131 was given. Six months later, she remained thyrotoxic (Table 1). Carbimazole was restarted and total thyroidectomy was offered. She opted for a third dose of I-131, and was given 16 mCi. Six months later, she was still thyrotoxic, with serum free T4 of 23 pmol/L and TSH <0.005 mIU/L. She was still taking high doses of carbimazole. The goitre was somewhat smaller, 60 to 80 g, but a bruit was audible and TRAb levels were greater than 40 IU/L. In July 2005, the free T3 remained elevated at 10.9 pmol/L.She finally underwent total thyroidectomy in July of 2005. The resected thyroid gland weighed 49 g. Histology revealed small, closely packed glands lined by follicular epithelial cells showing considerable nuclear pleomorphism. The colloid showed scalloping consistent with partially treated Graves disease.Three months postthyroidectomy a fourth dose of 12 mCi I-131 was administered in an attempt to ablate any thyroid remnants. She finally achieved normal thyroid function tests.DISCUSSIONIn normal people, the thyroid preferentially secretes T4 with a T4:T3 ratio of 11:1.3,4 Most T3 production is extrathyroidal and dependent on 5′deiodinase.5 With a normal T4 production rate of approximately 110 nmol/d, about 40 nmol/d of T3 is formed by peripheral deiodination and 10 nmol/d from thyroidal secretion, of which two thirds are derived from hydrolysis of Tg and one third from deiodination.6,7In Graves disease, hyperstimulation of the thyroid gland leads to a synthesis of Tg with a doubled T3 content and T4 content unchanged from normal.3,7–9 Intrathyroidal deiodination only contributes to 6% of daily T3 production in the normal state, 25% in most cases of Graves disease, and up to 50% in severe Graves disease.7 An overactive thyroid can deiodinate intrathyroidally both T4 released from Tg10 and T4 derived from the circulation via the rich vascular supply,11 thus raising the production of T3 above that of T4. This preferential secretion of T3 is not present in iodine-induced thyrotoxicosis cases, in which T4 secretion remains higher than T3.12T3-predominant Graves disease is characterized by persistently high serum T3 level, normal serum thyroxine (T4) level, and a high serum T3/T4 ratio during thionamide drug therapy.1,2 About 5% of patients with thyrotoxicosis have T3-predominant Graves disease.2,13 Closely related to this phenomenon is that of T3 toxicosis, a variant of hyperthyroidism which manifests itself with elevated serum T3 and suppressed TSH in the face of normal serum T4 levels. It is most often found in patients with iodine deficiency, nodular goitre, and those with multiple relapses after ATD therapy, I-131 therapy, or subtotal thyroidectomy, though the pathogenetic mechanisms differ somewhat in T3-toxicosis encountered in these other forms of hyperthyroidism.2Thyroid-stimulating immunoglobulins (TSI) are higher in patients with T3-predominant thyrotoxicosis.1,14,15 These patients tend to have larger thyroid glands that are more I-131 avid: the mean thyroid radioiodine uptake is higher at 3 hours when compared with that at 24 hours compared with the usual Graves disease patients.16 These patients also have a higher thyroid peroxidase (TPO) activity and a lower Tg iodine content after treatment.16 Takamatsu et al, suggest that in T3-predominant Graves disease, the TPO enzyme activity may favor triiodothyronine formation.17 Thus, the increased iodine turnover, low intrathyroidal iodine pool, and unique TPO enzyme activity could drive preferential T3 production (Table 2 and Fig. 1A and B). Histologically, thyrocytes from the thyroid glands of these patients are taller and larger with large intrafollicular colloidal vacuoles.18JOURNAL/endst/04.03/00019616-200803000-00012/table2-12/v/2021-02-17T201845Z/r/image-tiff Differences Between Usual Graves Disease and T3-Predominant Graves DiseaseJOURNAL/endst/04.03/00019616-200803000-00012/figure2-12/v/2021-02-17T201845Z/r/image-png Pathogenetic mechanisms in typical Graves disease compared with T3-predominant thyrotoxicosis. A, typical Graves disease. B, T3-predominant Graves disease.Thionamides divert oxidized TPO from the tyrosine residues in Tg to form inactive compounds and thus reduce the organification and coupling of Tg with decreased formation of T4 and T3. However, in patients with T3-predominant thyrotoxicosis, after initiation of ATD, there is a decreased formation of T4 levels with preferential secretion of T3. The decreased T4 would result in an up-regulation of half life of D2 by decreasing the rate of ubiquitination and proteasomal degradation,5 which in combination with increased D1 activity, will result in a further increase in T3. Moreover, these patients are unlikely to have a remission with ATD, as the features of T3-predominant Graves disease, namely a huge thyroid gland, high titres of TSI, and increased iodine turnover, are well-known poor prognostic makers for remission.1 Accordingly, patients with rapid thyrodial iodine turnover whose 3–4-hour RAIU is higher than the 24-hour RAIU will require significantly higher I-131 doses, and have predictably more dismal responses to I-131 treatment.18a For illustration, given our patient has a thyroid mass of at least 200 g, in order to deliver 160 μCi/g tissue with 24-hour RAIU of 60%, the administered dose would be (200 g × 160 μCi/g)/0.60 = 53.33 mCi. Hence, a single dose of I-131 was unlikely to achieve remission in our case, since the stipulated maximum outpatient dose allowed by regulations is 30 mCi. Indeed, our patient, who manifested T3-predominant thyrotoxicosis, failed to achieve remission despite sequential doses of I-131.In our case, the TRAb level was very high initially, which decreased over the course of ATD treatment but never normalized (Fig. 2). Even after 2 years of treatment, the level was 12.1 U/L. After 2 doses of I-131, the TRAb level rose above 40 U/L as expected in patients after I-131 therapy. Five months after total thyroidectomy, the TRAb level had declined to 26.6 IU/L and further decreased to 11.6 IU/L at 6 months after the final I-131 therapy.Some remnant tissue is inevitably left behind, after total thyroidectomy, which mandates the use of adjuvant I-131 postthyroidectomy for complete ablation. In Graves disease, where there is a significant amount of fibrosis and scarring of the thyroid gland, it may be even more difficult to resect the entire gland. One study reported a 3% relapse rate even after a total thyroidectomy.19 In another study, a relapse rate of 9.4% was found if 4 g thyroid tissue was left behind, in contrast with 0% if <2 g thyroid tissue was left behind.20 In a recent study of 714 consecutive patients with total or near total thyroidectomy, persistent hyperthyroidism was seen in 3 patients, suggesting that even with modern techniques of complete capsular removal, remnant tissue might be sufficient to lead to a relapse.21 Recurrence can be late. Leow and Loh reported a patient with fatal thyroid crisis 18 years after a near total thyroidectomy.22 Katz et al reported a case of Graves disease with increased TSI, which occurred 9 years after a total thyroidectomy.23 It has been seen that complete ablation of thyroid tissue results in the disappearance of antibodies to all major thyroid antigens.24 Because our patient had persistently high TRAb levels despite total thyroidectomy, we thought it prudent to perform a total thyroid ablation akin to the standard practice of I-131 remnant ablation after total thyroidectomy for thyroid cancer to minimize the risk of long-term relapse.CONCLUSIONSThe available evidence supports 3 main factors for T3-predominant Graves disease: (1) abnormally high and perhaps a qualitatively different TSI activating c-AMP dependent dio-1 and dio-2 promoters thereby leading to an overall accentuated 5′deiodinase activity; (2) an abnormally active TPO enzyme that alters iodotyrosyl coupling resulting in a higher T3:T4 ratio in thyroglobulin before hydrolysis, hence leading to a greater T3 production; (3) a very high iodine uptake and turnover causing a relative decline in intrathyroidal iodine content which favors the formation of T3 over T4. Patients with T3-predominant Graves thyrotoxicosis typically do not achieve spontaneous remission even after multiple courses of ATD therapy or I-131 therapy. In these cases, it may be prudent to consider total thyroidectomy early in the course.REFERENCES1. Takamatsu J, Sugawara M, Kuma K, et al. Ratio of serum triiodothyronine to thyroxine and the prognosis of triiodothyronine-predominant Graves’ disease. Ann Intern Med. 1984;100:372–375.[Context Link][CrossRef][Medline Link]2. Toft A, Beckett GJ. Measuring serum thyrotropin and thyroid hormone and assessing thyroid hormone transport. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the Thyroid: A Fundamental and Clinical Text. 9th ed. Philadelphia: Lippincott, Wilkins and Williams; 2005:329–344. Chap 13.[Context Link]3. Izumi M, Larsen PR. Triiodothyronine, thyroxine, and iodine in purified thyroglobulin from patients with Graves’ disease. J Clin Invest. 1977;59:1105–1112.[Context Link]4. Salvatore D, Tu H, Harney JW, et al. Type 2 iodothyronine deiodinase is highly expressed in human thyroid. J Clin Invest. 1996;98:962–968.[Context Link][Full Text][CrossRef][Medline Link]5. Larsen PR, Davies TF, Schlumberger MJ. Thyroid physiology and diagnostic evaluation of patients with thyroid disorders. In: Larsen PR, Kronenberg HM, Melmed S, et al, eds. Williams Textbook of Endocrinology. 10th ed. Philadelphia: WB Saunders; 2003:331–373. Chap 10.[Context Link]6. Bianco AC, Larsen PR. Intracellular pathways of iodothyronine metabolism. In: Braverman LE, Utiger RD, eds. Werner and Ingbar’s the Thyroid: A Fundamental and Clinical Text. 9th ed. Philadelphia: Lippincott, Wilkins and Williams; 2005:109–133. Chap 7.[Context Link]7. Laurberg P, Vestergaard H, Nielsen S, et al. Sources of circulating T3 in hyperthyroidism estimated after blocking of type 1 and type 2 iodothyronine deiodinases. J Clin Endocrinol Metab. 2007;92:2149–2156.[Context Link][Full Text][CrossRef][Medline Link]8. Dunn JT, Ray SC. Changes in the structure of thyroglobulin following the administration of thyroid-stimulating hormone. J Biol Chem. 1975;250:5801–5807.[Context Link][CrossRef][Medline Link]9. Laurberg P. Thyroxine and 3,5,3′-triiodothyronine content of thyroglobulin in thyroid needle aspirates in hyperthyroidism and hypothyroidism. J Clin Endocrinol Metab. 1987;64:969–974.[Context Link][CrossRef][Medline Link]10. Laurberg P. Mechanisms governing the relative proportions of thyroxine and 3,5,3′-triiodothyronine in thyroid secretion. Metabolism. 1984;33:379–392.[Context Link][CrossRef][Medline Link]11. Laurberg P. Thyroxine entering the thyroid gland via the vascular bed may leave the gland as triiodothyronines. Studies with perfused dog thyroid lobes. Endocrinology. 1986;118:895–900.[Context Link][CrossRef][Medline Link]12. Sobrino LG, Limbert ES, Santos MA. Thyroxine toxicosis in patients with iodine induced thyrotoxicosis. J Clin Endocrinol Metab. 1977;45:25–29.[Context Link][CrossRef][Medline Link]13. Chen JJ, Ladenson P. Discordant hypothyroxinemia and hypertriiodothyroninemia in treated patients with hyperthyroid Graves disease. J Clin Endocrinol Metab. 1986;63:102–106.[Context Link][CrossRef][Medline Link]14. Takamatsu J, Kuma K, Mozai T. serum triiiodothyronine to thyroxine ratio: a newly diagnosed predictor of outcome of hyperthyroidism due to Graves disease. J Clin Endocrinol Metab. 1986;62:980–983.[Context Link][CrossRef][Medline Link]15. Weetman AP, Shepherdley CA, Mansell P, et al. Thyroid over-expression of type 1 and type 2 deiodinase may account for the syndrome of low thyroxine and increasing triiodothyronine during propylthiouracil treatment. Eur J Endocrinol. 2003;149:443–447.[Context Link][CrossRef][Medline Link]16. Takamatsu J, Hosoya T, Naito N, et al. Enhanced iodine metabolism in patients with triiodothyronine-predominant Graves’ disease. J Clin Endocrinol Metab. 1988;66:147–152.[Context Link][CrossRef][Medline Link]17. Takamatsu J, Hosoya T, Ohmori T, et al. Enhanced coupling reaction by thyroid peroxidase in patients with triiodothyronine—predominant Graves’ disease. Presented at: 72nd Annual Meeting of the Endocrine Society, Atlanta, Georgia, June 20–23, 1990.[Context Link]18. Takamatsu J, Takeda K, Katayama S, et al. Epithelial hyperplasia and decreased colloid content of the thyroid gland in triiodothyronine-predominant Graves’ disease. J Clin Endocrinol Metab. 1992;75:1145–1150.[Context Link][CrossRef][Medline Link]18a. Aktay R, Rezai K, Seabold JE, Bar RS, Kirchner PT. Four- to twenty-four-hour uptake ratio: an index of rapid iodine-131 turnover in hyperthyroidism. J Nucl Med. 1996;37:815–819.[Context Link]19. Bottger T. Basedow’s disease-thyroidectomy or subtotal resection? Zentralbl Chir. 1997;122:231–235.[Context Link][Medline Link]20. Herrmann M, Rota R, Richter B, et al. Early relapse after operation for Graves’ disease: postoperative kinetics and outcome after subtotal, near total or total thyroidectomy. Surgery. 1998;124:894–900.[Context Link][CrossRef][Medline Link]21. Gaujoux S, Leenhardt L, Tresallet C, et al. Extensive thyroidectomy in Graves’ disease. J Am Coll Surg. 2006;202:868–873.[Context Link][Full Text][CrossRef][Medline Link]22. Leow MKS, Loh KC. Fatal thyroid crisis years after two thyroidectomies for Graves’ disease: is thyroid tissue autotransplantation for posthyroidectomy hypothyroidism worthwhile. J Am Coll Surg. 2002;195:434–435.[Context Link][Full Text][CrossRef][Medline Link]23. Katz SB, Garcia AJ, Niepomniszcze H. Development of Graves’ disease nine years after total thyroidectomy due to follicular carcinoma of the thyroid. Thyroid. 1997;7:909–911.[Context Link][CrossRef][Medline Link]24. Chiovato L, Latrofa F, Braverman LE, et al. Disappearance of humoral thyroid autoimmunity after complete removal of antigens. Ann Intern Med. 2003;139:346–351.[Context Link][Full Text][CrossRef][Medline Link]triiodothyronine; Graves’ disease; T3-predominant thyrotoxicosis; thyroxine00019616-200803000-0001200005822_1984_33_379_laurberg_triiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e614_citationRF_FLOATING))|11065213||ovftdb|SL0000582219843337911065213citation_FROM_JRF_ID_d3771e614_citationRF_FLOATING[CrossRef]10.1016%2F0026-0495%2884%2990203-800019616-200803000-0001200005822_1984_33_379_laurberg_triiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e614_citationRF_FLOATING))|11065405||ovftdb|SL0000582219843337911065405citation_FROM_JRF_ID_d3771e614_citationRF_FLOATING[Medline Link]636907200019616-200803000-0001200003571_1986_118_895_laurberg_triiodothyronines_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e640_citationRF_FLOATING))|11065213||ovftdb|SL00003571198611889511065213citation_FROM_JRF_ID_d3771e640_citationRF_FLOATING[CrossRef]10.1210%2Fendo-118-3-89500019616-200803000-0001200003571_1986_118_895_laurberg_triiodothyronines_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e640_citationRF_FLOATING))|11065405||ovftdb|SL00003571198611889511065405citation_FROM_JRF_ID_d3771e640_citationRF_FLOATING[Medline Link]394877800019616-200803000-0001200004678_1977_45_25_sobrino_thyrotoxicosis_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e665_citationRF_FLOATING))|11065213||ovftdb|SL000046781977452511065213citation_FROM_JRF_ID_d3771e665_citationRF_FLOATING[CrossRef]10.1210%2Fjcem-45-1-2500019616-200803000-0001200004678_1977_45_25_sobrino_thyrotoxicosis_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e665_citationRF_FLOATING))|11065405||ovftdb|SL000046781977452511065405citation_FROM_JRF_ID_d3771e665_citationRF_FLOATING[Medline Link]57749700019616-200803000-0001200004678_1986_63_102_chen_hypertriiodothyroninemia_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e700_citationRF_FLOATING))|11065213||ovftdb|SL0000467819866310211065213citation_FROM_JRF_ID_d3771e700_citationRF_FLOATING[CrossRef]10.1210%2Fjcem-63-1-10200019616-200803000-0001200004678_1986_63_102_chen_hypertriiodothyroninemia_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e700_citationRF_FLOATING))|11065405||ovftdb|SL0000467819866310211065405citation_FROM_JRF_ID_d3771e700_citationRF_FLOATING[Medline Link]242354700019616-200803000-0001200004678_1986_62_980_takamatsu_triiiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e730_citationRF_FLOATING))|11065213||ovftdb|SL0000467819866298011065213citation_FROM_JRF_ID_d3771e730_citationRF_FLOATING[CrossRef]10.1210%2Fjcem-62-5-98000019616-200803000-0001200004678_1986_62_980_takamatsu_triiiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e730_citationRF_FLOATING))|11065405||ovftdb|SL0000467819866298011065405citation_FROM_JRF_ID_d3771e730_citationRF_FLOATING[Medline Link]375426300019616-200803000-0001200023063_2003_149_443_weetman_triiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e765_citationRF_FLOATING))|11065213||ovftdb|SL00023063200314944311065213citation_FROM_JRF_ID_d3771e765_citationRF_FLOATING[CrossRef]10.1530%2Feje.0.149044300019616-200803000-0001200023063_2003_149_443_weetman_triiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e765_citationRF_FLOATING))|11065405||ovftdb|SL00023063200314944311065405citation_FROM_JRF_ID_d3771e765_citationRF_FLOATING[Medline Link]1458509200019616-200803000-0001200004678_1988_66_147_takamatsu_triiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e802_citationRF_FLOATING))|11065213||ovftdb|SL0000467819886614711065213citation_FROM_JRF_ID_d3771e802_citationRF_FLOATING[CrossRef]10.1210%2Fjcem-66-1-14700019616-200803000-0001200004678_1988_66_147_takamatsu_triiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e802_citationRF_FLOATING))|11065405||ovftdb|SL0000467819886614711065405citation_FROM_JRF_ID_d3771e802_citationRF_FLOATING[Medline Link]333560100019616-200803000-0001200004678_1992_75_1145_takamatsu_triiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e845_citationRF_FLOATING))|11065213||ovftdb|SL00004678199275114511065213citation_FROM_JRF_ID_d3771e845_citationRF_FLOATING[CrossRef]10.1210%2Fjc.75.4.114500019616-200803000-0001200004678_1992_75_1145_takamatsu_triiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e845_citationRF_FLOATING))|11065405||ovftdb|SL00004678199275114511065405citation_FROM_JRF_ID_d3771e845_citationRF_FLOATING[Medline Link]140088500019616-200803000-0001200000605_1984_100_372_takamatsu_triiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e393_citationRF_FLOATING))|11065213||ovftdb|SL00000605198410037211065213citation_FROM_JRF_ID_d3771e393_citationRF_FLOATING[CrossRef]10.7326%2F0003-4819-100-3-37200019616-200803000-0001200000605_1984_100_372_takamatsu_triiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e393_citationRF_FLOATING))|11065405||ovftdb|SL00000605198410037211065405citation_FROM_JRF_ID_d3771e393_citationRF_FLOATING[Medline Link]654648400019616-200803000-0001200008291_1997_122_231_bottger_thyroidectomy_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e927_citationRF_FLOATING))|11065405||ovftdb|SL00008291199712223111065405citation_FROM_JRF_ID_d3771e927_citationRF_FLOATING[Medline Link]922163200019616-200803000-0001200007719_1998_124_894_herrmann_postoperative_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e952_citationRF_FLOATING))|11065213||ovftdb|SL00007719199812489411065213citation_FROM_JRF_ID_d3771e952_citationRF_FLOATING[CrossRef]10.1016%2FS0039-6060%2898%2970014-500019616-200803000-0001200007719_1998_124_894_herrmann_postoperative_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e952_citationRF_FLOATING))|11065405||ovftdb|SL00007719199812489411065405citation_FROM_JRF_ID_d3771e952_citationRF_FLOATING[Medline Link]982340400019616-200803000-0001200019464_2006_202_868_gaujoux_thyroidectomy_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e989_citationRF_FLOATING))|11065404||ovftdb|SL00019464200620286811065404citation_FROM_JRF_ID_d3771e989_citationRF_FLOATING[Full Text]00019464-200606000-0000200019616-200803000-0001200019464_2006_202_868_gaujoux_thyroidectomy_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e989_citationRF_FLOATING))|11065213||ovftdb|SL00019464200620286811065213citation_FROM_JRF_ID_d3771e989_citationRF_FLOATING[CrossRef]10.1016%2Fj.jamcollsurg.2006.02.03100019616-200803000-0001200019464_2006_202_868_gaujoux_thyroidectomy_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e989_citationRF_FLOATING))|11065405||ovftdb|SL00019464200620286811065405citation_FROM_JRF_ID_d3771e989_citationRF_FLOATING[Medline Link]1673519900019616-200803000-0001200019464_2002_195_434_leow_autotransplantation_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e1027_citationRF_FLOATING))|11065404||ovftdb|SL00019464200219543411065404citation_FROM_JRF_ID_d3771e1027_citationRF_FLOATING[Full Text]00019464-200209000-0002100019616-200803000-0001200019464_2002_195_434_leow_autotransplantation_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e1027_citationRF_FLOATING))|11065213||ovftdb|SL00019464200219543411065213citation_FROM_JRF_ID_d3771e1027_citationRF_FLOATING[CrossRef]10.1016%2FS1072-7515%2802%2901283-800019616-200803000-0001200019464_2002_195_434_leow_autotransplantation_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e1027_citationRF_FLOATING))|11065405||ovftdb|SL00019464200219543411065405citation_FROM_JRF_ID_d3771e1027_citationRF_FLOATING[Medline Link]1222995500019616-200803000-0001200008379_1997_7_909_katz_thyroidectomy_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e1057_citationRF_FLOATING))|11065213||ovftdb|SL000083791997790911065213citation_FROM_JRF_ID_d3771e1057_citationRF_FLOATING[CrossRef]10.1089%2Fthy.1997.7.90900019616-200803000-0001200008379_1997_7_909_katz_thyroidectomy_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e1057_citationRF_FLOATING))|11065405||ovftdb|SL000083791997790911065405citation_FROM_JRF_ID_d3771e1057_citationRF_FLOATING[Medline Link]945963700019616-200803000-0001200000605_2003_139_346_chiovato_disappearance_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e1092_citationRF_FLOATING))|11065404||ovftdb|SL00000605200313934611065404citation_FROM_JRF_ID_d3771e1092_citationRF_FLOATING[Full Text]00000605-200309020-0001000019616-200803000-0001200000605_2003_139_346_chiovato_disappearance_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e1092_citationRF_FLOATING))|11065213||ovftdb|SL00000605200313934611065213citation_FROM_JRF_ID_d3771e1092_citationRF_FLOATING[CrossRef]10.7326%2F0003-4819-139-5_Part_1-200309020-0001000019616-200803000-0001200000605_2003_139_346_chiovato_disappearance_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e1092_citationRF_FLOATING))|11065405||ovftdb|SL00000605200313934611065405citation_FROM_JRF_ID_d3771e1092_citationRF_FLOATING[Medline Link]1296594300019616-200803000-0001200004686_1996_98_962_salvatore_iodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e468_citationRF_FLOATING))|11065404||ovftdb|SL0000468619969896211065404citation_FROM_JRF_ID_d3771e468_citationRF_FLOATING[Full Text]00004686-199608150-0001300019616-200803000-0001200004686_1996_98_962_salvatore_iodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e468_citationRF_FLOATING))|11065213||ovftdb|SL0000468619969896211065213citation_FROM_JRF_ID_d3771e468_citationRF_FLOATING[CrossRef]10.1172%2FJCI11888000019616-200803000-0001200004686_1996_98_962_salvatore_iodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e468_citationRF_FLOATING))|11065405||ovftdb|SL0000468619969896211065405citation_FROM_JRF_ID_d3771e468_citationRF_FLOATING[Medline Link]877086800019616-200803000-0001200004678_2007_92_2149_laurberg_triiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e522_citationRF_FLOATING))|11065404||ovftdb|SL00004678200792214911065404citation_FROM_JRF_ID_d3771e522_citationRF_FLOATING[Full Text]00004678-200706000-0002900019616-200803000-0001200004678_2007_92_2149_laurberg_triiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e522_citationRF_FLOATING))|11065213||ovftdb|SL00004678200792214911065213citation_FROM_JRF_ID_d3771e522_citationRF_FLOATING[CrossRef]10.1210%2Fjc.2007-017800019616-200803000-0001200004678_2007_92_2149_laurberg_triiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e522_citationRF_FLOATING))|11065405||ovftdb|SL00004678200792214911065405citation_FROM_JRF_ID_d3771e522_citationRF_FLOATING[Medline Link]1738970300019616-200803000-0001200004613_1975_250_5801_dunn_administration_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e559_citationRF_FLOATING))|11065213||ovftdb|SL000046131975250580111065213citation_FROM_JRF_ID_d3771e559_citationRF_FLOATING[CrossRef]10.1016%2FS0021-9258%2819%2941124-100019616-200803000-0001200004613_1975_250_5801_dunn_administration_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e559_citationRF_FLOATING))|11065405||ovftdb|SL000046131975250580111065405citation_FROM_JRF_ID_d3771e559_citationRF_FLOATING[Medline Link]115066000019616-200803000-0001200004678_1987_64_969_laurberg_3triiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e589_citationRF_FLOATING))|11065213||ovftdb|SL0000467819876496911065213citation_FROM_JRF_ID_d3771e589_citationRF_FLOATING[CrossRef]10.1210%2Fjcem-64-5-96900019616-200803000-0001200004678_1987_64_969_laurberg_3triiodothyronine_|00019616-200803000-00012#xpointer(id(citation_FROM_JRF_ID_d3771e589_citationRF_FLOATING))|11065405||ovftdb|SL0000467819876496911065405citation_FROM_JRF_ID_d3771e589_citationRF_FLOATING[Medline Link]3558731 Clinical Course and Investigations Graphical representation of the clinical course. Differences Between Usual Graves Disease and T3-Predominant Graves Disease Pathogenetic mechanisms in typical Graves disease compared with T3-predominant thyrotoxicosis. A, typical Graves disease. B, T3-predominant Graves disease.Phenotypic Expression and Challenges of a Distinct Form of Thyrotoxicosis: Triiodothyronine-Predominant Graves Disease—Aggressive, Refractory, and Anything but BanalDalan Rinkoo MBBS MRCP (UK); Kon, Winston MBBS (Lond), FRCP (Edin), FAMS (Endocrinology); Leow, Melvin Khee Shing MBBS, FACP (USA), FACE (USA)CME Review Article #5CME Review Article #5218p 90-94