Agoitrous Graves’ Hyperthyroidism with Markedly Elevated Thyroid Stimulating Immunoglobulin Titre displaying Rapid Response to Carbimazole with Discordant Thyroid Function
We characterize the clinical and laboratory characteristics of 5 patients with Graves’ thyrotoxicosis whose serum free thyroxine (fT4) concentration decreased unexpectedly to low levels on conventional doses of carbimazole (CMZ) therapy. The initial fT4 mean was 40.0 pM, range 25-69 pM. Thyroid volume by ultrasound measured as mean 11 ml, range 9.0-15.6 ml. Initial TSI levels measured 1487% to >4444%. Serum fT4 fell to low-normal or hypothyroid levels within 3.6 to 9.3 weeks of initiating CMZ 5 to 15 mg daily, and subsequently modulated by fine dosage adjustments. In one patient, serum fT4 fluctuated in a “yo-yo” pattern. There also emerged a pattern of low normal/low serum fT4 levels associated with discordant low/mid normal serum TSH levels respectively, at normal serum fT3 levels. The longterm daily-averaged CMZ maintenance dose ranged from 0.7 mg to 3.2 mg. Patients with newly diagnosed Graves' hyperthyroidism who have small thyroid glands and markedly elevated TSI titres appear to be “ATD dose sensitive.” Their TFT on ATD therapy may display a “central hypothyroid” pattern. We suggest finer CMZ dose titration at closer follow-up intervals to achieve biochemical euthyroidism.
Ross DS, Burch HB, Cooper DS, et al. 2016 American Thyroid Association Guidelines for diagnosis and management of hyperthyroidism and other causes of thyrotoxicosis. Thyroid. 2016;26(10):1343-1421.
Choi HS, Yoo WS. Free thyroxine, anti-thyroid stimulating hormone receptor antibody titres, and absence of goiter were associated with responsiveness to methimazole in patients with new onset Graves’ disease. Endocrinol Metab. 2017; 32(2):281-7. https://www.ncbi.nlm.nih.gov/pubmed/28685517. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503874. https://doi.org/10.3803/EnM.2017.32.2.281.
Dalan R, Leow MKS, Ng CE. High iodine (substrate) turnover Graves' disease: The intriguing 'rapid-responder' variant of thyrotoxicosis. Ann Clin Biochem 2008;45(Pt6):612-5.https://www.ncbi.nlm.nih.gov/pubmed/18941129. https://doi.org/10.1258/acb.2008.008098.
Takeshima K, Inaba H, Furukawa Y, et al. Elevated serum immunoglobulin G4 levels in patients with Graves‘ disease and their clinical implications. Thyroid 2014;24(4):736-43. https://www.ncbi.nlm.nih.gov/pubmed/24256421. https://doi.org/10.1089/thy.2013.0448
Gemma R, Nakamura H, Mori T, Andoh S, Suzuki Y, Yoshimi T. The change in 123I-uptake between 3- and 24-hours is useful in predicting early response to methimazole in patients with Graves’ disease. Endocr J. 1996;43(1):61-6. https://www.ncbi.nlm.nih.gov/pubmed/8732453. https://doi.org/10.1507/endocrj.43.61.
Astwood EB, Bissell A. Effect of thiouracil on the iodine content of the thyroid gland. Endocrinology. 1944;34:282-96. https://doi.org/10.1210/endo-34-4-282.
Lauberg P, Vestergaard H, Nielsen S, et al. Sources of circulating 3,5,3’- triiodothyronine in hyperthyroidism estimated after blocking of type 1 and type 2 iodothyronine deiodinases. J Clin Endocrinol Metab. 2007;92(6):2149-56. https://www.ncbi.nlm.nih.gov/pubmed/17389703. https://doi.org/10.1210/jc.2007-0178.
Abuid J, Larsen PR. Triidothyronine and thyroxine in hyperthyroidism. Comparison of the acute changes during therapy with antithyroid agents. J Clin Invest. 1974;54(1):201-8. https://www.ncbi.nlm.nih.gov/pubmed/4134836. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC301541. https://doi.org/10.1172/JCI107744.
Larsen PR. Thyroidal triiodothyronine and thyroxine in Graves’ disease: Correlation with presurgical treatment, thyroid status and iodine content. J Clin Endocrinol Metab. 1975;41(06):1098-104. https://www.ncbi.nlm.nih.gov/pubmed/54364. https://doi.org/10.1210/jcem-41-6-1098.
Engler H, Taurog A, Luthy C, Dorris ML. Reversible and irreversible inhibition of thyroid peroxidase-catalyzed iodination by thioureylene drugs. Endocrinology. 1983;112(1):86-95. https://www.ncbi.nlm.nih.gov/pubmed/6847836. https://doi.org/10.1210/endo-112-1-86.
Taurog A, Dorris ML, Guziec FS Jr. Metabolism of 35S- and 14C-labelled 1-methyl-2-mercaptoimidazole in vitro and in vivo. Endocrinology. 1989;124(1):30-9. https://www.ncbi.nlm.nih.gov/pubmed/2535809. https://doi.org/10.1210/endo-124-1-30.
Azizi F. Environmental iodine intake affects the response to methimazole in patients with diffuse toxic goiter. J Clin Endocrinol Metab. 1985;61(2):374-7. https://www.ncbi.nlm.nih.gov/pubmed/3839244. https://doi.org/10.1210/jcem-61-2-374.
Azizi F. Medical treatment of toxic goiter in an area of iodine deficiency. MJIRI 1988;2(2):119-22. http://mjiri.iums.ac.ir/article-1-1264-en.pdf.
Prummel MF, Brokken LJS, Wiersinga WM. Ultra-short-loop feedback of thyrotropin secretion. Thyroid. 2004;14(10): 825-9. https://www.ncbi.nlm.nih.gov/pubmed/15588378. https://doi.org/10.1089/thy.2004.14.825.
Brokken LJ, Scheenhart JW, Wiersinga WM, Prummel MF. Suppression of serum TSH by Graves’ Ig: Evidence for a functional pituitary TSH receptor. J Clin Endocrinol Metab. 2001;86(10): 4814-7. https://www.ncbi.nlm.nih.gov/pubmed/11600546. https://doi.org/10.1210/jcem.86.10.7922.
Prummel MF, Brokken LJ, Meduri G, Misrahi M, Bakker O, Wiersinga WM. Expression of the thyroid-stimulating hormone receptor in the folliculo-stellate cells of the human anterior pituitary. J Clin Endocrinol Metab. 2000;85(11):4347-53. https://www.ncbi.nlm.nih.gov/pubmed/11095478. https://doi.org/10.1210/jcem.85.11.6991.
Brokken LJS, Wiersinga WM, Prummel MF. Thyrotropin receptor autoantibodies are associated with continued thyrotropin suppression in treated euthyroid Graves’ disease patients. J Clin Endocrinol Metab. 2003;88:4135-8. https://doi.org/10.1210/jc.2003-030430.
Vagenakis AG, Braverman LE, Azizi F, Portnay GI, Ingbar SH. Recovery of pituitary thyrotrophic function after withdrawal of prolonged thyroid-suppression therapy. N Engl J Med. 1975;293(14):681-4. https://www.ncbi.nlm.nih.gov/pubmed/808728. https://doi.org/10.1056/NEJM197510022931402.
Lauberg P. Remission of Graves’ disease during anti-thyroid drug therapy. Time to reconsider the mechanism? Eur J Endocrinol. 2006;155(6):783-6. https://www.ncbi.nlm.nih.gov/pubmed/17132745. https://doi.org/10.1530/eje.1.02295.
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